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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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100861: 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.

100862: Aβ-induced synaptic injury is mediated by presynaptic expression of amyloid precursor protein (APP) in hippocampal neurons
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Posted 20 Jul 2020

Aβ-induced synaptic injury is mediated by presynaptic expression of amyloid precursor protein (APP) in hippocampal neurons
203 downloads bioRxiv neuroscience

Elena Vicario-Orri, Kensaku Kasuga, Sheue-Houy Tyan, Karen Chiang, Silvia Viana da Silva, Eric A Bushong, Katherine DeLoach, I-Fang Ling, Liqun Luo, Mark H Ellisman, Stefan Leutgeb, Edward H. Koo

The patterns of Aβ-induced synaptic injury were examined after targeting of the amyloid precursor protein (APP) preferentially to either CA1 or CA3 neurons using Cre-lox technology combined with tetracycline-regulated expression. Both CA1- and CA3-APP-expressing transgenic mouse lines exhibited reduction in long-term potentiation (LTP) only when APP was expressed in neurons presynaptic to the recording site, whereas LTP remained comparable to wild-type mice when APP was expressed in postsynaptic neurons. As quantified by both light and electron microscopy, this orientation-specific impairment in synaptic plasticity was mirrored by synaptic loss in regions receiving axonal inputs from neurons expressing APP. Furthermore, Aβ plaque deposition also occurred only in the postsynaptic axonal fields of APP-expressing neurons. These deficits were reversed not only with doxycycline to inhibit APP expression but also with γ-secretase and Fyn kinase inhibitors, supporting the interpretation that the observed synaptic injury was mediated by Aβ. Taken together, these results demonstrate that APP/Aβ-induced synaptic toxicity is preferentially initiated by signaling of presynaptically expressed APP to the postsynaptic compartment. ### Competing Interest Statement The authors have declared no competing interest.

100863: Translocation of an arctic seashore plant reveals signs of maladaptation to altered climatic conditions
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Posted 23 May 2020

Translocation of an arctic seashore plant reveals signs of maladaptation to altered climatic conditions
203 downloads bioRxiv ecology

M.H. Hällfors, S. Lehvävirta, T.R. Aandahl, I.-M. Lehtimäki, L.O. Nilsson, A.L. Ruotsalainen, L.E. Schulman, M.-T. Hyvärinen

Ongoing anthropogenic climate change alters the local climatic conditions to which species may be adapted. Information on species’ climatic requirements and their intraspecific variation is necessary for predicting the effects of climate change on biodiversity. We used a climatic gradient to test whether populations of two allopatric varieties of an arctic seashore herb ( Primula nutans ssp. finmarchica ) show adaptation to their local climates and how a future warmer climate may affect them. Our experimental set-up combined i) a reciprocal translocation within the distribution range of the species with ii) an experiment testing performance of the sampled populations in warmer climatic conditions south of their range. We monitored survival, size, and flowering over four growing seasons as measures of performance and, thus, proxies of fitness. We found that both varieties performed better in experimental gardens towards the north. Interestingly, highest up in the north, the southern variety outperformed the northern one. Supported by weather data, this suggests that the climatic optima of both varieties has moved at least partly outside their current range. Further warming would make the current environments of both varieties even less suitable. We conclude that Primula nutans ssp. finmarchica is already suffering from adaptation-lag due to climate change, and that further warming may be increase this maladaptation, especially for the northern variety. The study also highlights that it is not sufficient to run only reciprocal translocation experiments. Climate change is already shifting the optimum conditions for many species and adaptation needs also to be tested outside the current range of the focal taxon in order to include both historic conditions and future conditions. ### Competing Interest Statement The authors have declared no competing interest.

