Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 67,594 bioRxiv papers from 298,341 authors.
Most downloaded bioRxiv papers, since beginning of last month
66,293 results found. For more information, click each entry to expand.
7 downloads evolutionary biology
Gene duplication is a driver of the evolution of new functions. The duplication of genes encoding homomeric proteins leads to the formation of homomers and heteromers of paralogs, creating new complexes after a single duplication event. The loss of these heteromers may be required for the two paralogs to evolve independent functions. Using yeast as a model, we find that heteromerization is frequent among duplicated homomers and correlates with functional similarity between paralogs. Using in silico evolution, we show that for homomers and heteromers sharing binding interfaces, mutations in one paralog can have structural pleiotropic effects on both interactions, resulting in highly correlated responses of the complexes to selection. Therefore, heteromerization could be preserved indirectly due to selection for the maintenance of homomers, thus slowing down functional divergence between paralogs. We suggest that paralogs can overcome the obstacle of structural pleiotropy by regulatory evolution at the transcriptional and post-translational levels.
7 downloads neuroscience
Research in many fields has become increasingly reliant on large and complex datasets. "Big Data" holds untold promise to rapidly advance science by tackling new questions that cannot be answered with smaller datasets. While powerful, research with Big Data poses unique challenges, as many standard lab protocols rely on experts examining each one of the samples. This is not feasible for large-scale datasets because manual approaches are time-consuming and hence difficult to scale. Meanwhile, automated approaches lack the accuracy of examination by highly trained scientists and this may introduce major errors, sources of noise, and unforeseen biases into these large and complex datasets. Our proposed solution is to 1) start with a small, expertly labelled dataset, 2) amplify labels through web-based tools that engage citizen scientists, and 3) train machine learning on amplified labels to emulate expert decision making. As a proof of concept, we developed a system to quality control a large dataset of three-dimensional magnetic resonance images (MRI) of human brains. An initial dataset of 200 brain images labeled by experts were amplified by citizen scientists to label 722 brains, with over 80,000 ratings done through a simple web interface. A deep learning algorithm was then trained to predict data quality, based on a combination of the citizen scientist labels that accounts for differences in the quality of classification by different citizen scientists. In an ROC analysis (on left out test data), the deep learning network performed as well as a state-of-the-art, specialized algorithm (MRIQC) for quality control of T1-weighted images, each with an area under the curve of 0.99. Finally, as a specific practical application of the method, we explore how brain image quality relates to the replicability of a well established relationship between brain volume and age over development. Combining citizen science and deep learning can generalize and scale expert decision making; this is particularly important in emerging disciplines where specialized, automated tools do not already exist.
7 downloads biophysics
The shapes of epithelial tissues result from a complex interplay of contractile forces in the cytoskeleta of the cells in the tissue, and adhesion forces between them. A host of discrete, cell-based models describe these forces by assigning different surface tensions to the apical, basal, and lateral sides of the cells. These differential-tension models have been used to describe the deformations of epithelia in different living systems, but the underlying continuum mechanics at the scale of the epithelium are still unclear. Here, we derive a continuum theory for a simple differential-tension model of a two-dimensional epithelium and study the buckling of this epithelium under imposed compression. The analysis reveals how the cell-level properties encoded in the differential-tension model lead to linear, nonlinear as well as nonlocal elastic behavior at the continuum level.
7 downloads developmental biology
The skin constantly self-renews throughout adult life. Wnt/β-catenin signaling plays a key role in promoting keratinocyte proliferation in the hair follicles and in the interfollicular epidermis. A recent report demonstrated that epidermal YAP activity drives β-catenin activation to promote keratinocyte proliferation in the murine skin. However, it remains unclear whether this is caused by paracrine activation of canonical Wnt signaling or through other YAP/β-catenin regulatory interactions. In the present study, we found that XAV939-inhibition of canonical WNT signaling in skin of YAP2-5SA-ΔC mice resulted in diminished β-catenin activation, reduced keratinocyte proliferation, and a mitigation of the hyperplastic abnormalities in the interfollicular epidermis, signifying a canonical WNT ligand-dependent mechanism. Our subsequent analyses determined that WNT16 is produced in response to YAP activity in keratinocytes both in vitro and in vivo, and that WNT16 drives HaCaT keratinocyte proliferation via canonical WNT16/β-catenin signaling. We conclude that under normal physiological conditions WNT16 is the paracrine WNT ligand secreted in response to epidermal YAP activity that promotes cell proliferation in the interfollicular epidermis. This study delineates a fundamental YAP-driven mechanism that controls normal skin regeneration, and that may be perturbed in human regenerative disease displaying increased YAP and WNT signaling activity.
