bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysgraphic features in motor neuron disease: a review
Authors: Nicolò Aiello Edoardo , Feroldi Sarah , Preti Alice Naomi , Zago Stefano , Appollonio Ildebrando Marco
Published: February 2021

Background

Motor neuron disease (MND) patients can show oral language deficits mimicking those of frontotemporal degenerations (FTD). Although dysgraphic features have been also reported within the MND-FTD continuum, their characteristics and clinical relevance are still largely unexplored.

Aims

To profile writing disorders in MND patients can help further define their cognitive semiology and thus conveys relevant clinical entailments. Therefore, this study aimed at reviewing evidence of writing impairment in MND patients. This review was implemented and reported by consulting Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Qualitative/quantitative measures of writing abilities in MND patients was the primary outcome. Both group studies and case reports/series were taken into consideration. Twenty-four contributions were included out of an initial N=83. Potential biases in generalizing results were qualitatively controlled for by extracting background, disease-related, neuropsychological and neuroanatomofunctional secondary outcomes.

Main Contribution

Fifteen studies assessed writing abilities in Japaneses patients, whereas the remaining eight in western patients. Central dysgraphic features were reported in both neuropsychologically-impaired and –unimpaired MND patients. Phonetic/phonological paragraphias and morpho-syntactic errors were frequently reported. Although FTD was frequently co-occurent, neither cognitive nor language impairment fully accounted for writing impairment in some patients. By contrast, evidence of peripheral dysgraphia was scarce. Patients displaying writing deficits often presented with bulbar signs and perisylvian cortices involvement (including Exner’s area and the left angular gyrus). Writing deficits proved to be associated with abnormalities in executive functioning and its neural substrates. Writing-to-dictation tasks as well as writing samples assessment proved to be useful to detect writing errors.

Conclusions

Dysgraphic features in MND patients might be due to dysfunctions of the graphemic buffer – and possibly the phonological route. The lexico-semantic route appeared to be less involved. However, a mixed peripheral/central involvement cannot be ruled out. In this population, executive/attentive deficits are likely to contribute to writing errors as well. Writing deficits might thus be specific of MND patients’ cognitive/language impairment profile. The evaluation of writing abilities via writing-to-dictation/narrative writing tasks may be useful when assessing cognition/language in both neuropsychological-impaired and -unimpaired MND patients - especially when severe dysarthria/anarthria is present and prevents clinicians from assessing oral language.
Stay Home and Stay Active? The impact of stay-at-home restrictions on physical activity routines in the UK during the COVID-19 pandemic
Authors: Eshelby Victoria , Sogut Muhammed , Jolly Kate , Vlaev Ivo , Elliott Mark T.
Published: February 2021

Government restrictions applied during the COVID-19 pandemic in the UK led to the disruption of many people’s physical activity routines, with sports and leisure facilities closed and outdoor exercise only permitted once per day. In this study we investigated which population groups were impacted most in terms of reduced physical activity levels during these periods, and which groups benefitted in terms of increasing their usual level of physical activity. We surveyed UK residents, sampled through users of a rewards-for-exercise app (Sweatcoin; n=749) and an online panel (Prolific; n=907). Of the app users, n=487 further provided daily step-count data collected by the app, prior to, and during the periods of restrictions between March and June 2020. Regression models were applied to investigate factors associated with subjective change (perceived change in physical activity) and objective change (log-percentage change in daily step-count) in physical activity during the periods of restrictions. ANOVAs were used to further investigate the significant factors identified. Key factors associated with a substantial subjective reduction in physical activity included those classed as obese, gym users and people living in urban areas. All participants had a reduced step count during restrictions, with Black, Asian and minority ethnic (BAME) groups, students and urban dwellers showing the largest reductions. Therefore, targeted interventions are required to ensure that the physical and mental health impacts of sedentary behaviour are not exacerbated over the long-term by significant reductions in physical activity identified in these groups, particularly those who are also more vulnerable to the COVID-19 virus.
Molecular epidemiology of SARS-CoV-2 in Greece reveals low rates of onward virus transmission after lifting of travel restrictions based on risk assessment during summer 2020
Authors: Kostaki Evangelia Georgia , Pavlopoulos Georgios A. , Verrou Kleio-Maria , Ampatziadis-Michailidis Giannis , Harokopos Vaggelis , Hatzis Pantelis , Moulos Panagiotis , Siafakas Nikolaos , Pournaras Spyridon , Hadjichristodoulou Christos , Chatzopoulou Fani , Chatzidimitriou Dimitrios , Panagopoulos Periklis , Lourida Panagiota , Argyraki Aikaterini , Lytras Theodoros , Sapounas Spyros , Gerolymatos Gerasimos , Panagiotakopoulos Georgios , Prezerakos Panagiotis , Tsiodras Sotirios , Sypsa Vana , Hatzakis Angelos , Anastassopoulou Cleo , Spanakis Nikolaos , Tsakris Athanasios , Dimopoulos Meletios Athanasios , Kotanidou Anastasia , Sfikakis Petros , Kollias Georgios , Magiorkinis Gkikas , Paraskevis Dimitrios
Published: February 2021

