bluuebunny/crossref_metadata_2025 huggingface dataset:
The Tec kinase ITK differentially optimizes NFAT, NF-κB, and MAPK signaling during early T cell activation to regulate graded gene induction
Authors: Gallagher Michael P. , Conley James M. , Vangala Pranitha , Reboldi Andrea , Garber Manuel , Berg Leslie J.
Published: November 2020

The strength of peptide:MHC interactions with the T cell receptor (TCR) is correlated with the time to first cell division, the relative scale of the effector cell response, and the graded expression of activation-associated proteins like IRF4. To regulate T cell activation programming, the TCR and the TCR proximal kinase ITK simultaneously trigger many biochemically separate TCR signaling cascades. T cells lacking ITK exhibit selective impairments in effector T cell responses after activation, but under the strongest signaling conditions ITK activity is dispensable. To gain insight into whether TCR signal strength and ITK activity tune observed graded gene expression through unequal activation of disparate signaling pathways, we examined Erk1/2 activation and NFAT, NF-κB translocation in naive OT-I CD8+cell nuclei. We observed consistent digital activation of NFAT1 and Erk-MAPK, but NF-κB displayed dynamic, graded activation in response to variation in TCR signal strength and was tunable by treatment with an ITK inhibitor. Inhibitor-treated cells showed dampened induction of AP-1 factorsFosandFosb, NF-κB response gene transcripts, and survival factorIl2transcripts. ATAC-seq analysis also revealed genomic regions most sensitive to ITK inhibition were enriched for NF-κB and AP-1 motifs. Specific inhibition of NF-κB during peptide stimulation tuned expression of early gene products like c-Fos. Together, these data indicate a key role for ITK in orchestrating optimal activation of separate TCR downstream pathways, specifically aiding NF-κB activation. More broadly, we revealed a mechanism by which variation in TCR signal strength can produce patterns of graded gene expression in activated T cells.
Quantification ofBrucella abortuspopulation structure in a natural host
Authors: Fiebig Aretha , Vrentas Catherine E. , Le Thien , Huebner Marianne , Boggiatto Paola M. , Olsen Steven C. , Crosson Sean
Published: November 2020

Cattle are natural hosts of the intracellular pathogen,Brucella abortus, which inflicts a significant burden on the health and reproduction of these important livestock. The primary routes of infection in field settings have been described, but it is not known how the bovine host shapes the structure ofB. abortuspopulations during infection. We utilized a library of approximately 106uniquely barcodedB. abortusstrains to temporally and spatially quantify population structure at the strain level during colonization of cattle through a natural route of infection. Introducing 108bacteria from this barcoded library to the conjunctival mucosa resulted in expected levels of local lymph node colonization at a one-week timepoint. We leveraged variance in strain abundance in the library to demonstrate that only 1 in 10,000 brucellae introduced at the site of infection reached the parotid lymph nodes. Thus, cattle restrict the overwhelming majority ofB. abortusintroduced via the ocular conjunctiva at this dose. Individual strains were spatially restricted within the host tissue, and the totalB. abortuscensus was dominated by a small number of distinct strains in each lymph node. These results define a bottleneck thatB. abortusmust traverse to colonize local lymph nodes from the conjunctival mucosa. The data further support a model in which a small number of spatially isolated granulomas founded by unique strains are present one-week post infection. These experiments demonstrate the power of barcoded transposon tools to quantify infection bottlenecks and to define pathogen population structure in host tissues.

Significance statement

Understanding microbial population dynamics during infection has important implications for disease management, transmission and pathogen evolution. A quantitative analysis of microbial population structure requires the ability to track individual strains. We used a pool of individually barcoded strains to measure changes inBrucella abortuspopulation structure during infection of bovine hosts via the ocular conjunctiva, a natural route of entry. Cattle exert a severe bottleneck on the bacterial population entering through the conjunctival mucosa such that individual cells have a 0.0001 probability of colonizing a local draining lymph node. The populations in lymph nodes, even on different sides of the same animal, are distinct and dominated by a small number of highly abundant, spatially distinct clones.
SeqPIP-2020: Sequence based Protein Interaction Prediction Contest
Authors: Halder Anup Kumar , Mollah Ayatullah Faruk , Chatterjee Piyali , Kole Dipak Kumar , Basu Subhadip , Plewczyński Dariusz
Published: November 2020

