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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 84,956 bioRxiv papers from 365,408 authors.

Most downloaded bioRxiv papers, since beginning of last month

82,887 results found. For more information, click each entry to expand.

81341: Neural markers of category-based selective working memory in aging
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Posted to bioRxiv 05 Oct 2018

Neural markers of category-based selective working memory in aging
3 downloads neuroscience

Robert M. Mok, M. Clare O’Donoguhue, Nicholas E. Myers, Erin H.S. Drazich, Anna C. Nobre

Working memory (WM) is essential for normal cognitive function, but shows marked decline in aging. Studies have shown that the ability to attend selectively to relevant information amongst competing distractors is related to WM capacity. The extent to which WM deficits in aging are related to impairments in selective attention is unclear. To investigate the neural mechanisms supporting selective attention in WM in aging, we tested a large group of older adults using functional magnetic resonance imaging whilst they performed a category-based (faces/houses) selective-WM task. Older adults were able to use attention to encode targets and suppress distractors to reach high levels of task performance. A subsequent, surprise recognition-memory task showed strong consequences of selective attention. Attended items in the relevant category were recognised significantly better than items in the ignored category. Neural measures also showed reliable markers of selective attention during WM. Purported control regions including the dorsolateral and inferior prefrontal and anterior cingulate cortex were reliably recruited for attention to both categories. Activation levels in category-sensitive visual cortex showed reliable modulation according to attentional demands, and positively correlated with subsequent memory measures of attention and WM span. Psychophysiological interaction analyses showed that activity in category-sensitive areas were coupled with non-sensory cortex known to be involved in cognitive control and memory processing, including regions in the PFC and hippocampus. In summary, we found that brain mechanisms of attention for selective WM are relatively preserved in aging, and individual differences in these abilities corresponded to the degree of attention-related modulation in the brain.

81342: Slowly-conducting pyramidal tract neurons in macaque and rat
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Posted to bioRxiv 16 Sep 2019

Slowly-conducting pyramidal tract neurons in macaque and rat
3 downloads physiology

A. Kraskov, D Soteropoulos, I Glover, R.N. Lemon, SN Baker

Anatomical studies report a large proportion of fine myelinated fibres in the primate pyramidal tract (PT), while very few pyramidal tract neurons (PTNs) with slow conduction velocities (CV) (< ~10 m/s) are reported electrophysiologically. This discrepancy might reflect recording bias towards fast PTNs or prevention of antidromic invasion by recurrent inhibition of slow PTNs from faster axons. We investigated these factors in recordings made with a polyprobe (32 closely-spaced contacts) from motor cortex of anaesthetised rats (n=2) and macaques (n=3), concentrating our search on PTNs with long antidromic latencies. We identified 21 rat PTNs with antidromic latencies > 2.6 ms and estimated CV 3-8 m/s, and 67 macaque PTNs (> 3.9ms, CV 6-12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that recurrent inhibition prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs.

81343: An Algorithm for Cellular Reprogramming
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Posted to bioRxiv 13 Jul 2017

An Algorithm for Cellular Reprogramming
3 downloads bioinformatics

Scott Ronquist, Geoff Patterson, Markus Brown, Stephen M Lindsly, Haiming Chen, Lindsey A. Muir, Max Wicha, Anthony Bloch, Roger Brockett, Indika Rajapakse

The day we understand the time evolution of subcellular elements at a level of detail comparable to physical systems governed by Newton's laws of motion seems far away. Even so, quantitative approaches to cellular dynamics add to our understanding of cell biology, providing data-guided frameworks that allow us to develop better predictions about, and methods for, control over specific biological processes and system-wide cell behavior. In this paper, we describe an approach to optimizing the use of transcription factors (TFs) in the context of cellular reprogramming. We construct an approximate model for the natural evolution of a cell cycle synchronized population of human fibroblasts, based on data obtained by sampling the expression of 22,083 genes at several time points along the cell cycle. In order to arrive at a model of moderate complexity, we cluster gene expression based on the division of the genome into topologically associating domains (TADs) and then model the dynamics of the TAD expression levels. Based on this dynamical model and known bioinformatics, such as transcription factor binding sites (TFBS) and functions, we develop a methodology for identifying the top transcription factor candidates for a specific cellular reprogramming task. The approach used is based on a device commonly used in optimal control. Our data-guided methodology identifies a number of transcription factors previously validated for reprogramming and/or natural differentiation. Our findings highlight the immense potential of dynamical models, mathematics, and data-guided methodologies for improving strategies for control over biological processes.

