bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide binding analysis of 195 DNA Binding Proteins reveals “reservoir” promoters and human specific SVA-repeat family regulation
Authors: Shehata Soraya , Spradlin Savannah , Swearingen Alison , Wheeler Graycen , Das Arpan , Corbet Giulia , Nebenfuehr Benjamin , Ahrens Daniel , Tauber Devin , Lennon Shelby , Choi Kevin , Huynh Thao , Weiser Tom , Schneider Kristen , Bradshaw Michael , Lai Maria , Basken Joel , Read Tim , Demasi Jon , Hynes-Grace Matt , Timmons Dan , Smallegan Michael , Rinn John L. 
Published: July 2020

AbstractA key aspect in defining cell state is the complex choreography of DNA binding events in a given cell type, which in turn establishes a cell-specific gene-expression program. In the past two decades since the sequencing of the human genome there has been a deluge of genome-wide experiments which have measured gene-expression and DNA binding events across numerous cell-types and tissues. Here we re-analyze ENCODE data in a highly reproducible manner by utilizing standardized analysis pipelines, containerization, and literate programming with Rmarkdown. Our approach validated many findings from previous independent studies, underscoring the importance of ENCODE’s goals in providing these reproducible data resources. This approach also revealed several new findings: (i) 1,362 promoters, termed ‘reservoirs,’ have up to 111 different DNA binding-proteins localized on one promoter yet do not have any expression of steady-state RNA (ii) The human specific SVA repeat element may have been co-opted for enhancer regulation. Collectively, this study performed by the students of a CU Boulder computational biology class (BCHM 5631 – Spring 2020) demonstrates the value of reproducible findings and how resources like ENCODE that prioritize data standards can foster new findings with existing data in a didactic environment.
Delta/Theta band EEG activity shapes the rhythmic perceptual sampling of auditory scenes
Authors: Kubetschek Cora , Kayser Christoph 
Published: July 2020

AbstractMany studies speak in favor of a rhythmic mode of listening, by which the encoding of acoustic information is structured by rhythmic neural processes at the time scale of about 1 to 4 Hz. Indeed, psychophysical data suggest that humans sample acoustic information in extended soundscapes not uniformly, but weigh the evidence at different moments for their perceptual decision at the time scale of about 2 Hz. We here test the critical prediction that such rhythmic perceptual sampling is directly related to the state of ongoing brain activity prior to the stimulus. Human participants judged the direction of frequency sweeps in 1.2 s long soundscapes while their EEG was recorded. Computing the perceptual weights attributed to different epochs within these soundscapes contingent on the phase or power of pre-stimulus oscillatory EEG activity revealed a direct link between the 4Hz EEG phase and power prior to the stimulus and the phase of the rhythmic component of these perceptual weights. Hence, the temporal pattern by which the acoustic information is sampled over time for behavior is directly related to pre-stimulus brain activity in the delta/theta band. These results close a gap in the mechanistic picture linking ongoing delta band activity with their role in shaping the segmentation and perceptual influence of subsequent acoustic information.
Lactate promotes cardiomyocyte dedifferentiation through metabolic reprogramming
Authors: Ordoño Jesús , Pérez-Amodio Soledad , Ball Kristen , Aguirre Aitor , Engel Elisabeth 
Published: July 2020

