bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 transmission in a university setting: a rapid review of modelling studies
Authors: Christensen Hannah , Turner Katy , Trickey Adam , Booton Ross D. , Hemani Gibran , Nixon Emily , Relton Caroline , Danon Leon , Hickman Matthew , Brooks-Pollock Ellen ,   Part of the University of Bristol UNCOVER group
Published: September 2020

Managing COVID-19 within a university setting presents unique challenges. At the start of term, students arrive from geographically diverse locations and potentially have higher numbers of social contacts than the general population, particularly if living in university halls of residence accommodation. Mathematical models are useful tools for understanding the potential spread of infection and are being actively used to inform policy about the management of COVID-19. Our aim was to provide a rapid review and appraisal of the literature on mathematical models investigating COVID-19 infection in a university setting. We searched PubMed, Web of Science, bioRxiv/ medRxiv and sought expert input via social media to identify relevant papers. BioRxiv/ medRxiv and PubMed/Web of Science searches took place on 3 and 6 July 2020, respectively. Papers were restricted to English language. Screening of peer-reviewed and pre-print papers and contact with experts yielded five relevant papers – all of which were pre-prints. All models suggest a significant potential for transmission of COVID-19 in universities. Testing of symptomatic persons and screening of the university community regardless of symptoms, combined with isolation of infected individuals and effective contact tracing were critical for infection control in the absence of other mitigation interventions. When other mitigation interventions were considered (such as moving teaching online, social/physical distancing, and the use of face coverings) the additional value of screening for infection control was limited. Multiple interventions will be needed to control infection spread within the university setting and the interaction with the wider community is an important consideration. Isolation of identified cases and quarantine of contacts is likely to lead to large numbers of students requiring educational, psychological and behavioural support and will likely have a large impact on the attendance of students (and staff), necessitating online options for teaching, even where in-person classes are taking place. Models were highly sensitive to assumptions in the parameters, including the number and type of individuals’ contacts, number of contacts traced, frequency of screening and delays in testing. Future models could aid policy decisions by considering the incremental benefit of multiple interventions and using empirical data on mixing within the university community and with the wider community where available. Universities will need to be able to adapt quickly to the evolving situation locally to support the health and wellbeing of the university and wider communities.
Maternal and child genetic liability for smoking and caffeine consumption and
child mental health: An intergenerational genetic risk score analysis in the
ALSPAC cohort
Authors: Schellhas Laura , Haan Elis , Easey Kayleigh E , Wootton Robyn E , Sallis Hannah M , Sharp Gemma C , Munafò Marcus R , Zuccolo Luisa
Published: September 2020

Background and aims

Previous studies suggest an association between maternal tobacco and
caffeine consumption during and outside of pregnancy and offspring mental
health. We aimed to separate effects of the maternal environment
(intrauterine or postnatal) from pleiotropic genetic effects.

Design

Secondary analysis of a longitudinal study. We 1) validated smoking and
caffeine genetic risk scores (GRS) derived from published GWAS for use
during pregnancy, 2) compared estimated effects of maternal and offspring
GRS on childhood mental health outcomes, and 3) tested associations between
maternal and offspring GRS on their respective outcomes.

Setting

We used data from a longitudinal birth cohort study from England, the
Avon Longitudinal Study of Parents and Children (ALSPAC).

Participants

Our sample included 7921 mothers and 7964 offspring.

Measurements

Mental health and non-mental health phenotypes were derived from
questionnaires and clinical assessments: 79 maternal phenotypes assessed
during and outside of pregnancy, and 71 offspring phenotypes assessed in
childhood (<10 years) and adolescence (11-18 years).

Findings

The maternal smoking and caffeine GRS were associated with maternal
smoking and caffeine consumption during pregnancy (2nd
trimester: Psmoking = 3.0×10−7,
Pcaffeine = 3.28×10−5). Both
the maternal and offspring smoking GRS showed evidence of association with
reduced childhood anxiety symptoms (βmaternal = -0.033;
βoffspring= -0.031) and increased conduct disorder
symptoms (βmaternal= 0.024;
βoffspring= 0.030), after correcting for multiple
testing. Finally, the maternal and offspring smoking GRS were associated
with phenotypes related to sensation seeking behaviours in mothers and
adolescence (e.g., increased symptoms of externalising disorders,
extraversion, and monotony avoidance). The caffeine GRS showed weaker
evidence for associations with mental health outcomes.

Conclusions

We did not find strong evidence that maternal smoking and caffeine
genetic risk scores (GRS) have a causal effect on offspring mental health
outcomes. Our results confirm that the smoking GRS also captures liability
for sensation seeking personality traits.
Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression
Authors: Ji Hong-Long , Su Zhenlei , Zhao Runzhen , Komissarov Andrey A. , Yi Guohua , Liu Shan-Lu , Idell Steven , Matthay Michael A.
Published: September 2020

Background

How aberrant fibrinolysis influences the clinical progression of COVID-19 presents a clinicopathological dilemma challenging intensivists. To investigate whether abnormal fibrinolysis is a culprit or protector or both, we associated elevated plasma D-dimer with clinical variables to identify a panoramic view of the derangements of fibrinolysis that contribute to the pathogenesis of COVID-19 based on studies available in the literature.

