bluuebunny/crossref_metadata_2025 huggingface dataset:
Physician Engagement in Quality Improvement: A Cross-Sectional Pilot Study
Authors: Shea Christine , Perrier Laure , Prokopy Melissa , Herbert Monique , Sodhi Sundeep , Karsan Alia , Simard Julie , Perreira Tyrone A.
Published: May 2023

Background

To confirm the reliability of a survey investigating physician engagement in quality improvement (QI) among Ontario physicians. We conducted a pilot study to test the survey on physicians, evaluate a recruitment strategy, and assess preliminary data.

Methods

All Ontario physicians were invited to participate in the survey through province-wide online physician and hospital organization newsletters.

Results

Results indicate a need for solutions and standards for training physicians interested in participating in QI initiatives. Study objectives were reached, but recruitment remains challenging.

Conclusion

This pilot study supports conducting a full-scale survey that would result in more robust results.
Genome-wide association study identifies a new susceptibility locus inPLA2G4Cfor Multiple System Atrophy
Authors: Nakahara Yasuo , Mitsui Jun , Date Hidetoshi , Porto Kristine Joyce , Hayashi Yasuhiro , Yamashita Atsushi , Kusakabe Yoshio , Matsukawa Takashi , Ishiura Hiroyuki , Yasuda Tsutomu , Iwata Atsushi , Goto Jun , Ichikawa Yaeko , Momose Yoshio , Takahashi Yuji , Toda Tatsushi , Ohta Rikifumi , Yoshimura Jun , Morishita Shinichi , Gustavsson Emil K , Christy Darren , Maczis Melissa , Farrer Matthew J. , Kim Han-Joon , Park Sung-Sup , Jeon Beomseok , Zhang Jin , Gu Weihong , Scholz Sonja W. , Singleton Andrew B. , Houlden Henry , Yabe Ichiro , Sasaki Hidenao , Matsushima Masaaki , Takashima Hiroshi , Kikuchi Akio , Aoki Masashi , Hara Kenju , Kakita Akiyoshi , Yamada Mitsunori , Takahashi Hitoshi , Onodera Osamu , Nishizawa Masatoyo , Watanabe Hirohisa , Ito Mizuki , Sobue Gen , Ishikawa Kinya , Mizusawa Hidehiro , Kanai Kazuaki , Kuwabara Satoshi , Arai Kimihito , Koyano Shigeru , Kuroiwa Yoshiyuki , Hasegawa Kazuko , Yuasa Tatsuhiko , Yasui Kenichi , Nakashima Kenji , Ito Hijiri , Izumi Yuishin , Kaji Ryuji , Kato Takeo , Kusunoki Susumu , Osaki Yasushi , Horiuchi Masahiro , Yamamoto Ken , Shimada Mihoko , Miyagawa Taku , Kawai Yosuke , Nishida Nao , Tokunaga Katsushi , Dürr Alexandra , Brice Alexis , Filla Alessandro , Klockgether Thomas , Wüllner Ullrich , Tanner Caroline M. , Kukull Walter A. , Lee Virginia M.-Y. , Masliah Eliezer , Low Phillip A. , Sandroni Paola , Ozelius Laurie , Foroud Tatiana , Tsuji Shoji
Published: May 2023

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association (P= 6.5 × 10−7) that was replicated in additional Japanese samples (P= 2.9 × 10−6. OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data (P= 5.0 × 10-15. Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples (P=0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution inPLA2G4Cthat encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.
Epigenomic signature of major congenital heart defects in newborns with Down syndrome
Authors: Mouat Julia S. , Li Shaobo , Myint Swe Swe , Laufer Benjamin I. , Lupo Philip J. , Schraw Jeremy M. , Woodhouse John P. , de Smith Adam J. , LaSalle Janine M.
Published: May 2023

Background

Congenital heart defects(CHDs)affect approximately half of individuals with Down syndrome(DS)but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots(NDBS)of DS individuals with major CHDs compared to DS individuals without CHDs.

Methods

We used the Illumina EPIC array and whole-genome bisulfite sequencing(WGBS)to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: 1) 45 DS-CHD (27 female, 18 male) and 2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions(DMRs)in DS-CHD vs DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS vs typical development(TD)WGBS NDBS samples.

Results

We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3,938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS vs TD samples.

Conclusions

A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
Epidemiology and Survival of Primary Extraosseous Plasmacytoma: Insights from A Population-Based Study with A 20-Year Follow-Up
Authors: Wang Fan
Published: May 2023

Background

Primary extraosseous plasmacytoma (PEP) is a rare and localized form of plasmacytoma that is not well understood. This study aimed to investigate the clinical features and prognostic factors associated with PEP.

Methods

Using the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with PEP between 2000 and 2019 were extracted. Survival curves were calculated with the Kaplan-Meier method, and prognostic factors were identified based on the univariate and multivariate Cox regression analyses. A nomogram was constructed to predict survival at 3 and 5 years after diagnosis.