ABSTRACTCardiomyocytes undergo different metabolic changes during development and differentiation crucial for their maturation and adult function, such as contraction, growth and survival. Alterations of cardiac metabolism have been associated with multiple disease states and pathological hypertrophy. The shift in substrate preference can impair the stress response, but it may also have a role in cell growth and survival. Here, we evaluated the response of cardiomyocytes to the presence of exogenous lactate, an important metabolite for the fetal heart and cardiogenesis. Lactate-exposed mouse primary cardiomyocytes and human iPSC-derived cardiomyocytes quickly acquired a characteristic dedifferentiated phenotype, with enhanced proliferative capacity as determined by an increased expression of cell cycle (Ki67) and cytokinesis (Aurora-B) effectors. This effect was specific to cardiomyocytes and did not affect other heart cell populations (e.g. cardiac fibroblasts). Nevertheless, cardiac fibroblasts exposed to lactate promoted a pro-regenerative environment through the modulation of the release of cytokines (such as Fas, IL-13 or SDF1a). We characterized lactate-induced cardiomyocyte dedifferentiation through RNA-sequencing and gene expression analysis and identified increased expression of BMP10 (a TGFβ family protein involved in embryonic cardiomyocyte proliferation and stemness) and proteins associated to cell fate regulation (LIN28, TCIM) together with downregulation of cardiac maturation genes (GRIK1, DGKK). Bottom-up analysis suggested the phenotype promoted by lactate could be related to the activation of hypoxia signaling pathways. This finding indicated that, indeed, lactate may be a key player of hypoxic regenerative responses in the heart, as it usually accumulates as a result of glycolysis. In addition,ex vivoneonatal heart culture showed prolonged beating function and cardiac tissue integrity when culture media was supplemented with lactate. Thus, we conclude that lactate enhances cardiac proliferation by reprogramming cardiomyocytes towards a dedifferentiated stem cell-like state, supporting the notion that modulation of the metabolic microenvironment might be a powerful novel approach for promoting cardiac regeneration and tissue engineering applications.
Numerical simulation of the two-locus Wright-Fisher stochastic differential equation with application to approximating transition probability densities
Authors: He Zhangyi , Beaumont Mark , Yu Feng 
Published: July 2020

AbstractOver the past decade there has been an increasing focus on the application of the Wright-Fisher diffusion to the inference of natural selection from genetic time series. A key ingredient for modelling the trajectory of gene frequencies through the Wright-Fisher diffusion is its transition probability density function. Recent advances in DNA sequencing techniques have made it possible to monitor genomes in great detail over time, which presents opportunities for investigating natural selection while accounting for genetic recombination and local linkage. However, most existing methods for computing the transition probability density function of the Wright-Fisher diffusion are only applicable to one-locus problems. To address two-locus problems, in this work we propose a novel numerical scheme for the Wright-Fisher stochastic differential equation of population dynamics under natural selection at two linked loci. Our key innovation is that we reformulate the stochastic differential equation in a closed form that is amenable to simulation, which enables us to avoid boundary issues and reduce computational costs. We also propose an adaptive importance sampling approach based on the proposal introduced by Fearnhead (2008) for computing the transition probability density of the Wright-Fisher diffusion between any two observed states. We show through extensive simulation studies that our approach can achieve comparable performance to the method of Fearnhead (2008) but can avoid manually tuning the parameterρto deliver superior performance for different observed states.
Intranasal Vaccination with a Lentiviral Vector Strongly Protects against SARS-CoV-2 in Mouse and Golden Hamster Preclinical Models
Authors: Ku Min-Wen , Bourgine Maryline , Authié Pierre , Lopez Jodie , Nemirov Kirill , Moncoq Fanny , Noirat Amandine , Vesin Benjamin , Nevo Fabien , Blanc Catherine , Souque Philippe , Tabbal Houda , Simon Emeline , Le Dudal Marine , Guinet Françoise , Fiette Laurence , Mouquet Hugo , Anna François , Martin Annette , Escriou Nicolas , Majlessi Laleh , Charneau Pierre 
Published: July 2020

