bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteolytic processing of both RXLR and EER motifs in oomycete effectors
Authors: Xu Lin , Wang Shumei , Wang Wei , Wang Haixia , Welsh Lydia , Boevink Petra C , Whisson Stephen C , Birch Paul RJ
Published: April 2024

Arg-any amino acid-Leu-Arg (RXLR) effectors are central oomycete virulence factors that target diverse host proteins and processes to suppress plant immunity. Relatively little is known about how they are processed post-translationally before delivery into host cells. Proteolytic cleavage at the RXLR motif was observed to occur prior to secretion in allPhytophthora infestanseffectors tested, suggesting it is a general rule, and was observed to occur between the leucine and the second arginine. There was no cleavage of a naturally occurring second RXLR motif in a structured region of Pi21388/AvrBlb1, or one introduced at a similar position in effector Pi04314, in keeping with the motif being positionally constrained, potentially to disordered regions closely following the signal peptide. Remarkably, independent proteolytic cleavage of the Glu-Glu-Arg (EER) motif, often found immediately downstream of the RXLR, was also observed in diverse effectors, occurring immediately after the arginine. Expression of full-length effectors in host plantNicotiana benthamianarevealed that, although secreted, they were poorly processed, suggesting that RXLR and EER cleavage does not occur in all eukaryotic cells. Our observations indicate that, whether possessing both RXLR and EER, or either motif alone, these effectors are likely proteolytically processed prior to secretion in all cases.
Phytochemical studies and Antimicrobial Activity on the leaves ofAntigonon leptopusandEcbolium viridae
Authors: Rudhra S , Venkatesan A.
Published: April 2024

The aim of the present study is to investigate the in vitro Antibacterial activity ofAntigonon leptopusandEcbolium viridaemethanol, ethanol, acetone leaf extracts for against selected bacterial strains respectively. Preliminary phytochemical screening of the leaf crude extract revealed the presence of alkaloids, flavonoids, phenols, taninns, carbohydrates, saponins. The evaluation of leaf powder was supported by physico-chemical analysis. The antibacterial activities of leaf ofE.virideandAntigonon leptopusin successive different solvent were tested against gram +ve (Staphylococcus aureus, Streptococcus pyogenes) and gram −ve (Escherichia coli, Pseudomonas aeruginosa) Antibacterial activity of those crude extracts are determined by using agar well diffusion method and the zone of inhibition of microorganisms was measured in mm. Amphicillin is used as a positive control respectively.
Default mode network tau predicts future clinical decline in atypical early Alzheimer’s disease
Authors: Katsumi Yuta , Howe Inola A. , Eckbo Ryan , Wong Bonnie , Quimby Megan , Hochberg Daisy , McGinnis Scott M. , Putcha Deepti , Wolk David A. , Touroutoglou Alexandra , Dickerson Bradford C.
Published: April 2024

Identifying individuals with early stage Alzheimer’s disease (AD) at greater risk of steeper clinical decline would allow professionals and loved ones to make better-informed medical, support, and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau PET in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. In this study, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes (Posterior Cortical Atrophy, logopenic variant Primary Progressive Aphasia, and amnestic syndrome with multi-domain impairment and age of onset < 65 years). All patients underwent structural magnetic resonance imaging (MRI), tau (18F-Flortaucipir) PET, and amyloid (either18F-Florbetaben or11C-Pittsburgh Compound B) PET scans at baseline. Each patient’s longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Our sample of early atypical AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year:t(47) = 6.56,p< .001,d= 0.95. These AD patients showed prominent baseline tau burden in posterior cortical regions including the major nodes of the default mode network, including the angular gyrus, posterior cingulate cortex/precuneus, and lateral temporal cortex. Greater baseline tau in the broader default mode network predicted faster clinical decline. Tau in the default mode network was the strongest predictor of clinical decline, outperforming baseline clinical impairment, tau in other functional networks, and the magnitude of cortical atrophy and amyloid burden in the default mode network. Overall, these findings point to the contribution of baseline tau burden within the default mode network of the cerebral cortex to predicting the magnitude of clinical decline in a sample of atypical early AD patients one year later. This simple measure based on a tau PET scan could aid the development of a personalized prognostic, monitoring, and treatment plan tailored to each individual patient, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient’s tau burden while still early in the disease course.
Optimization of Multi-Ancestry Polygenic Risk Score Disease Prediction Models
Authors: Lerga-Jaso Jon , Terpolovsky Andrew , Novković Biljana , Osama Alex , Manson Charlie , Bohn Sandra , De Marino Adriano , Kunitomi Mark , Yazdi Puya G.
Published: April 2024

Background

Polygenic risk scores (PRS) have ushered in a new era in genetic epidemiology, offering insights into individual predispositions to a wide range of diseases. However, despite recent marked enhancements in their predictive power, there are still challenges that need to be overcome before PRS-based models can be broadly applied in the clinic, including sufficient accuracy, easy interpretability and portability across diverse populations.