Results

A total of 1044 PEP patients were included in this study. The average age was 60.3 ± 15.2 years, with 64.3% being male (male: female = 1.8:1) and 53.8% being over 60 years old. The most affected sites were the upper aerodigestive tract (42.6%). Most patients received radiotherapy (60.7%), followed by surgery (52.8%) and chemotherapy (15.1%). Overall survival (OS) rates were 88.3% at 1 year, 78.1% at 3 years, 70.7% at 5 years, and 56.0% at 10 years. Corresponding cancer-specific survival (CSS) rates were 92.1%, 85.8%, 82.5%, and 78.1%, respectively. Multivariate cox analysis indicated that age, race, marital status at diagnosis, radiotherapy, chemotherapy, and surgery were independent prognostic factors for OS, while age, race, radiotherapy, chemotherapy, and surgery were independent prognostic factors for CSS. Nomograms were further constructed to predict the possibility of OS and CSS with good performances.

Conclusions

The survival outcome of patients with PEP depends on several factors including age, race, marital status, and treatment options such as chemotherapy, radiotherapy, and surgery, which were also identified as independent predictors of OS for PEP. Patients who were younger, Asian or Pacific Islander, American Indian or Native American, and received radiotherapy or surgery had a more favorable prognosis, while those who underwent chemotherapy had poorer outcomes. This study provides valuable insights into the management of PEP.
Development and Validation of a Multiplex Real-Time PCR Assay for Detection and Quantification ofStreptococcus pneumoniaein Pediatric Respiratory Samples
Authors: Butler Molly , Breazeale Garrett , Mwangi Eric , Dowell Elaine , Dominguez Samuel R , Lamberth Linda , Hultén Kristina , Jung Sarah A
Published: May 2023

Streptococcus pneumoniae(Spn) is a bacterial pathogen that causes a range of disease manifestations in children, from acute otitis media to pneumonia, septicemia, and meningitis. PrimarySpnlaboratory diagnostic identification methods include culture, antigen testing, single-plex real-time PCR, and syndromic PCR panels. However, each method lacks sensitivity, specificity, and/or cost efficiency. We developed and validated a quantitative, multiplex PCR assay that uses threeSpngenomic targets (lytA, piaB, and SP2020) for improved sensitivity and specificity to detectSpnin pleural fluid (PF), bronchoalveolar lavage (BAL), tracheal aspirate (TA), and upper respiratory (UR, research only) samples. Validation testing included analytical sensitivity (limit of detection), specimen storage, analytical specificity (cross-reactivity), and accuracy studies. Limit of detection is 500 genome copies/mL in lower respiratory samples and 100 copies/mL in upper respiratory specimens, with quantification range of 1,000 to 10,000,000 copies/mL. Specimens can be stored frozen at least 60 days andSpnDNA is stable through 3 freeze-thaw cycles. No cross-reactivity was observed against 20 closely related microorganisms and/or microorganisms that can be detected in similar sample types, includingStreptococcus pseudopneumoniae. In reference range testing,Spnwas detected in 5 of 23 (21.7%) PF, 2 of 19 (10.5%) BAL, 1 of 20 (5.0%) TA, and 44 of 178 (24.7%) UR residual specimens. For accuracy studies, 98 specimens were tested and overall percent agreement with a qualitative,lytA-based comparator assay was 96.9% across all sample types. This multiplex, quantitative PCR assay is a sensitive and specific method forSpndetection in pediatric respiratory samples.
Improved access to diabetic retinopathy screening through primary care-based teleophthalmology during the COVID-19 pandemic
Authors: Dow Eliot R. , Chen Karen M. , Basina Marina , Dang Jimmy , Khan Nergis C. , Kim Michael , Levine Marcie , Mishra Kapil , Perera Chandrashan , Phadke Anuradha , Tan Marilyn , Weng Kirsti , Do Diana V. , Mahajan Vinit B. , Mruthyunjaya Prithvi , Leng Theodore , Myung David
Published: May 2023

Background

Primary care practices play a critical role in ensuring that patients with diabetes undergo an annual eye examination, the importance of which is underscored by the Healthcare Effectiveness Data and Information Set (HEDIS) quality measures. Store-and-forward teleophthalmology, where ocular images are read remotely by an ophthalmologist, has the potential to facilitate this role.

Methods

In this report, we aim to measure if using a primary care-based teleophthalmology program improves access to eye examinations for diabetic patients as reflected in HEDIS measures. Over a 20-month period, non-mydriatic fundus photographs were obtained at five primary care sites in the San Francisco Bay Area from patients with a new or existing diagnosis of diabetes mellitus type 1 or 2 who needed an annual eye examination. Collected photographs were evaluated remotely by vitreoretinal specialists for diabetic retinopathy. Our primary measures were the proportion and number of annual eye exams of diabetic patients in primary care clinics that participated in the teleophthalmology program compared to clinics that did not participate. Additional measures included the number of patients with DR who were identified through the program, gradeability of fundus photographs, and characteristics of the study population.

