bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a Pathway for Electron Uptake in Shewanella oneidensis
Authors: Rowe Annette R. , Salimijazi Farshid , Trutschel Leah , Sackett Joshua , Adesina Oluwakemi , Anzai Isao , Kugelmass Liat H. , Baym Michael H. , Barstow Buz
Published: January 2021

Extracellular electron transfer (EET) could enable electron uptake into microbial metabolism for the synthesis of complex, energy dense organic molecules from CO2 and renewable electricity1-6 . EET could do this with an efficiency comparable to H2 -oxidation7,8 but without the need for a volatile intermediate and the problems it causes for scale up9. However, naturally occurring electroactive organisms suffer from a number of technical drawbacks. Correcting these will require extensive knowledge of the genetics and mechanisms of electron uptake. To date, studies of electron uptake in electroactive microbes have focused on shared molecular machinery also used for anaerobic mineral reduction, like the Mtr EET complex in the electroactive microbe Shewanella oneidensis MR-110-14. However, this shared machinery cannot explain all features of electron uptake, hindering efforts to engineer electron uptake. To address this, we screened gene disruption mutants for 3,667 genes, representing ≈ 99% of all non-essential genes, from the S. oneidensis whole genome knockout collection using a redox dye oxidation assay as a proxy for electron uptake. Confirmation of electron uptake using electrochemical testing allowed us to identify five genes from S. oneidensis that are indispensable for electron uptake from a cathode. Knockout of each gene eliminates extracellular electron uptake, yet in 4 of the 5 cases produces no significant defect in electron donation to an anode, highlighting a distinct role for these loci in electron uptake vs. donation. This result highlights an electronic connection between aerobic and anaerobic electron transport chains that allow electrons from the reversible EET machinery to be coupled to different respiratory processes in S. oneidensis. Furthermore, we find homologs to these genes across many different genera suggesting that electron uptake by EET coupled to respiration could be a widespread phenomenon. These gene discoveries provide a foundation for studying this phenotype in exotic metal-oxidizing autotrophic microbes. Additionally, we anticipate that the characterization of these genes will allow for the genetic improvement of electron uptake in S. oneidensis; and genetically engineering electron uptake into a highly tractable host like E. coli to complement recent advances in synthetic CO2 fixation15.
Informative neural representations of unseen contents during higher-order processing in human brains and deep artificial networks
Authors: Mei Ning , Santana Roberto , Soto David
Published: January 2021

A framework to pinpoint the scope of unconscious processing is critical to improve our models of visual consciousness. Previous research observed brain signatures of unconscious processing in visual cortex but these were not reliably identified. Further, whether unconscious content is represented in high-level stages of the ventral visual stream and linked parieto-frontal areas remains unknown. Using a within-subject, high-precision fMRI approach, we show that unconscious contents can be decoded from multivoxel patterns that are highly distributed alongside the ventral visual pathway and also involving parieto-frontal substrates. Classifiers trained with multivoxel patterns of conscious items generalised to predict the unconscious counterparts, indicating that their neural representations overlap. These findings suggest revisions to models of consciousness such as the neuronal global workspace. We then provide a computational simulation of visual processing/representation without perceptual sensitivity by using deep neural networks performing a similar visual task. The work provides a framework for pinpointing the representation of unconscious knowledge across different task domains.
Super-Resolution Cryo-EM Maps With 3D Deep Generative Networks
Authors: Venkata Subramaniya Sai Raghavendra Maddhuri , Terashi Genki , Kihara Daisuke
Published: January 2021

An increasing number of biological macromolecules have been solved with cryo-electron microscopy (cryo-EM). Over the past few years, the resolutions of density maps determined by cryo-EM have largely improved in general. However, there are still many cases where the resolution is not high enough to model molecular structures with standard computational tools. If the resolution obtained is near the empirical border line (3-4 Å), a small improvement of resolution will significantly facilitate structure modeling. Here, we report SuperEM, a novel deep learning-based method that uses a three-dimensional generative adversarial network for generating an improved-resolution EM map from an experimental EM map. SuperEM is designed to work with EM maps in the resolution range of 3 Å to 6 Å and has shown an average resolution improvement of 1.0 Å on a test dataset of 36 experimental maps. The generated super-resolution maps are shown to result in better structure modelling of proteins.
Microtubule associated proteins and motors required for ectopic microtubule array formation inS. cerevisiae
Authors: King Brianna R. , Meehl Janet B. , Vojnar Tamira , Winey Mark , Muller Eric G. , Davis Trisha N.
Published: January 2021

