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8. Milagro limits and HAWC sensitivity for the rate-density of evaporating Primordial Black Holes

Author

Abdo, A.A., Abeysekara, A.U., Alfaro, R., Allen, B.T., Alvarez, C., Álvarez, J.D., Arceo, R., Arteaga-Velázquez, J.C., Aune, T., Ayala Solares, H.A., Barber, A.S., Baughman, B.M., Bautista-Elivar, N., Becerra Gonzalez, J., Belmont, E., BenZvi, S.Y., Berley, D., Bonilla Rosales, M., Braun, J., Caballero-Lopez, R.A., Caballero-Mora, K.S., Carramiñana, A., Castillo, M., Christopher, G.E., Cotti, U., Cotzomi, J., de la Fuente, E., De León, C., DeYoung, T., Diaz Hernandez, R., Diaz-Cruz, L., Díaz-Vélez, J.C., Dingus, B.L., DuVernois, M.A., Ellsworth, R.W., Fiorino, D.W., Fraija, N., Galindo, A., Garfias, F., González, M.M., Goodman, J.A., Grabski, V., Gussert, M., Hampel-Arias, Z., Harding, J.P., Hays, E., Hoffman, C.M., Hui, C.M., Hüntemeyer, P., Imran, A., Iriarte, A., Karn, P., Kieda, D., Kolterman, B.E., Kunde, G.J., Lara, A., Lauer, R.J., Lee, W.H., Lennarz, D., León Vargas, H., Linares, E.C., Linnemann, J.T., Longo, M., Luna-GarcIa, R., MacGibbon, J.H., Marinelli, A., Marinelli, S.S., Martinez, H., Martinez, O., Martínez-Castro, J., Matthews, J.A.J., McEnery, J., Mendoza Torres, E., Mincer, A.I., Miranda-Romagnoli, P., Moreno, E., Morgan, T., Mostafá, M., Nellen, L., Nemethy, P., Newbold, M., Noriega-Papaqui, R., Oceguera-Becerra, T., Patricelli, B., Pelayo, R., Pérez-Pérez, E.G., Pretz, J., Rivière, C., Rosa-González, D., Ruiz-Velasco, E., Ryan, J., Salazar, H., Salesa, F., Sandoval, A., Saz Parkinson, P.M., Schneider, M., Silich, S., Sinnis, G., Smith, A.J., Stump, D., Sparks Woodle, K., Springer, R.W., Taboada, I., Toale, P.A., Tollefson, K., Torres, I., Ukwatta, T.N., Vasileiou, V., Villaseñor, L., Weisgarber, T., Westerhoff, S., Williams, D.A., Wisher, I.G., Wood, J., Yodh, G.B., Younk, P.W., Zaborov, D., Zepeda, A., and Zhou, H.

Published
2015
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9. VAMOS: A pathfinder for the HAWC gamma-ray observatory

