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Instruct:
Identify the main category of Biorxiv papers based on the titles
Query:
Reliability and Stability Challenges in ABCD Task fMRI Data
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neuroscience
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Instruct:
Identify the main category of Biorxiv papers based on the titles and abstracts
Query:
RACK1 associates with RNA-binding proteins Vigilin and SERBP1 to control dengue virus replication
Dengue virus (DENV), a re-emerging virus transmitted by Aedes mosquitoes, causes severe pathogenesis in humans. No effective treatment is available against this virus. We recently identified the scaffold protein RACK1 as a component of the DENV replication complex, a macromolecular complex essential for viral genome amplification. Here, we show that RACK1 is important for DENV infection. RACK1 mediates DENV replication through binding to the 40S ribosomal subunit. Mass spectrometry analysis of RACK1 partners coupled to a loss-of-function screen identified the RNA binding proteins Vigilin and SERBP1 as DENV host dependency factors. Vigilin and SERBP1 interact with DENV viral RNA (vRNA), forming a ternary complex with RACK1 to mediate viral replication. Overall, our results indicate that RACK1 recruits Vigilin and SERBP1, linking the DENV vRNA to the translation machinery for optimal translation and replication.
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microbiology
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Instruct:
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Query:
Fast and memory-efficient mapping of short bisulfite sequencing reads using a two-letter alphabet
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bioinformatics
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Instruct:
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Query:
The effect of acute oral galactose administration on the redox system of the rat small intestine
Galactose is a ubiquitous monosaccharide with important yet incompletely understood nutritive and physiological roles. Chronic parenteral D-galactose administration is used for modeling aging-related pathophysiological processes in rodents due to its ability to induce oxidative stress (OS). Conversely, chronic oral D-galactose administration prevents and alleviates cognitive decline in a rat model of sporadic Alzheimers disease indicating galactose may exert beneficial health effects by acting in the gut. The present aim was to explore acute time-response of intestinal redox homeostasis following oral administration of D-galactose. Male Wistar rats were euthanized at baseline (n=6), 30 (n=6), 60 (n=6), and 120 (n=6) minutes following orogastric administration of D-galactose (200 mg/kg). The overall reductive capacity, lipid peroxidation, the concentration of low molecular weight thiols (LMWT) and protein sulfhydryls (SH), the activity of Mn and Cu/Zn superoxide dismutases (SOD), reduced and oxidized fractions of nicotinamide adenine dinucleotide phosphates (NADPH/NADP), and hydrogen peroxide dissociation rate were analyzed in duodenum and ileum. Acute oral administration of D-galactose increased the activity of SODs and decreased intestinal lipid peroxidation and nucleophilic substrates (LMWT, SH, NADPH) indicating activation of peroxidative damage defense pathways. The redox system of the small intestine can acutely tolerate even high luminal concentrations of galactose (0.55 M) and oral galactose treatment is associated with a reduction rather than the increment of the intestinal OS. The ability of oral D-galactose to modulate intestinal OS should be further explored in the context of intestinal barrier maintenance, and beneficial cognitive effects associated with long-term administration of low doses of D-galactose.
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biochemistry
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Instruct:
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Query:
Distinct cDC subsets co-operate in CD40 agonist response while suppressive microenvironments and lack of antigens subvert efficacy
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cancer biology
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Instruct:
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Query:
The response of Oligo-Miocene bivalve fauna of the Kutch Basin (western India) to regional changes in tectonics and climate
Tectonic changes has influenced the evolution of the marine community by changing the land and seaway configuration through time. Two such tectonic events during Oligo-Miocene times -- the closure of the Tethyan seaway due to development of the Gomphotherium-Landbridge leading to separation of the Arabian Sea from proto-Mediterranean Sea ([~]19 Ma) and significant uplift of the Tibetan plateu marking the initiation of the monsoon ([~]16 Ma) -- represent a classic case of tectonic shift influencing the regional environment of the Indian subcontinent. We investigated the taxonomic and body size related response of the shallow marine fauna to this regional change using bivalves from 11 time-constrained shellbeds of the Kutch Basin (western India) from three formations -- Maniyara Fort (Chattian), Khari Nadi (Aquitanian) and Chhasra (Burdigalian-Langian) representing a time span of [~]9 Ma (24.4 - 15 Ma).
Our collection of over 2000 individuals represents a total of 15 families and 61 morphospecies. The fossils are predominantly calcitic in nature and families of aragonitic composition are often preserved as molds indicating a potential negative effect of diagenesis. The taphonomic nature, however, does not vary substantially across shellbeds and hence, less likely produced a temporal pattern. The five most abundant species, Ostrea latimarginata, Ostrea angulata, Talochlamys articulata, Anomia primaeva and Placuna lamellata occur in all the formations. The species composition of the Maniyara Fort formation is substantially different from those of the younger formations implying the possible effect of biogeographic separation. Moreover, the absence of proto-Mediterranean taxa in Oligocene shellbeds support a limited faunal exchange as early as [~]24.4Ma (Chattian) ago. We observed a monotonic increase in the overall rarefied species richness and a decrease in evenness from the Maniyara Fort to the Chhasra Formation. However, shellbed analyses show a dominantly conservative behavior of diversity and body size without a strong directional trend through time. Although it is difficult to rule out the negative influence of taphonomy on the diversity of the studied fauna, Oligo-Miocene marine bivalve fauna of the Kutch Basin demonstrate little or no influence of the Tethyan closure and Himalayan upliftment.
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paleontology
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Instruct:
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Homogeneous inhibition is optimal for the phase precession of place cells in the CA1 field
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neuroscience
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Instruct:
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Query:
Neuron particles capture network topology and behavior from single units
While networks of neurons, glia and vascular systems enable and support brain functions, to date, mathematical tools to decode network dynamics and structure from very scarce and partially observed neuronal spiking behavior remain underdeveloped. Large neuronal networks contribute to the intrinsic neuron transfer function and observed neuronal spike trains encoding complex causal information processing, yet how this emerging causal fractal memory in the spike trains relates to the network topology is not fully understood. Towards this end, we propose a novel statistical physics inspired neuron particle model that captures the causal information flow and processing features of neuronal spiking activity. Relying on synthetic comprehensive simulations and real-world neuronal spiking activity analysis, the proposed fractional order operators governing the neuronal spiking dynamics provide insights into the memory and scale of the spike trains as well as information about the topological properties of the underlying neuronal networks. Lastly, the proposed model exhibits superior predictions of animal behavior during multiple cognitive tasks.
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neuroscience
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Instruct:
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Query:
Rapid tissue-specific screening of Wolbachia, Cardinium and Rickettsia in Flies (Diptera: Sepsidae; Drosophilidae)
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evolutionary biology
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Instruct:
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Query:
Extraversion is associated with lower brain amyloid deposition in cognitively normal older adults.
Emerging evidence suggests that some personality traits may link to the vulnerability to or protection for Alzheimers disease (AD). A causal mechanism underlying this relationship, however, remains largely unknown. Using 18F-Florbetaben positron emission tomography (PET) binding to beta-amyloid (A{beta}) plaques, a pathological feature of AD, and functional magnetic resonance imaging (fMRI), we investigated pathological and functional correlates of extraversion and neuroticism in a group of healthy young and older subjects. We quantified a level of brain A{beta} deposition in older individuals. Brain activity was measured in young adults using a task-switching fMRI paradigm. When we correlated personality scores of extraversion and neuroticism with these pathological and functional measures, higher extraversion, but not neuroticism, was significantly associated with lower global A{beta} measures among older adults, accounting for age and sex. This association was present across widespread brain regions. Among young subjects, higher extraversion was associated with lower activity during task switching in anterior cingulate cortex, left anterior insular cortex, left putamen, and middle frontal gyrus bilaterally, while higher neuroticism was associated with increased activity throughout the brain. The present results suggest that possibly via efficient neuronal activity, extraversion, one of lifelong personality traits, may confer the protective mechanism against the development of A{beta} pathology during aging.
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neuroscience
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Instruct:
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Query:
A cryo-ET survey of intracellular compartments within mammalian axons
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cell biology
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Instruct:
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Query:
A Hypoxia Sensitive to Hypoxia Resistant Transformation in Long-Lived Germline Mutants
Signals from the germline play a significant role in determining longevity in numerous animal models. In C. elegans, ablation of the germline leads to long life span and various other types of stress resistance. It has been reported that mutations that block oogenesis or an upstream step in germline development confer strong resistance to hypoxia. We report here that the hypoxia resistance of sterile mutants is dependent on developmental stage and age. In just a 12-hour period, sterile animals transform from hypoxia sensitive L4 larvae into highly hypoxia resistant adults. Since this transformation occurs in animals with no germline, the physiological programs that determine hypoxia sensitivity must occur independently of germline signals and instead rely on developmental signals from somatic tissues. Furthermore, we found two distinct mechanisms of hypoxia resistance in long-lived germline deficient animals. First, a DAF-16/FoxO independent mechanism that occurs in all hypoxia resistant sterile adults and, second, a DAF-16/FoxO dependent mechanism that confers an added layer of resistance, or "super-resistance", to animals with no germline as they age past day 1 of adulthood. RNAseq data showed that nearly all genes involved in both cytosolic and mitochondrial protein translation, as well as in mitochondrial protein import, are repressed in germline deficient adults and further repressed as they age. The hypoxia super-resistance of aging germline deficient animals was suppressed by dual mutation of ncl-1 and larp-1, two regulators of nucleolar biology and protein translation, demonstrating that the hypoxia super-resistance mechanism involves reduced protein translation. These studies provide novel insight into a profound physiological transformation that takes place in germline mutants during development, showing that some of the unique physiological properties of these long-lived animals are dependent on developmental repression of genes involved in protein translation, which operate independently of germline signals.
