bluuebunny/crossref_metadata_2025_split huggingface dataset:
S100a9 Attenuates Inflammation during Repeated Social Defeat Stress
Authors: Moshfegh Cassandra M. , Elkhatib Safwan K. , Watson Gabrielle F. , Drake John , Taylor Zachary N. , Reed Emily C. , Lauten Tatlock H. , Clopp Amelia J. , Vladimirov Vladimir I. , Case Adam J. 
Published: July 2022

AbstractPost-traumatic stress disorder (PTSD), a consequence of psychological trauma, is associated with increased inflammation and an elevated risk of developing comorbid inflammatory diseases. However, the mechanistic link between this mental health disorder and inflammation remains elusive. Using a pre-clinical model of PTSD known as repeated social defeat stress (RSDS), we previously identified that S100a8 and S100a9 mRNA, genes that encode the protein calprotectin, were significantly upregulated in T-lymphocytes after psychological trauma. Calprotectin expression positively correlated with inflammatory gene expression and the mitochondrial redox environment in T-lymphocytes, therefore, we hypothesized that genetic deletion of calprotectin would attenuate the inflammatory and redox phenotype displayed after RSDS. Using pharmacological and genetic manipulation of S100a9 (which functionally eliminates calprotectin) in mice, we unexpectedly observed worsening of behavioral pathology, inflammation, and the mitochondrial redox environment in mice after RSDS compared to wild-type (WT) animals. Furthermore, loss of calprotectin significantly enhanced the metabolic demand on T-lymphocytes suggesting this protein may play an undescribed role in mitochondrial regulation. This was further supported by single-cell RNA sequencing analysis demonstrating that RSDS and loss of S100a9 primarily altered genes associated with mitochondrial function and oxidative phosphorylation. Taken together, these data demonstrate the loss of calprotectin potentiates the RSDS-induced phenotype, which suggests its observed upregulation after psychological trauma may provide previously unexplored protective functions.
A resistome survey across hundreds of freshwater bacterial communities reveals the impacts of veterinary and human antibiotics use
Authors: Kraemer SA , Barbosa da Costa N , Oliva A , Huot Y , Walsh DA 
Published: July 2022

AbstractOur decreasing ability to fight bacterial infections is a major health concern. It is arising due to the evolution of antimicrobial resistance (AMR) in response to the mis- and overuse of antibiotics in both human and veterinary medicine. Lakes integrate watershed processes and thus may act as receptors and reservoirs of antibiotic resistance genes (ARGs) introduced into the watershed by human activities. The resistome - the diversity of ARGs – under varying anthropogenic watershed pressures has been previously studied either focused on few select genes or few lakes. Here, we link the resistome of ∼350 lakes sampled across Canada to human watershed activity, trophic status, as well as point sources of ARG pollution. A high percentage of the resistance genes detected was either unimpacted by human activity or highly prevalent in pristine lakes, highlighting the role of AMR in microbial ecology in aquatic systems, as well as a pool of genes available for potential horizontal gene transfer to pathogenic species. Nonetheless, watershed agricultural and pasture area significantly impacted the resistome. Moreover, the number of hospitals and the population density in a watershed, the volume of wastewater entering the lake, as well as the fraction of manure applied in the watershed as fertilizer significantly impacted ARG diversity. Together, these findings indicate that lake resistomes are regularly stocked with resistance genes evolved in the context of both veterinary and human antibiotics use and represent reservoirs of ARGs that require further monitoring.
Event integration and temporal differentiation: how hierarchical knowledge emerges in hippocampal subfields through learning
Authors: Bein Oded , Davachi Lila 
Published: July 2022

