bluuebunny/crossref_metadata_2025 huggingface dataset:
A new fMRI localizer for preoperative language mapping using a sentence completion task: Validity, choice of baseline condition, and test-retest reliability
Authors: Elin Kirill , Malyutina Svetlana , Bronov Oleg , Stupina Ekaterina , Marinets Aleksei , Dragoy Olga
Published: October 2021

To avoid post-neurosurgical language deficits, intraoperative mapping of the language function in the brain can be complemented with preoperative mapping with fMRI. The validity of an fMRI ‘language localizer’ paradigm crucially depends on the choice of an optimal language task and baseline condition. This study presents a new fMRI ‘language localizer’ in Russian using overt sentence completion, a task that comprehensively engages the language function by involving both production and comprehension at the word and sentence level. The paradigm was validated in 18 neurologically healthy volunteers who participated in two scanning sessions, for estimating test-retest reliability. For the first time, two baseline conditions for the sentence completion task were compared.

At the group level, the paradigm significantly activated both anterior and posterior language-related regions. Individual-level analysis showed that activation was elicited most consistently in the inferior frontal regions, followed by posterior temporal regions and the angular gyrus. Test-retest reliability of activation location, as measured by Dice coefficients, was moderate and thus comparable to previous studies. Test-retest reliability was higher in the frontal than temporo-parietal region and with the most liberal statistical thresholding compared to two more conservative thresholding methods. Lateralization indices were expectedly left-hemispheric, with greater lateralization in the frontal than temporo-parietal region, and showed moderate test-retest reliability. Finally, the pseudoword baseline elicited more extensive and more reliable activation, although the syllable baseline appears more feasible for future clinical use.

Overall, the study demonstrated the validity and reliability of the sentence completion task for mapping the language function in the brain. The paradigm needs further validation in a clinical sample of neurosurgical patients. Additionally, the study contributes to general evidence on test-retest reliability of fMRI
Intravenous corticosteroid treatment in adult patients with sepsis defined by the Sepsis-3 criteria: a systematic review and meta-analysis
Authors: Wu Yu-Pu , Lin Cheng-Kuan , Hamaya Rikuta , Huang Fei-Yang , Chien Yung-Shin , Hsu Yu-Tien , Chen Szu-Ta , Papatheodorou Stefania
Published: October 2021

Objectives

To summarize the effects of intravenous corticosteroid treatment for sepsis defined by the Sepsis-3 criteria in adult patients.

Design

Systematic review and meta-analysis.

Methods

We searched RCTs from PubMed, Embase,ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Web of Science, and International Clinical Trials Registry Platform from inception to July 12th, 2019 and updated on June 28th, 2020. Conference proceedings from relevant societies and the reference lists of previous reviews were manually screened. Abstract or full-text articles were screened by two independent investigators. We included RCTs where (1) the participants had infections and the baseline Sequential Organ Failure Assessment (SOFA) score ≥ 2 (the Sepsis-3 definitions) (2) the intervention involved any intravenous corticosteroids; (3) the control group received placebo or standard of care (4) the outcomes of interest included mortality or clinical recovery. We chose the 28-day mortality as the pre-specified primary outcome and risk ratio (RR) as the effect measure. We followed PRISMA guidelines and chose random-effects models for the pooled analyses.

Results

This study included 24 RCTs and 19 of them (7,115 participants) reported the 28-day mortality. Pooled analyses showed that intravenous corticosteroid treatment compared to placebo or standard of care was not associated with a lower risk of 28-day mortality (RR, 0.88; 95%CI, 0.73 to 1.05), but with a higher risk of hyperglycemia (RR, 1.16; 95%CI, 1.06 to 1.27). Sensitivity analysis of high-quality studies revealed a similar result for the 28-day mortality (RR, 0.95; 95%CI, 0.86 to 1.05).

Conclusions

Our findings suggested that intravenous corticosteroids compared to placebo or standard of care may not reduce the 28-day mortality in adult patients with sepsis defined by the Sepsis-3 criteria. Further studies are warranted to clarify the roles of disease severity and treatment timing in the effects of corticosteroid treatment in this population.

PROSPERO registration number

CRD42019143083

Strengths and limitations of this study

This is the first systematic review and meta-analysis that summarized the effects of intravenous corticosteroid treatments in patients with sepsis defined by the Sepsis-3 criteria.

We provide the quality of evidence to support the development of treatment guidelines specific to the Sepsis-3 cohort.

We only include randomized controlled trials in this systematic review and meta-analysis, which exclude less controlled evidences from clinical settings closer to our daily practice.

