bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Complex Structure Prediction Powered by Multiple Sequence Alignments of Interologs from Multiple Taxonomic Ranks and AlphaFold2
Authors: Si Yunda , Yan Chengfei 
Published: December 2021

AbstractAlphaFold2 is expected to be able to predict protein complex structures as long as a multiple sequence alignment (MSA) of the interologs of the target protein-protein interaction (PPI) can be provided. In this study, a simplified phylogeny-based approach was applied to generate the MSA of interologs, which was then used as the input to AlphaFold2 for protein complex structure prediction. Extensively benchmarked this protocol on non-redundant PPI dataset including 107 bacterial PPIs and 442 eukaryotic PPIs, we show complex structures of 79.5% of the bacterial PPIs and 49.8% of the eukaryotic PPIs can be successfully predicted, which yielded significantly better performance than the application of MSA of interologs prepared by two existing approaches. Considering PPIs may not be conserved in species with long evolutionary distances, we further restricted interologs in the MSA to different taxonomic ranks of the species of the target PPI in protein complex structure prediction. We found the success rates can be increased to 87.9% for the bacterial PPIs and 56.3% for the eukaryotic PPIs if interologs in the MSA are restricted to a specific taxonomic rank of the species of each target PPI. Finally, we show the optimal taxonomic ranks for protein complex structure prediction can be selected with the application of the predicted TM-scores of the output models.
From climate warming to accelerated cellular ageing: an experimental study in wild birds
Authors: Stier Antoine , Hsu Bin-Yan , Cossin-Sevrin Nina , Garcin Natacha , Ruuskanen Suvi 
Published: December 2021

AbstractClimate change is increasing both the average ambient temperature and the frequency and severity of heat waves. While direct mortality induced by heat waves is increasingly reported, sub-lethal effects are also likely to impact wild populations. We hypothesized that accelerated ageing could be a cost of being exposed to higher ambient temperature, especially in early-life when thermoregulatory capacities are not fully developed. We tested this hypothesis in wild great tit (Parus major) by experimentally increasing nest box temperature by ca. 2°C during postnatal growth and measuring telomere length, a biomarker of cellular ageing predictive of survival prospects in many bird species. While increasing early-life temperature does not affect growth or survival to fledging, it accelerates telomere shortening and reduces medium-term survival from 34% to 19%. Heat-induced telomere shortening was not explained by oxidative stress, but more likely by an increase in energy demand (i.e. higher thyroid hormones levels, increased expression of glucocorticoid receptor, increased mitochondrial density) leading to a reduction in telomere maintenance mechanisms (i.e. decrease in the gene expression of telomerase and protective shelterin). Our results thus suggest that climate warming can affect ageing rate in wild birds, with potential impact on population dynamics and persistence.Significance statementStressful environmental conditions are known to accelerate cellular ageing, especially when experienced early in life. One unexplored avenue through which climate warming might affect wild animal populations is accelerated ageing. Here we show that increasing nest temperature by ca. 2°C during postnatal growth in a wild bird species can impact numerous physiological pathways and medium-term survival. Notably, artificially warming nests accelerates the shortening of telomeres, which are the protective end-caps of chromosomes considered as a hallmark of ageing. We thus suggest that warm ambient temperatures might accelerate ageing in wild animals, which can potentially impact population dynamics and extinction risk in the face of climate change.
DNA fluctuations reveal the size and dynamics of topological domains
Authors: Vanderlinden Willem , Skoruppa Enrico , Kolbeck Pauline J. , Carlon Enrico , Lipfert Jan 
Published: December 2021

