Most downloaded biology preprints, since beginning of last month
133,761 results found. For more information, click each entry to expand.
1 download bioRxiv neuroscience
Olaia Lucas-Jiménez, Ibai Diez, Natalia Ojeda, Naroa Ibarretxe-Bilbao, Javier Peña, Beatriz Tijero, Marta Galdós, Ane Murueta-Goyena, Rocío Del Pino, Marian Acera, Juan Carlos Gómez-Esteban, Iñigo Gabilondo
Introduction The use of non-motor Parkinson's disease (PD) features and genetic PD variants for clustering analyses may refine the phenotypic classification of idiopathic Lewy body (LB) diseases. Methods One-hundred participants [n=7 E46K-SNCA (n=5 symptomatic and n=2 asymptomatic), n=4 PARK2, n=3 LRRK2, n=8 dementia with Lewy bodies (DLB), n=48 idiopathic PD (iPD), n=30 healthy controls (HC)] underwent a comprehensive evaluation of non-motor and motor PD features. Non-motor features were used to perform a hierarchical clustering analysis with patients and HC using a Scikit-learn toolkit. Results Clustering analysis suggested three clusters of subjects including Cluster 1 or “Normal-to-mild”: young iPD (< 60 years) classified together with most HC and the variable LB burden genetic PD variants (PARK2 and LRRK2) characterized by having normal-to-mild cognitive disabilities and mild-to-moderate motor disability with few axial symptoms; Cluster 2 or “Mild-to-moderate”: old iPD patients (>60 years) classified together with the lowest symptomatic E46K-SNCA, PARK2 carriers and HCs, characterizing by having mild-to-moderate cognitive and motor disabilities with few axial symptoms; and Cluster 3 or “Severe”: old iPD (>60 years) classified together with all DLB and the most symptomatic E46K-SNCA carriers, characterized by having severe pattern-specific cognitive disabilities (visual attention, perception, processing speed, memory and executive functions) and severe motor PD manifestations with marked axial symptoms. Conclusions Our study supports the potential value of incorporating genetic PD variants in data-driven iPD classification algorithms and the usefulness of non-motor PD features, especially visual cognition abnormalities, to facilitate the identification of aggressive LB diseases.
1 download bioRxiv molecular biology
There exist many phenotypically-varied prion strains, like viruses, despite the absence of conventional genetic material which codes the phenotypic information. As prion is composed solely of the pathological isoform (PrPSc) of prion protein (PrP), the strain-specific traits are hypothesized to be enciphered in the structural details of PrPSc. Identification of the structures of PrPSc is therefore vital for the understanding of prion biology, though they remain unidentified due to the incompatibility of PrPSc with conventional high-resolution structural analyses. Based on our previous hypothesis that the region between the first and the second α-helix (H1~H2) and the distal region of the third helix (Ctrm) of the cellular isoform of PrP (PrPC) have important roles for efficient interactions with PrPSc, we created series of mutant PrPs with two cysteine substitutions (C;C-PrP) which were systematically designed to form an intramolecular disulfide crosslink between H1~H2 and Ctrm and assessed their conformational changes by prions: Specifically, a cysteine substitution in H1~H2 from 165 to 169 was combined with cysteine-scanning along Ctrm from 220 to 229. C;C-PrPs with the crosslinks were expressed normally with the similar glycosylation patterns and subcellular localization as the wild-type PrP albeit with varied expression levels. Interestingly, some of the C;C-PrPs converted to the protease-resistant isoforms in the N2a cells persistently infected with 22L prion strain, whereas the same mutants did not convert in the cells infected with another prion strain Fukuoka1, indicating that local structures of PrPSc in these regions vary among prion strains and contribute to prion-strain diversity. Moreover, patterns of the crosslinks of the convertible C;C-PrPs implied drastic changes in positional relations of H1~H2 and Ctrm in the PrPSc-induced conformational changes by 22L prion. Thus, disulfide-crosslink scanning is a useful approach for investigation of strain-specific structures of PrPSc, and would be applicable to other types of amyloids as well.
