bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular complex detection in protein interaction networks through reinforcement learning
Authors: Palukuri Meghana V. , Patil Ridhi S. , Marcotte Edward M. 
Published: June 2022

AbstractMany, if not most, proteins assemble into higher-order complexes to perform their biological functions. Such protein-protein interactions (PPI) are often experimentally measured for pairs of proteins and summarized in a weighted PPI network, to which community detection algorithms can be applied to define the various higher-order protein complexes. Current methods, which include both unsupervised and supervised approaches, often assume that protein complexes manifest only as dense subgraphs, and in the case of supervised approaches, focus only on learning which subgraphs correspond to complexes, not how to find them in a network, a task that is currently solved using heuristics. However, learning to walk trajectories on a network with the goal of finding protein complexes lends itself naturally to a reinforcement learning (RL) approach, a strategy that has not been extensively explored for community detection. Here, we evaluated the use of a reinforcement learning pipeline for community detection in weighted protein-protein interaction networks to detect new protein complexes. Using known complexes, the algorithm is trained to calculate the value of different possible subgraph densities in the process of walking on the network to find a protein complex. Then, a distributed prediction algorithm scales the RL pipeline to search for protein complexes on large PPI networks. The reinforcement learning pipeline applied to a human PPI network consisting of 8k proteins and 60k PPI results in 1,157 protein complexes and shows competitive accuracy with improved speed when compared to previous algorithms. We highlight protein complexes harboring minimally characterized proteins including C4orf19, C18orf21, and KIAA1522, suggest TMC04 to be a putative additional subunit of the KICSTOR complex, and confirm the participation of C15orf41 in a higher-order complex with CDAN1, ASF1A, and HIRA by 3D structural modeling. Reinforcement learning offers several distinct advantages for community detection, including scalability and knowledge of the walk trajectories defining those communities.
High-throughput phenotyping of infection by diverse microsporidia species reveals a wildC. elegansstrain with opposing resistance and susceptibility traits
Authors: Mok Calvin , Xiao Meng A. , Wan Yin C. , Zhao Winnie , Ahmed Shanzeh M. , Luallen Robert J. , Reinke Aaron W. 
Published: June 2022

AbstractAnimals are under constant selective pressure from a myriad of diverse pathogens. Microsporidia are ubiquitous animal parasites, but the influence they exert on shaping animal genomes is mostly unknown. Using multiplexed competition assays, we measured the impact of four different species of microsporidia on 22 wild isolates ofCaenorhabditis elegans. This resulted in the identification and confirmation of 13 strains with significantly altered population fitness profiles under infection conditions. One of these identified strains, JU1400, is sensitive to an epidermal-infecting species by lacking tolerance to infection. JU1400 is also resistant to an intestinal-infecting species and can specifically recognize and destroy this pathogen. Genetic mapping of JU1400 demonstrates that these two opposing phenotypes are caused by separate loci. Transcriptional analysis reveals the JU1400 sensitivity to epidermal microsporidia infection results in a response pattern that shares similarity to toxin-induced responses. In contrast, we do not observe JU1400 intestinal resistance being regulated at the transcriptional level. The transcriptional response to these four microsporidia species is conserved, withC. elegansstrain-specific differences in potential immune genes. Together, our results show that phenotypic differences to microsporidia infection amongstC. elegansare common and that animals can evolve species-specific genetic interactions.
ztf-16 is a novel heterochronic modulator that opposes adult cell fate in dauer and continuous life histories in Caenorhabditis elegans
Authors: Hansen Mark A. , Dahal Anuja , Bernstein Taylor A. , Kohtz Chani , Ali Safiyah , Daul Aric L. , Montoye Eric , Panzade Ganesh P. , Alessi Amelia F. , Flibotte Stephane , Vargas Marcus L. , Bourgeois Jacob , Brown Campbell , Kim John K. , Rougvie Ann E. , Zinovyeva Anna , Karp Xantha 
Published: June 2022

