bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conserved reward-mediated, reinforcement-learning mechanisms in Pavlovian and instrumental tasks
Authors: Afshar Neema Moin , Cinotti François , Martin David , Khamassi Mehdi , Calu Donna J. , Taylor Jane R. , Groman Stephanie M. 
Published: June 2022

AbstractModel-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based, instrumental tasks parallel those engaged by Pavlovian based behavioral procedures. Recently, computational work has suggested that individual differences in the attribution of incentive salience to reward predictive cues, i.e., sign- and goal-tracking behaviors, are also governed by variations in model-free and model-based value representations that guide behavior. Moreover, it is not appreciated if these systems that are characterized computationally using model-free and model-based algorithms are conserved across tasks for individual animals. In the current study, we used a within- subject design to assess sign-tracking and goal-tracking behaviors using a Pavlovian conditioned approach task, and, then characterized behavior using an instrumental multi-stage decision-making (MSDM) task in rats. We hypothesized that both Pavlovian and instrumental learning processes may be driven by common reinforcement-learning mechanisms. Our data confirm that sign-tracking behavior was associated with greater reward-mediated, model-free reinforcement learning and that it was also linked to model-free reinforcement learning in the MSDM task. Computational analyses revealed that Pavlovian model-free updating was correlated with model-free reinforcement learning in the MSDM task. These data provide key insights into the computational mechanisms mediating associative learning that could have important implications for normal and abnormal states.Significance StatementModel-free and model-based computations that guide instrumental, decision-making processes may also be recruited in Pavlovian based behavioral procedures. Here, we used a within-subject design to test the hypothesis that both Pavlovian and instrumental learning processes were driven by common reinforcement-learning mechanisms. Sign- tracking and goal-tracking behaviors were assessed in rats using a Pavlovian conditioned approach task, and, then instrumental behavior characterized using a multi- stage decision-making (MSDM) task. We report that sign-tracking behavior was associated with greater model-free, but not model-based, learning in the MSDM task. These data suggest that Pavlovian and instrumental behaviors are driven by conserved reinforcement-learning mechanisms.
Transit-amplifying progenitor with maturation-dependent behavior contributes to epidermal renewal
Authors: Ghuwalewala Sangeeta , Jiang Kevin , Ragi Sara , Shalloway David , Tumbar Tudorita 
Published: June 2022

AbstractTransit-amplifying progenitor populations with phased behavior have long been postulated as essential to epidermal renewal, but not experimentally observed in vivo. Here we identify a population with bi-phasic behavior using CreER genetic cell-marking in mice for long-term lineage tracing and clonal analysis. Nascent, highly expressing Aspm cells undergo an amplification-phase followed by a timed transition into an extinction-phase, with near complete loss of descending cells from skin. Generalized birth-death modeling of Aspm-CreER and a Dlx1-CreER population that behaves like a stem cell demonstrates neutral competition for both populations, but neutral drift only for the stem cells. This work identifies a long-missing class of non-self-renewing epidermal progenitors with bi-phasic behavior that appears time-dependent as the lineage matures, indicative of a transit-amplifying cell. This has broad implications for understanding cell fate decisions and tissue renewal mechanisms.One-sentence summaryWe identify a long-missing class of non-self-renewing epidermal progenitors with bi-phasic and maturation-dependent behavior in vivo.
A neuron model with unbalanced synaptic weights explains asymmetric effects of ketamine in auditory cortex
Authors: López-Jury Luciana , García-Rosales Francisco , González-Palomares Eugenia , Wetekam Johannes , Hechavarria Julio C. 
Published: June 2022