Methods

We performed this systematic review based on both meta-analysis and meta-regression to compute the correlation of D-dimer at admission with clinical features of COVID-19 patients in retrospective studies or case series. We searched the databases until Aug 18, 2020, with no limitations by language. The first hits were screened, data extracted, and analyzed in duplicate. We did the random-effects meta-analyses and meta-regressions (both univariate and multivariate). D-dimer associated clinical variables and potential mechanisms were schematically reasoned and graphed.

Findings

Our search identified 42 observational, or retrospective, or case series from six countries (n=14,862 patients) with all races and ages from 1 to 98-year-old. The weighted mean difference of D-dimer was 0.97 μg/mL (95% CI 0.65, 1.29) between relatively mild (or healthy control) and severely affected groups with significant publication bias. Univariate meta-regression identified 58 of 106 clinical variables were associated with plasma D-dimer levels, including 3 demographics, 5 comorbidities, 22 laboratory tests, 18 organ injury biomarkers, 8 severe complications, and 2 outcomes (discharge and death). Of these, 11 readouts were negatively associated with the level of plasma D-dimer. Further, age and gender were confounding factors for the identified D-dimer associated variables. There were 22 variables independently correlated with the D-dimer level, including respiratory rate, dyspnea plasma K+, glucose, SpO2, BUN, bilirubin, ALT, AST, systolic blood pressure, and CK. We thus propose that insufficient hyperfibrinolysis (fibrinolysis is accelerated but unable to prevent adverse clinical impact for clinical deterioration COVID-19) as a peculiar mechanism.

Interpretation

The findings of this meta-analysis- and meta-regression-based systematic review supports elevated D-dimer as an independent predictor for mortality and severe complications. D-dimer-associated clinical variables draw a landscape integrating the aggregate effects of systemically suppressive and locally (i.e., in the lung) hyperactive derangements of fibrinolysis. D-dimer and associated clinical biomarkers and conceptually parameters could be combined for risk stratification, potentially for tracking thrombolytic therapy or alternative interventions.

Funding

National Institute of Health.
The influence of roads on the fine-scale population genetic structure of the dengue vectorAedes aegypti(Linnaeus)
Authors: Regilme Maria Angenica Fulo , Carvajal Thaddeus , Honnen Ann –Christin , Amalin Divina , Watanabe Kozo
Published: September 2020

Dengue is endemic in tropical and subtropical countries and is transmitted mainly byAedes aegypti. Mosquito movement can be affected by human-made structures such as roads that can act as a barrier. Roads can influence the population genetic structure ofAe. aegypti. We investigated the genetic structure and gene flow ofAe. aegyptias influenced by a primary road, España Boulevard (EB) with 2000-meter-long stretch and 24-meters-wide in a very fine spatial scale. We hypothesized thatAe. aegyptipopulations separated by EB will be different due to the limited gene flow as caused by the barrier effect of the road. A total of 376 adults and larvalAe. aegyptiwere collected from June to September 2017 in 21 sites across EB. North (N1-N11) and South (S1-S10) comprised of 211 and 165 individuals, respectively. All mosquitoes were genotyped at 11 microsatellite loci. AMOVAFSTindicated significant genetic differentiation across the road. The constructed UPGMA dendrogram found 4 genetic groups revealing the clear separation between North and South sites across the road. On the other hand, Bayesian cluster analysis showed four genetic clusters (K = 4) wherein each individual samples have no distinct genetic cluster thus genetic admixture. Moreover, significant positive spatial autocorrelation was observed at 100 - 200 m distance class, suggesting dispersal potential of the adult mosquitoes within a 200 m spatial scale. Our results suggest that human-made landscape features such as primary roads are potential barriers to mosquito movement thereby limiting its gene flow across the road. This information is valuable in designing an effective mosquito control program in a very fine spatial scale.

Author Summary

Dengue, a mosquito-borne viral infection is a serious health problem in tropical and subtropical countries such as Philippines. Most dengue prevention programs aim to eradicate its mosquito vector,Aedes aegypti.A successful population control program is reliant in understanding the mosquito behavior and ecology including how human-made structures such as roads influence its expansion and movement. Previous studies have discovered the barrier effect of roads in the movement of mosquitoes. In this study, we examined the influence of roads in the population genetic structure ofAe. aegyptiin a fine spatial scale using 11 microsatellite markers. We found significant genetic differentiation of mosquito populations across the road. Our results suggest limited gene flow across the road and supports our hypothesis that roads are potential barriers to mosquito dispersal. This information can be used in designing an effective mosquito population control zones in perceived barrier to mosquito dispersal such as roads.
Rapid Evolution of Plastic-degrading Enzymes Prevalent in the Global Ocean
Authors: Alam Intikhab , Aalismail Nojood , Martin Cecilia , Kamau Allan , Guzmán-Vega Francisco J. , Jamil Tahira , Momin Afaque A. , Acinas Silvia G. , Gasol Josep M. , Arold Stefan T. , Gojobori Takashi , Agusti Susana , Duarte Carlos M.
Published: September 2020

