bluuebunny/crossref_metadata_2025 huggingface dataset:
Duration of SARS-CoV-2 Sero-Positivity in a Large Longitudinal Sero-Surveillance Cohort: The COVID-19 Community Research Partnership
Authors: Herrington David M ,   The COVID-19 Community Research Partnership Study Group
Published: January 2021

Background: Estimating population prevalence and incidence of prior SARS-CoV-2 infection is essential to formulate public health recommendations concerning the COVID-19 pandemic. However, interpreting estimates based on sero-surveillance requires an understanding of the duration of elevated antibodies following SARS-CoV-2 infection, especially in the large number of people with pauci-symptomatic or asymptomatic disease.
Methods: We examined >30,000 serology assays for SARS-CoV-2 specific IgG and IgM assays acquired longitudinally in 11,468 adults between April and November 2020 in the COVID-19 Community Research Partnership.
Findings: Among participants with serologic evidence for infection but few or no symptoms or clinical disease, roughly 50% sero-reverted in 30 days of their initial positive test. Sero-reversion occurred more quickly for IgM than IgG and for antibodies targeting nucleocapsid protein compared with spike proteins, but was not associated with age, sex, race/ethnicity, or healthcare worker status.
Interpretation: The short duration of antibody response suggests that the true population prevalence of prior SARS-CoV-2 infection may be significantly higher than presumed based on earlier sero-surveillance studies. The impact of the large number of minimally symptomatic COVID-19 cases with only a brief antibody response on population immunity remains to be determined.
Safety and efficacy of long-acting insulins (degludec and glargine) among type 2 diabetic Asian Population: A Systematic Review and Meta-Analysis
Authors: Kant R , Yadav P , Garg M , Bahurupi Y , Kumar B
Published: January 2021

Background

According to IDF Diabetes Atlas 2019, globally, 463 million people live with Diabetes mellitus. Out of that, 88 million people are in South East Asia. By 2045, it is expected to increase by 51% globally and 74% in South East Asia. Global variation in susceptibility to diabetes, insulin sensitivity, and regimen intensity due to race and ethnic differences pose a challenge regarding the optimal choice of second-line therapy for clinicians. Asian populations are at higher risk of developing diabetes mellitus than the European population. The current study was carried out to see the relative efficacy of currently available long-acting insulins in reducing blood sugar, HbA1c and the occurrence of hypoglycemia as a complication associated with them.

Methods

A systematic literature search was done using various search engines (PubMed, Cochrane, Google Scholar, Scopus, and Embase) and included published RCTs in English before December 2019. Further, a manual search was performed by screening the reference list of the identified articles.

Results

We included four RCTs with 534 participants (349 in the insulin degludec group and 185 in the insulin glargine group) with T2DM. Results show that both insulin glargine and degludec are equally efficacious in reducing fasting blood glucose and HbA1c. However, insulin glargine was associated with lower risks of hypoglycemia.

Conclusions

Insulin glargine and degludec are comparable in achieving glycemic control with fewer hypoglycemic episodes in insulin glargine treated group.
Sequencing Data of North American SARS-CoV-2 Isolates Shows Widespread Complex Variants
Authors: Ford Colby T. , Scott Rachel , Machado Denis Jacob , Janies Daniel
Published: January 2021

Several new variants of the SARS-CoV-2 have been isolated in the United States, Mexico, and Canada. Many of the variants contain single variants of functional significance (e.g. S: N501Y increases transmissibility). To study the occurrence and co-circulation of these variants, we have developed an easy-to-use dashboard at janieslab.github.io/sars-cov-2.

We created a multiple sequence alignment workflow and processing script to generate a variant dataset, which populates this dashboard. We then use the features of the dashboard, such as visualization of the single and complex nucleotide variants geospatially and in a color-coded matrix format. Users also interact with the dashboard to filter the underlying data to regions of interest and or variants of interest. The user can export reports based on the desired filters, which we intend to be used for regionally specific pandemic response. We find in Genbank, an isolate from Massachusetts containing [(S: Q677H), (ORF3a: Q57H), (M: A85S), (N: D377Y)] collected on September 11, 2020.

Moreover, we find that many viral isolates bear a marker of increased transmissibility (S: N501Y) in linkage with at least one variant of concern isolated from Ohio also range across the Untied States and stretch from British Columbia, Canada to Mexico. When we analyze co-circulation of more complex variant constellations with (S: N501Y), we note that the Upper Midwest and Northeast United States contain these isolates.

