bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding and predicting ligand efficacy in the mu-opioid receptor through quantitative dynamical analysis of complex structures
Authors: Galdino Gabriel Tiago , Mailhot Olivier , Najmanovich Rafael
Published: January 2024

Theµ-opioid receptor (MOR) is a G-protein coupled receptor involved in nociception and is the primary target of opioid drugs. Understanding the relationships between ligand structure, receptor dynamics, and efficacy in activating MOR is crucial for drug discovery and development. Here, we use coarse-grained normal mode analysis to predict ligand-induced changes in receptor dynamics with the Quantitative Dynamics Activity Relationships (QDAR) DynaSig-ML methodology, training a LASSO regression model on the entropic signatures (ES) computed from ligand-receptor complexes. We train and validate the methodology using a dataset of 179 MOR ligands with experimentally measured efficacies split into strickly chemically different cross-validation sets. By analyzing the coefficients of the ES LASSO model, we identified key residues involved in MOR activation, several of which have mutational data supporting their role in MOR activation. Additionally, we explored a contacts-only LASSO model based on ligand-protein interactions. While the model showed predictive power, it failed at predicting efficacy for ligands with low structural similarity to the training set, emphasizing the importance of receptor dynamics for predicting ligand-induced receptor activation. Moreover, the low computational cost of our approach, at 3 CPU seconds per ligand-receptor complex, opens the door to its application in large-scale virtual screening contexts. Our work contributes to a better understanding of dynamics-function relationships in theµ-opioid receptor and provides a framework for predicting ligand efficacy based on ligand-induced changes in receptor dynamics.

Contact

rafael.najmanovich@umontreal.ca
Temperature-mediated dynamics: unraveling the impact of temperature on cuticular hydrocarbon profiles, mating behavior, and life history traits in threeDrosophilaspecies
Authors: Baleba Steve B. S. , Jiang Nan-Ji , Hansson Bill S.
Published: January 2024

In a world grappling with climate change, understanding the enduring impact of changes in temperature on insect adult traits is crucial. Here, we explored the intricate dynamics of exposure to different temperatures in threeDrosophilaspecies:Drosophila ezoanaoriginating in Arctic regions,D. novamexicanain arid, hot environments, and in the cosmopolitan speciesD. virilis. Rearing these flies at 15, 20, 25, and 30°C revealed striking variations in their cuticular hydrocarbon (CHC) profiles, known to mediate mate recognition and prevent water loss in insects. The cold-adaptedD. ezoanaconsistently exhibited reduced CHC levels with increasing temperatures, while the warm-adaptedD. novamexicanaand the cosmopolitanD. virilisdisplayed more nuanced responses. Additionally, we observed a significant influence of rearing temperature on the mating behavior of these flies, where those reared at the extreme tempreatures, 15 and 30°C, exhibiting reduced mating success. Consequently, this led to a decrease in the production of adult offspring. Also these adult offspring underwent notable alterations in life history traits, reaching adulthood more rapidly at 25 and 30°C but with lower weight and reduced longevity. Furthermore, among these offspring, those produced by the cold-adaptedD. ezoanawere more vulnerable to desiccation and starvation compared to those from the warm-adaptedD. novamexicanaand the cosmopolitanD. virilis. In summary, our research underscores the intricate interplay between temperature, ecological adaptation and various life history traits inDrosophilaspecies from distinct agro-ecological regions. The observed variations in CHC profiles, mating behavior, fertility and responses to environmental stressors collectively provide valuable insights into how environmental conditions shape the biology and ecology of insects.
Effects of mineral addition on the establishment of grazing lawns in a nutrient poor savanna
Authors: Schroder Bradley , Langevelde Frank Van , Schroder Nicola-Anne Hawkins , Prins Herbert H. T.
Published: January 2024