81344: Feasibility of real-time in vivo 89Zr-DFO-labeled CAR T-cell trafficking using PET imaging
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Posted to bioRxiv 01 Oct 2019

Feasibility of real-time in vivo 89Zr-DFO-labeled CAR T-cell trafficking using PET imaging
3 downloads cancer biology

Suk Hyun Lee, Hyunsu Soh, Jin Hwa Chung, Eun Hyae Cho, Sang Joo Lee, Ji-Min Ju, Joong Hyuk Shin, Hyori Kim, Seung Jun Oh, Sang-Jin Lee, Junho Chung, Seog-Young Kim, Jin-Sook Ryu

Introduction: Chimeric antigen receptor (CAR) T-cells have been developed recently, producing impressive outcomes in patients with hematologic malignancies. However, there is no standardized method for cell trafficking and in vivo CAR T-cell monitoring. We assessed the feasibility of real-time in vivo 89 Zr-p-Isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS, DFO) labeled CAR T-cell trafficking using positron emission tomography (PET). Results: The 89 Zr-DFO radiolabeling efficiency of Jurkat/CAR and human peripheral blood mononuclear cells (hPBMC)/CAR T-cells was 70–79%, and cell radiolabeling activity was 98.1–103.6 kBq/10 6 cells. Cell viability after radiolabeling was >95%. Compared with unlabeled cells, cell proliferation was not significantly different during the early period after injection; however, the proliferative capacity decreased over time ( p = 0.02, day 7 after labeling). IL-2 or IFN-g secretion was not significantly different between unlabeled and labeled CAR T-cells. PET/magnetic resonance images in the xenograft model showed that most of the 89 Zr-DFO-labeled Jurkat/CAR T-cells were distributed in the lung (24.4% ± 3.4%ID) and liver (22.9% ± 5.6%ID) by 1 hour after injection. The cells gradually migrated from lung to the liver and spleen by day 1, and remained stably until day 7 (on day 7: lung 3.9%  ± 0.3%ID, liver 36.4% ± 2.7%ID, spleen 1.4% ± 0.3%ID). No significant accumulation of labeled cells was identified in tumors. A similar pattern was observed in ex vivo biodistributions on day 7 (lung 3.0% ± 1.0%ID, liver 19.8% ± 2.2%ID, spleen 2.3% ± 1.7%ID). 89 Zr-DFO-labeled hPBMC/CAR T-cells showed the similar distribution on serial PET images as Jurkat/CAR T-cells. The distribution of CAR T-cells was cross-confirmed by flow cytometry, Alu polymerase chain reaction, and immunohistochemistry. Conclusion: Using PET imaging of 89 Zr-DFO-labeled CAR T-cells, real time in vivo cell trafficking is feasible. It can be used to investigate cellular kinetics, initial in vivo biodistribution, and the safety profile in future CAR T-cell development.

81345: A Long Lost Key Opens an Ancient Lock: Drosophila Myb Causes a Synthetic Multivulval Phenotype in Nematodes
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Posted to bioRxiv 01 Oct 2019

A Long Lost Key Opens an Ancient Lock: Drosophila Myb Causes a Synthetic Multivulval Phenotype in Nematodes
3 downloads molecular biology

Paul J Vorster, Paul Goetsch, Tilini U. Wijeratne, Keelan Z. Guiley, Laura Andrejka, Sarvind Tripathi, Braden J. Larson, Seth M. Rubin, Susan Strome, Joseph S. Lipsick

