bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of fractional clear sky over potential astronomical sites
Authors: Ningombam Shantikumar S , Song H-J , Mugil S K , Dumka Umesh Chandra , Larson E J L , Kumar Brijesh , Sagar Ram
Published: July 2021

The estimation of the night-time cloud fraction (CF) is found to be one of the key parameters for evaluating the number of useful nights at an astronomical site. This work evaluates useful astronomical night-time observation over eight sites using a minimum threshold of CF from 21 years (2000–2020) of ground-based hourly visual and daily satellite data along with 41 years (1980–2020) of long-term hourly reanalysis data. The estimated number of photometric nights is underestimated by 8–24 per cent using the reanalysis data at Indian Astronomical Observatory-Hanle in comparison with the visual observations, while the estimated number of spectroscopic nights is 70–75 per cent per year and in good agreement with the visual observations. Among the astronomical sites, Paranal is found to be the best for astronomical observations, with 87 per cent spectroscopic nights per year. On the other hand, Hanle, Ali and Devasthal, located in the Himalayan region, exhibit an average of 68–78 per cent spectroscopic nights per year based on long-term reanalysis data, while Merak exhibits 61–68 per cent spectroscopic nights per year. Vertical profiles and global horizontal distributions for CF and related variable parameters are further compared among the sites. Global CF trends based on 41 years of reanalysis data show a decreasing tendency over most land regions and an increasing tendency over oceanic regions as well as over the Sahara desert, Middle East, and Indian subcontinent along the adjacent Tibetan Plateau. Such different CF trends between the ocean and land regions are thought to be the result of differential surface warming and water vapour changes associated with climate change.
Electron-Impact Excitation of Ge iii and Photoionisation of Ge ii
Authors: Dunleavy N L , Ballance C P , Ramsbottom C A , Jeffery C S
Published: July 2021

Energy levels, Einstein A-values and oscillator strengths are calculated for doubly-ionised germanium (Ge iii). We have undertaken a study of the electron-impact excitation of Ge iii and have also completed a study of the photoionisation of Ge ii. Ge iii target structures were generated using the relativistic GRASP0 package. Several scattering models were investigated to assess the uncertainty quantification of our results. Initially, the lowest lying 64 jj fine-structure levels were included in the close-coupling expansion resulting from 14 non-relativistic configurations. A second larger model was subsequently generated using the GASP package and incorporated the lowest 589 jj fine-structure levels from 17 non-relativistic configurations. Both the DARC and Breit-Pauli parallel suite of R-matrix collision codes were utilised in the scattering calculations to generate the collision strengths for incident electron-energies between 0 and 5 Rydbergs and subsequently the Maxwellian averaged effective collision strengths for temperatures in the range 1000 to 200000 Kelvin. The photoionisation calculations comprised of two studies, a DARC and a Breit-Pauli calculation incorporating the 250 lowest lying levels. Photoionisation cross sections for Ge ii are presented in the range 0-5 Ryds. Due to the lack of data available in the literature, the present radiative data and electron-impact/photoionisation cross sections are compared between the models presented in this paper. To assess their significance for astrophysics, the data are incorporated into the stellar atmosphere package sterne. Test models for the heavy-metal subdwarf LSIV−14○116 are not affected by the new data, but models for cooler stars may be sensitive to them.
An Extended Admixture Pulse Model Reveals the Limitations to Human–Neandertal Introgression Dating
Authors: Iasi Leonardo N M , Ringbauer Harald , Peter Benjamin M
Published: July 2021

Neandertal DNA makes up 2–3% of the genomes of all non-African individuals. The patterns of Neandertal ancestry in modern humans have been used to estimate that this is the result of gene flow that occurred during the expansion of modern humans into Eurasia, but the precise dates of this event remain largely unknown. Here, we introduce an extended admixture pulse model that allows joint estimation of the timing and duration of gene flow. This model leads to simple expressions for both the admixture segment distribution and the decay curve of ancestry linkage disequilibrium, and we show that these two statistics are closely related. In simulations, we find that estimates of the mean time of admixture are largely robust to details in gene flow models, but that the duration of the gene flow can only be recovered if gene flow is very recent and the exact recombination map is known. These results imply that gene flow from Neandertals into modern humans could have happened over hundreds of generations. Ancient genomes from the time around the admixture event are thus likely required to resolve the question when, where, and for how long humans and Neandertals interacted.
RoboCOP: jointly computing chromatin occupancy profiles for numerous factors from chromatin accessibility data
Authors: Mitra Sneha , Zhong Jianling , Tran Trung Q , MacAlpine David M , Hartemink Alexander J
Published: July 2021

Chromatin is a tightly packaged structure of DNA and protein within the nucleus of a cell. The arrangement of different protein complexes along the DNA modulates and is modulated by gene expression. Measuring the binding locations and occupancy levels of different transcription factors (TFs) and nucleosomes is therefore crucial to understanding gene regulation. Antibody-based methods for assaying chromatin occupancy are capable of identifying the binding sites of specific DNA binding factors, but only one factor at a time. In contrast, epigenomic accessibility data like MNase-seq, DNase-seq, and ATAC-seq provide insight into the chromatin landscape of all factors bound along the genome, but with little insight into the identities of those factors. Here, we present RoboCOP, a multivariate state space model that integrates chromatin accessibility data with nucleotide sequence to jointly compute genome-wide probabilistic scores of nucleosome and TF occupancy, for hundreds of different factors. We apply RoboCOP to MNase-seq and ATAC-seq data to elucidate the protein-binding landscape of nucleosomes and 150 TFs across the yeast genome, and show that our model makes better predictions than existing methods. We also compute a chromatin occupancy profile of the yeast genome under cadmium stress, revealing chromatin dynamics associated with transcriptional regulation.
The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation
Authors: Sharma Tapan , Robinson Daniel C L , Witwicka Hanna , Dilworth F Jeffrey , Imbalzano Anthony N
Published: July 2021

