bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreases and Pronounced Geographic Variability in Antibiotic Prescribing in Medicaid
Authors: Aguilar Alexia G. , Canals Priscilla C. , Miller Kimberly A. , Piper Brian J.
Published: February 2023

Background

Antibiotic resistance is a persistent and growing concern. Our objective was to analyze antibiotic prescribing data in the United States (US) to identify trends in the Medical Expenditure Panel System (MEPS) and any state-level disparities to Medicaid patients.

Methods

We obtained total MEPS prescriptions for eight antibiotics from 2013 to 2020. We extracted prescribing rates per 1,000 Medicaid enrollees for two years, 2018 and 2019, for four broad spectrum (azithromycin, ciprofloxacin, levofloxacin, and moxifloxacin) and four narrow spectrum (amoxicillin, cephalexin, doxycycline, and trimethoprim/sulfamethoxazole) antibiotics.

Results

Antibiotics in MEPS decreased from 2013 to 2020 by −38.7% with a larger decline for broad (−53.7%) than narrow spectrum (−23.5%). Antibiotic prescriptions decreased from 2018 to 2019 and by −6.7% when correcting for the number of Medicaid enrollees. Amoxicillin was the predominant antibiotic followed by azithromycin, cephalexin, trimethoprim/sulfamethoxazole, doxycycline, ciprofloxacin, levofloxacin, and moxifloxacin. Substantial geographic variation in antibiotic prescribing existed with 2.8-fold between the highest (Kentucky = 855/1,000) and lowest (Oregon = 299) states. The South prescribed 52.2% more antibiotics (580/1,000) than the West (381/1,000). There were significant correlations across states in antibiotic prescribing.

Conclusions & Relevance

This study identified sizable disparities by geography in prescribing rates of eight antibiotics with over three-fold state level differences. The South had the highest prescribing rates among all the regions. Areas with high antibiotic prescribing rates, particularly for outpatients, may benefit from programs to reduce potentially unnecessary prescribing. Further analysis of state level Medicaid or prescribing policies is needed to identify reasons for the variation in prescribing rates.
Significance of headache in inflammatory bowel diseases
Authors: Khalid Baqir Ali , Ali Bilal , Shah Muhammad Nauman , Saleem Muhammad Asjad , Mohib Khadija , Alam Ehtisham , Wazir Sangeen Khan
Published: February 2023

Introduction

Research has shown clear correlation between inflammatory conditions and a prothrombotic state. Cerebral vein thrombosis can be fatal and diagnosis is challenging as symptoms are unspecific.

Objectives

The main objective of the study is to find the association between headache and inflammatory bowel diseases.

Material and methods

This cross-sectional study was conducted in Foundation University Islamabad and Dow Medical College Karachi during 2021 to 2022. Data was collected from 20 patients presenting in OPD of the hospital. Patients with inflammatory bowel disease unclassified presented to emergency department with a 3-day history of nausea, vomiting, headache and sporadic abdominal pain along with intermittent bloody stools in recent weeks.

Results

Data was collected from 20 patients. There were 8 males and 12 females with mean age of 45.67 ± 2.34 years. No differences were found when comparing the distribution of data including IBD and migraine or severe headache. The prevalence of migraine or severe headache and 95% confidence intervals (CIs) and by selected characteristics were calculated.

Conclusion

It is concluded that headache is frequent and disabling in IBD patients, highlighting the probable role of the brain–gut axis in this co-occurrence of pathologies.
Using Mendelian Randomization to model the causal effect of cancer on health economic outcomes and to simulate the cost-effectiveness of anti-cancer interventions
Authors: Dixon Padraig , Martin Richard M , Harrison Sean
Published: February 2023

BACKGROUND

Cancer is associated with significant economic impacts. Quantifying the scale of these impacts is challenged by confounding variables that jointly influence both cancer status and economic outcomes such as healthcare costs and quality of life. Moreover, the increasing costs attributed to cancer drug development complicate the cost-effective provision of cancer care.

METHODS

We address both challenges in this paper by using germline genetic variation in the risk of incident cancer as instrumental variables in Mendelian Randomization analyses of eight cancers. We developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate and thyroid cancers on healthcare costs and quality adjusted life years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used Mendelian Randomization to model a hypothetical population-wide preventative intervention based on a repurposed class of anti-diabetic drugs known as sodium-glucose co-transporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer.

RESULTS

Genetic liability to prostate cancer and to breast cancer had material causal impacts on healthcare costs and QALYs. Mendelian Randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anti-cancer indication.

