bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-scale models reveal hypertrophic cardiomyopathy MYH7 G256E mutation drives hypercontractility and elevated mitochondrial respiration
Authors: Lee Soah , Roest Alison S. Vander , Blair Cheavar A. , Kao Kerry , Bremner Samantha B. , Childers Matthew C , Pathak Divya , Heinrich Paul , Lee Daniel , Chirikian Orlando , Mohran Saffie , Roberts Brock , Smith Jacqueline E. , Jahng James W. , Paik David T. , Wu Joseph C. , Gunawardane Ruwanthi N. , Spudich James A. , Ruppel Kathleen , Mack David , Pruitt Beth L. , Regnier Michael , Wu Sean M. , Bernstein Daniel 
Published: June 2023

ABSTRACTRationaleOver 200 mutations in the sarcomeric protein β-myosin heavy chain (MYH7) have been linked to hypertrophic cardiomyopathy (HCM). However, different mutations in MYH7 lead to variable penetrance and clinical severity, and alter myosin function to varying degrees, making it difficult to determine genotype-phenotype relationships, especially when caused by rare gene variants such as the G256E mutation.ObjectiveThis study aims to determine the effects of low penetrant MYH7 G256E mutation on myosin function. We hypothesize that the G256E mutation would alter myosin function, precipitating compensatory responses in cellular functions.MethodsWe developed a collaborative pipeline to characterize myosin function at multiple scales (protein to myofibril to cell to tissue). We also used our previously published data on other mutations to compare the degree to which myosin function was altered.ResultsAt the protein level, the G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 50.9%, suggesting more myosins available for contraction. Myofibrils isolated from hiPSC-CMs CRISPR-edited with G256E (MYH7WT/G256E) generated greater tension, had faster tension development and slower early phase relaxation, suggesting altered myosin-actin crossbridge cycling kinetics. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. Single-cell transcriptomic and metabolic profiling demonstrated upregulation of mitochondrial genes and increased mitochondrial respiration, suggesting altered bioenergetics as an early feature of HCM.ConclusionsMYH7 G256E mutation causes structural instability in the transducer region, leading to hypercontractility across scales, perhaps from increased myosin recruitment and altered crossbridge cycling. Hypercontractile function of the mutant myosin was accompanied by increased mitochondrial respiration, while cellular hypertrophy was modest in the physiological stiffness environment. We believe that this multi-scale platform will be useful to elucidate genotype-phenotype relationships underlying other genetic cardiovascular diseases.
An exploratory study of behavioral traits and the establishment of social relationships in female laboratory rats
Authors: Hakataya Shiomi , Katsu Noriko , Okanoya Kazuo , Toya Genta 
Published: June 2023

AbstractThere is growing evidence that social relationships influence individual fitness through various effects. Clarifying individual differences in social interaction patterns and determinants for such differences will lead to better understanding of sociality and its fitness consequences for animals. Behavioral traits are considered one of the determining factors of social interaction. The purpose of this study was to explore the effects of individual behavioral traits on social relationship building in rats, a highly social species. Initially, the following behavioral characteristics were measured in individuals: tameness (glove test), activity (open field test), exploration (novel object test), sociability (three-chamber test), and boldness (elevated plus maze test). We then used DeepLabCut to behaviorally track three groups of four individuals (12 total) and analyze social behaviors such as approach and avoidance behaviors. Principal component analysis based on behavioral test results detected behavioral traits interpreted as related to exploration, boldness, activity, and tameness, but not sociability. In addition, behavioral tracking results showed consistent individual differences in social behavior indices such as isolation time and partner preference. Furthermore, we found that different components were correlated with different phases of social behavior; exploration and boldness were associated with the early stages of group formation, whereas activity was associated with later stages of relationship building. From these results, we derived hypothesize that personality traits related to the physical and social environment have a larger influence in the relationship formation phase, and the behavioral trait of activity becomes important in the maintenance phase of relationships. Future studies should examine this hypothesis by testing larger group sizes and ensuring there is no bias introduced into group composition.
Scots pine – panmixia and the elusive signal of genetic adaptation
Authors: Bruxaux Jade , Zhao Wei , Hall David , Curtu Alexandru Lucian , Androsiuk Piotr , Drouzas Andreas D. , Gailing Oliver , Konrad Heino , Sullivan Alexis R. , Semerikov Vladimir , Wang Xiao-Ru 
Published: June 2023

