bluuebunny/crossref_metadata_2025 huggingface dataset:
FLIP: Benchmark tasks in fitness landscape inference for proteins
Authors: Dallago Christian , Mou Jody , Johnston Kadina E. , Wittmann Bruce J. , Bhattacharya Nicholas , Goldman Samuel , Madani Ali , Yang Kevin K.
Published: November 2021

Machine learning could enable an unprecedented level of control in protein engineering for therapeutic and industrial applications. Critical to its use in designing proteins with desired properties, machine learning models must capture the protein sequence-function relationship, often termed fitness landscape. Existing bench-marks like CASP or CAFA assess structure and function predictions of proteins, respectively, yet they do not target metrics relevant for protein engineering. In this work, we introduce Fitness Landscape Inference for Proteins (FLIP), a benchmark for function prediction to encourage rapid scoring of representation learning for protein engineering. Our curated tasks, baselines, and metrics probe model generalization in settings relevant for protein engineering, e.g. low-resource and extrapolative. Currently, FLIP encompasses experimental data across adeno-associated virus stability for gene therapy, protein domain B1 stability and immunoglobulin binding, and thermostability from multiple protein families. In order to enable ease of use and future expansion to new tasks, all data are presented in a standard format. FLIP scripts and data are freely accessible at https://benchmark.protein.properties.
Weakly-Supervised Tumor Purity Prediction From Frozen H&E Stained Slides
Authors: Brendel Matthew , Getseva Vanesa , Assaad Majd Al , Sigouros Michael , Sigaras Alexandros , Kane Troy , Khosravi Pegah , Mosquera Juan Miguel , Elemento Olivier , Hajirasouliha Iman
Published: November 2021

Estimating tumor purity is especially important in the age of precision medicine. Purity estimates have been shown to be critical for correction of tumor sequencing results, and higher purity samples allow for more accurate interpretations from next-generation sequencing results. In addition, tumor purity has been shown to be correlated with survival outcomes for several diseases. Molecular-based purity estimates using computational approaches require sequencing of tumors, which is both time-consuming and expensive. Here we propose an approach, weakly-supervised purity (wsPurity), which can accurately quantify tumor purity within a slide, using multiple and different types of cancer. This approach allows for a flexible analysis of tumors from whole slide imaging (WSI) of histology hematoxylin and eosin (H&E) slides. Our model predicts tumor type with high accuracy (greater than 80% on an independent test cohort), and tumor purity at a higher accuracy compared to a comparable fully-supervised approach (0.1335 MAE on an independent test cohort). In addition to tumor purity prediction, our approach can identify high resolution tumor regions within a slide, to enrich tumor cell selection for downstream analyses. This model could also be used in a clinical setting, to stratify tumors into high and low tumor purity, using different thresholds, in a cancer-dependent manner, depending on what purity levels correlate with worse disease outcomes. In addition, this approach could be used in clinical practice to select the best tissue block for sequencing. Overall, this approach can be used in several different ways to analyze WSIs of tumor H&E sections.
Lossless Indexing with Counting de Bruijn Graphs
Authors: Karasikov Mikhail , Mustafa Harun , Rätsch Gunnar , Kahles André
Published: November 2021

Sequencing data is rapidly accumulating in public repositories. Making this resource accessible for interactive analysis at scale requires efficient approaches for its storage and indexing. There have recently been remarkable advances in building compressed representations ofannotated(orcolored)de Bruijn graphsfor efficiently indexing k-mer sets. However, approaches for representing quantitative attributes such as gene expression or genome positions in a general manner have remained underexplored. In this work, we proposeCounting de Bruijn graphs(Counting DBGs), a notion generalizing annotated de Bruijn graphs by supplementing each node-label relation with one or many attributes (e.g., a k-mer count or its positions). Counting DBGs index k-mer abundances from 2,652 human RNA-Seq samples in over 8-fold smaller representations compared to state-of-the-art bioinformatics tools and yet faster to construct and query. Furthermore, Counting DBGs with positional annotations losslessly represent entire reads in indexes on average 27% smaller than the input compressed withgzipfor human Illumina RNA-Seq and 57% smaller for PacBio HiFi sequencing of viral samples. A complete searchable index of all viral PacBio SMRT reads from NCBI’s SRA (152,884 samples, 875 Gbp) comprises only 178 GB. Finally, on the full RefSeq collection, we generate a lossless and fully queryable index that is 4.4-fold smaller than the MegaBLAST index. The techniques proposed in this work naturally complement existing methods and tools employing de Bruijn graphs and significantly broaden their applicability: from indexing k-mer counts and genome positions to implementing novel sequence alignment algorithms on top of highly compressed graph-based sequence indexes.
Photochemical pre-bleaching of formalin-fixed archival prostate tissues significantly reduces autofluorescence to facilitate multiplex immunofluorescence staining
Authors: Meeker Alan K. , Heaphy Christopher M. , Davis Christine M. , Roy Sujayita , Platz Elizabeth A.
Published: November 2021