IMPLICATIONS

Our new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision analytic models of cancer interventions such as screening programmes or simulations of longer-term outcomes associated with therapies investigated in RCTs with short follow-ups. Our new method allows us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anti-cancer intervention to inform and complement other means of assessing long-term intervention cost-effectiveness.
Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression
Authors: Thapaliya Bishal , Ray Bhaskar , Farahdel Britny , Suresh Pranav , Sapkota Ram ,   IMAGEN consortium,   cVEDA consortium, Holla Bharath , Mahadevan Jayant , Chen Jiayu , Vaidya Nilakshi , Perrone-Bizzozero Nora , Benegal Vivek , Schumann Gunter , Calhoun Vince D. , Liu Jingyu
Published: February 2023

Anxiety and depression in children and adolescents warrant special attention as a public health issue given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17) and IMAGEN (EUROPE, age of 14). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta-analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school risk had the most significant and consistent impact across all three cohorts. Both meta and mega-analysis identified a novel SNP rs79878474 in chr11p15 to be the most promising SNP associated with anxiety and depression. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine and a trend of enrichment in the cerebellum. Our findings provide evidence of consistent environmental impact from early life stress and school risks on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels along with the potential role of the cerebellum region, which are worthy of further investigation.
Use of wastewater metrics to track COVID-19 in the U.S.: a national time-series analysis over the first three quarters of 2022
Authors: Varkila Meri , Montez-Rath Maria , Salomon Joshua , Yu Xue , Block Geoffrey , Owens Douglas K. , Chertow Glenn M , Parsonnet Julie , Anand Shuchi
Published: February 2023

Background

Widespread use of at-home COVID-19 tests hampers determination of community COVID-19 incidence. Using nationwide data available through the US National Wastewater Surveillance System, we examined the performance of two wastewater metrics in predicting high case and hospitalizations rates both before and after widespread use of at-home tests.

Methods

We performed area under the receiver operating characteristic (ROC) curve analysis (AUC) for two wastewater metrics—viral concentration relative to the peak of January 2022 (“wastewater percentile”) and 15-day percent change in SARS-CoV-2 (“percent change”). Dichotomized reported cases (≥ 200 or <200 cases per 100,000) and new hospitalizations (≥ 10 or <10 per 100,000) were our dependent variables, stratified by calendar quarter. Using logistic regression, we assessed the performance of combining wastewater metrics.

Results

Among 268 counties across 22 states, wastewater percentile detected high reported case and hospitalizations rates in the first quarter of 2022 (AUC 0.95 and 0.86 respectively) whereas the percent change did not (AUC 0.54 and 0.49 respectively). A wastewater percentile of 51% maximized sensitivity (0.93) and specificity (0.82) for detecting high case rates. A model inclusive of both metrics performed no better than using wastewater percentile alone. The predictive capability of wastewater percentile declined over time (AUC 0.84 and 0.72 for cases for second and third quarters of 2022).

Conclusion

Nationwide, county wastewater levels above 51% relative to the historic peak predicted high COVID rates and hospitalization in the first quarter of 2022, but performed less well in subsequent quarters. Decline over time in predictive performance of this metric likely reflects underreporting of cases, reduced testing, and possibly lower virulence of infection due to vaccines and treatments.
Characteristics of COVID-19 in children and potential risk factors for requiring mechanical ventilation; an analysis of 22,490 cases from the United States
Authors: Verma Renuka , Ramphul Kamleshun , Lohana Petras , Sombans Shaheen , Ramphul Yogeshwaree , Pekyi-Boateng Prince Kwabla
Published: February 2023

The pandemic of Coronavirus disease 2019 (COVID-19) has lasted more than two years and caused millions of deaths. While the characteristics and outcomes have been more widely studied in the adult population, we conducted an in-depth analysis via the 2020 National Inpatient Sample to understand the characteristics and predictors for the use of mechanical ventilation in patients of ages 18 and less in the United States. Twenty-two thousand four hundred ninety hospitalizations involving COVID-19-positive children were found. 52.7% (11850 cases) were females, 37.0% were Hispanics, 38.0% (8555 cases) were in the first percentile 0-25th of Median household income, and 66.9% used Medicaid. In total, 1140 cases (5.1%) needed mechanical ventilation. Among factors such as obesity (aOR 1.662, 95%CI 1.368-2.019, p<0.001), Blacks (vs. White) (aOR 1.472, 95%CI 1.23-1.761, p<0.001), private insurances (aOR 1.241, 95%CI 1.06-1.453, p=0.007) or remaining forms of payment other than Medicaid or private insurances (aOR 1.763, 95%CI 1.428-2.177, p<0.001, vs. Medicaid), ages 6 to 10 years (aOR 1.531, 95%CI 1.259-1.862, p<0.001, vs. ages 0-5) showed higher odds of needing mechanical ventilation. On the contrary, Females (aOR 0.54, 95%CI 0.472-0.617, p<0.001, vs. Males), hospitalized patients in November (aOR 0.542, 95%CI 0.399-0.736, p<0.001) and December (aOR 0.446, 95%CI 0.329-0.606, p<0.001) (vs. April), Hispanics (aOR 0.832, 95%CI 0.699-0.99, p=0.038, vs. White), ages 16-18 years (aOR 0.804, 95%CI 0.673-0.96, p=0.016, vs. 0-5years), and in the 76th-100thmedian household income percentile (aOR 0.783, 95%CI 0.628-0.976, p=0.03, vs. 0-25th percentile) showed reduced odds. 9.6% of patients on mechanical ventilation died.
Using rapid response system trigger clusters to characterize patterns of clinical deterioration among hospitalized adult patients
Authors: Piasecki Rebecca J. , Hunt Elizabeth A. , Perrin Nancy , Spaulding Erin M. , Winters Bradford , Samuel Laura , Davidson Patricia M. , Strobos Nisha Chandra , Churpek Matthew , Himmelfarb Cheryl R. ,   the American Heart Association’s Get With The Guidelines®-Resuscitation Investigators
Published: February 2023