The mitotic spindle is resilient to perturbation due to the concerted, and sometimes redundant, action of motors and microtubule-associated proteins. Here we utilize an inducible ectopic microtubule nucleation site in the nucleus ofSaccharomyces cerevisiaeto study three necessary steps in the formation of a bipolar array: the recruitment of the γ-tubulin complex, nucleation and elongation of microtubules, and the organization of microtubules relative to each other. This novel tool, an Spc110 chimera, reveals previously unreported roles of the microtubule-associated proteins Stu2, Bim1, and Bik1, and the motors Vik1 and Kip3. We report that Stu2 and Bim1 are required for nucleation and that Bik1 and Kip3 promote nucleation at the ectopic site. Stu2, Bim1, and Kip3 join their homologs XMAP215, EB1 and kinesin-8 as promoters of microtubule nucleation, while Bik1 promotes MT nucleation indirectly via its role in SPB positioning. Further, we find that the nucleation activity of Stu2in vivocorrelates with its polymerase activityin vitro. Finally, we provide the first evidence that Vik1, a subunit of Kar3/Vik1 kinesin-14, promotes microtubule minus end focusing at the ectopic site.
Significant East Asian affinity of Chinese Hui genomic structure suggesting their predominant cultural diffusion model in the genetic formation process
Authors: Liu Yan , Yang Junbao , Li Yingxiang , Tang Renkuan , Yuan Didi , Wang Yicheng , Wang Peixin , Deng Shudan , Zeng Simei , Li Hongliang , Chen Gang , Zou Xing , Wang Mengge , He Guanglin
Published: January 2021

Ancestral origin and genomic history of Chinese Hui people remain to be explored due to the paucity of genome-wide data. Some evidence argued that an eastward migration of Central Asian given rise to modern Hui people, which was inferred as thedemic diffusion hypothesis, and others favored thecultural diffusion hypothesisthat posited indigenous East Asian adopted Muslim-like culture and formed the modern culturally different populations. However, the extent to which the observed Hui’s genetic structure was mediated by the movement of people or the assimilation of Muslim culture also remains one of the most contentious puzzles. Analyses of over 700K SNPs in 109 western Chinese individuals (49 Sichuan Hui and 60 geographically close Nanchong Han) together with the available ancient and modern Eurasians allowed us to fully explore the genomic makeup and origin of Huis and neighboring Hans. The results of the traditional and formal admixture-statistics (PCA, ADMIXTURE, and allele-sharing-basedf-statistics) illuminated a strong genomic affinity between Sichuan Hui and Neolithic-to-modern Northern East Asians, which suggested massive gene influx from East Asian into Sichuan Hui people. Three-way admixture models in theqpWave/qpAdmanalyses further revealed a small stream of gene influx from western Eurasian related to French or Andronovo into these Hui people, which was further directly confirmed via the admixture event from the temporally different western sources to Hui people in theqpGraph-based phylogenetic model, suggesting the key role of cultural diffusion model in the genetic formation of the modern East Asian Hui. ALDER-based admixture date estimation showed that this observed western Eurasian admixture signal was introduced into East Asian Hui during the historic periods, concordant with the extensive western-eastern communication in the Silk Road and historically documented Hui’s migration history. Summarily, although significant cultural differentiation among Hui and their neighbors existed, our genomic analysis showed their strong affinity with modern and ancient Northern East Asians. Our results supported that modern Chinese Hui arose from the mixture of minor western Eurasian ancestry and predominantly East Asian ancestry.
Novel CHD8 genomic targets identified in fetal mouse brain byin vivoTargeted DamID
Authors: Wade A. Ayanna , van den Ameele Jelle , Cheetham Seth W. , Yakob Rebecca , Brand Andrea H. , Nord Alex S.
Published: January 2021

Genetic studies of autism spectrum disorder (ASD) have revealed a causal role for mutations in chromatin remodeling genes. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeler with one of the highestde novomutation rates in sporadic ASD. However, the relationship between CHD8 genomic function and autism-relevant biology remains poorly elucidated. CHD8 binding studies have relied onChromatin Immunoprecipitation followed by sequencing (ChIP-seq), however, these datasets exhibit significant variability. ChIP-seq has technical limitations in the context of weak or indirect protein-DNA interactions or when high-performance antibodies are unavailable. Thus, complementary approaches are needed overall, and, specifically, to establish CHD8 genomic targets and regulatory function. Here we used Targeted DamIDin uteroto characterize CHD8 binding in developing embryonic mouse cortex. CHD8 Targeted DamID followed by sequencing (CHD8 TaDa-seq) revealed binding at previously identified targets as well as loci sensitive toChd8haploinsufficiency. CHD8 TaDa-seq highlighted CHD8 binding distal to a subset of genes specific to neurodevelopment and neuronal function. These studies establish TaDa-seq as a useful alternative for mapping protein-DNA interactionsin vivoand provide insights into the relationship between chromatin remodeling by CHD8 and autism-relevant pathophysiology associated withCHD8mutations.
An optimized FM-index library for nucleotide and amino acid search
Authors: Anderson Tim , Wheeler Travis J
Published: January 2021

