bluuebunny/crossref_metadata_2025 huggingface dataset:
Trial-by-trial modulation of express visuomotor responses induced by symbolic or barely detectable cues
Authors: Contemori Samuele , Loeb Gerald E. , Corneil Brian D. , Wallis Guy , Carroll Timothy J.
Published: February 2021

Human cerebral cortex can produce visuomotor responses that are modulated by contextual and task-specific constraints. However, the distributed cortical network for visuomotor transformations limits the minimal response time of that pathway. Notably, humans can generate express visuomotor responses that are inflexibly tuned to the target location and occur 80-120ms from stimulus presentation (stimulus-locked responses, SLRs). This suggests a subcortical pathway for visuomotor transformations involving the superior colliculus and its downstream reticulo-spinal projections. Here we investigated whether cognitive expectations can modulate the SLR. In one experiment, we recorded surface EMG from shoulder muscles as participants reached toward a visual target whose location was unpredictable in control conditions, and partially predictable in cue conditions by extrapolating a symbolic cue (75% validity). Valid symbolic cues led to faster and larger SLRs than control conditions; invalid symbolic cues produced slower and smaller SLRs than control conditions. This is consistent with a cortical top-down modulation of the putative subcortical SLR-network. In a second experiment, we presented high-contrast targets in isolation (control) or ~24ms after low-contrast stimuli, which could appear at the same (valid cue) or opposite (invalid cue) location as the target, and with equal probability (50% cue validity). We observed faster SLRs than control with the valid low-contrast cues, whereas the invalid cues led to the opposite results. These findings may reflect exogenous priming mechanisms of the SLR network, potentially evolving subcortically via the superior colliculus. Overall, our results support both top-down and bottom-up modulations of the putative subcortical SLR network in humans.

NEW & NOTEWORTHY

Express visuomotor responses in humans appear to reflect subcortical sensorimotor transformation of visual inputs, potentially conveyed via the tecto-reticulo-spinal pathway. Here we show that the express responses are influenced both by symbolic and barely detectable spatial cues about stimulus location. The symbolic cue-induced effects suggest cortical top-down modulation of the putative subcortical visuomotor network. The effects of barely detectable cues may reflect exogenous priming mechanisms of the tecto-reticulo-spinal pathway.
Mortality Risk and Temporal Patterns of Atrial Fibrillation in the Nationwide Registry
Authors: Apiyasawat Sirin , Kornbongkotmas Sakaorat , Chaichareon Ply , Krittayaphong Rungroj
Published: February 2021

Aims
Persistent and permanent atrial fibrillation (AF) often occurs in the presence of multiple comorbidities and is linked to adverse clinical outcomes. It is unclear whether the sustained pattern of AF itself is prognostic or if it is confounded by underlying comorbidities. Here, we tested the association between the temporal patterns of AF and the risks of ischemic stroke and all-cause mortality.
Methods and Results
In a prospective multicenter cohort, 3046 non-valvular AF patients were consecutively enrolled and followed for adverse outcomes of all-cause mortality and ischemic stroke. The risks of both outcomes were adjusted for underlying comorbidities, and compared between the patterns of AF. At baseline, the patients were classified as paroxysmal (N=963, 31.6%), persistent (N=604, 19.8%), and permanent AF (N=1479, 45.6%) according to the standard definition. Anticoagulants were administered in 75% of all patients and 83% of those with CHA2DS2-VASc score ≥2 in males or ≥3 in females . During a mean follow up of 26 (SD 10.5) months, all-cause mortality occurred less in paroxysmal AF (2.5 per 100 patient-years) than in persistent AF (4.4 per 100 patient-years; adjusted hazard ratio [HR] 0.66, 95% CI, 0.46-0.96; P = .029) and permanent AF (4.1 per 100 patient-years; adjusted HR 0.71, 95% CI, 0.52-0.98; P = .036). The risk of ischemic stroke was similar across all patterns of AF.
Conclusions
In this multicenter nationwide registry of AF patients, persistent and permanent AF was associated with higher all-cause mortality than paroxysmal AF, independent of baseline comorbidities.
Multicellular immune hubs and their organization in MMRd and MMRp colorectal cancer
Authors: Pelka Karin , Hofree Matan , Chen Jonathan , Sarkizova Siranush , Pirl Joshua D. , Jorgji Vjola , Bejnood Alborz , Dionne Danielle , Ge William H. , Xu Katherine H. , Chao Sherry X. , Zollinger Daniel R. , Lieb David J. , Reeves Jason W. , Fuhrman Christopher A. , Hoang Margaret L. , Delorey Toni , Nguyen Lan T. , Waldman Julia , Klapholz Max , Wakiro Isaac , Cohen Ofir , Smillie Christopher S. , Cuoco Michael S. , Wu Jingyi , Su Mei-ju , Yeung Jason , Vijaykumar Brinda , Magnuson Angela M. , Asinovski Natasha , Moll Tabea , Goder-Reiser Max N. , Applebaum Anise S. , Brais Lauren K. , DelloStritto Laura K. , Denning Sarah L. , Phillips Susannah T. , Hill Emma K. , Meehan Julia K. , Frederick Dennie T. , Sharova Tatyana , Kanodia Abhay , Todres Ellen Z. , Jané-Valbuena Judit , Biton Moshe , Izar Benjamin , Lambden Conner D. , Clancy Thomas E. , Bleday Ronald , Melnitchouk Nelya , Irani Jennifer , Kunitake Hiroko , Berger David L. , Srivastava Amitabh , Hornick Jason L. , Ogino Shuji , Rotem Asaf , Vigneau Sébastien , Johnson Bruce E. , Corcoran Ryan , Sharpe Arlene H. , Kuchroo Vijay K. , Ng Kimmie , Giannakis Marios , Nieman Linda T. , Boland Genevieve M. , Aguirre Andrew J. , Anderson Ana C. , Rozenblatt-Rosen Orit , Regev Aviv , Hacohen Nir
Published: February 2021

