bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Repeated Blood Cultures With Mortality in Adult Patients With Gram-Negative Bacilli Bacteremia: A Systematic Review and Meta-analysis
Authors: Shinohara Jun , Hanai Shogo , Jung Jongtak , Song Kyoung-Ho , Iwata Mitsunaga , Terasawa Teruhiko
Published: November 2022

Background

Performing repeat blood cultures after an initial positive culture (ie, follow-up blood cultures [FUBCs]) in patients with gram-negative bacilli (GNB) bacteremia is controversial. We aimed to comprehensively review the association of FUBCs with improvement in patient-relevant clinical outcomes in GNB bacteremia.

Methods

We performed a systematic review and random-effects meta-analysis to calculate summary effect estimates. We used hazard ratios as the effect measure. The primary outcome was 30-day or in-hospital mortality, and secondary outcomes were length of treatment and length of hospital stay. We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (Central) without language restrictions from inception to April 29, 2022. Original clinical studies evaluating the association between FUBCs and mortality in adult patients with GNB bacteremia were included. FUBC details were reviewed. Two independent reviewers used the Risk of Bias in Non-randomised Studies of Interventions tool.

Results

We identified 9 eligible retrospective studies. In total, 7778 hospitalized patients with GNB bacteremia were included. The studies were clinically heterogeneous and had a critical risk of bias. The utilization of FUBCs varied across studies (18%–89%). Random-effects meta-analysis of covariate-adjusted estimates found that FUBC use was associated with reduced mortality. Although not a result of the meta-analysis, lengths of treatment and hospital stay were longer for patients with FUBCs than for those without. Adverse events were not reported.

Conclusions

FUBC acquisition was associated with lower mortality and longer hospital stay and treatment duration in GNB bacteremia. The risk of bias was critical, and no firm data were available to support mechanisms.
Longitudinal Virological and Immunological Profile in a Case of Human Monkeypox Infection
Authors: Zingaropoli Maria Antonella , Parente Alberico , Kertusha Blerta , Campagna Roberta , Tieghi Tiziana , Garattini Silvia , Marocco Raffaella , Carraro Anna , Tortellini Eeva , Guardiani Mariasilvia , Dominelli Federica , Turriziani Ombretta , Ciardi Maria Rosa , Mastroianni Claudio Maria , Del Borgo Cosmo , Lichtner Miriam
Published: November 2022

In a male with severe proctitis, monkeypox virus DNA was detected in skin lesions, blood, the nasopharynx, and the rectum, underlying generalized viral spreading. Rectal involvement was still found when skin lesions disappeared. At this early stage, an increase of cytotoxic and activated T cells was observed, while a reduction in CD56dimCD57+ NK cells compared with recovery time point was observed.
Defining, conceptualizing and evaluating pragmatic qualities of quantitative instruments measuring implementation determinants and outcomes: a scoping and critical review of the literature and recommendations for future research
Authors: Hull Louise , Boulton Richard , Jones Fiona , Boaz Annette , Sevdalis Nick
Published: November 2022

The pragmatic (i.e., practical) quality of quantitative implementation measures has received increased attention in the implementation science literature in recent years. Implementation measures that are judged to be pragmatic by implementation stakeholders are thought to be more likely to be applied in research and practice. Despite the need for pragmatic implementation measures, ambiguity and uncertainty regarding what constitutes a pragmatic measure remains. This study sought to identify and critically appraise the published literature to understand (i) how pragmatism is defined as a measurement construct/quality of implementation determinants and outcome instruments; (ii) how pragmatic qualities of instruments are evaluated; (iii) identify key gaps and limitations of the current evidence-base and (iv) identify recommendations for future research. We conducted a scoping review of the literature also employing methods of critical review. PubMed and PsycINFO databases, using the OVID interface, were searched for relevant articles published between January 2010 and September 2020. Articles that contained a definition and/or described characteristics of “pragmatism” as a measurement construct of quantitative implementation outcomes (as defined by Proctor’s Implementation Outcomes taxonomy) and/or implementation determinants were eligible for inclusion. Nine articles met inclusion criteria. A degree of overlap in definitions and terms used to describe the pragmatic qualities of quantitative implementation determinant and outcome instruments were found. The most frequently cited descriptors of pragmatism were “not burdensome”, “brief”, “reliable”, “valid” and “sensitive to change”. 3 of the 9 included articles involved international implementation stakeholders in defining and conceptualizing pragmatism and employed specific methods to do so, including a systematic literature review, stakeholder interviews, concept mapping, and a Delphi process. All other articles defined pragmatism, with or without citing relevant literature. One article objectively assessed the pragmatic qualities, above and beyond the psychometric qualities, of implementation measures, using the Psychometric and Pragmatic Evidence Rating Scale (PAPERS). The evidence base within the implementation instrumentation literature on what pragmatism is and how it might be assessed is limited. Some of the research identified in the review provides a strong foundation to build upon, by testing its applicability in other settings (including healthcare areas and countries) and among a more diverse group of stakeholders. We discuss directions for further development of the concept of pragmatism relating to the measurement of implementation determinants and outcomes.
Piloting a Mobility Tech Role at an Academic Medical Center
Authors: James David , Harrell Shari , Labbe Valerie , Ray Midge
Published: November 2022

Introduction:

There is often a breakdown in communication between physical therapy and nursing regarding the responsibility of patient mobility. This communication problem contributes to mobility being the most frequently missed clinical intervention. To address this gap, a Mobility Tech (MT) role was implemented at a large academic medical center. The purpose of this article is to describe the implementation of this role.