Nutrient poor savannas are often characterized by inedible or rarely palatable grasses, which generally provide poor nutrition for mammalian grazers. So-called grazing lawns, with short, stoloniferous edible grasses, could provide high-quality food for grazers, but these lawn grasses are rare in nutrient poor savannas. We tested whether we could use mineral addition to establish grazing lawns in a nutrient poor African savanna, in order to achieve a switch from tall, nutritionally poor to short, highly nutritional grass species. The key finding is that phosphorus and lime, nitrogen and nitrogen and lime supplementation resulted in shift from tall to short grasses within three years, with a higher overall nutrient concentration in the grass leaf, than without supplementation. When grazed, the cover of lawn grasses was higher compared to the other grasses when not grazed, demonstrating the role of grazers in maintaining and expanding lawn grass patches. We conclude that local fertilisation in nutrient poor savannas is a viable method of increasing mineral levels in the soil and grass leaf. We also concluded that grazing results in an increase in lawn grass cover and a combination of fertilisation and grazing can improve forage quality to ensure higher nutrient availability to herbivores.
A novel zebrafish-basedin vivomodel of Zika virus infection unveils NS4A as a key viral determinant of neuropathogenesis
Authors: Sow Aïssatou Aïcha , Jamadagni Priyanka , Scaturro Pietro , Patten Shunmoogum A. , Chatel-Chaix Laurent
Published: January 2024

Infection of pregnant women by Zika virus (ZIKV) is associated with severe neurodevelopmental defects in newborns through poorly defined mechanisms. Here, we engineered a zebrafishin vivomodel of ZIKV infection to circumvent limitations of existing mammalian models. Leveraging the unique tractability of this system, we gained unprecedented access to the ZIKV-infected brain at early developmental stages. The infection of zebrafish larvae with ZIKV phenocopied the disease in mammals including a reduced head area and neural progenitor cells (NPC) infection and depletion. Moreover, transcriptomic analyses of ZIKV-infected NPCs revealed a distinct dysregulation of genes involved in survival and neuronal differentiation, including downregulation of the expression of the glutamate transportervglut1, resulting in an altered glutamatergic network in the brain. Mechanistically, ectopic expression of ZIKV protein NS4A in the larvae recapitulated the morphological defects observed in infected animals, identifying NS4A as a key determinant of neurovirulence and a promising antiviral target for developing therapies.
Predicting Prolonged Length of Stay For Hospitalized Stroke Patients Using Common Physiological Features
Authors: Murphy Zachary , Ainsworth Michael , Gong Kirby , Zink Elizabeth K. , Greenstein Joseph L. , Winslow Raimond L. , Bahouth Mona N.
Published: January 2024

Background and Purpose

Stroke is a leading cause of death and disability worldwide. Predicting which patients are at risk for a prolonged length of stay (LOS) could assist in coordination of care and serve as a rough measure of clinical recovery trajectory. During the acute stroke period, there is a disruption in the fidelity of the blood-brain barrier and cerebral autoregulation, and we hypothesize that trends in physiologic parameters early in a patient’s hospital course may be used to predict which patients are increased risk for a prolonged LOS. In this work we sought to create a model to predict prolonged LOS (defined as ≥ 7 days) from patient data available at admission as well as routinely collected physiologic (pulse, blood pressure, respiratory rate, temperature), and other data from the first 24 hours of admission.

Methods

This retrospective cohort study included stroke patients admitted to an urban comprehensive stroke center between 2016-2019. Data included common physiological parameters (pulse, temperature, blood pressure, respirations, and oxygen saturation) as well as demographic and comorbidity data. Raw time series data were transformed into statistical features for modeling. Logistic regression, random forest, and XGBoost models were trained on data collected during the first 24 hours after hospital admission to predict prolonged LOS and evaluated on a held-out test set.

Results

A total of 2,025 patients were included. Using an XGBoost classifier we obtained a ROC AUC of 0.85 and Precision-Recall AUC of 0.77, with the optimal operating point achieving an accuracy of 0.80, sensitivity of 0.78, specificity of 0.81.