The characterization of tissues using multiple different primary antibodies detected by secondary antibodies, each possessing a different colored fluorophore (multiplex immunofluorescence), is a powerful technique but often impaired by endogenous autofluorescence present in the specimen. Our current research involves the use of multiplex immunofluorescence to identify specific cell phenotypes within the tumor microenvironment in archival formalin-fixed paraffin-embedded human prostate cancer tissue specimens. These specimens frequently possess high levels of autofluorescence, in part due to the biological age of the tissues and long storage times. This autofluorescence interferes with and, in the worst cases, completely obscures the desired immunofluorescent signals, thus impeding analyses by decreasing signal-to-noise. Here, we demonstrate that a recently published protocol for photochemical bleaching significantly decreases autofluorescence (80% average decrease of the brightest autofluorescent signals), across the visible spectrum, in fixed, archival prostate tissue specimens from aged men, that have been sectioned onto glass slides and stored for several months. Importantly, the method is compatible with subsequent immunofluorescence staining and yields markedly improved signal-to-noise. Inclusion of this method should facilitate studies employing multiplex immunofluorescence in sections cut from archival fixed human prostate tissues.
Solanum galapagense-derived purple tomato fruit color is conferred by novel alleles of the Anthocyanin fruit and atroviolacium loci
Authors: Fenstemaker Sean , Sim Leah , Cooperstone Jessica , Francis David
Published: November 2021

One hypothesis for the origin of endemic species of tomato on the Galápagos islands postulates a hybridization of Solanum pimpinellifolium and S. habrochaites. S. galapagense accession LA1141 has purple fruit pigmentation which has previously been described in green-fruited wild tomatoes such as S. habrochaites. Characterization of LA1141 derived purple pigmentation provides a test of the hybridization hypothesis. Purple pigmentation was recovered in progenies derived from LA1141 and the anthocyanins malvidin 3(coumaroyl)rutinoside-5-glucoside, petunidin 3-(coumaroyl) rutinoside-5-glucoside, and petunidin 3-(caffeoyl)rutinoside-5-glucoside were abundant. Fruit color was evaluated in an introgression population and three quantitative trait loci (QTLs) were mapped and validated in subsequent populations. The loci atroviolacium on chromosome 7, Anthocyanin fruit on chromosome 10, and uniform ripening also on chromosome 10, underly these QTLs. Sequence analysis suggested that the LA1141 alleles of Aft and atv are unique relative to those previously described from S. chilense accession LA0458 and S. cheesmaniae accession LA0434, respectively. Phylogenetic analysis of the LA1141 Aft genomic sequence did not support a green-fruited origin and the locus clustered with members of the red-fruited tomato clade. The LA1141 allele of Aft is not the result of an ancient introgression and underlies a gain of anthocyanin pigmentation in the red-fruited clade.

Highlight

Anthocyanin fruit and atroviolacium confer purple pigmentation in Solanum galapagense LA1141 confirming a mechanism described for green-fruited tomatoes. LA1141 alleles cluster with red-fruited homologs suggesting an independent gain of pigmentation.
Photoimmunotherapy retains its anti-tumor efficacy with increasing stromal content in heterotypic pancreatic cancer spheroids
Authors: Saad Mohammad A. , Zhung Wonho , Stanley Margaret Elizabeth , Formica Sydney , Grimaldo-Garcia Stacey , Obaid Girgis , Hasan Tayyaba
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by increased levels of desmoplasia that contributes to reduced drug delivery and poor treatment outcomes. In PDAC, the stromal content can account for up to 90% of the total tumor volume. The complex interplay between stromal components, including pancreatic cancer associated fibroblasts (PCAFs), and PDAC cells in the tumor microenvironment (TME) have a significant impact on prognoses and thus needs to be recapitulated in vitro when evaluating various treatment strategies. This study is a systematic evaluation of photodynamic therapy (PDT) in 3D heterotypic coculture models of PDAC with varying ratios of patient derived PCAFs that simulate heterogenous PDAC tumors with increasing stromal content. The efficacy of antibody-targeted PDT (photoimmunotherapy; PIT) using cetuximab photoimmunoconjugates (PICs) of benzoporphyrin derivative (BPD) is contrasted with that of liposomal BPD (Visudyne®), which is currently in PDT clinical trials for PDAC. We demonstrate that both Visudyne®-PDT and PIT were effective in heterotypic PDAC 3D spheroids with a low stromal content. However, as the stromal content increases above 50% in the 3D spheroids, the efficacy of Visudyne®-PDT is reduced by up to 10-fold, while PIT retains its efficacy. PIT was found to be 10-fold, 19-fold and 14-fold more phototoxic in spheroids with 50%, 75% and 90% PCAFs, respectively, as compared to Visudyne®-PDT. This marked difference in efficacy is attributed to the ability of PICs to penetrate and distribute within spheroids with a higher stromal content, whereas Visudyne® is restricted to the spheroid periphery. This study thus demonstrates how the stromal content in PDAC spheroids directly impacts their responsiveness to PDT and proposes PIT to be a highly suited treatment option for desmoplastic tumors with particularly high degrees of stromal content.
Heterogeneous CaMKII-dependent synaptic compensations in CA1 pyramidal neurons from acute slices with dissected CA3
Authors: Vergara Pablo , Pino Gabriela , Vera Jorge , Sanhueza Magdalena
Published: November 2021