Computational protein-protein interaction (PPI) prediction techniques can contribute greatly in reducing time, cost and false-positive interactions compared to experimental approaches. Sequence is one of the key and primary information of proteins that plays a crucial role in PPI prediction. Several machine learning approaches have been applied to exploit the characteristics of PPI datasets. However, these datasets greatly influence the performance of predicting models. So, care should be taken on both dataset curation as well as design of predictive models. Here, we summarize the results of the SeqPIP competition whose objective was to develop comprehensive PPI predictive models from sequence information with high-quality bias-free interaction datasets. A training set of 2000 positive and 2000 negative interactions with sequences was given to each contestant. The methods were evaluated with three independent high-quality interaction test datasets.
MUNIn (Multiple sample UNifying long-range chromatin Interaction detector): a statistical framework for identifying long-range chromatin interactions from multiple samples
Authors: Liu Weifang , Abnousi Armen , Zhang Qian , Kubo Naoki , Martin Beem Joshua S. , Li Yun , Hu Ming , Yang Yuchen
Published: November 2020

Chromatin spatial organization (interactome) plays a critical role in genome function. Deep understanding of chromatin interactome can shed insights into transcriptional regulation mechanisms and human disease pathology. One essential task in the analysis of chromatin interactomic data is to identify long-range chromatin interactions. Existing approaches, such as HiCCUPS, FitHiC/FitHiC2 and FastHiC, are all designed for analyzing individual cell types or samples. None of them accounts for unbalanced sequencing depths and heterogeneity among multiple cell types or samples in a unified statistical framework. To fill in the gap, we have developed a novel statistical framework MUNIn (Multiple sampleUNifying long-range chromatinInteraction detector) for identifying long-range chromatin interactions from multiple samples. MUNIn adopts a hierarchical hidden Markov random field (H-HMRF) model, in which the status (peak or background) of each interacting chromatin loci pair depends not only on the status of loci pairs in its neighborhood region, but also on the status of the same loci pair in other samples. To benchmark the performance of MUNIn, we performed comprehensive simulation studies and real data analysis, and showed that MUNIn can achieve much lower false positive rates for detecting sample-specific interactions (33.1 - 36.2%), and much enhanced statistical power for detecting shared peaks (up to 74.3%), compared to uni-sample analysis. Our data demonstrated that MUNIn is a useful tool for the integrative analysis of interactomic data from multiple samples.
An evolutionary analysis of the SARS-CoV-2 genomes from the countries in the same meridian
Authors: Mastriani Emilio , Rakov Alexey V. , Liu Shu-Lin
Published: November 2020

In the current study we analyzed the genomes of SARS-CoV-2 strains isolated from Italy, Sweden, Congo (countries in the same meridian) and Brazil, as outgroup country. Evolutionary analysis revealed codon 9628 under episodic selective pressure for all four countries, suggesting it as a key site for the virus evolution. Belonging to the P0DTD3 (Y14_SARS2) uncharacterized protein 14, further investigation has been conducted showing the codon mutation as responsible for the helical modification in the secondary structure. According to the predictions done, the codon is placed into the more ordered region of the gene (41-59) and close the area acting as transmembrane (54-67), suggesting its involvement into the attachment phase of the virus. The predicted structures of P0DTD3 mutated and not confirmed the importance of the codon to define the protein structure and the ontological analysis of the protein emphasized that the mutation enhances the binding probability.
Characterization and significance of extracellular polymeric substances, reactive oxygen species, and extracellular electron transfer in methanogenic biocathode
Authors: Zakaria Basem S. , Dhar Bipro Ranjan
Published: November 2020

The microbial electrolysis cell assisted anaerobic digestion (MEC-AD) holds great promises over conventional anaerobic digestion. This article reports an experimental investigation of extracellular polymeric substances (EPS), reactive oxygen species (ROS), and the expression of genes associated with extracellular electron transfer (EET) in methanogenic biocathodes. The MEC-AD systems were examined using two cathode materials: carbon fibers and stainless-steel mesh. A higher abundance of hydrogenotrophicMethanobacteriumsp. and homoacetogenicAcetobacteriumsp. appeared to play a major role in superior methanogenesis from stainless steel biocathode than carbon fibers. Moreover, the higher secretion of EPS accompanied by the lower ROS level in stainless steel biocathode indicated that higher EPS perhaps protected cells from harsh metabolic conditions (possibly unfavorable local pH) induced by faster catalysis of hydrogen evolution reaction. In contrast, EET-associated gene expression patterns were comparable in both biocathodes. Thus, these results indicated hydrogenotrophic methanogenesis is the key mechanism, while cathodic EET has a trivial role in distinguishing performances between two cathode electrodes. These results provide new insights into the efficient methanogenic biocathode development.
Deep Semi-Supervised Learning Improves Universal Peptide Identification of Shotgun Proteomics Data
Authors: Halloran John T. , Urban Gregor , Rocke David , Baldi Pierre
Published: November 2020

