Author: "McConnell MJ" - Searchworks@Jio Institute Digital Library Search Results

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195 results on '"McConnell MJ"'

1. A Live Salmonella Vaccine Delivering PcrV through the Type III Secretion System Protects against Pseudomonas aeruginosa

Author: Universidad de Sevilla. Departamento de Genética, Aguilera Herce, Julia, García Quintanilla, Meritxell de Jesús, McConnell, MJ, Ramos Morales, Francisco, Romero Flores, Rocío, Universidad de Sevilla. Departamento de Genética, Aguilera Herce, Julia, García Quintanilla, Meritxell de Jesús, McConnell, MJ, Ramos Morales, Francisco, and Romero Flores, Rocío
Abstract: Pseudomonas aeruginosa is a common Gram-negative opportunistic pathogen that is intrinsically resistant to a wide range of antibiotics. The development of a broadly protective vaccine against P. aeruginosa remains a major challenge. Here, we used an attenuated strain of Salmonella enterica serovar Typhimurium as a vehicle to express P. aeruginosa antigens. A fusion between the S. enterica type III secretion effector protein SseJ and the P. aeruginosa antigen PcrV expressed under the control of the sseA promoter was translocated by Salmonella into host cells in vitro and elicited the generation of specific antibodies in mice. Mice immunized with attenuated Salmonella expressing this fusion had reduced bacterial loads in the spleens and lungs and lower serum levels of proinflammatory cytokines than control mice after P. aeruginosa infection. Importantly, immunized mice also showed significantly enhanced survival in this model. These results suggest that type III secretion effectors of S. enterica are appropriate carriers in the design of a live vaccine to prevent infections caused by P. aeruginosa IMPORTANCE The Gram-negative bacterium Pseudomonas aeruginosa is an important opportunistic pathogen that causes infections in cystic fibrosis and hospitalized patients. Therapeutic treatments are limited due to the emergence and spread of new antibiotic-resistant strains. In this context, the development of a vaccine is a priority. Here, we used an attenuated strain of Salmonella enterica serovar Typhimurium as a vehicle to express and deliver the Pseudomonas antigen PcrV. This vaccine induced the generation of specific antibodies in mice and protected them from lethal infections with P. aeruginosa This is an important step toward the development of an effective vaccine for the prevention of infections caused by P. aeruginosa in humans
Published: 2019

2. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network

Author: Mcconnell, Mj, Moran, Jv, Abyzov, A, Akbarian, S, Bae, T, Cortes-Ciriano, I, Erwin, Ja, Fasching, L, Flasch, Da, Freed, D, Ganz, J, Jaffe, Ae, Kwan, Ky, Kwon, M, Lodato, Ma, Mills, Re, Paquola, Acm, Rodin, Re, Rosenbluh, C, Sestan, N, Sherman, Ma, Shin, Jh, Song, S, Straub, Re, Thorpe, J, Weinberger, Dr, Urban, Ae, Zhou, B, Gage, Fh, Lehner, T, Senthil, G, Walsh, Ca, Chess, A, Courchesne, E, Gleeson, Jg, Kidd, Jm, Park, Pj, Pevsner, J, Vaccarino, Fm, Barton, Ar, Bekiranov, S, Bohrson, Cl, Burbulis, Ie, Chronister, W, Coppola, G, Daily, K, D'Gama, Am, Emery, Sb, Frisbie, Tj, Gao, T, Gulyás-Kovács, A, Haakenson, M, Keil, Jm, Kopera, Hc, Lam, Mm, Lee, Ea, Marques-Bonet, T, Mathern, Gw, Moldovan, Jb, Oetjens, Mt, Omberg, L, Peters, Ma, Pochareddy, S, Pramparo, T, Ratan, A, Sanavia, T, Shi, L, Skarica, M, Wang, J, Wang, M, Wang, Y, Wierman, M, Wolpert, M, Woodworth, M, Zhao, X, and Zhou, W
Subjects: DNA Replication, 0301 basic medicine, DNA Repair, Brain Somatic Mosaicism, Somatic cell, DNA Mutational Analysis, Genomics, Disease, Biology, Article, Germline, 03 medical and health sciences, Neural Stem Cells, Humans, Copy-number variation, Neurons, Genetics, Multidisciplinary, Genome, Human, Mosaicism, Mental Disorders, Brain, Phenotype, Germ Cells, 030104 developmental biology, Human genome, Nerve Net, Nervous System Diseases, Cell Division, Neurotypical, DNA Damage
Abstract: BACKGROUND Elucidating the genetic architecture of neuropsychiatric disorders remains a major scientific and medical challenge. Emerging genomic technologies now permit the analysis of somatic mosaicism in human tissues. The measured frequencies of single-nucleotide variants (SNVs), small insertion/deletion (indel) mutations, structural variants [including copy number variants (CNVs), inversions, translocations, and whole-chromosome gains or losses], and mobile genetic element insertions (MEIs) indicate that each neuron may harbor hundreds of somatic mutations. Given the long life span of neurons and their central role in neural circuits and behavior, somatic mosaicism represents a potential mechanism that may contribute to neuronal diversity and the etiology of numerous neuropsychiatric disorders. ADVANCES Somatic mutations that confer cellular proliferative or cellular survival phenotypes have been identified in patients with cortical malformations. These data have led to the hypothesis that somatic mutations may also confer phenotypes to subsets of neurons, which could increase the risk of developing certain neuropsychiatric disorders. Genomic technologies, including advances in long-read, next-generation DNA sequencing technologies, single-cell genomics, and cutting-edge bioinformatics, can now make it possible to determine the types and frequencies of somatic mutations within the human brain. However, a comprehensive understanding of the contribution of somatic mosaicism to neurotypical brain development and neuropsychiatric disease requires a coordinated, multi-institutional effort. The National Institute of Mental Health (NIMH) has formed a network of 18 investigative teams representing 15 institutions called the Brain Somatic Mosaicism Network (BSMN). Each research team will use an array of genomic technologies to exploit well-curated human tissue repositories in an effort to define the frequency and pattern of somatic mutations in neurotypical individuals and in schizophrenia, autism spectrum disorder, bipolar disorder, Tourette syndrome, and epilepsy patient populations. Collectively, these efforts are estimated to generate a community resource of more than 10,000 DNA-sequencing data sets and will enable a cross-platform integrated analysis with other NIMH initiatives, such as the PsychENCODE project and the CommonMind Consortium. OUTLOOK A fundamental open question in neurodevelopmental genetics is whether and how somatic mosaicism may contribute to neuronal diversity within the neurotypical spectrum and in diseased brains. Healthy individuals may harbor known pathogenic somatic mutations at subclinical frequencies, and the local composition of neural cell types may be altered by mutations conferring prosurvival phenotypes in subsets of neurons. By extension, the neurotypical architecture of somatic mutations may confer circuit-level differences that would not be present if every neuron had an identical genome. Given the apparent abundance of somatic mutations within neurons, an in-depth understanding of how different types of somatic mosaicism affect neural function could yield mechanistic insight into the etiology of neurodevelopmental and neuropsychiatric disorders. The BSMN will examine large collections of postmortem brain tissue from neurotypical individuals and patients with neuropsychiatric disorders. By sequencing brain DNA and single neuronal genomes directly, rather than genomic DNA derived from peripheral blood or other somatic tissues, the BSMN will test the hypothesis that brain somatic variants contribute to neuropsychiatric disease. Notably, it is also possible that some inherited germline variants confer susceptibility to disease, which is later exacerbated by somatic mutations. Confirming such a scenario could increase our understanding of the genetic risk architecture of neuropsychiatric disease and may, in part, explain discordant neuropsychiatric phenotypes between identical twins. Results from these studies may lead to the discovery of biomarkers and genetic targets to improve the treatment of neuropsychiatric disease and may offer hope for improving the lives of patients and their families.
Published: 2017

3. Th2 responses are primed by skin dendritic cells with distinct transcriptional profiles

Author: Connor, LM, Tang, S-C, Cognard, E, Ochiai, S, Hilligan, KL, Old, SI, Pellefigues, C, White, RF, Patel, D, Smith, AAT, Eccles, DA, Lamiable, O, McConnell, MJ, Ronchese, F, Connor, LM, Tang, S-C, Cognard, E, Ochiai, S, Hilligan, KL, Old, SI, Pellefigues, C, White, RF, Patel, D, Smith, AAT, Eccles, DA, Lamiable, O, McConnell, MJ, and Ronchese, F
Abstract: The dendritic cell signals required for the in vivo priming of IL-4-producing T cells are unknown. We used RNA sequencing to characterize DCs from skin LN of mice exposed to two different Th2 stimuli: the helminth parasite Nippostrongylus brasiliensis (Nb) and the contact sensitizer dibutyl phthalate (DBP)-FITC. Both Nb and DBP-FITC induced extensive transcriptional changes that involved multiple DC subsets. Surprisingly, these transcriptional changes were highly distinct in the two models, with only a small number of genes being similarly regulated in both conditions. Pathway analysis of expressed genes identified no shared pathways between Nb and DBP-FITC, but revealed a type-I IFN (IFN-I) signature unique to DCs from Nb-primed mice. Blocking the IFN-I receptor at the time of Nb treatment had little effect on DC migration and antigen transport to the LN, but inhibited the up-regulation of IFN-I-induced markers on DCs and effectively blunted Th2 development. In contrast, the response to DBP-FITC was not affected by IFN-I receptor blockade, a finding consistent with the known dependence of this response on the innate cytokine TSLP. Thus, the priming of Th2 responses is associated with distinct transcriptional signatures in DCs in vivo, reflecting the diverse environments in which Th2 immune responses are initiated.
Published: 2017

4. Iterative sorting reveals CD133+and CD133-melanoma cells as phenotypically distinct populations

Author: Grasso, C, Anaka, M, Hofmann, O, Sompallae, R, Broadley, K, Hide, W, Berridge, MV, Cebon, J, Behren, A, McConnell, MJ, Grasso, C, Anaka, M, Hofmann, O, Sompallae, R, Broadley, K, Hide, W, Berridge, MV, Cebon, J, Behren, A, and McConnell, MJ
Abstract: BACKGROUND: The heterogeneity and tumourigenicity of metastatic melanoma is attributed to a cancer stem cell model, with CD133 considered to be a cancer stem cell marker in melanoma as well as other tumours, but its role has remained controversial. METHODS: We iteratively sorted CD133+ and CD133- cells from 3 metastatic melanoma cell lines, and observed tumourigenicity and phenotypic characteristics over 7 generations of serial xeno-transplantation in NOD/SCID mice. RESULTS: We demonstrate that iterative sorting is required to make highly pure populations of CD133+ and CD133- cells from metastatic melanoma, and that these two populations have distinct characteristics not related to the cancer stem cell phenotype. In vitro, gene set enrichment analysis indicated CD133+ cells were related to a proliferative phenotype, whereas CD133- cells were of an invasive phenotype. However, in vivo, serial transplantation of CD133+ and CD133- tumours over 7 generations showed that both populations were equally able to initiate and propagate tumours. Despite this, both populations remained phenotypically distinct, with CD133- cells only able to express CD133 in vivo and not in vitro. Loss of CD133 from the surface of a CD133+ cell was observed in vitro and in vivo, however CD133- cells derived from CD133+ retained the CD133+ phenotype, even in the presence of signals from the tumour microenvironment. CONCLUSION: We show for the first time the necessity of iterative sorting to isolate pure marker-positive and marker-negative populations for comparative studies, and present evidence that despite CD133+ and CD133- cells being equally tumourigenic, they display distinct phenotypic differences, suggesting CD133 may define a distinct lineage in melanoma.
Published: 2016

5. Immunization with Lipopolysaccharide-Deficient Whole Cells Provides Protective Immunity in an Experimental Mouse Model of Acinetobacter baumannii Infection

Author: García Quintanilla, Meritxell de Jesús, Pulido, Marina R., Pachón Díaz, Jerónimo, McConnell, MJ, Universidad de Sevilla. Departamento de Microbiología, Universidad de Sevilla. Departamento de Medicina, and Universidad de Sevilla. CTS-203: Estudio de las Enfermedades Infecciosas
Subjects: Acinetobacter baumannii, Vaccines, Gram-negative bacteria, Morbidity, Mortality
Abstract: Editor: Gunnar F. Kaufmann The increasing clinical importance of infections caused by multidrug resistant Acinetobacter baumannii warrants the development of novel approaches for prevention and treatment. In this context, vaccination of certain patient populations may contribute to reducing the morbidity and mortality caused by this pathogen. Vaccines against Gram-negative bacteria based on inactivated bacterial cells are highly immunogenic and have been shown to produce protective immunity against a number of bacterial species. However, the high endotoxin levels present in these vaccines due to the presence of lipopolysaccharide complicates their use in human vaccination. In the present study, we used a laboratory-derived strain of A. baumannii that completely lacks lipopolysaccharide due to a mutation in the lpxD gene (IB010), one of the genes involved in the first steps of lipopolysaccharide biosynthesis, for vaccination. We demonstrate that IB010 has greatly reduced endotoxin content (,1.0 endotoxin unit/106 cells) compared to wild type cells. Immunization with formalin inactivated IB010 produced a robust antibody response consisting of both IgG1 and IgG2c subtypes. Mice immunized with IB010 had significantly lower post-infection tissue bacterial loads and significantly lower serum levels of the pro-inflammatory cytokines IL-1b, TNF-a and IL-6 compared to control mice in a mouse model of disseminated A. baumannii infection. Importantly, immunized mice were protected from infection with the ATCC 19606 strain and an A. baumannii clinical isolate. These data suggest that immunization with inactivated A. baumannii whole cells deficient in lipopolysaccharide could serve as the basis for a vaccine for the prevention of infection caused by A. baumannii. REIPI REIPI RD06/0008/0000 Consejería de Salud de la Junta de Andalucía (PI-0046-2011) Ministerio de Economía y Competitividad, Subprograma Miguel Servet (CP11/00314)
Published: 2014

