bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of the Novel Pyroptosis-Related Gene Signature in Patients with Esophageal Adenocarcinoma
Authors: Zeng Ruijie , Huang Shujie , Zhuo Zewei , Wu Huihuan , Sha Weihong , Chen Hao 
Published: July 2021

AbstractEsophageal adenocarcinoma (EAC) is a highly malignant type of digestive tract cancers with a poor prognosis despite therapeutic advances. Pyroptosis is an inflammatory form of programmed cell death, whereas the role of pyroptosis in EAC remains largely unknown. Herein, we identified a pyroptosis-related five-gene signature that was significantly correlated with the survival of EAC patients in The Cancer Genome Atlas (TCGA) cohort and an independent validation dataset. In addition, a nomogram based on the five-gene signature was constructed with novel prognostic values. Moreover, the genes in the pyroptosis-related signature,CASP1, GSDMB, IL1B, PYCARD, andZBP1, might be involved in immune response and regulation of the tumor microenvironment. Our findings indicate that the five-gene signature provides insights into the involvement of pyroptosis in EAC progression, and is promising in the risk assessment as well as prognosis for EAC patients in clinical practice.
Microbial diversity and sulfur cycling in an early earth analogue: From ancient novelty to modern commonality
Authors: Hahn C. Ryan , Farag Ibrahim F. , Murphy Chelsea L. , Podar Mircea , Elshahed Mostafa S. , Youssef Noha H. 
Published: July 2021

AbstractLife emerged and diversified in the absence of molecular oxygen. The prevailing anoxia and unique sulfur chemistry in the Paleo-, Meso- and Neoarchean, and early Proterozoic eons may have supported microbial communities that are drastically different than those currently thriving on the earth’s surface. Zodletone spring in southwestern Oklahoma represents a unique habitat where spatial sampling could substitute for geological eons: from the anoxic, surficial light exposed sediments simulating a preoxygenated earth, to overlaid water column where air exposure simulates the relentless oxygen intrusion during the Neo Proterozoic. We document a remarkably diverse microbial community in the anoxic spring sediments, with 340/516 (65.89%) of genomes recovered in a metagenomic survey belonging to 200 bacterial and archaeal families that were either previously undescribed or that exhibit an extremely rare distribution on the current earth. Such diversity is underpinned by the widespread occurrence of sulfite-, thiosulfate, tetrathionate-, and sulfur-reduction, and paucity of sulfate-reduction machineries in these taxa; hence greatly expanding lineages mediating reductive sulfur cycling processes in the tree of life. Analysis of the overlaying water community demonstrated that oxygen intrusion lead to the development of a significantly less diverse community dominated by well-characterized lineages and a prevalence of oxidative sulfur cycling processes. Such transition from ancient novelty to modern commonality underscores the profound impact of the great oxygenation event on the earth’s surficial anoxic community. It also suggests that novel and rare lineages encountered in current anaerobic habitats could represent taxa once thriving in an anoxic earth, but have failed to adapt to earth’s progressive oxygenation.
The relationship between mucosal microbiota, colitis and systemic inflammation in Chronic Granulomatous Disorder
Authors: Davrandi Mehmet , Harris Stephanie , Smith Philip J , Murray Charles D , Lowe David M 
Published: July 2021

AbstractBackgroundChronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by an inflammatory colitis and is associated with systemic inflammation.ObjectiveTo investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation.MethodsWe performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients’ colons, and conducted compositional and functional pathway prediction analyses.ResultsThe microbiota in samples from colitis patients demonstrated reduced taxonomic alpha diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilisation were enriched in patients with colitis and correlated positively with faecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by faecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into ‘High’ and ‘Low’ systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta diversity analyses.ConclusionThe microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition.Key MessagesThe colonic mucosal microbiome and bacterial metabolic pathways in patients with CGD colitis differ from patients without colitis, even in macroscopically normal bowel segments.The mucosal microbiome and bacterial metabolic pathways in patients with CGD also differ according to the extent of systemic inflammation, independently from the presence of colitis, suggesting a role for the gut microbiota in the inflammatory phenotype of this condition.Capsule summaryThe pathogenesis of chronic granulomatous disorder (CGD)-associated colitis and other inflammatory complications is unclear. We demonstrate potentially treatable alterations in the mucosa-associated microbiome in CGD colitis and microbial differences which associate with systemic inflammation independently of colitis status.
Inhibitory control of synaptic signals preceding motor action in mouse frontal cortex
Authors: Zhang Chun-Lei , Koukouli Fani , Allegra Manuela , Ortiz Cantin , Kao Hsin-Lun , Maskos Uwe , Changeux Jean-Pierre , Schmidt-Hieber Christoph 
Published: July 2021