In summary, the viral variants that have raised concern in a few US States in recent reports are widespread. Based on the increase in the proportion of variant viruses being sampled and some empirical evidence in the United Kingdom, South Africa, and Ohio, these variants are likely to lead to increased transmission of SARS-CoV-2 across North America in the coming months.
Risk perception of COVID-19 and its socioeconomic correlates in the United States: A social media analysis
Authors: Qiao Shan , Li Zhenlong , Liang Chen , Li Xiaoming , Rudisill Caroline Ann
Published: January 2021

Social media analysis provides a new approach to monitoring and understanding risk perceptions regarding COVID-19 over time. Our current understandings of risk perceptions regarding COVID-19 do not disentangle the three dimensions of risk perceptions (perceived susceptibility, perceived severity, and negative emotion) over a long enough timeframe to cover different pandemic phases. The impact of social determinants of health factors on COVID-19-related risk perceptions over time is also not clear. To address these two knowledge gaps, we extracted tweets regarding COVID-19-related risk perceptions and developed index indicators for three dimensions of risk perceptions based on over 297 million geotagged tweets posted by over 3.5 million Twitter users from January to October 2020 in the United States. We also examined correlations between index indicator scores and county-level social determinants of health factors. The three domains of risk perceptions demonstrate different trajectories. Perceived severity kept climbing throughout the whole study period. Perceived susceptibility and negative emotion declined and remained stable at a lower level after peaking on March 11 (WHO named COVID-19 a global pandemic). Attention on risk perceptions was not exactly in accordance with epidemic trends of COVID-19 (cases, deaths). Users from socioeconomically vulnerable counties showed lower attention on perceived severity and susceptibility of COVID-19 than those from wealthier counties. Examination of trends in tweets regarding the multiple domains of risk perceptions throughout stages of the COVID-19 pandemic can help policy makers frame in-time, tailored, and appropriate responses to prevent viral spread and encourage preventive behavior uptake in United States.
Effect of SARS-CoV-2 spike mutations on animal ACE2 usage and in vitro neutralization sensitivity
Authors: Yao Weitong , Ma Danting , Wang Haimin , Tang Xiaojuan , Du Chengzhi , Pan Hong , Li Chao , Lin Hua , Farzan Michael , Zhao Jincun , Li Yujun , Zhong Guocai
Published: January 2021

The emergence of SARS-CoV-2 variants poses greater challenges to the control of COVID-19 pandemic. Here, we parallelly investigated three important characteristics of seven SARS-CoV-2 variants, including two mink-associated variants, the B.1.617.1 variant, and the four WHO-designated variants of concerns (B.1.1.7, B.1.351, P.1, and B.1.617.2). We first investigated the ability of these variants to bind and use animal ACE2 orthologs as entry receptor. We found that, in contrast to a prototype variant, the B.1.1.7, B.1.351, and P.1 variants had significantly enhanced affinities to cattle, pig, and mouse ACE2 proteins, suggesting increased susceptibility of these species to these SARS-CoV-2 variants. We then evaluated in vitro neutralization sensitivity of these variants to four monoclonal antibodies in clinical use. We observed that all the variants were partially or completely resistant against at least one of the four tested antibodies, with B.1.351 and P.1 showing significant resistance to three of them. As ACE2-Ig is a broad-spectrum anti-SARS-CoV-2 drug candidate, we then evaluated in vitro neutralization sensitivity of these variants to eight ACE2-Ig constructs previously described in three different studies. All the SARS-CoV-2 variants were efficiently neutralized by these ACE2-Ig constructs. Interestingly, compared to the prototype variant, most tested variants including the variants of concern B.1.1.7, B.1.351, P.1, and B.1.617.2 showed significantly increased (up to ∼15-fold) neutralization sensitivity to ACE2-Ig constructs that are not heavily mutated in the spike-binding interface of the soluble ACE2 domain, suggesting that SARS-CoV-2 evolves toward better utilizing ACE2, and that ACE2-Ig is an attractive drug candidate for coping with SARS-CoV-2 mutations.
The successful use of volunteers to enhance NHS Test and Trace contact tracing of in-patients with Covid-19: a Pilot Study
Authors: Foster Rachel , Jones Bing , Carey Ian , Duda Andzelika , Reynolds Abigail , Czauderna Jack , Westran Alex ,   Consultant in Infectious Diseases Sheffield Teaching Hospital Foundation Trust
Published: January 2021

Contact tracing in the UK for Covid-19 is performed by NHS Test and Trace (NHSTT) via telephone or email. This study estimates how many patients who have been admitted to hospital are not reached by NHSTT and the number of their contacts who were not advised to self-isolate.

Medical Student volunteers conducted face to face interviews with patients diagnosed with Covid-19 on an infectious diseases ward. Data on their close contacts were sent to NHSTT.

20 cases were enrolled. 13(65%) did not engage with NHSTT, 4(20%) because they had no positive PCR, 9(45%) because of severity of illness, language or intellectual difficulties. 49 close contacts were identified of whom 33(67%) were from cases who had not engaged with NHSTT. “Backwards” contacts tracing information was collected from 11(55%) cases and 8(40%) gave detailed information.

These data suggest that NHSTT fails to engage nearly two thirds of Covid-19 in-patients and fails to advise two thirds of their close contacts to self isolate.Volunteers used face to face interviews to overcome false negative tests, illness and communication problems to identify both close contacts and data on sources of infection.
Ownership and COVID-19 in care homes for older people: A living systematic review of outbreaks, infections, and mortalities
Authors: Bach-Mortensen Anders Malthe , Verboom Ben , Movsisyan Ani , Esposti Michelle Degli
Published: January 2021

Background

The adult social care sector is increasingly outsourced to for-profit providers, who constitute the largest provider of care homes in many developed countries. During the COVID-19 pandemic, for-profit providers have been accused of failing their residents by prioritising profits over care, prevention, and caution, which has been reported to result in a higher prevalence of COVID-19 infections and deaths in for-profit care homes. Although many of these reports are anecdotal or based on news reports, there is a growing body of academic research investigating ownership variation across COVID-19 outcomes, which has not been systematically appraised and synthesised.