Author

Abeysekara, A.U., Alfaro, R., Alvarez, C., Álvarez, J.D., Ángeles, F., Arceo, R., Arteaga-Velázquez, J.C., Avila-Aroche, A., Ayala Solares, H.A., Badillo, C., Barber, A.S., Baughman, B.M., Bautista-Elivar, N., Becerra Gonzalez, J., Belmont, E., Benítez, E., BenZvi, S.Y., Berley, D., Bernal, A., Bonilla Rosales, M., Braun, J., Caballero-Lopez, R.A., Caballero-Mora, K.S., Cabrera, I., Carramiñana, A., Castañeda-Martínez, L., Castillo, M., Cotti, U., Cotzomi, J., de la Fuente, E., De León, C., DeYoung, T., Diaz-Azuara, A., Diaz-Cruz, L., Diaz Hernandez, R., Díaz-Vélez, J.C., Dingus, B.L., Dultzin, D., DuVernois, M.A., Ellsworth, R.W., Fernandez, A., Fiorino, D.W., Fraija, N., Galindo, A., García-Torales, G., Garfias, F., González, A., González, L.X., González, M.M., Goodman, J.A., Grabski, V., Gussert, M., Guzmán-Cerón, C., Hampel-Arias, Z., Harding, J.P., Hernández-Cervantes, L., Hui, C.M., Hüntemeyer, P., Imran, A., Iriarte, A., Karn, P., Kieda, D., Kunde, G.J., Langarica, R., Lara, A., Lara, G., Lauer, R.J., Lee, W.H., Lennarz, D., León Vargas, H., Linares, E.C., Linnemann, J.T., Longo, M., Luna-Garcia, R., Marinelli, A., Martínez, L.A., Martínez, H., Martínez, O., Martínez-Castro, J., Martos, M., Matthews, J.A.J., McEnery, J., Mendoza Torres, E., Miranda-Romagnoli, P., Moreno, E., Mostafá, M., Nava, J., Nellen, L., Newbold, M., Noriega-Papaqui, R., Oceguera-Becerra, T., Page, D.P., Patricelli, B., Pelayo, R., Pérez-Pérez, E.G., Pretz, J., Ramírez, I., Rentería, A., Rivière, C., Rosa-González, D., Ruiz-Sala, F., Ruiz-Velasco, E.L., Ryan, J., Sacahui, J.R., Salazar, H., Salesa, F., Sandoval, A., Santos, E., Schneider, M., Silich, S., Sinnis, G., Smith, A.J., Sparks Woodle, K., Springer, R.W., Suarez, F., Taboada, I., Tepe, A., Toale, P.A., Tollefson, K., Torres, I., Tinoco, S., Ukwatta, T.N., Valdés Galicia, J.F., Vanegas, P., Vázquez, A., Villaseñor, L., Wall, W., Weisgarber, T., Westerhoff, S., Wisher, I.G., Wood, J., Yodh, G.B., Younk, P.W., Zaborov, D., Zepeda, A., and Zhou, H.

Published
2015
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10. Sensitivity of the high altitude water Cherenkov detector to sources of multi-TeV gamma rays

Author

Abeysekara, A.U., Alfaro, R., Alvarez, C., Álvarez, J.D., Arceo, R., Arteaga-Velázquez, J.C., Ayala Solares, H.A., Barber, A.S., Baughman, B.M., Bautista-Elivar, N., Belmont, E., BenZvi, S.Y., Berley, D., Bonilla Rosales, M., Braun, J., Caballero-Lopez, R.A., Carramiñana, A., Castillo, M., Cotti, U., Cotzomi, J., de la Fuente, E., De León, C., DeYoung, T., Diaz Hernandez, R., Diaz-Velez, J.C., Dingus, B.L., DuVernois, M.A., Ellsworth, R.W., Fernandez, A., Fiorino, D.W., Fraija, N., Galindo, A., Garcia-Luna, J.L., Garcia-Torales, G., Garfias, F., González, L.X., González, M.M., Goodman, J.A., Grabski, V., Gussert, M., Hampel-Arias, Z., Hui, C.M., Hüntemeyer, P., Imran, A., Iriarte, A., Karn, P., Kieda, D., Kunde, G.J., Lara, A., Lauer, R.J., Lee, W.H., Lennarz, D., León Vargas, H., Linares, E.C., Linnemann, J.T., Longo, M., Luna-García, R., Marinelli, A., Martinez, O., Martínez-Castro, J., Matthews, J.A.J., Miranda-Romagnoli, P., Moreno, E., Mostafá, M., Nava, J., Nellen, L., Newbold, M., Noriega-Papaqui, R., Oceguera-Becerra, T., Patricelli, B., Pelayo, R., Pérez-Pérez, E.G., Pretz, J., Rivière, C., Ryan, J., Rosa-González, D., Salazar, H., Salesa, F., Sandoval, A., Santos, E., Schneider, M., Silich, S., Sinnis, G., Smith, A.J., Sparks, K., Springer, R.W., Taboada, I., Toale, P.A., Tollefson, K., Torres, I., Ukwatta, T.N., Villaseñor, L., Weisgarber, T., Westerhoff, S., Wisher, I.G., Wood, J., Yodh, G.B., Younk, P.W., Zaborov, D., Zepeda, A., and Zhou, H.

