bluuebunny/crossref_metadata_2025 huggingface dataset:
A process evaluation of integrated service delivery of self-collected HPV-based cervical cancer screening using RE-AIM in the ASPIRE Mayuge pragmatic randomized trial
Authors: Mithani Nadia , Gottschlich Anna , Payne Beth A. , Trawin Jessica , Albert Arianne , Jeronimo Jose , Mitchell-Foster Sheona , Namugosa Ruth , Naguti Priscilla , Rawat Angeli , Simelela Princess Nothemba , Singer Joel , Smith Laurie W. , van Niekerk Dirk , Orem Jackson , Nakisige Carolyn , Ogilvie Gina
Published: May 2023

Background

In many low-resourced settings, self-collected HPV-based cervical cancer screening (SCS) is being rolled out through task shifting to community health workers (CHWs). Process evaluations are needed to ensure SCS programs are effective and translate to community-based contexts.

Methods

The Advances in Screening and Prevention in Reproductive Cancers (ASPIRE) study in Mayuge, Uganda was a two-arm, pragmatic randomized trial comparing two SCS implementation strategies facilitated by CHWs: Door-to-door and Community health day recruitment. This adjunct study uses the RE-AIM evaluation framework to assess the Reach, Efficacy, Adoption, Implementation and Maintenance of each implementation strategy in a subpopulation using process data collected throughout the trial.

Results

Of the trial population (n=2019), 781 women participated in both the baseline and exit surveys (door-to-door: n=406; community health day: n=375) and are included in this analysis. Both implementation strategies demonstrated high Reach, Efficacy, Adoption, Implementation and Maintenance. Trial consent rate was high and 100% of consenting participants in both arms participated in SCS (Reach). Follow-up rates among HPV positive participants were also high in both arms (door-to-door: 84% and community health day: 74%) (Efficacy). The intervention employed 61 CHWs, 7 nurses, 3 health facilities and other local staff within the health system to implement the intervention (Adoption). The community health day arm received HPV screening results and visual inspection with acetic acid (VIA) quicker than the door-to-door arm, but reported higher dissatisfaction with wait times (Implementation). While women had knowledge of cervical cancer symptoms and prevention measures at six-months post-intervention, no one in either arm recalled that cervical cancer could be asymptomatic (Maintenance).

Conclusion

Both SCS implementation strategies performed well, demonstrating high Reach, Efficacy, Adoption, Implementation and Maintenance throughout participating communities. Implementing pragmatic approaches including task-shifting to CHWs can reduce health worker burden and improve screening access in low-resourced, community-based settings.
ChatGPT in Occupational Medicine: A Comparative Study with Human Experts
Authors: Padovan Martina , Cosci Bianca , Petillo Armando , Nerli Gianluca , Porciatti Francesco , Scarinci Sergio , Carlucci Francesco , Dell’Amico Letizia , Meliani Niccolo’ , Necciari Gabriele , Lucisano Vincenzo Carmelo , Marino Riccardo , Foddis Rudy , Palla Alessandro
Published: May 2023

Objectives

The objective of this study is to evaluate ChatGPT’s accuracy and reliability in answering complex medical questions related to occupational health and to explore the implications and limitations of AI in occupational health medicine while providing recommendations for future research in this area and informing decision-makers about AI impact in healthcare.

Methods

A group of physicians was enlisted to create a dataset of questions and answers on Italian occupational medicine legislation. They were divided into two teams, each assigned to a different subject area. ChatGPT was used to generate answers for each question with/without legislative context. The doctors evaluatedhumanand generated answers in blind, with both teams reviewing each other’s work.

Results

Occupational physicians perform better than ChatGPT in generating accurate questions on a 5-point likert score, while ChatGPT with access to legislative context is comparable to professional doctors in providing complete answers. Still, we found that users tend to prefer answers generated by humans, indicating that while ChatGPT is useful, users still value the opinions of occupational medicine professionals.