The five-protein MuvB core complex (LIN9/Mip130, LIN37/Mip40, LIN52, LIN54/Mip120, and LIN53/p55CAF1/RBBP4) has been highly conserved during the evolution of animals. This nuclear complex interacts with proteins encoded by the RB tumor suppressor gene family and its associated E2F-DP transcription factors to form DREAM complexes that repress the expression of genes that regulate cell cycle progression and cell fate. The MuvB core complex also interacts with proteins encoded by the Myb oncogene family to form the Myb-MuvB complexes that activate many of the same target genes. We show that animal-type Myb genes and proteins are present in Bilateria, Cnidaria, and Placozoa, the latter including some of the simplest known animal species. However, bilaterian nematode worms appear to have lost their animal-type Myb genes hundreds of millions of years ago. Nevertheless, the amino acids in the LIN9 and LIN52 proteins that directly interact with the MuvB-binding domains of human B-Myb and Drosophila Myb are conserved in C. elegans . Here we show that, despite greater than 500 million years since their last common ancestor, the Drosophila melanogaster Myb protein can bind to the nematode LIN9 and LIN52 family proteins in vitro and can cause a synthetic multivulval (synMuv) phenotype in vivo . This phenotype is similar to that caused by loss-of-function mutations in C. elegans synMuvB class genes including those that encode homologs of the MuvB core, RB, E2F, and DP. Furthermore, amino acid substitutions in the MuvB-binding domain of Drosophila Myb that disrupt its functions in vitro and in vivo also disrupt its activity in C. elegans . We speculate that nematodes and other animals may contain another protein that can bind to LIN9 and LIN52 in order to activate transcription of genes repressed by DREAM complexes.

81346: Plasma-derived HIV Nef+ exosomes persist in ACTG384 study participants despite successful virological suppression.
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Posted to bioRxiv 20 Jul 2019

Plasma-derived HIV Nef+ exosomes persist in ACTG384 study participants despite successful virological suppression.
3 downloads microbiology

Andrea D. Raymond, Michelle J. Lang, Jane Chu, Tamika Campbell-Sims, Mahfuz Khan, Vincent C. Bond, Richard B. Pollard, David M. Asmuth, Michael D. Powell

Human Immunodeficiency Virus (HIV) accessory protein Negative factor (Nef) is detected in the plasma of HIV+ individuals associated with exosomes. The role of Nef+ exosomes (exNef) in HIV pathogenesis is unknown. We perform a retrospective longitudinal analysis to determine correlative clinical associations of exNef plasma levels in ARV-treated HIV+ patients with or without immune recovery. exNef concentration in a subset of AIDS Clinical Trial Group (ACTG) 384 participants with successful virological suppression and with either high (? >100 CD4 cell recovery/High Immunological Responders (High-IR) or low (? ≤100 CD4 cell recovery/ Low Immunologic Responders (Low-IR) immunologic recovery was measured and compared for study weeks 48, 96, and 144. CD4 recovery showed a negative correlation with exNef at study week 144 (r = -0.3573, *p=.0366). Plasma exNef concentration in high IRs negatively correlated with naïve CD4 count and recovery (r = -0.3249, *p = 0. 0348 (High-IR); r =0.2981, *p= #0.0513 (Low-IR)). However, recovery of CD4 memory cells positively correlated with exNef (r =.4534, *p=.0358) in Low-IRs but not in High-IRs. Regimen A (Didanosine, Stavudine, Efavirenz) lowered exNef levels in IRs by 2-fold compared to other regimens. Nef+ exosomes persist in ART-treated HIV+ individuals despite undetectable viral loads, negatively correlates with naive and memory CD4 T cell restoration and may be associated with reduced immunological recovery. Taken together, these data suggest that exNef may represent a novel mechanism utilized by HIV to promote immune dysregulation.

81347: Additional analytical support for a new method to compute the likelihood of diversification models
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Posted to bioRxiv 04 Jul 2019

Additional analytical support for a new method to compute the likelihood of diversification models
3 downloads evolutionary biology

Giovanni Laudanno, Bart Haegeman, Rampal S. Etienne

Molecular phylogenies have been increasingly recognized as an important source of information on species diversification. For many models of macro-evolution, analytical likelihood formulas have been derived to infer macro-evolutionary parameters from phylogenies. A few years ago, a general framework to numerically compute such likelihood formulas was proposed, which accommodates models that allow speciation and/or extinction rates to depend on diversity. This framework calculates the likelihood as the probability of the diversification process being consistent with the phylogeny from the root to the tips. However, while some readers found the framework presented in Etienne et al. (2012) convincing, others still questioned it (personal communication), despite numerical evidence that for special cases the framework yields the same (i.e. within double precision) numerical value for the likelihood as analytical formulas do that were independently derived for these special cases. Here we prove analytically that the likelihoods calculated in the new framework are correct for all special cases with known analytical likelihood formula. Our results thus add substantial mathematical support for the overall coherence of the general framework.

