bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell RNA-seq identifies inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma
Authors: Chen Ling , Hoefel Gabriela Araujo , Pathinayake Prabuddha S. , Reid Andrew , Kelly Coady , HuiYing Tan , Kim Richard Y , Hansbro Philip M , Brody Steven L , Foster Paul S , Horvat Jay C , Riveros Carlos , Wark Peter AB , Kaiko Gerard E 
Published: April 2022

AbstractAsthma is the most common chronic airways disease worldwide and the severe treatment resistant subtype of asthma is responsible for the majority of disease burden. Asthma is heterogeneous in nature and can be classified according to airway infiltrates as eosinophilic or non-eosinophilic (sometimes referred to as Type 2 low), which is further divided into paucigranulocytic (low levels of granulocytes), or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in airway tissue, sputum, and bronchoalveolar lavage. Severe non-eosinophilic asthma currently has fewer effective treatment options and many of these patients fail to qualify for newer biologic monoclonal therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is a key protein whose function is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease (COPD) and has proven a valuable therapeutic target. Using human bronchial epithelial cells (hBECs) isolated differentiated at air-liquid interface we demonstrated a reduced function of the CFTR in non-eosinophilic asthma. Characterization of the cell and molecular differences in airway epithelial cells between severe asthma subtypes using single cell RNA-sequencing (scRNAseq) revealed that airway epithelial cells from non-eosinophilic asthma, and in particular neutrophilic asthma patients, fail to differentiate into CFTR-expressing ionocytes compared with eosinophilic asthma or healthy donors. We identified a novel ionocyte transcriptional signature, which was present in both bronchial and tracheal airway epithelial samples indicating conserved anatomical gene regulation. Using protein markers and immunofluorescent quantification loss of ionocytes was confirmed in non-eosinophilic asthma hBECs. Similarly, ioncytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic allergen asthma models. Furthermore, treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture, but not IL-13, led to loss of ionocytes primarily due to IFN-γ. Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target for this difficult-to-treat disease.
Mechanisms regulating the frequency of inhibition-based gamma oscillations in primate prefrontal and parietal cortices
Authors: Gonzalez-Burgos Guillermo , Miyamae Takeaki , Reddy Nita , Dawkins Sidney , Chen Chloe , Hill Avyi , Enwright John , Ermentrout G Bard , Lewis David A. 
Published: April 2022

AbstractIn primates, the dorsolateral prefrontal (DLPFC) and posterior parietal (PPC) cortices are critical nodes in the network mediating cognitive functions including attention and working memory. Notably, during working memory tasks, gamma oscillations, usually prominent in layer 3 (L3), are induced in both DLPFC and PPC but exhibit higher frequency in DLPFC. These oscillation frequency differences might be crucial for working memory function, but the mechanisms producing different oscillation frequencies in monkey DLPFC and PPC remain poorly understood.To investigate the basis of the DLPFC-PPC differences in oscillation frequency we studied GABAAR-mediated inhibition, which plays a crucial role in gamma oscillation production, in L3 pyramidal neurons (L3 PNs) from the rhesus monkey DLPFC or PPC. Recordings of GABAAR-mediated synaptic currents from L3 PNs, while suggesting a contribution to network synchronization in both areas, revealed no DLPFC-PPC differences in the strength or kinetics of GABAAR-mediated inhibition. Likewise, the expression of GABAAR genes in L3 PNs did not differ between regions.In the absence of differences in inhibition, DLPFC L3 PNs showed greater dendritic spine density and higher expression of AMPAR and NMDAR subunit genes relative to PPC L3 PNs, suggesting that the excitatory synaptic drive onto L3 PNs could be stronger in the DLPFC. Simulations in computational models of the cortical microcircuit showed that, with constant synaptic inhibition, increasing the strength of recurrent excitatory synaptic drive increased the network oscillation frequency. Hence, the DLPFC-PPC differences in gamma oscillation frequency could depend on stronger recurrent excitation in the DLPFC relative to PPC.Significance statementGamma oscillations may contribute to the neural substrate of working memory and exhibit a higher frequency in the prefrontal (DLPFC) than parietal (PPC) areas of primate cortex. To investigate the basis of these oscillation frequency differences which may be crucial for working memory encoding, we studied GABAAR-mediated inhibition on L3 pyramidal neurons (L3 PNs) from rhesus monkey DLPFC or PPC. Our data revealed no DLPFC-PPC differences in GABAAR-mediated inhibition but showed greater dendritic spine density in DLPFC L3 PNs, suggesting stronger excitatory synaptic drive. Simulations in computational network models showed that stronger recurrent excitatory synaptic drive increased the network oscillation frequency, suggesting that the higher oscillation frequency could depend on stronger recurrent excitation in the DLPFC relative to PPC.
Bacterial lipopolysaccharide modulates immune response in the colorectal tumor microenvironment
Authors: Sulit A.K. , Daigneault M. , Allen-Vercoe E. , Silander O.K. , Hock B. , McKenzie J. , Pearson J. , Frizelle F.A. , Schmeier S. , Purcell R. 
Published: April 2022