Semi-supervised machine learning post-processors critically improve peptide identification of shot-gun proteomics data. Such post-processors accept the peptide-spectrum matches (PSMs) and feature vectors resulting from a database search, train a machine learning classifier, and recalibrate PSMs using the trained parameters, often yielding significantly more identified peptides acrossq-value thresholds. However, current state-of-the-art post-processors rely on shallow machine learning methods, such as support vector machines. In contrast, the powerful training capabilities of deep learning models have displayed superior performance to shallow models in an ever-growing number of other fields. In this work, we show that deep models significantly improve the recalibration of PSMs compared to the most accurate and widely-used post-processors, such as Percolator and PeptideProphet. Furthermore, we show that deep learning is able to adaptively analyze complex datasets and features for more accurate universal post-processing, leading to both improved Prosit analysis and markedly better recalibration of recently developed database-search functions.
The Preclinical Inhibitor GS441524 in Combination with GC376 Efficaciously Inhibited the Proliferation of SARS-CoV-2 in the Mouse Respiratory Tract
Authors: Shi Yuejun , Shuai Lei , Wen Zhiyuan , Wang Chong , Yan Yuanyuan , Jiao Zhe , Guo Fenglin , Fu Zhen F. , Chen Huanchun , Bu Zhigao , Peng Guiqing
Published: November 2020

The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.

Importance

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has seriously threatened global public health and economic development. Currently, effective therapies to treat COVID-19 are urgently needed. In this study, we assessed the efficacy of the preclinical inhibitors GC376 and GS441524 using a mouse-adapted SARS-CoV-2 infected mouse model for the first time. Our results showed that low-dose combined application of GC376 and GS441524 could effectively protect mice from HRB26M infection in the upper and lower respiratory tracts. Hence, the combined application should be developed and considered for future clinic practice.
SARS-CoV-2 IgG antibody responses in rt-PCR positive cases: first report from India
Authors: Dash Girish Chandra , Parai Debaprasad , Choudhary Hari Ram , Peter Annalisha , Rout Usha Kiran , Nanda Rashmi Ranjan , Kshatri Jaya Singh , Kanungo Srikanta , Palo Subrata Kumar , Pati Sanghamitra , Bhattacharya Debdutta
Published: November 2020

The SARS-CoV-2 antibody responses remain poorly understood and the clinical utility of serological testing is still unclear. As it is thought to confer some degree of immunity, this study is carried out to know the relationship between demographics and ct value of confirmed rt-PCR patients. A total of 384 serum samples were collected between 4-6 weeks after confirmed SARS-CoV-2 infection. IgG positivity was found to be 80.2% (95% CI, 76.2 – 84.2). The IgG positivity increased with the decrease in the ct value, with highest of 87.6% positivity in individuals with <20 ct value. The mean (± SD) ct value of IgG positives and og IgG negatives was 23.34 (± 6.09) and 26.72 (± 7.031) respectively. There was no significant difference found between the demographic characteristics such as age, sex, symptoms and antibody response. The current study is first of its kind wherein we have assessed the correlation of ct of RT-PCR with development of IgG against SARS-CoV-2. Our study showed that although Ct value might not have any relation with severity of the diseases but is associated with the antibody response among the SARS-CoV-2 infected individual.
As above, so below: Whole transcriptome profiling supports the continuum hypothesis of avian dorsal and ventral pallium organization
Authors: Gedman Gregory , Haase Bettina , Durieux Gillian , Biegler Matthew , Fedrigo Olivier , Jarvis Erich D.
Published: November 2020

Over the last two decades, beginning with the Avian Brain Nomenclature Forum in 2000, major revisions have been made to our understanding of the organization and nomenclature of the avian brain. However, there are still unresolved questions on avian pallial organization, particularly whether the cells above the ventricle represent different populations to those below it. Concerns included limited number of genes profiled, biased selection of genes, and potential independent origins of cell types in different parts of the brain. Here we test two competing hypotheses, using RNA sequencing to profile the transcriptomes of the major avian pallial subdivisions dorsal and ventral to the ventricle boundary, and a new zebra finch genome assembly containing about 22,000 annotated, complete genes. We found that the transcriptomes of neural populations below and above the ventricle were remarkably similar. What had been previously named hyperpallium densocellulare above the ventricle had nearly the same molecular profile as the mesopallium below it; the hyperpallium apicale above was highly similar to the nidopallium below; the primary sensory intercalated hyperpallium apicale above was most similar to the sensory population below, although more divergent than the other populations were to each other. These shared population expression profiles define unique functional specializations in anatomical structure development, synaptic transmission, signaling, and neurogenesis. These findings support the continuum hypothesis of avian brain subdivisions above and below the ventricle space, with the pallium as a whole consisting of four major cell populations instead of seven and has some profound implications for our understanding of vertebrate brain evolution.
Reanalysis of in vivo drug synergy validation study rules out synergy in most cases
Authors: van Tellingen Olaf , de Menezes Renee X.
Published: November 2020