AUTHOR SUMMARYIn addition to being extremely long lived, germline deficient animals have other extraordinary properties, such as robust resistance to oxygen deprivation. Here we provide new insight into the mechanisms of hypoxia resistance in germline deficient animals. We demonstrate that, in just a 12-hour period, germline mutants transform from hypoxia sensitive larvae into highly hypoxia resistant adults. Therefore, hypoxia resistance is not a general property of germline ablated animals, but is instead "switched on" only in adult animals. We have found two distinct mechanisms of hypoxia resistance in germline deficient animals and both mechanisms are mediated by signals from somatic tissues and do not require the germline. We have determined that reduced transcription of genes involved in protein translation is one of the mechanisms of hypoxia resistance. Like hypoxia resistance, repression of protein translation genes only occurs in adults. Our findings establish that the unique physiological properties of germline-deficient animals are "switched" on in adults and therefore must be mediated by developmental signals from somatic tissues. We conclude that the L4/adult developmental switch in germline ablated animals presents an excellent system for investigating the longevity and hypoxia resistance of germline deficient animals.
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genetics
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Instruct:
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Query:
IL-21 signaling promotes the establishment of KSHV infection in human tonsil lymphocytes by increasing early targeting of plasma cells
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microbiology
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Instruct:
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Query:
Gigapixel behavioral and neural activity imaging with a novel multi-camera array microscope
The dynamics of living organisms are organized across many spatial scales. However, current cost-effective imaging systems can measure only a subset of these scales at once. We have created a scalable multi-camera array microscope (MCAM) that enables comprehensive high-resolution recording from multiple spatial scales simultaneously, ranging from cellular structures to large-group behavioral dynamics. By collecting data from up to 96 cameras, we computationally generate gigapixel-scale images and movies with a field of view over hundreds of square centimeters at 5um sensitivity. This allows us to observe the behavior and fine anatomical features of numerous freely moving model organisms on multiple spatial scales, including larval zebrafish, fruit flies, nematodes, carpenter ants, and slime mold. The MCAM architecture allows stereoscopic tracking of the z-position of organisms using the overlapping field of view from adjacent cameras. Further, we demonstrate the ability to acquire dual color fluorescence video of multiple freely moving zebrafish, recording neural activity via ratiometric calcium imaging. Overall, the MCAM provides a powerful platform for investigating cellular and behavioral processes across a wide range of spatial scales by removing the bottlenecks imposed by single-camera image acquisition systems.
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bioengineering
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Instruct:
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Query:
Disrupted social memory ensembles in the ventral hippocampus underlie social amnesia in autism-associated Shank3 mutant mice
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neuroscience
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Instruct:
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Query:
A systems biology approach to elucidate the post-translational regulome of coronary artery disease
Coronary Artery Disease is a major killer in India and world at large but the molecular regulators which modulate clinically relevant pathways are not completely understood. This study was aimed at identifying essential post-translational modifications (PTM) regulome network and its master regulator modulating the CAD associated pathways. 995 CAD associated genes were taken from InCardiome database (www.tri-incardiome.org) were analyzed for all possible PTMs. Two important interdependent molecular processes which define the function of a protein are protein-protein interactions and PTMs of which PTMs play regulatory role. Using PTMCode2 we evaluated the co-evolving amino acid residues for important PTMs and found that serine-serine phosphorylation is highly represented combinatorial regulator in these set of proteins. Furthermore, in the CAD associated pathways we again found that serine phosphorylation was dominant player in all the processes of atherosclerosis. In order to identify the master regulator kinase, we further assessed the kinome network associated with CAD and identified 5 most important kinases namely GSK3B, PRKCA, PRKCD, SRC and PRKACA which might modulate clinically important pathways. GSK3B with the highest network parameters (node degree and betweenness centrality) was identified as master regulator and 1 U/l increase of phsophoGSK3B (on a log scale) increased the odds ratio (OR) by 4.07 fold (AUC 0.620) and 6.27 fold (AUC 0.752) upon addition of conventional risk factors (CRFs).
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synthetic biology
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Instruct:
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Granulocyte Colony Stimulating Factor causes cerebellar deficits and anxiety in a mouse model of CSF-1 receptor-related leukoencephalopathy
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neuroscience
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Instruct:
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Query:
Rare genera differentiate urban green space soil bacterial communities in three cities across the world
Vegetation complexity is potentially important for urban green space designs aimed at fostering microbial biodiversity to benefit human health. Exposure to urban microbial biodiversity may influence human health outcomes via immune training and regulation. In this context, improving human exposure to microbiota via biodiversity-centric urban green space designs is an underused opportunity. There is currently little knowledge on the association between vegetation complexity (i.e., diversity and structure) and soil microbiota of urban green spaces. Here, we investigated the association between vegetation complexity and soil bacteria in urban green spaces in Bournemouth, UK; Haikou, China; and the City of Playford, Australia by sequencing the 16S rRNA V4 gene region of soil samples and assessing bacterial diversity. We characterized these green spaces as having low or high vegetation complexity and explored whether these two broad categories contained similar bacterial community compositions and diversity around the world. Within cities, we observed significantly different alpha and beta diversities between vegetation complexities; however, these results varied between cities. Rare genera (< 1 % relative abundance individually, on average 35 % relative abundance when pooled) were most likely to be significantly different in sequence abundance between vegetation complexities and therefore explained much of the differences in microbial communities observed. Overall, general associations exist between soil bacterial communities and vegetation complexity, although these are not consistent between cities. Therefore, more in-depth work is required to be done locally to derive practical actions to assist the conservation and restoration of microbial communities in urban areas.
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ecology
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Instruct:
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A massively parallel reporter assay reveals focused and broadly encoded RNA localization signals in neurons
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genomics
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Instruct:
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Query:
Mechanosensitive Ion Channel Piezo1 Regulates Myocyte Fusion during Skeletal Myogenesis
Mechanical stimuli such as stretch and resistance training are essential to regulate growth and function of skeletal muscle. However, the molecular mechanisms involved in sensing mechanical stress during muscle formation remain unclear. Here, we investigate the role of the mechano-sensitive ion channel Piezo1 during myogenic progression. Direct manipulation of Piezo1 in muscle stem cells alters their myogenic progression. Indeed, Piezo1 knockdown suppresses myoblast fusion leading to smaller myotubes. Such event is accompanied by significant downregulation of the fusogenic protein Myomaker. In parallel, while Piezo1 knockdown also lowers Ca2+ influx in response to stretch, Piezo1 activation increases Ca2+ influx in response to stretch and enhances myoblasts fusion. We believe these findings may help understand molecular defects present in some muscle diseases. Altogether our study shows that Piezo1 is essential for terminal muscle differentiation acting on myoblast fusion, suggesting that Piezo1 deregulation may have implications in muscle aging and degenerative diseases including muscular dystrophies.
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molecular biology
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Instruct:
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A non-adaptive demographic mechanism for genome expansion in Streptomyces
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microbiology
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Instruct:
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Query:
Large herbivore impact on plant biomass along multiple resource gradients in the Serengeti
Herbivores form an important link in the transfer of energy within a food web and are strongly influenced by bottom-up trophic cascades. Current hypotheses suggest that herbivore consumption and impact on plants should scale positively with plant resource availability. However, depending on the effect of resources on plant quantity and quality, herbivore impact may vary with different types of resources. We test four alternative hypotheses for the relationship between plant biomass, herbivore impact on plant biomass, and plant resource gradients, each based on how resources might affect plant abundance and quality to herbivores. We measured plant biomass for four non-consecutive years in a long-term grazing exclosure experiment in the Serengeti National Park that includes seven sites that vary substantially in rainfall and soil and plant nitrogen (N) and phosphorus (P). Our data supported the hypothesis that herbivore impact is controlled by plant quality, in this case driven by plant P, as herbivore effects on biomass decreased with higher rainfall but increased with greater plant P, but not N content. To our knowledge, this is the first experimental study to indicate that wild mammalian herbivory is associated with P availability rather than N. Our results suggest that P, in addition to water and N, may play a more important role in driving trophic interactions in terrestrial systems than previously realized.
