Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 84,910 bioRxiv papers from 365,224 authors.
Most downloaded bioRxiv papers, since beginning of last month
82,797 results found. For more information, click each entry to expand.
9 downloads cell biology
The Spindle Assembly Checkpoint (SAC) maintains genomic integrity by preventing anaphase until all kinetochores attach to the spindle. What specific signals are required for SAC satisfaction at mammalian kinetochores, and in what magnitude, are not well understood and central to understanding SAC signal processing and function. Here, we directly and independently tune candidate input signals - spindle forces and Hec1-microtubule binding - and map SAC outputs. By detaching microtubules from the spindle, we first demonstrate that the SAC does not respond to changes in spindle pulling forces. We then tune and fix the fraction of Hec1 molecules capable of microtubule binding, and interpret SAC output changes as coming from changes in binding, and not spindle forces. While the speed of satisfaction reduces with fewer attached microtubules, the kinetochore turns off the SAC even with few - approximately four - such microtubules. Thus, the mammalian kinetochore responds specifically to microtubule binding, and does so as a single, switch-like, sensitive unit. This may allow the kinetochore to rapidly react to attachments and maintain a robust response despite dynamic microtubule numbers.
9 downloads biochemistry
Site-specific arrest of RNA polymerase is fundamental to several technologies that measure RNA structure and function. Current in vitro transcription ‘roadblocking’ approaches inhibit transcription elongation using a protein blockade bound to the DNA template. One limitation of protein-mediated transcription roadblocking is that it requires the inclusion of a protein factor that is extrinsic to the minimal in vitro transcription reaction. In this work, we show that interrupting the transcribed DNA strand with an internal desthiobiotin-triethylene glycol modification efficiently and stably halts Escherichia coli RNA polymerase transcription. To facilitate diverse applications of chemical transcription roadblocking, we establish a simple and sequence-independent method for the preparation of internally modified double-stranded DNA templates by sequential PCR and translesion synthesis. By encoding an intrinsic stall site within the template DNA, our chemical transcription roadblocking approach enables nascent RNA molecules to be displayed from RNA polymerase in a minimal in vitro transcription reaction.
9 downloads genomics
Motivation: The emergence of techniques for the analysis of 5′-monophosphate mRNA degradation intermediates necessitates development of tools for automated analysis of 5′ endpoint distribution for inference on ribosome dynamics, mRNA cleavage patterns, binding sites, etc. Results: Here we present fivepseq: an easy-to-use command-line application for analysis and visualization of 5′ endpoint count distribution from RNA-seq datasets. It produces interactive reports for ease of exploratory analysis that provide single-nucleotide resolution reports on ribosome dynamics and degradation patterns. Availability: Fivepseq is available from http://pelechanolab.com/software/fivepseq, under BSD 3-Clause License.
9 downloads cell biology
Syntaxins - a conserved family of SNARE proteins - contain C-terminal transmembrane anchors required for their membrane fusion activity. Here we show that syntaxin 3 (Stx3) unexpectedly also functions as a nuclear regulator of gene expression. Alternative splicing leads to a soluble isoform, termed Stx3S, lacking the transmembrane anchor. Soluble Stx3S binds to the nuclear import factor RanBP5, targets to the nucleus and interacts physically and functionally with several transcription factors, including ETV4 and ATF2. Stx3S is differentially expressed in normal human tissues, during epithelial cell polarization, and in breast cancer vs. normal breast tissue. Inhibition of endogenous Stx3S expression leads to changes in the expression of cancer-associated genes and promotes cell proliferation. Similar nuclear-targeted, soluble forms of other syntaxins were identified suggesting that nuclear signaling is a conserved, novel function common among these membrane trafficking proteins.
9 downloads biophysics
Understanding biological complexity is one of the most important scientific challenges nowadays. Protein folding is a complex process involving many interactions between the molecules. Fractional calculus is an effective modeling tool for complex systems and processes. In this work we have proposed a new fractional field theoretical approach to protein folding.