Background

Many rapid response system (RRS) events are activated using multiple triggers. However, the patterns in which RRS triggers co-occur to activate the medical emergency team (MET) to respond to RRS events is unknown. The purpose of this study was to identify and describe the patterns (RRS trigger clusters) in which RRS triggers co-occur when used to activate the MET and determine the association of these clusters with outcomes using a sample of hospitalized adult patients.

Methods

RRS events among adult patients from January 2015 to December 2019 in the Get With The Guidelines-Resuscitation registry’s MET module were examined (n=134,406). A combination of cluster analyses methods was performed to group patients into RRS trigger clusters based on the triggers used to activate their RRS events. Pearson’s chi-squared and ANOVA tests were used to examine differences in patient characteristics across RRS trigger clusters. Multilevel logistic regression was used to examine the associations between RRS trigger clusters and outcomes following RRS events.

Results

Six RRS trigger clusters were identified in the study sample. The RRS triggers that predominantly identified each cluster were as follows: tachypnea, new onset difficulty in breathing, and decreased oxygen saturation (Cluster 1); tachypnea, decreased oxygen saturation, and staff concern (Cluster 2); respiratory depression, decreased oxygen saturation, and mental status changes (Cluster 3); tachycardia and staff concern (Cluster 4); mental status changes (Cluster 5); hypotension and staff concern (Cluster 6). Significant differences in patient characteristics were observed across RRS trigger clusters. Patients in Clusters 3 and 6 were associated with an increased likelihood of in-hospital cardiac arrest (IHCA [p<0.01]), while Cluster 4 was associated with a decreased likelihood of IHCA (p<0.01). All clusters were associated with an increased risk of mortality (p<0.01).

Conclusions

We discovered six novel RRS trigger clusters with differing relationships to adverse patient outcomes following RRS events. RRS trigger clusters may prove crucial in clarifying the associations between RRS events and adverse outcomes and may aid in clinician decision-making during RRS events.
Mitochondrial metabolism in primary and metastatic human kidney cancers
Authors: Bezwada Divya , Lesner Nicholas P. , Brooks Bailey , Vu Hieu S. , Wu Zheng , Cai Ling , Kasitinon Stacy , Kelekar Sherwin , Cai Feng , Aurora Arin B. , Patrick McKenzie , Leach Ashley , Ghandour Rashed , Zhang Yuanyuan , Do Duyen , Sudderth Jessica , Dumesnil Dennis , House Sara , Rosales Tracy , Poole Alan M. , Lotan Yair , Woldu Solomon , Bagrodia Aditya , Meng Xiaosong , Cadeddu Jeffrey A. , Mishra Prashant , Pedrosa Ivan , Kapur Payal , Courtney Kevin D. , Malloy Craig R. , Margulis Vitaly , DeBerardinis Ralph J.
Published: February 2023

Most kidney cancers display evidence of metabolic dysfunction1–4but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse13C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-13C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2-13C]acetate and [U-13C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.
Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug resistantMycobacterium tuberculosis
Authors: Harrison Gregory A. , Cho Kevin , Wang Erin R. , Sarkar Souvik , Almqvist Fredrik , Patti Gary J. , Stallings Christina L.
Published: February 2023

Of the approximately 10 million cases ofMycobacterium tuberculosis(Mtb) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor ofMtbrespiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for growth ofMtbin high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of theMtbelectron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causingMtbto become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability inMtbthat can be exploited to renderMtbsensitive to otherwise subinhibitory concentrations of InhA inhibitor.

