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Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program.

Understanding the reasons for and consequences of bodyweight change in people living with HIV initiating antiretroviral therapy (ART) is crucial to optimising long-term health and wellbeing. We aimed to examine bodyweight trends and associated factors among individuals with well estimated dates of HIV-1 seroconversion.

The intricate involvement of the serotonin 5-HT2Areceptor (5-HT2AR) both in schizophrenia and in the activity of antipsychotic drugs is widely acknowledged. The currently marketed antipsychotic drugs, although effective in managing the symptoms of schizophrenia to a certain extent, are not without their repertoire of serious side effects. There is a need for better therapeutics to treat schizophrenia for which understanding the mechanism of action of the current antipsychotic drugs is imperative. With bioluminescence resonance energy transfer (BRET) assays, we trace the signaling signature of six antipsychotic drugs belonging to three generations at the 5-HT2AR for the entire spectrum of signaling pathways activated by serotonin (5-HT). The antipsychotic drugs display previously unidentified pathway preference at the level of the individual Gα subunits and β-arrestins. In particular, risperidone, clozapine, olanzapine and haloperidol showed G protein-selective inverse agonist activity. In addition, G protein-selective partial agonism was found for aripiprazole and cariprazine. Pathway-specific apparent dissociation constants determined from functional analyses revealed distinct coupling-modulating capacities of the tested antipsychotics at the different 5-HT-activated pathways. Computational analyses of the pharmacological and structural fingerprints support a mechanistically based clustering that recapitulate the clinical classification (typical/first generation, atypical/second generation, third generation) of the antipsychotic drugs. The study provides a new framework to functionally classify antipsychotics that should represent a useful tool for the identification of better and safer neuropsychiatric drugs and allows formulating hypotheses on the links between specific signaling cascades and in the clinical outcomes of the existing drugs.

Un chat Bengal mâle castré de onze ans est présenté en consultation à la suite de l’apparition d’une masse cervicale ventrale droite associée à un syndrome de Claude Bernard-Horner ipsilatéral et répondant partiellement à des injections de corticoïdes et d’antibiotiques. La première analyse histologique est en faveur d’une inflammation granulomateuse et la seconde en faveur d’un lymphome malin de grade incertain. Le bilan d’extension ainsi que les analyses histologiques orientent le diagnostic vers un lymphome atypique de type Hodgkin-like. Une polychimiothérapie et une exérèse chirurgicale permettent d’obtenir une rémission clinique complète deux mois après le début de la prise en charge. L’analyse histologique en postopératoire est en faveur d’une population mixte pyogranulomateuse et lymphoïde. Le lymphome hodgkinien est un lymphome atypique peu décrit en médecine vétérinaire qui se développe généralement dans un seul nœud lymphatique ou une chaîne de nœuds lymphatiques. Celui-ci est souvent indolent et est parfois curable. Les objectifs sont de faire un état des lieux à travers ce cas des connaissances actuelles sur le lymphome hodgkinien chez le chat en comparaison avec les connaissances en cancérologie humaine.

Nitrate ions, which mainly come from human activities and are present in wastewater, surface water, and groundwater, are of great environmental concern. In the present work, the activated carbon (AC), chitosan (CH), and biocomposite activated carbon/chitosan (AC/CH) were successfully prepared and characterized using BET, SEM, AFM, elemental analysis, FTIR, PXRD, and TGA/DSC. AC and AC/CH, with specific surface areas of 1327 and 799 m2/g, respectively, were used to investigate the effect of contact time, initial nitrate ions concentrations, adsorbent dose, and foreign anions on the removal of nitrate ions by batch adsorption mode. The adsorption results showed that the prepared biocomposite (AC/CH) has a positive impact on the nitrate ion removal compared to AC, with an equilibrium time of 20 min, an optimal pH of 3, and an adsorption capacity of 58 mg/g at an initial concentration of 200 mg/L. Isotherm adsorption data reveal that AC and AC/CH best fitted Sips, Freundlich, and Temkin models while the pseudo-first-order kinetic model describes the adsorption process better than other kinetic models, implying that the adsorption process was mainly governed by physisorption. The biocomposite was found to be reusable after up to seven adsorption/desorption cycles. This study reveals that the prepared AC/CH biocomposite could be considered a promising adsorbent for nitrate ions removal.