9 downloads neuroscience
Due to its importance for successful human behavior, research into cognitive control functioning has gained increasing interest. The paced auditory serial addition task (PASAT) has been used to test and train this fundamental function. It is a challenging task, requiring a high cognitive load in a stressful and frustrating environment. Its underlying neural mechanisms, however, are still unclear. To explore the neural signatures of the PASAT and their link to ongoing cognitive processing, feedback locked event-related potentials were derived from healthy participants during an adaptive 2-back version of the PASAT. Larger neural activation after negative feedback was found for feedback related negativity (FRN), P300 and late positive potential (LPP). In early stages of feedback processing (FRN), a larger difference between positive and negative feedback responses was associated with poorer overall performance, whereas this association was inverted for the later stages (P300 and LPP). This indicates stage-dependent associations of neural activation after negative information and cognitive functioning. Conceivably, increased early responses to negative feedback signify distraction whereas higher activity at later stages reflect cognitive control processes to preserve ongoing performance.
9 downloads animal behavior and cognition
Tsetse flies ( Diptera: Glossinidae ) are the cyclical vectors of trypanosomes, the causative agents of African animal trypanosomosis or nagana in animals and human African trypanosomosis or sleeping sickness in humans. Tsetse flies are K-strategist species with the deposition of a single larva at 10 days intervals in specific sites. As larviposition site selection will strongly impact reproductive success, it is obvious that the selection of larviposition sites is not random and is under strong selective processes, probably mediated by specific cues as suggested by the existence of an aggregation factor in the Morsitans and Fusca groups. This study aimed to highlight the existence of an aggregation effect in the Palpalis group and to test for its chemical nature. We studied the larviposition site selection of Glossina palpalis gambiensis according to the presence of conspecific and heterospecific larvae buried in substrates in different settings. Three sets of experiments were performed with either individual or grouped (n = 50) gravid females, and with physical access to substrate or not. In both individual and grouped larviposition experiments, females selected significantly more often trays conditioned by larvae (P<0.005), either conspecific or heterospecific even in the absence of physical contact with the substrate. These results highlight the first evidence for larviposition site selection mediated by volatile semiochemicals of larval origin in Glossina palpalis gambiensis . However, these compounds seem not to be species-specific and therefore offer new avenues for the behavioural manipulation of these vectors and for the development of new vector control tools targeting gravid females.
9 downloads developmental biology
Gene expression studies have typically focused on finding differentially expressed genes or pathways between two or more conditions. More recently, single-cell RNA-seq has been established as a reliable and accessible technique enabling new types of analyses, such as the study of gene expression variation within cell types from cell lines or from relatively similar cells in tissues, organs or tumors. However, although single-cell RNA-seq provides quantitative and comprehensive expression data in a developing embryo, it is not yet clear whether this can replace conventional in situ screens for finding developmentally important genes; moreover, current single-cell data analysis approaches typically cluster cells into types based on a common set of genes or identify more variable or differentially expressed genes using predefined groups of cells, limiting their use for finding genes with novel expression patterns. Here we present a method that comprehensively finds cell-specific patterns of developmentally important regulators directly from single-cell gene expression data of the Ciona embryo, a marine chordate. We recover many of the known expression patterns directly from our single-cell RNA-seq data and despite extensive previous screens, we succeed in finding new cell-specific patterns and genes, which we validate by in situ and single-cell qPCR.
9 downloads cell biology
In this work, we have investigated in mammalian cells how microtubule nucleation at centrosome and Golgi apparatus are coordinated, using genetic ablation of three γ-TuRC binding proteins — AKAP450, Pericentrin and CDK5Rap2 — and the PLK4 inhibitor centrinone. We show that centrosomal microtubule nucleation is independent of Golgi activity whereas the converse is not true: nucleation on the Golgi negatively correlates with the number of centrosomes. In addition, depleting AKAP450 in cells lacking centrioles, that abolishes Golgi nucleation activity, leads to microtubule nucleation from numerous cytoplasmic Golgi unbound acentriolar structures containing Pericentrin, CDK5Rap2 and γ-tubulin. Strikingly, centrosome-less cells display twice higher microtubule density than normal cells, suggesting that the centrosome controls the spatial distribution of microtubules, not only by nucleating them, but also by acting as a negative regulator of alternative MTOCs. Collectively, the data reveals a hierarchical control of microtubule nucleation, with the centrosome regulating this process in a more complex manner than usually thought. It also unveils mechanisms that could help understanding MT network reorganization during cell differentiation.