6. Measurement of the bottom-strange meson mixing phase in the full CDF data set

Author: Aaltonen, T., Alvarez, González, Amerio, B., Amidei, S., Anastassov, D., Annovi, A., Antos, A., Apollinari, J., Appel, G., J. A., Arisawa, Artikov, T., Asaadi, A., Ashmanskas, J., Auerbach, W., Aurisano, B., Azfar, A., Badgett, F., Bae, W., Barbaro, Galtieri, Barnes, A., V. E., Barnett, B. A., Barria, Bartos, P., Bauce, P., Bedeschi, M., Behari, F., Bellettini, S., Bellinger, G., Benjamin, J., Beretvas, D., Bhatti, A., Bisello, A., Bizjak, D., Bland, I., K. R., Blumenfeld, Bocci, B., Bodek, A., Bortoletto, A., Boudreau, D., Boveia, J., Brigliadori, A., Bromberg, L., Brucken, C., Budagov, E., Budd, J., H. S., Burkett, Busetto, K., Bussey, G., Buzatu, P., Calamba, A., Calancha, A., Camarda, C., Campanelli, S., Campbell, M., Canelli, M., Carls, F., Carlsmith, B., Carosi, D., Carrillo, R., Carron, S., Casal, S., Casarsa, B., Castro, M., Catastini, A., Cauz, P., Cavaliere, D., Cavalli, Sforza, Cerri, M., Cerrito, A., Chen, L., Y. C., Chertok, Chiarelli, M., Chlachidze, G., Chlebana, G., Cho, F., Chokheli, K., Chung, D., W. H., Chung, Y. S., Ciocci, M. A., Clark, Clarke, A., Compostella, C., Convery, G., M. E., Conway, Corbo, J., Cordelli, M., Cox, M., C. A., Cox, D. J., Crescioli, Cuevas, F., Culbertson, J., Dagenhart, R., D'Ascenzo, D., Datta, N., Barbaro, De, Dell'Orso, Mauro, Demortier, M., Deninno, L., Devoto, M., D'Errico, F., Canto, Di, Ruzza, Di, Dittmann, B., J. R., D'Onofrio, Donati, Simone, Dong, P., Dorigo, M., Dorigo, T., Ebina, K., Elagin, A., Eppig, A., Erbacher, R., Errede, S., Ershaidat, N., Eusebi, R., Farrington, S., Feindt, M., Fernandez, J. P., Field, R., Flanagan, G., Forrest, R., Frank, M. J., Franklin, M., Freeman, J. C., Funakoshi, Y., Furic, I., Gallinaro, M., Garcia, J. E., Garfinkel, A. F., Garosi, P., Gerberich, H., Gerchtein, E., Giagu, S., Giakoumopoulou, V., Giannetti, P., Gibson, K., Ginsburg, C. M., Giokaris, N., Giromini, P., Giurgiu, G., Glagolev, V., Glenzinski, D., Gold, M., Goldin, D., Goldschmidt, N., Golossanov, A., Gomez, G., Gomez, Ceballos, Goncharov, G., González, M., Gorelov, O., Goshaw, I., A. T., Goulianos, Grillo, K., Grinstein, L., Grosso, Pilcher, Group, C., R. C., Guimaraes Da Costa, Hahn, J., S. R., Halkiadakis, Hamaguchi, E., Han, A., J. Y., Happacher, Hara, F., Hare, K., Hare, D., Harr, M., R. F., Hatakeyama, Hays, K., Heck, C., Heinrich, M., Herndon, J., Hewamanage, M., Hocker, S., Hopkins, A., Horn, W., Hou, D., Hughes, S., R. E., Hurwitz, Husemann, M., Hussain, U., Hussein, N., Huston, M., Introzzi, J., Iori, G., Ivanov, M., James, A., Jang, E., Jayatilaka, D., Jeon, B., E. J., Jindariani, Jones, S., Joo, M., K. K., Jun, S. Y., Junk, T. R., Kamon, Karchin, T., P. E., Kasmi, Kato, A., Ketchum, Y., Keung, W., Khotilovich, J., Kilminster, V., Kim, B., D. H., Kim, H. S., Kim, J. E., Kim, M. J., Kim, S. B., Kim, S. H., Kim, Y. K., Kim, Y. J., Kimura, Kirby, N., Klimenko, M., Knoepfel, S., Kondo, K., Kong, K., D. J., Konigsberg, Kotwal, J., A. V., Kreps, Kroll, M., Krop, J., Kruse, D., Krutelyov, M., Kuhr, V., Kurata, T., Kwang, M., Laasanen, S., A. T., Lami, Lammel, S., Lancaster, S., Lander, M., R. L., Lannon, Lath, K., Latino, A., Lecompte, G., Lee, T., Lee, E., H. S., Lee, J. S., Lee, S. W., Leo, Leone, S., Lewis, S., J. D., Limosani, Lin, A., C. J., Lindgren, Lipeles, M., Lister, E., Litvintsev, A., D. O., Liu, Liu, C., Liu, H., Liu, Q., Lockwitz, T., Loginov, S., Lucchesi, A., Lueck, D., Lujan, J., Lukens, P., Lungu, P., Lys, G., Lysak, J., Madrak, R., Maeshima, R., Maestro, K., Malik, P., Manca, S., Manousakis, Katsikakis, Margaroli, A., Marino, F., Martínez, C., Mastrandrea, M., Matera, P., Mattson, K., M. E., Mazzacane, Mazzanti, A., Mcfarland, P., K. S., Mcintyre, Mcnulty, P., Mehta, R., Mehtala, A., Mesropian, P., Miao, C., Mietlicki, T., Mitra, D., Miyake, A., Moed, H., Moggi, S., Mondragon, N., M. N., Moon, C. S., Moore, Morello, R., M. J., Morlock, Movilla, Fernandez, Mukherjee, P., Muller, A., Murat, T., Mussini, P., Nachtman, M., Nagai, J., Naganoma, Y., Nakano, J., Napier, I., Nett, A., Neu, J., Neubauer, C., M. S., Nielsen, Nodulman, J., Noh, L., S. Y., Norniella, Oakes, O., Oh, L., S. H., Oh, Y. D., Oksuzian, Okusawa, I., Orava, T., Ortolan, R., Pagan, Griso, Pagliarone, S., Palencia, C., Papadimitriou, E., Paramonov, V., A. A., Patrick, Pauletta, J., Paulini, G., Paus, M., Pellett, C., D. E., Penzo, Phillips, A., T. J., Piacentino, Pianori, G., Pilot, E., Pitts, J., Plager, K., Pondrom, C., Poprocki, L., Potamianos, S., Prokoshin, K., Pranko, F., Ptohos, A., Punzi, Giovanni, Rahaman, G., Ramakrishnan, A., Ranjan, V., Redondo, N., Renton, I., Rescigno, P., Riddick, M., Rimondi, T., Ristori, F., Robson, L., Rodrigo, A., Rodriguez, T., Rogers, T., Rolli, E., Roser, S., Ruffini, R., Ruiz, F., Russ, A., Rusu, J., Safonov, V., Sakumoto, A., W. K., Sakurai, Santi, Y., Sato, L., Saveliev, K., Savoy, Navarro, Schlabach, A., Schmidt, P., Schmidt, A., E. E., Schwarz, Scodellaro, T., Scribano, L., Scuri, A., Seidel, F., Seiya, S., Semenov, Y., Sforza, A., Shalhout, F., S. Z., Shears, Shepard, T., P. F., Shimojima, Shochet, M., Shreyber, Tecker, Simonenko, I., Sinervo, A., Sliwa, P., Smith, K., J. R., Snider, F. D., Soha, Sorin, A., Song, V., Squillacioti, H., Stancari, P., Denis, S. t., Stelzer, R., Stelzer, Chilton, Stentz, O., Strologas, D., Strycker, J., G. L., Sudo, Sukhanov, Y., Suslov, A., Takemasa, I., Takeuchi, K., Tang, Y., Tecchio, J., Teng, M., P. K., Thom, Thome, J., Thompson, J., G. A., Thomson, Toback, E., Tokar, D., Tollefson, S., Tomura, K., Tonelli, T., Torre, D., Torretta, S., Totaro, D., Trovato, P., Ukegawa, M., Uozumi, F., Varganov, S., Vázquez, A., Velev, F., Vellidis, G., Vidal, C., Vila, M., Vilar, I., Vizán, R., Vogel, J., Volpi, M., Wagner, G., Wagner, P., R. L., Wakisaka, Wallny, T., Wang, R., S. M., Warburton, Waters, A., Wester, D., W. C., Whiteson, Wicklund, D., A. B., Wicklund, Wilbur, E., Wick, S., Williams, F., H. H., Wilson, J. S., Wilson, Winer, P., B. L., Wittich, Wolbers, P., Wolfe, S., Wright, H., Wu, T., Wu, X., Yamamoto, Z., Yamato, K., Yang, D., Yang, T., U. K., Yang, Y. C., Yao, W. M., Yeh, G. P., Yi, Yoh, K., Yorita, J., Yoshida, K., Yu, T., G. B., Yu, Yu, I., S. S., Yun, J. C., Zanetti, Zeng, A., Zhou, Y., Zucchelli, C., Jy, S., Koh, Yh, Koike, M, Komatsu, M, Kominami, E, Kong, Hj, Kong, Wj, Korolchuk, Vi, Kotake, Y, Koukourakis, Mi, Kouri Flores JB, Kovács, Al, Kraft, C, Krainc, D, Krämer, H, Kretz Remy, C, Krichevsky, Am, Kroemer, G, Krüger, R, Krut, O, Ktistakis, Nt, Kuan, Cy, Kucharczyk, R, Kumar, A, Kumar, R, Kumar, S, Kundu, M, Kung, Hj, Kurz, T, Kwon, Hj, La Spada AR, Lafont, F, Lamark, T, Landry, J, Lane, Jd, Lapaquette, P, Laporte, Jf, László, L, Lavandero, S, Lavoie, Jn, Layfield, R, Lazo, Pa, Le, W, Le Cam, L, Ledbetter, Dj, Lee, Aj, Lee, Bw, Lee, Gm, Lee, J, Lee, Jh, Lee, M, Lee, Ms, Lee, Sh, Leeuwenburgh, C, Legembre, P, Legouis, R, Lehmann, M, Lei, Hy, Lei, Qy, Leib, Da, Leiro, J, Lemasters, Jj, Lemoine, A, Lesniak, Ms, Lev, D, Levenson, Vv, Levine, B, Levy, E, Li, F, Li, Jl, Li, L, Li, S, Li, W, Li, Xj, Li, Yb, Li, Yp, Liang, C, Liang, Q, Liao, Yf, Liberski, Pp, Lieberman, A, Lim, Hj, Lim, Kl, Lim, K, Lin, Cf, Lin, Fc, Lin, J, Lin, Jd, Lin, K, Lin, Ww, Lin, Wc, Lin, Yl, Linden, R, Lingor, P, Lippincott Schwartz, J, Lisanti, Mp, Liton, Pb, Liu, B, Liu, Cf, Liu, K, Liu, L, Liu, Qa, Liu, W, Liu, Yc, Liu, Y, Lockshin, Ra, Lok, Cn, Lonial, S, Loos, B, Lopez Berestein, G, López Otín, C, Lossi, L, Lotze, Mt, Lőw, P, Lu, B, Lu, Z, Luciano, F, Lukacs, Nw, Lund, Ah, Lynch Day MA, Ma, Y, Macian, F, Mackeigan, Jp, Macleod, Kf, Madeo, F, Maiuri, L, Maiuri, Mc, Malagoli, D, Malicdan, Mc, Malorni, W, Man, N, Mandelkow, Em, Manon, S, Manov, I, Mao, K, Mao, X, Mao, Z, Marambaud, P, Marazziti, D, Marcel, Yl, Marchbank, K, Marchetti, P, Marciniak, Sj, Marcondes, M, Mardi, M, Marfe, G, Mariño, G, Markaki, M, Marten, Mr, Martin, Sj, Martinand Mari, C, Martinet, W, Martinez Vicente, M, Masini, M, Matarrese, P, Matsuo, S, Matteoni, R, Mayer, A, Mazure, Nm, Mcconkey, Dj, Mcconnell, Mj, Mcdermott, C, Mcdonald, C, Mcinerney, Gm, Mckenna, Sl, Mclaughlin, B, Mclean, Pj, Mcmaster, Cr, Mcquibban, Ga, Meijer, Aj, Meisler, Mh, Meléndez, A, Melia, Tj, 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Rahaman, V. Ramakrishnan, N. Ranjan, I. Redondo, P. Renton, M. Rescigno, T. Riddick, F. Rimondi, L. Ristori, A. Robson, T. Rodrigo, T. Rodriguez, E. Roger, S. Rolli, R. Roser, F. Ruffini, A. Ruiz, J. Ru, V. Rusu, A. Safonov, W. Sakumoto, Y. Sakurai, L. Santi, K. Sato, V. Saveliev, A. Savoy-Navarro, P. Schlabach, A. Schmidt, E. Schmidt, T. Schwarz, L. Scodellaro, A. Scribano, F. Scuri, S. Seidel, Y. Seiya, A. Semenov, F. Sforza, S. Shalhout, T. Shear, P. Shepard, M. Shimojima, M. Shochet, I. Shreyber-Tecker, A. Simonenko, P. Sinervo, K. Sliwa, J. Smith, F. Snider, A. Soha, V. Sorin, H. Song, P. Squillacioti, M. Stancari, R. St. Deni, B. Stelzer, O. Stelzer-Chilton, D. Stentz, J. Strologa, G. Strycker, Y. Sudo, A. Sukhanov, I. Suslov, K. Takemasa, Y. Takeuchi, J. Tang, M. Tecchio, P. Teng, J. Thom, J. Thome, G. Thompson, E. Thomson, D. Toback, S. Tokar, K. Tollefson, T. Tomura, D. Tonelli, S. Torre, D. Torretta, P. Totaro, M. Trovato, F. Ukegawa, S. Uozumi, A. Varganov, F. Vázquez, G. Velev, C. Vellidi, M. Vidal, I. Vila, R. Vilar, J. Vizán, M. Vogel, G. Volpi, P. Wagner, R. Wagner, T. Wakisaka, R. Wallny, S. Wang, A. Warburton, D. Water, W. Wester, D. Whiteson, A. Wicklund, E. Wicklund, S. Wilbur, F. Wick, H. William, J. Wilson, P. Wilson, B. Winer, P. Wittich, S. Wolber, H. Wolfe, T. Wright, X. Wu, Z. Wu, K. Yamamoto, D. Yamato, T. Yang, U. Yang, Y. Yang, W.-M. Yao, G. Yeh, K. Yi, J. Yoh, K. Yorita, T. Yoshida, G. Yu, I. Yu, S. Yu, J. Yun, A. Zanetti, Y. Zeng, C. Zhou, S. Zucchelli, and Universidad de Cantabria
Subjects: FERMILAB TEVATRON COLLIDER, Particle physics, CP-violating asymmetries, Meson, B physic, General Physics and Astronomy, FOS: Physical sciences, B physics, Angle distribution, Branching ratio, CDF experiments, CP violations, CP-violating asymmetries, Data sample, Fermilab Tevatron collider, Integrated luminosity, Longitudinal polarization, Vector meson, Longitudinal polarization, 7. Clean energy, 01 natural sciences, High Energy Physics - Experiment, Vector meson, Physics and Astronomy (all), High Energy Physics - Experiment (hep-ex), High Energy Physics - Phenomenology (hep-ph), Mixing (mathematics), Strange b mesons, Phase (matter), 0103 physical sciences, STRANGE QUARK, mixing, Bottom-Strange Meson Mixing Phase, proton antiproton collisions, 010306 general physics, TEVATRON, Nuclear Experiment, BOTTOM QUARK, Physics, Integrated luminosity, 010308 nuclear & particles physics, Branching ratio, High Energy Physics - Phenomenology, CDF experiments, CP violations, Full data, Content (measure theory), Angle distribution, CDF, Production (computer science), High Energy Physics::Experiment, Data sample
Abstract: We report a measurement of the bottom-strange meson mixing phase βs using the time evolution of Bs0→J/ψ(→μ+μ-)ϕ(→K+K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at s=1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of βs and the Bs0 decay-width difference ΔΓs and measure βs∈[-π/2,-1.51]∪[-0.06,0.30]∪[1.26,π/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of βs, we also determine ΔΓs=0.068±0.026(stat)±0.009(syst) ps-1 and the mean Bs0 lifetime τs=1.528±0.019(stat)±0.009(syst) ps, which are consistent and competitive with determinations by other experiments., This work was supported by the U.S. Department of Energy and National Science Foundation; the Italian Istituto Nazionale di Fisica Nucleare; the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Natural Sciences and Engineering Research Council of Canada; the National Science Council of the Republic of China; the Swiss National Science Foundation; the A. P. Sloan Foundation; the Bundesministerium für Bildung und Forschung, Germany; the Korean World Class University Program, the National Research Foundation of Korea; the Science and Technology Facilities Council and the Royal Society, UK; the Russian Foundation for Basic Research; the Ministerio de Ciencia e Innovación, and Programa Consolider-Ingenio 2010, Spain; the Slovak R&D Agency; the Academy of Finland; and the Australian Research Council (ARC).
Published: 2012