AbstractDNA supercoiling is a key regulatory mechanism that orchestrates DNA readout, recombination, and genome maintenance. DNA-binding proteins often mediate these processes by bringing two distant DNA sites together, thereby inducing (transient) topological domains. In order to understand the dynamics and molecular architecture of protein induced topological domains in DNA, quantitative and time-resolved approaches are required. Here we present a methodology to determine the size and dynamics of topological domains in supercoiled DNA in real-time and at the single molecule level. Our approach is based on quantifying the extension fluctuations – in addition to the mean extension – of supercoiled DNA in magnetic tweezers. Using a combination of high-speed magnetic tweezers experiments, Monte Carlo simulations, and analytical theory, we map out the dependence of DNA extension fluctuations as a function of supercoiling density and external force. We find that in the plectonemic regime the extension variance increases linearly with increasing supercoiling density and show how this enables us to determine the formation and size of topological domains. In addition, we demonstrate how transient (partial) dissociation of DNA bridging proteins results in dynamic sampling of different topological states, which allows us to deduce the torsional stiffness of the plectonemic state and the kinetics of protein-plectoneme interactions. We expect our approach to enable quantification of the dynamics and reaction pathways of DNA processing enzymes and motor proteins, in the context of physiologically relevant forces and supercoiling densities.SignificanceIn the cell, long DNA molecules carry the genetic information and must be stored and maintained, yet remain accessible for read out and processing. DNA supercoiling facilitates compaction of DNA, modulates its accessibility, and spatially juxtaposes DNA sites distant in linear DNA sequence. By binding to two sites in supercoiled DNA, DNA bridging proteins can pinch off topological domains and alter DNA plectoneme dynamics. Here we show how DNA bridging and topological domain dynamics can be detected from changes in the extension fluctuations of supercoiled DNA molecules tethered in magnetic tweezers. Our work highlights how considering DNA extension fluctuations, in addition to the mean extension, provides additional information and enables the investigation of protein-DNA interactions that are otherwise invisible.
A network model of the modulation of gamma oscillations by NMDA receptors in cerebral cortex
Authors: Susin Eduarda , Destexhe Alain 
Published: December 2021

Psychotic drugs such as ketamine induce symptoms close to schizophrenia, and stimulate the production of gamma oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating gamma oscillations, and have integrated the action of drugs such as ketamine to partially block n-methyl-d-Aspartate (NMDA) receptors. The model can reproduce the paradoxical increase of gamma oscillations by NMDA-receptor antagonists, assuming that antagonists affect NMDA receptors with higher affinity on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channnels are diminished, an increase of gamma power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to gamma states, but was also present in asynchronous states with no apparent gamma. We conclude that NMDA antagonists induce an increased excitability state, which may or may not produce gamma oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations.Significance Statementn-methyl-d-Aspartate (NMDA) synaptic receptors mediate excitatory interactions using the neurotransmitter glutamate. NMDA receptors have been implicated in psychosis such as schizophrenia and are also targeted by hallucinogenic drugs like Ketamine. However, the exact mechanisms of action are sill unclear. Furthermore, Ketamine paradoxially leads to and excited state, while it is a blocker of NMDA receptors, therefore in principle diminishing excitation. Here, we use models of cortical networks generating gamma oscillations, and show that this model can explain the paradoxical exciting effect of Ketamine if one assumes a higher affinity on NMDA receptors of inhibitory interneurons. The simulated Ketamine effect reproduces known symptoms of psychosis such as increased gamma oscillations and exacerbated responses to external inputs, compatible with hallucinations.
Hemicentin mediated type IV collagen assembly strengthens juxtaposed basement membrane linkage
Authors: Gianakas Claire A. , Keeley Daniel P. , Ramos-Lewis William , Park Kieop , Jayadev Ranjay , Chi Qiuyi , Sherwood David R. 
Published: December 2021