AbstractAlthough new advances in neuroscience allow the study of vocal communication in awake animals, substantial progress in the processing of vocalizations has been made from brains of anaesthetized preparations. Thus, understanding how anaesthetics affect neuronal responses is of paramount importance. Here, we used electrophysiological recordings and computational modelling to study how the auditory cortex of bats responds to vocalizations under anaesthesia and in wakefulness. We found that multifunctional neurons that process echolocation and communication sounds were affected by ketamine anaesthesia in a manner that could not be predicted by known anaesthetic effects. In wakefulness, acoustic contexts (preceding echolocation or communication sequences) led to stimulus-specific suppression of lagging sounds, accentuating neuronal responses to sound transitions. However, under anaesthesia, communication contexts (but not echolocation) led to a global suppression of responses to lagging sounds. Such asymmetric effect was dependent on the frequency composition of the contexts and not on their temporal patterns. We constructed a neuron model that could replicate the data obtainedin vivo. In the model, anaesthesia modulates spiking activity in a channel-specific manner, decreasing responses of cortical inputs tuned to high-frequency sounds and increasing adaptation in the respective cortical synapses. Combined, our findings obtainedin vivoandin silicoreveal that ketamine anaesthesia does not reduce uniformly the neurons’ responsiveness to low and high frequency sounds. This effect depends on combined mechanisms that unbalance cortical inputs and ultimately affect how auditory cortex neurons respond to natural sounds in anaesthetized preparations.
Hotspot ofde novotelomere addition stabilizes linear amplicons in yeast grown in sulfate-limiting conditions
Authors: Hoerr Remington E. , Eng Alex , Payen Celia , Di Rienzi Sara C. , Raghuraman M. K. , Dunham Maitreya J. , Brewer Bonita J. , Friedman Katherine L. 
Published: June 2022

AbstractEvolution is driven by the accumulation of competing mutations that influence survival. A broad form of genetic variation is the amplification or deletion of DNA (≥50 bp) referred to as copy number variation. In humans, copy number variation may be inconsequential, contribute to minor phenotypic differences, or cause conditions such as birth defects, neurodevelopmental disorders, and cancers. To identify mechanisms that drive copy number variation, we monitored the experimental evolution ofSaccharomyces cerevisiaepopulations grown under sulfate-limiting conditions. Cells with increased copy number of the geneSUL1, which encodes a primary sulfate transporter, exhibit a fitness advantage. Previously, we reported interstitial inverted triplications ofSUL1as the dominant rearrangement in a haploid population. Here, in a diploid population, we find instead that small linear fragments containingSUL1form and are sustained over several generations. Many of the linear fragments are stabilized byde novotelomere addition within a telomere-like sequence nearSUL1(within theSNF5gene). Using an assay that monitors telomerase action following an induced chromosome break, we show that this region acts as a hotspot ofde novotelomere addition and that required sequences map to a region of <250 base pairs. Consistent with previous work showing that association of the telomere-binding protein Cdc13 with internal sequences stimulates telomerase recruitment, mutation of a four-nucleotide motif predicted to associate with Cdc13 abolishesde novotelomere addition. Our study suggests that internal telomere-like sequences that stimulatede novotelomere addition can contribute to adaptation by promoting genomic plasticity.
Targeted gene expression profiling for accurate endometrial receptivity testing
Authors: Meltsov Alvin , Saare Merli , Teder Hindrek , Paluoja Priit , Arffman Riikka , Piltonen Terhi , Laudanski Piotr , Wielgoś Mirosław , Gianaroli Luca , Koel Mariann , Peters Maire , Salumets Andres , Palta Priit , Krjutškov Kaarel 
Published: June 2022

AbstractSTUDY QUESTIONHow accurately can a targeted gene expression sequencing assay estimate endometrial receptivity corresponding to the window of implantation?DESIGNEndometrial biopsies (n=175) from healthy fertile volunteers (n=66), polycystic ovarian syndrome (PCOS) patients (n=39), and recurrent implantation failure (RIF) patients (n=44) were collected and sequenced with TAC-seq (Targeted Allele Counting by sequencing) method targeting 68 biomarker genes for endometrial receptivity. The expressional profiles were clustered, and differential expression analysis was performed on the model development group, using 63 endometrial biopsies spanning over proliferative (PE, n=18), early-secretory (ESE, n=18), mid-secretory (MSE, n=17) and late-secretory (LSE, n=10) endometrial phases. A quantitative predictor model was trained on the development group and validated on sequenced samples from healthy women, consisting of 52 paired samples taken from ESE and MSE phases and five LSE phase samples from 31 individuals. Finally, the developed test was applied to 44 MSE phase samples gathered from a study group of patients diagnosed with RIF.RESULTSThe developed assay successfully captures the unique receptivity profile of the endometrium using 68 biomarker genes. When compared to healthy women of the same cycle phase, we did not detect any significant gene expression bias caused by PCOS in PE, ESE, MSE, and LSE samples. In validation samples (n=57), we detected displaced WOI in 1.8% of the samples from fertile women. In the RIF study group, we detected a significantly higher proportion of the samples with shifted WOI than in the validation set of samples from fertile women, 15.9% and 1.8%, respectively.CONCLUSIONSThe developed beREADY screening test enables highly sensitive and dynamic detection of selected transcriptome biomarkers, providing a quantitative and accurate prediction of endometrial receptivity status for personalised embryo transfer.
Effects of hydrometeorological and other factors on SARS-CoV-2 reproduction number in three contiguous countries of Tropical Andean South America: a spatiotemporally disaggregated time series analysis
Authors: Colston Josh M. , Hinson Patrick , Nguyen Nhat-Lan H. , Chen Yen Ting , Badr Hamada S. , Kerr Gaige H. , Gardner Lauren M. , Martin David N. , Quispe Antonio M. , Schiaffino Francesca , Kosek Margaret N. , Zaitchik Benjamin F. 
Published: June 2022

AbstractBackgroundThe COVID-19 pandemic has caused societal disruption globally and South America has been hit harder than other lower-income regions. This study modeled effects of 6 weather variables on district-level SARS-CoV-2 reproduction numbers (Rt) in three contiguous countries of Tropical Andean South America (Colombia, Ecuador, and Peru), adjusting for environmental, policy, healthcare infrastructural and other factors.MethodsDaily time-series data on SARS-CoV-2 infections were sourced from health authorities of the three countries at the smallest available administrative level. Rtvalues were calculated and merged by date and unit ID with variables from a Unified COVID-19 dataset and other publicly available sources for May – December 2020. Generalized additive mixed effects models were fitted.FindingsRelative humidity and solar radiation were inversely associated with SARS-CoV-2 Rt. Days with radiation above 1,000 KJ/m2saw a 1.3%, and those with humidity above 50%, a 1.0% reduction in Rt. Transmission was highest in densely populated districts, and lowest in districts with poor healthcare access and on days with least population mobility. Temperature, region, aggregate government policy response and population age structure had little impact. The fully adjusted model explained 3.9% of Rtvariance.InterpretationDry atmospheric conditions of low humidity increase, and higher solar radiation decrease district-level SARS-CoV-2 reproduction numbers, effects that are comparable in magnitude to population factors like lockdown compliance. Weather monitoring could be incorporated into disease surveillance and early warning systems in conjunction with more established risk indicators and surveillance measures.FundingNASA’s Group on Earth Observations Work Programme (16-GEO16-0047).
GOntact: using chromatin contacts to infer Gene Ontology enrichments for cis-regulatory elements
Authors: Laverré Alexandre , Tannier Eric , Veber Philippe , Necsulea Anamaria 
Published: June 2022

AbstractWhile the genomic positions and the patterns of activity of enhancer elements can now be efficiently determined, predicting their target genes remains a difficult task. Although chromatin conformation capture data has revealed numerous long-range regulatory interactions between genes and enhancers, enhancer target genes are still traditionally inferred based on genomic proximity. This approach is at the basis of GREAT, a widely used tool for analyzing the functional significance of sets of cis-regulatory elements. Here, we propose a new tool, named GOntact, which infers regulatory relationships using promoter-capture Hi-C (PCHi-C) data and uses these predictions to derive Gene Ontology enrichments for sets of cis-regulatory elements. We apply GOntact on enhancer and PCHi-C data from human and mouse and show that it generates functional annotations that are coherent with the patterns of activity of enhancers. We find that there is substantial overlap between functional predictions obtained with GREAT and GOntact but that each method can yield unique testable hypotheses, reflecting the underlying differences in target gene assignment. With the increasing availability of high-resolution chromatin contact data, we believe that GOntact can provide better-informed functional predictions for cis-regulatory elements.
Characterizing the diversity of L2/3 human neocortical neurons in epilepsy
Authors: Kushner J. Keenan , Hoffman Paige B. , Brzezinski Christine , Huntsman Molly M. , Alexander Allyson L. 
Published: June 2022

AbstractIn the current study, we performed whole-cell current clamp recordings from human cortical neurons in layer 2/3 of the human neocortex in order to characterize the diversity of L2/3 human neocortical neurons in epileptic foci with various etiologies in order to begin to elucidate the underlying mechanisms of hyperexcitability which are still mostly unknown. We differentiated neuronal subtypes based on their firing patterns and AHP kinetics or epilepsy subtype (malformation of cortical development (MCD) vs. other (non-MCD)). We found that L2/3 pyramidal neurons have diverse firing properties and action potential kinetics, with some neurons looking remarkably similar to LTS interneurons. We also saw that L2/3 pyramidal neurons could be split into those with fast AHPs and those without, medium AHPs (mAHPs). Based on these parameters, we were unable to significantly differentiate neurons based on firing properties indicating that AHP component kinetics alone do not dictate L2/3 pyramidal neuron firing in human epileptic cortical slices. We also report significant differences in intrinsic properties between MCD and non-MCD and control L2/3 pyramidal neurons and are the first to characterize that wash on of the proconvulsant drug, 4-aminopyridine (4-AP), leads to increased AP duration, less firing rate (FR) accommodation, and slowed down AHPs. Overall, the present study is the first to characterize the large variability of L2/3 human neocortical pyramidal neurons, to compare between L2/3 pyramidal neurons within the epileptic foci between MCD and non-MCD cases, to use control tissue from tumor patients without incidence of seizure, and to determine the influence of 4-AP on L2/3 pyramidal neuron intrinsic properties.
Estimating Speed-Accuracy Trade-offs to Evaluate and Understand Closed-Loop Prosthesis Interfaces
Authors: Mamidanna Pranav , Dideriksen Jakob L , Dosen Strahinja 
Published: June 2022

AbstractObjectiveClosed-loop prosthesis interfaces, combining electromyography (EMG)-based control with non-invasive supplementary feedback, represent a promising direction to develop the next generation of user prosthesis interfaces. However, we still lack an understanding of how users make use of these interfaces, and how to evaluate competing interfaces. In this study we use the framework of speed accuracy trade-off functions (SAF) to understand, evaluate and compare the performance afforded by two closed-loop user-prosthesis interfaces.ApproachTen able-bodied participants and one amputee performed a force matching task in a functional box-and-blocks setup at 3 different speeds. All participants were subject to both interfaces in a crossover fashion with a one-week washout period. Importantly, both interfaces used (identical) direct proportional control but differed in the feedback provided to the participant – EMG feedback vs force feedback. We thereby estimated the SAFs afforded by the two interfaces, and additionally sought to understand how participants planned and executed the task in the various conditions.Main resultsWe found that execution speed significantly influenced the performance, and that EMG feedback afforded better performance overall. Notably, we found that there was a difference in SAF between the two interfaces, with EMG feedback enabling participants to attain higher accuracies faster than Force feedback. Further, both interfaces enabled participants to develop flexible control policies, while EMG feedback also afforded participants to generate smoother more repeatable EMG commands.SignificanceOverall, the results indicate that closed-loop prosthesis interfaces afford subjects to exhibit a wide range of performance, which is affected both by the interface and the execution speed. Thereby, we argue that it is important to consider the speed accuracy trade-offs to rigorously evaluate and compare (closed-loop) user-prosthesis interfaces.
Antigenic escape accelerated by the presence of immunocompromised hosts
Authors: Kumata Ryuichi , Sasaki Akira 
Published: June 2022