AbstractEveryday life is composed of events organized by changes in contexts, with each event containing an unfolding sequence of occurrences. A major challenge facing our memory systems is how to integrate sequential occurrences within events while also maintaining their details and avoiding over-integration across different contexts. Here we asked if and how distinct hippocampal subfields come to hierarchically, and in parallel, represent both event context and subevent occurrences with learning. Participants viewed sequential events defined as sequences of objects superimposed on shared color frames while undergoing high-resolution fMRI. Importantly, these events were repeated to induce learning. Event segmentation, as indexed by increased reaction times at event boundaries, was observed in all repetitions. Temporal memory decisions were quicker for items from the same event compared to across different events, indicating that events shaped memory behavior. With learning, hippocampal CA3 multivoxel activation patterns clustered to reflect the event context, with more clustering correlated with behavioral facilitation during event transitions. In contrast, in the dentate gyrus temporally proximal items that belonged to the same event became associated with more differentiated neural patterns. A computational model explained these results by dynamic inhibition in the dentate gyrus. Additional similarity measures support the notion that CA3 clustered representations reflect shared voxel populations, while dentate gyrus’ distinct item representations reflect different voxel populations. These findings suggest an interplay between temporal differentiation in dentate gyrus and attractor dynamics in CA3. They advance our understanding of how knowledge is structured through integration and separation across time and context.SignificanceA major challenge of our memory system is to integrate experiences occurring in the same context to generalize context-appropriate knowledge, while also maintaining distinct representations of these same occurrences to avoid confusion. Here, we uncover a novel mechanism for hierarchical learning in the human hippocampus that might help to resolve this tension. In the CA3 subregion of the hippocampus, the neural representations of items presented sequentially in the same context, but not in different contexts, became more overlapping with learning. In contrast, adjacent items, appearing close in time and in the same context, became increasingly more differentiated in the dentate gyrus. Thus, multiple representations in different hippocampal subregions encoded in parallel might enable simultaneous generalization and specificity in memory.
Fractionating distraction: how past- and future-relevant distractors influence integrated decisions
Authors: Barnes Lydia , Rangelov Dragan , Mattingley Jason B. , Woolgar Alexandra 
Published: July 2022

AbstractMany everyday tasks require us to integrate information from multiple steps to make a decision. Dominant accounts of flexible cognition suggest that we are able to navigate such complex tasks by attending to each step in turn, yet few studies measure how we direct our attention to immediate and future task steps. Here, we used a two-step task to test whether participants are sensitive to information that is currently irrelevant, but will be relevant in a future task step. Participants viewed two displays in sequence, each containing two superimposed moving dot clouds of different colours. Participants attended to one cued target colour in each display and reported the average direction of the two target dot clouds. In a subset of trials, we presented a “decoy” distractor: the second target colour appeared as the distractor in the first display. We regressed behavioural responses on the dot clouds’ motion directions to track how this future-relevant “decoy” distractor influenced participants’ reporting of the average target direction. We compared the influence of decoy distractors to never-relevant, recently relevant, and globally relevant distractor baselines. Across four experiments, we found that responses reflected what was immediately relevant, as well as the broader historical relevance of the distractors. However, relevance for a future task step did not reliably influence attention. We propose that attention in multi-step tasks is shaped by what has been relevant in the current setting, and by the immediate demands of each task step.Public SignificanceOur everyday functioning depends on our ability to piece together information to make coherent decisions. Understanding how we efficiently select and integrate goal-relevant information is critical if we wish to anticipate how decision-making can go wrong, whether because of fatigue, mental load, or illness. This study shows that decisions in multi-step tasks reflect two distinct processes: narrow focus on what is relevant in each step, alongside broader awareness of what has been relevant in this setting.
Cross-Modality and Self-Supervised Protein Embedding for Compound–Protein Affinity and Contact Prediction
Authors: You Yuning , Shen Yang 
Published: July 2022