AbstractImmune responses can have opposing effects in colorectal cancer (CRC), the balance of which may determine whether a cancer regresses, progresses, or potentially metastasizes. These effects are evident in CRC consensus molecular subtypes (CMS) where both CMS1 and CMS4 contain immune infiltrates yet have opposing prognoses. The microbiome has previously been associated with CRC and immune response in CRC but has largely been ignored in the CRC subtype discussion. Using CMS subtyping, we aimed to determine the contributions of the microbiome to the pleiotropic effects evident in immune-infiltrated subtypes. We integrated host gene-expression and meta-transcriptomic data to determine the link between immune characteristics and microbiome contributions in these subtypes and identified lipopolysaccharide (LPS) binding as a potential functional mechanism. We identified candidate bacteria with LPS properties that could affect immune response, focusing onFusobacterium periodonticumandBacteroides fragilisin CMS1, andPorphyromonas asaccharolyticain CMS4. Treatment of peripheral blood mononuclear cells (PBMCs) with LPS isolated from these bacteria showed thatF. periodonticumstimulates cytokine production in PBMCs while bothB. fragilisandP. asaccharolyticahad an inhibitory effect. Furthermore, LPS from the latter two species can inhibit the immunogenic properties ofF. periodonticumLPS when co-incubated with PBMCs. We propose that different microbes in the CRC tumor microenvironment can alter the local immune activity, with important implications for prognosis and treatment response.
Expression of cell-wall related genes is highly variable and correlates with sepal morphology
Authors: Hartasánchez Diego A. , Kiss Annamaria , Battu Virginie , Soraru Charline , Delgado-Vaquera Abigail , Massinon Florian , Brasó-Vives Marina , Mollier Corentin , Martin-Magniette Marie-Laure , Boudaoud Arezki , Monéger Françoise 
Published: April 2022

AbstractControl of organ morphology is a fundamental feature of living organisms. There is, however, observable variation in organ size and shape within a given genotype. Taking the sepal of Arabidopsis as a model, we investigated whether we can use variability of gene expression alongside variability of organ morphology to identify gene regulatory networks potentially involved in organ size and shape determination. We produced a dataset composed of morphological parameters and genome-wide transcriptome obtained from 27 individual sepals from wild-type plants with nearly identical genetic backgrounds, environment, and developmental stage. Sepals exhibited appreciable variability in both morphology and transcriptome, with response to stimulus genes and cell-wall related genes displaying high variability in expression. We additionally identified five modules of co-expressed genes which correlated significantly with morphology, revealing biologically relevant gene regulatory networks. Interestingly, cell-wall related genes were overrepresented in two of the top three modules. Overall, our work highlights the benefit of using coupled variation in gene expression and phenotype in wild-type plants to shed light on the mechanisms underlying organ size and shape determination. Although causality between gene expression and sepal morphology has not been established, our approach opens the way to informed analysis for mutant characterization and functional studies.
Weak seed banks influence the signature and detectability of selective sweeps
Authors: Korfmann Kevin , Awad Diala Abu , Tellier Aurélien 
Published: April 2022

