bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfer learning improves outcome predictions for ASD from gene expression in blood
Authors: Robasky Kimberly , Kim Raphael , Yi Hong , Xu Hao , Bao Bokan , Chiang Austin W.T. , Courchesne Eric , Lewis Nathan E. 
Published: June 2021

AbstractBackgroundPredicting outcomes on human genetic studies is difficult because the number of variables (genes) is often much larger than the number of observations (human subject tissue samples). We investigated means for improving model performance on the types of under-constrained problems that are typical in human genetics, where the number of strongly correlated genes (features) may exceed 10,000, and the number of study participants (observations) may be limited to under 1,000.MethodsWe created ‘train’, ‘validate’ and ‘test’ datasets from 240 microarray observations from 127 subjects diagnosed with autism spectrum disorder (ASD) and 113 ‘typically developing’ (TD) subjects. We trained a neural network model (a.k.a., the ‘naive’ model) on 10,422 genes using the ‘train’ dataset, composed of 70 ASD and 65 TD subjects, and we restricted the model to one, fully-connected hidden layer to minimize the number of trainable parameters, including a dropout layer to help prevent overfitting. We experimented with alternative network architectures and tuned the hyperparameters using the ‘validate’ dataset, and performed a single, final evaluation using the holdout ‘test’ dataset. Next, we trained a neural network model using the identical architecture and identical genes to predict tissue type in GTEx data. We transferred that learning by replacing the top layer of the GTEx model with a layer to predict ASD outcome and we retrained the new layer on the ASD dataset, again using the identical 10,422 genes.FindingsThe ‘naive’ neural network model had AUROC=0.58 for the task of predicting ASD outcomes, which saw a statistically significant 7.8% improvement from transfer learning.InterpretationWe demonstrated that neural network learning could be transferred from models trained on large RNA-Seq gene expression to a model trained on a small, microarray gene expression dataset with clinical utility for mitigating over-training on small sample sizes. Incidentally, we built a highly accurate classifier of tissue type with which to perform the transfer learning.FundingThis work was supported in part by NIMH R01-MH110558 (E.C., N.E.L.)Author SummaryImage recognition and natural language processing have enjoyed great success in reusing the computational efforts and data sources to overcome the problem of over-training a neural network on a limited dataset. Other domains using deep learning, including genomics and clinical applications, have been slower to benefit from transfer learning. Here we demonstrate data preparation and modeling techniques that allow genomics researchers to take advantage of transfer learning in order to increase the utility of limited clinical datasets. We show that a non-pre-trained, ‘naive’ model performance can be improved by 7.8% by transferring learning from a highly performant model trained on GTEx data to solve a similar problem.
tACS phase-specifically biases brightness perception of flickering light
Authors: Fiene Marina , Radecke Jan-Ole , Misselhorn Jonas , Sengelmann Malte , Herrmann Christoph S. , Schneider Till R. , Schwab Bettina C. , Engel Andreas K. 
Published: June 2021

AbstractBackgroundVisual phenomena like brightness illusions impressively demonstrate the highly constructive nature of perception. In addition to physical illumination, the subjective experience of brightness is related to temporal neural dynamics in visual cortex.ObjectiveHere, we asked whether biasing the temporal pattern of neural excitability in visual cortex by transcranial alternating current stimulation (tACS) modulates brightness perception of concurrent rhythmic visual stimuli.MethodsParticipants performed a brightness discrimination task of two flickering lights, one of which was targeted by same-frequency electrical stimulation at varying phase shifts. tACS was applied with an occipital and a periorbital active control montage, based on simulations of electrical currents using finite-element head models.ResultsExperimental results reveal that flicker brightness perception is modulated dependent on the phase shift between sensory and electrical stimulation, solely under occipital tACS. Phase-specific modulatory effects by tACS were dependent on flicker-evoked neural phase stability at the tACS-targeted frequency, recorded prior to electrical stimulation. The optimal timing of tACS application leading to enhanced brightness perception was further correlated with the neural phase delay of the cortical flicker response.ConclusionsOur results corroborate the role of temporally coordinated neural activity in visual cortex for brightness perception of rhythmic visual input in humans. Phase-specific behavioral modulations by tACS emphasize its efficacy to transfer perceptually relevant temporal information to the cortex. These findings provide an important step towards understanding the basis of visual perception and further confirm electrical stimulation as a tool for advancing controlled modulations of neural activity and related behavior.
Probing Specificities of Alcohol Acyltransferases for Designer Ester Biosynthesis with a High-Throughput Microbial Screening Platform
Authors: Lee Jong-Won , Seo Hyeongmin , Young Caleb , Trinh Cong T. 
Published: June 2021