Skeletal muscle regeneration is mediated by myoblasts that undergo epigenomic changes to establish the gene expression program of differentiated myofibers. mSWI/SNF chromatin remodeling enzymes coordinate with lineage-determining transcription factors to establish the epigenome of differentiated myofibers. Bromodomains bind to acetylated lysines on histone N-terminal tails and other proteins. The mutually exclusive ATPases of mSWI/SNF complexes, BRG1 and BRM, contain bromodomains with undefined functional importance in skeletal muscle differentiation. Pharmacological inhibition of mSWI/SNF bromodomain function using the small molecule PFI-3 reduced differentiation in cell culture and in vivo through decreased myogenic gene expression, while increasing cell cycle-related gene expression and the number of cells remaining in the cell cycle. Comparative gene expression analysis with data from myoblasts depleted of BRG1 or BRM showed that bromodomain function was required for a subset of BRG1- and BRM-dependent gene expression. Reduced binding of BRG1 and BRM after PFI-3 treatment showed that the bromodomain is required for stable chromatin binding at target gene promoters to alter gene expression. Our findings demonstrate that mSWI/SNF ATPase bromodomains permit stable binding of the mSWI/SNF ATPases to promoters required for cell cycle exit and establishment of muscle-specific gene expression.
Narrative, Second-Person Experience, and Self-Perception: A Reason it is Good to Conceive of One’s Life Narratively
Authors: Hibshman Grace
Published: July 2021

It is widely held that it is good to conceive of one's life narratively, but why this is the case has not been well established. I argue that conceiving of one's life narratively can contribute to one's flourishing by mediating to oneself a second-person experience of oneself, furnishing one with valuable second-personal productive distance from oneself and as a result self-understanding. Drawing on Eleonore Stump's theory that narratives re-present to their audiences the second-person experiences they depict, I argue that conceiving of one's life narratively facilitates taking on the second-person experience that an audience would have in hearing one's life narrative, mediating how someone from a second-person perspective might perceive oneself and as a result yielding valuable self-understanding. I conclude with some practical implications.
Disagreement in the Equity Options Market and Stock Returns
Authors: Golez Benjamin , Goyenko Ruslan
Published: July 2021

We estimate investor disagreement from synthetic long and short stock trades in the equity options market. We show that high disagreement predicts low stock returns after positive earnings surprises and high stock returns after negative earnings surprises. The negative effect is stronger for high-beta stocks and stocks that are more difficult to sell short. In the cross-section of all stocks and the subset of the 500 largest companies, high disagreement robustly predicts low monthly and weekly stock returns.
The Economics of Sick Calves: The Use of Calves for Smallpox Vaccine Lymph Production in Britain and its Empire, 1870s–1900s
Authors: Brig-Ortiz Kristin
Published: July 2021

In this essay, I explore how the production and distribution of animal lymph benefited public and private producers by allowing them to use the calf’s body to profit from compulsory vaccination legislation. Through this process, a market was created in which the state competed with and was beholden to commercial entities for public health administration. By establishing its own vaccine-producing sites, the state participated in this public health market, where it competed with private producers. Building on scholarly work on the history of public health and animal histories, the essay understands how late nineteenth-century British vaccine administration hinged on a view of lymph production that encompassed the calf’s importance to vaccine administration and the commodification of the resulting vaccine lymph. These perspectives shaped how the state and medical practitioners approached and administered vaccination, refashioning lymph from a free tool to a market commodity.
Root-Lesion Nematodes Affecting Dryland Cereals in the Semiarid Pacific Northwest U.S.A.
Authors: Smiley Richard W.
Published: July 2021

Root-lesion nematodes (Pratylenchus spp.) are parasites that invade and deteriorate roots, thereby reducing the efficiency of water and nutrient uptake. Pratylenchus neglectus and P. thornei are the two species that are most prevalent and cause reduced yields of rainfed wheat and barley in semiarid regions of the Pacific Northwest. They are particularly damaging where wheat and barley are produced without irrigation in areas receiving less than 450 mm (18 in.) of precipitation annually. This review is focused on the biology and management of P. neglectus and P. thornei in semiarid rainfed agriculture. Characteristics of climates, soils, and crop production systems are described as a preface to constraints placed upon management options. Discussions include the economic importance, host ranges, and protocols for sampling and species identification. Discussion of disease management options include crop rotation, genetic resistance and tolerance, planting date, trap and biofumigant crops, crop nutrition, chemical and biological nematicides, and tillage. Predictions for rainfed agriculture in a period of changing climate are presented, as are suggestions for important areas of research including crop genetics, nematode testing, and communication of results, Pratylenchus biology, mechanisms of resistance, the phytobiome, and closing the “yield gap” between actual and attainable yields.
Disparities in Access to High-Volume Surgeons Within High-Volume Hospitals for Hysterectomy
Authors: Knisely Anne , Huang Yongmei , Melamed Alexander , Gockley Allison , Tergas Ana I. , St. Clair Caryn M. , Hou June Y. , Khoury-Collado Fady , Accordino Melissa , Hershman Dawn L. , Wright Jason D.
Published: July 2021

OBJECTIVE:

To examine access to high-volume surgeons in comparison with low-volume surgeons who perform hysterectomies within high-volume hospitals and to compare perioperative morbidity and mortality between high-volume and low-volume surgeons within these centers.