81348: Epigenetic transmission of cardiometabolic risk in offspring discordant for maternal gestational metabolic fitness
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Posted to bioRxiv 04 Oct 2018

Epigenetic transmission of cardiometabolic risk in offspring discordant for maternal gestational metabolic fitness
3 downloads developmental biology

Frédéric Guénard, Simon Marceau, Serge Simard, John G. Kral, Marie-Claude Vohl, Picard Marceau

OBJECTIVE: Diabesity during gestation predisposes offspring to lifetime cardiometabolic risk. We demonstrated that maternal biliopancreatic diversion surgery (BPD) improved metabolic fitness and pregnancies reducing cardiometabolic risk in siblings born after (AMS) compared to before maternal surgery (BMS). We found differential methylation of inflammatory and glucoregulatory genes in peripheral blood cell DNA in offspring and in mothers after BPD compared to preoperative "control" women. Here we study offspring trajectories of cardiometabolic risk markers and determine persistence of the methylome related to body weight (BMI) and gestational weight gain (GWG). RESEARCH DESIGN AND METHODS: Prospective, cross-sectional study of 133 mothers with 89 BMS and 183 AMS offspring born mean 4 years after BPD and 83 unoperated control women was conducted, and differential methylation patterns in mothers were compared with those of offspring during 2-26 years. RESULTS: Independent of maternal or offspring BMI and GWG, postoperative maternal metabolic fitness was associated with improved cardiometabolic phenotype in AMS vs. BMS offspring sustained beyond puberty. BMS offspring exhibited increasing linear trajectories of weight, cardiometabolic and inflammation risk factors versus normative horizontal trajectories of AMS offspring. Methylation differences between AMS and BMS offspring identified 45 625 differentially methylated sites, 73% overlapping with those of mothers vs. controls; 4 446 demonstrated similar sustained directionality of differences in methylation levels; 154 sites exhibited significant correlation coefficients (r≥0.4) overrepresented within genes associated with cardiometabolic risk, growth and inflammation. CONCLUSION: Maternal BPD appears to epigenetically prevent transmission of cardiometabolic risk independent of BMI.

81349: Specification of the germline by Nanos-dependent down-regulation of the somatic synMuvB transcription factor LIN-15B
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Posted to bioRxiv 14 Jul 2017

Specification of the germline by Nanos-dependent down-regulation of the somatic synMuvB transcription factor LIN-15B
3 downloads cell biology

Chih-Yung S. Lee, Tu Lu, Geraldine Seydoux

The Nanos RNA-binding protein has been implicated in the specification of primordial germ cells (PGCs) in metazoans, but the underlying mechanisms remain poorly understood. We have profiled the transcriptome of PGCs lacking the nanos homologues nos-1 and nos-2 in C. elegans. nos-1nos-2 PGCs fail to silence hundreds of genes normally expressed in oocytes and somatic cells, a phenotype reminiscent of PGCs lacking the repressive PRC2 complex. The nos-1nos-2 phenotype depends on LIN-15B, a broadly expressed synMuvB class transcription factor known to antagonize PRC2 activity in somatic cells. LIN-15B is maternally-inherited by all embryonic cells and is down-regulated specifically in PGCs in a nos-1nos-2-dependent manner. Consistent with LIN-15B being a critical target of Nanos regulation, inactivation of maternal LIN-15B restores fertility to nos-1nos-2 mutants. These studies demonstrate a central role for Nanos in reprogramming the transcriptome of PGCs away from an oocyte/somatic fate by down-regulating an antagonist of PRC2 activity.

81350: Unbalanced Sample Size Introduces Spurious Correlations to Genome-wide Heterozygosity Analyses
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Posted to bioRxiv 07 Feb 2020

Unbalanced Sample Size Introduces Spurious Correlations to Genome-wide Heterozygosity Analyses
3 downloads bioinformatics