7 downloads neuroscience
Objective: Recently, we reported that stable-phase schizophrenia is characterized by two interrelated symptom dimensions: PHEMN (psychotic, hostility, excitation, mannerism and negative symptoms); and DAPS (depressive, anxiety and physio-somatic symptoms) and that Major Neuro-Cognitive psychosis (MNP) is the full blown phenotype of schizophrenia (largely overlapping with deficit schizophrenia). Herein we examined the effects of immune activation in association with tryptophan catabolite (TRYCAT) patterning and memory disorders on PHEMN/DAPS dimensions and MNP. Method: Serum levels of macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL-10, eotaxin, IgA/IgM responses to TRYCATs, and Consortium to Establish a Registry for Alzheimer's disease (CERAD) tests were assessed in 40 controls and 80 schizophrenia patients. Results: Schizophrenia and MNP were predicted by significantly increased levels of IL-10, eotaxin and TRYCATs. A large part of the variance in both PHEMN/DAPS symptom dimensions (42.8%) was explained by cytokine levels and TRYCATs combined. The MIP+sIL-1RA+IL-10 composite score and eotaxin explained each around 19% of the variance in symptom dimensions, and approximately 18% of memory deficits. Moreover, MIP+sIL-1RA+IL-10 was significantly associated with elevations in picolinic acid, xanthurenic acid and 3-OH-kynurenine. Partial Least Squares path modeling shows that the highly significant effects of MIP+sIL-1RA+IL-10 on symptomatology are mediated by the effects of noxious TRYCATs on memory deficits. Conclusions: Current findings indicate that in schizophrenia, immune activation may underpin activation of indoleamine-2,3-dioxygenase and kynurenine monooxygenase, while impairments in episodic and semantic memory may be caused by the neurotoxic effects of TRYCATs and eotaxin. The combined effects of immune activation, eotaxin and memory defects determine to a large extent PHEMN/DAPS symptoms and the MNP phenotype. These findings indicate that schizophrenia phenomenology is largely mediated by multiple neuro-immune pathways and that immune activation, increased production of eotaxin and neurotoxic TRYCATs (picolinic acid, xanthurenic acid and 3-HO-kynurenine) are new drug targets in schizophrenia and MNP.
7 downloads neuroscience
Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. US likely vibrates the cerebrospinal fluid in the brain, which is continuous with the fluid in the cochlea via cochlear aqueducts; thus, US can activate the ascending auditory pathways and other non-auditory regions through cross-modal projections. This finding of a cochlear fluid induced vibration mechanism challenges the idea that US can directly activate neurons in the intact brain,suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.
7 downloads bioinformatics
Motivation: The use of Normal Mode Analysis (NMA) methods to study both protein and nucleic acid dynamics is well established. However, the most widely used coarse-grained methods are based on backbone geometry alone and do not take into account the chemical nature of the residues. Elastic Network Contact Model (ENCoM) is a coarse-grained NMA method that includes a pairwise atom-type non-bonded interaction term, which makes it sensitive to the sequence of the studied molecule. We adapted ENCoM to simulate the dynamics of ribonucleic acid (RNA) molecules. Results: ENCoM outperforms the most commonly used coarse-grained model on RNA, Anisotropic Network Model (ANM), in the prediction of b-factors, in the prediction of conformational change as measured by overlap (a measure of effective prediction of structural transitions) and in the prediction of structural variance from NMR ensembles. These benchmarks were derived from the set of all RNA structures available from the Protein Data Bank (PDB) and contain more total cases than previous studies applying NMA to RNA. We thus established ENCoM as an attractive tool for fast and accurate exploration of the conformational space of RNA molecules.
7 downloads microbiology
Upon replication in mucosal epithelia and transmission to nerve endings, capsids of herpes simplex virus type I (HSV-1) travel retrograde within axons to peripheral ganglia where life-long latent infections are established. A capsid-bound tegument protein, pUL37, is an essential effector of retrograde axonal transport and also houses a deamidase activity that antagonizes innate immune signaling. In this report, we examined whether the deamidase of HSV-1 pUL37 contributes to the neuroinvasive retrograde axonal transport mechanism. We conclude that neuroinvasion is enhanced by the deamidase, but the critical contribution of pUL37 to retrograde axonal transport functions independently of this activity.
