bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice
Authors: Johnson Benjamin M. , Gaudreau Marie-Claude , Gudi Radhika , Brown Robert , Gilkeson Gary , Vasu Chenthamarakshan 
Published: October 2019

1.AbstractThe risk of developing systemic lupus erythematosus (SLE) is about 9 times higher among women compared to men. Our recent report, which used (SWRxNZB) F1 (SNF1) mouse model of spontaneous lupus, showed a potential link between immune response initiated in the gut mucosa at juvenile age (sex hormone independent) and SLE susceptibility. Here, this mouse model, we show that gut microbiota contributes to a pro-inflammatory immune response in the intestine and autoimmune progression, primarily in females, leading to an associated gender bias. We found that gut microbiota composition in male and female littermates are significantly different only at adult age and depletion of gut microbes causes suppression of autoimmune progression only in females. In agreement, microbiota depletion suppressed the pro-inflammatory cytokine response of gut mucosa in both juvenile and adult females. In male SNF1 mice, on the other hand, orchidectomy (castration) caused changes in the composition of gut microbiota and a modest acceleration of autoimmune progression. However, cecum microbiota transplantation studies failed to show superior protection of females from autoimmunity by androgen-influenced gut microbiota. Overall, our work shows that microbiota-dependent pro-inflammatory immune response in the gut mucosa of females initiated at juvenile ages and androgen-dependent protection of males contributes to gender differences in the intestinal immune phenotype and systemic autoimmune progression.
The seagrass methylome memorizes heat stress and is associated with variation in stress performance among clonal shoots
Authors: Jueterbock A , Boström C , Coyer James A , Olsen JL , Kopp M , Dhanasiri AKS , Smolina I , Arnaud-Haond S , Van de Peer Y , Hoarau G 
Published: October 2019

AbstractEvolutionary theory predicts that clonal organisms are more susceptible to extinction than sexually reproducing organisms, due to low genetic variation and slow rates of evolution. In agreement, conservation management considers genetic variation as the ultimate measure of a population’s ability to survive over time. However, clonal plants are among the oldest living organisms on our planet. Here, we test the hypothesis that clonal seagrass meadows display epigenetic variation that complements genetic variation as a source of phenotypic variation. In a clonal meadow of the seagrass Zostera marina we characterized DNA methylation among 42 shoots. We also sequenced the whole genome of 10 shoots to correlate methylation patterns with photosynthetic performance under exposure to, and recovery from 27°C, while controlling for somatic mutations. Here, we show for the first time that clonal seagrass shoots display DNA methylation variation that is associated with variation in fitness-related traits: photosynthetic performance and heat stress resilience. The co-variation in DNA methylation and phenotype may be linked via gene expression because methylation patterns varied in functionally relevant genes involved in photosynthesis, and in the repair and prevention of heat-induced protein damage. A >five week epigenetic heat stress memory may heat-harden previously heat-exposed shoots. While genotypic diversity has been shown to enhance stress resilience in seagrass meadows, we suggest that epigenetic variation plays a similar role in meadows dominated by a single genotype. Consequently, conservation management of clonal plants should consider epigenetic variation as indicator of resilience and stability, and restoration efforts may benefit from stress-priming transplanted seeds or shoots.
No statistical evidence for an effect of CCR5-∆32 on lifespan in the UK Biobank cohort
Authors: Maier Robert , Akbari Ali , Wei Xinzhu , Patterson Nick , Nielsen Rasmus , Reich David 
Published: October 2019

AbstractA recent study reported that a 32-base-pair deletion in the CCR5 gene (CCR5-∆32) is deleterious in the homozygous state in humans. Evidence for this came from a survival analysis in the UK Biobank cohort, and from deviations from Hardy-Weinberg equilibrium at a polymorphism tagging the deletion (rs62625034). Here, we carry out a joint analysis of whole-genome genotyping data and whole-exome sequencing data from the UK Biobank, which reveals that technical artifacts are a more plausible cause for deviations from Hardy-Weinberg equilibrium at this polymorphism. Specifically, we find that individuals homozygous for the deletion in the sequencing data are underrepresented in the genotyping data due to an elevated rate of missing data at rs62625034, possibly because the probe for this SNP overlaps with the ∆32 deletion. Another variant which has a higher concordance with the deletion in the sequencing data shows no associations with mortality. A phenome-wide scan for effects of variants tagging this deletion shows an overall inflation of association p-values, but identifies only one trait at p < 5×10−8, and no mediators for an effect on mortality. These analyses show that the original reports of a recessive deleterious effect of CCR5-∆32 are affected by a technical artifact, and that a closer investigation of the same data provides no positive evidence for an effect on lifespan.
Headwaters fed by subterranean ice: potential climate refugia for mountain stream communities?
Authors: Tronstad Lusha M. , Hotaling Scott , Giersch J. Joseph , Wilmot Oliver J. , Finn Debra S. 
Published: October 2019