AbstractThe repeated emergence of SARS-CoV-2 escape mutants from host immunity has obstructed the containment of the current pandemic and poses a serious threat to humanity. Prolonged infection in immunocompromised patients has received increasing attention as a driver of immune escape, and accumulating evidence suggests that viral genomic diversity and emergence of immune-escape mutants are promoted in immunocompromised patients. However, because immunocompromised patients comprise a small proportion of the host population, whether they have a significant impact on antigenic evolution at the population level is unknown. We used an evolutionary epidemiological model combining antigenic evolution and epidemiological dynamics in host populations with heterogeneity in immune competency to determine the impact of immunocompromised patients on the pathogen evolutionary dynamics of antigenic escape from host immunity. We derived analytical formulae of the speed of antigenic evolution in heterogeneous host populations and found that even a small number of immunocompromised hosts in the population significantly accelerates antigenic evolution. Our results demonstrate that immunocompromised hosts play a key role in viral adaptation at the population level and emphasize the importance of critical care and surveillance of immunocompromised hosts.
The association of catechol-O-methyltransferase genetic polymorphism rs4680 in physical activity among adult women
Authors: Gotlieb Lilach , Ben-Zaken Sigal 
Published: June 2022

AbstractBackgroundThe aim of the study was to explore associations between COMT A/G rs4680 polymorphisms and physical activity (PA) among healthy middle-aged women. PA is a multifactorial trait in which dopamine plays a pivotal role. The enzyme catecholamine O-methyl transferase (COMT) degrades dopamine in the synaptic area. The COMT rs4680 genetic polymorphism results in either COMT Met allele or COMT Val allele. This functional polymorphism causes differences in enzyme activity with low enzymatic activity (and higher dopamine levels), associated with the Met allele; high enzymatic activity is associated with the Val allele.MethodNinety healthy women, aged 47+5.5 years from similar demographic backgrounds, participated in the study. PA engagement was assessed by the BAECKA questionnaire of habitual physical activity PA. Genomic DNA was extracted from buccal epithelial cells for COMT rs4680 analysis.ResultsDespite a similar demographic background of the participants, a large variance was found in all PA indexes. A-allele carriers’ prevalence was the significantly higher (83%) among highly active women compared to its prevalence among moderate (64%) and low (47%) active women.ConclusionsIt seems that COMT A/G rs4680 A-allele carriers might be associated with a relatively high rate of PA practitioners in general and running in particular
Human innate lymphoid cell activation by adenoviruses is modified by host defence proteins and neutralizing antibodies
Authors: Paris Océane , Mennechet Franck JD , Kremer EJ 
Published: June 2022

AbstractInnate lymphoid cells (ILCs), the complements of diverse CD4 T helper cells, help maintain tissue homeostasis by providing a link between innate and adaptive immune responses. While pioneering studies over the last decade have advanced our understanding how ILCs influence adaptive immune responses to pathogens, far less is known about whether the adaptive immune response feeds back into an ILC response. In this study, we isolated ILCs from blood of healthy donors, fine-tuned culture conditions, and then directly challenged them with human adenoviruses (HAdVs), with HAdVs and host defence proteins (HDPs) or neutralizing antibodies (NAbs), to mimic interactions in a host with pre-existing immunity. Additionally, we developed anex vivoapproach to identify how bystander ILCs respond to the uptake of HAdVs ± neutralizing antibodies by monocyte-derived dendritic cells. We show that ILCs take up HAdVs, which induces phenotypic maturation and cytokine secretion. Moreover, NAbs and HDPs complexes modified the cytokine profile generated by ILCs, consistent with a feedback loop for host antiviral responses and potential to impact adenovirus-based vaccine efficacy.Author SummarySeveral studies have shown the importance of innate lymphoid cells (ILCs) both from an immune and physiological point of view, in particular for their role in the maintenance of tissue integrity, pathogens clearance, or in the establishment of immune tolerance. Our study focuses on the role of ILCs during direct challenge with prototype vaccines based on human adenoviruses (HAdVs) ± host defence proteins (HDPs) or neutralizing antibodies (NAbs) to mimic interactions in a host with pre-existing immunity. In parallel, through an ex vivo approach we observe how bystander ILCs respond to the uptake of HAdVs ± NAbs by monocyte-derived dendritic cells. We show that ILCs take up HAdVs, which induces pro- inflammatory and antiviral responses through phenotypic maturation and cytokine secretion. Moreover, HAdV-NAb and HAdV-HDP complexes modified the cytokine profile generated by ILCs, consistent with a feedback loop for host antiviral responses and potential to impact HAdV vaccine efficacy.