Li Liu, Richard J Caselli

Excess of heterozygosity (H) is a widely used measure of genetic diversity of a population. As high-throughput sequencing and genotyping data become readily available, it has been applied to investigating the associations of genome-wide genetic diversity with human diseases and traits. However, these studies often report contradictory results. In this paper, we present a meta-analysis of five whole-exome studies to examine the association of H scores with Alzheimer's disease. We show that the mean H score of a group is not associated with the disease status, but is associated with the sample size. Across all five studies, the group with more samples has a significantly lower H score than the group with fewer samples. To remove potential confounders in empirical data sets, we perform computer simulations to create artificial genomes controlled for the number of polymorphic loci, the sample size and the allele frequency. Analyses of these simulated data confirm the negative correlation between the sample size and the H score. Furthermore, we find that genomes with a large number of rare variants also have inflated H scores. These biases altogether can lead to spurious associations between genetic diversity and the phenotype of interest. Based on these findings, we advocate that studies shall balance the sample sizes when using genome-wide H scores to assess genetic diversities of different populations, which helps improve the reproducibility of future research.

81351: Structure of the archaellar motor and associated cytoplasmic cone in Thermococcus kodakaraensis
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Posted to bioRxiv 13 Feb 2017

Structure of the archaellar motor and associated cytoplasmic cone in Thermococcus kodakaraensis
3 downloads cell biology

Ariane Briegel, Catherine M. Oikonomou, Yi-Wei Chang, Andreas Kjaer, Audrey N. Huang, Ki Woo Kim, Debnath Ghosal, Robert P. Gunsalus, Grant J Jensen

Archaeal swimming motility is driven by rotary motors called archaella. The structure of these motors, and particularly how they are anchored in the absence of a peptidoglycan cell wall, is unknown. Here, we use electron cryotomography to visualize the archaellar motor in vivo in Thermococcus kodakaraensis. Compared to the homologous bacterial type IV pilus (T4P), we observe structural similarities as well as several unique features. While the position of the cytoplasmic ATPase appears conserved, it is not braced by linkages that extend upward through the cell envelope as in the T4P, but rather by cytoplasmic components that attach it to a large conical frustum up to 500 nm in diameter at its base. In addition to anchoring the lophotrichous bundle of archaella, the conical frustum associates with chemosensory arrays and ribosome-excluding material and may function as a polar organizing center for the coccoid cells.

81352: Novel Magnetic Resonance Imaging strategy targeting Neurotensin Receptors in detection of Prostate Cancer
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Posted to bioRxiv 24 Aug 2017

Novel Magnetic Resonance Imaging strategy targeting Neurotensin Receptors in detection of Prostate Cancer
3 downloads cancer biology

Mitul Desai, Neville N.C. Tam, Robert Carraway, Shuk-Mei Ho, Craig Ferris, Jean King

Prostate cancer is the second leading cause of all male cancer deaths. One of the factors present in malignant prostate cells and shown to support its metastatic growth is the neuropeptide neurotensin (NT). The primary goal of the present study was to establish the feasibility of using a newly developed paramagnetic receptor ligand for NT and non-invasive ultrahigh-field magnetic resonance (MR) imaging to visualize prostate cancer in rodents. Orthotropic xenografts were initiated in six-week old male BALB/c nu/nu athymic mice (n = 28) by intra-prostatic (ventral lobe) inoculation of human prostate cancer cells (10 μL of PC3 cells (10^6/100 μL)). Palpable tumors developed within 30-60 days. A micro-imager utilized in these studies was an actively shielded 9.4T, 89 mm bore, Oxford superconducting magnet with a 100 gauss/cm gradient system. Prior to contrast injection, T2 weighted anatomy scans were done to localize the tumor with a spin-echo multi-slice sequence with TR: 2000 TE: 40 and NEX: 1 in both coronal and axial planes. The paramagnetic ligand data sets were collected with a spin-echo, T1 weighted pulse sequence (MSME): TR 300 msec; TE 5 msec; NEX 4 in both axial and coronal planes. The data sets were taken initially at 5-min intervals post contrast injection for the first half hour and then at 15 min intervals for the next 1.5-2 hours for a time series analyses. The temporal distribution of MR signal intensity in various regions were determined in the absence and presence of NT. Our results confirm that the novel NT molecule was protected from enzymatic degradation and capable of forming a high-affinity paramagnetic NT ligand with an extended half-life. During the imaging studies, the signal intensity increased by 200% in the region of the tumor. This increase in signal intensity approached maximum binding within 30 minutes and remained visible for 1-hour post-injection of the contrast agent. Taken together, these findings suggest that it is feasible to detect and image prostate cancer using a paramagnetic NT ligand and the emergence of the NT receptor ligand that may be used as a diagnostic marker for prostate cancer in humans.