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ecology
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Instruct:
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Query:
Airborne environmental DNA for terrestrial vertebrate community monitoring
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molecular biology
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Instruct:
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Query:
The formation of the bacterial RNA polymerase-promoter open complex involves a branched pathway
The expression of most bacterial genes commences with the binding of RNA polymerase (RNAP)-{sigma}70 holoenzyme to the promoter DNA. This initial RNAP-promoter closed complex undergoes a series of conformational changes, including the formation of a transcription bubble on the promoter and the loading of template DNA strand into the RNAP active site; these changes lead to the catalytically active open complex (RPO) state. Recent cryo-electron microscopy studies have provided detailed structural insight on the RPO and putative intermediates on its formation pathway. Here, we employ single-molecule fluorescence microscopy to interrogate the conformational dynamics and reaction kinetics during real-time RPO formation. We find that the RPO pathway is branched, generating RPO complexes with different stabilities. The RNAP cleft loops, and especially the {beta} rudder, stabilise the transcription bubble. The RNAP interactions with the promoter upstream sequence (beyond -35) stimulate transcription bubble nucleation and tune the reaction path towards stable forms of the RPO. The mechanistic heterogeneity of the RPO pathway may be a prerequisite for its regulation since such heterogeneity allows the amplification of small promoter sequence or transcription-factor-dependent changes in the free energy profile of the RPO pathway to large differences in transcription efficiency.
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biochemistry
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Instruct:
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Computational and experimental studies of the breathing motion of a protein loop: implications in PfAMA1-PfRON2 late-stage binding event
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biochemistry
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Instruct:
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An additional area of apple domestication with crop-wild gene flow, and also cultivation of the local wild apple, in the Caucasus
Anthropogenic and natural divergence processes remain poorly studied in crop-wild fruit tree complexes, especially in the Caucasus, a pivotal region for plant domestication. We investigated anthropogenic and natural divergence processes in apples in the Caucasus using 26 microsatellite markers amplified in 550 wild and cultivated samples. We found two genetically distinct cultivated populations in Iran that are differentiated from Malus domestica, the standard cultivated apple worldwide. Coalescent-based inferences showed that these two cultivated populations originated from specific domestication events of M. orientalis in Iran. One of the Iranian clusters comprised both cultivated and forest trees, suggesting that either farmers use local wild apple for cultivation or that some forest trees are feral cultivars. We found evidence of substantial wild-crop and crop-crop gene flow in the Caucasus, as has been described in apple in Europe. In the Caucasus, we identified seven genetically differentiated populations of wild apple (Malus orientalis). Niche modeling combined with genetic diversity estimates indicated that these populations likely resulted from range changes during past glaciations. This study identifies Iran as a key region in the domestication of apple and M. orientalis as an additional contributor to the cultivated apple gene pool. Domestication of the apple tree therefore involved multiple origins of domestication in different geographic locations and substantial crop-wild hybridization, as found in other fruit trees. This study also highlights the impact of climate change on the natural divergence of a wild fruit tree and provides a starting point for apple conservation and breeding programs in the Caucasus.
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evolutionary biology
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Instruct:
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Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance
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neuroscience
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Diverse B-cell specific transcriptional contexts of the BCL2 oncogene in mouse models impacts pre-malignant development
Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells. The genetic hallmark that leads to the development of FL is the t(14:18) which occurs early in the bone marrow during B cell development, thereby placing the anti-apoptotic BCL2 gene under the direct control of the transcriptional enhancers in 3 of immunoglobulin heavy chain locus (IgH 3RR) and leading to the constitutive expression of the BCL2 protein. To assess the impact of the BCL2 deregulation on B-cell fate and try to reproduce FL development in mice, two models were designed: the Ig{kappa}-BCL2 (Knock in of the BCL2 in the light chain Ig kappa locus) and the 3RR-BCL2 (Transgene containing BCL2 and a micro-3RR), both containing the full BCL2 promoter region.
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immunology
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Instruct:
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Anatomical and Functional Gradients Shape Dynamic Functional Connectivity in the Human Brain
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neuroscience
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Efficacy of double-stranded RNA for the large-scale control and prevention of sacbrood virus in Apis cerana (Hymenoptera: Apidae) apiaries
Sacbrood virus (SBV) infection in Apis cerana has caused tremendous damage in India, Thailand, Vietnam, and China since the 1970s. The disease caused by this virus results in colony collapse disorder in A. cerana and is also a devastating disease affecting A. cerana in South Korean apiaries. It has almost resulted in the elimination of the species. Therefore, control measures for this emerging threat are urgently needed. SBV RNA interference (RNAi) targeting VP1 was prepared to test the safety and efficacy of protection and treatment in artificially infected larvae and in infected colonies in South Korean apiaries. The efficacy of VP1 double-stranded RNA (dsRNA) was confirmed for the protection and treatment of infected larvae by increasing the survival rate in comparison with that in untreated larvae. Furthermore, an optimal application procedure was established for the large-scale RNAi treatment of SBV in apiaries. The protection of healthy colonies from SBV by RNAi was demonstrated in 100% of apiaries, and the treatment results showed that after five administrations, the SBV in infected colonies was mitigated to a safe level at which no symptoms of the disease were observed. Importantly, the low cost of dsRNA production in this study enables its application as a specific drug in large scale in South Korean apiculture.
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microbiology
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DeepBacs: Bacterial image analysis using open-source deep learning approaches
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microbiology
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Instruct:
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A Humanized Antibody against LRG1 that Inhibits Angiogenesis and Reduces Retinal Vascular Leakage
Pathological angiogenesis contributes to morbidity in a number of diseases including cancer, diabetic retinopathy and the neovascular form of age-related macular degeneration, leading to significant efforts to develop effective anti-angiogenic therapeutics for these conditions. The field is dominated by inhibitors of vascular endothelial growth factor (VEGF), yet angiogenesis can also be driven and modified by other factors. We have previously demonstrated that leucine-rich alpha-2-glycoprotein 1 (LRG1) contributes to abnormal vessel growth by activating a TGF{beta} switch. Here we report the development and characterisation of a function-blocking fully humanised IgG4 and its Fab fragment, that bind to LRG1 with high affinity and specificity and inhibit vascular leakage in the mouse model of laser-induced choroidal neovascularisation. In summary, we have developed a therapeutic antibody that targets a VEGF-independent signalling axis, which may be effective in a number of conditions either as monotherapy or in combination with other vascular targeted therapies.
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pathology
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Interaction between BID and VDAC1 is required for mitochondrial demise and cell death in neurons
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molecular biology
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Instruct:
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Query:
Direct Reprogramming of Non-limb Fibroblasts toCells with Properties of Limb Progenitors
The early limb bud consists of mesenchymal progenitors (limb progenitors) derived from the lateral plate mesoderm (LPM) that produce most of the tissues of the mature limb bud. The LPM also gives rise to the mesodermal components of the trunk, flank and neck. However, the mesenchymal cells generated at these other axial levels cannot produce the variety of cell types found in the limb bud, nor can they be directed to form a patterned appendage-like structure, even when placed in the context of the signals responsible for organizing the limb bud. Here, by taking advantage of a direct reprogramming approach, we find a set of factors (Prdm16, Zbtb16, and Lin28) normally expressed in the early limb bud, that are capable of imparting limb progenitor-like properties to non-limb fibroblasts. Cells reprogrammed by these factors show similar gene expression profiles, and can differentiate into similar cell types, as endogenous limb progenitors. The further addition of Lin41 potentiates proliferation of the reprogrammed cells while suppressing differentiation. These results suggest that these same four key factors may play pivotal roles in the specification of endogenous limb progenitors.
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developmental biology
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Modelling eDNA transport in river networks reveals highly resolved spatio-temporal patterns of freshwater biodiversity
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ecology
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Instruct:
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Query:
Obsessive Compulsive Disorder and Response Inhibition: Meta-analysis of the Stop-Signal Task
This systematic review and meta-analysis updates evidence pertaining to deficient response inhibition in obsessive-compulsive disorder (OCD) as measured by the stop-signal task (SST). We conducted a meta-analysis of the literature to compare response inhibition in patients with OCD and healthy controls, meta-regressions to determine relative influences of age and sex on response inhibition impairment, and a risk of bias assessment for included studies using the Newcastle-Ottawa Scale (NOS). Stop-signal reaction time (SSRT), which estimates the latency of the stopping process deficit, was significantly longer in OCD samples than in controls, reflecting inferior inhibitory control (Raw mean difference = 23.43ms; p = <0.001; 95% CI = [17.42, 29.45]). We did not observe differences in mean reaction time (MRT) in OCD compared to controls (Raw mean difference = 2.51ms; p = 0.755; 95% CI = [-13.27, 18.30]). Age impacted effect size of SSRT, indicating a greater deficit in older patients than younger ones. We did not observe a significant effect of sex on SSRT or MRT scores.