ABSTRACTNear-term extirpations of macroinvertebrates are predicted for mountain streams worldwide as a warming climate drives the recession of high-elevation ice and snow. However, hydrological sources likely vary in their resistance to climate change and thus streams fed by more resistant sources could persist as climate refugia for imperiled biota. In 2015-2016, we measured habitat characteristics and quantified macroinvertebrate community structure along six alpine streams in the Teton Range, Wyoming, USA. Strong differences in habitat characteristics (e.g., temperature, bed stability, conductivity) confirmed three major stream sources: surface glaciers, perennial snowfields, and subterranean ice. Subterranean ice-fed streams – termed “icy seeps” – appear common in the Teton Range and elsewhere yet are globally understudied. Midges in the family Chironomidae dominated our study sites, representing 78.6% of all specimens sampled, with nematodes, caddisflies (Neothremma), and mayflies (Epeorus) also common. At the community-scale, glacier-and snowmelt-fed streams differed significantly in multivariate space, with icy-seep communities intermediate between them, incorporating components of both assemblages. Because the thermal environment of subterranean ice, including rock glaciers, is decoupled from large-scale climatic conditions, we predict that icy seeps will remain intact longer than streams fed by surface ice and snow. Furthermore, our results suggest that icy seeps are suitable habitat for many macroinvertebrates occupying streams fed by vulnerable hydrological sources. Thus, icy seeps may act as key climate refugia for mountain stream biodiversity, an idea in need of further investigation.
Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease
Authors: Wang Minghui , Li Aiqun , Sekiya Michiko , Beckmann Noam D. , Quan Xiuming , Schrode Nadine , Fernando Michael B. , Yu Alex , Zhu Li , Cao Jiqing , Lyu Liwei , Horgusluoglu Emrin , Wang Qian , Guo Lei , Wang Yuan-shuo , Neff Ryan , Song Won-min , Wang Erming , Shen Qi , Zhou Xianxiao , Ming Chen , Ho Seok-Man , Vatansever Sezen , Kaniskan H. Umit , Jin Jian , Zhou Ming-Ming , Ando Kanae , Ho Lap , Slesinger Paul A. , Yue Zhenyu , Zhu Jun , Gandy Sam , Ehrlich Michelle E. , Cai Dongming , Haroutunian Vahram , Iijima Koichi M. , Schadt Eric , Brennand Kristen J. , Zhang Bin 
Published: October 2019

SUMMARYTo study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer’s Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.
Suprathreshold contrast response in normal and anomalous trichromats
Authors: Knoblauch Kenneth , Marsh-Armstrong Brennan , Werner John S. 
Published: October 2019

AbstractMaximum Likelihood Difference Scaling was used to measure suprathreshold contrast response difference scales for low-frequency Gabor patterns modulated along luminance and L-M color directions in normal, protanomalous, and deuteranomalous observers. Based on a signal-detection model, perceptual scale values, parameterized as d′, were estimated by maximum likelihood. The difference scales were well fit by a Michaelis-Menten model, permitting estimates of response and contrast gain parameters for each subject. Anomalous observers showed no significant differences in response or contrast gain from normal observers for luminance contrast. For chromatic modulations, however, anomalous observers displayed higher contrast and lower response gain compared to normal observers. These effects cannot be explained by simple pigment shift models and support a compensation mechanism to optimize the mapping of the input contrast range to the neural response range. A linear relation between response and contrast gain suggests a neural trade-off between them.
“Dual protease type XIII/pepsin digestion offers superior resolution and overlap for the analysis of histone tails by HX-MS”
Authors: Mullahoo James , Zhang Terry , Clauser Karl , Carr Steven A. , Jaffe Jacob D. , Papanastasiou Malvina 
Published: October 2019