METHODS:

Women who underwent hysterectomy in New York State between 2000 and 2014 at a high-volume (top quartile by volume) hospital were included. Surgeons were classified into quartiles based on average annual hysterectomy volume. Multivariable models were used to determine characteristics associated with treatment by a low-volume surgeon in comparison with a high-volume surgeon and to estimate the association between physician volume, and morbidity and mortality.

RESULTS:

A total of 300,586 patients cared for by 5,505 surgeons at 59 hospitals were identified. Women treated by low-volume surgeons, in comparison with high-volume surgeons, were more often Black (19.4% vs 14.3%; adjusted odds ratio [aOR] 1.26; 95% CI 1.09–1.46) and had Medicare insurance (20.6% vs 14.5%; aOR 1.22; 95% CI 1.04–1.42). Low-volume surgeons were more likely to perform both emergent–urgent procedures (26.1% vs 6.4%; aOR 3.91; 95% CI 3.26–4.69) and abdominal hysterectomy, compared with minimally invasive hysterectomy (77.8% vs 54.7%; aOR 1.91; 95% CI 1.62–2.24). Compared with patients cared for by high-volume surgeons, those operated on by low-volume surgeons had increased risk of a complication (31.0% vs 10.3%; adjusted risk ratios [aRR] 1.84; 95% CI 1.71–1.98) and mortality (2.2% vs 0.2%; aRR 3.04; 95% CI 2.20–4.21). In sensitivity analyses, differences in morbidity and mortality remained for emergent–urgent procedures, elective operations, cancer surgery, and noncancer procedures.

CONCLUSION:

Socioeconomic disparities remain in access to high-volume surgeons within high-volume hospitals for hysterectomy. Patients who undergo hysterectomy at a high-volume hospital by a low-volume surgeon are at substantially greater risk for perioperative morbidity and mortality.
Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes
Authors: Urbanellis Peter , McEvoy Caitriona M. , Škrtić Marko , Kaths J. Moritz , Kollmann Dagmar , Linares Ivan , Ganesh Sujani , Oquendo Fabiola , Sharma Manraj , Mazilescu Laura , Goto Toru , Noguchi Yuki , John Rohan , Mucsi Istvan , Ghanekar Anand , Bagli Darius , Konvalinka Ana , Selzner Markus , Robinson Lisa A.
Published: July 2021

Background.

Normothermic ex vivo kidney perfusion (NEVKP) has demonstrated superior outcomes for donation-after-cardiovascular death grafts compared with static cold storage (SCS). To determine the mechanisms responsible for this, we performed an unbiased genome-wide microarray analysis.

Methods.

Kidneys from 30-kg Yorkshire pigs were subjected to 30 min of warm ischemia followed by 8 h of NEVKP or SCS, or no storage, before autotransplantation. mRNA expression was analyzed on renal biopsies on postoperative day 3. Gene set enrichment analysis was performed using hallmark gene sets, Gene Ontology, and pathway analysis.

Results.

The gene expression profile of NEVKP-stored grafts closely resembled no storage kidneys. Gene set enrichment analysis demonstrated enrichment of fatty acid metabolism and oxidative phosphorylation following NEVKP, whereas SCS-enriched gene sets were related to mitosis, cell cycle checkpoint, and reactive oxygen species (q < 0.05). Pathway analysis demonstrated enrichment of lipid oxidation/metabolism, the Krebs cycle, and pyruvate metabolism in NEVKP compared with SCS (q < 0.05). Comparison of our findings with external data sets of renal ischemia-reperfusion injury revealed that SCS-stored grafts demonstrated similar gene expression profiles to ischemia-reperfusion injury, whereas the profile of NEVKP-stored grafts resembled recovered kidneys.

Conclusions.

Increased transcripts of key mitochondrial metabolic pathways following NEVKP storage may account for improved donation-after-cardiovascular death graft function, compared with SCS, which promoted expression of genes typically perturbed during IRI.
Transplant of SARS-CoV-2–infected Living Donor Liver: Case Report
Authors: Nguyen Michelle C. , Lee Eliza J. , Avery Robin K. , Dioverti-Prono M. Veronica , Shoham Shmuel , Tobian Aaron A. R. , Bloch Evan M. , Gurakar Ahmet , Rizkalla Nicole A. , Cameron Andrew M. , King Elizabeth A. , Ottmann Shane , Garonzik-Wang Jacqueline M. , Wesson Russel N. , Philosophe Benjamin
Published: July 2021