Conclusions

The model suggests that prolonged LOS can be predicted with reasonable accuracy using clinical data obtained within the first 24 hours of hospitalization. This approach could provide the basis for development of a risk score and augment the care coordination process.
edgeR v4: powerful differential analysis of sequencing data with expanded functionality and improved support for small counts and larger datasets
Authors: Chen Yunshun , Chen Lizhong , Lun Aaron T. L. , Baldoni Pedro L. , Smyth Gordon K.
Published: January 2024

edgeR is an R/Bioconductor software package for differential analyses of sequencing data in the form of read counts for genes or genomic features. Over the past 15 years, edgeR has been a popular choice for statistical analysis of data from sequencing technologies such as RNA-seq or ChIP-seq. edgeR pioneered the use of the negative binomial distribution to model read count data with replicates and the use of generalized linear models to analyse complex experimental designs. edgeR implements empirical Bayes moderation methods to allow reliable inference when the number of replicates is small. This article announces edgeR version 4, which includes new developments across a range of application areas. Infrastructure improvements include support for fractional counts, implementation of model fitting in C, and a new statistical treatment of the quasi-likelihood pipeline that improves accuracy for small counts. The revised package has new functionality for differential methylation analysis, differential transcript expression, differential transcript and exon usage, testing relative to a fold-change threshold and pathway analysis. This article reviews the statistical framework and computational implementation of edgeR, briefly summarizing all the existing features and functionalities but with special attention to new features and those that have not been described previously.
Changes in spectral signature of leaves after desiccation: Implications for the prediction of leaf traits and plant-soil interaction in herbarium samples
Authors: Quinteros Casaverde Natalia L. , Serbin Shawn P. , Daly Douglas C.
Published: January 2024

The study investigated the impact of specimen desiccation on spectral signatures of plant tissue and its influence on models predicting biochemical and physiological traits, as well as ecosystem function.

Analyzing 56 species, this study quantified the impact of leaf desiccation on: (1) the degree of change in the reflectance intensity, and its first and second derivatives within the visible - shortwave infrared spectrum, (2) the difference in change between wavebands used by Radiative Transfer Models (RTMs) for predicting traits in fresh leaves, (3) the prediction of leaf traits using PROSPECT RTM, and (4) the prediction of soil nutrient components from the leaf.

Comparing desiccated specimens to fresh leaves, this study found the highest degree of change within the near infrared for the reflectance intensity, its first and second derivatives. Specific wavebands used for the prediction of leaf traits changed less that others in the VIS-SWIR. The prediction uncertainty for PROSPECT RTM differed for various leaf traits, showing an increase for equivalent water thickness, and carotene content, and a decrease in brown pigments and dry mass. Leaf traits predicted from desiccated leaves were better at predicting relationships with soil components, such as soil chemical properties and macro and micronutrients than fresh leaves.

Desiccated leaves preserve and improves the capacity to inform us about important aspects of ecosystem functioning, particularly nutrient transfer between leaf and soil.
STAR+WASP reduces reference bias in the allele-specific mapping of RNA-seq reads
Authors: Asiimwe Rebecca , Alexander Dobin
Published: January 2024

Allele-specific expression (ASE) is an important genetic phenomenon that impacts an individual’s phenotype and is relevant in various biological and medical contexts. Next-generation RNA sequencing technologies provide an unprecedented opportunity to measure ASE genome-wide across all heterozygous alleles expressed in a given sample. One of the major obstacles to the accurate calculation of ASE from RNA-seq data is the reference mapping bias, i.e., the preferential misalignment of the reads to the reference allele. Here, we present STAR+WASP, our reimplementation of WASP, a highly accurate algorithm for reducing the reference bias (Van De Geijnet al. 2015). We show that STAR+WASP is an order of magnitude faster than WASP while significantly reducing reference bias and providing ASE estimations similar to the original WASP algorithm.

Availability and Implementation

STAR+WASP is implemented within STAR as an integrated C++ module. STAR+WASP is open-source software, freely accessible at:http://code.google.com/p/rna-star/.