9 downloads neuroscience
Illusory contours (ICs) are borders that are perceived in the absence of contrast gradients. Until recently, IC processes were considered exclusively visual in nature and presumed to be unaffected by information from other senses. Electrophysiological data in humans indicates that sounds can enhance IC processes. Despite cross-modal enhancement being observed at the neurophysiological level, to date there is no evidence of direct amplification of behavioural performance in IC processing by sounds. We addressed this knowledge gap. Healthy adults (N=15) discriminated instances when inducers were arranged to form an IC from instances when no IC was formed (NC). Inducers were low-constrast and masked, and there was continuous background acoustic noise throughout a block of trials. On half of the trials, i.e. independently of IC vs. NC, a 1000Hz tone was presented synchronously with the inducer stimuli. Sound presence improved the accuracy of indicating when an IC was presented, but had no impact on performance with NC stimuli (significant IC presence/absence × Sound presence/absence interaction). There was no evidence that this was due to general alerting or to a speed-accuracy trade-off (no main effect of sound presence on accuracy rates and no comparable significant interaction on reaction times). Moreover, sound presence increased sensitivity and reduced bias on the IC vs. NC discrimination task. These results demonstrate that multisensory processes augment mid-level visual functions, exemplified by IC processes. Aside from the impact on neurobiological and computational models of vision our findings may prove clinically beneficial for low-vision or sight-restored patients. ### Competing Interest Statement The authors have declared no competing interest.
9 downloads biophysics
Hydrogels made from structured polyprotein domains combine the properties of cross-linked polymers with the unfolding phase transition. The use of protein hydrogels as an ensemble approach to study the physics of domain unfolding is limited by the lack of scaling tools and by the complexity of the system. Here we propose a model to describe the biomechanical response of protein hydrogels based on the unfolding and extension of protein domains under force. Our model takes into account the contributions on the network dynamics of the molecules inside the gels, which have random cross-linking points and random topology. This model reproduces reported macroscopic visco-elastic effects and constitutes an important step toward using rheometry on protein hydrogels to scale down to the average mechanical response of protein molecules.
9 downloads ecology
Establishment of new populations is contingent on overcoming abiotic and biotic barriers. While this applies to all species, these hurdles are at the forefront of invasion biology where prediction, prevention, eradication, and control strategies depend on an understanding and exploitation of barriers to establishment and spread. Arundina graminifolia and Dendrobium crumenatum are two invasive orchids spreading throughout Puerto Rico. Current records on their distributions across the island are sparse, and their interactions with the surrounding ecosystem are unknown. Through a direct population survey of all known localities, we identified a new, acquired enemy of both orchids: the orchid-specialist weevil, Stethobaris polita. In this study, we used niche modelling to identify suitable habitats for each orchid on the island and map their current distributions and interactions with S. polita, along with their distributions in the most extreme climate scenario in 2050, in order to contextualize projected patterns of establishment on the island. Our findings show that D. crumenatum flourishes in urban environments which also provide refugia from S. polita. In contrast, there is currently no refugia for A. graminifolia from S. polita attack, as it is more sensitive to the same climatic variables as S. polita. Furthermore, projections into the most extreme climate scenario suggests Puerto Rico will be unsuitable for A. graminifolia and S. politas survival, and become less suitable for D. crumenatum, by 2050.
9 downloads genetics
Sorghum is generally grown in water limited conditions and often lodges under post-anthesis drought, which reduces yield and quality. Due to its complexity, our understanding on the genetic control of lodging is very limited. We dissected the genetic architecture of lodging in grain sorghum through genome-wide association study (GWAS) on 2308 unique hybrids grown in 17 Australian sorghum trials over 3 years. The GWAS detected 213 QTL, the majority of which showed a significant association with leaf senescence and plant height (72% and 71% respectively). Only 16 lodging QTL were not associated with either leaf senescence or plant height. The high incidence of multi-trait association for the lodging QTL indicates that lodging in grain sorghum is mainly associated with plant height and traits linked to carbohydrate remobilisation. This result supported the selection for stay-green (delayed leaf senescence) to reduce lodging susceptibility, rather than selection for short stature and lodging resistance per se , which likely reduces yield. Additionally, our data suggested a protective effect of stay-green on weakening the association between lodging susceptibility and plant height. Our study also showed that lodging resistance might be improved by selection for stem composition but was unlikely to be improved by selection for classical resistance to stalk rots. Key message We detected 213 lodging QTL and demonstrated that drought induced stem lodging in grain sorghum is substantially associated with stay-green and plant height, suggesting a critical role of carbon remobilisation.