100864: Scalable Models of Antibody Evolution and Benchmarking of Clonal Tree Reconstruction Methods
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Posted 20 Sep 2020

Scalable Models of Antibody Evolution and Benchmarking of Clonal Tree Reconstruction Methods
203 downloads bioRxiv immunology

Chao Zhang, Andrey V. Bzikadze, Yana Safonova, Siavash Mirarab

Affinity maturation (AM) of antibodies through somatic hypermutations (SHMs) enables the immune system to evolve to recognize diverse pathogens. The accumulation of SHMs leads to the formation of clonal trees of antibodies produced by B cells that have evolved from a common naive B cell. Recent advances in high-throughput sequencing have enabled deep scans of antibody repertoires, paving the way for reconstructing clonal trees. However, it is not clear if clonal trees, which capture micro-evolutionary time scales, can be reconstructed using traditional phylogenetic reconstruction methods with adequate accuracy. In fact, several clonal tree reconstruction methods have been developed to fix supposed shortcomings of phylogenetic methods. Nevertheless, no consensus has been reached regarding the relative accuracy of these methods, partially because evaluation is challenging. Benchmarking the performance of existing methods and developing better methods would both benefit from realistic models of clonal tree evolution specifically designed for emulating B cell evolution. In this paper, we propose a model for modeling B cell clonal tree evolution and use this model to benchmark several existing clonal tree reconstruction methods. Our model, designed to be extensible, has several features: by evolving the clonal tree and sequences simultaneously, it allows modelling selective pressure due to changes in affinity binding; it enables scalable simulations of millions of cells; it enables several rounds of infection by an evolving pathogen; and, it models building of memory. In addition, we also suggest a set of metrics for comparing clonal trees and for measuring their properties. Our benchmarking results show that while maximum likelihood phylogenetic reconstruction methods can fail to capture key features of clonal tree expansion if applied naively, a very simple postprocessing of their results, where super short branches are contracted, leads to inferences that are better than alternative methods. ### Competing Interest Statement The authors have declared no competing interest.

100865: 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.

100866: Long-lasting event-related beta synchronizations of electroencephalographic activity in response to support-surface perturbations during upright stance
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Posted 08 Jun 2020

Long-lasting event-related beta synchronizations of electroencephalographic activity in response to support-surface perturbations during upright stance
203 downloads bioRxiv neuroscience

Akihiro Nakamura, Yasuyuki Suzuki, Matija Milosevic, Taishin Nomura

Movement related beta band cortical oscillations, including beta rebound after execution and/or suppression of movement, have drawn attention in upper extremity motor control literature. However, fewer study focused on beta band oscillations during postural control in upright stance. Here, we examined beta rebound and other components of electroencephalogram (EEG) activity during perturbed upright stance to investigate supraspinal contributions to postural stabilization. Particularly, we aimed to clarify the timing and duration of beta rebound within a non-sustained, but long-lasting, postural recovery process that occurs more slowly compared to upper extremities. To this end, EEG signals were acquired from nine healthy young adults in response to a support-surface perturbation, together with the center of pressure (CoP) and mass (CoM) and electromyogram (EMG) activities of ankle muscles. Event-related potentials (ERPs) and event-related spectral perturbations were computed from EEG data using the perturbation-onset as a triggering event. After short-latency (< 0.3 s) ERPs, our results showed high-beta band power decrease (event-related desynchronization), which was followed by an event-related synchronization at high-beta band and theta band desynchronization. Specifically, beta synchronization (beta rebound) was sustained for as long as three seconds. EMGs of the ankle muscles and the ankle and hip joint torques remained activated in the first half period of the beta rebound. They returned to the steady-state in the remaining phase, where the CoP/CoM were in their final approach to the equilibrium. We propose possible mechanistic causes of the long-lasting beta rebound, which may be related to underlying intermittent control strategy in upright stance. New & Noteworthy Beta rebound cortical activity was identified during postural recovery from a perturbed upright stance. Contrary to upper extremities, it was initiated before the recovery of motion was completed, and sustained for as long as three seconds. Those novel characteristics of the beta rebound might be caused by slow dynamics of the upright posture and by selections of on/off switching in an intermittent feedback controller, which was shown to stabilize upright posture. ### Competing Interest Statement The authors have declared no competing interest.

100867: A novel tool for standardizing clinical data in a realism-based common data model
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Posted 14 May 2020

A novel tool for standardizing clinical data in a realism-based common data model
203 downloads bioRxiv bioinformatics

Hayden G. Freedman, Heather Williams, Mark A. Miller, David Birtwell, Danielle L Mowery, Christian J Stoeckert

Standardizing clinical information in a common data model is important for promoting interoperability and facilitating high quality research. Semantic Web technologies such as Resource Description Framework can be utilized to their full potential when a clinical data model accurately reflects the reality of the clinical situation it describes. To this end, the Open Biomedical Ontologies Foundry provides a set of ontologies that conform to the principles of realism and can be used to create a realism-based clinical data model. However, the challenge of programmatically defining such a model and loading data from disparate sources into the model has not been addressed by pre-existing software solutions. The PennTURBO Semantic Engine is a tool developed at the University of Pennsylvania that works in conjunction with data aggregation software to transform source-specific RDF data into a source-independent, realism-based data model. This system sources classes from an application ontology and specifically defines how instances of those classes may relate to each other. Additionally, the system defines and executes RDF data transformations by launching dynamically generated SPARQL update statements. The Semantic Engine was designed as a generalizable RDF data standardization tool, and is able to work with various data models and incoming data sources. Its human-readable configuration files can easily be shared between institutions, providing the basis for collaboration on a standard realism-based clinical data model. ### Competing Interest Statement The authors have declared no competing interest.

100868: Harnessing Ultrasound-Stimulated Phase Change Contrast Agents to Improve Antibiotic Efficacy Against Methicillin-Resistant Staphylococcus aureus Biofilms
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Posted 01 Jun 2020

Harnessing Ultrasound-Stimulated Phase Change Contrast Agents to Improve Antibiotic Efficacy Against Methicillin-Resistant Staphylococcus aureus Biofilms
203 downloads bioRxiv microbiology

Phillip G. Durham, Ashelyn E Sidders, Paul A. Dayton, Brian P. Conlon, Virginie Papadopoulou, Sarah E. Rowe

Biofilms are associated with chronic infection and frequently require surgical intervention even after prolonged antibiotic therapy. Bactericidal antibiotics are often ineffective at eradicating genetically susceptible cells within a biofilm because: 1) most conventional antibiotics target ATP-dependent processes and so work poorly on metabolically indolent persister cells within a biofilm; and 2) the biofilm matrix can act as a physical barrier to drug diffusion of certain classes of antibiotics. Antibiotic therapy that fails to completely eradicate the pathogen leads to chronic and relapsing infections, major financial healthcare burdens and significant mortality. Numerous approaches have been taken to improve biofilm killing but these often fail to achieve eradication. We address this problem with a novel two-pronged strategy with the aim of eradicating biofilm infection using 1) antibiotics which target persister cells as well as 2) improving drug penetration using ultrasound-stimulated phase-change contrast agents (US-PCCA). We previously demonstrated that rhamnolipids, biosurfactant molecules produced by Pseudomonas aeruginosa, significantly potentiated aminoglycoside efficacy against S. aureus biofilm. We have also shown that US-PCCA can transiently disrupt biological barriers to therapeutic macromolecules. We hypothesized that combining antibiotics which target persister cells with US-PCCA to improve drug penetration could eradicate methicillin resistant S. aureus (MRSA) biofilms. To investigate this, we treated MRSA biofilms with a range of conventional and anti-persister antibiotics and/or US-PCCA. We found that vancomycin was significantly potentiated by US-PCCA, but a fraction of cells remained viable after the combination treatment. Aminoglycosides alone or in combination with US-PCCA displayed limited efficacy against MRSA biofilms. In contrast, the anti-persister combination of rhamnolipids and aminoglycosides combined with US-PCCA dramatically reduced biofilm viability, frequently culminating in complete eradication of the biofilm. These data demonstrate that biofilm eradication can be achieved using a combined approach improving drug penetration and therapeutics that target persister cells. ### Competing Interest Statement P.A.D declares that he is a co-inventor on a patent describing the formulation of low boiling-point perfluorocarbon agents and a cofounder of Triangle Biotechnology, a company that has licensed this patent. Additionally, P.G.D, P.A.D., B.P.C., V.P. and S.E.R. are all co-inventors on a provisional patent describing the use of low boiling-point phase change contrast agents for enhancing the delivery of therapeutics agents to biofilms. Additionally, B.P.C and S.E.R are co-inventors on a provisional patent describing the use of rhamnolipids for potentiating antibiotic efficacy. A.E.S declares that she has no competing interests.

100869: A reversible KO model reveals therapeutic 1 potentials of defective Tregs
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Posted 16 Sep 2019

A reversible KO model reveals therapeutic 1 potentials of defective Tregs
203 downloads bioRxiv immunology

Yongqin Li, Tian Chi

Tregs must be activated to suppress immune responses, but the transcriptional program controlling Treg activation remains incompletely understood. We previously found that Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg activation and causes fatal autoimmunity in mice. Here, using a method that allows gene KO to be reversed in a Tamoxifen-dependent manner, we addressed whether reinstating Brg1 expression in the defective Tregs in the sick mice could restore Treg function, and if so, whether such Tregs could stop and resolve the fatal inflammation. We found that reexpressing Brg1 unexpectedly converted the defective Tregs into highly potent SuperTregs, which effectively rescued the dying mice. Remarkably, Brg1 reexpression in as little as 8% of the Tregs sufficed for the rescue in some cases. Brg1-deleted Tregs in the inflamed mice experienced excessive cytokine stimulation, became hyperactivated upon Brg1 reexpression and then deactivated as the inflammation subsided, suggesting that BRG1 acted in conjunction with inflammation to induce and maintain the SuperTreg phenotype. These data illustrate the power of reversible KO models in uncovering gene functions, and suggest a novel therapeutic strategy for IPEX(-related) disorders that exploits the defective Tregs and the inflammatory environment preexisting within the patients.

100870: MorphOT: Transport-based interpolation between EM maps with UCSF ChimeraX
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Posted 09 Sep 2020

MorphOT: Transport-based interpolation between EM maps with UCSF ChimeraX
203 downloads bioRxiv bioinformatics

Arthur Ecoffet, Frédéric Poitevin, Khanh Dao Duc

Motivation Cryogenic Electron-Microscopy offers the unique potential to capture conformational heterogeneity, by solving multiple 3D classes that co-exist within a single cryo-EM image dataset. To investigate the extent and implications of such heterogeneity, we propose to use an optimal-transport based metric to interpolate barycenters between EM maps and produce morphing trajectories. While standard linear interpolation mostly fails to produce realistic transitions, our method yields continuous trajectories that displace densities to morph one map into the other, instead of blending them. Implementation Our method is implemented as a plug-in for ChimeraX called MorphOT , which allows the use of both CPU or GPU resources. The code is publicly available on GitHub (<https://github.com/kdd-ubc/MorphOT.git>), with documentation containing tutorial and datasets. Contact kdd{at}math.ubc.ca ### Competing Interest Statement The authors have declared no competing interest.

100871: Genetic diversity and population structure of razor clam Sinonovacula constricta in Ariake Bay, Japan, revealed using RAD-Seq SNP markers.
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Posted 28 Oct 2020

Genetic diversity and population structure of razor clam Sinonovacula constricta in Ariake Bay, Japan, revealed using RAD-Seq SNP markers.
203 downloads bioRxiv zoology

Ryo Orita, Yukio Nagano, Yoshio Kawamura, Kei Kimura, Genta Kobayashi

The razor clam Sinonovacula constricta is a commercially important bivalve in Japan. The current distribution of this species in Japan is limited to Ariake Bay, where the fishery stock is declining. It is necessary to understand the genetic population structure of this species in order to restore the fishery stock while preserving the genetic diversity of the clam. Here, we report for the first time the genetic population structure of S. constricta in Ariake Bay, Japan. Paired-end restriction site-associated DNA sequencing (RAD-Seq) analyzed samples of S. constricta collected from seven mudflats located along Ariake Bay. Two different genetic populations exist in Ariake Bay, one inhabiting wild habitats and the other inhabiting the transplanted area of artificial seedlings. Our results suggest that genetic differentiation occurred between these two populations (Fst value = 0.052), and a high level of genetic differentiation is maintained between the two groups. In the future, the two genetically distinct populations need to be available as fishery resources, while taking into account their conservation and hybridization status. ### Competing Interest Statement The authors have declared no competing interest.

100872: FastFeatGen: Faster parallel feature extraction from genome sequences and efficient prediction of DNA N6-methyladenine sites
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Posted 18 Nov 2019

FastFeatGen: Faster parallel feature extraction from genome sequences and efficient prediction of DNA N6-methyladenine sites
203 downloads bioRxiv bioinformatics

Md. Khaledur Rahman

N6-methyladenine is widely found in both prokaryotes and eukaryotes. It is responsible for many biological processes including prokaryotic defense system and human diseases. So, it is important to know its correct location in genome which may play a significant role in different biological functions. Few computational tools exist to serve this purpose but they are computationally expensive and still there is scope to improve accuracy. An informative feature extraction pipeline from genome sequences is the heart of these tools as well as for many other bioinformatics tools. But it becomes reasonably expensive for sequential approaches when the size of data is large. Hence, a scalable parallel approach is highly desirable. In this paper, we have developed a new tool, called FastFeatGen, emphasizing both developing a parallel feature extraction technique and improving accuracy using machine learning methods. We have implemented our feature extraction approach using shared memory parallelism which achieves around 10x speed over the sequential one. Then we have employed an exploratory feature selection technique which helps to find more relevant features that can be fed to machine learning methods. We have employed Extra-Tree Classifier (ETC) in FastFeatGen and performed experiments on rice and mouse genomes. Our experimental results achieve accuracy of 85.57% and 96.64%, respectively, which are better or competitive to current state-of-the-art methods. Our shared memory based tool can also serve queries much faster than sequential technique. All source codes and datasets are available at https://github.com/khaled-rahman/FastFeatGen.

100873: Side-Impact Collision: Mechanics of Obstacle Negotiation in Sidewinding Snakes
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Posted 24 Apr 2020

Side-Impact Collision: Mechanics of Obstacle Negotiation in Sidewinding Snakes
203 downloads bioRxiv animal behavior and cognition

Henry C. Astley, Jennifer M Rieser, Abdul Kaba, Veronica M. Paez, Ian Tomkinson, Joseph R. Mendelson, Daniel I Goldman

Snakes excel at moving through cluttered environments, and heterogeneities can be used as propulsive contacts for snakes performing lateral undulation. However, sidewinding, often associated with sandy deserts, cuts a broad path through the environment that may increase the vulnerability to obstacles. Our prior work demonstrated that sidewinding can be represented as a pair of orthogonal body waves (vertical and horizontal) that can be independently modulated to achieve high maneuverability and incline ascent, suggesting that sidewinders may also use template modulations to negotiate obstacles. To test this hypothesis, we recorded overhead video of four sidewinder rattlesnakes ( Crotalus cerastes ) crossing a line of vertical pegs placed in the substrate. Snakes used three methods to traverse the obstacles: a Propagate Through behavior in which the lifted moving portion of the snake was deformed around the peg and dragged through as the snake continued sidewinding (115/160 runs), Reversal turns that reorient the snake entirely (35/160), or switching to Concertina locomotion (10/160). The Propagate- Through response was only used if the anterior-most region of static contact would propagate along a path anterior to the peg, or if a new region of static contact could be formed near the head to satisfy this condition; otherwise, snakes could only use Reversal Turns or switch to Concertina locomotion. Reversal Turns allowed the snake to re-orient and either escape without further peg contact or resorting to Propagate Through. We developed an algorithm to reproduce the Propagate Through behavior in a robotic model using a modulation of the two-wave template. This range of behavioral strategies provides sidewinders with a versatile range of options for effectively negotiating obstacles in their natural habitat, as well as provide insights into the design and control of robotic systems dealing with heterogeneous habitats. ### Competing Interest Statement The authors have declared no competing interest.

100874: 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.

100875: Do human recordings reveal drastic modulations in the discharge of striatal projection neurons in Parkinson's disease?
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Posted 06 Mar 2020

Do human recordings reveal drastic modulations in the discharge of striatal projection neurons in Parkinson's disease?
203 downloads medRxiv neurology