ABSTRACTPreparatory activity in the frontal cortex preceding movement onset is thought to represent a neuronal signature of motor planning. However, how excitatory and inhibitory synaptic inputs to frontal neurons are integrated during movement preparation remains unclear. Here we address this question by performing in vivo whole-cell patch-clamp recordings in the secondary motor cortex (MOs) of head-fixed mice moving on a treadmill. We find that both superficial and deep principal neurons show slowly increasing (~10 s) membrane potential and spike rate ramps preceding the onset of spontaneous, self-paced running periods. By contrast, in animals trained to perform a goal-directed task, both membrane potential and spike ramps are characterized by larger amplitudes and accelerated kinetics during preparation of goal-driven movement. To determine the role of local inhibitory neurons in shaping these task-dependent preparatory signals, we chemogenetically suppressed the activity of specific interneuron subpopulations in untrained animals. Inactivation of parvalbumin-positive (PV+) interneurons leads to depolarized membrane potential ramps with increased amplitudes during preparation of movement, while inactivation of somatostatin-positive (SOM+) interneurons abolishes membrane potential ramps. A computational model of the local MOs circuit shows that SOM+-mediated inhibition of PV+ interneurons in conjunction with recurrent connectivity among the principal neurons can reproduce slow ramping signals, while plasticity of excitatory synapses on SOM+ interneurons can explain the acceleration of these signals in trained animals. Together, our data reveal that local inhibitory neurons play distinct roles in controlling task-dependent preparatory ramping signals when MOs neurons integrate external inputs during motor planning.HighlightsPrincipal neurons in MOs show slow preparatory membrane potential and firing rate ramps preceding the onset of spontaneous, self-paced running periods.In animals trained to perform a goal-directed task, both membrane potential and spike ramps are faster and larger in amplitude.Inactivation of PV+ interneurons disinhibits MOs principal neurons and increases the amplitude of membrane potential ramps, while inactivation of SOM+ interneurons abolishes membrane potential ramps.Our modeling results suggest that the concerted action of external inputs and local inactivation shapes task-dependent preparatory motor signals in MOs neurons.
Discrete Roles of the Ir76b Ionotropic Co-Receptor Impact Olfaction, Blood Feeding, and Mating in the Malaria Vector Mosquito Anopheles coluzzii
Authors: Ye Zi , Liu Feng , Sun Huahua , Baker Adam , Zwiebel Laurence J. 
Published: July 2021

AbstractAnopheline mosquitoes rely on their highly sensitive chemosensory apparatus to detect diverse chemical stimuli that drive the host-seeking and blood-feeding behaviors required to vector pathogens for malaria and other diseases. This process incorporates a variety of chemosensory receptors and transduction pathways. We have used advanced in vivo gene-editing and -labelling approaches to localize and functionally characterize the ionotropic co-receptor AcIr76b in the malaria mosquito Anopheles coluzzii, where it impacts both olfactory and gustatory systems. AcIr76b has a broad expression pattern in female adult antennal grooved pegs, T1 and T2 sensilla on the labellum, stylets, and tarsi, as well as the larval sensory peg. AcIr76b is co-localized with the Orco odorant receptor (OR) co-receptor in a subset of cells across the female antennae and labella. In contrast to Orco and Ir8a, chemosensory co-receptors that appear essential for the activity of their respective sets of chemosensory neurons in mosquitoes, AcIr76b-/- mutants maintain wild-type peripheral responses to volatile amines on the adult palps, labellum, and the larval sensory cone. Interestingly, AcIr76b-/- mutants display significantly increased responses to amines in antennal grooved peg sensilla while coeloconic sensilla reveal significant deficits in responses to several acids and amines. Behaviorally, AcIr76b mutants manifest significantly female-specific insemination deficits and, although AcIr76b-/- mutant females are able to locate, alight, and probe artificial blood hosts, they are incapable of blood feeding successfully. Taken together, our study reveals a multi-dimensional functionality of Ir76b in Anopheline olfactory and gustatory pathways that directly impacts the vectorial capacity of these mosquitoes.SummaryChemosensory receptors play crucial roles across mosquito lifecycles where they often form functional complexes that require cognate co-receptors. To better understand mosquito chemosensory pathways in the malaria vector mosquito An. coluzzii we have utilized advanced gene editing approaches to localize and functionally characterize the ionotropic receptor co-receptor AcIr76b. Expression of AcIr76b was observed in antennal grooved pegs and other accessory olfactory appendages. Mutagenesis of AcIr76b uncovers both reduced and elevated neuronal responses to amines, which suggests a role in response modulation. In addition to olfactory phenotypes, AcIr76b mutants display significantly impaired mating and blood feeding capabilities. Our data reveals discrete roles of AcIr76b across olfactory and gustatory pathways and shed lights on the potential molecular target for vector control strategies.
Antisense-mediated repression of SAGA-dependent genes involves the HIR histone chaperone
Authors: Soudet Julien , Beyrouthy Nissrine , Pastucha Anna Marta , Maffioletti Andrea , Bakir Zahra , Stutz Françoise 
Published: July 2021