1 download bioRxiv neuroscience
Divisive normalization has long been used to account for computations in various neural processes and behaviours. The model proposes that inputs into a neural system are divisively normalized by the total activity of the system. More recently, dynamical versions of divisive normalization have been shown to account for how neural activity evolves over time in value-based decision making. Despite its ubiquity, divisive normalization has not been studied in decisions that require evidence to be integrated over time. Such decisions are important when we do not have all the information available at once. A key feature of such decisions is how evidence is weighted over time, known as the integration 'kernel'. Here we provide a formal expression for the integration kernel in divisive normalization, and show that divisive normalization can quantitatively account for the perceptual decision making behaviour of 133 human participants, performing as well as the state-of-the-art Drift Diffusion Model, the predominant model for perceptual evidence accumulation.
1 download bioRxiv neuroscience
How deliberation on sensory cues and action selection interact in decision-related brain areas is still not well understood. Here, monkeys reached to one of two targets, whose colors alternated randomly between trials, by discriminating the dominant color of a checkerboard cue composed of different numbers of squares of the two target colors in different trials. In a "Targets First" task the colored targets appeared first, followed by the checkerboard; in a "Checkerboard First" task, this order was reversed. After both cues appeared in both tasks, responses of dorsal premotor cortex (PMd) neurons covaried with action choices, strength of evidence for action choices, and RTs--- hallmarks of decision-related activity. However, very few neurons were modulated by checkerboard color composition or the color of the chosen target, even in the Checkerboard First task. These findings implicate PMd in the action-selection but not the perceptual components of the decision-making process in these tasks.
1 download bioRxiv microbiology
Lipid homeostasis is essential for the maintenance of life. We previously reported that disruptions of the parasite Na+ homeostasis via inhibition of PfATP4 resulted in elevated cholesterol within the parasite plasma membrane as assessed by saponin sensitivity. A large number of compounds have been shown to target the parasite Na+ homeostasis. We therefore screened the same collection of 800 compounds to identify chemotypes that disrupted the parasite plasma membrane lipid homeostasis. Here, we show that the compounds disrupting parasite Na+ homeostasis also induced saponin sensitivity, an indication of parasite lipid homeostasis disruption. Remarkably, 13 compounds were identified that altered plasma membrane lipid composition independent of Na+ homeostasis disruption. Further studies suggest that these compounds target the Plasmodium falciparum Niemann-Pick Type C1-Related (PfNCR1) protein, which is hypothesized to be involved in maintaining plasma membrane lipid composition. PfNCR1, like PfATP4, appears to be targeted by multiple chemotypes with potential for drug discovery.
1 download bioRxiv genomics
Advancing our ability to predict who is likely to develop depression in response to stress holds great potential in reducing the burden of the disorder. Large-scale genome-wide association studies (GWAS) of depression have, for the first time, provided a basis for meaningful depression polygenic risk score construction (MDD-PRS). The Intern Health Study utilizes the predictable and large increase in depression with physician training stress to identify predictors of depression. Applying the MDD-PRS derived from the PGC2/23andMe GWAS to 5,227 training physicians, we found that MDD-PRS predicted depression under training stress (beta=0.082, p=2.1x10-12) and that MDD-PRS was significantly more strongly associated with depression under stress than at baseline (MDD-PRS x stress interaction - beta=0.029, p=0.02). While known risk factors accounted for 85.6% of the association between MDD-PRS and depression at baseline, they only accounted for 55.4% of the association between MDD-PRS and depression under stress, suggesting that MDD-PRS can add unique predictive power to existing models of depression under stress. Further, we found that low MDD-PRS may have particular utility in identifying individuals with high resilience. Together, these findings suggest that polygenic risk score holds promise in furthering our ability to predict vulnerability and resilience under stress.
