bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering compromised speech-in-noise intelligibility in older listeners: the role of cochlear synaptopathy
Authors: Garrett Markus , Vasilkov Viacheslav , Mauermann Manfred , Devolder Pauline , Wilson John L. , Gonzales Leslie , Henry Kenneth S. , Verhulst Sarah 
Published: June 2020

AbstractSpeech intelligibility declines with age and sensorineural hearing damage (SNHL). However, it remains unclear whether cochlear synaptopathy (CS), a recently discovered form of SNHL, significantly contributes to this issue. CS refers to damaged auditory-nerve synapses that innervate the inner hair cells and there is currently no go-to diagnostic test available. Furthermore, age-related hearing damage can comprise various aspects (e.g., hair cell damage, CS) that each can play a role in impaired sound perception. To explore the link between cochlear damage and speech intelligibility deficits, this study examines the role of CS for word recognition among older listeners. We first validated an envelope-following response (EFR) marker for CS using a Budgerigar model. We then applied this marker in human experiments, while restricting the speech material’s frequency content to ensure that both the EFR and the behavioral tasks engaged similar cochlear frequency regions. Following this approach, we identified the relative contribution of hearing sensitivity and CS to speech intelligibility in two age-matched (65-year-old) groups with clinically normal (n=15, 8 females) or impaired audio-grams (n=13, 8 females). Compared to a young normal-hearing control group (n = 13, 7 females), the older groups demonstrated lower EFR responses and impaired speech reception thresholds. We conclude that age-related CS reduces supra-threshold temporal envelope coding with subsequent speech coding deficits in noise that cannot be explained based on hearing sensitivity alone.Significance StatementTemporal bone histology reveals that cochlear synaptopathy (CS), characterized by damage to inner hair cell auditory nerve fiber synapses, precedes sensory cell damage and hearing sensitivity decline. Despite this, clinical practice primarily evaluates hearing status based on audiometric thresholds, potentially overlooking a prevalent aspect of sensorineural hearing damage due to aging, noise exposure, or ototoxic drugs—all of which can lead to CS. To address this gap, we employ a novel and sensitive EEG-based marker of CS to investigate its relationship with speech intelligibility. This study addresses a crucial unresolved issue in hearing science: whether CS significantly contributes to degraded speech intelligibility as individuals age. Our study-outcomes are pivotal for identifying the appropriate target for treatments aimed at improving impaired speech perception.
Histone deacetylase inhibition by gut microbe-generated short chain fatty acids entrains intestinal epithelial circadian rhythms
Authors: Luzader Deborah H. , Fawad Jibraan A. , Moutinho Thomas J. , Mitchell Paul G. , Brown-Steinke Kathleen , Zhao Jesse Y. , Rosselot Andrew E. , McKinney Craig A. , Hong Christian I. , Chou C. James , Papin Jason A. , Moore Sean R. 
Published: June 2020

ABSTRACTBackground and aimsThe circadian clock orchestrates ~24-hour oscillations of gastrointestinal (GI) epithelial structure and function that drive diurnal rhythms in the composition, localization, and metabolism of gut microbiota. Here, we use experimental and computational approaches in enteroids to reveal reciprocal effects of microbial metabolites on intestinal epithelial timekeeping by an epigenetic mechanism.MethodsWe cultured 3D PER2∷LUCIFERASE andBmal1-ELuciferasejejunal enteroids in media supplemented with sterile supernatants from the altered Schaedler Flora (ASF), a defined murine microbiota. Circadian oscillations of bioluminescent PER2 andBmal1were measured in enteroids cultured in the presence or absence of individual ASF supernatants. Separately, we applied machine learning to ASF metabolic profiles to identify phase-shifting metabolites.ResultsFiltrates from 3 of 7 ASF species (ASF360Lactobacillus intestinalis, ASF361Ligilactobacillus murinus, ASF502Clostridiumspp.) induced minimal alterations in circadian rhythms, whereas 4 ASF species (ASF356Clostridiumspp., ASF492Eubacterium plexicaudatum, ASF500Pseudoflavonifactorspp., ASF519Parabacteroides goldsteinii) induced profound, concentration-dependent phase delays. Random forest classification identified short chain fatty acids (SCFA: butyrate, propionate, acetate, and isovalerate) production as a discriminating feature of “shifters”, i.e., ASF taxa whose metabolites induce phase delay. Experiments with SCFAs confirmed machine learning predictions, with a median phase delay of 6.2 hours. Pharmacological or botanical HDAC inhibitors generated similar phase delays. Further, mithramycin A, an inhibitor of HDAC inhibition, abrogated SCFA-induced phase delays by 20% (P<0.05). Key findings were reproducible in humanBmal1-luciferaseenteroids.ConclusionsGut microbe-generated SCFAs entrain intestinal epithelial circadian rhythms, in part, by an HDACi-dependent mechanism, with critical implications for understanding microbial and circadian network regulation of intestinal epithelial homeostasis.
Idiosyncratic Perception: A Link Between Acuity, Perceived Position, and Apparent Size
Authors: Wang Zixuan , Murai Yuki , Whitney David 
Published: June 2020

