bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolutionarily diverse LIM domain-containing proteins bind stressed actin filaments through a conserved mechanism
Authors: Winkelman Jonathan D. , Anderson Caitlin A. , Suarez Cristian , Kovar David R. , Gardel Margaret L. 
Published: March 2020

SUMMARYThe actin cytoskeleton assembles into diverse load-bearing networks including stress fibers, muscle sarcomeres, and the cytokinetic ring to both generate and sense mechanical forces. The LIM (Lin11, Isl-1 & Mec-3) domain family is functionally diverse, but most members can associate with the actin cytoskeleton with apparent force-sensitivity. Zyxin rapidly localizes via its LIM domains to failing stress fibers in cells, known as strain sites, to initiate stress fiber repair and maintain mechanical homeostasis. The mechanism by which these LIM domains associate with stress fiber strain sites is not known. Additionally, it is unknown how widespread strain sensing is within the LIM protein family. We observe that many, but not all, LIM domains from functionally diverse proteins localize to spontaneous or induced stress fiber strain sites in mammalian cells. Additionally, the LIM domain region from the fission yeast protein paxillin like 1 (Pxl1) also localizes to stress fiber strain sites in mammalian cells, suggesting that the strain sensing mechanism is ancient and highly conserved. Sequence analysis and mutagenesis of the LIM domain region of zyxin indicate a requirement of tandem LIM domains, which contribute additively, for sensing stress fiber strain sites.In vitro, purified LIM domains from mammalian zyxin and fission yeast Pxl1 bind to mechanically stressed F-actin networks but do not associate with relaxed actin filaments. We propose that tandem LIM domains recognize an F-actin conformation that is rare in the relaxed state but is enriched in the presence of mechanical stress.
Understanding the adaptive evolution of mitochondrial genomes in intertidal chitons
Authors: Dhar Dipanjana , Dey Debayan , Basu Soumalee , Fortunato Helena 
Published: March 2020

AbstractMitochondria are the centre of energy metabolism in eukaryotic cells and its genes are thus key to the evolution of molecular mechanisms that metabolize cellular energy. Intertidal zone is one of the most stressful environments with extreme shifts in temperature, salinity, pH and oxygen concentrations. Marine molluscs, particularly chitons belong to the ecologically dominant organisms in this extreme environment, symbolizing an ideal model to understand mitochondrial stress adaptation. Here, we used concatenated mitochondrial genetic components separately from seven chitons of the intertidal zone to reconstruct phylogenetic relationships among these species. We performed selection analyses considering sites and branches of individual protein-coding genes to identify potentially adaptive residues and localize them in the protein structures of mt subunits. Our results exhibited significant amino acid changes in sites under diversifying selection of all the protein-coding genes, indicative of the adaptive evolution of mitochondrial genome in chitons. Furthermore, we obtained sites in the transmembrane helices lining the proton translocation channel as well as in surrounding loop regions, providing implication towards functional modification of the OXPHOS proteins essential for survival in dynamic environment of the intertidal zone.
Prior expectations of motion direction modulate early sensory processing
Authors: Aitken Fraser , Turner Georgia , Kok Peter 
Published: March 2020

AbstractPerception is a process of inference, integrating sensory inputs with prior expectations. However, little is known regarding the temporal dynamics of this integration. It has been proposed that expectation plays a role early in the perceptual process, by biasing early sensory processing. Alternatively, others suggest that expectations are integrated only at later, post-perceptual decision-making stages. The current study aimed to dissociate between these hypotheses. We exposed male and female human participants (N=24) to auditory cues predicting the likely direction of upcoming noisy moving dot patterns, while recording millisecond-resolved neural activity using magnetoencephalography (MEG). First, we found that participants’ reports of the moving dot directions were biased towards the direction predicted by the auditory cues. To investigate when expectations affected sensory representations, we used inverted encoding models to decode the direction represented in early sensory signals. Strikingly, the auditory cues modulated the direction represented in the MEG signal as early as 150ms after visual stimulus onset. This early neural modulation was related to perceptual effects of expectation: participants with a stronger perceptual bias towards the predicted direction also revealed a stronger reflection of the predicted direction in the MEG signal. For participants with this perceptual bias, a trial-by-trial correlation between decoded and perceived direction already emerged prior to visual stimulus onset (∼-150ms), suggesting that the pre-stimulus state of the visual cortex influences sensory processing. Together, these results suggest that prior expectations can influence perception by biasing early sensory processing, making expectation a fundamental component of the neural computations underlying perception.Significance statementPerception can be thought of as an inferential process in which our brains integrate sensory inputs with prior expectations to make sense of the world. This study investigated whether this integration occurs early or late in the process of perception. We exposed human participants to auditory cues which predicted the likely direction of visual moving dots, while recording neural activity with millisecond resolution using magnetoencephalography (MEG). Participants’ perceptual reports of the direction of the moving dots were biased towards the predicted direction. Additionally, the predicted direction modulated the neural representation of the moving dots just 150 ms after they appeared. This suggests that prior expectations affected sensory processing at very early stages, playing an integral role in the perceptual process.
Immunogenicity, safety and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs
Authors: Maria Blasi , Donatella Negri , Kevin Saunders O , Erich Baker J , Hannah Stadtler , Celia LaBranche , Benjamin Mildenberg , Georgeanna Morton , Andrew Ciarla , Xiaoying Shen , Yunfei Wang , Wes Rountree , Bala Balakumaran , Sampa Santra , Barton Haynes F , Anthony Moody M , Andrea Cara , Mary Klotman E 
Published: March 2020