Results

The program screened 760 unique patients, 84 of whom were found to have DR (11.1%). The rate of ungradable photos was 9.7%, which was greater for patients who self-reported as racially non-White. For the duration of the study, including during the COVID-19 pandemic, both the proportion and number of diabetic patients receiving annual eye examination increased (17.1% increase in proportion, 14.8% increase in number). In comparison, primary care sites that did not offer the teleophthalmology service declined in these measures (2.3% decrease in proportion, 17.0% decrease in number).

Conclusions

Primary care-based teleophthalmology improves access to eye exam for diabetic patients and identifies patients with diabetic retinopathy across diverse communities.
Deep Learning-based Workflow for Automatic Extraction of Atria and Epicardial Adipose Tissue on cardiac Computed Tomography in Atrial Fibrillation
Authors: Wang Guan-Jie , Kuo Ling , Chang Shih-Lin , Lin Yenn-Jiang , Chung Fa-Po , Lo Li-Wei , Hu Yu-Feng , Chao Tze-Fan , Tuan Ta-Chuan , Liao Jo-Nan , Chang Ting-Yung , Lin Chin-Yu , Liu Chih-Min , Liu Shin-Huei , Kuo Ming-Ren , Lee Guan-Yi , Huang Yu-Shan , Wu Cheng-I , Chen Shih-Ann , Lu Chia-Feng
Published: May 2023

Background

Preoperative measurements of left atrium (LA) and epicardial adipose tissue (EAT) volumes in computed tomography (CT) images have been reported to be associated with an increased risk of atrial fibrillation (AF) recurrence. We aimed to design a deep learning-based workflow to provide a reliable automatic segmentation of atria, pericardium and EAT, which can facilitate future applications in AF.

Methods

A total of 157 patients with AF who underwent radiofrequency catheter ablation were enrolled in this study. The 3D U-Net models of LA, right atrium (RA) and pericardium were used to develop the pipeline of total, LA-and RA-EAT automatic segmentation. We defined the attenuation range between -190 to -30 HU as fat within the pericardium to obtain total EAT. Regions between the dilated endocardial boundaries and endocardial walls of LA or RA within the pericardium were used to detect the voxels attributed to fat, resulting in LA-EAT and RA-EAT.

Results

The LA, RA and pericardium segmentation models achieved Dice coefficients of 0.960 ± 0.010, 0.945 ± 0.013 and 0.967 ± 0.006, respectively. The 3D segmentation models correlated well with ground truth for LA, RA and pericardium (r=0.99 and p < 0.001 for all). For the results of EAT, LA-EAT and RA-EAT segmentation, Dice coefficients of our proposed method were 0.870 ± 0.027, 0.846 ± 0.057 and 0.841 ± 0.071, respectively.

Conclusions

Our proposed workflow for automatic LA/RA and EAT segmentation applying 3D U-Nets on CT images was reliable in patients with AF.
Clinically validated metatranscriptomic analysis of human and microbial components of FFPE tissue biopsies
Authors: Toma Ryan , Hu Lan , Demusaj Diana , Mehrtash Mory , Wohlman Robert , Banavar Guru , Vuyisich Momchilo
Published: May 2023

Recent studies have identified microbial components in most tumors and invoked microorganisms in cancer onset and progression. The microbial functions responsible for these effects likely include production of genotoxins, modification of human gene expression, and protection of cancer cells from immune surveillance. Metatranscriptomics (MT) is a powerful tool for the development of potential cancer diagnostics and therapeutics, as well as investigating cancer initiation and progression. This is because MT data can quantify human and microbial gene expression, as well as provide strain level taxonomic classification of the microorganisms in the tumor microenvironment (TME). In addition, the microbial data derived from the MT method can easily be normalized across different samples, since many human transcripts can act as internal standards. When collecting tissue samples for clinical studies, researchers have the option of using fresh or Formalin-Fixed Paraffin-Embedded (FFPE) samples. FFPE samples are much easier to study, due to their widespread availability and ease of collection, storage, and handling. Little research exists comparing FFPE samples and fresh tissues, and there is no literature examining the differences in microbial signatures between these two sample preservation methods. In this study, we analyzed matched FFPE samples and fresh tissue samples from colon polyps of 13 participants for microbial and human components. We found that our clinically validated MT method generated equivalent data from FFPE samples and fresh tissue samples with high concordance for human gene expression (Pearson 0.70), microbial species (Pearson 0.94), and KEGG Orthologs (Pearson 0.97). These data indicate that FFPE samples are suitable for use in metatranscriptomic analyses, which will enable more diverse and larger oncology studies, as well as any other studies that benefit from MT analysis of tissue samples.
ST-segment depression on resting electrocardiogram in patients with out prior cardiac disease — a comparison with stress electrocardiogram and echocardiography —
Authors: Morita Masaki
Published: May 2023

Background

The clinical significance of ST-segment depression (STD) on electrocardiogram (ECG) in resting patients without prior cardiac disease and symptoms of angina pectoris in unclear. This study was aimed to elucidate this problem.