1 download bioRxiv plant biology
The circadian clock in all eukaryotes relies on the regulated degradation of clock proteins to maintain 24-hour rhythmicity. Despite this knowledge, we know very few of the components that mediate degradation of proteins to control clock function. This is likely due to high levels of gene duplication and functional redundancy within plant E3 ubiquitin ligase gene families. In order to overcome this issue and discover E3 ubiquitin ligases that control circadian clock function, we generated a library of transgenic Arabidopsis lines expressing dominant-negative "decoy" E3 ubiquitin ligases. We determined their effects on the plant circadian clock and identified dozens of new potential regulators of circadian clock function. To demonstrate the potency of the decoy screening methodology to overcome genetic redundancy and identify bona fide clock regulators, we performed follow-up studies on PUB59 and PUB60. Using knock-out studies, we show that they redundantly control circadian clock period by regulating gene splicing. Furthermore, we confirm that they are part of a conserved protein complex that mediates splicing in eukaryotes. This work demonstrates the viability of E3 ubiquitin ligase decoys as a scalable screening platform to overcome traditional genetic challenges and discover E3 ubiquitin ligases that regulate plant developmental processes.
1 download bioRxiv physiology
Context: Obesity is known to impact reproductive function in adults, but little is known about its effects on reproductive hormones during puberty or sex differences in these effects. Objective: To assess sex differences in effects of obesity on reproductive hormones and their relationship to insulin sensitivity and secretion. Design: Cross-sectional study including anthropometrics, serum and urine reproductive hormone concentrations, and intravenous glucose tolerance testing (IVGTT) to assess acute insulin response to glucose (AIRg) and insulin sensitivity (Si). Setting: Outpatient academic clinical research center. Patients: Fifty-one normal weight (NW, BMI-Z=-0.11 +/- 0.77, age=11.5 +/- 1.7 years) and 53 obese (BMI-Z=2.22 +/- 0.33, age=10.9 +/- 1.5 years) girls (n=54) and boys (n=50), Tanner stage 2-3. Results: Obese boys had lower total testosterone (p<0.0001) and higher concentrations of the urinary estradiol metabolite, E1c, (p=0.046) than NW boys. Obese girls had higher free androgen index (FAI, p=0.03) than NW girls. Both obese boys and girls had lower sex hormone-binding globulin (SHBG, p<0.0001) than NW. AIRg was inversely related to SHBG in boys (R2= 0.36, p<0.0001) and girls (R2=0.29, p=0.0001). Insulin resistance correlated with lower SHBG in boys (R2=0.45, p<0.0001) and girls (R2=0.24, p=0.0003), lower total testosterone for boys (R2=0.15, p=0.01), and higher FAI for girls (R2=0.08, p=0.04). Conclusion: Obese youth have lower SHBG than NW youth, but obesity has differential effects on reproductive hormones in girls vs. boys, which are apparent early in puberty. Ongoing longitudinal studies will evaluate the impact of obesity on reproductive hormones in girls and boys as puberty progresses.
1 download bioRxiv neuroscience
Synaptic inputs to neurons are distributed across extensive neurite arborizations. To what extent arbors process inputs locally or integrate them globally is, for most neurons, unknown. This question is particularly relevant for amacrine cells, a diverse class of retinal interneurons, which receive input and provide output through the same neurites. Here, we used two-photon Ca2+ imaging to analyze visual processing in VGluT3-expressing amacrine cells (VG3-ACs), an important component of object motion sensitive circuits in the retina. VG3-AC neurites differed in their preferred stimulus contrast (ON vs. OFF); and ON and OFF responses varied in transience and preferred stimulus size. Contrast preference changed predictably with the laminar position of neurites in the inner plexiform layer. Yet, neurites at all depths were strongly activated by local but not by global image motion. Thus, VG3-AC neurites process visual information locally, exhibiting diverse responses to contrast steps, but uniform object motion selectivity.
1 download bioRxiv bioinformatics
The probability of single base modifications (mutations and DNA/RNA modifications) is expected to be highly influenced by the flanking nucleotides that surround them, known as the sequence context. This phenomenon may be mainly attributed to the enzyme that modifies or mutates the genetic material, since most enzymes tend to have specific sequence contexts that dictate their activity. Thus, identification of context effects may lead to the discovery of additional editing sites or unknown enzymatic factors. Here, we develop a statistical model that allows for the detection and evaluation of the effects of different sequence contexts on mutation rates from deep population sequencing data. This task is computationally challenging, as the complexity of the model increases exponentially as the context size increases. We established our novel Bayesian method based on sparse model selection methods, with the leading assumption that the number of actual sequence contexts that directly influence mutation rates is minuscule compared to the number of possible sequence contexts. We show that our method is highly accurate on simulated data using pentanucleotide contexts, even when accounting for noisy data. We next analyze empirical population sequencing data from polioviruses and detect a significant enrichment in sequence contexts associated with deamination by the cellular deaminases ADAR 1/2. In the current era, where next generation sequencing data is highly abundant, our approach can be used on any population sequencing data to reveal context-dependent base alterations, and may assist in the discovery of novel mutable sites or editing sites.