AbstractA preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study we report the immunogenicity, safety and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Env induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA+/-protein immunizations using the same sequential envelopes. Compared to monkeys immunized with vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six month after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Our results show that while IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms, the use of non-stabilized sequential envelope trimers did not induce broadly neutralizing antibody responses.
PIP3 depletion rescues myoblast fusion defects in human rhabdomyosarcoma cells
Authors: Lian Yen-Ling , Chen Kuan-Wei , Chou Yu-Ting , Ke Ting-Ling , Chen Bi-Chang , Lin Yu-Chun , Chen Linyi 
Published: March 2020

AbstractMyoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. While the transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs, and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.Summary StatementThis study reveals a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma cells involving PIP3, whose depletion with PTEN rescues myoblast fusion defects.
Acute and long-term circuit-level effects in the auditory cortex after sound trauma
Authors: Jeschke Marcus , Happel Max F.K. , Tziridis Konstantin , Krauss Patrick , Schilling Achim , Schulze Holger , Ohl Frank W. 
Published: March 2020

AbstractHarmful environmental sounds are a prevailing source for chronic hearing impairments, including noise induced hearing loss, hyperacusis, or tinnitus. How these symptoms are related to pathophysiological damage to the sensory receptor epithelia and its effects along the auditory pathway, such as functional reorganizations in the auditory cortex (ACx), have been documented in numerous studies. An open question concerns the temporal evolution of maladaptive changes after damage and their manifestation in the balance between afferent thalamocortical input and corticocortical input to the ACx.To address this, we investigated the loci of plastic reorganizations across the tonotopic axis of the auditory cortex of male Mongolian gerbils (Meriones unguiculatus) acutely after a sound trauma and after several weeks. We used a laminar residual current-source density analysis to dissociate adaptations of intracolumnar input and horizontally relayed corticocortical input to synaptic populations across cortical layers in ACx. A pure tone-based sound trauma caused acute changes of subcortical inputs and corticocortical inputs at all tonotopic regions, particularly showing a broad elimination of tone-evoked inputs at tonotopic regions with a pre-trauma best frequency between 2-8 kHz. At other cortical sites, the overall columnar activity acutely decreased, while relative contributions of lateral corticocortical inputs increased. After 4-6 weeks, cortical activity to the altered sensory inputs showed a general increase of local thalamocortical input reaching levels higher than before the trauma. Hence, our results suggest a detailed mechanism for overcompensation of altered frequency input in the auditory cortex that relies on a changing balancing of thalamocortical and intracortical input and is confined to the spectral neighborhood of the trauma frequency.Significance statementHarmful noise exposure is a major anthropogenic cause of hearing disorders and is becoming an ever-increasing burden for human health and society. Damage to the sensory epithelia elicited by harmful sounds can subsequently lead to chronic hearing loss, hyperacusis or tinnitus. We still lack an understanding of the pathophysiological plastic processes and their evolution, particularly at the circuit level of the auditory cortex (ACx), which is fundamentally involved in auditory perception. We demonstrate that plastic changes in ACx after noise induced hearing loss (NIHL) occur over several weeks, and that changes in intracortical functional connectivity compensate the acute effects in the deafferentiated subcortical inputs. Such long-term changes may underlie the temporal evolution of hearing impairments or phantom sounds after NIHL.
Genotyping of Russian isolates of fungal pathogenTrichophyton rubrum, based on simple sequence repeat and single nucleotide polymorphism
Authors: Pchelin Ivan M. , Mochalov Yuri V. , Azarov Daniil V. , Romanyuk Sofya A. , Chilina Galina A. , Vybornova Irina V. , Bogdanova Tatiyana V. , Zlatogursky Vasily V. , Apalko Svetlana V. , Vasilyeva Natalia V. , Taraskina Anastasia E. 
Published: March 2020

