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Purpose: Robot-assisted total hip arthroplasty (RA-THA) helps with precise orientation of the prosthesis, but some RA-THA procedures are aborted intraoperatively and are converted to manual total hip arthroplasty (THA). This study aimed to analyse why RA-THA is sometimes aborted intraoperatively and to make recommendations accordingly., Methods: A total of 429 consecutive Mako THA cases in our prospective database from August 2018 to June 2021 were included in our study. All robotic procedures aborted intraoperatively for any reason were recorded. The patients' demographics, diagnoses, and surgeons' information were included in the statistical analysis to pinpoint the risk factors for intraoperative robot to manual conversion., Results: Intraoperative RA-THA abortions occurred in 17 cases (3.96%) and the patients had to be converted to manual THA. The adverse events leading to intraoperative abortions included pelvic array loosening or malposition (5, 1.17%), inaccurate bone mapping or construction (6, 1.40%), inaccurate initial registration (4, 0.93%), and other reasons (2, 0.47%)., Conclusion: Robot-related adverse events could be found in all perioperative steps of RA-THA, and some of these events might result in intraoperative abortion. Complex hip disease was a statistically significant factor for an increased risk of intraoperative abortion of RA-THA. Standardized surgical procedures and preoperative assessments can be helpful in reducing the rate of RA-THA abortions., (© 2024. The Author(s) under exclusive licence to SICOT aisbl.)

In this study, the effects of wheat flour treated with ball milling (BM) and maltodextrin on the oil absorption and textural characteristics of fried batter-coated cashews and almonds (BCAs) were investigated. The result showed that the crystallinity of the starch granules in wheat flour decreased after the BM treatment. Furthermore, the ΔH of the batter decreased as the BM time was elongated, but the addition of maltodextrin had no significant impact on ΔH. Both BM-treated wheat flour and maltodextrin increased the fracturability and decreased the oil content of the fried BCAs' batter. The addition of BM-treated wheat flour and maltodextrin decreased the oil content of the batter from 28.93% to 18.75% for batter-coated cashews and from 30.92% to 18.61% for batter-coated almonds. Overall, the addition of BM-treated wheat flour and maltodextrin in batter is an effective approach to decrease oil content and improve the textural quality of fried BCAs., 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. Published by Elsevier Ltd.)

Tauopathies are a group of neurodegenerative diseases characterized by the presence of tau inclusions. We have developed over fifty anti-tau single-domain antibodies (sdAbs) derived from phage display libraries of a llama immunized with recombinant and pathological tau immunogens. We examined the therapeutic potential of four of these sdAbs in a Drosophila tauopathy model following their transgenic expression either in all neurons or neuronal subtypes. Three of these sdAbs showed therapeutic potential in various assays, effectively clearing pathological tau and attenuating or preventing tau-induced phenotypes that typically manifest as defects in neuronal axonal transport, neurodegeneration, functional impairments, and shortened lifespan. Of these three, one sdAb was superior in every assay, which may at least in part be attributed to its tau-binding epitope. These findings support its development as a gene therapy for tauopathies., (© 2024. The Author(s).)

Bacteria dysbiosis and its accompanying inflammation or compromised mucosal integrity is associated with an increased risk of HIV-1 transmission. However, HIV-1 may also bind bacteria or bacterial products to impact infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, a part of the fimbriae shrouding the bacteria surface that recognizes α2,3 sialyated O -linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O -glycan-binding plant lectins, signifying the importance of O -glycans. N -glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O -glycans on HIV-1 Env, and increase HIV-1 resistance to neutralizing antibodies targeting different regions of Env. This study highlights the potential contribution of O -glycan-binding lectins from commensal bacteria at the mucosa in promoting HIV-1 infection., Competing Interests: The authors declare no competing interests, except for M.I.P. who is currently employed by Winclove Probiotics and serves as a consultant for academic and industrial representatives in the field of microbiome and probiotics. Her consultancy clients had no role in drafting this manuscript or the decision to submit the work for publication.

In this study, the effect of pre-drying and post-frying holding treatments on the oil absorption and the quality of the fried batter-coated peanuts were explored. The results showed that hot air drying and microwave drying induced the gelatinization of starch in the batter before frying. The thermodynamic properties of starch in the batter after frying indicated that pre-drying could protect the orderliness of the starch. CLSM images showed that the pre-drying treatment reduced the number of large oil spots on the surface of batter of fried batter-coated peanuts. SEM observation revealed that the structure of the batter treated with pre-drying was denser and the number of large pores was reduced after frying. The post-frying holding treatment improved the color and texture of the batter-coated peanuts. In conclusion, the pre-drying and post-frying holding treatment can reduce the oil content and improve the fracturability of the fried batter-coated peanuts., 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 Elsevier Ltd. All rights reserved.)

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4 CRBN , and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies., (© 2024. The Author(s).)

The vaccine elicitation of HIV tier-2-neutralization antibodies has been a challenge. Here, we report the isolation and characterization of a CD4-binding site (CD4bs) specific monoclonal antibody, HmAb64, from a human volunteer immunized with a polyvalent DNA prime-protein boost HIV vaccine. HmAb64 is derived from heavy chain variable germline gene IGHV1-18 and light chain germline gene IGKV1-39. It has a third heavy chain complementarity-determining region (CDR H3) of 15 amino acids. On a cross-clade panel of 208 HIV-1 pseudo-virus strains, HmAb64 neutralized 20 (10%), including tier-2 strains from clades B, BC, C, and G. The cryo-EM structure of the antigen-binding fragment of HmAb64 in complex with a CNE40 SOSIP trimer revealed details of its recognition; HmAb64 uses both heavy and light CDR3s to recognize the CD4-binding loop, a critical component of the CD4bs. This study demonstrates that a gp120-based vaccine can elicit antibodies capable of tier 2-HIV neutralization., (© 2024. The Author(s).)

A new glycoside ( 1 ) along with six known analogues ( 1-7 ) were isolated from Codonopsis pilosula collected at Shanxi in China. The structure of 1 was established based on comprehensive spectroscopic data and literature comparison. The anti-inflammatory effects of isolated compounds were further investigated in LPS-induced RAW264.7 macrophage.

The batter compositions can affect the oil uptake and texture of fried batter-coated nuts. In this study, the oil uptake and quality of fried batter-coated peanuts and sunflower seeds added with resistant starch and protein were investigated. The results demonstrated that the addition of resistant starch increased the batter hardness and fracturability of the fried batter-coated peanuts by 34.36 % and 33.73 %, respectively. The oil content of fried batter-coated peanuts and sunflower seeds were decreased by 17.98 % and 15.69 %, respectively, with the addition of protein. The microstructure and roughness of the batter revealed that the batter added with protein became denser and uniform. Furthermore, the protein in the batter added with 6 % soy protein isolate had a high surface hydrophobicity. In summary, the addition of resistant starch and protein in batter will be a promising strategy for reducing the oil content and improving the quality of fried batter-coated nuts., 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 © 2023 Elsevier Ltd. All rights reserved.)