Methods:

Using the Institute for health care improvement (IHI) model for improvement, iterative small tests of change were developed to integrate the MT role on four acute care units. Using process flow mapping, the team developed a MT workflow that was adapted to create MT protocols.

Results:

Program outcomes included fall rates and the highest level of mobility documented by staff. During the MT pilot from February 2020 through June 2020, MTs provided an average of over 500 interventions each month. There was a clinically and statistically significant increase in mobility noted in two of the four pilot units.

Conclusion:

We have demonstrated that MTs can be safely incorporated into acute care nursing workflow, and comments from staff and patients validate the role is “value added.”
Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data
Authors: Quintero Reis Andrea , Newton Brendan A , Kessler Ronald , Polimanti Renato , Wendt Frank R
Published: November 2022

Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functional levels using genome-wide data. We used summary association data from GWAS of four traits analyzed in 122,935 individuals of European ancestry:thought life was not worth living(TLNWL),thoughts of self-harm, actual self-harm, andattempted suicide. The fifth trait, suicidality, was constructed with phenotypically as an aggregate of these four traits and genetically using Genomic Structural Equation modeling. Suicidality and S-factor were compared at the level of SNP-heritability (h2), genetic correlation, partitionedh2, effect size distribution, transcriptomic effects in the brain, and cross-population polygenic scoring (PGS). The S-factor had good model fit (χ2=0.21, AIC=16.21, CFI=1.00, SRMR=0.024). Suicidality (h2=7.6%) had higherh2than the S-factor (h2=2.54, Pdiff=4.78×10-13). Although the S-factor had a larger number of non-null susceptibility loci (πc=0.010), these loci had small effect sizes compared to those influencing suicidality (πc=0.005, Pdiff=0.045). Theh2of both traits was enrichment for conserved biological pathways. Therg andρGEsupport highly overlapping genetic and transcriptomic features between suicidality and the S-factor. PGS using European-ancestry SNP effect sizes strongly associated with TLNWL in Admixed Americans: Nagelkerke’sR2=8.56%, P=0.009 (PGSsuicidality) and Nagelkerke’sR2=7.48%, P=0.045 (PGSS-factor). An aggregate suicidality phenotype was statistically more heritable than the S-factor across all analyses and may be more informative for future study genetic designs than individual suicidality indicator traits.
Rare coding variants inCHRNB2reduce the likelihood of smoking
Authors: Rajagopal Veera M. , Watanabe Kyoko , Mbatchou Joelle , Ayer Ariane , Quon Peter , Sharma Deepika , Kessler Michael D. , Praveen Kavita , Gelfman Sahar , Parikshak Neelroop , Otto Jacqueline M. , Bao Suyin , Chim Shek Man , Pavlopoulos Elias , Avbersek Andreja , Kapoor Manav , Chen Esteban , Jones Marcus B. , Leblanc Michelle , Emberson Jonathan , Collins Rory , Torres Jason , Morales Pablo Kuri , Tapia-Conyer Roberto , Alegre Jesus , Berumen Jaime ,   GHS-REGN DiscovEHR collaboration,   Regeneron Genetics Center, Shuldiner Alan R. , Balasubramanian Suganthi , Abecasis Goncalo R. , Kang Hyun M. , Marchini Jonathan , Stahl Eli A. , Jorgenson Eric , Sanchez Robert , Liedtke Wolfgang , Anderson Matthew , Cantor Michael , Lederer David , Baras Aris , Coppola Giovanni
Published: November 2022

Human genetic studies of smoking behavior have been so far largely limited to common variations. Studying rare coding variants has potential to identify new drug targets and refine our understanding of the mechanisms of known targets. We performed an exome-wide association study (ExWAS) of smoking phenotypes in up to 749,459 individuals across multiple ancestries and discovered a protective association signal inCHRNB2that encodes the β2 subunit of α4β2 nicotine acetylcholine receptor (nAChR). Rare predicted loss-of-function (pLOF) and likely deleterious missense variants inCHRNB2in aggregate were associated with a 35% decreased odds for smoking more than 10 cigarettes per day (OR=0.65, CI=0.56-0.76, P=1.9e-8). An independent common variant association in the protective direction (rs2072659; OR=0.96; CI=0.94-0.98; P=5.3e-6) was also evident, suggesting an allelic series. The protective effects of both rare and common variants were detectable to some extent on phenotypes downstream of smoking including lung function, emphysema, chronic obstructive pulmonary disease (COPD) and lung cancer. α4β2 is the predominant nAChR in human brain and is one of the targets of varenicline, a partial nAChR agonist/antagonist used to aid smoking cessation. Our findings in humans align with decades-old experimental observations in mice that β2 loss abolishes nicotine mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targetingCHRNB2in the brain for the treatment of nicotine addiction.
The Impact of COVID-19 on Life Expectancy among Asian American Subgroups
Authors: Park Sung S. , Goldman Noreen , Andrasfay Theresa
Published: November 2022