AbstractBasement membrane (BM) matrices surround and separate most tissues. However, through poorly understood mechanisms, BMs of adjacent tissues can also stably link to support organ structure and function. Using endogenous knock-in fluorescent proteins, conditional RNAi, optogenetics, and quantitative live imaging, we identified matrix proteins mediating a BM linkage (B-LINK) between the uterine utse and epidermal seam cell BMs in Caenorhabditis elegans that supports the uterus during egg-laying. We found that hemicentin is secreted by the utse and promotes fibulin-1 assembly to jointly initiate the B-LINK. During egg-laying, however, both proteins decline in levels and are not required for B-LINK maintenance. Instead, we discovered that hemicentin also promotes type IV collagen assembly, which accumulates to high levels during egg-laying and sustains the B-LINK during the mechanically active egg-laying period. This work reveals mechanisms underlying BM-BM connection maturation and identifies a crucial function for hemicentin and fibulin-1 in initiating attachment and type IV collagen in strengthening this specialized form of tissue linkage.SummaryTissue attachment through linking juxtaposed basement membranes (BMs) is crucial for the structure and function of many organs. Gianakas et al. identify a key role for hemicentin and fibulin-1 in initiating BM-BM attachment and type IV collagen in stabilizing this linkage and allowing it to resist high mechanical loads.
User-friendly analysis of droplet array images
Authors: Sanka Immanuel , Bartkova Simona , Pata Pille , Ernits Mart , Meinberg Monika , Agu Natali , Aruoja Villem , Smolander Olli-Pekka , Scheler Ott 
Published: December 2021

ABSTRACTWater-in-oil droplets allow researchers to perform massive experimental parallelization and high-throughput studies, such as single-cell experiments. However, the analysis of such vast arrays of droplets usually requires advanced expertise and sophisticated workflow tools, which limits the accessibility for wider user base in chemistry and biology. Thus, there is a need for more user-friendly tools for droplet analysis. In this article, we deliver a set of analytical pipelines for user-friendly analysis of typical scenarios in droplet-based experiments. We build the pipelines combining different open-source image-analysis software with the custom-developed data visualization tool “EasyFlow”. Our pipelines are designed to be applicable for the typical experimental scenarios users encounter with droplets: i) mono- and polydisperse droplets, ii) brightfield and fluorescent images, iii) droplet and object detection, iv) signal profile of droplets and objects (e.g., fluorescence).
A deep learning framework for predicting human essential genes from population and functional genomic data
Authors: LaPolice Troy M. , Huang Yi-Fei 
Published: December 2021

AbstractBeing able to predict essential genes intolerant to loss-of-function (LOF) mutations can dramatically improve our ability to identify genes associated with genetic disorders. Numerous computational methods have recently been developed to predict human essential genes from population genomic data; however, the existing methods have limited power in pinpointing short essential genes due to the sparsity of polymorphisms in the human genome. Here we present an evolution-based deep learning model, DeepLOF, which integrates population and functional genomic data to improve gene essentiality prediction. Compared to previous methods, DeepLOF shows unmatched performance in predicting ClinGen haploinsufficient genes, mouse essential genes, and essential genes in human cell lines. Furthermore, DeepLOF discovers 109 potentially essential genes that are too short to be identified by previous methods. Altogether, DeepLOF is a powerful computational method to aid in the discovery of essential genes.
The class I TCP transcription factor AtTCP8 is a modulator of phytohormone-responsive signaling networks
Authors: Spears Benjamin J. , McInturf Samuel A. , Chlebowski Meghann , Su Jianbin , Mendoza-Cózatl David G. , Gassmann Walter 
Published: December 2021

ABSTRACTThe plant-specific TEOSINTE BRANCHED1/ CYCLOIDEA/ PROLIFERATING CELL FACTOR (TCP) transcription factor family is most closely associated with regulating plant developmental programs. Recently, TCPs were also shown to mediate host immune signaling, both as targets of pathogen virulence factors and regulators of plant defense genes. However, any comprehensive characterization of TCP gene targets is still lacking. Loss of the class I TCP AtTCP8 attenuates early immune signaling, and when combined with mutations in AtTCP14 and AtTCP15, additional layers of defense signaling in Arabidopsis thaliana. Here we focus on TCP8, the most poorly characterized of the three to date. We use chIP and RNA-sequencing to identify TCP8-bound gene promoters and differentially regulated genes in the tcp8 mutant, data sets that are heavily enriched in signaling components for multiple phytohormone pathways, including brassinosteroids (BRs), auxin, and jasmonic acid (JA). Using BR signaling as a representative example, we show that TCP8 directly binds and activates the promoters of the key BR transcriptional regulators BZR1 and BZR2/BES1. Furthermore, tcp8 mutant seedlings exhibit altered BR-responsive growth patterns and complementary reductions in BZR2 transcript levels, while the expressed protein demonstrates BR-responsive changes in subnuclear localization and transcriptional activity. We conclude that one explanation for the significant targeting of TCP8 alongside other TCP family members by pathogen effectors may lie in its role as a modulator of brassinosteroid and other plant hormone signaling pathways.One Sentence SummaryOne member of a pathogen-targeted transcription factor family modulates phytohormone response networks and displays brassinosteroid-dependent cellular location and activity.
Isolating salient variations of interest in single-cell data with contrastiveVI
Authors: Weinberger Ethan , Lin Chris , Lee Su-In 
Published: December 2021