General Scientific SummaryDifficulty inhibiting responses is an hypothesized deficit in Obsessive-Compulsive Disorder (OCD). The results of this systematic review and meta-analysis of studies using the Stop Signal Task support the notion of deficient response inhibition in OCD and indicate that older individuals with OCD show greater impairments than younger ones.
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pathology
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Instruct:
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Human visual gamma for color stimuli: When LGN drive is equalized, red is not special
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neuroscience
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Xenogeneic Skin Transplantation Promotes Angiogenesis and Tissue Regeneration Through Vitamin D-Activated Trem2+ Macrophages
Skin allo- and xenotransplantation are the standard treatment for major burns when donor sites for autografts are not available and have been shown to significantly accelerate wound healing. Although the cellular elements of foreign grafts are rejected, the extracellular matrix components integrate into the wound and may underlie their beneficial effects on wound healing. The molecular mechanisms defining the relationship between the immune response to foreign grafts and their impact on wound healing have not been fully elucidated. Here, we investigated changes in collagen architecture after xenogeneic implantation of clinically available human biologic scaffolds. We show that collagen deposition in response to the implantation of human split-thickness skin grafts (hSTSG) containing live cells recapitulates normal skin architecture, whereas human acellular dermal matrix (ADM) grafts led to highly aligned collagen deposition, characteristic of fibrosis and scar. Using single-cell RNA-sequencing, we show that macrophage differentiation in response to hSTSG is driven by vitamin D (VD) signaling toward Trem2+ subpopulations with an enrichment of pro-angiogenic and anti-fibrotic transcriptomic programs. We subsequently induced this regenerative subpopulation in vitro by treating bone marrow-derived cells with vitamin D3 and found that hydrogel delivery of Trem2+ macrophages significantly accelerated wound closure in a human-like murine excisional wound model. Our study identifies the preclinical therapeutic potential of Trem2+ macrophages to mitigate fibrosis and promote wound healing and provides a novel effective strategy to develop advanced cell therapies for complex wounds.
One Sentence SummaryVitamin D-activated Trem2+ macrophages promote angiogenesis and mitigate fibrosis, providing a novel effective strategy to develop advanced cell therapies for complex wounds.
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immunology
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Instruct:
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The Genetics and Evolution of Eye Color in Domestic Pigeons (Columba livia)
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genetics
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Instruct:
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Taxonomic Monograph of Saxicolella (Podostemaceae), African waterfall plants highly threatened by Hydro-Electric projects, with five new species.
The genus Saxicolella Engl. (Podostemaceae) are African rheophytes, restricted to rapids and waterfalls as are all members of the family. Previously, Saxicolella sensu lato was shown to be polyphyletic with two separate clades in the molecular phylogenetic study of Koi et al. (2012). The name Pohliella Engl. was recently resurrected for one clade that is sister to the American genera Ceratolacis (Tul.)Wedd., Podostemum Michx. and all Old World Podostemoideae (podostemoids) (Cheek 2020). Pohliella has distichous phyllotaxy, bilocular ovaries, filiform roots with paired holdfasts, and rootcaps. The second clade, Saxicolella sensu stricto, including the type of the generic name, has spiral phyllotaxy, unilocular ovaries, ribbon-like or crustose roots that lack both holdfasts and rootcaps. Saxicolella sensu stricto, sampled from the type species, S. nana Engl. of Cameroon, is embedded within and near the base of the major clade of African podostemoids and is sister to all other African genera apart from Inversodicraea R.E.Fr. and Monandriella Engl. Recently reduced to three species in Cameroon and S.E. Nigeria by the resurrection of Pohliella (3 - 4 species in Ghana and Nigeria-Cameroon), Saxicolella sensu stricto is expanded to eight species in this monograph by description of five new taxa. Saxicolella futa Cheek and S. deniseae Cheek are newly described from Guinea, S. ijim Cheek from Cameroon, the informally named S. sp. A from Gabon, and S. angola Cheek from Angola. The known geographic range of the genus is thus expanded c. 2,500 km westwards to Guinea from eastern Nigeria and c.1,500 km southeastwards from near Yaounde to Cuanza do Sul, Angola. The greatest concentration of species occurs in the Cross-Sanaga interval of western Cameroon and eastern Nigeria, with three species. Cameroon (3 species) followed by Nigeria and Guinea (2 species each) are the countries with highest species diversity. The genus can be expected to be found in Sierra Leone, Liberia, Ivory Coast and Congo Republic. A classification is proposed grouping the species into three subgenera (Saxicolella, Butumia (G.Taylor) Cheek comb. et. stat. nov. and Kinkonia Cheek subgen. nov.) based on root morphology and shoot position and morphology.
The discovery, morphology, circumscription, distribution, and ecology of Saxicolella is reviewed, an identification key to the species is presented, together with descriptions, synonymy, links to illustrations, and extinction risk assessments for each of the eight species now recognised. All of the species are provisionally assessed as either Endangered or Critically Endangered using the IUCN 2012 standard, making this genus among the most threatened of its size globally. The major threats, above all, are hydro-electric projects. Saxicolella deniseae may already be globally extinct, and two of the four known locations of S. angola appear lost, S. sp. A of Gabon is threatened at at least one of its three locations, while Saxicolella futa is threatened at all three locations, all due to incipient or active hydro-electric projects. Contamination of watercourses by increased turbidity from silt-load due anthropic changes and by eutrophication from pollution are also threats for the majority of the species.
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plant biology
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Life without mismatch repair
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genomics
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MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma - namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, and targeted immunotherapies - may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest.
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cancer biology
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recount3: summaries and queries for large-scale RNA-seq expression and splicing
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genomics
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Integration of brief light flashes varying in intensity and duration by the human circadian system
The melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are characterised by a delayed off-time following light offset. Here, we exploited this unusual physiologic property to characterise the exquisite sensitivity of the human circadian system to flashed light. In a 34-hour in-laboratory between-subjects design, we examined variable-intensity (3-9500 photopic lux; n=28 participants) full-field flashes at fixed duration (2 ms), and variable-duration (10 s-10 s) full-field flashes at fixed intensity (2000 photopic lux; n=31 participants) delivered using eye masks. We measured the circadian phase shift of the dim-light melatonin onset (DLMO) on the subsequent evening, acute melatonin suppression, objective alertness, and subjective sleepiness during the flash sequence. We find a clear dose-response relationship between flash intensity and the induced circadian phase shift, with an approximate increase of 10 minutes of phase delay for each ten-fold increase in photopic illuminance, but no parametric relationship between flash duration and induced circadian phase shift.
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neuroscience
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Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery
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neuroscience
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Domestication and lowland adaptation of coastal preceramic maize from Paredones, Peru
Archaeological cobs from Paredones and Huaca Prieta (Peru) are phenotypically indistinguishable from modern maize. This contrasts with the earliest Mexican macro-specimens from Guila Naquitz and San Marcos, which are phenotypically intermediate even though they date more recently in time. These observations suggest at least two alternative scenarios, one in which maize was domesticated earlier than previously thought in the lowland Mesoamerica, followed by rapid lowland dispersal to Peru, and another in which maize was independently domesticated in South America and subsequently lost, as current evidence supports a single origin for all modern maize. To gain insights into the origins of ancient Peruvian maize, we sequenced DNA from three Paredones specimens dating 6775 to 5000 calibrated years before present (BP) and conducted comparative analyses with two teosinte subspecies (Zea mays ssp. mexicana and parviglumis) and extant maize, including highland and lowland landraces from Mesoamerica and South America. We show that Paredones maize originated from the same domestication event as Mexican maize and was domesticated by 6775 BP, implying rapid dispersal followed by improvement. Paredones maize show minimal levels of gene flow from mexicana, smaller than those observed in teosinte parviglumis. It also harbors significantly fewer alleles previously found to be adaptive to highlands, but not of alleles adaptive to lowlands, supporting a lowland migration route. Our overall results imply that Paredones maize originated in Mesoamerica, arrived in Peru without mexicana introgression through a rapid lowland migration route, and underwent improvements in both Mesoamerica and South America.
Significance StatementThe coastal Peruvian preceramic sites of Paredones and Huaca Prieta provide the earliest known maize macro-remains. Found more than 3,800 km away from the maize center of origin and presenting a phenotypically modern cob constitution relative to their antiquity, these specimens represent a paradox for understanding maize evolution and dispersal. We show that Paredones maize originated in Mesoamerica, like all known maize, and arrived in South America without introgression from the teosinte mexicana. Since modern maize has substantial contributions from mexicana, it raises the question of when mexicana introgression spread to South America. Paredones maize preferentially shares adaptive allelic diversity with lowland Mesoamerican samples, suggesting a migration route probably associated with a coastal corridor previously identified with archeological findings.