Methods

Patients with non-anginal chest pain or those who underwent ECG screening were enrolled. Echocardiography (Echo) and resting and stress ECG were performed.; stress ECG was recorded during exercise and recovery period. For stress ECG, ST-segment/heart-rate loop was adopted. The clinical results in patients with and without STD on resting ECG were compared.

Results

Eighty-two patients were included; a mean age of 61.4 ± 14.1 years old. ECG revealed that 13 (15.9%) patients had left ventricular hypertrophy (LVH; Sokolow-Lyon’s voltage > 3.5 mV), whereas 34 (41.5%) patients had STD (ST-segment voltage at the J point < –0.05 mV). Echo revealed a mean left ventricular mass (LVM) of 182 ± 74 g. The stress ECG revealed the mean recovery index was –1.2° ± 19.1°. A correlation of STD voltage with Romhilt-Estes score on resting ECG (r = –0.34, p = 0.0015) and LVM on Echo (r = –0.26, p = 0.018) were observed. From ROC curves, STD tended to diagnose more accurately than other ECG parameters. From multiple logistic analysis, age, Romhilt-Estes score and peak STD on stress ECG were independently correlated with STD on resting ECG.

Conclusion

In the patients without prior cardiac disease and anginal chest pain, STD on resting ECG was suggestive of older age, LVH on ECG (independent) and LVH on Echo (not independent).

Registration

URL:https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000050291

WHAT IS KNOWN

ST-segment depression (STD) on resting electrocardiogram (ECG) among the subjects without prior cardiac disease and symptoms of angina is suggested to imply left ventricular hypertrophy.

WHAT THE STUDY ADDS

In order to investigate the significance of STD on resting ECG among the subjects without history of cardiac disease or anginal chest pain, especially to rule out the incidence of silent myocardial ischemia, echocardiogram and stress ECG were contemporarily performed for them.
Protein phosphorylation and oxidative protein modification mediate plant photosystem II disassembly and repair
Authors: McKenzie Steven D. , Puthiyaveetil Sujith
Published: May 2023

The light-driven water-splitting reaction of photosystem II exposes its key reaction center core protein subunits to irreversible oxidative photodamage. A rapid repair cycle replaces photodamaged core subunits in plants, but how the large antenna-core supercomplex structures of plant photosystem II disassemble for repair is not currently understood. Phosphorylation of reaction center core protein subunits has been suggested as a mechanism of disassembly. Consistent with this, we find specific involvement of phosphorylation in removing peripheral antenna from the core and monomerization of the dimeric cores inArabidopsis. However, photosystem disassembly occurred to some degree even in the absence of phosphorylation as suggestive of other unknown mechanisms of disassembly. Here we show that the oxidative modifications of amino acid residues in core protein subunits of photosystem II are active mediators of disassembly. Exogenously-applied hydrogen peroxide induces photosystem disassembly, especially the conversion of the monomeric cores into two reaction center subcomplexes. We further show that the extent of monomer disassembly is proportional to the oxidative protein damage, with the fully disassembled reaction center subcomplexes containing more modifications. In the monomeric core, some amino acid oxidative modifications map at the D1-CP43 interface as consistent with a dissociation of the core along these subunits. Oxidative modifications thus likely disassemble only the damaged monomeric cores, ensuring an economical photosystem disassembly process. Our results suggest oxidative protein modification represents an ancient mechanism of photosystem disassembly, and that phosphorylation originated later in evolution to impart explicit control over the repair process.
Extreme mitochondrial reduction in a novel group of free-living metamonads
Authors: Williams Shelby K. , Jerlström Hultqvist Jon , Eglit Yana , Salas-Leiva Dayana E. , Curtis Bruce , Orr Russell J. S. , Stairs Courtney W. , Atalay Tuğba N. , MacMillan Naomi , Simpson Alastair G. B. , Roger Andrew J.
Published: May 2023

Metamonads are a diverse group of heterotrophic microbial eukaryotes adapted to living in hypoxic environments. All metamonads but one harbour metabolically altered ‘mitochondrion-related organelles’ (MROs) with reduced functions relative to aerobic mitochondria, however the degree of reduction varies markedly over the metamonad tree. To further investigate metamonad MRO diversity, we generated high quality draft genomes, transcriptomes, and predicted proteomes for five recently discovered free-living metamonads. Phylogenomic analyses placed these organisms in a group we informally named the ‘BaSk’ (Barthelonids+Skoliomonads) clade, which emerges as a deeply branching sister group to the Fornicata, a metamonad phylum that includes parasitic and free-living flagellates. Extensive bioinformatic analyses of the manually curated gene models showed that these organisms are predicted to have extremely reduced MRO proteomes in comparison to other free-living metamonads. Loss of the mitochondrial iron-sulfur cluster (ISC) assembly system in some organisms in this group appears to be linked to the acquisition in their common ancestral lineage of a SUF-like minimal system (SMS) Fe/S cluster pathway through lateral gene transfer (LGT). One of the isolates,Skoliomonas litria, appears to have undergone further mitochondrial reduction having lost all other known MRO pathways. No proteins were confidently assigned to the predicted MRO proteome of this organism suggesting that the organelle has been lost. The extreme mitochondrial reduction observed within this free-living anaerobic protistan clade is unprecedented and demonstrates that mitochondrial functions, under some conditions, may be completely lost even in free-living organisms.
cellsnake: a user-friendly tool for single-cell RNA sequencing analysis
Authors: Umu Sinan U. , Vander-Elst Karoline Rapp , Karlsen Victoria T. , Chouliara Manto , Bækkevold Espen Sønderaal , Jahnsen Frode Lars , Domanska Diana
Published: May 2023

