bluuebunny/crossref_metadata_2025 huggingface dataset:
scAMACE: Model-based approach to the joint analysis of single-cell data on chromatin accessibility, gene expression and methylation
Authors: Wangwu Jiaxuan , Sun Zexuan , Lin Zhixiang
Published: March 2021

The advancement in technologies and the growth of available single-cell datasets motivate integrative analysis of multiple single-cell genomic datasets. Integrative analysis of multimodal single-cell datasets combines complementary information offered by single-omic datasets and can offer deeper insights on complex biological process. Clustering methods that identify the unknown cell types are among the first few steps in the analysis of single-cell datasets, and they are important for downstream analysis built upon the identified cell types. We propose scAMACE for the integrative analysis and clustering of single-cell data on chromatin accessibility, gene expression and methylation. We demonstrate that cell types are better identified and characterized through analyzing the three data types jointly. We develop an efficient expectation-maximization (EM) algorithm to perform statistical inference, and evaluate our methods on both simulation study and real data applications. We also provide the GPU implementation of scAMACE, making it scalable to large datasets. The software and datasets are available athttps://github.com/cuhklinlab/scAMACE_py(python implementation) andhttps://github.com/cuhklinlab/scAMACE(R implementation).
LKB1 inactivation modulates chromatin accessibility to drive metastatic progression
Authors: Pierce Sarah E. , Granja Jeffrey M. , Corces M. Ryan , Brady Jennifer J. , Tsai Min K. , Pierce Aubrey B. , Tang Rui , Chu Pauline , Feldser David M. , Chang Howard Y. , Bassik Michael C. , Greenleaf William J. , Winslow Monte M.
Published: March 2021

Metastasis is the leading cause of cancer-related deaths, enabling cancer cells to expand to secondary sites and compromise organ function1. Given that primary tumors and metastases often share the same constellation of driver mutations2–4, the mechanisms driving their distinct phenotypes are unclear. Here, we show that inactivation of the frequently mutated tumor suppressor gene, liver kinase B1 (LKB1), has evolving effects throughout lung cancer progression, leading to the differential epigenetic re-programming of early-stage primary tumors compared to late-stage metastases. By integrating genome-scale CRISPR/Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin accessibility in lung adenocarcinoma primary tumors. Using an in vivo model of metastatic progression, we further reveal that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and a metastatic-like sub-population of cancer cells within primary tumors. SOX17 expression is necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can appear to change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.
Identification of biomarkers and pathways of mitochondria in sepsis patients
Authors: Yuan Gongsheng
Published: March 2021

Sepsis is a life-threatening condition associate with significant morbidity and mortality, but limited treatment. Mitochondria are recently recognized to be related to the pathophysiology of sepsis, and mitochondria could serve as a potential drug target. In our study, we aim to identify biological functions and pathways of mitochondria during the processes of sepsis by using a bioinformatics method to elucidate their potential pathogenesis. The gene expression profiles of the GSE167914 dataset were originally created by using the Nanostring nCounter Elements™ TagSet preselected for mitochondrial biogenesis and function panel. The biological pathways were analyzed by the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), Gene Ontology (GO), and Reactome enrichment. KEGG and GO results showed the Neurodegeneration pathways such as Huntington and Parkinson pathways were mostly affected in the development of sepsis. Moreover, we identified several mitochondrial genes including TOMM40, TOMM20, TIMM22, TIMM10, TIMM17A, TIMM9, TIMM44 were involved in the regulation of protein translocation into mitochondria. Further, we predicted several regulators that had the ability to affect the mitochondria during sepsis by L1000fwd analysis. Thus, this study provides further insights into the mechanism of mitochondrial function during sepsis.
Enhancing neuronal plasticity through intracranial theta burst stimulation in the human sensorimotor cortex
Authors: Herrero Jose L. , Smith Alexander , Mishra Akash , Markowitz Noah , Mehta Ashesh D. , Bickel Stephan
Published: March 2021

The progress of therapeutic neuromodulation greatly depends on improving stimulation parameters to most efficiently induce neuroplasticity effects. Intermittent Theta Burst stimulation (iTBS), a form of electrical stimulation that mimics the natural brain activity patterns, has shown efficacy in inducing such effects in animal studies and rhythmic Transcranial Magnetic Stimulation (rTMS) studies in humans. However, little is known about the potential neuroplasticity effects of iTBS applied through intracranial electrodes in humans which could have implications for deep brain stimulation therapies. This study characterizes the physiological effects of cortical iTBS in the human cortex and compare them with single pulse alpha stimulation, another frequently used paradigm in rTMS research. We applied these stimulation paradigms to well-defined regions in the sensorimotor cortex which elicited contralateral hand or arm muscle contractions during electrical stimulation mapping in epilepsy patients implanted with intracranial electrodes. Treatment effects were evaluated using effective connectivity and beta oscillations coherence measures in areas connected to the treatment site as defined with cortico-cortical evoked potentials. Our results show that iTBS increases beta band synchronization within the sensorimotor network indicating a potential neuroplasticity effect. The effect is specific to the sensorimotor system, the beta frequency band and the stimulation pattern (no effect was found with single-pulse alpha stimulation). The effects outlasted the stimulation by three minutes. By characterizing the neurophysiological effects of iTBS within well-defined cortical networks, we hope to provide an electrophysiological framework that allows clinicians and researchers to optimize brain stimulation protocols which may have translational value.
Dynamics of data availability in disease modeling: An example evaluating the trade-offs of ultra-fine-scale factors applied to human West Nile virus disease models in the Chicago area, USA
Authors: Uelmen J.A. , Irwin P. , Brown W.M. , Karki S. , Ruiz M.O. , Li B. , Smith R.L.
Published: March 2021

