bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of modified basic package of oral care on adolescents’ dental caries status in Copperbelt Province, Zambia; A Cluster Randomized Trial
Authors: Anthony Severine N , Mbawalla Hawa S , Kahabuka Febronia K , Siziya Seter , Åstrøm Anne N
Published: March 2024

Background

Dental caries remains the major oral health challenge affecting more than half of adolescents globally. Most of the disease remain untreated, therefore, negatively impacting adolescents’ general health, well-being, and quality of life. Basic Package of Oral Care (BPOC) is a potential solution to the challenge, however, evidence on its effectiveness is scarce. This study primarily assessed the effects of applying modified BPOC on dental caries prevalence and secondarily on knowledge and behaviors related to dental caries among adolescents in Copperbelt Province, Zambia.

Methods

A parallel arms cluster randomized field trial (Reg-PACTR202210624926299) including 22 public secondary schools in Copperbelt province, Zambia, was carried out between January 2021 and March 2023. A pre-tested questionnaire was used to collect socio-demographics, knowledge and dental caries related behaviors data, while dental caries was assessed clinically using the caries assessment spectrum and treatment (CAST) at baseline and the follow-ups. The 1stand 2ndfollow ups were conducted at 18-and 24months after baseline respectively. The analysis was based on intention-to-treat protocol using generalized estimating equations (GEE) and results are reported as OR (95% CI).

Results

Out of 1,794 participants at baseline, 1,690 (94.2%) and 1,597 (89.0%) were seen at 1stand 2ndfollow ups respectively. A significant interaction (BPOC x time) for dental caries models at 18 months {OR (95%CI) = 1.3 (1.1, 1.6), p=0.003)} and 24 months {OR (95%CI) = 1.3 (1.1, 1.6), p=0.004)} was observed. Secondary outcomes with significant interactions included adequate knowledge models at 18 months {OR (95%CI) =1.5 (1.2,1.8), p<0.001} and 24 months {OR (95%CI) = 1.6 (1.3, 2.0), p<0.001} as well as use of fluoridated toothpaste twice or more per day at 18 months {OR (95%CI) = 1.6 (1.3, 2.1), p<0.001)} and 24 months {OR (95%CI) = 1.4 (1.2, 1.6), p<0.001)}. Subgroup analysis showed that the intervention group had better outcomes than the control group in terms of dental caries prevalence, adequate knowledge, use of fluoridated toothpaste twice or more per day, at 18- and 24 months.

Conclusion

The modified BPOC was effective in reducing prevalence of dental caries, improving knowledge on dental caries, and the frequency of using fluoridated toothpaste among Zambian adolescents. Further studies need to be conducted in order to address other factors affecting oral health related behaviors such as the school and home environment, social and cultural factors.
Applying causal inference and Bayesian statistics to understanding vaccine safety signals — a simulation study
Authors: Tay Evelyn , Dymock Michael , Lopez Laura , Glover Catherine , Huang Yuanfei Anny , Shuvo Bakar K. , Snelling Thomas , Marsh Julie A. , Wu Yue
Published: March 2024

Community perception of the safety of vaccines in the interest of public health influences vaccine uptake. Challenges for active vaccine safety monitoring include survey response rates, unbiased reporting and the balance between specificity and sensitivity of signal detection methods. To address these problems, we used causal DAGs and statistical methods to guide understanding of biological and behavioural factors which may influence vaccine safety signal detection. The DAGs informed the generation of scenarios in which these factors were varied. A posterior predictive analysis (PPA) signal detection method, based upon a Bayesian logistic model, was used to detect signals across the scenarios. In the high probability of severe reaction scenarios, true signals were generated where there was higher survey participation with more survey responder AEFI data available for analysis. In the low probability of severe reaction scenarios, false signals were generated when there was a strong influence of reaction severity on survey participation and reports of severe reactions. Low rates of survey participation reduce the amount of data available to inform the parameters of the statistical model, and therefore reduce the certainty regarding the value of these parameters. We obtained insights into the value of the causal DAG to account for survey non-response, to guide understanding of short-term vaccine safety, interpret the results of the PPA analysis under plausible scenarios, and review implications for future vaccine safety monitoring
Generative Adversarial Implicit Successor Representation
Authors: Choi Whan-Hyuk , Ha Sukyeon , Choi Hansol
Published: March 2024

We propose a novel method to implicitly encode Successor Representations (SRs) using a Generative Adversarial Network (GAN). SRs are a method to encode states of the environment in terms of their predictive relationships with other states, which can be used to predict long-term future rewards. In standard explicit methods, the value of SR is found from an explicit map between future states after an action or to find an approximate function. Instead, our method encodes SR implicitly using a GAN. The distribution of samples generated by the GAN system approximates the successor representation. We also suggest an action decision procedure for the implicit encoding of SR. The system makes the decision using an analysis-by-synthesis procedure that it attempts to synthesize a sample that can explain the action decision constraints of the current and target states. Our system is different from the classical SR in several points. It can sample actual samples reflecting SR distribution, which is not easy for explicit models. It can also get around the issue of explicitly representing probabilities or successor representation values and doing math over them. We tested our system in a toy environment, where the agent could learn the implicit successor representation successfully and use it for action decisions.
Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies
Authors: Nazeen Sumaiya , Wang Xinyuan , Zielinski Dina , Lam Isabel , Hallacli Erinc , Xu Ping , Ethier Elizabeth , Strom Ronya , Zanella Camila A. , Nithianandam Vanitha , Ritter Dylan , Henderson Alexander , Saurat Nathalie , Afroz Jalwa , Nutter-Upham Andrew , Benyamini Hadar , Copty Joseph , Ravishankar Shyamsundar , Morrow Autumn , Mitchel Jonathan , Neavin Drew , Gupta Renuka , Farbehi Nona , Grundman Jennifer , Myers Richard H. , Scherzer Clemens R. , Trojanowski John Q. , Van Deerlin Vivianna M. , Cooper Antony A. , Lee Edward B. , Erlich Yaniv , Lindquist Susan , Peng Jian , Geschwind Daniel H , Powell Joseph , Studer Lorenz , Feany Mel B. , Sunyaev Shamil R. , Khurana Vikram
Published: March 2024