Background

Single-cell RNA sequencing (scRNA-seq) provides high-resolution transcriptome data to understand the heterogeneity of cell populations at the single-cell level. The analysis of scRNA-seq data requires the utilization of numerous computational tools. However, non-expert users usually experience installation issues, a lack of critical functionality or batch analysis modes, and the steep learning curves of existing pipelines.

Results

We have developed cellsnake, a comprehensive, reproducible, and accessible single-cell data analysis workflow, to overcome these problems. Cellsnake offers advanced features for standard users and facilitates downstream analyses in both R and Python environments. It is also designed for easy integration into existing workflows, allowing for rapid analyses of multiple samples.

Conclusion

As an open-source tool, cellsnake is accessible through Bioconda, PyPi, Docker, and GitHub, making it a cost-effective and user-friendly option for researchers. By using cellsnake, researchers can streamline the analysis of scRNA-seq data and gain insights into the complex biology of single cells.
Dynamics of a Lipid Vesicle across a Microfluidic Constriction: How does the Fluidity of the Encapsulation and its Micro-Environment Matter?
Authors: Kahali Tanoy , Panigrahi Devi Prasad , Chakraborty Suman
Published: May 2023

Constriction in the flow passage in the physiological circulatory system is central to the occurrence of several diseased conditions such as thrombosis and is also pivotal towards the understanding of several regulatory processes in the human microvasculature. It is, therefore, imperative to advance a mechanistic insight on the dynamics of the transiting cellular encapsulations in a physiologically-mimicking micro-confinement, with particular focus on deciphering the role of its mechano-physical properties. Here we bring out a quantitative depiction on the role of the membrane fluidity and the initial deflation (shape deviation from sphericity) of a lipid vesicle during its morphological transition from stretching to tumbling via rolling as it migrates across a microfluidic constriction. Based on our experimental observations as well as theoretical insights, we construct a regime map to elucidate the range of the key dimensionless parameters orchestrating the dynamic transition. Our results further bring out the role of the initial position of the lipid vesicle on its subsequent stretching dynamics, exhibiting characteristic nonlinearities and non-monotonic trends. In addition, our observations on the vesicle’s stretching dynamics emerge from mapping selectively with the viscosity contrast between the encapsulated and the suspending fluid medium, offering potential physiologically relevant cues on the impact of the aging of a cellular moiety on its deformability as it transits through a constricted path. Such mechanistic insights may potentially enable establishing quantitative correlations between the dynamical transition of a cellular encapsulation and its mechano-physical properties, which may in turn, have decisive implications in various states of health and disease while circulating across microvascular fluidic pathways.

Impact Statement

This study brings out a quantitative mechanistic insight into the dynamics of migrating lipid vesicles as they migrate through a constricted microfluidic passage. Having a direct similitude with the movement of red blood cells in human microvascular pathways, the resulting mapping between the initial shape and bending properties of the vesicle membrane with three distinct morphological transitions (stretching, rolling, and tumbling) provides cues for understanding the healthy and diseased states of the cells based on their morpho-dynamic features and establish exclusive connectivity of the same with the cell membrane as well as the cytoplasm properties, a paradigm that is currently non-existant. This, in turn, may lead to a novel mechanistic approach of label-free disease detection based on cellular imaging, for which the current understanding is mostly empirical rather than fundamental.
An operational methodology to identify Critical Ecosystem Areas to help nations achieve the Kunming-Montreal Global Biodiversity Framework
Authors: Venegas-Li Ruben , Grantham Hedley S. , Rainey Hugo , Diment Alex , Tizard Robert , Watson James E.M.
Published: May 2023

The Kunming-Montreal Global Biodiversity Framework (GBF) will become the most important multilateral agreement to guide biodiversity conservation actions globally over the coming decades. An ecosystem goal and various targets for maintaining integrity, restoring degraded ecosystems, and achieving representation in conservation areas feature throughout the GBF. Here, we propose an operational framework that combines disparate information on ecosystem type, extent, integrity, levels of protection, and risk of collapse to support the identification of irreplaceable ‘Critical Ecosystem Areas’ (CEAs), to help advance these ecosystem targets. The framework classifies each component ecosystem based on its integrity, importance in ensuring no ecosystem collapse and its relative value to achieving representation if protected. These CEAs are immediate conservation opportunities, given that they achieve multiple ecosystem goals and targets in the GBF. We showcase its application using Myanmar’s forested ecosystems as a case study and argue that it could be immediately used across all terrestrial ecosystems.
Enhancing drug repurposing on graphs by integrating drug molecular structure as feature
Authors: Ayuso-Muñoz Adrián , Prieto-Santamaría Lucía , Álverez-Pérez Andrea , Otero-Carrasco Belén , Serrano Emilio , Rodríguez-González Alejandro
Published: May 2023