AbstractEukaryotic genomes are pervasively transcribed by RNA polymerase II (RNAPII), and transcription of long non-coding RNAs often overlaps with coding gene promoters. This might lead to coding gene repression in a process named Transcription Interference (TI). In Saccharomyces cerevisiae (S. cerevisiae), TI is mainly driven by antisense non-coding transcription and occurs through re-shaping of promoter Nucleosome-Depleted Regions (NDRs). In this study, we developed a genetic screen to identify new players involved in Antisense-Mediated Transcription Interference (AMTI). Among the candidates, we found the HIR histone chaperone complex known to be involved in de novo histone deposition. Using genome-wide approaches, we reveal that HIR-dependent histone deposition represses the promoters of SAGA-dependent genes via antisense non-coding transcription. However, while antisense transcription is enriched at promoters of SAGA-dependent genes, this feature is not sufficient to define the mode of gene regulation. We further show that the balance between HIR-dependent nucleosome incorporation and transcription factor binding at promoters directs transcription into a SAGA- or TFIID-dependent regulation. This study sheds light on a new connection between antisense non-coding transcription and the nature of coding transcription initiation.
CRISPR-VAE: A Method for Explaining CRISPR/Cas12a Predictions, and an Efficiency-aware gRNA Sequence Generator
Authors: Obeid Ahmad , AlMarzouqi Hasan 
Published: July 2021

AbstractDeep learning has shown great promise in the prediction of the gRNA efficiency, which helps optimize the engineered gRNAs, and thus has greatly improved the usage of CRISPR-Cas systems in genome editing. However, the black box prediction of deep learning methods does not provide adequate explanation to the factors that increase efficiency; rectifying this issue promotes the usage of CRISPR-Cas systems in numerous domains. We put forward a framework for interpreting gRNA efficiency prediction, dubbed CRISPR-VAE, that improves understanding the factors that increase gRNA efficiency, and apply it to CRISPR/Cas12a (formally known as CRISPR/Cpf1). We further lay out a semantic articulation of such factors into position-wise k-mer rules. The paradigm consists of building an efficiency-aware gRNA sequence generator trained on available real data, and using it to generate a large amount of synthetic sequences with favorable traits, upon which the explanation of the gRNA prediction is based. CRISPR-VAE can further be used as a standalone sequence generator, where the user has low-level control ability. The framework can be readily integrated with different CRISPR-Cas tools and datasets, and its efficacy is confirmed. The complete implementation of the methods can be found at github.com/AhmadObeid/CRISPR-VAE.
Mapping the glycosyltransferase fold landscape using deep learning
Authors: Taujale Rahil , Zhou Zhongliang , Yeung Wayland , Moremen Kelley W , Li Sheng , Kannan Natarajan 
Published: July 2021

AbstractGlycosyltransferases (GTs) play fundamental roles in nearly all cellular processes through the biosynthesis of complex carbohydrates and glycosylation of diverse protein and small molecule substrates. The extensive structural and functional diversification of GTs presents a major challenge in mapping the relationships connecting sequence, structure, fold and function using traditional bioinformatics approaches. Here, we present a convolutional neural network with attention (CNN-attention) based deep learning model that leverages simple secondary structure representations generated from primary sequences to provide GT fold prediction with high accuracy. The model learned distinguishing features free of primary sequence alignment constraints and, unlike other models, is highly interpretable and helped identify common secondary structural features shared by divergent families. The model delineated sequence and structural features characteristic of individual fold types, while classifying them into distinct clusters that group evolutionarily divergent families based on shared secondary structural features. We further extend our model to classify GT families of unknown folds and variants of known folds. By identifying families that are likely to adopt novel folds such as GT91, GT96 and GT97, our studies identify targets for future structural studies and expand the GT fold landscape.
The Phytochemical Diversity of Commercial Cannabis in the United States
Authors: Smith Christiana J. , Vergara Daniela , Keegan Brian , Jikomes Nick 
Published: July 2021

AbstractThe legal status of Cannabis is changing, fueling an increased diversity of Cannabis-derived products. Because Cannabis contains dozens of chemical compounds with potential psychoactive or medicinal effects, understanding its phytochemical diversity is crucial. The legal Cannabis industry heavily markets products to consumers based on widely used labelling systems purported to predict the effects of different Cannabis “strains.” We analyzed the cannabinoid and terpene content of tens of thousands of commercial Cannabis samples across six US states, finding distinct chemical phenotypes (chemotypes) which are reliably present. After careful descriptive analysis of the phytochemical diversity and comparison to the commercial labels commonly attached to Cannabis samples, we show that commercial labels do not consistently align with the observed chemical diversity. However, certain labels are statistically overrepresented for specific chemotypes. These results have important implications for the classification of commercial Cannabis, the design of animal and human research, and the regulation of legal Cannabis marketing.
Variation in mechanical and structural properties of enamel in primate molars
Authors: Towle Ian , Loho Thomas , Salem Amira , Loch Carolina 
Published: July 2021