AbstractBackgroundTheTrichophyton rubrumspecies group consists of prevalent causative agents of human skin, nail and hair infections, includingT. rubrum sensu strictoandT. violaceum, as well as other less well established or debatable taxa likeT. soudanense,T. kuryangeiandT. megninii. Our previous study provided limited evidence in favour of the existence of two genetic lineages in the RussianT. rubrum sensu strictopopulation.ObjectivesWe aimed to study the genetic structure of the Russian population ofT. rubrum, and to identify factors shaping this structure.MethodsWe analysed the polymorphism of 12 simple sequence repeat (SSR, or microsatellite) markers and single-nucleotide polymorphism in the TERG_02941 protein-coding gene in 70T. rubrumisolates and performed a phylogenomic reconstruction.ResultsAll three types of data provided conclusive evidence that the population consists of two genetic lineages. Clustering, performed by means of microsatellite length polymorphism analysis, was strongly dependent on the number of nucleotide repeats in the 5’-area of the fructose-1,6-bisphosphate aldolase gene. Analysis of molecular variance (AMOVA) on the basis of SSR typing data indicated that 22–48% of the variability was among groups withinT. rubrum. There was no clear connection of population structure with types of infection, places of geographic origin, aldolase gene expression or urease activity.ConclusionOur results suggest that the Russian population ofT. rubrumconsists of two cosmopolitan genetic lineages.
Distinct Neuronal Populations Contribute to Trace Conditioning and Extinction Learning in the Hippocampal CA1
Authors: Mount Rebecca A. , Hansen Kyle R. , Sridhar Sudiksha , Mohammed Ali I. , Abdulkerim Moona , Kessel Robb , Nazer Bobak , Gritton Howard J. , Han Xue 
Published: March 2020

AbstractTrace conditioning and extinction learning depend on the hippocampus, but it remains unclear how ongoing neural activities in the hippocampus are modulated during different learning processes. To explore this question, we performed calcium imaging in a large number of individual CA1 neurons during both trace eye-blink conditioning and subsequent extinction learning in mice. Using trial-averaged calcium fluorescence analysis, we found direct evidence that in real time, as learning emerges, distinct populations of CA1 cells contribute to trace conditioned learning versus extinction learning. Furthermore, we examined network connectivity by calculating co-activity between CA1 neuron pairs, and found that CA1 network connectivity is different between conditioning and extinction and between correct versus incorrect behavioral responses during trace conditioned learning. However, the overall connectivity density remains constant across these behavioral conditions. Together, our results demonstrate that distinct populations of CA1 neurons, forming different sub-networks with unique connectivity patterns, encode different aspects of learning.
A transcriptomic census reveals that Rbfox contributes to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus
Authors: Jansen Kathrin , Shikama-Dorn Noriko , Attar Moustafa , Maio Stefano , Lopopolo Maria , Buck David , Holländer Georg A. , Sansom Stephen N. 
Published: March 2020

AbstractThymic epithelial cells (TEC) control the selection of a T-cell repertoire reactive to pathogens but tolerant of self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire the extent to which TEC recapitulate peripheral isoforms, and the mechanisms by which they do so, have remained largely unknown. We performed the first assembly-based transcriptomic census of transcript structures and splicing factor (SF) expression in mouse medullary TEC (mTEC) and 21 peripheral tissues. Mature mTEC expressed 60.1% of all protein-coding transcripts, more than was detected in any of the peripheral tissues. However, for genes with tissue-restricted expression, we found that mTEC produced fewer isoforms than did the relevant peripheral tissues. Analysis of exon inclusion revealed an absence of brain-specific micro-exons in mTEC. We did not find unusual numbers of novel transcripts in TEC and show thatAire, the facilitator of promiscuous gene expression, promotes usage of long transcripts but has only a limited impact on alternative splicing in mTEC. Comprehensive assessment of SF expression in mTEC identified a small set of non-promiscuously expressed SF genes amongst which we confirmed RBFOX to be present with AIRE in mTEC nuclei. Using a conditional loss of function approach, we show thatRbfox2promotes mTEC development and regulates the alternative splicing of promiscuously expressed genes. These data indicate that TEC recommission a small number of peripheral SFs, including members of the Rbfox family, to generate a broad but selective representation of the peripheral splice isoform repertoire.
Is male dimorphism under sexual selection in humans? A meta-analysis
Authors: Lidborg L. H. , Cross C. P. , Boothroyd L. G. 
Published: March 2020