In a recent paper in Nature Communications, Narayan et al1described the development of anin silicomethod to predict synergy of drug combinations, validatedin vivousing 5 different models for 5 different drug pairs. The published analysis of thein vivoexperimental data used the Chou and Talalay Combination Index, which ignores important aspects of the study design, including, but not limited to the variability between individual mice and the longitudinal nature of the data. Furthermore, the original publication reported the Combination Index as static numbers without properly accounting for experimental variability. When 95% confidence intervals are recalculated using bootstrapping methods, 4 out of 5 drug pairs do not show a statistically significant synergistic effect. Three models (originally figures 5A, B and E) are subject to severe inaccuracies in the data handling and reporting. In one model, (originally figure 5D), the data better supports an additive effect between drugs rather than synergy. As the Chou and Talalay Combination Index is poorly suited to this data, we applied mixed-effects models fitted to the longitudinal tumor growth data as an alternative means of estimating synergy. The results support the findings from the bootstrapping analysis, namely that the majority of the drug pairs do not achieve a synergistic effect. We conclude that thein vivovalidation of thein silicomethod to predict synergy of drug combinations as proposed by Narayan et al has a negative outcome when analyzed with appropriate statistical methods.
Sex-specific lipid profiles in the muscle of Atlantic salmon juveniles
Authors: House Andrew H. , Debes Paul V. , Kurko Johanna , Erkinaro Jaakko , Käkelä Reijo , Primmer Craig R.
Published: November 2020

Energy allocation in juvenile fish can have important implications for future life-history progression. Inherited and environmental factors determine when and where individuals allocate energy, and timely and sufficient energy reserves are crucial for reaching key life stages involved in the timing of maturation and sea migration. In Atlantic salmon, lipid reserves are predominantly found in the viscera and myosepta in the muscle and have been shown to play a key role in determining the timing of maturity. This life-history trait is tightly linked to fitness in many species and can be different between males and females, however, the details of relative energy allocation in juveniles of different sexes is not well understood. Therefore, the aim of this study was to investigate the effects of sex, genetics and environment during juvenile development of salmon on the amount and composition of their lipid reserves. To do so, juvenile salmon were fed one of two different lipid food contents during their first summer and autumn under common-garden conditions. Muscle lipid composition and concentrations were determined by thin layer chromatography. The muscle lipid class concentrations covaried negatively with body length and males showed higher concentrations than females for phosphatidylcholine, cholesterol, sphingomyelin, and triacylglycerol. This sex-specific difference in major lipid classes presents a new scope for understanding the regulation of lipids during juvenile development and gives direction for understanding how lipids may interact and influence major life-history traits in Atlantic salmon.
O mouse, where art thou? The Mouse Position Surveillance System (MoPSS) - an RFID based tracking system
Authors: Habedank Anne , Urmersbach Birk , Kahnau Pia , Lewejohann Lars
Published: November 2020

Existing methods for analysis of home cage based preference tests are either time consuming, not suitable for group management, expensive and/or based on proprietary equipment that is not freely available. For this reason, we developed an automated system for group housed mice based on radio frequency identification: the Mouse Position Surveillance System (MoPSS). The system uses an Arduino microcontroller with compatible components, it is affordable and easy to rebuild for every laboratory. The MoPSS was validated using female C57BL/6J mice and manual video comparison. It proved to be accurate even for fast moving mice (up to 100 % accuracy after logical reconstruction), and is already implemented in several studies in our laboratory. Here, we provide the complete construction description as well as the validation data and the results of an example experiment. This tracking system will allow group-based preference testing with individually identified mice to be carried out in a convenient manner, creating the foundation for better housing conditions from the animals’ perspective.
Epidural Electrical Stimulation of the Cervical Dorsal Roots Restores Voluntary Upper Limb Control in Paralyzed Monkeys
Authors: Barra B. , Conti S. , Perich M.G. , Zhuang K. , Schiavone G. , Fallegger F. , Galan K. , James N. D. , Barraud Q. , Delacombaz M. , Kaeser M. , Rouiller E. M. , Milekovic T. , Lacour S. , Bloch J. , Courtine G. , Capogrosso M.
Published: November 2020

Recovering arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control practically limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts targeting specific spinal segments produced sustained arm movements enabling monkeys with arm paralysis to perform an unconstrained reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that residual descending inputs were necessary to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.
Flexible fitting of PROTAC concentration-response curves with changepoint Gaussian Processes
Authors: Semenova Elizaveta , Guerriero Maria Luisa , Zhang Bairu , Hock Andreas , Hopcroft Philip , Kadamur Ganesh , Afzal Avid M. , Lazic Stanley E.
Published: November 2020

