bluuebunny/crossref_metadata_2025_split huggingface dataset:
REVEL is better at predicting pathogenicity of loss-of-function than gain-of-function variants
Authors: Hopkins Jasmin J , Wakeling Matthew N , Johnson Matthew B , Flanagan Sarah E , Laver Thomas W 
Published: June 2023

AbstractIn silicopredictive tools can help determine the pathogenicity of variants. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines recommended that scores from these tools can be used as supporting evidence of pathogenicity. A subsequent publication by the ClinGen Sequence Variant Interpretation Working Group suggested high scores from some tools were sufficiently predictive to be used as moderate or strong evidence of pathogenicity.REVEL is a widely used meta-predictor that uses the scores of 13 individualin-silicotools to calculate pathogenicity of missense variants. Its ability to predict missense pathogenicity has been assessed extensively, however, no study has previously tested whether its performance is affected by whether the missense variant acts via a loss of function (LoF) or gain of function (GoF) mechanism.We used a highly curated dataset of 66 confirmed LoF and 65 confirmed GoF variants to evaluate whether this affected the performance of REVEL.98% of LoF and 100% of GoF variants met the author-recommended REVEL threshold of 0.5 for pathogenicity, while 89% LoF and 88% GoF variants exceeded the 0.75 threshold. However, while 55% of LoF variants met the threshold recommended for a REVEL score to count as strong evidence of pathogenicity from the ACMG guidelines (0.932), only 35% of GoF variants met this threshold (P=0.0352).GoF variants are therefore less likely to receive the highest REVEL scores which would enable the REVEL score to be used as strong evidence of pathogenicity. This has implications for classification with the ACMG guidelines as GoF variants are less likely to meet the criteria for pathogenicity.
Age-dependent modulation of the excitability of layer V pyramidal neurons by dopamine D1 receptors in mice’s primary motor cortex
Authors: Plateau Valentin , Baufreton Jérôme , Le Bon-Jégo Morgane 
Published: June 2023

AbstractThe primary motor cortex (M1) receives dopaminergic (DAergic) projections from the midbrain which play a key role in modulating motor and cognitive processes, such as motor skill learning. However, little is known at the level of individual neurons about how dopamine (DA) and its receptors modulate the intrinsic properties of the different neuronal subpopulations in M1 and if this modulation depends on age. Using immunohistochemistry, we first mapped the cells expressing the DA D1 receptor across the different layers in M1, and quantified the number of pyramidal neurons (PNs) expressing the D1 receptor in the different layers, in young and adult mice. This work reveals that the spatial distribution and the molecular profile of D1 receptor-expressing neurons across M1 layers do not change with age. Then, combining whole-cell patch-clamp recordings and pharmacology, we exploredex vivoin young and adult mice the impact of activation or blockade of D1 receptors on PN intrinsic properties and identified a distinct modulation of intrinsic electrical properties of layer V PNs by D1 receptors depending on the age of the animal.HighlightsThe laminar distribution in M1 of cells expressing the dopamine D1 receptor is similar in young and adult miceMost of D1R-expressing cells in M1 also express Satb2D1R activation increases M1 layer V pyramidal neurons’ excitability both in young and adult miceThe effect of D1R blockade on M1 layer V pyramidal neurons’ excitability differs between young and adult mice
Motile bacteria leverage bioconvection for eco-physiological benefits in a natural aquatic environment
Authors: Nezio Francesco Di , Roman Samuele , Buetti-Dinh Antoine , Steiner Oscar Sepúlveda , Bouffard Damien , Sengupta Anupam , Storelli Nicola 
Published: June 2023