Pattern matching is a key step in a variety of biological sequence analysis pipelines. The FM-index is a compressed data structure for pattern matching, with search run time that is independent of the length of the database text. We present AvxWindowedFMindex (AWFM-index), an open-source, thread-parallel FM-index library written in C that is optimized for indexing nucleotide and amino acid sequences. AWFM-index is easy to incorporate into bioinformatics software and is able to perform exact match count and locate queries ~2-4x faster than SeqAn3’s FM-index implementation for nucleotide search, and ~2-6x faster for amino acid search in a single-threaded context. This performance is due to (i) a new approach to storing FM-index data in a strided bit-vector format that enables extremely efficient computation of the FM-index occurrence function via AVX2 bitwise instructions, and (ii) inclusion of a cache-efficient lookup table for partial k-mer searches. AWFM-index also trivially parallelizes to multiple threads with good scaling, and enables efficient on-disk storage of the memory-intensive suffix array. The open-source library is available for download athttps://github.com/TravisWheelerLab/AvxWindowFmIndex.
Longitudinal profiling of circulating tumour DNA for tracking tumour dynamics in pancreatic cancer
Authors: Sivapalan Lavanya , Thorn Graeme , Gadaleta Emanuela , Kocher Hemant , Ross-Adams Helen , Chelala Claude
Published: January 2021

The utility of circulating tumour DNA (ctDNA) for longitudinal tumour monitoring in pancreatic ductal adenocarcinoma (PDAC) has not been explored beyond mutations in theKRASproto-oncogene. Here, we follow 3 patients with resectable disease and 4 patients with advanced unresectable disease, using exome sequencing of resected tissues and plasma samples (n=20) collected over a ∼2-year period from diagnosis through treatment to death or last follow-up. This includes 4 patients with ≥3 serial follow-up samples, of whom 2 are exceptionally long survivors (>5 years). Plasma from 3 chronic pancreatitis cases and 3 healthy controls were used as comparison for analysis of ctDNA mutations. We show that somatic mutation profiles in ctDNA are representative of matched tumour genomes. Furthermore, we detect and track ctDNA mutations within core PDAC driver genes, includingKRAS, NRAS, HRAS, TP53, SMAD4andCDKN2A, in addition to patient-specific variants within alternative cancer drivers(TP53, MTOR, ERBB2, EGFR, PBRM1, RNF43). Multiple trackable (≥ 2 plasma) ctDNA alterations with potential for therapeutic actionability in PDAC are also identified. These include variants predictive of treatment response to platinum chemotherapy and/or PARP inhibition and a unique chromosome 17 kataegis locus co-localising withERBB2driver variants and hypermutation signatures in one long-surviving patient. Finally, we demonstrate that exome profiling can facilitate the assessment of clonality within ctDNA mutations, for the determination of total ctDNA burden alongside temporal evolutionary relationships. These findings provide proof-of-concept for the use of whole exome sequencing of serial plasma samples to characterise ctDNA load and mutational profiles in patients with PDAC.
Prospective screening of liver fibrosis in a primary care cohort using systematic calculation of fib-4 in routine results
Authors: Halfon Philippe , Ansaldi Christelle , Penaranda Guillaume , Chiche Laurent , Dukan Patrick , Stavris Chloé , Plauzolles Anne , Retornaz Frédérique , Bourliere Marc
Published: January 2021

Background & Aim

Liver fibrosis screening in primary care population is a major public health issue. The FIB-4 index is a simple non-invasive fibrosis test combining age, transaminases, platelets count, developed for the diagnosis of advanced fibrosis. The aim of our study was to evaluate the interest of liver fibrosis screening using systematic calculation of FIB-4 in routine blood analysis.

Methods

Between December 2018 and May 2019, we conducted a prospective screening of liver fibrosis in 134 158 patients during a medical check-up including routine blood analysis. Among these patients, 29 707 had transaminases and platelets counts available and benefited from an automatic calculation of FIB-4. Results were obtained from 21 French clinical laboratories in the Bouches du Rhône region.

Results

Among the 29 707 patients, 2160 (7.3%) had significant fibrosis (FIB-4>2.67). Individual investigation of patients with FIB-4>2.67 allowed to screen 1267 (1267/2160: 59%) patients who were not managed for any liver disease.

Conclusions

This work demonstrates the interest of FIB-4 for the screening of liver fibrosis in primary care population. Our study strongly supports this easy-to-implement strategy using a simple Fib-4 measure resulting from the use of available routine test results.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Clinical Registering Number

MR-0314071019 (INDS: French National Institute for Medical Data)
ImplementingEssential Coaching for EveryMother during COVID-19: A Pilot Pre-Post Intervention Study
Authors: Dol Justine , Aston Megan , Grant Amy , McMillan Douglas , Murphy Gail Tomblin , Campbell-Yeo Marsha
Published: January 2021

Objectives

The primary objective was to evaluate the preliminary impact ofEssential Coaching for Every Motheron self-efficacy, social support, postpartum anxiety and postpartum depression. The second objective was to explore the acceptability of theEssential Coaching for Every Motherprogram provided during the COVID-19 pandemic.

Methods

A prospective pre-post study was conducted with first time mothers in Nova Scotia, Canada between July 15thand September 19th, 2020. Participants completed a self-report survey at enrolment (after birth) and six-weeks postpartum. Various standardized measures were used and qualitative feedback on the program was also collected. Paired t-tests were carried out to determine changes from baseline to follow-up on psychosocial outcomes and qualitative feedback was analysed through thematic analysis.