A proteolysis targeting chimera (PROTAC) is a new technology that marks proteins for degradation in a highly specific manner. During screening, PROTAC compounds are tested in concentration-response (CR) assays to determine their potency, and parameters such as the half-maximal degradation concentration (DC50) are estimated from the fitted CR curves. These parameters are used to rank compounds, with lower DC50values indicating greater potency. However, PROTAC data often exhibit bi-phasic and poly-phasic relationships, making standard sigmoidal CR models inappropriate. A common solution includes manual omitting of points (the so called “masking” step) allowing standard models to be used on the reduced datasets. Due to its manual and subjective nature, masking becomes a costly and non-reproducible procedure. We, therefore, used a Bayesian changepoint Gaussian Processes model that can flexibly fit both non-sigmoidal and sigmoidal CR curves without user input. Parameters, such as the DC50, the maximum effectDmax, and the point of departure (PoD) are estimated from the fitted curves. We then rank compounds based on one or more parameters, and propagate the parameter uncertainty into the rankings, enabling us to confidently state if one compound is better than another. Hence, we used a flexible and automated procedure for PROTAC screening experiments. By minimizing subjective decisions, our approach reduces time, cost, and ensures reproducibility of the compound ranking procedure. The code and data are provided on GitHub (https://github.com/elizavetase-menova/gp_concentration_response).
HIV-1 uncoating by release of viral cDNA from capsid-like structures in the nucleus of infected cells
Authors: Müller Thorsten G. , Zila Vojtech , Peters Kyra , Schifferdecker Sandra , Stanic Mia , Lucic Bojana , Laketa Vibor , Lusic Marina , Müller Barbara , Kräusslich Hans-Georg
Published: November 2020

HIV-1 replication commences inside the cone-shaped viral capsid, but timing, localization and mechanism of uncoating are under debate. We adapted a strategy to visualize individual reverse-transcribed HIV-1 cDNA molecules and their association with viral and cellular proteins using fluorescence and correlative-light-and-electron-microscopy (CLEM). We specifically detected HIV-1 cDNA inside nuclei, but not in the cytoplasm. Nuclear cDNA initially co-localized with a fluorescent integrase fusion (IN-FP) and the viral CA (capsid) protein, but cDNA-punctae separated from IN-FP/CA over time. This phenotype was conserved in primary HIV-1 target cells, with nuclear HIV-1 complexes exhibiting strong CA-signals in all cell types. CLEM revealed cone-shaped HIV-1 capsid-like structures and apparently broken capsid-remnants at the position of IN-FP signals and elongated chromatin-like structures in the position of viral cDNA punctae lacking IN-FP. Our data argue for nuclear uncoating by physical disruption rather than cooperative disassembly of the CA-lattice, followed by physical separation from the pre-integration complex.
Community composition of microbial microcosms follows simple assembly rules at evolutionary timescales
Authors: Meroz Nittay , Tovi Nesli , Sorokin Yael , Friedman Jonathan
Published: November 2020

Managing and engineering microbial communities relies on the ability to predict their composition. While progress has been made on predicting compositions on short, ecological timescales, there is still little work aimed at predicting compositions on evolutionary timescales. Therefore, it is still unknown for how long communities typically remain stable after reaching ecological equilibrium, and how repeatable and predictable are changes when they occur. Here, we address this knowledge gap by tracking the composition of 87 two- and three-species bacterial communities for ~400 generations. We find that community composition typically changed during evolution, but that the composition of replicate communities remained similar. Furthermore, these changes were predictable in a bottom-up approach - changes in the composition of trios were consistent with those that occurred in pairs during coevolution. Our results demonstrate that simple assembly rules can hold even on evolutionary timescales, suggesting it may be possible to forecast the evolution of microbial communities.
Investigation of reward learning and feedback sensitivity in non-clinical participants with a history of early life stress
Authors: Wilkinson Matthew P , Slaney Chloe L , Mellor Jack R , Robinson Emma S J
Published: November 2020

Early life stress (ELS) is an important risk factor for the development of depression. Impairments in reward learning and feedback sensitivity are suggested to be an intermediate phenotype in depression aetiology therefore we hypothesised that similar impairments are present in healthy adults with a history of ELS. We recruited 64 adults with high levels of ELS and no diagnosis of a current mental health disorder and 65 controls. Participants completed the probabilistic reversal learning task and probabilistic reward task followed by depression, anhedonia, social status, and stress scales. Participants with high levels of ELS showed decreased positive feedback sensitivity in the probabilistic reversal learning task compared to controls. High ELS participants also trended towards possessing a decreased model-free learning rate. This was coupled with a decreased learning ability in the acquisition phase of block 1 following the practice session. Neither group showed a reward induced response bias in the probabilistic reward task however high ELS participants exhibited decreased stimuli discrimination. Due to the PRT not meeting its primary endpoint a separate cohort of control participants were tested in a modified PRT where they showed a response bias. This indicates the PRT can be successfully carried out online. Overall, these data suggest that healthy participants without a mental health diagnosis and high levels of ELS show deficits in positive feedback sensitivity and reward learning in the probabilistic reversal learning task that are distinct from depressed patients. These deficits may be relevant to increased depression vulnerability.
The effect of combined treatment of vitamin C and loperamide on intestinal sodium and potassium ion ATPase, alkaline phosphatase and lipid peroxidation on castor oil induced diarrheal rats
Authors: Iorhemba Aondowase Paul , Imolele Anthony Godswill
Published: November 2020