Prolonged changes in neural activity trigger homeostatic synaptic plasticity (HSP) allowing neuronal networks to operate in functional ranges. Cell-wide or input-specific adaptations can be induced by pharmacological or genetic manipulations of activity, and by sensory deprivation. Reactive functional changes caused by deafferentation may partially share mechanisms with HSP. Acute hippocampal slices constitute a suitable model to investigate relatively rapid (hours) pathway-specific modifications occurring after denervation and explore the underlying mechanisms. As Schaffer collaterals constitute a major glutamatergic input to CA1 pyramidal neurons, we conducted whole-cell recordings of miniature excitatory postsynaptic currents (mEPSCs) to evaluate changes over 12 hours after slice preparation and CA3 dissection. We observed an increment in mEPSCs amplitude and a decrease in decay time, suggesting synaptic AMPA receptor upregulation and subunit content modifications. Sorting mEPSC by rise time, a correlate of synapse location along dendrites, revealed amplitude raises at two separate domains. A specific frequency increase was observed in the same domains and was accompanied by a global, unspecific raise. Amplitude and frequency increments were lower at sites initially more active, consistent with local compensatory processes. Transient preincubation with a specific Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor either blocked or occluded amplitude and frequency upregulation in different synapse populations. Results are consistent with the concurrent development of different known CaMKII-dependent HSP processes. Our observations support that deafferentation causes rapid and diverse compensations resembling classical slow forms of adaptation to inactivity. These results may contribute to understand fast-developing homeostatic or pathological events after brain injury.
Predicting direct physical interactions in multimeric proteins with deep learning
Authors: Gao Mu , Nakajima An Davi , Parks Jerry M. , Skolnick Jeffrey
Published: November 2021

Accurate descriptions of protein-protein interactions are essential for understanding biological systems. Remarkably accurate atomic structures have been recently computed for individual proteins by AlphaFold2 (AF2). Here, we demonstrate that the same neural network models from AF2 developed for single protein sequences can be adapted to predict the structures of multimeric protein complexes without retraining. In contrast to common approaches, our method, AF2Complex, does not require paired multiple sequence alignments. It achieves higher accuracy than some complex protein-protein docking strategies and provides a significant improvement over AF-Multimer, a new development of AlphaFold for multimeric proteins. Moreover, we introduce metrics for predicting direct protein-protein interactions between arbitrary protein pairs and validate AF2Complex on some challenging benchmark sets and theE. coliproteome. Lastly, using the cytochromecbiogenesis system I as an example, we present high-confidence models of three sought-after assemblies formed by eight members of this system.
Characterization of scar tissue biomechanics during adult murine flexor tendon healing
Authors: Korcari Antonion , Buckley Mark R. , Loiselle Alayna E.
Published: November 2021

Tendon injuries are very common and result in significant impairments in mobility and quality of life. During healing, tendons produce a scar at the injury site, characterized by abundant and disorganized extracellular matrix and by permanent deficits in mechanical integrity compared to healthy tendon. Although a significant amount of work has been done to understand the healing process of tendons and to develop potential therapeutics for tendon regeneration, there is still a significant gap in terms of assessing the direct effects of therapeutics on the functional and material quality specifically of the scar tissue, and thus, on the overall tendon healing process. In this study, we focused on characterizing the mechanical properties of only the scar tissue in flexor digitorum longus (FDL) tendons during the proliferative and remodeling healing phases and comparing these properties with the mechanical properties of the composite healing tissue. Our method was sensitive enough to identify significant differences in structural and material properties between the scar and tendon-scar composite tissues. To account for possible inaccuracies due to the small aspect ratio of scar tissue, we also applied inverse finite element analysis (iFEA) to compute mechanical properties based on simulated tests with accurate specimen geometries and boundary conditions. We found that the scar tissue linear tangent moduli calculated from iFEA were not significantly different from those calculated experimentally at all healing timepoints, validating our experimental findings, and suggesting the assumptions in our experimental calculations were accurate. Taken together, this study first demonstrates that due to the presence of uninjured stubs, testing composite healing tendons without isolating the scar tissue overestimates the material properties of the scar itself. Second, our scar isolation method promises to enable more direct assessment of how different treatment regimens (e.g., cellular ablation, biomechanical and/or biochemical stimuli, tissue engineered scaffolds) affect scar tissue function and material quality in multiple different types of tendons.
Effects of tendon viscoelasticity in the distribution of forces over sutures in a model tendon-to-bone repair
Authors: Huang Yuxuan , Hoppe Ethan D. , Kurtaliaj Iden , Birman Victor , Thomopoulos Stavros , Genin Guy M.
Published: November 2021