AbstractPerceiving the positions of objects is a prerequisite for most other visual and visuomotor functions, but human perception of object position varies from one individual to the next. The source of these individual differences in perceived position and their perceptual consequences are unknown. Here, we tested whether idiosyncratic biases in the underlying representation of visual space propagate across different levels of visual processing. In Experiment 1, using a position matching task, we found stable, observer-specific compressions and expansions within local regions throughout the visual field. We then measured Vernier acuity (Experiment 2) and perceived size of objects (Experiment 3) across the visual field and found that individualized spatial distortions were closely associated with variations in both visual acuity and apparent object size. Our results reveal idiosyncratic biases in perceived position and size, originating from a heterogeneous spatial resolution that carries across the visual hierarchy.
Mendelian randomization identifies folliculin expression as a mediator of diabetic retinopathy
Authors: Skol Andrew D. , Jung Segun C. , Sokovic Ana Marija , Chen Siquan , Fazal Sarah , Sosina Olukayode , Borkar Poulami , Lin Amy , Sverdlov Maria , Cao Dingcai , Swaroop Anand , Bebu Ionut ,   DCCT/ EDIC Study group, Stranger Barbara E. , Grassi Michael A. 
Published: June 2020

AbstractThe goal of the study was to identify genes whose aberrant expression can contribute to diabetic retinopathy. We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes (T1D) with and without retinopathy. Those genes exhibiting the largest difference in glucose response between individuals with diabetes with and without retinopathy were assessed for association to diabetic retinopathy utilizing genotype data from a genome-wide association study meta-analysis. All genetic variants associated with gene expression (expression Quantitative Trait Loci, eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. We show that expression ofFLCNin response to glucose was greater in individuals with diabetic retinopathy compared to individuals with diabetes without retinopathy. Three large, independent cohorts of individuals with diabetes revealed an association ofFLCNeQTLs to diabetic retinopathy. Mendelian randomization further confirmed a direct positive effect of increasedFLCNexpression on retinopathy in individuals with diabetes. Together, our studies integrating genetic association and gene expression implicateFLCNas a disease gene for diabetic retinopathy.
Development of genetic tools for the thermophilic filamentous fungus Thermoascus aurantiacus
Authors: Gabriel Raphael , Prinz Julia , Jecmenica Marina , Romero-Vazquez Carlos , Chou Pallas , Harth Simon , Floerl Lena , Curran Laure , Oostlander Anne , Matz Linda , Fritsche Susanne , Gorman Jennifer , Schuerg Timo , Fleißner André , Singer Steven W. 
Published: June 2020