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd patients. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across patient tumors and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines. By identifying interacting cellular programs, we thus reveal the logic underlying spatially organized immune-malignant cell networks.
Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents
Authors: Chang Yao-Chuan , Ahmed Umair , Jayaprakash Naveen , Mughrabi Ibrahim , Lin Qihang , Wu Yi-Chen , Gerber Michael , Abbas Adam , Daytz Anna , Gabalski Arielle H. , Ashville Jason , Dokos Socrates , Rieth Loren , Datta-Chaudhury Timir , Tracey Kevin , Guo Tianruo , Al-Abed Yousef , Zanos Stavros
Published: February 2021

Afferent and efferent vagal fibers mediate bidirectional communication between the brain and visceral organs. Small, unmyelinated C-afferents constitute the majority of vagal fibers, play critical roles in numerous interoceptive circuits and autonomic reflexes in health and disease and may contribute to the efficacy and safety of vagus nerve stimulation (VNS). Selective engagement of C-afferents with electrical stimuli has not been feasible, due to the default fiber recruitment order: larger fibers first, smaller fibers last. Here, we determine and optimize an electrical stimulus that selectively engages vagal C-afferents. Intermittent KHz-frequency electrical stimulation (KES) activates motor and, preferentially, sensory vagal neurons in the brainstem. During KES, asynchronous activity of C-afferents increases, while that of larger fibers remains largely unchanged. In parallel, KES effectively blocks excitability of larger fibers while moderately suppressing excitability of C-afferents. By compiling selectivity indices in individual animals, we find that optimal KES parameters for C-afferents are >5KHz frequency and 7-10 times engagement threshold (×T) intensity in rats, 15-25×T in mice. These effects can be explained in computational models by how sodium channel responses to KES are shaped by axonal size and myelin. Our results indicate that selective engagement of vagal C-afferents is attainable by intermittent KES.
Small Intestinal Resident Eosinophils Maintain Gut Homeostasis Following Microbial Colonisation
Authors: Shah K. , Ignacio A. , Bernier-Latmani J. , Köller Y. , Coakley G. , Moyat M. , Hamelin R. , Armand F. , Wong N. C. , Ramay H. , Thomson C.A. , Burkhard R. , Dufour A. , Petrova T.V. , Harris N.L. , McCoy K. D.
Published: February 2021

Intestinal homeostasis following postnatal microbial colonization requires the coordination of multiple processes including the activation of immune cells, cell-cell communication, the controlled deposition of extracellular matrix, and epithelial cell turnover and differentiation. The intestine harbors the largest frequency of resident eosinophils of all homeostatic organs, yet the functional significance of eosinophil recruitment to this organ has long remained enigmatic. Eosinophils are equipped to both respond to, and modify, their local tissue environment and thus are able to regulate the adaption of tissues to environmental changes. We report a critical role for eosinophils in regulating villous structure, barrier integrity and motility in the small intestine. Notably, the microbiota was identified as a key driver of small intestinal eosinophil activation and function. Collectively our findings demonstrate a critical role for eosinophils in facilitating mutualistic interactions between host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.

HIGHLIGHTS

The microbiota is a critical regulator of eosinophil activation and turnover

Eosinophils uphold intestinal barrier integrity following microbial colonization

Loss of eosinophils at steady-state results in increased villous blunting and altered intestinal motility
PalaCell2D: A framework for detailed tissue morphogenesis
Authors: Conradin Raphaël , Coreixas Christophe , Latt Jonas , Chopard Bastien
Published: February 2021

In silico, cell based approaches for modeling biological morphogenesis are used to test and validate our understanding of the biological and mechanical process that are at work during the growth and the organization of multi-cell tissues. As compared to in vivo experiments, computer based frameworks dedicated to tissue modeling allow us to easily test different hypotheses, and to quantify the impact of various biophysically relevant parameters.