Results

A total of 88 women enrolled. Self-efficacy increased between baseline (B) and follow-up (F) (B:33.33;F:37.11,p=0.000) while anxiety (STAI) declined (B:38.49;F:34.79; p=0.004). In terms of acceptability, 89% of participants felt that the number of messages were just right, 84.5% felt the messages contained all the information they needed relative to caring for a newborn and 98.8% indicated they would recommend this program to other new mothers.

Conclusion

Essential Coaching for Every Mothermay play a role in increasing maternal self-efficacy and decreasing anxiety, although future work with a control group is needed to delineate the true effects of the program. Overall, mothers were satisfied with theEssential Coaching for Every Motherprogram and would recommend it for other mothers, during COVID-19 and beyond.
A Novel Multiplex PCR Based Detection Assay Using Saliva or Nasopharyngeal Samples for SARS-Cov-2, Influenza A and B – Clinical Validation and Utility for Mass Surveillance
Authors: Sahajpal Nikhil S , Mondal Ashis K , Ananth Sudha , Njau Allan , Ahluwalia Pankaj , Oza Eesha , Ross Ted M , Kota Vamsi , Kothandaraman Arvind , Fulzele Sadanand , Hegde Madhuri , Chaubey Alka , Rojiani Amyn M , Kolhe Ravindra
Published: January 2021

Background

The COVID-19 pandemic has resulted in a significant diversion of human and material resources to COVID-19 diagnostics, to the extent that testing of viral pathogens normally contributing to seasonal respiratory tract infections have been markedly neglected. The global health burden due to influenza viruses and co-infection in COVID-19 patients remains undocumented but clearly pose serious public health consequences. To address these clinical and technical challenges, we have optimized and validated a highly sensitive RT-PCR based multiplex assay for the detection of SARS-CoV-2, Influenza A and B viruses in a single test.

Methods

This study evaluated clinical specimens (n=1411) that included 1019 saliva and 392 nasopharyngeal swab (NPS) samples collected in either healthcare or community setting. Samples were tested using two assays: FDA-EUA approved SARS-CoV-2 assay that targets N and ORF1ab gene, and the PKamp RT-PCR based assay that targets SARS-CoV-2, Influenza viruses A and B. The limit of detection (LoD) studies was conducted as per the FDA guidelines using SARS-CoV-2 and Influenza A and B reference control materials.

Results

Of the 1019 saliva samples, 17.0% (174/1019) tested positive for SARS-CoV-2 using either assay. The detection rate for SARS-CoV-2 was higher with our multiplex assay compared to SARS-specific assay [91.9% (160/174) vs. 87.9% (153/174)], respectively. Of the 392 NPS samples, 10.4% (41/392) tested positive for SARS-CoV-2 using either assay. The detection rate for SARS-CoV-2 was higher with our multiplex assay compared to SARS-specific assay [97.5% (40/41) vs. 92.1% (39/41)], respectively. The Ct values for SARS-CoV-2 were comparable between the two assays, whereas the Ct values of the housekeeping gene was significantly lower with multiplex assay compared to SARS-specific assay. The LoD was established as 60 copies/ml for SARS-CoV-2 and 180 copies/ml for Influenza A and B viruses for both saliva and NPS samples.

Conclusion

This study presents clinical validation of a multiplex PCR assay for testing SARS-CoV-2, Influenza A and B viruses, using NPS and saliva samples, and demonstrates the feasibility of implementing the assay without disrupting the existing laboratory workflow. This novel assay uses the same instruments, sample types, supplies, and laboratory personnel as needed for the testing of SARS-CoV-2 virus.
Smartphone-based digital biomarkers for Parkinson’s disease in a remotely-administered setting
Authors: Goñi María , Eickhoff Simon B. , Far Mehran Sahandi , Patil Kaustubh R. , Dukart Juergen
Published: January 2021

Smartphone-based digital biomarker (DB) assessments provide objective measures of daily-life tasks and thus hold the promise to improve diagnosis and monitoring of Parkinson’s disease (PD). To date, little is known about which tasks perform best for these purposes and how different confounds including comorbidities, age and sex affect their accuracy. Here we systematically assess the ability of common self-administered smartphone-based tasks to differentiate PD patients and healthy controls (HC) with and without accounting for the above confounds. Using a large cohort of PD patients and healthy volunteers acquired in the mPower study, we extracted about 700 features commonly reported in previous PD studies for gait, balance, voice and tapping tasks. We perform a series of experiments systematically assessing the effects of age, sex and comorbidities on the accuracy of the above tasks for differentiation of PD patients and HC using several machine learning algorithms. When accounting for age, sex and comorbidities, the highest balanced accuracy on hold-out data (73%) was achieved using random forest when combining all tasks followed by tapping using relevance vector machine (67%). Only moderate accuracies were achieved for other tasks (60% for balance, 56% for gait and 53% for voice data). Not accounting for the confounders consistently yielded higher accuracies of up to 77% when combining all tasks. Our results demonstrate the importance of controlling DB data for age and comorbidities.
Mass Testing with Contact Tracing Compared to Test and Trace for Effective Suppression of COVID-19 in the UK: A rapid review
Authors: Mbwogge Mathew
Published: January 2021

Background

Making testing available to everyone and tracing contacts might be the gold standard towards the control of COVID-19, particularly when significant transmissions are without symptoms. This study evaluated the effectiveness of mass testing and contact tracing in the suppression of COVID-19 compared to conventional Test and Trace in the UK.