Whether neurodegenerative diseases linked to misfolding of the same protein share genetic risk drivers or whether different protein-aggregation pathologies in neurodegeneration are mechanistically related remains uncertain. Conventional genetic analyses are underpowered to address these questions. Through careful selection of patients based on protein aggregation phenotype (rather than clinical diagnosis) we can increase statistical power to detect associated variants in a targeted set of genes that modify proteotoxicities. Genetic modifiers of alpha-synuclein (ɑS) and beta-amyloid (Aβ) cytotoxicity in yeast are enriched in risk factors for Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively. Here, along with known AD/PD risk genes, we deeply sequenced exomes of 430 ɑS/Aβ modifier genes in patients across alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy). Beyond known PD genesGBA1andLRRK2, rare variants AD genes (CD33,CR1andPSEN2) and Aβ toxicity modifiers involved in RhoA/actin cytoskeleton regulation (ARGHEF1, ARHGEF28, MICAL3, PASK, PKN2, PSEN2) were shared risk factors across synucleinopathies. Actin pathology occurred in iPSC synucleinopathy models and RhoA downregulation exacerbated ɑS pathology. Even in sporadic PD, the expression of these genes was altered across CNS cell types. Genome-wide CRISPR screens revealed the essentiality ofPSEN2in both human cortical and dopaminergic neurons, andPSEN2mutation carriers exhibited diffuse brainstem and cortical synucleinopathy independent of AD pathology.PSEN2contributes to a common-risk signal in PD GWAS and regulates ɑS expression in neurons. Our results identify convergent mechanisms across synucleinopathies, some shared with AD.
A role for the S4-domain containing protein YlmH in ribosome-associated quality control inBacillus subtilis
Authors: Takada Hiraku , Paternoga Helge , Fujiwara Keigo , Nakamoto Jose A. , Park Esther N. , Dimitrova-Paternoga Lyudmila , Beckert Bertrand , Saarma Merilin , Tenson Tanel , Buskirk Allen R. , Atkinson Gemma C. , Chiba Shinobu , Wilson Daniel N. , Hauryliuk Vasili
Published: March 2024

Ribosomes trapped on mRNAs during protein synthesis need to be rescued for the cell to survive. The most ubiquitous bacterial ribosome rescue pathway is trans-translation mediated by tmRNA and SmpB. Genetic inactivation of trans-translation can be lethal, unless the ribosomes are rescued by ArfA or ArfB alternative rescue factors or the ribosome-associated quality control (RQC) system, which inB. subtilisinvolves MutS2, RqcH, RqcP and Pth. Using transposon sequencing in a trans-translation-incompetentB. subtilisstrain we identify a poorly characterized S4-domain-containing protein YlmH as a novel potential RQC factor. Cryo-EM structures reveal that YlmH binds peptidyl-tRNA-50S complexes in an position analogous to that of S4-domain-containing RqcP, and that, similarly to RqcP, YlmH can co-habit with RqcH. Consistently, we show that YlmH can assume the role of RqcP in RQC in facilitating the addition of polyalanine tails to the truncated nascent polypeptides. While inB. subtilisthe function of YlmH is redundant with RqcP, our taxonomic analysis reveals that in multiple bacterial phyla RqcP is absent, while YlmH and RqcH are present, suggesting that in these species the YlmH plays a central role in the RQC.
A resource to enable chemical biology and drug discovery of WDR Proteins
Authors: Ackloo Suzanne , Li Fengling , Szewczyk Magda , Seitova Almagul , Loppnau Peter , Zeng Hong , Xu Jin , Ahmad Shabbir , Arnautova Yelena A , Baghaie AJ , Beldar Serap , Bolotokova Albina , Centrella Paolo A , Chau Irene , Clark Matthew A , Cuozzo John W , Dehghani-Tafti Saba , Disch Jeremy S , Dong Aiping , Dumas Antoine , Feng Jianwen A. , Ghiabi Pegah , Gibson Elisa , Gilmer Justin , Goldman Brian , Green Stuart R , Guié Marie-Aude , Guilinger John P , Harms Nathan , Herasymenko Oleksandra , Houliston Scott , Hutchinson Ashley , Kearnes Steven , Keefe Anthony D , Kimani Serah W , Kramer Trevor , Kutera Maria , Kwak Haejin A , Lento Cristina , Li Yanjun , Liu Jenny , Loup Joachim , Machado Raquel AC , Mulhern Christopher J , Perveen Sumera , Righetto Germanna L , Riley Patrick , Shrestha Suman , Sigel Eric A , Silva Madhushika , Sintchak Michael D. , Slakman Belinda L , Taylor Rhys D , Thompson James , Torng Wen , Underkoffler Carl , von Rechenberg Moritz , Watson Ian , Wilson Derek J , Wolf Esther , Yadav Manisha , Yazdi Aliakbar K , Zhang Junyi , Zhang Ying , Santhakumar Vijayaratnam , Edwards Aled M , Barsyte-Lovejoy Dalia , Schapira Matthieu , Brown Peter J , Halabelian Levon , Arrowsmith Cheryl H
Published: March 2024