Contact

dobin@cshl.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinoma
Authors: Meisel Christian T. , Destefani Riccardo , Valookkaran Ilaria J. , Batavia Aashil , Rupp Niels , Porcheri Cristina , Mitsiadis Thimios A.
Published: January 2024

The Notch signaling pathway is frequently altered in oral squamous cell carcinoma (OSCC), the most common malignant neoplasm of the oral mucosa. This study aimed to elucidate the functional role of this pathway in both the initiation and progression of OSCC. Using transgenic animal models, advanced imaging, and next-generation-sequencing techniques, we analyzed Notch-dependent changes driving OSCC. We found specific expression patterns of Notch1 and Delta-like-4 confined to the malignant tissue, while Jagged1 was downregulated in OSCC. This mutually exclusive expression of Delta-like-4 and Jagged1 occurs at the early hyperplastic stage and persists until more advanced stages of the developing tumor. Transcriptomic analyses confirmed the dysregulation of the Notch pathway circuitry and of the genes associated with the undifferentiated state of OSCC cells. Furthermore, pharmacological Notch inhibition significantly impaired cancer cell motility. Taken together, these results reveal the pivotal importance of the Notch1/Delta-like-4 signaling axis as a central oncogenic driver in OSCC.

Graphical Abstract
New peptides against B16F10 interfere in cell cycle of melanoma cells
Authors: Xavier Eric Almeida
Published: January 2024

Peptides have fantastic functions, they can act interfering in various cellular mechanisms such as the cell cycle. Furthermore, because of their high specificity, peptides can be used in antitumor therapy against specific targets. In this work we describe thein vitroaction of four antitumor peptide against B16F10 melanoma cells, obtained from immunoglobulin genes. As a result, we show that peptides interfered in the cell cycle of B16F10 cells. In conclusion the present article describes a molecule from immunoglobulin with future potential forin vivotherapeutic test.
REPrise:de novointerspersed repeat detection using inexact seeding
Authors: Takeda Atsushi , Nonaka Daisuke , Imazu Yuta , Fukunaga Tsukasa , Hamada Michiaki
Published: January 2024

Motivation

Interspersed repeats occupy a large part of many eukaryotic genomes, and thus their accurate annotation is essential for various genome analyses. Database-freede novorepeat detection approaches are powerful for annotating genomes that lack well-curated repeat databases. However, existing tools do not yet have sufficient repeat detection performance.

Results

In this study, we developed REPrise, ade novointerspersed repeat detection software program based on a seed-and-extension method. Although the algorithm of REPrise is similar to that of RepeatScout, which is currently the de facto standard tool, we incorporated three unique techniques into REPrise: inexact seeding, affine gap scoring and loose masking. Analyses of rice and simulation genome datasets showed that REPrise outperformed RepeatScout in terms of sensitivity, especially when the repeat sequences contained many mutations. Furthermore, when applied to the complete human genome dataset T2T-CHM13, REPrise demonstrated the potential to detect novel repeat sequence families.

Availability

The source code of REPrise is freely available athttps://github.com/hmdlab/REPrise. Repeat annotations predicted for the T2T genome using REPrise are also available athttps://waseda.box.com/v/REPrise-data.

Contact

fukunaga@aoni.waseda.jpandmhamada@waseda.jp
WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer
Authors: Modekurty Suneeta
Published: January 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to changes in the work. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Parental migration, socioeconomic deprivation and hospital admissions in preschool children: national cohort study
Authors: Lewis Kate M , Burns Rachel , Cortina-Borja Mario , Heilmann Anja , Macfarlane Alison , Nath Selina , Salway Sarah , Saxena Sonia , Villarroel-Williams Nazmy , Viner Russell , Hardelid Pia
Published: January 2024

Background

A third of children born in England have at least one parent born outside the UK, yet family migration history is infrequently studied as a social determinant of child health. We describe differences in rates of hospital admissions in children aged up to five years by parental migration and socioeconomic group.