AbstractAnimal development is a complex yet robust process that can withstand lengthy and variable interruptions. In Caenorhabditis elegans, adverse conditions can trigger entry into dauer, a stress-resistant, developmentally arrested diapause stage that occurs midway through larval development. Favorable conditions promote recovery from dauer, and post-dauer larvae develop normally. During larval development, epidermal seam cells are multipotent and divide at each stage. At adulthood, seam cells differentiate and express the adult-specific COL-19 collagen. The progression of cell fates is controlled by a network of genes called the heterochronic pathway, including the LIN-29 transcription factor that directly activates col-19 expression, and the let-7 microRNA that indirectly promotes lin-29 expression. Notably, most known heterochronic genes that oppose adult cell fate act only during continuous development; these genes are dispensable after dauer. We performed a genetic screen for heterochronic genes that act after dauer and identified ztf-16, encoding a zinc finger transcription factor in the hunchback/Ikaros-like family. We found that ztf-16 is required to prevent precocious expression of the adult cell fate marker col-19p::gfp equally during both life histories, making ztf-16(-) the first precocious heterochronic mutant to be unaffected by dauer. Our data indicate that ztf-16 regulates col-19p::gfp via a novel, lin-29-independent mechanism. Endogenous ztf-16b::gfp expression is regulated by let-7 and ztf-16 acts genetically downstream of let-7, but lin-29 is not required for col-19p::gfp expression in ztf-16 mutant larvae or adults. Finally, mRNA-seq experiments identified genes whose expression is regulated by ztf-16 in each life history. Taken together, this work illuminates a novel aspect of the heterochronic pathway relevant to both dauer and non-dauer development.
Fear in action: Fear conditioning and alleviation through body movements
Authors: Alemany-González Maria , Wokke Martijn E. , Chiba Toshinori , Narumi Takuji , Kaneko Naotsugu , Yokoyama Hiraku , Watanabe Katsumi , Nakazawa Kimitaka , Imamizu Hiroshi , Koizumi Ai 
Published: June 2022

AbstractAcquisition of fear memories enhances survival especially when the memories guide defensive movements to minimize harm. Accordingly, fear memories and body movements have tight relationships in animals: Fear memory acquisition results in adapting reactive defense movements, while training active defense movements to avoid threat reduces fear memory. However, evidence in humans is scarce because their movements are typically marginalized in experiments. Here, we tracked participants’ whole-body motions while they underwent fear conditioning in a virtual 3D space. First, representational similarity analysis of body motions revealed that participants obtained distinct spatiotemporal movement patterns through fear conditioning. Second, subsequent training to actively avoid threats with naturalistic defensive actions led to a long-term (24 hrs) reduction of physiological and embodied conditioned responses, while extinction or vicarious training only transiently reduced the responses followed by their spontaneous return. Together, our results highlight the intrinsic role of body movements in human fear memory functions, suggesting the potential for improving fear memory interventions through embodiment.
“What” and “when” predictions modulate auditory processing in a contextually specific manner
Authors: Drew Cappotto , Dan Luo , Wai Lai Hiu , Fei Peng , Lucia Melloni , Wilbert Hendrik Schnupp Jan , Ryszard Auksztulewicz 
Published: June 2022

AbstractExtracting regularities from ongoing stimulus streams to form predictions is crucial for adaptive behavior. Such regularities exist in terms of the content of the stimuli (i.e., “what” it is) and their timing (i.e., “when” it will occur), both of which are known to interactively modulate sensory processing. In real-world stimulus streams, regularities also occur contextually - e.g. predictions of individual notes vs. melodic contour in music. However, it is unknown whether the brain integrates predictions in a contextually congruent manner (e.g., if slower “when” predictions selectively interact with complex “what” predictions), and whether integrating predictions of simple vs. complex features rely on dissociable neural correlates. To address these questions, our study employed “what” and “when” violations at different levels - single tones (elements) vs. tone pairs (chunks) - within the same stimulus stream, while neural activity was recorded using electroencephalogram (EEG) in participants (N=20) performing a repetition detection task. Our results reveal that “what” and “when” predictions interactively modulated stimulus-evoked response amplitude in a contextually congruent manner, but that these modulations were shared between contexts in terms of the spatiotemporal distribution of EEG signals. Effective connectivity analysis using dynamic causal modeling showed that the integration of “what” and “when” prediction selectively increased connectivity at relatively late cortical processing stages, between the superior temporal gyrus and the fronto-parietal network. Taken together, these results suggest that the brain integrates different predictions with a high degree of contextual specificity, but in a shared and distributed cortical network.Significance statementPredictions of stimulus features, present in different statistically-regular contexts in the environment, are crucial to forming adaptive behavior. However, it is unknown if the brain integrates predictions selectively according to such contextual differences. By recording human electroencephalography during experimental manipulations of time-based and content-based predictions, we found that those predictions interactively modulated neural activity in a contextually congruent manner, such that local (vs. global) time-based predictions modulated content-based predictions of sequence elements (vs. chunks). These modulations were shared between contextual levels in terms of the spatiotemporal distribution of neural activity. This suggests that the brain integrates different predictions with a high degree of contextual specificity, but in a shared and distributed cortical network.
TF-COMB - discovering grammar of transcription factor binding sites
Authors: Bentsen Mette , Heger Vanessa , Schultheis Hendrik , Kuenne Carsten , Looso Mario 
Published: June 2022

