bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular properties of RmlT, a wall teichoic acid rhamnosyltransferase that modulates virulence inListeria monocytogenes
Authors: Monteiro Ricardo , Cereija Tatiana B. , Pombinho Rita , Voskuilen Thijs , Codée Jeroen D.C. , Sousa Sandra , Morais-Cabral João H. , Cabanes Didier 
Published: January 2024

AbstractWall teichoic acids (WTAs) from the major Gram-positive foodborne pathogenListeria monocytogenesare peptidoglycan-associated glycopolymers decorated by monosaccharides that, while not essential for bacterial growth, are required for bacterial virulence and resistance to antimicrobials. Here we report the structure and function of a bacterial WTAs rhamnosyltransferase, RmlT, strictly required forL. monocytogenesWTAs rhamnosylation. In particular, we demonstrated that RmlT transfers rhamnose from dTDP-L-rhamnose to naked WTAs, and that specificity towards TDP-rhamnose is not determined by its binding affinity. Structures of RmlT with and without its substrates showed that this enzyme is a dimer, revealed the residues responsible for interaction with the substrates and that the catalytic residue pre-orients the acceptor substrate towards the nucleophilic attack to the sugar. Additionally, the structures provided indications for two potential interaction pathways for the long WTAs on the surface of RmlT. Finally, we confirmed that WTAs glycosyltransferases are promising targets for next-generation strategies against Gram-positive pathogens by showing that inactivation of the RmlT catalytic activity results in a decreased infectionin vivo.
CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment
Authors: Kar Meenakshi , Johnson Katherine E.E. , Vanderheiden Abigail , Elrod Elizabeth J. , Floyd Katharine , Geerling Elizabeth , Stone E. Taylor , Salinas Eduardo , Banakis Stephanie , Wang Wei , Sathish Shruti , Shrihari Swathi , Davis-Gardner Meredith E. , Kohlmeier Jacob , Pinto Amelia , Klein Robyn , Grakoui Arash , Ghedin Elodie , Suthar Mehul S. 
Published: January 2024

ABSTRACTSARS-CoV-2 is the causative agent of COVID-19 and continues to pose a significant public health threat throughout the world. Following SARS-CoV-2 infection, virus-specific CD4+ and CD8+ T cells are rapidly generated to form effector and memory cells and persist in the blood for several months. However, the contribution of T cells in controlling SARS-CoV-2 infection within the respiratory tract are not well understood. Using C57BL/6 mice infected with a naturally occurring SARS-CoV-2 variant (B.1.351), we evaluated the role of T cells in the upper and lower respiratory tract. Following infection, SARS-CoV-2-specific CD4+ and CD8+ T cells are recruited to the respiratory tract and a vast proportion secrete the cytotoxic molecule Granzyme B. Using antibodies to deplete T cells prior to infection, we found that CD4+ and CD8+ T cells play distinct roles in the upper and lower respiratory tract. In the lungs, T cells play a minimal role in viral control with viral clearance occurring in the absence of both CD4+ and CD8+ T cells through 28 days post-infection. In the nasal compartment, depletion of both CD4+ and CD8+ T cells, but not individually, results in persistent and culturable virus replicating in the nasal compartment through 28 days post-infection. Usingin situhybridization, we found that SARS-CoV-2 infection persisted in the nasal epithelial layer of tandem CD4+ and CD8+ T cell-depleted mice. Sequence analysis of virus isolates from persistently infected mice revealed mutations spanning across the genome, including a deletion in ORF6. Overall, our findings highlight the importance of T cells in controlling virus replication within the respiratory tract during SARS-CoV-2 infection.
Amelioration of age-related cognitive decline and anxiety in mice byCentella asiaticaextract varies by sex, dose and mode of administration
Authors: Gray Nora E , Hack Wyatt , Brandes Mikah S , Zweig Jonathan A , Yang Liping , Marney Luke , Choi Jaewoo , Magana Armando Alcazar , Cerruti Natasha , McFerrin Janis , Koike Seiji , Nguyen Thuan , Raber Jacob , Quinn Joseph F , Maier Claudia S , Soumyanath Amala 
Published: January 2024