The Sepsis-3 definitions will be retrospectively applied to the included studies, so clinical trials without enough reported baseline data available may be excluded.
Long-term manifestations and modifiers of prevalence estimates of the post-COVID-19 syndrome: A systematic review and meta-analysis
Authors: De-la-Rosa-Martinez Daniel , Delaye-Martínez Marco Antonio , Bello-Chavolla Omar Yaxmehen , Sicilia-Andrade Alejandro , Juárez-Cruz Isaac David , Fermín-Martínez Carlos A. , Márquez-Salinas Alejandro , Cañedo-Guerra Enrique , Fernández-Chirino Luisa , Martínez-Gutiérrez Mónica , Sandoval-Colin Daniel Eduardo , Vilar-Compte Diana
Published: October 2021

Background

Post-acute COVID-19 syndrome (PACS) is a multi-system disease comprising persistent symptomatology after the acute phase of infection. Long-term PACS effects significantly impact patient outcomes, but their incidence remains uncharacterized due to high heterogeneity between studies. Therefore, we aimed to summarize published data on PACS, characterizing the clinical presentation, prevalence, and modifiers of prevalence estimates.

Method

In this systematic review and meta-analysis, we research MEDLINE for original studies published from January 1st, 2020, to January 31st, 2021, that reported proportions of PACS manifestations. Studies were eligible for inclusion if they included patients aged ≥18 years with confirmed COVID-19 by RT-PCR or antigen testing and a minimum follow-up of 21 days. The prevalence of individual manifestations across studies was pooled using random-effects meta-analysis. For evaluating determinants of heterogeneity, meta-regression analysis was performed. This study was registered in PROSPERO (CRD42019125025).

Results

After screening 1,235 studies, we included 29 reports for analysis. Twenty-seven meta-analyses were performed, and 61 long-term manifestations were described. The pooled prevalence of PACS was 56% (95%CI 45-66%), with the most common manifestations being diminished health status, fatigue, asthenia, dyspnea, myalgias, hyposmia and dysgeusia. Most of the included studies presented high heterogeneity. After conducting the meta-regression analysis, we identified that age, gender, number of comorbidities, and reported symptoms significantly modify the prevalence estimation of PACS long-term manifestations.

Conclusion

PACS is inconsistently reported between studies, and population characteristics influence the prevalence estimates due to high heterogeneity. A systematized approach for the study of PACS is needed to characterize its impact adequately.

Funding

none
Doors and corners of variance partitioning in statistical ecology
Authors: Schulz Torsti , Saastamoinen Marjo , Vanhatalo Jarno
Published: October 2021

Variance partitioning is a common tool for statistical analysis and interpretation in both observational and experimental studies in ecology. Its popularity has led to a proliferation of methods with sometimes confusing or contradicting interpretations. Here, we present variance partitioning as a general tool in a model based Bayesian framework for summarizing and interpreting regression-like models. To demonstrate our approach we present a case study comprising of a simple occupancy model for a metapopulation of the Glanville fritillary butterfly. We pay special attention to the thorny issue of correlated covariates and random effects, and highlight uncertainty in variance partitioning. We recommend several alternative measures of variance, which jointly can be used to better interpret variance partitions. Additionally, we extend the general approach to encompass partitioning of variance within and between groups of observations, an approach very similar to analysis of variance. While noting that many troublesome issues relating to variance partitioning, such as uncertainty quantification, have been neglected in the literature, we likewise feel that the rather general applicability of the methods as an extension of statistical model-based analyses has not been fully utilized by the ecological research community either.
Evaluation role of miR-124 in neurodegenerative diseases: literature review and in silico analysis
Authors: Amini Javad , Bibak Bahram , Afshar Amir R , Sahebkar Amirhossein
Published: October 2021

Neurodegenerative diseases (ND) are characterized by loss of function and structure of neurons. NDs like Alzheimer’s disease (AD) and Parkinson’s disease (PD) have high burden on the society and patients. Currently microRNAs (miRNAs) approach is growing. miRNAs express in different tissues, especially in the central neuron systems (CNS). miRNAs have a dynamic role in the CNS among this miRNAs, miR-124 significantly express in the CNS. Studies on miR-124 have shown that miR-124 improves ND. In this study, we evaluated the role of miR-124 in the ND by literature review and in silico analysis. We used Pubmed database to find miR-124 function in the Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, Huntington’s disease and amyotrophic lateral sclerosis. To better understand the role of miR-124 in the neurons, RNA-seq data form miR-124-deleted neuronal cells extracted from GEO database and analyzed in Galaxy platform. According literature review miR-124 attenuates inflammation and apoptosis in the ND by target NF-kb signaling pathway and regulation of BAX/BCL-2. miR-124 targets BACE1 and decreases level of Aβ. RNA-seq data showed miR-124 downregulation, an increase in chemokine gene like CCL1 and cytokine-cytokine receptor-interaction, as well as MAPK-signaling pathway. Our study shows that miR-124 can be promising therapeutic approaches to ND.
Extrasynaptic NMDA receptors bidirectionally modulate intrinsic excitability of inhibitory neurons
Authors: Yao Lulu , Rong Yi , Ma Xiaoyan , Li Haifu , Deng Di , Chen YongJun , Yang Sungchil , Peng Tao , Ye Tao , Liang Feixue , Xu Nenggui , Zhou Qiang
Published: October 2021