AbstractBioconvection, the active self-sustaining transport phenomenon triggered by the accumulation of motile microbes under competing physico-chemical cues, has been long studied, with recent reports suggesting its role in driving ecologically-relevant fluid flows. Yet, how this collective behaviour impacts the ecophysiology of swimming microbes remains unexplored. Here, through physicochemical profiles and physiological characterizations analysis of the permanently stratified meromictic Lake Cadagno, we characterize the community structure of a dense layer of anaerobic phototrophic sulfur bacteria, and report that the associated physico-chemical conditions engender bioconvection when bulk of the motile purple sulfur bacteriumChromatium okeniisynchronize their movement against the gravity direction. The combination of flow cytometry and fluorescentin situhybridization (FISH) techniques uncover the eco-physiological effects resulting from bioconvection, and simultaneous measurements using dialysis bags and14C radioisotope, allowed us to quantifyin situthe diurnal and nocturnal CO2fixation activity of the three co-existing species in the bacterial layer. The results provide a direct measure of the cellular fitness, with comparative transcriptomics data – ofC. okeniipopulations present in regions of bioconvection vis-à-vis populations in bioconvection-free regions – indicating the transcripts potentially involved in the bioconvection process. This work provides direct evidence of the impact of bioconvection onC. okeniimetabolism, and highlights the functional role of bioconvection in enhancing the metabolic advantage ofC. okeniirelative to other microbial species inhabiting the microbial layer.
Pre-attentive representation of prediction certainty in autism: A mismatch negativity (MMN) study
Authors: Reisli Seydanur , Molholm Sophie 
Published: June 2023

ABSTRACTAccording to predictive processing theories of perception, the brain generates predictions to prepare for sensory input, and calibrates certainty of predictions based on their likelihood. When an input doesn’t match the prediction, an error signal leads to updating of the predictive model. Prior research suggests altered prediction certainty in autism, but predictive processing occurs across the cortical hierarchy, and the stage(s) of processing where prediction certainty breaks down is unknown. We therefore tested the integrity of prediction certainty in autism at pre-attentive and relatively automatic processing stages using the pre-attentive Mismatch Negativity (MMN) brain response. The MMN occurs in response to a “deviant” presented in a stream of “standards” and is measured while the participant performs an orthogonal task. Most critically, MMN amplitude typically varies with the level of certainty associated with the prediction. We recorded high-density EEG while presenting adolescents and young adults with and without autism with repetitive tones every half second (the standard) interspersed with infrequent pitch and inter-stimulus-interval (ISI) deviants. Pitch and ISI deviant probabilities were manipulated at 4, 8, or 16% within a block of trials to test whether MMN amplitude varied in a typical manner with respect to probability. For both groups, Pitch-MMN amplitude increased as the probability of deviance decreased. Unexpectedly, ISI-MMN amplitude did not reliably vary by probability in either group. Our Pitch-MMN findings suggest intact neural representation of pre-attentive prediction certainty in autism, addressing a critical knowledge gap in autism research. The implications of these findings are considered.LAY SUMMARYOur brains are always trying to predict what will happen next. For example, when you open your utensil drawer, it would be surprising to see books because your brain expected to see utensils. In our study, we looked at whether the brains of autistic individuals automatically and accurately recognize when something unexpected happens. Results showed similar brain patterns in individuals with and without autism, suggesting that responses to prediction violations are generated in a typical manner during early cortical information processing.
FloraTraiter: Automated parsing of traits from descriptive biodiversity literature
Authors: Folk R.A. , Guralnick R.P. , LaFrance R.T. 
Published: June 2023

Premise—Plant trait data are essential for quantifying biodiversity and function across Earth, but these data are challenging to acquire for large studies. Diverse strategies are needed, including the liberation of heritage data locked within specialist literature such as floras and taxonomic monographs. Here we report FloraTraiter, a novel approach using rule-based natural language processing (NLP) to parse computable trait data from biodiversity literature.Methods and Results—FloraTraiter was implemented through collaborative work between programmers and botanical experts, and customized for both online floras and scanned literature. We report a strategy spanning OCR, recognition of taxa, iterative building of traits, and establishing linkages among all of these, as well as curational tools and code for turning these results into standard morphological matrices. Over 95% of treatment content was successfully parsed for traits with < 1% error. Data for more than 700 taxa are reported including a demonstration of common downstream uses.Conclusions—We identify strategies, applications, tips, and challenges that we hope will facilitate future similar efforts to produce large open-source trait datasets for broad community reuse. Largely automated tools like FloraTraiter will be an important addition to the toolkit for assembling trait data at scale.
A Bayesian observer model reveals a prior for natural daylights in hue perception
Authors: Su Yannan , Shi Zhuanghua , Wachtler Thomas 
Published: June 2023