Significance

Isoniazid (INH) is a critical frontline antibiotic to treatMycobacterium tuberculosis(Mtb) infections. INH efficacy is limited by its suboptimal penetration of theMtb-containing lesion and by the prevalence of clinical INH-resistance. We previously discovered a compound, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a set of INH-resistant mutants to INH. Resistance is typically mediated bykatGmutations that decrease the activation of INH, which is required for INH to inhibit the essential enzyme InhA. Our current work demonstrates that C10 re-sensitizes INH-resistantkatG-hypomorphs without enhancing the activation of INH. We furthermore show that C10 causesMtbto become particularly vulnerable to InhA inhibition without compromising InhA activity on its own. Therefore, C10 represents a novel strategy to curtail the development of INH resistance and to sensitizeMtbto sub-lethal doses of INH, such as those achieved at the infection site.
Why Clinical Trials Stop: The Role of Genetics
Authors: Razuvayevskaya Olesya , Lopez Irene , Dunham Ian , Ochoa David
Published: February 2023

Many drug discovery projects are started, but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the freetext reasons for 28,842 clinical trials that stopped before their endpoints were met. We then evaluated these classes in the light of the underlying evidence for the therapeutic hypothesis and target properties. We show that trials are more likely to stop due to lack of efficacy in the absence of strong genetic evidence from human populations or genetically-modified animal models. Furthermore, trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is not selectively expressed. These results support the growing use of human genetics to evaluate targets for drug discovery programmes.
Gender differences in Pornography Use and Associated Factors among high school students: A Cross-Sectional Study
Authors: Mahmoud Ali Jotyar , Abdulqadir Hajar Hassan , Khalid Rojeen Chalabi , Dirbas Vindad Hashim , Hasan Doaa Farhad , Mahfodh Saman Sherwan , Naisan Kareen Yarwant , Arif Iman Mohammed , Yousif Iman Ramadhan , Mohammed Sana Najeeb , Haji Suzan Muhsin , Mohammed Suzan Taha , Hama Ali Alind Ari , Babakhani Siavash
Published: February 2023

Background and aim

The pornography consuming is increasing through the availability of the internet worldwide and the availability of the pornographic sites without any restriction, pornographic sites have many complications in the consumer and lacking survey in our country which make sense to conduct this study. This study aimed to measure the prevalence of pornography watching among high school students and factors associated with pornography viewing.

Materials and Methods

This cross-sectional study was conducted at Zakho independent administration, Kurdistan Region, Iraq among 5 different high school students and 2 institutions. This survey was conducted using a paper questionnaire administered to the participants between April and July 2022. Chi-square analysis was performed to identify possible risk factors for viewing porn and results were expressed as a p value

Results

Total number of the participants included in this study was 921 with an average age ± standard deviation (SD) of 16.78 years ±1.26. More than half of participants was male (54.83%), viewed pornography alone (49.08%) and about 69.71% disagree on watching porn. There were statistically significant differences (p <0.001) in the attitude and practice of men compared with women throughout all tested variables. About 50.71% of the participants were viewed pornography at least once in a lifetime, among those 65.1% are male and 34.9% of them are female and 92.55% of participants agree to close pornography sites

Conclusion

The prevalence of pornography among high school students is high. Young age, and male gender are predictors for higher pornography viewing and should be considered when designing public health intervention in a related context. Longitudinal studies for investigating pornography consumption among different educational levels are needed to assess the causal relationship between pornography consumption and associated factors.
Diagnostic Machine Learning Applications on Clinical Populations using Functional Near Infrared Spectroscopy: A Review
Authors: Eken Aykut , Nassehi Farhad , Eroğul Osman
Published: February 2023

Functional near-infrared spectroscopy (fNIRS) and its interaction with machine learning (ML) is a popular research topic for the diagnostic classification of clinical disorders due to the lack of robust and objective biomarkers. This review provides an overview of research on psychiatric diseases by using fNIRS and ML. Article search was carried out and 45 studies were evaluated by considering their sample sizes, used features, ML methodology, and reported accuracy. To our best knowledge, this is the first review that reports diagnostic ML applications using fNIRS. We found that there has been an increasing trend to perform ML applications on fNIRS-based biomarker research since 2010. The most studied populations are schizophrenia (n=12), attention deficit and hyperactivity disorder (n=7), and autism spectrum disorder (n=6) are the most studied populations. There is a significant negative correlation between sample size (>20) and accuracy values. Support vector machine (SVM) and deep learning (DL) approaches were the most popular classifier approaches (SVM = 20) (DL = 10). Eight of these studies recruited a number of participants more than 100 for classification. Change in oxy-hemoglobin (ΔHbO) based features were used more than change in deoxy-hemoglobin-based ones and the most popular ΔHbO-based features were mean ΔHbO (n=11) and ΔHbO-based functional connections (n=11). Using ML on fNIRS data might be a promising approach to reveal specific biomarkers for diagnostic classification.
Total and regional skeletal muscle mass references by sport participation and body size in youth
Authors: Correas-Gómez Lorena , Alvero-Cruz José Ramón , Barrera-Expósito Jesús , de Albornoz-Gil Margarita Carrillo , Quitério Ana L. , Carnero Elvis A.
Published: February 2023

Skeletal muscle mass (SMM) is a relevant indicator of adolescent health influenced by sport participation, body size, and maturation. However, limited data are available from techniques accessible to field professionals.