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plant biology
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Identifying Meta-QTLs for Stay-Green in Sorghum
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plant biology
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Probing the rules of cell coordination in live tissues by interpretable machine learning based on graph neural networks
Robustness in developing and homeostatic tissues is supported by various types of spatiotemporal cell-to-cell interactions. Although live imaging and cell tracking are powerful in providing direct evidence of cell coordination rules, extracting and comparing these rules across many tissues with potentially different length and timescales of coordination requires a versatile framework of analysis. Here we demonstrate that graph neural network (GNN) models are suited for this purpose, by showing how they can be applied to predict cell fate in tissues and utilized to infer the cell interactions governing the multicellular dynamics. Analyzing the live mammalian epidermis data, where spatiotemporal graphs constructed from cell tracks and cell contacts are given as inputs, GNN discovers distinct neighbor cell fate coordination rules that depend on the region of the body. This approach demonstrates how the GNN framework is powerful in inferring general cell interaction rules from live data without prior knowledge of the signaling involved.
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cell biology
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Predictive feedback, early sensory representations and fast responses to predicted stimuli depend on NMDA receptors
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neuroscience
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Active feature selection discovers minimal gene sets for classifying cell types and disease states with single-cell mRNA-seq data
Sequencing costs currently prohibit the application of single-cell mRNA-seq to many biological and clinical analyses. Targeted single-cell mRNA-sequencing reduces sequencing costs by profiling reduced gene sets that capture biological information with a minimal number of genes. Here, we introduce an active learning method (ActiveSVM) that identifies minimal but highly-informative gene sets that enable the identification of cell-types, physiological states, and genetic perturbations in single-cell data using a small number of genes. Our active feature selection procedure generates minimal gene sets from single-cell data through an iterative cell-type classification task where misclassified cells are examined at each round of analysis to identify maximally informative genes through an active support vector machine (ActiveSVM) classifier. By focusing computational resources on misclassified cells, ActiveSVM scales to analyze data sets with over a million single cells. We demonstrate that ActiveSVM feature selection identifies gene sets that enable 90% cell-type classification accuracy across a variety of data sets including cell atlas and disease characterization data sets. The method generalizes to reveal genes that respond to genetic perturbations and to identify region specific gene expression patterns in spatial transcriptomics data. The discovery of small but highly informative gene sets should enable substantial reductions in the number of measurements necessary for application of single-cell mRNA-seq to clinical tests, therapeutic discovery, and genetic screens.
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bioinformatics
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Effect of Geobacter metallireducens nanowire on electron transfer efficiency in MFC
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microbiology
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Structural insights into a novel family of integral membrane siderophore reductases
Gram-negative bacteria take up the essential ion Fe3+ as ferric-siderophore complexes through their outer membrane using TonB-dependent transporters. However, the subsequent route through the inner membrane differs across many bacterial species and siderophore chemistries and is not understood in detail. Here, we report the crystal structure of the inner membrane protein FoxB (from P. aeruginosa) that is involved in Fe-siderophore uptake. The structure revealed a novel fold with two tightly-bound heme molecules. In combination with functional studies these results establish FoxB as an inner membrane reductase involved in the release of iron from ferrioxamine during Fe-siderophore uptake.
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biochemistry
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The evolution of regulatory elements in the emerging promoter variant strains of HIV-1
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microbiology
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Modelling the spatiotemporal spread of beneficial alleles using ancient genomes
Ancient genome sequencing technologies now provide the opportunity to study natural selection in unprecedented detail. Rather than making inferences from indirect footprints left by selection in present-day genomes, we can directly observe whether a given allele was present or absent in a particular region of the world at almost any period of human history within the last 10,000 years. Methods for studying selection using ancient genomes often rely on partitioning individuals into discrete time periods or regions of the world. However, a complete understanding of natural selection requires more nuanced statistical methods which can explicitly model allele frequency changes in a continuum across space and time. Here we introduce a method for inferring the spread of a beneficial allele across a landscape using two-dimensional partial differential equations. Unlike previous approaches, our framework can handle time-stamped ancient samples, as well as genotype likelihoods and pseudohaploid sequences from low-coverage genomes. We apply the method to a panel of published ancient West Eurasian genomes, to produce dynamic maps showcasing the inferred spread of candidate beneficial alleles over time and space. We also provide estimates for the strength of selection and diffusion rate for each of these alleles. Finally, we highlight possible avenues of improvement for accurately tracing the spread of beneficial alleles in more complex scenarios.
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evolutionary biology
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Plant-associate interactions and diversification across trophic levels
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evolutionary biology
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WWP1 deficiency protects from cardiac remodeling induced by simulated microgravity
Cardiac muscle is extremely sensitive to changes in loading conditions, the microgravity during space flight can cause cardiac remodeling and function decline. At present, the mechanism of microgravity-induced cardiac remodeling remains to be revealed. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is an important activator of pressure-overload induced cardiac remodeling by stabilizing disheveled segment polarity proteins 2 (DVL2) and activating CaMKII/HDAC4/MEF2C axis. However, the role of WWP1 in the cardiac remodeling induced by microgravity is unknown. The purpose of this study was to determine whether WWP1 was also involved in the regulation of cardiac remodeling caused by microgravity. Firstly, we detected the expression of WWP1 and DVL2 in the heart from mice and monkeys after simulated microgravity using western blotting and Immunohistochemistry. Secondly, WWP1 knockout (KO) and wild type mice were subjected to hindlimb unloading (HU) to simulate microgravity effect. We assessed the cardiac remodeling in morphology and function through histological analysis and echocardiography. Finally, we detected the phosphorylation level of CaMKII and HDAC4 in the heart from WT and WWP1 KO mice after HU. The results revealed the increased expression of WWP1 and DVL2 in the heart both from mice and monkey after simulated microgravity. WWP1 deficiency protected against simulated microgravity-induced cardiac atrophy and function decline. Histological analysis demonstrated WWP1 KO inhibited the decreases in the size of individual cardiomyocytes of mice after hindlimb unloading. WWP1 KO can inhibit the activation of DVL2/CaMKII/HDAC4 pathway in heart of mice induced by simulated microgravity. These results demonstrated WWP1 as a potential therapeutic target for cardiac remodeling and function decline induced by simulated microgravity.
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physiology
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Existence of log-phase Escherichia coli persisters and lasting memory of a starvation pulse
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microbiology
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A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration
Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at Bact state, an active spliceosome but not catalytically primed, which depends on SNIP1 (Smad Nuclear Interacting Protein 1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and Bact component preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake for the spliceosome pausing, and that its misregulation contributes to neurodegeneration.
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cell biology
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An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome
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genomics
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RNA decay defines the therapeutic response to transcriptional perturbation in cancer
Transcriptionally dysregulated cancers are sensitive to the inhibition of RNA Polymerase II (RNAPII) - driven gene expression. The therapeutic effect is attributed to selective inhibition of discrete oncogenes regulated at the chromatin level, however the role of RNA stability remains largely unexplored. Using integrated transcriptomic technologies, we discovered that RNA decay is a key determinant in defining gene expression responses to transcriptional perturbation, where total RNA signatures are dominated with genes that have short transcript half-lives, including oncogenic drivers such as c-MYC. Experimentally increasing c-MYC RNA stability maintained total c-MYC RNA levels following RNAPII perturbation, despite a concordant decrease in nascent RNA. Taken together, these data demonstrate that RNA decay shapes the molecular and therapeutic response to transcriptional perturbation in cancer.
HIGHLIGHTSO_LISelective inhibition of oncogenic transcription in response to epigenetic and transcriptional inhibitors in cancer under-estimates the role of RNA decay
C_LIO_LIGene intrinsic RNA decay rates are a key determinant in shaping the total mRNA response to transcriptional perturbation in cancer
C_LIO_LISelective disruption of core-transcription factor networks is a result of short transcript half-lives
C_LIO_LIModulation of c-MYC decay rates can render it insensitive to transcriptional targeting
C_LI
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cancer biology
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Volumetric Semantic Instance Segmentation of the Plasma Membrane of HeLa Cells
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cell biology
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Co-linear chaining with overlaps and gap costs
Co-linear chaining has proven to be a powerful heuristic for finding near-optimal alignments of long DNA sequences (e.g., long reads or a genome assembly) to a reference. It is used as an intermediate step in several alignment tools that employ a seed-chain-extend strategy. Despite this popularity, efficient subquadratic-time algorithms for the general case where chains support anchor overlaps and gap costs are not currently known. We present algorithms to solve the co-linear chaining problem with anchor overlaps and gap costs in O(n) time, where n denotes the count of anchors. We also establish the first theoretical connection between co-linear chaining cost and edit distance. Specifically, we prove that for a fixed set of anchors under a carefully designed chaining cost function, the optimal anchored edit distance equals the optimal co-linear chaining cost. Finally, we demonstrate experimentally that optimal co-linear chaining cost under the proposed cost function can be computed orders of magnitude faster than edit distance, and achieves correlation coefficient above 0.9 with edit distance for closely as well as distantly related sequences.
