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Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 128,741 papers from 551,614 authors.

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100841: Water and phosphorus uptake by upland rice root systems unraveled under multiple scenarios: linking a 3D soil-root model and data
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Posted 27 Jan 2020

Water and phosphorus uptake by upland rice root systems unraveled under multiple scenarios: linking a 3D soil-root model and data
203 downloads bioRxiv developmental biology

Trung Hieu Mai, Pieterjan De Bauw, Andrea Schnepf, Roel Merckx, Erik Smolders, Jan Vanderborght

Background and aims: Upland rice is often grown where water and phosphorus (P) are limited and these two factors interact on P bioavailability. To better understand this interaction, mechanistic models representing small-scale nutrient gradients and water dynamics in the rhizosphere of full-grown root systems are needed. Methods: Rice was grown in large columns using a P-deficient soil at three different P supplies in the topsoil (deficient, suboptimal, non-limiting) in combination with two water regimes (field capacity versus drying periods). Root architectural parameters and P uptake were determined. Using a multiscale model of water and nutrient uptake, in-silico experiments were conducted by mimicking similar P and water treatments. First, 3D root systems were reconstructed by calibrating an architecure model with observed phenological root data, such as nodal root number, lateral types, interbranch distance, root diameters, and root biomass allocation along depth. Secondly, the multiscale model was informed with these 3D root architectures and the actual transpiration rates. Finally, water and P uptake were simulated. Key results: The plant P uptake increased over threefold by increasing P and water supply, and drying periods reduced P uptake at high but not at low P supply. Root architecture was significantly affected by the treatments. Without calibration, simulation results adequately predicted P uptake, including the different effects of drying periods on P uptake at different P levels. However, P uptake was underestimated under P deficiency, a process likely related to an underestimated affinity of P uptake transporters in the roots. Both types of laterals (i.e. S- and L-type) are shown to be highly important for both water and P uptake, and the relative contribution of each type depend on both soil P availability and water dynamics. Key drivers in P uptake are growing root tips and the distribution of laterals. Conclusions: This model-data integration demonstrates how multiple co-occurring single root phene responses to environmental stressors contribute to the development of a more efficient root system. Further model improvements such as the use of Michaelis constants from buffered systems and the inclusion of mycorrhizal infections and exudates are proposed.

100842: pH effect on strain-specific transcriptomes of the take-all fungus
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Posted 27 Jan 2020

pH effect on strain-specific transcriptomes of the take-all fungus
203 downloads bioRxiv pathology

Kévin Gazengel, Lionel Lebreton, Nicolas Lapalu, Joëlle Amselem, Anne-Yvonne Guillerm-Erckelboudt, Denis Tagu, Stéphanie Daval

The soilborne fungus Gaeumannomyces graminis var. tritici ( Ggt ) causes the take-all disease on wheat roots. Ambient pH has been shown to be critical in different steps of Ggt life cycle such as survival in bulk soil, saprophytic growth, and pathogenicity on plants. There are however intra-specific variations and we previously found two types of Ggt strains that grow preferentially either at acidic pH or at neutral/alkaline pH; gene expression involved in pH-signal transduction pathway and pathogenesis was differentially regulated in two strains representative of these types. To go deeper in the description of the genetic pathways and the understanding of this adaptative mechanism, transcriptome sequencing was achieved on two strains (PG6 and PG38) which displayed opposite growth profiles in two pH conditions (acidic and neutral). PG6, growing better at acidic pH, overexpressed in this condition genes related to energy production and protein deubiquitination. In contrast, PG38, which grew better at neutral pH, overexpressed in this condition genes involved in fatty acids metabolism. This strain also expressed stress resistance mechanisms at both pH, to assert a convenient growth under various ambient pH conditions. These differences in metabolic pathway expression between strains at different pH might buffer the effect of field or soil variation in wheat fields, and explain the success of the pathogen.

