bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kv12-Encoded K+Channels Drive the Day-Night Switch in the Repetitive Firing Rates of SCN Neurons
Authors: Hermanstyne Tracey O. , Yang Nien-Du , Granados-Fuentes Daniel , Li Xiaofan , Mellor Rebecca L. , Jegla Timothy , Herzog Erik D. , Nerbonne Jeanne M. 
Published: February 2023

AbstractConsiderable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K+) channels regulate daily oscillations in the rates of spontaneous action potential firing of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The K+conductance(s) driving these daily rhythms in repetitive firing rates, however, have not been identified. To test the hypothesis that subthreshold Kv12.1/Kv12.2-encoded K+channels play a role, we obtained current-clamp recordings from SCN neurons in slices prepared from adult mice harboring targeted disruptions in theKcnh8(Kv12.1−/−) orKcnh3(Kv12.2−/−) locus. We found that mean nighttime repetitive firing rates were higher in Kv12.1−/−and Kv12.2−/−, than in wild type (WT), SCN neurons. In marked contrast, mean daytime repetitive firing rates were similar in Kv12.1−/−, Kv12.2−/−and WT SCN neurons, and the day-night difference in mean repetitive firing rates, a hallmark feature of WT SCN neurons, was eliminated in Kv12.1−/−and Kv12.2−/−SCN neurons. Similar results were obtained within vivoshRNA-mediated acute knockdown of Kv12.1 or Kv12.2 in adult SCN neurons. Voltage-clamp experiments revealed that Kv12-encoded current densities in WT SCN neurons are higher at night than during the day. In addition, pharmacological block of Kv12-encoded currents increased the mean repetitive firing rate of nighttime, but not daytime, in WT SCN neurons. Dynamic clamp-mediated subtraction of modeled Kv12-encoded currents also selectively increased the mean repetitive firing rates of nighttime WT SCN neurons. Despite the elimination of nighttime decrease in the mean repetitive firing rates of SCN neurons, however, locomotor (wheel-running) activity remained rhythmic in Kv12.1−/−, Kv12.2−/−, Kv12.1-targeted shRNA-expressing, and Kv12.2-targeted shRNA-expressing animals.
Pancreatic Deletion of Mitogen-inducible Gene 6 Promotes Beta Cell Proliferation Following Destruction
Authors: El Kimberley , Bauer Brandon M. , Chen Yi-Chun , Jeong Jae-Wook , Fueger Patrick 
Published: February 2023

ABSTRACTType 1 Diabetes (T1D) is caused by autoimmune-mediated beta cell destruction. Following beta cell injury, the pancreas attempts to launch a cellular repair and regenerative program, yet it fails to completely restore functional beta cell mass. One component of this regenerative program is epidermal growth factor receptor (EGFR) signaling. However, upon irreparable beta cell damage, EGFR signaling is dampened, disrupting attempts to restore functional beta cell mass and maintain normoglycemia. We previously demonstrated that the negative feedback inhibitor of EGFR, Mitogen-inducible gene 6 (Mig6), is induced by the pro-inflammatory cytokines central to the autoimmune-mediated beta cell destruction. We also established that pro-inflammatory cytokines suppress EGFR activation, and siRNA-mediated suppression of Mig6 restores EGFR signaling. Thus, we hypothesized that pro-inflammatory cytokines induce nitric oxide production and that in turn induced Mig6, disrupting EGFR repair mechanisms. We determined that NO induces Mig6, attenuating EGFR signaling, and NO synthase inhibition blocks the cytokine-mediated induction of Mig6, thereby restoring cytokine-impaired EGFR signaling. To that end, we treated mice lacking pancreatic Mig6 and control mice with a streptozotocin (STZ) to induce beta cell death and diabetes in a way that mimics the onset and progression of T1D. Whereas STZ-treated control mice became hyperglycemic and had reduced beta cell mass, STZ-treated Mig6 pancreas-specific knock out (PKO) mice remained euglycemic and glucose tolerant due to preserved beta cell mass. The restoration of beta cell mass in PKO mice was accompanied by enhanced beta cell proliferation. Thus, our work suggests that Mig6 is a promising target to preserve beta cell mass before overt T1D.
Analysis of nucleotide variations in human g-quadruplex forming regions associated with disease states
Authors: Neupane Aryan , Chariker Julia H. , Rouchka Eric C. 
Published: February 2023