Conclusions

The study evaluated ChatGPT’s effectiveness in occupational medicine and identified crucial factors for its responsible use. It emphasizes ongoing dialogue and reflection for AI development in healthcare. ChatGPT provides 24/7 assistance to occupational physicians, increasing efficiency and reducing costs, monitoring workers’ health, and offering personalized service. It has the potential to transform occupational medicine and create safer work environments.
Natural Language Processing for the Ascertainment and Phenotyping of Left Ventricular Hypertrophy and Hypertrophic Cardiomyopathy on Echocardiogram Reports
Authors: Berman Adam N. , Ginder Curtis , Sporn Zachary A. , Tanguturi Varsha , Hidrue Michael K. , Borden Linnea R. , Zhao Yunong , Blankstein Ron , Turchin Alexander , Wasfy Jason H.
Published: May 2023

Objective

Extracting and accurately phenotyping electronic health documentation is critical for medical research and clinical care. While there are a variety of techniques to accomplish this task, natural language processing (NLP) has been developed for numerous domains to transform clinical documentation into data available for computational work. Accordingly, we sought to develop a highly accurate and open-source NLP module to ascertain and phenotype left ventricular hypertrophy (LVH) and hypertrophic cardiomyopathy (HCM) diagnoses on echocardiogram reports from a diverse hospital network.

Methods

700 echocardiogram reports from six hospitals were randomly selected from data repositories within the Mass General Brigham healthcare system and manually adjudicated by physicians for 10 subtypes of LVH and diagnoses of HCM. Using an open-source NLP system, the module was developed on 300 training set reports and validated on 400 reports. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated to assess the discriminative accuracy of the NLP module.

Results

The NLP demonstrated robust performance across the 10 LVH subtypes with overall sensitivity and specificity exceeding 96%. Additionally, the NLP module demonstrated excellent performance detecting HCM diagnoses, with sensitivity and specificity exceeding 93%.

Conclusion

We designed a highly accurate NLP module to determine the presence of LVH and HCM on echocardiogram reports. Our work demonstrates the feasibility of NLP to detect diagnoses on imaging reports, even when described in free-text. These modules have been placed in the public domain to advance research, trial recruitment, and population health management for individuals with LVH-associated conditions.
Prenatal Pb exposure is associated with reduced abundance of beneficial gut microbial cliques in late childhood: an investigation using Microbial Co-occurrence Analysis (MiCA)
Authors: Midya V , Lane JM , Gennings C , Torres-Olascoaga LA , Wright RO , Arora M , Téllez-Rojo MM , Eggers S
Published: May 2023

Background

Many analytical methods used in gut microbiome research focus on either single bacterial taxa or the whole microbiome, ignoring multi-bacteria relationships (microbial cliques). We present a novel analytical approach to identify multiple bacterial taxa within the gut microbiome of children at 9-11 years associated with prenatal Pb exposure.

Methods

Data came from a subset of participants (n=123) in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort. Pb concentrations were measured in maternal whole blood from the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the gut microbiome. Using a novel analytical approach, Microbial Co-occurrence Analysis (MiCA), we paired a machine-learning algorithm with randomization-based inference to first identify microbial cliques that were predictive of prenatal Pb exposure and then estimate the association between prenatal Pb exposure and microbial clique abundance.

Results

With second-trimester Pb exposure, we identified a 2-taxa microbial clique that includedBifidobacterium adolescentisandRuminococcus callidus, and a 3-taxa clique that addedPrevotella clara. Increasing second-trimester Pb exposure was associated with significantly increased odds of having the 2-taxa microbial clique below the 50thpercentile relative abundance (OR=1.03,95%CI[1.01-1.05]). In an analysis of Pb concentration at or above vs. below the United States and Mexico guidelines for child Pb exposure, odds of the 2-taxa clique in low abundance were 3.36(95%CI[1.32-8.51]) and 6.11(95%CI[1.87-19.93]), respectively. Trends were similar with the 3-taxa clique but not statistically significant.

Discussion

Using a novel combination of machine-learning and causal-inference, MiCA identified a significant association between second-trimester Pb exposure and reduced abundance of a probiotic microbial clique within the gut microbiome in late childhood. Pb exposure levels at the guidelines for child Pb poisoning in the United States, and Mexico are not sufficient to protect against the potential loss of probiotic benefits.