AbstractSeed banking (or dormancy) is a widespread bet-hedging strategy, generating a form of population overlap, which decreases the magnitude of genetic drift. The methodological complexity of integrating this trait implies it is ignored when developing tools to detect selective sweeps. But, as dormancy lengthens the ancestral recombination graph (ARG), increasing times to fixation, it can change the genomic signatures of selection. To detect genes under positive selection in seed banking species it is important to 1) determine whether the efficacy of selection is affected, and 2) predict the patterns of nucleotide diversity at and around positively selected alleles. We present the first tree sequence-based simulation program integrating a weak seed bank to examine the dynamics and genomic footprints of beneficial alleles in a finite population. We find that seed banking does not affect the probability of fixation and confirm expectations of increased times to fixation. We also confirm earlier findings that, for strong selection, the times to fixation are not scaled by the inbreeding effective population size in the presence of seed banks, but are shorter than would be expected. As seed banking increases the effective recombination rate, footprints of sweeps appear narrower around the selected sites and due to the scaling of the ARG are detectable for longer periods of time. The developed simulation tool can be used to predict the footprints of selection and draw statistical inference of past evolutionary events in plants, invertebrates, or fungi with seed banks.
Elongated Hypocotyl 5 (HY5) regulates BRUTUS (BTS) to maintain Iron homeostasis in Arabidopsis thaliana
Authors: Mankotia Samriti , Singh Dhriti , Monika Kumari , Meena Himani , Meena Varsha , Yadav Ram Kishor , Pandey Ajay Kumar , Satbhai Santosh B. 
Published: April 2022

ABSTRACTIron (Fe) is an essential micronutrient for both plants and animals. Fe limitation significantly reduces crop yield and therefore has adverse impacts on human nutrition. Owing to limited bioavailability of Fe, plants have adapted different strategies that regulate Fe uptake and homeostasis. Particularly, modifications of root growth traits are a key for the survival of plants on Fe-deficient soils. Understanding the molecular basis for these root growth responses will have critical implications for plant breeding. Fe uptake is regulated by a cascade of basic helix-loop-helix (bHLH) transcription factors. In our study, we show that HY5 (Elongated Hypocotyl 5), a member of the basic leucine zipper (bZIP) family of transcription factors plays an important role in the Fe deficiency signalling pathway in Arabidopsis thaliana. The hy5 mutant plants failed to mount an optimum Fe deficiency response and showed severe root growth defects under Fe limitation that could be partially reverted by complementation of hy5 mutant. qRT-PCR analysis revealed that the induction of the genes involved in Fe uptake pathway [FER-like iron deficiency-induced transcription factor (FIT), Ferric Reduction Oxidase 2 (FRO2) and Iron-Regulated Transporter1 (IRT1)] is significantly reduced in the hy5 mutants as compared to the wild-type plants under Fe deficiency. Moreover, we also found that HY5 function is critical for activating the expression of coumarin biosynthesis genes (F6’H1, S8H, PDR9 and BGLU42) under Fe deficiency. Interestingly, our results showed that HY5 acts as a negative regulator of BRUTUS (BTS) which is known to negatively regulate Fe deficiency response. Chromatin Immunoprecipitation followed by qPCR revealed direct binding of HY5 to the promoter of BTS. Altogether, our results showed that HY5 plays an important role in regulation of Fe deficiency responses in Arabidopsis.
Differentiation of thermal reaction norms between marginal and core populations of a northward expanding parasitoid
Authors: Delava Emilie , Fleury Frederic , Gibert Patricia 
Published: April 2022