SummaryScots pine is the foundation species of diverse forested ecosystems across Eurasia and displays remarkable ecological breadth, occurring in environments ranging from temperate rainforests to arid tundra margins. Such expansive distributions can be favored by various demographic and adaptive processes and the interactions between them.To understand the impact of neutral and selective forces on genetic structure in Scots pine, we conducted range-wide population genetic analyses on 2,321 trees from 202 populations using genotyping-by-sequencing, reconstructed the recent demography of the species, and examined signals of genetic adaptation.We found a high and uniform genetic diversity across the entire range (globalFST0.048), no increased genetic load in expending populations and minor impact of the last glacial maximum on historical population sizes. Genetic-environmental associations identified only a handful of SNPs significantly linked to environmental gradients.The results suggest that extensive gene flow is predominantly responsible for the observed genetic patterns in Scots pine. The apparent missing signal of genetic adaptation is likely attributed to the intricate genetic architecture controlling adaptation to multi-dimensional environments. The panmixia metapopulation of Scots pine offers a good study system for further exploration into how genetic adaptation and plasticity evolve under gene flow and changing environment.
Spatiotemporal organization of prefrontal norepinephrine influences neuronal activity
Authors: Glaeser-Khan Samira , Savalia Neil K. , Cressy Jianna , Feng Jiesi , Li Yulong , Kwan Alex C. , Kaye Alfred P. 
Published: June 2023

AbstractNorepinephrine (NE), a neuromodulator released by locus coeruleus neurons throughout cortex, influences arousal and learning through extra-synaptic vesicle exocytosis. While NE within cortical regions has been viewed as a homogenous field, recent studies have demonstrated heterogeneous axonal dynamics and advances in GPCR-based fluorescent sensors permit direct observation of the local dynamics of NE at cellular scale. To investigate how the spatiotemporal dynamics of NE release in the PFC affect neuronal firing, we employed in-vivo two-photon imaging of layer 2/3 of PFC in order to observe fine-scale neuronal calcium and NE dynamics concurrently. We found that local and global NE fields can decouple from one another, providing a substrate for local NE spatiotemporal activity patterns. Optic flow analysis revealed putative release and reuptake events which can occur at the same location, albeit at different times, indicating the potential to create a heterogeneous NE field. Utilizing generalized linear models, we demonstrated that cellular Ca2+ fluctuations are influenced by both the local and global NE field. However, during periods of local/global NE field decoupling, the local field drives cell firing dynamics rather than the global field. These findings underscore the significance of localized, phasic NE fluctuations for structuring cell firing, which may provide local neuromodulatory control of cortical activity.
On the Mathematics of RNA Velocity II: Algorithmic Aspects
Authors: Li Tiejun , Wang Yizhuo , Yang Guoguo , Zhou Peijie 
Published: June 2023

AbstractIn a previous paper [CSIAM Trans. Appl. Math. 2 (2021), 1-55], the authors proposed a theoretical framework for the analysis of RNA velocity, which is a promising concept in scRNA-seq data analysis to reveal the cell state-transition dynamical processes underlying snapshot data. The current paper is devoted to the algorithmic study of some key components in RNA velocity workflow. Four important points are addressed in this paper: (1) We construct a rational time-scale fixation method which can determine the global gene-shared latent time for cells. (2) We present an uncertainty quantification strategy for the inferred parameters obtained through the EM algorithm. (3) We establish the optimal criterion for the choice of velocity kernel bandwidth with respect to the sample size in the downstream analysis and discuss its implications. (4) We propose a temporal distance estimation approach between two cell clusters along the cellular development path. Some illustrative numerical tests are also carried out to verify our analysis. These results are intended to provide tools and insights in further development of RNA velocity type methods in the future.
Development of cell-free transcription-translation systems in three soil Pseudomonads
Authors: Meyerowitz Joseph T. , Larsson Elin M. , Murray Richard M. 
Published: June 2023