Objectives

To identify, appraise, and synthesise the available research on ownership variation in COVID-19 outcomes (outbreaks, infections, deaths, shortage of personal protective equipment (PPE) and staff) across for-profit, public, and non-profit care homes for older people, and to update our findings as new research becomes available.

Design

Living systematic review.

Methods

This review was prospectively registered with Prospero (CRD42020218673). We searched 17 databases and performed forward and backward citation tracking of all included studies. Search results were screened and reviewed in duplicate. Risk of bias (RoB) was assessed in duplicate according to the COSMOS-E guidance. Data was extracted by ABM and independently validated. The results were synthesised by country, RoB, and model adjustments, and visualised using harvest plots.

Results

Twenty-nine studies across five countries were included, with 75% of included studies conducted in the Unites States. For-profit ownership was not consistently associated with a higher probability of a COVID-19 outbreak. However, there was compelling evidence of worse COVID-19 outcomes following an outbreak, with for-profit care homes having higher rates of accumulative infections and deaths. For-profit providers were also associated with shortages in PPE, which may have contributed to the higher incidence of infections and deaths in the early stages of the pandemic. Chain affiliation was often correlated with an increased risk of outbreak but was usually not reported to be associated with higher rates of deaths and infections.

Conclusion

For-profit ownership was a consistent risk factor for higher cumulative COVID-19 infections and deaths in the first wave of the pandemic. Thus, ownership and the characteristics associated with FP care home providers may present key regulatable factors that can be addressed to improve health outcomes in vulnerable populations and reduce health disparities. This review will be updated as new research becomes published, which may change the conclusion of our synthesis.
UK osteopathic practice in 2019: a retrospective analysis of practice data
Authors: Plunkett Austin , Fawkes Carol , Carnes Dawn
Published: January 2021

Background

This study describes osteopathic activity, scope of practice and the osteopathic patient profile in order to understand the role osteopathy plays within the UK health system a decade after our previous survey.

Method

We used a retrospective questionnaire survey design to ask about osteopathic practice and audit patient case notes. All UK registered osteopaths were invited to participate in the survey.

The survey was conducted using a web-based system. Each participating osteopath was asked about themselves, their practice and asked to randomly select and extract data from up to 8 random new patient health records during 2018. All patient related data were anonymised.

Results

The survey response rate was 500 osteopaths (9.4% of the profession) who provided information about 395 patients and 2,215 consultations.

Most osteopaths were self-employed (81.1%; 344/424 responses) working alone either exclusively or often (63.9%; 237/371) and were able to offer 48.6% of patients an appointment within 3 days (184/379).

Patient ages ranged from 1 month to 96 years (mean 44.7 years, Std Dev. 21.5), of these 58.4% (227/389) were female. Infants <1 years old represented 4.8% (18/379) of patients.

The majority of patients presented with musculoskeletal complaints (81.0%; 306/378). Persistent complaints (present for more than 12 weeks before appointment) were the most common (67.9%; 256/377) and 41.7% (156/374) of patients had co-existing medical conditions. The most common treatment approaches used at the first appointment were soft-tissue techniques (73.9%; 292/395), articulatory techniques (69.4%; 274/395) and high velocity low amplitude thrust (34.4%; 136/395). The mean number of treatments per patient was 7 (mode 4).

Conclusion

To better understand the role of osteopathy in UK health service delivery, the profession needs to do more research with patients in order to understand their needs and their expected outcomes of care, and for this to inform osteopathic practice and education.
Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma
Authors: Pamukcu Sarah , Cerutti Aude , Bordat Yann , Hem Sonia , Rofidal Valerie , Besteiro Sebastien
Published: January 2021

Iron-sulfur (Fe-S) clusters are one of the most ancient and ubiquitous prosthetic groups, and they are required by a variety of proteins involved in important metabolic processes. Apicomplexan parasites have inherited different plastidic and mitochondrial Fe-S clusters biosynthesis pathways through endosymbiosis. We have investigated the relative contributions of these pathways to the fitness ofToxoplasma gondii, an apicomplexan parasite causing disease in humans, by generating specific mutants. Phenotypic analysis and quantitative proteomics allowed us to highlight notable differences in these mutants. Both Fe-S cluster synthesis pathways are necessary for optimal parasite growth in vitro, but their disruption leads to markedly different fates: impairment of the plastidic pathway leads to a loss of the organelle and to parasite death, while disruption of the mitochondrial pathway trigger differentiation into a stress resistance stage. This highlights that otherwise similar biochemical pathways hosted by different sub-cellular compartments can have very different contributions to the biology of the parasites, which is something to consider when exploring novel strategies for therapeutic intervention.