Estimates of marine plastic stocks, a major threat to marine life (1), are far lower than expected from exponentially-increasing litter inputs, suggesting important loss factors (2, 3). These may involve microbial degradation, as the plastic-degrading polyethylene terephthalate enzyme (PETase) has been reported in marine microbial communities (4). An assessment of 416 metagenomes of planktonic communities across the global ocean identifies 68 oceanic PETase variants (oPETase) that evolved from ancestral enzymes degrading polycyclic aromatic hydrocarbons. Twenty oPETases show predicted efficiencies comparable to those of laboratory-optimized PETases, suggesting strong selective pressures directing the evolution of these enzymes. We found oPETases in 90.1% of samples across all oceans and depths, particularly abundant at 1,000 m depth, with a strong dominance ofPseudomonadalescontaining putative highly-efficient oPETase variants in the dark ocean. Enzymatic degradation may be removing plastic from the marine environment while providing a carbon source for bathypelagic microbial communities.
Variable bites and dynamic populations; new insights inLeishmaniatransmission
Authors: Carmichael Samuel , Powell Ben , Hoare Thomas , Walrad Pegine , Pitchford Jon
Published: September 2020

Leishmaniasis is a neglected tropical disease which kills an estimated 50000 people each year, with its deadly impact confined mainly to lower to middle income countries.Leishmaniaparasites are transmitted to human hosts by sand fly vectors during blood feeding. Recent experimental work shows that transmission is modulated by the patchy landscape of infection in the host’s skin, and the parasite population dynamics within the vector. Here we assimilate these new findings into a simple probabilistic model for disease transmission which replicates recent experimental results, and assesses their relative importance. The results of subsequent simulations, describing random parasite uptake and dynamics across multiple blood meals, show that skin heterogeneity is important for transmission by short-lived flies, but that for longer-lived flies with multiple bites the population dynamics within the vector dominate transmission probability. Our results indicate that efforts to reduce fly lifespan beneath a threshold of around two weeks may be especially helpful in reducing disease transmission.
Longitudinal immune profiling of mild and severe COVID-19 reveals innate and adaptive immune dysfunction and provides an early prediction tool for clinical progression
Authors: Rendeiro André F. , Casano Joseph , Vorkas Charles Kyriakos , Singh Harjot , Morales Ayana , DeSimone Robert A. , Ellsworth Grant B. , Soave Rosemary , Kapadia Shashi N. , Saito Kohta , Brown Christopher D. , Hsu JingMei , Kyriakides Christopher , Chiu Steven , Cappelli Luca , Cacciapuoti Maria Teresa , Tam Wayne , Galluzzi Lorenzo , Simonson Paul D. , Elemento Olivier , Salvatore Mirella , Inghirami Giorgio
Published: September 2020

With a rising incidence of COVID-19-associated morbidity and mortality worldwide, it is critical to elucidate the innate and adaptive immune responses that drive disease severity. We performed longitudinal immune profiling of peripheral blood mononuclear cells from 45 patients and healthy donors. We observed a dynamic immune landscape of innate and adaptive immune cells in disease progression and absolute changes of lymphocyte and myeloid cells in severe versus mild cases or healthy controls. Intubation and death were coupled with selected natural killer cell KIR receptor usage and IgM+ B cells and associated with profound CD4 and CD8 T cell exhaustion. Pseudo-temporal reconstruction of the hierarchy of disease progression revealed dynamic time changes in the global population recapitulating individual patients and the development of an eight-marker classifier of disease severity. Estimating the effect of clinical progression on the immune response and early assessment of disease progression risks may allow implementation of tailored therapies.
Modelling the epidemic growth of preprints on COVID-19 and SARS-CoV-2
Authors: Vasconcelos Giovani L. , Cordeiro Luan P. , Duarte-Filho Gerson C. , Brum Arthur A.
Published: September 2020

The response of the scientific community to the global health emergency caused by the COVID-19 pandemic has produced an unprecedented number of manuscripts in a short period of time, the vast majority of which have been shared in the form of preprints posted on online preprint repositories before peer review. This surge in preprint publications has in itself attracted considerable attention, although mostly in the bibliometrics literature. In the present study we apply a mathematical growth model, known as the generalized Richards model, to describe the time evolution of the cumulative number of COVID-19 related preprints. This mathematical approach allows us to infer several important aspects concerning the underlying growth dynamics, such as its current stage and its possible evolution in the near future. We also analyze the rank-frequency distribution of preprints servers, ordered by the number of COVID-19 preprints they host, and find that it follows a power law in the low rank (high frequency) region, with the high rank (low frequency) tail being better described by a q-exponential function. The Zipf-like law in the high frequency regime indicates the presence of a cumulative advantage effect, whereby servers that already have more preprints receive more submissions.
A systematic review on improving implementation of the revitalised integrated disease surveillance and response system in the African region: a health workers’ perspective
Authors: Ng’etich Arthur K. S. , Voyi Kuku , Kirinyet Ruth C. , Mutero Clifford M.
Published: September 2020