AbstractWe have previously reported that a water extract (CAW) of the Ayurvedic plantCentella asiaticaadministered in drinking water can improve cognitive deficits in mouse models of aging and neurodegenerative diseases. Here we compared the effects of CAW administered in drinking water or the diet on cognition, measures of anxiety and depression-like behavior in healthy aged mice.Three- and eighteen-month-old male and female C57BL6 mice were administered rodent AIN-93M diet containing CAW (0, 0.2, 0.5 or 1% w/w) to provide 0, 200 mg/kg/d, 500 mg/kg/d or 1000 mg/kg/d for a total of 5 weeks. An additional group of eighteen-month-old mice were treated with CAW (10 mg/mL) in their drinking water for a total of five weeks to deliver the same exposure of CAW as the highest dietary dose (1000 mg/kg/d). CAW doses delivered were calculated based on food and water consumption measured in previous experiments. In the fourth and fifth weeks, mice underwent behavioral testing of cognition, anxiety and depression (n=12 of each sex per treatment group in each test).Aged mice of both sexes showed cognitive deficits relative to young mice while only female aged mice showed increased anxiety compared to the young female mice and no differences in depression were observed between the different ages. CAW (1000 mg/kg/d) in the drinking water improved deficits in aged mice in learning, executive function and recognition memory in both sexes and attenuated the increased measures of anxiety observed in the aged female mice. However, CAW in the diet only improved executive function in aged mice at the highest dose (1000 mg/kg/d) in both sexes and did so less robustly than when given in the water. There were no effects of CAW on depression-like behavior in aged animals regardless of whether it was administered in the diet or the water.These results suggest that CAW can ameliorate age-related changes in measures of anxiety and cognition and that the mode of administration is important for the effects of CAW on resilience to these age-related changes.
Improving estimates of negative selection in human genome using CAPS
Authors: Gudkov Mikhail , Thibaut Loïc , Giannoulatou Eleni 
Published: January 2024

AbstractDespite ongoing efforts, variant interpretation in disease sequencing studies is often hindered by the lack of well-established ways of determining the potential pathogenicity of genetic variation, especially for understudied classes of single-nucleotide variants (SNVs). Population genetics methods offer an attractive solution to this problem by enabling the assessment of the effects of SNVs through their distributions in human populations.For instance, negative selection is known to shift site-frequency spectra of genetic variation, thus affecting the ratio of singleton variants. It has been shown that the extent of negative selection can serve as a proxy for deleteriousness. An example of this approach is the Mutability-Adjusted Proportion of Singletons (MAPS) metric. Although MAPS proves a useful instrument for the assessment of selection-based deleteriousness in SNVs, it is highly sensitive to the calibration of the singletons-by-mutability model, which results in potentially biased estimates for some classes of variants.Building up on the methodology used in MAPS, we developed a novel metric of negative selection in the human genome — CAPS, or Context-Adjusted Proportion of Singletons. Compared to its predecessor, CAPS provides estimates of negative selection that are less biased and have more accurate confidence intervals. CAPS inherits some of the same features that make MAPS useful for studying SNVs, yet the key difference of our method is the complete elimination of the mutability layer in the model, which makes the metric more robust and reliable.We believe that CAPS holds promise for improving the discovery of new disease-variant associations in clinical and research settings.
Mouse Adaptation of Human Inflammatory Bowel Diseases Microbiota Enhances Colonization Efficiency and Alters Microbiome Aggressiveness Depending on Recipient Colonic Inflammatory Environment
Authors: Gray Simon M. , Moss Anh D. , Herzog Jeremy W. , Kashiwagi Saori , Liu Bo , Young Jacqueline B. , Sun Shan , Bhatt Aadra , Fodor Anthony A. , Sartor R. Balfour 
Published: January 2024

AbstractUnderstanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMAIl-10-/-mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipientIl-10-/-mice. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamedIl-10-/-host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant toIl-10-/-mice than the distinct microbiota reassembled in non-inflamed WT hosts. Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.
Discovery and engineering of the antibody response against a prominent skin commensal
Authors: Bousbaine Djenet , Bauman Katherine D. , Chen Y. Erin , Yu Victor K. , Lalgudi Pranav V. , Naziripour Arash , Veinbachs Alessandra , Phung Jennie L. , Nguyen Tam T.D. , Swenson Joyce M. , Lee Yue E. , Dimas Alex , Jain Sunit , Meng Xiandong , Pham Thi Phuong Thao , Zhao Aishan , Barkal Layla , Gribonika Inta , Van Rompay Koen K.A. , Belkaid Yasmine , Barnes Christopher O. , Fischbach Michael A. 
Published: January 2024

ABSTRACTThe ubiquitous skin colonistStaphylococcus epidermidiselicits a CD8+T cell response pre-emptively, in the absence of an infection1. However, the scope and purpose of this anti-commensal immune program are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable, and specific antibody response that is conserved in humans and non-human primates. A series ofS. epidermidiscell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain ofS. epidermidisin which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain ofS. epidermidisexpressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labeled commensal elicits high titers of antibody under conditions of physiologic colonization, including a robust IgA response in the nasal mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a novel form of topical vaccination.
Evaluation of Precision of thePlasmodium knowlesiGrowth Inhibition Assay forPlasmodium vivaxDuffy-Binding Protein-based Malaria Vaccine Development
Authors: Mertens Jonas E. , Rigby Cassandra A. , Bardelli Martino , Quinkert Doris , Hou Mimi M. , Diouf Ababacar , Silk Sarah E. , Chitnis Chetan E. , Minassian Angela M. , Moon Robert W. , Long Carole A. , Draper Simon J. , Miura Kazutoyo 
Published: January 2024