Despite recognition of the diversity of the Asian American population, the mortality impact of the COVID-19 pandemic has been limited to estimates for non-Hispanic Asian Americans in aggregate. This study provides estimates of life expectancy at birth before (2019) and during the pandemic, along with a broad set of demographic, health-related, and socioeconomic risk factors for COVID-19, for the six largest Asian American subgroups: Asian Indians, Chinese, Filipino, Japanese, Korean, and Vietnamese. Our study places these estimates in the context of the broader U.S. population by including the corresponding estimates for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, and non-Hispanic Native Americans. We use data on age-specific all-cause mortality from CDC WONDER and population estimates from the 2015-2019 American Community Survey to construct life tables for each Asian subgroup by year. While losses in life expectancy during the second year of the pandemic diminished significantly among all racial/ethnic and Asian subgroups, these improvements do not compensate for the large increases in death rates in 2020. All major Asian subgroups except Japanese experienced greater losses of life in 2019-2020 as well as cumulatively (2019-2021) than Whites, with Vietnamese, Filipinos, and other South/Southeast Asians having suffered the largest declines in life expectancy among non-Hispanic Asians. Vietnamese and other Southeast Asians experienced the greatest cumulative losses across all racial/ethnic groups except Native Americans. Our findings underscore the heterogeneity of loss in life expectancy within the Asian American population while identifying some of the risk factors that likely underlie this large variation.
Best Practices for Interpretable Machine Learning in Computational Biology
Authors: Chen Valerie , Yang Muyu , Cui Wenbo , Kim Joon Sik , Talwalkar Ameet , Ma Jian
Published: November 2022

Advances in machine learning (ML) have enabled the development of next-generation prediction models for complex computational biology problems. These developments have spurred the use of interpretable machine learning (IML) to unveil fundamental biological insights through data-driven knowledge discovery. However, in general, standards and guidelines for IML usage in computational biology have not been well-characterized, representing a major gap toward fully realizing the potential of IML. Here, we introduce a workflow on the best practices for using IML methods to perform knowledge discovery which covers verification strategies that bridge data, prediction model, and explanation. We outline a workflow incorporating these verification strategies to increase an IML method’s accountability, reliability, and generalizability. We contextualize our proposed workflow in a series of widely applicable computational biology problems. Together, we provide an extensive workflow with important principles for the appropriate use of IML in computational biology, paving the way for a better mechanistic understanding of ML models and advancing the ability to discover novel biological phenomena.
Cholesterol-containing liposomes decorated with Au nanoparticles as minimal tunable fusion machinery
Authors: Canepa Ester , Bochicchio Davide , Jacob Silva Paulo Henrique , Stellacci Francesco , Dante Silvia , Rossi Giulia , Relini Annalisa
Published: November 2022

Membrane fusion is essential for the basal functionality of eukaryotic cells. In physiological conditions, fusion events are regulated by a wide range of specialized proteins, as well as by a finely tuned local lipid composition and ionic environment. SNARE proteins, for example, provide the mechanical energy necessary to achieve vesicle fusion in neuromediator release, and their action is assisted by other soluble proteins, membrane cholesterol, and calcium ions. Similar cooperative effects must be explored when considering synthetic approaches to achieve controlled and selective membrane fusion. Here we show that liposomes decorated with amphiphilic Au nanoparticles (AuLips) can act as minimal tunable fusion machinery. AuLips fusion is triggered by divalent ions, while the number of fusion events dramatically depends on, and can be finely tuned by, the liposome cholesterol content. Our results, obtained via a combination of experimental (Quartz-Crystal-Microbalance with Dissipation monitoring, Fluorescence assays, Small-Angle X-ray Scattering) and computational techniques (Molecular Dynamics with coarse-grained resolution), reveal new mechanistic details on the fusogenic activity of amphiphilic Au nanoparticles in synergy with membrane cholesterol, and demonstrate the ability of these synthetic nanomaterials to induce fusion regardless of the divalent ion used (Ca2+or Mg2+). This evidence provides a novel contribution to the development of new artificial fusogenic agents for next-generation biomedical applications that require tight control of the rate of fusion events (e.g., targeted drug delivery).
Long-term Association between NO2and Human Mobility: A Two-year Spatiotemporal Study during the COVID-19 Pandemic in Southeast Asia
Authors: Liu Zhaoyin , Li Yangyang , Law Andrea , Tan Jia Yu Karen , Chua Wee Han , Zhu Yihan , Feng Chen-Chieh , Luo Wei
Published: November 2022