The NMDA subtype glutamate receptors (NMDARs) play important roles in both physiological and pathological processes in the brain. Comparing to their critical roles in synaptic modifications and excitotoxicity in the excitatory neurons, much less is understood about the functional contributions of NMDARs to the inhibitory/GABAergic neurons. By using selective NMDAR inhibitors and potentiators, we here show that NMDARs bi-directionally modulate the intrinsic excitability (defined as spontaneous/evoked spiking activity and EPSP-spike coupling) in the inhibitory/GABAergic neurons. This modulation depends on GluN2C/2D-but not GluN2A/2B-containing NMDARs. We further show that NMDAR modulator EU1794-4 mostly enhances extrasynaptic NMDAR activity, and by using it we demonstrate a significant contribution of extrasynaptic NMDARs to the modulation of intrinsic excitability in the inhibitory neurons. Altogether, this bidirectional modulation of intrinsic excitability reveals a previously less appreciated importance of NMDARs in the second-to-second functioning of inhibitory/GABAergic neurons.
Improving MHC Class I antigen processing predictions using representation learning and cleavage site-specific kernels
Authors: Lawrence Patrick J. , Ning Xia
Published: October 2021

In this work, we propose a new deep learning model, MHCrank, to predict the probability that a peptide will be processed for presentation within the MHC Class I pathway. We find that the performance of our model is significantly higher than two previously published baseline methods: MHCflurry and netMHCpan. Gains in performance result from the utilization of cleavage site-specific kernels and learned representations for amino acids. By visualizing the site-specific amino acid enrichment among top-ranked peptides, we find MHCrank’s top-ranked peptides are enriched at biologically relevant positions with amino acids that are consistent with previous work. Furthermore, the cosine similarity matrix derived from MHCrank’s learned embeddings for amino acids correlate highly with physiochemical properties that have been experimentally shown to be important in determining a peptide’s favorability to be processed. Altogether, the results reported in this work indicate that the proposed MHCrank demonstrates strong performance compared to existing methods and could have vast applicability to aid drug and vaccine development.
Identification of age-associated proteins and functional alterations in human primary retinal pigment epithelium cells
Authors: Jin Xiuxiu , Liu Jingyang , Wang Weiping , Li Jiangfeng , Liu Guangming , Qiu Ruiqi , Yang Mingzhu , Liu Meng , Yang Lin , Du Xiaofeng , Lei Bo
Published: October 2021

Background

Retinal pigmented epithelium (RPE) has essential functions to nourish and support the neural retina, and is of vital importance in the pathogenesis of age-related retinal degeneration. However, the exact molecular changes of RPE in aging remain poorly defined.

Methods

We isolated human primary RPE (hRPE) cells from 18 eye donors distributed over a wide age range (10 - 67 years). A quantitative proteomic analysis was performed to analyze their intracellular and secreted protein changes, and potential age-associtated mechanisms were validated by ARPE-19 and hRPE cells.

Results

Age-stage related subtypes and age-associtated proteins and functional alterations were revealed. Proteomic data and verifications showed that RNF123 and RNF149 related ubiquitin-mediated proteolysis might be an important clearance mechanism in elimination of oxidative damaged proteins in aged hRPE. In older hRPE cells, apoptotic signaling related pathways were up-regulated and endoplasmic reticulum organization was down-regulated both in intracellular and secreted proteome.

Conclusions

This work paints a detailed molecular picture of human RPE in aging process and provides new insights for molecular characteristics of RPE in aging and related clinical retinal conditions.
Elevated islet prohormone ratios as indicators of insulin dependency in islet transplant recipients
Authors: Chen Yi-Chun , Klimek-Abercrombie Agnieszka M. , Potter Kathryn J. , Pallo Lindsay P. , Soukhatcheva Galina , Lei Dai , Bellin Melena D. , Verchere C. Bruce
Published: October 2021

Autologous pancreatic islet transplantation is an established therapy for patients with chronic pancreatitis. However, the long-term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control. To this end, we analyzed beta cell prohormone peptide levels in a retrospective cohort of total pancreatectomy autologous islet transplant patients (n=28). Proinsulin-to-C-peptide (PI/C) and proIAPP-to-total IAPP (proIAPP/IAPP) ratios measured at 3 months post-transplant were significantly higher in patients who remained insulin dependent at 1 year follow-up. In a mouse model of human islet transplantation, recipient mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic. Histological analysis of islet grafts showed reduced insulin- and proinsulin-positive area, but elevated glucagon-positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 was detected in glucagon-positive cells, and glucagon-like peptide 1 (GLP-1) area was elevated in grafts from mice that displayed hyperglycemia or elevated plasma PI/C ratios, demonstrating intra-islet incretin production in metabolically challenged human islet grafts. These data indicate that in failing grafts, alpha cell prohormone processing is likely altered, and incomplete beta cell prohormone processing may be an early indicator of insulin dependency.
SIMBA: SIngle-cell eMBedding Along with features
Authors: Chen Huidong , Ryu Jayoung , Vinyard Michael E. , Lerer Adam , Pinello Luca
Published: October 2021