Given the high community prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), transplant programs will encounter SARS-CoV-2 infections in living donors or recipients in the perioperative period. There is limited data on SARS-CoV-2 viremia and organotropism beyond the respiratory tract to inform the risk of transplant transmission of SARS-CoV-2. We report a case of a living donor liver transplant recipient who received a right lobe graft from a living donor with symptomatic PCR-confirmed SARS-CoV-2 infection 3 d following donation. The donor was successfully treated with remdesivir, dexamethasone, and coronavirus disease 2019 (COVID-19) convalescent plasma. No viral transmission was identified, and both donor and recipient had excellent postoperative outcomes.
Global Monitoring of the Impact of COVID-19 Pandemic through Online Surveys Sampled from the Facebook User Base
Authors: Astley Christina M. , Tuli Gaurav , Cord - De Iaco Kimberly A. Mc , Cohn Emily L. , Rader Benjamin , Chiu Samantha , Deng Xiaoyi , Stewart Kathleen , Farag Tamer H. , Barkume Kris M. , LaRocca Sarah , Morris Katherine A. , Kreuter Frauke , Brownstein John S.
Published: July 2021

Simultaneously tracking the global COVID-19 impact across multiple populations is challenging due to regional variation in resources and reporting. Leveraging self-reported survey outcomes via an existing international social media network has the potential to provide reliable and standardized data streams to support monitoring and decision-making world-wide, in real time, and with limited local resources. The University of Maryland Global COVID Trends and Impact Survey (UMD-CTIS), in partnership with Facebook, invites daily cross-sectional samples from the social media platform’s active users to participate in the survey since launch April 23, 2020. COVID-19 indicators through December 20, 2020, from N=31,142,582 responses representing N=114 countries, weighted for nonresponse and adjusted to basic demographics, were benchmarked with government data. COVID-19-related signals showed similar concordance with reported benchmark case and test positivity. Bonferroni significance and minimal Spearman correlation strength thresholds were met in the majority. Light Gradient Boost machine learning trained on national and pooled global data verified known symptom indicators, and predicted COVID-19 trends similar to other signals. Risk mitigation behavior trends are correlated with, but sometimes lag, risk perception trends. In regions with strained health infrastructure, but active social media users, we show it is possible to define suitable COVID-19 impact trajectories. This syndromic surveillance public health tool is the largest global health survey to date, and, with brief participant engagement, can provide meaningful, timely insights into the COVID-19 pandemic and response in regions under-represented in epidemiological analyses.

Significance Statement

The University of Maryland Global COVID Trends and Impact Survey (UMD-CTIS), launched April 23, 2020, is the largest remote global health monitoring system. This study includes about 30 million UMD-CTIS responses over 34 weeks (through December 2020) from N=114 countries with survey-weights to adjust for nonresponse and demographics. Using limited self-reported data, sampled daily from an international cohort of Facebook users, we demonstrate validity and utility for COVID-19 impacts trends, even in regions with scant or delayed government data. We predict COVID-19 cases in the absence of testing, and characterize perceived COVID-19 risk versus risk-lowering measures. The UMD-CTIS has the potential to support existing monitoring systems for the COVID-19 pandemic, as well as other new, as-yet-undefined global health threats.
Mitigating outbreaks in congregate settings by decreasing the size of the susceptible population
Authors: Blumberg Seth , Lu Phoebe , Hoover Christopher M. , Lloyd-Smith James O. , Kwan Ada T. , Sears David , Bertozzi Stefano M. , Worden Lee
Published: July 2021

While many transmission models have been developed for community spread of respiratory pathogens, less attention has been given to modeling the interdependence of disease introduction and spread seen in congregate settings, such as prisons or nursing homes. As demonstrated by the explosive outbreaks of COVID-19 seen in congregate settings, the need for effective outbreak prevention and mitigation strategies for these settings is critical. Here we consider how interventions that decrease the size of the susceptible populations, such as vaccination or depopulation, impact the expected number of infections due to outbreaks. Introduction of disease into the resident population from the community is modeled as a branching process, while spread between residents is modeled via a compartmental model. Control is modeled as a proportional decrease in both the number of susceptible residents and the reproduction number. We find that vaccination or depopulation can have a greater than linear effect on anticipated infections. For example, assuming a reproduction number of 3.0 for density-dependent COVID-19 transmission, we find that reducing the size of the susceptible population by 20% reduced overall disease burden by 47%. We highlight the California state prison system as an example for how these findings provide a quantitative framework for implementing infection control in congregate settings. Additional applications of our modeling framework include optimizing the distribution of residents into independent residential units, and comparison of preemptive versus reactive vaccination strategies.
Progressive Increase in Virulence of Novel SARS-CoV-2 Variants in Ontario, Canada
Authors: Fisman David N. , Tuite Ashleigh R.
Published: July 2021

Background

The period from February to June 2021 was one during which initial wild-type SARS-CoV-2 strains were supplanted in Ontario, Canada, first by variants of concern (VOC) with the N501Y mutation (Alpha/B1.1.17, Beta/B.1.351 and Gamma/P.1 variants), and then by the Delta/B.1.617 variant. The increased transmissibility of these VOCs has been documented but data for increased virulence is limited. We used Ontario’s COVID-19 case data to evaluate the virulence of these VOCs compared to non-VOC SARS-CoV-2 infections, as measured by risk of hospitalization, intensive care unit (ICU) admission, and death.