Since the COVID-19 pandemic, governments have implemented lockdowns and movement restrictions to contain the disease outbreak. Previous studies have reported a significant positive correlation between NO2and mobility level during the lockdowns in early 2020. Though NO2level and mobility exhibited similar spatial distribution, our initial exploration indicated that the decreased mobility level did not always result in concurrent decreasing NO2level during a two-year time period in Southeast Asia with human movement data at a very high spatial resolution (i.e., Facebook origin-destination data). It indicated that factors other than mobility level contributed to NO2level decline. Our subsequent analysis used a trained Multi-Layer Perceptron model to assess mobility and other contributing factors (e.g., travel modes, temperature, wind speed) and predicted future NO2levels in Southeast Asia. The model results suggest that, while as expected mobility has a strong impact on NO2level, a more accurate prediction requires considering different travel modes (i.e., driving and walking). Mobility shows two-sided impacts on NO2level: mobility above the average level has a high impact on NO2, whereas mobility at a relatively low level shows negligible impact. The results also suggest that spatio-temporal heterogeneity and temperature also have impacts on NO2and they should be incorporated to facilitate a more comprehensive understanding of the association between NO2and mobility in the future study.
Investigation of intra-subtype recombination in Zimbabwean HIV 1 subtype C using bioinformatics. (December 2019)
Authors: Kambarami Milton S , Justen Manasa
Published: November 2022

Intra-subtyperecombination is a common phenomenon among HIV strains which involves transfer of genetic information between two viral strains belonging to the same HIV subtype. However, more research has been done oninter-subtyperecombination which is the transfer of genetic information between two strains belonging to different HIV subtypes. In this study HIV 1 subtype Cenvsequences from Zimbabwean nucleotide sequences (n=2 915) downloaded from Los Alamos HIV databases were used to investigate intra-subtype recombination. Using the GENECUTTER tool, ∼44.4% of whole genomes were selected to have informativeenvregions (n = 1 295). Clustal was used for Multiple Sequence Alignment and RDP 4 was used for analysis and detection of Intra-subtype recombination. Apparently, GENECONV included in RDP 4 detected 47 recombination events. One of the most informative recombination events was further analysed using UPGMA phylogenetic tree to understand the extent of the intra-subtype recombination.
How density dependence, genetic erosion, and the extinction vortex impact evolutionary rescue
Authors: Nordstrom Scott W. , Hufbauer Ruth A. , Olazcuaga Laure , Durkee Lily F. , Melbourne Brett A.
Published: November 2022

Following severe environmental change that reduces mean population fitness below replacement, populations must adapt to avoid eventual extinction, a process called evolutionary rescue. Models of evolutionary rescue demonstrate that initial size, genetic variation, and degree of maladaptation influence population fates. However, many models feature populations that grow without negative density dependence or with constant genetic diversity despite precipitous population decline, assumptions likely to be violated in conservation settings. We examined the simultaneous influences of density-dependent growth and erosion of genetic diversity on populations adapting to novel environmental change using stochastic, individual-based simulations. Density dependence decreased the probability of rescue and increased the probability of extinction, especially in large and initially well-adapted populations that previously have been predicted to be at low risk. Increased extinction occurred shortly following environmental change, as populations under density dependence experienced more rapid decline and reached smaller sizes. Populations that experienced evolutionary rescue lost genetic diversity through drift and adaptation, particularly under density dependence.

Populations that declined to extinction entered an extinction vortex, where small size increased drift, loss of genetic diversity, and the fixation of maladaptive alleles, hindered adaptation, and kept populations at small densities where they were vulnerable to extinctionviademographic stochasticity.
Different genetic architectures of complex traits and their relevance to polygenic score performance in diverse populations
Authors: Carvalho Nuno R. G. , Harris Adrian M. , Lachance Joseph
Published: November 2022

Background

Despite the many insights gleaned from GWAS, polygenic predictions of complex traits have had limited success, particularly when these predictions are applied to individuals of non-European descent. A deeper understanding of the genetic architecture of complex traits may inform why some traits are easier to predict than others.

Methods

Examining 163 complex traits from the UK Biobank, we compared and contrasted three aspects of genetic architecture (SNP heritability, LD variability, and genomic inequality) with three aspects of polygenic score performance (prediction accuracy in the source population, portability across populations, and trait divergence across populations). Here, genomic inequality refers to how unequally the genetic variance of each trait is distributed across the top trait-associated SNPs, as quantified via a novel application of Gini coefficients.