Recent advances in single-cell omics technologies enable the individual and joint profiling of cellular measurements. Currently, most single-cell analysis pipelines are cluster-centric and cannot explicitly model the interactions between different feature types. In addition, single-cell methods are generally designed for a particular task as distinct single-cell problems are formulated differently. To address these current shortcomings, we present SIMBA, a graph embedding method that jointly embeds single cells and their defining features, such as genes, chromatin accessible regions, and transcription factor binding sequences into a common latent space. By leveraging the co-embedding of cells and features, SIMBA allows for the study of cellular heterogeneity, clustering-free marker discovery, gene regulation inference, batch effect removal, and omics data integration. SIMBA has been extensively applied to scRNA-seq, scATAC-seq, and dual-omics data. We show that SIMBA provides a single framework that allows diverse single-cell analysis problems to be formulated in a unified way and thus simplifies the development of new analyses and integration of other single-cell modalities. SIMBA is implemented as an efficient, comprehensive, and extensible Python library (https://simba-bio.readthedocs.io) for the analysis of single-cell omics data using graph embedding.
Rvb1/Rvb2 proteins couple transcription and translation during glucose starvation
Authors: Chen Yang S. , Tracy Sharon , Harjono Vince , Xu Fan , Moresco James J. , Yates John R. , Zid Brian M.
Published: October 2021

During times of unpredictable stress, organisms must adapt their gene expression to maximize survival. Along with changes in transcription, one conserved means of gene regulation during conditions that quickly represses translation is the formation of cytoplasmic phase-separated mRNP granules such as P-bodies and stress granules. Previously, we identified that distinct steps in gene expression can be coupled during glucose starvation as promoter sequences in the nucleus are able to direct the subcellular localization and translatability of mRNAs in the cytosol. Here, we report that Rvb1 and Rvb2, conserved ATPase proteins implicated as protein assembly chaperones and chromatin remodelers, were enriched at the promoters and mRNAs of genes involved in alternative glucose metabolism pathways that we previously found to be transcriptionally upregulated but translationally downregulated during glucose starvation in yeast. Engineered Rvb1/Rvb2-binding on mRNAs was sufficient to sequester the mRNAs into phase-separated granules and repress their translation. Additionally, this Rvb-tethering to the mRNA drove further transcriptional upregulation of the target genes. Overall, our results point to Rvb1/Rvb2 coupling transcription, mRNA granular localization, and translatability of mRNAs during glucose starvation. This Rvb-mediated rapid gene regulation could potentially serve as an efficient recovery plan for cells after stress removal.
Waist circumference thresholds predicting incident dysglycemia and type 2 diabetes in Black African men and women
Authors: Goedecke Julia H. , Nguyen Kim , Kufe Clement , Masemola Maphoko , Chikowore Tinashe , Mendham Amy E. , Norris Shane A. , Crowther Nigel J. , Karpe Fredrik , Olsson Tommy , Kengne Andre Pascal , Micklesfield Lisa K
Published: October 2021

Objective

To determine the waist circumference (WC) thresholds for the prediction of incident dysglycemia and type 2 diabetes in Black South African (SA) men and women and compare these to advocated International Diabetes Federation (IDF) Europid thresholds.

Research design and method

In this prospective study, Black SA men (n=502) and women (n=527) from the Middle Aged Sowetan Cohort (MASC) study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up through 2017-2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL-cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycemia and type 2 diabetes.

Results

In men, the optimal WC threshold was 96.8 cm for both dysglycemia and type 2 diabetes (sensitivity 56 and 70%, specificity 74 and 70%, respectively), which performed similarly to the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycemia was 91.8 cm (sensitivity 86%, specificity 37%) and for type 2 diabetes was 95.8 cm (sensitivity 85%, specificity 45%). In comparison, the IDF threshold of 80 cm in women had higher sensitivity (97 and 100%), but lower specificity (12 and 11%) to predict incident dysglycemia and type 2 diabetes, respectively.

Conclusions

In this first prospective study of incident type 2 diabetes in Africa, we show that African-specific WC thresholds perform better than the IDF WC thresholds to predict incident dysglycemia and type 2 diabetes.
Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding
Authors: Blumer Moritz , Brown Tom , Freitas Mariella Bontempo , Destro Ana Luiza , Oliveira Juraci A. , Morales Ariadna , Schell Tilman , Greve Carola , Pippel Martin , Jebb David , Hecker Nikolai , Ahmed Alexis-Walid , Kirilenko Bogdan , Foote Maddy , Janke Axel , Lim Burton K. , Hiller Michael
Published: October 2021