Purpose

To provide reference data of regional and total-body SMM and fat-free mass (FFM) derived from anthropometry among groups of age, sex, and sport participation in healthy Caucasian children and adolescents.

Materials and methods

A cross-sectional dataset of 1,438 participants aged 8-18 years were analyzed for this study. Regional and total-body SMM and FFM were estimated from anthropometric variables. Sport participation was obtained byad hocquestionnaires and maturity offset was calculated using predictive equations. General linear model of mixed factors was used to analyze the variance of FFM or SMM across groups and confounders. Ln-ln regression analysis was applied to describe the scaling relationship between SMM and height.

Results

Positive interactions were found between sex, sport participation, and age for regional muscle variables (P<0.05). Adjusted total and regional SMM significantly increased along school-age periods in the active groups (∼2.2 kg gain,P<0.05, boys and girls; arm, ∼1.3 cm gain,P<0.01, boys), and allometric values were higher in boys than girls for regional muscle (P<0.01).

Discussion

The novel contribution of this analysis includes regional indicators of SMM and the relevance of sport participation on SMM accrual in post-pubertal boys. Also, confirms that muscle growth rate varies across sex and phases of puberty, which arises a plausible sexual phenotype/dysmorphism of regional SMM influenced by sport participation.
Modification of gene expression after internalization of Growth Hormone (GH) into the cell nucleus
Authors: Morel Gerard
Published: February 2023

Growth hormone (GH) and many other hormones or growth factors have been shown to be rapidly internalized and translocated into the nucleus. The first event of peptide action is binding to its receptor which initiates both signal transduction pathways and internalization. The latter process involves the nucleus and probably gene transcription. In order to analyze the consequences of internalization of GH on gene expression, we used different populations of CHO cells, transfected with either full length GH receptor, or with defective receptor unable to trigger either signal transduction (deletion of box1) or the internalization of GH (Phe346mutation in Ala). In addition, functional isolated nuclei were incubated 10 and 30 min with 50 nM GH in order to analyze the direct effect of GH on gene expression without surrounding cytoplasmic structures. The genes involved in signal transduction pathways were not revealed if GH internalization is the only functional activity in the whole cell as well as with isolated nuclei. In intact cell, internalization increased expression of 297 genes and decreased fewer than 10% of those known to be influenced by GH. Variations of expression in purified nuclei showed large variations with time. If cell signaling was not modified, cellular growth and proliferation, nucleic acid metabolism, cellular development, cell cycle and gene expression showed many variations with time. GH internalization shows direct effects on gene expression, different from those stimulated by signal transduction.
A General Fluorescence-Based Method for Quantifying and Mapping Biomolecular Polarity In Vitro and In Cells
Authors: Owyong Tze Cin , O’Shea Riley , Lee Mihwa , White Jonathan M. , Donnelly Paul S. , Hinde Elizabeth , Wong Wallace W. H. , Hong Yuning
Published: February 2023

Spatial discretization of biomolecules in the complex cellular environment is crucial for biomolecular form and function. The ability to better understand the driving force of spatial discretization of biomolecules in the complex cellular matrix remains a challenging task. We report on the robust polarity sensitive solvatochromic probe,FLAM, in conjunction with spectral phasor analysis as a general method for studying environmental polarity in biological systems. We find that phase separated proteins of SFPQ have distinct polarity depending on the type of phase separation occurring, suggesting that polarity plays a role in the formation of phase separated condensates. When usingFLAMin cells, distinct subcellular environmental polarity distribution but similar trend of changes is observed for cells under similar type of stressors. Taken together, our method puts forth an exciting development in the tool set for the study of phase separation.
Ferroptosis is determined by chloride ions
Authors: Huang Dichun , Dai Zhangshuai , Wang Chao , Mai Haiying , Zhao Junyi , Cao Lingbo , Wang Sijie , Dai Zhun , Xu Kun , He Ronghan , Zhu Shaoshen , Chen Yanchen , Bing Tiejun , Zhu Xinzhou , Chew Ting Gang , Huang Junqi
Published: February 2023