AbstractHumans are sexually dimorphic: men and women differ in body build and composition, craniofacial structure, and voice pitch, likely mediated in part by developmental testosterone. Sexual selection hypotheses posit that, ancestrally, more ‘masculine’ men may have acquired more mates and/or sired more viable offspring. Thus far, however, evidence for either association is unclear. Here, we meta-analyze the relationships between six masculine traits and mating/reproductive outcomes (96 studies, 474 effects,N= 177,044). Voice pitch, height, and testosterone all predicted mating; however, strength/muscularity was the strongest and only consistent predictor of both mating and reproduction. Facial masculinity and digit ratios did not significantly predict either. There was no clear evidence for any effects of masculinity on offspring viability. Our findings support arguments that strength/muscularity can be considered sexually selected in humans, but raise concerns over other forms of masculinity and highlight the need to increase tests of evolutionary hypotheses outside of industrialized populations.
Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation
Authors: Dobersch Stephanie , Rubio Karla , Singh Indrabahadur , Günther Stefan , Graumann Johannes , Cordero Julio , Castillo-Negrete Rafael , Huynh Minh Bao , Mehta Aditi , Braubach Peter , Cabrera-Fuentes Hector , Bernhagen Jürgen , Chao Cho-Ming , Bellusci Saverio , Günther Andreas , Preissner Klaus T , Dobreva Gergana , Wygrecka Malgorzata , Braun Thomas , Papy-Garcia Dulce , Barreto Guillermo 
Published: March 2020

SUMMARYIn addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure the integrity of the genome.
A numerical study about the flight of the dragonfly: 2D gliding and 3D hovering regimes
Authors: Benedetti Lorenzo , Bianchi Giovanni , Cinquemani Simone , Belloli Marco 
Published: March 2020

AbstractThe dragonfly’s ability of gliding and performing dexterous maneuvers during flight attracts the interest of scientists and engineers who aim at replicating its performances in micro air vehicles. The great efficiency of its flight is achieved thanks to the vortices generated by wing movements and thanks to the corrugations on their surfaces. The high freedom of control of each wing has been proved to be the secret behind the dragonfly capability to carry out incredible flight manoeuvers. The study presented in this paper analyzes two of the most common flight regimes of the dragonfly. Firstly, some CFD simulations of gliding are performed and drag and lift coefficients have been calculated, showing a good match with experimental data found in literature. Then, hovering has been studied using a methodology inspired to the Blade Element Momentum (BEM) theory, which is usually applied in the context of wind turbines design. The lift force calculated with this simulation corresponds to the weight of dragonfly, suggesting the correctness of this analysis.
A fast and efficient smoothing approach to Lasso regression and an application in statistical genetics: polygenic risk scores for chronic obstructive pulmonary disease (COPD)
Authors: Hahn Georg , Lutz Sharon M. , Laha Nilanjana , Cho Michael H. , Silverman Edwin K. , Lange Christoph 
Published: March 2020

AbstractHigh dimensional linear regression problems are often fitted using Lasso approaches. Although the Lasso objective function is convex, it is not differentiable everywhere, making the use of gradient descent methods for minimization not straightforward. To avoid this technical issue, we apply Nesterov smoothing to the original (unsmoothed) Lasso objective function. We introduce a closed-form smoothed Lasso which preserves the convexity of the Lasso function, is uniformly close to the unsmoothed Lasso, and allows us to obtain closed-form derivatives everywhere for efficient and fast minimization via gradient descent. Our simulation studies are focused on polygenic risk scores using genetic data from a genome-wide association study (GWAS) for chronic obstructive pulmonary disease (COPD). We compare accuracy and run-time of our approach to the current gold standard in the literature, the FISTA algorithm. Our results suggest that the proposed methodology provides estimates with equal or higher accuracy than the FISTA algorithm while having the same asymptotic runtime scaling. The proposed methodology is implemented in the R-packagesmoothedLasso, available on the Comprehensive R Archive Network (CRAN).