Methods

We created a retrospective cohort of people in Ontario testing positive for SARS-CoV-2 and screened for VOCs, with dates of test report between February 7 and June 27, 2021 (n=212,332). We constructed mixed effects logistic regression models with hospitalization, ICU admission, and death as outcome variables. Models were adjusted for age, sex, time, vaccination status, comorbidities, and pregnancy status. Health units were included as random intercepts.

Results

Compared to non-VOC SARS-CoV-2 strains, the adjusted elevation in risk associated with N501Y-positive variants was 52% (43-62%) for hospitalization; 89% (67-116%) for ICU admission; and 51% (30-74%) for death. Increases with Delta variant were more pronounced: 108% (80-138%) for hospitalization; 234% (164-331%) for ICU admission; and 132% (47-230%) for death.

Interpretation

The progressive increase in transmissibility and virulence of SARS-CoV-2 VOCs will result in a significantly larger, and more deadly, pandemic than would have occurred in the absence of VOC emergence.
Clonotype pattern in T-cell lymphomas map the cell of origin to immature lymphoid precursors
Authors: Iyer Aishwarya , Hennessey Dylan , Gniadecki Robert
Published: July 2021

Background

Mature T-cell lymphomas (TCLs) are rare, clinically heterogeneous hematologic cancers of high medical need. TCLs have inferior prognosis compared with their B-cell counterparts, which is attributed to poor understanding of their pathogenesis. Based on phenotypic similarities between normal and neoplastic lymphocytes it has been assumed that TCLs develop in the periphery, directly from various subtypes of normal T-cells.

Methods and findings

To address the debated question of the cell of origin in TCLs we analyzed to identify the highly variable complementarity determining regions (CDR3) regions of T-cell receptor (TCR) to trace the clonal history of the T-cells. We have collected previously published whole genome-exome, and -transcriptome sequencing data from 574 TCL patients comprising five nodal lymphomas [anaplastic large cell lymphoma (n=67), peripheral T-cell lymphoma (PTCL, n=55), adult T-cell lymphoma/leukemia (n=135), natural killer T-cell lymphoma (NKCL, n=25), not specified/other (n=30)] and three extranodal, cutaneous T-cell lymphomas [mycosis fungoides (n=122), Sezary syndrome (n=130), and subcutaneous panniculitis-like T-cell lymphoma (n=10)]. TCR clonotypes contained in the tumor cell fraction, representing the clonotypes of malignant cells, were identified by de novo assembly of CDR3 regions of TCR γ, β and α. We have found that the vast majority of TCLs are clonotypically oligoclonal, although the pattern oligoclonality varied. Anaplastic large cell lymphoma was most diverse comprising multiple clonotypes of TCRγ, β and α whereas adult T-cell lymphoma/leukemia and peripheral T-cell lymphomas often showed monoclonality for TCRγ and β but had diverse TCRα clonotypes. These patterns of rearrangements were not compatible with the current mature T-cell precursor model and indicated that TCLs are initiated at the level of the lymphoid precursor. In keeping with this hypothesis, TCR rearrangements in TCLs resembled the pattern seen in the human thymus showing biased usage of V and J segments of high combinatorial probability resulting in recurrent, “public” CDR3 sequences shared between unrelated patients and across different clinical TCL entities. Frequencies of malignant clonotypes followed Zipf-Mandelbrot scaling law suggesting that TCLs comprise an interconnected system of expanding tumor clones.

The major limitation of this study is that it is based on the analysis of the TCR clonotypes and does not directly inform about developmental trajectories of cellular clones.

Conclusions

Lymphoid precursors are the likely cells of origin for mature T-cell lymphomas. Anaplastic large cell lymphoma seems to be derived from the most immature precursors with germline TCR whereas peripheral T-cell lymphoma and adult T-cell lymphoma/leukemia map to the later stages after TCRβ rearrangement stage. Clonotypically diverse initiating cells may seed target tissues being responsible for disease relapses after therapy.
RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer
Authors: Engebraaten Olav , Yau Christina , Berg Kristian , Borgen Elin , Garred Øystein , Berstad Maria E.B. , Fremstedal Ane S.V. , De Michele Angela , van’t Veer Laura , Esserman Laura , Weyergang Anette
Published: July 2021

PURPOSE

Targeted therapeutics strongly depends on validated biomarkers in order to select patients most likely to benefit from the treatment. HER2 serves as a predictive biomarker for HER2-targeted tyrosine kinase inhibitors and monoclonal antibodies. HER2 may, however, also be utilized as a transport gate for delivery of cytotoxic agents into the cell, such as for HER2-targeted antibody drug conjugates (ADCs; e.g. trastuzumab emtansine (T-DM1)). The predictive biomarkers for such ADCs may be more complex, also reflecting the intracellular transport.

METHODS

Five HER2-positive breast and ovarian cancer cell lines were evaluated with respect to T-DM1 sensitivity and correlated to the expression levels of proteins involved in endocytic trafficking including RAB4A, RAB5A and RAB11A, with possible impact on ADC pharmacology. The results were confirmed in a clinical cohort consisting of patients from the adaptive breast cancer clinical trial I-SPY2 where pathological complete response (pCR) was correlated to the RNA expression level of RAB4A, RAB5A and RAB11A. A subset of the clinical KAMILLA trial including 19 patients was used as a verification cohort where semi-quantitative IHC of RAB5A was correlated to progression free survival (PFS).