AbstractIncorporating statistical characteristics of stimuli in perceptual processing can be highly beneficial for reliable estimation from noisy sensory measurements but may generate perceptual bias. According to Bayesian inference, perceptual biases arise from integrating internal priors with noisy sensory inputs. We used a Bayesian observer model to derive biases and priors in hue perception based on discrimination data for hue ensembles with varying levels of chromatic noise. For isoluminant stimuli with hue defined by azimuth angle in cone-opponent color space, discrimination thresholds showed a bimodal pattern, with lowest thresholds near a non-cardinal blue-yellow axis that aligns closely with the variation of natural daylights. Perceptual biases showed zero crossings around this axis, indicating repulsion away from yellow and attraction towards blue. The biases could be explained by the Bayesian observer model through a non-uniform prior with a preference for blue. Our results suggest that visual processing exploits knowledge of the distribution of colors in natural environments for hue perception.
Quantifying and predicting chromatic thresholds
Authors: Zhou Jingyang 
Published: June 2023

AbstractPerceptual thresholds measured in the two-dimensional chromatic diagram are elliptical in shape. Across different parts of the chromatic diagram, these ellipses vary in their sizes, their tilting angles, and in how much they elongate. Overall, the chromatic thresholds exhibit intriguing patterns that were reflected in McAdam’s measurements in 1942. Previously, da Fonseca and Samengo (2016) used a neural model combined with Fisher information (a quantification of perceptual thresholds) to predict the pattern of chromatic thresholds measured in human observers. The model assumes linear cone responses paired with Poisson noise. I furthered the analysis, and studied two additional aspects of chromatic perception. First, I quantified how the pattern of chromatic thresholds vary when the proportion of three cone types (short-, mid-, and long-wavelength) varies. This analysis potentially leads to efficient estimation of thresholds across the chromatic diagram. Second, I analyzed to what extent the assumption of Poisson noise contributes to the threshold predictions. Surprisingly, eliminating Poisson noise betters the model prediction. So in addition to Poisson noise, I examined three alternative noise assumptions, and achieved improved predictions to MacAdam’s data. At last, I examined an application using the improved model-predictions. The total number of cones, as well as the proportion ofScone vary across retinal eccentricities. I showed that these two variations predict chromatic threshold patterns across retinal eccentricities are drastically different.
Multi-study fMRI outlooks on subcortical BOLD responses in the stop-signal paradigm
Authors: Isherwood S.J.S. , Kemp S.A. , Miletić S. , Stevenson N. , Bazin P-L. , Forstmann B.U. 
Published: June 2023

AbstractThis study investigates the functional network underlying response inhibition in the human brain, particularly the role of the basal ganglia in successful action cancellation. Functional magnetic resonance imaging (fMRI) approaches have frequently used the stop-signal task (SST) to examine this network. We merge five such datasets, using a novel aggregatory method allowing the unification of raw fMRI data across sites. This meta-analysis, along with other recent aggregatory fMRI studies, does not find evidence for the innervation of thehyperdirectorindirectcortico-basal-ganglia pathways in successful response inhibition. What we do find, is large subcortical activity profiles forfailed stoptrials. We discuss possible explanations for the mismatch of findings between the fMRI results presented here and results from other research modalities that have implicated nodes of the basal ganglia in successful inhibition. We also highlight the substantial effect smoothing can have on the conclusions drawn from task-specific GLMs. First and foremost, this study presents a proof of concept for meta-analytical methods that enable the merging of extensive, unprocessed or unreduced datasets. It demonstrates the significant potential that open-access data sharing can offer to the research community. With an increasing number of datasets being shared publicly, researchers will have the ability to conduct meta-analyses on more than just summary data.
CRISPR-Cas12a-Based Rapid and Sensitive Detection ofrpoBL378R inMycobacterium tuberculosis
Authors: Yang Li , Li Xiaoyu , Tang Jing , Zhu Yue , Ma Kai , Yang Yuma , Hui Zhaoyuan , Qin Yanyan , Lei Hetian , Shan Minghai , Yang Yanhui 
Published: June 2023