Design

A rapid review of available evidence

Primary research question

Is there evidence that mass testing and tracing could suppress community spread of SARS-CoV-2 infections better than Test and Trace?

Secondary research question

What is the proportion of asymptomatic cases of SARS-CoV-2 reported during mass testing interventions?

Methods

Literature was searched in September through December 2020 in Google Scholar, ScienceDirect, Mendeley and PubMed.

Results

Literature search yielded 286 articles from Google Scholar, 20 from Science Direct, 14 from Mendeley, 27 from Pubmed and 15 through manual search. Altogether 35 articles were included, making a sample size of close to a million participants.

Conclusion

There was a very low level but promising evidence of 76.9% (95% CI: 46.2 – 95.0, P=0.09) majority vote in favour of the intervention under the primary objective. The overall proportion of asymptomatic cases among those tested positive and tested sample populations under the secondary objective was 40.7% (95% CI: 38.8– 42.5) and 0.01% (95% CI: 0.01 – 0.012) respectively. Conventional test and trace should be superseded by a decentralised and regular mass rapid testing and contact tracing, championed by GP surgeries and low cost community services.
Optimal piecewise constant vaccination and lockdown policies for COVID-19
Authors: Salcedo-Varela Gabriel A. , Peñuñuri F. , González-Sánchez D. , Díaz-Infante Saúl
Published: January 2021

We formulate a controlled system of ordinary differential equations, with vaccination and lockdown interventions as controls, to simulate the mitigation of COVID-19. The performance of the controls is measured through a cost functional involving vaccination and lockdown costs as well as the burden of COVID19 quantified in DALYs. We calibrate parameters with data from Mexico City and Valle de Mexico. By using differential evolution, we minimize the cost functional subject to the controlled system and find optimal policies that are constant in time intervals of a given size. The main advantage of these policies relies on its practical implementation since the health authority has to make only a finite number of different decisions. Our methodology to find optimal policies is relatively general, allowing changes in the dynamics, the cost functional, or the frequency the policymaker changes actions.
Systematic identification of cis-interacting lncRNAs and their targets
Authors: Agrawal Saumya , Kulakovskiy Ivan V. , Severin Jessica , Koido Masaru , Alam Tanvir , Abugessaisa Imad , Buyan Andrey , Chang Howard Y. , Dostie Josee , Itoh Masayoshi , Kere Juha , Kondo Naoto , Li Yunjing , Makeev Vsevolod J. , Mendez Mickaël , Okazaki Yasushi , Ramilowski Jordan A. , Sigorskikh Andrey I. , Strug Lisa J. , Yagi Ken , Yasuzawa Kayoko , Yip Chi Wai , Hon Chung Chau , Hoffman Michael M. , Terao Chikashi , Kasukawa Takeya , Shin Jay W. , Carninci Piero , de Hoon Michiel JL
Published: January 2021

The human genome is pervasively transcribed and produces a wide variety of long non-coding RNAs (lncRNAs), constituting the majority of transcripts across human cell types. Studying lncRNAs is challenging due to their low expression level, cell type-specific occurrence, poor sequence conservation between orthologs, and lack of information about RNA domains. LncRNAs direct the regulatory factors in the locations that are in cis to their transcription sites. We designed a model to predict if an lncRNA acts in cis based on its features and trained it using RNA-chromatin interaction data. The trained model is cell type-independent and does not require RNA-chromatin data. Combining RNA-chromatin and Hi-C data, we showed that lncRNA-chromatin binding sites are determined by chromosome conformation. For each lncRNA, the spatially proximal genes were identified as their potential targets by combining Hi-C and Cap Analysis Gene Expression (CAGE) data in 18 human cell types. RNA-protein and RNA-chromatin interaction data suggested that lncRNAs act as scaffolds to recruit regulatory proteins to target promoters and enhancers. We provide the data through an interactive visualization web portal athttps://fantom.gsc.riken.jp/zenbu/reports/#F6_3D_lncRNA.
Inferring long-term effective population size with Mutation-Selection models
Authors: Latrille T. , Lanore V. , Lartillot N.
Published: January 2021