AbstractCooperativity between transcription factors is important to regulate target gene expression. In particular, the binding grammar of TFs in relation to each other, as well as in the context of other genomic elements, is crucial for TF functionality. However, tools to easily uncover co-occurrence between DNA-binding proteins, and investigate the regulatory modules of TFs, are limited. Here we present TF-COMB (Transcription Factor Co-Occurrence using Market Basket analysis) - a tool to investigate co-occurring TFs and binding grammar within regulatory regions. We found that TF-COMB can accurately identify known co-occurring TFs from ChIP-seq data, as well as uncover preferential localization to other genomic elements. With the use of ATAC-seq footprinting and TF motif locations, we found that TFs exhibit both preferred orientation and distance in relation to each other, and that these are biologically significant. Finally, we extended the analysis to not only investigate individual TF pairs, but also TF pairs in the context of networks, which enabled the investigation of TF complexes and TF hubs. In conclusion, TF-COMB is a flexible tool to investigate various aspects of TF binding grammar.Graphical abstract
The Histopathological Assesments of Effecting Fe and Zn Heavy Metals in Cerebrum and Cerebellum Tissues of Rats
Authors: Şenol N. , Şahin M. 
Published: June 2022

AbstractHeavy metals left intensively to the environment cause different healthy problems on people by entering the food chain heavy metals. Our aim is to provide determinig effect of in tissues especially in central nervous system as a result of consuming cause foods included heavy metals and water. Five groups were constituded by using 35 adult male Wistar-Albino sexual rats. Hematoxylin-eosin (H&E) staining was applied to determine the histological sides of the damages of heavy metals in cerebrum and cerebellum tissues and effects of given juglone (5-hydroxy-1,4-naphthoquinone) for reducing these damages. Besides, immunohistochemical TUNNEL method was applied to determine DNA damages in cell. Density of damage in cerebrum of Fe and Fe+Juglone groups were higher than in the control group. Apoptotic cells number was decreased in the group consisting of juglone. There was little damage and less apoptotic cells in treated Zn group. In the cerebellum similar cerebrum results were obtained. There were much degeneration Fe and Fe+Juglone groups cerebellum. Apoptotic cells were increased Fe groups. Fe/600 ppm. doses heavy metals have created a toxic effect on the cerebrum and cerebellum tissues.
Increased S6K1 phosphorylation protects against early steps of Tau aggregation under long-term mitochondrial stress
Authors: Samluk Lukasz , Ostapczuk Piotr , Malicka Dorota , Dziembowska Magdalena 
Published: June 2022

AbstractMany studies demonstrated the influence of mitochondrial stress on cytosolic signaling pathways. Here, we found that in cells upon long-term mitochondrial stress, phosphorylation of S6K1 protein, which is the mTOR pathway component, was increased, like in brains of Alzheimer’s disease (AD) patients. We checked if increased S6K1 phosphorylation was involved in Tau protein aggregation, which is one of AD hallmarks. HEK239T NDUFA11-deficient cells treatment with the mTOR inhibitor, INK128, or with S6K1 inhibitor, PF-4708671, caused the elevation of Tau aggregation. In contrast, stable overactivation of the mTOR pathway caused a further increase of S6K1 phosphorylation and reduced Tau oligomerization in HEK239T NDUFA11-deficient cells. Thus, we conclude that the increase in S6K1 phosphorylation is protective against Tau aggregation under mitochondrial stress.
Simultaneous multifunctional transcriptome engineering by CRISPR RNA scaffold
Authors: Liu Zukai , Robson Paul , Cheng Albert 
Published: June 2022