Molecular epidemiology has provided an additive value to traditional public health tools by identifying SARS-CoV-2 clusters, or providing evidence that clusters based on virus sequences and contact tracing are highly concordant. Our aim was to infer the levels of virus importation and to estimate the impact of public health measures related to travel restrictions to local transmission in Greece. Our phylogenetic and phylogeographic analyses included 389 SARS-CoV-2 sequences collected during the first 7 months of the pandemic in Greece and a random collection in 5 replicates of 3,000 sequences sampled globally, as well as the best hits to our dataset identified by BLAST. Phylogenetic analyses revealed the presence of 70 genetically distinct viruses identified as independent introductions into Greece. The proportion of imported strains was 41%, 11.5%, and 8.8% during the three periods of sampling, namely, March (no travel restrictions), April to June (strict travel restrictions), and July to September (lifting of travel restrictions based on a thorough risk assessment), respectively. These findings reveal low levels of onward transmission from imported cases during summer and underscore the importance of targeted public health measures that can increase the safety of international travel during a pandemic.
Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells
Authors: Pickard Adam , Calverley Ben C. , Chang Joan , Garva Richa , Lu Yinhui , Kadler Karl E.
Published: February 2021

COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, vaccine escape variants might arise leading to a re-emergence of COVID. In anticipation of such a scenario, the identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2- DOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in- line with reported proteinuria and liver damage in patients with COVID-19. We identified 35 drugs that reduced viral replication in Vero and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.
Protein model accuracy estimation empowered by deep learning and inter-residue distance prediction in CASP14
Authors: Chen Xiao , Liu Jian , Guo Zhiye , Wu Tianqi , Hou Jie , Cheng Jianlin
Published: February 2021

The inter-residue contact prediction and deep learning showed the promise to improve the estimation of protein model accuracy (EMA) in the 13th Critical Assessment of Protein Structure Prediction (CASP13). During the 2020 CASP14 experiment, we developed and tested several EMA predictors that used deep learning with the new features based on inter-residue distance/contact predictions as well as the existing model quality features. The average global distance test (GDT-TS) score loss of ranking CASP14 structural models by three multi-model MULTICOM EMA predictors (MULTICOM-CONSTRUCT, MULTICOM-AI, and MULTICOM-CLUSTER) is 0.073, 0.079, and 0.081, respectively, which are ranked first, second, and third places out of 68 CASP14 EMA predictors. The single-model EMA predictor (MULTICOM-DEEP) is ranked 10th place among all the single-model EMA methods in terms of GDT_TS score loss. The results show that deep learning and contact/distance predictions are useful in ranking and selecting protein structural models.
Environmental enrichment induces epigenomic and genome organization changes relevant for cognitive function
Authors: Espeso-Gil Sergio , Holik Aliaksei , Bonnin Sarah , Jhanwar Shalu , Chandrasekaran Sandhya , Pique-Regi Roger , Albaigès-Ràfols Júlia , Maher Michael , Permanyer Jon , Irimia Manuel , Friedländer Marc R. , Pons-Espinal Meritxel , Akbarian Schahram , Dierssen Mara , Maass Philipp G. , Hor Charlotte N. , Ossowski Stephan
Published: February 2021

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization.

Highlights

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Environmental enrichment (EE) alters chromatin conformation, CTCF binding, and spatially 3D genome changes, thereby regulating cognitive function during the first steps of life after birth.

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Transcription-associated gene body marks H3K79me2 and H3K36me3 are differently influenced by EE in cortical brain cells and binding is exacerbated upon stimulation in an age-dependent manner.

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EE-induced changes of 3D genome organization increaseinter-chromosomal interactions of genes associated with synaptic transmission and AMPA receptor genes on chromosomes 7 and 17.
Deep learning integration of molecular and interactome data for protein-compound interaction prediction
Authors: Watanabe Narumi , Ohnuki Yuuto , Sakakibara Yasubumi
Published: February 2021

Motivation

Virtual screening, which can computationally predict the presence or absence of protein-compound interactions, has attracted attention as a large-scale, low-cost, and short-term search method for seed compounds. Existing machine learning methods for predicting protein-compound interactions are largely divided into those based on molecular structure data and those based on network data. The former utilize information on proteins and compounds, such as amino acid sequences and chemical structures, while the latter utilize interaction network data, such as data on protein-protein interactions and compound-compound interactions. However, few attempts have been made to combine both types of data in molecular information and interaction networks.