Protein class-focused drug discovery has a long and successful history in pharmaceutical research, yet most members of druggable protein families remain unliganded, often for practical reasons. Here we combined experiment and computation to enable discovery of ligands for WD40 repeat (WDR) proteins, one of the largest human protein families. This resource includes expression clones, purification protocols, and a comprehensive assessment of the druggability for hundreds of WDR proteins. We solved 21 high resolution crystal structures, and have made available a suite of biophysical, biochemical, and cellular assays to facilitate the discovery and characterization of small molecule ligands. To this end, we use the resource in a hit-finding pilot involving DNA-encoded library (DEL) selection followed by machine learning (ML). This led to the discovery of first-in-class, drug-like ligands for 9 of 20 targets. This result demonstrates the broad ligandability of WDRs. This extensive resource of reagents and knowledge will enable further discovery of chemical tools and potential therapeutics for this important class of proteins.
Long-term Metabolic Side Effects of Second-Generation Antipsychotics in Chinese Patients with Schizophrenia: A Within-Subject Approach with modelling of dosage effects
Authors: Wong Kenneth C.Y. , Leung Perry B.M. , Lee Benedict K.W. , Sham Pak C. , Lui Simon S.Y. , So Hon-Cheong
Published: March 2024

Background

Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia (SCZ), but SGAs may differ in the severity of side effects. Previous observational studies had limitations like failing to account for confounding factors and short follow-up periods. This study compared the long-term metabolic and anthropometric side effects of seven second-generation antipsychotics (SGAs) in a Chinese schizophrenia population, using a within-subject approach to reduce risk of confounding.

Methods

Longitudinal data on SGA prescriptions, concomitant medications, fasting blood glucose, lipid profiles, and BMI were collected from 767 schizophrenia patients, with follow-up up to 18.7 years (median ∼6.2 years). Linear mixed models estimated the effects of SGAs, as binary predictors and by dosage, on metabolic profiles.

Results

When considering SGAs as binary predictors, clozapine and olanzapine were associated with the most substantial worsening of lipid profiles and BMI, while clozapine alone showed a significant increase in blood glucose. Amisulpride, paliperidone, and quetiapine worsened lipid profiles and increased BMI. Conversely, aripiprazole improved lipid profiles but slightly increased BMI. Examining dosage effects showed consistent results overall. At minimum effective doses, clozapine had the most severe metabolic side effects, followed by olanzapine. Risperidone and aripiprazole had the least metabolic impact, with aripiprazole significantly lowering lipids.

Conclusions

This study clarified the long-term, dose-dependent metabolic and anthropometric effects of different SGAs in Chinese schizophrenia patients. Our findings may inform clinicians and SCZ patients of SGA choices.
Effects of maternal exercise on infant mesenchymal stem cell mitochondrial function, insulin action, and body composition in early infancy
Authors: Jevtovic Filip , Zheng Donghai , Claiborne Alex , Biagioni Ericka M. , Wisseman Breanna L. , Krassovskaia Polina M. , Collier David N. , Isler Christy , DeVente James E. , Neufer P. Darrell , Houmard Joseph A. , May Linda E.
Published: March 2024

Objective

Rates of pediatric obesity are continuously rising and are likely to translate into a high incidence of metabolic disease later in life. Maternal exercise (ME) has been established as a useful non-pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), and remain involved in mature tissue maintenance. Importantly, these cells maintain metabolic characteristics of an offspring donor and provide a model for the investigation of mechanisms behind infant metabolic health improvements.

Methods

We used undifferentiated MSC to investigate if ME affects infant MSC mitochondrial function and insulin action, and if these adaptations are associated with lower infant adiposity.

Results

We found that infants from exercising mothers have improvements in MSC insulin signaling are related to higher MSC respiration and fat oxidation, and expression and activation of energy-sensing and redox-sensitive proteins. Further, we found that infants exposed to exercise in utero were seemingly leaner at 1-month of age, with a significant inverse correlation between infant MSC respiration and infant adiposity at 6-months of age.

Conclusion

These data suggest that infants from exercising mothers are relatively leaner and this is associated with higher infant MSC mitochondrial respiration, fat use, and insulin action.
Enhancing COVID-19 Case Forecasting in the United States: A Comparative Analysis of ARIMA, SARIMA, and RNN Models with Grid Search Optimization
Authors: Nichols Samira , Abolmaali Saina
Published: March 2024

The COVID-19 pandemic has resulted in a substantial number of fatalities in the United States since its onset in January 2020. In an effort to mitigate the spread of this highly infectious disease, a range of measures, including social distancing, mask-wearing, lockdowns, and vaccination campaigns, have been implemented. However, despite these extensive efforts, the persistent transmission of the virus can be attributed to a combination of vaccine hesitancy among certain individuals and the emergence of new viral strains. To effectively manage the ongoing pandemic, healthcare providers and government officials rely on infectious disease modeling to anticipate and secure the necessary resources. Accurate short-term case number forecasting is of paramount importance for healthcare systems.