Here, we propose a formalism based on a detailed, yet simple, description of cells that accounts for intra-, inter- and extra-cellular mechanisms. More precisely, the cell growth and division is described through the space and time evolution of the membrane vertices. These vertices follow a Newtonian dynamics, meaning that their evolution is con-trolled by different types of forces: a membrane force (spring and bending), an adherence force (inter-cellular spring), external and internal pressure forces. Different evolution laws can be applied on the internal pressure, depending on the intra-cellular mechanism of interest. In addition to the cells dynamics, our formalism further relies on a lattice Boltzmann method, using the Palabos library, to simulate the diffusion of chemical signals. The latter aims at driving the growth and migration of a tissue by simply changing the state of the cells.

All of this leads to an accurate description of the growth and division of cells, with realistic cell shapes and where membranes can have different properties. While this work is mainly of methodological nature, we also propose to validate our framework through simple, yet biologically relevant benchmark tests at both single-cell and full tissue scales. This includes free and chemically controlled cell tissue growth in an unbounded domain. The ability of our framework to simulate cell migration, cell compression and morphogenesis under external constraints is also investigated in a qualitative manner.
Thermodynamic modeling reveals widespread multivalent binding by RNA-binding proteins
Authors: Sohrabi-Jahromi Salma , Söding Johannes
Published: February 2021

Motivation

Understanding how proteins recognize their RNA targets is essential to elucidate regulatory processes in the cell. Many RNA-binding proteins (RBPs) form complexes or have multiple domains that allow them to bind to RNA in a multivalent, cooperative manner. They can thereby achieve higher specificity and affinity than proteins with a single RNA-binding domain. However, current approaches to de-novo discovery of RNA binding motifs do not take multivalent binding into account.

Results

We present Bipartite Motif Finder (BMF), which is based on a thermodynamic model of RBPs with two cooperatively binding RNA-binding domains. We show that bivalent binding is a common strategy among RBPs, yielding higher affinity and sequence specificity. We furthermore illustrate that the spatial geometry between the binding sites can be learned from bound RNA sequences. These discovered bipartite motifs are consistent with previously known motifs and binding behaviors. Our results demonstrate the importance of multivalent binding for RNA-binding proteins and highlight the value of bipartite motif models in representing the multivalency of protein-RNA interactions.

Availability

BMF source code is available athttps://github.com/soedinglab/bipartite_motif_finderunder a GPL license. The BMF web server is accessible athttps://bmf.soedinglab.org.
Is energetics or competition a stronger driver of male smallmouth bass seasonal reproductive timing?
Authors: Laroche Robert A.S. , Weinersmith Kelly L. , Angeloni Lisa , Baylis Jeffrey R. , Newman Steven P. , Egan Scott P. , Wiegmann Daniel D.
Published: February 2021

Intraspecific competitive ability is often associated with body size and has been shown to influence reproductive timing in many species. However, energetic constraints provide an alternative explanation for size-related differences of reproductive timing. In temperate fishes that experience a winter starvation period, for instance, a negative allometric relationship between body size and winter energy loss might explain why larger males spawn earlier in a season than smaller males, especially in fishes that exhibit paternal care, which is energetically costly and limits parental foraging opportunities. Male smallmouth bass,Micropterus dolomieu, defend nesting territories in which they care for offspring over an extended period. In northern populations, males rely on energy reserves over a winter starvation period and in spring must recoup energy losses before initiating reproduction, making them ideal systems in which to study contributions of competition and energetic allometry on differences of reproductive timing. Here, we harness data on parental maleM. dolomieufrom a 10-year study and show that larger males required fewer degree days-a measure of thermal energy experienced-in spring before they spawned each year and that the time of peak seasonal reproduction in the population was negatively related to the number of degree days accumulated before reproduction started. Furthermore, we found that growth of individual males between seasons better predicted changes in timing of reproduction than changes in size relative to competitors. Together, these results suggest that timing of reproduction in this population is more strongly influenced by energetic constraints than size-based competition amongst males.
Super-delta2: An Enhanced Differential Expression Analysis Procedure for Multi-Group Comparisons of RNA-seq Data
Authors: Cui Zihan , Liu Yuhang , Zhang Jinfeng , Qiu Xing
Published: February 2021

Background

We developedsuper-delta2, a differential gene expression analysis pipeline designed for multi-group comparisons for RNA-seq data. It includes a customized one-way ANOVA F-test and a post-hoc test for pairwise group comparisons; both are designed to work with a multivariate normalization procedure to reduce technical noise. It also includes a trimming procedure with bias-correction to obtain robust and approximately unbiased summary statistics used in these tests. We demonstrated the asymptotic applicability ofsuper-delta2to log-transformed read counts in RNA-seq data by large sample theory based on Negative Binomial Poisson (NBP) distribution.