1 download bioRxiv bioinformatics
Motivation: Phosphoproteomic experiments are increasingly used to study the changes in signalling occurring across different conditions. It has been proposed that changes in phosphorylation of kinase target sites can be used to infer when a kinase activity is under regulation. However, these approaches have not yet been benchmarked due to a lack of appropriate benchmarking strategies. Results: We curated public phosphoproteomic experiments to identify a gold standard dataset containing a total of 184 kinase-condition pairs where regulation is expected to occur. A list of kinase substrates was compiled and used to estimate changes in kinase activities using the following methods: Z-test, Kolmogorov Smirnov test, Wilcoxon rank sum test, gene set enrichment analysis (GSEA), and a multiple linear regression model (MLR). We also tested weighted variants of the Z-test, and GSEA that include information on kinase sequence specificity as proxy for affinity. Finally, we tested how the number of known substrates and the type of evidence (in vivo, in vitro or in silico) supporting these influence the predictions. Conclusions: Most models performed well with the Z-test and the GSEA performing best as determined by the area under the ROC curve (Mean AUC=0.722). Weighting kinase targets by the kinase target sequence preference improves the results only marginally. However, the number of known substrates and the evidence supporting the interactions has a strong effect on the predictions.
1 download bioRxiv neuroscience
Reliable propagation of firing rate, specifically slow modulation of asynchronous spikes in fairly short time windows [20-500]ms across multiple layers of a feedforward network (FFN) receiving background synaptic noise has proven difficult to capture in spiking models. We, in this paper, explore how information of asynchronous spikes disrupted in the first layer of a typical FFN, and which factors can enable reliable information representation. Our rationale is that the reliable propagation of information across layers of a FFN is likely if that information can be preserved in the first layer of the FFN. In a typical FFN, each layer comprises a certain number (network size) of excitatory neurons, leaky integrate and fire (LIF) model neuron in this paper, receiving correlated input (common stimulus from the upstream layer) plus independent background synaptic noise. We develop a reduced network model of FFN which captures main features of a conventional all to all connected FFN. Exploiting the reduced network model, synaptic weights are calculated using a closed form optimization framework that minimizes the mean squared error between reconstructed stimulus (by spikes of the first layer of FFN) and the original common stimulus. We further explore how representation of asynchronous spikes in a FFN changes with respect to other factors like the network size and the level of background synaptic noise while synaptic weights are optimized for each scenario. We show that not only synaptic weights but also the network size and the level of background synaptic noise are crucial to preserve a reliable representation of asynchronous spikes in the first layer of a FFN. This work sheds light in better understanding of how information of slowly time varying fluctuations of the firing rate can be transmitted in multi-layered FFNs.
1 download bioRxiv biochemistry
Suppressor of copper sensitivity protein C from Proteus mirabilis (PmScsC) is a homotrimeric disulfide isomerase that plays a role in copper tolerance - a key virulence trait of the uropathogen. Each protomer of the enzyme has an N-terminal trimerisation stem (59 residues) containing a flexible linker (11 residues) connected to a thioredoxin-fold-containing catalytic domain (163 residues). Here, we characterise two PmScsC variants, PmScsCΔN and PmScsCΔLinker. PmScsCΔN, is an N-terminally truncated form of the protomer with two helices of the trimerisation stem removed, generating a protein with dithiol oxidase rather than disulfide isomerase activity. The crystal structure of PmScsCΔN reported here reveals - as expected - a monomer that is structurally similar to the catalytic domain of native PmScsC. The second variant PmScsCΔLinker was designed to remove the 11 amino acid linker and we show that it generates a protein that has neither disulfide isomerase nor dithiol oxidase activity. The crystal structure of PmScsCΔLinker reveals a trimeric arrangement, with the catalytic domains packed together very closely. Small angle X-ray scattering analysis found that native PmScsC is predominantly trimeric in solution even at low concentration, whereas PmScsCΔLinker exists as an equilibrium between monomeric, dimeric and trimeric states, with the monomeric form dominating at low concentrations. These findings increase our understanding of disulfide isomerase activity, showing how (i) oligomerisation, (ii) spacing between, and (iii) dynamic motion of, catalytic domains in PmScsC all contribute to its native function.