Published
2013
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13. On the sensitivity of the HAWC observatory to gamma-ray bursts

Author

Abeysekara, A.U., Aguilar, J.A., Aguilar, S., Alfaro, R., Almaraz, E., Álvarez, C., Álvarez-Romero, J. de D., Álvarez, M., Arceo, R., Arteaga-Velázquez, J.C., Badillo, C., Barber, A., Baughman, B.M., Bautista-Elivar, N., Belmont, E., Benítez, E., BenZvi, S.Y., Berley, D., Bernal, A., Bonamente, E., Braun, J., Caballero-Lopez, R., Cabrera, I., Carramiñana, A., Carrasco, L., Castillo, M., Chambers, L., Conde, R., Condreay, P., Cotti, U., Cotzomi, J., D’Olivo, J.C., de la Fuente, E., De León, C., Delay, S., Delepine, D., DeYoung, T., Diaz, L., Diaz-Cruz, L., Dingus, B.L., Duvernois, M.A., Edmunds, D., Ellsworth, R.W., Fick, B., Fiorino, D.W., Flandes, A., Fraija, N.I., Galindo, A., Garcı´a-Luna, J.L., Garcı´a-Torales, G., Garfias, F., González, L.X., González, M.M., Goodman, J.A., Grabski, V., Gussert, M., Guzmán-Ceron, C., Hampel-Arias, Z., Harris, T., Hays, E., Hernandez-Cervantes, L., Hüntemeyer, P.H., Imran, A., Iriarte, A., Jimenez, J.J., Karn, P., Kelley-Hoskins, N., Kieda, D., Langarica, R., Lara, A., Lauer, R., Lee, W.H., Linares, E.C., Linnemann, J.T., Longo, M., Luna-García, R., Martı´nez, H., Martínez, J., Martı´nez, L.A., Martı´nez, O., Martı´nez-Castro, J., Martos, M., Matthews, J., McEnery, J.E., Medina-Tanco, G., Mendoza-Torres, J.E., Miranda-Romagnoli, P.A., Montaruli, T., Moreno, E., Mostafa, M., Napsuciale, M., Nava, J., Nellen, L., Newbold, M., Noriega-Papaqui, R., Oceguera-Becerra, T., Olmos Tapia, A., Orozco, V., Pérez, V., Pérez-Pérez, E.G., Perkins, J.S., Pretz, J., Ramirez, C., Ramírez, I., Rebello, D., Rentería, A., Reyes, J., Rosa-González, D., Rosado, A., Ryan, J.M., Sacahui, J.R., Salazar, H., Salesa, F., Sandoval, A., Santos, E., Schneider, M., Shoup, A., Silich, S., Sinnis, G., Smith, A.J., Sparks, K., Springer, W., Suárez, F., Suarez, N., Taboada, I., Tellez, A.F., Tenorio-Tagle, G., Tepe, A., Toale, P.A., Tollefson, K., Torres, I., Ukwatta, T.N., Valdes-Galicia, J., Vanegas, P., Vasileiou, V., Vázquez, O., Vázquez, X., Villaseñor, L., Wall, W., Walters, J.S., Warner, D., Westerhoff, S., Wisher, I.G., Wood, J., Yodh, G.B., Zaborov, D., and Zepeda, A.

Published
2012
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23. Chemical, structural and magnetic properties of the Fe/Sb2Te3 interface

Author

Longo, E, Wiemer, C, Cecchini, R, Longo, M, Lamperti, A, Khanas, A, Zenkevich, A, Fanciulli, M, Mantovan, R, Longo, E., Wiemer, C., Cecchini, R., Longo, M., Lamperti, A., Khanas, A., Zenkevich, A., Fanciulli, M., Mantovan, R., Longo, E, Wiemer, C, Cecchini, R, Longo, M, Lamperti, A, Khanas, A, Zenkevich, A, Fanciulli, M, Mantovan, R, Longo, E., Wiemer, C., Cecchini, R., Longo, M., Lamperti, A., Khanas, A., Zenkevich, A., Fanciulli, M., and Mantovan, R.