Background

The revised integrated disease surveillance and response (IDSR) guidelines adopted by African member states in 2010 aimed at strengthening surveillance systems critical capacities. Milestones achieved through IDSR strategy implementation prior to adopting the revised guidelines are well documented; however, there is a dearth of knowledge on the progress made post-adoption. This study aimed to review key recommendations resulting from surveillance assessment studies to improve implementation of the revitalised IDSR system in the African region based on health workers’ perspectives. The review focused on literature published between 2010 and 2019 post-adopting the revised IDSR guidelines in the African region.

Methods

A systematic literature search in PubMed, Web of Science and Cumulative Index for Nursing and Allied Health Literature was conducted. In addition, manual reference searches and grey literature searches using World Health Organisation Library and Information Networks for Knowledge databases were undertaken. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement checklist for systematic reviews was utilised for the review process.

Results

Thirty assessment studies met the inclusion criteria. IDSR implementation under the revised guidelines could be improved considerably bearing in mind critical findings and recommendations emanating from the reviewed surveillance assessment studies. Key recommendations alluded to provision of laboratory facilities and improved specimen handling, provision of reporting forms and improved reporting quality, surveillance data accuracy and quality, improved knowledge and surveillance system performance, utilisation of up-to-date information and surveillance system strengthening, provision of resources, enhanced reporting timeliness and completeness, adopting alternative surveillance strategies and conducting further research.

Conclusion

Recommendations on strengthening IDSR implementation in the African region post-adopting the revised guidelines mainly identify surveillance functions focused on reporting, feedback, training, supervision, timeliness and completeness of the surveillance system as aspects requiring policy refinement.

Systematic Review Registration

PROSPERO registration number CRD42019124108.
Analysis of internet trends related to medications for COVID-19 in ten countries with the highest number of cases
Authors: Chire Saire Josimar E. , Lemus-Martin Roselyn
Published: September 2020

During the last months, the pandemic generated by coronavirus SARS-CoV-2 moved governments, research groups and health organizations to plan, test and execute health policies. At the beginning, the treatment was not clear but in the next months, research groups have conducted studies to recommend or ban some medicines. At the same time, countries with most cases were changing from Asia, Europe to America. Different treatments and medications have been tested and recommended in many countries, such as Hydroxycloroquine, Ivermectin, Azithromycin, Dexamethasone, Prednisone, Remdesivir. This paper is a preliminary study about which medications people are searching on the Internet, considering ten countries with most cases in the world such as Chile, Spain, United Kingdom, Brazil, United States, India, Russia, South Africa, Peru and Mexico.
Is zebrafish heart regeneration “complete”? Lineage-restricted cardiomyocytes proliferate to pre-injury numbers but some fail to differentiate in fibrotic hearts
Authors: Bertozzi Alberto , Wu Chi-Chung , Nguyen Phong D. , Vasudevarao Mohankrishna Dalvoy , Mulaw Medhanie A. , Koopman Charlotte D. , de Boer Teun P. , Bakkers Jeroen , Weidinger Gilbert
Published: September 2020

Adult zebrafish are frequently described to be able to “completely” regenerate the heart. Yet, the extent to which cardiomyocytes lost to injury are replaced is unknown, since only indirect or non-quantitative evidence for cardiomyocyte proliferation exists. We established stereological methods to quantify the number of cardiomyocytes at several time-points post cryoinjury. Intriguingly, after cryoinjuries that killed about 1/3 of the ventricular cardiomyocytes, pre-injury cardiomyocyte numbers were restored already within 30 days. Yet, many hearts retained small residual scars, and a subset of cardiomyocytes bordering these fibrotic areas remained smaller, lacked differentiated sarcomeric structures, and displayed defective calcium signaling. Thus, a subset of regenerated cardiomyocytes failed to fully mature. While lineage-tracing experiments have shown that regenerating cardiomyocytes are derived from differentiated cardiomyocytes, technical limitations have previously made it impossible to test whether cardiomyocyte trans-differentiation contributes to regeneration of non-myocyte cell lineages. Using Cre responder lines that are expressed in all major cell types of the heart, we found no evidence for cardiomyocyte transdifferentiation into endothelial, epicardial, fibroblast or immune cell lineages. Overall, our results imply a refined answer to the question whether zebrafish can completely regenerate the heart: in response to cryoinjury, preinjury cardiomyocyte numbers are indeed completely regenerated, while restoration of cardiomyocyte differentiation and function, as well as resorption of scar tissue, is less robustly achieved.
Many bat species are not potential hosts of SARS-CoV and SARS-CoV-2: Evidence from ACE2 receptor usage
Authors: Yan Huan , Jiao Hengwu , Liu Qianyun , Zhang Zhen , Wang Xin , Guo Ming , Wang Bing-Jun , Lan Ke , Chen Yu , Zhao Huabin
Published: September 2020