ABSTRACTAlcohol acyltransferases (AATs) enables microbial biosynthesis of a large space of esters by condensing an alcohol and an acyl CoA. However, substrate promiscuity of AATs prevents microbial biosynthesis of designer esters with high selectivity. Here, we developed a high-throughput microbial screening platform that facilitates rapid identification of AATs for designer ester biosynthesis. First, we established a microplate-based culturing technique with in situ fermentation and extraction of esters. We validated its capability in rapid profiling of the alcohol substrate specificity of 20 chloramphenicol acetyltransferase variants derived from Staphylococcus aureus (CATSa) for microbial biosynthesis of acetate esters with various exogeneous alcohol supply. By coupling the microplate-based culturing technique with a previously established colorimetric assay, we developed a high-throughput microbial screening platform for AATs. We demonstrated that this platform could not only confirm CATSa F97W with enhanced isobutyl acetate synthesis but also identify three ATF1Sc (P348M, P348A, and P348S) variants, derived from Saccharomyces cerevisiae’s AAT and engineered by model-guided protein design, for enhanced butyl acetate production. We anticipate the high-throughput microbial screening platform is a useful tool to identify novel AATs that have important roles in nature and industrial biocatalysis for designer bioester production.
MicroRNA-202 prevents precocious spermatogonial differentiation and meiotic initiation during mouse spermatogenesis
Authors: Chen Jian , Gao Chenxu , Lin Xiwen , Ning Yan , He Wei , Zheng Chunwei , Zhang Daoqin , Yan Lin , Jiang Binjie , Zhao Yuting , Hossen Md Alim , Han Chunsheng 
Published: June 2021

AbstractSpermatogonial differentiation and meiotic initiation during spermatogenesis are tightly regulated by a number of genes including those coding enzymes for miRNA biogenesis. However, whether and how single miRNAs regulate these processes remain unclear. Here, we report that miR-202, a member of the let-7 family, prevents precocious spermatogonial differentiation and meiotic initiation in spermatogenesis by regulating the timely expression of many genes including those for other key regulators. In miR-202 knockout (KO) mice, the undifferentiated spermatogonial pool is reduced, ultimately causing agametic seminiferous tubules. SYCP3, STRA8 and DMRT6 are expressed earlier in KO mice than in wild-type (WT) littermates, and Dmrt6 mRNA is a direct target of miR-202-5p. Moreover, the precocious spermatogonial differentiation and meiotic initiation were also observed in KO spermatogonial stem cells when cultured and induced in vitro, and could be rescued by the knockdown of Dmrt6. Therefore, we have not only shown that miR-202 is a novel regulator of meiotic initiation but also added a new module to the underlying regulatory network.Summary statementA single miRNA, miR-202, prevents precocious differentiation and meiotic initiation during spermatogenesis. miR-202, DMRT6 and STRA8 act together as a novel module in the regulatory network of meiotic initiation.
Herbivore feeding behavior validates optimal defense theory for specialized metabolites within plants
Authors: Hunziker Pascal , Lambertz Sophie Konstanze , Weber Konrad , Crocoll Christoph , Halkier Barbara Ann , Schulz Alexander 
Published: June 2021