AbstractBackgroundFungal enzymes are vital for industrial biotechnology, including the conversion of plant biomass to biofuels and bio-based chemicals. In recent years, there is increasing interest in using enzymes from thermophilic fungi, which often have higher reaction rates and thermal tolerance compared to currently used fungal enzymes. The thermophilic filamentous fungus Thermoascus aurantiacus produces large amounts of highly thermostable plant cell wall degrading enzymes. However, no genetic tools have yet been developed for this fungus, which prevents strain engineering efforts. The goal of this study was to develop strain engineering tools such as a transformation system, a CRISPR/Cas9 gene editing system and a sexual crossing protocol to improve enzyme production.ResultsHere we report Agrobacterium tumefaciens-mediated transformation (ATMT) of T. aurantiacus using the hph marker gene, conferring resistance to hygromycin B. The newly developed transformation protocol was optimized and used to integrate an expression cassette of the transcriptional xylanase regulator xlnR, which led to up to 500% increased xylanase activity. Furthermore, a CRISPR/Cas9 gene editing system was established in this fungus, and two different gRNAs were tested to delete the pyrG orthologue with 10% and 35% deletion efficiency, respectively. Lastly, a sexual crossing protocol was established using a hygromycin B- and a 5-fluororotic acid-resistant parent strain. Crossing and isolation of progeny on selective media was completed in a week.ConclusionThe genetic tools developed for T. aurantiacus can now be used individually or in combination to further improve thermostable enzyme production by this fungus.
Signalome-wide assessment of erythrocyte response toPlasmodiumreveals novel targets for host-directed antimalarial intervention
Authors: Adderley Jack D. , von Freyend Simona John , Jackson Sarah A. , Bird Megan J. , Burns Amy L. , Anar Burcu , Metcalf Tom , Semblat Jean-Philippe , Billker Oliver , Wilson Danny W. , Doerig Christian 
Published: June 2020

AbstractIntracellular pathogens are known to mobilise host signaling pathways to manipulate gene expression in their host cell to promote their own survival. Surprisingly, evidence is emerging that specific signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap by providing a comprehensive and dynamic assessment of host erythrocyte signaling during the course of infection withPlasmodium falciparum. We used an antibody microarray that comprises 878 antibodies directed against human signaling proteins, >600 of which are phospho-specific, to interrogate the status of host erythrocyte signaling pathways at three stages of parasite development during the asexual cycle. This confirmed the pre-existing fragmentary data on the activation of a PAK-MEK pathway, and revealed the modulation of a large number of additional signaling elements during infection.We focussed on the receptor tyrosine kinase c-MET, also known as the hepatocyte growth factor receptor, and the MAP kinase pathway component B-Raf that is reported to lie downstream of c-MET in a number of cell types. Array data validated by Western blotting revealed that activation sites of c-MET are phosphorylated in trophozoite-infected erythrocytes, and we show that treatment of parasite cultures with c-MET or B-Raf selective inhibitors have nanomolar potency againstin vitroproliferation ofP. falciparumand the phylogenetically distant speciesP. knowlesi. Furthermore, we demonstrate that a c-MET inhibitor impairsin vivoproliferation of the rodent malaria parasiteP. bergheiin mice.Overall, we provide a comprehensive dataset on the modulation of host erythrocyte signaling during infection with malaria parasites, as well as a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.
Zinc deficiency decreases bone mineral density of rat by calmodulin-induced change in calcium metabolism
Authors: Yu Qingli , Zhao Jiali , Chen Yanfeng , Li Zixiang , Sun Yongzhi , Fan Lina , Wang Maoqing , Peng Chenghai 
Published: June 2020

Abstract(1)BackgroundZinc deficiency decreases bone mineral density (BMD), but it is not known whether decreased BMD is a result of altered calcium absorption, excretion, and/or tissue distribution. To identified the associations between zinc deficiency, calcium metabolism and decreased BMD.(2)Methodswe performed two zinc deficiency experiments. In the first experiment, male rats (5-week-old) were fed a low zinc diet for four weeks. We measured serum zinc, alkaline phosphatase, Ca2+, osteocalcin, calcitonin, parathyroid hormone (PTH), calcium concentrations in feces and urine, BMD, and femur bone length and weight. In the second experiment, male rats (3-week-old) were fed a low zinc diet for five weeks. In addition to the aforesaid indicators, we measured the concentrations of zinc, total calcium, and calmodulin in multiple tissues.(3)ResultsIn both experiments, serum zinc, alkaline phosphatase, fecal and urine calcium, BMD, and bone weight of the low zinc diet group (LZG) were reduced compared with the normal zinc diet group (NZG)and pair-fed group (PZG); PTH increased significantly. Serum Ca2+, osteocalcin, and calcitonin concentrations were unchanged and not associated with decreased BMD. In the second experiment, zinc concentrations were reduced in serum, skeletal muscle, feces, and urine of LZG animals compared with NZG and PZG. Calmodulin in serum and skeletal muscle of the LZG group was decreased. Zinc deficiency increased total calcium concentrations in serum and skeletal muscle by promoting a decrease in calmodulin. To maintain blood Ca2+ balance, elevated PTH increased calcium reabsorption, reduced calcium excretion, stimulated bone resorption, mobilized bone calcium, and decreased BMD. (4) Conclusions: Decreased calmodulin and increased PTH induced by zinc deficiency altered calcium tissue distribution and decreased BMD of rat.
Bayesian investigation of SARS-CoV-2-related mortality in France
Authors: Duchemin Louis , Veber Philippe , Boussau Bastien 
Published: June 2020