AbstractMechanical properties of enamel are known to vary across molar crowns in some primates, but the association of this variation with phylogeny, structural properties and tribological behaviour is not well understood. In this study, 20 molars from a range of primate taxa (n=15) were studied using nanoindentation, micro-CT scanning, and SEM imaging. After micro-CT scanning, teeth were sectioned in the lingual-buccal plane through the mesial cusps. Five positions (buccal lateral, buccal cuspal, occlusal middle, lingual cuspal, lingual lateral) were studied in three locations (inner, middle, outer enamel regions). The results show middle enamel had the highest hardness and elastic modulus values in all positions. ‘Non-functional’ molar sides (lingual in lower molars and buccal in upper molars) had higher hardness values than their ‘functional’ counterparts. Increase in prism size was associated with a decrease in hardness in some tooth positions, and mineral density showed a significant relationship with elastic modulus values. Variation in enamel structure variation (e.g., enamel Schmelzmuster, Hunter-Schreger band thickness), may also be crucial in explaining variation in mechanical properties, with decussation zones associated with higher mechanical properties values. Primate enamel is not a homogeneous material, with variation in mechanical and structural properties across the crown likely associated with functional differences and variation in force distribution. Overall structural and mechanical patterns were similar in the primate species studied despite substantial differences in diet, suggesting these properties are potentially evolutionary conserved.
Predicting RNA splicing from DNA sequence using Pangolin
Authors: Zeng Tony , Li Yang I 
Published: July 2021

AbstractRecent progress in deep learning approaches have greatly improved the prediction of RNA splicing from DNA sequence. Here, we present Pangolin, a deep learning model to predict splice site strength in multiple tissues that has been trained on RNA splicing and sequence data from four species. Pangolin outperforms state of the art methods for predicting RNA splicing on a variety of prediction tasks. We use Pangolin to study the impact of genetic variants on RNA splicing, including lineage-specific variants and rare variants of uncertain significance. Pangolin predicts loss-of-function mutations with high accuracy and recall, particularly for mutations that are not missense or nonsense (AUPRC = 0.93), demonstrating remarkable potential for identifying pathogenic variants.
Target-specific control of olfactory bulb periglomerular cells by GABAergic and cholinergic basal forebrain inputs
Authors: De Saint Jan Didier 
Published: July 2021

AbstractThe olfactory bulb (OB), the first relay for odor processing, receives dense GABAergic and cholinergic long-range projections from basal forebrain (BF) nuclei that provide information about the internal state and behavioral context of the animal. However, the targets, impact and dynamics of these afferents are still unclear. I studied how BF synaptic inputs modulate activity in diverse subtypes of periglomerular (PG) interneurons using optogenetic stimulation and loose cell-attached or whole-cell patch-clamp recording in OB slices from adult mice. GABAergic BF inputs potently blocked PG cells firing except in a minority of calretinin-expressing cells in which GABA release elicited spiking. Parallel cholinergic projections excited a previously overlooked PG cell subtype via synaptic activation of M1 muscarinic receptors. Low frequency stimulation of the cholinergic axons drove persistent firing in these PG cells thereby increasing tonic inhibition in principal neurons. Taken together, these findings suggest that modality-specific BF inputs can orchestrate inhibition in OB glomeruli using multiple, potentially independent, inhibitory or excitatory target-specific pathways.
Developmental increase of inhibition drives decorrelation of neural activity
Authors: Chini Mattia , Pfeffer Thomas , Hanganu-Opatz Ileana L. 
Published: July 2021

AbstractThroughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet the mechanisms underlying this process are unknown. The developmental transition has important functional consequences, as the latter state allows for more efficient storage, retrieval and processing of information. Here, we show that, in the mouse medial prefrontal cortex (mPFC), neural activity during the first two postnatal weeks decorrelates following specific spatial patterns. This process is accompanied by a concomitant tilting of excitation/inhibition (E-I) ratio towards inhibition. Using optogenetic manipulations and neural network modeling, we show that the two phenomena are mechanistically linked, and that a relative increase of inhibition drives the decorrelation of neural activity. Accordingly, in two mouse models of neurodevelopmental disorders, subtle alterations in E-I ratio are associated with specific impairments in the correlational structure of spike trains. Finally, capitalizing on EEG data from newborn babies, we show that an analogous developmental transition takes place also in the human brain. Thus, changes in E-I ratio control the (de)correlation of neural activity and, by these means, its developmental imbalance might contribute to the pathogenesis of neurodevelopmental disorders.