AbstractUnderstanding the speed of and the type of mechanisms that species use to adapt to rapid change is a central question in evolutionary biology. Classically, the two mechanisms denoted in the literature that allow individuals to address these environmental changes are either phenotypic plasticity or rapid evolutionary changes. However, phenotypic plasticity itself can evolve rapidly. In this study, we investigated the genetic differentiation between marginal and core populations of a high-trophic level insect,Leptopilina boulardi, aDrosophilaparasitoid, which has exhibited a very rapid progression northward of its geographical range. Several life history traits have been investigated in different populations according to four fluctuating thermal regimes that mimic the thermal conditions in the field. We found that at low developmental temperature, the two northern marginal populations that have to face a colder winter, survive longer than the two core populations. In addition, the northernmost populations exhibit a higher potential fecundity, a higher starvation resistance and a larger amount of energy at low temperatures. These significant genetic differentiations with genotype-by-environment interactions show that a rapid genetic differentiation of the shape of thermal reaction norms is possible when populations have to cope with new environments.
Voltammetry in the spleen assesses real-time anti-inflammatory norepinephrine release elicited by autonomic neurostimulation
Authors: Mughrabi Ibrahim T. , Gerber Michael , Jayaprakash Naveen , Palandira Santhoshi P. , Al-Abed Yousef , Datta-Chaudhuri Timir , Smith Corey , Pavlov Valentin A. , Zanos Stavros 
Published: April 2022

AbstractBackgroundThe noradrenergic innervation of the spleen is implicated in the autonomic control of inflammation and has been the target of neurostimulation therapies for inflammatory diseases. However, there is no real-time marker of its successful activation, which hinders the optimization of anti- inflammatory neurostimulation therapies and mechanistic studies in anti-inflammatory neural circuits.MethodsIn mice, we performed fast-scan cyclic voltammetry (FSCV) in the spleen during intravascular injections of norepinephrine (NE), or during stimulation of the vagus, splanchnic, or splenic nerves. We defined the stimulus-elicited charge generated at the oxidation potential for NE (∼0.8 V) as the “NE voltammetry signal” and quantified the dependence of the signal on NE or nerve stimulation dose. We correlated the NE voltammetry signal in response to splenic nerve stimulation (SpNS) with the latter’s anti-inflammatory effect in a model of lipopolysaccharide- (LPS) induced endotoxemia, quantified as suppression of TNF release.ResultsWe found that the NE voltammetry signal is proportional to injected amount and estimated peak NE concentration, with 0.3 μM detection threshold. In response to SpNS, the signal increases within seconds, returns to baseline minutes later and is blocked by interventions that deplete NE or inhibit NE release. The signal is elicited by efferent, but not afferent, electrical or optogenetic vagus nerve stimulation, and by splanchnic nerve stimulation. The magnitude of the signal during SpNS is inversely correlated with subsequent TNF suppression in endotoxemia and explains 40% of the variance in TNF measurements.ConclusionFSCV in the spleen provides a marker for real-time monitoring of anti-inflammatory activation of the splenic innervation during autonomic stimulation.
Functional genomics analysis identifies impairment of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome
Authors: Thomson Ella , Tran Minh , Robevska Gorjana , Ayers Katie , Bhaskaran Prarthna Gopalakrishnan , Haan Eric , Cereghini Silvia , Vash-Margita Alla , Margetts Miranda , Hensley Alison , Nguyen Quan , Sinclair Andrew , Koopman Peter , Pelosi Emanuele 
Published: April 2022

AbstractMayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital condition characterized by aplasia or hypoplasia of the uterus and vagina in women with a typical 46,XX karyotype. This condition can occur as type I when isolated or as type II when associated with extragenital anomalies including kidney and skeletal abnormalities. The genetic basis of MRKH syndrome remains unexplained and several candidate genes have been proposed to play a role in its etiology, including HNF1B, LHX1, and WNT4. Here, we conducted a genomic analysis of 13 women affected by MRKH syndrome, resulting in the identification of candidate genes, including several novel candidates. We focused on HNF1B for further investigation due to its known association with, but unknown etiological role in, MRKH syndrome. We ablated Hnf1b specifically in the epithelium of the Müllerian ducts in mice, and found that this caused hypoplastic development of both the epithelial and stromal compartments of the uterus, as well as kidney anomalies, closely mirroring the MRKH type II phenotype. Using single-cell RNA sequencing of uterine tissue in the Hnf1b-ablated embryos, we analyzed the molecules and pathways downstream of Hnf1b, revealing a dysregulation of processes associated with cell proliferation, migration, and differentiation. Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype, and generate the first mouse model of MRKH syndrome type II. Our results support the diagnostic value of HNF1B in clinical genetic testing for MRKH syndrome, and shed new light on the genetic causes of this poorly understood condition in women’s reproductive health.
Systematic Replication Enables Normalization of High-throughput Imaging Assays
Authors: Hunt Gregory J. , Dane Mark A. , Korkola James E. , Heiser Laura M. , Gagnon-Bartsch Johann A. 
Published: April 2022