Mutation-selection phylogenetic codon models are grounded on population genetics first principles and represent a principled approach for investigating the intricate interplay between mutation, selection and drift. In their current form, mutation-selection codon models are entirely characterized by the collection of site-specific amino-acid fitness profiles. However, thus far, they have relied on the assumption of a constant genetic drift, translating into a unique effective population size (Ne) across the phylogeny, clearly an unreasonable hypothesis. This assumption can be alleviated by introducing variation inNebetween lineages. In addition toNe, the mutation rate (μ) is susceptible to vary between lineages, and both should co-vary with life-history traits (LHTs). This suggests that the model should more globally account for the joint evolutionary process followed by all of these lineage-specific variables (Ne,μ, and LHTs). In this direction, we introduce an extended mutation-selection model jointly reconstructing in a Bayesian Monte Carlo framework the fitness landscape across sites and long-term trends inNe,μand LHTs along the phylogeny, from an alignment of DNA coding sequences and a matrix of observed LHTs in extant species. The model was tested against simulated data and applied to empirical data in mammals, isopods and primates. The reconstructed history ofNein these groups appears to correlate with LHTs or ecological variables in a way that suggests that the reconstruction is reasonable, at least in its global trends. On the other hand, the range of variation in Ne inferred across species is surprisingly narrow. This last point suggests that some of the assumptions of the model, in particular concerning the assumed absence of epistatic interactions between sites, are potentially problematic.
Multichannel optogenetics combined with laminar recordings for ultra-controlled neuronal interrogation
Authors: Eriksson David , Schneider Artur , Thirumalai Anupriya , Alyahyay Mansour , de la Crompe Brice , Sharma Kirti , Ruther Patrick , Diester Ilka
Published: January 2021

Simultaneous large-scale recordings and optogenetic interventions hold the promise to decipher the fast-paced and multifaceted dialogue between neurons that sustains brain function. Here we developed unprecedentedly thin, cell-sized Lambertian side-emitting optical fibers and combined them with silicon probes to achieve high quality recordings and ultrafast multichannel optogenetic inhibition in freely moving animals. Our new framework paves the way for large-scale photo tagging and controlled interrogation of rapid neuronal communication in any combination of brain areas.

Highlights

To combine large-scale recordings with optical perturbation we have developed a number of new techniques such as thin optical side-emitting fibers, a fiber matrix connector for thin fibers, an electro-optical commutator for multiple thin fibers, an active patch cord, a flexible fiber bundle ribbon cable, and a modular multi-optrode implantation holder.
Mapping individual differences across brain network structure to function and behavior with connectome embedding
Authors: Levakov Gidon , Faskowitz Joshua , Avidan Galia , Sporns Olaf
Published: January 2021

The connectome, a comprehensive map of the brain’s anatomical connections, is often summarized as a matrix comprising all dyadic connections among pairs of brain regions. This representation cannot capture higher-order relations within the brain graph. Connectome embedding (CE) addresses this limitation by creating compact vectorized representations of brain nodes capturing their context in the global network topology. Here, nodes “context” is defined as random walks on the brain graph and as such, represents a generative model of diffusive communication around nodes. Applied to group-averaged structural connectivity, CE was previously shown to capture relations between inter-hemispheric homologous brain regions and uncover putative missing edges from the network reconstruction. Here we extend this framework to explore individual differences with a novel embedding alignment approach. We test this approach in two lifespan datasets (NKI: n=542; Cam-CAN: n=601) that include diffusion-weighted imaging, resting-state fMRI, demographics and behavioral measures. We demonstrate that modeling functional connectivity with CE substantially improves structural to functional connectivity mapping both at the group and subject level. Furthermore, age-related differences in this structure-function mapping are preserved and enhanced. Importantly, CE captures individual differences by out-of-sample prediction of age and intelligence. The resulting predictive accuracy was higher compared to using structural connectivity and functional connectivity. We attribute these findings to the capacity of the CE to incorporate aspects of both anatomy (the structural graph) and function (diffusive communication). Our novel approach allows mapping individual differences in the connectome through structure to function and behavior.
Evolutionary Perspective and Expression Analysis of Intronless Genes Highlight the Conservation on Their Regulatory Role
Authors: Aviña-Padilla Katia , Ramírez-Rafael José Antonio , Herrera-Oropeza Gabriel Emilio , Muley Vijaykumar , Valdivia Dulce I. , Díaz-Valenzuela Erik , García-García Andrés , Varela-Echavarría Alfredo , Hernández-Rosales Maribel
Published: January 2021

Eukaryotic gene structure is a combination of exons generally interrupted by intragenic non-coding DNA regions termed introns removed by RNA splicing to generate the mature mRNA. Thus, eukaryotic genes can be either single exon genes (SEGs) or multiple exon genes (MEGs). Among SEGs, intronless genes (IGs) are a subgroup that additionally lacks introns at their UTRs, and code for proteins essentially involved in development, growth, and cell proliferation. Gene expression of IGs has been proposed to be highly specialized for neuro-specific functions and linked to cancer, neuropathies, and developmental disorders. The abundant presence of introns in eukaryotic genomes is pivotal for the precise control of gene expression. Notwithstanding, IGs exempting splicing events entail a higher transcriptional fidelity, making them even more valuable for regulatory roles. This work aimed to infer the functional role and evolutionary history of IGs using the mouse genome. Intronless protein-coding genes consist of a subgroup of ~6 % of a total of 21,527 genes with one exon. To understand the prevalence, biological relevance, and evolution, we identified and studied their 1,116 functional proteins. We validated differential expression in transcriptomics data of early embryo stages using mouse telencephalon tissue. Our results showed that expression levels of IGs are lower compared to MEGs. However, strongly upregulated IGs include transcription factors (TFs) such as the class 3 of POU (HMG Box),Neurog1, Olig1, andBHLHe22, BHLHe23,among other essential genes including the beta cluster of protocadherins. Most striking was the finding that IG-encoded BHLH TFs qualify the criteria to be referred to as microprotein candidates. Finally, predicted protein orthologs in other six genomes confirmed a high conservancy of IGs associated with regulating neurobiological processes and with chromatin organization and epigenetic regulation inVertebrata. Moreover, this study highlights that IGs are essential modulators of regulatory processes, as Wnt signaling pathway and biological processes as pivotal as sensory organs developing at a transcriptional and post-translational level. Overall, our results suggest that IG proteins have specialized, prevalent, and unique biological roles and that functional divergence between IGs and MEGs is likely to be the result of specific evolutionary constraints.
Using Deep Learning to Predict Human Decisions, and Cognitive Models to Explain Deep Learning Models
Authors: Fintz Matan , Osadchy Margarita , Hertz Uri
Published: January 2021