AbstractThe SARS-CoV-2 epidemic in France has focused a lot of attention as it has had one of the largest death tolls in Europe. It provides an opportunity to examine the effect of the lockdown and of other events on the dynamics of the epidemic. In particular, it has been suggested that municipal elections held just before lockdown was ordered may have helped spread the virus. In this manuscript we use Bayesian models of the number of deaths through time to study the epidemic in 13 regions of France. We found that the models accurately predict the number of deaths 2 to 3 weeks in advance, and recover estimates that are in agreement with recent models that rely on a different structure and different input data. In particular, the lockdown reduced the viral reproduction number by ≈ 80%. However, using a mixture model, we found that the lockdown had had different effectiveness depending on the region, and that it had been slightly more effective in decreasing the reproduction number in denser regions. The mixture model predicts that 2.08 (95% CI: 1.85-2.47) million people had been infected by May 11, and that there were 2567 (95% CI: 1781-5182) new infections on May 10. We found no evidence that the reproduction numbers differ between week-ends and week days, and no evidence that the reproduction numbers increased on the election day. Finally, we evaluated counterfactual scenarios showing that ordering the lockdown 1 to 7 days sooner would have resulted in 19% to 76% fewer deaths, but that ordering it 1 to 7 days later would have resulted in 21% to 266% more deaths. Overall, the predictions of the model indicate that holding the elections on March 15 did not have a detectable impact on the total number of deaths, unless it motivated a delay in imposing the lockdown.
AP-2γ is Required for Maintenance of Pluripotent Mammary Stem Cells
Authors: Gu Vivian W. , Cho Edward , Thompson Dakota T. , Cassady Victoria C. , Borcherding Nicholas , Koch Kelsey E. , Wu Vincent T. , Lorenzen Allison W. , Kulak Mikhail V. , Williams Trevor , Zhang Weizhou , Weigel Ronald J. 
Published: June 2020

SUMMARYMammary gland ductal morphogenesis depends on the differentiation of mammary stem cells (MaSCs) into basal and luminal lineages. The AP-2γ transcription factor, encoded byTfap2c, has a central role in mammary gland development but its effect in mammary lineages and specifically MaSCs is largely unknown. Herein, we utilized an inducible, conditional knockout ofTfap2cto elucidate the role of AP-2γ in maintenance and differentiation of MaSCs. Loss of AP-2γ in the basal epithelium profoundly altered the transcriptomes and decreased the number of cells within several clusters of mammary epithelial cells, including adult MaSCs and luminal progenitors.AP-2γ regulated the expression of genes known to be required for mammary development includingC/EBPβ, IκBα, andRspo1. As a result, AP-2γ-deficient mice exhibited repressed mammary gland ductal outgrowth and inhibition of regenerative capacity. The findings demonstrate that AP-2γ is required for maintenance of pluripotent MaSCs and their ability to develop mammary gland structures.HighlightsAP-2γ-deficient mice exhibited repressed ductal outgrowth and regenerative capacityLoss of AP-2γ reduced the number of mammary stem and luminal progenitor cellsAP-2γ target genes, includingC/EBPβ, IκBα, andRspo1, regulate mammary developmentAP-2γ is required for maintenance of pluripotent mammary stem cellseTOC blurbGu, Cho and colleagues utilized a conditional knockout ofTfap2cto examine transcriptional effects of AP-2γ on mammary stem cells. Single cell analysis demonstrated that AP-2γ-deficient mice have decreased numbers of mammary stem cells and alteration of genes required for mammary development includingC/EBPβ, IκBα, andRspo1. They demonstrate that AP-2γ is necessary for maintenance of pluripotent mammary stem cells.
Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice
Authors: Sahadevan Sonu , Hembach Katharina M. , Tantardini Elena , Pérez-Berlanga Manuela , Hruska-Plochan Marian , Weber Julien , Schwarz Petra , Dupuis Luc , Robinson Mark D. , De Rossi Pierre , Polymenidou Magdalini 
Published: June 2020

AbstractFUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages, accompanied by alterations in density and size of GABAergic synapses. RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS accumulation at the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
Group and Individual Level Variations between Symmetric and Asymmetric DLPFC Montages for tDCS over Large Scale Brain Network Nodes
Authors: Soleimani Ghazaleh , Saviz Mehrdad , Bikson Marom , Towhidkhah Farzad , Kuplicki Rayus , Paulus Martin P. , Ekhtiari Hamed 
Published: June 2020

AbstractTwo challenges to optimizing transcranial direct current stimulation (tDCS) are selecting between, often similar, electrode montages and accounting for inter-individual differences in response. These two factors are related by how tDCS montage determines current flow through the brain considered across or within individuals. MRI-based computational head models (CHMs) predict how brain anatomy determine electric field (EF) patterns for a given tDCS montage. Because conventional tDCS produces diffuse brain current flow, stimulation outcomes may be understood as modulation of global networks. Therefore, we developed network-led, rather than region-led, approach. We specifically considered two common frontal tDCS montages that nominally target the dorsolateral prefrontal cortex; asymmetric unilateral (anode/cathode: F4/Fp1) and symmetric bilateral (F4/F3) electrode montages. CHMs of 66 participants were constructed. We showed that cathode location significantly affects EFs in the limbic network. Furthermore, using a finer parcellation of large-scale networks, we found significant differences in some of main nodes within a network, even if there is no difference at the network level. This study generally demonstrates a methodology for considering the components of large-scale networks in CHMs instead of targeting a single region and specifically provides insight into how symmetric vs asymmetric frontal tDCS may differentially modulate networks across a population.
Entraining corticocortical plasticity changes oscillatory activity in action control and inhibition
Authors: Sel Alejandra , Verhagen Lennart , Angerer Katharina , David Raluca , Klein-Flügge Miriam , Rushworth Matthew 
Published: June 2020

SummaryOscillatory activity may reflect interactions between brain areas[1]. Here we tested whether inducing corticocortical plasticity in a specific set of connections changes oscillatory activity and cortico-cortical interactions and, if this is the case, whether the changes manifest in a manner that is behaviour state-dependent. We either increased or decreased the influence of activity in human ventral premotor cortex (PMv) over activity in primary motor cortex (M1) using cortico-cortical paired associative stimulation (ccPAS)[2, 3]. Before and after stimulation participants performed a Go/No-Go task. While M1 TMS pulses revealed the excitatory state of the motor system at specific time points, the electroencephalogram (EEG) revealed the evolution of oscillatory activity dynamics in the motor system over several hundreds of milliseconds before, during, and after each movement. Augmenting cortical connectivity between PMv and M1, by evoking synchronous pre- and postsynaptic activity in the PMv-M1 pathways, led to a state-dependent modulation of the causal influence of PMv over M1, and at the same time, enhanced oscillatory beta and theta rhythms in Go and No-Go trials, respectively. No changes were observed in the alpha rhythm. The plasticity induction effect was dependent on PMv-M1 stimulation order; the opposite patterns of results were observed after an equal amount of stimulation of PMv and M1 but applied in a temporal pattern that did not augment PMv’s influence over M1. These results are consistent with Hebbian principles of synaptic plasticity[4] and show that artificial manipulation of cortico-cortical connectivity produces state-dependent functional changes in the spectral fingerprints of the motor circuit.