Graphical Abstract
The Role of Oestrogen in Female Skeletal Muscle Ageing: A Systematic Review
Authors: Critchlow Annabel J. , Hiam Danielle , Williams Ross , Scott David , Lamon Séverine
Published: May 2023

Ageing is associated with a loss of skeletal muscle mass and function that negatively impacts the independence and quality of life of older individuals. Females demonstrate a distinct pattern of muscle ageing compared to males, potentially due to menopause where endogenous sex hormone production declines. This systematic review aims to investigate the current knowledge about the role of oestrogen in female skeletal muscle ageing. A systematic search of MEDLINE complete, Global Health, Embase, PubMed, SPORTDiscus, and CINHAL was conducted. Studies were considered eligible if they compared a state of oestrogen deficiency (e.g. postmenopausal females) or supplementation (e.g. oestrogen replacement therapy) to normal oestrogen conditions (e.g. premenopausal females or no supplementation). Outcome variables of interest included measures of skeletal muscle mass, function, damage/repair, and energy metabolism. Quality assessment was completed with the relevant Johanna Briggs critical appraisal tool, and data were synthesised in a narrative manner. Thirty-two studies were included in the review. Compared to premenopausal females, postmenopausal females display reduced muscle mass and strength, but the effect of menopause on markers of muscle damage and expression of the genes involved in metabolic signalling pathways remains unclear. Some studies suggest a beneficial effect of oestrogen replacement therapy on muscle size and strength, but evidence is largely conflicting and inconclusive, potentially due to large variations in the reporting and status of exposure and outcomes. The findings from this review points toward a potential negative effect of oestrogen deficiency in ageing skeletal muscle, but further mechanistic evidence is needed to clarify its role.

Graphical abstract figure

The role of oestrogen in female skeletal muscle ageing. ↑ = significant increase, ↓ = significant decrease, ≠ = significantly different, ? = mixed evidence, p<0.05. ALM: appendicular lean mass; AMPK: adenosine monophosphate kinase; CSA: cross-sectional area; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Created withBioRender.com.
Optimizing the balance between heterologous acetate- and CO2-reduction pathways in anaerobic cultures ofSaccharomyces cerevisiaestrains engineered for low glycerol production
Authors: Aalst Aafke C.A. van , Geraats Ellen H. , Jansen Mickel L.A. , Mans Robert , Pronk Jack T.
Published: May 2023

In anaerobicSaccharomyces cerevisiaecultures, NADH-cofactor balancing by glycerol formation constrains ethanol yields. Introduction of an acetate-to-ethanol reduction pathway based on heterologous acetylating acetaldehyde dehydrogenase (A-ALD) can replace glycerol formation as ‘redox-sink’ and improve ethanol yields in acetate-containing media. Acetate concentrations in feedstock for first-generation bioethanol production are, however, insufficient to completely replace glycerol formation. An alternative glycerol-reduction strategy bypasses the oxidative reaction in glycolysis by introducing phosphoribulokinase (PRK) and ribulose-1,5-bisphosphate carboxylase (RuBisCO). For optimal performance in industrial settings, yeast strains should ideally first fully convert acetate and, subsequently, continue low-glycerol fermentation via the PRK-RuBisCO pathway. However, anaerobic batch cultures of a strain carrying both pathways showed inferior acetate reduction relative to a strain expressing only the A-ALD pathway. Complete A-ALD-mediated acetate reduction by a dual-pathway strain, grown anaerobically on 50 g L-1glucose and 5 mmol L-1acetate, was achieved upon reducing PRK abundance by a C-terminal extension of its amino-acid sequence. Yields of glycerol and ethanol on glucose were 55% lower and 6% higher, respectively, than those of a non-engineered reference strain. The negative impact of the PRK-RuBisCO pathway on acetate reduction was attributed to sensitivity of the reversible A-ALD reaction to intracellular acetaldehyde concentrations.
Whether core stability training has a positive therapeutic effect on LBP patients: a Meta-analysis
Authors: Li Zecheng , Liu Xuebin , Li Siya
Published: May 2023

Objective

The main goal of this study is to determine whether engaging in core stability exercises benefits LBP sufferers.

Background

As a common exercise therapy, core stability training has gradually become the main treatment for LBP patients to relieve pain. Although many similar researches have showed a significant impact of core stability training on LBP, many scholars still have the opposite experimental conclusion, that is, core stability training has no significant therapeutic effect on LBP patients.