7 downloads ecology
Both individual variation in dispersal tendency and animal personalities have been shown to be widespread in nature. They are often associated in personality-dependent dispersal, and both have major but underappreciated consequences for ecological and evolutionary dynamics. In addition, personalities are not stable over time and changes can appear through ontogeny, leading to life stage-dependent behaviours. We investigated relationships between dispersal, life stage and boldness in an invertebrate with between- and within-life stages variation in dispersal tendency, the land snail Cornu aspersum. Latency to resume activity following a simulated attack was repeatable, indicating boldness is a personality trait in Cornu aspersum. Subadults were bolder and more dispersive than adults. Dispersers were bolder than non-dispersers, independently of boldness changes between life stages. We discuss how these results can be explained in relation with life history strategies in this hermaphrodite species, in particular risk management in the context of reproductive investment.
7 downloads ecology
Sessile invertebrate prey that detect waterborne predator cues often respond by strengthening their structural defenses. Experimental evidence of the functional significance of such modifications using field-raised organisms is lacking. This study addresses that gap using intertidal mussels and predatory dogwhelks from Atlantic Canada. During the spring and summer of 2016, we ran a field experiment that manipulated dogwhelk presence to test their nonconsumptive effects on mussel traits. Dogwhelk cues elicited thickening at the lip, centre, and base of mussel shells, although simultaneously limiting shell growth in length. As shell mass was unaffected by dogwhelk presence, a trade-off between shell thickening and elongation was revealed. Thickening was strongest at the thinnest parts of the shell. Using the field-raised organisms, a lab experiment found that dogwhelks took, on average, 55 % longer to drill and consume mussels previously exposed to dogwhelk cues than mussels grown without such a cue exposure. Dogwhelks drilled at the thinnest parts of the shell but, nonetheless, the consumed cue-exposed mussels had thicker shells at the borehole than the consumed mussels not exposed to cues, which likely explains the observed difference in handling time. As handling time normally decreases predation success, this study indicates that the plastic structural modifications in mussels triggered by dogwhelk cues in the field hinder predation by these drilling predators.
7 downloads neuroscience
Depression, anxiety, and stress are common in pregnant women. One of the primary pharmacological treatments for anxiety and depression is the antidepressant fluoxetine (Flx). Maternal stress, depression, and Flx exposure are known to effect neurodevelopment of the offspring, however, their combined effects have been scarcely studied, especially in female offspring. The present study investigated the combined effects of maternal stress during pregnancy and perinatal exposure to Flx on the behaviour of female mice as adults. METHODS: Mouse dams were exposed to either chronic unpredictable stress (embryonic (E) day 7 to E18), or FLX (E15- postnatal day 12), or a combination of stress and FLX or left untreated. At two months of age, the female offspring went through a comprehensive behavioural test battery. RESULTS: Maternal stress led to increased activity and alterations of prepulse inhibition in the adult female offspring. Maternal treatment with Flx had a potentially beneficial effect on spatial memory. The combination of prenatal stress and perinatal Flx exposure did not interact in their effects. These results suggest that gestational Flx exposure may have a limited negative impact on female offspring.
7 downloads cancer biology
Peiminine is a compound that is isolated from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae family), which has demonstrated antitumor activities. Its precise molecular mechanisms underlying antitumor activity remain elusive. In this study, peiminine-induced apoptosis towards human hepatocellular carcinoma and its molecular mechanisms were investigated. MTT assay was employed to assess anticancer effects of peiminine at concentrations of 2, 4, 6, 8, 10, 12, and 14 µg/ml after 24, 48, or 72 h. Nuclear staining and flow cytometry were carried out to further assess apoptosis. Mitochondrial membrane potential evaluation and Western blot analysis were performed to investigate the mechanism of peiminine-induced apoptosis. Peiminine reduced the viability of HepG2 cells in a time- and dose-dependent manner and had an IC50 of 4.58 μg/mL at 24h. Flow cytometry assessment indicated that peiminine markedly increased the cell number of apoptotic cells and the mitochondrial membrane potential dose-dependently in HepG2 cells.The results of Western blotting showed the expression of Bcl-2, procaspase-3, procaspase-8, procaspase-9, and PARP1 decreased in HepG2 cells treated with peiminine, while the expression of Bax, caspase-3, caspase-8, caspase-9, and cleaved PARP1 increased. The result suggest taht peiminine can induce apoptosis in human hepatocellular carcinoma HepG2 cells through both extrinsic and intrinsic apoptotic pathways .
7 downloads neuroscience
In the mouse olfactory system, spatially regulated expression of > 1,000 olfactory receptors (ORs) - a phenomenon termed "zones" - forms a topological map in the main olfactory epithelium (MOE). However, the zones of most ORs are currently unknown. By sequencing mRNA of 12 isolated MOE pieces, we mapped out zonal information for 1,033 OR genes with an estimated accuracy of 0.3 zones, covering 81% of all intact OR genes and 99.4% of total OR mRNA abundance. Zones tend to vary gradually along chromosomes. We further identified putative non-OR genes that may exhibit zonal expression.