SummaryNumerous plants protect themselves from attackers using specialized metabolites. The biosynthesis of these deterrent, often toxic metabolites is costly, as their synthesis diverts energy and resources on account of growth and development. How plants diversify investments into growth and defense is explained by the optimal defense theory. The central prediction of the optimal defense theory is that plants maximize growth and defense by concentrating specialized metabolites in tissues that are decisive for fitness. To date, supporting physiological evidence merely relies on the correlation between plant metabolite distribution and animal feeding preference. Here, we use glucosinolates as a model to examine the effect of changes in chemical defense distribution on actual feeding behavior. Taking advantage of the uniform glucosinolate distribution in transporter mutants, we show that high glucosinolate accumulation in tissues important to fitness protects them by guiding larvae of a generalist herbivore to feed on other tissues. Moreover, we show that mature leaves of Arabidopsis thaliana supply young leaves with glucosinolates to optimize defense against herbivores. Our study provides physiological evidence for the central hypothesis of the optimal defense theory and sheds light on the importance of integrating glucosinolate biosynthesis and transport for optimizing plant defense.
Kidney organoids: A system to study human basement membrane assembly in health and disease
Authors: Morais Mychel Raony Paiva Teixeira , Tian Pinyuan , Lawless Craig , Murtuza-Baker Syed , Hopkinson Louise , Woods Steven , Mironov Aleksandr , Long David Andrew , Gale Daniel , Zorn Telma Maria Tenorio , Kimber Susan , Zent Roy , Lennon Rachel 
Published: June 2021

SUMMARYBasement membranes (BMs) are complex macromolecular networks underlying all continuous layers of cells. Essential components include type IV collagen and laminins, which are affected by human genetic defects leading to a range of debilitating conditions including kidney, muscle, and cerebrovascular phenotypes. We investigated the dynamics of BM assembly in human pluripotent stem cell-derived kidney organoids. We resolved their global BM composition and discovered a conserved temporal sequence in BM assembly that paralleled mammalian fetal kidneys. We identified the emergence of key BM isoforms, which were altered by a pathogenic variant in COL4A5. Integrating organoid, fetal and adult kidney proteomes we found dynamic regulation of BM composition through development to adulthood, and with single-cell transcriptomic analysis we mapped the cellular origins of BM components. Overall, we define the complex and dynamic nature of vertebrate BM assembly and provide a platform for understanding its wider relevance in human development and disease.
LIM domain-wide comprehensive mutagenesis reveals the role of leucine in CSRP3 protein stability
Authors: Chauhan Pankaj Kumar , Sowdhamini R. 
Published: June 2021

AbstractCardiomyopathies are a severe and chronic cardiovascular burden worldwide, affecting a large cohort in the general population. Cysteine and glycine-rich protein 3 (CSRP3) is one of key proteins implicated in dominant dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). In this study, we device a rapid in-silico screening protocol that creates a mutational landscape map for all possible allowed and disallowed substitutions in the protein of interest. This map provides the structural and functional insights on the stability of LIM domains of CSRP3. Further, the sequence analysis delineates the eukaryotic CSRP3 protein orthologs which complements the mutational map. Next, we also evaluated the effect of HCM/DCM mutations on these domains. One of highly destabilising mutations - L44P (also disease causing) and a neutral mutation - L44M were further subjected to molecular dynamics (MD) simulations. The results establish that L44P substitution affects the LIM domain structure. The present study provides a useful perspective to our understanding of the role of mutations in the CSRP3 LIM domains and their evolution. Experimentally verifying every reported mutation can become challenging both in time and resources used. This study provides a novel screening method for quick identification of key mutation sites for specific protein structures that can reduce the burden on experimental research.
Contraction-dependent intracortical inhibition supports gravity-efficient motor control
Authors: Gueugneau Nicolas , Martin Alain , Gaveau Jérémie , Papaxanthis Charalambos 
Published: June 2021

ABSTRACTEfficient control of voluntary movements along the gravity axis requires adapted shifts in muscular contraction modes. In daily life, rising the arm up involves shortening (i.e., concentric) contractions of arm flexors, while the reverse movement can rely on lengthening (i.e., eccentric) contractions of the same muscles with the help of gravity force. Although this muscular-control mode is universal, the neuromuscular mechanisms that subserve the control of such gravity-oriented movements remain unknown. In this study, we designed two neurophysiological experiments that allowed tracking modulations of cortical, spinal, and muscular outputs of arm flexors while healthy humans carried out vertical pointing movements. In conditions where upward and downward movements revealed kinematic features reminiscent of optimal motor commands (i.e., directional asymmetries), we report fine contraction-dependent modulations of the corticospinal output. The overall corticospinal excitability dropped during lengthening contractions (downward movements) compared with shortening contractions (upward movements). Specifically, we did not observe any change in spinal motoneuron responsiveness from cervicomedullary stimulations but a specific increase in intracortical inhibition during lengthening vs. shortening contractions. We discuss these fine contraction-dependent modulations of the supraspinal motor output in the light of feedforward mechanisms that may support gravity-tuned motor control. Generally, these results shed a new perspective on the neural policy that optimize movement control along the gravity axis.
Identification and characterisation of splicing regulators in Toxoplasma gondii
Authors: Lee V Vern , Seizova Simona , McMillan Paul J. , McHugh Emma , Tonkin Christopher J. , Ralph Stuart A. 
Published: June 2021