7. Immunization with Lipopolysaccharide-Deficient Whole Cells Provides Protective Immunity in an Experimental Mouse Model of Acinetobacter baumannii Infection

Author: Universidad de Sevilla. Departamento de Microbiología, Universidad de Sevilla. Departamento de Medicina, Universidad de Sevilla. CTS-203: Estudio de las Enfermedades Infecciosas, García Quintanilla, Meritxell de Jesús, Pulido, Marina R., Pachón Díaz, Jerónimo, McConnell, MJ, Universidad de Sevilla. Departamento de Microbiología, Universidad de Sevilla. Departamento de Medicina, Universidad de Sevilla. CTS-203: Estudio de las Enfermedades Infecciosas, García Quintanilla, Meritxell de Jesús, Pulido, Marina R., Pachón Díaz, Jerónimo, and McConnell, MJ
Abstract: The increasing clinical importance of infections caused by multidrug resistant Acinetobacter baumannii warrants the development of novel approaches for prevention and treatment. In this context, vaccination of certain patient populations may contribute to reducing the morbidity and mortality caused by this pathogen. Vaccines against Gram-negative bacteria based on inactivated bacterial cells are highly immunogenic and have been shown to produce protective immunity against a number of bacterial species. However, the high endotoxin levels present in these vaccines due to the presence of lipopolysaccharide complicates their use in human vaccination. In the present study, we used a laboratory-derived strain of A. baumannii that completely lacks lipopolysaccharide due to a mutation in the lpxD gene (IB010), one of the genes involved in the first steps of lipopolysaccharide biosynthesis, for vaccination. We demonstrate that IB010 has greatly reduced endotoxin content (,1.0 endotoxin unit/106 cells) compared to wild type cells. Immunization with formalin inactivated IB010 produced a robust antibody response consisting of both IgG1 and IgG2c subtypes. Mice immunized with IB010 had significantly lower post-infection tissue bacterial loads and significantly lower serum levels of the pro-inflammatory cytokines IL-1b, TNF-a and IL-6 compared to control mice in a mouse model of disseminated A. baumannii infection. Importantly, immunized mice were protected from infection with the ATCC 19606 strain and an A. baumannii clinical isolate. These data suggest that immunization with inactivated A. baumannii whole cells deficient in lipopolysaccharide could serve as the basis for a vaccine for the prevention of infection caused by A. baumannii.
Published: 2014

8. Guidelines for the use and interpretation of assays for monitoring autophagy.

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Pandey, Ub, Papackova, Z, Papassideri, I, Paris, I, Park, J, Park, Ok, Parys, Jb, Parzych, Kr, Patschan, S, Patterson, C, Pattingre, S, Pawelek, Jm, Peng, J, Perlmutter, Dh, Perrotta, I, Perry, G, Pervaiz, S, Peter, M, Peters, Gj, Petersen, M, Petrovski, G, Phang, Jm, Piacentini, M, Pierre, P, Pierrefite-Carle, V, Pierron, G, Pinkas-Kramarski, R, Piras, A, Piri, N, Platanias, Lc, Pöggeler, S, Poirot, M, Poletti, A, Poüs, C, Pozuelo-Rubio, M, Prætorius-Ibba, M, Prasad, A, Prescott, M, Priault, M, Produit-Zengaffinen, N, Progulske-Fox, A, Proikas-Cezanne, T, Przedborski, S, Przyklenk, K, Puertollano, R, Puyal, J, Qian, Sb, Qin, L, Qin, Zh, Quaggin, Se, Raben, N, Rabinowich, H, Rabkin, Sw, Rahman, I, Rami, A, Ramm, G, Randall, G, Randow, F, Rao, Va, Rathmell, Jc, Ravikumar, B, Ray, Sk, Reed, Bh, Reed, Jc, Reggiori, F, Régnier-Vigouroux, A, Reichert, A, Reiners JJ, Jr, Reiter, Rj, Ren, J, Revuelta, Jl, Rhodes, Cj, Ritis, K, Rizzo, E, Robbins, J, Roberge, M, Roca, H, Roccheri, Mc, Rocchi, S, Rodemann, Hp, Rodríguez de Córdoba, S, Rohrer, B, Roninson, Ib, Rosen, K, Rost-Roszkowska, Mm, Rouis, M, Rouschop, Km, Rovetta, F, Rubin, Bp, Rubinsztein, Dc, Ruckdeschel, K, Rucker EB, 3rd, Rudich, A, Rudolf, E, Ruiz-Opazo, N, Russo, R, Rusten, Te, Ryan, Km, Ryter, Sw, Sabatini, Dm, Sadoshima, J, Saha, T, Saitoh, T, Sakagami, H, Sakai, Y, Salekdeh, Gh, Salomoni, P, Salvaterra, Pm, Salvesen, G, Salvioli, R, Sanchez, Am, Sánchez-Alcázar, Ja, Sánchez-Prieto, R, Sandri, M, Sankar, U, Sansanwal, P, Santambrogio, L, Saran, S, Sarkar, S, Sarwal, M, Sasakawa, C, Sasnauskiene, A, Sass, M, Sato, K, Sato, M, Schapira, Ah, Scharl, M, Schätzl, Hm, Scheper, W, Schiaffino, S, Schneider, C, Schneider, Me, Schneider-Stock, R, Schoenlein, Pv, Schorderet, Df, Schüller, C, Schwartz, Gk, Scorrano, L, Sealy, L, Seglen, Po, Segura-Aguilar, J, Seiliez, I, Seleverstov, O, Sell, C, Seo, Jb, Separovic, D, Setaluri, V, Setoguchi, T, Settembre, C, Shacka, Jj, Shanmugam, M, Shapiro, Im, Shaulian, E, Shaw, Rj, Shelhamer, Jh, Shen, Hm, Shen, Wc, Sheng, Zh, Shi, Y, Shibuya, K, Shidoji, Y, Shieh, Jj, Shih, Cm, Shimada, Y, Shimizu, S, Shintani, T, Shirihai, O, Shore, Gc, Sibirny, Aa, Sidhu, Sb, Sikorska, B, Silva-Zacarin, Ec, Simmons, A, Simon, Ak, Simon, Hu, Simone, C, Simonsen, A, Sinclair, Da, Singh, R, Sinha, D, Sinicrope, Fa, Sirko, A, Siu, Pm, Sivridis, E, Skop, V, Skulachev, Vp, Slack, R, Smaili, S, Smith, Dr, Soengas, M, Soldati, T, Song, X, Sood, Ak, Soong, Tw, Sotgia, F, Spector, Sa, Spies, Cd, Springer, W, Srinivasula, Sm, Stefanis, L, Steffan, J, Stendel, R, Stenmark, H, Stephanou, A, Stern, St, Sternberg, C, Stork, B, Strålfors, P, Subauste, C, Sui, X, Sulzer, D, Sun, J, Sun, Sy, Sun, Zj, Sung, Jj, Suzuki, K, Suzuki, T, Swanson, M, Swanton, C, Sweeney, St, Sy, Lk, Szabadkai, G, Tabas, I, Taegtmeyer, H, Tafani, M, Takács-Vellai, K, Takano, Y, Takegawa, K, Takemura, G, Takeshita, F, Talbot, Nj, Tan, K, Tanaka, K, Tang, D, Tanida, I, Tannous, Ba, Tavernarakis, N, Taylor, G, Taylor, Ga, Taylor, Jp, Terada, L, Terman, A, Tettamanti, G, Thevissen, K, Thompson, Cb, Thorburn, A, Thumm, M, Tian, F, Tian, Y, Tocchini-Valentini, G, Tolkovsky, Am, Tomino, Y, Tönges, L, Tooze, Sa, Tournier, C, Tower, J, Towns, R, Trajkovic, V, Travassos, Lh, Tsai, Tf, Tschan, Mp, Tsubata, T, Tsung, A, Turk, B, Turner, L, Tyagi, Sc, Uchiyama, Y, Ueno, T, Umekawa, M, Umemiya-Shirafuji, R, Unni, Vk, Vaccaro, Mi, Valente, Em, Van den Berghe, G, van der Klei, Ij, van Doorn, W, van Dyk, Lf, van Egmond, M, van Grunsven, La, Vandenabeele, P, Vandenberghe, Wp, Vanhorebeek, I, Vaquero, Ec, Velasco, G, Vellai, T, Vicencio, Jm, Vierstra, Rd, Vila, M, Vindis, C, Viola, G, Viscomi, Maria Teresa, Voitsekhovskaja, Ov, von Haefen, C, Votruba, M, Wada, K, Wade-Martins, R, Walker, Cl, Walsh, Cm, Walter, J, Wan, Xb, Wang, A, Wang, C, Wang, D, Wang, F, Wang, G, Wang, H, Wang, Hg, Wang, Hd, Wang, J, Wang, K, Wang, M, Wang, Rc, Wang, X, Wang, Yj, Wang, Y, Wang, Z, Wang, Zc, Wansink, Dg, Ward, Dm, Watada, H, Waters, Sl, Webster, P, Wei, L, Weihl, Cc, Weiss, Wa, Welford, Sm, Wen, Lp, Whitehouse, Ca, Whitton, Jl, Whitworth, Aj, Wileman, T, Wiley, Jw, Wilkinson, S, Willbold, D, Williams, Rl, Williamson, Pr, Wouters, Bg, Wu, C, Wu, Dc, Wu, Wk, Wyttenbach, A, Xavier, Rj, Xi, Z, Xia, P, Xiao, G, Xie, Z, Xu, Dz, Xu, J, Xu, L, Xu, X, Yamamoto, A, Yamashina, S, Yamashita, M, Yan, X, Yanagida, M, Yang, D, Yang, E, Yang, Jm, Yang, Sy, Yang, W, Yang, Wy, Yang, Z, Yao, Mc, Yao, Tp, Yeganeh, B, Yen, Wl, Yin, Jj, Yin, Xm, Yoo, Oj, Yoon, G, Yoon, Sy, Yorimitsu, T, Yoshikawa, Y, Yoshimori, T, Yoshimoto, K, You, Hj, Youle, Rj, Younes, A, Yu, L, Yu, Sw, Yu, Wh, Yuan, Zm, Yue, Z, Yun, Ch, Yuzaki, M, Zabirnyk, O, Silva-Zacarin, E, Zacks, D, Zacksenhaus, E, Zaffaroni, N, Zakeri, Z, Zeh HJ, 3rd, Zeitlin, So, Zhang, H, Zhang, Hl, Zhang, J, Zhang, Jp, Zhang, L, Zhang, My, Zhang, Xd, Zhao, M, Zhao, Yf, Zhao, Y, Zhao, Zj, Zheng, X, Zhivotovsky, B, Zhong, Q, Zhou, Cz, Zhu, C, Zhu, Wg, Zhu, Xf, Zhu, X, Zhu, Y, Zoladek, T, Zong, Wx, Zorzano, A, Zschocke, J, Zuckerbraun, B., and Viscomi M. T. (ORCID:0000-0002-9096-4967)
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused o
Published: 2012

9. Posterior Cruciate Ligament Preservation versus Posterior Cruciate Ligament Sacrifice: Comparing Patient Outcomes in Medial Congruent Total Knee Arthroplasty.