SummaryTo develop a vaccine candidate against COVID-19, we generated a Lentiviral Vector (LV), eliciting neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Systemic vaccination by this vector in mice, in which the expression of the SARS-CoV-2 receptor hACE2 has been induced by transduction of respiratory tract cells by an adenoviral vector, conferred only partial protection, despite an intense serum neutralizing activity. However, targeting the immune response to the respiratory tract through an intranasal boost with this LV resulted in > 3 log10 decrease in the lung viral loads and avoided local inflammation. Moreover, both integrative and non-integrative LV platforms displayed a strong vaccine efficacy and inhibited lung deleterious injury in golden hamsters, which are naturally permissive to SARS-CoV-2 replication and restitute the human COVID-19 physiopathology. Our results provide evidence of marked prophylactic effects of the LV-based vaccination against SARS-CoV-2 and designate the intranasal immunization as a powerful approach against COVID-19.HighlightsA lentiviral vector encoding for Spike predicts a promising COVID-19 vaccineTargeting the immune response to the upper respiratory tract is key to protectionIntranasal vaccination induces protective mucosal immunity against SARS-CoV-2Lung anti-Spike IgA responses correlate with protection and reduced inflammation
Effects of early life stress on bone homeostasis in mice and humans
Authors: Wuertz-Kozak Karin , Roszkowski Martin , Cambria Elena , Block Andrea , Kuhn Gisela A. , Abele Thea , Hitzl Wolfgang , Drießlein David , Müller Ralph , Rapp Michael A. , Mansuy Isabelle M. , Peters Eva M. J. , Wippert Pia M. 
Published: July 2020

AbstractBone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined on bone microarchitecture (μCT), metabolism (qPCR), and neuronal stress mediator expression (qPCR) and contrasted with a sample of depressive patients with or without early life stress by analyzing bone mineral density [BMD] (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone micro-CT. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.
TRPC5-CaV3 complex mediates Leptin-induced excitability in hypothalamic neurons
Authors: Perissinotti Paula P. , Martínez-Hernández Elizabeth , Piedras-Rentería Erika S. 
Published: July 2020

ABSTRACTLeptin regulates hypothalamic POMC+(pro-opiomelanocortin) neurons by inducing TRPC (Transient Receptor Potential Cation) channel-mediate membrane depolarization. Here we assessed the role of T-type channels on POMC neuron excitability and leptin-induced depolarizationin vitro. We demonstrate T-type currents are indispensable for both processes, as treatment with NNC-55-0396 prevented the membrane depolarization and rheobase changes induced by leptin in cultured mouse POMC neurons. Furthermore, we demonstrate TRPC1/C5 channels and CaV3.1 and CaV3.2 channels co-exist in complex. The functional relevance of this complex was corroborated using intracellular Ca2+chelators; intracellular BAPTA (but not EGTA) application was sufficient to preclude POMC neuron excitability by preventing leptin-induced calcium influx through TRPC channels and T-type channel function.We conclude T-type channels are integral in POMC neuron excitability. Leptin activation of TRPC channels existing in a macromolecular complex with T-type channels recruits the latter by locally-induced membrane depolarization, further depolarizing POMC neurons, triggering action potentials and excitability.
The TAZ2 domain of CBP/p300 directs acetylation towards H3K27 within chromatin
Authors: Sheahan Thomas W. , Major Viktoria , Webb Kimberly M. , Bryan Elana , Voigt Philipp 
Published: July 2020

AbstractThe closely related acetyltransferases CBP and p300 are key regulators of gene expression in metazoans. CBP/p300 acetylate several specific lysine residues within nucleosomes, including histone H3 lysine 27 (H3K27), a hallmark of active enhancers and promoters. However, it has remained largely unclear how specificity of CBP/p300 towards H3K27 is achieved. Here we show that the TAZ2 domain of CBP is required for efficient acetylation of H3K27, while curbing activity towards other lysine residues within nucleosomes. We find that TAZ2 is a sequence-independent DNA binding module, promoting interaction between CBP and nucleosomes, thereby enhancing enzymatic activity and regulating substrate specificity of CBP. TAZ2 is further required to stabilize CBP binding to chromatin in mouse embryonic stem cells, facilitating specificity towards H3K27 and modulating gene expression. These findings reveal a crucial role of TAZ2 in regulating H3K27ac, while highlighting the importance of correct site-specific acetylation for proper regulation of gene expression.
Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion
Authors: Ferstl Magdalena , Teckentrup Vanessa , Lin Wy Ming , Kräutlein Franziska , Kühnel Anne , Klaus Johannes , Walter Martin , Kroemer Nils B. 
Published: July 2020