Background

Diarrhea is distinguished by prevalence of bowel movement accompanied by a loose consistency of stools, resulting from hyper peristalsis of the small intestine or colon, Diarrhea is a major challenge among infants and growing children. The study was carried out to assess the result of combined treatment of vitamin C and loperamide on intestinal Na+, K+- ATPase, alkaline phosphatase, and lipid peroxidation in castor oil induced diarrheal wistar rats.

Method

A total of 18 wistar rats weighing 180-200g were randomly divided into 6 groups, (Group 1 Normal control no castor oil, no treatment administered, Group 2 Experimental control were given castor oil 3.0 ml/kg body weight with no treatment, Group 3 Standard control were given castor oil 3.0 ml/kg body weight + loperamide, Group 4 Treatment 1 were administered 3.0 ml/kg body weight + 25 mg/kg combined effect of vitamin C and loperamide, Group 5 Treatment 2 were administered 3.0 ml/kg body weight + 50 mg/kg combined effect of vitamin C and loperamide, and Group 6 were administered 3.0 ml/kg body weight + 100 mg/kg combined effect of vitamin C and loperamide) with 3 rats per group; the experiment lasted for 24 hours. The action of intestinal alkaline phosphatase, Na+, K+- ATPase and malondialdehyde were determined.

Result

Descriptive statistical analysis was adopted using SPSS version 20. Combined effect of vitamin C and loperamide significantly (p<0.05) lowered the elevated levels of malondialdehyde caused by castor oil induced diarrhea; the Na+, K+- ATPase intestinal activity treatment with both vitamin C and loperamide significantly elevated the activity of Na+, K+ATPase when compared with the normal control, but both treatments (loperamide alone and vitamin C plus loperamide were not significantly different (p<0.05) to themselves. However, at 50 mg/kg body weight of combined effect of vitamin C and loperamide it showed significant difference in the action of intestinal alkaline phosphatase.

Conclusion

Findings of this study therefore, indicate that a combined effect of loperamide and vitamin C will be an effective therapeutic agent in the management of diarrhea by scavenging of free radicals generated in the cause of diarrheal to reduce lipid peroxidation. Therefore, combined effect of vitamin C and loperamide should be encouraged in the management of diarrhea. Further research should be directed towards assessing the therapeutic action of vitamin C only in the management of diarrhea.
A model of resource partitioning between foraging bees based on positive and negative associations
Authors: Dubois Thibault , Pasquaretta Cristian , Barron Andrew B. , Gautrais Jacques , Lihoreau Mathieu
Published: November 2020

Central place foraging pollinators tend to develop multi-destination routes (traplines) to visit patchily distributed plant resources. While the formation of traplines by individual pollinators has been studied in details, how populations of foragers exploit resources in a common area is an open question, difficult to address experimentally. We explored conditions for the emergence of resource partitioning among traplining bees using agent-based models built from experimental data of bumblebees foraging on artificial flowers. In the models, bees learn to develop routes as a consequence of feedback loops that change their probabilities of moving between flowers. While a positive reinforcement of movements leading to rewarding flowers is sufficient for the emergence of resource partitioning when flowers are evenly distributed, addition of negative reinforcement of movements leading to unrewarding flowers is necessary when flowers are patchily distributed. In environments with more complex spatial structure, the negative experiences of individual bees on flowers favour spatial segregation and efficient collective foraging.
Profiling ofNUMTs in Gingivobuccal Oral Cancer
Authors: Palodhi Arindam , Singla Tanisha , Maitra Arindam
Published: November 2020

Very little information exists on the NUclear MiTochondrial sequences (NUMTs) in oral squamous cell carcinoma-gingivobuccal (OSCC-GB). We analysed whole genome sequences obtained from paired tumour and blood DNA from 25 patients of OSCC-GB for detectingNUMTs. Nine potential somaticNUMTs and 78 germlineNUMTs were identified in these patients. None of the somaticNUMTs could be confirmed by PCR assay. None of the germlineNUMTs were found to be specific for OSCC-GB. Although there have been recent reports on detection of somaticNUMTs in other cancer types, our results suggestNUMTs, both somatic and germline, are not involved in OSCC-GB.
Efficient simultaneous mutagenesis of multiple genes in specific plant tissues by multiplex CRISPR
Authors: Bollier Norbert , Buono Rafael Andrade , Jacobs Thomas B. , Nowack Moritz K.
Published: November 2020