Methods

Only randomized controlled could be included in this study, and we used the Web of Science, Cochrane Library, Embase, CNKI databases, China Science and Technology Journal Database and PubMed for article retrieval. Among them, non-LBP patients, non-core training, and articles with imperfect outcome indicators were not included.

Results

This analysis incorporated findings from 21 relevant studies in total. The results showed that, although that the overall effect was not significant, core stability training was helpful for LBP patients. The results of two secondary outcomes (generic health and specific function) showed that core stability training had no practical significance for the improvement of generic health and specific function of LBP patients. The specific results are as follows: pain (SMD = 2.74, 95%CI: 1.40-4.08, P < 0.0001), disability (SMD = 2.52, 95%CI: 1.69-3.36, P <0.00001), generic health (SMD = 1.08, 95%CI: 0.07-2.08, P = 0.04), specific function (SMD = 1.99, 95%CI: −0.04-4.02, P = 0.05).

Conclusions

We recommend that core stability training be used for short-term therapy, but not for long-term therapy.
No Relationship between Male Pubertal Timing and Depression – New Insights from Epidemiology and Mendelian Randomization
Authors: Hirtz Raphael , Grasemann Corinna , Hölling Heike , Albers Nicola , Hinney Anke , Hebebrand Johannes , Peters Triinu
Published: May 2023

Background

In males, the relationship between pubertal timing and depression is understudied and less consistent than in females, likely for reasons of unmeasured confounding. To clarify this relationship, a combined epidemiological and genetic approach was chosen to exploit the methodological advantages of both approaches.

Methods

Data from 2,026 males from a nationwide study (KiGGS) were used to investigate the non-/linear relationship between pubertal timing defined by the age at voice break and major depressive disorder (MDD), considering a multitude of potential confounders and their interactions with pubertal timing. This analysis was complemented by Mendelian Randomization (MR), which is robust to inferential problems inherent to epidemiological studies. We used 71 single nucleotide polymorphisms related to pubertal timing in males as instrumental variable to clarify its causal relationship with MDD based on data from 807,553 individuals (246,363 cases and 561,190 controls) by univariable and multivariable MR, including BMI as pleiotropic phenotype.

Results

Univariable MR indicated a causal effect of pubertal timing on MDD risk (inverse-variance weighted: OR=0.93, 95%-CI [0.87–0.99)], p=.03). However, this was not confirmed by multivariable MR (inverse-variance weighted: OR=0.95, 95%-CI [0.88–1.02)], p=.13), consistent with the epidemiological approach (OR=1.01, 95%-CI [0.81–1.26], p=.93). Instead, the multivariable MR study indicated a causal relationship of BMI with MDD by two of three methods.

Conclusions

Pubertal timing is not related to MDD risk in males. Considering the adverse health outcomes of higher BMI levels, our findings support the rationale for preventive measures to address obesity and its related risk factors.
Aging affects ciliated cells development in the human endometrial epithelium
Authors: Loid Marina , Obukhova Darina , Kask Keiu , Meltsov Alvin , Derks Kasper , Altmäe Signe , Saare Merli , Peters Maire , Minajeva Ave , Adler Priit , Krjutškov Kaarel , Esteki Masoud Zamani , Salumets Andres
Published: May 2023

The twenties are typically considered the prime reproductive years for women. However, in today’s modern world, many women are choosing to delay family planning, resulting in an increase of females in their forties seeking fertility treatment. Althoughin vitrofertilization (IVF) with donated oocytes and preimplantation genetic testing may help to address the impact of maternal age, the success rate for IVF treatment in this age group is still significantly lower. While endometrial changes, such as abnormal endometrial thickness, inflammatory background, and altered hormone response signaling, are associated with aging, little is known about the molecular features of endometrial aging and their impact on the ability to support embryo implantation. To better understand age-specific changes, we performed endometrial transcriptome profiling of young and advanced age females, undergoing hormonal replacement therapy (HRT) before frozen embryo transfer, followed by immunohistology analysis and single-cell-based deconvolution. Here, we identified 491 differentially expressed genes pointing to the effect of aging on decidualization, cell signaling, inflammation and endometrial receptivity. Our results indicate that p16INK4amay be involved in cellular senescence and the suppression of metabolic and inflammatory processes essential for endometrial preparation for embryo implantation. We have also shown that the proportion of ciliated cells along with ciliary processes is affected by endometrial aging. These findings have important implications for future strategies aimed at improving infertility treatment in women of advanced reproductive age.
Pandemic Lessons of Sustainability: Higher Covid-19 Mortality in Less Sustainable US States
Authors: Liu Lee
Published: May 2023