Results

We comparedsuper-delta2with three commonly used RNA-seq data analysis methods: limma/voom, edgeR, and DESeq2 using both simulated and real datasets. In all three simulation settings,super-delta2not only achieved the best overall statistical power, but also was the only method that controlled type I error at the nominal level. When applied to a breast cancer dataset to identify differential expression pattern associated with multiple pathologic stages,super-delta2selected more enriched pathways than other methods, which are directly linked to the underlying biological condition (breast cancer).

Conclusions

By incorporating trimming and bias-correction in the normalization step,super-delta2was able to achieve tight control of type I error. Because the hypothesis tests are based on asymptotic normal approximation of the NBP distribution,super-delta2does not require computationally expensive iterative optimization procedures used by methods such as edgeR and DESeq2, which occasionally have convergence issues.
CSF Aβ38 levels are associated with Alzheimer-related decline: implications for γ-secretase modulators
Authors: Cullen Nicholas C. , Janelidze Shorena , Palmqvist Sebastian , Stomrud Erik , Mattsson-Carlgren Niklas , Hansson Oskar
Published: February 2021

Objective

Shorter Aβ species might modulate disease progression in Alzheimer’s disease (AD). Here we studied whether Aβ38 levels in cerebrospinal fluid (CSF) are associated with risk of developing AD dementia and cognitive decline.

Methods

CSF Aβ38 levels were measured in 656 individuals across two clinical cohorts – the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cox regression models were used to evaluate the association between baseline Aβ38 levels and risk of AD dementia in AD-biomarker positive individuals (AD+; determined by CSF P-tau/Aβ42 ratio) with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Linear mixed effects models were used to evaluate the association between baseline Aβ38 levels and cognitive decline as measured by MMSE in AD+ participants with SCD, MCI or AD dementia.

Results

In the BioFINDER cohort, high Aβ38 levels were associated with slower decline in MMSE (β = 0.30 points / sd., P = 0.001) and with lower risk of conversion. To AD dementia (HR = 0.83 per sd., P = 0.03). In the ADNI cohort, higher Aβ38 levels were associated with less decline in MMSE (β = 0.27, P = 0.01), but not risk of conversion to AD dementia (P = 0.66). Aβ38 levels in both cohorts remained significantly associated with both outcomes when adjusted for CSF P-tau levels and remained associated with cognition when adjusted for CSF Aβ42 levels.

Conclusions

Higher CSF Aβ38 levels are associated with lower risk of AD-related changes in two independent clinical cohorts. These findings may have implications for γ-secretase modulators as potential disease-altering therapy.
Language impairment in motor neuron disease phenotypes different from classical amyotrophic lateral sclerosis: a review
Authors: Sbrollini Benedetta , Preti Alice Naomi , Zago Stefano , Papagno Costanza , Appollonio Ildebrando Marco , Nicolò Aiello Edoardo
Published: February 2021

Background

Up to 35-40% of patients with amyotrophic lateral sclerosis (ALS) present with language deficits falling within the spectrum of frontotemporal degeneration (FTD). It is currently debated whether frontotemporal involvement occurs or not in motor neuron disease (MND) phenotypes that differ from classical ALS (i.e., both non-ALS MNDs and non-classical ALS endo-phenotypes) - this stance being supported by the notion of a common pathology underlying MNDs. To investigate whether language dysfunctions also occur in patients with different-from-classical-ALS MNDs can; a) help determine whether the MND-FTDcontinuumcould be broadened at a neuropsychological level; b) convey relevant entailments to cognitive diagnostics in these populations.

Aims

The present study thus aimed at reviewing evidence regarding language impairment in different-from-classical-ALS MND patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were consulted to implement and report the present review. Studies were included if a) language was quantitatively assessed b) in patients diagnosed with different-from-classical-ALS MND phenotypes. Studies assessing demented patients only were excluded. From an originalN=1117 contributions,N=20 group studies were finally included. Secondary outcomes were taken into account for qualitatively assessing potential biases in generalizing results.

Main contribution

Studies were divided into those assessing predominant-upper vs. - lower MND patients (UMND/LMND). Language dysfunctions appeared to be more prevalent and severe in UMND patients. Language screeners were able to detect language deficits in both groups. Lexical-semantic deficits appeared to be highly prevalent in both groups and a selective difficulty in action-vs. object-naming was systematically detected. Morpho-syntactic deficits were seldom reported in both groups. Phonological deficits and central dysgraphic features were found in UMND patients only.

Conclusion

Patients with different-from-classical-ALS MND phenotypes display language deficits similar to those of classical ALS patients (as far as both prevalence and type are concerned) and thus could be validly included in the MND-FTDcontinuumat a neuropsychological level. A greater cortical involvement might account for language deficits being more severe in UMND patients. Consistently with guidelines for cognitive assessment in ALS patients, action-naming tasks might represent a valid and sensitive tool for assessing language in UMND/LMND patients too.
Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2 infection (PASC)
Authors: Chun Hyung J. , Coutavas Elias , Pine Alexander , Lee Alfred I. , Yu Vanessa , Shallow Marcus , Giovacchini Coral X. , Mathews Anne , Stephenson Brian , Que Loretta G. , Lee Patty J. , Kraft Bryan D.
Published: February 2021

Introduction

Subjects recovering from COVID-19 frequently experience persistent respiratory ailments; however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.