Bats are the suggested natural hosts for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, the latter of which caused the coronavirus disease 2019 (COVID-19) pandemic. The interaction of viral Spike proteins with their host receptor angiotensin-converting enzyme 2 (ACE2) is a critical determinant of potential hosts and cross-species transmission. Here we use virus-host receptor binding and infection assays to show that ACE2 orthologs from 24, 21, and 16 of 46 phylogenetically diverse bat species – including those in close and distant contact with humans – do not support entry of SARS-CoV, SARS-CoV-2, and both of these coronaviruses, respectively. Furthermore, we used genetic and functional analyses to identify genetic changes in bat ACE2 receptors associated with viral entry restrictions. Our study demonstrates that many – if not most – bat species are not potential hosts of SARS-CoV and SARS-CoV-2, and provides important insights into pandemic control and wildlife conservation.
Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology
Authors: Lazari Alberto , Lipp Ilona
Published: September 2020

Recent years have seen an increased understanding of the importance of myelination in healthy brain function and neuropsychiatric diseases. Non-invasive microstructural magnetic resonance imaging (MRI) holds the potential to expand and translate these insights to basic and clinical human research, but the sensitivity and specificity of different MR markers to myelination is a subject of debate.

To consolidate current knowledge on the topic, we perform a systematic review and meta-analysis of studies that validate microstructural imaging by combining it with myelin histology.

We find meta-analytic evidence for correlations between myelin histology and markers from different MRI modalities, including fractional anisotropy, radial diffusivity, macromolecular pool, magnetization transfer ratio, susceptibility and longitudinal relaxation rate, but not mean diffusivity. Meta-analytic correlation effect sizes range widely, betweenR2= 0.26 andR2= 0.82. However, formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias, thus preventing the establishment of a single most sensitive strategy to measure myelin with MRI.

To facilitate further progress, we provide a detailed characterisation of the evaluated studies as an online resource. We also share a set of 12 recommendations for future studies validating putative MR-based myelin markers and deploying themin vivoin humans.

Highlights

Systematic review and meta-analysis of studies validating microstructural imaging with myelin histology

We find many MR markers are sensitive to myelin, including FA, RD, MP, MTR, Susceptibility, R1, but not MD

Formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias

Results emphasize the advantage of using multimodal imaging when testing hypotheses related to myelin in vivo in humans.
Hepatoprotective Activity of Melittin on Isoniazid and Rifampicin Induced Liver Damage in Male Albino Rats
Authors: Naji Khalid M. , Al-Khatib Bushra Y. , Al-Haj Nora Saif , D’souza Myrene R.
Published: September 2020

Objective

The present study aimed to investigate the ameliorative effect of melittin, a major polypeptide in the venom of honeybee (Apis mellifera) on isoniazid (INH) and rifampicin (RIF) induced hepatotoxicity in male albino rats.Method: The rats (140-200g) were divided into five groups (n=6): normal control (NC); toxic (T) group treated with INH+RIF (100 mg/kg, p.o.); melittin-treated (Mel15, Mel30) group (15 or 30 µg/kg s.c); and normal recovery (NR) group. Blood and liver samples were collected for biochemical, hematological and histopathological studies respectively.

Results

The administration of melittin was found to prevent the antitubercular drug-induced alterations in the diagnostic markers; reduced glutathione (GSH), direct bilirubin (DB), total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and total serum protein (TSP). Besides, hematological alterations were significantly high (P<0.0001) in Mel-treated groups when compared to the toxic control. The NR group exhibited lower levels of DB, TB, ALP, LDH and TSP. In addition, treatment with melittin offered protection in the NR group with respect to MDA levels.

Conclusion

Evidence from this study indicate that melittin is beneficial for the prevention of acute hepatic failure in antitubercular drug-induced hepatoxicity.
The Arf-GEF Steppke promotes F-actin accumulation, cell protrusions and tissue sealing during Drosophila dorsal closure
Authors: West Junior J. , Harris Tony J. C.
Published: September 2020