Abstract

Interfacing topological insulators (TI) with ferromagnetic (FM) layers is a promising route towards the next generation of ultra-low power spintronic devices based on charge-to-spin current conversion. Here, we present the Fe/Sb2Te3 interface structure, its chemical composition and magnetic properties. Thin films (30 nm) of the topological insulator Sb2Te3 were synthesized by Metal Organic Chemical Vapor Deposition (MOCVD) at room temperature on Si/SiO2 substrates, then capped with a 54Fe(10 nm)/57Fe(1 nm) bilayer by Pulsed Laser Deposition (PLD) to allow interface-sensitive Conversion Electron Mössbauer Spectroscopy (CEMS). X-ray diffraction (XRD) showed the polycrystalline nature of both the Fe and Sb2Te3 layers. X-ray reflectivity (XRR) identified a non-trivial layered structure with the presence of an intermixed layer at the Fe/Sb2Te3 interface. Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) confirmed the partial elemental interdiffusion between the Fe and Sb2Te3 layers. Interface-sensitive CEMS evidenced that about a half of the 1-nm-thick 57Fe layer in contact with Sb2Te3 coordinates ferromagnetically, whereas the remaining paramagnetic fraction preferentially bonds with Te. The Fe/Sb2Te3 system was shown to have a far from sharp interface, exhibiting a marked chemical reactivity already at room temperature. The tendency of Fe to preferentially bond with the chalcogenide element of topological insulators has been previously observed for the interface with Bi2Se3 and Bi2Te3, thus suggesting a possible universal behavior at the interface between Fe and chalcogenide-based TI.

Published
2019

28. Neurotensin up-regulation is associated with advanced fibrosis and hepatocellular carcinoma in patients with MAFLD

Author

Dongiovanni, P., Meroni, M., Petta, S., Longo, M., Alisi, A., Soardo, G., Valenti, L., Miele, Luca, Grimaudo, S., Pennisi, G., Antonio, G., Consonni, D., Fargion, S., Fracanzani, A. L., Miele L. (ORCID:0000-0003-3464-0068), Dongiovanni, P., Meroni, M., Petta, S., Longo, M., Alisi, A., Soardo, G., Valenti, L., Miele, Luca, Grimaudo, S., Pennisi, G., Antonio, G., Consonni, D., Fargion, S., Fracanzani, A. L., and Miele L. (ORCID:0000-0003-3464-0068)

Abstract

Background & aims: Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients. Results: The NTS rs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02–1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03–1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07–2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24–3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05). Conclusions: NTS rs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453 NTSR1 gene variant synergizes with NTS rs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression.

Published
2020

32. Hadronic Cross Sections for Neutrino Production in MIPP

Author

Paley, Jonathan M., Abrams, R.L., Akgun, U., Aydin, G., Baker, W., Barnes, P.D., Jr., Bergfeld, T., Bujak, A., Carey, D., Dukes, C., Duru, F., Feldman, G., Fisyak, Y., Graf, N., Godley, A., Gunaydin, Y., Gustafson, H.R., Gutay, L., Hartouni, E., Hanlet, P., Heffner, M., Hylen, J., Johnstone, C., Kaplan, D., Kamaev, O., Klay, J., Kostin, M., Lange, D., Lebedev, A., Longo, M., Maternick, C., Messier, M., Meyer, H., Miller, D.E., Mishra, S.R., Mokhov, N., Nelson, K., Nigmanov, T., Norman, A., Onel, Y., Paley, J., Para, A., Park, H.K., Penzo, A., Peterson, R.J., Raja, R., Rajaram, D., Ratnikov, D., Rosenfeld, C., Rubin, H., Seun, S., Solomey, N., Soltz, R., Swallow, E., Torun, Y., Winston, R., Wright, D., and Wu, K.

Published
2011
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39. Coronary arteriovenous malformation in a dog with a complex arrhythmia and hypothyroidism.

Author

Blake, R.R., Longo, M., Santarelli, G., Liuti, T., and Martinez-Pereira LdaVet, Y.

Abstract

A four-year-old Japanese Akita was referred for investigation of lethargy, exercise intolerance, and an irregular heart rhythm. He was diagnosed with atrial fibrillation, a complex ventricular arrhythmia, and hypothyroidism. Echocardiography identified a nest of anomalous vessels surrounding the heart and shunting into the pulmonary artery. Computed tomography confirmed a coronary arteriovenous malformation consisting of a coronary-to-pulmonary arterial communication and an associated complex nest of tortuous vessels, which was thought to be an incidental finding. Clinical signs improved with levothyroxine and antiarrhythmic treatment. Describing an unusual coronary artery anomaly as well, this case serves as a reminder to critically evaluate the hemodynamic significance of structural cardiac disease and to screen for systemic disease in patients with arrhythmias. [ABSTRACT FROM AUTHOR]

Published
2019
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41. Combined hepatic and adipose tissue transcriptomics highlights circulating NASH biomarkers.