Methods

We performed a prospective cohort study of subjects with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.

Results

Sixty-one subjects were enrolled across two academic medical centers at a median of 9 weeks (interquartile range 6-10) after COVID-19 illness: n=13 subjects (21%) mild/non-hospitalized, n=30 (49%) hospitalized/non-critical, and n=18 subjects (30%) hospitalized/intensive care (“ICU”). Fifty-three subjects (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P<0.05), but did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered subjects by past COVID-19 severity. Lipocalin 2 (LCN2), matrix metalloproteinase-7 (MMP-7), and hepatocyte growth factor (HGF) identified by the model were significantly higher in the ICU group (P<0.05) and inversely correlated with FVC and DLCO (P<0.05), and were confirmed in a separate validation cohort (n=53).

Conclusions

Subjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.

Funding

The study was funded in part by the NHLBI (K08HL130557 to BDK and R01HL142818 to HJC), the DeLuca Foundation Award (AP), a donation from Jack Levin to the Benign Hematology Program at Yale, and Divisional/Departmental funds from Duke University.
Cellular substrates of functional network integration and memory in temporal lobe epilepsy
Authors: Douw Linda , Nissen Ida A. , Fitzsimmons Sophie M.D.D. , Santos Fernando A.N. , Hillebrand Arjan , van Straaten Elisabeth C.W. , Stam Cornelis J. , De Witt Hamer Philip C. , Baayen Johannes C. , Klein Martin , Reijneveld Jaap C. , Heyer Djai B. , Verhoog Matthijs B. , Wilbers René , Hunt Sarah , Mansvelder Huibert D. , Geurts Jeroen J.G. , de Kock Christiaan P.J. , Goriounova Natalia A.
Published: February 2021

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of therapy-resistant TLE patients, who underwent fMRI, MEG and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.
Crystal structure determination of the armadillo repeat domain ofDrosophilaSARM1 using MIRAS phasing
Authors: Gu Weixi , Luo Zhenyao , Vonrhein Clemens , Jia Xinying , Ve Thomas , Nanson Jeffrey D. , Kobe Boštjan
Published: February 2021

We describe the crystal structure determination of the ARM domain ofDrosophilaSARM1 (dSARM1ARM), which required combination of a number of sources of phase information in order to obtain interpretable electron density maps. SARM1 is a central executioner of the process of axon degeneration, a common feature of the early phase of a range of neurodegenerative diseases. SARM1 is held in the inactive state in healthy axons by its N-terminal auto-inhibitory ARM domain, and is activated to cleave NAD+upon injury, triggering the subsequent axon degeneration. To characterize the molecular mechanism of SARM1 activation, we sought to determine the crystal structure of the SARM1 ARM domain. Here we describe the recombinant production and crystallization of dSARM1ARM, as well as unconventional process used for structure determination. Crystals were obtained in the presence of NMN, a precursor of NAD+and a potential activator of SARM1, only afterin situproteolysis of the N-terminal 63 residues. After molecular replacement attempts failed, we determined the crystal structure of dSARM1ARMat 1.65 Å resolution using the MIRAS phasing technique with the program autoSHARP, combining data from the native, SeMet-labelled, and Br-soaked crystals. The structure will further our understanding of the regulation of SARM1.
AMycobacterium tuberculosiseffector targets mitochondrion, controls energy metabolism and limits cytochrome c exit
Authors: Martin Marianne , deVisch Angelique , Boudehen Yves-Marie , Barthe Philippe , Gutierrez Claude , Turapov Obolbek , Aydogan Talip , Heriaud Laurène , Gracy Jerome , Neyrolles Olivier , Mukamolova Galina V. , Letourneur François , Cohen-Gonsaud Martin
Published: February 2021

Host metabolism reprogramming is a key feature ofMycobacterium tuberculosis (Mtb)infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein fromMtb,Rv1813c manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway. Furthermore, the release of cytochrome c from mitochondria, an early apoptotic event in response to short-term oxidative stress, is delayed in Rv1813c expressing cells. This study reveals a novel class of mitochondria targeting effectors fromMtbwhich might participate in host cells metabolic reprogramming and apoptosis control duringMtbinfections.
Independent duplications of the Golgi phosphoprotein 3 oncogene in birds
Authors: Opazo Juan C. , Vandewege Michael W. , Gutierrez Javier , Zavala Kattina , Vargas-Chacoff Luis , Morera Francisco J. , Mardones Gonzalo A.
Published: February 2021