AbstractThe splicing of mRNA constitutes a major source of co- and post-transcriptional regulation in metazoans. In particular, members of the serine/arginine (SR) protein family are essential splicing factors that are implicated in the regulation of gene expression and RNA metabolism. However, very little is known about these proteins in apicomplexans, a phylum that includes some of the most important global parasites. In this study, we investigated the suite of three uncharacterised SR proteins in Toxoplasma gondii and show that all three are found localised to nuclear speckles. We show, by genetic ablation, that TgSR1 is particularly important for T. gondii growth. Using RNA-seq, we also characterised the global gene expression and splicing regulation of these proteins. We find that the SR proteins regulate several types of alternative splicing of distinct but overlapping subsets of transcripts, as well as impacting transcript abundance. Most of the alternative splicing events are non-productive intron retention events that do not appear to affect transcript abundance. The splicing sites of the impacted transcripts are enriched in characteristic SR binding motifs. We also identified and conditionally knocked down two putative kinases of SR proteins. The kinases are localised to nuclear speckles and are essential to parasite survival. Their perturbation resulted in widespread changes to splicing, but the affected transcripts did not mirror the patterns seen in knockouts of individual SRs, suggesting an absence of a simple relationship between SRs and these putative kinase regulators. Overall, this study reveals a complex system of splicing factors and kinases that post-transcriptionally regulate gene expression in T. gondii.
Evolution and favored change: a principle of least selection
Authors: Yarus Michael 
Published: June 2021

AbstractFavored biological characteristics can evolve by a subtle path, but beneficial selection has predictable qualities to guide thought. These favored pathways are paths of “least selection”. Faster evolution is least selection, more probable because earlier evolutionary success is simply, “success”. A more likely path also requires least selection in the form of least selected change. Truncation selections, accepting only extreme values of a distributed quantity, produce greater change in population means. Truncation selection therefore readily offers a least selection. Assuming selection for a Normally-distributed quality, truncation is enhanced via simple dependences on increased standard deviation and higher selection threshold (consistent with some population survival). Least selection applies to both chemical and biological evolution, and can be estimated in general form, without reference to its genetics, from an underlying phenotypic distribution. Chemical truncation selection is free of the Haldane cost of natural selection; potentially yielding very rapid early evolution. Notably, a principle of least selection unifies prior examples of quick evolution. For example: the ‘crescendo’ of accurate codes leading to the Standard Genetic Code facilitates a least selection. More generally, evolutionary extinctions and radiations are events with multiple coercive thresholds; thus Earth’s history offers many wide-ranging truncation/least selection events.
Stress decreases serotonin tone in the nucleus accumbens to promote aversion and potentiate cocaine preference via decreased stimulation of 5-HT1B receptors
Authors: Fontaine Harrison M , Silva Phillip R , Neiswanger Carlie , Tran Rachelle , Abraham Antony D , Land Benjamin B , Neumaier John F , Chavkin Charles 
Published: June 2021