Methods

Birth registrations linked to Hospital Episode Statistics were used to derive a cohort of 4,174,596 children born in state-funded hospitals in England between 2008 and 2014, with follow-up until age five years. We looked at eight maternal regions of birth, maternal country of birth for the 6 most populous groups and parental migration status for the mother and second parent (UK-born/non-UK-born). We used Index of Multiple Deprivation (IMD) quintiles to indicate socioeconomic deprivation. We fitted negative binomial/Poisson regression models to model associations between parental migration groups and the risk of hospital admissions, including interactions with IMD group.

Findings

Children of UK-born (73.6% of the cohort) mothers had the highest rates of emergency admissions (171.6 per 1000 child-years, 95% confidence interval (CI) 171.4-171.9), followed by South Asia-born mothers (155.9 per 1000, 95% CI 155.1-156.7). The high rates estimated in the South Asia group were driven by children of women born in Pakistan (186.8 per 1000, 95% CI 185.4, 188.2). A socioeconomic gradient in emergency admissions was present across all maternal region of birth groups, but most pronounced among children of UK-born mothers (incidence rate ratio 1.43, 95% CI 1.42-1.44, high vs. low IMD group). Overall, children whose parents were both born abroad had lower emergency admission rates than children whose parents were both born in the UK. Patterns of planned admissions followed a similar socioeconomic gradient and were highest among children with mothers born in Middle East and North Africa, and South Asia.

Interpretation

This research indicates that children whose parents who have migrated to the UK generally have lower overall usage of NHS emergency inpatient services than children of UK-born parents. Our study revealed a socioeconomically graded patterns of hospital admissions for all children born in England, which were highest amongst those with mothers born in the UK, South Asia, and the Middle East and North Africa. Future research using linked primary and secondary care datasets will improve understanding on whether healthcare use is proportionate to need.

Funding

National Institute for Health Research.
Exploring the discrepancies between clinical trials and real-world data by accounting for Selection criteria, Operations, and Measurements of Outcome
Authors: Marzano Luca , Darwich Adam S. , Dan Asaf , Tendler Salomon , Lewensohn Rolf , De Petris Luigi , Raghothama Jayanth , Meijer Sebastiaan
Published: January 2024

The potential of real-world data to inform clinical trial design and supplement control arms has gained much interest in recent years. The most common approach relies on reproducing control arm outcomes by matching real-world patient cohorts to clinical trial baseline populations. However, recent studies pointed out that there is a lack of replicability, generalisability, and consensus. Further, few studies consider differences in operational processes. Discovering and accounting for confounders, including hidden effects related to the treatment process and clinical trial study protocol, would potentially allow for improved translation between clinical trials and real-world data. In this paper, we propose an approach that aims to explore and examine these confounders by investigating the impact of selection criteria and operations on the measurements of outcome. We tested the approach on a dataset consisting of small cell lung cancer patients receiving platinum-based chemotherapy regimens from a real-world data cohort (n=223) and six clinical trial control arms (n=1,224). The results showed that the discrepancy between real-world and clinical trial data potentially depends on differences in both patient populations and operational conditions (e.g., frequency of assessments, and censoring), for which further investigation is required. The outcomes of this work suggest areas of improvement for systematically exploring and accounting for differences in outcomes between study cohorts. Continued development of the method presented here could pave the way for transferring learning across clinical studies and developing mutual translation between the real-world and clinical trials to inform clinical study design.
Mortality according to gender identity and sexual orientation: Data relationship strategies for Rio de Janeiro, Brazil
Authors: Rafael Ricardo de Mattos Russo , Silva Kleison Pereira da , Santos Helena Gonçalves de Souza , Depret Davi Gomes , Caravaca-Morera Jaime Alonso , Breda Karen Marie Lucas
Published: January 2024

Objective

To evaluate the accuracy, potential, and limits of probabilistic data relationships to yield information on deaths according to sex identity and sexual orientation in the state of Rio de Janeiro.

Methods

This study evaluated the accuracy of the probabilistic relationship of data to obtain information on deaths according to gender and sexual orientation. Data from two information systems were used from June 15, 2015 to December 31, 2020. We constructed nine probabilistic data relationship strategies and identified the performance and cutoff points of the best strategy.