AbstractIn vitrotranscription-translation (TX-TL) can enable faster engineering of biological systems. This speed-up can be significant, especially in difficult-to-transform chassis. This work shows the successful development of TX-TL systems using three soil-derived wild-type Pseudomonads known to promote plant growth:Pseudomonas synxantha, Pseudomonas chlororaphis, andPseudomonas aureofaciens. One,P. synxantha, was further characterized. A lysate test ofP. synxanthashowed a maximum protein yield of 2.5μM at 125 proteins per DNA template and a maximum protein synthesis rate of 20 nM/min. A set of different constitutive promoters driving mNeonGreen expression were tested in TX-TL and integrated into the genome, showing similar normalized strengths forin vivoandin vitrofluorescence. This correspondence between the TX-TL derived promoter strength and thein vivopromoter strength indicates these lysate-based cell-free systems can be used to characterize and engineer biological parts without genome integration, enabling a faster designbuild-test cycle.
Weak local adaptation to drought in seedlings of a widespread conifer
Authors: Candido-Ribeiro Rafael , Aitken Sally N. 
Published: June 2023

AbstractThere is an urgent need for better understanding how populations of trees will respond to predictable changes in climate and the intensification of extreme weather events such as droughts. The distribution of adaptive traits in seedlings is a crucial component of population adaptive potential and its characterization is important for development of management approaches mitigating the effects of climate change on forests. In this study, we used a large-scale common garden drought experiment to characterize the variation in drought tolerance, growth, and plastic responses to extreme summer drought in seedlings of 73 natural provenances of the two main varieties of Douglas-fir (Pseudotsuga menziesiivar.menziesiiand var.glauca), sampled across most of their extensive natural ranges. We detected large differences between the two Douglas-fir varieties for all traits assessed, with var.glaucashowing higher tolerance to drought but slower height growth and less plasticity than var.menziesii. Surprisingly, signals of local adaptation to drought within varieties were weak within var.glaucaand nearly absent within var.menziesii. Temperature-related variables were identified as the main climatic drivers of clinal variation in drought tolerance and height growth species-wide, and in height growth within var.menziesii. Furthermore, our data indicate that higher plasticity under extreme droughts could be maladaptive in var.menziesii. Overall, our study suggests that genetic variation for drought tolerance in seedlings is maintained primarily within rather than among provenances within varieties and does not compromise growth at early stages of plant development. Given these results, assisted gene flow is unlikely to help facilitate adaptation to drought within Douglas-fir varieties, but selective breeding within provenances could accelerate adaptation.
Acyl-AcpB, a FabT co-repressor inStreptococcus pyogenes
Authors: Lambert Clara , d’Orfani Alice , Gaillard Marine , Zhang Qiufen , Gloux Karine , Poyart Claire , Fouet Agnès 
Published: June 2023