Results

We developed a deep learning-based method that integrates protein features, compound features, and multiple types of interactome data to predict protein-compound interactions. We designed three benchmark datasets with different difficulties and evaluated the performance on them. The performance evaluations show that our deep learning framework for integrating molecular structure data and interactome data outperforms state-of-the-art machine learning methods for protein-compound interaction prediction tasks. The performance improvement is proven to be statistically significant by the Wilcoxon signed-rank test. This reveals that the multi-interactome captures different perspectives than amino acid sequence homology and chemical structure similarity, and both type of data have a synergistic effect in improving prediction accuracy. Furthermore, experiments on three benchmark datasets show that our method is more robust than existing methods in accurately predicting interactions between proteins and compounds that are unseen in the training samples.
Expression of human ACE2 N-terminal domain, part of the receptor for SARS-CoV-2, in fusion with maltose binding protein,E. coliribonuclease I and human RNase A
Authors: Xu Shuang-yong , Fomenkov Alexey , Chen Tien-Hao , Yigit Erbay
Published: February 2021

The SARS-CoV-2 viral genome contains a positive-strand single-stranded RNA of ~30 kb. Human ACE2 protein is the receptor for SARS-CoV-2 virus attachment and initiation of infection. We propose to use ribonucleases (RNases) as antiviral agents to destroy the viral genomein vitro.In the virions the RNA is protected by viral capsid proteins, membrane proteins and nucleocapsid proteins. To overcome this protection we set out to construct RNase fusion with human ACE2 receptor N-terminal domain (ACE2NTD). We constructed six proteins expressed inE. colicells: 1) MBP-ACE2NTD, 2) ACE2NTD-GFP, 3) RNase I (6xHis), 4) RNase III (6xHis), 5) RNase I-ACE2NTD (6xHis), and 6) human RNase A-ACE2NTD150 (6xHis). We evaluated fusion expression in differentE. colistrains, partially purified MBP-ACE2NTD protein from the soluble fraction of bacterial cell lysate, and refolded MBP-ACE2NTD protein from inclusion body. The engineered RNase I-ACE2NTD (6xHis) and hRNase A-ACE2NTD (6xHis) fusions are active in cleaving COVID-19 RNAin vitro.The recombinant RNase I (6xHis) and RNase III (6xHis) are active in cleaving RNA and dsRNA in test tube. This study provides a proof-of-concept for construction of fusion protein between human cell receptor and nuclease that may be used to degrade viral nucleic acids in our environment.

Graphical Abstract

Cartoon illustration part of this work (Human ACE2 N-terminal domain tethered to RNase A and RNA degradation by the fusion enzyme).
Territory-level temperature influences breeding phenology and reproductive output in three forest passerine birds
Authors: Shutt Jack D , Bell Sophie C , Bell Fraser , Castello Joan , Harouchi Myriam El , Burgess Malcolm D
Published: February 2021

Temperature plays an important role in determining breeding phenology of temperate birds, with higher spring temperatures associated with earlier breeding. However, the effect of localised territory-scale temperature variations is poorly understood, with relationships between temperature and breeding phenology mostly studied using coarse-grained climatic indices. Here, we interpolate spring temperatures recorded at 150 m2grid intersections encompassing 417 ha of forest to examine the influence of territory-scale temperature, and its interaction with mean annual temperature, on territory selection, breeding phenology, clutch size and fledgling success for three co-occurring single-brooded passerine birds using data from 672 nests over four years. All species exhibited significant trends in reproductive traits associated with territory-scale temperature. Pied flycatchersFicedula hypoleucasettled in cooler territories first, where they raised more fledglings. Blue titsCyanistes caeruleuslaid larger clutches in warmer territories in warm years and always laid earlier at warmer territories irrespective of annual temperature variation. Contrastingly, pied flycatcher and wood warblerPhylloscopus sibilatrixbreeding phenology was earlier at warmer territories in cool years and cooler territories in warm years, with wood warbler clutch size responding similarly to this interaction. Greater previous breeding experience and increased higher rates of historical territory occupancy (territory quality) also predicted earlier breeding phenology and higher fledging success for pied flycatchers. We suggest that the migratory pied flycatcher and wood warbler are best synchronised with their prey availability in cooler years at a local population level while resident blue tits match local phenology across all years, which is potentially advantageous under warmer predicted climate change scenarios. We conclude that temperature at the territory scale can be an important driver of settlement and breeding phenology and influence reproductive traits.
Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD
Authors: Burt Joshua B. , Preller Katrin H. , Demirtaş Murat , Ji Jie Lisa , Krystal John H. , Vollenweider Franz X. , Anticevic Alan , Murray John D.
Published: February 2021

Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically-induced effects. This paradigm has revealed that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to its agonist activity at the serotonin-2A receptor. Here, we integrate brainwide transcriptomics with biophysically-based large-scale circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical dynamics. Our model captures the topographic effects of LSD-induced changes in cortical BOLD functional connectivity. These findings suggest that serotonin-2A-mediated modulation of pyramidal cell gain is the circuit mechanism through which LSD alters cortical functional topography. Individual-subject fitting reveals that the model captures patterns of individual neural differences in drug response that predict altered states of consciousness. This work establishes a framework for linking molecular-level manipulations to salient changes in brain function, with implications for precision medicine.
Mn2+coordinates Cap-0-RNA to align substrates for efficient 2′-O-methyl transfer by SARS-CoV-2 nsp16
Authors: Minasov George , Rosas-Lemus Monica , Shuvalova Ludmilla , Inniss Nicole L. , Brunzelle Joseph S. , Daczkowski Courtney M. , Hoover Paul , Mesecar Andrew D. , Satchell Karla J. F.
Published: February 2021

Capping viral messenger RNAs is essential for efficient translation and prevents their detection by host innate immune responses. For SARS-CoV-2, RNA capping includes 2′-O-methylation of the first ribonucleotide by methyltransferase nsp16 in complex with activator nsp10. The reaction requires substrates, a short RNA and SAM, and is catalyzed by divalent cations, with preference for Mn2+. Crystal structures of nsp16-nsp10 with capped RNAs revealed a critical role of metal ions in stabilizing interactions between ribonucleotides and nsp16, resulting in precise alignment of the substrates for methyl transfer. An aspartate residue that is highly conserved among coronaviruses alters the backbone conformation of the capped RNA in the binding groove. This aspartate is absent in mammalian methyltransferases and is a promising site for designing coronavirus-specific inhibitors.
Multiplexed activation in mammalian cells using dFnCas12a-VPR
Authors: Bryson James W. , Auxillos Jamie Y. , Rosser Susan J.
Published: February 2021

The adoption of CRISPR systems for the generation of synthetic transcription factors has greatly simplified the process for upregulating endogenous gene expression, with a plethora of applications in cell biology, bioproduction and cell reprogramming. In particular the recently discovered Cas12a systems offer extended potential, as Cas12a is capable of processing its own crRNA array to provide multiple individual crRNAs for subsequent targeting from a single transcript. Here we show the application of dFnCas12a-VPR in mammalian cells, with FnCas12a possessing a shorter PAM sequence than As or Lb variants, enabling denser targeting of genomic loci. We observe that synergistic activation and multiplexing can be achieved using crRNA arrays but also show that crRNAs expressed towards the 5’ of 6-crRNA arrays show evidence of enhanced activity. This not only represents a more flexible tool for transcriptional modulation but further expands our understanding of the design capabilities and limitations when considering longer crRNA arrays for multiplexed targeting.
CSF metabolites associate with CSF tau and improve prediction of Alzheimer’s disease status
Authors: Dong Ruocheng , Darst Burcu F. , Deming Yuetiva , Ma Yue , Lu Qiongshi , Zetterberg Henrik , Blennow Kaj , Carlsson Cynthia M. , Johnson Sterling C. , Asthana Sanjay , Engelman Corinne D.
Published: February 2021

INTRODUCTION

Cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) are biomarkers of Alzheimer’s disease (AD), yet much is unknown about AD-associated changes in tau metabolism and tau tangle etiology.

METHODS

We assessed the variation of t-tau and p-tau explained by 38 previously identified CSF metabolites using linear regression models in middle-age controls from the Wisconsin Alzheimer’s Disease Research Center, and predicted AD/mild cognitive impairment (MCI) vs. an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO).

RESULTS

The 38 CSF metabolites explained 70.3% and 75.7% of the variance in t-tau and p-tau. Of these, 7 LASSO-selected metabolites improved the prediction ability of AD/MCI vs. older controls (AUC score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model.

DISCUSSION

These tau-correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology.
Risk factors for SARS-CoV-2 infection among farmworkers in Monterey County, California
Authors: Mora Ana M. , Lewnard Joseph A. , Kogut Katherine , Rauch Stephen A. , Morga Norma , Hernandez Samantha , Wong Marcus P. , Huen Karen , Chang Cynthia , Jewell Nicholas P. , Holland Nina , Harris Eva , Cuevas Maximiliano , Eskenazi Brenda
Published: February 2021

Importance

Essential workers in agriculture and food production have been severely affected by the ongoing COVID-19 pandemic.

Objective

To identify risk factors associated with SARS-CoV-2 shedding and antibody response in farmworkers in California.