9 downloads evolutionary biology
Two datasets, the geologic record and the genetic content of extant organisms, provide complementary insights into the history of how key molecular components have shaped or driven global environmental and macroevolutionary trends. Changes in global physicochemical modes over time are thought to be a consistent feature of this relationship between Earth and life, as life is thought to have been optimizing protein functions for the entirety of its ~3.8 billion years of history on Earth. Organismal survival depends on how well critical genetic and metabolic components can adapt to their environments, reflecting an ability to optimize efficiently to changing conditions. The geologic record provides an array of biologically independent indicators of macroscale atmospheric and oceanic composition, but provides little in the way of the exact behavior of the molecular components that influenced the compositions of these reservoirs. By reconstructing sequences of proteins that might have been present in ancient organisms, we can identify a subset of possible sequences that may have been optimized to these ancient environmental conditions. How can extant life be used to reconstruct ancestral phenotypes? Configurations of ancient sequences can be inferred from the diversity of extant sequences, and then resurrected in the lab to ascertain their biochemical attributes. One way to augment sequence-based, single-gene methods to obtain a richer and more reliable picture of the deep past, is to resurrect inferred ancestral protein sequences in living organisms, where their phenotypes can be exposed in a complex molecular-systems context, and to then link consequences of those phenotypes to biosignatures that were preserved in the independent historical repository of the geological record. As a first-step beyond single molecule reconstruction to the study of functional molecular systems, we present here the ancestral sequence reconstruction of the beta-carbonic anhydrase protein. We assess how carbonic anhydrase proteins meet our selection criteria for reconstructing ancient biosignatures in the lab, which we term paleophenotype reconstruction.
9 downloads cancer biology
Telomerase is pathologically reactivated in most human cancers, where it maintains chromosomal telomeres and allows immortalization. Because telomerase reverse transcriptase (TERT) is usually the limiting component for telomerase activation, numerous studies have measured TERT mRNA levels in populations of cells or in tissues. However, little is known about TERT expression at the single-cell and single-molecule level. Here we analyzed TERT expression across 10 human cancer lines using single-molecule RNA FISH and made several unexpected findings. First, there was substantial cell-to-cell variation in number of transcription sites and ratio of transcription sites to gene copies. Second, previous classification of lines as having monoallelic or biallelic TERT expression was found to be inadequate for capturing the TERT gene expression patterns. Finally, TERT mRNA had primarily nuclear localization in cancer cells and induced pluripotent stem cells (iPSCs), in stark contrast to the expectation that mature mRNA should be predominantly cytoplasmic. These data reveal unappreciated heterogeneity, complexity, and unconventionality in TERT expression across human cancer cells.
9 downloads developmental biology
Background As a result of decades of effort by many investigators we now have an advanced level of understanding about several molecular systems involved in the control of gene expression. Examples include CpG islands, promoters, mRNA splicing and epigenetic signals. It is less clear, however, how such systems work together to integrate the functions of a living organism. Here I describe the results of a study to test the idea that a contribution might be made by focusing on genes specifically expressed in a particular tissue, the human testis. Experimental Design A database of 239 testis-specific genes was accumulated and each was examined for the presence of features relevant to control of gene expression. These include: (1) the presence of a promoter, (2) the presence of a CpG island (CGI) within the promoter, (3) the presence in the promoter of a transcription factor binding site near the transcription start site, (4) the level of gene expression, and (5) the above features in genes of cell types such as spermatocyte and spermatid that differ in their extent of differentiation. Results Of the 107 database genes with an annotated promoter, 56 were found to have one or more transcription factor binding sites near the transcription start site. Three of the binding sites observed, Pax-5, AP-2αA and GRα, stand out in abundance suggesting they may be involved in testis-specific gene expression. Compared to less differentiated testis-specific cells, genes of more differentiated cells were found to be (1) more likely to lack a CGI, (2) more likely to lack introns and (3) higher in expression level. The results suggest genes of more differentiated cells have a reduced need for CGI-based regulatory repression, reduced usage of gene splicing and a smaller set of expressed proteins.