Author summary

Toxoplasma gondiiis a ubiquitous unicellular parasite that harbours two organelles of endosymbiotic origin: the mitochondrion, and a relict plastid named the apicoplast. Each one of these organelles contains its own machinery for synthesizing iron-sulfur clusters, which are important protein co- factors. In this study, we show that interfering with either the mitochondrial or the plastidic iron- sulfur cluster synthesizing machinery has a profound impact on parasite growth. However, while disrupting the plastidic pathway led to an irreversible loss of the organelle and subsequent death of the parasite, disrupting the mitochondrial pathway led to conversion of the parasites into a stress resistance form. We used a comparative quantitative proteomic analysis of the mutants, combined with experimental validation, to provide mechanistic clues into these different phenotypic outcomes. Although the consequences of disrupting each pathway were manifold, our data highlighted distinct changes at the metabolic level. For instance, the plastidic iron-sulfur cluster synthesis pathway is likely important for maintaining the lipid homeostasis of the parasites, while the mitochondrial pathway is clearly crucial for maintaining their respiratory capacity. Interestingly, we have discovered that other mutants severely impacted for mitochondrial function, in particular the respiratory chain, are able to survive and initiate conversion to the stress resistance form. This illustrates a different capacity forT. gondiito adapt for survival in response to distinct metabolic dysregulations.
Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals
Authors: McCulloch Drummond E-Wen , Madsen Martin Korsbak , Stenbæk Dea Siggard , Kristiansen Sara , Ozenne Brice , Jensen Peter Steen , Knudsen Gitte Moos , Fisher Patrick MacDonald
Published: January 2021

Background

Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans.

Aims

Evaluate changes in resting-state functional connectivity (RSFC) at one-week and three-months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures.

Methods

Participants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state fMRI scans at baseline, one-week and three-months post-administration and [11C]Cimbi-36 PET scans at baseline and one-week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding.

Results

Psilocybin was well tolerated and produced positive changes in well-being. At one-week only, executive control network (ECN) RSFC was significantly decreased (Cohen’s d=-1.73, pFWE=0.010). We observed no other significant changes in RSFC at one-week or three-months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at one-week predicted increased mindfulness at three-months (r =-0.65).

Conclusions

These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic “afterglow” period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at three-months, when personality changes are observed, remain to be identified.
A quick and versatile protocol for the 3D visualization of transgene expression across the whole body of larvalDrosophila
Authors: Kobler Oliver , Weiglein Aliće , Hartung Kathrin , Chen Yi-chun , Gerber Bertram , Thomas Ulrich
Published: January 2021

LarvalDrosophilaare used as a genetically accessible study case in many areas of biological research. Here we report a fast, robust and user-friendly procedure for the whole-body multifluorescence imaging ofDrosophilalarvae; the protocol has been optimized specifically for larvae by systematically tackling the pitfalls associated with clearing this small but cuticularized organism. Tests on various fluorescent proteins reveal that the recently introduced monomeric infrared fluorescent protein (mIFP) is particularly suitable for our approach. This approach comprises an effective, low-cost clearing protocol with minimal handling time and reduced toxicity in the reagents employed. It combines a success rate high enough to allow for small-scale screening approaches and a resolution sufficient for cellular-resolution analyses with light sheet and confocal microscopy. Given that publications and database documentations typically specify expression patterns of transgenic driver lines only within a given organ system of interest, the present procedure should be versatile enough to extend such documentation systematically to the whole body. As examples, the expression patterns of transgenic driver lines covering the majority of neurons, or subsets of chemosensory, central brain or motor neurons, are documented in the context of whole larval body volumes (using nsyb-Gal4, IR76b-Gal4, APL-Gal4 and mushroom body Kenyon cells, or OK371-Gal4, respectively). Notably, the presented protocol allows for triple-color fluorescence imaging with near-infrared, red and yellow fluorescent proteins.
Sex-dependent gene regulation of human atherosclerotic plaques by DNA methylation and transcriptome integration points to smooth muscle cell involvement in women
Authors: Hartman Robin J. G. , Siemelink Marten A. , Haitjema Saskia , Dekkers Koen F. , Slenders Lotte , Boltjes Arjan , Mokry Michal , Timmerman Nathalie , de Borst Gert J. , Heijmans Bastiaan T. , Asselbergs Folkert W. , Pasterkamp Gerard , van der Laan Sander W. , den Ruijter Hester M.
Published: January 2021

