bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasticity and repeatability in spring migration and parturition dates with implications for annual reproductive success
Authors: Laforge Michel P. , Webber Quinn M. R. , Vander Wal Eric
Published: August 2021

Animals are faced with unprecedented challenges as environmental conditions change. Animals must display behavioral plasticity to acclimate to changing conditions, or phenotypic variation must exist within the population to allow for natural selection to change the distribution of trait values. The timing of migration and parturition relative to important annual environmental changes such as snowmelt and vegetation green-up and how they co-vary may influence reproductive success. We tested for plasticity and individual differences in migration and parturition timing as a function of the timing of snowmelt and green-up in a migratory herbivore (caribou;Rangifer tarandus,n= 92) using behavioral reaction norms. We tested whether timing of parturition, plasticity in parturition timing, or timing of green-up were correlated with calf survival. Migration and parturition timing were plastic to the timing of spring conditions, and we found moderate repeatability for migration timing, but no repeatability in timing of parturition. We detected a novel behavioral syndrome where timing of migration and timing of parturition were correlated. Our results suggest that observed shifts in caribou parturition timing in other populations are due to plasticity as opposed to an evolutionary response to changing conditions. We did not detect a correlation between annual reproductive success and either the timing of spring or plasticity to the timing of spring events. While this provides evidence that many populations may be buffered from the consequences of climate change via plasticity, we caution that a lack of repeatability in parturition timing could impede adaptation as climate warming increases.

Significance Statement

Animals have evolved to reproduce when resources are abundant. Climate change has altered the timing of annual events, resulting in earlier peaks in resource abundance. Animals can cope with this change in two ways. Individuals can display plasticity and alter the timing of reproductive activities to match the change in the environment, or consistent differences among individuals can result in sufficient variation to drive an evolutionary response. We tested these two alternative hypotheses in caribou (Rangifer tarandus) using an individual-based modelling framework. Caribou displayed plasticity in both when they migrated and gave birth, suggesting they can acclimate to changing conditions, but we did not find evidence of differences among individuals that would be likely to result in an evolutionary response.
Clinically-relevant T cell expansion protocols activate distinct cellular metabolic programs and phenotypes
Authors: MacPherson Sarah , Keyes Sarah , Kilgour Marisa , Smazynski Julian , Sudderth Jessica , Turcotte Tim , Devlieger Adria , Yu Jessie , Huggler Kimberly S. , Cantor Jason R. , DeBerardinis Ralph J. , Siatskas Christopher , Lum Julian J.
Published: August 2021

Ex vivo expansion conditions used to generate T cells for immunotherapy are thought to adopt metabolic phenotypes that impede therapeutic efficacy in vivo. The comparison of five different culture media used for clinical T cell expansion revealed unique optima based on different output variables including proliferation, differentiation, function, activation and mitochondrial phenotypes. T cells adapted their metabolism to match their media expansion condition as shown by glucose and glutamine uptake, and patterns of glucose isotope labeling. However, adoption of these metabolic phenotypes was uncoupled to T cell function. Furthermore, T cell products cultured in ascites from ovarian cancer patients displayed suppressed mitochondrial activity and function irrespective of the ex vivo expansion media. In one case, culturing in ascites resulted in increased glucose uptake which was insufficient to rescue T cell function. Thus, ex vivo T cell expansion conditions have profound impacts on metabolism and function.
Pairs and Pairix: a file format and a tool for efficient storage and retrieval for Hi-C read pairs
Authors: Lee Soohyun , Vitzthum Carl , Alver Burak H. , Park Peter J.
Published: August 2021

As the amount of three-dimensional chromosomal interaction data continues to increase, storing and accessing such data efficiently becomes paramount. We introduce Pairs, a block-compressed text file format for storing paired genomic coordinates from Hi-C data, and Pairix, an open-source C application to index and query Pairs files. Pairix (also available in Python and R) extends the functionalities of Tabix to paired coordinates data. We have also developed PairsQC, a collapsible HTML quality control report generator for Pairs files.

Availability

The format specification and source code are available at https://github.com/4dn-dcic/pairix, https://github.com/4dn-dcic/Rpairix and https://github.com/4dn-dcic/pairsqc.

Contact

peter_park@hms.harvard.edu or burak_alver@hms.harvard.edu
A Scale-Free Gradient of Cognitive Resource Disruptions in Childhood Psychopathology
Authors: Stier Andrew J. , Cardenas-Iniguez Carlos , Kardan Omid , Moore Tyler M. , Meyer Francisco A. C. , Rosenberg Monica D. , Kaczkurkin Antonia N. , Lahey Benjamin B. , Berman Marc G.
Published: August 2021