Deep neural networks (DNN) models have the potential to provide new insights in the study of human decision making, due to their high capacity and data-driven design. While these models may be able to go beyond theory-driven models in predicting human behaviour, their opaque nature limits their ability to explain how an operation is carried out. This explainability problem remains unresolved. Here we demonstrate the use of a DNN model as an exploratory tool to identify predictable and consistent human behaviour in value-based decision making beyond the scope of theory-driven models. We then propose using theory-driven models to characterise the operation of the DNN model. We trained a DNN model to predict human decisions in a four-armed bandit task. We found that this model was more accurate than a reinforcement-learning reward-oriented model geared towards choosing the most rewarding option. This disparity in accuracy was more pronounced during times when the expected reward from all options was similar, i.e., no unambiguous good option. To investigate this disparity, we introduced a reward-oblivious model, which was trained to predict human decisions without information about the rewards obtained from each option. This model captured decision-sequence patterns made by participants (e.g., a-b-c-d). In a series of experimental offline simulations of all models we found that the general model was in line with a reward-oriented model’s predictions when one option was clearly better than the others.

However, when options’ expected rewards were similar to each other, it was in-line with the reward-oblivious model’s pattern completion predictions. These results indicate the contribution of predictable but task-irrelevant decision patterns to human decisions, especially when task-relevant choices are not immediately apparent. Importantly, we demonstrate how theory-driven cognitive models can be used to characterise the operation of DNNs, making them a useful explanatory tool in scientific investigation.

Author Summary

Deep neural networks (DNN) models are an extremely useful tool across multiple domains, and specifically for performing tasks that mimic and predict human behaviour. However, due to their opaque nature and high level of complexity, their ability to explain human behaviour is limited. Here we used DNN models to uncover hitherto overlooked aspects of human decision making, i.e., their reliance on predictable patterns for exploration. For this purpose, we trained a DNN model to predict human choices in a decision-making task. We then characterised this data-driven model using explicit, theory-driven cognitive models, in a set of offline experimental simulations. This relationship between explicit and data-driven approaches, where high-capacity models are used to explore beyond the scope of established models and theory-driven models are used to explain and characterise these new grounds, make DNN models a powerful scientific tool.
Using ICD-10-based Social Determinants of Health Categories to Assess Patients Risk for Acute Care Utilization
Authors: Nguyen Peter H. , Wang James , Garcia-Filion Pamela , Dominick Deborah , Abbaszadegan Hamed , Hernandez Graciela Gonzalez , O’Connor Karen , Rehman Shakaib U. , Panchanathan Sarada S.
Published: January 2021

Background

There has been an increasing recognition of the influence of social, behavioral, economic, and environmental factors on overall patient health. The purpose of this project was to leverage the ICD-10 codes to identify and link social determinants of health (SDoH) to patients with a high probability of utilizing acute care services and to determine if social service intervention reduced care utilization.

Methods

We analyzed retrospective data for active patients at a Department of Veterans Affairs Medical Center (VAMC) from 2015-2017. Eleven categories of SDoH were developed based on existing literature of the social determinants; the relevant ICD-10 codes were divided among these categories. Emergency Room (ER) visits, hospital admissions, and social work visits were determined for each patient in the cohort.

Results

In a cohort of 44,401 patients, the presence of ICD-10 codes within the EHR in the 11 SDoH categories was positively correlated with increased acute care utilization. Veterans with at least one SDoH risk factor were 71% (95%CI: 68% - 75%) more likely to use the ED and 71% (95%CI: 65%-77%) more likely to be admitted to the hospital. Utilization decreased with social service interventions.

Conclusion

This project demonstrates a potentially meaningful method to capture patient social risk profiles through existing EHR data in the form of ICD-10 codes, which can be used to identify the highest risk patients for intervention with the understanding that not all SDoH codes are uniformly used and some SDoHs may not be captured.
Posttraumatic Stress Disorder and the Nature of Trauma in Patients with Cardiovascular Diseases: A Case-Control study
Authors: Cyr Samuel , Marcil Marie-Joëlle , Long Valérie , De Marco Corrado , Dyrda Katia , Brouillette Judith
Published: January 2021

Introduction

A large body of evidence indicates a significant and morbid association between posttraumatic stress disorder (PTSD) and cardiovascular disease (CVD). Few studies, however, have addressed the range of trauma in this medical population, from massive heart attack, to defibrillator shock to previous interpersonal aggression.