AbstractSingle-cell datasets are routinely collected to investigate changes in cellular state between control cells and corresponding cells in a treatment condition, such as exposure to a drug or infection by a pathogen. To better understand heterogeneity in treatment response, it is desirable to disentangle latent structures and variations uniquely enriched in treated cells from those shared with controls. However, standard computational models of single-cell data are not designed to explicitly separate these variations. Here, we introduce Contrastive Variational Inference (contrastiveVI; https://github.com/suinleelab/contrastiveVI), a framework for analyzing treatment-control scRNA-seq datasets that explicitly disentangles the data into shared and treatment-specific latent variables. Using four treatment-control scRNA-seq dataset pairs, we apply contrastiveVI to perform a broad set of standard analysis tasks, including visualization, clustering, and differential expression testing. In each case, we find that our method consistently achieves results that agree with known biological ground truths, while previously proposed methods often fail to do so. We conclude by generalizing our framework to multimodal measurements and applying it to analyze a single-cell dataset with joint transcriptome and surface protein measurements.
Opioid withdrawal abruptly disrupts amygdala circuit function by reducing peptide actions
Authors: Gregoriou Gabrielle C. , Patel Sahil D. , Pyne Sebastian , Winters Bryony L. , Bagley Elena E. 
Published: December 2021

SummaryOpioid withdrawal drives relapse and contributes to compulsive drug use through disruption of endogenous opioid dependent learning circuits in the amygdala. Normally, endogenous opioids control these circuits by inhibiting glutamate release from basolateral amygdala principal neurons onto GABAergic intercalated cells. Using patch-clamp electrophysiology in rat brain slices, we reveal that opioid withdrawal dials down this endogenous opioid inhibition of synaptic transmission. Peptide activity is dialled down due to a protein kinase A dependent increase in the activity of the peptidase, neprilysin. This disrupts peptidergic control of both GABAergic and glutamatergic transmission through multiple amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent learning processes in the amygdala during withdrawal. and may direct behaviour towards compulsive drug use. Restoration of endogenous peptide activity during withdrawal may be a viable option to normalise synaptic transmission in the amygdala and restore normal reward learning.In BriefWe find that opioid withdrawal dials down inhibitory neuropeptide activity in the amygdala. This disrupts both GABAergic and glutamatergic transmission through amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent learning processes in the amygdala during withdrawal and may direct behaviour towards compulsive drug use.HighlightsDuring opioid withdrawal, peptidase activity is upregulated in an amygdala circuitPeptidase upregulation occurs via a PKA-dependent mechanismIncreased peptidase activity limits peptidergic control of synaptic transmissionOpioid withdrawal disrupts the balance of excitation and inhibition in the amygdala
In vivo reprogramming and epigenetic rejuvenation of adult cardiomyocytes ameliorate heart failure in mice
Authors: de Lázaro Irene , Zhang Bohan , Makarova Nadezhda E , Mariotti Marco , Orejón-Sánchez Tiara L , Tringides Christina M , Gladyshev Vadim N , Mooney David J 
Published: December 2021

