bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher hyperpolarization activated current (Ih) in a subpopulation of interneurons in stratum oriens of area CA1 in the hippocampus of Fragile X mice
Authors: Hewitt Lauren T. , Brager Darrin H. 
Published: December 2022

AbstractFragile X syndrome is the most common inherited form of intellectual disability and the leading monogenetic cause of autism. Studies in mouse models of autism spectrum disorders, including the Fmr1 knockout (FX) mouse, suggest that abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. We and others previously identified changes in multiple voltage-gated ion channels in hippocampal excitatory pyramidal neurons in FX mice. Whether the intrinsic properties of hippocampal inhibitory interneurons are altered in FX remains largely unknown. We made whole-cell current clamp recordings from three types of interneurons in stratum oriens of the hippocampus: fast-spiking (FS) cells and two classes of low threshold spiking cells, oriens-lacunosum moleculare (OLM) and low-threshold high Ih(LTH) neurons. We found that in FX mice, input resistance and action potential firing frequency were lower in LTH, but not FS or OLM, interneurons compared to wild type. Bath application of the h-channel blocker ZD7288 had a larger effect on input resistance in FX LTH cells and normalized input resistance between wild type and FX LTH cells, suggesting a greater contribution of Ihin FX LTH cells. In agreement, voltage clamp recordings showed that Ihwas higher in FX LTH cells compared to wild type. Our results suggest that the intrinsic excitability of LTH inhibitory interneurons may contribute to altered inhibition in the hippocampus of FX mice.Significance statementChanges in the balance between excitation and inhibition underlie many neurodevelopmental disorders. Changes in several voltage-gated ion channels, which contribute to altered intrinsic excitability, were previously identified in excitatory hippocampal neurons in the Fmr1 mouse model of Fragile X syndrome. In this paper we use physiological and biochemical approaches to investigate the intrinsic excitability of inhibitory interneurons in hippocampal area CA1 of the Fragile X mouse. We found that higher Ihlowers the intrinsic excitability of one specific type of interneuron. This study highlights how changes to voltage-gated ion channels in specific neuronal populations may contribute to the altered excitatory/inhibitory balance in Fragile X syndrome.
EPEK: creation and analysis of an Ectopic Pregnancy Expression Knowledgebase
Authors: Natarajan Ananya , Chivukula Nikhil , Dhanakoti Gokul Balaji , Sahoo Ajaya Kumar , Ravichandran Janani , Samal Areejit 
Published: December 2022

AbstractEctopic pregnancy (EP) is one of the leading causes of maternal mortality, where the fertilized embryo grows outside of the uterus. Recent experiments on mice have uncovered the importance of genetic factors in the transport of embryos inside the uterus. In the past, efforts have been made to identify possible gene or protein markers in EP in humans through multiple expression studies. Although there exist comprehensive gene resources for other maternal health disorders, there is no specific resource that compiles the genes associated with EP from such expression studies. Here, we address that knowledge gap by creating a computational resource, Ectopic Pregnancy Expression Knowledgebase (EPEK), that involves manual compilation and curation of expression profiles of EP in humans from published articles. In EPEK, we compiled information on 314 differentially expressed genes, 17 metabolites, and 3 SNPs associated with EP. Computational analyses on the gene set from EPEK showed the implication of cellular signaling processes in EP. We also identified possible exosome markers that could be clinically relevant in the diagnosis of EP. In a nutshell, EPEK is the first and only dedicated resource on the expression profile of EP in humans. EPEK is accessible athttps://cb.imsc.res.in/epek.
Switching between external and internal attention in hippocampal networks
Authors: Poskanzer Craig , Aly Mariam 
Published: December 2022