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bioinformatics
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The Resting-State Causal Human Connectome is Characterized by Hub Connectivity of Executive and Attentional Networks
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neuroscience
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Vaccination decreases the risk of influenza A virus reassortment with a concomitant increase in subgenomic genetic variation in pigs
Although vaccination is broadly used in North American swine breeding herds, managing swine influenza is challenging primarily due to the continuous evolution of influenza A virus (IAV) and the ability of the virus to transmit among vaccinated pigs. Studies that have simultaneously assessed the impact of vaccination on the emergence of IAV reassortment and genetic variation in pigs are limited. Here we directly sequenced 28 bronchoalveolar lavage fluid (BALF) samples collected from vaccinated and unvaccinated pigs co-infected with H1N1 and H3N2 IAV strains, and characterized 202 individual viral plaques recovered from 13 BALF samples. We identified 54 reassortant viruses that were grouped in 16 distinct and 18 mixed genotypes. Notably, we found that prime-boost vaccinated pigs had less reassortant viruses than non-vaccinated pigs, likely due to a reduction in the number of days pigs were co-infected with both challenge viruses. However, direct sequencing from BALF samples revealed limited impact of vaccination on viral variant frequency, evolutionary rates, and nucleotide diversity in any IAV coding regions. Overall, our results highlight the value of IAV vaccination not only at limiting virus replication in pigs but also at protecting public health by restricting the generation of novel reassortants with zoonotic and/or pandemic potential.
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microbiology
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Inference of recent admixture using genotype data
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genetics
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High Gamma and Beta Temporal Interference Stimulation in the Human Motor Cortex Improves Motor Functions
BackgroundTemporal interference (TI) stimulation is a new technique of noninvasive brain stimulation. Envelope-modulated waveforms with two high-frequency carriers can activate neurons in target brain regions without stimulating the overlying cortex, which has been validated in mouse brains. However, whether TI stimulation can work on the human brain has not been elucidate.
ObjectiveTo assess the effectiveness and safety aspect of the envelope-modulated waveform of TI stimulation on human primary motor cortex (M1).
MethodsParticipants attended three sessions of 30-min TI stimulation at 2 mA during a random reaction time task (RRTT) or a serial reaction time task (SRTT). Motor cortex excitability was measured before and after TI stimulation.
ResultsIn the RRTT experiment, only 70 Hz TI stimulation had a promoting effect on the reaction time (RT) performance and excitability of the motor cortex compared to sham stimulation. Meanwhile, compared with the sham condition, only 20 Hz TI stimulation significantly facilitated motor learning in the SRTT experiment, which was significantly positively correlated with the increase in motor evoked potential.
ConclusionThese results indicate that the envelope-modulated waveform of TI stimulation has a significant promoting effect on human motor functions, experimentally suggesting the effectiveness of TI stimulation in humans for the first time and pave the way for further explorations.
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neuroscience
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Modular development enables rapid design of media for alternative hosts
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microbiology
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Intergenerational microbial transmission in the little skate (Leucoraja erinacea)
BackgroundMicrobial transmission from parent to offspring is hypothesized to be widespread in vertebrates. However, evidence for this is limited as many evolutionarily important clades remain unexamined. There is currently no data on the microbiota associated with any Chondrichthyan species during embryonic development, despite the global distribution, ecological importance, and phylogenetic position of this clade. In this study, we take the first steps towards filling this gap by investigating the microbiota associated with embryonic development in the little skate, Leucoraja erinacea, a common North Atlantic species and popular system for chondrichthyan biology.
MethodsTo assess the potential for bacterial transmission in an oviparous chondrichthyan, we used 16S rRNA amplicon sequencing to characterize the microbial communities associated with the skin, gill, and egg capsule of the little skate, at six points during ontogeny. Community composition was analyzed using the QIIME2 pipeline and microbial continuity between stages was tracked using FEAST.
ResultsWe identify site-specific and stage-specific microbiota dominated by the bacterial phyla Proteobacteria and Bacteroidetes. This composition is similar to, but distinct from, that of previously published data on the adult microbiota of other chondrichthyan species. Our data reveal that the skate egg capsule harbors a highly diverse bacterial community-particularly on the internal surface of the capsule-and facilitates intergenerational microbial transfer to the offspring. Embryonic skin and external gill tissues host similar bacterial communities; the skin and gill communities later diverge as the internal gills and skin denticles develop.
ConclusionsOur study is the first exploration of the chondrichthyan microbiota throughout ontogeny and provides the first evidence of vertical transmission in this group.
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microbiology
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Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis
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microbiology
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Mutualism-enhancing mutations dominate early adaptation in a microbial community
Species interactions drive species evolution while evolution shapes these interactions. The resulting eco-evolutionary dynamics, their outcomes and their repeatability depend on how adaptive mutations available to community members affect fitness and ecologically relevant traits. However, the diversity of adaptive mutations available to community members is not well characterized, and we do not know how this diversity is affected by the ecological milieu. Here we use barcode lineage tracking to address this gap in a competitive mutualism between the yeast Saccharomyces cerevisiae and the alga Chlamydomonas reinhardtii. We find that yeast has access to many adaptive mutations with diverse ecological consequences, in particular, those that increase and reduce the yields of both species. The presence of alga does not change which mutations are adaptive in yeast (i.e., there is no fitness trade-off for yeast between growing alone or with alga), but rather shifts selection to favor yeast mutants that increase the yields of both species and make the mutualism stronger. Thus, in the presence of alga, we find that yeast repeatably evolves to become more cooperative, even though cooperativity is not directly favored by natural selection in our system. Our results demonstrate that ecological interactions not only alter the trajectory of evolution but also dictate its repeatability; in particular, weak mutualisms can repeatably evolve to become stronger.
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evolutionary biology
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The gut microbiome is associated with cocaine behavior and predicts addiction vulnerability in adult male rats
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neuroscience
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Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells
Injured neurons in the adult mammalian central nervous system often die and seldom regenerate axons. To uncover transcriptional pathways that could ameliorate these disappointing responses we analyzed three interventions that increase survival and regeneration of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC) injury, albeit not to a clinically useful extent. We assessed gene expression in each of 46 RGC types by single cell transcriptomics following ONC and treatment. We also compared RGCs that regenerated to those that survived but did not regenerate. Each intervention enhanced survival of most RGC types, but type-independent axon regeneration required manipulation of multiple pathways. Distinct computational methods converged on separate sets of genes selectively expressed by RGCs likely to be dying, surviving, or regenerating. Overexpression of genes associated with the regeneration program enhanced axon regeneration in vivo, indicating that mechanistic analysis can be used to identify novel methods for promoting regeneration of injured neurons.
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neuroscience
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Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder
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neuroscience
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Riboswitch Folds to Holo-Form Like Structure Even in the Absence of Cognate Ligand at High Mg2+ Concentration
Riboswitches are non-coding RNA that regulate gene expression by folding into specific three-dimensional structures (holo-form) upon binding by their cognate ligand in the presence of Mg2+. Riboswitch functioning is also hypothesized to be under kinetic control requiring large cognate ligand concentrations. We ask the question under thermodynamic conditions, can the riboswitches populate holo-form like structures in the absence of their cognate ligands only in the presence of Mg2+. We addressed this question using thiamine pyrophosphate (TPP) riboswitch as a model system and computer simulations using a coarse-grained model for RNA. The folding free energy surface (FES) shows that with the initial increase in Mg2+ concentration ([Mg2+]), TPP AD undergoes a barrierless collapse in its dimensions. On further increase in [Mg2+], intermediates separated by barriers appear on the FES, and one of the intermediates has a TPP ligand-binding competent structure. We show that site-specific binding of the Mg2+ aids in the formation of tertiary contacts. For [Mg2+] greater than physiological concentration, AD folds into its holo-form like structure even in the absence of the TPP ligand. The folding kinetics shows that it populates an intermediate due to the misalignment of the two arms in the TPP AD, which acts as a kinetic trap leading to larger folding timescales. The predictions of the intermediate structures from the simulations are amenable for experimental verification.
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biophysics
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Advancing motion denoising of multiband resting state functional connectivity fMRI data
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neuroscience
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Differences in durability of PARP inhibition by clinically approved PARP inhibitors: implications for combinations and scheduling
Five PARP inhibitors (PARPi) are approved for cancer treatment, they exploit cancer-specific defects in homologous recombination repair (HRR) to selectively kill tumour cells. Continuous PARP inhibition is required for single-agent anticancer activity. PARPi are also being investigated with ATR inhibitors clinically. We previously showed rucaparib caused prolonged PARP inhibition. Here we aimed to determine if this property was unique to rucaparib or common to other PARPis and the implications for scheduling with an ATR inhibitor (VE-821). Durability of PARP inhibition was determined at 0, 1, 24, 48 and 72 h after a 1 h pulse of 1M of rucaparib, olaparib, niraparib, talazoparib or pamiparib in IGROV-1 (human ovarian cancer) cells. Inhibition of PARP was sustained to a variable degree with all inhibitors, but reduced with time. Rucaparib caused the most persistent inhibition of PARP activity, which was maintained at [≥]75% for 72 h after drug withdrawal. In contrast, only 12% inhibition remained at this time with talazoparib and pamiparib and no detectable inhibition with olaparib and niraparib. Rucaparib enhanced VE-821 cytotoxicity to a similar extent in a sequential schedule as in co-exposure studies (PF50: 2.6 vs. 2.7) and there was even an approx. 2-fold enhancement after a 24 h delay between rucaparib and VE-821. Olaparib and niraparib produced similar enhancement of VE-821 cytotoxicity if co-exposed but were ineffective in sequential exposures. These data have clinical implications for both schedules of current PARPi monotherapy and the scheduling of PARPi in combination with ATRi and other cytotoxic drugs.