Background

Since 1999, West Nile virus (WNV) has moved rapidly across the United States, resulting in tens of thousands of human cases. Both the number of human cases and the minimum infection rate (MIR) in vector mosquitoes vary across time and space and are driven by numerous abiotic and biotic forces, ranging from differences in microclimates to socio-demographic factors. Because the interactions among these multiple factors affect the locally variable risk of WNV illness, it has been especially difficult to model human disease risk across varying spatial and temporal scales. Cook and DuPage Counties, comprising the city of Chicago and surrounding suburbs, experience some of the highest numbers of human neuroinvasive cases of WNV in the United States. Despite active mosquito control efforts, there is consistent annual WNV presence, resulting in more than 285 confirmed WNV human cases and 20 deaths from the years 2014-2018 in Cook County alone.

Methods

A previous Chicago-area WNV model identified the fifty-five most high and low risk locations in the Northwest Mosquito Abatement District (NWMAD), an enclave ¼ the size of the combined Cook and DuPage county area. In these locations, human WNV risk was stratified by model performance, as indicated by differences in studentized residuals. Within these areas, an additional two-years of field collections and data processing was added to a 12-year WNV dataset that includes human cases, MIR, vector abundance, and land-use, historical climate, and socio-economic and demographic variables, and was assessed by an ultra-fine-scale (1 km spatial × 1 week temporal resolution) multivariate logistic regression model.

Results

Multivariate statistical methods applied to the ultra-fine-scale model identified fewer explanatory variables while improving upon the fit of the previous model. Beyond MIR and climatic factors, efforts to acquire additional covariates only slightly improved model predictive performance.

Conclusions

These results suggest human WNV illness in the Chicago area may be associated with fewer, but increasingly critical, key variables at finer scales. Given limited resources, these findings suggest large variations in model performance occur, depending on covariate availability, and provide guidance in variable selection for optimal WNV human illness modeling.
Hybrid histidine kinase BinK repressesVibrio fischeribiofilm signaling at multiple developmental stages
Authors: Ludvik Denise A. , Bultman Katherine M. , Mandel Mark J.
Published: March 2021

The symbiosis between the Hawaiian bobtail squid,Euprymna scolopes, and its exclusive light-organ symbiont,Vibrio fischeri, provides a natural system in which to study host-microbe specificity and gene regulation during the establishment of a mutually-beneficial symbiosis. Colonization of the host relies on bacterial biofilm-like aggregation in the squid mucus field. Symbiotic biofilm formation is controlled by a two-component signaling (TCS) system consisting of regulators RscS-SypF-SypG, which together direct transcription of the Syp symbiotic polysaccharide. TCS systems are broadly important for bacteria to sense environmental cues and then direct changes in behavior. Previously, we identified hybrid histidine kinase BinK as a strong negative regulator ofV. fischeribiofilm regulation, and here we further explore the function of BinK. To inhibit biofilm formation, BinK requires the predicted phosphorylation sites in both the histidine kinase (H362) and receiver (D794) domains. Furthermore, we show that RscS is not essential for host colonization whenbinKis deleted from strain ES114, and imaging of aggregate size revealed no benefit to the presence of RscS in a background lacking BinK. Strains lacking RscS still suffered in competition. Finally, we show that BinK functions to inhibit biofilm gene expression in the light organ crypts, providing evidence for biofilm gene regulation at later stages of host colonization. Overall, this study provides direct evidence for opposing activities of RscS and BinK and yields novel insights into biofilm regulation during the maturation of a beneficial symbiosis.