Golgi phosphoprotein 3 (GOLPH3) was the first reported oncoprotein of the Golgi apparatus. It was identified as an evolutionarily conserved protein upon its discovery about 20 years ago, but its function remains puzzling in normal and cancer cells. The GOLPH3 gene is part of a group of genes that also includes the GOLPH3L gene. Because cancer has deep roots in multicellular evolution, studying the evolution of the GOLPH3 gene family in non-model species represents an opportunity to identify new model systems that could help better understand the biology behind this group of genes. The main goal of this study is to explore the evolution of the GOLPH3 gene family in birds as a starting point to understand the evolutionary history of this oncoprotein. We identified a repertoire of three GOLPH3 genes in birds. We found duplicated copies of the GOLPH3 gene in all main groups of birds other than paleognaths, and a single copy of the GOLPH3L gene. We suggest there were at least three independent origins for GOLPH3 duplicates. Amino acid divergence estimates show that most of the variation is located in the N-terminal region of the protein. Our transcript abundance estimations show that one paralog is highly and ubiquitously expressed, and the others were variable. Our results are an example of the significance of understanding the evolution of the GOLPH3 gene family, especially for unraveling its structural and functional attributes.
Genomic Considerations for FHIR; eMERGE Implementation Lessons
Authors: Murugan Mullai , Babb Lawrence J. , Taylor Casey Overby , Rasmussen Luke V. , Freimuth Robert R. , Venner Eric , Yan Fei , Yi Victoria , Granite Stephen J. , Zouk Hana , Aronson Samuel J. , Power Kevin , Fedotov Alex , Crosslin David R. , Fasel David , Jarvik Gail P. , Hakonarson Hakon , Bangash Hana , Kullo Iftikhar J. , Connolly John J. , Nestor Jordan G. , Caraballo Pedro J. , Wei WeiQi , Wiley Ken , Rehm Heidi L. , Gibbs Richard A.
Published: February 2021

Structured representation of clinical genetic results is necessary for advancing precision medicine. The Electronic Medical Records and Genomics (eMERGE) Network’s Phase III program initially used a commercially developed XML message format for standardized and structured representation of genetic results for electronic health record (EHR) integration. In a desire to move towards a standard representation, the network created a new standardized format based upon Health Level Seven Fast Healthcare Interoperability Resources (HL7 FHIR), to represent clinical genomics results. These new standards improve the utility of HL7 FHIR as an international healthcare interoperability standard for management of genetic data from patients. This work advances the establishment of standards that are being designed for broad adoption in the current health information technology landscape.
TheGiardialamellipodium-like ventrolateral flange supports attachment and rapid cytokinesis
Authors: Hardin William R. , Alas Germain C. M. , Taparia Nikita , Thomas Elizabeth B. , Steele-Ogus Melissa , Hvorecny Kelli L. , Halpern Aaron R. , Tůmová Pavla , Kollman Justin M. , Vaughan Joshua C. , Sniadecki Nathan J. , Paredez Alexander R.
Published: February 2021

Attachment to the intestinal epithelium is critical to the lifestyle of the ubiquitous parasiteGiardia lamblia. The microtubule cytoskeleton plays a well characterized role in attachment via the ventral adhesive disc, whereas the role of the unconventional actin cytoskeleton is controversial. We identified a novel actin associated protein with putative WH2-like actin binding domains we named Flangin. Flangin complexes withGiardiaactin and is enriched in the ventrolateral flange (VLF), a lamellipodium-like membrane protrusion at the interface between parasites and attached surfaces. Live imaging revealed that the VLF grows to ~1 μm in width after cytokinesis, then remains size-uniform in interphase, grows during mitosis, and is resorbed during cytokinesis. A Flangin truncation mutant stabilizes the VLF and blocks cytokinesis, indicating that the VLF is a membrane reservoir supporting rapid myosin-independent cytokinesis inGiardia. Rho family GTPases are important regulators of membrane protrusions,GlRac, the sole Rho family GTPase inGiardia, was localized to the VLF. Knockdown of Flangin, actin, andGlRac result in VLF formation defects indicating a conserved role forGlRac andactin in forming membrane protrusions, despite the absence of canonical actin binding proteins that link Rho GTPase signaling to lamellipodia formation. Flangin-depleted parasites challenged with fluid shear force in flow chambers had a reduced ability to remain attached, indicating a role for the VLF in attachment. This secondary attachment mechanism complements the microtubule based adhesive ventral disc, a feature that is particularly important during mitosis when the parental ventral disc begins disassembly in preparation for cytokinesis.