Novelty and ImpactPARPi are a new class of anticancer agent. We demonstrate for the first time that 5 PARPi continue to suppress cellular PARP activity after drug removal to a variable extent. Rucaparib caused the most durable PARP inhibition, olaparib and niraparib the least. Rucaparib enhanced ATR inhibitor cytotoxicity in sequential and co-exposures, olaparib and niraparib were only active in co-exposure settings. These data have implications for the clinical use of PARPi, particularly in combination with other drugs.
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pharmacology and toxicology
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The neural code for 'face cells' is not face specific
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neuroscience
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The regulatory protein ChuP connects heme and siderophore-mediated iron acquisition systems required for Chromobacterium violaceum virulence
Chromobacterium violaceum is an environmental Gram-negative beta-proteobacterium that causes systemic infections in humans. C. violaceum uses siderophore-based iron acquisition systems to overcome the host-imposed iron limitation, but its capacity to use other iron sources is unknown. In this work, we characterized ChuPRSTUV as a heme utilization system employed by C. violaceum to explore an important iron reservoir in mammalian hosts, free heme and hemoproteins. We demonstrate that the chuPRSTUV genes comprise a Fur-repressed operon that is expressed under iron limitation. The chu operon potentially encodes a small regulatory protein (ChuP), an outer membrane TonB-dependent receptor (ChuR), a heme degradation enzyme (ChuS), and an inner membrane ABC transporter (ChuTUV). Our nutrition growth experiments using C. violaceum chu deletion mutants revealed that, with the exception of chuS, all genes of the chu operon are required for heme and hemoglobin utilization in C. violaceum. The mutant strains without chuP displayed increased siderophore halos on CAS plate assays. Significantly, we demonstrate that ChuP connects heme and siderophore utilization by acting as a positive regulator of chuR and vbuA, which encode the TonB-dependent receptors for the uptake of heme (ChuR) and the siderophore viobactin (VbuA). Our data favor a model of ChuP as a heme-binding post-transcriptional regulator. Moreover, our virulence data in a mice model of acute infection demonstrate that C. violaceum uses both heme and siderophore for iron acquisition during infection, with a preference for siderophores over the Chu heme utilization system.
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microbiology
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Contrasting resistance and resilience to light variation of the coupled oxic and anoxic componentsof an experimental microbial ecosystem
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microbiology
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Remdesivir, Zidovudine (AZT) and Nevirapine inhibit Chandipura virus replication through high energy interactions with the RdRp domain of the polymerase protein L
Chandipura Virus (CHPV), a rhabdovirus belonging to mononegavirales, is an emerging pathogen in Indian subcontinent. The virus infection causes fever, brain encephalitis among the young children below 14 yrs of age. In recent past, several outbreaks and deaths among children were reported from in India. There are no targeted drugs or vaccines available against CHPV and symptomatic treatments are the only option. In this background, we aimed to investigate the inhibitory effects of some priviously known viral RNA polymerase inhibitor drugs on CHPV replication. First, we examined remdesivir, which is known to inhibit HCV, Ebola and SARS-CoV-2 replication and close structural similarity along with conserved residues in the finger region of RNA dependent RNA polymerase (RdRp) domain is the basis of replication inhibition. Our results showed that remdesivir inhibits CHPV replication in vero E6 cells to a significant level. In this study we have also included non-nucleoside anti-retroviral inhibitor (NNRTI) drug nevirapine, and nucleoside inhibitor (NRTI) drug AZT (Zidovudine) to determine if these are also able to inhibit CHPV replication. Interestingly, we observed inhibition of CHPV replication by both nevirapine and AZT (in the order nevirapine>AZT), albeit to a lesser extent compared to remdesivir. We next performed molecular docking and modeling study to get an insight about the interactions of these drugs with CHPV polymerase protein. Modeling study predicts that remdesivir has most favourable CHPV polymerase binding energy among these three drugs. Both remdesivor and AZT binds near the polymerase active site through interctions with residues in finger and palm regions of RdRp. In contrast, nevirapine binds to the N-terminal domain (NTD) of the RdRp. In summary, we found remdesivir as a potent inhibitor of CHPV. A combination therapy including remdesivir, nevirapine and AZT may be a better drug cocktail to treat CHPV disease. Our findings warrant further studies of these drugs against CHPV in animal models for clinical use in near future.
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microbiology
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In silico modeling and interactive profiling of BPH resistant R genes with elicitor molecules of rice planthoppers
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plant biology
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Insights into long non-coding RNA regulation of anthocyanin carrot root pigmentation
Carrot (Daucus carota L.) is one of the most cultivated vegetable in the world and of great importance in the human diet. Its storage organs can accumulate large quantities of anthocyanins, metabolites that confer the purple pigmentation to carrot tissues and whose biosynthesis is well characterized. Long non-coding RNAs (lncRNAs) play critical roles in regulating gene expression of various biological processes in plants. In this study, we used a high throughput stranded RNA-seq to identify and analyze the expression profiles of lncRNAs in phloem and xylem root samples using two genotypes with a strong difference in anthocyanin production. We discovered and annotated 8484 new genes, including 2095 new protein-coding and 6373 non-coding transcripts. Moreover, we identified 639 differentially expressed lncRNAs between the phenotypically contrasted genotypes, including certain only detected in a particular tissue. We then established correlations between lncRNAs and anthocyanin biosynthesis genes in order to identify a molecular framework for the differential expression of the pathway between genotypes. A specific natural antisense transcript (NAT) linked to the DcMYB7 key anthocyanin biosynthetic transcription factor suggested how the regulation of this pathway may have evolved between genotypes.
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genomics
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Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells
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cell biology
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Canada's human footprint reveals large intact areas juxtaposed against areas under immense anthropogenic pressure
Efforts are underway in Canada to set aside terrestrial lands for conservation, thereby protecting them from anthropogenic pressures. Here we produce the first Canadian human footprint map to identify intact and modified lands and ecosystems. Our results showed strong spatial variation in pressures across the country, with just 18% of Canada experiencing measurable human pressure. However, some ecosystems are experiencing very high pressure, such as the Great Lakes Plains and Prairies national ecological areas which have over 75% and 56% of their areas, respectively, with a high human footprint. In contrast, the Arctic and Northern Mountains have less than 0.02% and 0.2% under high human footprint. A validation of the final map resulted in a Cohen Kappa statistic of 0.911, signifying an almost perfect agreement between the human footprint and the validation data set. By increasing the number and accuracy of mapped pressures, our map demonstrates much more widespread pressures in Canada than were indicated by previous global mapping efforts, demonstrating the value in specific national data applications. Ecological areas with immense anthropogenic pressure, highlight challenges that may arise when planning for ecologically representative protected areas.
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ecology
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Sensitive visualization of SARS-CoV-2 RNA with CoronaFISH
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microbiology
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Spatial and temporal expression of PORCN is highly dynamic in the developing mouse cochlea.
The mammalian organ of Corti is a highly specialized sensory organ of the cochlea with a fine-grained pattern that is essential for auditory function. The sensory epithelium, the organ of Corti consists of a single row of inner hair cells and three rows of outer hair cells that are intercalated by support cells in a mosaic pattern. Previous studies show that the Wnt pathway regulates proliferation, promotes medial compartment formation in the cochlea, differentiation of the mechanosensory hair cells and axon guidance of Type II afferent neurons. WNT ligand expressions are highly dynamic throughout development but are insufficient to explain the roles of the Wnt pathway. We address a potential way for how WNTs specify the medial compartment by characterizing the expression of Porcupine (PORCN), an O-acyltransferase that is required for WNT secretion. We show PORCN expression across embryonic ages (E)12.5 - E14.5, E16.5, and postnatal day (P)1. Our results showed enriched PORCN in the medial domains during early stages of development, indicating that WNTs have a stronger influence on patterning of the medial compartment. PORCN was rapidly downregulated after E14.5, following the onset of sensory cell differentiation; residual expression remained in some hair cells and supporting cells. On E14.5 and E16.5, we also examined the spatial expression of Gsk3{beta}, an inhibitor of canonical Wnt signaling to determine its potential role in radial patterning of the cochlea. Gsk3{beta} was broadly expressed across the radial axis of the epithelium; therefore, unlikely to control WNT-mediated medial specification. In conclusion, the spatial expression of PORCN enriches WNT secretion from the medial domains of the cochlea to influence the specification of cell fates in the medial sensory domain.