81353: Cryo-EM structure of adenovirus type 3 fibre with desmoglein 2 shows a novel mode of receptor engagement
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Posted to bioRxiv 16 Nov 2018

Cryo-EM structure of adenovirus type 3 fibre with desmoglein 2 shows a novel mode of receptor engagement
3 downloads microbiology

Emilie Vassal-Stermann, Gregory Effantin, Chloe Zubieta, Wim Burmeister, Frédéric Iseni, Hongjie Wang, André Lieber, Guy Schoehn, Pascal Fender

Attachment of adenovirus (HAd) to host cell is a critical step of infection. This work reports the cryo-electron microscopy (cryo-EM) structure of a non-symmetrical complex smaller than 100kDa formed by the trimeric human adenovirus of type 3 fibre knob (HAd3K) and human desmoglein 2 (DSG2). The structure reveals a unique stoichiometry, shedding light to new adenovirus infection strategies and providing new insights for adenoviral vector development.

81354: AICM: A Genuine Framework for Correcting Inconsistency Between Large Pharmacogenomics Datasets
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Posted to bioRxiv 07 Aug 2018

AICM: A Genuine Framework for Correcting Inconsistency Between Large Pharmacogenomics Datasets
3 downloads bioinformatics

Zhiyue Tom Hu, Yuting Ye, Patrick A. Newbury, Haiyan Huang, Bin Chen

The inconsistency of open pharmacogenomics datasets produced by different studies limits the usage of pharmacogenomics in biomarker discovery. Investigation of multiple pharmacogenomics datasets confirmed that the pairwise sensitivity data correlation between drugs, or rows, across different studies (drug-wise) is relatively low, while the pairwise sensitivity data correlation between cell-lines, or columns, across different studies (cell-wise) is considerably strong. This common interesting observation across multiple pharmacogenomics datasets suggests the existence of subtle consistency among the different studies (i.e., strong cell-wise correlation). However, significant noises are also shown (i.e., weak drug-wise correlation) and have prevented researchers from comfortably using the data directly. Motivated by this observation, we propose a novel framework for addressing the inconsistency between large-scale pharmacogenomics data sets. Our method can significantly boost the drug-wise correlation and can be easily applied to re-summarized and normalized datasets proposed by others. We also investigate our algorithm based on many different criteria to demonstrate that the corrected datasets are not only consistent, but also biologically meaningful. Eventually, we propose to extend our main algorithm into a framework, so that in the future when more data-sets become publicly available, our framework can hopefully offer a "ground-truth" guidance for references.

81355: The heterogeneous functional architecture of the posteromedial cortex is associated with selective functional connectivity differences in Alzheimer's disease
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Posted to bioRxiv 12 Jul 2019

The heterogeneous functional architecture of the posteromedial cortex is associated with selective functional connectivity differences in Alzheimer's disease
3 downloads neuroscience

Wasim Khan, Ali Amad, Vincent Giampietro, Emilio Werden, Sara De Simoni, Jonathan O’Muircheartaigh, Eric Westman, Owen O’Daly, Steve CR Williams, Amy Brodtmann

The posteromedial cortex (PMC) is a key region involved in the development and progression of Alzheimer disease (AD). Previous studies have demonstrated a heterogenous functional architecture of the region, with different subdivisions reflecting distinct connectivity profiles. However, little is understood about PMC functional connectivity and its differential vulnerability to AD pathogenesis. Using a data-driven approach, we applied a constrained independent component analysis (ICA) on healthy adults from the Human Connectome Project (HCP) to characterise the distinct functional subdivisions and unique functional-anatomic connectivity patterns of the PMC. These connectivity profiles were subsequently quantified in the Alzheimers Disease Neuroimaging Initiative (ADNI) study, to examine functional connectivity differences in (1) AD patients and cognitively normal (CN) participants and (2) the entire AD pathological spectrum, ranging from CN participants and participants with subjective memory complaints (SMC), through to those with mild cognitive impairment (MCI), and finally, patients diagnosed with AD. Our findings revealed decreased functional connectivity in the anterior precuneus, dorsal posterior cingulate cortex, and the central precuneus in AD patients compared to CN participants. Functional abnormalities in these subdivisions were also related to high amyloid burden and lower hippocampal volumes. Across the entire AD spectrum, functional connectivity of the central precuneus was associated with disease progression and specific deficits in memory and executive function. These findings provide new evidence showing that specific vulnerabilities in PMC functional connectivity are associated with large-scale network disruptions in AD and that these patterns may be useful for elucidating potential biomarkers for measuring disease progression in future work.