The Hurst exponent (H) isolated in fractal analyses of neuroimaging time-series is implicated broadly in cognition. The connection between H and the mathematics of criticality makes it a candidate measure of individual differences in cognitive resource allocation. Relationships between H and multiple mental disorders have been detected, suggesting that H is transdiagnostically associated with psychopathology. Here, we demonstrate a gradient of decreased H with increased general psychopathology and attention-deficit/hyperactivity extracted factor scores during a working memory task which predicts concurrent and future working memory performance in 1,839 children. This gradient defines psychological and functional axes which indicate that psychopathology is associated with an imbalance in resource allocation between fronto-parietal and sensory-motor regions, driven by reduced resource allocation to fonto-parietal regions. This suggests the hypothesis that impaired cognitive function associated with psychopathology follows from a reduced cognitive resource pool and a reduction in resources allocated to the task at hand.
Biochemically distinct cohesin complexes mediate positioned loops between CTCF sites and dynamic loops within chromatin domains
Authors: Liu Yu , Dekker Job
Published: August 2021

The ring-like cohesin complex mediates sister chromatid cohesion by encircling pairs of sister chromatids. Cohesin also extrudes loops along chromatids. Whether the two activities involve similar mechanisms of DNA engagement is not known. We implemented an experimental approach based on isolated nuclei carrying engineered cleavable RAD21 proteins to precisely control cohesin ring integrity so that its role in chromatin looping could be studied under defined experimental conditions. This approach allowed us to identify cohesin complexes with distinct biochemical, and possibly structural properties, that mediate different sets of chromatin loops. When RAD21 is cleaved and the cohesin ring is opened, cohesin complexes at CTCF sites are released from DNA and loops at these elements are lost. In contrast, cohesin-dependent loops within chromatin domains and that are not anchored at CTCF sites are more resistant to RAD21 cleavage. The results show that the cohesin complex mediates loops in different ways depending on genomic context and suggests that it undergoes structural changes as it dynamically extrudes and encounters CTCF sites.
Distinct Multivariate Structural Brain Profiles Are Related to Variations in Short- and Long-Delay Memory Consolidation Across Children and Young Adults
Authors: Schommartz Iryna , Lembcke Philip F. , Pupillo Francesco , Schuetz Henriette , de Chamorro Nina Wald , Bauer Martin , Kaindl Angela M. , Buss Claudia , Shing Yee Lee
Published: August 2021

From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to the memory consolidation processes. The present study examined system-level memory consolidations of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory consolidation were related to structural brain measures. Our results showed that children, in comparison to young adults, consolidate correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal subfield structures was found to be associated with variation in short-delay memory consolidation. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory consolidation. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.

RESEARCH HIGHLIGHTS

Short- and long-delay memory consolidation is less robust in children than in young adults

Short-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regions

Long-delay brain profile comprised of neocortical and selected hippocampal brain regions.

Brain profiles differ between children and young adults.
Utilizing Pine Needles to Temporally and Spatially Profile Per- and Polyfluoroalkyl Substances
Authors: Kirkwood Kaylie I. , Fleming Jonathon , Nguyen Helen , Reif David M. , Baker Erin S. , Belcher Scott M.
Published: August 2021

As concerns continue to mount over exposure to per- and polyfluoroalkyl substances (PFAS), novel methods of profiling their presence and modifications are greatly needed as some have known toxic and bioaccumulative characteristics while others have unknown effects. This task however is not simple as over 5000 PFAS of interest have been named by the Environmental Protection Agency and this list continues to grow daily. In this work, we utilized widely available archived and field-sampled pine needles and a novel non-targeted analytical method to evaluate the temporal and spatial presence of numerous PFAS. Over 70 PFAS were detected in the pine needles from this study, providing information from the last six decades related to PFAS exposure, contamination, and reduction.
Effective Ensemble of Deep Neural Networks Predicts Neural Responses to Naturalistic Videos
Authors: Yang Huzheng , Zhang Shanghang , Wu Yifan , Li Yuanning , Gu Shi
Published: August 2021

This report provides a review of our submissions to the Algonauts Challenge 2021. In this challenge, neural responses in the visual cortex were recorded using functional neuroimaging when participants were watching naturalistic videos. The goal of the challenge is to develop voxel-wise encoding models which predict such neural signals based on the input videos. Here we built an ensemble of models that extract representations based on the input videos from 4 perspectives: image streams, motion, edges, and audio. We showed that adding new modules into the ensemble consistently improved our prediction performance. Our methods achieved state-of-the-art performance on both the mini track and the full track tasks.
Waning of BNT162b2 vaccine protection against SARS-CoV-2 infection in Qatar
Authors: Chemaitelly Hiam , Tang Patrick , Hasan Mohammad R. , AlMukdad Sawsan , Yassine Hadi M. , Benslimane Fatiha M. , Al Khatib Hebah A. , Coyle Peter , Ayoub Houssein H. , Kanaani Zaina Al , Kuwari Einas Al , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul Rahim Hanan F. , Nasrallah Gheyath K. , Al Kuwari Mohamed Ghaith , Al Romaihi Hamad Eid , Butt Adeel A. , Al-Thani Mohamed H. , Khal Abdullatif Al , Bertollini Roberto , Abu-Raddad Laith J.
Published: August 2021

BACKGROUND

Waning of vaccine protection against SARS-CoV-2 infection or COVID-19 disease is a concern. This study investigated persistence of BNT162b2 (Pfizer-BioNTech) vaccine effectiveness against infection and disease in Qatar, where the Beta and Delta variants have dominated incidence and PCR testing is done at a mass scale.