Tears to the rotator cuff often require surgical repair. These repairs often culminate in re-tearing when sutures break through the tendon in the weeks following repair. Although numerous studies have been performed to identify suturing strategies that reduce this risk by balancing forces across sutures, none have accounted for how the viscoelastic nature of tendon influences load sharing. With the aim of providing insight into this problem, we studied how tendon viscoelasticity, tendon stiffness, and suture anchor spacing affect this balancing of forces across sutures. Results from a model of a three-row sutured re-attachment demonstrated that optimized distributions of suture stiffnesses and of the spacing of suture anchors can balance the forces across sutures to within a few percent, even when accounting for tendon viscoelasticity. Non-optimized distributions resulted in concentrated force, typically in the outermost sutures. Results underscore the importance of accounting for viscoelastic effects in the design of tendon to bone repairs.
Impact of the COVID-19 pandemic on routine surveillance for adults with chronic hepatitis B virus (HBV) infection in the UK
Authors: Campbell Cori , Wang Tingyan , Smith David A , Freeman Oliver , Noble Theresa , Várnai Kinga A , Harris Steve , Salih Hizni , Roadknight Gail , Little Stephanie , Glampson Ben , Mercuri Luca , Papadimitriou Dimitri , Jones Christopher R , Taylor Vince , Chaudhry Afzal , Phan Hang , Borca Florina , Olza Josune , Warricker Frazer , Romão Luis , Ramlakhan David , English Louise , Klenerman Paul , Andersson Monique I. , Collier Jane , Nastouli Eleni , Khakoo Salim I , Gelson William , Cooke Graham S , Woods Kerrie , Davies Jim , Barnes Eleanor , Matthews Philippa C
Published: November 2021

Background and aims

To determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (ALT and HBV viral load).

Methods

We used anonymised electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK NHS Trusts.

Results

We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient.

Conclusions

Further investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.
SARS-CoV-2 RNA is enriched by orders of magnitude in solid relative to liquid wastewater at publicly owned treatment works
Authors: Kim Sooyeol , Kennedy Lauren C. , Wolfe Marlene K. , Criddle Craig S. , Duong Dorothea H. , Topol Aaron , White Bradley J. , Kantor Rose S. , Nelson Kara L. , Steele Joshua A. , Langlois Kylie , Griffith John F. , Zimmer-Faust Amity G. , McLellan Sandra L. , Schussman Melissa K. , Ammerman Michelle , Wigginton Krista R. , Bakker Kevin M. , Boehm Alexandria B.
Published: November 2021

Wastewater-based epidemiology has gained attention throughout the world for detection of SARS-CoV-2 RNA in wastewater to supplement clinical testing. Methods have been developed using both the liquid and the solid fraction of wastewater, with some studies reporting higher concentrations in solids. To investigate this relationship further, we collaborated with six other laboratories to conduct a study across five publicly owned treatment works (POTWs) where both primary solids and raw wastewater influent samples were collected and quantified for SARS-CoV-2 RNA. Solids and influent samples were processed by participating laboratories using their respective methods and retrospectively paired based on date of collection. SARS-CoV-2 RNA concentrations by mass (gene copies per gram) were higher in solids than in influent by approximately three orders of magnitude. Concentrations in matched solids and influent were positively and significantly correlated at all five POTWs. RNA concentrations in both solids and influent were correlated to COVID-19 incidence rates in the sewershed and thus representative of disease burden; the solids methods appeared to produce a comparable relationship between SARS-CoV-2 RNA concentration measurements and incidence rates across all POTWs. Solids and influent methods showed comparable sensitivity, N gene detection frequency, and calculated empirical incidence rate lower limits. Analysis of solids has the advantage of using less sample volume to achieve similar sensitivity to influent methods.
Gut microbiome composition is predictive of incident type 2 diabetes
Authors: Ruuskanen Matti O. , Erawijantari Pande P. , Havulinna Aki S. , Liu Yang , Méric Guillaume , Inouye Michael , Jousilahti Pekka , Salomaa Veikko , Jain Mohit , Knight Rob , Lahti Leo , Niiranen Teemu J.
Published: November 2021

OBJECTIVE

To examine the previously unknown long-term association between gut microbiome composition and incident type 2 diabetes in a representative population cohort.

RESEARCH DESIGN AND METHODS

We collected fecal samples of 5 572 Finns (mean age 48.7 years, 54.1% women) in 2002 who were followed up for incident type 2 diabetes until Dec 31st, 2017. The samples were sequenced using shotgun metagenomics. We examined associations between gut microbiome compositions and incident diabetes using multivariable-adjusted Cox regression models. We first used the Eastern Finland sub-population to obtain initial findings and validated these in the Western Finland sub-population.

RESULTS

Altogether 432 cases of incident diabetes occurred over the median follow-up of 15.8 years. We detected 4 species and 2 clusters consistently associated with incident diabetes in the validation models. These 4 species wereClostridium citroniae(HR, 1.21; 95% CI, 1.04-1.42),C. bolteae(HR, 1.20; 95% CI, 1.04-1.39),Tyzzerella nexilis(HR, 1.17; 95% CI, 1.01-1.36), andRuminococcus gnavus(HR = 1.17; 95% CI, 1.01-1.36). The positively associated clusters, cluster 1 (HR, 1.18; 95% CI, 1.02-1.38) and cluster 5 (HR, 1.18; 95% CI, 1.02-1.36), mostly consisted of these same species.