Drug repurposing has become increasingly important, particularly in light of the COVID-19 pandemic. This process involves identifying new therapeutic uses for existing drugs, which can significantly reduce the cost, risk, and time associated with developing new drugs,de novodevelopment. A previous conducted study proved that Deep Learning can be used to streamline this process by identifying drug repurposing hypotheses. The study presented a model called REDIRECTION, which utilized the rich biomedical information available in graph form and combined it with Geometric Deep Learning to find new indications for existing drugs. The reported metrics for this model were 0.87 for AUROC and 0.83 for AUPRC. In this current study, the importance of node features in GNNs is explored. Specifically, the study used GNNs to embed two-dimensional drug molecular structures and obtain corresponding features. These features were incorporated into the drug repurposing graph, along with some other enhancements, resulting in an improved model called DMSR. Performance score for the reported metrics values raised by 0.0448 in AUROC and 0.0919 in AUPRC. Based on these findings, we believe that the method used for embedding drug molecular structures is interesting and captures valuable information about drugs. Its incorporation in the graph for drug repurposing can significantly benefit the process, leading to improved performance evaluation metrics.
Polyphosphate uses mTOR, pyrophosphate, and Rho GTPase components to potentiate bacterial survival inDictyostelium
Authors: Rahman Ryan J. , Rijal Ramesh , Jing Shiyu , Chen Te-An , Ismail Issam , Gomer Richard H.
Published: May 2023

Human macrophages and the eukaryotic microbeDictyostelium discoideumingest bacteria by phagocytosis, and then kill the ingested bacteria. Some pathogenic bacteria secrete linear chains of phosphate residues (polyphosphate; polyP), and the polyP causes the phagocytes to not kill the ingested bacteria. InD. discoideum, the effect of polyP requires the G protein-coupled receptor GrlD, suggesting that polyP uses a signal transduction pathway to inhibit killing of ingested bacteria. Here we show that in addition to GrlD, theD. discoideumpolyP signaling pathway requires the GPCR interacting arrestin-like protein AdcB, inositol hexakisphosphate kinase A (I6kA), the Rho GTPase RacE, and the TOR component Lst8.D. discoideumalso secretes polyP, and at high concentrations polyP inhibitsD. discoideumcytokinesis. The polyP inhibition of bacterial killing pathway does not appear to involve many of the polyP inhibition of cytokinesis pathway components. These data suggest the intriguing possibility that if there is a similar polyP inhibition of bacterial killing pathway in macrophages, pharmacologically blocking this pathway could potentiate macrophage killing of pathogenic bacteria.

Importance

Although most bacteria are quickly killed after phagocytosis by a eukaryotic cell, some pathogenic bacteria prevent their killing after phagocytosis. PathogenicMycobacteriumspecies secrete polyP, and the polyP is necessary for the bacteria to prevent their killing after phagocytosis. Conversely, exogenous polyP prevents the killing of ingested bacteria that are normally killed after phagocytosis by human macrophages and the eukaryotic microbeDictyostelium discoideum. This suggests the possibility that in these cells, a signal transduction pathway is used to sense polyP and prevent killing of ingested bacteria. In this report, we identify key components of the polyP signal transduction pathway inD. discoideum. In cells lacking these components, polyP is unable to inhibit killing of ingested bacteria. The pathway components have orthologues in human cells, and an exciting possibility is that pharmacologically blocking this pathway in human macrophages would cause them to kill ingested pathogens such asM. tuberculosis.
Patterns of evolution of TRIM genes highlight the evolutionary plasticity of antiviral effectors in mammals
Authors: Fernandes Alexandre P. , OhAinle Molly , Esteves Pedro J.
Published: May 2023

The innate immune system of mammals is formed by a complex web of interacting proteins, which together constitute the first barrier of entry for infectious pathogens. Genes from the E3-ubiquitin ligase tripartite motif (TRIM) family have been shown to play an important role in the innate immune system by restricting the activity of different retrovirus species. For example, TRIM5 and TRIM22, have both been associated with HIV restriction, and are regarded as crucial parts of the antiretroviral machinery of mammals. Our analyses of positive selection corroborate the great significance of these genes for some groups of mammals. However, we also show that many organisms lack TRIM5 and TRIM22 altogether. By analyzing a large number of mammalian genomes, here we provide the first comprehensive view of the evolution of these genes in eutherians, showcasing that the pattern of accumulation of TRIM genes has been dissimilar across mammalian orders. Our data suggests that these differences are caused by evolutionary plasticity of the immune system of eutherians, which have adapted to use different strategies to combat retrovirus infections. Altogether, our results provide insights into the dissimilar evolution of a representative family of restriction factors, highlighting a great example of adaptive and idiosyncratic evolution in the innate immune system.
Small-molecule binding to an intrinsically disordered protein revealed by experimental NMR19F transverse spin-relaxation
Authors: Heller Gabriella T. , Shukla Vaibhav Kumar , Figueiredo Angelo M. , Hansen D. Flemming
Published: May 2023

Intrinsically disordered proteins are highly dynamic biomolecules that rapidly interconvert between many structural conformations. Traditionally, these proteins have been considered un-druggable because of their lack of classical long-lived binding pockets. Recent evidence suggests that intrinsically disordered proteins can bind small, drug-like molecules, however, there are limited approaches to characterize these interactions experimentally. Here we demonstrate that ligand-detected19F transverse relaxation rates (R2) obtained from Nuclear Magnetic Resonance spectroscopy are highly sensitive to the interaction between a small-molecule and an intrinsically disordered protein, in contrast to chemical shift perturbations which are minimally sensitive for this interaction. With this method, we show that the small molecule, 5-fluoroindole, interacts with the disordered domains of non-structural protein 5A from hepatitis C virus with aKdof 260 ± 110 μM. We also demonstrate that 5-fluoroindole remains highly dynamic in the bound form. Our findings suggest that ligand-detected19F transverse relaxation measurements could represent a highly effective screening strategy to identify molecules capable of interacting with these traditionally elusive, dynamic biomolecules.
Orphan Drugs and Rare Diseases: Unveiling Biological Patterns through Drug Repurposing
Authors: Otero-Carrasco Belén , Romero-Brufau Santiago , Álvarez-Pérez Andrea , Ayuso-Muñoz Adrián , Prieto-Santamaría Lucía , Hernández Juan Pedro Caraça-Valente , Rodríguez-González Alejandro
Published: May 2023

Rare diseases are a collection of unusual pathologies that afflict millions of individuals globally. However, the creation of treatments for these conditions is frequently limited due to the high expenses and lack of profitability associated with drug development. Orphan drugs, which are medications specifically designed for rare diseases, have played a pivotal role in treating these diseases over the past several years. Nevertheless, their creation remains challenging, and many rare diseases lack approved therapies. Therefore, drug repurposing has emerged as a viable strategy for identifying potential new treatments for these pathologies, a technique consists in using existing drugs to treat a new disease different from the one that they were developed for. This approach can significantly reduce the time and cost of drug development while increasing the likelihood of success. In this paper, we examined the temporal progression of orphan drugs since their introduction and assess the impact of drug repositioning on treatments for rare diseases. Additionally, we aim to identify biological patterns that may be unique to rare diseases treated with repurposed orphan drugs. To this end, we analyzed various biological components associated with these diseases, categorized linked diseases, and obtained the type of orphan drug associated with them. Lastly, we evaluated the phenotypic similarity between diseases treated with an orphan drug through repurposing. Through these findings, we have gained insight into the evolution of orphan drug development in recent years and identified specific patterns that characterize rare diseases associated with them.
Comparison of online and offline applications of dual-site transcranial alternating current stimulation (tACS) on functional connectivity between pre-supplementary motor area (preSMA) and right inferior frontal gyrus (rIFG) for improving response inhibition
Authors: Fujiyama Hakuei , Williams Alexandra G. , Tan Jane , Levin Oron , Hinder Mark R.
Published: May 2023

Background

The efficacy of transcranial alternating current stimulation (tACS) is thought to be brain state-dependent, such that tACS during task performance would be hypothesised to offer greater potential for inducing beneficial electrophysiological changes in the brain and associated behavioural improvement compared to tACS at rest. However, to date, no empirical study has directly tested this postulation.

Objective

Here we compared the effects of tACS applied during a stop signal task (online) to the effects of the same tACS protocol applied prior to the task (offline) and a sham control stimulation.

Methods

A total of 53 young, healthy adults (32 female; 18-35 yrs) received dual-site beta tACS over the right inferior frontal gyrus (rIFG) and pre-supplementary motor area (preSMA), which are thought to play critical roles in action cancellation, with phase-synchronised stimulation for 15 min with the aim of increasing functional connectivity.

Results

EEG connectivity analysis revealed significantly increased task-related functional connectivity following online but not offline tACS. Correlation analyses suggested that an increase in functional connectivity in the beta band at rest following online tACS was associated with an improvement in response inhibition. Interestingly, despite the lack of changes in functional connectivity at the target frequency range following offline tACS, significant improvements in response inhibition were still observed, suggesting offline tACS may still be efficacious in inducing behavioural changes, likely via a post-stimulation early plasticity mechanism.