Since the beginning of the pandemic, numerous models have been employed to forecast the number of confirmed cases. In this study, we undertake a comparative analysis of six time-series techniques: Simple Moving Average (SMA), Exponentially Weighted Moving Average (EWMA), Holt-Winters Double Exponential Smoothing Additive (HWDESA), Autoregressive Integrated Moving Average (ARIMA), Seasonal Autoregressive Integrated Moving Average (SARIMA), and Recurrent Neural Network (RNN), with regard to their modeling and forecasting capabilities. SMA, EWMA, and HWDESA were employed for predictive modeling, while the ARIMA, SARIMA, and RNN models were utilized for case number forecasting. A comprehensive grid search was carried out to determine the optimal parameter combinations for both the ARIMA and SARIMA models. Our research findings demonstrate that the Holt-Winters Double Exponential model outperforms both the Exponentially Weighted Moving Average and Simple Moving Average in predicting the number of cases. On the other hand, the RNN model surpasses conventional time-series models such as ARIMA and SARIMA in terms of its forecasting accuracy. The finding of this study emphasizes the importance of accurately predicting the number of COVID-19 cases, given the substantial loss of lives caused by both the virus itself and the societal responses to it. Equipping healthcare managers with precise tools like Recurrent Neural Networks (RNNs) can enable them to forecast future cases more accurately and enhance their preparedness for effective response.
Trends in fluoroquinolone prescribing in UK primary and secondary care between 2019 and 2023
Authors: Hamilton Fergus , Darley Elizabeth , MacGowan Alasdair
Published: March 2024

Introduction

Fluoroquinolones are important, widely used antibiotics but have associations with a significant number of adverse outcomes. A recent (January 2024) decision by the UK drug regulator, the Medicines and Health Regulatory Authority (MHRA), restricted systemic use of these antibiotics to when only absolutely necessary with immediate eSect. One stated reason for the ban was the failure of previous guidance (2019, 2023), to impact prescribing, with the 2023 MHRA Drug Safety Update stating there had been “no change in prescribing” of fluoroquinolones in relation to guidance.

Methods

We evaluated the trend in prescribing of fluoroquinolones and comparator antibiotics using national data for all primary care practices in England from 2019 to 2023. We calculated the percent change in prescribing of fluoroquinolones using linear regression, comparing with other antibacterials Analyses were then performed at the integrated care board (ICB) level. We also performed a similar analysis on secondary care prescribing and included hospital inpatient stay data.

Results

In primary care, there was a clear negative trend in fluoroquinolone (particularly ciprofloxacin) item dispensing, with a 4.2% reduction in items dispended per year, 95% confidence interval, CI (−5.2%; −3.3%, p = 6 x 10-13). This occurred despite no change in overall antibacterial prescription (+2% −0.56%; +4.6%, p = 0.12) and no decrease in comparator antibiotics. These occurred across nearly all (97/101) ICBs. Secondary care data showed stable prescription of fluoroquinolones, but other comparator antibiotics increased, leading to relatively fewer prescriptions compared to other agents.

Conclusions

There was a marked reduction in fluoroquinolone prescribing in primary care in England in both absolute terms and relative to other antibiotics between 2019 to 2023. Relative reductions have occurred in secondary care.

Funding

Wellcome Trust (222894/Z/21/Z)
Learning the Relationship Between Variants, Metabolic Fluxes and Phenotypes
Authors: Kim Dongin , Han Seokjin , Nam Seong-Hyeuk , Kim Tae Yong
Published: March 2024

In the dynamic field of cancer research, the fusion of genetics and machine learning presents a groundbreaking opportunity to understand the intricate links between genomic variations and cancer phenotypes. Despite the wealth of genetic data, translating it into actionable insights remains a challenge, particularly in the context of complex cellular metabolism. VaMP (Variants,Metabolic Fluxes &Phenotypes), our novel approach, addresses this by integrating neural networks and metabolic models, offering a comprehensive framework for deciphering cancer biology. The developed method leverages a novel end-to-end neural network architecture, integrating genome-scale metabolic models (GSMs) to capture the intricate relationship between genetic variations and cellular phenotypes. VaMP’s encoder maps genetic variants to metabolic fluxes through a series of carefully designed steps utilizing neural network and GSM, while the decoder predicts phenotype probabilities using the differences between input and reference fluxes. The training data comprise mutation information and phenotypes, eliminating the need for explicit metabolic flux data preparation. Validation experiments on five cancer types demonstrate VaMP’s ability to identify significant genes and metabolic signatures. Further utilizing SCREENER and co-occurrence analyses, the assessment reveals VaMP’s capacity to anticipate established gene-disease relationships. The identified metabolic signatures are robustly substantiated by diverse literature grounded in experimental studies. Furthermore, an in-depth exploration of the outcomes from five VaMP models involved the correlation analysis for variants and fluxes to establish connections between significant genes and cancer-causing variants. Overall, VaMP can be used as a promising tool for unraveling the complex interplay between genetic alterations and cancer phenotypes, with implications for understanding disease mechanisms and identifying novel therapeutic targets.
The inflammatory micro-environment induced by targeted CNS radiotherapy is underpinned by disruption of DNA methylation
Authors: Millner TO , Panday P , Xiao Y , Boot JR , Nicholson J , Arpe Z , Stevens P , Rahman N , Zhang X , Mein C , Kitchen N , McEvoy AW , McKintosh E , McKenna G , Paraskevopoulos D , Lewis R , Badodi S , Marino S
Published: March 2024