Author: Guild GN 3rd, McConnell MJ, Najafi F, Naylor BH, DeCook CA, and Bradbury TL
Subjects: Humans, Retrospective Studies, Male, Female, Aged, Middle Aged, Osteoarthritis, Knee surgery, Postoperative Complications etiology, Treatment Outcome, Knee Prosthesis, Arthroplasty, Replacement, Knee, Posterior Cruciate Ligament surgery, Patient Reported Outcome Measures
Abstract: This study aimed to compare outcomes and complication rates between posterior cruciate ligament (PCL) retention and excision utilizing a medial congruent (MC) polyethylene insert in total knee arthroplasty (TKA) in a specialized ambulatory surgery center (ASC) dedicated to hip and knee arthroplasty. A retrospective review was performed between May 2023 and October 2023 analyzing 398 patients who underwent primary MC TKA by high-volume joint arthroplasty surgeons ( n = 9) with either PCL preservation ( n = 264) or sacrifice ( n = 134) in a single free-standing ASC. Patients were matched chronologically on a 2:1 basis. Demographics, baseline function, 90-day complications, and patient-reported outcomes were recorded for each patient. There were no differences in preoperative baseline function or patient-reported outcome measures, Charlson Comorbidity Index, or American Society of Anesthesiologists class among patient groups. The PCL-preserve and PCL-sacrifice cohorts showed significant variation in 12-week postoperative Knee Injury and Osteoarthritis Outcome, Junior (KOOS, JR.) scores. Specifically, the number of patients who achieved the minimal clinically important difference (MCID) in KOOS, JR. scores was higher in the PCL-sacrifice group ( p < 0.05). Yet, no complications within the 90-day period were associated with PCL status and other patient-reported outcomes. This study comparing outcomes between MC TKAs with PCL retention and sacrifice suggests that both techniques are viable options with similar functional outcomes, pain scores, and complication rates, which may have benefits in an ASC setting. The PCL-sacrifice group exhibited a statistically significant increase in patients who achieved the MCID in KOOS, JR. score compared with the PCL-preserving at early follow-up. Future research should employ prospective, randomized designs to further validate these findings and explore long-term implications., Competing Interests: None declared., (Thieme. All rights reserved.)
Published: 2025
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10. Evaluating Knee Recovery Beyond Patient Reports: A Comparative Study of Smart Implantable Device-Derived Gait Metrics Versus Patient-Reported Outcome Measures in Total Knee Arthroplasty.

Author: Guild GN 3rd, Najafi F, DeCook CA, Levit C, McConnell MJ, Bradbury TL, and Naylor BH
Subjects: Humans, Male, Female, Aged, Retrospective Studies, Middle Aged, Treatment Outcome, Aged, 80 and over, Knee Prosthesis, Arthroplasty, Replacement, Knee instrumentation, Patient Reported Outcome Measures, Gait physiology, Recovery of Function, Range of Motion, Articular, Osteoarthritis, Knee surgery, Knee Joint surgery, Knee Joint physiopathology
Abstract: Background: Total Knee Arthroplasty (TKA) is frequently performed for advanced osteoarthritis, with patient-reported outcome measures (PROMs) traditionally reporting on efficacy. These subjective evaluations, although useful, may inaccurately reflect post-TKA activity levels. With technological advancements, smart implantable devices (SIDs) offer objective, real-time gait metrics, potentially providing a more accurate postoperative recovery assessment. This study compares these objective metrics with PROMs to evaluate TKA success more effectively., Methods: We conducted a retrospective cohort study with 88 participants undergoing TKA using a SID. Eligible patients were aged 18 years or older and had advanced osteoarthritis. We excluded those who had bilateral TKAs, joint infections, or neuromuscular disease. The SID system collected daily gait metrics, including step count, distance traveled, walking speed, stride length, cadence, and functional knee range of motion. The PROMs, including Knee Injury and Osteoarthritis Outcome Score-Joint Replacement, Veterans Rand 12 Physical Component Summary, and Veterans Rand 12 Mental Component Summary, were analyzed against SID gait metrics. Among the 88 patients, 80 provided continuous data over 12 weeks., Results: All gait metrics, except stride length, significantly increased at the 12-week point (P < .05). The PROMs also significantly improved postoperatively (P < .05). Initial low positive correlations between 12-week PROMs and SID metrics decreased after adjusting for demographic variables, leaving only weak correlations between the Veterans Rand 12 Physical Component Summary and Knee Injury and Osteoarthritis Outcome Score-Joint Replacement with functional knee range of motion (r = 0.389, P = .002; r = 0.311, P = .014, respectively), and Veterans Rand 12 Mental Component Summary with step count (r = 0.406, P = .001) and distance traveled (r = 0.376, P = .003)., Conclusions: This study indicates that both PROMs and SID gait metrics show significant improvements post-TKA, though they correlate weakly with each other, suggesting a possible discrepancy between perceived recovery and actual functional improvement. The SID gait metrics might provide a valuable addition to traditional PROMs by offering an objective representation of physical capabilities unaffected by patient compliance or subjective perceptions of recovery. Further research is needed to validate these findings in larger populations and to explore whether integrating SID metrics can enhance long-term functional outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)
Published: 2024
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11. Total Hip Surgical Approach Efficiency Outside of Surgical Time in the Ambulatory Surgical Center.

Author: Guild GN lll, Bradbury TL, Huang N, Schwab J, McConnell MJ, Najafi F, and DeCook CA
Abstract: Background: Demand for total hip arthroplasty (THA) in ambulatory surgery centers (ASCs) is rapidly increasing. Increased efficiency is crucial in ASCs to manage this rising demand, particularly considering different surgical approaches and their varying time requirements. Optimizing efficiency can help meet the demand while ensuring safe and timely same-day discharge (SDD). This study examined the time spent in each care phase for THA patients in an outpatient ASC, the success rate and delays of SDD, and operative outcomes including estimated blood loss, 90-day complication rates, and 1-year patient-reported outcomes., Methods: A retrospective review was performed between January 1, 2019 and January 1, 2021 for all primary THA patients in a single free-standing ASC. Demographics, baseline functions, phase of care times, perioperative outcomes, 90 day complications, and patient-reported outcomes were recorded and compared stratified by surgical approach. Comparison was done using two-tailed t-tests and Fisher's exact tests. Multivariate both-direction stepwise regression analyses were performed to control for differences in group demographic factors such as age, sex, body mass index (BMI), preoperative assistive device use, attendance at preoperative class, American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index, and preoperative diagnosis., Results: Our groups differed in age, BMI, assistive device use, preoperative class attendance, and preoperative Veterans Rand 12 Item Health Survey (VR-12) physical component score (PCS). The direct anterior approach (DAA) and posterior approach (PA) cohorts varied significantly in minutes spent in each phase of care except for Spinal Time and Total physical therapy (PT) Time in Post-Anesthesia Care Unit (PACU). Direct Anterior Approach was faster that PA in Spinal State to Incision Time (26.8 ± 10.9 versus 35.0 ± 10.1; P < 0.001), Set-up/Take-down Time (20.5 ± 5.8 versus 30.2 ± 8.2; P < 0.001), Operative Time (37.5 ± 14.5 versus 50.4 ± 6.7; P < 0.001), Total operating room (OR) Time (57.8 ± 17.4 versus 80.5 ± 11.4; P < 0.001), and Arrival to Discharge Time (383.8 ± 71.2 versus 418.4 ± 60.8; P < 0.001). The PA was faster than DAA in Time to Initiation of PT (46.3 ± 25.1 versus 71.4 ± 34.7; P < 0.001), PACU Arrival to PT Cleared Time (124.9 ± 42.3 versus 144.3 ± 47.8; P < 0.001), and Total PACU Time (127.8 ± 47.4 versus 143.4 ± 47.8; P < 0.001). Surgical approach, age, BMI, and preoperative use of an assistive device were the most common predictive factors for phase of care time differences. Excessive spinal was the most common reason to delay physical therapy. The 90 day complications were not associated with surgical approach and patient-reported outcomes at 12, 26, or 52 weeks showed no significant differences., Conclusion: Direct anterior surgical approach showed shorter arrival to discharge time, and total OR time compared to PA with similar patient-reported outcomes (PROs) and complications. Both approaches were equally effective at achieving SDD. Operative time and set-up/take-down time were the main drivers of improved efficiency in the DAA group. Time to initiation of PT was prolonged in the DAA group, due to a standard spinal block time with a shorter OR time., (Copyright © 2024 Elsevier Inc. All rights reserved.)
Published: 2024
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12. A Remote Physical Therapy Program Demonstrates Similar Outcomes Compared to In-Person, Supervised Physical Therapy After Same-Day Discharge Total Knee Arthroplasty: A Randomized Clinical Trial.

Author: Bradbury TL, McConnell MJ, Whitacre D, Naylor BH, Gibson BT, and DeCook CA
Subjects: Humans, Male, Female, Aged, Middle Aged, Treatment Outcome, Knee Joint surgery, Knee Joint physiopathology, Recovery of Function, Osteoarthritis, Knee surgery, Patient Satisfaction, Arthroplasty, Replacement, Knee rehabilitation, Physical Therapy Modalities, Patient Discharge, Range of Motion, Articular
Abstract: Background: A growing number of total knee arthroplasty (TKA) patients are candidates for same-day discharge (SDD). Previous research has shown that internet-based remote physical therapy (RPT) can produce equivalent outcomes to supervised outpatient physical therapy (OPT) after TKA. We sought to compare outcomes between RPT and OPT in patients undergoing SDD TKA using an electronic remote perioperative management (ERPM) program., Methods: Patients undergoing SDD TKA were enrolled in an ERPM program and randomized to ERPM + RPT or ERPM + OPT. Preoperative and 6-week functional assessments included knee range of motion, timed up and go, and 4-meter gait speed. Numerical Rating Scale pain scores were evaluated preoperatively, at 6 and 12 weeks, and satisfaction was assessed at 6, 12, and 52 weeks postoperatively. Participants completed the Veterans Rand 12 Item Health Survey and Knee Injury and Osteoarthritis Outcome Score preoperatively and at 6, 12, and 52 weeks postoperatively. OPT utilization was collected 90 days postoperatively., Results: Of 197 initially randomized patients, 76 remained in the ERPM + RPT group and 95 in the ERPM + OPT group after withdrawals and crossovers. Baseline characteristics showed no differences between the 2 groups. No clinically relevant differences were observed in knee range of motion, Numerical Rating Scale pain, patient-reported outcomes, functional assessments, or satisfaction at any follow-up time. Participants in the ERPM + OPT group attended an average of 11.57 physical therapy sessions, incurring a total cost of $462.8 and 133 minutes of travel. Conversely, the ERPM + RPT group experienced no expenses or travel time., Conclusions: Patients in the ERPM + RPT group had similar outcomes, lower costs, and saved time compared to patients in the ERPM + OPT group after SDD TKA. Further analysis is needed to determine predictive indicators for crossovers., (Copyright © 2024 Elsevier Inc. All rights reserved.)
Published: 2024
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13. Deep Intraclonal Analysis for the Development of Vaccines against Drug-Resistant Klebsiella pneumoniae Lineages.

Author: Tajuelo A, Gato E, Oteo-Iglesias J, Pérez-Vázquez M, McConnell MJ, Martín-Galiano AJ, and Pérez A
Subjects: Humans, Drug Resistance, Multiple, Bacterial genetics, Antigens, Bacterial immunology, Antigens, Bacterial genetics, Vaccine Development, Bacterial Proteins immunology, Bacterial Proteins genetics, Epitopes, B-Lymphocyte immunology, Klebsiella pneumoniae immunology, Klebsiella pneumoniae genetics, Bacterial Vaccines immunology, Klebsiella Infections prevention & control, Klebsiella Infections microbiology, Klebsiella Infections immunology
Abstract: Despite its medical relevance, there is no commercial vaccine that protects the population at risk from multidrug-resistant (MDR) Klebsiella pneumoniae infections. The availability of massive omic data and novel algorithms may improve antigen selection to develop effective prophylactic strategies. Up to 133 exposed proteins in the core proteomes, between 516 and 8666 genome samples, of the six most relevant MDR clonal groups (CGs) carried conserved B-cell epitopes, suggesting minimized future evasion if utilized for vaccination. Antigens showed a range of epitopicity, functional constraints, and potential side effects. Eleven antigens, including three sugar porins, were represented in all MDR-CGs, constitutively expressed, and showed limited reactivity with gut microbiota. Some of these antigens had important interactomic interactions and may elicit adhesion-neutralizing antibodies. Synergistic bivalent to pentavalent combinations that address expression conditions, interactome location, virulence activities, and clone-specific proteins may overcome the limiting protection of univalent vaccines. The combination of five central antigens accounted for 41% of all non-redundant interacting partners of the antigen dataset. Specific antigen mixtures represented in a few or just one MDR-CG further reduced the chance of microbiota interference. Rational antigen selection schemes facilitate the design of high-coverage and "magic bullet" multivalent vaccines against recalcitrant K. pneumoniae lineages.
Published: 2024
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14. Loss of Lipooligosaccharide Synthesis in Acinetobacter baumannii Produces Changes in Outer Membrane Vesicle Protein Content.

Author: Cano-Castaño B, Corral-Lugo A, Gato E, Terrón MC, Martín-Galiano AJ, Sotillo J, Pérez A, and McConnell MJ
Subjects: Acinetobacter Infections microbiology, Animals, Mice, Tandem Mass Spectrometry, Bacterial Outer Membrane metabolism, Acinetobacter baumannii metabolism, Acinetobacter baumannii genetics, Lipopolysaccharides biosynthesis, Bacterial Outer Membrane Proteins metabolism, Bacterial Outer Membrane Proteins genetics
Abstract: Outer membrane vesicles (OMVs) are nanostructures derived from the outer membrane of Gram-negative bacteria. We previously demonstrated that vaccination with endotoxin-free OMVs isolated from an Acinetobacter baumannii strain lacking lipooligosaccharide (LOS) biosynthesis, due to a mutation in lpxD , provides full protection in a murine sepsis model. The present study characterizes the protein content of highly-purified OMVs isolated from LOS-replete and LOS-deficient strains. Four purification methods were evaluated to obtain highly purified OMV preparations: ultracentrifugation, size exclusion chromatography (SEC), ultracentrifugation followed by SEC, and Optiprep™. OMVs from each method were characterized using nanoparticle tracking analysis and electron microscopy. OMVs from LOS-deficient and LOS-replete strains purified using the Optiprep™ method were subjected to LC-MS/MS analysis to determine protein content. Significant differences in protein composition between OMVs from LOS-deficient and LOS-replete strains were found. Computational analyses using Bepipred 3.0 and SEMA 2.0 indicated that the lack of LOS led to the overexpression of immunogenic proteins found in LOS-containing OMVs and the presence of immune-stimulating proteins absent in LOS-replete OMVs. These findings have important implications for developing OMV-based vaccines against A. baumannii , using both LOS-containing and LOS-free OMVs preparations.
Published: 2024
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15. BCL6 is a context-dependent mediator of the glioblastoma response to irradiation therapy.