Results

Consistent with reduced statistical power, polygenic predictions of binary traits performed worse than predictions of quantitative traits. Traits with low Gini coefficients (i.e., highly polygenic architectures) include hip circumference as well as systolic and diastolic blood pressure. Traits with large population-level differences in polygenic scores include skin pigmentation and hair color. Focusing on 96 quantitative traits, we found that highly heritable traits were easier to predict and had predictions that were more portable to other ancestries. Traits with highly divergent polygenic score distributions across populations were less likely to have portable predictions. Intriguingly, LD variability was largely uninformative regarding the portability of polygenic predictions. This suggests that factors other than the differential tagging of causal SNPs drive the reduction in polygenic score accuracy across populations. Subsequent analyses identified suites of traits with similar genetic architecture and polygenic score performance profiles. Importantly, lifestyle and psychological traits tended to have low heritability, as well as poor predictability and portability.

Conclusions

Novel metrics capture different aspects of trait-specific genetic architectures and polygenic score performance. Our findings also caution against the application of polygenic scores to traits like general happiness, alcohol frequency, and average income, especially when polygenic scores are applied to individuals who have an ancestry that differs from the original source population.
Genetic variants of human platelet antigens in the Indian population from 1029 whole genomes
Authors: Rophina Mercy , Bhoyar Rahul C , Imran Mohamed , Senthivel Vigneshwar , Divakar Mohit Kumar , Mishra Anushree , Jolly Bani , Sivasubbu Sridhar , Scaria Vinod
Published: November 2022

Background

Genetic variants in human platelet antigens (HPAs) considered as allo- or auto antigens are associated with various disorders including neonatal alloimmune thrombocytopenia, platelet transfusion refractoriness and post-transfusion purpura. While global differences in genotype frequencies were observed, the distribution of HPA variants in the Indian population are largely unknown. This study aims to explore the landscape of HPA variants in India to provide a basis for risk assessment and management of related complications.

Materials and methods

Population specific frequencies of genetic variants associated with the 35 classes of HPAs (HPA-1 to HPA-35) were estimated by systematically analyzing genomic variations of 1029 healthy Indian individuals as well as from global population genome datasets..

Results

Allele frequencies of the most clinically relevant HPA systems in the Indian population were found as follows, HPA-1a – 0.89, HPA-1b – 0.15, HPA-2a – 0.94, HPA-2b – 0.05, HPA-3a – 0.66, HPA-3b – 0.36, HPA-4a – 1.00, HPA-4b – 0, HPA-5a – 0.92, HPA-5b – 0.08, HPA-6a – 1.00, HPA-6b – 0, HPA-15a – 0.58 and HPA-15b – 0.42. In addition, HPA-4b allele frequencies were found to be significantly higher in India in comparison to global populations.

Conclusion

This study provides the first comprehensive analysis of HPA allele and genotype frequencies using large scale representative whole genome sequencing data of the Indian population.
Photonic-Plasmonic Coupling Enhanced Fluorescence Enabling Digital-Resolution Ultrasensitive Protein Detection
Authors: Barya Priyash , Xiong Yanyu , Shepherd Skye , Gupta Rohit , Akin Lucas D. , Tibbs Joseph , Lee Han Keun , Singamaneni Srikanth , Cunningham Brian T.
Published: November 2022

Assays utilizing molecular fluorophores are common throughout life science research and diagnostic testing, although detection limits are generally limited by weak emission intensity, thus requiring many labeled target molecules to combine their output to achieve signal-to-noise greater than the background. Here, we describe how the synergistic coupling of plasmonic and photonic resonance modes can significantly boost the emission from fluorescent dye molecules without increasing the illumination intensity while utilizing a microscopy approach with a broad field of view. By optimally matching the resonant modes of a plasmonic fluor (PF) nanoparticle and a photonic crystal (PC) surface with the absorption and emission spectrum of the PF’s fluorescent dye, we observe a 52-fold improvement in signal intensity, enabling individual PFs to be observed and digitally counted, using an approach in which one PF tag represents detection of one target molecule. The photonic amplification from the PF can be attributed to the strong near-field enhancement due to the cavity-induced activation of the PF, PC band structure-mediated improvement in collection efficiency of emitted photons, and increased rate of spontaneous emission. We demonstrate the applicability of the method by dose-response characterization of a sandwich immunoassay for human interleukin-6, a biomarker commonly used to assist diagnosis of cancer, inflammation, sepsis, and autoimmune disease. We achieve a limit of detection of 10 fg/ml, representing a capability three orders of magnitude lower than standard immunoassays.
Causal factors in primary open angle glaucoma: a phenome-wide Mendelian randomisation study
Authors: Julian Thomas H , Girach Zain , Sanderson Eleanor , Guo Hui , Yu Jonathan , Cooper-Knock Johnathan , Black Graeme C. , Sergouniotis Panagiotis I
Published: November 2022