CONCLUSIONS

We observed robust species-level taxonomic features predictive of incident type 2 diabetes over a long-term follow-up. These findings build on and extend previous mainly cross-sectional evidence and further support links between dietary habits, metabolic diseases, and type 2 diabetes that are modulated by the gut microbiome. The gut microbiome could potentially be used to improve risk prediction and to uncover novel therapeutic targets for diabetes.
Survey of residential indoor Particulate Matter measurements 1990-2019
Authors: Ilacqua Vito , Scharko Nicole , Zambrana Jordan , Malashock Daniel
Published: November 2021

We surveyed literature on measurements of indoor particulate matter in all size fractions, in residential environments free of solid fuel combustion. Data from worldwide studies from 1990-2019 were assembled into the most comprehensive collection to date. Out of 2,752 publications retrieved, 538 articles from 433 research projects met inclusion criteria and reported unique data, from which more than 2,000 unique sets of indoor PM measurements were collected. Distributions of mean concentrations were compiled, weighted by study size. Long-term trends, the impact of non-smoking, air cleaners, and the influence of outdoor PM were also evaluated. Similar patterns of indoor PM distributions for North America and Europe could reflect similarities in the indoor environments of these regions. Greater observed variability for all regions of Asia may reflect greater heterogeneity in indoor conditions, but also low numbers of studies for some regions. Indoor PM concentrations of all size fractions were mostly stable over the survey period, with the exception of observed declines in PM2.5in European and North American studies, and in PM10in North America. While outdoor concentrations were correlated with indoor concentrations across studies, indoor concentrations had higher variability, illustrating a limitation of using outdoor measurements to approximate indoor PM exposures.

Practical implications

Residential indoor PM concentration ranges for several size fractions measured in different worldwide regions are provided and may inform future public health research and practice, including PM exposure and risk assessment, and evaluation of IAQ-related interventions and consumer products, such as portable air cleaners.

This long-term indoor PM concentration record provides insights regarding the degree of change in observed indoor PM concentrations by world region and some of the factors contributing to increasing or decreasing temporal trends.

Outdoor air pollution remains a major influence on indoor concentrations of PM of all sizes.

Greater variability of indoor concentrations of PM relative to outdoor concentrations demonstrate the potential for exposure misclassification when using outdoor concentrations to estimate indoor exposures and risk.

IAQ interventions, including removing environmental tobacco smoke or using filtration-based portable air cleaners, can produce major improvements in IAQ through reduced indoor particle concentrations.
NEMoE: A nutrition aware regularized mixture of experts model addressing diet-cohort heterogeneity of gut microbiota in Parkinson’s disease
Authors: Xu Xiangnan , Lubomski Michal , Holmes Andrew J. , Sue Carolyn M. , Davis Ryan L. , Muller Samuel , Yang Jean Y.H.
Published: November 2021

The microbiome plays a fundamental role in human health and diet is one of the strongest modulators of the gut microbiome. However, interactions between microbiota and host health are complex and diverse. Understanding the interplay between diet, the microbiome and health state could enable the design of personalized intervention strategies and improve the health and wellbeing of affected individuals. A common approach to this is to divide the study population into smaller cohorts based on dietary preferences in the hope of identifying specific microbial signatures. However, classification of patients based solely on diet is unlikely to reflect the microbiome-host health relationship or the taxonomic microbiome makeup. To this end, we present a novel approach, the Nutrition-Ecotype Mixture of Experts (NEMoE) model, for establishing associations between gut microbiota and health state that accounts for diet-specific cohort variability using a regularized mixture of experts model framework with an integrated parameter sharing strategy to ensure data driven diet-cohort identification consistency across taxonomic levels. The success of our approach was demonstrated through a series of simulation studies, in which NEMoE showed robustness with regard to parameter selection and varying degrees of data heterogeneity. Further application to real-world microbiome data from a Parkinson’s disease cohort revealed that NEMoE is capable of not only improving predictive performance for Parkinson’s Disease but also for identifying diet-specific microbiome markers of disease. Our results indicate that NEMoE can be used to uncover diet-specific relationships between nutritional-ecotype and patient health and to contextualize precision nutrition for different diseases.
Disparities in COVID-19 Fatalities among Working Californians
Authors: Cummings Kristin J. , Beckman John , Frederick Matthew , Harrison Robert , Nguyen Alyssa , Snyder Robert , Chan Elena , Gibb Kathryn , Rodriguez Andrea , Wong Jessie , Murray Erin L. , Jain Seema , Vergara Ximena
Published: November 2021

Background

Information on the occupational distribution of COVID-19 mortality is limited.

Objective

To characterize COVID-19 fatalities among working Californians.

Design

Retrospective study of laboratory-confirmed COVID-19 fatalities with dates of death from January 1 to December 31, 2020.

Setting

California.

Participants

COVID-19 accounted for 8,050 (9.9%) of 81,468 fatalities among Californians 18-64 years old. Of these decedents, 2,486 (30.9%) were matched to state employment records and classified as “confirmed working.” The remainder were classified as “likely working” (n=4,121 [51.2%]) or “not working” (n=1,443 [17.9%]) using death certificate and case registry data.

Measurements

We calculated age-adjusted overall and occupation-specific COVID-19 mortality rates using 2019 American Community Survey denominators.