Cytohesin Arf-GEFs promote actin polymerization and protrusions of cultured cells, whereas the Drosophila cytohesin, Steppke, antagonizes actomyosin networks in several developmental contexts. To reconcile these findings, we analyzed epidermal leading edge actin networks during Drosophila embryo dorsal closure. Here, Steppke is required for F-actin of the actomyosin cable and for actin-based protrusions.steppkemutant defects in the leading edge actin networks are associated with improper sealing of the dorsal midline, but are distinguishable from effects of myosin mis-regulation. Steppke localizes to leading edge cell-cell junctions with accumulations of the F-actin regulator Enabled emanating from either side. Enabled requires Steppke for full leading edge recruitment, and genetic interaction shows the proteins cooperate for dorsal closure. Steppke over-expression induces ectopic, actin-rich, lamellar cell protrusions, an effect dependent on the Arf-GEF activity and PH domain of Steppke, but independent of Steppke recruitment to myosin-rich AJs via its coiled-coil domain. Thus, Steppke promotes actin polymerization and cell protrusions, effects that occur in conjunction with Steppke’s previously reported regulation of myosin contractility during dorsal closure.
AnnapuRNA: a scoring function for predicting RNA-small molecule interactions
Authors: Stefaniak Filip , Bujnicki Janusz M.
Published: September 2020

RNA is considered as an attractive target for new small molecule drugs. Designing active compounds can be facilitated by computational modeling. Most of the available tools developed for these prediction purposes, such as molecular docking or scoring functions, are parametrized for protein targets. The performance of these methods, when applied to RNA-ligand systems, is insufficient. To overcome these problems, we developed AnnapuRNA, a new knowledge-based scoring function designed to evaluate RNA-ligand complex structures, generated by any computational docking method. We also evaluated three main factors that may influence the structure prediction, i.e., starting conformer of a ligand, the docking program, and the scoring function used. We applied the AnnapuRNA method for apost-hocstudy of the recently published structures of the FMN riboswitch. Software is available athttps://github.com/filipspl/AnnapuRNA

Author Summary

Drug development is a lengthy and complicated process, which requires costly experiments on a very large number of chemical compounds. The identification of chemical molecules with desired properties can be facilitated by computational methods. A number of methods were developed for computer-aided design of drugs that target protein molecules. However, recently the ribonucleic acid (RNA) emerged as an attractive target for the development of new drugs. Unfortunately, the portfolio of the computer methods that can be applied to study RNA and its interactions with small chemical molecules is very limited. This situation motivated us to develop a new computational method, with which to predict RNA-small molecule interactions. To this end, we collected the information on the statistics of interactions in experimentally determined structures of complexes formed by RNA with small molecules. We then used the statistical data to train machine learning methods aiming to distinguish between RNA-ligand interactions observed experimentally and other interactions that can be observed in theoretical analyses, but are not observed in nature. The resulting method called AnnapuRNA is superior to other similar tools and can be used to predict preferred ligands of RNA molecules and how RNA and small molecules interact with each other.
What determines the FDC polarization and GC size in affinity maturation
Authors: Yan Zishuo , Qi Hai , Lan Yueheng
Published: September 2020

Germinal center (GC) is a particular biological structure produced for affinity maturation in the lymphoid follicle during the T-dependent immune response and is an important component of the humoral immune system. However, the impact of morphological features of the GC on antibody production is not clear. According to the latest biological experiments, we establish a spatiotemporal stochastic model to simulate the whole self-organization process of the GC including the appearance of two specific zones: the dark zone(DZ) and the light zone (LZ). We find that the development of light and dark zones in GC serves to maintain an effective competition among different cells and promote affinity maturation. On the other hand, by varying the GC size, a phase transition is discovered, which determines a critical GC volume for best performance in both the stochastic and the deterministic model. This critical volume is determined by the distance between the activated B Cell Receptor(BCR) and the target epitope of the antigen. The conclusion is confirmed in both the 2D and the 3D simulations and explains partly the variability in the GC size.

Author summary

Germinal center (GC) is an important component of the humoral immune system, which supports antibody affinity maturation and the generation of immunity memory. However, the impact of special morphological features of the GC on antibody production is not clear. According to the latest biological experiments, we establish a spatiotemporal stochastic model to simulate the whole self-organization process of the GC. We use the mixing index of different B cells to quantitatively describe the polarization in GC. With the increase of the mixing index, the affinity of plasma cells decreases gradually, even GC might collapse. Therefore, the development of light and dark zones in GC serves to maintain effective competition among different cells and promote affinity maturation. On the other hand, by varying the GC volume, a phase transition is discovered, which determines a critical GC volume for best performance in both the stochastic and the deterministic model. This critical volume is determined by the distance between the activated B Cell Receptor (BCR) and the target epitope of antigen. The conclusion is confirmed in both the 2D and the 3D simulations and explains partly the variability in the GC size.
Aberrant regulation of RNA splicing in sunflower hybrids may underlie intrinsic incompatibilities
Authors: Smith Chris C R , Rieseberg Loren H , Hulke Brent S , Kane Nolan C
Published: September 2020

Alternative spicing is an integral part of gene expression in multicellular organisms that allows for diverse mRNA transcripts and proteins to be produced from a single gene. However, most existing analyses have focused on macro-evolution, with only limited research on splice site evolution over shorter term, micro-evolutionary time scales. Here we examine splicing evolution that has occurred during domestication and observe 45 novel splice forms with strongly transgressive isoform compositions, representing 0.24% of analyzed transcripts. We identify loci associated with variation in the levels of these splice forms, finding that many novel transcripts were regulated by multiple alleles with non-additive interactions. A subset of these interactions involved the expression of individual spliceosome components. These overdominant and epistatic interactions often resulted in alteration in the protein-coding regions of the transcripts, resulting in frameshifts and truncations. By associating the splice variation in these genes with size and growth rate measurements, we found that none of the individual splice variants affected these plant traits significantly, but the cumulative expression of all aberrant transcripts did show a significant reduction in growth rate associated with higher proportions of disrupted transcripts. This demonstrates the importance of co-evolution of the different spliceosomal components and their regulators and suggests that these genes may contribute to evolution of reproductive isolation as Bateson-Dobzhansky-Muller incompatibility loci.