100843: The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk
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Posted 20 Apr 2020

The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk
203 downloads bioRxiv neuroscience

Alish B Palmos, Rodrigo R.R. Duarte, Demelza M Smeeth, Erin C Hedges, Douglas F. Nixon, Sandrine Thuret, Timothy R. Powell

Telomere shortening is one hallmark of cell ageing that can limit the proliferative capacity of cell populations and increase risk for age-related disease. It has been hypothesized that short telomeres, and subsequently a limited proliferative capacity of hippocampal progenitor cells, could contribute to smaller hippocampal volumes and impaired cognition, amongst psychiatric disorder patients. The current study employed a systematic, multidisciplinary approach which aimed to model the effects of telomere shortening on human hippocampal neurogenesis, and to explore its relationship with cognition and psychiatric disorder risk. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Aged progenitors demonstrated shorter telomeres (p<0.05), and reduced rates of cell proliferation, as marked by bromodeoxyuridine staining (p<0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene set enrichment analysis revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts showed a significant overlap with genes regulating cognitive function and risk for schizophrenia and bipolar disorder. Collectively, our results suggest that reductions in adult hippocampal neurogenesis, caused by telomere shortening, could represent a cellular mechanism contributing to age-related cognitive impairment and psychiatric disorder risk. ### Competing Interest Statement The authors have declared no competing interest.

100844: Temporal regulation of motor behavior on a modified forelimb dexterity test in mice
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Posted 19 Oct 2020

Temporal regulation of motor behavior on a modified forelimb dexterity test in mice
203 downloads bioRxiv neuroscience

Hisham Mohammed, Yue Li, Paola Di Grazia, Amanda Bernstein, Sydney Agger, Edmund Hollis

Hand and arm manual dexterity is a hallmark of humans and non-human primates. While rodents are less dexterous than primates, they provide powerful models for testing neural circuit function in behavioral output, including dexterous behaviors. In rodents, the single pellet reach task has been used extensively to study both dexterous forelimb motor learning as well as recovery from injury; however, mice exhibit high variability in task acquisition in comparison to rats and a significant percentage fail to learn the task. We have created a recessed version of the task that requires greater dexterity. This subtle modification increases both task difficulty as well as the proportion of mice that show an improvement with training. Furthermore, motor cortex inactivation shows a greater effect on the execution of the recessed forelimb reach task, with distinct effects on reach targeting vs grasping components depending on the timing of inhibitory activation. Kinematic analysis revealed differences in reach targeting upon transient cortical inhibition prior to reach onset. In summary, the recessed single pellet reach task provides a robust assessment of forelimb dexterity in mice and a tool for studying skilled motor acquisition and execution. ### Competing Interest Statement The authors have declared no competing interest.

100845: miRViz: a novel webserver application to visualize and interpret microRNA datasets
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Posted 22 Oct 2019

miRViz: a novel webserver application to visualize and interpret microRNA datasets
203 downloads bioRxiv genomics

Pierre Giroux, Ricky Bhajun, Stéphane Segard, Claire Picquenot, Céline Charavay, Lise Desquilles, Guillaume Pinna, Christophe Ginestier, Josiane Denis, Nadia Cherradi, Laurent Guyon

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the regulation of major pathways in eukaryotic cells through repression of their target genes at the post-transcriptional level. While high-throughput approaches are broadly used to decipher the biological relevance of miRNAs, extraction of significant information from large miRNA datasets remains challenging. For example, sequencing technologies can quantify the relative expression of up to thousands of mature miRNAs under various experimental conditions. However, in such datasets, small subsets of miRNAs can often show significant differential expression, and deciding which one(s) should be further analyzed can prove difficult. Thus, the current challenge resides in objective analysis, interpretation and visualization of these large datasets, for which specifically suited methods are lacking. Here, we present miRViz (http://mirviz.prabi.fr/), a webserver application designed to visualize and interpret large miRNA datasets, with no need for programming skills. MiRViz has two main goals: (1) to help biologists to raise data-driven hypotheses; and (2) to share miRNA datasets in a straightforward way through publishable quality data representation, with emphasis on relevant groups of miRNAs.