AbstractRifampin is the most effective drug in the treatment of tuberculosis, whose major pathogen isMycobacterium tuberculosis(MTB), whereas there are still certain MTB strains resistant to the therapy of rifampin. TherpoBmutations play a central role in MTB resistance to the rifampin therapy, so it is crucial to identify these mutations in order to discover novel therapeutic approaches to these drug-resistant MTB strains. Here we show that a CRISPR-Cas12a-based detection platform with recombinase polymerase amplification and fluorescence reporter can be utilized to detect and visualize an MTB drug-resistant point mutation (rpoBL378R) from itsrpoBwild type. Notably, this detection system is highly specific because it did not cross-react with contrived reference samples containing the genomes of MTBH37Rv,Mycobacterium smegmatis(M. smegmatis),Mycobacterium aureus(M. aureus), andEscherichia coli(E. coli). Collectively, this strategy based on CRISPR-Cas12a that we show in this report is simple, sensitive as well as specific for detection of the rifampin-resistant MTBH37Rvwith therpoBL378R mutation, indicating that this CRISPR-Cas12a-based detection platform has high potential to be exploited for clinic application to identify MTB mutations.
Widespread impact of immunoglobulin V gene allelic polymorphisms on antibody reactivity
Authors: Yuan Meng , Feng Ziqi , Lv Huibin , So Natalie , Shen Ivana R. , Tan Timothy J.C. , Teo Qi Wen , Ouyang Wenhao O. , Talmage Logan , Wilson Ian A. , Wu Nicholas C. 
Published: June 2023

ABSTRACTThe ability of human immune system to generate antibodies to any given antigen can be strongly influenced by immunoglobulin V gene (IGV) allelic polymorphisms. However, previous studies have provided only a limited number of examples. Therefore, the prevalence of this phenomenon has been unclear. By analyzing >1,000 publicly available antibody-antigen structures, we show that many IGV allelic polymorphisms in antibody paratopes are determinants for antibody binding activity. Biolayer interferometry experiment further demonstrates that paratope allelic mutations on both heavy and light chain often abolish antibody binding. We also illustrate the importance of minor IGV allelic variants with low frequency in several broadly neutralizing antibodies to SARS-CoV-2 and influenza virus. Overall, this study not only highlights the pervasive impact of IGV allelic polymorphisms on antibody binding, but also provides mechanistic insights into the variability of antibody repertoires across individuals, which in turn have important implications for vaccine development and antibody discovery.
Prior experience with behavioral control over stress facilitates social dominance
Authors: Coleman Philip T. , Costanza-Chavez Gabriel W. , Martin Heather N. , Amat Jose , Frank Matthew G. , Sanchez Rory J. , Potter Garrett J. , Mellert Simone M. , Carter Rene K. , Bonnici Gianni N. , Maier Steven F. , Baratta Michael V. 
Published: June 2023

AbstractDominance status has extensive effects on physical and mental health, and an individual’s relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats. Prior experience of controllable, but not physically identical uncontrollable, stress increased later effortful behavior and occupation of the warm spot. Controllable stress subjects consistently ranked higher than did uncontrollable stress subjects. Pharmacological inactivation of the prelimbic (PL) cortex during behavioral control prevented later facilitation of dominance. Next, we explored whether repeated winning experiences produced later resistance against the typical sequelae of uncontrollable stress. To establish dominance status, triads of rats were given five sessions of warm spot competition. Reversible inactivation of the PL or NMDA receptor blockade in the dorsomedial striatum led to a long-term reduction in social rank. Stable dominance blunted the later stress-induced increase in dorsal raphe nucleus serotonergic activity, as well as prevented stress-induced social avoidance. In contrast, endocrine and neuroimmune responses to uncontrollable stress were unaffected, indicating a selective impact of prior dominance. Together, these data demonstrate that instrumental control over stress promotes later dominance, but also reveal that winning experiences buffer against the neural and behavioral outcomes of future adversity.
In silicoandin vitrocharacterization of the mycobacterial protein Ku to unravel its role in non-homologous end-joining DNA repair
Authors: Baral Joydeep , Bhattacharje Gourab , Dash Sagarika , Samanta Dibyendu , Hinde Elizabeth , Rouiller Isabelle , Das Amit Kumar 
Published: June 2023