Primary open angle glaucoma (POAG) is a chronic, adult-onset optic neuropathy associated with characteristic optic disc and/or visual field changes. With a view to identifying modifiable risk factors for this debilitating condition, we performed a ‘phenome-wide’ univariable Mendelian randomisation (MR) study and analysed the relationship between 9,661 traits and POAG. Data were analysed using the weighted median method, weighted mode based estimation, the Mendelian randomisation (MR) Egger method and the inverse variance weighted approach. Our analysis identified 11 traits related to POAG risk including: serum levels of the angiopoietin-1 receptor (OR [odds ratio] = 1.11, IVW [inverse variance weighted] p= 2.34E-06) and the cadherin 5 protein (OR= 1.06, IVW p= 1.31E-06); intraocular pressure (OR=2.46 - 3.79, MRE IVW p=8.94E-44 - 3.00E-27); diabetes (beta=1.64, IVW p = 9.68E-04); and waist circumference (OR = 0.79, IVW p=1.66E-05). Future research focussing on the effects of diabetes, waist circumference, serum cadherin 5 and serum angiopoietin-1 receptor on POAG development and progression is expected to provide key insights that might inform the provision of lifestyle modification advice and/or the development of novel therapies.
A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease
Authors: Bharat Vinita , Durairaj Aarooran S. , Vanhauwaert Roeland , Li Li , Muir Colin M. , Chandra Sujyoti , Kwak Chulhwan S. , Guen Yann Le , Nandakishore Pawan , Hsieh Chung-Han , Rensi Stefano E. , Altman Russ B. , Greicius Michael D. , Feng Liang , Wang Xinnan
Published: November 2022

Dysregulated iron or Ca2+homeostasis has been reported in Parkinson’s disease (PD) models. Here we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+overflow, through an interaction of Fe2+with Mitochondrial Calcium Uniporter. In PD neurons, iron accumulation-triggered Ca2+influx across the mitochondrial surface leads to spatially confined Ca2+elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover FDA-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology, and drug targets and candidates coupled with a convenient stratification method.
Practice walking on a treadmill-mounted balance beam modifies beam walking sacral movement and alters performance in other balance tasks
Authors: Symeonidou Evangelia-Regkina , Esposito Nicole M. , Reyes Roehl D. , Ferris Daniel P.
Published: November 2022

The goals of this study were to determine if a single 30-minute session of practice walking on a treadmill-mounted balance beam: 1) altered sacral marker movement kinematics during beam walking, and 2) affected measures of balance during treadmill walking and standing balance. Two groups of young, healthy human subjects practiced walking on a treadmill-mounted balance beam for thirty minutes. One group trained with intermittent visual occlusions and the other group trained with unperturbed vision, providing greater variation in the balance performance outcomes. We hypothesized that the subjects would show changes in sacrum movement kinematics after training and that there would be group differences due to larger improvements in beam walking performance by the visual occlusions group. We also investigated if there was any balance transfer from training on the beam to treadmill walking (margin of stability) and to standing static balance (center of pressure excursion). We found significant differences in sacral marker maximal velocity after training for both groups, but no significant differences between the two groups from training. There was limited evidence of balance transfer from beam walking practice to gait margin of stability for treadmill walking and for single-leg stance balance, but not for tandem stance balance. The number of step-offs while walking on a narrow beam had the largest change with training (partial η2=0.7), in accord with task specificity. Other balance metrics indicative of transfer had lower effect sizes (partial η2<0.5). Given the limited transfer across balance training tasks, future work should examine how intermittent visual occlusions during multi-task training improve real world functional outcomes.
Population genomic evidence of adaptive response during the invasion history ofPlasmodium falciparumin the Americas
Authors: Lefebvre Margaux J. M. , Daron Josquin , Legrand Eric , Fontaine Michael C. , Rougeron Virginie , Prugnolle Franck
Published: November 2022

Plasmodium falciparum, the most virulent agent of human malaria, spread from Africa to all continents following the out-of-Africa human migrations. During the transatlantic slave trade between the 16thand 19thcenturies, it was introduced twice independently to the Americas where it adapted to new environmental conditions (new human populations and mosquito species). Here, we analyzed the genome-wide polymorphisms of 2,635 isolates across the currentP. falciparumdistribution range in Africa, Asia, Oceania, and the Americas to investigate its genetic structure, invasion history, and selective pressures associated with its adaptation to the American environment. We confirmed that American populations originated from Africa with at least two independent introductions that led to two genetically distinct clusters, one in the North (Haiti and Columbia) and one in the South (French Guiana and Brazil), and the admixed Peruvian group. Genome scans revealed recent and more ancient signals of positive selection in the American populations. Particularly, we detected positive selection signals in genes involved in interactions with host (human and mosquito) cells and in genes involved in resistance to malaria drugs in both clusters. We found that some genes were under selection in both clusters. Analyses suggested that for five genes, adaptive introgression between clusters or selection on standing variation was at the origin of this repeated evolution. This study provides new genetic evidence onP. falciparumcolonization history and on its local adaptation in the Americas.
High-Throughput Library Transgenesis inCaenorhabditis elegansvia Transgenic Arrays Resulting in Diversity of Integrated Sequences (TARDIS)
Authors: Stevenson Zachary C. , Moerdyk-Schauwecker Megan J. , Banse Stephen A. , Patel Dhaval S. , Lu Hang , Phillips Patrick C.
Published: November 2022