METHODS

A matched test-negative, case-control study design was used to estimate vaccine effectiveness against SARS-CoV-2 infection and against any severe, critical, or fatal COVID-19 disease, between January 1, 2021 to August 15, 2021.

RESULTS

Estimated BNT162b2 effectiveness against any infection, asymptomatic or symptomatic, was negligible for the first two weeks after the first dose, increased to 36.5% (95% CI: 33.1-39.8) in the third week after the first dose, and reached its peak at 72.1% (95% CI: 70.9-73.2) in the first five weeks after the second dose. Effectiveness declined gradually thereafter, with the decline accelerating ≥15 weeks after the second dose, reaching diminished levels of protection by the 20thweek. Effectiveness against symptomatic infection was higher than against asymptomatic infection, but still waned in the same fashion. Effectiveness against any severe, critical, or fatal disease increased rapidly to 67.7% (95% CI: 59.1-74.7) by the third week after the first dose, and reached 95.4% (95% CI: 93.4-96.9) in the first five weeks after the second dose, where it persisted at about this level for six months.

CONCLUSIONS

BNT162b2-induced protection against infection appears to wane rapidly after its peak right after the second dose, but it persists at a robust level against hospitalization and death for at least six months following the second dose.
Using telehealth consultations for healthcare provision to patients from racial/ethnic minorities: A systematic review
Authors: Truong Mandy , Yeganeh Ladan , Cook Olivia , Crawford Kimberley , Wong Pauline , Allen Jacqueline
Published: August 2021

Objective

The COVID-19 pandemic has seen a rapid adoption of telehealth consultations, potentially creating new barriers to healthcare access for racial/ethnic minorities. This systematic review explored the use of telehealth consultations for people from racial/ethnic minority populations in relation to health outcomes, access to care, implementation facilitators and barriers, and satisfaction with care.

Materials and Methods

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis and the JBI Manual for Evidence Synthesis. Five major databases were searched to identify relevant studies. Screening, full-text review, quality appraisal and data extraction were all completed independently and in duplicate. A convergent integrated approach to data synthesis was applied with findings reported narratively.

Results

A total of 28 studies met the inclusion criteria. Telehealth-delivered interventions were mostly effective for the treatment/management of physical and mental health conditions including depression, diabetes and hypertension. In several studies, telehealth improved access to care by providing financial and time benefits to patients. Technological difficulties were the main barriers to effective telehealth consultation, although overall satisfaction with telehealth-delivered care was high.

Discussion

Telehealth-delivered care for racial/ethnic minorities offers promise across a range of conditions and outcomes, particularly when delivered in the patient’s preferred language. However, telehealth may be problematic for some due to cost and limited digital and health literacy.

Conclusion

The development and implementation of guidelines, policies and practices in relation to telehealth consultations for racial/ethnic minorities should consider the barriers and facilitators identified in this review to ensure existing health disparities are not exacerbated.
Facility-based HIV self-testing strategies may substantially increase number of men and youth tested for HIV in Malawi: results from a data-driven individual-based model
Authors: Nichols Brooke E , de Nooy Alexandra , Benade Mariet , Balakasi Kelvin , Mphande Misheck , Rao Gabriella , Claassen Cassidy W , Khan Shaukat , Stillson Christian , Doi Naoko , Dovel Kathryn
Published: August 2021

Background

Malawi is rapidly closing the gap in achieving the UNAIDS 95-95-95 targets, with 90% of people living with HIV in Malawi aware of their status. As we approach epidemic control, interventions to improve coverage will become more costly. There is therefore an urgent need to identify innovative and low-cost strategies to maintain and increase testing coverage without diverting resources from other HIV services.

Methods

A data-driven individual-based model was parameterized with data from a community-representative survey (sociodemographic, health service utilization, HIV testing history) of men and youth in Malawi (data collected 08/2019). 79 different strategies for the implementation of HIV self-testing (HIVST) and provider-initiated-testing-and-counselling at the outpatient department (OPD) were evaluated. Outcomes included percent of men/youth tested for HIV in a 12-month period, cost-effectiveness, and human resource requirements. Testing yield was assumed to be constant across the scenarios.

Findings

Facility-based HIVST offered year-round resulted in the greatest increase in proportion of men and youth tested in the OPD (from 45% to 72%-83%), was considered cost-saving for HIVST kit priced at $1.00, and generally reduced required personnel as compared to the status quo. At higher HIVST kit prices, and more relaxed eligibility criteria, all scenarios that considered year-round HIVST in the OPD remained on the cost-effectiveness frontier.

Interpretation

Facility-based HIVST is a cost-effective strategy to increase the proportion of men/youth tested for HIV and decreases the human resource requirements for HIV testing in the OPD-providing additional health care worker time for other priority health care activities.

