bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous recording of ultrasonic vocalizations and sniffing from socially interacting individual rats using a miniature microphone
Authors: John Shanah Rachel , Tiwari Rishika , Goussha Yizhaq , Amar Rotem , Bizer Alex , Netser Shai , Wagner Shlomo 
Published: September 2023

SummaryVocalizations are pivotal in mammalian communication, especially in humans. Rodents accordingly rely on ultrasonic vocalizations (USVs) that reflect their internal state as a primary channel during social interactions. However, attributing vocalizations to specific individuals remains challenging, impeding internal state assessment. Rats emit 50 kHz USVs to indicate positive states and intensify sniffing during alertness and social interactions. Here, we present a method involving a miniature microphone attached to the rat nasal cavity that allows to capture both male and female individual rat vocalizations and sniffing patterns during social interactions. We found that while the emission of 50 kHz USVs increases during close interactions, these signals lack specific behavioral associations. Moreover, a previously unreported low-frequency vocalization type marking rat social interactions was uncovered. Finally, different dynamics of sniffing and vocalization activities point to distinct underlying internal states. Thus, our method facilitates the exploration of internal states concurrent with social behaviors.MotivationHere, we sought to solve the problem of identifying the emitter of a specific vocalization during free social interaction of animal models. The use of a miniature microphone carried by the subject and connected to its nasal cavity solved this challenge and allowed for assignment of any vocalization recorded during a social interaction to a specific individual. Moreover, the miniature microphone enabled simultaneous recording of sniffing and vocalization activities of an individual, thus facilitating recognition of the internal states underlying these traits.
Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need
Authors: Tan Bowen , Browne Caleb J. , Nöbauer Tobias , Vaziri Alipasha , Friedman Jeffrey M. , Nestler Eric J. 
Published: September 2023

AbstractAddiction prioritizes drug use over innate needs by “hijacking” brain circuits that direct motivation, but how this develops remains unclear. Using whole-brain FOS mapping andin vivosingle-neuron calcium imaging, we find that drugs of abuse augment ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining “FOS-Seq”, CRISPR-perturbations, and snRNA-seq, we identifyRhebas a shared molecular substrate that regulates cell-type-specific signal transductions in NAc while enabling drugs to suppress natural reward responses. Retrograde circuit mapping pinpoints orbitofrontal cortex which, upon activation, mirrors drug effects on innate needs. These findings deconstruct the dynamic, molecular, and circuit basis of a common reward circuit, wherein drug value is scaled to promote drug-seeking over other, normative goals.
Gene and protein sequence features augment HLA class I ligand predictions
Authors: Bresser Kaspar , Nicolet Benoit P , Jeko Anita , Wu Wei , Loayza-Puch Fabricio , Agami Reuven , Heck Albert JR , Wolkers Monika C , Schumacher Ton N 
Published: September 2023

AbstractThe sensitivity of malignant tissues to T cell-based cancer immunotherapies is dependent on the presence of targetable HLA class I ligands on the tumor cell surface. Peptide intrinsic factors, such as HLA class I affinity, likelihood of proteasomal processing, and transport into the ER lumen have all been established as determinants of HLA ligand presentation. However, the role of sequence features at the gene and protein level as determinants of epitope presentation has not been systematically evaluated. To address this, we performed HLA ligandome mass spectrometry on patient-derived melanoma lines and used this data-set to evaluate the contribution of 7,124 gene and protein sequence features to HLA sampling. This analysis reveals that a number of predicted modifiers of mRNA and protein abundance and turn-over, including predicted mRNA methylation and protein ubiquitination sites, inform on the presence of HLA ligands. Importantly, integration of gene and protein sequence features into a machine learning approach augments HLA ligand predictions to a comparable degree as predictive models that include experimental measures of gene expression. Our study highlights the value of gene and protein features to HLA ligand predictions.
Sodium channels expressed in nociceptors contribute distinctly to action potential subthreshold phase, upstroke and shoulder
Authors: Köster Phil Alexander , Leipold Enrico , Tigerholm Jenny , Maxion Anna , Namer Barbara , Stiehl Thomas , Lampert Angelika 
Published: September 2023