Although targeted radiotherapy (RT) is integral to the increasing survival of cancer patients, it has significant side-effects, the cellular and molecular mechanisms of which are not fully understood. During RT epigenetic changes occur in neoplastic tissue, but few studies have assessed these in non-neoplastic tissue and results are highly variable. Using bulk DNA methylation and RNA sequencing as well as spatial transcriptomics (ST) in a unique cohort of patient tissue samples, we show distinct differences in DNA methylation patterns in irradiated brain tissue, whilst ST characterisation identifies specific micro-environmental niches present after irradiation and highlights neuropeptides that could be propagating neuroinflammation. We also show that in a cerebral organoid (CO) model of early changes in neurons after irradiation there are similar DNA methylation alterations and disruption of the DNA methylation machinery, suggesting that early but persistent epigenetic dysregulation plays a role in neurotoxicity. We provide a link between radiotherapy induced neuroinflammation and disruption of DNA methylation for the first time and suggest possible driving mechanisms for this chronic neuroinflammation.
Wolbachiainfection inAedes aegyptidoes not affect its vectorial capacity forDirofilaria immitis
Authors: Shirozu Takahiro , Regilme Maria Angenica F , Ote Manabu , Sasaki Mizuki , Soga Akira , Bochimoto Hiroki , Kawabata Hidenobu , Umemiya-Shirafuji Rika , Kanuka Hirotaka , Fukumoto Shinya
Published: March 2024

Mosquito-borne diseases such as dengue and filariasis are a growing public health concern in endemic countries. Biological approaches, such as the trans-infection ofWolbachia pipientisin mosquitoes, are an alternative vector control strategy, especially for arthropod-borne viruses such as dengue. In the present study, the effect ofWolbachia(wMel strain) on the vectorial capacity ofAedes aegyptiforDirofilaria immitiswas studied. Our results showed thatWolbachiadoes not affect the phenotype of mosquito survival or the prevalence, number, and molting rate of third-stage larvae in both susceptible and resistant strains ofAe.aegypti. RNA-seq analysis of Malpighian tubules at 2 days post-infection withD. immitisshowed the differentially expressed genes (DEGs) with and without wMel infection. No characteristic immune-related gene expression patterns were observed among the DEGs. No significant change in the amount ofWolbachiawas observed in theAe. aegyptiafterD. immitisinfection. Our results suggest that infection ofD. immitisinAe. aegyptipopulations will not interfere withWolbachia-based vector control strategies in dengue-endemic areas where cases ofD. immitisare present. This study demonstrated the veterinary medical validity of a dengue control program usingWolbachia.
Identification of Southeast AsianAnophelesmosquito species using MALDI-TOF mass spectrometry
Authors: Chaumeau Victor , Piarroux Martine , Kulabkeeree Thithiworada , Sawasdichai Sunisa , Inta Aritsara , Watthanaworawit Wanitda , Nosten François , Piarroux Renaud , Nabet Cécile
Published: March 2024

Malaria control in South-East Asia remains a challenge, underscoring the importance of accurately identifying malaria mosquitoes to understand transmission dynamics and improve vector control. Traditional methods such as morphological identification require extensive training and cannot distinguish between sibling species, while molecular approaches are costly for extensive screening. Matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) has emerged as a rapid and cost-effective tool forAnophelesspecies identification, yet its current use is limited to few specialized laboratories. This study aimed to develop and validate an online reference database for MALDI-TOF MS identification of Southeast AsianAnophelesspecies. The database, constructed using the in-house data analysis pipeline MSI2 (Sorbonne University), comprised 2046 head mass spectra from 209 specimens collected at the Thailand-Myanmar border. Molecular identification via COI and ITS2 DNA barcodes enabled the identification of 20 sensu stricto species and 5 sibling species complexes. The high quality of the mass spectra was demonstrated by a MSI2 median score (min-max) of 61.62 (15.94-77.55) for correct answers, using the best result of four technical replicates of a test panel. Applying an identification threshold of 45, 93.9% (201/214) of the specimens were identified, with 98.5% (198/201) consistency with the molecular taxonomic assignment. In conclusion, MALDI-TOF MS holds promise for malaria mosquito identification and can be scaled up for entomological surveillance in Southeast Asia. The free online sharing of our database on the MSI2 platform represents an important step towards the broader use of MALDI-TOF MS in malaria vector surveillance.

Author summary

Mosquito-borne diseases like malaria are on the rise globally, and climate change may exacerbate this global threat. Accurate identification ofAnophelesmosquitoes, the malaria vectors, is crucial for understanding and controlling the disease. Unfortunately, morphological identification methods require extensive training and molecular methods can be time-consuming, especially when analyzing large samples. In this study, we established a reference database for identifying 25 species of Southeast AsianAnophelesusing mass spectrometry, a rapid method based on protein fingerprinting. Using a test panel, we demonstrated the effectiveness of this innovative approach in identifying Southeast AsianAnophelesvectors. Importantly, the online sharing of our database marks an important step towards wider application of the tool, thereby contributing to the global effort to combat malaria.
Cryo-EM Structure of the R388 plasmid conjugative pilus reveals a helical polymer characterised by an unusual pilin/phospholipid binary complex
Authors: Vadakkepat Abhinav K. , Xue Songlin , Redzej Adam , Smith Terry K. , Ho Brian , Waksman Gabriel
Published: March 2024