Results

Confirmed and likely working COVID-19 decedents were predominantly male (76.3%), Latino (68.7%), and foreign-born (59.6%), with high school or less education (67.9%); 7.8% were Black. The overall age-adjusted COVID-19 mortality rate was 30.0 per 100,000 workers (95% confidence interval [CI], 29.3-30.8). Workers in nine occupational groups had mortality rates higher than this overall rate, including those in farming (78.0; 95% CI, 68.7-88.2); material moving (77.8; 95% CI, 70.2-85.9); construction (62.4; 95% CI, 57.7-67.4); production (60.2; 95% CI, 55.7-65.0); and transportation (57.2; 95% CI, 52.2-62.5) occupations. While occupational differences in mortality were evident across demographic groups, mortality rates were three-fold higher for male compared with female workers and three- to seven-fold higher for Latino and Black workers compared with Asian and White workers.

Limitations

The requirement that fatalities be laboratory-confirmed and the use of 2019 denominator data may underestimate the occupational burden of COVID-19 mortality.

Conclusion

Californians in manual labor and in-person service occupations experienced disproportionate COVID-19 mortality, with the highest rates observed among male, Latino, and Black workers.
Use of repeated mammograms to evaluate risk of breast cancer: a systematic review of methods used in the literature
Authors: Anandarajah Akila , Chen Yongzhen , Stoll Carolyn , Hardi Angela , Jiang Shu , Colditz Graham A.
Published: November 2021

Objective

This systematic review aimed to assess methods used to relate repeated mammographic images to breast cancer risk, including the time from mammogram to diagnosis of breast cancer, and methods for analysis of data from either one or both breasts (averaged or assessed individually).

Design

A systematic review was performed.

Setting

The databases including Medline (Ovid) 1946-, Embase.com 1947-, CINAHL Plus 1937-, Scopus 1823-, Cochrane Library (including CENTRAL), and Clinicaltrials.gov were searched through October 2021 to extract published articles in English describing the relationship of change in mammographic features with risk of breast cancer.

Participants

Women with mammogram images.

Main outcome measure

Breast cancer incidence.

Results

Twenty articles were included in the final review. We found that BIRADs and Cumulus were most commonly used for classifying mammographic density and automated assessment was used on more recent digital mammograms. Time between mammograms varied from 1 to median of 4.1 years, and only 9 of the studies used more than 2 mammograms to quantify features. One study used a prediction horizon of 5 and 10 years, one used 5 years only and another 10 years only, while in the others the prediction horizon was not clearly defined with investigators using the next screening mammogram.

Conclusion

This review provided an updated overview of the state of the art and revealed research gaps; based on these, we provide recommendations for future studies using repeated measure methods for mammogram images to make the use of accumulating image data. By following these recommendations, we expect to improve risk classification and risk prediction for women to tailor screening and prevention strategies to level of risk.

Article summary

Strengths and limitations of the study

To the best of our knowledge, this is the most recent systematic review on the topic of using multiple mammogram images to define risk of breast cancer.

This review was performed strictly following systematic review guidelines including a medical librarian with expertise in searching, multiple independent reviewers involved in study selection and data extraction, and reporting following PRISMA 2020 guidelines.

Due to heterogeneity of methods for assessment and classification (categorical and continuous) of mammographic features including breast density and time to breast cancer, we did not perform risk of bias or conduct a meta-analysis.

Few studies looked at repeated measures of non-density features.
Selective clonal persistence of human retroviruses in vivo: radial chromatin organization, integration site and host transcription
Authors: Melamed Anat , Fitzgerald Tomas W , Wang Yuchuan , Ma Jian , Birney Ewan , Bangham Charles R M
Published: November 2021

The human retroviruses HTLV-1 and HIV-1 persist in vivo, despite the host immune response and antiretroviral therapy, as a reservoir of latently infected T-cell clones. It is poorly understood what determines which clones survive in the reservoir and which are lost. We compared >160,000 HTLV-1 integration sites from T-cells isolated ex vivo from naturally-infected subjects with >230,000 integration sites from in vitro infection, to identify the genomic features that determine selective clonal survival. Three factors explained >40% of the observed variance in clone survival of HTLV-1 in vivo: the radial intranuclear position of the provirus, its absolute genomic distance from the centromere, and the intensity of host genome transcription flanking the provirus. The radial intranuclear position of the provirus and its distance from the centromere also explained ~7% of clonal persistence of HIV-1 in vivo. Selection for transcriptionally repressive nuclear compartments favours clonal persistence of human retroviruses in vivo.
8 Å structure of the nuclear ring of the Xenopus laevis nuclear pore complex solved by cryo-EM and AI
Authors: Ren He , Tai Linhua , Zhu Yun , Huang Xiaojun , Sun Fei , Zhang Chuanmao
Published: November 2021