This paper intends to contribute to the current debate over what lessons the United States should take away from the Covid-19 pandemic. It focuses on the role that sustainability played in shaping different pandemic outcomes among the 50 states. By the end of 2021, Mississippi reported the highest standardized death rate from Covid-19 in the country, more than five times higher than Vermont, which reported the lowest standardized death rate. If Mississippi had the same rate as Vermont, approximately 83% of the lives lost (7,958 individuals) could have been saved. If all 50 states had the same rate as Vermont, approximately 583,296 individuals (76% of the total deceased) would have survived. The inter-state difference in excess death rates was even larger. It was 18.19% in Arizona, 8.5 times as high as in Hawaii. Political ideology is currently a popular possible explanation for discrepancies among states in pandemic outcomes, given that Republican states tended to have higher death rates compared to Democratic ones. Additionally, partisan politics have been criticized for hindering the US pandemic response, especially in the early stages of the pandemic. However, the current debate lacks an attention to sustainability. This study demonstrates that indicators of sustainability may serve as more significant predictors of the death rates among the US states than political affiliation. Using the percentage of votes for Trump per state in 2020 as a proxy variable, this study found that the correlation between political affiliation and the death rates was significant only when it was the lone parameter. Its effects were overshadowed when vaccination rates and eco-friendliness were included in the equation. Above all, when the Sustainable Development Goal (SDG) index was added to the regression, it became the only significant predictor of the death rates. This suggests that it was not “red” or “blue,” but rather “green” that was the most important factor in determining Covid-19 mortality. Pandemic lessons are lessons of sustainability.
The benefit of hypothermic targeted temperature management decreases when post-arrest care improves
Authors: Chen Wei-Ting , Tien Yu-Tzu , Huang Chien-Hua , Wang Chih-Hung , Chang Wei-Tien , Ong Hooi-Nee , Chen Wen-Jone , Tsai Min-Shan
Published: May 2023

Background

Several clinical trials and cohort studies in the past two decades have demonstrated inconsistent results regarding survival and neurologic recovery benefits for patients undergoing targeted temperature management (TTM) at 33℃ as compared to those undergoing TTM at 36℃ or normothermia. Whether the improved quality of post-arrest care over time contributes to diminishing benefit of TTM at 33℃ remains un-investigated.

Methods

There were 1,809 adult non-traumatic cardiac arrest survivors during 2011-2020. After excluding patients with pre-arrest poor conscious level defined as Glasgow-Pittsburgh Cerebral Performance Category (CPC) >2 (n=258), patients who regained clear consciousness after return of spontaneous circulation (ROSC) (n=300), patients with active bleeding or intracranial hemorrhage (n=48) and patients who underwent TTM of 36℃ due to unstable hemodynamic (n=11), a total of 1,192 eligible candidates for TTM of 33℃ were finally enrolled and classified into Period 1 (during 2011-2015, n = 449) and Period 2 (during 2016-2020, n = 693).

Results

Patients in Period 2 received more diagnostics procedures and specific therapies than those in Period 1. The proportion of patients with good neurological recovery at hospital discharge in Period 2 is significantly higher than that in Period 1 (21.4% vs.14.0%, adjusted odds ratio [aOR] 1.60, 95% confidence interval [CI] 1.14-2.26). TTM was beneficial for the outcomes in both Period 1 and 2, with patients in Period 1 having higher chances of survival and good neurological outcome than those in Period 2 (survival: aOR 5.66, 95% CI 3.49-9.18 vs. aOR 2.91, 95% CI 1.98-4.28; good neurological recovery: aOR 3.92, 95% CI 2.12-7.25 vs. aOR 2.19, 95% CI 1.43-3.34). Among patients with low-risk and medium-risk severity of illness, TTM benefited survival and neurological outcomes, regardless of time period. But the chance of beneficial outcomes decreased consistently from Period 1 to Period 2.