Author: Tribe AKW, Peng L, Teesdale-Spittle PH, and McConnell MJ
Subjects: Humans, Cell Line, Tumor, Gene Expression Regulation, Neoplastic radiation effects, DNA Damage, Brain Neoplasms radiotherapy, Brain Neoplasms metabolism, Glioblastoma radiotherapy, Glioblastoma metabolism, Proto-Oncogene Proteins c-bcl-6 metabolism, Proto-Oncogene Proteins c-bcl-6 genetics
Abstract: Glioblastoma is a rapidly fatal brain cancer that does not respond to therapy. Previous research showed that the transcriptional repressor protein BCL6 is upregulated by chemo and radiotherapy in glioblastoma, and inhibition of BCL6 enhances the effectiveness of these therapies. Therefore, BCL6 is a promising target to improve the efficacy of current glioblastoma treatment. BCL6 acts as a transcriptional repressor in germinal centre B cells and as an oncogene in lymphoma and other cancers. However, in glioblastoma, BCL6 induced by therapy may not be able to repress transcription. Using a BCL6 inhibitor, the whole proteome response to irradiation was compared with and without BCL6 activity. Acute high dose irradiation caused BCL6 to switch from repressing the DNA damage response to promoting stress response signalling. Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) enabled comparison of BCL6 partner proteins between untreated and irradiated glioblastoma cells. BCL6 was associated with transcriptional coregulators in untreated glioblastoma including the known partner NCOR2. However, this association was lost in response to acute irradiation, where BCL6 unexpectedly associated with synaptic and plasma membrane proteins. These results reveal the activity of BCL6 under therapy-induced stress is context-dependent, and potentially altered by the intensity of that stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2024
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16. Mapping recurrent mosaic copy number variation in human neurons.

Author: Sun C, Kathuria K, Emery SB, Kim B, Burbulis IE, Shin JH, Weinberger DR, Moran JV, Kidd JM, Mills RE, and McConnell MJ
Subjects: Humans, Alleles, DNA Copy Number Variations, Neurons metabolism, Mosaicism
Abstract: When somatic cells acquire complex karyotypes, they often are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, "CNV neurons"), but previous analyses of CNV neurons are limited by relatively small sample sizes. Here, we develop an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We apply this approach to 2,125 frontal cortical neurons from a neurotypical human brain. SCOVAL identifies 226 CNV neurons, which include a subclass of 65 CNV neurons with highly aberrant karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we find that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contain fewer, but longer, genes., (© 2024. The Author(s).)
Published: 2024
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17. Interleukin-7-based identification of liver lymphatic endothelial cells reveals their unique structural features.

Author: Yang Y, Jeong J, Su T, Lai S, Zhang P, Garcia-Milian R, Graham M, Liu X, McConnell MJ, Utsumi T, Pereira J, and Iwakiri Y
Abstract: Background & Aims: The lymphatic system plays crucial roles in maintaining fluid balance and immune regulation. Studying the liver lymphatics has been considered challenging, as common lymphatic endothelial cell (LyEC) markers are expressed by other liver cells. Additionally, isolation of sufficient numbers of LyECs has been challenging because of their extremely low abundance (<0.01% of entire liver cell population) in a normal liver., Methods: Potential LyEC markers was identified using our published single-cell RNA sequencing (scRNA-seq) dataset (GSE147581) in mouse livers. Interleukin-7 (IL7) promoter-driven green fluorescent protein knock-in heterozygous mice were used for the validation of IL7 expression in LyECs in the liver, for the development of liver LyEC isolation protocol, and generating liver ischemia/reperfusion (I/R) injury. Scanning electron microscopy was used for the structural analysis of LyECs. Changes in LyEC phenotypes in livers of mice with I/R were determined by RNA-seq analysis., Results: Through scRNA-seq analysis, we have identified IL7 as an exclusive marker for liver LyECs, with no overlap with other liver cell types. Based on IL7 expression in liver LyECs, we have established an LyEC isolation method and observed distinct cell surface structures of LyECs with fenestrae and cellular pores (ranging from 100 to 400 nm in diameter). Furthermore, we identified LyEC genes that undergo alterations during I/R liver injuries., Conclusions: This study not only identified IL7 as an exclusively expressed gene in liver LyECs, but also enhanced our understanding of LyEC structures and demonstrated transcriptomic changes in injured livers., Impact and Implications: Understanding the lymphatic system in the liver is challenging because of the absence of specific markers for liver LyEC. This study has identified IL7 as a reliable marker for LyECs, enabling the development of an effective method for their isolation, elucidating their unique cell surface structure, and identifying LyEC genes that undergo changes during liver damage. The development of IL7 antibodies for detecting it in human liver specimens will further advance our understanding of the liver lymphatic system in the future., Competing Interests: The authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Author(s).)
Published: 2024
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18. Special Issue: Vaccines against Antibiotic-Resistant Bacteria: From Bench to Bedside.

Author: López-Siles M, Corral-Lugo A, and McConnell MJ
Abstract: The emergence and global dissemination of bacterial strains from numerous species with resistance to multiple antibiotic classes has increased in recent years, both in the healthcare and the community setting [...].
Published: 2024
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19. The Sympathetic Nervous System Promotes Hepatic Lymphangiogenesis, which Is Protective Against Liver Fibrosis.

Author: Tanaka M, Jeong J, Thomas C, Zhang X, Zhang P, Saruwatari J, Kondo R, McConnell MJ, Utsumi T, and Iwakiri Y
Subjects: Rats, Humans, Animals, Lymphangiogenesis, Rats, Sprague-Dawley, Disease Models, Animal, Liver Cirrhosis pathology, Liver pathology, Sympathetic Nervous System, Vascular Endothelial Growth Factor C, Vascular Diseases pathology
Abstract: Liver is the largest lymph-producing organ. In cirrhotic patients, lymph production significantly increases concomitant with lymphangiogenesis. The aim of this study was to determine the mechanism of lymphangiogenesis in liver and its implication in liver fibrosis. Liver biopsies from portal hypertensive patients with portal-sinusoidal vascular disease (n = 22) and liver cirrhosis (n = 5) were evaluated for lymphangiogenesis and compared with controls (n = 9 and n = 6, respectively). For mechanistic studies, rats with partial portal vein ligation (PPVL) and bile duct ligation (BDL) were used. A gene profile data set (GSE77627), including 14 histologically normal liver, 18 idiopathic noncirrhotic portal hypertension, and 22 cirrhotic patients, was analyzed. Lymphangiogenesis was significantly increased in livers from patients with portal-sinusoidal vascular disease, cirrhotic patients, as well as PPVL and BDL rats. Importantly, Schwann cells of sympathetic nerves highly expressed vascular endothelial growth factor-C in PPVL rats. Vascular endothelial growth factor-C neutralizing antibody or sympathetic denervation significantly decreased lymphangiogenesis in livers of PPVL and BDL rats, which resulted in progression of liver fibrosis. Liver specimens from cirrhotic patients showed a positive correlation between sympathetic nerve/Schwann cell-positive areas and lymphatic vessel numbers, which was supported by gene set analysis from patients with noncirrhotic portal hypertension and cirrhotic patients. Sympathetic nerves promote hepatic lymphangiogenesis in noncirrhotic and cirrhotic livers. Increased hepatic lymphangiogenesis can be protective against liver fibrosis., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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20. An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver.

Author: Jeong J, Tanaka M, Yang Y, Arefyev N, DiRito J, Tietjen G, Zhang X, McConnell MJ, Utsumi T, and Iwakiri Y
Subjects: Rats, Humans, Mice, Animals, Liver pathology, Bile Ducts, Liver Cirrhosis pathology, Lymphatic Vessels diagnostic imaging, Lymphatic Vessels pathology, Cholestasis pathology
Abstract: The liver lymphatic system is essential for maintaining tissue fluid balance and immune function. The detailed structure of lymphatic vessels (LVs) in the liver remains to be fully demonstrated. The aim of this study is to reveal LV structures in normal and diseased livers by developing a tissue-clearing and coimmunolabeling protocol optimized for the tissue size and the processing time for three-dimensional (3-D) visualization and quantification of LVs in the liver. We showed that our optimized protocol enables in-depth exploration of lymphatic networks in the liver, consisting of LVs along the portal tract (deep lymphatic system) and within the collagenous Glisson's capsule (superficial lymphatic system) in different species. With this protocol, we have shown 3-D LVs configurations in relation to blood vessels and bile ducts in cholestatic mouse livers, in which LVs were highly dilated and predominantly found around highly proliferating bile ducts and peribiliary vascular plexuses in the portal tract. We also established a quantification method using a 3-D volume-rendering approach. We observed a 1.6-fold ( P < 0.05) increase in the average diameter of LVs and a 2.4-fold increase ( P < 0.05) in the average branch number of LVs in cholestatic/fibrotic livers compared with control livers. Furthermore, cholestatic/fibrotic livers showed a 4.3-fold increase ( P < 0.05) in total volume of LVs compared with control livers. Our optimized protocol and quantification method demonstrate an efficient and simple liver tissue-clearing procedure that allows the comprehensive analysis of liver lymphatic system. NEW & NOTEWORTHY This article showed a comprehensive 3-D-structural analysis of liver lymphatic vessel (LV) in normal and diseased livers in relation to blood vessels and bile ducts. In addition to the LVs highly localized at the portal tract, we revealed capsular LVs in mouse, rat, and human livers. In cholestatic livers, LVs are significantly increased and dilated compared with normal livers. Our optimized protocol provides detailed spatial information for LVs remodeling in normal and pathological conditions.
Published: 2023
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21. Mutation Analysis in Regulator DNA-Binding Regions for Antimicrobial Efflux Pumps in 17,000 Pseudomonas aeruginosa Genomes.

Author: Pérez-Vázquez M, López-Causapé C, Corral-Lugo A, McConnell MJ, Oteo-Iglesias J, Oliver A, and Martín-Galiano AJ
Abstract: Mutations leading to upregulation of efflux pumps can produce multiple drug resistance in the pathogen Pseudomonas aeruginosa . Changes in their DNA binding regions, i.e., palindromic operators, can compromise pump depression and subsequently enhance resistance against several antibacterials and biocides. Here, we have identified (pseudo)palindromic repeats close to promoters of genes encoding 13 core drug-efflux pumps of P. aeruginosa . This framework was applied to detect mutations in these repeats in 17,292 genomes. Eighty-nine percent of isolates carried at least one mutation. Eight binary genetic properties potentially related to expression were calculated for mutations. These included palindromicity reduction, mutation type, positioning within the repeat and DNA-bending shift. High-risk ST298, ST308 and ST357 clones commonly carried four conserved mutations while ST175 and the cystic fibrosis-linked ST649 clones showed none. Remarkably, a T-to-C transition in the fourth position of the upstream repeat for mexEF - oprN was nearly exclusive of the high-risk ST111 clone. Other mutations were associated with high-risk sublineages using sample geotemporal metadata. Moreover, 1.5% of isolates carried five or more mutations suggesting they undergo an alternative program for regulation of their effluxome. Overall, P. aeruginosa shows a wide range of operator mutations with a potential effect on efflux pump expression and antibiotic resistance.
Published: 2023
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22. Aryl-functionalised α,α'-Trehalose 6,6'-Glycolipid Induces Mincle-independent Pyroptotic Cell Death.

Author: Kodar K, Dangerfield EM, Foster AJ, Forsythe D, Ishizuka S, McConnell MJ, Yamasaki S, Timmer MSM, and Stocker BL
Subjects: Mice, Animals, Humans, Trehalose metabolism, NLR Family, Pyrin Domain-Containing 3 Protein, Furylfuramide, Lectins, C-Type metabolism, Glycolipids pharmacology, Glycolipids metabolism, Pyroptosis
Abstract: α,α'-Trehalose 6,6'-glycolipids have long been known for their immunostimulatory properties. The adjuvanticity of α,α'-trehalose 6,6'-glycolipids is mediated by signalling through the macrophage inducible C-type lectin (Mincle) and the induction of an inflammatory response. Herein, we present an aryl-functionalised trehalose glycolipid, AF-2, that leads to the release of cytokines and chemokines, including IL-6, MIP-2 and TNF-α, in a Mincle-dependent manner. Furthermore, plate-coated AF-2 also leads to the Mincle-independent production of IL-1β, which is unprecedented for this class of glycolipid. Upon investigation into the mode of action of plate-coated AF-2, it was observed that the treatment of WT and Mincle -/- bone marrow derived macrophages (BMDM), murine RAW264.7 cells, and human monocytes with AF-2 led to lytic cell death, as evidenced using Sytox Green and lactate dehydrogenase assays, and confocal and scanning electron microscopy. The requirement for functional Gasdermin D and Caspase-1 for IL-1β production and cell death by AF-2 confirmed pyroptosis as the mode of action of AF-2. The inhibition of NLRP3 and K + efflux reduced AF-2 mediated IL-1β production and cell death, and allowed us to conclude that AF-2 leads to Capase-1 dependent NLRP3 inflammasome-mediated cell death. The unique mode of action of plate-coated AF-2 was surprising and highlights how the physical presentation of Mincle ligands can lead to dramatically different immunological outcomes., (© 2023. The Author(s).)
Published: 2023
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23. The evolving role of liver sinusoidal endothelial cells in liver health and disease.

Author: McConnell MJ, Kostallari E, Ibrahim SH, and Iwakiri Y
Subjects: Humans, Liver pathology, Fibrosis, Inflammation metabolism, Endothelial Cells metabolism, Liver Diseases pathology
Abstract: LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research., (Copyright © 2023 American Association for the Study of Liver Diseases.)
Published: 2023
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24. Editorial: Resistant pathogens: from distribution to emerging therapies.

Author: García-Ríos E, McConnell MJ, Pérez-Romero P, and López-Siles M
Abstract: Competing Interests: MM and PP-R are founders and stockholders of the biotechnology spin-off company Vaxdyn, which develops vaccines for infections caused by MDR bacteria. Vaxdyn had no role in the elaboration of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Published: 2023
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25. Fecal carriage of extended-spectrum beta-lactamase-producing Enterobacterales in healthy Spanish schoolchildren.