Methods

Leveraging trans-ancestry genome-wide association study (GWAS) meta-analysis, we generated novel, diverse summary statistics for 30 medically-related traits which were used to benchmark the performance of six existing PRS algorithms using UK biobank. Observing that SBayesRC had the best overall performance but recognizing strengths in each method, we developed an ensemble PRS model using logistic regression to combine outputs from top-performing algorithms. This ensemble model was validated on the diverse eMERGE and PAGE MEC cohorts, and the performance was compared against current state-of-the-art PRS models. To enhance predictive accuracy for clinical application, we incorporated easily-accessible clinical characteristics such as age, gender, ancestry and risk factors, creating disease prediction models intended as prospective diagnostic tests, with easily interpretable positive or negative outcomes.

Results

Predictive performance of PRS models improved with trans-ancestry GWAS meta-analysis and was further enhanced by the ensemble model, which surpassed state-of-art PRS models. When applied to external cohorts, performance drops were minimal, indicating good calibration. After adding clinical characteristics, 12 out of 30 models surpassed 80% AUC. Further, 25 traits exceeded the diagnostic odds ratio (DOR) of 5 and 19 traits exceeded DOR of 10 for all ancestry groups, indicating high predictive value. The highest DOR in a population with a sufficient number of cases was 66.2 for Alzheimer’s disease in Europeans. Our PRS model for coronary artery disease identified 55-80 times more true coronary events than rare pathogenic variant models, reinforcing its clinical potential. The polygenic component modulated the effect of high-risk rare variants, stressing the need to consider all genetic components in clinical settings.

Conclusions

Newly developed PRS-based disease prediction models have sufficient accuracy and portability to warrant consideration of being used in the clinic.
Media-driven adaptive behavior in pandemic modeling and data analysis
Authors: Yu Zhiyuan , Gurarie David , Huang Qimin
Published: April 2024

1

Human behavior and public attitudes towards preventive control measures, such as personal protection, screening, isolation, and vaccine acceptance, play a crucial role in shaping the course of a pandemic. These attitudes and behaviors are often influenced by various information sources, most prominently by social media platforms.

The primary information usually comes from government bodies, e.g. CDC, responsible for public health mandates. However, social media can amplify, modify, or distort this information in numerous ways. The dual nature of social media can either raise awareness and encourage protective behaviors and reduce transmission, or have the opposite effect by spreading misinformation and fostering non-compliance.

To analyze the interplay between these components, we have developed a coupled SIR-type dynamical model that integrates three essential components: (i) disease spread, as reported by official sources; (ii) the response of social media to this information; and (iii) the subsequent modification of human behavior, which directly impacts the spread of disease.

To calibrate and validate our model, we utilized available data sources on the Covid-19 pandemic from a one-year period (2021-2022) in the United States, as well as data on social media responses, particularly tweets. By analyzing the data and conducting model simulations, we have identified significant inputs and parameters, such as initial compliance levels and behavioral transition rates. These factors enable a quantitative assessment of their contributions to disease outcomes, including cumulative outbreak size and its dynamic trajectory.

This modeling approach gives some valuable insights into the relationship between public attitudes, information dissemination, and their impact on the progression of the pandemic. By understanding these dynamics, we can inform policy decisions, public health campaigns, and interventions to effectively combat the spread of Covid-like pathogens and future pandemics.
Sociodemographic and geographic variation in mortality attributable to air pollution in the United States
Authors: Geldsetzer Pascal , Fridljand Daniel , Kiang Mathew V. , Bendavid Eran , Heft-Neal Sam , Burke Marshall , Thieme Alexander H. , Benmarhnia Tarik
Published: April 2024

There are large differences in premature mortality in the USA by racial/ethnic, education, rurality, and social vulnerability index groups. Using existing concentration-response functions, particulate matter (PM2.5) air pollution, population estimates at the tract level, and county-level mortality data, we estimated the degree to which these mortality discrepancies can be attributed to differences in exposure and susceptibility to PM2.5. We show that differences in mortality attributable to PM2.5were consistently more pronounced between racial/ethnic groups than by education, rurality, or social vulnerability index, with the Black American population having by far the highest proportion of deaths attributable to PM2.5in all years from 1990 to 2016. Over half of the difference in age-adjusted all-cause mortality between the Black American and non-Hispanic White population was attributable to PM2.5in the years 2000 to 2011.
Validation of an in vitro diagnostic test for endometriosis: impact of confounding medical conditions and lesion location
Authors: Daoud Elza , Archer David F. , Herranz-Blanco Bárbara
Published: April 2024

With the aim to shorten the time for diagnosis and accelerate access to correct management, a non-invasive diagnostic test for endometriosis was developed and validated. The IVD test combines an ELISA test kit to quantify CA125 and BDNF concentrations in serum and a data treatment algorithm hosted in medical software processing results from the ELISA test and responses to six clinical variables. Serum samples and clinical variables extracted from psychometric questionnaires from 77 patients were collected from the Oxford Endometriosis CaRe Centre biobank (UK). Case/control classification was performed based on laparoscopy and histological verification of the excised lesions. Biomarkers serum concentrations and clinical variables were introduced to the software, which generates the qualitative diagnostic result (“positive” or “negative”). This test allowed the detection of 32% of cases with superficial endometriosis, which is an added value given the limited efficacy of existing imaging techniques. Even in the presence of various confounding medical conditions, the test maintained a specificity of 100%, supporting its suitability for use in patients with underlying medical conditions.
Study protocol for the Multimodal Approach to Preventing Suicide in Schools (MAPSS) project: A regionally based feasibility trial of an integrated response to suicide risk among UK secondary school pupils
Authors: Ashworth Emma , McCarthy Molly , Wynne Sio , Robinson Jo , McKay Samuel , Lane Steven , Richardson Gerry , Boardman Neil , Henderson Kate , Crosbie Vivienne , Humphrey Neil , York Sian , Michail Maria , Hart Damian , Clacy David , Jalota Mani , Saini Pooja
Published: April 2024