100846: The C-terminal domain of Clostridioides difficile TcdC is exposed on the bacterial cell surface
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Posted 11 Dec 2019

The C-terminal domain of Clostridioides difficile TcdC is exposed on the bacterial cell surface
203 downloads bioRxiv microbiology

Ana M. Oliveira Paiva, Leen de Jong, Annemieke H. Friggen, Wiep Klaas Smits, Jeroen Corver

Clostridioides difficile is an anaerobic gram-positive bacterium that can can produce the large clostridial toxinsoxin A and Toxin B, encoded within the pathogenicity locus (PaLoc). The PaLoc also encodes the sigma factor TcdR, that positively regulates toxin gene expression, and TcdC, a putative negative regulator of toxin expression. TcdC is proposed to be an anti-sigma factor, however, several studies failed to show an association between tcdC genotype and toxin production. Consequently, TcdC function is not yet fully understood. Previous studies have characterized TcdC as a membrane-associated protein with the ability to bind G-quadruplex structures. The binding to the DNA secondary structures is mediated through the OB-fold domain present at the C-terminus of the protein. This domain was previously also proposed to be responsible for the inhibitory effect on toxin gene expression, implicating a cytoplasmic localization of the C-terminal OB-fold. In this study we aimed to obtain topological information on the C-terminus of TcdC. Using Scanning Cysteine Accessibility Mutagenesis and a HiBiT-based system, we demonstrate that the C-terminus of TcdC is located extracellularly. The extracellular location of TcdC is not compatible with direct binding of the OB-fold domain to intracellular nucleic acid or protein targets, and suggests a mechanism of action that is different from characterized anti-sigma factors.

100847: Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection
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Posted 20 May 2020

Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection
203 downloads bioRxiv microbiology

Jyoti Batra, Manu Anantpadma, Gabriel I. Small, Olena Shtanko, Mengru Zhang, Dandan Liu, Caroline G. Williams, Nadine Biedenkopf, Stephan Becker, Michael L Gross, Daisy W. Leung, Robert A Davey, Gaya K Amarasinghe, Nevan J Krogan, Christopher F Basler

The Ebola virus VP30 protein interacts with the viral nucleoprotein and with host protein RBBP6 via PPxPxY motifs. In these interactions the largely alpha-helical carboxy-terminal domain of the EBOV VP30 engages with the motif such that the prolines adopt non-canonical orientations, as compared to other proline-rich motifs. Affinity tag-purification mass spectrometry identified additional PPxPxY-containing host proteins, including hnRNP L, hnRNPUL1 and PEG10, as VP30 interactors. Of these, hnRNP L and PEG10, like RBBP6, inhibit viral RNA synthesis and EBOV replication, whereas hnRNPUL1 enhances. Further, double knockdown studies support additive effects of RBBP6 and hnRNP L. Binding studies demonstrate variable capacity of PPxPxY motifs to bind VP30 and the extended motif PxPPPPxY is demonstrated to confer optimal binding and to inhibit RNA synthesis, with the fifth proline and the tyrosine being most critical. Competition binding and hydrogen-deuterium exchange studies demonstrate that each protein binds a similar interface on VP30 and impacts VP30 phosphorylation. VP30 therefore represents a novel proline recognition domain that allows multiple host proteins to target a single viral protein-protein interface to modulate viral transcription. ### Competing Interest Statement The authors have declared no competing interest.

100848: Robust differentiation of human enteroendocrine cells from intestinal stem cells
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Posted 21 Sep 2020

Robust differentiation of human enteroendocrine cells from intestinal stem cells
203 downloads bioRxiv developmental biology

Daniel Zeve, Eric Stas, Xiaolei Yin, Sarah Dubois, Manasvi S. Shah, Erin P. Syverson, Sophie Hafner, Jeffrey M. Karp, Diana L. Carlone, David T. Breault

Enteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells, ex vivo , have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of key transcriptional regulators, GATA4, JNK and FOXO1, known to mediate endodermal development and hormone production, together with directed differentiation of human ISCs. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, and GIP upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics. ### Competing Interest Statement The author J.M.K. holds equity in Frequency Therapeutics, a company that has an option to license IP generated by J.M.K and that may benefit financially if the IP is licensed and further validated. The interests of J.M.K. was reviewed and are subject to a management plan overseen by their institutions in accordance with their conflict of interest policies.

100849: Automatic subtyping of individuals with Primary Progressive Aphasia
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Posted 05 Apr 2020

Automatic subtyping of individuals with Primary Progressive Aphasia
203 downloads bioRxiv neuroscience

Charalambos Themistocleous, Bronte Ficek, Kimberly Webster, Dirk-Bart den Ouden, Argye E. Hillis, Kyrana Tsapkini

Background: The classification of patients with Primary Progressive Aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. Objective The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA. Methods In this paper, we present a machine learning model based on Deep Neural Networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as expert clinicians' classifications. Results: The DNN model outperformed the other machine learning models with 80% classification accuracy, providing reliable subtyping of patients with PPA into variants and it even outperformed auditory classification of patients into variants by clinicians. Conclusions: We show that the combined speech and language markers from connected speech productions provide information about symptoms and variant subtyping in PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick and inexpensive classification of patients with PPA. ### Competing Interest Statement The authors have declared no competing interest.

100850: P- wave Centric Ambulatory ECG Monitoring in Infants and Young Children
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Posted 20 Jun 2020

P- wave Centric Ambulatory ECG Monitoring in Infants and Young Children
203 downloads medRxiv pediatrics

Angela Romme, Hoang Nguyen

Background: P-wave centric ambulatory ECG monitoring has emerged as an important tool aiding the diagnosis of arrhythmias. However, with no specific pediatric approved ambulatory monitors, efficacy and user experience with these devices in young infants have not been established. Objective: To evaluate tracings quality in children less than 10 kilograms who have been prescribed the P-wave centric Carnation Ambulatory Monitor (CAM) patch by Bardy Diagnostics Inc. Methods: We performed an observational, retrospective study on patients prescribed 48-hour ambulatory Holter monitoring. We aimed to detail our experience with using the CAM patch with a patient population smaller than the recommended weight set forth by Bardy Diagnostics Inc. All patients less than 10 kg who were prescribed a 48-hour CAM patch were included in this review. Additionally, 2 different monitor locations (over the sternum and horizontal over the left axilla) were assessed to address the optimal placement in small children less than 10 kg. Results: A total of 33 CAM reports from 25 patients, aged 0-15 months were included in the study. Mean patient age was 4.2 months {+/-} 5.0 and mean weight was 5.3 kg {+/-} 2.4. Twenty-Four percent of patients (8/33) had known congenital heart disease. Indications for monitoring included: tachyarrhythmia (15/33, 45%), bradycardia (6/33, 18%), ectopic rhythm (9/33, 27%), cardiac tumor (1/33, 1%), and prolonged QT interval (1/33, 1%). All CAM reports showed clear, identifiable P waves which were diagnostic and lead to changes in medical management for 30% of patients (i.e. medication adjustments or discharge from cardiology care). When comparing the P wave between a 12-lead ECG and the CAM patch, 77% of patients had the same or similar P wave morphology to lead aVF. We found the recommended, upright placement over the sternum performed better than the horizontal placement over the left axilla for small infants and children less than 10 kg. Conclusion: A P-wave centric Holter monitor is helpful in providing accurate diagnostics tracings even in infants and small children aiding in their clinical management.

100851: In-silico screening of drug candidates for thermoresponsive liposome formulations
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Posted 12 May 2020

In-silico screening of drug candidates for thermoresponsive liposome formulations
203 downloads bioRxiv pharmacology and toxicology

Martin Balouch, Martin Srejber, Marek Soltys, Petra Janska, Frantisek Stepanek, Karel Berka

Liposomal formulations can be advantageous in a number of scenarios such as targeted delivery to reduce the systemic toxicity of highly potent Active Pharmaceutical Ingredients (APIs), to increase drug bioavailability by prolonging systemic circulation, to protect labile APIs from degradation in the gastrointestinal tract, or to improve skin permeation in dermal delivery. However, not all APIs are suitable for encapsulation in liposomes. Some of the issues are too high permeability of the API across the lipid bilayer, which may lead to premature leakage, too low permeability, which may hinder the drug release process, or too strong membrane affinity, which may reduce the overall efficacy of drug release from liposomes. Since the most reliable way to test API encapsulation and release from liposomes so far has been experimental, an in silico model capable of predicting API transport across the lipid bilayer might accelerate formulation development. In this work, we demonstrate a new in silico approach to compute the temperature dependent permeability of a set of compounds across the bilayer of virtual liposomes constructed by molecular dynamics simulation. To validate this approach, we have conducted a series of experiments confirming the model predictions using a homologous series of fluorescent dyes. Based on the performance of individual molecules, we have defined a set of selection criteria for identifying compatible APIs for stable encapsulation and thermally controlled release from liposomes. To further demonstrate the in silico-based methodology, we have screened the DrugBank database, identified potent drugs suitable for liposome encapsulation and successfully carried out the loading and thermal release of one of them - an antimicrobial compound cycloserine. ### Competing Interest Statement The authors have declared no competing interest.

100852: Running rabid: modelling of European bat lyssavirus (EBLV) pathways in a bat population
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Posted 07 Oct 2019

Running rabid: modelling of European bat lyssavirus (EBLV) pathways in a bat population
203 downloads bioRxiv ecology

Carys Breeze, James Aegerter, Graham C Smith

Worldwide the 16 species of lyssaviruses all exhibit a similar pathology in most mammals, including man; with successful infections usually ending with death. Recently it has been demonstrated that European bat lyssaviruses (EBLV) are not invariably fatal in their wild reservoir host bat species, however the mechanisms and epidemiological consequences of this resistance are interesting and unexplored and the fundamental pathology in bats is still unclear. Here we modelled alternative pathological pathways to explore which appear most plausible, with respect to our limited knowledge of bat-rabies epidemiology and also host population dynamics. Two models were created, one based on a standard progression of disease (classic SEIR model) and the other modified to allow for animals to become either rabid or immune (flexible model). Of these our flexible model was found to be more plausible, demonstrating a much lower sensitivity to epidemiological parameters and by inference the more likely to represent the real-life process occurring in wild European bat populations, with a comparative state space ratio of 1:47. This result implies that it is highly probable survival and post-infection immunity is a widespread epidemiological phenomenon rather than an infrequent consequence of an aborted infection in few individuals. These results can be used to inform laboratory studies on bat immunology and future bat modelling work.

100853: Gait variability and its progression over time in Parkinson's disease is linked to the cortical cholinergic system
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Posted 16 May 2020

Gait variability and its progression over time in Parkinson's disease is linked to the cortical cholinergic system
203 downloads medRxiv neurology

Kevin B Wilkins, Jordan E. Parker, Helen M Bronte-Stewart

Parkinson's disease (PD) is a systemic brain disorder where the cortical cholinergic network begins to degenerate early in the disease process. Readily accessible, quantitative, and specific behavioral markers of the cortical cholinergic network are lacking. Although degeneration of the dopaminergic network may be responsible for deficits in cardinal motor signs, the control of gait is a complex process and control of higher-order aspects of gait, such as gait variability, may be influenced by cognitive processes attributed to cholinergic networks. We investigated whether swing time variability, a metric of gait variability that is independent from gait speed, was a quantitative behavioral marker of cortical cholinergic network integrity in PD. Twenty-two individuals with PD and twenty-nine age-matched controls performed a validated stepping-in-place (SIP) task to assess swing time variability off all therapy. The PD cohort also underwent structural MRI scans to measure gray matter volume of the Nucleus Basalis of Meynert (NBM), the key node in the cortical cholinergic network. Swing time variability was also measured ON subthalamic nucleus (STN) deep brain stimulation (DBS) in PD individuals. A subset of eleven individuals with PD completed the SIP task again off all therapy after three years of continuous DBS. Clinical motor assessments were performed for each condition. Swing time variability was significantly greater (i.e., worse) in PD compared to controls and greater swing time variability was related to greater atrophy of the NBM. STN DBS significantly improved cardinal motor signs but did not improve swing time variability. Swing time variability worsened in PD, off therapy, after three years of continuous STN DBS, and NBM atrophy predicted the degree of increase. In contrast, cardinal motor signs did not progress. These results demonstrate that swing time variability is a reliable marker of cortical cholinergic health, and support a framework in which higher-order aspects of gait control in PD are reliant on the cortical cholinergic system, in contrast to other motor aspects of PD that rely on the dopaminergic network.

100854: Self-Organizing 3D Human Choroid Plexus-Ventricle-Cortical Organoids
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Posted 01 Oct 2020

Self-Organizing 3D Human Choroid Plexus-Ventricle-Cortical Organoids
203 downloads bioRxiv neuroscience

Mohammed R Shaker, Justin Cooper-White, Ernst J. Wolvetang

Both the choroid plexus (CP) and the cortex are derived from the rostral neural tube during early embryonic development. In addition to producing CSF, the CP secretes essential factors that orchestrate cortical development and later neurogenesis. Previous brain modeling efforts with human pluripotent stem cells (hPSCs) generated either cortical or CP tissues in 3D culture. Here, we used hPSC-derived neuroectodermal cells, the building blocks of the anterior body, to simultaneously generate CP that forms ventricles and cortical cells in organoids (CVCOs), which can be maintained as 3D organoid cultures. Large scale culture revealed reproducibility of the protocol independent of cell lines, clones or batches. CVCOs contain mature and functional CP that projects multiple cilia into the ventricle-like fluid filled cysts and is in direct contact with appropriately patterned cortical cells. CVCOs thus recapitulate key features of developing forebrain structures observed in in vivo and constitute a useful for dissecting the role of CP in human forebrain development in health and disease. ### Competing Interest Statement The authors have declared no competing interest.

100855: Toxicities of PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
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Posted 22 Jul 2020

Toxicities of PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
203 downloads medRxiv oncology

Xiangy Kong, Li Chen, Ryan J Sullivan, Zhihong Qi, Yulu Liu, Yi Fang, Lin Zhang, Jing Wang

Background: Immunotherapy, especially immune-checkpoint inhibitors (PD-1 and PD-L1 inhibitors), is now one of the mainstays of cancer treatment. Several studies have analyzed treatment-related toxicities of immunotherapy. However, small sample size, rough and unspecific stratification, and lack of comparison (pure sing-arm studies) are common limitations. Detailed organ- and system-specific toxicities remain not clear enough. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and others (CNKI), from database inception to Mar 31, 2020, for randomized controlled trials (RCTs) related to PD-1/PD-L1 inhibitors that had available toxicity data. We excluded non-randomized trials. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. We calculated the pooled relative risks (RRs) and corresponding 95% confidence intervals (95% CIs) using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on toxicity grade (severity), system and organ, treatment regimens in the intervention arm and control arm, PD-1/PD-L1 inhibitor drug type, and cancer histotype. We applied the five-point Jadad ranking system to evaluate the quality of the selected studies. We performed multivariate meta-regression analyses to explore the proportion of between-study variance. Results: A total of 29 eligible RCTs including 8067 patients were selected for the meta-analysis based on specified inclusion and exclusion criteria. Patients treated with PD-1/PD-L1 inhibitors were at lower risks of overall toxicities (all grades: RR 0.91, 95% CI 0.89-0.92; grade 3~4: RR 0.76, 95% CI 0.74-0.78), including gastrointestinal toxicity (all grades: RR 0.68, 95% CI 0.60-0.77; grade 3~4: RR 0.71, 95% CI 0.43-1.20), hematologic toxicity (all grades: RR 0.66, 95% CI 0.51-0.85; grade 3~4: RR 0.55, 95% CI 0.37-0.83), and treatment event leading to discontinuation (all grades: RR 0.78, 95% CI 0.72-0.84; grade 3~4: RR 0.58, 95% CI 0.49-0.67); but were at higher risks for respiratory toxicity (all grades: RR 1.74, 95% CI 1.33-2.28; grade 3~4: RR 1.92, 95% CI 1.45-2.55) and endocrine toxicity (all grades: RR 1.70, 95% CI 0.62-4.69; grade 3~4: RR 1.29, 95% CI 0.45-3.69). The subgroup analyses indicated that when compared with the control, toxicity comparison tendency for PD-1/PD-L1 inhibitors varied with the toxicity grade, affected system and organ, treatment regimens in the intervention arm and control arm, drug type, and cancer histotype. The male-female ratio was a statistically significant variable in the Meta-Regression analysis (I2=89.1,{tau}2=0.01, and P=0.001). Conclusion: For most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and CTLA-4 inhibitors. However, for some specific toxicities including respiratory, cutaneous, and endocrine toxicities, the case was the opposite. The toxicity grade, system and organ, treatment regimens, drug type, and cancer histotype were all influencing factors. To our knowledge, this was by far the most comprehensive meta-analysis of RCTs on toxicities of immune-checkpoint inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations.