9 downloads developmental biology
During eye embryogenesis, neural crest cells (NCC) of the periocular mesenchyme (POM) migrate to the anterior segment (AS) of the eye and then differentiate into the corneal stroma and endothelium, ciliary body, iris stroma, and the trabecular meshwork. Defective development of these structures leads to anterior segment dysgenesis (ASD) that in 50% of the cases leads to glaucoma, a leading cause of blindness. Here, we show that the primary cilium is indispensable for normal AS development and that its ablation in NCC induces ASD phenotypes including; small and thin cornea, impaired stromal keratocyte organization, abnormal iridocorneal angle with reduced anterior chamber and corneal neovascularization. These defects are similar to those described in patients with AS conditions such as Axenfeld-Rieger syndrome and Peter's anomaly. Mechanistically, disruption of the primary cilium in the NCC resulted in reduced hedgehog (Hh) signaling in the POM, canonically activated by the Indian Hedgehog ligand expressed by endothelial cells of the choroid. This caused decreased cell proliferation in a subpopulation of POM cells surrounding the retinal pigmented epithelium. Moreover, primary cilium ablation in NCC also led to a decreased expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. These findings suggest that primary cilia are indispensable for NCC to form normal AS structures via Hh signaling. Defects in primary cilia could, therefore, contribute to the pathogenesis of ASD, and to their complications such as congenital glaucoma.
9 downloads microbiology
The phyllosphere hosts a variety of microorganisms, including bacteria, which can play a positive role in the success of the host plant. Bacterial communities in the phylloplane are influenced by both biotic and abiotic factors, including host plant surface topography and chemistry, which change in concert with microbial communities as the plant leaves develop and age. We examined how Zea mays leaf microbial community structure changed with plant age. Ribosomal spacer length (ARISA) and scanning electron microscopic (size trait) imaging strategies were used to assess microbial community composition across maize plant ages, using a novel staggered experimental design. Significant changes in community composition were observed for both molecular and imaging analyses, and the two analysis methods provided complementary information about bacterial community structure within each leaf developmental stage. Both taxonomic and cell-size trait patterns provided evidence for niche-based contributions to microbial community development on leaves.
9 downloads evolutionary biology
Standard models of molecular evolution cannot estimate absolute speciation times alone, and require external calibrations to do so. Because fossil calibration methods rely on the unreliable fossil record, most nodes in the tree of life are dated with poor accuracy. However, many major paleogeographical events are dated, and since biogeographic processes depend on paleogeographical conditions, biogeographic dating may be used as an alternative or complementary method to fossil dating. I demonstrate how a time-stratified biogeographic stochastic process may be used to estimate absolute divergence times by conditioning on dated paleogeographical events. Informed by the current paleogeographical literature, I construct an empirical dispersal graph using 25 areas and 26 epochs for the past 540 Ma of Earth's history. Simulations indicate biogeographic dating performs well so long as paleogeography imposes constraint on biogeographic character evolution. To gauge whether biogeographic dating may have any practical use, I analyze the well-studied turtle clade (Testudines) then assess how well biogeographic dating fares compared to heavily fossil-calibrated dating results as reported in the literature. Fossil-free biogeographic dating estimated the age of the most recent common ancestor of extant turtles to be approximately 201 Ma, which is consistent with fossil-based estimates. Accuracy improves further when including a root node fossil calibration. The described model, paleogeographical dispersal graph, and analysis scripts are available for use with RevBayes.
9 downloads biophysics
Model approaches to nuclear architecture have traditionally ignored the biophysical consequences of ATP-fueled active processes acting on chromatin. However, transcription-coupled activity is a source of stochastic forces that are substantially larger than the Brownian forces present at physiological temperatures. Here, we describe a first-principles approach to large-scale nuclear architecture in metazoans that incorporates cell-type-specific active processes. The model predicts the statistics of positional distributions, shapes and overlaps of each chromosome. Our simulations reproduce common organising principles underlying large-scale nuclear architecture across human cell nuclei in interphase. These include the differential positioning of euchromatin and heterochromatin, the territorial organisation of chromosomes including both gene-density-based and size-based chromosome radial positioning schemes, the non-random locations of chromosome territories and the shape statistics of individual chromosomes. We propose that the biophysical consequences of the distribution of transcriptional activity across chromosomes should be central to any chromosome positioning code.
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