Bacterial conjugation is a process by which DNA is transferred unidirectionally from a donor cell to a recipient cell. It is the main means by which antibiotics resistance genes spread among bacterial populations. It is crucially dependent upon the elaboration of an extracellular appendage, termed “pilus”, by a large double-membrane spanning secretion system termed conjugative “type IV secretion system”. Here we present the structure of the conjugative pilus encoded by the R388 plasmid. We demonstrate that, as opposed to all conjugative pili produced so far for cryo-EM structure determination, that encoded by the R388 plasmid is greatly stimulated by the presence of recipient cells. Comparison of its cryo-EM structure with existing conjugative pilus structures highlights a number of important differences between the R388 pilus structure and that of its homologues, the most prominent being the highly distinctive conformation of its bound lipid.
Proteome-scale tissue mapping using mass spectrometry based on label-free and multiplexed workflows
Authors: Kwon Yumi , Woo Jongmin , Yu Fengchao , Williams Sarah M. , Markillie Lye Meng , Moore Ronald J. , Nakayasu Ernesto S. , Chen Jing , Campbell-Thompson Martha , Mathews Clayton E. , Nesvizhskii Alexey I. , Qian Wei-Jun , Zhu Ying
Published: March 2024

Multiplexed bimolecular profiling of tissue microenvironment, or spatial omics, can provide deep insight into cellular compositions and interactions in healthy and diseased tissues. Proteome-scale tissue mapping, which aims to unbiasedly visualize all the proteins in a whole tissue section or region of interest, has attracted significant interest because it holds great potential to directly reveal diagnostic biomarkers and therapeutic targets. While many approaches are available, however, proteome mapping still exhibits significant technical challenges in both protein coverage and analytical throughput. Since many of these existing challenges are associated with mass spectrometry-based protein identification and quantification, we performed a detailed benchmarking study of three protein quantification methods for spatial proteome mapping, including label-free, TMT-MS2, and TMT-MS3. Our study indicates label-free method provided the deepest coverages of ∼3500 proteins at a spatial resolution of 50 µm and the highest quantification dynamic range, while TMT-MS2 method holds great benefit in mapping throughput at >125 pixels per day. The evaluation also indicates both label-free and TMT-MS2 provide robust protein quantifications in identifying differentially abundant proteins and spatially co-variable clusters. In the study of pancreatic islet microenvironment, we demonstrated deep proteome mapping not only enables the identification of protein markers specific to different cell types, but more importantly, it also reveals unknown or hidden protein patterns by spatial co-expression analysis.
Periplasmic carbonic anhydrase CAH1 contributes to high inorganic carbon affinity inChlamydomonas reinhardtii
Authors: Shimamura Daisuke , Ikeuchi Tomoaki , Tsuji Yoshinori , Fukuzawa Hideya , Yamano Takashi
Published: March 2024

Carbonic anhydrase (CA), an enzyme conserved across species, is pivotal in the interconversion of inorganic carbon (Ci; CO2and HCO3−). Compared to the well-studied intracellular CA, the specific role of extracellular CA in photosynthetic organisms is still not well understood. In the green algaChlamydomonas reinhardtii, CAH1, located at the periplasmic space, is strongly induced under CO2-limiting conditions by the Myb transcription factor LCR1. While it has been observed that thelcr1mutant shows decreased Ci-affinity, the detailed mechanisms behind this phenomenon are yet to be elucidated. In this study, we aimed to unravel the LCR1-dependent genes essential for maintaining high Ci-affinity. To achieve this, we identified a total of 12 LCR1-dependent inducible genes under CO2-limiting conditions, focusing specifically on the most prominent ones -CAH1,LCI1,LCI6, andCre10.g426800. We then created mutants of these genes using the CRISPR-Cas9 system, all from the same parental strain, and compared their Ci-affinity. Contrary to earlier findings (Van and Spalding, 1999) that reported no reduction in Ci-affinity in thecah1mutant, our newly createdcah1-1 mutant exhibited a significant decrease in Ci-affinity under high HCO3−/CO2-ratio conditions. Additionally, when we treated wild-type cells with a CA inhibitor with low membrane permeability, a similar reduction in Ci-affinity was observed. Moreover, the addition of exogenous CA to thecah1mutant restored the decreased Ci-affinity. These results, highlighting the crucial function of the periplasmic CAH1 in maintaining high Ci-affinity inChlamydomonascells, provide new insights into the functions of periplasmic CA in algal carbon assimilation.

One-sentence summary

CAH1, a periplasmic carbonic anhydrase inChlamydomonas reinhardtii, plays a crucial role in maintaining a high affinity for inorganic carbon, particularly under CO2-limiting conditions.
Comprehensive analysis of CXXX sequence space reveals thatS. cerevisiaeGGTase-I mainly relies on a2X substrate determinants
Authors: Sarkar Anushka , Hildebrandt Emily R. , Patel Khushi V. , Mai Emily T. , Shah Sumil S. , Kim June H. , Schmidt Walter K.
Published: March 2024

Many proteins undergo a post-translational lipid attachment, which increases their hydrophobicity, thus strengthening their membrane association properties or aiding in protein interactions. Geranylgeranyltransferase-I (GGTase-I) is an enzyme involved in a three-step post-translational modification (PTM) pathway that attaches a 20-carbon lipid group called geranylgeranyl at the carboxy-terminal cysteine of proteins ending in a canonical CaaL motif (C - cysteine, a - aliphatic, L - often leucine, but can be phenylalanine, isoleucine, methionine, or valine). Genetic approaches involving two distinct reporters were employed in this study to assessS. cerevisiaeGGTase-I specificity, for which limited data exists, towards all 8000 CXXX combinations. Orthogonal biochemical analyses and structure-based alignments were also performed to better understand the features required for optimal target interaction. These approaches indicate that yeast GGTase-I best modifies the Cxa[L/F/I/M/V] sequence that resembles but is not an exact match for the canonical CaaL motif. We also observed that minor modification of non-canonical sequences is possible. A consistent feature associated with well-modified sequences was the presence of a non-polar a2residue and a hydrophobic terminal residue, which are features recognized by mammalian GGTase-I. These results thus support that mammalian and yeast GGTase-I exhibit considerable shared specificity.