ABSTRACTPartial cell reprogramming has been demonstrated in certain mouse tissues by in situ overexpression ofOct3/4,Klf4,Sox2andcMyc(OKSM) transcription factors, and can induce rejuvenation and/or augment regeneration. Reprogramming of adult cardiomyocytes has been elusive until recently, but its success could help overcome the lack of endogenous regenerative capacity of the mammalian myocardium. Here, we generated cardiomyocyte-specific, doxycycline-inducible, reprogrammable mice and demonstrated that sustained OKSM induction reprograms cardiomyocytes fully into teratoma-forming pluripotent cells. However, we also showed that cyclic OKSM upregulation induces significant decrease of epigenetic age in the cardiomyocytes without de-differentiation or reacquisition of pluripotency. In mice with progressive heart failure, cardiomyocyte epigenetic rejuvenation correlated with stabilization of systolic heart function. These findings confirm that OKSM can reprogram adult mouse cardiomyocytes to different states depending on the duration of their expression, and provide further evidence that partially reprogrammed cardiomyocytes may contribute to ameliorate cardiac disease.
Dissociable roles for the striatal cholinergic system in different flexibility contexts
Authors: Williams Brendan , Christakou Anastasia 
Published: December 2021

AbstractThe production of behavioural flexibility requires the coordination and integration of information from across the brain, by the dorsal striatum. In particular, the striatal cholinergic system is thought to be important for the modulation of striatal activity. Research from animal literature has shown that chemical inactivation of the dorsal striatum leads to impairments in reversal learning. Furthermore, proton magnetic resonance spectroscopy work has shown that the striatal cholinergic system is also important for reversal learning in humans. Here, we aim to assess whether the state of the dorsal striatal cholinergic system at rest is related to flexible behaviour in reversal learning. We provide preliminary results showing that variability in choline in the dorsal striatum is significantly related to both the number perseverative and regressive errors that participants make, and their rate of learning from positive and negative prediction errors. These findings, in line with previous work, suggest the resting state of dorsal striatal cholinergic system has important implications for producing flexible behaviour. However, these results also suggest the system may have heterogeneous functionality across different types of tasks measuring behavioural flexibility. These findings provide a starting point for further interrogation into understanding the functional role of the striatal cholinergic system in flexibility.
Super-resolution vibrational imaging using expansion stimulated Raman scattering microscopy
Authors: Shi Lixue , Klimas Aleksandra , Gallagher Brendan , Cheng Zhangyu , Fu Feifei , Wijesekara Piyumi , Miao Yupeng , Ren Xi , Zhao Yongxin , Min Wei 
Published: December 2021

AbstractStimulated Raman scattering (SRS) microscopy is an emerging technology that provides high chemical specificity for endogenous biomolecules and can circumvent common constraints of fluorescence microscopy including limited capabilities to probe small biomolecules and difficulty resolving many colors simultaneously due to spectral overlap. However, the resolution of SRS microscopy remains governed by the diffraction limit. To overcome this, we describe a new technique called Molecule Anchorable Gel-enabled Nanoscale Imaging of Fluorescence and stImulatEd Raman Scattering microscopy (MAGNIFIERS), that integrates SRS microscopy with expansion microscopy (ExM). ExM is a powerful strategy providing significant improvement in imaging resolution by physical magnification of hydrogel-embedded preserved biological specimens. MAGNIFIERS offers chemical-specific nanoscale imaging with sub-50 nm resolution and has scalable multiplexity when combined with multiplex Raman probes and fluorescent labels. We used MAGNIFIERS to visualize nanoscale features in a label-free manner with C-H vibration of proteins, lipids and DNA in a broad range of biological specimens, from mouse brain, liver and kidney to human lung organoid. In addition, we applied MAGNIFIERS to track nanoscale features of protein synthesis in protein aggregates using metabolic labeling of small metabolites. Finally, we used MAGNIFIERS to demonstrate 8-color nanoscale imaging in an expanded mouse brain section. Overall, MAGNIFIERS is a valuable platform for super-resolution label-free chemical imaging, high-resolution metabolic imaging, and highly multiplexed nanoscale imaging, thus bringing SRS to nanoscopy.