Importance

The ventrolateral flange (VLF) is a lamellipodium-like structure found at the host-parasite interface that has long been thought to be involved in parasite attachment. The proteins responsible for building the VLF have remained unidentified precluding manipulation of the VLF to determine its role inGiardiabiology. We identified Flangin, a novel actin associated protein that localizes to the VLF, implicatingGiardiaactin in VLF formation. We demonstrate that: 1.) Flangin, actin, andGlRac are required for VLF formation, 2.) the VLF serves as a membrane reservoir to supportGiardia’sincredibly fast cytokinesis, and 3) the VLF augments attachment, which is critical to parasitism. The microtubule-based adhesive ventral disc and the actin-based ventrolateral flange represent redundant means of maintaining attachment, the presence of redundant systems illustrate the importance of attachment to the lifestyle of this ubiquitous parasite.
The carbon footprint of meat and dairy proteins: a practical perspective to guide low carbon footprint dietary choices
Authors: Gaillac R. , Marbach S.
Published: February 2021

Meat and dairy products in the food industry represent a significant portion of anthropogenic green house gas emissions. To meet the Intergovernemental Panel on Climate Change recommendations to limit global warming, these emissions should be reduced. Meat and dairy products are also responsible for the majority of our daily, vital, protein intake. Yet, meat and dairy products contain very different amounts of proteins, making it difficult in general to rationalize which protein source has the lowest carbon footprint. Here we present a practical and pedagogical review, comparing the carbon footprint of a variety of meat and dairy products with respect to their protein content. We investigate the carbon footprint of different dietary choices for several countries, by keeping the total number of meat and dairy proteins constant. Interestingly, we find that dairy-only diets are in general only a little less carbon intensive than current diets. However, 50% carbon footprint reduction may be obtained, throughout the world, with a “low CO2”-tailored diet including only small poultry, eggs and yogurt. Such a dietary pattern suggests easy to follow consumer guidelines for reduced carbon footprint. We report further on a number of consumer oriented questions (local or imported? organic or not? cow or goat milk? hard or soft cheese?). Our methodology may be applied to broader questions, such as the carbon footprint of proteins in general (including fish and plant proteins). We hope our work will drive more studies focusing on consumer-oriented questions.
β-importins Tnpo-SR and Cadmus and the small GTPase Ran promote ovarian cyst formation inDrosophila
Authors: Beachum Allison N. , Hinnant Taylor D. , Williams Anna E. , Powell Amanda M. , Ables Elizabeth T.
Published: February 2021

Germ cells undergo mitotic expansion via incomplete cytokinesis, forming cysts of undifferentiated cells that remain interconnected prior to meiotic initiation, through mechanisms that are not well-defined. In somatic cells, Ras-related nuclear protein (Ran) spatiotemporally regulates mitotic spindle assembly, cleavage furrow formation and abscission. Here, we identify Ran and β-importins as critical regulators of cyst development in theDrosophilaovary. Depletion ofRanor the β-importinsTnpo-SRandcadmusdisrupts oocyte selection and results in egg chambers with variable numbers of germ cells, suggesting abnormal cyst development and cyst fragmentation. We demonstrate that Ran, Tnpo-SR, and Cadmus regulate key cellular processes during cyst formation, including cell cycle dynamics, fusome biogenesis, and ring canal stability, yet do so independently of mitotic spindle assembly. Further, Tnpo-SR and Cadmus control cyclin accumulation and suppress cytokinesis independent of Ran-GTP, suggesting that β-importins sequester protein cargos that normally promote the mitotic-to-meiotic transition. Our data demonstrates that Ran and β-importins are critical for germ cell cyst formation, a role that is likely conserved in other organisms.

SUMMARY STATEMENT

Ran and two β-importins function coordinately to promote oocyte selection and cyst development in theDrosophilaovary.
A topological characterization of DNA sequences based on chaos geometry and persistent homology
Authors: Nguyen Dong Quan Ngoc , Le Phuong Dong Tan , Xing Lin , Lin Lizhen
Published: February 2021

Methods for analyzing similarities among DNA sequences play a fundamental role in computational biology, and have a variety of applications in public health, and in the field of genetics. In this paper, a novel geometric and topological method for analyzing similarities among DNA sequences is developed, based on persistent homology from algebraic topology, in combination with chaos geometry in 4-dimensional space as a graphical representation of DNA sequences. Our topological framework for DNA similarity analysis is general, alignment-free, and can deal with DNA sequences of various lengths, while proving first-of-the-kind visualization features for visual inspection of DNA sequences directly, based on topological features of point clouds that represent DNA sequences. As an application, we test our methods on three datasets including genome sequences of different types of Hantavirus, Influenza A viruses, and Human Papillomavirus.
A deep network-based model of hippocampal memory functions under normal and Alzheimer’s disease conditions
Authors: Kanagamani Tamizharasan , Chakravarthy V. Srinivasa , Ravindran Balaraman
Published: February 2021