AbstractThe N-terminal regions of histone proteins (tails) are dynamic elements that protrude from the nucleosome and are involved in many aspects of chromatin organization. Their epigenetic role is well-established, and post-translational modifications (PTMs) present on these regions contribute to transcriptional regulation. While hydrogen/deuterium exchange mass spectrometry (HX-MS) is well-suited for the analysis of dynamic structures, it has seldom been employed to analyze histones due to the poor N-terminal coverage obtained using pepsin. Here, we test the applicability of a dual protease type XIII/pepsin digestion column to this class of proteins. We optimize online digestion conditions using the H4 monomer, and extend the method to the analysis of histones in monomeric states and nucleosome core particles (NCPs). We show that the dual protease column generates many short and overlapping N-terminal peptides. We evaluate our method by performing hydrogen exchange experiments of NCPs for different time points and present full coverage of the tails at excellent resolution. We further employ electron transfer dissociation (ETD) and showcase an unprecedented degree of overlap across multiple peptides that is several fold higher than previously reported methods. The method we report here may be readily applied to the HX-MS investigation of histone dynamics and to the footprints of histone binding proteins on nucleosomes.
Lipid Chaperoning of a Thylakoid Protease Whose Stability is Modified by the Protonmotive Force
Authors: McKinnon Lucas J. , Fukushima Jeremy , Inoue Kentaro , Theg Steven M. 
Published: October 2019

AbstractProtein folding is a complex cellular process often assisted by chaperones but can also be facilitated by interactions with lipids. Disulfide bond formation is a common mechanism to stabilize a protein. This can help maintain functionality amidst changes in the biochemical milieu which are especially common across energy-transducing membranes. Plastidic Type I Signal Peptidase 1 (Plsp1) is an integral thylakoid membrane signal peptidase which requires an intramolecular disulfide bond forin vitroactivity. We have investigated the interplay between disulfide bond formation, lipids, and pH in the folding and activity of Plsp1. By combining biochemical approaches with a genetic complementation assay, we provide evidence that interactions with lipids in the thylakoid membrane have chaperoning activity towards Plsp1. Further, the disulfide bridge appears to prevent an inhibitory conformational change resulting from proton motive force-mimicking pH conditions. Broader implications related to the folding of proteins in energy-transducing membranes are discussed.
Promoting neuronal outgrowth using ridged scaffolds coated with extracellular matrix proteins
Authors: Siddiqui Ahad M. , Brunner Rosa , Harris Gregory M. , Miller Alan.L. , Waletzki Brian E. , Schwarzbauer Jean E. , Schwartz Jeffrey , Yaszemski Michael J. , Windebank Anthony J. , Madigan Nicolas N. 
Published: October 2019

AbstractSpinal cord injury (SCI) results in cell death, demyelination, and axonal loss. The spinal cord has a limited ability to regenerate and current clinical therapies for SCI are not effective in helping promote neurologic recovery. We have developed a novel scaffold biomaterial that is fabricated from the biodegradable hydrogel oligo[poly(ethylene glycol)fumarate] (OPF). We have previously shown that positively charged OPF scaffolds (OPF+) in an open spaced, multichannel design can be loaded with Schwann cells to support axonal generation and functional recovery following SCI. We have now developed a hybrid OPF+ biomaterial that increases the surface area available for cell attachment and that contains an aligned microarchitecture and extracellular matrix (ECM) proteins to better support axonal regeneration. OPF+ was fabricated as 0.08 mm thick sheets containing 100 μm high polymer ridges that self-assembles into a spiral shape when hydrated. Laminin, fibronectin, or collagen I coating promoted neuron attachment and axonal outgrowth on the scaffold surface. In addition, the ridges aligned axons in a longitudinal bipolar orientation. Decreasing the space between the ridges increased the number of cells and neurites aligned in the direction of the ridge. Schwann cells seeded on laminin coated OPF+ sheets aligned along the ridges over a 6-day period and could myelinate dorsal root ganglion neurons over 4 weeks. The OPF+ sheets support axonal regeneration when implanted into the transected spinal cord. This novel scaffold design, with closer spaced ridges and Schwann cells is a novel biomaterial construct to promote regeneration after SCI.Graphical Abstract
Somatic hypermutation analysis for improved identification of B cell clonal families from next-generation sequencing data
Authors: Nouri Nima , Kleinstein Steven H. 
Published: October 2019