Funding

FCDO; USAID
Differentials and predictors of hospitalization among the elderly people in India: Evidence from 75thround of National Sample Survey (2017-18)
Authors: Akhtar Saddaf Naaz , Saikia Nandita
Published: August 2021

Introduction

There are limited evidences on the determinants of hospitalization and its causes in India. We examined the differential in the hospitalization rates and its socio-economic determinants. We also examined the causes of diseases in hospitalization among the elderly (≥60 years) in India.

Methods

We used data from 75thround of the National Sample Survey Organizations (NSSO), collected from July 2017 to June 2018. The elderly samples in this survey are 42759, where 11070 were hospitalized, and 31,689 were not hospitalized in the last year or 365 days. We estimated hospitalization rates and carried out binary logistic regression analysis to examine the associations of hospitalization with the background variables. The cause of diseases in hospitalizations were also calculated.

Results

Hospitalization rate was lower among female elderly compared to male elderly. Elderly who belongs to middle-old aged groups, non-married, North-Eastern region, Southern region, general caste, health insurance, partially & fully economically dependent elderly have a higher chance of being hospitalized. About 38% elderly were hospitalized due to communicable diseases (CDs), 52% due to non-communicable diseases (NCDs) and 10% due to Injuries & others. Nearly 40% elderly were hospitalized in public hospitals due to CDs, while 52% were hospitalized in private hospitals due to NCDs and 11% due to Injuries & others.

Conclusions

Raising awareness, promoting a healthy lifestyle, and improving the quality of good healthcare provisions at the primary level is necessary. Early screening and early treatment for NCDs are needed, which is non-existent in almost all parts of India.
Transient DUX4 expression induces blastomere-like expression program that is marked by SLC34A2
Authors: Yoshihara Masahito , Kirjanov Ida , Nykänen Sonja , Sokka Joonas , Weltner Jere , Lundin Karolina , Gawriyski Lisa , Jouhilahti Eeva-Mari , Varjosalo Markku , Tervaniemi Mari H. , Otonkoski Timo , Trokovic Ras , Katayama Shintaro , Vuoristo Sanna , Kere Juha
Published: August 2021

DUX4 has recently been recognized as a key regulator in human embryonic genome activation (EGA). The exact role of DUX4 in human embryo is still elusive, partly due to the cytotoxicity of persistent DUX4 expression in cellular models. We report here that a transient DUX4 expression in human embryonic stem cells (hESCs) retains cell viability while inducing an EGA-like expression program in a subpopulation of the cells. These cells showed resemblance to 8-cell stage blastomeres and were thus named induced blastomere-like (iBM) cells. Trajectory inference from the single-cell RNA-seq data suggested that the expression profile of these cells progressed in a manner similar to the morula to blastocyst transition in human embryo. Finally, viable iBM cells could be enriched using an antibody against NaPi2b (SLC34A2), paving the way for further experimental approaches. The iBM cells can become a powerful tool to model transcriptional dynamics and regulation during early human embryogenesis.
Diterpenoid Vinigrol activates ATF4/DDIT3-mediated PERK/eIF2α arm of unfolded protein response to drive breast cancer cell death
Authors: Wei Wencheng , Li Yunfei , Wang Chuanxi , Gao Sanxing , Wang Hao , Zhao Yan , Gao Ziying , Jiang Yanxiang , Gao Hao , Yao Xinsheng , Hu Yuhui
Published: August 2021

Vinigrol is a natural diterpenoid with unprecedented chemical structure, driving great efforts into its total synthesis and the chemical analogs in the past decades. Despite its pharmacological efficacies reported on anti-hypertension and anti-clot, comprehensive functional investigations on Vinigrol and the underlying molecular mechanisms are entirely missing. In this study, we carried out a complete functional prediction of Vinigrol using a transcriptome-based strategy, Connectivity Map, and identified “anti-cancer” as the most prominent biofunction ahead of anti-hypertension and anti-depression/psychosis. A broad cytotoxicity was subsequently confirmed on multiple cancer types. Further mechanistic investigation on MCF7 cells revealed that its anti-cancer effect is mainly through activating PERK/eIF2α arm of unfolded protein response (UPR) and subsequent upregulation of p53/p21 to halt the cell cycle. The other two branches of UPR, IRE1α and ATF6, are functionally irrelevant to Vinigrol-induced cell death. CRISPR/Cas9-based gene activation, repression, and knockout systems identified essential contribution of ATF4/DDIT3 not ATF6 to the death process. This study unraveled a broad anti-cancer function of Vinigrol and its underlying targets and regulatory mechanisms, and also paved the way for further inspection on the structure-efficacy relationship of the whole compound family, making them a novel cluster of chemical hits for cancer therapy.
Does genetic differentiation underlie behavioral divergence in response to migration barriers in sticklebacks? A common garden experiment
Authors: Ramesh A. , Domingues M. M. , Stamhuis E.J. , Groothuis A.G.G. , Weissing F.J. , Nicolaus M.
Published: August 2021