ABSTRACTRNA processing and metabolism are subjected to precise regulation in the cell to ensure integrity and functions of RNA. Though targeted RNA engineering has become feasible with the discovery and engineering of the CRISPR-Cas13 system, simultaneous modulation of different RNA processing steps remains unavailable. In addition, off-target events resulting from effectors fused with dCas13 limit its application. Here we developed a novel platform, Combinatorial RNA Engineering via Scaffold Tagged gRNA (CREST), which can simultaneously execute multiple RNA modulation functions on different RNA targets. In CREST, RNA scaffolds are appended to the 3’ end of Cas13 gRNA and their cognate RNA binding proteins are fused with enzymatic domains for manipulation. We show that CREST is capable of simultaneously manipulating RNA alternative splicing and A-to-G or C-to-U base editing. Furthermore, by fusing two split fragments of the deaminase domain of ADAR2 to dCas13 and PUFc respectively, we reconstituted its enzyme activity at target sites. This split design can reduce more than 90% of off-target events otherwise induced by a full-length effector. The flexibility of the CREST framework will enrich the transcriptome engineering toolbox for the study of RNA biology and the development of RNA-focused therapeutics.
Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models
Authors: Nourse J. Brucker , Russell Shannon N. , Moniz Nathan A. , Scott Madison , Park Han-A , Caldwell Kim A. , Caldwell Guy A. 
Published: June 2022

AbstractWhole exome sequencing of Parkinson’s disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in theTNK2gene. AlthoughTNK2encodes a non-receptor tyrosine kinase that has been shown to prevent the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2 in PD remains unresolved. We postulated that specific recessive mutations in patients resulted in aberrant or prolonged overactivity as a consequence of failed negative regulation by an E3 ubiquitin ligase, NEDD4. Interestingly, the soleCaenorhabditis elegansortholog of TNK2, termed SID-3, is an established mediator of epigenetic gene silencing and systemic RNA interference facilitated by the SID-1 dsRNA transporter. While SID-3 had no prior association to dopamine neurotransmission inC. elegans, we hypothesized that TNK2/SID-3 represented a node of integrated dopaminergic and epigenetic signaling essential to neuronal homeostasis. Using genetic and chemical modifiers, including a TNK2 inhibitor (AIM-100) and NEDD4 activator (NAB2), in bioassays for dopamine uptake or RNAi in dopaminergic neurons ofC. elegans, we determined thatsid-3mutants displayed neuroprotection from 6-hydroxydopamine (6-OHDA) exposure, as did wildtype animals treated with AIM-100 or NAB2. Additionally, NAB2 treatment of rat primary neurons correlated with a reduction of TNK2 levels and the attenuation of 6-OHDA neurotoxicity. Notably, CRISPR-modified nematodes engineered with genomic mutations insid-3analogous to PD patient-associated SNPs inTNK2circumvented the resistance to RNAi characteristic of SID-3 dysfunction and furthermore exhibited enhanced susceptibility to neurodegeneration. This study describes a molecular etiology for PD whereby dysfunctional cellular dynamics, dopaminergic, and epigenetic signaling intersect to cause neurodegeneration.Significance StatementThe progressive loss of dopamine neurons is a pathological hallmark of Parkinson’s disease (PD). Distinctions between resilience or susceptibility to neurodegeneration in PD are a combined consequence of genetic predisposition and environmental factors, the latter often manifesting as changes in gene expression that are coordinately controlled by small RNA molecules. This research reveals a functional convergence of proteins that modulate uptake of both dopamine and small RNAs, as a regulatory intersection for the integrated control of dopamine neuron health. Analysis of PD-patient mutations in the central protein associated with this functional interface further illustrated the clinical significance of this regulatory mechanism, as well as its potential for therapeutic intervention to prevent neurodegeneration through the fine-tuning of dopamine levels.
HDL-C as a potential medium between depletion of Lachnospiraceae genera and hypertension under high-calorie diet
Authors: Lan Yongmei , Ning Kang , Ma Yanqing , Zhao Jin , Ci Caihong , Yang Xiao , An Fulong , Zhang Zilong , An Yan , Cheng Mingyue 
Published: June 2022