Objective

The main objective of this study was to examine the nature of trauma associated with the development of PTSD in CVD patients. More precisely, we were interested in knowing if trauma was medical in nature and whether cumulative trauma resulted in PTSD.

Methods

We performed a 1:3 case-control study. The authors compared CVD patients diagnosed with PTSD (n=37) to those with adjustment disorder (n=111) in terms of trauma/stressor types and medical and demographic characteristics.

Results

Half (51%) of CVD patients suffering from PTSD had endured a medical trauma, 35% an external (non-medical) trauma, and 14% both. There were no significant differences with CVD patients diagnosed with adjustment disorder, 40% of them having experienced a medical stressor, 40% an external (non-medical) stressor and 20% both. Cumulative trauma was seen in only 19% of CVD patients suffering from PTSD. Traditional risk factors (female sex, younger age) were not prominent in CVD patients with PTSD as compared to those with adjustment disorder. Cases were, however, significantly more likely to have psychiatric antecedents and recent surgical interventions.

Conclusions

By uncovering characteristics of PTSD patients/trauma in CVD patients, this work will serve future research and clinical initiatives to better screen at-risk patients or at-risk medical situations.
Susceptibility vessel sign as a predictor for recanalization and clinical outcome in acute ischaemic stroke: A Systematic Review and Meta-analysis
Authors: Tang Si Zhao , Sen Jon
Published: January 2021

T2*-weighted MRI using GRE and SWI sequences can potentially prognosticate the recanalization rate and clinical outcomes in patients with acute ischaemic stroke, using susceptibility vessel sign (SVS) and prominent hypointense vessel sign (PHVS).

A literature search on PubMed, EMBASE databases and other sources from inception up to 01 February 2020 was conducted. 15 studies which reported SVS and PHVS were included in qualitative synthesis. 9 studies on SVS were included in quantitative synthesis i.e. meta-analysis.

Meta-analysis did not show any significant difference in the recanalization rate between SVS (+) group and SVS (-) group (RR = 0.95, 95% CI = 0.87–1.05, p = 0.33). Treatment subgroup analysis (intravenous thrombolysis, IVT- or mechanical thrombectomy, MT-only) does not show significant association between the SVS and IVT-only (RR = 0.73, 95% CI = 0.51-1.05, P=0.09); or MT-only groups (RR = 0.99, 95% CI = 0.90-1.09, P=0.90). No significant association between poor clinical outcome at 3 months and presence of SVS (RR = 1.42, 95% CI = 0.79–2.57, p = 0.24). Treatment subgroup analysis revealed significant association of the SVS and poor clinical outcome at 3 months in the MT-only (RR = 0.67, 95% CI = 0.55–0.82, p = 0.0001) or no thrombolytic treatment (RR = 2.83, 95% CI = 1.69-4.75, p < 0.0001).

In conclusion, there is a significant association between the presence of SVS and poor clinical outcome in patients who underwent MT or without treatment, and no definitive association between the presence of SVS and recanalization rate for acute ischemic stroke.
The Use of Procalcitonin as an Antimicrobial Stewardship Tool and a Predictor of Disease Severity in COVID-19
Authors: Drewett George P , Smibert Olivia C , Holmes Natasha E , Trubiano Jason A
Published: January 2021

In our study, procalcitonin was associated with both antibiotic use and duration in patients with COVID-19, as well as established biochemical markers of COVID-19 disease severity and oxygen requirement, suggesting a potential role for procalcitonin in COVID-19 antimicrobial stewardship.
S. Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense
Authors: Gutiérrez Saray , Fischer Julia , Ganesan Raja , Cildir Gökhan , Wolke Martina , Pessia Alberto , Frommolt Peter , Desiderio Vincenzo , Velagapudi Vidya R , Robinson Nirmal
Published: January 2021

Regulation of the cellular metabolism is now recognized as a crucial mechanism for the homeostasis of innate and adaptive immune cells upon diverse extracellular stimuli. Macrophages, for instance, increase glycolysis upon stimulation with pathogen-associated molecular patterns (PAMPs). Conceivably, pathogens also counteract these metabolic changes for their own survival in the host. However, despite this dynamic interplay in host-pathogen interactions, the role of immunometabolism in the context of intracellular bacterial infections is still unclear. Here, employing unbiased metabolomic and transcriptomic approaches, we investigated the role of metabolic adaptations of macrophages uponSalmonella entericaserovar Typhimurium (S. Typhimurium) infections. Importantly, our results suggested thatS. Typhimurium abrogates glycolysis and its modulators such as insulin-signaling to impair macrophage defense. Mechanistically, glycolytic enzyme aldolase A is critical for v-ATPase assembly and the acidification of phagosomes uponS. Typhimurium infection, and impairment in the glycolytic machinery eventually leads to decreased bacterial clearance and antigen presentation in macrophages. Collectively, our results highlight a vital molecular link between metabolic adaptation and phagosome maturation in macrophages, which is targeted byS. Typhimurium to evade cell-autonomous defense.