AbstractMotivationComputational methods for compound–protein affinity and contact (CPAC) prediction aim at facilitating rational drug discovery by simultaneous prediction of the strength and the pattern of compound–protein interactions. Although the desired outputs are highly structure-dependent, the lack of protein structures often makes structure-free methods rely on protein sequence inputs alone. The scarcity of compound–protein pairs with affinity and contact labels further limits the accuracy and the generalizability of CPAC models.ResultsTo overcome the aforementioned challenges of structure naivety and labelled-data scarcity, we introduce cross-modality and self-supervised learning, respectively, for structure-aware and task-relevant protein embedding. Specifically, protein data are available in both modalities of 1D amino-acid sequences and predicted 2D contact maps, that are separately embedded with recurrent and graph neural networks, respectively, as well as jointly embedded with two cross-modality schemes. Furthermore, both protein modalities are pretrained under various self-supervised learning strategies, by leveraging massive amount of unlabelled protein data. Our results indicate that individual protein modalities differ in their strengths of predicting affinities or contacts. Proper cross-modality protein embedding combined with self-supervised learning improves model generalizability when predicting both affinities and contacts for unseen proteins.AvailabilityData and source codes are available at https://github.com/Shen-Lab/CPAC.Contactyshen@tamu.eduSupplementary informationSupplementary data are included.
Cumulative incidence of SARS-CoV-2 infection in the general population of the Valencian Community (Spain) after the surge of the Omicron BA.1 variant
Authors: Camacho Jorge , Giménez Estela , Albert Eliseo , Zulaica Joao , Álvarez-Rodríguez Beatriz , Torres Ignacio , Rusu Luciana , Burgos Javier S. , Peiró Salvador , Vanaclocha Hermelinda , Limón Ramón , Jesús Alcaraz María , Sánchez-Payá José , Díez-Domingo Javier , Comas Iñaki , Gonzáles-Candelas Fernando , Geller Ron , Navarro David 
Published: July 2022

SUMMARYBackgroundStudies investigating the cumulative incidence of and immune status against SARS-CoV-2 infection provide valuable information for shaping public health decision-making.MethodsThe current cross-sectional, population-based study, conducted in April 2022 in the Valencian Community (VC), recruited 935 participants of all ages. Anti-SARS-CoV-2-Receptor Binding Domain-RBD-total antibodies and anti-Nucleocapsid (N)- IgGs were measured by electrochemiluminescence assays. To account for past SARS-CoV-2 infection the VC microbiology registry (RedMiVa) was interrogated. |Quantitation of neutralizing antibodies (NtAb) against the ancestral and Omicron BA.1 and BA.2 (sub)variants by an S-pseudotyped neutralization assay and for enumeration of SARS-CoV-2-S specific-IFNγ-producing CD4+ and CD8+ T cells by Intracellular Cytokine Staining assay was performed in a subset of participants (n=100 and 137, respectively).FindingsThe weighted cumulative incidence was 51□9% (95% CI, 48□7–55□1), and was inversely related to age. Anti-RBD total antibodies were detected in 906/931 (97□3%) participants, those vaccinated and SARS-CoV-2-experienced (VAC-ex;=442) displaying higher levels (P<0.001) than vaccinated/naïve (VAC-n;(n=472) and non-vaccinated/experienced (UNVAC-ex; n(n=63). Antibody levels correlated inversely with the time elapsed since receipt of last vaccine dose in VAC-n (Rho, -0□52; 95% CI, -0□59 to -0□45; P<0.001) but not in VAC-ex. NtAbs against Omicron BA.1 were detected in 94%, 75% and 50% of VAC-ex, VAC-n and UNVAC-ex groups, respectively, while in 97%, 84% and 40%, against Omicron BA.2. SARS-CoV-2-S-reactive IFN-γ T cells were detected in 73%, 75%, and 64% for VAC-ex, VAC-n, UNVAC-ex, respectively.InterpretationBy April 2022 around half of the VC population had been infected with SARS-CoV-2 and due to extensive vaccination display hybrid immunity. The large percentage of participants with detectable functional antibody and T-cell responses against SARS-CoV-2, which may be cross-reactive to some extent, points towards lower expected severity than in previous waves.FundingThis research was supported in part by the European Commission NextGenerationEU fund (CSIC’s Global Health Platform).
Menstrual cycle and exogenous attention toward emotional expressions
Authors: Álvarez Fátima , Uxía Fernández-Folgueiras , Méndez-Bértolo Constantino , Kessel Dominique , Carretié Luis 
Published: July 2022

