bluuebunny/crossref_metadata_2025 huggingface dataset:
Post SARS-CoV-2 cell mediated Immune profiles; Case studies
Authors: Singh Rajveer , Ravichandiran Velayutham , Ghosh Dipanjan , Ray Ujjaini , Dasgupta Sarbani , Dutta Soma , Saha Aditi , Roy Debabrota , Ghosh Srinika , Somasundaram A. , Dutta Pallab , Ganguly N K , Datta Debatosh
Published: July 2022

Cell-mediated immunity (CMI), which includes T-cells (both T helper and cytotoxic), is critical for effective antiviral defenses against coronavirus disease-2019 (COVID-19). To better understand the immunological characteristics of CD markers on T-cells in post-COVID-19 patients, we investigated the expression of differential CD markers in the patient groups in this study.

Flow cytometry was used to quantify total lymphocyte count and assess the levels of expression of CD markers in the samples. The percentage of Lymphocytes decreased significantly in the post-SARS-COV-2 patients in comparison to normal subjects, which is usually happening in any viral infection. In contrast to that, expression of CD8 was increased in the patient group having long SARS-COV-2 infection with comorbid complications with respect to the normal individuals and long SARS-COV-2 infection without comorbid complications. This data revealed that the cellular immunological responses corroborated with an earlier report of COVID-19 infection were mediated by CD8 upregulation and cytotoxic T lymphocyte hyperactivation.
Using machine learning probabilities to identify effects of COVID-19
Authors: Ramlall Vijendra , May Benjamin , Tatonetti Nicholas P
Published: July 2022

COVID-19, the disease caused by the SARS-CoV-2 virus, has had and continues to have extensive economic, social and public health impacts in the United States and around the world. To date, there have been more than 500 million reported cases of SARS-CoV-2 infection worldwide with more than 6 million reported deaths, more than 80 million of those cases and more than 1 million of those deaths have been reported in the United States. Retrospective analysis throughout the pandemic, which identified comorbidities, risk factors and treatments, has underpinned the response COVID-19. As the situation transitions from a pandemic to an endemic, retrospective analyses using electronic health records will be increasingly important to identify long term effects of COVID-19. However, these analyses can be complicated by the incompleteness of electronic health records, which in turns makes it difficult to differentiate visits where the patient has COVID-19. To address this, we trained a random forest classifier to assign a probability of a patient having been diagnosed with COVID-19 during each visit using demographic data, temporal data and visit-specific diagnoses (Training AUROC = 0.9867, Training OOB AUROC = 0.8957, Evaluation AUROC = 0.8958). Using these probabilities, we identified conditions associated with higher COVID-19 probabilities irrespective of clinical history and when accounting for previous diagnosis and estimated the hazards ratio for myocardial infarction (Hazards ratio = 121.736 (87.375, 169.611),p= 3.796E-177 and Hazards ratio = 80.262 (4.134, 4.637),p= 4.543E-256, respectively), urinary tract infection (Hazards ratio = 72.021 (58.116 - 89.253),p< 2.225E-308 and Hazards ratio = 61.380 (51.273 - 73.479),p< 2.225E-308, respectively), acute renal failure (Hazards ratio = 1.264E4 (9.278E4 - 1.724E4),p< 2.225E-308 and Hazards ratio = 6.333E3 (4.947E3 - 8.108E3),p< 2.225E-308, respectively) and type 2 diabetes (Hazards ratio = 345.730 (283.180 - 422.098),p< 2.225E-308 and Hazards ratio = 217.271 (187.898 - 251.235),p= 1.39E-22, respectively) when accounting for demographics and the ten most common clinical conditions.
Environmental surveillance of poliovirus in four districts within two regions of Ghana
Authors: Obese-Djomoah Ernest , Obodai Evangeline , Gberbi Emmanuel , Duker Ewurabena , Attiku Keren , Eshun Miriam , Boahene Bismarck , Nuvor Samuel Victor , Odoom John Kofi
Published: July 2022

The eradication of poliovirus is at its last phase through the efforts and strategies of Global Polio Eradication Initiation (GPEI). There are very few countries that are still endemic with wild poliovirus (WPV) and others with circulating vaccine derived poliovirus (cVDPV). The aim of the study was to detect silent circulation of WPV and VDPV in four districts within the Eastern and Volta region of Ghana. A systematic longitudinal design was used for the study. The convenient sampling technique was used to collect the samples every four weeks from two open and close sewage systems. The open sewage systems were located in New Juabeng and Ho districts while the close sewage systems were located in Asuogyaman and Ketu South districts. A total of 35 sewage samples were collected from September 2018 to May 2019. L20B and RD cell lines were used for the purification of poliovirus (PV) while real-time reverse transcriptase polymerase chain reaction (rRT-PCR) was use to characterize the serotypes of the PVs. The findings of the study showed that the prevalence of non-polio enterovirus (NPEV) and Sabin were 65.71% and 14.29% respectively. The characterized Sabins were serotype 1 and serotype 3 which were circulating in the two districts within the Eastern Region. The study did not detect any WPV and VDPV but isolated Sabin strains of the poliovirus. This necessitates the need for continuous environmental surveillance for poliovirus nationwide.
Membrane curvature sensing and symmetry breaking of the M2 proton channel from Influenza A
Authors: Helsell Cole V. M. , Marcoline Frank V. , Lincoff James , Natale Andrew M. , Grabe Michael
Published: July 2022