Author

Meroni, M., De Caro, E., Chiappori, F., Longo, M., Paolini, E., Mosca, E., Merelli, I., Lombardi, R., Badiali, S., Maggioni, M., Orro, A., Mezzelani, A., Valenti, L., Fracanzani, A.L., and Dongiovanni, P.

Abstract

Obesity represents the main contributor to nonalcoholic fatty liver disease (NAFLD) and adipose tissue is strongly interlaced with the liver in the disease pathogenesis and progression. Previous studies were restricted to investigate the hepatic transcriptome across the entire spectrum of NAFLD, whereas the transcriptomic changes which occur in white adipose tissue (WAT) in relation to liver damage have been poorly investigated. Therefore, we aimed to compare hepatic and adipose tissue transcriptome in NAFLD patients with the purpose to identify shared biomarkers useful for the diagnosis of advanced liver damage. We performed high-throughput RNA-sequencing in 167 hepatic samples from obese patients and in a subset of 79 matched adipose tissues. Patients were subdivided in normal liver, mild and severe NAFLD according to histology. Circulating cathepsin D (CTSD) was assessed by ELISA. We identified a specific transcriptomic signature that may discriminate patients with severe NAFLD and isolated steatosis, including 424 deregulated genes in liver and 209 in adipose tissue. According to pathway and network analyses, inflammation, ECM remodeling and mitochondrial dysfunction were upregulated whereas oxidative phosphorylation was downregulated in both tissues. We highlighted 13 genes commonly deregulated in both tissues and among them, CTSD showed the most robust diagnostic accuracy in discriminating mild and severe NAFLD. In 52 obese subjects and in a validation cohort of 432 histologically-characterized NAFLD patients, serum CTSD progressively increased from normal liver to severe NAFLD and it was associated with steatosis, necroinflammation, fibrosis, steatohepatitis (NASH) and NAS>5. The area under the curve (AUC) weighted for transaminases to foresee severe NAFLD versus mild and normal liver was 0.78 and 0.87, respectively. CTSD may be a possible biomarker of severe NAFLD since its hepatic/adipose tissue expression as well as circulating levels correlated with liver damage thus allowing to discriminate advanced disease. [ABSTRACT FROM AUTHOR]

Published
2023
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46. Gelatine based gel polymer electrolyte towards more sustainable Lithium-Oxygen batteries.

Author

Longo, M., Gandolfo, M., Francia, C., Bodoardo, S., Sangermano, M., and Amici, J.

Subjects
*POLYELECTROLYTES, *LITHIUM-air batteries, *POLYMER colloids, *GELATIN, *IONIC conductivity, *ENERGY density
Abstract

• Single step methacrylation of gelatine from the fishing industry waste • One pot photoreticulation of methacrylated gelatine with liquid electrolyte • High ionic conductivity of 2.51 mS cm−1 and lithium transference number of 0.54 • More than 100 cycles at 0.1 mA cm−2, under constant O 2 flow, at room temperature • Reduced solvent degradation thanks to the bio-renewable polymer The lithium-oxygen battery has attracted wide interest thanks to its very high theoretical energy density, and as such it is considered by many as a valid battery of the future candidate. However, the challenges in its practical application are many, such as liquid electrolyte evaporation in semi-open systems, as well as solvents instability in a highly oxidizing environment. In this work, we propose to use gelatin, from cold water fish skin, a waste from the fishing industry, to prepare an efficient gel electrolyte for future Li-O 2 battery applications. After a single step methacrylation in water, methacrylated gelatine is directly cross-linked in presence of liquid electrolyte through UV- initiated radical polymerization. The obtained gel polymer electrolytes present good thermal and mechanical properties, good electrochemical stability against Li metal and ionic conductivities as high as 2.51 mS cm−1 at room temperature. the Li-O 2 cells assembled with this bio-renewable gel polymer electrolytes were able to perform more than 100 cycles at 0.1 mA cm−2, under constant O 2 flow, at room temperature and at a fixed capacity of 0.2 mAh cm−2. Cathodes post- mortem analysis confirmed that the cross-linked gelatin matrix was able to slow down solvent degradation and therefore enhance the cell reversibility. [ABSTRACT FROM AUTHOR]

Published
2023
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48. Ovarian Embryonal Carcinoma in a Dog.