RESULTS

The early endosome marker RAB5A, was found to correlate positively to T-DM1 sensitivity in the cell line panel. Correlation between RAB5A expression and T-DM1 sensitivity (pCR) was confirmed in patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial, but not in the trastuzumab/paclitaxel control arm. The clinical correlation was verified in the patients from the KAMILLA trial where semi-quantitative RAB5A IHC staining correlated significantly positive to PFS.

CONCLUSION

The present results indicate that RAB5A is a predictive biomarker for T-DM1 and outline, for the first time, proteins involved in endocytic trafficking as predictive biomarkers for ADCs.
Next-generation Serology by Mass Spectrometry: Readout of the SARS-CoV-2 Antibody Repertoire
Authors: Melani Rafael D. , Soye Benjamin J. Des , Kafader Jared O. , Forte Eleonora , Hollas Michael , Blagojevic Voislav , Negrão Fernanda , McGee John P. , Drown Bryon , Lloyd-Jones Cameron , Seckler Henrique S. , Camarillo Jeannie M. , Compton Philip D. , LeDuc Richard D. , Early Bryan , Fellers Ryan T. , Cho Byoung-Kyu , Mattamana Basil Baby , Goo Young Ah , Thomas Paul M. , Ash Michelle K. , Bhimalli Pavan P. , Al-Harthi Lena , Sha Beverly E. , Schneider Jeffrey R. , Kelleher Neil L.
Published: July 2021

Methods of antibody detection are used to assess exposure or immunity to a pathogen. Here, we presentIg-MS, a novel serological readout that captures the immunoglobulin (Ig) repertoire at molecular resolution, including entire variable regions in Ig light and heavy chains. Ig-MS uses recent advances in protein mass spectrometry (MS) for multi-parametric readout of antibodies, with new metrics like Ion Titer (IT) and Degree of Clonality (DoC) capturing the heterogeneity and relative abundance of individual clones without sequencing of B cells. We apply Ig-MS to plasma from subjects with severe & mild COVID-19, using the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as the bait for antibody capture. Importantly, we report a new data type for human serology, with compatibility to any recombinant antigen to gauge our immune responses to vaccination, pathogens, or autoimmune disorders.
A cross-sectional study investigating the prevalence and causes of vision impairment in Northwest Portugal using capture-recapture
Authors: Ramos Pedro Lima , Santana Rui , Marques Ana Patrícia , Sousa Inês , Rocha-Sousa Amândio , Macedo Antonio Filipe
Published: July 2021

Objectives

The aim of this study was to estimate the prevalence and causes of vision impairment (VI) in Portugal.

Setting

Information about people with VI was obtained from Primary Care Centres, blind association (ACAPO) and from hospitals (the PCVIP-study) in the Northwest of Portugal during a period spanning years 2014-2015. Causes of VI were obtained from hospitals.

Participants

Administrative and medical records of people with visual acuity in the better seeing eye of 0.5 decimal (0.30logMAR) or worse and/or visual field less than 20 degrees were investigated. Capture-recapture with log-linear models was applied to estimate the number of individuals missing from lists of cases obtained from available sources.

Primary and secondary outcome measures

Log-linear models were used to estimate the crude prevalence and the category specific prevalence of VI.

Results

Crude prevalence of VI was 1.97% (95%CI=1.56-2.54), and standardized prevalence was 1% (95%CI=0.78-1.27). The age-specific prevalence was 3.27% (95% CI=2.36-4.90), older than 64 years, 0.64% (95%CI=0.49-0.88), aged 25-64 years, and 0.07% (95%CI=0.045-0.13), aged less than 25 years. The female-to-male ratio was1.3, that is, higher prevalence amongst females. The five leading causes of VI were Diabetic Retinopathy, Cataract, Age-related Macular Degeneration, Glaucoma and Disorders of the Globe.

Conclusions

The prevalence of VI in Portugal was within the expected range and in line with other European countries. A significant number of cases of VI might be due to preventable cases and, therefore, a reduction of the prevalence of VI in Portugal seems possible. Women and old people were more likely to have VI and, therefore, these groups require extra attention. Future studies are necessary to characterize temporal changes in prevalence of VI in Portugal.

Strengths and limitations of this study

Medical records and registers of people with vision impairment were used to determine the number of cases in these sources.

Data from 3 sources (lists) with records about people with vision impairment were combined using log-linear models to determine the number of “uncaptured” cases.

Capture-recapture methods were used to determine the prevalence of vision impairment in the Northwest Portugal.

Capture-recapture methods to compute prevalence are more accurate than pure case counting from lists and more affordable than cross-sectional studies.

A limitation of the current study was the low completeness, that is, the number of cases captured compared with the number of uncaptured cases.
Mental Illness Self-Stigma in Young People: A Scoping Review Protocol
Authors: Taylor Rachel , Cogan Nicola , Jenkins Pamela , Liu Xi , Flowers Paul , Hunter Simon C. , Corrigan Patrick
Published: July 2021

Background

Self-stigma (the internalisation of negative stereotypes) is known to reduce help-seeking behaviours and treatment adherence in people who have a mental illness, resulting in worsening health outcomes. Moreover, self-stigma diminishes self-esteem and self-efficacy, and leads to higher levels of depression. Half of all lifetime cases of mental illness have manifested by the age of 14, and therefore young people are vulnerable to the negative impact of suffering mental illness self-stigma. While literature in this field has been flourishing in recent years, mental illness self-stigma remains poorly understood in youth. It is important that we seek to understand what is currently known about mental illness self-stigma in young people, and subsequently use this information to guide future research to advance knowledge of this topic. To date, a scoping review which maps the available literature on mental illness self-stigma in young people has yet to be conducted. Here, we outline the protocol for a scoping review on mental illness self-stigma in young people.