Author summary

In multicellular organisms, it is common that segments of pre-mRNA molecules are physically removed, and the remaining segments are spliced back together. Through splicing alternative combinations of segments together, organisms produce various mRNA molecules, and thus multiple proteins, using the information encoded in a single gene. Here, we investigated the RNA of two sunflower genotypes, one wild and one domesticated, as well as the hybrid offspring resulting from a cross between the two genotypes. We found certain mRNA molecules that were spliced exclusively in the hybrids and were absent in the examined parental lines. These unique hybrid mRNAs were predicted to be consequential for the hybrids’ health, and thus represented a malfunction in the mechanisms that regulate splicing. These results improve our understanding of the genetic regulation of alternative splicing and how alternative splice forms evolve. Our findings may lead to further inquiries about how aberrant splicing promotes the formation of new species in nature.
SWATH-MS co-expression profiles reveal paralogue interference in protein complex evolution
Authors: Stalder Luzia , Banaei-Esfahani Amir , Ciuffa Rodolfo , Payne Joshua L , Aebersold Ruedi
Published: September 2020

Understanding the conservation and evolution of protein complexes is of critical value to decode their function in physiological and pathological processes. One prominent proposal posits gene duplication as a potential mechanism for protein complex evolution. In this study we take advantage of large-scale proteome expression datasets to systematically investigate the role of paralogues, and specifically self-interacting paralogues, in shaping the evolutionary trajectories of protein complexes. First, we show that protein co-expression derived from quantitative proteomic matrices is a good indicator for complex membership and is conserved across species. Second, we suggest that paralogues are commonly strongly co-expressed and that for the subset of paralogues that show diverging co-expression patterns, the divergent co-expression patterns reflect both sequence and functional divergence. Finally, on this basis, we show that homomeric paralogues known to be part of protein complexes display a unique co-expression pattern distribution, with a subset of them being highly diverging. These findings support the idea that homomeric paralogues can avoid cross-interference by diversifying their expression patterns, and corroborates the role of this mechanism as a force shaping protein complex evolution and specialization.
CBP/p300orthologsCBP2andCBP3play distinct roles in planarian stem cell function
Authors: Stelman Clara R. , Smith Britessia M. , Chandra Bidushi , Roberts-Galbraith Rachel H.
Published: September 2020

Chromatin modifications function as critical regulators of gene expression and cellular identity, especially in the regulation and maintenance of the pluripotent state. However, many studies of chromatin modification in stem cells—and pluripotent stem cells in particular—are performed in mammalian stem cell culture, anin vitrocondition mimicking a very transient state during mammalian development. Thus, new models for study of pluripotent stem cellsin vivocould be helpful for understanding the roles of chromatin modification, for confirming priorin vitrostudies, and for exploring evolution of the pluripotent state. The freshwater flatworm,Schmidtea mediterranea, is an excellent model for studying adult pluripotent stem cells, particularly in the context of robust, whole-body regeneration. To identify chromatin modifying and remodeling enzymes critical for planarian regeneration and stem cell maintenance, we took a candidate approach and screened planarian homologs of 26 genes known to regulate chromatin biology in other organisms. Through our study, we identified six genes with novel functions in planarian homeostasis, regeneration, and behavior. We also identified in our list five planarian homologs of the mammalian CREB-Binding Protein (CBP) family of histone acetyltransferases, representing an expansion of this family in planarians. We find that two planarian CBP family members are required for planarian survival, with knockdown ofSmed-CBP2andSmed-CBP3causing distinct defects in stem cell maintenance or function. Loss of CBP2 causes a quick, dramatic loss of stem cells, while knockdown of CBP3 more narrowly affects stem cells, preferentially decreasing markers of neural progenitors. We propose that the division of labor among a diversified CBP family in planarians presents an opportunity to dissect specific functions of a broadly important histone acetyltransferase family in stem cell biology.
Learning compositional sequences with multiple time scales through a hierarchical network of spiking neurons
Authors: Maes Amadeus , Barahona Mauricio , Clopath Claudia
Published: September 2020