AbstractVoltage-gated sodium channels (VGSC) in the peripheral nervous system shape action potentials (AP) and thereby support the detection of sensory stimuli. Most of the nine mammalian VGSC subtypes are expressed in nociceptors, but predominantly, three are linked to several human pain syndromes: while Nav1.7 is suggested to be a (sub-)threshold channel, Nav1.8 is thought to support the fast AP upstroke. Nav1.9, as it produces large persistent currents, is attributed a role in determining the resting membrane potential.We characterized gating of Nav1.1-Nav1.3 and Nav1.5-Nav1.9 in manual patch clamp with focus on the AP subthreshold depolarization phase. Nav1.9 exhibited the most hyperpolarized activation while its fast inactivation resembled the depolarized inactivation of Nav1.8. For some VGSCs (e.g., Nav1.1 and Nav1.2), a positive correlation between ramp current and window current was detected.Using a modified Hodgkin-Huxley model which accounts for the time needed for inactivation to occur, we used the acquired data to simulate two nociceptive nerve fiber types (an Aδ-and a mechano-insensitive C-nociceptor) containing VGSC conductances according to published human RNAseq data. Our simulations suggest that Nav1.9 is supporting both the AP upstroke and its shoulder. A reduced threshold for AP generation was induced by enhancing Nav1.7 conductivity or shifting its activation to more hyperpolarized potentials, as observed in Nav1.7-related pain disorders.Here, we provide a comprehensive, comparative functional characterization of VGSCs relevant in nociception and describe their gating with Hodgkin-Huxley-like models, which can serve as a tool to study their specific contributions to AP shape and sodium channel-related diseases.DisclaimerParts of this study were published as a preprint on bioRxiv: Köster, P.A., T. Stiehl, J. Tigerholm, A. Maxion, B. Namer, and A. Lampert. 2023. Biophysics of sodium channels during subthreshold depolarizationin vitroandin silico. bioRxiv. doi.org/10.1101/2023.09.03.556095 (Preprint posted September 6, 2023)SummarySubthreshold gating of seven sodium channels (Nav1.1-3, Nav1.5-8) is determined by manual patch clamp and, together with Nav1.9, integrated into a computer model of an Aδ-and a mechano-insensitive nociceptor (CMi). Simulations reveal contribution of Nav1.9 to the action potential upstroke and shoulder and prove useful for Nav1.7-related disease modelling.
Excitotoxic glutamate levels cause the secretion of resident endoplasmic reticulum proteins
Authors: Dossat Amanda M. , Trychta Kathleen A. , Fortuno Lowella V. , Richie Christopher T. , Harvey Brandon K. 
Published: September 2023

AbstractDysregulation of synaptic glutamate levels can lead to excitotoxicity such as that observed in stroke, traumatic brain injury, and epilepsy. The role of increased intracellular calcium (Ca2+) in the development of excitotoxicity is well established. However, less is known regarding the impact of glutamate on endoplasmic reticulum (ER)-Ca2+-mediated processes such as proteostasis. To investigate this, we expressed a secreted ER Ca2+modulated protein (SERCaMP) in primary cortical neurons to monitor exodosis, a phenomenon whereby ER calcium depletion causes the secretion of ER resident proteins that perform essential functions to the ER and the cell. Activation of glutamatergic receptors (GluRs) led to an increase in SERCaMP secretion indicating that normally ER resident proteins are being secreted in a manner consistent with ER Ca2+depletion. Antagonism of ER Ca2+channels attenuated the effects of glutamate and GluR agonists on SERCaMP release. We also demonstrate that endogenous proteins containing an ER retention sequence (ERS) are secreted in response to GluR activation supporting that neuronal activation by glutamate promotes ER exodosis. Ectopic expression of KDEL receptors attenuated the secretion of ERS-containing proteins caused by GluR agonists. Taken together, our data indicate that excessive GluR activation causes disruption of neuronal proteostasis by triggering the secretion of ER resident proteins through ER Ca2+depletion and describes a new facet of excitotoxicity.SignificanceDuring excitotoxicity, the excessive activation of glutamate receptors causes elevated intracellular calcium (Ca2+) that promotes cellular dysfunction and death. While the role of cytosolic Ca2+in excitotoxicity has been well-studied, the consequences of changes in endoplasmic reticulum (ER) Ca2+during excitotoxicity remains unclear. The relatively high concentration of calcium in the ER is necessary for ER resident proteins to function prop out essential functions and maintain cellular proteostasis. We show here that excitotoxic conditions destabilize the ER proteome by triggering ER resident protein secretion. Stabilizing ER Ca2+or overexpressing receptors that interact with ER resident proteins can prevent disruption of proteostasis associated with excitotoxicity. The present study provides a new link between excitotoxicity, ER Ca2+homeostasis, and the ER proteome.
How prior and p-value heuristics are used when interpreting data
Authors: Hermer Ethan , Irwin Ashley A. , Roche Dominique G. , Dakin Roslyn 
Published: September 2023