Ferroptosis has emerged as a deliberate type of programmed cell death that manifests marked importance ubiquitously in health and diseases. However, after a decade of research, the mechanisms of ferroptosis execution remain unclear. Here we identify chloride ions (Cl-) as essential determinants of ferroptosis. Water homeostasis manipulated by extracellular solute concentration disrupts ferroptotic cell death. Hyperosmotic stress attenuates ferroptosis and endues cells with high lipid peroxidation. Analyses of a fluorescent chloride probe show that Cl-fluxes into the cytoplasm during ferroptosis, substantiating a role for Cl-to drive water flow. Depletion of extracellular chloride ions ([Cl-]o) from culture media congruously confers resistance to ferroptosis. The [Cl-]o-depleted ferroptotic cells fall into two populations: cells with low lipid peroxidation; cells with high lipid peroxidation but not cell swelling or cell rupture. Contrarily, solitary [Cl-]ooverload is sufficient to elicit ferroptosis without canonical ferroptosis inducers. Further experiments show that ferroptotic cells depolarize and [Cl-]ois positively correlated with this process. Membrane depolarization upregulates the level of lipid peroxidation, suggesting that membrane potential may be a universal mechanism governing ferroptosis. Together, our findings reveal that ferroptosis is determined by chloride ions.
Plant spectral diversity from high-resolution multispectral imagery detects functional diversity patterns in coastal dune communities
Authors: Beccari Eleonora , Carmona Carlos Pérez , Tordoni Enrico , Petruzzellis Francesco , Martinucci Davide , Casagrande Giulia , Pavanetto Nicola , Rocchini Duccio , D’Antraccoli Marco , Ciccarelli Daniela , Bacaro Giovanni
Published: February 2023

Remote sensing is a fundamental tool to monitor biodiversity over large spatial extents. However, it is still not clear whether spectral diversity (SD - variation of spectral response across a set of pixels) may represent a fast and reliable proxy for different biodiversity facets such as taxonomic (TD) and functional diversity (FD) across different spatial scales.

We used fine resolution (3 cm) multispectral imagery on coastal dune communities in Italy to explore SD patterns across spatial scales and assess SD relationships with TD and FD along the environmental gradient.

We measured TD as species richness, while SD and FD were computed using probability densities functions based on pixels and species position in multivariate spaces based on pixel values and traits, respectively. We assessed how SD is related to TD and FD, we compared SD and FD patterns in multivariate space occupation, and we explored diversity patterns across spatial scales using additive partitioning (i.e., plot, transect, and study area).

We found a strong correspondence between the patterns of occupation of the functional and spectral spaces and significant relationships were found along the environmental gradient. TD showed no significant relationships with SD. However, TD and SD showed higher variation at broader scale while most of FD variation occurred at plot level.

By measuring FD and SD with a common methodological framework, we demonstrate the potential of SD in approximating functional patterns in plant communities. We show that SD can retrieve information about FD at very small scale, which would otherwise require very intensive sampling efforts. Overall, we show that SD retrieved using high resolution images is able to capture different aspects of FD, so that the occupation of the spectral space is analogous to the occupation of the functional space. Studying the occupation of both spectral and functional space brings a more comprehensive understanding of the factors that influence the distribution and abundance of plant species across environmental gradients.
RxRx3: Phenomics Map of Biology
Authors: Fay Marta M. , Kraus Oren , Victors Mason , Arumugam Lakshmanan , Vuggumudi Kamal , Urbanik John , Hansen Kyle , Celik Safiye , Cernek Nico , Jagannathan Ganesh , Christensen Jordan , Earnshaw Berton A. , Haque Imran S. , Mabey Ben
Published: February 2023

The combination of modern genetic perturbation techniques with high content screening has enabled genome-scale cell microscopy experiments that can be leveraged to constructmaps of biology. These are built by processing microscopy images to produce readouts in unified and relatable representation space to capture known biological relationships and discover new ones. To further enable the scientific community to develop methods and insights from map-scale data, here we releaseRxRx3, the first ever public high-content screening dataset combining genome-scale CRISPR knockouts with multiple-concentration screening of small molecules (a set of FDA approved and commercially available bioactive compounds). The dataset contains 6-channel fluorescent microscopy images and associated deep learning embeddings from over 2.2 million wells that span 17,063 CRISPR knockouts and 1,674 compounds at 8 doses each.RxRx3is one of the largest collections of cellular screening data, and as far as we know, the largest generated consistently via a common experimental protocol within a single laboratory. Our goal in releasingRxRx3is to demonstrate the benefits of generating consistent data, enable the development of the machine learning methods on this scale of data and to foster research, methods development, and collaboration.