Author: López-Siles M, Moure Z, Muadica AS, Sánchez S, Cruces R, Ávila A, Lara N, Köster PC, Dashti A, Oteo-Iglesias J, Carmena D, and McConnell MJ
Abstract: Background: Extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) are a serious threat among emerging antibiotic resistant bacteria. Particularly, the number of cases of ESBL-E infections reported in children has been increasing in recent years, and approved antibiotic treatments for this age group are limited. However, information regarding the prevalence of colonization in European children, risk factors associated with colonization, and the characteristics of the colonizing strains is scarce. The aims of this study were to determine the prevalence of ESBL-E colonization in fecal samples of apparently healthy schoolchildren, to identify lifestyle routines associated with colonization, and to characterize clonal relationships and mechanisms of resistance in ESBL-E isolates., Methods: A cohort of 887 healthy children (3-13 years old) from seven primary and secondary schools in the Madrid metropolitan area was recruited between April-June 2018, and sociodemographic information and daily habits were collected. Fecal samples were screened for ESBL-E carriage in selective medium. ESBL-E isolates were further characterized by assessing molecular epidemiology (PFGE and MLST), ESBL gene carriage, and antibiotic resistance profile. This information was analyzed in conjunction with the metadata of the participants in order to identify external factors associated with ESBL-E carriage., Results: Twenty four ESBL-E, all but one Escherichia coli, were detected in 23 children (prevalence: 2.6%; 95% CI: 1.6-3.6%). Of these, seven contained the bla CTX-M-14 allele, five the bla CTX-M-15 , five the bla SHV-12 , three the bla CTX-M-27 , three the bla CTX-M-32 , and one the bla CTX-M-9 . Significant clonal diversity was observed among the isolates that grouped into 22 distinct clusters (at <85% similarity of PFGE profile). ESBL-producing E. coli isolates belonged to 12 different STs, with ST10 (25%) and ST131 (17%) being the most frequent. Apart from ß-lactams, resistance to trimethoprim/sulfamethoxazole (46%), ciprofloxacin (33%), levofloxacin (33%), tobramycin (21%), and gentamicin (8%) were the most frequently detected., Conclusion: The prevalence of ESBL-E in the studied cohort of children was lower than the average colonization rate previously detected in Europe for both children and adults. E. coli was the main ESBL-producing species detected and CTX-M were the most frequently identified ESBLs. High ST diversity suggests polyclonal dissemination. Compared to other STs, ST131 isolates were associated with resistance to various antimicrobials., Competing Interests: MM was founder and stockholder of the biotechnology spin-off company Vaxdyn, which develops vaccines for infections caused by MDR bacteria. Vaxdyn had no role in the elaboration of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 López-Siles, Moure, Muadica, Sánchez, Cruces, Ávila, Lara, Köster, Dashti, Oteo-Iglesias, Carmena and McConnell.)
Published: 2023
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26. Mapping the Complex Genetic Landscape of Human Neurons.

Author: Sun C, Kathuria K, Emery SB, Kim B, Burbulis IE, Shin JH, Weinberger DR, Moran JV, Kidd JM, Mills RE, and McConnell MJ
Abstract: When somatic cells acquire complex karyotypes, they are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, "CNV neurons"), but previous analyses of CNV neurons have been limited by relatively small sample sizes. Here, we developed an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We applied this approach to 2,125 frontal cortical neurons from a neurotypical human brain. This approach identified 226 CNV neurons, as well as a class of CNV neurons with complex karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we found that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contained fewer, but longer, genes., Competing Interests: Competing interests J.V.M. is an inventor on patent US6150160, is a paid consultant for Gilead Sciences, serves on the scientific advisory board of Tessera Therapeutics Inc. (where he is paid as a consultant and has equity options), has licensed reagents to Merck Pharmaceutical, and recently served on the American Society of Human Genetics Board of Directors. The other authors do not declare competing interests.
Published: 2023
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27. Role of peptidoglycan recycling enzymes AmpD and AnmK in Acinetobacter baumannii virulence features.

Author: Tajuelo A, Terrón MC, López-Siles M, and McConnell MJ
Subjects: Virulence, Peptidoglycan metabolism, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents metabolism, Biofilms, Drug Resistance, Multiple, Bacterial, Fosfomycin pharmacology, Acinetobacter baumannii metabolism
Abstract: Acinetobacter baumannii is an important causative agent of hospital acquired infections. In addition to acquired resistance to many currently-available antibiotics, it is intrinsically resistant to fosfomycin. It has previously been shown that AmpD and AnmK contribute to intrinsic fosfomycin resistance in A. baumannii due to their involvement in the peptidoglycan recycling pathway. However, the role that these two enzymes play in the fitness and virulence of A. baumannii has not been studied. The aim of this study was to characterize several virulence-related phenotypic traits in A. baumannii mutants lacking AmpD and AnmK. Specifically, cell morphology, peptidoglycan thickness, membrane permeability, growth under iron-limiting conditions, fitness, resistance to disinfectants and antimicrobial agents, twitching motility and biofilm formation of the mutant strains A. baumannii ATCC 17978 Δ ampD ::Kan and Δ anmK ::Kan were compared to the wild type strain. Our results demonstrate that bacterial growth and fitness of both mutants were compromised, especially in the Δ ampD ::Kan mutant. In addition, biofilm formation was decreased by up to 69%, whereas twitching movement was reduced by about 80% in both mutants. These results demonstrate that, in addition to increased susceptibility to fosfomycin, alteration of the peptidoglycan recycling pathway affects multiple aspects related to virulence. Inhibition of these enzymes could be explored as a strategy to develop novel treatments for A. baumannii in the future. Furthermore, this study establishes a link between intrinsic fosfomycin resistance mechanisms and bacterial fitness and virulence traits., Competing Interests: MM is founder and stockholder of the biotechnology spin-off company Vaxdyn, which develops vaccines for infections caused by MDR bacteria. Vaxdyn had no role in the elaboration of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tajuelo, Terrón, López-Siles and McConnell.)
Published: 2023
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28. Portal Hypertension in Alcohol-Associated Hepatitis.

Author: McConnell MJ and Iwakiri Y
Abstract: Purpose of Review: This review article will examine portal hypertension in alcoholic hepatitis (AH) from both a basic mechanistic and a clinical perspective., Recent Findings: Alcoholic hepatitis is a major public health problem in the USA, accounting for over 300,000 hospital admissions in a recent year of data (Jinjuvadia et al. J Clin Gastroenterol. 60;49:506-511). Portal hypertension is a key consequence of AH and a driver of liver-related morbidity and mortality. Alcohol may directly mediate portal hypertension via multiple possible mechanisms, including increased portal inflow, increased intrahepatic vasoconstriction, inflammation, and changes in the liver vasculature such as perisinusoidal fibrosis and phlebosclerosis., Summary: Portal hypertension is a key consequence of AH and a critical area for future research., Competing Interests: Conflict of InterestThe authors have nothing to disclose., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
Published: 2023
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29. Unsupervised Machine Learning Organization of the Functional Dark Proteome of Gram-Negative "Superbugs": Six Protein Clusters Amenable for Distinct Scientific Applications.

Author: Sicilia C, Corral-Lugo A, Smialowski P, McConnell MJ, and Martín-Galiano AJ
Abstract: Uncharacterized proteins have been underutilized as targets for the development of novel therapeutics for difficult-to-treat bacterial infections. To facilitate the exploration of these proteins, 2819 predicted, uncharacterized proteins (19.1% of the total) from reference strains of multidrug Acinetobacter baumannii , Klebsiella pneumoniae , and Pseudomonas aeruginosa species were organized using an unsupervised k-means machine learning algorithm. Classification using normalized values for protein length, pI, hydrophobicity, degree of conservation, structural disorder, and %AT of the coding gene rendered six natural clusters. Cluster proteins showed different trends regarding operon membership, expression, presence of unknown function domains, and interactomic relevance. Clusters 2, 4, and 5 were enriched with highly disordered proteins, nonworkable membrane proteins, and likely spurious proteins, respectively. Clusters 1, 3, and 6 showed closer distances to known antigens, antibiotic targets, and virulence factors. Up to 21.8% of proteins in these clusters were structurally covered by modeling, which allowed assessment of druggability and discontinuous B-cell epitopes. Five proteins (4 in Cluster 1) were potential druggable targets for antibiotherapy. Eighteen proteins (11 in Cluster 6) were strong B-cell and T-cell immunogen candidates for vaccine development. Conclusively, we provide a feature-based schema to fractionate the functional dark proteome of critical pathogens for fundamental and biomedical purposes., Competing Interests: The authors declare the following competing financial interest(s): MM is a founder and shareholder in the biotechnology company Vaxdyn, S.L., (© 2022 The Authors. Published by American Chemical Society.)
Published: 2022
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30. Transcription-associated DNA DSBs activate p53 during hiPSC-based neurogenesis.

Author: Michel N, Young HMR, Atkin ND, Arshad U, Al-Humadi R, Singh S, Manukyan A, Gore L, Burbulis IE, Wang YH, and McConnell MJ
Subjects: DNA genetics, DNA metabolism, DNA Repair, Humans, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, DNA Breaks, Double-Stranded, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Neurogenesis
Abstract: Neurons are overproduced during cerebral cortical development. Neural progenitor cells (NPCs) divide rapidly and incur frequent DNA double-strand breaks (DSBs) throughout cortical neurogenesis. Although half of the neurons born during neurodevelopment die, many neurons with inaccurate DNA repair survive leading to brain somatic mosaicism. Recurrent DNA DSBs during neurodevelopment are associated with both gene expression level and gene length. We used imaging flow cytometry and a genome-wide DNA DSB capture approach to quantify and map DNA DSBs during human induced pluripotent stem cell (hiPSC)-based neurogenesis. Reduced p53 signaling was brought about by knockdown (p53 KD ); p53 KD led to elevated DNA DSB burden in neurons that was associated with gene expression level but not gene length in neural progenitor cells (NPCs). Furthermore, DNA DSBs incurred from transcriptional, but not replicative, stress lead to p53 activation in neurotypical NPCs. In p53 KD NPCs, DNA DSBs accumulate at transcription start sites of genes that are associated with neurological and psychiatric disorders. These findings add to a growing understanding of how neuronal genome dynamics are engaged by high transcriptional or replicative burden during neurodevelopment., (© 2022. The Author(s).)
Published: 2022
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31. Towards Control and Oversight of SARS-CoV-2 Diagnosis and Monitoring through Multiplexed Quantitative Electroanalytical Immune Response Biosensors.

Author: Torrente-Rodríguez RM, Montero-Calle A, San Bartolomé C, Cano O, Vázquez M, Iglesias-Caballero M, Corral-Lugo A, McConnell MJ, Pascal M, Mas V, Pingarrón JM, Barderas R, and Campuzano S
Abstract: The development of versatile and sensitive biotools to quantify specific SARS-CoV-2 immunoglobulins in SARS-CoV-2 infected and non-infected individuals, built on the surface of magnetic microbeads functionalized with nucleocapsid (N) and in-house expressed recombinant spike (S) proteins is reported. Amperometric interrogation of captured N- and S-specific circulating total or individual immunoglobulin (Ig) isotypes (IgG, IgM, and IgA), subsequently labelled with HRP-conjugated secondary antibodies, was performed at disposable single or multiplexed (8×) screen-printed electrodes using the HQ/HRP/H 2 O 2 system. The obtained results using N and in-house expressed S ectodomains of five SARS-CoV-2 variants of concern (including the latest Delta and Omicron) allow identification of vulnerable populations from those with natural or acquired immunity, monitoring of infection, evaluation of vaccine efficiency, and even identification of the variant responsible for the infection., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Angewandte Chemie published by Wiley-VCH GmbH.)
Published: 2022
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32. Corrigendum: Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients.

Author: Tajuelo A, Carretero O, García-Ríos E, López-Siles M, Cano O, Vázquez M, Más V, Rodríguez-Goncer I, Lalueza A, López-Medrano F, San Juan R, Fernández-Ruiz M, Aguado JM, McConnell MJ, and Pérez-Romero P
Abstract: [This corrects the article DOI: 10.3389/fimmu.2022.878812.]., (Copyright © 2022 Tajuelo, Carretero, García-Ríos, López-Siles, Cano, Vázquez, Más, Rodríguez-Goncer, Lalueza, López-Medrano, San Juan, Fernández-Ruiz, Aguado, McConnell and Pérez-Romero.)
Published: 2022
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33. Identification of Promoter Region Markers Associated With Altered Expression of Resistance-Nodulation-Division Antibiotic Efflux Pumps in Acinetobacter baumannii .

Author: López-Siles M, McConnell MJ, and Martín-Galiano AJ
Abstract: Genetic alterations leading to the constitutive upregulation of specific efflux pumps contribute to antibacterial resistance in multidrug resistant bacteria. The identification of such resistance markers remains one of the most challenging tasks of genome-level resistance predictors. In this study, 487 non-redundant genetic events were identified in upstream zones of three operons coding for resistance-nodulation-division (RND) efflux pumps of 4,130 Acinetobacter baumannii isolates. These events included insertion sequences, small indels, and single nucleotide polymorphisms. In some cases, alterations explicitly modified the expression motifs described for these operons, such as the promoter boxes, operators, and Shine-Dalgarno sequences. In addition, changes in DNA curvature and mRNA secondary structures, which are structural elements that regulate expression, were also calculated. According to their influence on RND upregulation, the catalog of upstream modifications were associated with "experimentally verified," "presumed," and "probably irrelevant" degrees of certainty. For experimental verification, DNA of upstream sequences independently carrying selected markers, three for each RND operon, were fused to a luciferase reporter plasmid system. Five out of the nine selected markers tested showed significant increases in expression with respect to the wild-type sequence control. In particular, a 25-fold expression increase was observed with the IS Aba 1 insertion sequence upstream the adeABC pump. Next, overexpression of each of the three multi-specific RND pumps was linked to their respective antibacterial substrates by a deep A. baumannii literature screen. Consequently, a data flow framework was then developed to link genomic upregulatory RND determinants to potential antibiotic resistance. Assignment of potential increases in minimal inhibitory concentrations at the "experimentally verified" level was permitted for 42 isolates to 7-8 unrelated antibacterial agents including tigecycline, which is overlooked by conventional resistome predictors. Thus, our protocol may represent a time-saving filter step prior to laborious confirmation experiments for efflux-driven resistance. Altogether, a computational-experimental pipeline containing all components required for identifying the upstream regulatory resistome is proposed. This schema may provide the foundational stone for the elaboration of tools approaching antibiotic efflux that complement routine resistome predictors for preventing antimicrobial therapy failure against difficult-to-threat bacteria., Competing Interests: MM is a founder and shareholder in the biotechnology company Vaxdyn, S.L. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 López-Siles, McConnell and Martín-Galiano.)
Published: 2022
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34. Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients.