81356: Computational simulation of the reactive oxygen species and redox network in the regulation of chloroplast metabolism
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Posted to bioRxiv 14 May 2019

Computational simulation of the reactive oxygen species and redox network in the regulation of chloroplast metabolism
3 downloads plant biology

Melanie Gerken, Sergej Kakorin, Kamel Chibani, Karl-Josef Dietz

Cells contain a thiol redox regulatory network to coordinate metabolic and developmental activities with exogenous and endogenous cues. This network controls the redox state and activity of many target proteins. Electrons are fed into the network from metabolism and reach the target proteins via redox transmitters such as thioredoxin (TRX) and NADPH-dependent thioredoxin reductases (NTR). Electrons are drained from the network by reactive oxygen species (ROS) through thiol peroxidases, e.g., peroxiredoxins (PRX). Mathematical modeling promises access to quantitative understanding of the network function and was implemented for the photosynthesizing chloroplast by using published kinetic parameters combined with fitting to known biochemical data. Two networks were assembled, namely the ferredoxin (FDX), FDX-dependent TRX reductase (FTR), TRX, fructose-1,6-bisphosphatase pathway with 2-cysteine PRX/ROS as oxidant, and separately the FDX, FDX-dependent NADP reductase (FNR), NADPH, NTRC-pathway for 2-CysPRX reduction. Combining both modules allowed drawing several important conclusions of network performance. The resting H2O2 concentration was estimated to be about 30 nM in the chloroplast stroma. The electron flow to metabolism exceeds that into thiol regulation of FBPase more than 7000-fold under physiological conditions. The electron flow from NTRC to 2-CysPRX is about 5.46-times more efficient than that from TRX-f1 to 2-CysPRX. Under severe stress (30 µM H2O2) the ratio of electron flow to the thiol network relative to metabolism sinks to 1:251 whereas the ratio of electron flow from NTRC to 2-CysPRX and TRX-f1 to 2-CysPRX rises up to 1:80. Thus, the simulation provides clues on experimentally inaccessible parameters and describes the functional state of the chloroplast thiol regulatory network.

81357: Toward a Genome Scale Sequence Specific Dynamic Model of Cell-Free Protein Synthesis in Escherichia coli
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Posted to bioRxiv 06 Nov 2017

Toward a Genome Scale Sequence Specific Dynamic Model of Cell-Free Protein Synthesis in Escherichia coli
3 downloads synthetic biology

Nicholas Horvath, Michael Vilkhovoy, Joseph A. Wayman, Kara Calhoun, James Swartz, Jeffrey D. Varner

Cell-free protein expression systems have become widely used in systems and synthetic biology. In this study, we developed an ensemble of dynamic E. coli cell-free protein synthesis (CFPS) models. Model parameters were estimated from a training dataset for the cell-free production of a protein product, chloramphenicol acetyltransferase (CAT). The dataset consisted of measurements of glucose, organic acids, energy species, amino acids, and CAT. The ensemble accurately predicted these measurements, especially those of the central carbon metabolism. We then used the trained model to evaluate the optimality of protein production. CAT was produced with an energy efficiency of 12%, suggesting that the process could be further optimized. Reaction group knockouts showed that protein productivity and the metabolism as a whole depend most on oxidative phosphorylation and glycolysis and gluconeogenesis. Amino acid biosynthesis is also important for productivity, while the overflow metabolism and TCA cycle affect the overall system state. In addition, the translation rate is shown to be more important to productivity than the transcription rate. Finally, CAT production was robust to allosteric control, as was most of the network, with the exception of the organic acids in central carbon metabolism. This study is the first to use kinetic modeling to predict dynamic protein production in a cell-free E. coli system, and should provide a foundation for genome scale, dynamic modeling of cell-free E. coli protein synthesis.