IMPORTANCE

Bacteria are often in a biofilm state, and transitions between planktonic and biofilm lifestyles are important for pathogenic, beneficial, and environmental microbes. The critical nature of biofilm formation duringVibrio fischericolonization of the Hawaiian bobtail squid light organ provides an opportunity to study development of this processin vivousing a combination of genetic and imaging approaches. The current work refines the signaling circuitry of the biofilm pathway inV. fischeri, provides evidence that biofilm regulatory changes occur in the host, and identifies BinK as one of the regulators of that process. This study provides information about how bacteria regulate biofilm gene expression in an intact animal host.
Genome sequencing and functional genes comparison betweenSphingopyxisUSTB-05 andSphingomonas morindaeNBD5
Authors: Liu Chao , Xu Qianqian , Zhao Zhenzhen , Ahmad Shahbaz , Zhang Haiyang , Zhang Yufan , Pang Yu , Aikemu Abudumukeyiti , Liu Yang , Yan Hai
Published: March 2021

Sphingomonadaceae has a large number of strains that can biodegrade hepatotoxins or environmental pollutants. The latest research reported that certain strains can also produce lutein. Based on the third-generation sequencing technology, we analyzed the whole genome sequence and compared related functional genes of two strains of Sphingomonadaceae isolated from different habitats. The genome ofSphingopyxisUSTB-05 was 4,679,489 bp and contained 4312 protein coding genes. The 4,239,716 bp nuclear genome ofSphingomonas morindaeNBD5, harboring 3882 protein coding genes, has two sets of chromosomes. Both strains had lutein synthesis metabolism pathway sharing identical synthetic genes ofcrtB,crtE,crtI,crtQ,crtL,crtR,atoB,dxs,dxr,ispD,ispE,ispDF,gcpE,ispG,ispH,ispA,ispBandispU.SphingopyxisUSTB-05 had hepatotoxins microcystins and nodularin metabolic pathways related to 16 genes (ald,ansA,gdhA,crnA,phy,ocd,hypdh,spuC,nspC,speE,murI,murD,murC,hmgL,bioAandglsA), while these genes were not found inSphingomonas morindaeNBD5. The unique protein sequences of strain NBD5 and strain USTB-05 were 155 and 199, respectively. The analysis of whole genome of the two Sphingomonadaceae strains provides insights into prokaryote evolution, the new pathway for lutein production and the new genes for environmental pollutant biodegradation.

IMPORTANCE

Understanding the functional genes related to the special functions of strains is essential for humans to utilize microbial resources. The ability ofSphingopyxisUSTB-05 to degrade hepatotoxins microcystins and nodularin has been studied in depth, however the complete metabolic process still needs further elucidation.Sphingomonas morindaeNBD5 can produce lutein, and it is necessary to determine whether there is a new pathway of lutein. In this study, the whole genome sequencing ofSphingopyxisUSTB-05 andSphingomonas morindaeNBD5 were performed for the first time. Lutein synthesis metabolic pathways and synthetic genes were discovered in Sphingomonadaceae. We predicted the existence of new lutein synthesis pathways and revealed most of the genes of the new synthesis pathways. A comparative analysis of the functional genes of the two strains revealed thatSphingopyxisUSTB-05 contains a large number of functional genes related to the biodegradation of hepatotoxins or hexachlorocyclohexane. Among them, the functional genes related to the biodegradation and metabolism of hexachlorocyclohexane had not been previously reported. These findings lay the foundation for the biosynthesis of lutein usingSphingomonas morindaeNBD5 orSphingopyxisUSTB-05 and the application ofSphingopyxisUSTB-05 for the biodegradation of hepatotoxins microcystins and nodularin or environmental pollutants.
Validity of markers and indexes of systemic inflammation in predicting mortality in COVID 19 infection : A hospital based cross sectional study
Authors: Archana B , Shyamsunder Shylaja , Das Rinki
Published: March 2021

Background

COVID-19 is an ongoing global pandemic. It is a systemic infection with a significant impact on the hematopoietic and the immune system. In this study we aimed to evaluate the different inflammatory markers and indexes of systemic inflammatory response in predicting the mortality in patients with COVID 19.

Methods

In this cross sectional study, various inflammatory markers like D-dimer, CRP, serum ferritin, LDH and CBC derived indexes of inflammation were analyzed in predicting mortality in COVID 19 infection.

Results

We enrolled 302 COVID 19 patients who had a mean age of 54.51±15.39 yrs with 210 (69.5%) males. Among them 21% were asymptomatic and fever was the commonest among symptomatic patients. Majority of patients (66.7%) had no comorbidities and 20% had multiple comorbidities. On analyzing different hematological variables, survivors had statistically significant higher hemoglobin count, lymphocytes, monocytes, eosinophil and platelet count and lower leukocyte, neutrophil count. Inflammatory markers D-dimer, serum ferritin and LDH were significantly elevated among non survivors. Among the indexes of inflammation, only NLR showed significant higher values among non survivors.

All the inflammatory markers were able to predict mortality among the COVID 19 infected cases with a sensitivity and specificity of 85% and 65% for d dimer levels, 85% and 72% for serum ferritin, 85% and 72% for LDH, 85% and 51% for CRP levels respectively. Among the indexes of inflammation, validity of NLR was best in predicting mortality with 85% sensitivity and 51% specificity.