ABSTRACTWhile the role of G4 G quadruplex structures has been identified in cancers and metabolic disorders, single nucleotide variations (SNVs) and their effect on G4s in disease contexts have not been extensively studied. The COSMIC and CLINVAR databases were used to detect SNVs present in G4s to identify sequence level changes and their effect on alteration of G4 secondary structure. 37,515 G4 SNVs in the COSMIC database and 2,115 in CLINVAR were identified. Of those, 7,236 COSMIC (19.3%) and 416 (18%) of the CLINVAR variants result in G4 loss, while 2,728 (COSMIC) and 112 (CLINVAR) SNVs gain a G4 structure. The gene ontology term “GnRH (Gonadotropin-releasing hormone) secretion” is enriched in 21 genes in this pathway that have a G4 destabilizing SNV. Analysis of mutational patterns in the G4 structure show a higher selective pressure (3-fold) in the coding region on the template strand compared to the non-template strand. At the same time, an equal proportion of SNVs were observed among intronic, promoter and enhancer regions across strands. Using GO and pathway enrichment, genes with SNVs for G4 forming propensity in the coding region are enriched for Regulation of Ras protein signal transduction and Src homology 3 (SH3) domain binding.
Temporal regulation of AgRP neurons mediates context-induced feeding
Authors: Reed Felicia , Dempsey Harry , Clarke Rachel E , Reichenbach Alex , Mequinion Mathieu , Stark Romana , Rawlinson Sasha , Foldi Claire J , Lockie Sarah H. , Andrews Zane B. 
Published: February 2023

AbstractAn environment can have a powerful influence over appetite and feeding behaviour. For example, an environmental context, which reliably predicts food, will increase the appetitive food drive to the same environment context. Interestingly, mice are required to be hungry to develop such a context-induced feeding (CIF) response, suggesting the neural circuits sensitive to hunger play an important role to associate an internal energy state with a particular environment context. Hunger-sensing Agouti related peptide (AgRP) neurons are activated by circulating signals of energy deficit and reset to a silenced state by gut feedback mechanisms following food consumption. We hypothesised that AgRP neurons are both necessary and sufficient to drive CIF in the absence of hunger. While fasting increased CIF, chemogenetic inhibition of AgRP neurons during context acquisition prevented this effect. Intriguingly, chemogenetic activation of AgRP neurons during context acquisition did not increase CIF, suggesting precise temporal firing properties may be required. Indeed, photostimulation of AgRP neurons, only during context exposure (ON-OFF in context), increased CIF. Moreover, AgRP photostimulation prior to context exposure, coupled with the termination of photostimulation in the context in the absence of food consumption, was sufficient to drive a subsequent CIF. Our results suggest that AgRP neurons regulate the acquisition of CIF when the temporal firing properties are matched to context exposure. These results further highlight that acute AgRP inhibition is a salient neural event underscoring the effect of hunger on associative learning.
The combined impact of killer whale consumptive and non-consumptive effects on northern sea otter population viability in the Western Aleutians Archipelago, Alaska
Authors: Tinker Tim , Schuette Paul , Weitzman Benjamin , Eisaguirre Joseph , Beatty William 
Published: February 2023