Article Summary

This work investigates yeast GGTase-I specificity through genetics, high throughput sequencing, and two distinct reporter systems. This approach allows for comprehensive evaluation of all CXXX sequence space, which has not been possible with earlier approaches. We identified CXXX sequences supporting geranylgeranylation that differ from the historically defined CaaL sequence often cited in the literature as the GGTase-I target motif, and our results indicate that the last two amino acids of the target motif largely dictate GGTase-I specificity.
Contrasting patterns ofAsaiasp association withPlasmodium falciparumbetween field collectedAnopheles gambiaeandAnopheles coluzziifrom Cameroon
Authors: Maffo Claudine Grâce Tatsinkou , Sandeu Maurice Marcel , Tchoupo Micareme , Kamga Fleuriane Metissa Dondji , Mugenzi Leon M.J. , Njiokou Flobert , Hughes Grant L. , Wondji Charles S.
Published: March 2024

The presence of bacteria of the genusAsaiain mosquitoes makes them suitable candidates for malaria paratrangenic control. To better understand whether this bacterium could be used for malaria control, we investigated and quantifiedAsaiainfluence inAn.Lgambiae slpopulations naturally infected by the malaria parasitePlasmodium falciparum.AdultAnophelesmosquitoes were collected across two different eco-geographical localities in Cameroon, during the dry and wet seasons. DNA was extracted from the whole individual mosquitoes andAsaiawas quantified using real-time Q-PCR by amplification of 16S ribosomal RNA gene. We also detected and quantifiedPlasmodium falciparuminfection in same mosquitoes. The density ofAsaiawas quantified in 864 mosquitoes. This included 439An. gambiaecollected from Bankeng and 425An. coluzziicollected from Gounougou. The prevalence ofAsaiainAn. gambiaeandAn. coluzziiwas 88.3% and 80.9% respectively, withAn. gambiaewere more heavily infected byAsaiathanAn. coluzzii.There was also a significant difference between the infection densities ofAsaiaper season in the two localities. We also had a significant difference between the infection densities ofAsaiaaccording toPlasmodiuminfection status in the two localities. However, no correlation was observed between the amount ofAsaiaandP. falciparuminfection. This study provides evidence that naturally occurringAsaiainfection is not correlated toP. falciparumdevelopment withinAn. gambiaeandAn. coluzzii.Further studies as experimental infection and innate immune response are required to better investigate the correlation betweenAnophelesmosquitoes,AsaiaandPlasmodium.

Importance

Malaria control relies mainly on insecticide-based tools. However, the effectiveness of these tools is threatened by the widespread insecticide resistance in malaria vectors highlighting the need for alternative control approaches. The endosymbiontAsaiahas emerged as a promising candidate for paratransgenic control of malaria, but its biology and genetics still need to be further analyzed across Africa. Here, we investigated and quantifiedAsaiainfluence inAn.Lgambiae slpopulations naturally infected by the malaria parasitePlasmodium falciparum.DNA was extracted from the whole individual mosquitoes collected from two localities, and thenAsaiawas quantified using real-time Q-PCR by amplification of 16S ribosomal RNA gene. We also detected and quantifiedPlasmodium falciparuminfection in same mosquitoes and correlatedPlasmodiuminfection them with the presence ofAsaiainfection. This study provides evidence that naturally occurringAsaiainfection is not correlated toP. falciparumdevelopment withinAn. gambiaeandAn. coluzzii.
Pervasive mitochondrial tRNA gene loss in the clade B of haplosclerid sponges (Porifera, Demospongiae)
Authors: Lavrov Dennis V. , Turner Thomas L. , Vicente Jan
Published: March 2024

Abstract

Mitochondrial tRNA gene loss and cytosolic tRNA import to mitochondria are two common phenomena in mitochondrial biology, but their importance is often under-appreciated in animals. This is because most bilaterally symmetrical animals (Bilateria) encode a complete set of tRNAs needed for mitochondrial translation. By contrast, studies of mitochondrial genomes in non-bilaterian animals have shown a reduced tRNA gene content in several lineages, necessitating tRNA import. Interestingly, in most of these lineages tRNA gene content appears to be set early in the evolution of the group and conserved thereafter. Here we demonstrate that Clade B of Haplosclerid Sponges (CBHS) represent an exception to this pattern. We determined mt-genome sequences for eight species from this group and analyzed them with six that had been previously available. In addition, we determined mt-genome sequences for two species of haploslerid sponges outside the CBHS and used them with eight previously available sequences as outgroups. We found that tRNA gene content varied widely among CBHS species: from three in an undescribedHaliclonaspecies (Haliclona sp. TLT785) to 25 inXestospongia mutaandX. testudinaria. Furthermore, we found that all CBHS species outside the genusXestospongialackedatp9, while some also lackedatp8. Analysis of nuclear sequences fromNiphates digitalisrevealed that bothatp8andatp9had transferred to the nuclear genome, while the absence of mt-tRNA genes represented their genuine loss. Overall, CBHS can be a useful animal system to study mt-tRNA genes loss, mitochondrial import of cytosolic tRNA, and the impact of both of these processes on mitochondrial evolution.