Conclusion

Abnormalities in peripheral blood parameters and increase in inflammatory markers are common findings in COVID 19 infection. NLR was best at predicting mortality followed by D-dimer and serum ferritin levels

Contribution details
Sex differences in opioid and psychostimulant craving and relapse: a critical review
Authors: Nicolas Céline , Zlebnik Natalie E. , Farokhnia Mehdi , Leggio Lorenzo , Ikemoto Satoshi , Shaham Yavin
Published: March 2021

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones’ role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.

The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not sufficiently powered, and/or not a priori designed to detect sex differences. Additionally, fMRI studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed provide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving, but not cue- or cocaine priming-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or heroin in rodent models.
Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms
Authors: Sen Onur , Harrison Jonathan U. , Burroughs Nigel J. , McAinsh Andrew D.
Published: March 2021

Chromosome mis-segregation during mitosis leads to daughter cells with deviant karyotypes (aneuploidy) and an increased mutational burden through chromothripsis of mis-segregated chromosomes. The rate of mis-segregation and the aneuploidy state are hallmarks of cancer and linked to cancer genome evolution. Errors can manifest as “lagging chromosomes” in anaphase, although the mechanistic origins and likelihood of correction are incompletely understood. Here we combine lattice light sheet microscopy, endogenous protein labelling and computational analysis to define the life history of > 104kinetochores throughout metaphase and anaphase from over 200 cells. By defining the “laziness” of kinetochores in anaphase, we reveal that chromosomes are at a considerable and continual risk of mis-segregation. We show that the majority of kinetochores are corrected rapidly in early anaphase through an Aurora B dependent process. Moreover, quantitative analyses of the kinetochore life histories reveal a unique dynamic signature of metaphase kinetochore oscillations that forecasts their fate in the subsequent anaphase. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with a new layer of early anaphase error correction required for stable karyotype propagation.
Eosinophils restrict diesel exhaust particles induced cell proliferation of lung epithelial A549 cells, vial interleukin-13 mediated mechanisms: implications for tissue remodelling and fibrosis
Authors: Niranjan Rituraj , Subramanian Muthukumaravel , Panneer D. , Ojha Sanjay Kumar
Published: March 2021

Diesel exhaust particulates (DEPs) affect lung physiology and cause serious damage to the lungs. A number of studies have demonstrated that eosinophils play a very important role in the development of lung tissue remodelling and fibrosis. However, the exact mechanism of its pathogenesis is not known. We for the first time demonstrate that, Interleukin-13 plays a very important role in the development of tissue remodelling and fibrosis. We demonstrate that, Diesel exhaust particle significantly induce eosinophils cell proliferation and interleukin-13 release in invitro culture conditions. Supernatant collected from DEP induced eosinophils cells significantly restrict cell proliferation of epithelial cells due to exposure of diesel exhast particles. Furthermore, purified interleukin-13 decreases the proliferation of A549 cells. Notably, Etoricoxib (selective COX-2 inhibitor) did not inhibit DEP-triggered release of interleukin-13, suggesting another cell signalling pathway. In, vivo exposer of DEP to the mice lung, resulted in the high level of eosinophils degranulation as depicted by the EPX-1 immunostaining and altered level of mRNA expressions of inflammatory genes. We also found that, a-SMA, fibroblast specific protein (FSP-1) has been changed in response to DEP in the mice lungs along with the mediators of inflammation. Altogether, we elucidated the mechanistic role of eosinophils in the DEP triggered proliferation of lungs cells thus providing an inside in the pathophysiology of tissue remodelling and fibrosis of lungs.
Severity of SARS-CoV-2 infection as a function of the interferon landscape across the respiratory tract of COVID-19 patients
Authors: Sposito Benedetta , Broggi Achille , Pandolfi Laura , Crotta Stefania , Ferrarese Roberto , Sisti Sofia , Clementi Nicola , Ambrosi Alessandro , Liu Enju , Frangipane Vanessa , Saracino Laura , Marongiu Laura , Facchini Fabio A , Bottazzi Andrea , Fossali Tommaso , Colombo Riccardo , Clementi Massimo , Tagliabue Elena , Pontiroli Antonio E , Meloni Federica , Wack Andreas , Mancini Nicasio , Zanoni Ivan
Published: March 2021

The COVID-19 outbreak driven by SARS-CoV-2 has caused more than 2.5 million deaths globally, with the most severe cases characterized by over-exuberant production of immune-mediators, the nature of which is not fully understood. Interferons of the type I (IFN-I) or type III (IFN-III) families are potent antivirals, but their role in COVID-19 remains debated. Our analysis of gene and protein expression along the respiratory tract shows that IFNs, especially IFN-III, are over-represented in the lower airways of patients with severe COVID-19, while high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity; also, IFN expression varies with abundance of the cell types that produce them. Our data point to a dynamic process of inter- and intra-family production of IFNs in COVID-19, and suggest that IFNs play opposing roles at distinct anatomical sites.
Colonial choanoflagellate isolated from Mono Lake harbors a microbiome
Authors: Hake K. H. , West P.T. , McDonald K. , Laundon D. , Garcia De Las Bayonas A. , Feng C. , Burkhardt P. , Richter D.J. , Banfield J.F. , King N.
Published: March 2021