Design

This cross-sectional study collected survey data and determined current SARS-CoV-2 shedding and seropositivity among 1,107 farmworkers in California’s Salinas Valley from 16 July to 30 November 2020.

Setting

Farmworkers receiving transcription-mediated amplification (TMA) tests for SARS-CoV-2 infection at federally qualified community clinics and community sites were invited to participate in our study.

Participants

Individuals were eligible if they were not pregnant, ≥18 years old, had conducted farm work since the pandemic started, and were proficient in English or Spanish.

Exposures

Sociodemographic, household, community, and workplace characteristics.

Main Outcome(s) and Measure(s)

Current (as indicated by TMA positivity) and historical (as indicated by IgG seropositivity) SARS-CoV-2 infection.

Results

Most farmworkers enrolled in the study were born in Mexico, had primary school or lower levels of educational attainment, and were overweight or obese. Current SARS-CoV-2 shedding was associated in multivariable analyses with attained only primary or lower educational levels (RR=1.32; 95% CI: 0.99-1.76), speaking an indigenous language at home (RR=1.30; 0.97-1.73), working in the fields (RR=1.60; 1.03-2.50), and exposure to known or suspected COVID-19 case at home (RR=2.98; 2.06-4.32) or in the workplace (RR=1.59; 1.18-2.14). Antibody detection was associated with residential exposures including living in crowded housing (RR=1.23; 0.98-1.53), with children (RR=1.40; 1.1-1.76) or unrelated roommates (RR=1.40; 1.19-1.64), and with a known or suspected COVID-19 case (RR=1.59; 1.13-2.24). Those who were obese (RR=1.65; 1.01-2.70) or diabetic (RR=1.31; 0.98-1.75) were also more likely to be seropositive. Farmworkers who lived in rural areas other than Greenfield (RR=0.58; 0.47-0.71), worked indoors (RR=0.68; 0.61-0.77), or whose employer provided them with information on how to protect themselves at work (RR=0.59; 0.40-0.86) had lower risk of prior infection.

Conclusions and Relevance

Our findings suggest both residential and workplace exposures are contributing to SARS-CoV-2 infection among farmworkers in California. Urgent distribution of COVID-19 vaccines is warranted given this population’s increased risk of infection and the essential nature of their work.
Hierarchical modelling of functional brain networks in population and individuals from big fMRI data
Authors: Farahibozorg Seyedeh-Rezvan , Bijsterbosch Janine D , Gong Weikang , Jbabdi Saad , Smith Stephen M , Harrison Samuel J , Woolrich Mark W
Published: February 2021

A major goal of large-scale brain imaging datasets is to provide resources for investigating heterogeneous populations. Characterisation of functional brain networks for individual subjects from these datasets will have an enormous potential for prediction of cognitive or clinical traits. We propose for the first time a technique, Stochastic Probabilistic Functional Modes (sPROFUMO), that is scalable to UK Biobank (UKB) with expected 100,000 participants, and hierarchically estimates functional brain networks in individuals and the population, while allowing for bidirectional flow of information between the two. Using simulations, we show the model’s utility, especially in scenarios that involve significant cross-subject variability, or require delineation of fine-grained differences between the networks. Subsequently, by applying the model to resting-state fMRI from 4999 UKB subjects, we mapped resting state networks (RSNs) in single subjects with greater detail than has been possible previously in UKB (>100 RSNs), and demonstrate that these RSNs can predict a range of sensorimotor and higher-level cognitive functions. Furthermore, we demonstrate several advantages of the model over independent component analysis combined with dual-regression (ICA-DR), particularly with respect to the estimation of the spatial configuration of the RSNs and the predictive power for cognitive traits. The proposed model and results can open a new door for future investigations into individualised profiles of brain function from big data.

Highlights

We introduce stochastic PROFUMO (sPROFUMO) for inferring functional brain networks from big data

sPROFUMO hierarchically estimates fMRI networks for the population and every individual

We characterised high dimensional resting state fMRI networks from UK Biobank

Model outperforms ICA and dual regression for estimation of individual-specific network topography

We demonstrate the model’s utility for predicting cognitive traits, and capturing subject variability in network topographies versus connectivity
PACAS: pairwise comparisons of aligned subsequences
Authors: DeMonn Kenneth , Powell Christopher L. E. , Battistuzzi Fabia U.
Published: February 2021

Evaluation of conservation levels of alignments is a pivotal step for evolutionary analyses. Commonly used software to analyze alignments produce either site-by-site or overall measures of conservation without the ability of performing comparative analyses among sub-regions of the alignment. We have developed a stand-alone alignment analyzer (PairwiseComparisons ofAlignedSubsequences) that uses user-defined sub-regions to report various measures of conservation among pairs of sequences and between the sub-regions and the rest of the alignment. We then used this method to analyze the repetitive regions (low complexity regions; LCRs) of two genes in Plasmodium: AMA1 and CSP. We found that LCRs are not always associated with high entropy (low conservation) suggesting that some LCRs may be less likely to mutate than others.