AbstractPredators can alter the abundance, distribution, and behavior of prey populations through consumptive and non-consumptive effects. In the Aleutian Archipelago of Alaska, killer whales (Orcinus orca) are considered the most probable cause of northern sea otter (Enhydra lutris kenyoni) population declines in the southwestern Alaska stock, which led to their listing as a threatened distinct population segment under the Endangered Species Act. Much of the research attention in the Aleutian Archipelago region has focused on the consumptive effects of killer whales on sea otter population dynamics. Here, we explore non-consumptive effects by accounting for restricted sea otter habitat use within discrete predation refuges characterized by areas of shallow, complex reef habitats close to shore. We constructed Population Viability Analysis (PVA) models that incorporated sea otter count data collected by aerial and skiff-based methods over six decades (1959 – 2021) to inform uplisting (to endangered) and downlisting (delisting from ESA) criteria. Our models incorporated both density-dependent effects and density-independent effects on sex and age structure, which we termed predation hazards. Prior to 1990, predation hazards were negligible, fluctuated at high values between 1990 and the early 2000s, and then declined as sea otter populations reached low densities. We estimated a current regional abundance of 2,405 sea otters (95%CI = 1,734 – 3,238) in the Western Aleutians Management Unit. Our base PVA model that considered only inter-island fragmentation indicated the risk of the regional sea otter population becoming endangered was <5% when there were at least 1,500 otters (95%CI = 1,200 – 2,100), and provided a delisting threshold of 2,100 sea otters. A PVA model that accounted for restricted habitat use of sea otters within discrete predation refuges (i.e. inter-island and intra-island fragmentation) indicated a less encouraging potential for sea otter recovery. The probability of the population becoming endangered increased to >10% and the delisting threshold increased to >10,000 sea otters (nearly 5x higher). Our results indicate sea otters within fragmented predation refuges could be more susceptible to the effects of stochastic processes with potentially limited ability for rescue effects. Overall, our research reveals the importance of evaluating both consumptive and non-consumptive effects when considering conservation and management plans for at-risk populations thought to be limited by a predator.
Diversity of ribosomes at the level of rRNA variation associated with human health and disease
Authors: Rothschild Daphna , Susanto Teodorus Theo , Sui Xin , Spence Jeffrey P. , Rangan Ramya , Genuth Naomi R. , Sinnott-Armstrong Nasa , Wang Xiao , Pritchard Jonathan K. , Barna Maria 
Published: February 2023

SummaryRibosomal DNA and RNA (rDNA and rRNA) sequences are usually discarded from sequencing analyses. But with hundreds of copies of rDNA genes it is unknown whether they possess sequence variations that form different types of ribosomes that affect human physiology and disease. Here, we developed an algorithm for variant-calling between paralog genes (termed RGA) and compared rDNA variations found in short- and long-read sequencing data from the 1,000 Genomes Project (1KGP) and Genome In A Bottle (GIAB). We additionally developed a novel protocol for long-read sequencing full-length rRNA (RIBO-RT) from actively translating ribosomes. Our analyses identified hundreds of rDNA variants, most of which, surprisingly, are short insertion-deletions (indels) and dozens of highly abundant rRNA variants that are incorporated into translationally active ribosomes. To visualize variant ribosomes at the single cell level, we developed anin-siturRNA sequencing method (SWITCH-seq) which revealed that variants are co-expressed within individual cells. Strikingly, by analyzing rDNA, we found that variants assemble into distinct ribosome subtypes. We discovered that these subtypes acquire different rRNA structures by successfully employing dimethyl sulfate (DMS) probing of full length rRNA. With this atlas we investigated rRNA variation changes across human tissues and cancer types. This revealed tissue-specific rRNA subtype expression in endoderm/ectoderm-derived tissues. In cancer, low abundant rRNA variants can become highly expressed, which suggests the presence of cancer-specific ribosomes. Together, this study identifies and comprehensively characterizes the diversity of ribosomes at the level of rRNA variants which is dominated by indel variants, their chromosomal location and unique structure as well as the association of ribosome variation with tissue-specific biology and cancer.
Alcohol tolerance encoding in sleep regulatory circadian neurons in Drosophila
Authors: Lange Anthony P. , Wolf Fred W. 
Published: February 2023

AbstractAlcohol tolerance is a simple form of behavioral and neural plasticity that occurs with the first drink. Neural plasticity in tolerance is likely a substrate for longer term adaptations that can lead to alcohol use disorder. Drosophila develop tolerance with characteristics similar to vertebrates, and it is useful model for determining the molecular and circuit encoding mechanisms in detail. Rapid tolerance, measured after the first alcohol exposure is completely metabolized, is localized to specific brain regions that are not interconnected in an obvious way. We used a forward neuroanatomical screen to identify three new neural sites for rapid tolerance encoding. One of these was comprised of two groups of neurons, the DN1a and DN1p glutamatergic neurons, that are part of the Drosophila circadian clock. We localized rapid tolerance to the two DN1a neurons that regulate arousal by light at night, temperature-dependent sleep timing, and night-time sleep. Two clock neurons that regulate evening activity, LNd6 and the 5th LNv, are postsynaptic to the DN1as and they promote rapid tolerance via the metabotropic glutamate receptor. Thus, rapid tolerance to alcohol overlaps with sleep regulatory neural circuitry, suggesting a mechanistic link.
Neural effects of TMS trains on the human prefrontal cortex
Authors: Ross Jessica M. , Cline Christopher C. , Sarkar Manjima , Truong Jade , Keller Corey J. 
Published: February 2023