Choanoflagellates offer key insights into bacterial influences on the origin and early evolution of animals. Here we report the isolation and characterization of a new colonial choanoflagellate species,Barroeca monosierra,that, unlike previously characterized species, harbors a microbiome.B. monosierrawas isolated from Mono Lake, California and forms large spherical colonies that are more than an order of magnitude larger than those formed by the closely relatedSalpingoeca rosetta. By designing fluorescencein situhybridization probes from metagenomic sequences, we found thatB. monosierracolonies are colonized by members of the halotolerant and closely relatedSaccharospirillaceaeandOceanospirillaceae,as well as purple sulfur bacteria (Ectothiorhodospiraceae) and non-sulfurRhodobacteraceae.This relatively simple microbiome in a close relative of animals presents a new experimental model for investigating the evolution of stable interactions among eukaryotes and bacteria.

IMPORTANCE

The animals and bacteria of Mono Lake (California) have evolved diverse strategies for surviving the hypersaline, alkaline, arsenic-rich environment. We sought to investigate whether the closest living relatives of animals, the choanoflagellates, exist among the relatively limited diversity of organisms in Mono Lake. We repeatedly isolated members of a single species of choanoflagellate, which we have namedBarroeca monosierra,suggesting that it is a stable and abundant part of the ecosystem. Characterization ofB. monosierrarevealed that it forms large spherical colonies that each contain a microbiome, providing an opportunity to investigate the evolution of stable physical associations between eukaryotes and bacteria.
Can Stephen Curry really know? - Conscious access to outcome prediction of motor actions
Authors: Maurer Lisa K. , Maurer Heiko , Hegele Mathias , Müller Hermann
Published: March 2021

The NBA player Stephen Curry has a habit of turning away from the basket right after taking three-point shots, presumably because he can predict the success of his shot. For such a consciously accessible prediction to be possible, Stephen Curry needs access to internal processes of outcome prediction and valuation. Computational simulations and empirical data suggest that the quality of internal prediction processes is related to motor expertise. Whether the results of internal predictions can reliably be consciously accessed is less clear. In the current study, 30 participants each practiced a virtual goal-oriented throwing task for 1000 trials. Every second trial, they were required to verbally predict the success of the current throw. Results showed that on average, conscious prediction accuracy was above an individually computed chance level, taking into account individual success rates and response strategies. Furthermore, prediction accuracy was related to throwing performance. Participants with better performance predicted the success of their throws more accurately than participants with poorer performance. Moreover, for the poorer performing individuals, movement execution was negatively affected by the verbalized predictions required, and they did not show variation in speech characteristics (response latency) between correct and incorrect predictions. This indicates reduced quality of conscious access to internal processes of outcome prediction.
ATP allosterically stabilizes Integrin-linked kinase for efficient force generation
Authors: Martin Isabel M. , Nava Michele M. , Wickström Sara A. , Gräter Frauke
Published: March 2021

Focal adhesions link the actomyosin cytoskeleton to the extracellular matrix regulating cell adhesion, shape, and migration. Adhesions are dynamically assembled and disassembled in response to extrinsic and intrinsic forces, but how the essential adhesion component intergrin-linked kinase (ILK) dynamically responds to mechanical force and what role ATP bound to this pseudokinase plays remains elusive. Here, we apply force-probe molecular dynamics simulations of human ILK:α-parvin coupled to traction force microscopy to explore ILK mechanotransducing functions. We identify two key saltbridge-forming arginines within the allosteric, ATP-dependent force-propagation network of ILK. Disrupting this network by mutation impedes parvin binding, focal adhesion stabilization, force generation, and thus migration. Under tension, ATP shifts the balance from rupture of the complex to protein unfolding, indicating that ATP increases the force threshold required for focal adhesion disassembly. Our study proposes a new role of ATP as an obligatory binding partner for structural and mechanical integrity of the pseudokinase ILK, ensuring efficient cellular force generation and migration.
Effects on brain activity after creative mathematical reasoning when considering individual differences in cognitive ability
Authors: Wirebring Linnea Karlsson , Wiklund-Hörnqvist Carola , Stillesjö Sara , Granberg Carina , Lithner Johan , Andersson Micael , Nyberg Lars , Jonsson Bert
Published: March 2021