Study design National cross-sectional study.Objective Thoracic kyphosis (TK) is related to sagittal parameters as pelvic tilt (PT), lumbar lordosis (LL) and pelvic incidence (PI). The equation TK = 2 (PT+LL–PI) was validated for adolescents. The purpose of this study was to investigate if this equation correctly predicts TK regardless of age.Methods Sagittal alignment parameters were assessed on full spine radiographs of 2599 individuals without spine pathology (1488 females, 1111 males). Calculated TK (CTK) = 2 (PT+LL–PI) and measured TK (MTK) were compared by calculating the gap and using a linear regression between both parameters. Subgroup analyses were performed for gender, age, TK groups (≤20°, 21°-40°, 41°-60°, >60°), and PI groups (<45°, 45°-60°, >60°).Results Average values in the total population were: MTK 45.0°, CTK 36.9°. Average TK gap was 8.1°, 5.2° in females (intercept 11.7, slope .61) and 11.9° in males (intercept 7.1, slope .58). The mean gap was 3.6° for 15-34 years, 5.7° under 15 years and it increased progressively after 35 years with a maximum of 19.9° over 80 years. The gap also increased with the amount of MTK: -3.5° for TK<20° up to 17.3° for TK >60°. Differences in gaps were minor between PI groups. The intercept was smallest and slopes >.6 for PI <45° and TK ≤20°.Conclusion The formula TK=2 (PT+LL-PI) yielded moderate accuracy for adolescents and young adults, but did not fit for over 35 years and under 15. The amount and variance in TK increased in elderly subjects, which made the formula less accurate.

This article presents the first demonstration of beamforming, detection, and bearing estimation of an underwater acoustic source from an eight-element thin line hydrophone array towed behind the AutoNaut wave-propelled uncrewed surface vessel. This has been achieved in situ and in real time during an experimental sea trial off the coast of Plymouth, U.K. A controlled acoustic source was towed from a support vessel while emitting seven tonals with frequencies between 480–1630 Hz and source levels between 93–126 dB. This allowed the detection performance of the array to be assessed and demonstrated for an acoustic source with known bearing and range. In postprocessing, the shape of the array was estimated using a cubic spline model, exploiting measurements from pressure and three-axis compass sensors integrated at each end of the array. The beamforming was repeated using the estimated array shape to infer the hydrophone positions, which resulted in a median improvement of 0.38 dB and maximum of 5.8 dB in the MUSIC beamforming output, and a potential reduction in the left/right bearing estimation ambiguities. The outcomes of this work demonstrate that the AutoNaut is an effective platform for towed array passive acoustic monitoring.

Epithelial organoids are most efficiently grown from mouse-tumour-derived, reconstituted extracellular matrix hydrogels, whose poorly defined composition, batch-to-batch variability and immunogenicity limit clinical applications. Efforts to replace such ill-defined matrices for organoid culture have largely focused on non-adaptable hydrogels composed of covalently crosslinked hydrophilic macromolecules. However, the excessive forces caused by tissue expansion in such elastic gels severely restrict organoid growth and morphogenesis. Chemical or enzymatic degradation schemes can partially alleviate this problem, but due to their irreversibility, long-term applicability is limited. Here we report a family of synthetic hydrogels that promote extensive organoid morphogenesis through dynamic rearrangements mediated by reversible hydrogen bonding. These tunable matrices are stress relaxing and thus promote efficient crypt budding in intestinal stem-cell epithelia through increased symmetry breaking and Paneth cell formation dependent on yes-associated protein 1. As such, these well-defined gels provide promising versatile matrices for fostering elaborate in vitro morphogenesis.