1 download bioRxiv molecular biology
Rhea R. Datta, Jia Ling, Jesse Kurland, Xiaotong Ren, Zhe Xu, Gozde Yucel, Jackie Moore, Leila Shokri, Isabel Baker, Timothy Bishop, Paolo Struffi, Rimma Levina, Martha L. Bulyk, Robert J. Johnston, Stephen Small
The K50 homeodomain (K50HD) protein Orthodenticle (Otd) is critical for anterior embryo patterning in most metazoans. Another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in Drosophila. Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated in embryo patterning is unknown. Here we define three classes of enhancers that respond differentially to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are bound by both proteins, activated by Bcd, and maintained by Otd via a feed-forward relay (FFR). Enhancers in class 2 and class 3 are bound uniquely by Bcd or Otd, respectively. Different enhancer responses are controlled by suboptimal DNA motifs preferred by Bcd or Otd, and the presence or absence of cofactor binding sites. Our results define specific patterning roles for Bcd and Otd, and provide a timing mechanism for coordinating gene expression patterns during embryonic development.
1 download bioRxiv biochemistry
Lipid antigens are presented on the surface of cells by the CD1 family of glycoproteins, which have structural and functional similarity to MHC class I molecules. The hydrophobic lipid antigens are embedded in membranes and inaccessible to the lumenal lipid-binding domain of CD1 molecules. Therefore, CD1 molecules require lipid transfer proteins for lipid loading and editing. CD1d is loaded with lipids in late endocytic compartments, and lipid transfer proteins of the saposin family have been shown to play a crucial role in this process. However, the mechanism by which saposins facilitate lipid binding to CD1 molecules is not known and is thought to involve transient interactions between protein components to ensure CD1-lipid complexes can be efficiently trafficked to the plasma membrane for antigen presentation. Of the four saposin proteins, the importance of Saposin B (SapB) for loading of CD1d is the most well-characterised. However, a direct interaction between CD1d and SapB has yet to be described. In order to determine how SapB might load lipids onto CD1d, we used purified, recombinant CD1d and SapB and carried out a series of highly sensitive binding assays to monitor direct interactions. Using equilibrium binding analysis, chemical cross-linking and co-crystallisation experiments, under a range of different conditions, we could not demonstrate a direct interaction. This work establishes comprehensively that the role of SapB in lipid loading does not involve direct binding to CD1d. We discuss the implication of this for our understanding of lipid loading of CD1d and propose several factors that may influence this process.
1 download bioRxiv neuroscience
Large-scale structural brain networks encode white-matter connectivity patterns among distributed brain areas. These connection patterns are believed to support cognitive processes and, when compromised, can lead to neurocognitive deficits and maladaptive behavior. A powerful approach for studying the organizing principles of brain networks is to construct group-representative networks from multi-subject cohorts. Doing so amplifies signal to noise ratios and provides a clearer picture of brain network organization. Here, we show that current approaches for generating group-representative networks over-estimate the proportion of short-range connections present in a network and, as a result, fail to match subject-level networks along a wide range of network statistics. We present an alternative approach that preserves the connection-length distribution of individual subjects. Due to this simple modification, the networks generated using this novel approach successfully recapitulate subject-level properties, outperforming all existing approaches by better preserving features that promote integrative brain function rather than segregative. The method developed here holds promise for future studies investigating basic organizational principles and features of large-scale structural brain networks.