AbstractEveryday experience requires processing external signals from the world around us and internal information retrieved from memory. To do both, the brain must fluctuate between states that are optimized for external vs. internal attention. Here, we focus on the hippocampus as a region that may serve at the interface between these forms of attention, and ask how it switches between prioritizing sensory signals from the external world vs. internal signals related to memories and thoughts. Pharmacological, computational, and animal studies have identified input from the cholinergic basal forebrain as important for biasing the hippocampus towards processing external information, whereas complementary research suggests the dorsal attention network (DAN) may aid in allocating attentional resources towards accessing internal information. We therefore tested the hypothesis that the basal forebrain and DAN drive the hippocampus towards external and internal attention, respectively. We used data from 29 human participants (17 female) who completed 2 attention tasks during fMRI. One task (“memory-guided”) required proportionally more internal attention, and proportionally less external attention, than the other (“explicitly instructed”). We discovered that background functional connectivity between the basal forebrain and hippocampus was stronger during the explicitly instructed vs. memory-guided task. In contrast, DAN-hippocampus background connectivity was stronger during the memory-guided vs. explicitly instructed task. Finally, the strength of DAN-hippocampus background connectivity was correlated with performance on the memory-guided but not explicitly instructed task. Together, these results provide evidence that the basal forebrain and DAN may modulate the hippocampus to switch between external and internal attention.Significance StatementHow does the brain balance the need to pay attention to internal thoughts and external sensations? We focused on the human hippocampus, a region that may serve at the interface between internal and external attention, and asked how its functional connectivity varies based on attentional states. The hippocampus was more strongly coupled with the cholinergic basal forebrain when attentional states were guided by the external world rather than retrieved memories. This pattern flipped for functional connectivity between the hippocampus and dorsal attention network, which was higher for attention tasks that were guided by memory rather than external cues. Together, these findings show that distinct networks in the brain may modulate the hippocampus to switch between external and internal attention.
Designing epitope-focused vaccinesviaantigen reorientation
Authors: Xu Duo , Li Chunfeng , Utz Ashley , Weidenbacher Payton A.B. , Tang Shaogeng , Sanyal Mrinmoy , Pulendran Bali , Kim Peter S. 
Published: December 2022

ABSTRACTA major challenge in vaccine development, especially against rapidly evolving viruses, is the ability to focus the immune response toward evolutionarily conserved antigenic regions to confer broad protection. For example, while many broadly neutralizing antibodies against influenza have been found to target the highly conserved stem region of hemagglutinin (HA-stem), the immune response to seasonal influenza vaccines is predominantly directed to the immunodominant but variable head region (HA-head), leading to narrow-spectrum efficacy. Here, we first introduce an approach to controlling antigen orientation based on the site-specific insertion of short stretches of aspartate residues (oligoD) that facilitates antigen-binding to alum adjuvants. We demonstrate the generalizability of this approach to antigens from the Ebola virus, SARS-CoV-2, and influenza and observe enhanced antibody responses following immunization in all cases. Next, we use this approach to reorient HA in an “upside down” configuration, which we envision increases HA-stem exposure, therefore also improving its immunogenicity compared to HA-head. When applied to HA of H2N2 A/Japan/305/1957, the reoriented H2 HA (reoH2HA) on alum induced a stem-directed antibody response that cross-reacted with both group 1 and 2 influenza A HAs. Our results demonstrate the possibility and benefits of antigen reorientationviaoligoD insertion, which represents a generalizable immunofocusing approach readily applicable for designing epitope-focused vaccine candidates.GRAPHICAL ABSTRACTSeasonal influenza vaccines induce a biased antibody response against the variable head of hemagglutinin, whereas conserved epitopes on the stem are a target for universal vaccines. Here we show that reorienting HA in an “upside-down” configuration sterically occludes the head and redirects the antibody response to the more exposed stem, thereby inducing broad cross-reactivity against hemagglutinins from diverse influenza strains.
Scoring thermal limits in small insects using open-source, computer assisted motion detection
Authors: Perez-Galvez Fernan R , Wilson Annabelle C , Zhou Sophia , Awde David N , Teets Nicholas M 
Published: December 2022