Conclusion

Overall, the results indicate that online and offline dual-site beta tACS are beneficial in improving inhibitory control via distinct underlying mechanisms.
Concordance of weight status between mothers and children: A secondary analysis of the Pakistan Demographic and Health Survey VII
Authors: Alam Faiz , Ali Mohammed K. , Patel Shivani A. , Iqbal Romaina
Published: May 2023

Familial concordance of nutritional status is an emerging field of study that may guide the development of interventions that operate beyond the individual and within the family context. Little published data exist for concordance of nutritional status within Pakistani households. We assessed the associations between weight status of mothers and their children in a nationally representative sample of households in Pakistan using Demographic and Health Survey data. Our analysis included 3465 mother-child dyads, restricting to children under-five years of age with body mass index (BMI) information on their mothers. We used linear regression models to assess the associations between maternal BMI category (underweight, normal weight, overweight, obese) and child’s weight-for-height z-score (WHZ), accounting for socio-demographic characteristics of mothers and children. We assessed these relationships in all children under-five and also stratified by age of children (younger than 2 years and 2 to 5 years). In all children under-five and in children 2 to 5 years, maternal BMI was positively associated with child’s WHZ, while there was no association between maternal BMI and child WHZ for children under-two. The findings indicate that the weight status of mother’s is positively associated with that of their children. These associations have implications for interventions aimed at healthy weights of families.
Exploring Factors Affecting the Adoption and Continuance Usage of Drone in Healthcare: The Role of the Environment
Authors: Marfo John Serbe , Asamoah Pasty , Owusu-Bio Matilda Kokui , Asare Marfo Afia Frimpomaa , Kyeremeh Kwadwo
Published: May 2023

Drone technologies and healthcare delivery have attracted scholarly attention over the years. Studies have acknowledged the positive impact of the adoption and usage of drone technologies for healthcare delivery. We argue however that, knowledge is lacking on the role of the environment in drone technologies adoption, usage and continuance usage. An examination of 330 health facilities that engage in the use of drone services from Zipline Ghana showed that the environment inversely moderates the relationship between actual usage and intention to continue usage, suggesting that reducing the influence of environmental factors will increase the impact actual usage has on the continuance usage of drone technology in healthcare delivery.
Long-read sequencing and profiling of RNA-binding proteins reveals the pathogenic mechanism of aberrant splicing of anSCN1Apoison exon in epilepsy
Authors: Happ Hannah C , Schneider Patricia N , Hong Jung Hwa , Goes Eleanor , Bandouil Masha , Biar Carina G. , Ramamurthy Aishwarya , Reese Fairlie , Engel Krysta , Weckhuysen Sarah , Scheffer Ingrid E , Mefford Heather C , Calhoun Jeffrey D , Carvill Gemma L
Published: May 2023

Pathogenic loss-of-functionSCN1Avariants cause a spectrum of seizure disorders. We previously identified variants in individuals withSCN1A-related epilepsy that fall in or near a poison exon (PE) inSCN1Aintron 20 (20N). We hypothesized these variants lead to increased PE inclusion, which introduces a premature stop codon, and, therefore, reduced abundance of the full-lengthSCN1Atranscript and Nav1.1 protein. We used a splicing reporter assay to interrogate PE inclusion in HEK293T cells. In addition, we used patient-specific induced pluripotent stem cells (iPSCs) differentiated into neurons to quantify 20N inclusion by long and short-read sequencing and Nav1.1 abundance by western blot. We performed RNA-antisense purification with mass spectrometry to identify RNA-binding proteins (RBPs) that could account for the aberrant PE splicing. We demonstrate that variants in/near 20N lead to increased 20N inclusion by long-read sequencing or splicing reporter assay and decreased Nav1.1 abundance. We also identified 28 RBPs that differentially interact with variant constructs compared to wild-type, including SRSF1 and HNRNPL. We propose a model whereby 20N variants disrupt RBP binding to splicing enhancers (SRSF1) and suppressors (HNRNPL), to favor PE inclusion. Overall, we demonstrate thatSCN1A20N variants cause haploinsufficiency andSCN1A-related epilepsies. This work provides insights into the complex control of RBP-mediated PE alternative splicing, with broader implications for PE discovery and identification of pathogenic PE variants in other genetic conditions.
Sex differences in the relationship between maternal and foetal glucocorticoids in a free-ranging large mammal
Authors: Amin Bawan , Fishman Ruth , Quinn Matthew , Matas Devorah , Palme Rupert , Koren Lee , Ciuti Simone
Published: May 2023

Maternal phenotypes can have long-term effects on offspring phenotypes. These maternal effects may begin during gestation, when maternal glucocorticoid (GC) levels may affect foetal GC levels, thereby having an organizational effect on the offspring phenotype. Recent studies have showed that maternal effects may be different between the sexes. However, how maternal GC levels relate to foetal levels is still not completely understood. Here we related, for the first time in a free-ranging large mammal, the fallow deer (Dama dama), maternal GC levels with foetalin uteroGC levels. We did this in a non-invasive way by quantifying cortisol metabolites from faecal samples collected from pregnant does during late gestation, as proxy for maternal GC level. These were then related to GC levels from hair of their neonate offspring (n = 40). We have shown that maternal GC levels were positively associated with foetal GC levels, but only in female offspring. These findings highlight sex differences, which may have evolved to optimize male growth at the cost of survival.