Feeding exclusively on blood, vampire bats represent the only obligate sanguivorous lineage among mammals. To uncover genomic changes associated with adaptations to this unique dietary specialization, we generated a new haplotype-resolved reference-quality genome of the common vampire bat (Desmodus rotundus) and screened 26 bat species for genes that were specifically lost in the vampire bat lineage. We discovered previously-unknown gene losses that relate to metabolic and physiological changes, such as reduced insulin secretion (FFAR1,SLC30A8), limited glycogen stores (PPP1R3E), and a distinct gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2,CTRL) and distinct pathogen diversity of blood (RNASE7). Interestingly, the loss ofREP15likely helped vampire bats to adapt to high dietary iron levels by enhancing iron excretion and the loss of the 24S-hydroxycholesterol metabolizing enzymeCYP39A1could contribute to their exceptional cognitive abilities. Finally, losses of key cone phototransduction genes (PDE6H,PDE6C) suggest that these strictly-nocturnal bats completely lack cone-based vision. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to sanguivory.
Lactate Increases Stemness of CD8+ T Cells to Augment Anti-Tumor Immunity
Authors: Feng Qiang , Liu Zhida , Yu Xuexin , Huang Tongyi , Chen Jiahui , Wang Jian , Wilhelm Jonathan , Li Suxin , Song Jiwon , Li Wei , Sun Zhichen , Sumer Baran , Li Bo , Fu Yang-Xin , Gao Jinming
Published: October 2021

Nutrients and metabolites play important roles in immune functions. Recent studies show lactate instead of glucose can serve as a primary carbon fuel source for most tissues. The role of lactate in tumor immunity is not well understood with immune suppressive functions reported for lactic acid, the conjugate acid form of lactate. In this study, we report lactate increases the stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of lactate but not glucose shows CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis revealed lactate treatment increased a subpopulation of stem-like TCF-1-expressing CD8+ T cells, which is further validated by ex vivo culture of CD8+ T cells from mouse splenocytes and human peripheral blood mononuclear cells. The inhibition of histone deacetylase activity by lactate increased acetylation in the histone H3K27 site at the Tcf7 super enhancer locus and increased the gene expression of Tcf7. Adoptive transfer of CD8+ T cells pretreated with lactate in vitro showed potent tumor growth inhibition in vivo. Our results elucidate the immune protective role of lactate in anti-tumor immunity without the masking effect of acid. These results may have broad implications for T cell therapy and the understanding of lactate in immune metabolism.
nQMaker: estimating time non-reversible amino acid substitution models
Authors: Dang Cuong Cao , Minh Bui Quang , McShea Hanon , Masel Joanna , James Jennifer Eleanor , Vinh Le Sy , Lanfear Robert
Published: October 2021

Amino acid substitution models are a key component in phylogenetic analyses of protein sequences. All amino acid models available to date are time-reversible, an assumption designed for computational convenience but not for biological reality. Another significant downside to time-reversible models is that they do not allow inference of rooted trees without outgroups. In this paper, we introduce a maximum likelihood approach nQMaker, an extension of the recently published QMaker method, that allows the estimation of time non-reversible amino acid substitution models and rooted phylogenetic trees from a set of protein sequence alignments. We show that the non-reversible models estimated with nQMaker are a much better fit to empirical alignments than pre-existing reversible models, across a wide range of datasets including mammals, birds, plants, fungi, and other taxa, and that the improvements in model fit scale with the size of the dataset. Notably, for the recently published plant and bird trees, these non-reversible models correctly recovered the commonly known root placements with very high statistical support without the need to use an outgroup. We provide nQMaker as an easy-to-use feature in the IQ-TREE software (http://www.iqtree.org), allowing users to estimate non-reversible models and rooted phylogenies from their own protein datasets.
Systems-level analysis of transcriptome reorganization during liver regeneration
Authors: Porukala Manisri , Vinod P K
Published: October 2021

Tissue homeostasis and regeneration depend on the reversible transitions between quiescence (G0) and proliferation. The liver has a remarkable capacity to regenerate after injury or resection by cell growth and division. During regeneration, the liver needs to maintain the essential metabolic tasks and meet the metabolic requirements for hepatocyte growth and division. Understanding the regulatory mechanisms involved in balancing the liver function and proliferation demand after injury or resection is crucial. In this study, we analyzed high-resolution temporal RNA sequencing data of liver regeneration after two-thirds partial hepatectomy (PHx) using network inference and mathematical modeling approaches. The reconstruction of the dynamic regulatory network of liver regeneration reveals the trajectories of different metabolic pathways, protein processing in the endoplasmic reticulum (ER), ribosome biogenesis, RNA transport, spliceosome, immune response, and cell cycle. We further developed a mathematical model of the integrated circuit of liver regeneration that accounts for underlying features of compensatory metabolism, proliferation, and epithelial-to-mesenchymal transition during liver regeneration. We show that a mutually exclusive behavior emerges due to the bistable inactivation of HNF4A, which controls the initiation and termination of liver regeneration and different population-level expressions observed in single-cell RNA sequencing data of liver regeneration.
A common neural currency account for social and non-social decisions
Authors: Arabadzhiyska Desislava H. , Garrod Oliver G. B. , Fouragnan Elsa , De Luca Emanuele , Schyns Philippe G. , Philiastides Marios G.
Published: October 2021