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases., Competing Interests: Competing interests statement:Authors are inventors on intellectual property related to this work that is owned by Stanford University and New York University. J.W. is on the Scientific Advisory Board of Rootpath Genomics and is a consultant for BMS (Relatlimab Advisory Council) and Beijing Hanmi Pharmaceutical Co., LTD. J.R.C. is a cofounder and equity holder of Combangio, Inc. (now Kala Bio), xCella Biosciences (now OmniAb), Charged Biotherapeutics, TwoStep Therapeutics, and Red Tree Venture Capital; has financial interests in Aravive, Inc.; is a member of the Board of Directors of OmniAb, Revel Pharmaceuticals, Excellergy Therapeutics, Rondo Therapeutics, Tachyon Therapeutics, and Biograph 55; and is a Board Observer at Acrigen Biosciences. The other authors have no competing interests.

Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.

Chitosan has emerged as a promising biopolymer carrier for the sustained release of pesticides owing to its good biocompatibility, biodegradability, and bioactivity. In this work, a controlled-release formulation of insecticide chlorantraniliprole was fabricated through coprecipitation-based synchronous encapsulation with chitosan, where the optimum preparation conditions, storage stability, deposition behavior, and application potential were investigated. Preparation of optimization data from response surface methodology showed high correlation coefficient ( R 2 ) of 0.9875 and adjusted coefficient ( R adj 2 ) of 0.9715. The resulting formulation displayed good loading content of 28.39%, high encapsulation efficiency of 75.71%, and good storage stability. Compared with the commercial suspension concentrate, the formulation exhibited better wettability and retention behaviors on plant leaves. Excitingly, effective control against one species of mealybug genus Paraputo Laing (outside the killing spectrum) on the Hippeastrum reticulatum plant was successfully achieved by spraying the controlled-release formulation at different time intervals. This work indicates the good potential of the developed formulation in expanding the application scope of chlorantraniliprole, which shows a new strategy for sustainable pest management., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Introduction: Neutralizing antibodies (Abs) are one of the immune components required to protect against viral infections. However, developing vaccines capable of eliciting neutralizing Abs effective against a broad array of HIV-1 isolates has been an arduous challenge., Objective: This study sought to test vaccines aimed to induce Abs against neutralizing epitopes at the V1V2 apex of HIV-1 envelope (Env)., Methods: Four groups of rabbits received a DNA vaccine expressing the V1V2 domain of the CRF01_AE A244 strain on a trimeric 2J9C scaffold (V1V2-2J9C) along with a protein vaccine consisting of an uncleaved prefusion-optimized A244 Env trimer with V3 truncation (UFO-BG.ΔV3) or a V1V2-2J9C protein and their respective immune complexes (ICs). These IC vaccines were made using 2158, a V1V2-specific monoclonal Ab (mAb), which binds the V2i epitope in the underbelly region of V1V2 while allosterically promoting the binding of broadly neutralizing mAb PG9 to its V2 apex epitope in vitro ., Results: Rabbit groups immunized with the DNA vaccine and uncomplexed or complexed UFO-BG.ΔV3 proteins (DNA/UFO-UC or IC) displayed similar profiles of Env- and V1V2-binding Abs but differed from the rabbits receiving the DNA vaccine and uncomplexed or complexed V1V2-2J9C proteins (DNA/V1V2-UC or IC), which generated more cross-reactive V1V2 Abs without detectable binding to gp120 or gp140 Env. Notably, the DNA/UFO-UC vaccine elicited neutralizing Abs against some heterologous tier 1 and tier 2 viruses from different clades, albeit at low titers and only in a fraction of animals, whereas the DNA/V1V2-UC or IC vaccines did not. In comparison with the DNA/UFO-UC group, the DNA/UFO-IC group showed a trend of higher neutralization against TH023.6 and a greater potency of V1V2-specific Ab-dependent cellular phagocytosis (ADCP) but failed to neutralize heterologous viruses., Conclusion: These data demonstrate the capacity of V1V2-2J9C-encoding DNA vaccine in combination with UFO-BG.ΔV3, but not V1V2-2J9C, protein vaccines, to elicit homologous and heterologous neutralizing activities in rabbits. The elicitation of neutralizing and ADCP activities was modulated by delivery of UFO-BG.ΔV3 complexed with V2i mAb 2158., Competing Interests: Author MT was employed by company Molsoft L.L.C. MT, XJ, X-PK, and SZ-P are inventors in the U.S. Patent 10,568,969 for the V1V2-2J9C construct. A provisional patent application is submitted for the UFO-BG.DeltaV3 construct; CEH and MT are listed as inventors in this application. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Hioe, Liu, Banin, Heindel, Klingler, Rao, Luo, Jiang, Pandey, Ordonez, Barnette, Totrov, Zhu, Nádas, Zolla-Pazner, Upadhyay, Shen, Kong and Hessell.)

Background: Controlled-release pesticide formulations have emerged as a promising approach towards sustainable pest control. Herein, an environment-friendly formulation of insecticide chlorantraniliprole (CAP) was fabricated through a simple approach of coprecipitation-based synchronous encapsulation by chitosan (CTS), with carrier-pesticide interaction mechanism and release behavior investigated., Results: The resulting CAP/CTS controlled-release formulation (CCF) showed a good loading content of 28.1% and a high encapsulation efficiency of 75.6%. Instrument determination in combination with molecular dynamics (MD) simulations displayed that the primary interactions between CAP and CTS were physical adsorption and complicated hydrogen (H)-bonds, which formed dominantly between NH in amides [or nitrogen (N) in ring structures] of CAP and hydroxyl (or amino) groups of CTS, as well as oxygen (O) in CAP with hydrogen in CTS or H 2 O molecules. The in vitro release tests exhibited obvious pH/temperature sensitivity, with release dynamics following the first-order or Ritger-Peppas model. As the temperature increased, the CAP release process of the Ritger-Peppas model changed from Case-II to anomalous transport, and ultimately to a Fickian diffusion mechanism. The control effect against Plutella xylostella larvae also was evaluated by toxicity tests, where comparable efficacy of CCF to the commercial suspension concentrate was obtained., Conclusion: The innovative, easy-to-prepare CCF can be used as a formulation with obvious pH/temperature sensitivity and good efficacy on target pests. This work contributes to the development of efficient and safe pesticide delivery systems, especially using the natural polymer materials as carriers. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Diets comprising selenium-deficient crops have been linked to immune disorders and cardiomyopathy. Selenium nanoparticles (SeNPs) have emerged as a promising nanoplatform for selenium-biofortified agriculture. However, SeNPs fail to reach field-scale applications due to a poor understanding of the fundamental principles of its behavior. Here, we describe the transport, transformation, and bioavailability of SeNPs through a combination of in vivo and in vitro experiments. We show synthesized amorphous SeNPs, when sprayed onto the leaves of Arabidopsis thaliana , are rapidly biotransformed into selenium(IV), nonspecifically incorporated as selenomethionine (SeMet), and specifically incorporated into two selenium-binding proteins (SBPs). The SBPs identified were linked to stress and reactive oxygen species (mainly H 2 O 2 and O 2 - ) reduction, processes that enhance plant growth and primary root elongation. Selenium is transported both upwards and downwards in the plant when SeNPs are sprayed onto the leaves. With the application of Silwet L-77 (a common agrochemical surfactant), selenium distributed throughout the whole plant including the roots, where pristine SeNPs cannot reach. Our results demonstrate that foliar application of SeNPs promotes plant growth without causing nanomaterial accumulation, offering an efficient way to obtain selenium-fortified agriculture.