Many learning opportunities of mathematical reasoning in school encourage imitative learning procedures (algorithmic reasoning, AR) instead of engaging in more constructive reasoning processes (e.g.,creative mathematical reasoning, CMR). Here, we employed a within-subject intervention in the classroom with pupils in upper secondary schools followed by a test situation during brain imaging with fMRI one week later. We hypothesized that learning with CMR compared to AR should lead to a CMR-effect, characterized by better performance and differential brain activity during test. We observed higher brain activity in key regions for mathematical cognition such as left angular gyrus and left inferior frontal gyrus on tasks previously learnt with CMR compared to AR. The effects remained when controlling for individual differences in cognitive abilities, as well as performance and response time differences between the two conditions. Encouraging pupils to engage in constructive processes when learning mathematical reasoning might thus have lasting beneficial effects.
To catch a hijacker: abundance, evolution and genetic diversity of P4-like bacteriophage satellites
Authors: Sousa Jorge A. Moura de , Rocha Eduardo P.C.
Published: March 2021

Bacteriophages (phages) are bacterial parasites that can themselves be parasitized by phage satellites. The molecular mechanisms used by satellites to hijack phages are sometimes understood in great detail, but the origins, abundance, distribution, and composition of these elements are poorly known. Here, we show that P4-like elements are present in more than 10% of the genomes of Enterobacterales, and in almost half of those ofEscherichia coli, sometimes in multiple distinct copies. We identified over 1000 P4-like elements with very conserved genetic organization of the core genome and a few hotspots with highly variable genes. These elements are never found in plasmids and have very little homology to known phages, suggesting an independent evolutionary origin. Instead, they are scattered across chromosomes, possibly because their integrases are often exchanged with other elements. The rooted phylogenies of hijacking functions are correlated and suggest longstanding co-evolution. They also reveal broad host ranges in P4-like elements, since almost identical elements can be found in distinct bacterial genuses. Our results show that P4-like phage satellites constitute a very distinct, widespread and ancient family of mobile genetic elements. They pave the way for studying the molecular evolution of antagonistic interactions between phages and their satellites.
Epigenetic clock and methylation studies in dogs
Authors: Horvath Steve , Lu Ake T. , Haghani Amin , Zoller Joseph A. , Brooke Robert T. , Raj Ken , Plassais Jocelyn , Hogan Andrew N. , Ostrander Elaine A.
Published: March 2021

DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging but the principles underpinning them appear to be evolutionarily conserved, as they have now been successfully developed for over 120 mammalian species. Here we describe reliable and highly accurate epigenetic clocks shown to apply to 51 domestic dog breeds. The methylation profiles were generated using a custom array with DNA sequences that are conserved across all mammalian species (HorvathMammalMethylChip40). Canine epigenetic clocks were constructed to estimate age and also predict mortality risk by estimating average time-to-death. We also present two highly accurate human-dog dual species epigenetic clocks (R=0.97), which may facilitate the ready translation from canine to human use (or vice versa) of anti-aging treatments being developed for longevity and preventive medicine. Finally, epigenome-wide association studies herein reveal individual methylation sites that may underlie the inverse relationship between breed weight and lifespan. Overall, we describe robust biomarkers to measure aging and potentially health status in canines.
Inhibition of selective autophagy by members of the herpesvirus ubiquitin-deconjugase family
Authors: Ylä-Anttila Päivi , Masucci Maria G.
Published: March 2021

Autophagy is an important component of the innate immune response that restricts infection by different types of pathogens. Viruses have developed multiple strategies to avoid autophagy to complete their replication cycle and promote spreading to new hosts. Here we report that the ubiquitin deconjugases encoded in the N-terminal domain of the large tegument proteins of Epstein-Barr virus (EBV), Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV), but not herpes simplex virus-1 (HSV-1), regulate selective autophagy by inhibiting the activity of the autophagy receptor SQSTM1/p62. We found that all the homologs bind to and deubiquitinate SQSTM1/p62 but with variable efficiency, which correlates with their capacity to prevent the colocalization of LC3 with SQSTM1/p62 aggregates and promote the accumulation of a model autophagy substrate. The findings highlight important differences in the strategies by which herpesviruses interfere with selective autophagy.
Are narrow-ranging species doomed to extinction? Projected dramatic decline in future climate suitability of two highly threatened species
Authors: Dubos Nicolas , Montfort Frederique , Grinand Clovis , Nourtier Marie , Deso Gregory , Probst Jean-Michel , Razafimanahaka Julie Hanta , Andriantsimanarilafy Raphali Rodlis , Rakotondrasoa Eddie Fanantenana , Razafindraibe Pierre , Jenkins Richard , Crottini Angelica
Published: March 2021