AbstractHow does a train of TMS pulses modify neural activity in humans? Despite adoption of repetitive TMS (rTMS) for the treatment of neuropsychiatric disorders, we still do not understand how rTMS changes the human brain. This limited understanding stems in part from a lack of methods for noninvasively measuring the neural effects of a single TMS train — a fundamental building block of treatment — as well as the cumulative effects of consecutive TMS trains. Gaining this understanding would provide foundational knowledge to guide the next generation of treatments. Here, to overcome this limitation, we developed methods to noninvasively measure causal and acute changes in cortical excitability and evaluated this neural response to single and sequential TMS trains. In 16 healthy adults, standard 10 Hz trains were applied to the dorsolateral prefrontal cortex (dlPFC) in a randomized, sham-controlled, event-related design and changes were assessed based on the TMS-evoked potential (TEP), a measure of cortical excitability. We hypothesized that single TMS trains would induce changes in the local TEP amplitude and that those changes would accumulate across sequential trains, but primary analyses did not indicate evidence in support of either of these hypotheses. Exploratory analyses demonstrated non-local neural changes in sensor and source space and local neural changes in phase and source space. Together these results suggest that single and sequential TMS trains may not be sufficient to modulate local cortical excitability indexed by typical TEP amplitude metrics but may cause neural changes that can be detected outside the stimulation area or using phase or source space metrics. This work should be contextualized as methods development for the monitoring of transient noninvasive neural changes during rTMS and contributes to a growing understanding of the neural effects of rTMS.
A random forest model for predicting exosomal proteins using evolutionary information and motifs
Authors: Arora Akanksha , Patiyal Sumeet , Sharma Neelam , Devi Naorem Leimarembi , Kaur Dashleen , Raghava Gajendra P. S. 
Published: February 2023

AbstractIdentification of secretory proteins in body fluids is one of the key challenges in the development of non-invasive diagnostics. It has been shown in the part that a significant number of proteins are secreted by cells via exosomes called exosomal proteins. In this study, an attempt has been made to build a model that can predict exosomal proteins with high precision. All models are trained, tested, and evaluated on a non-redundant dataset comprising 2831 exosomal and 2831 non-exosomal proteins, where no two proteins have more than 40% similarity. Initially, the standard similarity-based method BLAST was used to predict exosomal proteins, which failed due to low-level similarity in the dataset. To overcome this challenge, machine learning based models have been developed using compositional features of proteins and achieved highest AUROC of 0.70. The performance of the ML-based models improved significantly to AUROC of 0.73 when evolutionary information in the form of PSSM profiles was used for building models. Our analysis indicates that exosomal proteins have wide range of motifs. In addition, it was observed that exosomal proteins contain different types of sequence-based motifs, which can be used for predicting exosomal proteins. Finally, a hybrid method has been developed that combines a motif-based approach and an ML-based model for predicting exosomal proteins, achieving a maximum AUROC 0.85 and MCC of 0.56 on an independent dataset. The hybrid model in this study performs better than the presently available methods when assessed on an independent dataset. A web server and a standalone software ExoProPred has been created for the scientific community to provide service, code, and data. (https://webs.iiitd.edu.in/raghava/exopropred/).KeypointsExosomal proteins or non-classical secretory proteins are secreted by via exosomesA method has been developed for predicting exosomal proteinsModels have been trained, tested, and evaluated on non-redundant datasetWide range of sequence motifs have been discovered in exosomal proteinsA web server and standalone software have been developed
Induction of transmucosal protection by oral vaccination with an attenuatedChlamydia
Authors: Wang Yihui , He Rongze , Winner Halah , Gauduin Marie-Claire , Zhang Nu , He Cheng , Zhong Guangming 
Published: February 2023