Sequential behaviour is often compositional and organised across multiple time scales: a set of individual elements developing on short time scales (motifs) are combined to form longer functional sequences (syntax). Such organisation leads to a natural hierarchy that can be used advantageously for learning, since the motifs and the syntax can be acquired independently. Despite mounting experimental evidence for hierarchical structures in neuroscience, models for temporal learning based on neuronal networks have mostly focused on serial methods. Here, we introduce a network model of spiking neurons with a hierarchical organisation aimed at sequence learning on multiple time scales. Using biophysically motivated neuron dynamics and local plasticity rules, the model can learn motifs and syntax independently. Furthermore, the model can relearn sequences efficiently and store multiple sequences. Compared to serial learning, the hierarchical model displays faster learning, more flexible relearning, increased capacity, and higher robustness to perturbations. The hierarchical model redistributes the variability: it achieves high motif fidelity at the cost of higher variability in the between-motif timings.
Highly enriched hiPSC-derived midbrain dopaminergic neurons robustly models Parkinson’s disease
Authors: Virdi Gurvir S , Choi Minee L , Yao Zhi , Evans James R , Athauda Dilan , Melandri Daniela , Sylantyev Sergiy , Abramov Andrey Y , Patani Rickie , Gandhi Sonia
Published: September 2020

The development of human induced pluripotent stem cells (hiPSC) has greatly aided our ability to model neurodegenerative diseases. However, generation of midbrain dopaminergic (mDA) neurons is a major challenge and protocols are variable. Here, we developed a method to differentiate hiPSCs into enriched populations (>80%) of mDA neurons using only small molecules. We confirmed the identity of the mDA neurons using single-cell RNA-sequencing and detection of classical markers. Single-cell live imaging demonstrated neuronal calcium signalling and functional dopamine transport. Electrophysiology measures highlighted the ability to form synapses and networks in culture. Patient-specific hiPSC lines differentiated to produce functional mDA neurons that exhibit the hallmarks of synucleinopathy including: aggregate formation, oxidative stress as well as mitochondrial dysfunction and impaired lysosomal dynamics. In summary, we establish a robust differentiation paradigm to generate enriched mDA neurons from hiPSCs, which can be used to faithfully model key aspects of Parkinson’s disease (PD), providing the potential to further elucidate molecular mechanisms contributing to disease development.
Ly6C defines a subset of memory-like CD27+γδ T cells with inducible cancer-killing function
Authors: Wiesheu Robert , Edwards Sarah C. , Hedley Ann , Kirschner Kristina , Tosolini Marie , Fournie Jean-Jacques , Kilbey Anna , Remak Sarah-Jane , Miller Crispin , Blyth Karen , Coffelt Seth B.
Published: September 2020

In mice, IFNγ-producing γδ T cells that express the co-stimulatory molecule, CD27, play a critical role in host defence and anti-tumour immunity. However, their phenotypic diversity, composition in peripheral and secondary lymphoid organs, similarity to αβ T cells as well as homology with human γδ T cells is poorly understood. Here, using single cell RNA sequencing, we show that CD27+γδ T cells consist of two major clusters, which are distinguished by expression of Ly6C. We demonstrate that CD27+Ly6C—γδ T cells exhibit a naïve T cell-like phenotype, whereas CD27+Ly6C+γδ T cells display a memory-like phenotype, produce several NK cell-related and cytotoxic molecules and are highly similar to both mouse CD8+T cells and mature human γδ T cells. In a breast cancer mouse model, depletion of CD27+γδ T cells failed to affect tumour growth, but these cells could be coerced into killing cancer cells after expansionex vivo. These results identify novel subsets of γδ T cells in mice that are comparable to human γδ T cells, opening new opportunities for γδ T cell-based cancer immunotherapy research.
Effects of prefrontal theta burst stimulation on neuronal activity and subsequent eating behavior: an interleaved rTMS and fNIRS study
Authors: Fatakdawala Idris , Ayaz Hasan , Safati Adrian , Sakib Mohammad Nazmus , Hall Peter A.
Published: September 2020

The dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC) are important nodes for self-control and decision-making, but through separable processes (cognitive control versus evaluative processing). This study aimed to examine the effects of excitatory brain stimulation (intermittent theta-burst stimulation; iTBS) targeting the dlPFC and dmPFC on food choice. iTBS was hypothesized to decrease consumption of appetitive snack foods, via enhanced interference control for dlPFC stimulation and reduced delay discounting for dmPFC stimulation. Using a single-blinded, between-subjects design, participants (N= 43) were randomly assigned to of the three conditions: 1) iTBS targeting the left dlPFC, 2) iTBS targeting bilateral dmPFC, or 3) sham. Participants then completed two cognitive tasks (delay discounting (DD) and Flanker), followed by a taste test. fNIRS imaging revealed increases in medial PFC activity were evident in the dmPFC stimulation group during the DD task; likewise, a neural efficiency effect was observed in the dlPFC stimulation group during the Flanker. Gender significantly moderated consumption during the taste test, with females in the dmPFC showing paradoxical increases in food consumption compared to sham. Findings are consistent with possible amplification of positive evaluative processing in the presence of dietary restraint, vis-à-vis excitation of the mPFC.