AbstractScoring large amounts of thermal tolerance traits live or with recorded video can be time consuming and susceptible to investigator bias, and as with many physiological measurements, there can be trade-offs between accuracy and throughput. Recent studies show that particle tracking is a viable alternative to manually scoring videos, although it may not detect subtle movements, and many of the software options are proprietary and costly. In this study, we present a novel strategy for automated scoring of thermal tolerance videos by inferring motor activity with motion detection using an open-source Python command line application called DIME (Detector of Insect Motion Endpoint). We apply our strategy to both dynamic and static thermal tolerance assays, and our results indicate that DIME can accurately measure thermal acclimation responses, generally agrees with visual estimates of thermal limits, and can significantly increase the throughput over manual methods.Summary statementMotion detection algorithm for reliable, automatic scoring of thermal limits in insects with open-source tool
Thermal cycling-hyperthermia down-regulates liposaccharide-induced inflammation in human blood and helps with clearance of herpes simplex virus type 1
Authors: Kuo Yu-Yi , Lin Guan-Bo , Chen Wei-Ting , Chen You-Ming , Liu Hsu-Hsiang , Chao Chih-Yu 
Published: December 2022

AbstractInfection would lead to temperature increase in the affected region or entire human body, in order to weaken the pathogens, such as virus, or activate the immune system. As an alternative therapy with extensive application for various diseases, hyperthermia (HT) can regulate the release of pro-inflammatory cytokines and the antiviral activity of immune system. However, existing studies have found that overheating impairs healthy tissues and immune cells. The study puts forth a modified HT treatment, thermal cycling-hyperthermia (TC-HT), looking into its effect on immunomodulation and cellular viabilities. It shows that TC-HT can reduce the secretion of pro-inflammatory cytokines, induced by lipopolysaccharide (LPS) bothex vivoandin vitro, and elevate the efficacy of U-937 macrophages in clearing herpes simplex virus type 1 (HSV-1)in vitro. Furthermore, via optimizing its parameters, TC-HT can boost the efficacy of U-937 macrophage in clearing HSV-1, which may be attributed to the enhancement of actin polymerization and phagocytosis activity via TC-HT. In sum, TC-HT outperforms HT in safety and therapeutic effect in immunomodulation, shedding light on its potential in the treatment of immunological diseases.
Benchmark of force fields to characterize the intrinsically disordered R2-FUS-LC region
Authors: Chan-Yao-Chong Maud , Chan Justin , Kono Hidetoshi 
Published: December 2022

ABSTRACTAmyloid fibrils formations are involved in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Amyotrophic Lateral Sclerosis (ALS) and others. The proteins associated with the formation of amyloid fibrils are Intrinsically Disordered Proteins (IDP) in the unbound state. Nevertheless, this type of proteins can self-aggregate and form cross-β amyloid fibrils structures at physiological condition.Due to the flexibility of these IDPs, no single experimental approach could completely characterize this system, especially in the unbound state. All-atom molecular dynamics (MD) simulations could be used to study the conformational ensemble of IDPs. Unfortunately, force fields (FF) and water models (WM) were developed to simulate one structure of folded proteins. Recently, several FF/WM were improved to properly generate conformational ensembles of IDP. However, it is unknown if the force fields (FF) can properly reproduce the behavior of IDP and also self-aggregate in cross-β amyloid fibrils structures.In this paper, we will focus of the R2 region of the FUS-LC domain (R2-FUS-LC region) which is an Intrinsically Disordered Region (IDR) of 16 residues in the unbound state but forms cross-β fibrils in the bound state. For the R2-FUS-LC region, we benchmarked thirteen commonly used FFs for studying IDPs. We show that CHARMM36m (updated in 2021) with mTIP3P water model performs the best to generate extended structures and cross-β amyloid fibril.
The SOCS1 KIR and SH2 domain are both required for suppression of cytokine signalingin vivo
Authors: Doggett Karen , Keating Narelle , Dehkhoda Farhad , Bidgood Grace M. , Leong Evelyn , Kueh Andrew , Nicola Nicos A. , Kershaw Nadia J. , Babon Jeffrey J. , Alexander Warren S. , Nicholson Sandra E. 
Published: December 2022