Several XBB subvariants such as XBB.1.5, XBB.1.9, XBB.1.16 and XBB.2.3 co-circulate in Singapore. Despite the different viral properties of XBB.1.16 as compared to other XBB subvariants, comparison on their severity is limited. In this study, we investigate the outcomes of hospitalisation and severe COVID-19 infection in individuals infected with different XBB subvariants, adjusted for potential confounders such as age and vaccination history. Overall, our preliminary analysis showed that the risk of severe outcomes when infected with XBB.1.16 is higher than that of XBB.1.5 or XBB.1.9 but there is no difference in the risk of hospitalisation across different XBB subvariants., Competing Interests: The authors declare no competing interest., (© 2023 The Author(s).)

Developing a safe and effective preventive for HIV-1 remains the hope for controlling the global AIDS epidemic. Recently, mRNA vaccines have emerged as a promising alternative to conventional vaccine approaches, primarily due to their rapid development and potential for low-cost manufacture. Despite the advantages of mRNA vaccines, challenges remain, especially due to the adverse effects of the delivery vehicle and low delivery efficiency. As a result, Luna Labs is developing a short carbon nanotube-based delivery platform (NanoVac) that can co-deliver mRNA and HIV-1 glycoproteins to the immune system efficiently with negligible toxicity. Surface chemistries of NanoVac were optimized to guide antigen/mRNA loading density and presentation. Multiple formulations were engineered for compatibility with both intramuscular and intranasal administration. NanoVac candidates demonstrated immunogenicity in rabbits and generated human-derived humoral and cellular responses in humanized mice (HIS). Briefly, 33% of the HIV-1-infected HIS mice vaccinated with NanoVac-mRNA was cleared of virus infection by 8-weeks post-infection. Finally, NanoVac stabilized the loaded mRNA against degradation under refrigeration for at least three months, reducing the cold chain burden for vaccine deployment.

Intracellular deposition of α-synuclein and tau are hallmarks of synucleinopathies and tauopathies, respectively. Recently, several dye-based imaging probes with selectivity for tau aggregates have been developed, but suitable imaging biomarkers for synucleinopathies are still unavailable. Detection of both of these aggregates early in the disease process may allow for prophylactic therapies before functional impairments have manifested, highlighting the importance of developing specific imaging probes for these lesions. In contrast to the β sheet dyes, single-domain antibodies, found in camelids and a few other species, are highly specific, and their small size allows better brain entry and distribution than whole antibodies. Here, we have developed such imaging ligands via phage display libraries derived from llamas immunized with α-synuclein and tau preparations, respectively. These probes allow noninvasive and specific in vivo imaging of α-synuclein versus tau pathology in mice, with the brain signal correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic since December 2019, and with it, a push for innovations in rapid testing and neutralizing antibody treatments in an effort to solve the spread and fatality of the disease. One such solution to both of these prevailing issues is targeting the interaction of SARS-CoV-2 spike receptor binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2) receptor protein. Structural studies have shown that the N-terminal alpha-helix comprised of the first 23 residues of ACE2 plays an important role in this interaction. Where it is typical to design a binding domain to fit a target, we have engineered a protein that relies on multivalency rather than the sensitivity of a monomeric ligand to provide avidity to its target by fusing the N-terminal helix of ACE2 to the coiled-coil domain of the cartilage oligomeric matrix protein. The resulting ACE-MAP is able to bind to the SARS-CoV-2 RBD with improved binding affinity, is expressible in E. coli , and is thermally stable and relatively small (62 kDa). These properties suggest ACE-MAP and the MAP scaffold to be a promising route towards developing future diagnostics and therapeutics to SARS-CoV-2., Competing Interests: 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., (© 2022 Elsevier B.V. All rights reserved.)

Background: Eleven tau immunoglobulin G (IgG) antibodies have entered clinical trials to treat tauopathies, including Alzheimer's disease, but it is unclear which IgG subclass/subtype has the ideal efficacy and safety profile. Only two subtypes, with or without effector function, have been examined in the clinic and not for the same tau antibody. The few preclinical studies on this topic have only compared two subtypes of one antibody each and have yielded conflicting results., Methods: We selected two single domain antibodies (sdAbs) derived from a llama immunized with tau proteins and utilized them to generate an array of Fc-(sdAb) 2 subclasses containing identical tau binding domains but differing Fc region. Unmodified sdAbs and their IgG subclasses were tested for efficacy in primary cultures and in vivo microdialysis using JNPL3 tauopathy mice., Findings: Unmodified sdAbs were non-toxic, blocked tau toxicity and promoted tau clearance. However, the efficacy/safety profile of their Fc-(sdAb) 2 subclasses varied greatly within and between sdAbs. For one of them, all its subtypes were non-toxic, only those with effector function cleared tau, and were more effective in vivo than unmodified sdAb. For the other sdAb, all its subtypes were toxic in tauopathy cultures but not in wild-type cells, suggesting that bivalent binding of its tau epitope stabilizes a toxic conformation of tau, with major implications for tau pathogenesis. Likewise, its subclasses were less effective than the unmodified sdAb in clearing tau in vivo., Interpretation: These findings indicate that tau antibodies with effector function are safe and better at clearing pathological tau than effectorless antibodies, Furthermore, tau antibodies can provide a valuable insight into tau pathogenesis, and some may aggravate it., Funding: Funding for these studies was provided by the National Institute of Health (R01 AG032611, R01 NS077239, RF1 NS120488, R21 AG 069475, R21 AG 058282, T32AG052909), and the NYU Alzheimer's Disease Center Pilot Grant Program (via P30 AG008051)., Competing Interests: Declaration of interests EMS is an inventor on patents on tau immunotherapies and related diagnostics, which are assigned to New York University, and some of those are licensed to H. Lundbeck A/S. Notably, this licensing does not include tau sdAbs such as the 2B8 and 1D9 antibodies used in these experiments. All other authors have nothing to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Developing a safe and effective malaria vaccine is critical to reducing the spread and resurgence of this deadly disease, especially in children. In recent years, vaccine technology has seen expanded development of subunit protein, peptide, and nucleic acid vaccines. This is due to their inherent safety, the ability to tailor their immune response, simple storage requirements, easier production, and lower expense compared to using attenuated and inactivated organism-based approaches. However, these new vaccine technologies generally have low efficacy. Subunit vaccines, due to their weak immunogenicity, often necessitate advanced delivery vectors and/or the use of adjuvants. A new area of vaccine development involves design of synthetic micro- and nano-particles and adjuvants that can stimulate immune cells directly through their physical and chemical properties. Further, the unique and complex life cycle of the Plasmodium organism, with multiple stages and varying epitopes/antigens presented by the parasite, is another challenge for malaria vaccine development. Targeting multistage antigens simultaneously is therefore critical for an effective malaria vaccine. Here, we rationally design a layer-by-layer (LbL) antigen delivery platform (we called LbL NP) specifically engineered for malaria vaccines. A biocompatible modified chitosan nanoparticle (trimethyl chitosan, TMC) was synthesized and utilized for LbL loading and release of multiple malaria antigens from pre-erythrocytic and erythrocytic stages. LbL NP served as antigen/protein delivery vehicles and were demonstrated to induce the highest Plasmodium falciparum Circumsporozoite Protein (PfCSP) specific T-cell responses in mice studies as compared to multiple controls. From immunogenicity studies, it was concluded that two doses of intramuscular injection with a longer interval (4 weeks) than traditional malaria vaccine candidate dosing would be the vaccination potential for LbL NP vaccine candidates. Furthermore, in PfCSP/Py parasite challenge studies we demonstrated protective efficacy using LbL NP. These LbL NP provided a significant adjuvant effect since they may induce innate immune response that led to a potent adaptive immunity to mediate non-specific anti-malarial effect. Most importantly, the delivery of CSP full-length protein stimulated long-lasting protective immune responses even after the booster immunization 4 weeks later in mice., Competing Interests: Authors YX, ZZ, BB, TF, JO and CT were employed by company Luna Labs USA. 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 Xu, Zhou, Brooks, Ferguson, Obliosca, Huang, Kaneko, Iwanaga, Yuda, Tsuji, Zhang, Luo, Jiang, Kong, Tsuji and Tison.)

Purpose: This clinical research aims to assess the safety and efficacy of a combination of fusiform capsulectomy of the posterior capsule and percutaneous flexion tendon release in the treatment of a fused knee with severe flexion contracture during total knee arthroplasty (TKA)., Methods: A retrospective analysis was performed in three patients (six knees) who had preoperative severe bony fused flexion contracture (>80°) prior to TKA and received a combination of fusiform capsulectomy of posterior capsule and percutaneous flexion tendon release during TKA between January 2016 and December 2019. The range of motion (ROM), knee functional score, postoperative complications, and radiographic results were evaluated., Result: Three patients (six knees) were enrolled in this study. The mean duration of follow-up was 42.83 ± 15.77 months. The postoperative knee ROM was 100.0 (76.0, 102.75) ( p  < 0.01). The knee society score (KSS) clinical score increased from a preoperative 30.0 (25.0, 36.0) to a postoperative 64.0 (65.0, 78.0) ( p  < 0.01), and the KSS function score increased from a preoperative 0.0 (0.0, 30.0) to a postoperative 55.0 (40.0, 55.0) ( p  < 0.01). No implant loosening, infection, neurovascular complications, or revision were recorded in the cohort until the last follow-up., Conclusion: The technique of a combination of fusiform capsulectomy of the posterior capsule and percutaneous flexion tendon release is an effective and safe method during primary TKA for a fused knee with severe flexion contracture., 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 © 2022 Chen, He, Cao, Kong, Wang and Chai.)

The HIV-1 envelope glycoprotein spike is the target of antibodies, and therefore represents the main viral antigen for antibody-based vaccine design. One of the challenges in HIV-1 vaccine development is finding efficient ways for the immune system to recognize and respond to HIV-1 without establishing an infection. Since HIV-1 enters the body at mucosal surfaces, induction of immune response at these sites is a preferred preventive approach. Nasal administration is a very effective route for mucosal immunization since it can stimulate mucosal immune responses both locally and distantly. In this paper, Luna develops a safe, short carbon nanotube (CNT)-based, needle-free delivery platform known as "CNTVac". The size of short CNT was controlled to possess HIV-1 particle-like morphology (100-200 nm) capable of efficiently delivering a broad range of antigens intranasally. PEG-Lipid served as the antigen conformation protector and mucosal barrier penetration enhancer (Schematic Figure) was localized between V1V2 antigens, which caused highly enhanced local IgA and systemic antibody IgG responses in mice and rabbits. The short CNT incorporated with PEG-Lipid could not only serve as efficient delivery system but also reduce the amount of lipid usage in order to balance the vaccine dosage in order to eliminate the potential adverse effect. These data suggest a promising platform technology for vaccine delivery.

Aims: Total hip arthroplasty (THA) in patients with hip-dislocation dysplasia remains challenging. This study aims to evaluate whether these patients may benefit from robotic-assisted techniques., Methods: We reviewed 135 THAs (108 conventional THAs and 27 robotic-assisted THAs) for Crowe type III or IV from January 2017 to August 2019 in our institution. Robotic-assisted THAs were matched with conventional THAs at a 1:1 ratio (27 hips each group) using propensity score matching. The accuracy of cup positioning and clinical outcomes were compared between groups., Results: The inclination of the cup for conventional THAs and robotic THAs was 42.1 ± 5.7 and 41.3 ± 4.6 (p = 0.574), respectively. The anteversion of the cup for conventional THAs was significantly greater than that of robotic THAs (29.5 ± 8.1 and 18.0 ± 4.6; p < 0.001), respectively. The ratio of the acetabular cup in the Lewinnek safe zone was 37% (10/27) in conventional THAs and 96.3% (26/27) in robotic THAs (p < 0.001). Robotic THAs did not achieve better leg length discrepancy than that of conventional THAs (- 0.4 ± 10.9 mm vs. 0.4 ± 8.8 mm, p = 0.774). There was no difference in Harris Hip Score and WOMAC Osteoarthritis index between groups at the 2-year follow-up. No dislocation occurred in all cases at the final follow-up., Conclusion: Robotic-assisted THA for patients with high dislocation improves the accuracy of the implantation of the acetabular component with respect to safe zone., (© 2021. The Author(s) under exclusive licence to SICOT aisbl.)

Solar-driven conversion of CO 2 is considered an efficient way to tackle the energy and environmental crisis. However, the photocatalytic performance is severely restricted due to the insufficient accessible active sites and inhibited electron transfer efficiency. This work demonstrates a general in situ topological transformation strategy for the integration of uniform Co-based species to fabricate a series of multishelled superstructures (MSSs) for CO 2 photocatalytic conversion. Thorough characterizations reveal the obtained MSSs feature ultrathin Co-based nanosheet assembled polyhedral structures with tunable shell numbers, inner cavity sizes, and compositions. The superstructures increase the spatial density of Co-based active sites while maintaining their high accessibility. Further, the ultrathin nanosheets also facilitate the transfer of photogenerated electrons. As a result, the ZnCo bimetallic hydroxide featuring an ultrathin nanosheet assembled quadruple-shell hollow structure (ZnCo-OH QUNH) exhibits high photocatalytic efficiency toward CO 2 reduction with a CO evolution rate of 134.2 μmol h -1 and an apparent quantum yield of 6.76% at 450 nm. The quasi in situ spectra and theoretical calculations disclose that Co sites in ZnCo-OH QUNH act as highly active centers to stabilize the COOH* intermediate, while Zn species play the role of adsorption sites for the [Ru(bpy) 3 ] 2+ molecules.

V2p and V2i antibodies (Abs) that are specific for epitopes in the V1V2 region of the HIV gp120 envelope (Env) do not effectively neutralize HIV but mediate Fc-dependent anti-viral activities that have been correlated with protection from, or control of HIV, SIV and SHIV infections. Here, we describe a novel molecular toolbox that allows the discrimination of antigenically and functionally distinct polyclonal V2 Ab responses. We identify different patterns of V2 Ab induction by SHIV infection and three separate vaccine regimens that aid in fine-tuning an optimized immunization protocol for inducing V2p and V2i Abs. We observe no, or weak and sporadic V2p and V2i Abs in non-vaccinated SHIV-infected NHPs, but strong V2p and/or V2i Ab responses after immunization with a V2-targeting vaccine protocol. The V2-focused vaccination is superior to both natural infection and to immunization with whole Env constructs for inducing functional V2p- and V2i-specific responses. Strikingly, levels of V2-directed Abs correlate inversely with Abs specific for peptides of V3 and C5. These data demonstrate that a V1V2-targeting vaccine has advantages over the imprecise targeting of SIV/SHIV infections and of whole Env-based immunization regimens for inducing a more focused functional V2p- and V2i-specific Ab response., (© 2022. The Author(s).)

Combinational antiretroviral therapy (cART) is the most effective tool to prevent and control HIV-1 infection without an effective vaccine. However, HIV-1 drug resistance mutations (DRMs) and naturally occurring polymorphisms (NOPs) can abrogate cART efficacy. Here, we aimed to characterize the HIV-1 pol mutation landscape in Cameroon, where highly diverse HIV clades circulate, and identify novel treatment-associated mutations that can potentially affect cART efficacy. More than 8,000 functional Cameroonian HIV-1 pol sequences from 1987 to 2020 were studied for DRMs and NOPs. Site-specific amino acid frequencies and quaternary structural features were determined and compared between periods before (≤2003) and after (2004-2020) regional implementation of cART. cART usage in Cameroon induced deep mutation imprints in reverse transcriptase (RT) and to a lower extent in protease (PR) and integrase (IN), according to their relative usage. In the predominant circulating recombinant form (CRF) 02&#95;AG (CRF02&#95;AG), 27 canonical DRMs and 29 NOPs significantly increased or decreased in RT during cART scale-up, whereas in IN, no DRM and only seven NOPs significantly changed. The profound genomic imprints and higher prevalence of DRMs in RT compared to PR and IN mirror the dominant use of reverse transcriptase inhibitors (RTIs) in sub-Saharan Africa and the predominantly integrase strand transfer inhibitor (InSTI)-naïve study population. Our results support the potential of InSTIs for antiretroviral treatment in Cameroon; however, close surveillance of IN mutations will be required to identify emerging resistance patterns, as observed in RT and PR. Population-wide genomic analyses help reveal the presence of selective pressures and viral adaptation processes to guide strategies to bypass resistance and reinstate effective treatment., 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. The funders had no role in the design or conduct of the study., (Copyright © 2022 Bimela, Nanfack, Yang, Dai, Kong, Torimiro and Duerr.)

We studied the contribution of the light chain to functions of human monoclonal antibodies (mAbs) by measuring the relationships between the rate of mutations and cross-reactivity, binding affinity and neutralization activity. We analyzed 12 mAbs of two clonal families specific to the V2 region of HIV-1 derived from two chronically HIV-1 infected individuals. The clonal mAbs exhibited a range of reactivities, and the clones with superior properties were associated with the rate of mutations and the presence of particular mutated residues in the light chains, but not in the heavy chains. Our observations suggest that for some antibodies, the light chains play a vital role in antibody evolution toward more efficient ones and also suggest the importance of optimal residues rather than the rate of mutations in the variable fragment of the antibody., 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., (Published by Elsevier Inc.)

Identification of vulnerable sites defined by broadly neutralizing antibodies (bNAbs) on HIV-1 envelope (Env) is crucial for vaccine design, and we present here a vulnerable site defined by bNAb M4008&#95;N1, which neutralizes about 40% of a tier-2 virus panel. A 3.2 Å resolution cryo-EM structure of M4008&#95;N1 in complex with BG505 DS-SOSIP reveals a large, shallow protein epitope surface centered at the V3 crown of gp120 and surrounded by key glycans. M4008&#95;N1 interacts with gp120 primarily through its hammerhead CDR H3 to form a β-sheet interaction with the V3 crown hairpin. This makes M4008&#95;N1 compatible with the closed conformation of the prefusion Env trimer, and thus distinct from other known V3 crown mAbs. This mode of bNAb approaching the immunogenic V3 crown in the native Env trimer suggests a strategy for immunogen design targeting this site of vulnerability., (© 2021. The Author(s).)

Controlled-release pesticide formulations using natural polymers as carriers are highly desirable owing to their good biocompatibility, biodegradability, and improved pesticide utilization. In this study, the application potential of our previously prepared spinosad/chitosan controlled-release suspension (SCCS) was evaluated through both toxicity and dissipation tests. A comparison with the spinosad suspension concentrate and the commercial spinosad emulsion in water showed that the insecticidal activity of SCCS against Plutella xylostella larvae displayed the best quick-acting performance as well as long-term efficacy of more than 20 days. The 48 h LC 50 for a 20-day efficacy was calculated to be 29.36 mg/L. The dissipation behavior of spinosad in the spinosad/chitosan microparticles in soil was found to follow the first-order kinetics, with a relatively shorter half-life (2.1 days) than that observed for the unformulated spinosad (3.1 days). This work showed the positive effect of chitosan on spinosad in improving insecticidal activity and reducing environmental risks in soil, which provided useful information on the application potential of pesticide-carrier systems based on natural polymer materials in crop protection and food safety., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Wastewater-based epidemiology is a useful approach to estimate population-level exposure to a wide range of substances (e.g., drugs, chemicals, biological agents) by wastewater analysis. An important uncertainty in population normalized loads generated is related to the size and variability of the actual population served by wastewater treatment plants (WWTPs). Here, we built a population model using location-based services (LBS) data to estimate dynamic consumption of illicit drugs. First, the LBS data from Tencent Location Big Data and resident population were used to train a linear population model for estimating population (r 2  = 0.92). Then, the spatiotemporal accuracy of the population model was validated. In terms of temporal accuracy, we compared the model-based population with the time-aligned ammonia nitrogen (NH 4 -N) population within the WWTP of SEG, showing a mean squared error of < 10%. In terms of spatial accuracy, we estimated the model-based population of 42 WWTPs in Dalian and compared it with the NH 4 -N and design population, indicating good consistency overall (5% less than NH 4 -N and 4% less than design). Furthermore, methamphetamine consumption and prevalence based on the model were calculated with an average of 111 mg/day/1000 inhabitants and 0.24%, respectively, and dynamically displayed on a visualization system for real-time monitoring. Our study provided a dynamic and accurate population for estimating the population-level use of illicit drugs, much improving the temporal and spatial trend analysis of drug use. Furthermore, accurate information on drug use could be used to assess population health risks in a community., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Rationally tailoring the coordination environments of metal single atoms (SAs) is an effective approach to promote their catalytic performances, which, however, remains as a challenge to date. Here, we report a novel misplaced deposition strategy for the fabrication of differently coordinated dual-metal hetero-SAs. Systematic characterization results imply that the as-synthesized dual-metal hetero-SAs (exemplified by Cu and Co) are affixed to a hierarchical carbon support via Cu-C 4 and Co-N 4 coordination bonds. Density functional theory studies reveal that the strong synergistic interactions between the asymmetrically deployed CuC 4 and CoN 4 sites lead to remarkably polarized charge distributions, i.e., electron accumulation and deficiency around CuC 4 and CoN 4 sites, respectively. The obtained CuC 4 /CoN 4 @HC catalyst exhibits significantly enhanced capability in substrate adsorption and O 2 activation, achieving superior catalytic performances in the oxidative esterification of aromatic aldehydes in comparison with the Cu- and Co-based SA counterparts.

Visible-light-driven photocatalytic CO 2 reduction is considered an appealing strategy to mitigate the energy crisis and environmental issues, whereas the reactivity is limited due to the difficulties in activation of inert CO 2 molecule and efficient transportation of photoinduced carriers. Herein, we report the design of novel Fe doped CoP hierarchical double-shelled nanocages (Fe-CoP HDSNC) via a MOF-templated approach for highly efficient visible-light-driven CO 2 reduction. The unique hierarchical double-shelled hollow architectures can greatly shorten the charge transfer distances and also expose abundant reactive sites. Moreover, Fe atoms doping is able to reduce the CO 2 activation energy barrier through stabilizing the *COOH intermediates and promote the CO desorption by destabilizing the CO* adduct. As expected, the Fe-CoP HDSNC achieves an unprecedented catalytic efficiency in visible-light-driven CO 2 reduction with an up to 3.25% apparent quantum yield and 90.3% CO selectivity, superior to most of the state-of-the-art photocatalysts under comparable conditions. More importantly, the Fe-CoP HDSNC is also highly effective under diluted CO 2 atmosphere, suggesting the practicability of the present photocatalytic system.

The repertoire of antibodies (Abs) produced upon vaccination against a particular antigenic site is rarely studied due to the complexity of the immunogens. We received such an opportunity when one rhesus macaque was immunized six times at 0, 4, 10, 16, 32, and 143 weeks with C4-447 peptide containing the 8-mer epitope for human monoclonal Ab (mAb) 447-52D specific to the V3 region of gp120 HIV-1. Strong anti-V3 antibody responses reached 50% binding titer in serum of 10 -5 at week 10 that declined to 10 -3 by week 70. After an additional boost of C4-447 peptide at week 143, titers rebounded to 10 -5 at week 146, or 2.7 years after the first immunization. Using the blood sample at week 146, we produced 41 V3-specific recombinant mAbs by single B cell isolation and cloning. Sequence analysis revealed 21B cell lineages, single and clonally related, based on immunoglobulin gene usage and CDR3s. The broad repertoire of Abs directed to a small antigenic site shows the targeting potency of a vaccine-elicited immune response in rhesus macaques., 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., (Published by Elsevier Ltd.)

Ketamine (KET) analogs are increasingly emerging as new psychoactive substances (NPS). The present report describes the first detection of the KET analog, 2-fluorodeschloroketamine (2F-DCK), in influent samples collected from nine wastewater treatment plants in seven major Chinese cities from 2018 to 2020 by wastewater-based epidemiology (WBE). An analytical method based on solid-phase extraction and subsequent gas chromatography-mass spectrometry was developed for the detection of 2F-DCK and KET. The stability experiments showed that 2F-DCK and KET remained stable in wastewater for 15 days at room and frozen temperatures, and at two pH values (pH = 7 and pH = 2), with residue amounts between 90% and 110%. KET was detected in all samples, whereas 2F-DCK was detected in only four samples: from Guangzhou in 2018, Shenzhen in 2019, and Quanzhou and Nanning in 2020, indicating that 2F-DCK has been used as early as 2018 in China. The renal clearance of 2F-DCK was predicted based on the quantitative structure-pharmacokinetic relationship model, which was used to calculate an excretion factor of 3.7. The 2F-DCK consumption in four cities ranged from 3.71 ± 0.05 to 55 ± 0.09 mg/day/1000 inh, and KET ranged from 1.3 ± 0.04 to 76.5 ± 4.63 mg/day/1000 inh. This is the first study to investigate 2F-DCK by WBE, which provides relevant real-time data on the growth of NPS use, as well as useful information for the government to develop new policies., (© 2021 John Wiley & Sons, Ltd.)