AbstractChlamydia muridarumhas been used to study chlamydial pathogenesis since it induces mice to develop hydrosalpinx, a pathology observed inC. trachomatis-infected women. We identified aC. muridarummutant that is no longer able to induce hydrosalpinx. In the current study, we evaluated the mutant as an attenuated vaccine. Following an intravaginal immunization with the mutant, mice were protected from hydrosalpinx induced by wild typeC. muridarum. However, the mutant itself productively colonized the mouse genital tract and produced infectious organisms in vaginal swabs. Nevertheless, the mutant failed to produce infectious shedding in the rectal swabs following an oral inoculation. Importantly, mice orally inoculated with the mutant mounted transmucosal immunity against challenge infection of wild typeC. muridarumin the genital tract. The protection was detected as early as day 3 following the challenge infection and the immunized mice were protected from any significant pathology in the upper genital tract. However, the same orally immunized mice failed to prevent the colonization of wild typeC. muridarumin the gastrointestinal tract. The transmucosal immunity induced by the oral mutant was further validated in the airway. The orally vaccinated mice were protected from both lung infection and systemic toxicity caused by intranasally inoculated wild typeC. muridarumalthough the same mice still permitted the gastrointestinal colonization by the wild typeC. muridarum. These observations suggest that the mutantC. muridarummay be developed into anintracellularoralvaccine vector (or IntrOv) for selectively inducing transmucosal immunity in extra-gut tissues.
A rapid approach for sex assignment by RAD-seq using a reference genome
Authors: Peralta Diego M. , Túnez Juan I. , Rodríguez Cruz Ulises E. , Ceballos Santiago G. 
Published: February 2023

AbstractSex identification is a common objective in molecular ecology. While many vertebrates display sexual dimorphism, determining the sex can be challenging in certain situations, such as species lacking clear sex-related phenotypic characteristics or in studies using non-invasive methods. In these cases, DNA analyses serve as valuable tools not only for sex determination but also for validating sex assignment based on phenotypic traits. In this study, we developed a bioinformatic framework for sex assignment using genomic data obtained through GBS, and having an available closely related genome assembled at the chromosome level. Our method consists of twoad hocindexes that rely on the different properties of the mammalian heteromorphic sex chromosomes. For this purpose, we mapped RAD-seq loci to a reference genome and then obtained missingness and coverage depth values for the autosomes and X and Y chromosomes of each individual. Our methodology successfully determined the sex of 165 fur seals that had been phenotypically sexed in a previous study and 40 sea lions sampled in a non-invasive way. Additionally, we evaluated the accuracy of each index in sequences with varying average coverage depths, with Index Y proving greater reliability and robustness in assigning sex to individuals with low-depth coverage. We believe that the approach presented here can be extended to any animal taxa with known heteromorphic XY/ZW sex chromosome systems and that it can tolerate various qualities of GBS sequencing data.
Cohort profile: Virus Watch: Understanding community incidence, symptom profiles, and transmission of COVID-19 in relation to population movement and behaviour
Authors: Byrne Thomas , Kovar Jana , Beale Sarah , Braithwaite Isobel , Fragaszy Ellen , Fong Wing Lam Erica , Geismar Cyril , Hoskins Susan , Navaratnam Annalan M D , Nguyen Vincent , Patel Parth , Shrotri Madhumita , Yavlinsky Alexei , Hardelid Pia , Wijlaars Linda , Nastouli Eleni , Spyer Moira , Aryee Anna , Cox Ingemar , Lampos Vasileios , McKendry Rachel A , Cheng Tao , Johnson Anne M , Michie Susan , Gibbs Jo , Gilson Richard , Rodger Alison , Abubakar Ibrahim , Hayward Andrew , Aldridge Robert W 
Published: February 2023

Key FeaturesVirus Watch is a national community cohort study of COVID-19 in households in England and Wales, established in June 2020. The study aims to provide evidence on which public health approaches are most effective in reducing transmission, and investigate community incidence, symptoms, and transmission of COVID-19 in relation to population movement and behaviours.28,527 households and 58,628 participants of age (0-98 years, mean age 48), were recruited between June 2020 - July 2022Data collected include demographics, details on occupation, co-morbidities, medications, and infection-prevention behaviours. Households are followed up weekly with illness surveys capturing symptoms and their severity, activities in the week prior to symptom onset and any COVID-19 test results. Monthly surveys capture household finance, employment, mental health, access to healthcare, vaccination uptake, activities and contacts. Data have been linked to Hospital Episode Statistics (HES), inpatient and critical care episodes, outpatient visits, emergency care contacts, mortality, virology testing and vaccination data held by NHS Digital.Nested within Virus Watch are a serology & PCR cohort study (n=12,877) and a vaccine evaluation study (n=19,555).Study data are deposited in the Office of National Statistics (ONS) Secure Research Service (SRS). Survey data are available under restricted access upon request to ONS SRS.