For more information aboutRxRx3please visit RxRx.ai/rxrx3
Target-specific requirements for RNA interference can arise through restricted RNA amplification despite the lack of specialized pathways
Authors: Knudsen-Palmer Daphne R. , Raman Pravrutha , Ettefa Farida , De Ravin Laura , Jose Antony M.
Published: February 2023

Since double-stranded RNA (dsRNA) is effective for silencing a wide variety of genes, all genes are typically considered equivalent targets for such RNA interference (RNAi). Yet, loss of some regulators of RNAi in the nematodeC. eleganscan selectively impair the silencing of some genes. Here we show that such selective requirements can be explained by an intersecting network of regulators acting on genes with differences in their RNA metabolism. In this network, the Maelstrom domain-containing protein RDE-10, the intrinsically disordered protein MUT-16, and the Argonaute protein NRDE-3 work together so that any two are required for silencing one somatic gene, but each is singly required for silencing another somatic gene, where only the requirement for NRDE-3 can be overcome by enhanced dsRNA processing. Quantitative models and their exploratory simulations led us to find that (1) changingcis-regulatory elements of the target gene can reduce the dependence on NRDE-3, (2) animals can recover from silencing in non-dividing cells and (3) cleavage and tailing of mRNAs with UG dinucleotides, which makes them templates for amplifying small RNAs, is enriched within ‘pUG zones’ matching the dsRNA. Similar crosstalk between pathways and restricted amplification could result in apparently selective silencing by endogenous RNAs.
Behavioral and neural evidence for the underestimated attractiveness of faces synthesized using an artificial neural network
Authors: Nishida Satoshi
Published: February 2023

Despite recent advantages in artificial intelligence (AI), the potential human aversion to AI has not been dispelled yet. If such aversion degrades the human preference to AI-synthesized visual information, the preference should be reduced solely by the human belief that the information is synthesized by AI, independently of its appearance. To test this hypothesis, this study designed a task paradigm in which naïve participants rated the attractiveness of various faces synthesized using an artificial neural network, under the fake instruction that half of the faces were synthetic and the other half were real. This design allowed evaluating the effect of participants’ beliefs on their attractiveness ratings separately from the effect of facial appearance. In addition, to investigate the neural substrates of the belief effect, brain responses to faces were collected using fMRI during this task. It is found that participants’ ratings declined when the faces were believed to be synthetic. Furthermore, the belief changed the responsiveness of fMRI signals to facial attractiveness in the right fusiform cortex. These behavioral and neural findings support the notion that the human preference to visual information becomes lower solely due to the beliefs that the information is synthesized by AI.
Neutralization of SARS-CoV-2 BQ.1.1 and XBB.1.5 by Breakthrough Infection Sera from Previous and Current Waves in China
Authors: Wang Xun , Jiang Shuai , Jiang Shujun , Li Xiangnan , Ai Jingwen , Lin Ke , Lv Shiyun , Zhang Shixuan , Li Minghui , He Xinyi , Li Dingding , Li Chen , Zhao Chaoyue , Zhao Xiaoyu , Qiao Rui , Cui Yuchen , Chen Yanjia , Li Jiayan , Cai Guonan , Li Jixi , Dai Lili , Hu Zixin , Zhang Wenhong , Zhang Yanliang , Wang Pengfei
Published: February 2023

SARS-CoV-2 is continuing to evolve and diversify, with an array of various Omicron sub-lineages, including BA.5, BA.2.75, BN.1, BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5, now circulating globally at recent time. In this study, we evaluated the neutralization sensitivity of a comprehensive panel of Omicron subvariants to sera from different clinical cohorts, including individuals who received homologous or heterologous booster vaccinations, vaccinated people who had Delta or BA.2 breakthrough infection in previous waves, and patients who had BA.5 or BF.7 breakthrough infection in the current wave in China. All the Omicron subvariants exhibited substantial neutralization evasion, with BQ.1, BQ.1.1, XBB.1, and XBB.1.5 being the strongest escaped subvariants. Sera from Omicron breakthrough infection, especially the recent BA.5 or BF.7 breakthrough infection, exhibited higher neutralizing activity against all Omicron sub-lineages, indicating the chance of BA.5 and BF.7 being entirely replaced by BQ or XBB subvariants in China in a short-term might be low. We also demonstrated that the BQ and XBB subvariants were the most resistant viruses to monoclonal antibodies. Continuing to monitor the immune escape of SARS-CoV-2 emerging variants and developing novel broad-spectrum vaccines and antibodies are still crucial.
Dogs and cats are less susceptible to the omicron variant of concern of SARS-CoV-2 – a field study
Authors: Klein Constantin , Michelitsch Anna , Allendorf Valerie , Conraths Franz Josef , Beer Martin , Denzin Nicolai , Wernike Kerstin
Published: February 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic of unprecedented extent. Beside humans, a number of animal species can be infected, however, in some species differing susceptibilities were observed depending on the virus variant. Here, we serologically investigated cats and dogs living in households with human COVID-19 patients. The study was conducted during the transition period from delta as the dominating variant of concern (VOC) to omicron (BA.1/BA.2) to investigate the frequency of virus transmission of both VOCs from infected owners to their pets. The animal sera were tested by surrogate virus neutralization tests (sVNT) using either the original receptor-binding domain (RBD), enabling the detection of antibodies against the delta variant, or an omicron-specific RBD. Of the 290 canine samples, 20 tested positive by sVNT, but there were marked differences between the sampling time, and, related thereto, the virus variants, the dogs had contact to. While in November 2021 infected owners led to 50% seropositive dogs (18/36), only 0.8% (2/254) of animals with household contacts to SARS-CoV-2 between December 2021 and April 2022 tested positive. In all cases, the positive reaction was recorded against the original RBD. For cats, a similar pattern was seen, as in November 2021 38.1% (16/42) tested positive and between December 2021 and March 2022 only 5.0% (10/199). The markedly reduced ratio of seropositive animals during the period of omicron circulation suggests a considerably lower susceptibility of dogs and cats to this VOC.