Author: Tajuelo A, Carretero O, García-Ríos E, López-Siles M, Cano O, Vázquez M, Más V, Rodríguez-Goncer I, Lalueza A, López-Medrano F, Juan RS, Fernández-Ruiz M, Aguado JM, McConnell MJ, and Pérez-Romero P
Subjects: Adult, Antibodies, Neutralizing, Antibodies, Viral, Cross-Sectional Studies, Humans, Immunity, Humoral, Immunoglobulin G, Immunoglobulin M, Oxygen, Prospective Studies, Research Report, SARS-CoV-2, COVID-19, Respiratory Insufficiency
Abstract: Introduction: There is robust evidence indicating that the SARS-CoV-2-specific humoral response is associated with protection against severe disease. However, relatively little data exist regarding how the humoral immune response at the time of hospital admission correlates with disease severity in unimmunized patients. Our goal was toidentify variables of the humoral response that could potentially serve as prognostic markers for COVID-19 progressionin unvaccinated SARS-CoV-2 patients., Methods: A prospective cross-sectional study was carried out in a cohort of 160 unimmunized, adult COVID-19 patients from the Hospital Universitario 12Octubre. Participants were classified into four clinical groups based on disease severity: non-survivors with respiratory failure (RF), RF survivors, patients requiring oxygen therapy and those not receiving oxygen therapy. Serum samples were taken on admission and IgM, IgG, IgG subclass antibody titers were determined by ELISA, and neutralizing antibody titersusing a surrogate neutralization assay. The differences in the antibody titers between groups and the association between the clinical and analytical characteristics of the patients and the antibody titers were analyzed., Results: Patients that developed RF and survived had IgM titers that were 2-fold higher than non-survivors ( p = 0.001), higher levels of total IgG than those who developed RF and succumbed to infection ( p < 0.001), and than patients who required oxygen therapy ( p < 0.05), and had 5-fold higher IgG1 titers than RF non-survivors ( p < 0.001) and those who needed oxygen therapy ( p < 0.001), and 2-fold higher than patients that did not require oxygen therapy during admission ( p < 0.05). In contrast, RF non-survivorshad the lowest neutralizing antibodylevels, which were significantly lower compared those with RF that survived ( p = 0.03). A positive correlation was found between IgM, total IgG, IgG1 and IgG3 titers and neutralizing antibody titers in the total cohort (p ≤ 0.0036)., Conclusions: We demonstrate that patients with RF that survived infection had significantly higher IgM, IgG, IgG1 and neutralizing titers compared to patients with RF that succumb to infection, suggesting that using humoral response variables could be used as a prognostic marker for guiding the clinical management of unimmunized patients admitted to the hospital for SARS-CoV-2 infection., Competing Interests: MJM and PPR are founders and stockholders of the biotech-nology spin-off company Vaxdyn, which develops vaccines for infections caused by MDR bacteria. Vaxdyn had no role in the elaboration of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tajuelo, Carretero, García-Ríos, López-Siles, Cano, Vázquez, Más, Rodríguez-Goncer, Lalueza, López-Medrano, Juan, Fernández-Ruiz, Aguado, McConnell and Pérez-Romero.)
Published: 2022
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35. Cross-Recognition of SARS-CoV-2 B-Cell Epitopes with Other Betacoronavirus Nucleoproteins.

Author: Tajuelo A, López-Siles M, Más V, Pérez-Romero P, Aguado JM, Briz V, McConnell MJ, Martín-Galiano AJ, and López D
Subjects: Adult, Amino Acid Sequence, COVID-19 immunology, COVID-19 virology, Cohort Studies, Coronavirus Nucleocapsid Proteins chemistry, Coronavirus Nucleocapsid Proteins genetics, Coronavirus OC43, Human genetics, Coronavirus OC43, Human physiology, Cross Reactions genetics, Enzyme-Linked Immunosorbent Assay methods, Epitopes, B-Lymphocyte metabolism, HEK293 Cells, Health Personnel statistics & numerical data, Humans, Protein Domains, SARS-CoV-2 genetics, SARS-CoV-2 physiology, Sequence Homology, Amino Acid, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology, Coronavirus Nucleocapsid Proteins immunology, Coronavirus OC43, Human immunology, Cross Reactions immunology, Epitope Mapping methods, Epitopes, B-Lymphocyte immunology, SARS-CoV-2 immunology
Abstract: The B and T lymphocytes of the adaptive immune system are important for the control of most viral infections, including COVID-19. Identification of epitopes recognized by these cells is fundamental for understanding how the immune system detects and removes pathogens, and for antiviral vaccine design. Intriguingly, several cross-reactive T lymphocyte epitopes from SARS-CoV-2 with other betacoronaviruses responsible for the common cold have been identified. In addition, antibodies that cross-recognize the spike protein, but not the nucleoprotein (N protein), from different betacoronavirus have also been reported. Using a consensus of eight bioinformatic methods for predicting B-cell epitopes and the collection of experimentally detected epitopes for SARS-CoV and SARS-CoV-2, we identified four surface-exposed, conserved, and hypothetical antigenic regions that are exclusive of the N protein. These regions were analyzed using ELISA assays with two cohorts: SARS-CoV-2 infected patients and pre-COVID-19 samples. Here we describe four epitopes from SARS-CoV-2 N protein that are recognized by the humoral response from multiple individuals infected with COVID-19, and are conserved in other human coronaviruses. Three of these linear surface-exposed sequences and their peptide homologs in SARS-CoV-2 and HCoV-OC43 were also recognized by antibodies from pre-COVID-19 serum samples, indicating cross-reactivity of antibodies against coronavirus N proteins. Different conserved human coronaviruses (HCoVs) cross-reactive B epitopes against SARS-CoV-2 N protein are detected in a significant fraction of individuals not exposed to this pandemic virus. These results have potential clinical implications.
Published: 2022
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36. Predicted impact of the viral mutational landscape on the cytotoxic response against SARS-CoV-2.

Author: Foix A, López D, Díez-Fuertes F, McConnell MJ, and Martín-Galiano AJ
Subjects: Epitopes genetics, Epitopes immunology, Gene Frequency, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Humans, Viral Proteins genetics, Viral Proteins immunology, COVID-19 immunology, COVID-19 virology, Genome, Viral genetics, Genome, Viral immunology, Immune Evasion genetics, Immune Evasion immunology, Mutation genetics, Mutation immunology, SARS-CoV-2 genetics, SARS-CoV-2 immunology
Abstract: The massive assessment of immune evasion due to viral mutations that increase COVID-19 susceptibility can be computationally facilitated. The adaptive cytotoxic T response is critical during primary infection and the generation of long-term protection. Here, potential HLA class I epitopes in the SARS-CoV-2 proteome were predicted for 2,915 human alleles of 71 families using the netMHCIpan EL algorithm. Allele families showed extreme epitopic differences, underscoring genetic variability of protective capacity between humans. Up to 1,222 epitopes were associated with any of the twelve supertypes, that is, allele clusters covering 90% population. Next, from all mutations identified in ~118,000 viral NCBI isolates, those causing significant epitope score reduction were considered epitope escape mutations. These mutations mainly involved non-conservative substitutions at the second and C-terminal position of the ligand core, or total ligand removal by large recurrent deletions. Escape mutations affected 47% of supertype epitopes, which in 21% of cases concerned isolates from two or more sub-continental areas. Some of these changes were coupled, but never surpassed 15% of evaded epitopes for the same supertype in the same isolate, except for B27. In contrast to most supertypes, eight allele families mostly contained alleles with few SARS-CoV-2 ligands. Isolates harboring cytotoxic escape mutations for these families co-existed geographically within sub-Saharan and Asian populations enriched in these alleles according to the Allele Frequency Net Database. Collectively, our findings indicate that escape mutation events have already occurred for half of HLA class I supertype epitopes. However, it is presently unlikely that, overall, it poses a threat to the global population. In contrast, single and double mutations for susceptible alleles may be associated with viral selective pressure and alarming local outbreaks. The integration of genomic, geographical and immunoinformatic information eases the surveillance of variants potentially affecting the global population, as well as minority subpopulations., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MJM is a founder and shareholder in the company Vaxdyn, S.L. Vaxdyn played no role in the present study. No other competing interest is declared for the remaining co-authors.
Published: 2022
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37. Covid-19 and Liver Injury: Role of Inflammatory Endotheliopathy, Platelet Dysfunction, and Thrombosis.

Author: McConnell MJ, Kondo R, Kawaguchi N, and Iwakiri Y
Subjects: Blood Platelet Disorders immunology, Blood Platelet Disorders physiopathology, COVID-19 immunology, Endothelium, Vascular immunology, Endothelium, Vascular physiopathology, Humans, Inflammation immunology, Inflammation physiopathology, Liver Diseases immunology, Liver Diseases physiopathology, Thrombosis immunology, Thrombosis physiopathology, Blood Platelet Disorders virology, COVID-19 physiopathology, Endothelium, Vascular virology, Inflammation virology, Liver Diseases virology, Thrombosis virology
Abstract: Liver injury, characterized predominantly by elevated aspartate aminotransferase and alanine aminotransferase, is a common feature of coronavirus disease 2019 (COVID-19) symptoms caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Additionally, SARS-CoV-2 infection is associated with acute-on-chronic liver failure in patients with cirrhosis and has a notably elevated mortality in patients with alcohol-related liver disease compared to other etiologies. Direct viral infection of the liver with SARS-CoV-2 remains controversial, and alternative pathophysiologic explanations for its hepatic effects are an area of active investigation. In this review, we discuss the effects of SARS-CoV-2 and the inflammatory environment it creates on endothelial cells and platelets more generally and then with a hepatic focus. In doing this, we present vascular inflammation and thrombosis as a potential mechanism of liver injury and liver-related complications in COVID-19., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Published: 2022
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38. Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH.

Author: Maeda H, Ishima Y, Saruwatari J, Mizuta Y, Minayoshi Y, Ichimizu S, Yanagisawa H, Nagasaki T, Yasuda K, Oshiro S, Taura M, McConnell MJ, Oniki K, Sonoda K, Wakayama T, Kinoshita M, Shuto T, Kai H, Tanaka M, Sasaki Y, Iwakiri Y, Otagiri M, Watanabe H, and Maruyama T
Subjects: Animals, Antioxidants therapeutic use, Humans, Kupffer Cells metabolism, Mice, Nitric Oxide metabolism, Non-alcoholic Fatty Liver Disease drug therapy, Non-alcoholic Fatty Liver Disease metabolism
Abstract: Kupffer cells are a key source of reactive oxygen species (ROS) and are implicated in the development of steatohepatitis and fibrosis in nonalcoholic steatohepatitis (NASH). We recently developed a polythiolated and mannosylated human serum albumin (SH-Man-HSA), a nano-antioxidant that targets Kupffer cells, in which the mannosyl units on albumin allows their specific uptake by Kupffer cells via the mannose receptor C type 1 (MRC1), and in which the polythiolation confers antioxidant activity. The aim of this study was to investigate the therapeutic potential of SH-Man-HSA in NASH model mice. In livers from mice and/or patients with NASH, we observed a reduced blood flow in the liver lobes and the down-regulation in MRC1 expression in Kupffer cells, and SH-Man-HSA alone failed to improve the pathological phenotype in NASH. However, the administration of a nitric oxide (NO) donor restored hepatic blood flow and increased the expression of the mannose receptor C type 2 (MRC2) instead of MRC1. Consequently, treatment with a combination of SH-Man-HSA and an NO donor improved oxidative stress-associated pathology. Finally, we developed a hybrid type of nano-antioxidant (SNO-Man-HSA) via the S-nitrosation of SH-Man-HSA. This nanomedicine efficiently delivered both NO and thiol groups to the liver, with a hepatoprotective effect that was comparable to the combination therapy of SH-Man-HSA and an NO donor. These findings suggest that SNO-Man-HSA has the potential for functioning as a novel nano-therapy for the treatment of NASH., (Copyright © 2021. Published by Elsevier B.V.)
Published: 2022
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39. Subinhibitory Concentrations of Clinically-Relevant Antimicrobials Affect Resistance-Nodulation-Division Family Promoter Activity in Acinetobacter baumannii .

Author: Prieto Martin Gil S, Tajuelo A, López-Siles M, and McConnell MJ
Abstract: Efflux pumps contribute to multidrug resistance in Acinetobacter baumannii due to their ability to expel a wide variety of structurally unrelated compounds. This study aimed to characterize the effect of subinhibitory concentrations of clinically-relevant antibiotics and disinfectants on the promoter activity of members of the Resistance-Nodulation-Division (RND) family in A. baumannii . The promoter regions from three RND efflux pumps (AdeABC, AdeFGH and AdeIJK) and the AdeRS regulatory system from three different A. baumannii strains (ATCC 17961, ATCC 17978, and ATCC 19606) were cloned into a luciferase reporter system (pLPV1Z). Promoter activity was quantitatively assessed in both exponential and stationary phase cultures after exposure to subinhibitory concentrations of four antibiotics from different classes (rifampicin, meropenem, tigecycline and colistin) and two disinfectants (ethanol and chlorhexidine). Subinhibitory concentrations of the compounds tested had variable effects on promoter activity that were highly dependent on the A. baumannii strain, the compound tested and the growth phase. Fold changes in AdeABC promoter activity ranged from 1.97 to 113.7, in AdeFGH from -5.6 to 1.13, in AdeIJK from -2.5 to 2, and in AdeRS from -36.2 to -1.32. Taken together, these results indicate that subinhibitory concentrations of clinically-relevant antibiotics and disinfectants affect the promoter activity of RND family members in A. baumannii in a strain and growth phase dependent manner. These results may have important implications for the treatment of infections caused by A. baumannii ., Competing Interests: MJM is founder and stockholder of the biotechnology spin-off company Vaxdyn, which develops vaccines for infections caused by MDR bacteria. Vaxdyn had no role in the elaboration of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Prieto Martin Gil, Tajuelo, López-Siles and McConnell.)
Published: 2021
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40. Predicted Epitope Abundance Supports Vaccine-Induced Cytotoxic Protection Against SARS-CoV-2 Variants of Concern.

Author: Martín-Galiano AJ, Díez-Fuertes F, McConnell MJ, and López D
Subjects: Alleles, COVID-19 prevention & control, COVID-19 virology, Epitopes, B-Lymphocyte metabolism, Epitopes, T-Lymphocyte metabolism, Female, Genes, MHC Class I genetics, Genes, MHC Class I immunology, Humans, Immunogenicity, Vaccine immunology, Mutation, SARS-CoV-2 genetics, SARS-CoV-2 physiology, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes virology, Vaccination, Vaccine Efficacy, COVID-19 immunology, COVID-19 Vaccines immunology, Epitopes, B-Lymphocyte immunology, Epitopes, T-Lymphocyte immunology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology
Abstract: The effect of emerging SARS-CoV-2 variants on vaccine efficacy is of critical importance. In this study, the potential impact of mutations that facilitate escape from the cytotoxic cellular immune response in these new virus variants for the 551 most abundant HLA class I alleles was analyzed. Computational prediction showed that most of these alleles, that cover >90% of the population, contain enough epitopes without escape mutations in the principal SARS-CoV-2 variants. These data suggest that the cytotoxic cellular immune protection elicited by vaccination is not greatly affected by emerging SARS-CoV-2 variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Martín-Galiano, Díez-Fuertes, McConnell and López.)
Published: 2021
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41. Effect of Subinhibitory Concentrations of Antibiotics and Disinfectants on IS Aba -Mediated Inactivation of Lipooligosaccharide Biosynthesis Genes in Acinetobacter baumannii .