AbstractMembranes are a universal barrier to all cells. Phospholipids, essential bacterial membrane components, are composed of a polar head and apolar fatty acid (FA) chains. Most bacterial FA are synthesized by the FA synthesis pathway (FASII). In streptococcaceae, enterococci andLactococcus lactis, a unique feedback mechanism controls the FASII gene expression. FabT, encoded in the FASII main locus, is the repressor and it is activated by acyl-ACP. Many Streptococci,Enterococcus faecalis, but notL. lactis, possess two ACPS. AcpA encoding gene is within the FASII locus and is, to a certain extent, coregulated with the FASII genes. Acyl-AcpA is the end product of FASII. AcpB encoding gene is in operon withplsX. The role of AcpB as FabT corepressor is controversial.Streptococcus pyogenes, which causes a wide variety of diseases ranging from mild non-invasive to severe invasive infections, possesses AcpB. In this study, we show by comparing gene repression of FASII genes in wild-type,fabTmutant andacpBmutant strains grown in the presence and the absence of exogenous FAs, that AcpB isS. pyogenesFabT main co-repressor. Also,acpBdeletion impacts the membrane FA composition and adhesion to eucaryotic cells, highlighting the role of AcpB.
Robust Optogenetic Inhibition with Red-light-sensitive Anion-conducting Channelrhodopsins
Authors: Oppermann Johannes , Rozenberg Andrey , Fabrin Thomaz , González-Cabrera Cristian , Parker Rafael E. S. , Béjà Oded , Prigge Matthias , Hegemann Peter 
Published: June 2023

AbstractChannelrhodopsins (ChRs) are light-gated ion channels widely used to optically activate or silence selected electrogenic cells, such as individual brain neurons. Here, we describe identifying and characterizing a set of anion-conducting ChRs (ACRs) from diverse taxa and representing various branches of the ChR phylogenetic tree. TheMantoniella squamataACR (MsACR1) showed high sensitivity to yellow-green light (λmaxat 555 nm) and was further engineered for optogenetic applications. A single amino-acid substitution that mimicked red-light sensitive rhodopsins like Chrimson shifted the photosensitivity 20 nm towards red light and accelerated photocurrent kinetics. Hence, it was named red and accelerated ACR, raACR. Both wild-type and mutant are capable optical silencers at low light intensities in mouse neuronsin vitroandin vivo,while raACR offers a higher temporal resolution.
Neuropathy target esterase activity predicts retinopathy amongPNPLA6disorders
Authors: Liu James , He Yi , Lwin Cara , Han Marina , Guan Bin , Naik Amelia , Bender Chelsea , Moore Nia , Huryn Laryssa A. , Sergeev Yuri , Qian Haohua , Zeng Yong , Dong Lijin , Liu Pinghu , Lei Jingqi , Haugen Carl J. , Prasov Lev , Shi Ruifang , Dollfus Hélène , Aristodemou Petros , Laich Yannik , Németh Andrea H. , Taylor John , Downes Susan , Krawczynski Maciej , Meunier Isabelle , Strassberg Melissa , Tenney Jessica , Gao Josephine , Shear Matthew A. , Moore Anthony T. , Duncan Jacque L. , Menendez Beatriz , Hull Sarah , Vincent Andrea , Siskind Carly E. , Traboulsi Elias I. , Blackstone Craig , Sisk Robert , Utz Virginia , Webster Andrew R. , Michaelides Michel , Arno Gavin , Synofzik Matthis , Hufnagel Robert B 
Published: June 2023

AbstractBiallelic pathogenic variants in thePNPLA6gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies.PNPLA6encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals withPNPLA6variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed acrossPNPLA6-associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifyingPNPLA6variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus,PNPLA6disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.
Structural basis of the interaction between ESV1 and LESV fromArabidopsis thalianawith starch glucans
Authors: Osman Rayan , Bossu Mélanie , Dauvillée David , Spriet Corentin , Liu Chun , Zeeman Samuel , D’Hulst Christophe , Bompard Coralie 
Published: June 2023