AbstractSuppressor Of Cytokine Signaling (SOCS) 1 is a critical negative regulator of cytokine signaling and required to protect against an excessive inflammatory response. Genetic deletion ofSocs1results in unrestrained cytokine signaling and neonatal lethality, characterised by an inflammatory immune infiltrate in multiple organs. Overexpression and structural studies have suggested that the SOCS1 kinase inhibitory region (KIR) and Src homology 2 (SH2) domain are important for interaction with and inhibition of the receptor-associated JAK1, JAK2 and Tyk2 tyrosine kinases, which initiate downstream signaling. To investigate the role of the KIR and SH2 domain in SOCS1 function, we independently mutated key conserved residues in each domain and analysed the impact on cytokine signaling, and thein vivoimpact on SOCS1 function. Mutation of the SOCS1-KIR or SH2 domain had no impact on the integrity of the SOCS box complex, however, mutation within the phosphotyrosine binding pocket of the SOCS1-SH2 domain specifically disrupted SOCS1 interaction with phosphorylated JAK1. In contrast, mutation of the KIR did not affect the interaction with JAK1, but did prevent SOCS1 inhibition of JAK1 autophosphorylation. In human and mouse cell lines, both mutants impacted the ability of SOCS1 to restrain cytokine signaling, and crucially,Socs1-R105AandSocs1-F59Amice displayed a neonatal lethality and excessive inflammatory phenotype similar to SOCS1 null mice. This study defines a critical and non-redundant role for both the KIR and SH2 domain in endogenous SOCS1 function.
A small excitation window allows long-duration single-molecule imaging, with reduced background autofluorescence, inC. elegansneurons
Authors: Mitra Aniruddha , Loseva Elizaveta , Haasnoot Guus H. , Peterman Erwin J.G. 
Published: December 2022

AbstractSingle-particle imaging using laser-illuminated widefield epi-fluorescence microscopy is a powerful tool to investigate molecular processesin vivo. Performing high-quality single-molecule imaging in such biological systems, however, remains a challenge due to difficulties in controlling the number of fluorescing molecules, photobleaching, and the autofluorescence background. Here, we show that by exciting only a small, 5-15 µm wide region in chemosensory neurons in liveC. elegans, we can significantly improve the duration and quality of single-molecule imaging. Small-window illumination microscopy (SWIM) allows long-duration single-particle imaging since fluorescently labelled proteins are only excited upon entering the small excited area, limiting their photobleaching. Remarkably, we also find that using a small excitation window significantly improves the signal-to-background ratio of individual particles. With the help of theoretical calculations, we explain that the improved signal-to-background ratio is due to reduced background, mostly caused by out-of-focus autofluorescence. We demonstrate the potential of this approach by studying the dendritic transport of a ciliary calcium channel protein, OCR-2, in the chemosensory neurons ofC. elegans. We reveal that OCR-2-associated vesicles are continuously transported back and forth along the length of the dendrite and can switch between directed and diffusive states. Furthermore, we perform single-particle tracking of OCR-2-associated vesicles to quantitatively characterize the transport dynamics. SWIM can be readily applied to otherin vivosystems where intracellular transport or cytoskeletal dynamics occur in elongated protrusions, such as axons, dendrites, cilia, microvilli and extensions of fibroblasts.
Dynamic evolution of retroviral envelope genes in egg-laying mammalian genomes
Authors: Kitao Koichi , Shoji Hiyori , Miyazawa Takayuki , Nakagawa So 
Published: December 2022