Water management measures in the 1970s in the Netherlands have produced a large number of ‘resident’ populations of three-spined sticklebacks that are no longer able to migrate to the sea. This may be viewed as a replicated field experiment, allowing us to study how the resident populations are coping with human-induced barriers to migration. We have previously shown that residents are smaller, bolder, more exploratory, more active, more aggressive, exhibited lower shoaling and lower migratory tendencies compared to their ancestral ‘migrant’ counterparts. However, it is not clear if these differences in wild-caught residents and migrants reflect genetic differentiation, rather than different developmental conditions. To investigate this, we raised offspring of four crosses (migrant ♂ x migrant ♀, resident ♂ x resident ♀, migrant ♂ x resident ♀, resident ♂ x migrant ♀) under similar controlled conditions and tested for differences in morphology and behavior as adults. We found that lab-raised resident sticklebacks exhibited lower shoaling and migratory tendencies as compared to lab-raised migrants, retaining the differences in their wild-caught parents. This indicates genetic differentiation of these traits. For all other traits, the lab-raised sticklebacks of the various crosses did not differ significantly, suggesting that the earlier-found contrast between wild-caught fish reflect differences in their environment. Our study shows that barriers to migration can lead to rapid differentiation in behavioral tendencies over contemporary timescales (∼50 generations), and that part of these differences reflects genetic differentiation.

Significance statement

Many organisms face changes to their habitats due to human activities. Much research is therefore dedicated to the question whether and how organisms are able to adapt to novel conditions. We address this question in three-spined sticklebacks, where water management measures cut off some populations, prohibiting their seasonal migration to the North Sea. In a previous study, we showed that wild-caught ‘resident’ fish exhibited markedly different behavior than migrants. To disentangle whether these differences reflect genetic differentiation or differences in the conditions under which the wild-caught fish grew up, we conducted crosses, raising the F1 offspring under identical conditions. As their wild-caught parents, the F1 of resident x resident crosses exhibited lower migratory and shoaling tendencies than the F1 of migrant x migrant crosses, while the F1 of hybrid crosses were intermediate. This suggests that ∼50 years of isolation are sufficient to induce behaviorally relevant genetic differentiation.
Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations
Authors: Snellings Daniel A. , Girard Romuald , Lightle Rhonda , Srinath Abhinav , Romanos Sharbel , Li Ying , Chen Chang , Ren Aileen A. , Kahn Mark L. , Awad Issam A. , Marchuk Douglas A.
Published: August 2021

Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically in otherwise healthy individuals, or be inherited by autosomal dominant mutations in the genes that encode the proteins of the CCM signaling complex (KRIT1, CCM2, or PDCD10)1–4. CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene5–8. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis9–11; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM. Using single-nucleus DNA sequencing, we show that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. Furthermore, we identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). It has long been known that sporadic CCM often develop in the vicinity of a DVA. However, the underlying cause of this association is unknown12–14. In this first report of the molecular pathology of CCM-associated DVA, we find that the identical PIKC3A mutation is found in both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.
A hierarchical GBP network promotes cytosolic LPS recognition and sepsis
Authors: Park Eui-Soon , Kim Bae-Hoon , Kumar Pradeep , Tretina Kyle , Maminska Agnieszka , Philbrick William M. , Flavell Richard A. , MacMicking John D.
Published: August 2021

Bacterial lipopolysaccharide (LPS) is one of the most bioactive substances known. Trace amounts trigger robust immunity to infection but also life-threatening sepsis causing millions of deaths each year. LPS contamination of the cytosol elicits a caspase-dependent inflammasome pathway promoting cytokine release and host cell death. Here, we report an immune GTPase network controls multiple steps in this pathway by genome-engineering mice to lack 7 different guanylate-binding proteins (GBPs). Gbp2-/- and Gbp3-/- mice had severe caspase-11-driven defects that protected them from septic shock. Gbp2 recruited caspase-11 for LPS recognition whereas Gbp3 assembled and trafficked the pyroptotic pore-forming protein, gasdermin D, after caspase-11 cleavage. Together, our results identify a new functional hierarchy wherein different GBPs choreograph sequential steps in the non-canonical inflammasome pathway to control Gram-negative sepsis.

One-Sentence Summary

Immune GTPase network orchestrates hierarchical immunity to bacterial products in vivo
Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains
Authors: Ying Baoling , Whitener Bradley , VanBlargan Laura A. , Hassan Ahmed O. , Shrihari Swathi , Liang Chieh-Yu , Karl Courtney E. , Mackin Samantha , Chen Rita E. , Kafai Natasha M. , Wilks Samuel H. , Smith Derek J. , Carreño Juan Manuel , Singh Gagandeep , Krammer Florian , Carfi Andrea , Elbashir Sayda , Edwards Darin K. , Thackray Larissa B. , Diamond Michael S.
Published: August 2021