The M2 proton channel aids in the exit of mature influenza viral particles from the host plasma membrane through its ability to stabilize regions of high negative gaussian curvature (NGC) that occur at the neck of budding virions. The channels are homo-tetramers that contain a cytoplasm-facing amphipathic helix (AH) that is necessary and sufficient for NGC generation; however, constructs containing the transmembrane spanning helix, which facilitates tetramerization, exhibit enhanced curvature generation. Here we used all-atom molecular dynamics (MD) simulations to explore the conformational dynamics of M2 channels in lipid bilayers revealing that the AH is dynamic, quickly breaking the 4-fold symmetry observed in most structures. Next, we carried out MD simulations with the protein restrained in 4-fold and 2-fold symmetric conformations to determine the impact on the membrane shape. While each pattern was distinct, all configurations induced pronounced curvature in the outer leaflet with rather subtle lipid tilt, while conversely, the inner leaflets adjacent to the AHs showed minimal curvature and significant lipid tilt. The MD-generated profiles at the protein-membrane interface were then extracted and used as boundary conditions in a continuum elastic membrane model to calculate the membrane bending energy of each conformation embedded in different membrane surfaces characteristic of a budding virus. The calculations show that all three M2 conformations are stabilized in concave spherical caps and destabilized in convex spherical caps, the latter reminiscent of a budding virus. Only C2-broken symmetry conformations are stabilized in NGC surfaces, by 1-3 kBT depending on the AH domain arrangement. The most favored conformation is stabilized in saddles with curvatures corresponding to 33 nm radii. In total, our work provides atomistic insight into the curvature sensing capabilities of M2 channels and how enrichment in the nascent viral particle depends on protein shape and membrane geometry.
Clinical characteristics and factors associated with COVID-19-related mortality and hospital admission in 5 rural provinces in Indonesia: a retrospective cohort study
Authors: Surendra Henry , Praptiningsih C Yekti , Ersanti Arina M , Rahmat Mariati , Noviyanti Widia , Harmani Joshua AD , Mansur Erni NA , Suleman Yana Y , Sudrani Sitti , Rosalina Rosalina , Mukhtar Ismen , Rosadi Dian , Fauzi Lukman , Elyazar Iqbal RF , Hawley William A , Wibisono Hariadi
Published: July 2022

Background

Data on COVID-19 clinical characteristics and severity from resource-limited settings are limited. This study examined clinical characteristics and factors associated with COVID-19 mortality and hospitalisation in rural settings of Indonesia, from 1 January to 31 July, 2021.

Methods

This retrospective cohort included individuals diagnosed with COVID-19 based on polymerase chain reaction or rapid antigen diagnostic test, from Lampung, Gorontalo, Central Sulawesi, Southeast Sulawesi, and East Nusa Tenggara Provinces. We extracted demographic and clinical data, including hospitalisation and mortality from COVID-19 surveillance records. We used mixed-effect logistic regression to examine factors associated with COVID-19-related mortality and hospitalisation.

Results

Of 6,583 confirmed cases, 205 (3.1%) died, and 1,727 (26%) were hospitalised. The median age was 37 years (IQR 26-52), with 825 (12·53%) under 20 years, and 3,371 (51.21%) females. 4,533 (68.86%) cases were symptomatic, 319 (4.85%) had a clinical diagnosis of pneumonia, and 945 (14.36%) with at least one pre-existing comorbidity. The mortality and hospitalisation rate ranged from 2.0% and 13.4% in East Nusa Tenggara to 4.3% and 36·1% in Lampung. Age-specific mortality rates were 0.9% (2/340) for 0-4 years; 0% (0/112) for 5-9 years; 0.2% (1/498) for 10-19 years; 0.8% (11/1,385) for 20-29 years; 0.9% (12/1,382) for 30-39 years; 2% (23/1,095) for 40-49 years; 5% (57/1,064) for 50-59 years; 11% (62/576) for 60-69 years; 16% (37/232) for ≥70 years. Older age, pre-existing diabetes, liver diseases, malignancy, and pneumonia were associated with higher risk of mortality and hospitalisation. Pre-existing hypertension, cardiac diseases, chronic kidney disease, COPD, and immunocompromised condition were associated with risk of hospitalisation but not with mortality.

Conclusion

Clinical characteristics and risk factors of severe COVID-19 outcomes in rural provinces were broadly similar to those in urban settings. The risk of COVID-19-related mortality and hospitalisation was associated with higher age, pre-existing chronic comorbidities, and clinical presentation of pneumonia.
Tissue confinement regulates cell growth and size in epithelia
Authors: Devany John , Falk Martin J , Holt Liam J , Murugan Arvind , Gardel Margaret L
Published: July 2022

Cell proliferation is a central process in tissue development, homeostasis and disease. Yet how proliferation is regulated in the tissue context remains poorly understood. Here, we introduce a quantitative framework to elucidate how tissue growth dynamics regulate cell proliferation. We show that tissue growth causes confinement that suppresses cell growth; however, this confinement does not directly affect the cell cycle. This leads to uncoupling between rates of cell growth and division in epithelia and, thereby, reduces cell size. Division becomes arrested at a minimal cell size, which is consistent across diverse epithelia in vivo. Here, the nucleus approaches a volume limit set by the compacted genome. The loss of Cyclin D1-dependent cell size regulation results in an abnormally high nuclear-to-cytoplasmic volume ratio and DNA damage. Overall, we demonstrate how epithelial proliferation is regulated by the interplay between tissue confinement and cell size regulation.