Pollution related to pesticides has become a global problem due to their low utilization and non-targeting application, and nanotechnology has shown great potential in promoting sustainable agriculture. Nowadays, mesoporous silica-based nanomaterials have garnered immense attention for improving the efficacy and safety of pesticides due to their distinctive advantages of low toxicity, high thermal and chemical stability, and particularly size tunability and versatile functionality. Based on the introduction of the structure and synthesis of different types of mesoporous silica nanoparticles (MSNs), the multiple roles of mesoporous silica in safe pesticide application using nanotechnology are discussed in this Review: (i) as nanocarrier for sustained/controlled delivery of pesticides, (ii) as adsorbent for enrichment or removal of pesticides in aqueous media, (iii) as support of catalysts for degradation of pesticide contaminants, and (iv) as support of sensors for detection of pesticides. Several scientific issues, strategies, and mechanisms regarding the application of MSNs in the pesticide field are presented, with their future directions discussed in terms of their environmental risk assessment, in-depth mechanism exploration, and cost-benefit consideration for their continuous development. This Review will provide critical information to related researchers and may open up their minds to develop new advances in pesticide application.

Topological materials with robust topological surface states appear to be well-suited as electrochemical catalysts. However, few studies have been published on the development of non-noble metal topological catalysts, most likely because the topological properties tend to be attributed to the s and p orbital electrons, while transition-metal catalysis mainly involves d orbital electrons. Herein, we proposed a topological semimetallic (TSM) compound, VAl 3 , with a surface state consisting mainly of d orbital electrons, as an electrocatalyst for the hydrogen evolution reaction (HER). Density functional theory (DFT) calculations showed that the surface state electrons enhanced the adsorption of H atoms. Moreover, the transfer of surface state electrons between the surface and adsorbed H atoms was optimized through nickel doping. We experimentally prepared single-crystals VAl 3 and V 0.75 Ni 0.25 Al 3 alloys. Electrochemical analysis showed that not only did V 0.75 Ni 0.25 Al 3 outperform VAl 3 but also it was among the best non-noble metal topological HER electrocatalysts currently available.

Corylin, a flavonoid isolated from the fruit of Psoralea corylifolia , has an osteogenic effect on osteoblasts in vitro and bone micromass ex vivo. However, the effect and mechanism of corylin in regulating osteoclastogenesis remain unknown. By using murine bone marrow macrophages as the osteoclast precursor, corylin was found to inhibit the receptor activator of nuclear factor (NF) κB ligand (RANKL)-induced osteoclast differentiation via down-regulating osteoclastic marker genes. In parallel, F-actin formation and osteoclast migration were diminished in corylin-treated cultured osteoclasts, and subsequently the expressions of osteoclastic proteins were suppressed: the suppression of protein expression was further illustrated by transcriptomic analysis. Furthermore, corylin inhibited the nuclear translocation of p65, giving rise to a restraint in osteoclastic differentiation through the attenuation of transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor of activated T cells c1 (NFATc1). There was no obvious change in apoptosis when the RANKL-induce osteoclasts were cultured in the presence of corylin. The finding supports the potential development of corylin as an osteoclast inhibitor against osteoporosis.

HIV-1 envelope (Env) is a trimer of gp120-gp41 heterodimers, synthesized from a precursor gp160 that contains an ER-targeting signal peptide (SP) at its amino-terminus. Each trimer is swathed by ~90 N-linked glycans, comprising complex-type and oligomannose-type glycans, which play an important role in determining virus sensitivity to neutralizing antibodies. We previously examined the effects of single point SP mutations on Env properties and functions. Here, we aimed to understand the impact of the SP diversity on glycosylation of virus-derived Env and virus neutralization by swapping SPs. Analyses of site-specific glycans revealed that SP swapping altered Env glycan content and occupancy on multiple N-linked glycosites, including conserved N156 and N160 glycans in the V1V2 region at the Env trimer apex and N88 at the trimer base. Virus neutralization was also affected, especially by antibodies against V1V2, V3, and gp41. Likewise, SP swaps affected the recognition of soluble and cell-associated Env by antibodies targeting distinct V1V2 configurations, V3 crown, and gp41 epitopes. These data highlight the contribution of SP sequence diversity in shaping the Env glycan content and its impact on the configuration and accessibility of V1V2 and other Env epitopes., Competing Interests: The authors declare no competing interests.

The RV144 vaccine trial revealed a correlation between reduced risk of HIV infection and the level of nonneutralizing-antibody (Ab) responses targeting specific epitopes in the second variable domain (V2) of the HIV gp120 envelope (Env) protein, suggesting this region as a target for vaccine development. To favor induction of V2-specific Abs, we developed a vaccine regimen that included priming with DNA expressing an HIV V1V2 trimeric scaffold immunogen followed by booster immunizations with a combination of DNA and protein in rhesus macaques. Priming vaccination with DNA expressing the HIV recombinant subtype CRF01&#95;AE V1V2 scaffold induced higher and broader V2-specific Ab responses than vaccination with DNA expressing CRF01&#95;AE gp145 Env. Abs recognizing the V2 peptide that was reported as a critical target in RV144 developed only after the priming immunization with V1V2 DNA. The V2-specific Abs showed several nonneutralizing Fc-mediated functions, including ADCP and C1q binding. Importantly, robust V2-specific Abs were maintained upon boosting with gp145 DNA and gp120 protein coimmunization. In conclusion, priming with DNA expressing the trimeric V1V2 scaffold alters the hierarchy of humoral immune responses to V2 region epitopes, providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection. IMPORTANCE The aim of this work was to design and test a vaccine regimen focusing the immune response on targets associated with infection prevention. We demonstrated that priming with a DNA vaccine expressing only the HIV Env V1V2 region induces Ab responses targeting the critical region in V2 associated with protection. This work shows that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region, in the absence of immune interference by other epitopes. This induced immune responses with improved recognition of epitopes important for protective immunity, namely, V2-specific humoral immune responses inversely correlating with HIV risk of infection in the RV144 trial., (Copyright © 2020 Devasundaram et al.)

Stephaniae tetrandrae radix (STR) is a commonly used traditional Chinese medicine in alleviating edema by inducing diuresis. In the clinic, STR extracts or its components are widely used in the treatment of edema, dysuria, and rheumatism for the regulation of water metabolism. Furthermore, STR has been used in treating emotional problems for years by combining with other Chinese herbs. However, the material basis and mechanism of STR on the nervous system have not been revealed. Here, the main components of STR extracts with different extracting solvents were identified, including three major alkaloids, i.e., cyclanoline, fangchinoline, and tetrandrine. The cholinesterase inhibitory activity of STR extracts and its alkaloids was determined using the Ellman assay. Both cyclanoline and fangchinoline showed acetylcholinesterase (AChE) inhibitory activity, demonstrating noncompetitive enzyme inhibition. In contrast, tetrandrine did not show enzymatic inhibition. The synergism of STR alkaloids with huperzine A or donepezil was calculated by the median-effect principle. The drug combination of fangchinoline-huperzine A or donepezil synergistically inhibited AChE, having a combination index (CI) < 1 at F a = 0.5. Furthermore, the molecular docking results showed that fangchinoline bound with AChE residues in the peripheral anionic site, and cyclanoline bound with AChE residues in the peripheral anionic site, anionic site, and catalytic site. In parallel, cyclanoline bound with butyrylcholinesterase (BChE) residues in the anionic site, catalytic site, and aromatic site. The results support that fangchinoline and cyclanoline, alkaloids derived from STR, could account for the anti-AChE function of STR. Thus, STR extract or its alkaloids may potentially be developed as a therapeutic strategy for Alzheimer's patients.

Controlled release pesticide formulation with long-term efficacy is highly desirable for improving pesticide utilization and reducing adverse effects. In this study, an environment-friendly controlled release formulation of biological insecticide spinosad was fabricated through the coprecipitation-based synchronous encapsulation with chitosan. The resulted spinosad/chitosan formulation showed an excellent encapsulation efficiency of 60 %, obvious pH and temperature sensitivity, and outstanding ultraviolet shielding ability. The in vitro release tests displayed long sustained-release time (>18 d) and high cumulative release (>80 %) under neutral and weakly alkaline conditions. The primary interaction between spinosad and chitosan has been found to be physical adsorption and adhesion, with the release dynamics following Fickian diffusion mechanism of Ritger-Peppas model. This work contributes to the development of pesticide carrier system of natural polymer materials, with a great potential for insect pest control., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The HIV vaccine field now recognizes the potential importance of generating polyfunctional antibodies (Abs). The only clinical HIV vaccine trial to date to show significant efficacy (RV144) found that reduced infection rates correlated with the level of nonneutralizing Abs specific for the V2 region of the envelope glycoprotein. We have conducted a comprehensive preclinical reverse vaccinology-based vaccine program that has included the design and production and testing of numerous scaffolded V2 region immunogens. The most immunogenic vaccine regimen in nonhuman primates among those studied as part of this program consisted of a cocktail of three immunogens presenting V2 from different viruses and clades in the context of different scaffolds. Presently we demonstrate that the V2-specific Ab response from this regimen was highly durable and functionally diverse for the duration of the study (25 weeks after the final immunization). The total IgG binding response at this late time point exhibited only an ∼5× reduction in potency. Three immunizations appeared essential for the elicitation of a strong Ab-dependent cellular cytotoxicity (ADCC) response for all animals, as opposed to the Ab-dependent cellular phagocytosis (ADCP) and virus capture responses, which were comparably potent after only 2 immunizations. All functionalities measured were highly durable through the study period. Therefore, testing this vaccine candidate for its protective capacity is warranted. IMPORTANCE The only HIV vaccine trial for which protective efficacy was detected correlated this efficacy with V2-specific Abs that were effectively nonneutralizing. This result has fueled a decade of HIV vaccine research focused on designing an HIV vaccine capable of eliciting V2-focused, polyfunctional Abs that effectively bind HIV and trigger various leukocytes to kill the virus and restrict viral spread. From the numerous vaccine candidates designed and tested as part of our V2-focused preclinical vaccine program, we have identified immunogens and a vaccine regimen that induces a highly durable and polyfunctional V2-focused Ab response in rhesus macaques, described herein., (Copyright © 2020 American Society for Microbiology.)

Background: According to traditional Chinese medicine (TCM) theory, the herbal property is the most important guiding principle of ancient medication in China. The classification of warm- and cold-stimulating TCM is defined mainly based on the effects of herbs in regulating body temperature; however, the underlying mechanism of such distinction has not been fully identified., Methods: Here, four commonly used spleen-meridian herbs, Ginseng Radix and Astragali Radix as typical warm-stimulating herbs, and Nelumbinis Semen and Coicis Semen as typical cold-stimulating herbs, were selected to test their effects in regulating body temperature, as well as its triggered thermo-regulatory factors and energy related metabolites, in yeast-induced fever rats., Results: The intake of Astragali Radix increased body temperature in yeast-induced fever rats; while Coicis Semen showed cooling effects in such rats. In parallel, the levels of cAMP, PGE 2 and thermo-related metabolites, including choline, creatine, alanine, lactate and leucine, in the blood of yeast-induced rats were increased significantly by the intake of Astragali Radix. Oppositely, the cold-stimulating herbs, Nelumbinis Semen and Coicis Semen, showed cooling effects by increasing certain metabolites, e.g. histidine, tyrosine, lipid, myo-inositol, as well as AVP level., Conclusion: Here, we compared different effects of warm and cooling spleen-meridian herbs in the regulation of body temperature. By providing an intuitive comparison of thermo-regulatory factors and related metabolites after intake of selected herbs, the mechanism behind the warm and cooling effects of specific herbs were revealed., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The present study aimed to evaluate the stem cell markers, characteristics and biological functions of cancer stem‑like side population (SP) cells in human oral cancer. SP cells were isolated from the human oral squamous cell carcinoma Tca8113 cell line by Hoechst 33342 fluorescence dye and flow cytometry. The colony forming and proliferative capability of SP and non‑SP cells were detected using a live‑cell analysis system in vitro. The number of cells expressing stem cell markers was compared between SP cells and non‑SP cells by flow cytometry. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the mRNA and protein expression levels of stem cell genes, respectively. Differential expression of microRNAs (miRNAs) in SP and non‑SP cells was determined by microarray hybridization and an miRNA regulation network was produced. With regard to the proliferation capability, SP cells reached 60.0% confluence after 40 h of growth compared with 35.1% confluence for non‑SP cells (P<0.05). The number of colonies in SP cells was 43.1±9.2 compared with 33.0±8.2 of non‑SP cells (P<0.05). The aldehyde dehydrogenase‑1 (ALDH1)‑positive cell number in the SP cells was increased by 10 times compared with the non‑SP cells (P<0.01). The mRNA and protein expression levels of ALDH1, SRY‑box 2, POU class 5 homeobox 1 and Nanog homeobox in SP cells were significantly higher compared with non‑SP cells (P<0.05). Microarray hybridization demonstrated that 21 miRNAs were upregulated and 13 miRNAs were downregulated in SP cells compared with non‑SP cells. SP cells in Tca8113 demonstrated greater capability of proliferation and colony formation compared with non‑SP cells in vitro. Stem cell markers were overexpressed in SP cells compared with non‑SP cells.