Narrow-ranging species are usually omitted from Species distribution models (SDMs) due to statistical constraints, while they are predicted to be particularly vulnerable to climate change. The recently available high-resolution environmental predictors, along with recently developed methods enable to increase the eligibility of narrow-ranging species for SDMs, provided their distribution is well known. We fill a gap of knowledge on the effect of predicted climate change on narrow-ranging species. We modelled the distribution of the golden mantella frog Mantella aurantiaca and the Manapany day gecko Phelsuma inexpectata, for which the distribution of their occurrence records is well documented. Our modelling scheme included a range of processes susceptible to address statistical issues related to narrow-ranging species. We predict an alarming decline in climate suitability in the whole current distribution area of both species by 2070, potentially leading to a complete extinction in most scenarios. We identified the areas with the best climate suitability in the future, but these remain largely suboptimal regarding species climatic niche. The high level of habitat fragmentation suggests that both species likely need to be at least partly translocated. Climate change may not only drive range contractions or distribution shifts in narrow-ranging species, but may lead to the complete extirpation of suitable environments across their entire region. This study suggests that the level of threats of narrow-ranging species already identified as threatened may be underestimated, especially in heterogeneous tropical areas. We stress the need to develop sampling campaigns and implement proactive actions for narrow-ranging species in the tropics.
Drift correction in localization microscopy using entropy minimization
Authors: Cnossen Jelmer , Cui Tao Ju , Joo Chirlmin , Smith Carlas
Published: March 2021

Localization microscopy offers resolutions down to a single nanometer, but currently requires additional dedicated hardware or fiducial markers to reduce resolution loss from drift of the sample. Drift estimation without fiducial markers is typically implemented using redundant cross correlation (RCC). We show that RCC has sub-optimal precision and bias, which leaves room for improvement. Here, we minimize a bound on the entropy of the obtained localizations to efficiently compute a precise drift estimate. Within practical compute-time constraints, simulations show a 5x improvement in drift estimation precision over the widely used RCC algorithm. The algorithm operates directly on fluorophore localizations and is tested on simulated and experimental datasets in 2D and 3D. An open source implementation is provided, implemented in Python and C++, and can utilize a GPU if available.
Caloric restriction overcomes pre-diabetic and hypertension induced by high fat diet and renal artery stenosis
Authors: de Souza Nunes Faria Michelle Sabino , Pimentel Vinicíus Eduardo , Helaehil Júlia Venturini , Bertolo Mayara Correa , Santos Nathalia Tonus Horas , da Silva-Neto Pedro Vieira , Thomazini Bruna Fontana , de Oliveira Camila Andréa , do Amaral Maria Esméria Corezola
Published: March 2021

Background

Caloric restriction (CR) is a type of dietary intervention enjoyed as an essential tool in weight loss by modulating critical pathways of metabolic control, although it is not yet clear what repercussions this intervention model results when associated with renovascular hypertension. Here we demonstrate that CR can be beneficial in obese and hypertensive animals.

Methods

Rats were divided into groups: SHAM, and two groups underwent surgery to clip the left renal artery, to induce renovascular hypertension (OH and OHR). The SHAM diet was performed: 14 weeks normolipidic diet; OH: 2 weeks normolipidic diet + 12 weeks hyperlipidic diet, both ad libitum; OHR: 2 weeks normolipidic diet + 8 weeks ad libitum high fat diet + 4 weeks restricted 40% high fat diet.

Results

the OHR group dissipated blood pressure, body weight and glucose homeostasis. Reductions in insulinemia, lipids, islets fibrotic areas in the OHR group were observed along with increased insulin sensitivity and normalization of the insulin-degrading enzyme. Nicotinamide phosphoribosyltransferase, insulin receptor, Sirtuin 1 and complex II protein were modulated in liver tissue in the OHR group. Strong correlations, direct or indirect, were evaluated by Spearman’s model between SIRT1, AMPK, NAMPT, PGC-1α and NNMT with the reestablishment of blood pressure, weight loss, glycidic and lipid panel and mitochondrial adaptation.

Conclusion

CR provided short-term beneficial effects to recover physiological parameters induced by a high-fat diet and renal artery stenosis in obese and hypertensive animals. These benefits, even in the short term, can bring physiological benefits in the long run.
Organelle calcium-derived voltage oscillations in pacemaker neurons drive food-seeking behavior inAplysia
Authors: Bédécarrats Alexis , Puygrenier Laura , O’Byrne John Castro , Lade Quentin , Simmers John , Nargeot Romuald
Published: March 2021

The expression of motivated behaviors depends on both external and internally-arising neural stimuli, yet the intrinsic releasing mechanisms for such variably occurring behaviors remain elusive. In isolated nervous system preparations ofAplysia, we have found that irregularly expressed cycles of motor output underlying food-seeking behavior arise from regular membrane potential oscillations of varying magnitude in an identified pair of interneurons (B63) in the bilateral buccal ganglia. This rhythmic signal, which is endogenous and specific to the B63 cells, is generated by organelle-derived intracellular calcium fluxes that activate voltage-independent plasma membrane channels. The resulting voltage oscillation spreads throughout a subset of gap junction-coupled buccal network neurons and by triggering plateau potential-mediated bursts in B63, can initiate motor output driving food-seeking action. Thus, an atypical neuronal pacemaker mechanism, based on rhythmic intracellular calcium store release and intercellular propagation, can act as an autonomous intrinsic releaser for the occurrence of a motivated behavior.
Distinct “driving” versus “modulatory” influences of different visual corticothalamic pathways
Authors: Kirchgessner Megan A. , Franklin Alexis D. , Callaway Edward M.
Published: March 2021