Although mRNA vaccines prevent COVID-19, variants jeopardize their efficacy as immunity wanes. Here, we assessed the immunogenicity and protective activity of historical (mRNA-1273, designed for Wuhan-1 spike) or modified (mRNA-1273.351, designed for B.1.351 spike) preclinical Moderna mRNA vaccines in 129S2 and K18-hACE2 mice. Immunization with high or low dose formulations of mRNA vaccines induced neutralizing antibodies in serum against ancestral SARS-CoV-2 and several variants, although levels were lower particularly against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. Nonetheless, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, and serve as a possible model for waning immunity, showed breakthrough lung infection and pneumonia with B.1.617.2. Thus, as levels of immunity induced by mRNA vaccines decline, breakthrough infection and disease likely will occur with some SARS-CoV-2 variants, suggesting a need for additional booster regimens.
Robust, Universal Tree Balance Indices
Authors: Lemant Jeanne , Sueur Cécile Le , Manojlović Veselin , Noble Robert
Published: August 2021

Balance indices that quantify the symmetry of branching events and the compactness of trees are widely used to compare evolutionary processes or tree-generating algorithms. Yet existing indices have important shortcomings, including that they are unsuited to the tree types commonly used to describe the evolution of tumours, microbial populations, and cell lines. The contributions of this article are twofold. First, we define a new class of robust, universal tree balance indices. These indices take a form similar to Colless’ index but account for node sizes, are defined for trees with any degree distribution, and enable more meaningful comparison of trees with different numbers of leaves. Second, we show that for bifurcating and all other full m-ary cladograms (in which every internal node has the same out-degree), one such Colless-like index is equivalent to the normalised reciprocal of Sackin’s index. Hence we both unify and generalise the two most popular existing tree balance indices. Our indices are intrinsically normalised and can be computed in linear time. We conclude that these more widely applicable indices have potential to supersede those in current use.
Structural Analysis of Receptor Binding Domain Mutations in SARS-CoV-2 Variants of Concern that Modulate ACE2 and Antibody Binding
Authors: Mannar Dhiraj , Saville James W , Zhu Xing , Srivastava Shanti S. , Berezuk Alison M. , Zhou Steven , Tuttle Katharine S. , Kim Andrew , Li Wei , Dimitrov Dimiter S. , Subramaniam Sriram
Published: August 2021

The recently emerged SARS-CoV-2 South African (B. 1.351) and Brazil/Japan (P.1) variants of concern (VoCs) include a key mutation (N501Y) found in the UK variant that enhances affinity of the spike protein for its receptor, ACE2. Additional mutations are found in these variants at residues 417 and 484 that appear to promote antibody evasion. In contrast, the Californian VoCs (B.1.427/429) lack the N501Y mutation, yet exhibit antibody evasion. We engineered spike proteins to express these RBD VoC mutations either in isolation, or in different combinations, and analyzed the effects using biochemical assays and cryo-EM structural analyses. Overall, our findings suggest that the emergence of new SARS-CoV-2 variant spikes can be rationalized as the result of mutations that confer either increased ACE2 affinity, increased antibody evasion, or both, providing a framework to dissect the molecular factors that drive VoC evolution.
The impact of genetic modifiers on variation in germline mutation rates within and among human populations
Authors: Milligan William R. , Amster Guy , Sella Guy
Published: August 2021

Mutation rates and spectra differ among human populations. Here, we examine whether this variation could be explained by evolution at mutation modifiers. To this end, we consider genetic modifier sites at which mutations, “mutator alleles”, increase genome-wide mutation rates and model their evolution under purifying selection due to the additional deleterious mutations that they cause, genetic drift, and demographic processes. We solve the model analytically for a constant population size and characterize how evolution at modifier sites impacts variation in mutation rates within and among populations. We then use simulations to study the effects of modifier sites under a plausible demographic model for Africans and Europeans. When comparing populations that evolve independently, weakly selected modifier sites (2Nes ≈ 1), which evolve slowly, contribute the most to variation in mutation rates. In contrast, when populations recently split from a common ancestral population, strongly selected modifier sites (2Nes ≫ 1), which evolve rapidly, contribute the most to variation between them. Moreover, a modest number of modifier sites (e.g., 10 per mutation type in the standard classification into 96 types) subject to moderate to strong selection (2Nes > 1) could account for the variation in mutation rates observed among human populations. If such modifier sites indeed underlie differences among populations, they should also cause variation in mutation rates within populations and their effects should be detectable in pedigree studies.
Evolutionarily conserved genetic interactions between nphp-4 and bbs-5 mutations exacerbate ciliopathy phenotypes
Authors: Bentley-Ford Melissa R. , LaBonty Melissa , Thomas Holly R. , Haycraft Courtney J. , Scott Mikyla , LaFayette Cameron , Croyle Mandy J. , Parant John M. , Yoder Bradley K.
Published: August 2021