We present a deep network-based model of the associative memory functions of the hippocampus. The proposed network architecture has two key modules: 1) an autoencoder module which represents the forward and backward projections of the cortico-hippocampal projections and 2) a module that computes familiarity of the stimulus and implements hill-climbing over the familiarity which represents the dynamics of the loops within the hippocampus. The proposed network is used in two simulation studies. In the first part of the study, the network is used to simulate image pattern completion by autoassociation under normal conditions. In the second part of the study, the proposed network is extended to a heteroassociative memory and is used to simulate picture naming task in normal and Alzheimer’s disease (AD) conditions. The network is trained on pictures and names of digits from 0 – 9. The encoder layer of the network is partly damaged to simulate AD conditions. As in case of AD patients, under moderate damage condition, the network recalls superordinate words (“odd” instead of “nine”). Under severe damage conditions, the network shows a null response (“I don’t know”). Neurobiological plausibility of the model is extensively discussed.
Neural mechanism underlying task-specific enhancement of motor learning by concurrent transcranial direct current stimulation
Authors: Wang Ying , Wang Jixian , Zhang Qing-fang , Xiao Ke-wei , Wang Liang , Yu Qing-ping , Xie Qing , Poo Mu-ming , Wen Yunqing
Published: February 2021

The optimal protocol for neuromodulation by transcranial direct current stimulation (tDCS) remains unclear. Using rotarod paradigm, we found that mouse motor learning was enhanced by anodal tDCS (3.2 mA/cm2) during but not before or after task performance. Dual-task experiments showed that motor learning enhancement was specific to the task accompanied by concurrent anodal tDCS. Studies using stroke model mice induced by middle cerebral artery occlusion (MCAO) showed that concurrent anodal tDCS restored motor learning capability in a task-specific manner. Transcranialin vivocalcium imaging further showed that anodal and cathodal tDCS elevated and suppressed neuronal activity in the primary motor cortex (M1), respectively. Anodal tDCS specifically promoted the activity of task-related M1 neurons during task performance, suggesting that elevated Hebbian synaptic potentiation in task-activated circuits accounts for motor learning enhancement. Thus, application of tDCS concurrent with the targeted behavioral dysfunction could represent a more effective approach for treating brain disorders.
The Reactobiome Unravels a New Paradigm in Human Gut Microbiome Metabolism
Authors: Bidkhori Gholamreza , Lee Sunjae , Edwards Lindsey A. , Chatelier Emmanuelle Le , Almeida Mathieu , Ezzamouri Bouchra , Onate Florian Plaza , Ponte Nicolas , Shawcross Debbie L. , Proctor Gordon , Nielsen Lars , Nielsen Jens , Uhlen Mathias , Ehrlich Stanislav Dusko , Shoaie Saeed
Published: February 2021

Changes in microbial metabolism have been used as the main approach to assess function and elucidate environmental and host-microbiome interactions. This can be hampered by uncharacterised metagenome species and lack of metabolic annotation. To address this, we present a comprehensive computational platform for population stratification based on microbiome composition, the underlying metabolic potential and generation of metagenome species and community level metabolic models. We revisit the concepts of enterotype and microbiome richness introducing the reactobiome as a stratification method to unravel the metabolic features of the human gut microbiome. The reactobiome encapsulates resilience and microbiome dysbiosis at a functional level. We describe five reactotypes in healthy populations from 16 countries, with specific amino acid, carbohydrate and xenobiotic metabolic features. The validity of the approach was tested to unravel host-microbiome and environmental interactions by applying the reactobiome analysis on a one-year Swedish longitudinal cohort, integrating gut metagenomics, plasma metabolomics and clinical data.
Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease
Authors: Colom-Cadena Martí , Toombs Jamie , Simzer Elizabeth , Tulloch Jane , Jackson Rosemary J , Catterson James H , Rose Jamie , Waybright Lora , Caggiano Anthony O , Davies Caitlin , Hooley Monique , Dunnett Sophie , Tempelaar Robert , Tzioras Makis , Hamby Mary E , Izzo Nicholas J , Catalano Susan M. , Smith Colin , Dando Owen , Spires-Jones Tara L.
Published: February 2021

Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how amyloid beta leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds amyloid beta and mediates toxicity. While many candidates have been observed in model systems, their relevance to human AD brain remains unknown. This is in part due to methodological limitations preventing visualization of amyloid beta binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Förster resonance energy transfer (FRET) to image over 1 million individual synaptic terminals in temporal cortex from AD (n=9) and age matched control cases (n=6). Within postsynaptic densities, amyloid beta generates a FRET signal with transmembrane protein 97, cellular prion protein, and postsynaptic density 95. Transmembrane protein 97 is also present in a higher proportion of postsynapses in Alzheimer’s brain compared to controls. Further, we inhibited amyloid beta / transmembrane protein 97 interaction in a mouse model of amyloidopathy by treating with the an allosteric modulator CT1812 or vehicle. CT1812 drug concentration correlated negatively with synaptic FRET signal between transmembrane protein 97 and amyloid beta. In human induced pluripotent stem cell derived neurons challenged with human Alzheimer’s brain homogenate, transmembrane protein 97 and amyloid beta are present in synapses. Transcriptional changes are induced by Aβ including changes in genes involved in neurodegeneration and neuroinflammation. CT1812 treatment of these neurons caused changes in gene sets involved in synaptic function. These data support a role for transmembrane protein 97 in the synaptic binding of amyloid beta in human Alzheimer’s disease brain where it may mediate synaptotoxicity.