ABSTRACTGut microbial dysbiosis has been associated with hypertension. An extremely high incidence of essential hypertension was found in the Han and the Yugur who resided in Sunan county in East Asia’s nomadic steppes with little population movement. In attempt to investigate the gut microbial role in hypertension, we recruited a total of 1, 242 Yugur and Han people, who had resided in Sunan County for more than 15 years and accounted for 3% of the local population. The epidemiological survey of 1,089 individuals indicated their nearly 1.8 times higher prevalence of hypertension (38.2–43.3%) than the average in China (23.2%), under a special high-calorie diet based on wheat, cattle, mutton, and animal offal. The 16S rRNA gene sequencing on the fecal samples of 153 individuals revealed that certain Lachnospiraceae genera were negatively correlated with high-density lipoprotein cholesterol (HDL-C, P = 5.46 × 10−6), systolic blood pressure (SBP, P = 7.22 × 10−3), diastolic blood pressure (DBP, P = 1.8 × 10−3). HDL-C was positively correlated with SBP (P = 0.023). We further observed that serum butyrate content was lower in both Han (P = 1.99 × 10−3) and Yugur people (P = 0.031) with hypertension than those without hypertension. This study gives a novel insight into the role of gut microbial dysbiosis in hypertension modulation under a high-calorie diet, where the notable depletion of Lachnospiraceae genera might lead to less production of butyrate, contributing to the lower level of HDL-C, and elevating blood pressure in hypertension.IMPORTANCEDietary nutrients can be converted by gut microbiota into metabolites such as short-chain fatty acids, which may serve as disease-preventing agents in hypertension. Due to limited population mobility and a unique high-calorie dietary habit, the recruited cohort in this study could be a representative for elucidating the associations between gut microbiota and hypertension under high-calorie diet. Moreover, low levels of HDL-C have previously been associated with an increased risk of various cardiovascular diseases (CVDs). Our findings provide a new insight that low levels of HDL-C may be a potential medium between depletion of Lachnospiraceae genera and hypertension under high-calorie diet, which might also be a potential candidate for other CVDs.
Natural course of post COVID-19 condition and implications for trial design and outcome selection: A population-based longitudinal cohort study
Authors: Ballouz Tala , Menges Dominik , Anagnostopoulos Alexia , Domenghino Anja , Aschmann Hélène E , Frei Anja , Fehr Jan S , Puhan Milo A 
Published: June 2022

AbstractBackgroundEvidence from population-based studies on the longer-term natural course of post COVID-19 condition is limited, but crucial for informing patients and healthcare providers and for effectively designing clinical trials.ObjectivesTo evaluate longer-term symptoms and health outcomes within a cohort of SARS-CoV-2 infected individuals.DesignPopulation-based, longitudinal cohort.SettingGeneral population, Canton of Zurich, Switzerland.Patients1543 adults with confirmed SARS-CoV-2 infection and 628 adults without infection.MeasurementsChanges in self-reported health status over time, factors associated with persistence of non-recovery, and prevalence and excess risk of symptoms at 6 and 12 months post-infection compared to non-infected individuals.Results25% of SARS-CoV-2 infected individuals did not recover by 6 months. Of those, 67% and 58% also did not recover at 12 and 18 months after infection, respectively. Hospitalization for acute COVID-19, pre-existing fatigue and pain or discomfort, and presence of specific systemic, cardiovascular, or musculoskeletal symptoms at 6 months were associated with persistent non-recovery. Symptom prevalence was higher among infected individuals compared to non-infected individuals at 6 months (adjusted risk difference (aRD)=17%) and 12 months (aRD=20%). aRDs for individual symptoms ranged from 2% to 12%, with the highest excess risks observed for altered taste or smell, post-exertional malaise, fatigue, and reduced concentration and memory.LimitationsWe relied on self-reported assessments and did not assess the effects of vaccination or infection with emerging variants of concern.ConclusionThese findings emphasize the need for effective interventions to reduce the burden of post COVID-19 condition. They further demonstrate the importance of using multiple outcome measures and of considering the expected rates of natural recovery and heterogenous patient trajectories in the design and interpretation of clinical trials.