High-throughput transgenesis using synthetic DNA libraries is a powerful method for systematically exploring genetic function. Diverse synthesized libraries have been used for protein engineering, identification of protein-protein interactions, characterization of promoter libraries, developmental and evolutionary lineage tracking, and various other exploratory assays. However, the need for library transgenesis has effectively restricted these approaches to single-cell models. Here we present Transgenic Arrays Resulting in Diversity of Integrated Sequences (TARDIS), a simple yet powerful approach to large-scale transgenesis that overcomes typical limitations encountered in multicellular systems. TARDIS splits the transgenesis process into a two-step process: creation of individuals carrying experimentally introduced sequence libraries, followed by inducible extraction and integration of individual sequences/library components from the larger library cassette into engineered genomic sites. Thus, transformation of a single individual, followed by lineage expansion and functional transgenesis, gives rise to thousands of genetically unique transgenic individuals. We demonstrate the power of this system using engineered, split selectable TARDIS sites in Caenorhabditis elegans to generate (1) a large set of individually barcoded lineages and (2) transcriptional reporter lines from pre-defined promoter libraries. We find that this approach increases transformation yields up to approximately 1000-fold over current single-step methods. While we demonstrate the utility of TARDIS using C. elegans, in principle the process is adaptable to any system where experimentally generated genomic loci landing pads and diverse, heritable DNA elements can be generated.
The undue influence of genetic information on medical students’ treatment decisions
Authors: Lane Andrew S. , Lynch Kate E. , Arnold Mark , Dar-Nimrod Ilan , Morandini James , Gawronski Stefan A. , Griffiths Paul E.
Published: November 2022

Introduction

Knowledge of the genetic basis of health conditions can influence how the public perceives their own and others’ health. When there are known genetic associations for such conditions, genetic essentialist biases facilitate deterministic thinking and an over-emphasis of genetic causality. This study investigates the role that genetic essentialist biases play in medical decision making.

Methods

Third- and fourth- year medical students (N = 102) read a scenario in which a patient presents with gastroenterological symptoms. Half of the students were told that the patient tested positive for HLADQ2 – a gene implicated in, but not deterministic of, coeliac disease. The other half received no genetic information. Students were assessed on their recommendations for investigation and management using a multiple-choice questionnaire. Twenty-two of these students participated in a qualitative follow-up which used semi-structured interviews to explore the reasoning behind students’ responses.

Results

Management recommendations differed between the two groups, with those receiving genetic information more likely to recommend a gluten free diet. Recommendations for further investigation did not differ significantly between groups. Interviews suggested that these findings arose despite the students’ good understanding of the common non-deterministic nature of genes, such as HLADQ2. Differences in management recommendations suggest that the inclusion of genetic information unduly biased students towards a premature diagnosis of a serious health condition–coeliac disease. Follow-up interviews introduce the possibility that observed manipulation-based differences may have been based on anticipated expectations of examiners. Thus, research in clinical settings is needed to ascertain whether genetic essentialist biases are implicitly influencing medical students under examination conditions or whether they react to the assumptive genetic biases of examiners.

Conclusion

The present findings indicate that genetic essentialist biases may affect clinical decision making of senior medical students. While the findings may also arise as an artifact of a conscious exam-taking strategy, there are substantial arguments against this interpretation.
Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma
Authors: Recouvreux Maria Victoria , Galapate Cheska Marie , Grenier Shea , Esparza Edgar , Zhang Yijuan , Maganti Swetha , Naeem Razia , Scott David A. , Lowy Andrew M. , Tiriac Hervé , Commisso Cosimo
Published: November 2022

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Despite this established dependency, the targeting of specific enzymes involved in glutamine metabolism is yet to yield any clinical benefit. Here, we have examined the therapeutic potential of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism. We found that DON treatment significantly blocks PDAC tumor growth and attenuates metastasis. Interestingly, we link the effectiveness of DON in PDAC to asparagine (Asn) metabolism. By inhibiting asparagine synthetase (ASNS), DON significantly reduces intracellular Asn production and Asn supplementation rescues the anti-proliferative effects of DON. We discern that PDAC cells upregulate expression of ASNS as a metabolic adaptation and that modulating ASNS levels can impact DON efficacy. Strikingly, in patient-derived organoids, DON responsiveness is inversely correlated with ASNS expression, a feature that is not observed for other metabolic enzymes targeted by DON. We find that treatment with L-asparaginase (ASNase), an enzyme that catabolizes free Asn, synergizes with DON to impact the viability of PDAC cells. Finally, we identify that a combination therapy of DON and ASNase has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of co-targeting adaptive responses to control PDAC progression.
Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells
Authors: Sakata Yuka , Cheng Keren , Mayama Michinori , Seita Yasunari , Detlefsen Andrea J. , Mesaros Clementina A. , Penning Trevor M. , Shishikura Kyosuke , Yang Wenli , Auchus Richard J. , Strauss Jerome F. , Sasaki Kotaro
Published: November 2022

The mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems. Herein, we faithfully recapitulate human fetal adrenal cortex specification processes through stepwise induction of human induced pluripotent stem cells through posterior intermediate mesoderm-like and adrenal progenitor-like states to ultimately generate fetal zone adrenal cortex-like cells (FZLCs), as evidenced by histomorphological, ultrastructural, and transcriptome features and adrenocorticotropic hormone (ACTH)-independent Δ5 steroid biosynthesis. Furthermore, FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN and WNT signaling, and that steroid synthesis is amplified by ACTH/PKA signaling and blocked by inhibitors of Δ5 steroid synthesis enzymes. Finally, NR5A1 promotes FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro paving the way for cell-based therapies of adrenal insufficiency.
RSV-induced Expanded Ciliated Cells Contribute to Bronchial Wall Thickening
Authors: Talukdar Sattya N. , Osan Jaspreet , Ryan Ken , Grove Bryon , Perley Danielle , Kumar Bony D. , Yang Shirley , Dallman Sydney , Hollingsworth Lauren , Bailey Kristina L. , Mehedi Masfique
Published: November 2022

Viral infection, particularly respiratory syncytial virus (RSV), causes inflammation in the bronchiolar airways (bronchial wall thickening, also known as bronchiolitis), reducing airflow through the bronchioles. This bronchial wall thickening is a common pathophysiological feature in RSV infection, but it causes more fatalities in infants than in children and adults. However, the molecular mechanism of RSV-induced bronchial wall thickening remains unknown, particularly in healthy adults. RSV infection in the airway epithelium of healthy adult bronchial cells reveals RSV-infects primarily ciliated cells. RSV infection expands the cell cytoskeleton substantially without compromising epithelial membrane integrity and ciliary functions. The RSV-induced actin cytoskeleton expansion increases ununiformly epithelial height, and cytoskeletal (actin polymerization), immunological (INF-L1, TNF-α, IP10/CXCL10), and viral (NS2) factors are probably responsible. Interestingly, RSV-infected cell cytoskeleton’s expansion resembles a noncanonical inflammatory phenotype, which contributes to bronchial wall thickening, and is termed cytoskeletal inflammation.

Author Summary

RSV infects everyone. Although RSV-induced fatal pathophysiology (e.g., bronchiolitis) is more common in infants than adults, this bronchiolitis (or bronchial wall thickening) is common in the lower respiratory tract due to RSV infection in all ages. To determine the molecular mechanism of RSV-induced bronchial wall thickening, we infectedin vitroadult airway epithelium with RSV. We found that RSV-infection induced a substantial actin-cytoskeleton expansion, consequently increased the height of the epithelium. We identified actin polymerization, secretion of proinflammatory cytokines and chemokines, and viral proteins contribute to the RSV-induced cytoskeletal expansion. Our results suggest that RSV-induces a novel noncanonical epithelial host response termed cytoskeletal inflammation, which may contribute to bronchial wall thickening.
Structural basis of Irgb6 inactivation byToxoplasma gondiithrough the phosphorylation of switch I
Authors: Okuma Hiromichi , Saijo-Hamano Yumiko , Sherif Aalaa Alrahman , Hashizaki Emi , Sakai Naoki , Kato Takaaki , Imasaki Tsuyoshi , Nitta Eriko , Sasai Miwa , Maniwa Yoshimasa , Kosako Hidetaka , Standley Daron M , Yamamoto Masahiro , Nitta Ryo
Published: November 2022

Upon infection withToxoplasma gondii, host cells produce immune-related GTPases (IRGs) to kill the parasite.T. gondiicounters this response by releasing ROP18 kinase, which inactivates IRG GTPases and inhibits their recruitment to theT. gondiiparasitophorous vacuole (PV). However, the molecular mechanisms of this process are entirely unknown. Here we report the atomic structures of Irgb6 with a phosphomimetic mutation by ROP18. The mutant has lower GTPase activity and is not recruited to the PV membrane (PVM). The crystal structure shows the mutant exhibit a distinct conformation from the physiological nucleotide-free form, thus preventing GTPase cycling. This change allosterically modifies the conformation of the membrane-binding interface, preventing physiological PVM-binding. Docking simulation of PI5P also supports the impaired binding of the mutant to PVM. We thus demonstrate the structural basis forT. gondiiescape from host cell-autonomous defense, and provide a structural model for regulating enzymatic activity by phosphorylation.
An optimised method for the recovery of laboratory generated SARS-CoV-2 aerosols by plaque assay
Authors: Byrne Rachel L , Gould Susan , Edwards Thomas , Wooding Dominic , Atkinson Barry , Moore Ginny , Collings Kieran , Boisdon Cedric , Maher Simon , Biagini Giancarlo , Adams Emily R , Fletcher Tom , Pennington Shaun H
Published: November 2022

We present an optimised method for the recovery of laboratory generated SARS-CoV-2 virus by plaque assay. This method allows easy incorporation into existing standard operating procedures of biological containment level 3 (BCL3) laboratories.