To date, social and non-social decisions have been studied in isolation. Consequently, the extent to which social and non-social forms of decision uncertainty are integrated using shared neurocomputational resources remains elusive. Here, we address this question using simultaneous EEG-fMRI and a task in which decision evidence in social and non-social contexts varies along comparable scales. First, we identify comparable time-resolved build-up of activity in the EEG, akin to a process of evidence accumulation. We then use the endogenous trial-by-trial variability in the slopes of these accumulating signals to construct parametric fMRI predictors. We show that a region of the posterior-medial frontal cortex (pMFC) uniquely explains trial-wise variability in the process of evidence accumulation in both the social and non-social contexts. We further demonstrate a task-dependent coupling between the pMFC and regions of the human valuation system in dorso- and ventro-medial prefrontal cortex (dmPFC/vmPFC) across both contexts. Finally, we report domain-specific representations in regions known to encode the early decision evidence for each context. These results are suggestive of a domain-general decision-making architecture, whereupon domain-specific information is likely converted into a “common currency” in the dmPFC/vmPFC and accumulated for the decision in the pMFC.
Pathogen-derived 9-methyl sphingoid base is perceived by a lectin receptor kinase in Arabidopsis
Authors: Kato H. , Nemoto K. , Shimizu M. , Abe A , Asai S. , Ishihama N. , Daimon T. , Ojika M. , Kawakita K. , Onai K. , Shirasu K. , Ishiura M. , Takemoto D. , Takano Y. , Terauchi R.
Published: October 2021

In plants, many invading microbial pathogens are recognized by cell-surface pattern recognition receptors (PRRs), inducing defense responses; yet how PRRs perceive pathogen sphingolipids remains unclear. Here, we show that the ceramide Pi-Cer D from a plant pathogenic oomycetePhytophthora infestanstriggers defense responses in Arabidopsis. Pi-Cer D is cleaved by an Arabidopsis apoplastic ceramidase, NCER2, and the resulting 9-methyl-branched sphingoid base is recognized by a plasma membrane lectin receptor-like kinase, RDA2. Importantly, 9-methyl-branched sphingoid base, which is unique to microbes, induces plant immune responses by interacting with RDA2. Loss ofRDA2orNCER2function compromised Arabidopsis resistance against an oomycete pathogen, indicating that these are crucial for defense. We provide new insights that help elucidate the recognition mechanisms of pathogen-derived lipid molecules in plants.

One Sentence Summary

Oomycete-derived ceramide is cleaved into sphingoid base by ceramidase and recognized by an Arabidopsis receptor kinase.
Different brain systems support the aversive and appetitive sides of human pain-avoidance learning
Authors: Jepma Marieke , Roy Mathieu , Ramlakhan Kiran , van Velzen Monique , Dahan Albert
Published: October 2021

Both unexpected pain and unexpected pain absence can drive avoidance learning, but whether they do so via shared or separate neural and neurochemical systems is largely unknown. To address this issue, we combined an instrumental pain-avoidance learning task with computational modeling, functional magnetic resonance imaging (fMRI) and pharmacological manipulations of the dopaminergic (100 mg levodopa) and opioidergic (50 mg naltrexone) systems (N=83). Computational modeling provided evidence that untreated participants learned more from received than avoided pain. Our dopamine and opioid manipulations negated this learning asymmetry by selectively increasing learning rates for avoided pain. Furthermore, our fMRI analyses revealed that pain prediction errors were encoded in subcortical and limbic brain regions, whereas no-pain prediction errors were encoded in frontal and parietal cortical regions. However, we found no effects of our pharmacological manipulations on the neural encoding of prediction errors. Together, our results suggest that human pain-avoidance learning is supported by separate threat- and safety-learning systems, and that dopamine and endogenous opioids specifically regulate learning from successfully avoided pain.
Investigating the interaction between inter-locus and intra-locus sexual conflict using hemiclonal analysis in Drosophila melanogaster
Authors: Arun Manas Geeta , Chechi Tejinder Singh , Meena Rakesh , Bhosle Shradha Dattaraya , Srishti  , Prasad Nagaraj Guru
Published: October 2021

Divergence in the evolutionary interests of males and females leads to sexual conflict. Traditionally, sexual conflict has been classified into two types: inter-locus sexual conflict (IeSC) and intra-locus sexual conflict (IaSC). IeSC is modeled as a conflict over outcomes of intersexual reproductive interactions mediated by loci that are sex-limited in their effects. IaSC is thought to be a product of selection acting in opposite directions in males and females on traits with a common underlying genetic basis. While in their canonical formalisms IaSC and IeSC are mutually exclusive, there is growing support for the idea that the two may interact. Empirical evidence for such interactions, however, is limited. Here, we investigated the interaction between IeSC and IaSC in Drosophila melanogaster. Using hemiclonal analysis, we sampled 39 hemigenomes from a laboratory-adapted population of D. melanogaster. We measured the contribution of each hemigenome to adult male and female fitness at three different intensities of IeSC, obtained by varying the operational sex-ratio. Subsequently, we estimated the intensity of IaSC at each sex-ratio by calculating the intersexual genetic correlation for fitness and the proportion of sexually antagonistic fitness-variation. Our results indicate a statistically non-significant trend suggesting that increasing the strength of IeSC ameliorates IaSC in the population.
Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity
Authors: Pogacar Ziva , Johnson Jackie L. , Krenning Lenno , De Conti Giulia , Lieftink Cor , Velds Arno , Wardak Leyma , Jochems Fleur , Groot Kelvin , Schepers Arnout , Wang Liqin , Song Ji-Ying , van de Ven Marieke , van Tellingen Olaf , Medema Rene H. , Beijersbergen Roderick L. , Bernards Rene , de Oliveira Rodrigo Leite
Published: October 2021

Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.
Analysis of vascular architecture and parenchymal damage generated by reduced blood perfusion in decellularized porcine kidneys using a gray level co-occurrence matrix
Authors: Pantić Igor V. , Sharkeel Adeeba , Petroianu Georg A. , Corridon Peter R.
Published: October 2021

There is no cure for kidney failure, but a bioartificial kidney may help address this global problem. Decellularization provides a promising platform to generate transplantable organs. However, maintaining a viable vasculature is a significant challenge to this technology. Even though angiography offers a valuable way to assess scaffold structure/function, subtle changes are overlooked by specialists. In recent years, innovative image analysis methods in radiology have been suggested to detect and identify subtle changes in tissue architecture. The aim of our research was to apply one of these methods based on a gray level co-occurrence matrix (GLCM) computational algorithm in the analysis of vascular architecture and parenchymal damage generated by hypoperfusion in decellularized porcine. Perfusion decellularization of the whole porcine kidneys was performed using previously established protocols. We analyzed and compared angiograms of kidneys subjected to pathophysiological arterial perfusion of whole blood. For regions of interest (ROIs) covering kidney medulla and the main elements of the vascular network, five major GLCM features were calculated: angular second moment as an indicator of textural uniformity, inverse difference moment as an indicator of textural homogeneity, GLCM contrast, GLCM correlation, and sum variance of the co-occurrence matrix. In addition to GLCM, we also performed discrete wavelet transform analysis of angiogram ROIs by calculating the respective wavelet coefficient energies using high and low-pass filtering. We report statistically significant changes in GLCM and wavelet features, including the reduction of the angular second moment and inverse difference moment, indicating a substantial rise in angiogram textural heterogeneity. Our findings suggest that the GLCM method can be successfully used as an addition to conventional fluoroscopic angiography analyses of micro/macrovascular integrity following in vitro blood perfusion to investigate scaffold integrity. This approach is the first step toward developing an automated network that can detect changes in the decellularized vasculature.
Topological analysis of a bacterial DedA protein associated with alkaline tolerance and antimicrobial resistance
Authors: Scarsbrook Hollie L , Urban Roman , Streather Bree R. , Moores Alexandra , Mulligan Christopher
Published: October 2021

Maintaining membrane integrity is of paramount importance to the survival of bacteria as the membrane is the site of multiple crucial cellular processes including energy generation, nutrient uptake, and antimicrobial efflux. The DedA family of integral membrane proteins are widespread in bacteria and are associated with maintaining the integrity of the membrane. In addition, DedA proteins have been linked to resistance to multiple classes of antimicrobials in various microorganisms. Therefore, the DedA family are attractive targets for the development of new antibiotics. Despite DedA family members playing a key physiological role in many bacteria, their structure, function and physiological role remain unclear. To help illuminate the structure of the bacterial DedA proteins, we have performed substituted cysteine accessibility method (SCAM) analysis on the most comprehensively characterized bacterial DedA protein, YqjA from Escherichia coli. By probing the accessibility of 15 cysteine residues across the length of YqjA using thiol reactive reagents, we have mapped the topology of the protein. Using these data, we have experimentally validated a structural model of YqjA generated using evolutionary co-variance, which consists of an α-helical bundle with two re-entrant hairpin loops reminiscent of several secondary active transporters. In addition, our cysteine accessibility data suggests that YqjA forms an oligomer wherein the protomers are arranged in a parallel fashion. This experimentally verified model of YqjA lays the foundation for future work in understanding the function and mechanism of this interesting and important family.
Structural basis for activation and gating of IP3 receptors
Authors: Schmitz Emily A. , Takahashi Hirohide , Karakas Erkan
Published: October 2021

Calcium (Ca2+) is a universal and versatile cellular messenger used to regulate numerous cellular processes in response to external or internal stimuli. A pivotal component of the Ca2+ signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs), which mediate Ca2+ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca2+ concentrations1-3. IP3Rs are activated by IP3 and Ca2+, inhibited by Ca2+ at high concentrations, and potentiated by ATP1-3. However, the underlying molecular mechanisms are unclear due to the lack of structures in the active conformation. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP3R in multiple gating conformations; IP3-ATP bound pre-active states with closed channels, IP3-ATP-Ca2+ bound active state with an open channel, and IP3-ATP-Ca2+ bound inactive state with a closed channel. The structures demonstrate how IP3-induced conformational changes prime the receptor for activation by Ca2+, how Ca2+ binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism of the receptor activation and gating.
Degradation of ribosome and chaperone proteins is attenuated during the Differentiation of Replicatively Aged C2C12 Myoblasts
Authors: Brown Alexander D. , Stewart Claire E. , Burniston Jatin G.
Published: October 2021