Availability and Implementation

PACAS is publicly available athttps://github.com/BlabOaklandU/PACAS

Contact

Fabia U. Battistuzzibattistu@oakland.edu

Supplementary information

n/a
Rapid fall in circulating non-classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury
Authors: Marsh Sarah A. , Park Catherine , Redgrave Rachael E. , Singh Esha , Draganova Lilia , Boag Stephen E. , Spray Luke , Ali Simi , Spyridopoulos Ioakim , Arthur Helen M.
Published: February 2021

Objective

Myocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischaemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes.

Approach and Results

We retrospectively analysed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (p<0.05) and correlated inversely with left ventricular function (r=0.41, p=0.04). The early fall in NC monocytes post reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischaemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury.

Conclusions

Rapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.

Graphical Abstract

Highlights

3-5 bullet points that summarize the major findings of the study.

Circulating non classical monocytes show a rapid fall in STEMI patients within 90 minutes of re-opening the culprit coronary artery.

The extent of the drop in non classical monocytes correlates with loss of cardiac function and increased infarct size.

A mouse model of cardiac ischaemia and reperfusion shows rapid margination of monocytes to the coronary vasculature
The conserved serine transporter SdaC moonlights to enable self recognition
Authors: Chittor Achala , Gibbs Karine A.
Published: February 2021

Cells can use self recognition to achieve cooperative behaviors. Self-recognition genes principally evolve in tandem with partner self-recognition alleles. However, other constraints on protein evolution could exist. Here, we have identified an interaction outside of self-recognition loci that could constrain the sequence variation of a self-recognition protein. We show that during collective swarm expansion inProteus mirabilis, self-recognition signaling co-opts SdaC, a serine transporter. Serine uptake is crucial for bacterial survival and colonization. Single-residue variants of SdaC reveal that self recognition requires an open conformation of the protein; serine transport is dispensable. A distant ortholog fromEscherichia coliis sufficient for self recognition; however, a homologous serine transporter, YhaO, is not. Thus, SdaC couples self recognition and serine transport, likely through a shared molecular interface. Understanding molecular and ecological constraints on self-recognition proteins can provide insights into the evolution of self recognition and emergent collective behaviors.

Abstract Figure
Energy content of anchovy and sardine using surrogate calorimetry methods
Authors: Campanini Claudia , Albo-Puigserver Marta , Gérez Sara , Lloret-Lloret Elena , Giménez Joan , Pennino Maria Grazia , Bellido Jose Maria , Colmenero Ana I. , Coll Marta
Published: February 2021

European anchovy (Engraulis encrasicolus) and sardine (Sardina pilchardus) are crucial species for the marine ecosystem of the Northwestern Mediterranean Sea. They account for a high percentage of fish landings and they represent an important economic income. Concerns over their stock status are rising in recent years as biomass, growth, reproductive capacity and body condition of both species are declining. Therefore, there is an urgent need for a continuous and fast body condition monitoring scheme. Energy storage variability has important implications for both fish recruitment and population structure. Direct condition indices, such as bomb calorimetry, are highly reliable for measuring the energy content, but extremely time-consuming. Alternatively, fatmeter analysis and relative condition index (Kn) have been proposed as effective indirect methods. The aim of this study is to test the application of fatmeter as a surrogate of bomb calorimetry to infer the energy content of both small pelagic fishes. For the validation, fatmeter values were compared with both energy density (ED; via bomb calorimetry) and Kn values. Individuals of both species were sampled monthly in Barcelona harbor for a year in order to assess seasonal variations in energy content. Our results highlight that fatmeter measurements are strongly correlated with calorimetry for sardine, while a weaker but significant correlation was found for anchovy. The observed differences between the two species are related to their breeding strategies. Based on this study, fatmeter analysis appears to be a faster and suitable method to evaluate the energy content of both species routinely., In addition, we provide a linear model to infer ED from fatmeter values of both small pelagic fish. Eventually, these findings could allow for the avoidance of bomb calorimetry and could be used to implement body condition monitoring protocols, and to boost continuous large-scale monitoring.
Input-independent homeostasis of developing thalamocortical activity
Authors: Riyahi Pouria , Phillips Marnie A , Colonnese Matthew T
Published: February 2021