ABSTRACTScientific conclusions are based on the ways that researchers interpret data, a process that is shaped by psychological and cultural factors. When researchers use shortcuts known as heuristics to interpret data, it can sometimes lead to errors. To test the use of heuristics, we surveyed 623 researchers in biology and asked them to interpret scatterplots that showed ambiguous relationships, altering only the labels on the graphs. Our manipulations tested the use of two heuristics based on major statistical frameworks: (1) the strong prior heuristic, where a relationship is viewed as stronger if it is expecteda priori, following Bayesian statistics, and (2) the p-value heuristic, where a relationship is viewed as stronger if it is associated with a small p-value, following null hypothesis statistical testing. Our results show that both the strong prior and p-value heuristics are common. Surprisingly, the strong prior heuristic was more prevalent among inexperienced researchers, whereas its effect was diminished among the most experienced biologists in our survey. By contrast, we find that p-values cause researchers at all levels to report that an ambiguous graph shows a strong result. Together, these results suggest that experience in the sciences may diminish a researcher’s Bayesian intuitions, while reinforcing the use of p-values as a shortcut for effect size. Reform to data science training in STEM could help reduce researchers’ reliance on error-prone heuristics.Significance StatementScientific researchers must interpret data and statistical tests to draw conclusions. When researchers use shortcuts known as heuristics, it can sometimes lead to errors. To test how this occurs, we asked biologists to interpret graphs that showed an ambiguous relationship between two variables, and report whether the relationship was strong, weak, or absent. We altered features of the graph to test whether prior expectations or a statistic called the p-value could influence their interpretations. Our results indicate that both prior expectations and p-values can increase the probability that researchers will report that ambiguous data shows a strong result. These findings suggest that current training and research practices promote the use of error-prone shortcuts in decision-making.
Establishing a comprehensive web-based analysis platform forNicotiana benthamianagenome and transcriptome
Authors: Kurotani Ken-ichi , Hirakawa Hideki , Shirasawa Kenta , Tagiri Koya , Mori Moe , Ichihashi Yasunori , Suzuki Takamasa , Tanizawa Yasuhiro , Nakamura Yasukazu , Isobe Sachiko , Notaguchi Michitaka 
Published: September 2023