Sex differences are evident in the clinical presentation and underlying histology of atherosclerotic disease with women developing more stable atherosclerotic lesions than men. It is unknown whether this is explained by sex differences in gene regulation in cellular compartments of atherosclerotic plaques. To study sex differences in gene regulation we performed genome-wide DNA methylation and transcriptomics analysis on plaques of 485 carotid endarterectomy patients (31% female). Sex-differential DNA methylation at 4,848 sites in the autosome was enriched for cell-fate commitment and developmental processes, and its deconvolution predicted more smooth muscle cells in females, as compared to more immune cells in males. RNA-sequencing of the same plaques corroborated the sex differences in DNA methylation predicted cell-types, in which genes that were higher expressed in females were enriched for TGF-beta signaling and extracellular matrix biology. In addition, female-biased genes were enriched for targeting by regulatory loci based on sex differential methylation. Lastly, by using single-cell RNA sequencing we showed that these female-biased genes are mostly expressed in smooth muscle cells, and higher expressed in smooth muscle cells from female (predominantly stable) plaques as compared to male (relatively unstable) plaques. Our approach identified female-biased genes in smooth muscle cells in fibrous atherosclerotic plaques. This points towards new mechanisms in smooth muscle cell biology of stable atherosclerotic plaques and offers new directions for research to develop new sex-specific therapeutics for atherosclerotic disease.
Interpretable prioritization of splice variants in diagnostic next-generation sequencing
Authors: Danis Daniel , Jacobsen Julius O.B. , Carmody Leigh , Gargano Michael , McMurry Julie A , Hegde Ayushi , Haendel Melissa A , Valentini Giorgio , Smedley Damian , Robinson Peter N
Published: January 2021

A critical challenge in genetic diagnostics is the computational assessment of candidate splice variants, specifically the interpretation of nucleotide changes located outside of the highly conserved dinucleotide sequences at the 5′ and 3′ ends of introns. To address this gap, we developed the Super Quick Informationcontent Random-forest Learning of Splice variants (SQUIRLS) algorithm. SQUIRLS generates a small set of interpretable features for machine learning by calculating the information-content (IC) of wildtype and variant sequences of canonical and cryptic splice sites, assessing changes in candidate splicing regulatory sequences, and incorporating characteristics of the sequence such as exon length, disruptions of the AG exclusion zone, and conservation. We curated a comprehensive collection of disease-associated splicealtering variants at positions outside of the highly conserved AG/GT dinucleotides at the termini of introns. SQUIRLS trains two random-forest classifiers for the donor and for the acceptor and combines their outputs by logistic regression to yield a final score. We show that SQUIRLS transcends previous state of the art accuracy in classifying splice variants as assessed by rank analysis in simulated exomes and is significantly faster than competing methods. SQUIRLS provides tabular output files for incorporation into diagnostic pipelines for exome and genome analysis, as well as visualizations that contextualize predicted effects of variants on splicing to make it easier to interpret splice variants in diagnostic settings
Strobemers: an alternative to k-mers for sequence comparison
Authors: Sahlin Kristoffer
Published: January 2021

K-mer-based methods are widely used in bioinformatics for various types of sequence comparison. However, a single mutation will mutatekconsecutive k-mers and makes most k-mer based applications for sequence comparison sensitive to variable mutation rates. Many techniques have been studied to overcome this sensitivity,e.g., spaced k-mers and k-mer permutation techniques, but these techniques do not handle indels well. For indels, pairs or groups of small k-mers are commonly used, but these methods first produce k-mer matches, and only in a second step, a pairing or grouping of k-mers is performed. Such techniques produce many redundant k-mer matches due to the size ofk.

Here, we proposestrobemersas an alternative to k-mers for sequence comparison. Intuitively, strobemers consist of linked minimizers. We use simulated data to show that strobemers provide more evenly distributed sequence matches and are less sensitive to different mutation rates than k-mers and spaced k-mers. Strobemers also produce a higher match coverage across sequences. We further implement a proof-of-concept sequence matching tool StrobeMap, and use synthetic and biological Oxford Nanopore sequencing data to show the utility of using strobemers for sequence comparison in different contexts such as sequence clustering and alignment scenarios. A reference implementation of our tool StrobeMap together with code for analyses is available athttps://github.com/ksahlin/strobemers.
A reduction methodology for fluctuation driven population dynamics
Authors: Goldobin Denis , di Volo Matteo , Torcini Alessandro
Published: January 2021

Lorentzian distributions have been largely employed in statistical mechanics to obtain exact results for heterogeneous systems. Analytic continuation of these results is impossible even for slightly deformed Lorentzian distributions, due to the divergence of all the moments (cumulants). We have solved this problem by introducing apseudo-cumulants’expansion. This allows us to develop a reduction methodology for heterogeneous spiking neural networks subject to extrinsinc and endogenous fluctuations, thus obtaining an unified mean-field formulation encompassing quenched and dynamical disorder sources.
Correlated dipolar and dihedral fluctuations in a protein
Authors: Moulick Abhik Ghosh , Chakrabarti J.
Published: January 2021

Correlation between dihedral fluctuations is a possible way to understand coordination between various amino acid residues of the protein. The nanosecond timescales of correlated fluctuations of dihedral angle do not allow direct probing by experimental methods. However, NMR experiments probe dipolar fluctuations given in terms of cross correlated relaxation (CCR) rates, expressed as zero frequency spectral density function (J) of the fluctuations of the mutual orientation of two spatially separated dipole vectors. Here we illustrate the correlation of protein dipolar and dihedral angle using molecular dynamics simulation of protein Ubiquitin (Ub) and GB3. We calculate CCR rates between protein bond vector from simulation and compare with CCR data obtained from NMR experiments. A good correlation between theoretical and experimental values is found. We further show that the zero frequency spectral functions of backbone dihedral ψ auto-correlation function and dipole orientation fluctuations show strong correlations. These correlations are not sensitive to protein and forcefield parameters. Hence, CCR may act as a marker for protein backbone dihedral fluctuations.
Organelle bottlenecks facilitate evolvability by traversing heteroplasmic fitness valleys
Authors: Radzvilavicius Arunas L. , Johnston Iain G.
Published: January 2021

Bioenergetic organelles – mitochondria and plastids – retain their own genomes, and these organelle DNA (oDNA) molecules are vital for eukaryotic life. Like all genomes, oDNA must be able to evolve to suit new environmental challenges. However, mixed oDNA populations can challenge cellular bioenergetics, providing a penalty to the appearance and adaptation of new mutations. Here we show that organelle ‘bottlenecks’, mechanisms increasing cell-to-cell oDNA variability during development, can overcome this mixture penalty and facilitate the adaptation of beneficial mutations. We show that oDNA heteroplasmy and bottlenecks naturally emerge in evolutionary simulations subjected to fluctuating environments, demonstrating that this evolvability is itself evolvable. Usually thought of as a mechanism to clear damaging mutations, organelle bottlenecks therefore also resolve the tension between intracellular selection for pure oDNA populations and the ‘bet-hedging’ need for evolvability and adaptation to new environments. This general theory suggests a reason for the maintenance of organelle heteroplasmy in cells, and may explain some of the observed diversity in organelle maintenance and inheritance across taxa.
Network Pharmacology Analysis of the active components and anticancer targets of Rhubarb
Authors: Junrui Hu , Yongqiang Duan , Gongning Cui , Qiang Luo , Shanshan Xi , Rui Huang , Jun Ma , Min Bai , Hongyan Wu
Published: January 2021

To investigate the mechanisms and active components governing the anticancer activity of rhubarb.The TCMSP database was screened to identify the active components of rhubarb and Swiss target predictions were generated to predict their cellular targets. TTD and OMIM databases were used to predict tumor-related target genes. "Cytoscape" was used to construct drug targets. PPI network analysis, GO enrichment analysis and KEGG pathway analysis of the key targets were investigated using String and David databases. A total of 33 components and 116 corresponding targets were screened. Amongst them, the key active compounds in rhubarb included emodin, aloe emodin, β-sitosterol, emodin methyl ether and rhein, which were predicted to target TP53, AKT1, STAT3, PIK3CA, HRAS, and VEGFA. GO analysis revealed that the cellular targets clustered into 159 biological processes, including those involved in cellular composition (n=24) and molecular functions (n=42, P<0.01). KEGG pathway analysis revealed 85 (P < 0.01) pathways related to cancer. The active compounds in rhubarb target TP53, AKT1 and PIK3CA. Rhubarb therefore regulates cancer development through an array of biological pathways.
Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
Authors: Oliveira Antonio B. , Lin Xingcheng , Kulkarni Prakash , Onuchic José N. , Roy Susmita , Leite Vitor B.P.
Published: January 2021

Intrinsically disordered proteins (IDPs) lack a rigid 3D structure and populate a polymorphic ensemble of conformations. Because of the lack of a reference conformation, their energy landscape representation in terms of reaction coordinates presents a daunting challenge. Here, our newly developed Energy Landscape Visualization Method (ELViM), a reaction coordinate-free approach, shows its prime application to explore frustrated energy landscapes of an intrinsically disordered protein, Prostate-Associated Gene 4 (PAGE4). PAGE4 is a transcriptional coactivator that potentiates the oncogene c-Jun. Two kinases, namely HIPK1 and CLK2, phosphorylate PAGE4 generating variants phosphorylated at different serine/threonine residues (HIPK1-PAGE4 and CLK2-PAGE4, respectively) with opposing functions. While HIPK1-PAGE4 predominantly phosphorylates Thr51 and potentiates c-Jun, CLK2-PAGE4 hyper-phosphorylates PAGE4 and attenuates transactivation. To understand the underlying mechanisms of conformational diversity among different phosphoforms, we have analyzed their atomistic trajectories simulated using AWSEM forcefield and the energy landscapes were elucidated using ELViM. This method allows us to identify and compare the population distributions of different conformational ensembles of PAGE4 phosphoforms using the same effective phase space. The results reveal a predominant conformational ensemble with an extended C-terminal segment of WT PAGE4, which exposes a functional residue Thr51, implying its potential of undertaking a fly-casting mechanism while binding to its cognate partner. In contrast, for HIPK1-PAGE4, a compact conformational ensemble enhances its population sequestering phosphorylated-Thr51. This clearly explains the experimentally observed weaker affinity of HIPK1-PAGE4 for c-Jun. ELViM appears as a powerful tool especially to analyze the highly-frustrated energy landscape representation of IDPs where appropriate reaction coordinates are hard to apprehend.
A hetero-oligomeric remorin-receptor complex regulates plant development
Authors: Abel Nikolaj B. , Buschle Corinna A. , Hernandez-Ryes Casandra , Burkart Sandy S. , Deroubaix Anne-Flore , Mergner Julia , Gronnier Julien , Jarsch Iris K. , Folgmann Jessica , Braun Karl Heinz , Bayer Emmanuelle , Germain Véronique , Derbyshire Paul , Menke Frank L.H. , Kemmerling Birgit , Zipfel Cyril , Küster Bernhard , Mongrand Sébastien , Marín Macarena , Ott Thomas
Published: January 2021