AbstractSeveral studies suggest that the menstrual cycle affects emotional processing. However, these results may be biased by including women with premenstrual syndrome (PMS) in the samples. PMS is characterized by negative emotional symptomatology, such as depression and/or anxiety, during the luteal phase. This study aimed to explore the modulation of exogenous attention to emotional facial expressions as a function of the menstrual cycle in women without PMS. For this purpose, 55 women were selected (from an original volunteer sample of 790) according to rigorous exclusion criteria. Happy, angry, and neutral faces were presented as distractors, while both behavioral performance in a perceptual task and event-related potentials (ERPs) were recorded. This task was applied during both phases of the menstrual cycle (luteal and follicular, counterbalanced), and premenstrual symptomatology was monitored daily. Traditional and Bayesian ANOVAs on behavioral data (reaction times and errors in the task) and ERP indices (P1, N170, N2, and LPP amplitudes) confirmed the expected lack of an interaction of phase and emotion. Taken together, these results indicate that women free of PMS present steady exogenous attention levels to emotionally positive and negative stimuli regardless of the menstrual phase.
Group 3 Innate Lymphoid Cells are regulated by WASP in a microbiota-dependent manner
Authors: Biswas Amlan , Redhu Naresh S , Nandy Anubhab , Kang Yu Hui , Field Michael , Kelly Ryan , Konnikova Liza , Goettel Jeremy A. , Tsou Amy M. , Horwitz Bruce , Snapper Scott B. 
Published: July 2022

AbstractWiskott-Aldrich syndrome protein (WASP) is a cytoskeletal regulator that is largely restricted to hematopoietic cells. While WASP expression in both lymphocytes and macrophages play a critical role in maintaining intestinal homeostasis, the function of WASP in innate lymphoid cells is unknown. Here we analyzed the role of WASP in the differentiation and function of group 3 innate lymphoid cells (ILC3s). WASP-deficient mice (Was-/-) have a marked reduction in ILC3s. Moreover, antimicrobial peptide expression in response to ILC3-derived IL-22 was also reduced in the absence of WASP. In Was-/- mice, we observed a reduction in CCR6+ ILC3s, cells known to restrict immune responses to commensal bacteria. WASP-deficient mice were more susceptible to Citrobacter rodentium, an enteric infection controlled by ILC3s. Interestingly, there was no reduction in ILC3s in Was-/- germ-free mice when compared to WT germ-free mice. ILC3s lacking WASP expression also demonstrated microbially-dependent alterations in gene expression associated with cell migration. Finally, ILC3-like (Rorgt+CD3-) cells were reduced in the GI tract of WASP-deficient patients. In conclusion, ILC3-specific expression of WASP is critical for the generation and function of ILC3s in the presence of commensal microflora. Aberrant ILC3 function in the setting of WASP-deficiency may contribute to underlying disease pathogenesis.
On the importance of data transformation for data integration in single-cell RNA sequencing analysis
Authors: Park Youngjun , Hauschild Anne-Christin 
Published: July 2022

AbstractRecent advances in single-cell RNA (scRNA) sequencing have opened a multitude of possibilities to study tissues down to the level of cellular populations. Subsequently, this enabled various scRNA studies that reported novel or previously undetected subpopulations and their functions by integrating multiple datasets. However, the heterogeneity in single-cell sequencing data makes it unfeasible to adequately integrate multiple datasets generated from different studies. This heterogeneity originates from various sources of noise due to technological limitations. Thus, particular procedures are required to adjust such effects prior to further integrative analysis. Over the last years, numerous single-cell data analysis workflows have been introduced, implementing various read-count transformation methods for de-noising and batch correction. A detailed review of recent single-cell studies shows while many analysis procedures employ various preprocessing steps, they often neglect the importance of a well-chosen and optimized data transformation. This fact is particularly alarming since these data transformations can alter data distribution and thus have a crucial impact on subsequent downstream cell clustering results. Therefore, this study investigates the effects of the various data transformation methods on three different public data scenarios and evaluates them with the most commonly used dimensionality reduction and clustering analysis. Additionally, we discuss its implications for the subsequent application of different deep neural network approaches, such as auto encoders and transfer learning. In summary, our benchmark analysis shows that a large portion of batch effects and noise can be mitigated by simple but well-chosen data transformation methods. We conclude that such optimized preprocessing is crucial and should be the baseline for all comparative single-cell sequencing studies, particularely for integrative analysis of multiple data sets.
Raltitrexed and Edatrexate drug molecules against human Proton Coupled Folate Transporter to cure cancer
Authors: Raja Yashpal Singh , Mishra Surya , Bhushan Shikha 
Published: July 2022