AbstractMood plays an important role in our life which is illustrated by the disruptive impact of aberrant mood states in depression. Although vagus nerve stimulation (VNS) has been shown to improve symptoms of depression, the exact mechanism is still elusive, and it is an open question whether non-invasive VNS could be used to swiftly and robustly improve mood. Here, we investigated the effect of left- and right-sided transcutaneous auricular VNS (taVNS) versus a sham control condition on mood after exertion of physical and cognitive effort in 82 healthy participants (randomized cross-over design). Using linear mixed-effects and hierarchical Bayesian analyses of mood ratings, we found that 90 min of either left-sided or right-sided taVNS improved positive mood (b= 5.11, 95% credible interval, CI [1.39, 9.01], 9.6% improvement relative to the mood intercept, BF10= 7.69,pLME= .017), yet only during the post stimulation phase. Moreover, lower baseline scores of positive mood were associated with greater taVNS-induced improvements in motivation (r= −.42, 95% CI [−.58, −.21], BF10= 249). We conclude that taVNS boosts mood after a prolonged period of effort exertion with concurrent stimulation and that acute motivational effects of taVNS are partly dependent on initial mood states. Collectively, our results show that taVNS may help quickly improve affect after a mood challenge, potentially by modulating interoceptive signals contributing to reappraisal of effortful behavior. This suggests that taVNS could be a useful add-on to current behavioral therapies.
An online headphone screening test based on dichotic pitch
Authors: Milne Alice E. , Bianco Roberta , Poole Katarina C. , Zhao Sijia , Oxenham Andrew J. , Billig Alexander J. , Chait Maria 
Published: July 2020

AbstractOnline experimental platforms can be used as an alternative, or complement, to lab-based research. However, when conducting auditory experiments via online methods, the researcher has limited control over the participants’ listening environment. We offer a new method to probe one aspect of that environment, headphone use. Headphones not only provide better control of sound presentation but can also “shield” the listener from background noise. Here we present a rapid (< 3 minute) headphone screening test based on Huggins Pitch (HP), a perceptual phenomenon that can only be detected when stimuli are presented dichotically. We validate this test using a cohort of “Trusted” online participants who completed the test using both headphones and loudspeakers. The same participants were also used to test an existing headphone test (AP test; Woods et al., 2017,Attention Perception Psychophysics). We demonstrate that compared to the AP test, the HP test has a higher selectivity for headphone users, rendering it as a compelling alternative to existing methods. Overall, the new HP test correctly detects 80% of headphone users and has a false positive rate of 20%. Moreover, we demonstrate that combining the HP test with an additional test - either the AP test or an alternative based on a beat test (BT) - can lower the false positive rate to ∼7%. This should be useful in situations where headphone use is particularly critical (e.g. dichotic or spatial manipulations). Code for implementing the new tests is publicly available in JavaScript and through Gorilla (gorilla.sc).
Form, function, and divergence of a generic fin shape in small cetaceans
Authors: Pavlov Vadim , Vincent Cecile , Mikkelsen Bjarni , Lebeau Justine , Ridoux Vincent , Siebert Ursula 
Published: July 2020

AbstractTail flukes as well as the dorsal fin are the apomorphic traits of cetaceans appeared during evolutionary process of adaptation to the aquatic life. Both appendages present a generic wing-like shape associated with lift generation and low drag. Variability of the form of appendages was studied in seven species of cetaceans having different body size, external morphology, and specialization. Hydrodynamic performance of the fin cross-sections was examined with the CFD software and compared with similar engineered airfoils. Affinity of hydrodynamic design of both appendages was found in a wing-like planform and cross-sectional design optimized for lift generation. Distinctions in the planform and cross-sections were found related with the fin specialization in thrust production or swimming stability control. Cross-sectional design of the dorsal fin was found to be optimized for the narrow range of small angles of attack. Cross-sections of tail flukes were found to be more stable for higher angles of attack and had gradual stall characteristics that is associated with their propulsive efficiency as oscillating foils. The results obtained are the evidence of divergent evolutionary pathways of a generic wing-like shape of the fins of cetaceans under specific demands of thrust production and swimming stability control.
Rostro-caudal specificity of corticospinal tract projections in mice
Authors: Steward Oswald , Yee Kelly M. , Metcalfe Mariajose , Willenberg Rafer , Luo Juan , Azevedo Ricardo , Martin-Thompson Jacob H. , Gandhi Sunil P. 
Published: July 2020