Dan Valsky, Zvi Israel, Thomas Boraud, Hagai Bergman, Marc Deffains

Dopamine depletion of the striatum plays a key role in the pathophysiology of Parkinsons disease (PD), but our understanding of the changes in the discharge rate and pattern of the striatal projection neurons (SPNs) remains limited. Here, we recorded multi-unit signals from the striatum of PD (N = 934) and dystonic (N = 718) patients undergoing deep brain stimulation surgeries. Using an innovative automated data-driven approach to classify striatal units, we showed that the SPN discharge rate is inversely proportional to the isolation quality and stationarity of the SPNs. In contrast to earlier studies in both PD patients and the non-human primate model of PD, we found no drastic changes in the spiking activity (discharge rate and pattern) of the well-isolated and stationary SPNs of PD patients compared to either dystonic patients or the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations. There was therefore no specific SPN subpopulation (D1 or D2 SPNs) strongly affected by the pathological state. Instead, our results suggest that moderate changes in SPN discharge are most likely amplified by basal ganglia downstream structures, thus leading to the clinical (motor and non-motor) symptoms of PD. Significance statementIn Parkinsons disease (PD), the loss of the midbrain dopaminergic neurons leads to massive striatal dopamine depletion that provokes abnormal activity throughout the basal ganglia. However, the impact of dopamine depletion on neuronal activity in the striatum is still highly debated. We recorded and examined the neuronal activity in striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. We found that striatal activity was not drastically higher in PD patients compared to either dystonic patients or the normal levels of striatal activity reported in animal studies. In PD, moderate changes in striatal basal activity are therefore most likely amplified by basal ganglia downstream structures.

100876: Origin, Conservation, and Loss of Alternative Splicing Events that Diversify the Proteome in Saccharomycotina Budding Yeasts
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Posted 14 Apr 2020

Origin, Conservation, and Loss of Alternative Splicing Events that Diversify the Proteome in Saccharomycotina Budding Yeasts
203 downloads bioRxiv genetics

Jennifer E. Hurtig, Minseon Kim, Luisa J. Orlando-Coronel, Jellisa Ewan, Michelle Foreman, Lee-Ann Notice, Michelle A. Steiger, Ambro van Hoof

Many eukaryotes use alternative splicing to express multiple proteins from the same gene. However, while the majority of mammalian genes are alternatively spliced, other eukaryotes use this process less frequently. The budding yeast Saccharomyces cerevisiae has been successfully used to study the mechanism of splicing and the splicing machinery, but alternative splicing in yeast is relatively rare and has not been extensively studied. We have recently shown that the alternative splicing of SKI7/HBS1 is widely conserved, but that yeast and a few other eukaryotes have replaced this one alternatively spliced gene with a pair of duplicated unspliced genes as part of a whole genome doubling (WGD). Here we show that other examples of alternative splicing that were previously found to have functional consequences are widely conserved within the Saccharomycotina. We also show that the most common mechanism by which alternative splicing has disappeared is by the replacement of an alternatively spliced gene with duplicate genes. Saccharomycetaceae that diverged before WGD use alternative splicing more frequently than S. cerevisiae. This suggests that the WGD is a major reason for the low frequency of alternative splicing in yeast. We anticipate that whole genome doublings in other lineages may have had the same effect. ### Competing Interest Statement The authors have declared no competing interest.

100877: Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration
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Posted 12 Nov 2019

Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration
203 downloads bioRxiv neuroscience

Ling Sun, Jie Zhang, Wenfeng Chen, Yun Chen, Xiaohui Zhang, Mingjuan Yang, Min Xiao, Fujun Ma, Yizhou Yao, Meina Ye, Zhenkun Zhang, Kai Chen, Fei Chen, Yujun Ren, Shiwei Ni, Xi Zhang, Zhangming Yan, Zhi-Rong Sun, Hai-Meng Zhou, Hongqin Yang, Shusen Xie, M Emdadul Haque, Kun C. Huang, Yufeng Yang

Parkinson's disease (PD) is a complex disease with high heterogeneity. How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in PD is largely unclear. Here, we applied frequent gene co-expression analysis on human patient substantia nigra-specific microarray datasets to identify potential novel disease-related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK-ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in vivo. Drug inhibition of MEK/ERK also mitigated mitochondrial defects in PD gene-deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in a broad range of aging-related disorders including PD.