Higher-order (HO) thalamic nuclei interact extensively with the cerebral cortex and are innervated by excitatory corticothalamic (CT) populations in layers 5 and 6. While these distinct CT projections have long been thought to have different functional influences on the HO thalamus, this has never been directly tested. By optogenetically inactivating different CT populations in the primary visual cortex (V1) of awake mice, we demonstrate that layer 5, but not layer 6, CT projections drive visual responses in the HO visual pulvinar, even while both pathways provide retinotopic, baseline excitation to their thalamic targets. Inactivating the superior colliculus also suppressed visual responses in the pulvinar, demonstrating that cortical layer 5 and subcortical inputs both contribute to HO visual thalamic activity - even at the level of putative single neurons. Altogether, these results indicate a functional division of driver and modulator CT pathways from V1 to the visual thalamusin vivo.
Identification of Target Objects from Gaze Behavior during a Virtual Navigation Task
Authors: Enders Leah R. , Smith Robert J. , Gordon Stephen M. , Ries Anthony J. , Touryan Jonathan
Published: March 2021

Eye tracking has been an essential tool within the vision science community for many years. However, the majority of studies involving eye-tracking technology employ a relatively passive approach through the use of static imagery, prescribed motion, or video stimuli. This is in contrast to our everyday interaction with the natural world where we navigate our environment while actively seeking and using task-relevant visual information. For this reason, vision researchers are beginning to use virtual environment platforms, which offer interactive, realistic visual environments while maintaining a substantial level of experimental control. Here, we recorded eye movement behavior while participants freely navigated through a complex virtual environment. Within this environment, participants completed a visual search task where they were asked to find and count occurrence of specific targets among numerous distractor items. We assigned each participant into one of four target groups: Humvees, motorcycles, aircraft, or furniture. Our results show a significant relationship between gaze behavior and target objects across subject groups. Specifically, we see an increased number of fixations and increase dwell time on target relative to distractor objects. In addition, we included a divided attention task to investigate how search patterns changed with the addition of a secondary task. With increased cognitive load, subjects slowed their speed, decreased gaze on objects, and increased the number of objects scanned in the environment. Overall, our results confirm previous findings from more controlled laboratory settings and demonstrate that complex virtual environments can be used for active visual search experimentation, maintaining a high level of precision in the quantification of gaze information and visual attention. This study contributes to our understanding of how individuals search for information in a naturalistic virtual environment. Likewise, our paradigm provides an intriguing look into the heterogeneity of individual behaviors when completing an un-timed visual search task while actively navigating.
Integrating reward information for prospective behaviour
Authors: Hall-McMaster Sam , Stokes Mark G. , Myers Nicholas E.
Published: March 2021

Value-based decision-making is often studied in a static context, where participants decide which option to select from those currently available. However, everyday life often involves an additional dimension: decidingwhento select to maximise reward. Recent evidence suggests that agents track the latent reward of an option, updating changes in their latent reward estimate, to achieve appropriate selection timing (latent reward tracking). However, this strategy can be difficult to distinguish from one in which the optimal selection time is estimated in advance, allowing an agent to wait a pre-determined amount of time before selecting, without needing to monitor an option’s latent reward (distance-to-goal tracking). Here we show that these strategies can in principle be dissociated. Human brain activity was recorded using electroencephalography (EEG) while female and male participants performed a novel decision task. Participants were shown an option and decided when to select it, as its latent reward changed from trial-to-trial. While the latent reward was uncued, it could be estimated using cued information about the option’s starting value and value growth rate. We then used representational similarity analysis to assess whether EEG signals more closely resembled latent reward tracking or distance-to-goal tracking. This approach successfully dissociated the strategies in this task. Starting value and growth rate were translated into a distance-to-goal signal, far in advance of selecting the option. Latent reward could not be independently decoded. These results demonstrate the feasibility of using high temporal resolution neural recordings to identify internally computed decision variables in the human brain.

Significance Statement

Reward-seeking behaviour involves acting at the right time. However, the external world does not always tell us when an action is most rewarding, necessitating internal representations that guide action timing. Specifying this internal neural representation is challenging because it might stem from a variety of strategies, many of which make similar predictions about brain activity. This study used a novel approach to test whether alternative strategies could be dissociated in principle. Using representational similarity analysis, we were able to distinguish between candidate internal representations for selection timing. This shows how pattern analysis methods can be used to measure latent decision information in non-invasive neural data.