Results

The best data blocking strategy was established through logical blocks with the first and last names, birthdate, and mother’s name in the pairing strategy. With a population base of 80,178 records, 1556 deaths were retrieved. With an area under the curve of 0.979, this strategy presented 93.26% accuracy, 98.46% sensitivity, and 90.04% specificity for the cutoff point ≥ 17.9 of the data relationship score. The adoption of the cutoff point optimized the manual review phase, identifying 2259 (90.04%) of the 2509 false pairs and identifying 1532 (98.46%) of the 1556 true pairs. A crude mortality rate of 19.11 deaths per 1,000 people was observed, where women who had sex with women, transvestites, and transgender women had higher mortality rates than heterosexual cisgender women. Neither men nor men with gender markers had higher mortality rates than heterosexual cisgender women.

Conclusion

With the identification of possible strategies for determining probabilistic data relationships, the retrieval of information on mortality according to sexual and sex markers has become feasible. Based on information from the daily routine of health services, the formulation of public policies that consider the LGBT+ population more closely reflects the reality experienced by these population groups.
The changes of BMI in prediction of 10-year-hypertension risk in United States population- a historical cohort study
Authors: Zou Haoxuan , Wang Chumeng , Sun Wei , Kong Xiangqing , Jiang Ming , Zou Huayiyang
Published: January 2024

BACKGROUND

This is a historical cohort study, utilizing data from the US National Health and Nutrition Examination Survey (NHANES) 2007-2018 to predict 10-year- hypertension-risk based on body mass index (BMI) variations.

METHOD

Participants aged 40-79 without a hypertension diagnosis 10 years before the baseline interview were included. Subjects were categorized based on five major BMI variation patterns. Various statistical analyses, including Chi-square test, T test, univariate and multivariate logistic regression, and P-trend analysis, were employed to assess hypertension incidence among groups. Restricted cubic splines (RCS) were used to examine the age-hypertension correlation.

RESULTS

Among 13,287 participants, Stable-Norm (maintaining normal BMI) exhibited the lowest 10-year hypertension risk. Other patterns—Max-OW (maximum BMI in overweight), OB-nOB (obese to non-obese), nOB-OB (non-obese to obese), and Stable-OB (maintaining obese)—showed increasing risks. Hypertension risk correlated quasi-linearly with age. Subgroups analysis suggested certain specific BMI variation modes and absolute weight change groups demonstrated equivalent risks to stable normal/weight groups, while others presented higher risks.

CONCLUSION

Maintaining normal BMI had the lowest 10-year hypertension risk, and returning to normal BMI showed equivalent risk. Weight gain remained a significant hypertension risk factor in US adults, particularly with advancing age.
IL-17A/IFN-γ producing γδ T cell functional dichotomy impacts cutaneous leishmaniasis in mice
Authors: dos-Santos Júlio Souza , Firmino-Cruz Luan , Oliveira-Maciel Diogo , da Fonseca-Martins Alessandra Marcia , Ramos Tadeu Diniz , Nunes-Souza Letícia , Soares Rodrigo Pedro , Gomes Daniel Claudio Oliveira , Mengel José , Silva-Santos Bruno , de Matos Guedes Herbert Leonel
Published: January 2024

γδ T cells are innate-like lymphocytes with pleiotropic roles in immune responses to pathogens, often ascribed to their IL-17A-producing or IFN-γ-producing γδ T cell subsets. Here we investigated the impact of this functional dichotomy on cutaneous leishmaniasis, a set of neglected diseases caused by parasites of theLeishmaniagenus. We demonstrate that in Sv129 mice susceptible toLeishmania amazonensis, Vγ4+γδ T cells are the main source of IL-17A. Furthermore, in type 1 interferon receptor-deficient (A129) mice presenting increased susceptibility to infection, there is a higher frequency of IL-17A-producing γδ T cells when compared to wild-type mice. Mechanistically, we demonstrate that lipophosphoglycan (LPG) ofL. amazonensisinduces IL-17A-producing γδ T cells. Importantly, C57Bl/6 mice deficient in γδ T cells or in IL-17 receptor (IL-17RA) show reduced lesion sizes, consistent with a pathogenic role of IL-17A-producing γδ T cells in cutaneous leishmaniasis. Conversely, the adoptive transfer of FACS-sorted γδ T cells led to an accumulation of IFN-γ-producing γδ T cells in various susceptible strains of mice which associated with control of lesion development. These data demonstrate a pathophysiological dichotomy in which IL-17A-producing γδ T cells promote pathogenesis, whereas IFN-γ-producing γδ T cells display therapeutic potential in cutaneous leishmaniasis.
Genome-informed trophic classification and functional characterization of virulence proteins from the maize tar spot pathogenPhyllachora maydis
Authors: Rogers Abigail , Jaiswal Namrata , Roggenkamp Emily , Kim Hye-Seon , MacCready Joshua S. , Chilvers Martin I. , Scofield Steven R. , Iyer-Pascuzzi Anjali S. , Helm Matthew
Published: January 2024

Phyllachora maydisis an ascomycete foliar fungal pathogen and the causal agent of tar spot in maize. ThoughP. maydisis considered one of the most economically important foliar pathogens of maize, our general knowledge of the trophic lifestyle and functional role of effector proteins from this fungal pathogen remains limited. Here, we utilized a genome-informed approach to predict the trophic lifestyle ofP. maydisand functionally characterized a subset of candidate effectors from this fungal pathogen. Leveraging the most recentP. maydisgenome annotation and the CATAStrophy pipeline, we show this fungal pathogen encodes a predicted Carbohydrate-active enzymes (CAZymes) repertoire consistent with that of biotrophs (monomertrophs). To investigate fungal pathogenicity, we selected eighteen candidate effector proteins that were previously shown to be expressed during primary disease development. We assessed whether these putative effectors share predicted structural similarity with other characterized fungal effectors and determined whether any suppress plant immune responses. Using AlphaFold2 and Foldseek, we showed one candidate effector, PM02_g1115, adopts a predicted protein structure similar to that of an effector fromVerticillium dahlia. Furthermore, transient expression of candidate effector-fluorescent protein fusions inNicotiana benthamianarevealed that most effector proteins localize to both the nucleus and the cytosol. Importantly, three candidate effectors consistently attenuated chitin-mediated reactive oxygen species production inN. benthamiana. Collectively, these results presented herein provide valuable insights into the predicted trophic lifestyle and putative functions of effectors fromP. maydisand will likely stimulate continued research to elucidate the molecular mechanisms used byP. maydisto induce tar spot.
Treatment effects in epilepsy: a mathematical framework for understanding response over time
Authors: Harrington Gwen , Kissack Peter , Terry John R. , Woldman Wessel , Junges Leandro
Published: January 2024

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting over 65 million people worldwide. Treatment typically commences with the use of anti-seizure medications, both mono- and poly-therapy. However more invasive therapies such as surgery, electrical stimulation and focal drug delivery may also be considered in an attempt to render the person seizure free. Although a significant portion ultimately benefit from these treatment options, treatment responses often fluctuate over time.The physiological mechanisms underlying these temporal variations are poorly understood, making prognosis one of the biggest challenges for treating epilepsy. In this work, we use a dynamic network model of seizure transition to understand how seizure propensity may vary over time as a consequence of changes in excitability. Through computer simulations, we explore the relationship between the impact of treatment on dynamic network properties and their vulnerability over time that permit a return to states of high seizure propensity. We show that, for small networks, vulnerability can be fully characterised by the size of the first transitive component (FTC). For larger networks, we find measures of network efficiency, incoherence and heterogeneity (degree variance) correlate with robustness of networks to increasing excitability. These results provide a set of potential prognostic markers for therapeutic interventions in epilepsy. Such markers could be used to support the development of personalized treatment strategies, ultimately contributing to understanding of long-term seizure freedom.
Identification of a Binding Site for Small Molecule Inhibitors Targeting Human TRPM4
Authors: Ekundayo Babatunde , Arullampalam Prakash , Gerber Christian E. , Hämmerli Anne-Flore , Guichard Sabrina , Boukenna Mey , Ross-Kaschitza Daniela , Lochner Martin , Rougier Jean-Sebastien , Stahlberg Henning , Abriel Hugues , Ni Dongchun
Published: January 2024

Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determined three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and a new anthranilic acid derivative, IBA. We found that the small molecules NBA and IBA were bound in a pocket formed between the S3, S4, and TRP helices and the S4-S5 linker of TRPM4. Our structural data and results from patch clamp experiments enable validation of a binding site for small molecule inhibitors, paving the way for further drug development targeting TRPM4.
Redox-dependent formation of a viral amyloid and functional impact
Authors: Gondelaud Frank , Lalande Alexandre , Pesce Giulia , Bignon Christophe , Fourquet Patrick , Ptchelkine Denis , Brouilly Nicolas , Lozach Pierre-Yves , Gerlier Denis , Mathieu Cyrille , Longhi Sonia
Published: January 2024

The Hendra and Nipah viruses (HeV and NiV) are zoonotic biosafety level-4 pathogens within theParamyxoviridaefamily. We previously showed that their W proteins form amyloid-like fibrilsin vitro. Here, we demonstrate that W also forms fibrilsin cellulaand that cysteine residues are crucial in dictating the ability of W proteins to fibrillate. The cysteine oxidation state acts as a switch to generate either amorphous aggregates or flexible fibrils. Ectopic expression of WHeVinduces an oxidative stress and WHeVfibrils were observed in the nuclei of different cell lines, with fibrillation being impaired by cysteine substitutions. Finally, nuclear fibrils are associated with an impairment of the NF-κB pathway in WHeVtransfected cells. This work provides experimental evidence for the ability ofHenipavirusW proteins to fibrillate in transfected cells and the first clues on their functional impact.

Significance Statement

Nipah and Hendra viruses are severe pathogens infecting humans and livestock, classified among the 8 highest priorities for research by the WHO. The W protein, along with the V protein, is a virulence factor responsible for antiviral response inhibition and we demonstrate here that its fibrillation into amyloid-like fibrils occurs in the nucleus of transfected cells, with their formation being dependent of the redox state of the W cysteine residues. The sole transfection of W provokes the production of reactive oxygen species, creating a suitable environment for the fibrils to form. Finally, we show that W fibrils enhance the repression of the antiviral response, thus pointing to W fibrillation as a new promising antiviral target.
Molecular mechanism of β-arrestin-2 interaction with phosphatidylinositol 4,5-bisphosphate
Authors: Kim Kiae , Chung Ka Young
Published: January 2024

Phosphorylated residues of G protein-coupled receptors bind to the N-domain of arrestin, resulting in βXX release. This induces further allosteric conformational changes, such as polar core disruption, alteration of interdomain loops, and domain rotation, which transform arrestins into the active state. It is widely accepted that arrestin activation occurs by conformational changes propagated from the N-to the C-domain. However, recent studies have revealed that binding of phosphatidylinositol 4,5-bisphosphate (PIP2) to the C-domain transforms arrestins into an active state. In this study, we aimed to elucidate the mechanisms underlying PIP2-induced arrestin activation. We compared the conformational changes of β-arrestin-2 upon binding of PIP2or phosphorylated C-tail peptide of vasopressin receptor type 2 using hydrogen/deuterium exchange mass spectrometry (HDX-MS). Introducing point mutations on the potential routes of the allosteric conformational changes and analyzing these mutant constructs with HDX-MS revealed that PIP2-binding at the C-domain affects the back loop, which destabilizes the gate loop and βXX to transform β-arrestin-2 into the pre-active state.
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

Wall 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

SARS-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

We 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

Despite 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

Understanding 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.