AbstractNon-homologous end-joining DNA repair is essential for the survival and sustenance ofM. tuberculosis(Mtb) in the dormant stage of its life cycle. The ability of Mtb to sustain itself in the inactive form has been reported to be the critical factor for its resilience over the years. To unravel one of the salient features of the Mtb’s arsenal, we exploitedin silicoandin vitrotools to characterize the DNA binding properties of mycobacterial protein Ku (mKu) and its role in mycobacterial NHEJ. Here, we report the strong affinity of mKu for linear dsDNA exhibiting positive cooperativity for dsDNAs (ζ40bp). Molecular dynamics complemented within vitroexperiments showed that the DNA binding of mKu provides stability to both mKu homodimer and the DNA. Furthermore, mKu end-capping of DNA was seen to protect the DNA termini against nucleolytic degradation by exonuclease. The DNA-mKu association formed higher-order oligomers probably due to the lodgement of two DNA molecules at opposite ends of the mKu homodimer. The ability of mKu to form continuous filament-like structures with DNA indicated its potential role in mycobacterial NHEJ synapsis.
The intra-individual reliability of1H-MRS measurement in the anterior cingulate cortex across one year
Authors: Wang Meng-Yun , Korbmacher Max , Eikeland Rune , Craven Alexander R. , Specht Karsten 
Published: June 2023

AbstractMagnetic resonance spectroscopy (MRS) is the primary method that can measure the levels of metabolites in the brain in vivo. To achieve its potential in clinical usage, the reliability of the measurement requires further articulation. Although there are many studies that investigate the reliability of gamma-aminobutyric acid (GABA), comparatively few studies have investigated the reliability of other brain metabolites, such as glutamate (Glu), N-acetyl-aspartate (NAA), creatine (Cr), phosphocreatine (PCr), or myo-inositol (mI), which all play a significant role in brain development and functions. In addition, previous studies which predominately used only two measurements (two datapoints) failed to provide the details of the time effect (e.g., time-of-day) on MRS measurement within subjects. Therefore, in this study, MRS data located in the anterior cingulate cortex (ACC) were repeatedly recorded across one year leading to at least 25 sessions for each subject with the aim of exploring the variability of other metabolites by using the index coefficient of variability (CV); the smaller the CV, the more reliable the measurements. We found that the metabolites of NAA, tNAA, and tCr showed the smallest CVs (between 1.61 and 4.90 %), and the metabolites of Glu, Glx, mI, and tCho showed modest CVs (between 4.26 and 7.89 %). Furthermore, we found that the concentration reference of the ratio to water with tissue correction results in smaller CVs compared to the ratio to tCr. In addition, we did not find any time-of-day effect on the MRS measurements. Collectively, the results of this study indicate that the MRS measurement is reasonably reliable in quantifying the levels of metabolites.Key pointsThe MRS measurement is reliable within subject.The ratio to water provides more reliable results compared to the ratio to tCr.The ratio to water is recommended as the internal concentration reference.
Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes
Authors: Nelson A.T. , Cicardi M.E. , Markandaiah S.S. , Han J. , Philp N. , Welebob E. , Haeusler A.R. , Pasinelli P. , Manfredi G. , Kawamata H. , Trotti D. 
Published: June 2023

AbstractThe most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)nnucleotide repeat expansion (NRE) occurring in the first intron of theC9orf72gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.