7 downloads ecology
Spatial heterogeneity in parasite susceptibility and exposure is a common source of confounding variation in disease ecology studies. However, it is not known whether spatial autocorrelation acts on immunity in particular at small scales, within wild animal populations, and whether this predicts spatial patterns in infection. Here we used a well-mixed wild population of individually recognised red deer (Cervus elaphus) inhabiting a heterogeneous landscape to investigate fine-scale spatial patterns of immunity and parasitism. We noninvasively collected 842 faecal samples from 141 females with known ranging behaviour over two years. We quantified total and helminth-specific mucosal antibodies and counted propagules of three gastrointestinal helminth taxa. These data were analysed with linear mixed models using the Integrated Nested Laplace Approximation (INLA), using a Stochastic Partial Differentiation Equation approach (SPDE) to control for and quantify spatial autocorrelation. We also investigated whether spatial patterns of immunity and parasitism changed seasonally. We discovered substantial spatial heterogeneity in general and helminth-specific antibody levels and parasitism with two helminth taxa, all of which exhibited contrasting seasonal variation in their spatial patterns. Notably, strongyle nematode intensity did not align with density hotspots, while Fasciola hepatica intensity appeared to be strongly influenced by the presence of wet grazing. In addition, antibody hotspots did not correlate with distributions of any parasites. Our results suggest spatial heterogeneity may be an important factor affecting immunity and parasitism in a wide range of study systems. We discuss these findings with regards to the design of sampling regimes and public health interventions, and suggest that disease ecology studies investigate spatial heterogeneity more regularly to enhance their results, even when examining small geographic areas.
7 downloads epidemiology
This study sought to map and review validated health-based survey instruments in Brunei Darussalam. A scoping search of relevant articles was carried out. Six health-based survey tools have been psychometrically evaluated in Brunei Darussalam, 4 in Brunei-Malay (SF-36v2, EQ-5D/VAS, CPQ11-14, and m-SEQ-12) and 2 in English (OFER and WPBA) languages. Two studies (m-SEQ-12, CPQ11-14) translated tools in English into Brunei-Malay. Two studies (SF-36v2, EQ-5D) cross-culturally adapted the Malaysian and Singaporean versions of the tools into Brunei-Malay. Four studies were adult- and hospital-based, among healthcare workers (OFER, WPBA) and patients with chronic diseases (SF-36v2, EQ-5D); and 2 studies (m-SEQ-12, CPQ11-14) were non-adult- and secondary school-based. Pretesting was carried out in 4 studies (SF-36v2, EQ-5D, CPQ11-14, and m-SEQ-12) on a sample of 5 to 20 volunteers. The sample size for validation ranged from 40 to 457. Reliability tests, Cronbach's alpha and intra-class coefficient (n=3), Cohen's Kappa (n=1), and 5-point scale qualitative assessment (n=1) were measured. Validity tests included face validity (n=2), discriminant validity (n=2), convergent validity (n=2), construct validity (n=2), factorial validity (n=2), and 5-point scale qualitative assessment (n=1). There is a need for more psychometric evaluation of questionnaires in Brunei Darussalam. Importantly, large heterogeneous participants, more languages, and varied psychometric tests should be considered.
7 downloads genetics
Development of the anterior segment of the vertebrate eye is a highly coordinated process. Genetic mutations in factors guiding this process result in Anterior Segment Dysgenesis (ASD), a spectrum of disorders affecting the iris, cornea, trabecular meshwork and/or other iridocorneal angle structures and associated with glaucoma. One of the first factors linked to ASD in humans was PITX2, a homeodomain containing transcription factor with a role in Axenfeld-Rieger syndrome (ARS). In addition to pathogenic alleles within the coding region of PITX2, deletions affecting the distant upstream region, but not PITX2 itself, have also been reported in ARS. Consistent with this, the distant upstream region was shown to contain multiple conserved elements (CE) with pitx2-related enhancer activity identified through studies in zebrafish. The two smallest human deletions reported to date encompass conserved elements 5-11 (ΔCE5-11) or 5-7 (ΔCE5-7). We previously reported the generation of ΔCE5-11 in zebrafish and we have now replicated the smallest deletion, ΔCE5-7, in the same model and studied the associated phenotype, expression, and DNA methylation profiles; we also performed further phenotypic examinations of the pitx2ΔCE5-11 fish. We show that the expression changes and phenotypes observed in the two lines are variable but that the severity generally correlates with the size of the deletion and the number of affected CEs; pitx2 promoter and a nearby region were hypermethylated in the pitx2ΔCE5-7 embryonic eyes. In addition, a subset of pitx2ΔCE5-11 animals were found to have a severe retinal phenotype suggesting that additional factors may modify the effects of this allele. These data provide further insight into functional sequences in the PITX2/pitx2 genomic region that coordinate PITX2/pitx2 expression during eye development and provide the basis for future studies into PITX2/pitx2 upstream regulators and modifiers.