Background

Suicide is the leading cause of death of children and young people under 35 in the UK, and suicide rates are rising in this age group. Schools are considered an appropriate and logical setting for youth suicide prevention activities, with universal, selective, and indicated approaches all demonstrating efficacy. Given that international best practice recommends suicide prevention programmes combine these approaches, and that to date this has not been done in school settings in the UK, this study aims to evaluate the feasibility of delivering a suicide prevention programme incorporating universal, selective, and indicated components in UK schools.

Methods

This study is a feasibility cluster-randomised controlled trial (RCT) of an adapted version of the Multimodal Approach to Preventing Suicide in Schools (MAPSS) programme. The programme, initially developed in Australia, involves delivering universal psychoeducation to all pupils, screening them for suicide risk, and delivering Internet-based Cognitive Behavioural Therapy (Reframe IT-UK) to those students identified as being at high-risk for suicide. The programme will be trialled in six secondary schools in Northwest England and will target Year 10 students (14- and 15-year-olds). The primary aims are to assess: 1) the acceptability and safety of delivering MAPSS in a school setting in the UK; 2) the social validity of the MAPSS programme; and 3) the feasibility of delivering a large-scale, appropriately powered, cluster-RCT and economic evaluation of this intervention in the future. Secondary aims are to assess changes over time in mental health and wellbeing outcomes.

Discussion

This study is the first to evaluate a suicide prevention programme comprising universal, selective, and indicated components in UK schools. If the programme is found to be feasible, it could be more widely tested in schools and may ultimately lead to reduced rates of suicide and suicidal behaviour in young people.
A standardised, high-throughput approach to diagnostic group testing method validation
Authors: Unruh Leonhardt A. H. , Crone Michael A. , Freemont Paul S. , Chindelevitch Leonid
Published: April 2024

1

Background

Group testing, combining the samples of multiple patients into a single pool to be tested for infection, is an approach to increase throughput in clinical diagnostic and population testing by reducing the number of tests required. In order to further increase the throughput and accuracy of these approaches, mathematicians regularly devise novel combinatorial methods. However, although these novel methods are easily validated in silico, they are often never implemented in diagnostic laboratories because of the lack of clear and standardised pathways to clinical validation.

Methods

We develop a standardised analytical workflow that makes use of high-throughput automation and virus-like particle standards to validate theoretical group testing approaches. We then utilise specially developed virus-like particles for SARS-CoV-2, Influenza A, Influenza B, and Respiratory Syncytial Virus (RSV) to develop and validate a novel multiplex group testing approach based on simulated annealing and Bayesian optimization. Our approach improves the inference of positive samples in group testing, leveraging the quantitative nature of RT-qPCR test results.

Results

Our results show a higher positive predictive value of our novel approach for the inference of positive samples compared to the standard approach using binary test outcomes. In large-scale surveillance testing our method can greatly reduce the number of false positive identifications. Our in vitro findings show the viability of group testing for multiplexed testing of respiratory infections and demonstrate the potential of a novel inference method. Both innovations increase the number of people that can be tested with the available resources, which is particularly important in low-resource settings.
Prevalence and clinical presentations of post-COVID-19 conditions in Nepal
Authors: Basnet Lila Bahadur , Thapa Pomawati , Bastola Anup , Khanal Narendra , Panta Niranjan , Thapaliya Sabin , Kleine Bingham Melissa Beth , Shrestha Saugat , Adhikari Shital , Khadka Sudesha , Shrestha Priyanka , Paudel Sadhana , Devapitchai Kamaraj Arulmozhi
Published: April 2024

Introduction

The COVID-19 pandemic affected millions worldwide. While the major focus was on diagnosis and treatment of the acute phase of the disease, many individuals experienced long-term health even after recovery. These post-COVID-19 conditions encompass a broad range of physical, psychological, and cognitive symptoms that persist beyond the acute phase of the illness. The aim of this study was to find the prevalence and reported presentations of post-COVID-19 conditions in Nepal.

Method

This is a retrospective cross-sectional study using structured questionnaire to collect hospital-based data available in the record of Curative Service Division, Department of Health Services of Nepal from October 2021 to September 2022. A total of 6151 cases were recorded in the study. Descriptive analysis was done for demographic and symptoms variable. Association of variables to post-COVID-19 condition are shown using univariate and multivariate logistic regression.

Results

Among 6151 respondents (62.25% males), more than half (59.03%) had at least one symptom after recovery from acute COVID-19. The most common symptoms were anxiety (28.5%), loss of appetite (25.3%), shortness of breath (24.13%), fatigue (23.24%), depressed mood (18.79%), muscle ache (17.59%), chest pain (16.81%), headache (14.78%), and palpitation (13%). Multivariate analysis showed increased odds of post-COVID-19 conditions in smokers (adjusted OR [aOR] 1.53), those with chronic lung disease (aOR 1.71), neurological disorder (aOR 2.43) and those with use of supplementary oxygen during acute illness of COVID-19 (aOR 3.37).

Conclusion

The prevalence of post-COVID-19 symptoms among the study population is found to be high. The main symptoms from our study and similar studies are anxiety, fatigue, loss of appetite, shortness of breath, muscle pain, headaches. Patients with smoking, hypoxia during acute illness and presence of chronic lung disease and neurological disorder had higher odds of getting post-COVID-19 conditions. Citing the findings, health system should focus upon the management and recording of such conditions for further evidence.
Prediction of Complicated Ovarian Hyperstimulation Syndrome in Assisted Reproductive Treatment Through Artificial Intelligence
Authors: Ziaee Arash , Khosravi Hamed , Sadeghi Tahereh , Ahmed Imtiaz , Mahmoudinia Maliheh
Published: April 2024

Background

This study explores the utility of machine learning (ML) models in predicting complicated Ovarian Hyperstimulation Syndrome (OHSS) in patients undergoing infertility treatments, addressing the challenge posed by highly imbalanced datasets.

Objective

This research fills the existing void by introducing a detailed structure for crafting diverse machine learning models and enhancing data augmentation methods to predict complicated OHSS effectively. Importantly, the research also concentrates on pinpointing critical elements that affect OHSS.

Method

This retrospective study employed a ML framework to predict complicated OHSS in patients undergoing infertility treatment. The dataset included various patient characteristics, treatment details, ovarian response variables, oocyte quality indicators, embryonic development metrics, sperm quality assessments, and treatment specifics. The target variable was OHSS, categorized as painless, mild, moderate, or severe. The ML framework incorporated Ray Tune for hyperparameter tuning and SMOTE-variants for addressing data imbalance. Multiple ML models were applied, including Decision Trees, Logistic Regression, SVM, XGBoost, LightGBM, Ridge Regression, KNN, and SGD. The models were integrated into a voting classifier, and the optimization process was conducted. The SHAP package was used to interpret model outcomes and feature contributions.

Results

The best model incorporated IPADE-ID augmentation along with an ensemble of classifiers (SGDClassifier, SVC, RidgeClassifier), reaching a recall of 0.9 for predicting OHSS occurrence and an accuracy of 0.76. SHAP analysis identified key factors: GnRH antagonist use, longer stimulation, female infertility factors, irregular menses, higher weight, hCG triggers, and, notably, higher number of embryos.

Conclusion

This novel study demonstrates ML’s potential for predicting complicated OHSS. The optimized model provides insights into contributory factors, challenging certain conventional assumptions. The findings highlight the importance of considering patient-specific factors and treatment details in OHSS risk assessment.
A preventive school-based paradigm using virtual reality technologies for improving emotional regulation, depressive and anxiety symptoms in children and adolescents (e-Emotio project): a randomized controlled pilot trial
Authors: Carballo-Marquez Anna , Garcia-Casanovas Anna , Ampatzoglou Aikaterini , Rojas-Rincon Juliana , Fernández-Capo María , Gámiz-Sanfeliu María , Freixa Maite Garolera- , Porras-Garcia Bruno
Published: April 2024

Introduction

Preventive transdiagnostic interventions for depression and anxiety symptoms in children and adolescents are important in reducing the development of disorders later in life, and emotion regulation (ER) is one potentially relevant factor to consider. Impairments in executive functions play a critical role in emotion development and regulation in these ages. Immersive Virtual Reality (IVR) technology has exhibited potential to augment traditional cognitive training interventions. In this project, we propose to use Enhance IVR, a gamified cognitive training that can be tailored to specific ER strategies that individuals may face, such as difficulty with attention control, inhibition, or cognitive flexibility.

Methods and analysis

This is a longitudinal, parallel, single-blind, randomized, controlled pilot trial with an estimated sample of 160 participants. The first group (experimental group) will receive the gamified IVR program (Enhance IVR), while the second group (active control group) will receive a comparable IVR relaxation experience. Both Enhance IVR and the control IVR interventions will last five weeks, two times a week, 30 minutes (10 sessions per participant). Participants will undergo a baseline assessment that includes several measures related to mental health, ER, executive functioning, and cognitive performance, and another post intervention assessment with the same measures. Finally, variables related to system usability and cybersickness with the IVR tool will be evaluated for both groups.

Ethics and dissemination

This study was approved by the Ethical Committee of the International University of Catalonia (PSI-2023-04). The findings will be disseminated through peer-reviewed journals, reports, conferences, and other scientific events.

Strengths and limitations of this study

This is a controlled, randomized, and single-blind design, which provides rigorous evidence for a virtual reality (VR) intervention effect.

The intervention has a strong ecological validity as it is done in the participants’ natural context (i.e. school) and the assessment involves students, family, and school.

The gamified VR design is innovative and engaging, and there is an equivalent active-based VR control condition.

One limitation is there is no follow-up assessment and no double-blind experimental design due to the nature of the study.

A second limitation is the potential drop-out rates due the preventive nature of the interventions.
Behavior-driven forecasts of neighborhood-level COVID-19 spread in New York City
Authors: Zhang Renquan , Tai Jilei , Yao Qing , Yang Wan , Ruggeri Kai , Shaman Jeffrey , Pei Sen
Published: April 2024

The COVID-19 pandemic in New York City (NYC) was characterized by marked disparities in disease burdens across neighborhoods. Accurate neighborhood-level forecasts are critical for planning more equitable resource allocation; however, such spatially high-resolution forecasts remain scarce in operational use. Here, we analyze aggregated foot traffic data derived from mobile devices to measure the connectivity among 42 NYC neighborhoods driven by various human activities such as dining, shopping, and entertainment. Using real-world time-varying contact patterns in different place categories, we develop a parsimonious behavior-driven epidemic model that incorporates population mixing, indoor crowdedness, dwell time, and seasonality of virus transmissibility. This process-based model supports accurate modeling of neighborhood-level SARS-CoV-2 transmission throughout 2020. In the best-fitting model, we estimate that the force of infection in indoor settings increases sublinearly with crowdedness and dwell time. Retrospective forecasting demonstrates that this behavior-driven model generates improved short-term forecasts in NYC neighborhoods. This model may be adapted for use with other respiratory pathogens sharing similar transmission routes.
Cost Savings Associated with Extended Battery Longevity in Cardiac Resynchronization Therapy Defibrillators (CRT-D)
Authors: Williams Jeffrey L. , Sato Ryoko , Jacobsen Caroline M.
Published: April 2024

Background

Cardiac resynchronization therapy-defibrillators (CRT-D) are devices established as treatment for symptomatic heart failure patients with an indication for CRT and at risk of sudden cardiac death. However, battery depletion poses a significant clinical and economic burden; extended service life may reduce costs due to generator changes and associated complications. The purpose of this study was to estimate the potential cost-savings associated with extended battery longevity in a Medicare patient population receiving CRT-D implantation.

Methods

A decision tree was used to explore three battery capacities, which represent the leading device manufacturers available in the US: 1.0 ampere-hours (Ah), 1.6Ah, and 2.1Ah. Yearly risk of all-cause mortality, device-related complications, and end of battery life were estimated. Over a time horizon of 6 years, estimated costs included device implantation, replacement, follow-up appointments, and complications. Costs were discounted at 3%. Univariate deterministic sensitivity analysis was completed for patient survival, battery survival, complication incidence and costs, procedure costs, and time horizon.

Results

In the base-case, the average total costs to Medicare over 6 years were $41,527, $48,515, and $56,647 per person (USD 2023) for the 2.1Ah, 1.6Ah, and 1.0Ah devices, respectively. The total per-person replacement cost for the 1.0Ah devices was more than 4 times that of the 2.1Ah devices ($20,126 versus $5,006). When extrapolated to the total number of CRT-D implants each year over a 6-year period, the difference in costs between the extended (2.1Ah) and lowest (1.0Ah) battery capacity exceeded $500 million.

Conclusions

Extended longevity CRT-D batteries demonstrate significant cost savings to Medicare over 6 years compared to those with lower battery capacity. These data indicate long-term economic considerations should be included in device selection.
Bubbles help in troubles: contrast-enhanced ultrasound (CEUS) as predictor of recurrence for TIA/stroke in low-grade internal carotid artery stenosis
Authors: D’Auria Francesca , Santo Danilo Flavio
Published: April 2024

Introduction

Contrast-enhanced ultrasound (CEUS) allows to visualize atherosclerotic plaque neo-vessels which are the hallmark of carotid plaque instability.

Aim

Aim of our prospective study was to check the correlation between carotid CEUS analysis and the recurrence of TIA/stroke in patients with a previous recent TIA/stroke and neurological impairment congruent with the vascular stenosis.

Materials and Methods

From November 2021 to May 2023, 62 consecutive patients (mean age 73.8 +/- 12.2, female 51) with a TIA/stroke in the previous 30 days, underwent carotid ultrasound and carotid CEUS in outpatients setting after 10 days from the acute event. Inclusion criteria was one atherosclerotic plaque inside the internal carotid artery, congruent with symptoms, which was causing a stenosis less than 50% (low-grade stenosis). Carotid plaque neovascularization scoring method was: score 0: no visible microbubbles within the plaque (A); score 1: minimal microbubbles confined to periadventitial (B); and score 2: microbubbles present throughout the plaque core (C). During the six-month follow-up, we checked TIA/stroke recurrences. A multivariable logistic regression analysis was performed.

Results

In our series, 22% of patients have CEUS score 0, 35% CEUS score 1, and 43% CEUS score 2. At six-month follow-up we found 21% TIA/stroke recurrences in CEUS score 2, despite of the ongoing best medical therapy as per guidelines. In Cox regression analysis, CEUS-detected neovascularization was independently associated with TIA/stroke recurrence (hazard ratio, 5.37; 95% confidence interval, 1.36–2.31).

Conclusions

Plaque neovascularization, detected by CEUS, is an independent predictor of TIA/stroke recurrence at six-month follow-up in patients with carotid atherosclerosis despite of low-grade stenosis.
From raw microalgae to bioplastics: conversion ofChlorella vulgarisstarch granules into thermoplastic starch
Authors: Six A. , Dauvillée D. , Lancelon-Pin C. , Dimitriades-Lemaire A. , Compadre A. , Dubreuil C. , Alvarez P. , Sassi J.-F. , Li-Beisson Y. , Putaux J.-L. , Le Moigne N. , Fleury G.
Published: April 2024

Microalgae are emerging as a promising feedstock for bioplastics, withChlorella vulgarisyielding significant amounts of starch. This polysaccharide is convertible into thermoplastic starch (TPS), a biodegradable plastic of industrial relevance. In this study, we developed a pilot-scale protocol for extracting and purifying starch from starch-enrichedChlorella vulgarisbiomass. From 430.3 ± 0.5 g (dry weight - DW) of microalgae biomass containing 42.2 ± 3.4 % of starch, we successfully extracted 205.8 ± 1.2 gDWof purified starch extract containing 86.9 ± 3.0 % of starch, resulting in a final recovery yield of 98.5%. We have characterized this extracted starch and processed it into TPS using twin-screw extrusion and injection molding. Microalgal starch showed similar properties to those of native plant starch, but with smaller granules. We compared the mechanical properties of microalgal TPS with two controls, namely a commercial TPS and a TPS prepared from commercial potato starch granules. TPS prepared from microalgal starch showed a softer and more ductile behavior compared to the reference materials. This study demonstrates the feasibility of recovering high-purity microalgal starch on a pilot scale with high yields, and highlights the potential of microalgal starch for the production of TPS using industrially relevant processes.

Graphical abstract
A Futile Cycle? Tissue Homeostatic Trans-Membrane Water Co-Transport: Kinetics, Thermodynamics, Metabolic Consequences
Authors: Springer Charles S. , Pike Martin M. , Barbara Thomas M.
Published: April 2024

The phenomenon of active trans-membrane water cycling (AWC) has emerged in little over a decade. Here, we consider H2O transport across cell membranes from the origins of its study. Historically, trans-membrane water transport processes were classified into: A) compensating bidirectional fluxes (“exchange”), and B) unidirectional flux (“net flow”) categories. Recent literature molecular structure determinations and molecular dynamic (MD) simulations indicate probably all the many different hydrophilic substrate membrane co-transporters have membrane-spanning hydrophilic pathways and co-transport water along with their substrates, and that they individually catalyze category A and/or B water flux processes, although usually not simultaneously. The AWC name signifies that, integrated over the all the cell’s co-transporters, the rate ofhomeostatic, bidirectional trans-cytolemmal water exchange (category A) is synchronized with the metabolic rate of the crucial Na+,K+-ATPase (NKA) enzyme. A literature survey indicates the stoichiometric (category B) water/substrate ratios of individual co-transporters are often very large. The MD simulations also suggest how different co-transporter reactions can bekineticallycoupled molecularly.

Is this (Na+,K+-ATPase rate-synchronized) cycling futile, or is it consequential? Conservatively representative literature metabolomic and proteinomic results enable comprehensive free energy analyses of the many transport reactions with known water stoichiometries. Free energy calculations, using literature intracellular pressure (Pi) values reveals there is anoutwardtrans-membrane H2O barochemical gradient of magnitude comparable to that of the well-knowninwardNa+electrochemical gradient. For most co-influxers, these gradients are finely balanced to maintain intracellular metabolite concentration values near their consuming enzyme Michaelis constants. The thermodynamic analyses include glucose, glutamate-, gamma-aminobutyric acid (GABA), and lactate-transporters. 2%-4% Pialterations can lead to disastrous concentration levels. For the neurotransmitters glutamate-and GABA, very small astrocytic Pichanges can allow/disallow synaptic transmission. Unlike the Na+and K+electrochemical steady-states, the H2O barochemicalsteady-stateis in (or near) chemicalequilibrium. The analyses show why the presence of aquaporins (AQPs) does not dissipate the trans-membrane pressure gradient. A feedback loop inherent in the opposing Na+electrochemical and H2O barochemical gradients regulates AQP-catalyzed water flux as an integral AWC aspect. These results also require a re-consideration of the underlying nature of Pi. Active trans-membrane water cycling is not futile, but is inherent to the cell’s “NKA system” - a new, fundamental aspect of biology.

SYNOPSIS

Viaintracellular pressure, membrane co-transported water influences thermodynamic control of cell metabolite maintenance.
Human natural killer cells can activate NLRP1 and NLRP3 inflammasomes and drives pyroptosis
Authors: Astorga-Gamaza Antonio , Muela-Zarzuela Inés , Suárez-Rivero Juan Miguel , López-Pérez Juan , de la Varga-Martínez Raquel , Mazuecos Auxiliadora , Cordero Mario D.
Published: April 2024

Innate immunity relies on inflammasomes as key components, defending the host against diverse harmful stimuli by orchestrating the release of pro-inflammatory cytokines and initiating pyroptotic cell death. While extensively studied in myeloid cells, the involvement of natural killer (NK) cells in inflammatory responses through inflammasome signaling remains underexplored. In this study, we elucidate the activation of the inflammasome sensors NLRP1 and NLRP3 in human primary NK cells upon treatment with nigericin and blockade of dipeptidyl peptidases (DPP) using Talabostat (Val-boroPro). Our findings demonstrate the induction of pyroptotic cell death in a subset of NK cells following these stimuli, characterized by the cleavage and activation of gasdermin D, a lytic pore-forming protein. Moreover, we observe the release of lactate dehydrogenase (LDH) and small amounts of interleukin-18 (IL-18). Notably, differential responses are noted between CD56dimand CD56brightNK cell subsets following pro-inflammatory stimulation. Furthermore, analysis of samples from patients with renal dysfunction reveals sustained inflammasome activation in NK cells, particularly NLRP1 and NLRP3, with a tendency towards a more pro-inflammatory phenotype shortly post-kidney transplantation. These findings underscore the significance of considering NK cells in the context of inflammation studies.
Accurate evaluation of live-virus microneutralization for SARS-CoV-2 variant JN.1
Authors: Dowgier Giulia , Hobbs Agnieszka , Greenwood David , Shawe-Taylor Marianne , Stevenson-Leggett Phoebe , Bazire James , Penn Rebecca , Harvey Ruth ,   Crick COVID serology pipeline, Legacy Investigators, Libri Vincenzo , Kassiotis George , Gamblin Steve , Lewis Nicola S , Williams Bryan , Swanton Charles , Gandhi Sonia , Bauer David LV , Carr Edward J , Wall Emma C , Wu Mary Y
Published: April 2024

Emerging SARS-CoV-2 variants require rapid assessments of pathogenicity and evasion of existing immunity to inform policy. A crucial component of these assessments is accurate estimation of serum neutralising antibody titres using cultured live virus isolates. Here, we report our updated culture methods for Omicron sub-variant JN.1 using Caco-2 cells and the subsequent evaluation of neutralising antibody titres (nAbTs) in recipients of BNT162b2-XBB.1.5 monovalent and the Ancestral/BA.5 containing bivalent vaccines. We compared culture of JN.1 in either Vero V1 cells or Caco-2 cells, finding culture in Vero V1 either resulted in low-titre stocks or induced crucial mutations at the Spike furin cleavage site. Using the sequence-clean culture stocks generated in Caco-2 cells, we assessed serum samples from 71 healthy adults eligible for a COVID-19 vaccination given as a 5thdose booster: all participants had detectable nAbs against JN.1 prior to vaccination, with baseline/pre-existing nAbTs between both vaccine groups comparable (p = 0.240). However, nAbTs against JN.1 post-vaccination were 2.6-fold higher for recipients of the monovalent XBB1.5 vaccine than the BA.4/5 bivalent vaccine (p<0.001). Regular re-appraisal of methods involved in the evaluation of new variants is required to ensure robust data are used to underpin crucial severity assessments as variants arise and vaccine strain selection decisions.
DANTE and DANTE_LTR: Lineage-centric annotation pipelines for long terminal repeat retrotransposons in plant genomes
Authors: Novák Petr , Hoštáková Nina , Neumann Pavel , Macas Jiří
Published: April 2024

Long terminal repeat (LTR) retrotransposons constitute a predominant class of repetitive DNA elements in most plant genomes. With the increasing number of sequenced plant genomes, there is an ongoing demand for computational tools facilitating efficient annotation and classification of LTR retrotransposons in plant genome assemblies. Herein, we introduce DANTE, a computational pipeline for Domain-based ANnotation of Transposable Elements, designed for sensitive detection of these elements via their conserved protein domain sequences. The identified protein domains are subsequently inputted into the DANTE_LTR pipeline to annotate complete element sequences by detecting their structural features, such as LTRs, in adjacent genomic regions. Leveraging domain sequences allows for precise classification of elements into phylogenetic lineages, offering a more granular annotation compared with coarser conventional superfamily-based classification methods. The efficiency and accuracy of this approach were evidenced via annotation of LTR retrotransposons in 93 plant genomes. Results were benchmarked against several established pipelines, showing that DANTE_LTR is capable of identifying significantly more intact LTR retrotransposons. DANTE and DANTE_LTR are provided as user-friendly Galaxy tools accessible via a public server (https://repeatexplorer-elixir.cerit-sc.cz), installable on local Galaxy instances from the Galaxy tool shed or executable from the command line.
Genome wide inherited modifications of the tomato epigenome by trans-activated bacterial CG methyltransferase
Authors: Pavan Kumar Bapatla Kesava , Beaubiat Sébastien , Yadav Chandra Bhan , Eshed Ravit , Arazi Tzahi , Sherman Amir , Bouché Nicolas
Published: April 2024