The nuclear pore complex (NPC), one of the largest protein complexes in eukaryotes, serves as a physical gate to regulate nucleocytoplasmic transport. Here, we determined the 8 Å resolution cryo-electron microscopic (cryo-EM) structure of the nuclear ring (NR) from the Xenopus laevis NPC, with local resolutions reaching 4.9 Å. With the aid of AlphaFold2, we managed to build a pseudoatomic model of the NR, including the Y complexes and flanking components. In this most comprehensive and accurate model to date, the almost complete Y complex structure exhibits much tighter interaction in the hub region. Each NR asymmetric subunit contains two copies of Y complexes, one copy of Nup205 that connects the Y complexes to the neighbouring complex, one copy of ELYS that stabilizes the long arm region of the inner Y complex, and one copy of newly identified Nup93 that forms a bridge across the stems of Y complexes. These in-depth structural features represent a great advance in understanding the assembly of NPCs.
Discovery of Potent Inhibitors of α-Synuclein Aggregation Using Structure-Based Iterative Learning
Authors: Horne Robert I. , Andrzejewska Ewa , Alam Parvez , Brotzakis Z. Faidon , Srivastava Ankit , Aubert Alice , Nowinska Magdalena , Gregory Rebecca C. , Staats Roxine , Possenti Andrea , Chia Sean , Sormanni Pietro , Ghetti Bernardino , Caughey Byron , Knowles Tuomas P. J. , Vendruscolo Michele
Published: November 2021

Machine learning methods hold the promise to reduce the costs and the failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where the development of disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine learning approach to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson’s disease and other synucleinopathies. Because the proliferation of α-synuclein aggregates takes place through autocatalytic secondary nucleation, we aim to identify compounds that bind the catalytic sites on the surface of the aggregates. To achieve this goal, we use structure-based machine learning in an iterative manner to first identify and then progressively optimize secondary nucleation inhibitors. Our results demonstrate that this approach leads to the facile identification of compounds two orders of magnitude more potent than previously reported ones.
The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function
Authors: Liu Zhiyu , Shi Herong , Liu Jun
Published: November 2021

Tetraspanin proteins are a unique family of highly conserved four-pass transmembrane proteins in metazoans. While much is known about their biochemical properties, the in vivo functions and distribution patterns of different tetraspanin proteins are less understood. Previous studies have shown that two paralogous tetraspanins that belong to the TspanC8 subfamily, TSP-12 and TSP-14, function redundantly to promote both Notch signaling and bone morphogenetic protein (BMP) signaling in C. elegans. TSP-14 has two isoforms, TSP-14A and TSP-14B, where TSP-14B has an additional 24 amino acids at its N-terminus compared to TSP-14A. By generating isoform specific knock-ins and knock-outs using CRISPR, we found that TSP-14A and TSP-14B share distinct as well as overlapping expression patterns and functions. While TSP-14A functions redundantly with TSP-12 to regulate body size and embryonic and vulva development, TSP-14B primarily functions redundantly with TSP-12 to regulate postembryonic mesoderm development. Importantly, TSP-14A and TSP-14B exhibit distinct subcellular localization patterns. TSP-14A is localized apically and on early and late endosomes. TSP-14B is localized to the basolateral cell membrane. We further identified a di-leucine motif within the N-terminal 24 amino acids of TSP-14B that serves as a basolateral membrane targeting sequence, and showed that the basolateral membrane localization of TSP-14B is important for its function. Our work highlights the diverse and intricate functions of TspanC8 tetraspanins in C. elegans, and demonstrates the importance of dissecting the functions of these important proteins in an intact living organism.

Author summary

Tetraspanin proteins are a unique family of highly conserved four-pass transmembrane proteins in higher eukaryotes. Abnormal expression of certain tetraspanins is associated with various types of diseases, including cancer. Understanding the functions of different tetraspanin proteins in vivo is crucial in deciphering the link between tetraspanins and their associated disease states. We have previously identified two tetraspanins, TSP-12 and TSP-14, that share redundant functions in regulating multiple aspects of C. elegans development. Here we show that TSP-14 has two protein isoforms. Using CRISPR knock-in and knock-out technology, we have found that the two isoforms share unique, as well as overlapping expression patterns and functions. Furthermore, they exhibit distinct subcellular localization patterns. Our work highlights the diverse and intricate functions of tetraspanin proteins in a living multicellular organism, and demonstrates that protein isoforms are another mechanism C. elegans uses to increase the diversity and versatility of its proteome.
First evidence of in vitro cytotoxic effects of marine microlitter on Merluccius merluccius and Mullus barbatus, two Mediterranean commercial fish species
Authors: Miccoli A , Mancini E , Saraceni PR , Della Ventura G , Scapigliati G , Picchietti S
Published: November 2021

Marine litter is composed mainly of plastics and is recognized as a serious threats to marine ecosystems. Ecotoxicological approaches have started elucidating the potential severity of microplastics (MPs) in controlled laboratory studies with pristine materials but no information exist on marine environmental microlitter as a whole. Here, we characterized the litter in the coastal Northern Tyrrhenian sea and in the stomach of two fish species of socio-economic importance, and exposed primary cell cultures of mucosal and lymphoid organs to marine microlitter for evaluating possible cytotoxic effects. An average of 0.30 ± 0.02 microlitter items m-3 was found in water samples. μFT-IR analysis revealed that plastic particles, namely HDPE, polyamide and polypropylene were present in 100% and 83.3% of Merluccius merluccius and Mullus barbatus analyzed, which overall ingested 14.67 ± 4.10 and 5.50 ± 1.97 items/individual, respectively. Moreover, microlitter was confirmed as a vector of microorganisms. Lastly, the apical end-point of viability was found to be significantly reduced in splenic cells exposed in vitro to two microlitter conditions. Considering the role of the spleen in the mounting of adaptive immune responses, our results warrant more in-depth investigations for clarifying the actual susceptibility of these two species to anthropogenic microlitter.