ABSTRACTProton pump inhibitors (PPIs) (e.g.: - rabeprazole, pantoprazole, omeprazole, lansoprazole, and esomeprazole) are widely used to treat gastroesophageal reflux disease and other acid-related disorders. Folic acid transport is important for proper cell proliferation. In human, folic acid is not synthesized in the body, it is obtained externally. Therefore, specific transporters are involved in absorption of folic acid, which is concentrated in intestine. Malignant cancer cells require this folic acid very frequently in large quantities for the rapid reproduction of cancer cell. In the current study, we compared different types of proton pump inhibitor drug molecules that may be potential candidates for preventing the absorption of folate by (hPCFT), its responsible for unusually large and frequent folate production. Each of these anti-drug candidates has 27 finalists based on previous studies. Among these competitors, leukovorin and noletraxid molecules were found to be particularly associated with the hPCFT transporter’s key active site loop(G155XXG158).
WNT stimulation induced conformational dynamics in the Frizzled-Dishevelled interaction
Authors: Bowin Carl-Fredrik , Kozielewicz Pawel , Grätz Lukas , Kowalski-Jahn Maria , Schihada Hannes , Schulte Gunnar 
Published: July 2022

AbstractFrizzleds (FZD1-10) are G protein-coupled receptors containing an extracellular cysteine-rich-domain (CRD) that presents the orthosteric binding site of the 19 mammalian WNTs, the endogenous agonists of FZDs. FZDs signal via a diverse set of effector proteins, of which Dishevelled (DVL1-3) is the most well studied and which acts as a hub for several FZD-mediated signaling pathways. However, the mechanistic details of how FZD-DVL interaction mediate pathway initiation and provide pathway selectivity remain an enigma. Here, we use bioluminescence resonance energy transfer-based assays employing Venus-tagged DVL2 together with NanoLuciferase-tagged FZD5 to investigate the WNT-3A- and WNT-5A-induced dynamics of the FZD-DVL interaction. Our biophysical assessment suggests that the ligand-induced BRET changes over time originate from conformational dynamics in the FZD5-DVL2 complex rather than recruitment dynamics of DVL2 to FZD5. Thus, we suggest that extracellular agonist and intracellular transducers could cooperate with each other through allosteric interaction with FZDs in a ternary complex reminiscent of that of classical GPCRs.One Sentence SummaryAnalysis of the interaction of FZD5 and DVL2 uncovers WNT-induced conformational dynamics of a WNT-FZD5-DVL2 complex.
Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies
Authors: Engdahl Taylor B. , Binshtein Elad , Brocato Rebecca L. , Kuzmina Natalia A. , Principe Lucia M , Kwilas Steven A. , Kim Robert K. , Chapman Nathaniel S. , Porter Monique S. , Guardado-Calvo Pablo , Rey Felix A. , Handal Laura S. , Diaz Summer M. , Zagol-Ikapitte Irene A. , Reidy Joseph X. , Trivette Andrew , Bukreyev Alexander , Hooper Jay W. , Crowe James. E. 
Published: July 2022

AbstractHantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While sporadic in North and South America, many infections occur in Europe and Asia, with mortality ranging from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity across hantavirus species. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines.