bluuebunny/crossref_metadata_2025 huggingface dataset:
Deprivation effect on COVID-19 cases incidence and severity: a geo-epidemiological study in PACA region, France
Authors: Gaubert Guillaume , Nauleau Steve , Franke Florian , Rebaudet Stanislas , Mosnier Emilie , Landier Jordi , Chaud Pascal , Malfait Philippe , Vandentorren Stéphanie , Huart Michael , Ramdani Alaa , Bendiane Marc-Karim , Danjou Fabrice , Gaudart Jean
Published: April 2023

Introduction

The spread of the COVID-19 pandemic, and its severity, is spatially heterogenous. At the individual level, the socioeconomic status (SES) profile is known to be associated with COVID-19 incidence and severity. The aim of this geo epidemiological study was to investigate the link between SES profile and potential confounders, and COVID-19 incidence and hospitalization rates, at a fine geographical scale.

Methods

We analyzed COVID-19 incidence and severity during two epidemic waves between September 2020 and June 2021, in Provence Alpes Côtes d’Azur, a 5 million inhabitants’ French region. The region is divided into sub-municipal areas that we have classified according to their SES profile. We then conducted a spatial analysis of COVID-19 indicators depending on SES profile, age structure, and health services provision. This analysis considered spatial autocorrelation between areas.

Results

COVID-19 incidence rates in more deprived areas were similar to those in wealthiest ones. Hospitalization rates of COVID-19 cases in conventional care units were greater in more deprived vs wealthiest areas: Standardized Incidence Ratio (SIR) were respectively 1.34 [95% confidence interval 1.18 - 1.52] and 1.25 [1.13 - 1.38] depending on the epidemic wave. This gap was even greater regarding hospitalization rates of cases in critical care units: SIR = 1.64 [1.30 - 2.07] then 1.33 [1.14 - 1.55] depending on the epidemic wave. Hospitalization rates of COVID-19 cases in conventional care units were also greater in areas with high proportion of elderly people vs young people: SIR respectively 1.24 [1.11 - 1.38] and 1.22 [1.13 - 1.32] depending on the wave.

Conclusion

Considering age structure and health services provision, a deprived SES profile is associated to a greater COVID-19 severity in terms of hospitals admissions, in conventional care units and in critical care units. This result implies targeting risk prevention efforts on these areas in pandemic situations, and highlights the need to develop access to healthcare to deprived populations in anticipation of periods of crisis.

Key messages

What is already known on this topic- Socioeconomic status is associated to COVID-19 incidence and severity, at an individual scale or at a large spatial scale.

What this study adds- We showed the positive relationship between deprivation and COVID-19 incidence and hospitalization rates at a fine sub-municipal geographical scale. We considered confusion factors like demographic structure and health services provision.

How this study might affect research, practice or policy- These findings may help predict at a fine scale where the impact will be most severe in pandemic situations and make it possible to target risk prevention efforts on these areas.
Baseline expression of immune gene modules in blood is associated with primary response to anti-TNF therapy in Crohn’s disease patients
Authors: Bai Benjamin Y. H. , Reppell Mark , Smaoui Nizar , Waring Jeffery F. , Pivorunas Valerie , Guay Heath , Lin Simeng , Chanchlani Neil , Bewshea Claire , Goodhand James R. ,   UK Inflammatory Bowel Disease Pharmacogenetics Study Group, Kennedy Nicholas A. , Ahmad Tariq , Anderson Carl A.
Published: April 2023

Background and Aims

Anti-TNF therapy is widely used for treatment of inflammatory bowel disease (IBD), yet many patients are primary non-responders (PNR), failing to respond to induction therapy. We aimed to identify blood gene expression differences between primary responders (PR) and primary non-responders to anti-TNF monoclonal antibodies (infliximab and adalimumab); and to predict response status from blood gene expression and clinical data.

Methods

The Personalised Anti-TNF Therapy in Crohn’s Disease (PANTS) study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF naive Crohn’s disease (CD) patients (ClinicalTrials.govidentifier:NCT03088449). Blood gene expression in 324 unique patients was measured by RNA-seq at baseline (week 0), and at weeks 14, 30, and 54 after treatment initiation (total sample size = 814).

Results

After adjusting for clinical covariates and estimated blood cell composition, baseline expression of MHC, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders. Expression changes from baseline to week 14 were generally of consistent direction across patients but with greater magnitude in responders, with the exception of interferon-related genes that were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at week 30 and week 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor.

Conclusions

Baseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these expression differences were insufficient for clinically useful prediction of response.
Assessing Willingness to receive COVID-19 Vaccines, associated factors and reasons for hesitancy among persons aged 13-80 years in Central Uganda. A population-based surveillance Cohort
Authors: Daama Alex , Rashid Naziru , Asani Kasango , Nalwoga Grace Kigozi , Nalugoda Fred , Bulamba Robert , Kyasanku Emmanuel , Nakigozi Gertrude , Kigozi Godfrey , Kagaayi Joseph , Mugamba Stephen
Published: April 2023

Background

Vaccination is essential for controlling the COVID-19 pandemic. However adequate vaccine coverage is a critical to the effectiveness of the vaccine at a population level. Data on to acceptability of the vaccine in Urban areas are limited. This study examined the prevalence, factors associated with willingness to receive COVID-19 vaccine and reasons for hesitancy in the predominantly urban in central Uganda (Wakiso)

Methods

Data were obtained from a cross-sectional study conducted from March 1st, 2021, to September 30th, 2021 in the urban population-based cohort of the Africa Medical and behavioral Sciences Organization (AMBSO). Multivariable modified Poisson regression analysis was used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals of willingness to accept the COVID-19 vaccine.

Results

A total of 1,903 participants were enrolled in the study; 61% of whom were females. About 63% of participants indicated willingness to accept the COVID-19 vaccine. Younger age groups (13-19 and 20-29) were less likely to accept the vaccine compared to the persons ages 40-49 years (aPR=0.79; 95% CI: 0.74, 0.84 for the 13-19 years and 0.93; 95% CI: 0.88, 0.98 for age group 20-29, compared to those ages 40–49 years. Post-primary education (aPR=1.05; 95% CI: 1.02, 1.09 compared to primary level), being a students and government staff (APR=1.13; 95% CI: 1.04, 1.23 compared to construction and Mechanic workers) were associated with willingness to receive COVID-19 vaccine. Some of the reported reasons for hesitancy included; concerns about side effects 154(57.0%), about 64(23.7%) did not think the vaccines were effective, and those who did not like the vaccines 32(11.9%).

Conclusion

A substantial proportion of individuals were not willingness to receive the COVID-19 vaccine. More effort is needed to reduce vaccine hesitancy, especially among the young and people with lower formal education.
Performance of a diagnostic model for the presence of unruptured intracranial aneurysms in the general population
Authors: Klieverik Vita M. , Roozenbeek Bob , Cras Tim Y. , Vernooij Meike W. , Geerlings Mirjam I. , Bos Daniel , Ruigrok Ynte M.
Published: April 2023

Background

The prevalence of unruptured intracranial aneurysms (UIAs) in the general population is 3%. Aneurysmal subarachnoid hemorrhage can be prevented by screening for UIAs followed by preventive treatment of identified UIAs. We developed a diagnostic model for presence of UIAs in the general population to help identify persons at high risk of having UIAs.

Methods

Between 2005-2015, middle aged and elderly participants from the population-based Rotterdam Study underwent brain magnetic resonance imaging at 1.5 Tesla, on which presence of incidental UIAs was evaluated. A multivariable logistic regression model with diagnostic markers sex, age, hypertension, smoking, hypercholesterolemia, diabetes, and alcohol, and their interactions, was developed. We corrected for overfitting using bootstrapping. Model performance was assessed with discrimination, calibration, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results

5835 persons were included (55.0% women, mean age 64.9±10.9 years) with a 2.2% UIA prevalence. Sex, age, hypertension, smoking, diabetes, and interactions of sex with age, hypertension, and smoking were independent diagnostic markers. The resulting model had a c-statistic of 0.65 (95% confidence interval [CI] 0.60–0.68) and 56% sensitivity, 52% specificity, 98% PPV, and 3% NPV for UIA presence at a cut-off value of 4% prevalence. Because of interactions with sex, additional models for men and women separately were developed. The model for men had a c-statistic of 0.70 (95%CI 0.62–0.78) with age, hypertension, and smoking as diagnostic markers and comparable additional performance values as for the full model. The model for women had a c-statistic of 0.58 (95%CI 0.52–0.63) with smoking as the only diagnostic marker.

Conclusion

Our diagnostic model had insufficient performance to help identify persons at high risk of having UIAs in the general population. Rather, it provides insight in risk factors contributing to UIA risk and shows that these may be in part sex-specific.
Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes
Authors: Ramessur Anisha , Ambasager Bana , Aramburu Iker Valle , Peakman Freddie , Gleason Kelly , Lehmann Christoph , Papayannopoulos Venizelos , Coombes Raoul Charles , Malanchi Ilaria
Published: April 2023

Purpose

A high number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear.

Patients and Methods

Here, we investigate changes in circulating neutrophils from newly diagnosed breast cancer patients before any therapeutic interventions. To do this, we assessed their lifespan and their broader intracellular kinase network activation states by using the Pamgene Kinome assay which measures the activity of neutrophil kinases.

Results

We found sub-type specific L-selectin (CD62L) changes in circulating neutrophils as well as perturbations in their overall global kinase activity. Strikingly, breast cancer patients of different subtypes (HR+, HER2+, triple negative) exhibited distinct neutrophil kinase activity patterns indicating that quantifiable perturbations can be detected in circulating neutrophils from early breast cancer patients, that are sensitive to both hormonal and HER-2 status. We also detected an increase in neutrophils lifespan in cancer patients, independently of tumour subtype.

Conclusions

Our results suggest that the tumour-specific kinase activation patterns in circulating neutrophils may be used in conjunction with other markers to identify patients with cancer from those harbouring only benign lesions of the breast. Given the important role neutrophil in breast cancer progression, the significance of this sub-type of specific priming warrants further investigation.

Clinical Relevance

The current study aims to investigate cancer-specific changes in circulating neutrophils in patients with newly diagnosed early breast cancer before any therapeutic intervention. We found L-selectin (CD62L) changes in circulating neutrophils from patients with early-stage breast cancer compared to healthy volunteers, which is an indication of an early phenotypical change. Moreover, these changes in CD62L were dependent on the breast cancer sub-type, showing opposing trends according to the hormonal receptor status of the tumour. Importantly, this subtype dependent phenotypic alteration was reflected in broader intracellular signalling perturbation when measuring intracellular kinase activity. Moreover, those cancer perturbed neutrophils, show expanded life span when cultured ex vivo, suggesting an alteration in their physiologic state. The tumour-specific kinase activation patterns in circulating neutrophils may be useful in conjunction with other markers to distinguish patients with cancer from those with benign lesions of the breast.
Retinoids and EZH2 inhibitors cooperate to orchestrate cytotoxic effects on bladder cancer cells
Authors: Ozgun Gizem , Yaras Tutku , Landman Nick , Karakülah Gökhan , van Lohuizen Maarten , Senturk Serif , Ozhan Serap Erkek
Published: April 2023

Emerging evidence has highlighted the importance of targeting EZH2 in bladder cancer owing to the highly mutated nature of bladder cancers harboring mutations in chromatin regulatory genes opposing Polycomb-mediated repression. Besides, enhanced expression of EZH2 contributes to pathogenesis. Furthermore, the critical role of the retinoic acid signaling pathway in the development and homeostasis of the urothelium is well established. Here we report that coordinated targeting of EZH2 and the retinoic acid signaling pathway caused cytotoxic effects on bladder cancer cells by inducing a synergistic reduction in proliferative potential that was associated with increased apoptosis and cell cycle arrest in a cooperative and orchestrated manner. Moreover, combined treatment caused the modulation of the expression of genes associated with an anti-oncogenic profile, as reflected by the stimulation of marker genes associated with apoptosis and differentiation. We further portrayed a molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of certain genes associated with unfolded protein response and some metabolic processes. This work also characterized an apoptotic program centered on the master transcriptional regulators C/EBPβ and CHOP. These findings highlight the importance of co-targeting the EZH2/retinoic acid pathway in bladder cancers and encourage the design of novel treatments employing retinoids coupled with EZH2 inhibitors in bladder carcinoma.
RhoA GEF Mcf2lb regulates rosette integrity during collective cell migration
Authors: Olson Hannah M. , Maxfield Amanda , Calistri Nicholas L. , Heiser Laura M. , Nechiporuk Alex V.
Published: April 2023

During development, multicellular rosettes serve as important cellular intermediates in the formation of diverse organ systems. Multicellular rosettes are transient epithelial structures that are defined by the apical constriction of cells towards the rosette center. Due to the important role these structures play during development, understanding the molecular mechanisms by which rosettes are formed and maintained is of high interest. Utilizing the zebrafish posterior lateral line primordium (pLLP) as a model system, we identify the RhoA GEF Mcf2lb as a regulator of rosette integrity. The pLLP is a group of ∼150 cells that migrates along the zebrafish trunk and is organized into epithelial rosettes; these are deposited along the trunk and will differentiate into sensory organs called neuromasts (NMs). Using single-cell RNA sequencing and whole-mount in situ hybridization, we showed thatmcf2lbis expressed in the pLLP during migration. Given the known role of RhoA in rosette formation, we asked whether Mcf2lb plays a role in regulating apical constriction of cells within rosettes. Live imaging and subsequent 3D analysis ofmcf2lbmutant pLLP cells showed disrupted apical constriction and subsequent rosette organization. This in turn resulted in a unique posterior Lateral Line phenotype: an excess number of deposited NMs along the trunk of the zebrafish. Cell polarity markers ZO-1 and Par-3 were apically localized, indicating that pLLP cells are normally polarized. In contrast, signaling components that mediate apical constriction downstream of RhoA, Rock-2a and non-muscle Myosin II were diminished apically. Altogether our results suggest a model whereby Mcf2lb activates RhoA, which in turn activates downstream signaling machinery to induce and maintain apical constriction in cells incorporated into rosettes.
Context-Aware Stress Monitoring using Wearable and Mobile Technologies in Everyday Settings
Authors: Aqajari Seyed Amir Hossein , Labbaf Sina , Tran Phuc Hoang , Nguyen Brenda , Mehrabadi Milad Asgari , Levorato Marco , Dutt Nikil , Rahmanit Amir M.
Published: April 2023

Background

Daily monitoring of stress is a critical component of maintaining optimal physical and mental health. Physiological signals and contextual information have recently emerged as promising indicators for detecting instances of heightened stress. Nonetheless, developing a real-time monitoring system that utilizes both physiological and contextual data to anticipate stress levels in everyday settings while also gathering stress labels from participants represents a significant challenge.

Objective

We present a monitoring system that objectively tracks daily stress levels by utilizing both physiological and contextual data in a daily-life environment. Additionally, we have integrated a smart labeling approach to optimize the ecological momentary assessment (EMA) collection, which is required for building machine learning models for stress detection. We propose a three-tier Internet-of-Things-based system architecture to address the challenges.

Methods

A group of university students (n=11) consisting of both males (n=4) and females (n=7) with ages ranging from 18 to 37 years (Mean = 22.91, SD = 5.05) were recruited from the University of California, Irvine. During a period of two weeks, the students wore a smartwatch that continuously monitored their physiology and activity levels. A context-logging application was also installed on their smartphone. They were asked to respond to several EMAs daily through a smart EMA query system. We employed three different machine learning algorithms to evaluate the performance of our system. The mean decrease impurity approach was employed to identify the most significant features. The k-nearest neighbor imputation technique was used to fill out the missing contextual features.

Results

F1-score is the performance metric used in our study. We utilized a cross-validation technique to accurately estimate the performance of our stress models. We achieved the F1-score of 70% with a Random Forest classifier using both PPG and contextual data, which is considered an acceptable score in models built for everyday settings. Whereas using PPG data alone, the highest F1-score achieved is approximately 56%, emphasizing the significance of incorporating both PPG and contextual data in stress detection tasks.

Conclusion

We proposed a system for monitoring daily-life stress using both physiological and smartphone data. The system includes a smart query module to capture high-quality labels. This is the first system to employ both physiology and context data for stress monitoring and to include a smart query system for capturing frequent self-reported data throughout the day.
The extent of regeneration is impacted by the stage of amputation in ladybird beetles: a case study inCheilomenes sexmaculata
Authors: Alam Hera , Rai Shriza , Verma Praveen C , Mishra Geetanjali
Published: April 2023

Regeneration is a topic of interest for centuries and arthropods are no exception. Trade-offs associated with regeneration are likely to indicate the reallocation of resources from other metabolic activities such as growth, development, or reproduction to regrowth of the lost body part. This may confer negative selection to some of the developmental traits of the organism despite regeneration being overall advantageous. Our hypothesis for the study was that the extent of regeneration and trade-offs associated with it may be stage-specific. To test this hypothesis, the right forelimb of all four larval stages of the ladybird beetle (Cheilomenes sexmaculata) was amputated. The amputated stages were reared till adulthood and all developmental transitions were recorded. Leg size was measured and compared with control. The result showed that the regenerated legs of all the treatments were smaller than the control and the regenerative potency of early larval stage was higher than late larval stages. Regeneration causes delay in post-amputation duration in all the treatments, increasing their total development period. However, insignificant difference was observed between the fresh body weight of regenerated and control adults. The length of unamputated left foreleg was reduced in regenerated beetles, showing some internal trade-off.
Multiscalar electrical spiking inSchizophyllum commune
Authors: Adamatzky Andrew , Schunselaar Ella , Wösten Han A. B. , Ayres Phil
Published: April 2023

Growing colonies of the split-gill fungusSchizophyllum communeshow action potential-like spikes of extracellular electrical potential. We analysed several days of electrical activity recording of the fungus and discovered three families of oscillatory patterns. Very slow activity at a scale of hours, slow activity at a scale of tens minutes and very fast activity at scale of half-minute. We simulated the spiking behaviour using FitzHugh-Nagume model, uncovered mechanisms of spike shaping. We speculated that spikes of electrical potential might be associated with transportation of nutrients and metabolites.
Protein-lipid charge interactions control the folding of OMPs into asymmetric membranes
Authors: Machin Jonathan , Kali Antreas C. , Ranson Neil A. , Radford Sheena E.
Published: April 2023

Biological membranes consist of two leaflets of phospholipid molecules that form a bilayer, and typically the composition of lipids in each leaflet is distinct. This asymmetry is created and maintainedin vivoby dedicated biochemical pathways, but difficulties in creating stable asymmetric membranesin vitrohave restricted our understanding of how bilayer asymmetry modulates the folding, stability and function of membrane proteins. Here we employ cyclodextrin mediated lipid exchange to generate asymmetric liposomes and use these to characterize the stability and folding kinetics of two bacterial outer membrane proteins (OMPs). We show that excess negative charge in the outer leaflet of a liposome impedes the membrane insertion and folding of OmpA and BamA, while excess negative charge in the inner leaflet accelerates their folding, relative to symmetric liposomes with the same membrane composition. Three positively charged residues in the extracellular loops of OmpA that play a critical role in folding are identified using molecular dynamics simulations and mutational analyses. Bioinformatic analysis was then used to identify a conserved patch of positive residues in the extracellular loops of OMPs generally that lies 6-8Å from the membrane surface. Together, the the results rationalise the well known ‘positive outside’ rule for OMP sequences and suggest new insights into the mechanisms that drive OMP folding and assemblyin vitroandin vivo.
What controls carbon sequestration in plants under which conditions?
Authors: Nies Tim , van Aalst Marvin , Saadat Nima , Ebeling Josha , Ebenhöh Oliver
Published: April 2023

Plants use photosynthesis to harvest sunlight and convert the solar energy into chemical energy, which is then used to reduce atmospheric carbon dioxide into organic molecules. This process forms the basis of all life on Earth, and stands at the beginning of the food chain which feeds the world population. Not surprisingly, many research efforts are currently ongoing aiming at improving plant growth and crop yield, and several of these activities directly target the photosynthetic pathways. Metabolic Control Analysis (MCA) shows that, in general, the control over a metabolic flux, such as carbon fixation, is distributed among several steps and highly dependent on the external conditions. Therefore, the concept of a single ‘rate-limiting’ step is hardly ever applicable, and as a consequence, any strategy relying on improving a single molecular process in a complex metabolic system is bound to fail to yield the expected results. In photosynthesis, reports on which processes exert the highest control over carbon fixation are contradictory. This refers to both, the photosynthetic ‘light’ reactions harvesting photons, and the ‘dark’ reactions of the CalvinBenson-Bassham Cycle (CBB cycle). Here, we employ a recently developed mathematical model, which describes photosynthesis as an interacting supply-demand system, to systematically study how external conditions affect the control over carbon fixation fluxes.
Acceptability of the Venting Wisely Pathway for use in Critically ill Adults with Hypoxemic Respiratory Failure and Acute Respiratory Distress Syndrome (ARDS): A qualitative study protocol
Authors: Krewulak Karla , Knight Gwen , Irwin Andrea , Morrissey Jeanna , Stelfox Henry T. , Bagshaw Sean , Zuege Danny J. , des Ordons Amanda Roze , Fiest Kirsten M. , Parhar Ken Kuljit S
Published: April 2023

Introduction

Hypoxemic respiratory failure (HRF) affects nearly 15% of critically ill adults admitted to an intensive care unit (ICU). An evidence based, stakeholder informed multidisciplinary care pathway (Venting Wisely) was created to standardize the diagnosis and management of patients with HRF and Acute Respiratory Distress Syndrome (ARDS). Successful adherence to the pathway requires a coordinated team-based approach by the clinician team. The overall aim of this study is to describe the acceptability of theVenting Wiselypathway among critical care clinicians. Specifically, this will allow us to: 1) better understand the user’s experience with the intervention and 2) determine if the intervention was delivered as intended.

Methods and analysis

This qualitative study will conduct focus groups with nurse practitioners, physicians, registered nurses, and registered respiratory therapists from 17 Alberta ICUs. We will use template analysis to describe the acceptability of a multi component care pathway according to seven constructs of acceptability: 1) Affective attitude; 2) Burden; 3) Ethicality; 4) Intervention coherence; 5) Opportunity costs; 6) Perceived effectiveness; and 7) Self-efficacy. This study will contribute to a better understanding of the acceptability of theVenting Wiselypathway. Identification of areas of poor acceptability will be used to refine the pathway and implementation strategies as ways to improve adherence to the pathway and promote its sustainability.

Ethics and dissemination

The study was approved by the University of Calgary Conjoint Health Research Ethics Board (CHREB). The results will be submitted for publication in a peer-reviewed journal and presented at a scientific conference.

STRENGTHS AND LIMITATIONS

This qualitative study will provide vital information about why the implementation of theVenting Wiselypathway may or may not have worked as anticipated.

Findings will identify opportunities to improve pathway adherence and provide insights on how to sustain the intervention and scale to other sites.

Acceptance and adherence of theVenting Wiselypathway has the potential to increase and standardize the use of evidence-informed, life-saving therapies for mechanically ventilated patients; this may improve outcomes and save costs to the healthcare system.

Focus groups will be conducted with a wide variety of clinicians (nurse practitioners, physicians, registered nurses, registered respiratory therapists), and within various intensive care units (general systems, cardiovascular surgery, and neurosciences), and hospitals (regional, community, and tertiary).

The study is being conducted in one province in Canada, which may limit generalizability.
Data Management Plan for Healthcare: Following FAIR Principles and Addressing Cybersecurity Aspects. A Systematic Review using InstructGPT
Authors: Stanciu Alexandru
Published: April 2023

Abstract

This study focuses on data-related aspects and emphasizes the importance of producing a data management plan (DMP) to address the challenges specific to the collection, processing, storage, security, documentation, sharing, and distribution of data in research projects in the healthcare sector. It provides an overview of the DMP and offers guidelines for creating an effective plan that incorporates the FAIR principles. Additionally, the study outlines the main aspects of data management in the healthcare domain and analyzes several security issues, such as cryptography, biometrics, and digital watermarking, that should be considered for healthcare data. A systematic review of the literature is performed to explore the critical aspects of data management and identify emerging trends, challenges, and innovative solutions that can be incorporated into DMPs. Part of the analysis of this survey was performed with the InstructGPT language model.
Context-Aware Deep Learning Enables High-Efficacy Localization of High Concentration Microbubbles for Super-Resolution Ultrasound Localization Microscopy
Authors: Shin YiRang , Lowerison Matthew R. , Wang Yike , Chen Xi , You Qi , Dong Zhijie , Anastasio Mark A. , Song Pengfei
Published: April 2023

Ultrasound localization microscopy (ULM) is an emerging super-resolution imaging technique for deep tissue microvascular imaging. However, conventional localization methods are constrained by low microbubble (MB) concentration, as accurate localization requires a strict separation of MB point spread functions (PSFs). Furthermore, deep learning-based localization techniques are often limited in their ability to generalize toin vivoultrasound data due to challenges in accurately modeling highly variable MB PSF distributions and ultrasound imaging conditions. To address these limitations, we propose a novel deep learning-pipeline, LOcalization with Context Awareness (LOCA)-ULM, which employs simulation that incorporates MB context to generate synthetic data that closely resemble real MB signals, and a loss function that considers both MB count and localization loss. Inin silicoexperiments, LOCA-ULM outperformed conventional localization with superior MB detection accuracy (94.0% vs. 74.9%) and a significantly lower MB missing rate (13.2% vs 74.8%).In vivo, LOCA-ULM achieved up to three-fold increase in MB localization efficiency and a × 9.5 faster vessel saturation rate than conventional ULM.
How hibernation in frogs drives brain and reproductive evolution in opposite directions
Authors: Liao Wen Bo , Jiang Ying , Jin Long , Lüpold Stefan
Published: April 2023

Environmental seasonality can promote the evolution of larger brains through cognitive and behavioral flexibility but can also hamper it when temporary food shortage is buffered by stored energy. Multiple hypotheses linking brain evolution with resource acquisition and allocation have been proposed for warm-blooded organisms, but it remains unclear how these extend to cold-blooded taxa whose metabolism is tightly linked to ambient temperature. Here, we integrated these hypotheses across frogs and toads in the context of varying brumation (‘hibernation’) durations and their environmental correlates. We showed that protracted brumation covaried negatively with brain size but positively with reproductive investment, likely in response to brumation-dependent changes in the socio-ecological context and associated selection on different tissues. Our results provide novel insights into resource allocation strategies and possible constraints in trait diversification, which may have important implications for the adaptability of species under sustained environmental change.
A Key Piece of the Puzzle: The central tetramer of theSaccharomyces cerevisiaeseptin protofilament and Its Implications for Self-Assembly
Authors: Marques da Silva Rafael , dos Reis Saladino Giovanna Christe , Leonardo Diego Antonio , Pereira Humberto D’Muniz , Sculaccio Susana Andréa , Ulian Araujo Ana Paula , Garratt Richard Charles
Published: April 2023

Septins, often described as the fourth component of the cytoskeleton, are structural proteins found in a vast variety of living beings. They are related to small GTPases and thus, generally, present GTPase activity which may play an important (although incompletely understood) role in their organization and function. Septins polymerase into long non-polar filaments, in which each subunit interacts with two others by alternating interfaces, NC and G. InSaccharomyces cerevisiaefour septins are organized in the following manner, [Cdc11-Cdc12-Cdc3-Cdc10- Cdc10-Cdc3-Cdc12-Cdc11]nin order to form filaments. Although septins were originally discovered in yeast and much is known regarding their biochemistry and function, only limited structural information about them is currently available. Here we present crystal structures of Cdc3/Cdc10 which provide the first view of the physiological interfaces formed by yeast septins. The G-interface has properties which place it in between that formed by SEPT2/SEPT6 and SEPT7/SEPT3 in human filaments. Switch I from Cdc10 contributes significantly to the interface, whereas in Cdc3 it is largely disorded. However, the significant negative charge density of the latter suggests it may have a unique role. At the NC-interface, we describe an elegant means by which the sidechain of a glutamine from helix α0imitates a peptide group in order to retain hydrogen-bond continuity at the kink between helices α5and α6in the neighbouring subunit, thereby justifying the conservation of the helical distortion. Its absence from Cdc11, along with this structure’s other unusual features are critically discussed by comparison with Cdc3 and Cdc10.

GRAPHICAL ABSTRACT

HIGHLIGHTS

The first crystal structure of a yeast septin heterodimer (Cdc3-Cdc10) provides important insights into their structural biology.

Identification of common features and differences between yeast and human septins, sheds light on the unique characteristics of yeast septin filaments.

The Cdc3G-Cdc10Δ1-10crystal structure could be a crucial piece of the puzzle towards obtaining a high-resolution cryo-EM structure of the yeast septin octamer.
Machine Learning-based Phenotypic Imaging to Characterise the Targetable Biology ofPlasmodium falciparumMale Gametocytes for the Development of Transmission-Blocking Antimalarials
Authors: Tsebriy Oleksiy , Khomiak Andrii , Miguel-Blanco Celia , Sparkes Penny C. , Gioli Maurizio , Santelli Marco , Whitley Edgar , Gamo Francisco-Javier , Delves Michael J.
Published: April 2023

Preventing parasite transmission from humans to mosquitoes is recognised to be critical for achieving elimination and eradication of malaria. Consequently developing new antimalarial drugs with transmission-blocking properties is a priority. Large screening campaigns have identified many new transmission-blocking molecules, however little is known about how they target the mosquito-transmissiblePlasmodium falciparumstage V gametocytes, or how they affect their underlying cell biology. To respond to this knowledge gap, we have developed a machine learning image analysis pipeline to characterise and compare the cellular phenotypes generated by transmission-blocking molecules during male gametogenesis. Using this approach, we studied 40 molecules, categorising their activity based upon timing of action and visual effects on the organisation of tubulin and DNA within the cell. Our data both proposes new modes of action and corroborates existing modes of action of identified transmission-blocking molecules. Furthermore, the characterised molecules provide a new armoury of tool compounds to probe gametocyte cell biology and the generated imaging dataset provides a new reference for researchers to correlate molecular target or gene deletion to specific cellular phenotype. Our analysis pipeline is not optimised for a specific organism and could be applied to any fluorescence microscopy dataset containing cells delineated by bounding boxes, and so is extendible to any disease model.
Genomic and radiocarbon insights into the mystery of mouse mummies on the summits of >6000 m Andean volcanoes
Authors: Storz Jay F. , Liphardt Schuyler , Quiroga-Carmona Marcial , Bautista Naim M. , Opazo Juan C. , Wheeler Timothy B. , D’Elía Guillermo , Good Jeffrey M.
Published: April 2023

Our understanding of the limits of animal life is continually revised by scientific exploration of extreme environments. Here we report the discovery of numerous mummified cadavers of leaf-eared mice,Phyllotis vaccarum, from the summits of three different Andean volcanoes at elevations 6029-6233 m (19,780-20,449 ft) above sea level in the Puna de Atacama (Chile-Argentina). Such extreme elevations were previously assumed to be completely uninhabitable by mammals. In combination with a live-captured specimen of the same species from the nearby summit of Volcán Llullaillaco (6739 m [=22,110 ft]), the 13 summit mummies represent the highest physical records of mammals in the world. We report a chromosome-level genome assembly forP. vaccarumin combination with a whole-genome re-sequencing analysis and radiocarbon dating analysis that provide insights into the provenance and antiquity of the summit mice. We test alternative hypotheses to explain the existence of mouse graveyards on the summits of Atacama volcanoes. Radiocarbon data indicate that the most ancient of the mummies were at most a few centuries old. Genomic polymorphism data revealed a high degree of continuity between the summit mice and conspecifics from lower elevations in the surrounding Altiplano. Genomic data also revealed equal numbers of males and females among the summit mice and evidence of close kinship between some individuals from the same summit groups. These findings bolster evidence for self-sustaining populations ofPhyllotisat elevations >6000 m and challenge assumptions about the environmental limits of vertebrate life and the physiological tolerances of small mammals.
The Cyclimids: Degron-inspired cereblon binders for targeted protein degradation
Authors: Ichikawa Saki , Payne N. Connor , Xu Wenqing , Chang Chia-Fu , Vallavoju Nandini , Frome Spencer , Flaxman Hope A. , Mazitschek Ralph , Woo Christina M.
Published: April 2023

Cereblon (CRBN) is an E3 ligase substrate adapter widely exploited for targeted protein degradation (TPD) strategies. However, achieving efficient and selective target degradation is a preeminent challenge with ligands that engage CRBN. Here, we report that the cyclimids, ligands derived from the C-terminal cyclic imide degrons of CRBN, exhibit distinct modes of interaction with CRBN and offer a facile approach for developing potent and selective bifunctional degraders. Quantitative TR-FRET-based characterization of 60 cyclimid degraders in binary and ternary complexes across different substrates revealed that ternary complex binding affinities correlated strongly with cellular degradation efficiency. Our studies establish the unique properties of the cyclimids as versatile warheads in TPD and a systematic biochemical approach for quantifying ternary complex formation to predict their cellular degradation activity, which together will accelerate the development of degraders that engage CRBN.
Infant Left Amygdala Volume Is Negatively Associated with Fecal Microbiota Diversity
Authors: Aatsinki Anna-Katariina , Tuulari Jetro J. , Munukka Eveliina , Lahti Leo , Keskitalo Anniina , Kailanto Henna-Maria , Nolvi Saara , Scheinin Noora M. , Saunavaara Jani , Parkkola Riitta , Lewis John D. , Hashempour Niloofar , Shulist Satu J. , Karlsson Linnea , Karlsson Hasse
Published: April 2023

Introduction

Rodent studies have addressed the importance of early life gut microbiota in the development of emotional and social functioning. Studies in human infants are still scarce, but associations with cognition and temperament have been reported. Neuroimaging studies have linked the amygdala with fecal microbiota diversity in infants, but crucially these studies have not covered the neonatal period, and the current study addressed this gap.

Methods

The study population included 65 infants drawn from the ongoing, general population based FinnBrain Birth Cohort Study. Brain MRI was performed around the age of one month (mean age 25 days). Fecal microbiota profiles (mean 68 days) were assessed by 16s rRNA amplicon sequencing at the age of 2.5 months.

Results

We found a negative association between infant left amygdala volume and alpha diversity (n=52, beta =-0.0043, p=0.034, adjusted for infant sex, breastfeeding, delivery mode, age during fecal sampling, age from conception during scan, and intracranial volume, Fig.1). Amygdala volumes were not associated with beta diversity (p=0.21), nor with the abundances of individual genera when adjusted for the same covariates and multiple testing.

Conclusion

Our results provide first evidence for associations between the brain and fecal microbiota in human neonates. Although the reported data do not allow investigation of underlying mechanisms, i.e. about the directionality of the hypothesized gut-brain connection, the reported connection encourages for future investigations of manifestations of gut-brain axis in early life.
Plasmodium falciparuminfection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis
Authors: Feldman Tamar P. , Ryan Yana , Egan Elizabeth S.
Published: April 2023

During development down the erythroid lineage, hematopoietic stem cells undergo dramatic changes to cellular morphology and function in response to a complex and tightly regulated program of gene expression. In malaria infection,Plasmodium spp. parasites accumulate in the bone marrow parenchyma, and emerging evidence suggests erythroblastic islands are a protective site for parasite development into gametocytes. While it has been observed thatPlasmodium falciparuminfection of late-stage erythroblasts can delay terminal erythroid differentiation and enucleation, the mechanism(s) underlying this phenomenon are unknown. Here, we apply RNA-seq after fluorescence-activated cell sorting (FACS) of infected erythroblasts to identify transcriptional responses to direct and indirect interaction withPlasmodium falciparum. Four developmental stages of erythroid cells were analyzed: proerythroblast, basophilic erythroblast, polychromatic erythroblast, and orthochromatic erythroblast. We found extensive transcriptional changes in infected erythroblasts compared to uninfected cells in the same culture, including dysregulation of genes involved in erythroid proliferation and developmental processes. Whereas some indicators of cellular oxidative and proteotoxic stress were common across all stages of erythropoiesis, many responses were specific to cellular processes associated with developmental stage. Together, our results evidence multiple possible avenues by which parasite infection can induce dyserythropoiesis at specific points along the erythroid continuum, advancing our understanding of the molecular determinants of malaria anemia.

Key Points

Erythroblasts at different stages of differentiation have distinct responses to infection byPlasmodium falciparum.

P. falciparuminfection of erythroblasts alters expression of genes related to oxidative and proteotoxic stress and erythroid development.
Urine metabolomic profiles of autism and autistic traits – a twin study
Authors: Arora Abishek , Mastropasqua Francesca , Bölte Sven , Tammimies Kristiina
Published: April 2023

Currently, there are no reliable biomarkers for autism diagnosis. The heterogeneity of autism and several co-occurring conditions are key challenges to establishing these. Here, we used untargeted mass spectrometry-based urine metabolomics to investigate metabolic differences for autism diagnosis and autistic traits in a well-characterized twin cohort (N=105). We identified 208 metabolites in the urine samples of the twins. No clear, significant metabolic drivers for autism diagnosis were detected when controlling for other neurodevelopmental conditions. However, we identified nominally significant changes for several metabolites. For instance, phenylpyruvate (p=0.019) and taurine (p=0.032) were elevated in the autism group, while carnitine (p=0.047) was reduced. We furthermore accounted for the shared factors, such as genetics within the twin pairs, and report additional metabolite differences. Based on the nominally significant metabolites for autism diagnosis, the arginine and proline metabolism pathway (p=0.024) was enriched. We also investigated the association between quantitative autistic traits, as measured by the Social Responsiveness Scale 2nd Edition, and metabolite differences, identifying a greater number of nominally significant metabolites and pathways. A significant positive association between indole-3-acetate and autistic traits was observed within the twin pairs (adjusted p=0.031). The utility of urine biomarkers in autism, therefore, remains unclear, with mixed findings from different study populations.

Lay summary

Earlier literature has suggested that there are chemical molecules (metabolites) in the urine samples of autistic individuals that could be linked with their diagnosis of autism. However, there are still mixed results and uncertainty if any of these metabolites could be used as biomarkers (chemical molecules that indicate a biological condition). In this study, we analysed urine samples of 105 twins from Sweden, of which 48 were identical or fraternal twins, and the analysed metabolite levels were compared between those twins diagnosed with autism and those without a diagnosis. Additionally, we tested if the metabolite levels were different in relation to the level of autistic behaviour. The metabolite levels were measured using mass spectrometry, allowing us to identify hundreds of chemical molecules present in a urine sample followed with testing their significance for autism diagnosis or autistic traits. No single metabolite was found to be highly associated with a diagnosis of autism. However, indole-3-acetate, a metabolite produced by the breakdown of the amino acid tryptophan, was associated with the level of autistic behaviour within the twins. Nevertheless, several metabolites showed some association with autism or the level of autistic behaviour, while revealing interesting pathways for studies in the future.