HighlightsO_LIWnt ligands are broadly expressed during cochlear development.
C_LIO_LIPORCN expression is highly dynamic during early cochlear development
C_LIO_LIPORCN becomes restricted to the medial domains along the longitudinal axis.
C_LIO_LIWnt medial specification is regulated at the level of WNT ligand secretion.
C_LI
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developmental biology
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Elucidating the acid-base mechanisms underlying otolith overgrowth in fish exposed to ocean acidification
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physiology
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Adaptive and maladaptive expression plasticity underlying herbicide resistance in an agricultural weed.
Plastic phenotypic responses to environmental change are common, yet we lack a clear understanding of the fitness consequences of these plastic responses. Here, we use the evolution of herbicide resistance in the common morning glory (Ipomoea purpurea) as a model for understanding the relative importance of adaptive and maladaptive gene expression responses to herbicide. Specifically, we compare leaf gene expression changes caused by herbicide to the expression changes that evolve in response to artificial selection for herbicide resistance. We identify a number of genes that show plastic and evolved responses to herbicide and find that for the majority of genes with both plastic and evolved responses, plastic responses appear to be adaptive. We also find that selection for herbicide response increases gene expression plasticity. Overall, these results show the importance of adaptive plasticity for herbicide resistance in a common weed and that expression changes in response to strong environmental change can be adaptive.
Impact statementPredicting whether and how organisms will adapt to environmental change is a crucial goal. However, this goal can be complicated because environmental change can alter traits, in a process called plasticity. The extent and fitness consequences of plasticity will have important effects on the adaptive process. In this study, we use adaptation to herbicide in the agricultural weed, the common morning glory, as a model for understanding the extent and fitness consequences of plasticity in gene expression. We find evidence that gene expression plasticity is adaptive in the presence of herbicide, suggesting that understanding plasticity is crucial for understanding how organisms adapt to new environments.
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evolutionary biology
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Ssdp influences Wg expression and embryonic somatic muscle identity in Drosophila melanogaster
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developmental biology
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Isolation and characterization of SARS-CoV-2 VOC, 20H/501Y.V2, from UAE travelers
Multiple SARS-CoV-2 variants have been emerged and created serious public health in the affected countries. The variant of Concern associated with high transmissibility, disease severity and escape mutations is threat to vaccination program across the globe. Travel has been important factor in spread of SARS-CoV-2 variants worldwide. India has also witnessed the dreadful effect of these SARS-CoV-2 variants. Here, we report the Isolation and characterization of SARS-CoV-2 VOC, 20H/501Y.V2 (B.1.351), from UAE travelers to India. The virus isolate would be useful to determine the efficacy of the currently available vaccines in India.
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microbiology
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Functional characterization of the thrombospondin-related paralogous proteins rhoptry discharge factor 1 and 2 unveils phenotypic plasticity in Toxoplasma gondii rhoptry exocytosis
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microbiology
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The Evolutionary History of Small RNAs in the Solanaceae
The Solanaceae or "nightshade" family is an economically important group that harbors a remarkable amount of diversity. To gain a better understanding of how the unique biology of the Solanaceae relates to the familys small RNA genomic landscape, we downloaded over 255 publicly available small RNA datasets that comprise over 2.6 billion reads of sequence data. We applied a suite of computational tools to predict and annotate two major small RNA classes: (1) microRNAs (miRNAs), typically 20-22 nt RNAs generated from a hairpin precursor and functioning in gene silencing, and (2) short interfering RNAs (siRNAs), including 24-nt heterochromatic siRNAs (hc-siRNAs) typically functioning to repress repetitive regions of the genome via RNA-directed DNA methylation, as well as secondary phased siRNAs (phasiRNAs) and trans-acting siRNAs (tasiRNAs) generated via miRNA-directed cleavage of a Pol II-derived RNA precursor. Our analyses described thousands of small RNA loci, including poorly-understood clusters of 22-nt siRNAs that accumulate during viral infection. The birth, death, expansion, and contraction of these small RNA loci are dynamic evolutionary processes that characterize the Solanaceae family. These analyses indicate that individuals within the same genus share similar small RNA landscapes, whereas comparisons between distinct genera within the Solanaceae reveal relatively few commonalities.
ONE-SENTENCE SUMMARYWe use over 255 publicly-available small RNA datasets to characterize the small RNA landscape for the Solanaceae family.
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plant biology
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Transgenic Drosophila lines for LexA-dependent gene and growth regulation
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genetics
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Pleiotropy drives repeatability in the genetic basis of adaptation
Studies of trait-mapping and local adaptation often identify signatures of genetically parallel evolution, where different species evolve similar phenotypes using the same genes. Such patterns appear incongruent with current estimations of quantitative trait architecture. With hundreds or thousands or genes contributing to a trait, why would selection make repeated use of the same genes? Here, we use individual-based simulations to explore a two-patch model with quantitative, pleiotropic traits to understand the parameters which may lead to repeated use of a particular locus during independent bouts of adaptation. We find that repeatability can be driven by increased phenotypic effect size, a reduction in trait dimensionality and a reduction in mutational correlations at a particular locus relative to other loci in the genome, and that these patterns are magnified by increased migration between demes. These results suggest that evolutionary convergence can arise from multiple characteristics of a locus, and provide a framework for the interpretation of quantitative signatures of convergence in empirical studies.
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genetics
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Biparatopic sybody constructs neutralize SARS-CoV-2 variants of concern and mitigate emergence of drug resistance
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biochemistry
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Prospective cohort study reveals unexpected aetiologies of livestock abortion in northern Tanzania
Livestock abortion is an important cause of productivity losses worldwide and many infectious causes of abortion are zoonotic pathogens that impact on human health. Little is known about the relative importance of infectious causes of livestock abortion in Africa, including in subsistence farming communities that are critically dependent on livestock for food, income, and wellbeing. We conducted a prospective cohort study of livestock abortion, supported by cross-sectional serosurveillance, to determine aetiologies of livestock abortions in livestock in Tanzania. This approach generated several important findings including detection of a Rift Valley fever virus outbreak in cattle; high prevalence of C. burnetii infection in livestock; and the first report of Neospora caninum, Toxoplasma gondii, and pestiviruses associated with livestock abortion in Tanzania. Our approach provides a model for abortion surveillance in resource-limited settings. Our findings add substantially to current knowledge in sub-Saharan Africa, providing important evidence from which to prioritise disease interventions.
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systems biology
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Comparative genomics of Acinetobacter baumannii and therapeutic bacteriophages from a patient undergoing phage therapy
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microbiology
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Maize AFP1 confers antifungal activity by inhibiting chitin deacetylases from a broad range of fungi
Adapted plant pathogenic fungi deacetylate chitin to chitosan to avoid host perception and disarm the chitin-triggered plant immunity. Whether plants have evolved factors to counteract this fungal evasion mechanism in the plant-pathogen interface remains obscure. Here, we decipher the underlying mechanism of maize cysteine-rich receptor-like secreted proteins (CRRSPs)-AFP1, which exhibits mannose-binding dependent antifungal activity. AFP1 initials the action by binding to specific sites on the surface of yeast-like cells, filaments, and germinated spores of the biotrophic fungi Ustilago maydis. This could result in fungal cell growth and cell budding inhibition, delaying spore germination and subsequently reducing fungal viability in a mannose-binding dependence manner. The antifungal activity of AFP1 is conferred by its interaction with the PMT-dependent mannosylated chitin deacetylases (CDAs) and interfering with the conversion of chitin. Our finding that AFP1 targets CDAs from pathogenic fungi and nonpathogenic budding yeast suggests a potential application of the CRRSP in combating fungal diseases and reducing threats posed by the fungal kingdom.
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microbiology
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An Autoantigen Profile from Jurkat T-Lymphoblasts Provides a Molecular Guide for Investigating Autoimmune Sequelae of COVID-19
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immunology
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Event-driven acquisition for content-enriched microscopy
In fluorescence microscopy, the amount of information that can be collected from the sample is limited, often due to constraints imposed by photobleaching and phototoxicity. Here, we report an event-driven acquisition (EDA) framework, which combines real-time, neural network-based recognition of events of interest with automated control of the imaging parameters in an instant structured illumination microscope (iSIM). On-the-fly prioritization of imaging rate or experiment duration is achieved by switching between a slow imaging rate to detect the onset of biological events of interest and a fast imaging rate to enable high information content during their progression. In this way, EDA allows the data capture of mitochondrial and bacterial divisions at imaging rates that match their dynamic timescales, while extending the accessible imaging duration, and thereby increases the density of relevant information in the acquired data.
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cell biology
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