7 downloads cancer biology
While the class I of PI3Ks has been deeply studied due to its clear implication in cancer development, little is known about the class II of PI3Ks. However, recent accumulation of data is now revealing that PI3KC2β, one isoform of this class of PI3Ks, may also play a role in cancer. Specifically, recent studies have suggested an implication of PI3KC2β in metastasis formation through the promotion of epithelial to mesenchymal transition (EMT). Here, we report that the overexpression of PI3KC2β in the epidermal squamous cell carcinoma (ESCC) cells A431 promotes apparent EMT transformation. We further confirm this EMT by showing modification in several biochemical markers (E-cadherin, β-catenin, Snail, Twist1 and Vimentin). Furthermore, an intracellular co-localization of E-cadherin, β-catenin and EGFR was observed. This transformation decreased EGFR signaling and the sensitivity to inhibitors targeting this receptor. To confirm our results, we have used the colon adenocarcinoma cells HT29 and induced overexpression of PI3KC2β in these cells. We could recapitulate in this model some of our major findings regarding EMT in the PI3KC2β overexpressing A431 cells. Taken together, these data support a role of PI3KC2β in promoting EMT.
7 downloads microbiology
Hopanoids are steroid-like bacterial lipids that enhance membrane rigidity and promote bacterial growth under diverse stresses. Hopanoid biosynthesis genes are conserved in nitrogen-fixing plant symbionts, and we previously found that the extended (C35) class of hopanoids in Bradyrhizobium diazoefficiens are required for efficient symbiotic nitrogen fixation in the tropical legume host Aeschynomene afraspera. Here we demonstrate that the nitrogen fixation defect conferred by extended loss can fully be explained by a reduction in root nodule sizes rather than per-bacteroid nitrogen fixation levels. Using a single nodule tracking approach to track A. afraspera nodule development, we provide a quantitative model of root nodule development in this host, uncovering both the baseline growth parameters for wild-type nodules and a surprising heterogeneity of extended hopanoid mutant developmental phenotypes. These phenotypes include a delay in root nodule initiation and presence of a subpopulation of nodules with slow growth rates and low final volumes, which are correlated with reduced motility and surface attachment in vitro and lower bacteroid densities in planta, respectively. This work provides a quantitative reference point for understanding the phenotypic diversity of ineffective symbionts in A. afraspera and identifies specific developmental stages affected by extended hopanoid loss for future mechanistic work.
7 downloads neuroscience
State-of-the-art techniques allow researchers to record large numbers of spike trains parallel for many hours. With enough such data, we should be able to infer the connectivity among neurons. Here we develop a computationally realizable method for reconstructing neuronal circuitry by applying a generalized linear model (GLM) to spike cross-correlations. Our method estimates interneuronal connections in units of postsynaptic potentials and the amount of spike recording needed for verifying connections. The performance of inference is optimized by counting the estimation errors using synthetic data from a network of Hodgkin-Huxley type neurons. By applying our method to rat hippocampal data, we show that the numbers and types of connections estimated from our calculations match the results inferred from other physiological cues. Our method provides the means to build a circuit diagram from recorded spike trains, thereby providing a basis for elucidating the differences in information processing in different brain regions.
7 downloads bioinformatics
Experimental structure probing data has been shown to improve thermodynamics-based RNA secondary structure prediction. To this end, chemical reactivity information (as provided by SHAPE) is incorporated, which encodes whether or not individual nucleotides are involved in intra-molecular structure. Since inter-molecular RNA-RNA interactions are often confined to unpaired RNA regions, SHAPE data is even more promising to improve interaction prediction. Here we show how such experimental data can be incorporated seamlessly into accessibility-based RNA-RNA interaction prediction approaches, as implemented in IntaRNA. This is possible via the computation and use of unpaired probabilities that incorporate the structure probing information. We show that experimental SHAPE data can significantly improve RNA-RNA interaction prediction. We evaluate our approach by investigating interactions of the spliceosomal U1 snRNA with its target splice sites. When SHAPE data is incorporated, known target sites are predicted with increased precision and specificity. Availability: https://github.com/BackofenLab/IntaRNA
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