AbstractIndependently acquired envelope (env) genes from endogenous retroviruses have contributed to the placental trophoblast cell-cell fusion in therian mammals. Egg-laying mammals (monotremes) are an important sister clade for understanding mammalian placental evolution, but theenvgenes in their genomes have yet to be investigated. Here,env-derived open reading frames (env-ORFs) encoding more than 400 amino-acid lengths were searched in the genomes of two monotremes: platypus and echidna. Only twoenv-ORFs were present in the platypus genome, whereas 121env-ORFs were found in the echidna genome. The echidnaenv-ORFs were phylogenetically classified into seven groups named env-Tac1 to -Tac7. Among them, the env-Tac1 group contained only a single gene, and its amino acid sequence showed high similarity to those of the RD114/simian type D retroviruses. Using the pseudotyped virus assay, we demonstrated that the Env-Tac1 protein utilizes echidna sodium-dependent neutral amino acid transporter type 1 and 2 (ASCT1 and ASCT2) as entry receptors. Moreover, the Env-Tac1 protein caused cell-cell fusion in human 293T cells depending on the expression of ASCT1 and ASCT2. These results illustrate that fusogenicenvgenes are not restricted to placental mammals, providing insights into the evolution of retroviral genes and the placenta.
Exogenous chromosomes reveal how sequence composition drives chromatin assembly, activity, folding and compartmentalization
Authors: Chapard Christophe , Meneu Léa , Serizay Jacques , Westbrook Alex , Routhier Etienne , Ruault Myriam , Bignaud Amaury , Thierry Agnès , Gourgues Géraldine , Lartigue Carole , Piazza Aurèle , Taddei Angela , Beckouët Frédéric , Mozziconacci Julien , Koszul Romain 
Published: December 2022

AbstractGenomic sequences co-evolve with DNA-associated proteins to ensure the multiscale folding of long DNA molecules into functional chromosomes. In eukaryotes, different molecular complexes organize the chromosome’s hierarchical structure, ranging from nucleosomes and cohesin- mediated DNA loops to large scale chromatin compartments. To explore the relationships between the DNA sequence composition and the spontaneous loading and activity of these DNA-associated complexes in the absence of co-evolution, we characterized chromatin assembly and activity in yeast strains carrying exogenous bacterial chromosomes that diverged from eukaryotic sequences over 1.5 billion years ago. We show that nucleosome assembly, transcriptional activity, cohesin-mediated looping, and chromatin compartmentalization can occur in a bacterial chromosome with a largely divergent sequence integrated in a eukaryotic host, and that the chromatinization of bacterial chromosomes is highly correlated with their sequence composition. These results are a step forward in understanding how foreign sequences are interpreted by a host nuclear machinery during natural horizontal gene transfers, as well as in synthetic genomics projects.
The effect of pH alterations on TDP-43 in a cellular model of amyotrophic lateral sclerosis
Authors: Al Ojaimi Yara , Slek Charlotte , Osman Samira , Alarcan Hugo , Marouillat Sylviane , Corcia Philippe , Vourc’h Patrick , Lanznaster Débora , Blasco Hélène 
Published: December 2022

AbstractAmyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate. However to our knowledge, no studies have been conducted yet in a cellular setting, in the context of ALS. We therefore tested the effect of cellular pH alterations on the localization and aggregation of TDP-43. HEK293T cells overexpressing wildtype TDP-43 were incubated for 1h with solutions of different pH (6.4, 7.2, and 8). Incubation of cells for 1h in solutions of pH 6.4 and 8 led to an increase in TDP-43-positive puncta, an effect that was lost after 2h of incubation. This was accompanied by the mislocalization of TDP-43 from the nucleus to the cytoplasm. Our resulats suggest that small alterations in cellular pH affect TDP-43 and increase its mislocalization into cytoplasmic TDP-43-positive puncta, which might suggest a role of TDP-43 in the response of cells to pH alterations.