AbstractStarch is the major energy storage compound in plants. Whether it is transient or stored, it is accumulated in the form of insoluble, semi-crystalline granules. The structure of these granules is related to the structure of the main component: amylopectin. Amylopectin consists of linear polymers of glucose units linked by α-1,4 bonds, forming double helices that combine to form the semi-crystalline lamellae of the granules, and α-1,6 branching points that form the amorphous lamellae. This particular structure of amylopectin is linked to the action of isoamylases, which cut the excess of branching points and allow the granules to be structured. For a long time, it was thought that the action of these enzymes was responsible for the structuring of starch granules. Recently, two new proteins, LESV and ESV1, have been characterized and are involved in the phase transition of amylopectin (LESV) or in the maintenance of the granule structure (ESV1). These proteins share a tryptophan-rich domain folded into an antiparallel β-sheet that is particularly well suited to bind amylopectin double helices. In this paper we present the structural study of these interactions using integrative structural biology approaches and show that LESV, in contrast to ESV1 can intervenes during amylopectin biosynthesis.
From gonadogenesis to testicular cancer: Unravelling the novel regulators and identification of drug candidates against FGF9 and PTGDS
Authors: Kumar Cash , Singh Vinay Kumar , Roy Jagat Kumar 
Published: June 2023

AbstractSex determination is the preliminary step toward gonadogenesis in mammals. Antagonistic interactions of key regulators have been only fragmentarily mentioned so far. Therefore, exploring regulators underlying the phenomena is required to solve questions, especially regarding female gonad development and gonadal disorders in congenital or adults. Inhibiting discrepancies in PPI pathways and combating related disorders are of urgent necessity, for which novel drugs are constantly required. Here, we performedin silicoanalysis using robust bioinformatics methods, which is unprecedented work in sex determination studies, providing large-scale analysis without exorbitant wet lab procedures. Analyzed regulators were overlapped with our RNA-seq data for authentication, to obtain differentially expressed elements. Additionally, CADD approach was used to discover inhibitors for FGF9 and PTGDS to search for potential drugs combating gonadal disorders in adults. Along with druggable properties, only FGF9 and PTGDS had full-length protein structures available, among 25 key genes under investigation. Our large-scale analysis of PPIN, produced highly interacting hub-bottleneck nodes as novel genes. Further, functional enrichment analysis revealed importance of these regulators in gonadogenesis. We identified sex-specific novel genes, miRNAs-target pairs, and lncRNAs-target pairs, which appear to play an important role in regulation of ovary development. CADD with molecular docking, MD simulations, and molecular mechanics confirmed stability of two novel compounds, DB12884 and DB12412 that could potentially inhibit FGF9 and PTGDS respectively. Taken together our study provides valuable information regarding involvement of crucial regulators in antagonistic mechanism of gonadogenesis and their related disorders, which will further assist in refining wet lab experiments.
The effects of data leakage on connectome-based machine learning models
Authors: Rosenblatt Matthew , Tejavibulya Link , Jiang Rongtao , Noble Stephanie , Scheinost Dustin 
Published: June 2023

AbstractPredictive modeling has now become a central technique in neuroimaging to identify complex brain-behavior relationships and test their generalizability to unseen data. However, data leakage, which unintentionally breaches the separation between data used to train and test the model, undermines the validity of predictive models. Previous literature suggests that leakage is generally pervasive in machine learning, but few studies have empirically evaluated the effects of leakage in neuroimaging data. Although leakage is always an incorrect practice, understanding the effects of leakage on neuroimaging predictive models provides insight into the extent to which leakage may affect the literature. Here, we investigated the effects of leakage on machine learning models in two common neuroimaging modalities, functional and structural connectomes. Using over 400 different pipelines spanning four large datasets and three phenotypes, we evaluated five forms of leakage fitting into three broad categories: feature selection, covariate correction, and lack of independence between subjects. As expected, leakage via feature selection and repeated subjects drastically inflated prediction performance. Notably, other forms of leakage had only minor effects (e.g., leaky site correction) or even decreased prediction performance (e.g., leaky covariate regression). In some cases, leakage affected not only prediction performance, but also model coefficients, and thus neurobiological interpretations. Finally, we found that predictive models using small datasets were more sensitive to leakage. Overall, our results illustrate the variable effects of leakage on prediction pipelines and underscore the importance of avoiding data leakage to improve the validity and reproducibility of predictive modeling.