Author

Banco, B., Ferrari, R., Stefanello, D., Groppetti, D., Pecile, A., Faverzani, S., Longo, M., Zani, D.D., Ravasio, G., Caniatti, M., and Grieco, V.

Subjects
EMBRYONAL tumors, CANCER in dogs, DOBERMAN pinscher, TUMORS in animals, DOG diseases, CANIS, NECROSIS
Abstract

Summary A 17-month-old female doberman pinscher was referred for an abdominal mass and ascites. Exploratory laparotomy revealed the presence of a large neoplastic mass replacing the right ovary and associated with multiple mesovarian, mesometrial and peritoneal nodules. An ovariohysterectomy was performed. Grossly, the tumour was soft and multilocular with large areas of haemorrhage and necrosis. Microscopically, it was infiltrative and composed of round and polygonal cells arranged respectively in solid sheets or forming distorted tubular structures separated by thick fibrovascular septae. Tubules contained necrotic debris, proteinaceous fluid or small endoluminal papillary structures. Marked cellular atypia, multiple neoplastic emboli and high mitotic count were observed. Immunohistochemically, the round cells uniformly expressed placental alkaline phosphatase, while the polygonal cells arranged in tubules and papillae expressed cytokeratin (CK) AE1/AE3 and CK7. A final diagnosis of metastasizing ovarian embryonal carcinoma (EC), a primitive germ cell tumour characterized by rudimentary epithelial differentiation was made. Canine ovarian EC should be considered as a differential diagnosis for undifferentiated aggressive ovarian tumours in young dogs. [ABSTRACT FROM AUTHOR]

Published
2017
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50. B-Klotho deficiency in hepatic stellate cells (HSCs) prompts inflammation, oxidative stress and a pro-fibrotic phenotype.

Author

Tria, G., Paolini, E., Longo, M., Panera, N., Piciotti, R., Alisi, A., Meroni, M., and Dongiovanni, P.

Abstract

β-Klotho (KLB) gene encodes the hepatic co-receptor of fibroblast growth factor receptor 4 (FGFR4). We previously reported that the rs17618244 G>A KLB gene variant dampened KLB hepatic and plasma levels, leading to inflammation, ballooning and fibrosis both in pediatric and adult patients with nonalcoholic fatty liver disease (NAFLD). Hepatic stellate cells (HSCs) are directly involved in the fibrotic processes, playing a crucial role in the switching to severe forms of NAFLD. To generate a new cell line of hepatic stellate cells (HSCs), responsible for hepatic fibrosis, which are deleted for KLB , by using Crispr/Cas9 and to investigate the impact of its deficiency on their pro-fibrotic phenotype, inflammation and oxidative stress. We stably silenced KLB gene in LX2 cells (referred to as HSCs KLB−/−) by Crispr-Cas9 technology. Then, markers of activation, cellular stress, inflammation and proliferation have been investigated. KLB mRNA and protein levels were reduced in HSC KLB −/- cells (p<0.05). Markers of activation (i.e., aSMA, COL1A1/3A1/4A1, TGFb, PDGFRB, BAMBI) were increased in KLB−/− cells at both gene and protein levels. Accordingly, retinol synthesis (RALDH) was reduced (p<0.05), suggesting a more pro-fibrotic phenotype. Moreover, KLB deletion strongly induced oxidative stress, enhancing ROS/reactive nitrite species (RNS) and lactate production, aldehyde derivate concentrations (MDA) (p<0.05). These events triggered the release of pro-inflammatory cytokines (TNFα, IL1β and IL6) into the KLB −/- cultured media. Finally, KLB −/- cells also showed an elevated proliferative rate (p<0.05). We generated, for the first time, a stable knock-out of KLB in HSCs. Our preliminary results outlined that KLB deficiency induced an enhanced pro-fibrotic phenotype with increased proliferation, inflammation and oxidative stress, thus possibly explaining the association between the rs17618244 KLB at-risk variant and more severe forms of liver damage. Altogether, these observations pointed KLB a novel target to prevent severe NAFLD. [ABSTRACT FROM AUTHOR]

Published
2023
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