100878: Frequency Conservation Score (FCS): the power of conservation and allele frequency for variant pathogenic prediction
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Posted 15 Oct 2019

Frequency Conservation Score (FCS): the power of conservation and allele frequency for variant pathogenic prediction
203 downloads bioRxiv bioinformatics

Jose Luis Cabrera, Jose Antonio Enriquez, Fatima Sanchez-Cabo

Background: Prediction of pathogenic variants is one of the biggest challenges for researchers and clinicians in the time of next-generation sequencing technologies. Stratification of individuals based on truly pathogenic variants might lead to improved, personalized treatments. Results: We present Frequency Conservation Score (FCS) and Frequency Conservation Score for Mitochondrial DNA (FCSMt) two methods for the detection of pathogenic single nucleotide variants in nuclear and mitochondrial DNA, respectively. These scores are based in a random forest model trained over a set of potentially relevant predictors: (i) conservation scores (PhastCons and phyloP); (ii) locus variability at each genomic position built from gnomAD database and (iii) physicochemical distance for amino acids substitutions and the impact/consequence over the canonical transcript. FCS showed an AUC of 98% for deleteriousness in an independent validation dataset, outperforming other scores such as metaLR, metaSVM, REVEL, DANN, CADD, SIFT, PROVEAN or FATHMM-MKL. Moreover, FCSMt presented an AUC=0.92 for pathogenic mitochondrial SNVs detection. The tool is available at http://bioinfo.cnic.es/FCS . Conclusions: FCS and FCS-Mt improve pathogenic mutation detection, allowing the prioritization of relevant variants in Whole Exome and Whole Genome Sequencing Analysis.

100879: Architectural Affordance Impacts Human Sensorimotor Brain Dynamics
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Posted 18 Oct 2020

Architectural Affordance Impacts Human Sensorimotor Brain Dynamics
203 downloads bioRxiv neuroscience

Zakaria Djebbara, Lars Brorson Fich, Klaus Gramann

Action is a medium of collecting sensory information about the environment, which in turn is shaped by architectural affordances. Affordances characterize the fit between the physical structure of the body and capacities for movement and interaction with the environment, thus relying on sensorimotor processes associated with exploring the surroundings. Central to sensorimotor brain dynamics, the attentional mechanisms directing the gating function of sensory signals share neuronal resources with motor-related processes necessary to inferring the external causes of sensory signals. Such a predictive coding approach suggests that sensorimotor dynamics are sensitive to architectural affordances that support or suppress specific kinds of actions for an individual. However, how architectural affordances relate to the attentional mechanisms underlying the gating function for sensory signals remains unknown. Here we demonstrate that event-related desynchronization of alpha-band oscillations in parieto-occipital and medio-temporal regions covary with the architectural affordances. Source-level time-frequency analysis of data recorded in a motor-priming Mobile Brain/Body Imaging experiment revealed strong event-related desynchronization of the alpha band to originate from the posterior cingulate complex and bilateral parahippocampal areas. Our results firstly contribute to the understanding of how the brain resolves architectural affordances relevant to behaviour. Second, our results indicate that the alpha-band originating from the posterior cingulate complex covaries with the architectural affordances before participants interact with the environment. During the interaction, the bilateral parahippocampal areas dynamically reflect the affordable behaviour as perceived through the visual system. We conclude that the sensorimotor dynamics are developed for processing behaviour-relevant features in the designed environment. ### Competing Interest Statement The authors have declared no competing interest.

100880: Higher-order thalamic implication in the processing of bilateral sensory events
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Posted 03 May 2020

Higher-order thalamic implication in the processing of bilateral sensory events
203 downloads bioRxiv neuroscience

Carlos Castejon, Angel Nuñez

In the rodent whisker system, it is well assumed that VPM and POm encode stimulations of the contralateral whisker pad. However, during tactile exploration whiskers are usually stimulated bilaterally. Accordingly, the integration of tactile information from the two sides of the body seems to be fundamental in the processing of these events. Here, to investigate whether POm could be able to codify these bilateral dynamics, whisker-evoked responses in this thalamic nucleus were examined by in vivo extracellular recordings in anesthetized rats using contralateral and ipsilateral stimuli. Strikingly, we found that POm is also able to respond to tactile stimulation of ipsilateral whiskers. Our findings reveal the implication of POm in the representation of bilateral tactile events by integrating simultaneous signals arising from both whisker pads and demonstrate the implication of the higher-order sensory thalamus in the encoding of bilateral sensory events. This can have important implications in bilateral perceptual function. ### Competing Interest Statement The authors have declared no competing interest.

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