Methods

This protocol outlines the process of conducting a scoping review of primary research concerning mental illness self-stigma in young people. The Joanna Briggs Institute guidance on best practice for conducting a scoping review will utilised throughout. A systematic search of appropriate databases will be conducted which will allow for a two-step screening process and data charting. Inclusion criteria for this review dictates that eligible studies will i) include a population within the age range of 10-35 (or mean age within this range), ii) include the term ‘self-stigma’ or ‘internalised stigma’ relating to mental health/illness/disorder, iii) be primary research, iv) be published post-2009 (following the seminal study by Moses, 2009) and v) be published in English.

Discussion

The findings of the scoping review outlined in this protocol will be used to inform future research which aims to explore self-stigmatising attitudes and beliefs of young people experiencing mental illness. This research will result in co-produced, impactful resources for young people on the topic of mental illness self-stigma with the aim of raising awareness and stigma reduction.
Impairment Of Aversive Episodic Memories During COVID-19 Pandemic: The Impact Of Emotional Context On Memory Processes
Authors: Sofía León Candela , Matías Bonilla , Benítez Facundo Urreta , Ignacio Brusco Luis , Jingyi Wang , Cecilia Forcato
Published: July 2021

The threatening context of the COVID-19 pandemic provided a unique setting to study the effects of negative psychological symptoms on memory processes. Episodic memory is an essential function of the human being related to the ability to store and remember experiences and anticipate possible events in the future. Studying this function in this context is crucial to help understand what effects the pandemic will have on the formation of episodic memories. To study this, the formation of episodic memories was evaluated by free recall, recognition, and episode order tasks for an aversive and neutral content. The results indicated that aversive episodic memory is impaired both in the free recall task and in the recognition task. Even the beneficial effect that emotional memory usually has for the episodic order was undermined as there were no differences between the neutral and aversive condition. The present work adds to the evidence that indicates that the level of activation does not modify memory processes in a linear way, which also depends on the type of evocation that people are asked and the characteristics of the content to be encoded.
Global Effects of a PD Risk-SNP at the Alpha-Synuclein Locus
Authors: Prahl Jordan , Pierce Steven E. , van der Schans Edwin JC , Coetzee Gerhard A. , Tyson Trevor
Published: July 2021

One of the most significant Parkinson’s disease (PD) risk variants, rs356182, is located at the PD-associated locus near the alpha-synuclein encoding gene, SNCA. SNCA-proximal variants, including rs356182, are thought to function in PD via allele-specific regulatory effects on SNCA expression. However, this interpretation discounts the complex activity of genetic enhancers and possible nonconical effects of alpha-synuclein. Here we investigate a novel risk mechanism for rs356182. We use CRISPR-Cas9 in LUHMES cells, a model for dopaminergic neurons, to generate precise hemizygous lesions at rs356182. The PD-protective (A/-), PD-risk (G/-), and WT (A/G) strains are differentiated into dopaminergic neurons then compared transcriptionally and morphologically. We observe effects not typically ascribed to SNCA; hundreds of differentially expressed genes associated with neuronal differentiation and axonogenesis. Together, the data implicate a risk mechanism for rs356182 in which the risk-allele (G) is associated with abnormal neuronal differentiation. We speculate the disease-relevant effect originates as a diminished population of DA neurons leading to the predisposition for PD later in life.
Identification of the functions of 4-coumarate-CoA ligase/ acyl-CoA synthetase paralogs in potato
Authors: Valiñas Matías Ariel , Have Arjen ten , Andreu Adriana Balbina
Published: July 2021

Background

The 4CL/ ACS protein family is well known for its 4-coumarate-CoA ligase (4CL) enzymes but there are many aspects of this family that are still unclear or generally known. Cytosolic class I and class II 4CL enzymes control the biosynthesis of lignin/ suberin and flavonoids, respectively. Many 4CL homologs have broad substrate permissiveness in vitro and have no clear cut function. However, it has been demonstrated unequivocally that a peroxisomal 4CL-like homolog from Arabidopsis efficiently uses p-coumarate for ubiquinone biosynthesis. Another homolog has been shown to act as a fatty acyl-CoA synthetase and yet another as OPDA-CoA ligase. Hence, despite this knowledge, most homologs remain annotated as “4CL-like” whereas other researches study the ACS protein family.