AbstractMotivationAdaptive immune receptor repertoire sequencing (AIRR-Seq) offers the possibility of identifying and tracking B cell clonal expansions during adaptive immune responses. Members of a B cell clone are descended from a common ancestor and share the same initial V(D)J rearrangement, but their B cell receptore (BCR) sequence may differ due to the accumulation of somatic hypermutations (SHMs). Clonal relationships are learned from AIRR-seq data by analyzing the BCR sequence, with the most common methods focused on the highly diverse junction region. However, clonally related cells often share SHMs which have been accumulated during affinity maturation. Here, we investigate whether shared SHMs in the V and J segments of the BCR can be leveraged along with the junction sequence to improve the ability to identify clonally related sequences. We develop independent distance functions that capture junction similarity and shared mutations, and combine these in a spectral clustering framework to infer the BCR clonal relationships. Using both simulated and experimental data, we show that this model improves both the sensitivity and specificity for identifying B cell clones.AvailabilitySource code for this method is freely available in theSCOPer(Spectral Clustering for clOne Partitioning) R package (version 0.2 or later) in the Immcantation framework:www.immcantation.orgunder the CC BY-SA 4.0 license.Contactsteven.kleinstein@yale.edu
Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain
Authors: Ye Hui , Ojelade Shamsideen , Li-Kroeger David , Zuo Zhongyuan , Wang Liping , Li Yarong , Gu Jessica Y. J. , Tepass Ulrich , Rodal Avital A. , Bellen Hugo J. , Shulman Joshua M. 
Published: October 2019

AbstractRetromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson’s and Alzheimer’s disease, our understanding of retromer function in the adult brain remains limited, in part becauseVps35andVps26are essential for development. InDrosophila, we find thatVps29is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, inVps29mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further,Vps29phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.Impact StatementVps29 promotes retromer localization in the adultDrosophilabrain, engaging Rab7 and TBC1D5, and its loss triggers age-dependent neuronal impairments in endolysosomal trafficking and synaptic transmission.
Circadian- and sex-dependent increases in intravenous cocaine self-administration inNpas2mutant mice
Authors: DePoy Lauren M. , Becker-Krail Darius D. , Zong Wei , Petersen Kaitlyn , Shah Neha M. , Brandon Jessica H. , Miguelino Alyssa M. , Tseng George C. , Logan Ryan W. , McClung Colleen A. 
Published: October 2019

AbstractSubstance use disorder is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) andNpas2mutant mice at different times of day. In the light (inactive) phase, cocaine reinforcement was increased in allNpas2mutants, while self-administration and motivation were affected sex-dependently. These sex differences were amplified during the dark (active) phase withNpas2mutation increasing self-administration, reinforcement, motivation, extinction responding and reinstatement in females, but only reinforcement in males. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT andNpas2mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated inNpas2mutant females, we measured cocaine-induced ΔFosB expression. Relative to WT, ΔFosB expression was increased in D1+ neurons in the nucleus accumbens core and dorsolateral striatum inNpas2mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine inNpas2mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect ofNpas2mutation in females.Significance StatementCircadian disruptions are a common symptom of substance use disorders and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent substance use. Diurnal rhythms are commonly found in behavioral responses to drugs of abuse with drug sensitivity and motivation peaking during the dark (active) phase in nocturnal rodents. Emerging evidence links disrupted circadian genes to substance use vulnerability and drug-induced alterations to these genes may augment drug-seeking. The circadian transcription factor NPAS2 is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration in wild-type andNpas2mutant mice at different times of day.
Relationship between simultaneously recorded spiking activity and fluorescence signal in GCaMP6 transgenic mice
Authors: Huang Lawrence , Knoblich Ulf , Ledochowitsch Peter , Lecoq Jérôme , Reid R. Clay , de Vries Saskia E. J. , Buice Michael A. , Murphy Gabe J. , Waters Jack , Koch Christof , Zeng Hongkui , Li Lu 
Published: October 2019

AbstractTwo-photon calcium imaging is often used with genetically encoded calcium indicators (GECIs) to investigate neural dynamics, but the relationship between fluorescence and action potentials (spikes) remains unclear. Pioneering work linked electrophysiology and calcium imaging in vivo with viral GECI expression, albeit in a small number of cells. Here we characterized the spikefluorescence transfer function in vivo of 91 layer 2/3 pyramidal neurons in primary visual cortex in four transgenic mouse lines expressing GCaMP6s or GCaMP6f. We found that GCaMP6s cells have spike-triggered fluorescence responses of larger amplitude, lower variability and greater single-spike detectability than GCaMP6f. Mean single-spike detection rates at high spatiotemporal resolution measured in our data was >70% for GCaMP6s and ~40-50% for GCaMP6f (at 5% false positive rate). These rates are estimated to decrease to 25-35% for GCaMP6f under generally used population imaging conditions. Our ground-truth dataset thus supports more refined inference of neuronal activity from calcium imaging.