Plant growth and development are modulated by both biotic and abiotic stress. Increasing evidence suggests that cellular integration of the corresponding signals occurs within preformed hubs at the plasma membrane called nanodomains. These membrane sub-compartments are organized by multivalent molecular scaffold proteins, such as remorins. Here, we demonstrate that Group 1 remorins form a hetero-oligomeric complex at the plasma membrane. While these remorins are functionally redundant for some pathways their multivalency also allows the recruitment of specific interaction partners. One of them, the receptor-like kinase REMORIN-INTERACTING RECEPTOR 1 (RIR1), that acts redundantly with the closely related receptor NILR2, is specifically recruited by REM1.2 in a phosphorylation-dependent manner. Overlapping developmental phenotypes suggest that the REM/RIR complex regulates key developmental pathways.
Targeting cellular metabolism to inhibit synergistic biofilm formation of multi-species isolated from a cooling water system
Authors: Kang Dingrong , Liu Wenzheng , kakahi Fatemeh Bajoul , Delvigne Frank
Published: January 2021

Biofilm is ubiquitous in natural environments, causing biofouling in industrial water systems and leading to liquidity and heat transfer efficiency decreases. In particular, multi-species coexistence in biofilms can provide the synergy needed to boost biomass production and enhance treatment resistance. In this study, a total of 37 bacterial strains were isolated from a cooling tower where acetic acid and propionic acid were used as the primary carbon sources. These isolates mainly belonged to Proteobacteria and Firmicutes, which occupied more than 80% of the total strains according to the 16S rRNA gene amplicon sequencing. Four species (Acinetobactersp. CTS3, Corynebacteriumsp. CTS5, Providenciasp. CTS12, andPseudomonassp. CTS17) were observed to co-exist in the synthetic medium, showing a synergistic effect towards biofilm formation. Three metabolic inhibitors (sulfathiazole, 3-Bromopyruvic acid, and 3-Nitropropionic acid) were employed as possible treatments against biofilm formation due to their inhibition effect on c-di-GMP biosynthesis or assimilation of volatile fatty acids. All of them displayed evident inhibition profiles to biofilm formation. Notably, the combination of these three inhibitors possessed a remarkable ability to block the development of a multi-species biofilm with lower concentrations, suggesting an enhanced effect with their simultaneous use. This study demonstrates that targeting cellular metabolism is an effective way to inhibit biofilm formation derived from multi-species.
Occasional paternal inheritance of the germline-restricted chromosome in songbirds
Authors: Pei Yifan , Forstmeier Wolfgang , Ruiz-Ruano Francisco J. , Mueller Jakob C. , Cabrero Josefa , Camacho Juan Pedro. M. , Alché Juan D. , Franke Andre , Hoeppner Marc , Börno Stefan , Gessara Ivana , Hertel Moritz , Teltscher Kim , Knief Ulrich , Suh Alexander , Kempenaers Bart
Published: January 2021

All songbirds have one special accessory chromosome1–4, the so-called germline-restricted chromosome (GRC)4–7, which is only present in germline cells and absent from all somatic tissues. Earlier work on the zebra finch (Taeniopygia guttata castanotis) showed that the GRC is inherited only through the female line4,6,8,9– like mitochondrial DNA7,9–12– and is eliminated from the sperm during spermatogenesis5,7,9–11. Here we show that the GRC can also be paternally inherited. Confocal microscopy using GRC-specific FISH probes indicated that a considerable fraction of sperm heads (1-19%) in zebra finch ejaculates still contained the GRC. In line with these cytogenetic data, sequencing of ejaculates revealed that individual males from two families differed strongly and consistently in the number of GRCs in their ejaculates. Examining a captive-bred population of hybrids of the two zebra finch subspecies (T. g. guttataandT. g. castanotis) revealed that the descendants inherited their mitochondria from acastanotismother but their GRC from aguttatafather. Moreover, GRC haplotypes across nine differentcastanotismatrilines showed at best a weak tendency to be co-inherited with mtDNA haplotypes. Withincastanotis, the GRC showed little variability, while the mtDNA of matrilines was highly divergent. This suggests that a single GRC haplotype has recently spread across the entirecastanotispopulation, crossing the matriline boundaries via paternal spillover. Our findings raise the possibility that certain GRC haplotypes could selfishly spread through the population, via additional paternal transmission, thereby outcompeting other GRC haplotypes that were limited to strict maternal inheritance, even if this was partly detrimental to organismal fitness.
Multisensory correlation computations in the human brain uncovered by a time-resolved encoding model
Authors: Lerousseau Jacques Pesnot , Parise Cesare , Ernst Marc O. , van Wassenhove Virginie
Published: January 2021