Age-related impairments in myoblast differentiation may contribute to reductions in muscle function in older adults, however, the underlying proteostasis processes are not well understood. Young (P6-10) and replicatively aged (P48-50) C2C12 myoblast cultures were investigated during early (0h-24h) and late (72h-96h) stages of differentiation using deuterium oxide (D2O) labelling and mass spectrometry. The absolute dynamic profiling technique for proteomics (Proteo-ADPT) was applied to quantify the absolute rates of abundance change, synthesis and degradation of individual proteins. Proteo-ADPT encompassed 116 proteins and 74 proteins exhibited significantly (P<0.05, FDR <5 %) different changes in abundance between young and aged cells at early and later periods of differentiation. Young cells exhibited a steady pattern of growth, protein accretion and fusion, whereas aged cells failed to gain protein mass or undergo fusion during later differentiation. Maturation of the proteome was retarded in aged myoblasts at the onset of differentiation, but their proteome appeared to ‘catch up’ with the young cells during the early phase of the differentiation period. However, this ‘catch up’ process in aged cells was not accomplished by higher levels of protein synthesis. Instead, a lower level of protein degradation in aged cells was responsible for the elevated gains in protein abundance. Our novel data point to a loss of proteome quality as a precursor to the lack of fusion of aged myoblasts and highlights dysregulation of protein degradation, particularly of ribosomal and chaperone proteins, as a key mechanism that may contribute to age-related declines in the capacity of myoblasts to undergo differentiation.
Behavioral phenotyping of Zip8 393T-KI mice for in vivo study of schizophrenia pathogenesis
Authors: Terrillion Chantelle E. , Kang Byung-hak , Melia Joanna M.P.
Published: October 2021

Genetic studies have informed on the genetic landscape of schizophrenia, and the next challenge is to link the genetic associations to mechanistic studies. A common single nucleotide polymorphism in the zinc and manganese transporter ZIP8 (rs13107325; ZIP8 A391T) is a top candidate to prioritize for functional studies because it is a missense mutation that results in hypomorphic protein function. With this goal, we have established a mouse model (Zip8 393T-knock-in (KI)), and here, we report the results of brain necropsy and initial behavioral phenotyping experiments in the KI mice using open field testing, elevated plus maze, Y-maze, and trace fear conditioning. Overall, male, homozygous KI mice may exhibit subtle defects in cognition and spatial learning, otherwise the baseline testing supports minimal behavioral differences between wild-type and Zip8 393T-KI mice. There were no genotype-specific alterations of gross or microscopic neuroanatomy. These experiments are important to establish the baseline characteristics of the Zip8 393T-KI mice that may be perturbed in animal models of schizophrenia and position the Zip8 393T-KI mouse as an important model for translational studies of schizophrenia pathogenesis.
A peroxide-responding sRNA evolved from a peroxidase mRNA
Authors: Krieger Madeline C. , Dutcher H. Auguste , Ashford Andrew J. , Raghavan Rahul
Published: October 2021

Small RNAs (sRNAs) are critical regulators of gene expression in bacteria, but we lack a clear understanding of how new sRNAs originate and get integrated into regulatory networks. A major obstacle to elucidating their evolution is the difficulty in tracing sRNAs across large phylogenetic distances. To overcome this roadblock, we investigated the prevalence of sRNAs in more than a thousand genomes across Enterobacterales, a bacterial order with a rare confluence of factors that allows robust genome-scale sRNA analyses: several well-studied organisms with fairly conserved genome structures, an established phylogeny, and substantial nucleotide diversity within a narrow evolutionary space. Using a covariance modeling-based approach, we analyzed the presence of hundreds of sRNAs and discovered that a majority of sRNAs arose recently, and uncovered protein-coding genes as a potential source for the generation of new sRNA genes. A detailed investigation of the emergence of OxyS, a peroxide-responding sRNA, demonstrated that it evolved from a 3′ end fragment of a peroxidase mRNA. Collectively, our data show that the erosion of protein-coding genes can result in the formation of new sRNAs that continue to be part of the original protein’s regulon. This novel insight provides a fresh framework for understanding how new sRNAs originate and get incorporated into preexisting regulatory networks.

AUTHOR SUMMARY

Small RNAs (sRNAs) are important gene regulators in bacteria, but it is unclear how new sRNAs originate and become part of regulatory networks that coordinate bacterial response to environmental stimuli. Here, we show that new sRNAs could arise from protein-coding genes and potentially be incorporated into the ancestral proteins’ regulatory networks. We illustrate this process by defining the origin of OxyS. This peroxide-responding sRNA evolved from and replaced a peroxidase gene, but continues to be part of the peroxide-response regulon. In sum, we describe the source from which OxyS, one of the most well-studied sRNAs, arose, identify protein-coding genes as a potential raw material from which new sRNAs could emerge, and suggest a novel evolutionary path through which new sRNAs could get incorporated into pre-existing regulatory networks.