Author: Olmeda-López H, Corral-Lugo A, and McConnell MJ
Abstract: Inactivation of the lipooligosaccharide (LOS) biosynthesis genes lpxA , lpxC and lpxD by IS Aba insertion elements results in high-level resistance to colistin in A. baumannii . In the present study, we quantify the rate of spontaneous insertional inactivation of LOS biosynthesis genes by IS Aba elements in the ATCC 19606-type strain and two multidrug clinical isolates. Using insertional inactivation of lpxC by IS Aba 11 in the ATCC 19606 strain as a model, we determine the effect of several subinhibitory concentrations of the antibiotics, namely tetracycline, ciprofloxacin, meropenem, kanamycin and rifampicin, as well as the disinfectants ethanol and chlorhexidine on IS Aba 11 insertion frequencies. Notably, subinhibitory concentrations of tetracycline significantly increased IS Aba 11 insertion, and rifampicin completely inhibited the emergence of colistin resistance due to IS Aba 11 inactivation of lpxC . Sequencing of IS Aba 11 insertion sites within the lpxC gene demonstrated that insertions clustered between nucleotides 382 and 618 (58.3% of unique insertions detected), indicating that this may be a hotspot for IS Aba 11 insertion. The alignment of insertion sites revealed a semi-conserved AT-rich consensus sequence upstream of the IS Aba 11 insertion site, suggesting that IS Aba 11 insertion sites may be sequence-dependent. This study explores previously uncharacterized aspects regarding the acquisition of colistin resistance through insertional activation in LOS biosynthesis genes in A. baumannii .
Published: 2021
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42. Optimization of a Lambda-RED Recombination Method for Rapid Gene Deletion in Human Cytomegalovirus.

Author: García-Ríos E, Gata-de-Benito J, López-Siles M, McConnell MJ, and Pérez-Romero P
Subjects: Bacteriophage lambda metabolism, Cell Line, Cloning, Molecular methods, Cytomegalovirus Infections virology, Genome, Viral genetics, HEK293 Cells, Humans, Mutation, Plasmids genetics, Reproducibility of Results, Bacteriophage lambda genetics, Chromosomes, Artificial, Bacterial genetics, Cytomegalovirus genetics, Escherichia coli genetics, Gene Deletion, Recombination, Genetic
Abstract: Human cytomegalovirus (HCMV) continues to be a major cause of morbidity in transplant patients and newborns. However, the functions of many of the more than 282 genes encoded in the HCMV genome remain unknown. The development of bacterial artificial chromosome (BAC) technology contributes to the genetic manipulation of several organisms including HCMV. The maintenance of the HCMV BAC in E. coli cells permits the rapid generation of recombinant viral genomes that can be used to produce viral progeny in cell cultures for the study of gene function. We optimized the Lambda-Red Recombination system to construct HCMV gene deletion mutants rapidly in the complete set of tested genes. This method constitutes a useful tool that allows for the quick generation of a high number of gene deletion mutants, allowing for the analysis of the whole genome to improve our understanding of HCMV gene function. This may also facilitate the development of novel vaccines and therapeutics.
Published: 2021
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43. The Big Picture of Glioblastoma Malignancy: A Meta-Analysis of Glioblastoma Proteomics to Identify Altered Biological Pathways.

Author: Tribe AKW, McConnell MJ, and Teesdale-Spittle PH
Abstract: Glioblastoma is a highly malignant cancer with no effective treatment. It is vital to elucidate the mechanisms which drive glioblastoma in order to identify therapeutic targets. The differences in protein expression between glioblastoma, grade I-III glioma, and normal brain tissue reflect the functional alterations driving malignancy. However, proteomic analysis of glioblastoma has been hampered by the heterogeneity of glioblastoma and the variety of methodology used in its study. To reduce these inconsistencies, we performed a meta-analysis of the literature published since 2015, including 14 datasets from eight papers comparing the whole proteome of glioblastoma to normal brain or grade I-III glioma. We found that 154 proteins were commonly upregulated and 116 proteins were commonly downregulated in glioblastoma compared to normal brain. Meanwhile, 240 proteins were commonly upregulated and 125 proteins were commonly downregulated in glioblastoma compared to grade I-III glioma. Functional enrichment analysis revealed upregulation of proteins involved in mRNA splicing and the immune system and downregulation of proteins involved in synaptic signaling and glucose and glutamine metabolism. The identification of these altered biological pathways provides a basis for deeper investigation in the pursuit of an effective treatment for glioblastoma., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)
Published: 2021
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44. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

Author: McConnell MJ, Kawaguchi N, Kondo R, Sonzogni A, Licini L, Valle C, Bonaffini PA, Sironi S, Alessio MG, Previtali G, Seghezzi M, Zhang X, Lee AI, Pine AB, Chun HJ, Zhang X, Fernandez-Hernando C, Qing H, Wang A, Price C, Sun Z, Utsumi T, Hwa J, Strazzabosco M, and Iwakiri Y
Subjects: Adult, Blood Coagulation Disorders etiology, Fibrinogen analysis, Humans, Interleukin-6 blood, Janus Kinase 1 metabolism, Nitriles, Pyrazoles pharmacology, Pyrimidines, Retrospective Studies, STAT3 Transcription Factor metabolism, Signal Transduction physiology, von Willebrand Factor analysis, COVID-19 complications, Endothelial Cells pathology, Interleukin-6 physiology, Liver Diseases etiology, SARS-CoV-2
Abstract: Background and Aims: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19., Methods: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism., Results: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling., Conclusion: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients., Lay Summary: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Published: 2021
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45. Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: A series of 43 cases.

Author: Kondo R, Kawaguchi N, McConnell MJ, Sonzogni A, Licini L, Valle C, Bonaffini PA, Sironi S, Alessio MG, Previtali G, Seghezzi M, Zhang X, Sun Z, Utsumi T, Strazzabosco M, and Iwakiri Y
Abstract: Aim: Coronavirus disease (COVID-19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID-19 patients. The aim of this study is to identify pathological microthrombi in COVID-19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation., Methods: Forty-three post-mortem liver biopsy samples from COVID-19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated., Results: We found liver sinusoidal microthrombosis in 23 COVID-19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10-fold, p = 0.04; AST: 11-fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p < 0.01), whereas SEA was not (p = 0.73). In COVID-19 livers, strong vWF staining in liver sinusoidal endothelial cells was associated with significantly increased platelet adhesion (1.7-fold, p = 0.0016), compared to those with weak sinusoidal vWF (2-fold, p < 0.0001). Sinusoidal erythrocyte aggregation in 19 (83%) liver samples was mainly seen in zone 2. Livers with SEA had significantly higher fibrinogen (1.6-fold, p = 0.031) compared to those without SEA in COVID-19 patients., Conclusions: Liver PMT is a pathologically important thrombosis associated with liver injury in COVID-19, while SEA is a unique morphological feature of COVID-19 patient livers. Sinusoidal vWF and hyperfibrinogenemia could contribute to PMT and SEA formation., (© 2021 The Japan Society of Hepatology.)
Published: 2021
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46. Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease.

Author: Yang Y, Sangwung P, Kondo R, Jung Y, McConnell MJ, Jeong J, Utsumi T, Sessa WC, and Iwakiri Y
Subjects: Adult, Alcohol Drinking adverse effects, Alcohol Drinking physiopathology, Analysis of Variance, Animals, Endothelial Cells drug effects, Endothelial Cells enzymology, HSP90 Heat-Shock Proteins, Humans, Liver Diseases, Alcoholic etiology, Mice, Rats, Acetylation drug effects, Liver Diseases, Alcoholic genetics
Abstract: Background & Aims: Liver sinusoidal endothelial cell (LSEC) dysfunction has been reported in alcohol-related liver disease, yet it is not known whether LSECs metabolize alcohol. Thus, we investigated this, as well as the mechanisms of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury., Methods: Primary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs via adeno-associated virus (AAV)-mediated gene delivery to decrease heat shock protein 90 (Hsp90) acetylation in ethanol-fed mice., Results: LSECs expressed CYP2E1 and alcohol dehydrogenase 1 (ADH1) and metabolized alcohol. Ethanol induced CYP2E1 in LSECs, but not ADH1. Alcohol metabolism by CYP2E1 increased Hsp90 acetylation and decreased its interaction with endothelial nitric oxide synthase (eNOS) leading to a decrease in nitric oxide (NO) production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyperacetylation mutant decreased NO production. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. AAV8-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90's interaction with eNOS and ameliorated alcohol-induced liver injury in mice., Conclusion: Restoring LSEC function is important for ameliorating alcohol-induced liver injury. To this end, blocking acetylation of Hsp90 specifically in LSECs via AAV-mediated gene delivery has the potential to be a new therapeutic strategy., Lay Summary: Alcohol metabolism in liver sinusoidal endothelial cells (LSECs) and the mechanism of alcohol-induced LSEC dysfunction are largely unknown. Herein, we demonstrate that LSECs can metabolize alcohol. We also uncover a mechanism by which alcohol induces LSEC dysfunction and liver injury, and we identify a potential therapeutic strategy to prevent this., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Published: 2021
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47. Quantum computing at the frontiers of biological sciences.

Author: Emani PS, Warrell J, Anticevic A, Bekiranov S, Gandal M, McConnell MJ, Sapiro G, Aspuru-Guzik A, Baker JT, Bastiani M, Murray JD, Sotiropoulos SN, Taylor J, Senthil G, Lehner T, Gerstein MB, and Harrow AW
Subjects: Algorithms, Big Data, Computers, Genetics, Genomics, Humans, Nervous System Diseases etiology, Neuroimaging methods, Quantum Theory, Sequence Analysis, Biological Science Disciplines, Computing Methodologies
Published: 2021
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48. Inhibition of LpxC Increases the Activity of Iron Chelators and Gallium Nitrate in Multidrug-Resistant Acinetobacter baumannii .

Author: Vinuesa V, Cruces R, Nonnoi F, and McConnell MJ
Abstract: Infections caused by multidrug-resistant Acinetobacter baumannii would benefit from the development of novel treatment approaches. Compounds that interfere with bacterial iron metabolism, such as iron chelators and gallium nitrate, have previously been shown to have antimicrobial activity against A. baumannii . In this study, we characterize the effect of LpxC inhibitors on the antimicrobial activity of previously characterized iron chelators, 2,2'-bipyridyl (BIP) and deferiprone (DFP), and gallium nitrate (Ga(NO 3 ) 3 ) against A. baumannii reference strains and multidrug-resistant clinical isolates. The LpxC inhibitor LpxC-2 was synergistic with BIP for 30% of strains tested (FICI values: 0.38-1.02), whereas inhibition with LpxC-4 was synergistic with BIP for 60% of strains tested (FICI values: 0.09-0.75). In time-kill assays, combinations of BIP with both LpxC inhibitors demonstrated synergistic activity, with a more than 3 log 10 reduction in bacterial counts compared to BIP alone. LpxC-2 was synergistic with Ga(NO 3 ) 3 for 50% of strains tested (FICI values: 0.27-1.0), whereas LpxC-4 was synergistic with Ga(NO 3 ) 3 for all strains tested (FICI values: 0.08-≤0.50). In time-kill assays, combinations of Ga(NO 3 ) 3 with LpxC-2 and LpxC-4 decreased the growth of both strains compared to each compound separately; however, only the combination with LpxC-4 met the defined criteria for synergy. These results identify a novel synergy between two antimicrobial classes against A. baumannii strains.
Published: 2021
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49. Vaccines for multidrug resistant Gram negative bacteria: lessons from the past for guiding future success.

Author: López-Siles M, Corral-Lugo A, and McConnell MJ
Subjects: Anti-Bacterial Agents pharmacology, Drug Resistance, Multiple, Bacterial, Gram-Negative Bacteria drug effects, Humans, Bacterial Vaccines, Gram-Negative Bacterial Infections prevention & control
Abstract: Antimicrobial resistance is a major threat to global public health. Vaccination is an effective approach for preventing bacterial infections, however it has not been successfully applied to infections caused by some of the most problematic multidrug resistant pathogens. In this review, the potential for vaccines to contribute to reducing the burden of disease of infections caused by multidrug resistant Gram negative bacteria is presented. Technical, logistical and societal hurdles that have limited successful vaccine development for these infections in the past are identified, and recent advances that can contribute to overcoming these challenges are assessed. A synthesis of vaccine technologies that have been employed in the development of vaccines for key multidrug resistant Gram negative bacteria is included, and emerging technologies that may contribute to future successes are discussed. Finally, a comprehensive review of vaccine development efforts over the last 40 years for three of the most worrisome multidrug resistant Gram negative pathogens, Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa is presented, with a focus on recent and ongoing studies. Finally, future directions for the vaccine development field are highlighted., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)
Published: 2021
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50. Single-cell sequencing of the small and AT-skewed genome of malaria parasites.

Author: Liu S, Huckaby AC, Brown AC, Moore CC, Burbulis I, McConnell MJ, and Güler JL
Subjects: Computational Biology methods, DNA Copy Number Variations, Erythrocytes parasitology, Humans, Malaria parasitology, Plasmodium falciparum genetics, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Base Composition, Genome, Protozoan, Genomics methods, High-Throughput Nucleotide Sequencing, Plasmodium genetics, Single-Cell Analysis methods
Abstract: Single-cell genomics is a rapidly advancing field; however, most techniques are designed for mammalian cells. We present a single-cell sequencing pipeline for an intracellular parasite, Plasmodium falciparum, with a small genome of extreme base content. Through optimization of a quasi-linear amplification method, we target the parasite genome over contaminants and generate coverage levels allowing detection of minor genetic variants. This work, as well as efforts that build on these findings, will enable detection of parasite heterogeneity contributing to P. falciparum adaptation. Furthermore, this study provides a framework for optimizing single-cell amplification and variant analysis in challenging genomes.
Published: 2021
Full Text: View/download PDF

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