Highlights

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In epithelia, regulation of cell growth and cycle are uncoupled

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Cell growth is regulated by tissue-scale dynamics, which determine confinement

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Cell volume in epithelial tissue is described by G1 sizer model with a tunable growth rate

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Volume of cells in epithelial tissues is near a minimum set by genome size
Spatial and Temporal Origin of The Third SARS-Cov-2 Outbreak in Taiwan
Authors: Tai Jui-Hung , Low Yu Ken , Wang Selina Cai-Ling , Lin Hsin-Fu , Wang Tzi-Yuan , Wang Jann-Tay , Liu Yu-Shu , Lin You-Yu , Foster Charles S.P. , van Hal Sebastiaan J. , Lai Ya-Yun , Yeh Shiou-Hwei , Chang Sui-Yuan , Chen Pei-Jer , Chaw Shu-Miaw
Published: July 2022

Since the first report of SARS-CoV-2 in December 2019, Taiwan has gone through three local outbreaks. Unlike the first two outbreaks, the spatial and temporal origin of the third outbreak (April 20 to November 5, 2021) is still unclear. We assembled and analyzed a data set of more than 6,000 SARS-CoV-2 genomes, including 300 from Taiwan and 5812 related sequences downloaded from GISAID as of 2021/12/08. We found that the third outbreak in Taiwan was caused by a single virus lineage belonging to Alpha (B.1.1.7) strain. This lineage, T-III (the third outbreak in Taiwan), carries a distinct genetic fingerprint, consisting of spike M1237I (S-M1237I) and three silent mutations, C5812T, C15895T, and T27869C. The T-III is closest to the sequences derived from Turkey on February 8, 2021. The estimated age of the most recent common ancestor (TMRCA) of T-III is March 23, 2021 (95% highest posterior density [HPD] February 24 - April 13, 2021), almost one month before the first three confirmed cases on April 20, 2021. The effective population size of the T-III showed approximately 20-fold increase after the onset of the outbreak and reached a plateau in early June 2021. Our results reconcile several unresolved observations, including the occurrence of two infection clusters at the same time without traceable connection and several airline pilots who were PCR negative but serum IgM-/IgG+ for SARS-CoV-2 in late April. Therefore, in contrast to the general notion that the third SARS-CoV-2 outbreak in Taiwan was sparked by two imported cases from USA on April 20, 2021, which, in turn, was caused by the partial relaxation of entry quarantine measures in early April 2021, our comprehensive analyses demonstrated that the outbreak was most likely originated from Europe in February 2021.
The Hidden Model Space of Phylogenetic State-Dependent Diversification Models (SSEs): Congruence, Challenges, and Opportunities
Authors: Tarasov Sergei , Uyeda Josef
Published: July 2022

A recent study (Louca and Pennell, 2020) spotlighted the issue of model congruence, or asymptotic unidentifiability, in time-dependent birth-death models used for reconstructing species diversification histories on phylogenetic trees. The present work investigates this issue in state-dependent speciation and extinction (SSE) models, commonly used to study trait-dependent diversification. We found that model unidentifiability is universal due to hidden states, with every SSE belonging to an infinite congruence class. Notably, any trait-independent model is congruent with trait-dependent models, raising concerns for hypothesis testing. To address this, we propose an analytical solution that resolves model selection within a congruence class. Our findings show that this type of congruence is the only one possible, and with our solution in place, model unidentifiability in SSEs becomes absolutely harmless for inference. However, model selection across congruence classes remains challenging due to extremely high false positive rates. The discovered congruence offers a clear explanation of this issue and suggests potential ways forward.
Large-scale expansions and replication stalling of Friedreich’s ataxia GAA repeats in an experimental mammalian system
Authors: Rastokina Anastasia , Cebrián Jorge , Mandel Nicholas , Zain Rula , Lopes Massimo , Mirkin Sergei M.
Published: July 2022

1

Human disease Friedreich’s ataxia (FRDA) is caused by large-scale expansions of (GAA)n repeats in the first intron of the FXN gene. While repeat expansions during intergenerational transmissions are causative for the disease development, somatic expansions additionally contribute to the disease progression. We and others have previously shown that (GAA)n repeats transiently pause the replication fork progression in cultured human cells. However, whether and by which mechanisms fork stalling underlies repeat expansions remained unclear. Here we developed a new genetically tractable experimental system to simultaneously analyze repeat-mediated fork stalling and large-scale repeat expansions in cultured human cells. It is based on a mammalian/yeast shuttle vector that can transiently replicate from the SV40 replication origin in human HEK-293T cells or be stably maintained in S. cerevisiae utilizing ARS4-CEN6; it also contains a cassette for selecting repeat expansions in yeast. Repeat expansions accumulate in mammalian cells and are then detected upon plasmid transformation into yeast. We found that large-scale expansions of (GAA)n repeats do occur in this experimental mammalian system. Further, we observed that repeat expansions’ frequency depends on several previously implicated proteins in replication fork stalling, reversal, and restart. These proteins include SHPRH, RAD52, ZRANB3, DDX11, SMARCAL1, HLTF, RECQ1 and WRN. Therefore, we propose that GAA repeat expansions might occur as a consequence of deregulated replication fork regression and restoration process.
Point-of-care thermal imaging tool assisting in the development of imaging biomarker as pre-diagnostics of graves’ disease
Authors: Sharma Vaishali , Dhingra Vandana K , Kumar Ashok , Shakya Snehlata , Goswami Mayank
Published: July 2022

This article presents the development of a tool to address the scarcity of clinically validated datasets for Thyroid related abnormalities. Infrared thermography Images are taken from each of the sixty persons of different age groups and gender. Scintigraphy and standard thyroid blood test results are used to categorize these persons into thirty-three females and thirteen males suffering from graves’ disease. Eleven females and three males are found to be in healthy conditions and used as control. An Artificial Intelligence algorithm is used to automatically segment and extract the histogram-associated information within the thyroid and cheek region from the collected images. A very simple and novel imaging biomarker is found to be moderately correlated w.r.t age and gender. A smartphone app integrated with a dedicated smartphone-based compact IR camera add-on is developed and deployed in a clinical environment to enrich the analysis. This point-of-care tool is expected to categorize healthy cases from patients automatically. It is to reduce the ethical burden on clinicians’ shoulders before recommending radioactive contamination-prone Scintigraphy and/or expensive and relatively slower thyroid blood tests. If adopted, such preliminary tests will save costs on patients’ end and burden at pathology labs, especially in densely populated countries such as India.
Proximity to livestock farms and COVID-19 in the Netherlands, 2020-2021
Authors: Hogerwerf Lenny , Post Pim M. , Bom Ben , van der Hoek Wim , van de Kassteele Jan , Stemerding Annette M. , de Vries Wilco , Houthuijs Danny
Published: July 2022

Objectives

In the Netherlands, during the first phase of the COVID-19 epidemic, the hotspot of COVID-19 overlapped with the country’s main livestock area, while in subsequent phases this distinct spatial pattern disappeared. Previous studies show that living near livestock farms influence human respiratory health and immunological responses. This study aimed to explore whether proximity to livestock was associated with SARS-CoV-2 infection.

Methods

The associations between residential (6-digit postal-code) distance to the nearest livestock farm and individuals’ SARS-CoV-2 status was studied in multilevel logistic regression models, comparing individuals notified with a positive SARS-CoV-2 test to the general population in the Netherlands. Data included all reported Dutch laboratory-confirmed patients with disease onset before 1 January 2022. Individuals living in strongly urbanised areas and border areas were excluded. Models were adjusted for individuals’ age categories, the social status of the postal code area, particulate matter (PM10)-and nitrogen dioxide (NO2)-concentrations. We analysed data for the entire period and population as well as separately for eight time periods (Jan-Mar, Apr-Jun, Jul-Sep and Oct-Dec in 2020 and 2021), four geographic areas of the Netherlands (north, east, west and south), and for five age categories (0-14, 15-24, 25-44, 45-64 and > 65 years).

Results

Over the period 2020-2021, individuals’ SARS-CoV-2 status was associated with living closer to livestock farms. This association increased from an Odds Ratio (OR) of 1.01 (95% Confidence Interval [CI] 1.01-1.02) for patients living at a distance of 751-1000 m to a farm to an OR of 1.04 (95% CI 1.04-1.04), 1.07 (95% CI 1.06-1.07) and 1.11 (95% CI 1.10-1.12) for patients living in the more proximate 501-750 m, 251-500m and 0-250 m zones around farms, all relative to patients living further than 1000 m around farms. This association was observed in three out of four quarters of the year in both 2020 and 2021, and in all studied geographic areas and age groups.

Conclusions

In this exploratory study with individual SARS-CoV-2 notification data and high-resolution spatial data associations were found between living near livestock farms and individuals’ SARS-CoV-2 status in the Netherlands. Verification of the results in other countries is warranted, as well as investigations into possible underlying mechanisms.
Real-world experience with molnupiravir during the period of SARS-CoV-2 Omicron variant dominance
Authors: Flisiak Robert , Zarębska-Michaluk Dorota , Rogalska Magdalena , Kryńska Justyna Anna , Kowalska Justyna , Dutkiewicz Ewa , Dobrowolska Krystyna , Jaroszewicz Jerzy , Moniuszko-Malinowska Anna , Rorat Marta , Podlasin Regina , Tronina Olga , Rzymski Piotr
Published: July 2022

Background

The real-world effectiveness of molnupiravir (MOL) during the dominance of Omicron SARS-CoV-2 lineage is urgently needed since the available data relates to the period of circulation of other viral variants. Therefore, this study assessed the efficacy of MOL in patients hospitalized for COVID-19 in a real-world clinical practice during the wave of Omicron infections.

Methods

Among 11822 patients hospitalized after 1 March 2020 and included in the SARSTer national database, 590 were treated between 1 January and 31 April 2022, a period of dominance of the Omicron SARS-CoV-2 variant. MOL was administered to 203 patients, whereas 387 did not receive any antiviral regimen. Both groups were similar in terms of sex, BMI and age allowing for direct comparisons

Results

Patients who did not receive antiviral therapy significantly more often required the use of Dexamethasone and Baricitinib. Treatment with MOL resulted in a statistically significant reduction in mortality during the 28-day follow-up (9.9 vs. 16.3%), which was particularly evident in the population of patients over 80 years of age treated in the first 5 days of the disease (14.6 vs. 35.2%). MOL therapy did not affect the frequency of the need for mechanical ventilation, but patients treated with MOL required oxygen supplementation less frequently than those without antivirals (31.7 vs. 49.2%). The time of hospitalization did not differ between groups.

Conclusions

The use of molnupiravir in patients hospitalized for COVID-19 during the dominance of Omicron variant reduced mortality. This effect is particularly evident in patients over 80 years of age.
The causal effect of cigarette smoking on healthcare costs
Authors: Dixon Padraig , Sallis Hannah , Munafo Marcus , Smith George Davey , Howe Laura
Published: July 2022

Knowledge of the impact of smoking on healthcare costs is important for establishing the external effects of smoking and for evaluating policies intended to modify this behavior. Conventional analysis of this association is difficult because of omitted variable bias, reverse causality, and measurement error. We approached these challenges using a Mendelian Randomization study design, in which genetic variants associated with smoking behaviors were used as instrumental variables. We undertook genome wide association studies to identify genetic variants associated with smoking initiation and a composite index of lifetime smoking on up to 300,045 individuals in the UK Biobank cohort. These variants were used in two-stage least square models and a variety of sensitivity analyses. All results were concordant in indicating a substantial impact of each smoking exposure on annual inpatient hospital costs Our results indicate a substantial impact of smoking on hospital costs. Genetic liability to initiate smoking – ever versus never having smoked – was estimated to increase mean per-patient annual hospital costs by £477 (95% confidence interval (CI): £187 to £766). A one unit change in genetic liability a composite index reflecting the cumulative health impacts of smoking was estimated to increase these costs by £204 (95% CI: £105 to £303). Models conditioning on the causal effect of risk tolerance were not robust to weak instruments for this exposure. Our findings have implications for the scale of external effects that smokers impose on others, and on the probable cost-effectiveness of smoking interventions.
Genome-wide association meta-analysis of spontaneous coronary artery dissection reveals common variants and genes related to artery integrity and tissue-mediated coagulation
Authors: Adlam David , Berrandou Takiy-Eddine , Georges Adrien , Nelson Christopher P. , Giannoulatou Eleni , Henry Joséphine , Ma Lijiang , Blencowe Montgomery , Turley Tamiel N. , Yang Min-Lee , Braund Peter S. , Sadeg-Sayoud Ines , Iismaa Siiri E. , Kosel Matthew L. , Zhou Xiang , Hamby Stephen E. , Cheng Jenny , Liu Lu , Tarr Ingrid , Muller David W.M. , d’Escamard Valentina , King Annette , Brunham Liam R. , Baranowska-Clarke Ania A. , Debette Stéphanie , Amouyel Philippe , Olin Jeffrey W. , Patil Snehal , Hesselson Stephanie E. , Junday Keerat , Kanoni Stavroula , Aragam Krishna , Butterworth Adam S. ,   CARDIoGRAMPlusC4D,   MEGASTROKE,   International stroke genetics consortium (ISGC) intracranial aneurysm working group, Tweet Marysia S. , Gulati Rajiv , Combaret Nicolas ,   DISCO register investigators, Kadian-Dodov Daniella , Kalman Jon , Fatkin Diane , Saw Jacqueline , Webb Tom R. , Hayes Sharonne N. , Yang Xia , Ganesh Santhi K. , Olson Timothy M. , Kovacic Jason C. , Graham Robert M. , Samani Nilesh J. , Bouatia-Naji Nabila
Published: July 2022

Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Through a meta-analysis of genome-wide association studies including 1917 cases and 9292 controls of European ancestry, we identified 17 risk loci, including 12 new, with odds ratios ranging from 2.04 (95%CI 1.77-2.35) on chr21 to 1.25 (95%CI 1.16-1.35) on chr4. A locus on chr1 containing the tissue factor gene (F3), which is involved in blood coagulation cascade, appears to be specific for SCAD risk. Prioritized genes were mainly expressed in vascular smooth muscle cells and fibroblasts of arteries and are implicated predominantly in extracellular matrix biology (e.g. COL4A1/A2, HTRA1 and TIMP3). We found that several variants associated with SCAD had diametrically opposite associations with CAD suggesting that shared biological processes contribute to both diseases but through different mechanisms. We also demonstrated an inferred causal role for high blood pressure, but not other CAD risk factors, in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and prevention for this disease.
Reproducibility of neuroimaging studies of brain disorders with hundreds -not thousands- of participants
Authors: Libedinsky Ilan , Helwegen Koen , Dannlowski Udo , Fornito Alex , Repple Jonathan , Zalesky Andrew ,   Alzheimer’s Disease Neuroimaging Initiative,   Alzheimer’s Disease Repository Without Borders Investigators, Breakspear Michael , van den Heuvel Martijn P.
Published: July 2022

An important current question in neuroimaging concerns the sample sizes required for producing reliable and reproducible results. Recent findings suggest that brain-wide association studies (BWAS) linking neuroimaging features with behavioural phenotypes in the general population are characterised by (very) weak effects and consequently need large samples sizes of 3000+ to lead to reproducible findings. A second, important goal in neuroimaging is to study brain structure and function under disease conditions, where effects are likely much larger. This difference in effect size is important. We show by means of power calculations and empirical analysis that neuroimaging studies in clinical populations need hundreds -and not necessarily thousands-of participants to lead to reproducible findings.
Phosphorylation of aldose-6-phosphate reductase from Prunus persica leaves
Authors: Hartman Matías D. , Rojas Bruno E. , Ferrero Danisa M. L. , Leyva Alejandro , Durán Rosario , Iglesias Alberto A. , Figueroa Carlos M.
Published: July 2022

Sugar-alcohols are major photosynthates in plants from the Rosaceae family. Expression of the gene encoding aldose-6-phosphate reductase (Ald6PRase), the critical enzyme for glucitol synthesis in rosaceous species, is regulated by physiological and environmental cues. Additionally, Ald6PRase is inhibited by small molecules (hexose-phosphates and inorganic orthophosphate) and oxidizing compounds. This work demonstrates that Ald6PRase from peach leaves is phosphorylated in planta at the N-terminus. We also show in vitro phosphorylation of recombinant Ald6PRase by a partially purified kinase extract from peach leaves containing Ca2+-dependent protein kinases (CDPKs). Moreover, phosphorylation of recombinant Ald6PRase was inhibited by hexose-phosphates, phosphoenolpyruvate and pyrophosphate. We further show that phosphorylation of recombinant Ald6PRase was maximal using recombinant CDPKs. Overall, our results suggest that phosphorylation could fine-tune the activity of Ald6PRase.
Understanding The Role of Heparinoids on the SARS-CoV-2 Spike Protein through Molecular Dynamics Simulations
Authors: Pipitò Ludovico , Reynolds Christopher A. , Deganutti Giuseppe
Published: July 2022

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a threat, with an estimated number of deaths exceeding 5 million. SARS-CoV-2 entry into the cell is mediated by its transmembrane spike glycoprotein (S protein), and the angiotensin-converting enzyme 2 (ACE2) receptor on the human cell surface. The extracellular heparan sulphate (EcHS) enhances the S protein binding through a mechanism that is still unknown. Surprisingly, low molecular weight heparin (LMWH) and HS in the disaccharide form (dHS) hinder the S protein binding to ACE2, despite the similarity with EcHS. We investigated the molecular mechanism behind this inhibition through molecular dynamics (MD) simulations to understand the interaction pattern of the heparinoids with S protein and ACE2 receptor.
Local changes dominate variation in biotic homogenization and differentiation
Authors: Blowes Shane A. , McGill Brian , Brambilla Viviana , Chow Cher F. Y. , Engel Thore , Fontrodona-Eslava Ada , Martins Inês S. , McGlinn Daniel , Moyes Faye , Sagouis Alban , Shimadzu Hideyasu , van Klink Roel , Xu Wu-Bing , Gotelli Nicholas J. , Magurran Anne , Dornelas Maria , Chase Jonathan M.
Published: July 2022

It is commonly thought that the biodiversity crisis includes widespread decreases in the uniqueness of different sites in a landscape (biotic homogenization). Using a typology relating homogenization and differentiation to local and regional diversity changes, we synthesize patterns across 283 metacommunities surveyed for 10-91 years, and 54 species checklists (13-500+ years). On average, there is a 0.2% increase in species shared among communities/year (i.e., weak homogenization), but across data sets, differentiation frequently occurs, with no statistically significant change being most common. Local (not regional) diversity frequently underlies composition change, and homogenization is strongly associated with checklist data that have longer durations and large spatial scales. Conservation and management can benefit from the multiscale perspective used here as it disentangles the implications of both the differentiation and homogenization currently unfolding.

One-Sentence Summary

Biotic homogenization is most prevalent at large temporal and spatial scales.
Metagenomics and metabarcoding experimental choices and their impact on microbial community characterization in freshwater recirculating aquaculture systems
Authors: Rieder Jessica , Kapopoulou Adamandia , Bank Claudia , Adrian-Kalchhauser Irene
Published: July 2022

Recirculating aquaculture systems (RAS) heavily depend on microbial communities to maintain water quality. These communities therefore influence the growth, development, and welfare of farmed fish. With the increasing socio-economic role of fish farming e.g. regarding food security, an in-depth understanding of aquaculture microbial communities is also relevant from a management perspective. However, the data situation regarding the composition of microbial communities within RAS is patchy. Since this is partly ascribed to method choices, there clearly is a need for accurate, standardized, and user-friendly methods to study microbial communities in aquaculture systems.

Here, we compare the performance of 16S amplicon sequencing, Pac-Bio long-read amplicon sequencing, and amplification-free shotgun metagenomics in the characterization of microbial communities in two commercial-size RAS fish farms. We show that, even though primer choice affects read quality, diversity, and assigned taxa, distinct primer pairs uncover similar spatio-temporal patterns between sample types, farms, and time points. We find that long-read amplicons underperform regarding quantitative resolution of spatio-temporal patterns, but allow for species-level identification of functional services and pathogens. Finally, shotgun metagenomics data identified fungi, viruses, and bacteriophages, opening avenues for an exploration of natural approaches regarding antipathogenic treatments. Overall, the datasets agreed on major prokaryotic players.

In conclusion, different sequencing approaches yield overlapping and highly complementary results, with each contributing data no other approach could. Such a tiered approach therefore constitutes a practical and cost-effective strategy for obtaining the maximum amount of information on aquaculture microbial communities. These data could lead to better farm management practices and at the same time inform basic research on community evolution dynamics.
TLR4 signaling in presence of HIV-induced activation enhances programmed death ligand-1 expression on human plasmacytoid dendritic cells and modulates their function
Authors: Patel Meher , Singh Sukhwinder , Davidow Amy , Dai Jihong , Fitzgerald-Bocarsly Patricia
Published: July 2022

Human Plasmacytoid dendritic cells (pDC) only comprise a minute fraction of human mononuclear leukocytes, but are important anti-viral responders that mediate both innate as well as adaptive immune responses. Persistent activation of pDC enhances HIV pathogenesis by promoting immune suppressive mechanisms such as T regulatory cells. It is therefore important to identify the sources of pDC activation in the context of HIV infection. HIV-associated disruption of gut mucosa associated lymphoid tissue introduces normal flora-lipopolysaccharide (LPS) into systemic circulation, which exacerbates HIV-induced immune activation. We report here that pDC are capable of mediating functional TLR4 signaling upon LPS stimulation, and that pDC of HIV-infected individuals have enhanced TLR4 expression compared to healthy individuals. How TLR4 signaling affects pDC function in HIV infection has not been examined before. Hence we examined the influence of TLR4 signaling in presence of HIVstimulation on pDC and found that it not only potentiated HIV-induced activation but also strongly up-regulated Programmed death ligand-1 (PD-L1) expression and Interleukin-6 synthesis. TLR4 signaling specifically up-regulated PD-L1 expression on activated pDC in presence of HIV stimulation. LPS and HIV co-stimulated pDC demonstrated enhanced migratory potential and repressed T cell proliferation. Together, these results suggest that in the setting of HIV infection enhancement of pDC immune suppressive mechanisms such as PD-L1 may be an outcome of HIV-associated immune activation potentiated by TLR4 signaling.
High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults
Authors: Weinhouse Caren , Perez Luiza , Ryde Ian , Goodrich Jaclyn M. , Miranda J. Jaime , Hsu-Kim Heileen , Murphy Susan K. , Meyer Joel N. , Pan William K.
Published: July 2022

I.

Background

Epigenome-wide association studies (EWAS) are a highly promising approach that can inform precision environmental health. However, current EWAS are underpowered for biomarker detection and increasing sample sizes will require substantial resources. Therefore, alternative approaches for identifying candidate biomarkers through EWAS are critical for moving the field forward.

Objectives

To provide proof-of-principle that maximizing exposure variance in EWAS by selecting participants from disproportionately exposed global populations enables effective candidate biomarker detection, even in small sample sizes.

Methods

We profiled genome-wide DNA methylation using Illumina Infinium MethylationEPIC BeadChip in whole blood from N=32 individuals from Madre de Dios, Peru with high methylmercury (MeHg) exposure due to artisanal and small-scale gold mining. We compared DNA methylation in N=16 individuals with high (>10 μg/g) vs. N=16 individuals with low (<1 μg/g) total hair mercury (a proxy for methylmercury exposure), matched on age and sex.

Results

We identified nine differentially methylated CpG sites (FDR<0.05), including several with known links to MeHg toxicity. The most significantly different CpG site was in an intronic enhancer of theSLC5A7gene, which encodes the L-type amino acid transporter 1 (LAT1) that facilitates MeHg transport into protein-rich tissue, including muscle and brain. Our Gene Ontology and transcription factor motif enrichment analyses identified differential methylation of genes involved in several outcomes with established links to MeHg, including immune response, neurotoxicity, and type 2 diabetes (T2D) risk. Last, we identified candidate epigenetic biomarkers of PUFA-mediated protection against MeHg toxicity.

Discussion

Here, we show that a small EWAS on samples with high MeHg exposure variance can detect candidate differentially methylated CpGs and pathways of interest relevant to MeHg biology. Similar EWAS in global populations with known high exposure variance can be leveraged to develop targeted, custom sequencing panels and microarrays limited to replicated, validated biomarkers of a given exposure.
Daily movement behaviours and cognition in mid-life: A cross-sectional compositional analysis of the 1970 British Cohort Study
Authors: Mitchell JJ , Blodgett JM , Chastin S , Jefferis BJ , Wannamethee G , Hamer M
Published: July 2022

IMPORTANCE

Movement behaviours (e.g. sedentary behaviour (SB), moderate and vigorous physical activity (MVPA), light intensity physical activity (LIPA) and sleep) are linked to cognition, yet the relative importance of each component is unclear, and not yet explored with compositional methodologies.

OBJECTIVE

To examine how time spent in one behaviour (e.g. SB, MVPA, LIPA, sleep) relative to all others is associated with overall cognition, including executive function and memory.

DESIGN, SETTING, AND PARTICIPANTS

The 1970 British Cohort Study (BCS70) is an ongoing prospective birth cohort study of adults born in England, Scotland and Wales in a single week. At age 46, participants wore an accelerometer device and completed cognitive screening. Linear regression was used to examine cross-sectional associations between movement behaviours and cognitive scores, using a compositional approach. Isotemporal substitution was performed to model the effect of reallocating time between components of daily movement on cognition.

EXPOSURES

A thigh-mounted activPAL accelerometer device was worn without removal for one week. Daily time in SB, MVPA, LIPA and sleep were derived using a validated processing algorithm.

MAIN OUTCOMES AND MEASURES

Standardised scores of executive function (letter cancellation and verbal fluency), memory (immediate and delayed wordlist recall) and a composite score were derived from computer administered cognitive tasks.

RESULTS

The sample comprised 4,481 participants (52% female). Time in MVPA relative to SB, LIPA and sleep was positively associated with cognition after adjustments for education and occupational physical activity, but additional adjustment for health status attenuated associations. SB relative to all other movements was robustly positively associated with cognition. Modelling time reallocation between components revealed a higher cognition percentile after MVPA theoretically replaced just 9 minutes of SB (+1.31; 95% CI: 0.09, 2.50), 7 minutes of LIPA (+1.27; 0.07, 2.46) or 7 minutes of sleep (+1.20; 0.01, 2.39).

CONCLUSIONS AND RELEVANCE

Relative to time spent in other behaviours, more time spent in MVPA and SB was associated with higher cognitive scores. Displacement of MVPA time, given its smaller relative amount, appear most deleterious. Efforts should be made to preserve MVPA time, or reinforce it with time taken from other behaviours.
Systematic comparison of family history and polygenic risk across 24 common diseases
Authors: Mars Nina , Lindbohm Joni V. , Briotta Parolo Pietro della , Widén Elisabeth , Kaprio Jaakko , Palotie Aarno ,   FinnGen, Ripatti Samuli
Published: July 2022

Family history is the standard indirect measure of inherited susceptibility in clinical care, while polygenic risk scores (PRS) have more recently demonstrated potential for more directly capturing genetic risk in many diseases. No studies have systematically compared how these overlap and complement each other across common diseases. Within FinnGen (N=306,418), we leverage family relationships, up to 50 years of nationwide registries, and genome-wide genotyping to examine the interplay of family history and genome-wide PRSs. We explore the dynamic for three types of family history across 24 common diseases: first- and second-degree family history, and parental causes of death. Covering a large proportion of the burden of non-communicable diseases in adults, we show that family history and PRS are independent and not interchangeable measures, but instead provide complementary information of inherited disease susceptibility. The PRSs explained on average 10% of the effect of first-degree family history, and first-degree family history 3% of PRSs, and PRS effects were independent of both early- and late-onset family history. The PRS stratified the risk similarly in individuals with and without family history. In most diseases, including coronary artery disease, glaucoma, and type 2 diabetes, a positive family history with a high PRS was associated with a considerably elevated risk, whereas a low PRS compensated completely for the risk implied by positive family history. This study provides a catalogue of risk estimates for both family history of disease and PRSs, and highlights opportunities for a more comprehensive way of assessing inherited disease risk across common diseases.
Trust in the attending rheumatologist, health-related hope, and medication adherence among Japanese patients with systemic lupus erythematosus: the TRUMP2-SLE project
Authors: Kurita Noriaki , Oguro Nao , Miyawaki Yoshia , Hidekawa Chiharu , Sakurai Natsuki , Ichikawa Takanori , Ishikawa Yuichi , Hayashi Keigo , Shidahara Kenta , Kishida Dai , Yoshimi Ryusuke , Sada Ken-ei , Shimojima Yasuhiro , Yajima Nobuyuki
Published: July 2022

Objectives

Poor medication adherence among patients with systemic lupus erythematosus (SLE) is a critical problem associated with adverse outcomes. This study examined the relationship between trust in one’s physician and goal-oriented thinking, hope, and medication adherence among Japanese patients with SLE who were ethnically matched to their physicians.

Methods

This cross-sectional study was conducted in the rheumatology outpatient clinics at five academic centers. Patients with SLE who were prescribed oral medications were included. The main exposure was trust in one’s physician measured via the 5-item Japanese version of the Wake Forest Physician Trust Scale and the 18-item Health-related Hope Scale, with each score ranging from 0 to 100 points. The outcome was medication adherence measured using the 12-item Medication Adherence Scale with scores ranging from 5 to 60 points. A general linear model was created after adjusting for demographics, socioeconomic status, disease activity, disease duration, basic health literacy, depression, medication variables, experiencing adverse effects, and concerns regarding lupus medications.

Results

Altogether, 373 patients with SLE were included. The mean age of the patients was 46.4 years, and among them, 329 (88.2%) were women. Both trust in one’s physician (per 10-point increase: 0.88, 95% confidence interval [95%CI]: 0.53 to 1.24) and the Health-related Hope score (per 10-point increase: 0.64, 95%CI: 0.33 to 0.95) were associated with better medication adherence.

Conclusions

Physician communication to build trust and coaching on self-management to maintain or achieve what is important in the patient’s life and to enhance hope may lead to better medication adherence.

Key messages

What is already known on this topic

The possible association of loss of trust in the attending physician with medication adherence in systemic lupus erythematosus has been conflicting in previous research, in which the effect of physician–patient racial mismatch has not been considered. The protective role of hope and goal-oriented thinking for mental symptoms has been suggested among patients with SLE.

What this study adds

This study revealed that both trust in one’s physician and health-related hope were associated with better medication adherence in Japanese patients who were ethnically matched to their physicians.

How this study may affect research, practice, or policy

The results indicated that physician communication to build trust and coaching on self-management to maintain or achieve what is important in the patient’s life may lead to better medication adherence.