81358: MG7: Configurable and scalable 16S metagenomics data analysis
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Posted to bioRxiv 28 Sep 2015

MG7: Configurable and scalable 16S metagenomics data analysis
3 downloads bioinformatics

Alexey Alekhin, Evdokim Kovach, Marina Manrique, Pablo Pareja-Tobes, Eduardo Pareja, Raquel Tobes, Eduardo Pareja-Tobes

As part of the Cambrian explosion of omics data, metagenomics brings to the table a specific, defining trait: its social essence. The *meta* prefix exerts its influence, with multitudes manifesting themselves everywhere; from samples to data analysis, from actors involved to (present and future) applications. Of these dimensions, data analysis is where needs lay further from what current tools provide. Key features are, among others, scalability, reproducibility, data provenance and distribution, process identity and versioning. These are the goals guiding our work in MG7, a 16S metagenomics data analysis system. The basic principle is a new approach to data analysis, where configuration, processes, or data locations are static, type-checked and subject to the standard evolution of a well-maintained software project. Cloud computing, in its Amazon Web Services incarnation, when coupled with these ideas, produces a robust, safely configurable, scalable tool. Processes, data, machine behaviors and their dependencies are expressed using a set of libraries which bring as much as possible checking and validation to the type level, without sacrificing expressiveness. Together they form a toolkit for defining scalable cloud-based workflows composed of stateless computations, with a static reproducible specification of dependencies, behavior and wiring of all steps. The modeling of taxonomy data is done using Bio4j, where the new paradigm of graph databases allows for both a simple expression of taxonomic assignment tasks and the calculation of taxa abundance values considering the hierarchic structure of the taxonomy tree. MG7 includes a new 16S reference database, *16S-DB7*, built with a flexible and sustainable update system, and the possibility of project-driven personalization. The first and second authors contributed equally to this work.

81359: GPU-accelerated alignment of bisulfite-treated short-read sequences
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Posted to bioRxiv 25 Aug 2017

GPU-accelerated alignment of bisulfite-treated short-read sequences
3 downloads bioinformatics

Richard Wilton, Xin Li, Andrew P. Feinberg, Alexander S. Szalay

The alignment of bisulfite-treated DNA sequences (BS-seq reads) to a large genome involves a significant computational burden beyond that required to align non-bisulfite-treated reads. In the analysis of BS-seq data, this can present an important performance bottleneck that can potentially be addressed by appropriate software-engineering and algorithmic improvements. One strategy is to integrate this additional programming logic into the read-alignment implementation in a way that the software becomes amenable to optimizations that lead to both higher speed and greater sensitivity than can be achieved without this integration. We have evaluated this strategy using Arioc, a short-read aligner that uses GPU (general-purpose graphics processing unit) hardware to accelerate computationally-expensive programming logic. We integrated the BS-seq computational logic into both GPU and CPU code throughout the Arioc implementation. We then carried out a read-by-read comparison of Arioc's reported alignments with the alignments reported by the most widely used BS-seq read aligners. With simulated reads, Arioc's accuracy is equal to or better than the other read aligners we evaluated. With human sequencing reads, Arioc's throughput is at least 10 times faster than existing BS-seq aligners across a wide range of sensitivity settings. The Arioc software is available at https://github.com/RWilton/Arioc. It is released under a BSD open-source license.

81360: Taking sharper pictures of malaria with CAMERAs: Combined Antibodies to Measure Exposure Recency Assays
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Posted to bioRxiv 11 Apr 2018

Taking sharper pictures of malaria with CAMERAs: Combined Antibodies to Measure Exposure Recency Assays
3 downloads epidemiology

Bryan Greenhouse, David L. Smith, Isabel Rodríguez-Barraquer, Ivo Mueller, Chris J Drakeley

Antibodies directed against malaria parasites are easy and inexpensive to measure but remain an underutilized surveillance tool due to a lack of consensus on what to measure and how to interpret results. High throughput screening of antibodies from well-characterized cohorts offers a means to substantially improve existing assays by rationally choosing the most informative sets of responses and analytical methods. Recent data suggest that high-resolution data on malaria exposure can be obtained from a small number of samples by measuring a handful of properly chosen antibody responses. In this review, we will discuss how standardized multi-antibody assays can be developed and efficiently integrated into existing surveillance activities, with great potential to greatly augment the breadth and quality of information available to direct and monitor malaria control and elimination efforts.

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