Multiplex CRISPR approaches enable mutating multiple genes in plants, however it is unclear how feasible this is in tissue-specific mutagenesis. Here we simultaneously mutated six genes either ubiquitously or exclusively in the root cap of Arabidopsis. The mutation frequencies for all target genes were positively correlated and unaffected by the order of gRNAs in the vector, indicating that efficient higher-order mutagenesis in specific plant tissues can be readily achieved.
Epidermal stem cell compartment remains unaffected through aging in naked mole-rats
Authors: Savina A. , Jaffredo T. , Saldmann F. , Faulkes C.G. , Moguelet P. , Leroy C. , Del Marmol D. , Codogno P. , Foucher L. , Viltard M. , Friedlander G. , Aractingi S. , Fontaine R.H.
Published: November 2020

Skin represents an informative and convenient organ for the analysis of the aging process. Naked mole-rats (NMR) are subterranean rodents remarkable for their longevity, with unexplained resistance to skin aging. In middle-aged NMR, extensivein situanalysis indicated that skin compartments and cell types remained similar to young animals. Using single-cell RNA-sequencing, we found three classical cellular states defining a unique keratinocyte differentiation trajectory that did not appear to be altered during aging after pseudotemporal reconstruction. Finally, NMR skin healing closure was strictly comparable between the two age groups. These results indicate that the content in stem cell populations as well as the differentiation process are preserved during aging in NMR and that such properties are related to the healing process.
The Impact of Neuron Morphology on Cortical Network Architecture
Authors: Udvary Daniel , Harth Philipp , Macke Jakob H. , Hege Hans-Christian , de Kock Christiaan P.J. , Sakmann Bert , Oberlaender Marcel
Published: November 2020

It has become increasingly clear that the neurons in the cerebral cortex are not randomly interconnected. This wiring specificity can result from synapse formation mechanisms that interconnect neurons depending on their activity or genetically defined identity. Here we report that in addition to these synapse formation mechanisms, the structural composition of the neuropil provides a third prominent source by which wiring specificity emerges in cortical networks. This structurally determined wiring specificity reflects the packing density, morphological diversity and similarity of the dendritic and axonal processes. The higher these three factors are, the more recurrent the topology of the networks. Conversely, low density, diversity and similarity yield feedforward networks. These principles predict connectivity patterns from subcellular to network scales that are remarkably consistent with empirical observations from a rich body of literature. Thus, cortical network architectures reflect the specific morphological properties of their constituents to much larger degrees than previously thought.
Substrate-induced modulation of protein-protein interactions within human mitochondrial cytochrome P450-dependent system
Authors: Yablokov E.O. , Sushko T.A. , Kaluzhskiy L.A. , Kavaleuski A.A , Mezentsev Y.V. , Ershov P.V. , Gilep A.A , Ivanov A.S. , Strushkevich N.V.
Published: November 2020

Steroidogenesis is strictly regulated at multiple levels, as produced steroid hormones are crucial to maintain physiological functions. Cytochrome P450 enzymes are key players in adrenal steroid hormone biosynthesis and function within short redox-chains in mitochondria and endoplasmic reticulum. However, mechanisms regulating supply of reducing equivalents in the mitochondrial CYP-dependent system are not fully understood. In the present work, we aimed to estimate how the specific steroids, substrates, intermediates and products of multistep reactions modulate protein-protein interactions between adrenodoxin (Adx) and mitochondrial CYP11s. Using the SPR technology we determined that steroid substrates affect affinity and stability of CYP11s – Adx complexes in an isoform-specific mode. In particular, cholesterol induces a 4-fold increase in the rate of CYP11A1 – Adx complex formation without significant effect on dissociation (koffdecreased ~1.5-fold), overall increasing complex affinity. At the same time steroid substrates decrease the affinity of both CYP11B1 – Adx and CYP11B2 – Adx complexes, predominantly reducing their stability (4-7 fold). This finding reveals differentiation of protein-protein interactions within the mitochondrial pool of CYPs, which have the same electron donor. The regulation of electron supply by the substrates might affect the overall steroid hormones production. Our experimental data provide further insight into protein-protein interactions within CYP-dependent redox chains involved in steroidogenesis.
Evaluation of feeding behaviour traits to predict efficiency traits in pigs using partial least square regression
Authors: Ewaoluwagbemiga E. , Bee G. , Kasper C.
Published: November 2020