AbstractMotivationHigh-throughput fluorescent microscopy is a popular class of techniques for studying tissues and cells through automated imaging and feature extraction of hundreds to thousands of samples. Like other high-throughput assays, these approaches can suffer from unwanted noise and technical artifacts that obscure the biological signal. In this work we consider how an experimental design incorporating multiple levels of replication enables removal of technical artifacts from such image-based platforms.ResultsWe develop a general approach to remove technical artifacts from high-throughput image data that leverages an experimental design with multiple levels of replication. To illustrate the methods we consider microenvironment microarrays (MEMAs), a high-throughput platform designed to study cellular responses to microenvironmental perturbations. In application on MEMAs, our approach removes unwanted spatial artifacts and thereby enhances the biological signal. This approach has broad applicability to diverse biological assays.AvailabilityRaw data is on synapse (syn2862345), analysis code is on github (gjhunt/mema norm), a Docker image is available on dockerhub (gjhunt/memanorm). online.
Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation and gut microbiota composition in a twin study
Authors: Lapatto Helena , Kuusela Minna , Heikkinen Aino , Muniandy Maheswary , van der Kolk Birgitta W. , Gopalakrishnan Swetha , Sandvik Martin , Schmidt Mark S. , Heinonen Sini , Saari Sina , Pöllänen Noora , Kuula Juho , Hakkarainen Antti , Tampio Janne , Saarinen Tuure , Taskinen Marja-Riitta , Lundbom Nina , Groop Per-Henrik , Tiirola Marja , Katajisto Pekka , Lehtonen Marko , Brenner Charles , Kaprio Jaakko , Pekkala Satu , Ollikainen Miina , Pietiläinen Kirsi H. , Pirinen Eija 
Published: April 2022

SummaryNAD+ precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have failed to report positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twins from 22 BMI-discordant monozygotic pairs were supplemented with an escalating dose of NR (250-1000 mg/day) for 5 months (clinicaltrials.gov entry NCT03951285). NR improved blood and tissue NAD+ metabolism, muscle mitochondrial number, myoblast differentiation and gut microbiota composition independent of BMI. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.
Gestational Early-Time Restricted Feeding Results in Sex-Specific Glucose Intolerance in Adult Male Mice
Authors: Mulcahy Molly C. , Habbal Noura El , Snyder Detrick , Redd JeAnna R. , Sun Haijing , Gregg Brigid E. , Bridges Dave 
Published: April 2022

AbstractThe timing of food intake is a novel dietary component that can impact health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. During pregnancy, one may experience disruptions to food intake for diverse reasons (e.g. nausea and vomiting of pregnancy, food insecurity, desire to manage gestational weight gain, disordered eating behaviors, changes in taste and food preferences, etc) and therefore may experience periods of intentional or unintentional fasting similar to TRF protocols. Because interest in TRF is gaining popularity and feeding may be interrupted in those who are pregnant, it is important to understand the long-term effects of TRF during pregnancy on the resultant offspring. Using a mouse model, we tested the effects of gestational exposure to early TRF (eTRF) over the life course of both male and female offspring. Offspring body composition was similar between experimental groups in both males and females from weaning (day 21) to adulthood (day 70), with minor increases in food intake in eTRF females and improved glucose tolerance in males. After 10 weeks of high fat, high sucrose diet feeding, male eTRF offspring were more sensitive to insulin but developed glucose intolerance with impaired insulin secretion. As such, gestational eTRF causes sex-specific deleterious effects on glucose homeostasis after chronic high fat, high sucrose diet feeding in male offspring. Further studies are needed to determine the effect gestational eTRF has on the male pancreas as well as to elucidate the mechanisms that protect females from this metabolic dysfunction.