Significance statement

It is generally believed that the gene content is stable in animal mitochondrial (mt) DNA. Indeed, mtDNA in most bilaterally symmetrical animals encompasses a conserved set of 37 genes coding for 13 proteins, two rRNAs and 22 tRNAs. By contrast, mtDNA in non-bilaterian animals shows more variation in mt gene content, in particular in the number of tRNA genes. However, most of this variation occurs between major non-bilaterian lineages. Here we demonstrate that a group of demosponges called Clade B of Haplosclerid Sponges (CBHS) represents a fascinating exception to this pattern, with species experiencing recurrent losses of up to 22 mt-tRNA genes. We argue that this group constitutes a promising system to investigate the effects of tRNA gene loss on evolution of mt-genomes as well as mitochondrial tRNA import machinery.
Multimessenger Constraints on Radiatively Decaying Axions from GW170817
Authors: Diamond M. , Fiorillo D. , Marques-Tavares G. , Tamborra I. , Vitagliano E.
Published: March 2024

The metastable hypermassive neutron star produced in the coalescence of two neutron stars can copiously produce axions that radiatively decay into O(100)  MeV photons. These photons can form a fireball with characteristic temperature smaller than 1 MeV. By relying on x-ray observations of GW170817/GRB 170817A with CALET CGBM, Konus-Wind, and Insight-HXMT/HE, we present new bounds on the axion-photon coupling for axion masses in the range 1–400 MeV. We exclude couplings down to 5×10−11  GeV−1, complementing and surpassing existing constraints. Our approach can be extended to any feebly interacting particle decaying into photons.

Published by the American Physical Society
2024
Chiral Meissner state in time-reversal invariant Weyl superconductors
Authors: Shyta Vira , van den Brink Jeroen , Nogueira Flavio S.
Published: March 2024

Weyl semimetals have nodes in their electronic structure at which electrons attain a definite chirality. Due to the chiral anomaly, the nonconservation of charges with given chirality, the axion term appears in their effective electromagnetic action. We determine how this affects the properties of time-reversal invariant Weyl superconductors (SCs) in the London regime. For type II SCs the axion coupling generates magnetic B fields transverse to vortices, which become unstable at a critical coupling so that a transition into type I SC ensues. In this regime an applied B field not only decays inside the SC within the London penetration depth, but the axion coupling generates an additional perpendicular field. Consequently, when penetrating into the bulk the B field starts to steadily rotate away from the applied field. At a critical coupling the screening of the magnetic field breaks down. The novel chiral superconducting state that emerges has a periodically divergent susceptibility that separates onsets of chiral Meissner regimes. The chiral anomaly thus leaves very crisp experimental signatures in structurally chiral Weyl SCs with an axion response.

Published by the American Physical Society
2024
Active learning approach to simulations of strongly correlated matter with the ghost Gutzwiller approximation
Authors: Frank Marius S. , Artiukhin Denis G. , Lee Tsung-Han , Yao Yongxin , Barros Kipton , Christiansen Ove , Lanatà Nicola
Published: March 2024

Quantum embedding (QE) methods such as the ghost Gutzwiller approximation (gGA) offer a powerful approach to simulating strongly correlated systems, but come with the computational bottleneck of computing the ground state of an auxiliary embedding Hamiltonian (EH) iteratively. In this work, we introduce an active learning (AL) framework integrated within the gGA to address this challenge. The methodology is applied to the single-band Hubbard model and results in a significant reduction in the number of instances where the EH must be solved. Through a principal component analysis (PCA), we find that the EH parameters form a low-dimensional structure that is largely independent of the geometric specifics of the systems, especially in the strongly correlated regime. Our AL strategy enables us to discover this low-dimensionality structure on the fly, while leveraging it for reducing the computational cost of gGA, laying the groundwork for more efficient simulations of complex strongly correlated materials.

Published by the American Physical Society
2024
Remote work’s impact on well-being: longitudinal analysis and the influence of gender, household size and childcare
Authors: Prati Gabriele
Published: March 2024

Purpose

The aim of the study was to investigate the relationship between remote work and subjective well-being and the potential moderating role of gender, household size and childcare.

Design/methodology/approach

The current research used data from the 2016 and 2020 editions of the Survey on Household Income and Wealth (SHIW) of the Bank of Italy. Italian workers were asked to report their subjective well-being and how many days per month they work remotely (at the time of the COVID-19 pandemic). Cross-sectional and longitudinal analyses were conducted on a sample of 1.103 and 184 participants, respectively.

Findings

After controlling for the effects of gender, age, education and perceived economic condition, ordered probit models revealed that the relationship between remote work and subjective well-being was nonsignificant. Moreover, gender, household size and childcare did not play a moderating role in the relationship between remote work and subjective well-being.

Practical implications

The findings of the current study suggest that an individualized approach is required to maximize the possible benefits of remote work.

Originality/value

The potential positive effects of remote work on subjective well-being might be overestimated.