Results

We set out identify the specific functions of 4CL/ ACS homologs, specifically in order to study the 4CL family in Solanum tuberosum. An in depth phylogenetic analysis was done. Using clustering techniques, functional annotation and taxonomic signals, three major clades were depicted. Clade 1 is composed of class I from monocotyledons, class I from dicotyledons and class II canonical 4CL enzymes subclades. Specificity determining positions and 3D structure analysis shows that clade 2 cytosolic 4CL-like enzymes show a rather different binding cleft and presumably use medium- to long-chain fatty acids. Clade 3 is composed of five subclades, four of which have a broad taxonomic contribution and a similar binding cleft as 4CLs whereas a fifth, specific for dicotyledons shows a significantly different binding pocket. The potato 4CL family comprises four class I (St4CL-I(A-D)) and one class II (St4CL-II) members. Transcript levels of St4CLs and of marker genes of the flavonoid (chalcone synthase, CHS) and suberin (feruloyl-CoA transferase, FHT) pathways were determined by qRT-PCR in flesh and skin from Andean varieties. St4CL-IA was barely detected in the skin of some varieties whereas St4CL-IB did not show a clear pattern. St4CL-IC and St4CL-ID could not be detected. St4CL-II expression pattern was similar to CHS. St4CL-IA and St4CL-IB were induced by wounding as did FHT whereas St4CL-II and CHS expression was repressed. Constitutive and wound-induced expression suggests that St4CL-IA and St4CL-IB isoforms are likely involved in soluble and/ or suberin-bound phenolic compounds while St4CL-II appears to be involved in flavonoid biosynthesis.
Rapid speciation and karyotype evolution in Orthoptera
Authors: Palacios-Gimenez Octavio M.
Published: July 2021

To test the hypothesis that high speciation rate in groups is coupled with high rate of karyotype evolution but also that younger groups having a higher rate of karyotypic diversity, I estimated rates of speciation and rates of karyotype evolution in 1,177 species belonging to 26 families in the insect order Orthoptera. Rates of karyotype evolution were estimated using the diploid number and the number of chromosome arms (fundamental number) from published karyotypes of Orthoptera. Rates of speciation were quantified considering the number of species examined karyotypically in each family, the most recent common ancestor of each family and the information about extinction rate. The rate of speciation was strongly correlated with rate of karyotype evolution and the average rates of speciation was nearly ~177 times higher than the background rate estimated for Orthoptera based on acoustic communication using phylogenomic data, as well as 8.4 and 35.6 times higher than the estimated speciation rate in vertebrates and bivalve mollusks respectively, indicating that Orthoptera has evolved very fast at chromosomal level. The findings supported the hypothesis of a high speciation rate in lineages with high rate of chromosomal evolution but there were not evidences that younger groups tended to have higher rate of karyotypic diversity. Furthermore, rates of karyotype evolution most closely fitted the punctuational evolutionary model indicating the existence of long periods of stasis of karyotype change with most karyotype change occurring quickly over short evolutionary times. I discussed genetic drift, divergent selection and meiotic drive as potential biological mechanisms to explain karyotype evolution allowing or impeding for the fixation of chromosomal rearrangements and in turn speciation in orthopterans lineages.
Approximation of the age distribution of cancer incidence using a mutational model
Authors: Tetearing Alexandr N.
Published: July 2021

The approximation of the age distributions of cancers was carried out using a complex mutational model presented in our work [1]. Datasets from the American National Cancer Institute (SEER program) were used.

We approximated the datasets for the age distributions of lung, stomach, colon and breast cancer in women; cancer of the lung, stomach, colon and prostate in men.

The average number of mutations (required for cancer formation) averaged over the four types of cancer is 5 mutations per cell in women and in men. The average (over the four types of cancer) mutation rate is estimated as 1.0 · 10 −1 mutations per year per cell for women and 3.8 · 10 −1 mutations per year per cell for men.

This article is a continuation of work [1].
Receptor-binding domain recombinant protein on alum-CpG induces broad protection against SARS-CoV-2 variants of concern
Authors: Pollet Jeroen , Strych Ulrich , Chen Wen-Hsiang , Versteeg Leroy , Keegan Brian , Zhan Bin , Wei Junfei , Liu Zhuyun , Lee Jungsoon , Kundu Rakhi , Adhikari Rakesh , Poveda Cristina , Villar Maria Jose , Thimmiraju Syamala Rani , Lopez Brianna , Gillespie Portia M. , Ronca Shannon , Kimata Jason T. , Reers Martin , Paradkar Vikram , Hotez Peter , Bottazzi Maria Elena
Published: July 2021

We conducted preclinical studies in mice using a yeast-produced SARS-CoV-2 RBD subunit vaccine candidate formulated with aluminum hydroxide (alum) and CpG deoxynucleotides. This formulation is equivalent to the CorbevaxTM vaccine that recently received emergency use authorization by the Drugs Controller General of India. We compared the immune response of mice vaccinated with RBD/alum to mice vaccinated with RBD/alum+CpG. We also evaluated mice immunized with RBD/alum+CpG and boosted with RBD/alum. Mice were immunized twice intramuscularly at a 21-day interval. Compared to two doses of the /alum formulation, the RBD/alum+CpG vaccine induced a stronger and more balanced Th1/Th2 cellular immune response, with high levels of neutralizing antibodies against the original Wuhan isolate of SARS-CoV-2 as well as the B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 and (Delta) variants. Neutralizing antibody titers against the B.1.1.529 (BA.1, Omicron) variant exceeded those in human convalescent plasma after Wuhan infection but were lower than against the other variants. Interestingly, the second dose did not benefit from the addition of CpG, possibly allowing dose-sparing of the adjuvant in the future. The data reported here reinforces that the RBD/alum+CpG vaccine formulation is suitable for inducing broadly neutralizing antibodies against SARS-CoV-2 including variants of concern.