Epigenetic variation is mediated by epigenetic marks such as DNA methylation occurring in all cytosine contexts in plants. CG methylation plays a critical role in silencing transposable elements and regulating gene expression. The establishment of CG methylation occurs via the RNA-directed DNA methylation pathway and CG methylation maintenance relies on METHYLTRANSFERASE1, the homologue of the mammalian DNMT1. Here, we examined the capacity to stably alter the tomato genome methylome by a bacterial CG-specificM.SssImethyltransferase expressed through the LhG4/pOP transactivation system. Methylome analysis ofM.SssIexpressing plants revealed that their euchromatic genome regions are specifically hypermethylated in the CG context, and so are most of their genes. However, changes in gene expression were observed only with a set of genes exhibiting a greater susceptibility to CG hypermethylation near their transcription start site. Unlike gene rich genomic regions, our analysis revealed that heterochromatic regions are slightly hypomethylated at CGs only. Notably, someM.SssI-induced hypermethylation persisted even without the methylase or transgenes, indicating inheritable epigenetic modification. Collectively our findings suggest that heterologous expression ofM.SssIcan create new inherited epigenetic variations and changes in the methylation profiles on a genome wide scale. This open avenues for the conception of epigenetic recombinant inbred line populations with the potential to unveil agriculturally valuable tomato epialleles.
FGF2 binds to the allosteric site (site 2) and activates αvβ3 integrin and FGF1 binds to site 2 but suppresses integrin activation by FGF2: a potential mechanism of anti-inflammatory action of FGF1
Authors: Takada Yoko K , Wu Xueson , Wei David , Hwang Samuel , Takada Yoshikazu
Published: April 2024

FGF1 is known as an anti-inflammatory and has suppresses insulin resistance. Its homologue FGF2 is pro-inflammatory. Mechanism of FGF1’s anti-inflammatory action and FGF2’s pro-inflammatory action are unknown. Several inflammatory cytokines (e.g., CX3CL1, CCL5, and CXCL12, and CD40L) bind to the classical ligand (RGD)-binding site (site 1) of integrin αvβ3. In addition, they bind to the allosteric site (site 2) of αvβ3, which is distinct from site 1, and allosterically activate αvβ3. Site 2 is involved in inflammatory signals since inflammatory lipid mediator 5-hydroxycholesterol binds to site 2 and induces integrin activation and inflammatory signals (e.g., TNF and IL-6 secretion). We thus hypothesized that FGF1 and FGF2 bind to site 2 and affect activation status of integrins. Here we describe that FGF2 bound to site 2 and allosterically activated αvβ3 integrin. Point mutations in the site 2-binding interface of FGF2 suppressed this activation, indicating that FGF2 binding to site 2 is required for inducing integrin activation. In contrast, FGF1 bound to site 2 but did not activate αvβ3, and instead suppressed integrin activation induced by FGF2, indicating that FGF1 acts as an antagonist of site 2. These findings suggest that FGF1’s anti-inflammatory action is mediated by blocking site 2. FGF1 has potential as an anti-inflammatory agent, but is not appropriate for long-term use since it is potent mitogen. A non-mitogenic FGF1 mutant (R50E), which is defective in binding to site 1 of αvβ3, suppressed αvβ3 activation by FGF2 as effectively as WT FGF1. We propose that FGF1 R50E has therapeutic potential for inflammatory diseases.
Molecular basis of proton-sensing by G protein-coupled receptors
Authors: Howard Matthew K. , Hoppe Nicholas , Huang Xi-Ping , Macdonald Christian B. , Mehrota Eshan , Rockefeller Grimes Patrick , Zahm Adam , Trinidad Donovan D. , English Justin , Coyote-Maestas Willow , Manglik Aashish
Published: April 2024

Three proton-sensing G protein-coupled receptors (GPCRs), GPR4, GPR65, and GPR68, respond to changes in extracellular pH to regulate diverse physiology and are implicated in a wide range of diseases. A central challenge in determining how protons activate these receptors is identifying the set of residues that bind protons. Here, we determine structures of each receptor to understand the spatial arrangement of putative proton sensing residues in the active state. With a newly developed deep mutational scanning approach, we determined the functional importance of every residue in proton activation for GPR68 by generating ∼9,500 mutants and measuring effects on signaling and surface expression. This unbiased screen revealed that, unlike other proton-sensitive cell surface channels and receptors, no single site is critical for proton recognition in GPR68. Instead, a network of titratable residues extend from the extracellular surface to the transmembrane region and converge on canonical class A GPCR activation motifs to activate proton-sensing GPCRs. More broadly, our approach integrating structure and unbiased functional interrogation defines a new framework for understanding the rich complexity of GPCR signaling.

One-sentence summary

The protonation networks governing activation of human pH-sensing GPCRs are uncovered by integrative cryo-EM and deep mutational scanning.
Effect of different odors on the rat urine proteome
Authors: Liu Yuqing , Wang Haitong , Gao Youhe
Published: April 2024

Do rats have corresponding changes in their urinary proteome when smelling different odors? In this study, urine samples were collected from six rats after smelling sesame oil and essential balm for three days. And samples were collected before and on the third and fourth days. Comparing the urinary protein groups of Day0 and Day4 of the sesame oil group, 143 differential proteins were identified, and the average number of randomly generated differential proteins was 7.3, which means that about 95% of the differential proteins could not be randomly generated. in the sesame oil group, differential proteins such as low-density lipoprotein receptor-related protein 2 and fetuin B, a biomarker of COPD, which are associated with olfaction, were identified. While uteroglobulin, trichothecene factor 3, and visfatin 2 were identified in the essential balm group, which had significant changes and were related to the production of olfactory sensation. It is noteworthy that we identified odor-binding protein 2A in the essential balm group, which was present in the e-cigarette model. This study demonstrates that odor can affect rat urinary proteome, with different odors affecting it differently. This provides a new approach to explore the biological process of olfaction.