Highlights

0.30 ± 0.02 microlitter items m-3 were found at the surface of coastal Northern Tyrrhenian sea

14.67 ± 4.10 and 5.50 ± 1.97 items/individual were retrieved from the stomach of hakes and mullets

The ingested microlitter contained plastic items

Microlitter was validated as a carrier of bacteria, fungi and flagellates

Splenic cells exposed to two microlitter conditions for 72 hours suffered cytotoxicity
Functional but not obligatory link between microsaccades and neural modulation by covert spatial attention
Authors: Liu Baiwei , Nobre Anna C. , Ede Freek van
Published: November 2021

Covert spatial attention is associated with spatially specific modulation of neural activity as well as with directional biases in fixational eye-movements known as microsaccades. Recently, this link has been suggested to be obligatory, such that modulation of neural activity by covert spatial attention occurs only when paired with microsaccades toward the attended location. Here we revisited this link between microsaccades and neural modulation by covert spatial attention in humans. We investigated spatial modulation of 8-12 Hz EEG alpha activity and microsaccades in a context with no incentive for overt gaze behaviour: when attention is directed internally within the spatial layout of visual working memory. In line with a common attentional origin, we show that spatial modulations of alpha activity and microsaccades co-vary: alpha lateralisation is stronger in trials with microsaccades toward compared to away from the memorised location of the to-be-attended item and occurs earlier in trials with earlier microsaccades toward this item. Critically, however, trials without attention-driven microsaccades nevertheless showed clear spatial modulation of alpha activity – comparable to the neural modulation observed in trials with attention-driven microsaccades. Thus, directional biases in microsaccades are correlated with neural signatures of covert spatial attention, but they are not a prerequisite for neural modulation by covert spatial attention to be manifest.
Establishment of well-differentiated camelid airway cultures to study Middle East respiratory syndrome coronavirus
Authors: Gultom Mitra , Kratzel Annika , Portmann Jasmine , Stalder Hanspeter , Bätzner Astrid Chanfon , Gantenbein Hans , Gurtner Corinne , Ebert Nadine , Posthaus Horst , Zanolari Patrik , Pfaender Stephanie , Thiel Volker , Dijkman Ronald
Published: November 2021

In 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in Saudi Arabia and was mostly associated with severe respiratory illness in humans. Dromedary camels are the zoonotic reservoir for MERS-CoV. To investigate the biology of MERS-CoV in camelids, we developed a well-differentiated airway epithelial cell (AEC) culture model for Llama glama and Camelus bactrianus. Histological characterization revealed progressive epithelial cellular differentiation with well-resemblance to autologous ex vivo tissues. We demonstrate that MERS-CoV displays a divergent cell tropism and replication kinetics profile in both AEC models. Furthermore, we observed that in the camelid AEC models MERS-CoV replication can be inhibited by both type I and III interferons (IFNs). In conclusion, we successfully established camelid AEC cultures that recapitulate the in vivo airway epithelium and reflect MERS-CoV infection in vivo. In combination with human AEC cultures, this system allows detailed characterization of the molecular basis of MERS-CoV cross-species transmission in respiratory epithelium.
Heritability of hippocampal functional and microstructural organisation
Authors: Bayrak Şeyma , Vos de Wael Reinder , Schaare H. Lina , Hettwer Meike D. , Caldairou Benoit , Bernasconi Andrea , Bernasconi Neda , Bernhardt Boris C. , Valk Sofie L.
Published: November 2021

The hippocampus is a uniquely infolded allocortical structure in the medial temporal lobe that consists of the microstructurally and functionally distinct subregions: subiculum, cornu ammonis, and dentate gyrus. The hippocampus is a remarkably plastic region that is implicated in learning and memory. At the same time it has been shown that hippocampal subregion volumes are heritable, and that genetic expression varies along a posterior to anterior axis. Here, we studied how a heritable, stable, hippocampal organisation may support its flexible function in healthy adults. Leveraging the twin set-up of the Human Connectome Project with multimodal neuroimaging, we observed that the functional connectivity between hippocampus and cortex was heritable and that microstructure of the hippocampus genetically correlated with cortical microstructure. Moreover, both functional and microstructural organisation could be consistently captured by anterior-to-posterior and medial-to-lateral axes across individuals. However, heritability of functional, relative to microstructural, organisation was found reduced, suggesting individual variation in functional organisation of subfields is under low genetic control. Last, we demonstrate that structure and function couple along its genetic axes, suggesting an interplay of stability and plasticity within the hippocampus. Our study provides new insights on the heritability of the hippocampal formation and illustrates how genetic axes may scaffold hippocampal structure and function.