To examine the effect of BA.2, BA.4 and BA.5 omicron subvariants, sera taken in the second and third quarter of 2022 from randomly selected cats were investigated. 2.3% (11/372) tested seropositive and all of them showed a stronger reaction against the original RBD, further supporting the assumption of a lower susceptibility of companion animals to the omicron VOC.
A Bayesian inference method to estimate transmission trees with multiple introductions; applied to SARS-CoV-2 in Dutch mink farms
Authors: Van der Roest Bastiaan R. , Bootsma Martin C.J. , Fischer Egil A.J. , Klinkenberg Don , Kretzschmar Mirjam E.E.
Published: February 2023

Knowledge of who infected whom during an outbreak of an infectious disease is important to determine risk factors for transmission and to design effective control measures. Both whole-genome sequencing of pathogens and epidemiological data provide useful information about the transmission events and underlying processes. Existing models to infer transmission trees usually assume that the pathogen is introduced only once from outside into the population of interest. However, this is not always true. For instance, SARS-CoV-2 is suggested to be introduced multiple times in mink farms in the Netherlands from the SARS-CoV-2 pandemic among humans. Here, we developed a Bayesian inference method combining whole-genome sequencing data and epidemiological data, allowing for multiple introductions of the pathogen in the population. Our method does not a priori split the outbreak into multiple phylogenetic clusters, nor does it break the dependency between the processes of mutation, within-host dynamics, transmission, and observation. We implemented our method as an additional feature in the R-packagephybreak. On simulated data, our method identifies the number of introductions with high accuracy. Moreover, when a single introduction was simulated, our method produces similar estimates of parameters and transmission trees as the existing package. When applied to data from a SARS-CoV-2 outbreak in Dutch mink farms, the method provides strong evidence for 13 introductions, which is 20 percent of all infected farms. Using the new feature of thephybreakpackage, transmission routes of a more complex class of infectious disease outbreaks can be inferred which will aid infection control in future outbreaks.
Paclitaxel- and vincristine-induced neurotoxicity and drug transport in sensory neurons
Authors: Mortensen Christina , Chua Katherina C. , Hammer Helen S. , Nielsen Flemming , Pötz Oliver , Svenningsen Åsa Fex , Kroetz Deanna L. , Stage Tore Bjerregaard
Published: February 2023

Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and the lack of therapies for treatment and prevention. Patients with CIPN primarily present with sensory symptoms, such as sensory disturbances that may progress to neuropathic pain in hands and feet. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. We utilized a model of human sensory neurons derived from induced pluripotent stem cells (iPSC-SNs) to provide mechanistic understanding of CIPN caused by paclitaxel and vincristine. The morphological phenotype of iPSC-SNs following paclitaxel exposure was characterized by retraction and thickening of axons while vincristine caused fragmentation and abolishment of axons. Both agents increased the mRNA expression of the pain receptor, transient receptor potential vanilloid (TRPV1), and highly induced neuronal damage, as measured by activating transcription factor 3 (ATF3) mRNA. iPSC-SNs express the efflux transporters, P-glycoprotein (P-gp, encoded byABCB1) and multidrug resistance-associated protein 1 (MPR1, encoded byABCC1). Inhibition of P-gp and MRP1 in iPSC-SNs exacerbated neurotoxicity of paclitaxel and vincristine respectively. We further show that pre-treatment with the P-gp inducer rifampicin alleviated chemotherapy-induced structural and transcriptional alterations in iPSC-SNs. iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters play a critical role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system.