AbstractRecent data indicate increasing disease burden and importance ofPlasmodium vivax(Pv) malaria. A robust assay will be essential for blood-stagePvvaccine development. Results of thein vitrogrowth inhibition assay (GIA) with transgenicP. knowlesi(Pk) parasites expressing thePvDuffy-binding protein region II (PvDBPII) correlate within vivoprotection in the firstPvDBPII controlled human malaria infection (CHMI) trials, making thePkGIA an ideal selection tool once the precision of the assay is defined. To determine the precision in percentage of inhibition in GIA (%GIA) and in GIA50(antibody concentration that gave 50 %GIA), ten GIAs with transgenicPkparasites were conducted evaluating four different anti-PvDBPII human monoclonal antibodies (mAbs) at different concentrations, and three GIAs were conducted testing eighty anti-PvDBPII human polyclonal antibodies (pAbs) at 10 mg/mL. A significant assay-to-assay variation was observed, and the analysis revealed a standard deviation (SD) of 13.1 in the mAb and 5.94 in the pAb dataset for %GIA, with a LogGIA50SD of 0.299 (for mAbs). Moreover, the ninety-five percent confidence interval (95%CI) for %GIA or GIA50in repeat assays was calculated in this investigation. These results will support the development of future blood-stage malaria vaccines, specifically second generationPvDBPII-based formulations.
The bistable mitotic switch in fission yeast
Authors: Novák Béla , Tyson John J. 
Published: January 2024

AbstractIn most situations, eukaryotic cells proceed irreversibly through the cell division cycle (G1-S-G2-M) in order to produce two daughter cells with the same number and identity of chromosomes of their progenitor. The integrity of this process is maintained by ‘checkpoints’ that hold a cell at particular transition points of the cycle until all requisite events are completed. The crucial functions of these checkpoints seem to depend on irreversible bistability of the underlying checkpoint control systems. Bistability of cell cycle transitions has been confirmed experimentally in frog egg extracts, in budding yeast cells and in mammalian cells. For fission yeast cells, a recent paper by Patterson et al. (1) provides experimental evidence for an abrupt transition from G2 phase into mitosis, and we show that these data are consistent with a stochastic model of a bistable switch governing the G2/M checkpoint. Interestingly, our model suggests that their experimental data could also be explained by a reversible/sigmoidal switch, and stochastic simulations confirm this supposition. We propose a simple modification of their experimental protocol that could provide convincing evidence for (or against) bistability of the G2/M transition in fission yeast.
Development of Ingenui-T, a Novel Vein-to-Vein Solution for Rapid Autologous CAR T-Cell Manufacturing Starting From Whole Blood, for the Treatment of Autoimmune Diseases
Authors: Anaya Daniel , Kwong Brandon , Park Soo , Biswas Sunetra , Jeevan Jeevitha , Strobach Madison , Khoshnoodi Nicole , Register Ames , Klasson Timothy D , Foos-Russ Santiago , Zeng Jennifer , Banuelos Jesus , Gibson Candice , Bravo Jazmin , Flandez Jeanne , Van Blarcom Tom , Walker Karen 
Published: January 2024

ABSTRACTApheresis, a conventional starting point for manufacturing chimeric antigen receptor (CAR) T-cell therapy, poses challenges due to the length and invasiveness of the procedure, the high demand for and limited quantity of apheresis beds, and additional resource constraints at collection centers. Furthermore, traditional CAR T-cell manufacturing often involves extended cell culture periods, leading to a final product that has progressed through the differentiation process and contains a higher frequency of cells with phenotypes that are indicative of lower functionality or potency.1Here, we show that anti-CD19 CAR T-cells manufactured from fresh whole blood with minimal ex vivo expansion using Ingenui-T exhibit comparable or superior CAR-mediated and CD19-dependent functional activity compared to CAR T-cells manufactured from cryopreserved leukapheresis material following the a conventional manufacturing process. Anti-CD19 CAR T-cell production, manufactured from whole blood in less than 3 days of in vitro culture using Ingenui-T, yielded an average of about 40 million cells per 100 mL with high CD3 purity and viability. Furthermore, the final product was composed of cells with less differentiated phenotypes and sustained cytotoxic activity against CD19+target cells at a lower dose than conventionally manufactured CAR T cells in preclinical in vitro assays. Ingenui-T is an innovative vein-to-vein solution, aimed at enhancing the patient experience, feasibility, and accessibility of CAR T-cell therapy by alleviating challenges linked to apheresis-based methods, with its patient-friendly nature, cost-effectiveness, and distinctive methodology.
Biophysical Essentials – A Full Stack Open-Source Software Framework for Conserved and Advanced Analysis of Patch-Clamp Recordings
Authors: Zimmermann David , Kress Michaela , Zeidler Maximilian 
Published: January 2024