1 download bioRxiv immunology
Background Diabetes autoantibodies are indispensable markers of diabetes classification. Objective to research autoantibodies anti-GAD and anti-IA2 in type 1A diabetics (T1D) aged 5 to 21 years, and to follow the progression of these autoantibodies in T1D patients, in Côte d'Ivoire. Methods The study population composed of 28 T1D patients, aged 5 to 21 years. T1D were followed up in two diabetes care centers in Abidjan district, Endocrinology departments of U.H.C of Yopougon and Treichville. Anti-GAD and anti-IA2 autoantibodies were researched by ELISA. Results anti-GAD and anti-IA2 were present in T1D and their siblings. After 2 years of diabetes, the titer of the anti-GAD autoantibodies increased to the mean value of 677.10 ± 353.20 IU / ml. Then, a fall of the anti-GAD autoantibodies until the cancellation was observed from the 8th to the 9th with values of 117 IU / ml to 10.14 IU / ml. Anti-IA2 autoantibodies fall at 9th year of diabetes with a value of 55.10 IU / ml. Conclusion anti-GAD and anti-IA2 autoantibodies persist after 9 years of diabetes, causing total destruction over time of the pancreatic β-cell mass in patients from Côte d'Ivoire, leading them to the death.
1 download bioRxiv ecology
The dynamics and stability of ecological communities are intimately linked with the specific interactions - like cooperation or predation - between constituent species. In microbial communities, like those found in soils or the mammalian gut, physical anisotropies produced by fluid flow and chemical gradients impact community structure and ecological dynamics, even in structurally isotropic environments. Though natural communities existing in physically unstructured environments is rare, the role of environmental structure in determining community dynamics and stability remains poorly studied. To address this gap, we used modified Lotka-Volterra simulations of competitive microbial communities to characterize the effects of surface structure on community dynamics. We find that environmental structure has profound effects on communities, in a manner dependent on the specific pattern of interactions between community members. For two mutually competing species, eventual extinction of one competitor is effectively guaranteed in isotropic environments. However, addition of environmental structure enables long-term coexistence of both species via local 'pinning' of competition interfaces, even when one species has a significant competitive advantage. In contrast, while three species competing in an intransitive loop (as in a game of rock-paper-scissors) coexist stably in isotropic environments, structural anisotropy disrupts the spatial patterns on which coexistence depends, causing chaotic population fluctuations and subsequent extinction cascades. These results indicate that the stability of microbial communities strongly depends on the structural environment in which they reside. Therefore, a more complete ecological understanding, including effective manipulation and interventions in natural communities of interest, must account for the physical structure of the environment.
1 download bioRxiv neuroscience
Visual calibration of auditory space requires re-alignment of representations differing in 1) format (auditory hemispheric channels vs. visual maps) and 2) reference frames (head-centered vs. eye-centered). Here, a ventriloquism paradigm from Kopčo et al. (J Neurosci, 29, 13809-13814) was used to examine these processes in humans and monkeys for ventriloquism induced within one spatial hemifield. Results show that 1) the auditory representation is adapted even by aligned audio-visual stimuli, and 2) the spatial reference frame is primarily head-centered in humans but mixed in monkeys. These results support the view that the ventriloquism aftereffect is driven by multiple spatially non-uniform processes.
1 download bioRxiv biophysics
The heat shock protein 70 (Hsp70) chaperones, vital to the proper folding of proteins inside cells, consume ATP and require cochaperones in assisting protein folding. It is unclear whether Hsp70 can utilize the free energy from ATP hydrolysis to fold a protein into a native state that is thermodynamically unstable in the chaperone-free equilibrium. Here we present a model of Hsp70-mediated protein folding, which predicts that Hsp70, as a result of differential stimulation of ATP hydrolysis by its Hsp40 cochaperone, dissociates faster from a substrate in fold-competent conformations than from one in misfolding-prone conformations, thus elevating the native concentration above and suppressing the misfolded concentration below their respective equilibrium values. Previous models would not make or imply these predictions, which are experimentally testable. Our model quantitatively reproduces experimental refolding kinetics, predicts how modulations of the Hsp70/Hsp40 chaperone system affect protein folding, and suggests new approaches to regulating cellular protein quality.
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