ABSTRACTRostro-caudal specificity of corticospinal tract (CST) projections from different areas of the cortex was assessed by retrograde labeling with fluorogold and retrograde transfection following retro-AAV/Cre injection into the spinal cord of tdT-reporter mice. Injections at C5 led to retrograde labeling of neurons throughout forelimb area of the sensorimotor cortex, the rostral forebrain area (RFA), and a region in the lateral cortex near the barrel field. Injections at L2 led to retrograde labeling of neurons in the posterior sensorimotor cortex (hindlimb area) but not the RFA or lateral cortex. With BDA injections into the main sensorimotor cortex (forelimb region), labeled axons terminated selectively at cervical levels. With BDA injections into caudal sensorimotor cortex (hindlimb region), labeled axons passed through cervical levels without sending collaterals into the gray matter and then elaborated terminal arbors at thoracic-sacral levels. With BDA injections into the RFA and lateral cortex near the barrel field, labeled axons terminated at high cervical levels. Axons from medial sensorimotor cortex terminated primarily in intermediate laminae; Axons from lateral sensorimotor cortex terminated primarily in deep layers of the dorsal horn. One of the descending pathways seen in rats (the ventral CST) was not observed in most mice.SIGNIFICANCEMice are used extensively for studies of regeneration following spinal cord injury because of the ability to create genetic modifications to explore ways to enhance repair and enable axon regeneration. A particular focus has been the corticospinal tract (CST) because of its importance for voluntary motor function. Here, we document features of the rostro-caudal specificity of CST
Calretinin and calbindin architecture of the midline thalamus associated with prefrontal-hippocampal circuitry
Authors: Viena Tatiana D. , Rasch Gabriela E. , Silva Daniela , Allen Timothy A. 
Published: July 2020

ABSTRACTThe midline thalamus bi-directionally connects the medial prefrontal cortex (mPFC) and hippocampus (HC) creating a unique cortico-thalamo-cortico circuit fundamental to memory and executive function. While the anatomical connectivity of midline thalamus has been thoroughly investigated, little is known about its cellular organization within each nucleus. Here we used immunohistological techniques to examine cellular distributions in the midline thalamus based on the calcium binding proteins parvalbumin (PV), calretinin (CR), and calbindin (CB). We also examined these calcium binding proteins in a population of reuniens cells known to project to both mPFC and HC using a dual fluorescence retrograde adenoassociated virus (AAV) based tracing approach. These dual reuniens mPFC-HC projecting cells, in particular, are thought to be important for synchronizing mPFC and HC activity. First, we confirmed the absence of PV+neurons in the midline thalamus. Second, we found a common pattern of CR+and CB+cells throughout midline thalamus with CR+cells running along the nearby third ventricle (3V) and penetrating the midline. CB+cells were consistently more lateral and toward the middle of the dorsal-ventral extent of the midline thalamus. Notably, single-labeled CR+and CB+zones were partially overlapping and included dual-labeled CR+/CB+cells. Within RE, we also observed a CR and CB subzone specific diversity. Interestingly, dual mPFC-HC projecting neurons in RE expressed none of the calcium binding proteins examined, but were contained in nests of CR+and CB+cells. Overall, the midline thalamus was well organized into CR+and CB+rich zones distributed throughout the region, with dual mPFC-HC projecting cells in reuniens representing a unique cell population. These results provide a cytoarchitectural organization in the midline thalamus based on calcium binding protein expression, and sets the stage for future cell-type specific interrogations of the functional role of these different cell populations in mPFC-HC interactions.