SummaryNicotiana benthamianahas long served as a crucial plant material extensively used in plant physiology research, particularly in the field of plant pathology, because of its high susceptibility to plant viruses. Additionally, it serves as a production platform to test vaccines and other valuable substances. Among its approximately 3.1 Gb genome, 57,583 genes have been annotated within a 61 Mb region. We created a comprehensive and easy-to-use platform to use transcriptomes for modern annotation. These tools allow to visualize gene expression profiles, draw molecular evolutionary phylogenetic trees of gene families, perform functional enrichment analyses, and facilitate output downloads. To demonstrate their utility, we analyzed the gene expression profiles of enzymes within the nicotine biosynthesis pathway, a secondary metabolic pathway characteristic of theNicotianagenus. Using the developed tool, expression profiles of the nicotine biosynthesis pathway genes were generated. The expression patterns of eight gene groups in the pathway were strongly expressed in the roots and weakly expressed in leaves and flowers ofN. benthamiana. The results were consistent with the established gene expression profiles inNicotiana tabacumand provided insights into gene family composition and expression trends. The compilation of this database tool can facilitate genetic analysis ofN. benthamianain the future.Significance statementA tool was developed to visualize gene expression profiles, draw molecular evolutionary phylogenetic trees of gene families, perform functional enrichment analyses, and facilitate output downloads ofNicotiana benthamiana. The database developed using the tool can evolve into a comprehensive all-in-one analysis platform by continuously incorporating transcriptome data released to date, newly released RNA-seq data, and annotations in the future.
Structure and flexibility of the DNA polymerase holoenzyme of vaccinia virus
Authors: Burmeister Wim P. , Boutin Laetitia , Balestra Aurelia C. , Gröger Henri , Ballandras-Colas Allison , Hutin Stephanie , Kraft Christian , Grimm Clemens , Böttcher Bettina , Fischer Utz , Tarbouriech Nicolas , Iseni Frédéric 
Published: September 2023

AbstractThe year 2022 was marked by the mpox outbreak caused by human monkeypox virus (MPXV), which is about 98 % identical to vaccinia virus (VACV) at the sequence level regarding the proteins involved in DNA replication. We present the strategy for the production of the VACV DNA polymerase holoenzyme composed of the E9 polymerase associated with its co-factor, the A20-D4 heterodimer, which led to the 3.8 Å cryo-electron microscopy (cryo-EM) structure of the DNA-free form of the holoenzyme. Model building used high-resolution structures of components of the complex and the A20 structure predicted by AlphaFold 2. The structure of E9 does not change in context of the holoenzyme compared to the crystal structure. As for the MPXV holoenzyme, a contact between E9 and D4 is mediated by a cluster of hydrophobic residues. The holoenzyme structure is quite compact and surprisingly similar to the MPXV holoenzyme in presence of a DNA template, with the exception of a movement of the finger domain and the thumb domain, which becomes ordered in presence of DNA. Even in absence of DNA, the VACV holoenzyme structure is too compact for an agreement with SAXS data. This suggests the presence of more open conformations in solution, which are also predicted by Alphafold 2 indicating hinge regions located within A20. Using biolayer interferometry we showed that indeed, the E9-D4 interaction is weak and transient although very important as it has not been possible to obtain viable viruses carrying mutations of key residues in the E9-D4 interface.Author SummaryThe 2022 outbreak of mpox is caused by monkeypox virus closely related to the best studied model, vaccinia virus. Genome replication, which takes place largely autonomously in the cytosol of the infected cell, is still not really understood. Viral DNA synthesis involves a DNA repair enzyme, the uracil-DNA glycosylase D4 linked to the structural protein A20 forming the processivity factor, which in turn binds to E9 forming the complex required for processive DNA synthesis. Here we present the first structure of the vaccinia virus polymerase holoenzyme E9-A20-D4 at 3.8 Å obtained by cryo-electron microscopy. This structure, together with several recent structures from monkeypox virus, provide a static view of the complex with a previously undescribed contact between E9 and D4. Our small-angle scattering data show that other conformations, taking advantage of 2 hinge regions in A20, exist in solution. Using site-directed mutagenesis and binding studies we show that the contact between E9 and D4, which serves to encircle the template strand, is important, but transient. Thus the current model of the orientation of the holoenzyme on the replication fork may not be the only one possible.
Population-based Risk of Psychiatric Disorders Associated with Recurrent CNVs
Authors: Vaez Morteza , Montalbano Simone , Calle Sánchez Xabier , Georgii Hellberg Kajsa-Lotta , Rasekhi Dehkordi Saeid , Dybdahl Krebs Morten , Meijsen Joeri , Shorter John , Byberg-Grauholm Jonas , Mortensen Preben B , Børglum Anders D , Hougaard David M , Nordentoft Merete , Geschwind Daniel H , Buil Alfonso , Schork Andrew J ,   iPSYCH Investigators, Helenius Dorte , Raznahan Armin , Thompson Wesley K , Werge Thomas , Ingason Andrés 
Published: September 2023

AbstractRecurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We provide population-based estimates of rCNV-associated risk of neuropsychiatric disorders for 34 rCNVs in the iPSYCH2015 case-cohort sample (n=120,247).Most observed significant increases in rCNV-associated risk for ADHD, autism or schizophrenia were moderate (HR:1.42-5.00), and risk estimates were highly correlated across these disorders, the most notable exception being high autism-associated risk with Prader-Willi/ Angelman Syndrome duplications (HR=20.8). No rCNV was associated with significant increase in depression risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint. Comparison with published rCNV studies suggests that prevalence of some rCNVs is higher, and risk of psychiatric disorders lower, than previously estimated.In an era where genetics is increasingly being clinically applied, our results highlight the importance of population-based risk estimates for genetics-based predictions.
Wastewater-based surveillance of respiratory syncytial virus epidemic at the national level in Finland
Authors: Länsivaara Annika , Lehto Kirsi-Maarit , Hyder Rafiqul , Luomala Oskari , Lipponen Anssi , Hokajärvi Anna-Maria , Heikinheimo Annamari , Pitkänen Tarja , Oikarinen Sami ,   WastPan Study Group
Published: September 2023

AbstractThe purpose of this study was to evaluate the potential of wastewater-based surveillance in the monitoring of epidemics at the national level in Finland. To discover the correlation of wastewater data and register data, the 2021–2022 respiratory syncytial virus (RSV) epidemic in Finland was analyzed from wastewater and the Finnish National Infectious Diseases Register. The study was performed using samples that were collected monthly from May 2021 to July 2022 from ten wastewater treatment plants that cover 40% of the Finnish population. Respiratory syncytial virus detection in 24-h composite samples of influent wastewater was performed using RT-qPCR. Respiratory syncytial virus wastewater data were positively correlated with the National Infectious Diseases Register data for the sampling week (correlation coefficient, CC min = 0.412, max = 0.865). Furthermore, the cumulative incidence of respiratory syncytial virus from the sampling week to three weeks afterward was strongly correlated with the wastewater data (CC min = 0.482, max = 0.814), showing the potential of wastewater-based surveillance for use in estimating the course of the epidemic. When the register-based incidence of RSV was at least four cases/100,000 persons/week in the sampling week, it was detected in all wastewater samples. This study showed that wastewater surveillance is useful in the surveillance of respiratory syncytial virus epidemics, and its potential in the surveillance of other epidemics should be explored further.SynopsisEnvironmental surveillance has been previously used to monitor viruses such as poliovirus and SARS-CoV-2. This study shows that wastewater-based surveillance can be used to surveil the respiratory syncytial virus and its epidemics, at a national level.
Psychotherapies and Psychological Support for Individuals Facing Psychological Distress during the COVID-19 Pandemic: A Scoping Review
Authors: Yagihashi Mao , Sakuma Atsushi , Murakami Michio 
Published: September 2023

AbstractIn this scoping review, we investigated psychotherapies and psychological support provided the coronavirus disease 2019 (COVID-19) pandemic to clarify its recipients and the methods employed. We used Scopus and PubMed as the search engines on October 18, 2022, employing specific search terms ("COVID*" AND ("Psychotherap*" OR "psychological support*") AND "psychological distress*"). The initial search yielded 153 articles, of which 18 met the eligibility criteria after two rounds of screening. The distribution of participants ranged from the general population to patients with COVID-19 and those who had recovered. However, no studies of patients with post-COVID-19 sequelae were found. The distribution of the types of and psychological support varied and the use of new technology was suggested. Online interventions comprised the majority of the means of psychotherapies and psychological support. This study suggests that psychotherapies and psychological support during the COVID-19 pandemic were influenced by the social situation.