The improvement of efficiency traits, such as protein efficiency (PE), digestible energy efficiency (EnE) and lipid gain (LipG), are relevant given their associations with environmental pollution, cost of productions, and the quality of meat. However, these traits are difficult traits to measure and usually require slaughtering of pigs. Efficiency traits are complex, and several factors, such as genetic predisposition, feed composition, but also individual feeding behaviour may contribute to efficiency. The objective of this study was therefore to evaluate the potential of using feeding behaviour traits to predict efficiency traits under dietary protein restriction. A total of 587 Swiss Large White pigs, consisting of 312 females and 275 castrated males, hadad libitumaccess to feed and water, and were fed a protein-reduced diet (80% of recommended digestible protein and essential amino acids) from 22.5 ± 1.6 to 106.6 ± 4.6 kg BW. Individual feed intake was monitored and carcass composition (lean and fat mass) at slaughter was determined by dual-energy X-ray absorptiometry (DXA). The PE and EnE were calculated as the ratio of protein or energy in the carcass (estimated by DXA) to the total protein or energy consumed. Feeding behaviour traits monitored were daily feed intake (DFI; g/day), feed intake per meal (FIM; g/meal), number of daily meals (NDM; meals/day), duration of meal (DUM; min/meal), feeding rate (FR; g/min), and feeder occupation (FO; min/day). A partial least square (PLS) regression was used to predict PE, EnE and LipG from feeding behaviour traits, while including farrowing series (for PE only), age at slaughter and body weight at slaughter. Accuracy of PLS regression was assessed based on RMSE and R2for calibration and validation sets, and on concordance correlation coefficient (CCC), which were estimated over 100 replicates of calibration and validation sets. Models with a number of latent variables of 5, 2 and 3 were identified as optimal for PE, EnE, and LipG, which explained 34.64%, 55.42% and 82.68% of the total variation in PE, EnE, and LipG, respectively. Significant CCC were found between predicted and observed values for PE (0.50), EnE (0.70), and LipG (0.90). In conclusion, individual feeding behaviour traits can better predict EnE and LipG than for PE under dietary protein restriction when fedad libitum.

Implications

This study suggests that five feeding behaviour traits, which are automatically recorded via feeder stations in large numbers with little effort, together with body weight and age, may be used to predict protein efficiency, energy efficiency and lipid gain in Swiss Large White pigs receiving a protein reduced diet with considerable accuracy. This will allow for easy collection of large amounts of data on these traits for precision feeding and genetic selection strategies, especially when additional traits are added in the future to further improve accuracy.
Gene expression profiling of malaria parasites reveals common virulence gene expression in adult first-time infected patients and severe cases
Authors: Wichers Jan Stephan , Tonkin-Hill Gerry , Thye Thorsten , Krumkamp Ralf , Kreuels Benno , Strauss Jan , von Thien Heidrun , Scholz Judith Anna Marie , Hansson Helle Smedegaard , Jensen Rasmus Weisel , Turner Louise , Lorenz Freia-Raphaella , Schöllhorn Anna , Bruchhaus Iris , Tannich Egbert , Fendel Rolf , Otto Thomas Dan , Lavstsen Thomas , Gilberger Tim-Wolf , Duffy Michael Frank , Bachmann Anna
Published: November 2020

Sequestration ofPlasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derivedPfEMP1 adhesion proteins is central to the development of malaria pathogenesis.PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring each parasite a similar array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32P. falciparuminfected adult travelers returning to Germany. Patients were categorized into either malaria naïve (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. For differential expression analysis ofPfEMP1-encodingvargene transcripts werede novoassembled from RNA-seq data and, in parallel,varexpressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated withPfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-bindingPfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenicPfEMP1 variants are more common in patients with a naïve immune status and/or adverse inflammatory host responses to first infections favors growth of EPCR-binding parasites.
Genetic-epigenetic tissue mapping for plasma DNA: applications in prenatal testing, transplantation and oncology
Authors: Gai Wanxia , Zhou Ze , Agbor-Enoh Sean , Fan Xiaodan , Lian Sheng , Jiang Peiyong , Cheng Suk Hang , Wong John , Chan Stephen L. , Jang Moon Kyoo , Yang Yanqin , Liang Raymond H. S. , Chan Wai Kong , Ma Edmond S. K. , Leung Tak Y. , Chiu Rossa W. K. , Valantine Hannah , Chan K. C. Allen , Lo Y. M. Dennis
Published: November 2020

We developedGenetic-EpigeneticTissueMapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung-transplant recipients, we showed that, at 72 hours after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring and cancer screening.
BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome
Authors: Fursova Nadezda A. , Turberfield Anne H. , Blackledge Neil P. , Findlater Emma L. , Lastuvkova Anna , Huseyin Miles K. , Dobrinić Paula , Klose Robert J.
Published: November 2020

Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (H2AK119ub1) which is enriched at Polycomb-repressed gene promoters, but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification, without the need for elaborate gene-specific targeting mechanisms.