100856: Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform.
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Posted 21 Nov 2019

Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform.
203 downloads bioRxiv genetics

Guy Helman, Asako Takanohashi, Tracy L. Hagemann, Ming D. Perng, Marzena Walkiewicz, Sarah Woidill, Sunetra Sase, Zachary Cross, Yangzhu Du, Ling Zhao, Amy Waldman, Bret C. Haake, Ali Fatemi, Michael B Brenner, Omar Sherbini, Albee Messing, Adeline Vanderver, Cas Simons

Alexander disease results from gain of function mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for approximately 90% of GFAP protein in the central nervous system. Here we describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre-mRNA and result in upregulation of a previously uncharacterised GFAP lambda isoform (NM\_001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM\_001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini-gene splicing reporter assay, we demonstrate both variants result in upregulation of the lambda isoform. We assessed other GFAP variants in the ClinVar database for predicted aberrant splicing and, using the same assay, demonstrated significant changes to splicing for two selected variants. In one case, we found that altered splicing due to a +5 intronic variant resulted in the inclusion of the GFAP kappa isoform. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing in order to inform future pathophysiologic and therapeutic study for Alexander disease.

100857: Cardiometabolic risk factors and preclinical target organ damage among adults in Ghana: Findings from a national study
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Posted 03 May 2020

Cardiometabolic risk factors and preclinical target organ damage among adults in Ghana: Findings from a national study
203 downloads medRxiv cardiovascular medicine

Jie Li, Isaac Kofi Owusu, Qingshan Geng, Aba Ankomaba Folson, Zhichao Zheng, Yaw Adu-Boakye, Xinran Dong, Wen-Chih Wu, Francis Agyekum, Hongwen Fei, Harold Ayetey, Mulan Deng, Fred Adomako-Boateng, Zuxun Jiang, Braimah Baba Abubakari, Zhao Xian, Forster Nketiah Fokuoh, Lambert Tetteh Appiah, Simin Liu, Chunying Lin

Background: Sub Saharan Africa (SSA) has the highest prevalence of cardiovascular diseases (CVD). Nevertheless, very few studies have directly examined the development of and risk factors for CVD among Africans. Objective: To examine CVD risk factors and outcomes particularly in the early stage of CVD development among adults in Ghana. Methods: Using a stratified multistage random sampling method, 1,106 participants were recruited as a nationally representative sample of the general population [&ge;]18 years in Ghana from 2016 to 2017. For each participant, we measured CVD risk factors and preclinical target organ damage (TOD) for CVD development. Results: The prevalence of CVD risk factors was 21.1% for obesity, 10.8% for diabetes, 55.4% for hypertension, 37.3% for dyslipidemia, 12.8% for hyperuricemia, and 39.3% for hsCRP>3 mg/L in the recruited population. The prevalence of preclinical TOD was 8.6% for peripheral artery disease (PAD), 14.7% for carotid thickening, 5.9% for left ventricular hypertrophy (LVH), and 4.4% for chronic kidney disease (CKD). Three CVD risk factors appeared to play most prominent roles in TOD development, including obesity for PAD (OR 1.88, 95% CI 1.13, 3.09), hypertension for carotid thickening (OR 1.57, 95% CI 0.99, 2.54) and LVH (OR 6.25, 95% CI 2.98, 14.50), and hyperuricemia for CKD (OR 5.56, 95% CI 2.79, 11.15). Conclusions: The prevalence of CVD risk factors and early outcomes have reached epidemic proportions among Ghanaian adults. The distinct patterns of risk factors in the development of TOD presents important challenges and opportunities for interventions to improve cardiometabolic health among adults in Ghana.