The isocortex of all mammals studied to date shows a progressive increase in the amount and continuity of background activity during early development. In humans the transition from a discontinuous (mostly silent, intermittently bursting) cortex to one that is continuously active is complete soon after birth and is a critical prognostic indicator in newborns. In the visual cortex of rodents this switch from discontinuous to continuous background activity occurs rapidly during the two days before eye-opening, driven by activity changes in relay thalamus. The factors that regulate the timing of continuity development, which enables mature visual processing, are unknown. Here we test the role of the retina, the primary input, in the development of continuous spontaneous activity in the visual system of mice using depth electrode recordings of cortical activity from enucleated micein vivo. Bilateral enucleation at postnatal day (P)6, one week prior to the onset of continuous activity, acutely silences cortex, yet firing rates and early oscillations return to normal within two days and show a normal developmental trajectory through P12. Enucleated animals showed differences in silent period duration and continuity on P13 that resolved on P16, and an increase in low frequency power that did not. Our results show that the timing of cortical activity development isnotdetermined by the major driving input to the system. Rather, homeostatic mechanisms in thalamocortex regulate firing rates and continuity even across periods of rapid maturation.
Genome-wide analysis of the apple family 1 glycosyltransferases identified a flavonoid-modifying UGT, MdUGT83L3, which is targeted by MdMYB88 and contributes to stress adaptation
Authors: Li Yanjie , Li Pan , Zhang Lei , Shu Jing , Court Michael H , Sun Zhuojing , Jiang Lepu , Zheng Chengchao , Shu Huairui , Hou Bingkai , Ji Lusha , Zhang Shizhong
Published: February 2021

Nowadays, the plant family 1 UDP-glycosyltransferases (UGTs) are more and more investigated owing to their contribution to the plant secondary metabolism and diverse biological roles. Apple (Malus domestica) is one of the most widely cultivated fruit trees with great economical importance. However, poor knowledge is known about the apple UGTs. In this study, we identified 229 members of family 1 through a genome-wide analysis of the apple UGTs, which were clustered into 18 groups, from A to R. We also performed detailed analysis to 34 apple UGTs with quantitavive RT-PCR, and discovered a number of stress-regulated UGTs. Among them, we characterized the role of MD09G1064900, also named as MdUGT83L3, which is significantly induced by salt and cold. In vivo analysis showed that it has high activity towards cyanidin, and moderate activity towards quercetin and keampferol. The transgenic callus and regenerated apple plants overexpressing MdUGT83L3 showed enhanced tolerance to salt and cold treatments. Overexpression of MdUGT83L3 also increased anthocyanin accumulation in the callus tissues and enhanced ROS clearing upon exposed to salt and cold stresses. Futhermore, via yeast-two-hybrid assay, EMSA and CHIP analysis, we also found that MdUGT83L3 could be directly regualted by MdMYB88. Our study indicated that MdUGT83L3, under the regulation of MdMYB88, plays important roles in salt and cold stress adaptation via modulating flavonoid metabolism in apple.
A catalogue of omics biological ageing clocks reveals substantial commonality and associations with disease risk
Authors: Macdonald-Dunlop Erin , Taba Nele , Klaric Lucija , Frkatovic Azra , Walker Rosie , Hayward Caroline , Esko Tonu , Haley Chris , Fischer Krista , Wilson James F , Joshi Peter K
Published: February 2021

Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to create eleven omics ageing clocks, with correlations of 0.45-0.97 with chronAge, even with substantial sub-setting of biomarkers. These clocks track common aspects of ageing with 94% of the variance in chronAge being shared among clocks. The difference between BA and chronAge - omics clock age acceleration (OCAA) - often associates with health measures. One year’s OCAA typically has the same effect on risk factors/10-year disease incidence as 0.46/0.45 years of chronAge. Epigenetic and IgG glycomics clocks appeared to track generalised ageing while others capture specific risks. We conclude BA is measurable and prognostic and that future work should prioritise health outcomes over chronAge.
The beta component of gamma-band auditory steady-state responses in patients with schizophrenia
Authors: Metzner Christoph , Steuber Volker
Published: February 2021