Neural mechanisms that arbitrate between integrating and segregating multisensory information are essential for complex scene analysis and for the resolution of the multisensory correspondence problem. However, these mechanisms and their dynamics remain largely unknown, partly because classical models of multisensory integration are static. Here, we used the Multisensory Correlation Detector, a model that provides a good explanatory power for human behavior while incorporating dynamic computations. Participants judged whether sequences of auditory and visual signals originated from the same source (causal inference) or whether one modality was leading the other (temporal order), while being recorded with magnetoencephalography. To test the match between the Multisensory Correlation Detector dynamics and the magnetoencephalographic recordings, we developed a novel dynamic encoding-model approach of electrophysiological activity, which relied on temporal response functions. First, we confirm that the Multisensory Correlation Detector explains causal inference and temporal order patterns well. Second, we found strong fits of brain activity to the two outputs of the Multisensory Correlation Detector in temporo-parietal cortices, a region with known multisensory integrative properties. Finally, we report an asymmetry in the goodness of the fits, which were more reliable during the causal inference than during the temporal order judgment task. Overall, our results suggest the plausible existence of multisensory correlation detectors in the human brain, which explain why and how causal inference is strongly driven by the temporal correlation of multisensory signals.
Two step PCR method to exchange the resistance cassette of a vector
Authors: Cremer Nils , Diehl Anne
Published: January 2021

For co-transformation of two plasmids, both have to possess different antibiotic selection markers. If that is not the case, normally the gene of interest (GOI) is subcloned into another vector. Here we introduce a fast and easy method to exchange the antibiotic resistance cassette (ARC) in only two PCR steps.

Method Summary

To shuttle the antibiotic resistance cassette (ARC) from one vector to another, one can amplify the ARC of interest and use the resulting PCR-product as a primer pair for the next amplification step. Simply remove parental DNA template byDpnI digestion, transform PCR product directly inE. coli cells, select transformants on an appropriate agar plate and isolate target vector by plasmid preparation.
SMILE: Mutual Information Learning for Integration of Single Cell Omics Data
Authors: Xu Yang , Das Priyojit , McCord Rachel Patton
Published: January 2021

Deep learning approaches have empowered single-cell omics data analysis in many ways, generating new insights from complex cellular systems. As there is an increasing need for single cell omics data to be integrated across sources, types, and features of data, the challenges of integrating single-cell omics data are rising. Here, we present a deep clustering algorithm that learns discriminative representation for single-cell data via maximizing mutual information, SMILE (Single-cellMutualInformationLearning). Using a unique cell-pairing design, SMILE successfully integrates multi-source single-cell transcriptome data, removing batch effects and projecting similar cell types, even from different tissues, into the same representation space. SMILE can also integrate data from two or more modalities, such as joint profiling technologies using singlecell ATAC-seq, RNA-seq, DNA methylation, Hi-C, and ChIP data. SMILE works well even when feature types are unmatched, such as genes for RNA-seq and genome wide peaks for ATAC-seq.
A unified mechanism for innate and learned visual landmark guidance in the insect central complex
Authors: Goulard Roman , Buehlmann Cornelia , Niven Jeremy E. , Graham Paul , Webb Barbara
Published: January 2021

Insects can navigate efficiently in both novel and familiar environments, and this requires flexiblity in how they are guided by sensory cues. A prominent landmark, for example, can ellicit strong innate behaviours (attraction or menotaxis) but can also be used, after learning, as a specific directional cue as part of a navigation memory. However, the mechanisms that allow both pathways to co-exist, interact or override each other are largely unknown. Here we propose a model for the behavioural integration of innate and learned guidance based on the neuroanatomy of the central complex (CX), adapted to control landmark guided behaviours. We consider a reward signal provided either by an innate attraction to landmarks or a long-term visual memory in the mushroom bodies (MB) that modulates the formation of a local vector memory in the CX. Using an operant strategy for a simulated agent exploring a simple world containing a single visual cue, we show how the generated short-term memory can support both innate and learned steering behaviour. In addition, we show how this architecture is consistent with the observed effects of unilateral MB lesions in ants that cause a reversion to innate behaviour. We suggest the formation of a directional memory in the CX can be interpreted as transforming rewarding (positive or negative) sensory signals into a mapping of the environment that describes the geometrical attractiveness (or repulsion). We discuss how this scheme might represent an ideal way to combine multisensory information gathered during the exploration of an environment and support optimized cue integration.

1

Author summary

In this paper, we modeled the neural pathway allowing insects to perform landmark guided behaviours using their internal compass. First, we observed the intrinsic property of the connectome, extracted from drosophila online database, between the internal compass neurons and the steering neurons to support an oriented behaviour towards a single landmark. Then, we proposed and evaluated an adaptation of the bees path integration neural circuit, to sustain flexible landmark guidance behaviours such as attraction or menotaxis. We showed the model ability to form a memory during the exploration of the local environment to support both innate or learned navigation behaviour using a single landmark in the environment. In addtion, we demonstrated the transformation of a simple goodness/badness signal, from innate or long-term memory pathways, into an oriented steering signal that could be applied to other sensory pathways. Furthermore, by reproducing lesion experiments in the mushroom bodies of wood ants we highlight the consistency of the model with biological observation. We then discuss the different emergent properties and the potential outcome that this local, and operant, memory supports.