Primary cilia are sensory and signaling hubs with a protein composition that is distinct from the rest of the cell due to the barrier function of the transition zone (TZ) at the base of the cilium. Protein transport across the TZ is mediated in part by the BBSome, and mutations disrupting TZ and BBSome proteins cause human ciliopathy syndromes. Ciliopathies have phenotypic variability even among patients with identical genetic variants, suggesting a role for modifier loci. To identify potential ciliopathy modifiers, we performed a mutagenesis screen on nphp-4 mutant C. elegans and uncovered a novel allele of bbs-5. Nphp-4;bbs-5 double mutant worms have phenotypes not observed in either individual mutant strain. To test whether this genetic interaction is conserved, we also analyzed zebrafish and mice mutants. While Nphp4 mutant zebrafish appeared overtly normal, Bbs5 mutants exhibited scoliosis. When combined, Nphp4;Bbs5 double mutant zebrafish did not exhibit synergistic effects, but the lack of a phenotype in Nphp4 mutants makes interpreting these data difficult. In contrast, viable Nphp4;Bbs5 double mutant mice were not obtained and there were fewer mice than expected carrying three mutant alleles. Additionally, postnatal loss of Bbs5 in mice using a conditional allele compromised survival when combined with a Nphp4 allele. As cilia are formed in the double mutant mice, the exacerbated phenotype is likely a consequence of disrupted ciliary signaling. Collectively, these data support an evolutionarily conserved genetic interaction between Bbs5 and Nphp4 alleles that may contribute to the variability in ciliopathy phenotypes.
A quantitative mapping approach to identify direct interactions within complexomes
Authors: Trepte Philipp , Secker Christopher , Choi Soon Gang , Olivet Julien , Ramos Eduardo Silva , Cassonnet Patricia , Golusik Sabrina , Zenkner Martina , Beetz Stephanie , Sperling Marcel , Wang Yang , Hao Tong , Spirohn Kerstin , Twizere Jean-Claude , Calderwood Michael A. , Hill David E. , Jacob Yves , Vidal Marc , Wanker Erich E.
Published: August 2021

Complementary methods are required to fully characterize all protein complexes, or the complexome, of a cell. Affinity purification coupled to mass-spectrometry (AP-MS) can identify the composition of complexes at proteome-scale. However, information on direct contacts between subunits is often lacking. In contrast, solving the 3D structure of protein complexes can provide this information, but structural biology techniques are not yet scalable for systematic, proteome-wide efforts. Here, we optimally combine two orthogonal high-throughput binary interaction assays, LuTHy and N2H, and demonstrate that their quantitative readouts can be used to differentiate direct interactions from indirect associations within multiprotein complexes. We also show that LuTHy allows accurate distance measurements between proteins in live cells and apply these findings to study the impact of the polyglutamine expansion mutation on the structurally unresolved N-terminal domain of Huntingtin. Thus, we present a new framework based on quantitative interaction assays to complement structural biology and AP-MS techniques, which should help to provide first-approximation contact maps of multiprotein complexes at proteome-scale.

Graphical Abstract
MicroRNA-27a-5p inhibits proliferation, migration and invasion and promotes apoptosis of Wilms tumor cell by targeting PBOV1
Authors: Guo Zheng-Tuan , Yu Qiang , Miao Chunlin , Ge Wenan , Li Peng
Published: August 2021

Wilms tumor is the most common type of renal tumor in children. MicroRNAs (miRNA) are small non-coding RNAs that play crucial regulatory roles in tumorigenesis. We aimed to study the expression profile and function of miR-27a-5p in Wilms tumor. MiR-27a-5p expression was downregulated in human Wilms tumor tissues. Functionally, overexpression of miR-27a-5p promoted cell apoptosis of Wilms tumor cells. Furthermore, upregulated miR-27a-5p delayed xenograft Wilms tumor tumorigenesis in vivo. Bioinformatics analysis predicted miR-27-5p directly targeted to the 3’-untranslated region (UTR) of PBOV1 and luciferase reporter assay confirmed the interaction between miR-27a-5p and PBOV1. The function of PBOV1 in Wilms tumor was evaluated in vitro and knockdown of PBOV1 dampened cell migration. In addition, overexpression of PBOV1 antagonized the tumor-suppressive effect of miR-27a-5p in Wilms tumor cells. Collectively, our findings reveal the regulatory axis of miR-27-5p/PBOV1 in Wilms tumor and miR-27a-5p might serve as a novel therapeutic target in Wilms tumor.
Drivers of genomic landscapes of differentiation acrossPopulusdivergence gradient
Authors: Shang Huiying , Rendón-Anaya Martha , Paun Ovidiu , Field David L , Hess Jaqueline , Vogl Claus , Liu Jianquan , Ingvarsson Pär K. , Lexer Christian , Leroy Thibault
Published: August 2021