AbstractPatch-Clamp recordings allow for in depth electrophysiological characterization of single cells, their general biophysical properties as well as characteristics of voltage- and ligand-gated ionic currents. Different acquisition modes, such as whole-cell patch-clamp recordings in the current or voltage clamp configuration, capacitance measurements or single channel recordings from cultured cells as well as acute brain slices are routinely performed for these purposes. Nevertheless, multipurpose transparent and adaptable software tools to perform reproducible state-of-the-art analysis of multiple experiment types and to manage larger sets of experimental data are currently unavailable. We therefore developed Biophysical Essentials (BPE) as an open-source python software for transparent and reproducible analysis of electrophysiological recordings. While initially designed to improve time consuming and repetitive analysis steps, BPE was optimized to cover entire workflows from data acquisition, preprocessing, visualization and normalization of single recordings up to stacked calculations and statistics of multiple experiments. BPE can operate with different file formats from different amplifier systems and producers. An in-process database logs all analysis steps for later review and serves as a central storage point for recordings. Statistical testing as well as advanced analysis functions like Boltzmann-fitting and dimensional reduction methods further support the researchers’ needs in projects involving electrophysiology techniques.Impact statementBiophysical Essentials provides fundamental support for transparent patch-clamp analysis to improve reproducibility in electrophysiology research.
An inductive bias for slowly changing features in human reinforcement learning
Authors: Hedrich Noa L. , Schulz Eric , Hall-McMaster Sam , Schuck Nicolas W. 
Published: January 2024

AbstractIdentifying goal-relevant features in novel environments is a central challenge for efficient behaviour. We asked whether humans address this challenge by relying on prior knowledge about common properties of reward-predicting features. One such property is the rate of change of features, given that behaviourally relevant processes tend to change on a slower timescale than noise. Hence, we asked whether humans are biased to learn more when task-relevant features are slow rather than fast. To test this idea, 295 human participants were asked to learn the rewards of two-dimensional bandits when either a slowly or quickly changing feature of the bandit predicted reward. Across two experiments and one preregistered replication, participants accrued more reward when a bandit’s relevant feature changed slowly, and its irrelevant feature quickly, as compared to the opposite. We did not find a difference in the ability to generalise to unseen feature values between conditions. Testing how feature speed could affect learning with a set of four function approximation Kalman filter models revealed that participants had a higher learning rate for the slow feature, and adjusted their learning to both the relevance and the speed of feature changes. The larger the improvement in participants’ performance for slow compared to fast bandits, the more strongly they adjusted their learning rates. These results provide evidence that human reinforcement learning favours slower features, suggesting a bias in how humans approach reward learning.Author summaryLearning experiments in the laboratory are often assumed to exist in a vacuum, where participants solve a given task independently of how they learn in more natural circumstances. But humans and other animals are in fact well known to “meta learn”, i.e. to leverage generalisable assumptions abouthow to learnfrom other experiences. Taking inspiration from a well-known machine learning technique known as slow feature analysis, we investigated one specific instance of such an assumption in learning: the possibility that humans tend to focus on slowly rather than quickly changing features when learning about rewards. To test this, we developed a task where participants had to learn the value of stimuli composed of two features. Participants indeed learned better from a slowly rather than quickly changing feature that predicted reward. Computational modelling of participant behaviour indicated that participants had a higher learning rate for slowly changing features from the outset. Hence, our results support the idea that human reinforcement learning reflects a priori assumptions about the reward structure in natural environments.
Preparation of Matrix Product States with Log-Depth Quantum Circuits
Authors: Malz Daniel , Styliaris Georgios , Wei Zhi-Yuan , Cirac J. Ignacio 
Published: January 2024

We consider the preparation of matrix product states (MPS) on quantum devices via quantum circuits of local gates. We first prove that faithfully preparing translation-invariant normal MPS of N sites requires a circuit depth T=Ω(logN). We then introduce an algorithm based on the renormalization-group transformation to prepare normal MPS with an error ε in depth T=O[log(N/ε)], which is optimal. We also show that measurement and feedback leads to an exponential speedup of the algorithm to T=O[loglog(N/ε)]. Measurements also allow one to prepare arbitrary translation-invariant MPS, including long-range non-normal ones, in the same depth. Finally, the algorithm naturally extends to inhomogeneous MPS.

Published by the American Physical Society
2024