100858: A novel and conserved cell wall enzyme that can substitute for the Lipid II synthase MurG
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Posted 12 Oct 2020

A novel and conserved cell wall enzyme that can substitute for the Lipid II synthase MurG
203 downloads bioRxiv microbiology

Lei Zhang, K. Ramijan, V.J. Carrión, L.T. van der Aart, J. Willemse, Gilles P. van Wezel, D. Claessen

The cell wall is a stress-bearing structure and a unifying trait in bacteria. Without exception, synthesis of the cell wall involves formation of the precursor molecule Lipid II by the activity of the essential biosynthetic enzyme MurG, which is encoded in the division and cell wall synthesis (dcw) gene cluster. Here we present the discovery of a novel cell wall enzyme that can substitute for MurG. A mutant of Kitasatospora viridifaciens lacking a significant part of the dcw cluster including murG surprisingly produced Lipid II and wild-type peptidoglycan. Genomic analysis identified a distant murG paralogue, which encodes a putative enzyme that shares only around 31% aa sequence identity with MurG. We show that this enzyme can replace the canonical MurG, and we therefore designated it MurG2. Orthologues of murG2 are present in 38% of all genomes of Kitasatosporae and members of the sister genus Streptomyces. CRISPRi experiments showed that K. viridifaciens murG2 can also functionally replace murG in Streptomyces coelicolor, thus validating its bioactivity and demonstrating that it is active in multiple genera. Altogether, these results identify MurG2 as a bona fide Lipid II synthase, thus demonstrating plasticity in cell wall synthesis. ### Competing Interest Statement The authors have declared no competing interest.

100859: Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c
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Posted 31 May 2020

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c
203 downloads bioRxiv neuroscience

Cezar M. Tigaret, Tzu-Ching E. Lin, Edward Morrell, Lucy Sykes, Michael C O'Donovan, Michael J Owen, Lawrence S Wilkinson, Matt W Jones, Kerrie L Thomas, Jeremy Hall

Genetic variation in CACNA1C , which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of altered Cacna1c dosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signaling in dendritic spines and decreased signaling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioral and synaptic plasticity deficits in Cacna1c+/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder. ### Competing Interest Statement The authors have declared no competing interest.

100860: Schizophrenia patients show aberrant brain dynamics associated with gestalt-perception and corollary discharge: Reflections from ERP and fMRI findings
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Posted 11 Nov 2019

Schizophrenia patients show aberrant brain dynamics associated with gestalt-perception and corollary discharge: Reflections from ERP and fMRI findings
203 downloads bioRxiv neuroscience

Arun Sasidharan, Ajay Kumar Nair, Vrinda Marigowda, Ammu Lukose, John P. John, Bindu M. Kutty

Background: Schizophrenia is a disorder of higher mental attributes, and is characterized by psychotic symptoms that are believed to involve a basic inability to make valid predictions about expected sensations and experiences. These have been reported separately while monitoring either externally generated environmental patterns (e.g. gestalt-perception) or self-generated sensory experiences (e.g. corollary-discharge). As the pathophysiology behind predictive dysfunction is better viewed as an aberration in brain's functional synchrony, a whole brain assessment using electroencephalographic (EEG) event related potential (ERP) and functional magnetic resonance imaging (fMRI) techniques, would offer a wider perspective to brain network abnormalities in schizophrenia. Method: We used our lab-developed game-based task which presents degraded two-tone images to assess gestalt-perception, and simultaneously alters the congruency between participant's button-press response and its auditory feedback to assess corollary-discharge. In both patients with schizophrenia and age-matched healthy controls, we explored event-related changes in an EEG-ERP study (n=21 each) and whole brain functional connectivity changes in a fMRI study (patients,n=12; controls,n=16), using the same task. Results: Patients showed reduced event-related EEG dynamics during both the error-prediction conditions (gestalt-perception and corollary-discharge), which include reduction in average waveforms (around N170 and N1-P2 complex, respectively) and altered theta dynamics (power and phase). Source-level EEG measures were clustered around the cingulo-insular network. fMRI functional connectivity analysis also found the abnormality in these brain regions, forming significantly weak connections with right insular/opercular cortex. Conclusions: This is the first study to explore thalamo-cortical dysfunction hypothesis in schizophrenia by integrating prediction-error-coding during perception (gestalt-perception) and action (corollary-discharge) using two neuroimaging modalities (EEG-ERP and fMRI). Besides adding to the knowledgebase of schizophrenia research, our novel task design and findings on theta-oscillation could benefit in the development of effective neuromodulatory therapeutic tools for patients with schizophrenia such as neurofeedback and transcranial brain stimulation.

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