AbstractStress-induced release of dynorphins (Dyn) activates kappa opioid receptors (KOR) in monoaminergic neurons to produce dysphoria and potentiate drug reward; however, the circuit mechanisms responsible for this effect are not known. We found that conditional deletion of KOR from Slc6a4 (SERT)-expressing neurons blocked stress-induced potentiation of cocaine conditioned place preference (CPP). Within the dorsal raphe nucleus (DRN), two overlapping populations of KOR-expressing neurons: Slc17a8 (VGluT3) and SERT, were distinguished functionally and anatomically. Optogenetic inhibition of these SERT+ neurons potentiated subsequent cocaine CPP, whereas optical inhibition of the VGluT3+ neurons blocked subsequent cocaine CPP. SERT+/VGluT3− expressing neurons were concentrated in the lateral aspect of the DRN. SERT projections from the DRN were observed in the medial nucleus accumbens (mNAc), but VGluT3 projections were not. Optical inhibition of SERT+ neurons produced place aversion, whereas optical stimulation of SERT+ terminals in the mNAc attenuated stress-induced increases in forced swim immobility and subsequent cocaine CPP. KOR neurons projecting to mNAc were confined to the lateral aspect of the DRN, and the principal source of dynorphinergic (Pdyn) afferents in the mNAc was from local neurons. Excision of Pdyn from the mNAc blocked stress-potentiation of cocaine CPP. Prior studies suggested that stress-induced dynorphin release within the mNAc activates KOR to potentiate cocaine preference by a reduction in 5-HT tone. Consistent with this hypothesis, a transient pharmacological blockade of mNAc 5-HT1B receptors potentiated subsequent cocaine CPP. 5-HT1B is known to be expressed on 5-HT terminals in NAc, and 5-HT1B transcript was also detected in Pdyn+, Adora2a+ and ChAT+ (markers for direct pathway, indirect pathway, and cholinergic interneurons, respectively). Following stress exposure, 5-HT1B transcript was selectively elevated in Pdyn+ cells of the mNAc. These findings suggest that Dyn/KOR regulates serotonin activation of 5HT1B receptors within the mNAc and dynamically controls stress response, affect, and drug reward.
Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi
Authors: Peterson Mariko S. , Joyner Chester J. , Brady Jessica A. , Wood Jennifer S. , Cabrera-Mora Monica , Saney Celia L. , Fonseca Luis L. , Cheng Wayne T. , Jang Jianlin , Lapp Stacey A. , Soderberg Stephanie R. , Nural Mustafa V. , Humphrey Jay C. , Hankus Allison , Machiah Deepa , Karpuzoglu Ebru , DeBarry Jeremy D. ,   MaHPIC-Consortium, Tirouvanziam Rabindra , Kissinger Jessica C. , Moreno Alberto , Gumber Sanjeev , Voit Eberhard O. , Gutiérrez Juan B. , Cordy Regina Joice , Galinski Mary R. 
Published: June 2021

ABSTRACTBackgroundKra monkeys (Macaca fascicularis), a natural host of Plasmodium knowlesi, control parasitaemia caused by this parasite species and escape death without treatment. Knowledge of the disease progression and resilience in kra monkeys will aid the effective use of this species to study mechanisms of resilience to malaria. This longitudinal study aimed to define clinical, physiological and pathological changes in kra monkeys infected with P. knowlesi, which could explain their resilient phenotype.MethodsKra monkeys (n = 15, male, young adults) were infected intravenously with cryopreserved P. knowlesi sporozoites and the resulting parasitaemias were monitored daily. Complete blood counts, reticulocyte counts, blood chemistry and physiological telemetry data (n = 7) were acquired as described prior to infection to establish baseline values and then daily after inoculation for up to 50 days. Bone marrow aspirates, plasma samples, and 22 tissue samples were collected at specific time points to evaluate longitudinal clinical, physiological and pathological effects of P. knowlesi infections.ResultsAs expected, the kra monkeys controlled parasitaemia and remained with low-level, persistent parasitaemias without antimalarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopaenia, and moderate to severe anaemia. Mathematical modeling and the reticulocyte production index indicated that the anaemia was largely due to the removal of uninfected erythrocytes and not impaired production of erythrocytes. Mild tissue damage was observed, and tissue parasite load was associated with tissue damage even though parasite accumulation in the tissues was generally low.ConclusionsKra monkeys experimentally infected with P. knowlesi sporozoites presented with multiple clinical signs of malaria that varied in severity among individuals. Overall, the animals shared common mechanisms of resilience characterized by controlling parasitaemia 3-5 days after patency, and controlling fever, coupled with physiological and bone marrow responses to compensate for anaemia. Together, these responses likely minimized tissue damage while supporting the establishment of chronic infections, which may be important for transmission in natural endemic settings. These results provide new foundational insights into malaria pathogenesis and resilience in kra monkeys, which may improve understanding of human infections.