Over the past 5 years, our laboratory has systematically developed a structure-guided library approach to evolve new adeno-associated virus (AAV) capsids with altered tissue tropism, higher transduction efficiency and the ability to evade pre-existing humoral immunity. Here, we provide a detailed protocol describing two distinct evolution strategies using structurally divergent AAV serotypes as templates, exemplified by improving CNS gene transfer efficiency in vivo. We outline four major components of our strategy: (i) structure-guided design of AAV capsid libraries, (ii) AAV library production, (iii) library cycling in single versus multiple animal models, followed by (iv) evaluation of lead AAV vector candidates in vivo. The protocol spans ~95 d, excluding gene expression analysis in vivo, and can vary depending on user experience, resources and experimental design. A distinguishing attribute of the current protocol is the focus on providing biomedical researchers with 3D structural information to guide evolution of precise ‘hotspots’ on AAV capsids. Furthermore, the protocol outlines two distinct methods for AAV library evolution consisting of adenovirus-enabled infectious cycling in a single species and noninfectious cycling in a cross-species manner. Notably, our workflow can be seamlessly merged with other RNA transcript-based library strategies and tailored for tissue-specific capsid selection. Overall, the procedures outlined herein can be adapted to expand the AAV vector toolkit for genetic manipulation of animal models and development of human gene therapies.

Antibodies effective against the recent Omicron sublineages are missing. By taking advantage of a multi-centric prospective cohort of immunocompromised individuals treated for mild-to-moderate COVID-19, Bruel et al. show that administration of 500 mg of sotrovimab induces serum neutralization and antibody-dependent cellular cytotoxicity of BQ.1.1 and XBB.1.5. Therefore, sotrovimab may remain a therapeutic option against these variants.

Study design Descriptive radiographic analysis of a prospective multi-center database.Objective This study aims to provide normative values of spinopelvic parameters and their correlations according to age and pelvic incidence (PI) of subjects without spinal deformity.Methods After Institutional Review Board (IRB) approval, 1540 full spine radiographs were analyzed. Subjects were divided into 3 groups of PI: low PI < 45°, intermediate PI 45–60°, high PI > 60°, and then stratified by age (20–34, 35–49, 50–64, > 65 Y.O). Pelvic and spinal parameters were measured. Statistical analysis between parameters was performed using Bayesian inference and correlation.Results Mean age was 53.5 years (845 females, 695 males, range 20–93 years). In low PI group, lumbar lordosis (LL) decrease was mainly observed in the 2 younger age groups. In medium and high PI groups, loss of lordosis was linear during aging and occurred mainly on the distal arch of lordosis. Moderate PI group had a stable lordosis apex and thoracolumbar inflection point. High PI group had a stable thoracolumbar inflection point and a more distal lordosis apex in elderly subjects. For all subjects, kyphosis and pelvic tilt (PT) increased with age. There was a constant chain of correlation between PI and age groups. Proximal lumbar lordosis (PLL) was correlated with kyphosis and sagittal vertical axis (SVA C7), while the distal lumbar lordosis (DLL) was correlated with PI and PT.Conclusion This study provides a detailed repository of sagittal spinopelvic parameters normative values with detailed analysis of segmental kyphosis and lordosis distribution according to gender, age, and PI.

Les fusions circonférentielles par voie antérieure (ALIF) ou transforaminale (TLIF) associées à une ostéosynthèse postérieure sont des techniques couramment utilisées dans le traitement chirurgical des spondylolisthésis par lyse isthmique de bas grade. Mais il n’existe que peu d’études comparant les résultats cliniques et radiologiques des différentes techniques de fusions intersomatiques. L’objectif de cette étude était de comparer les résultats cliniques et radiologiques de deux techniques d’arthrodèse : TLIF versus ALIF associée à une instrumentation postérieure à deux ans postopératoires d’un spondylolisthésis par lyse isthmique de l’adulte.

Salmonellagenus harbors five Type VI Secretion System (T6SS) gene clusters. The T6SS encoded in SPI-6 (T6SSSPI-6) contributes to SalmonellaTyphimurium colonization of chickens and mice, while the T6SS encoded in SPI-19 (T6SSSPI-19) of SalmonellaGallinarum contributes to chicken colonization. Interestingly, the T6SSSPI-19of SalmonellaGallinarum complemented the defect in chicken colonization of a SalmonellaTyphimurium strain that lacks the T6SSSPI-6, suggesting that both T6SSs are interchangeable. Here we show that the transfer of SalmonellaGallinarum T6SSSPI-19complemented the defect in mice colonization of a SalmonellaTyphimurium ΔT6SSSPI-6strain, indicating that both T6SSs are functionally redundant during host colonization.