Speciation, the continuous process by which new species form, is often investigated by looking at the variation of nucleotide diversity and differentiation across the genome (hereafter genomic landscapes). A key challenge lies in how to determine the main evolutionary forces at play shaping these patterns. One promising strategy, albeit little used to date, is to comparatively investigate these genomic landscapes as a progression through time by using a series of species pairs along a divergence gradient. Here, we resequenced 201 whole-genomes from eight closely relatedPopulusspecies, with pairs of species at different stages along the divergence gradient to learn more about speciation processes. Using population structure and ancestry analyses, we document extensive introgression between some species pairs, especially those with parapatric distributions. We further investigate genomic landscapes, focusing on within-species (nucleotide diversity and recombination rate) and among-species (relative and absolute divergence) summary statistics of diversity and divergence. We observe highly conserved patterns of genomic divergence across species pairs. Independent of the stage across the divergence gradient, we find support for signatures of linked selection (i.e., the interaction between natural selection and genetic linkage) in shaping these genomic landscapes, along with gene flow and standing genetic variation. We highlight the importance of investigating genomic patterns on multiple species across a divergence gradient and discuss prospects to better understand the evolutionary forces shaping the genomic landscapes of diversity and differentiation.
Structural remodeling of SARS-CoV-2 spike protein glycans reveals the regulatory roles in receptor binding affinity
Authors: Hsu Yen-Pang , Mukherjee Debopreeti , Shchurik Vladimir , Makarov Alexey , Mann Benjamin F.
Published: August 2021

Glycans of the SARS-CoV-2 spike protein are speculated to play functional roles in the infection processes as they extensively cover the protein surface and are highly conserved across the variants. To date, the spike protein has become the principal target for vaccine and therapeutic development while the exact effects of its glycosylation remain elusive. Experimental reports have described the heterogeneity of the spike protein glycosylation profile. Subsequent molecular simulation studies provided a knowledge basis of the glycan functions. However, there are no studies to date on the role of discrete glycoforms on the spike protein pathobiology. Building an understanding of its role in SARS-CoV-2 is important as we continue to develop effective medicines and vaccines to combat the disease. Herein, we used designed combinations of glycoengineering enzymes to simplify and control the glycosylation profile of the spike protein receptor-binding domain (RBD). Measurements of the receptor binding affinity revealed the regulatory effects of the RBD glycans. Remarkably, opposite effects were observed from differently remodeled glycans, which presents a potential strategy for modulating the spike protein behaviors through glycoengineering. Moreover, we found that the reported anti-SARS-CoV-(2) antibody, S309, neutralizes the impact of different RBD glycoforms on the receptor binding affinity. Overall, this work reports the regulatory roles that glycosylation plays in the interaction between the viral spike protein and host receptor, providing new insights into the nature of SARS-CoV-2. Beyond this study, enzymatic remodeling of glycosylation offers the opportunity to understand the fundamental role of specific glycoforms on glycoconjugates across molecular biology.

Covert art Legends

The glycosylation of the SARS-CoV-2 spike protein receptor-binding domain has regulatory effects on the receptor binding affinity. Sialylation or not determines the “stabilizing” or “destabilizing” effect of the glycans. (Protein structure model is adapted from Protein Data Bank: 6moj. The original model does not contain the glycan structure.)

Significance

Glycans extensively cover the surface of SARS-CoV-2 spike (S) protein but the relationships between the glycan structures and the protein pathological behaviors remain elusive. Herein, we simplified and harmonized the glycan structures in the S protein receptor-binding domain and reported their regulatory roles in human receptor interaction. Opposite regulatory effects were observed and were determined by discrete glycan structures, which can be neutralized by the reported S309 antibody binding to the S protein. This report provides new insight into the mechanism of SARS-CoV-2 S protein infection as well as S309 neutralization.
Characterization and computational simulation of human Syx, a RhoGEF implicated in glioblastoma
Authors: Boyd Ryan J , Olson Tien L. , Zook James D. , Aceves Manuel , Stein Derek , Lin Wan-Hsin , Craciunescu Felicia M. , Hansen Debra T. , Anastasiadis Panos Z. , Singharoy Abhishek , Fromme Petra
Published: August 2021

Structural discovery of guanine nucleotide exchange factor (GEF) protein complexes is likely to become increasingly relevant with the development of new therapeutics targeting small GTPases and development of new classes of small molecules that inhibit protein-protein interactions. Syx (also known as PLEKHG5 in humans) is a RhoA GEF implicated in the pathology of glioblastoma (GBM). Here we investigated protein expression and purification of ten different human Syx constructs and performed biophysical characterizations and computational studies that provide insights into why expression of this protein was previously intractable. We show that human Syx can be expressed and isolated and Syx is folded as observed by circular dichroism (CD) spectroscopy and actively binds to RhoA as determined by co-elution during size exclusion chromatography (SEC). This characterization may provide critical insights into the expression and purification of other recalcitrant members of the large class of oncogenic — Diffuse B-cell lymphoma (Dbl) homology GEF proteins. In addition, we performed detailed homology modeling and molecular dynamics simulations on the surface of a physiologically realistic membrane. These simulations reveal novel insights into GEF activity and allosteric modulation by the plekstrin homology (PH) domain. These newly revealed interactions between the GEF PH domain and the membrane embedded region of RhoA support previously unexplained experimental findings regarding the allosteric effects of the PH domain from numerous activity studies of Dbl homology GEF proteins. This work establishes new hypotheses for structural interactivity and allosteric signal modulation in Dbl homology RhoGEFs.