The mechanisms underlying circuit dysfunctions in schizophrenia (SCZ) remain poorly understood. Auditory steady-state responses (ASSRs), especially in the gamma and beta band, have been suggested as a potential biomarker for SCZ. While the reduction of 40Hz power for 40Hz drive has been well established and replicated in SCZ patients, studies are inconclusive when it comes to an increase in 20Hz power during 40Hz drive. There might be several factors explaining the inconsistencies, including differences in the sensitivity of the recording modality (EEG vs MEG), differences in stimuli (click-trains vs amplitude-modulated tones) and large differences in the amplitude of the stimuli. Here, we used a computational model of ASSR deficits in SCZ and explored the effect of three SCZ-associated microcircuit alterations: reduced GABA activity, increased GABA decay times and NMDA receptor hypofunction. We investigated the effect of input strength on gamma (40 Hz) and beta (20 Hz) band power during gamma ASSR stimulation and saw that the pronounced increase in beta power during gamma stimulation seen experimentally could only be reproduced in the model when GABA decay times were increased and only for a specific range of input strengths. More specifically, when the input was in this specific range, the rhythmic drive at 40Hz produced a strong 40Hz rhythm in the control network; however, in the ‘SCZ-like’ network, the prolonged inhibition led to a so-called ‘beat-skipping’, where the network would only strongly respond to every other input. This mechanism was responsible for the emergence of the pronounced 20Hz beta peak in the power spectrum. The other two microcircuit alterations were not able to produce a substantial 20 Hz component but they further narrowed the input strength range for which the network produced a beta component when combined with increased GABAergic decay times. Our finding that the beta component only existed for a specific range of input strengths might explain the seemingly inconsistent reporting in experimental studies and suggests that future ASSR studies should systematically explore different amplitudes of their stimuli. Furthermore, we provide a mechanistic link between a microcircuit alterations and an electrophysiological marker in schizophrenia and argue that more complex ASSR stimuli are needed to disentangle the nonlinear interactions of microcircuit alterations. The computational modelling approach put forward here is ideally suited to facilitate the development of such stimuli in a theory-based fashion.
Preparatory activity links frontal eye field activity with small amplitude motor unit recruitment of neck muscles during gaze planning
Authors: Rungta Satya P. , Basu Debaleena , Sendhilnathan Naveen , Murthy Aditya
Published: February 2021

A hallmark of intelligent behavior is that we can separate intention from action. To understand the mechanism that gates the flow of information between motor planning and execution, we compared the activity of frontal eye field neurons with motor unit activity from neck muscles in the presence of an intervening delay period in which spatial information regarding the target was available to plan a response. Whereas we could infer spatially-specific delayed period activity from the activity of frontal eye field neurons, neck motor unit activity during the delay period could not be used to infer the direction of an upcoming movement, Nonetheless, motor unit activity was correlated with the time it took to initiate saccades. Interestingly, we observed a heterogeneity of responses amongst motor units, such that only units with smaller amplitudes showed a clear modulation during the delay period. These small amplitude motor units also had higher spontaneous activity compared to the units which showed modulation only during the movement epoch. Taken together, our results suggest that the temporal information is visible in the periphery amongst smaller motor units during eye movement planning and explains how the delay period primes muscle activity leading to faster reaction times.

Significance statement

This study shows that the temporal aspects of a motor plan in the oculomotor circuitry can be accessed by peripheral neck muscles hundreds of milliseconds prior to the instruction to initiate a saccadic eye movement. The coupling between central and peripheral processes during the delay time is mediated by the recruitment pattern of motor units with smaller amplitude in the periphery. Besides giving insight into how information processed in cortical areas is read out by the muscles, these findings could be useful to decode intentional signals from the periphery to control brain machine interface devices.
Development and validation of a cellular host response test as an early diagnostic for sepsis
Authors: Guillou Lionel , Sheybani Roya , Jensen Anne E. , Di Carlo Dino , Caffery Terrell , Thomas Christopher , Shah Ajay M. , Tse Henry T. K. , O’Neal Hollis R.
Published: February 2021

Sepsis must be diagnosed quickly to avoid morbidity and mortality. However, the clinical manifestations of sepsis are highly variable and emergency department (ED) clinicians often must make rapid, impactful decisions before laboratory results are known. We previously developed a technique that allows the measurement of the biophysical properties of white blood cells as they are stretched through a microfluidic channel. In this study we describe and validate the resultant output as a model and score – the IntelliSep Index (ISI) – that aids in the diagnosis of sepsis in patients with suspected or confirmed infection from a single blood draw performed at the time of ED presentation. By applying this technique to a high acuity cohort with a 23.5% sepsis incidence (n=307), we defined specific metrics – the aspect ratio and visco-elastic inertial response – that are more sensitive than cell size or cell count in predicting disease severity. The final model was trained and cross-validated on the high acuity cohort, and the performance and generalizability of the model was evaluated on a separate low acuity cohort with a 6.4% sepsis incidence (n=94) and healthy donors (n=72). For easier clinical interpretation, the ISI is divided into three interpretation bands of Green, Yellow, and Red that correspond to increasing disease severity. The ISI agreed with the diagnosis established by retrospective physician adjudication, and accurately identified subjects with severe illness as measured by SOFA, APACHE-II, hospital-free days, and intensive care unit admission. Measured using routinely collected blood samples, with a short run-time and no requirement for patient or laboratory information, the ISI is well suited to aid ED clinicians in rapidly diagnosing sepsis.