Conclusion

Among cardiac arrest survivors, improvement in the quality of post-cardiac arrest care over time is associated with better neurological recovery. TTM remains beneficial for survival and neurological outcomes following cardiac arrest, regardless of the time period. However, the benefit of TTM may diminish when post-cardiac arrest care improves.
Compositionally aware estimation of cross-correlations for microbiome data
Authors: Jensen Ib Thorsgaard , Janss Luc , Radutoiu Simona , Waagepetersen Rasmus
Published: May 2023

In the field of microbiome studies, it is of interest to infer correlations between abundances of different microbes (here referred to as operational taxonomic units, OTUs). Several methods taking the compositional nature of the sequencing data into account exist. However, these methods cannot infer correlations between OTU abundances and other variables. In this paper we introduce the methods SparCEV (Sparse Correlations with External Variables) and SparXCC (Sparse Cross-Correlations between Compositional data) for quantifying correlations between OTU abundances and either continuous phenotypic variables or components of other compositional datasets, such as transcriptomic data. We compare these new methods to empirical Pearson cross-correlations after applying naive transformations of the data (log and log-TSS). Additionally, we test the centered log ratio transformation (CLR) and the variance stabilising transformation (VST). We find that CLR and VST outperform naive transformations, except when the correlation matrix is dense. For large numbers of OTUs, SparCEV and SparXCC perform similarly to CLR and VST. SparCEV outperforms all other tested methods when the number of OTUs is small (less than 100). SparXCC outperforms all tested methods when at least one of the compositional datasets has few variables (less than 50), and more so when both datasets have few variables.

Author summary

Sequencing data of the microbiome posses a unique and challenging structure that renders many standard statistical tools invalid. Features such as compositionality and sparsity complicates statistical analysis, and as a result, specialized tools are needed. Practitioners have long been interested in the construction of correlation networks within the microbiome, and several methods for accomplishing this exist. However, less attention has been paid to the estimation of cross-correlations between microbial abundances and other variables (such as gene expression data or environmental and phenotypic variables). Here, we introduce novel approaches, SparCEV and SparXCC, for inferring such cross-correlations, and compare these to transformation-based approaches, namely log, log-TSS, CLR and VST. In some cases, SparCEV and SparXCC yield superior results, while in other cases, a simpler transformation-based approach suffices. The methods are used to study cross-correlations between bacterial abundances in the skin microbiome and the severity of atopic dermatitis, as well as cross-correlations between fungal and bacterial OTUs in the root microbiome of the legumeLotus japonicus.
BioModelsML: Building a FAIR and reproducible collection of machine learning models in life sciences and medicine for easy reuse
Authors: Tiwari Divyang Deep , Hoffmann Nils , Didi Kieran , Deshpande Sumukh , Ghosh Sucheta , Nguyen Tung V. N. , Raman Karthik , Hermjakob Henning , Sheriff Rahuman
Published: May 2023

Machine learning (ML) models are widely used in life sciences and medicine; however, they are scattered across various platforms and there are several challenges that hinder their accessibility, reproducibility and reuse. In this manuscript, we present the formalisation and pilot implementation of community protocol to enable FAIReR (Findable, Accessible, Interoperable, Reusable, and Reproducible) sharing of ML models. The protocol consists of eight steps, including sharing model training code, dataset information, reproduced figures, model evaluation metrics, trained models, Dockerfiles, model metadata, and FAIR dissemination. Applying these measures we aim to build and share a comprehensive public collection of FAIR ML models in the BioModels repository through incentivized community curation. In a pilot implementation, we curated diverse ML models to demonstrate the feasibility of our approach and we discussed the current challenges. Building a FAIReR collection of ML models will directly enhance the reproducibility and reusability of ML models, minimising the effort needed to reimplement models, maximising the impact on the application and significantly accelerating the advancement in the field of life science and medicine.
Saxitoxin potentiates Zika virus-induced cell death in human neurons but not in neural progenitors and astrocytes
Authors: Souza Leticia R. Q. , Pedrosa Carolina da S. G. , Puig-Pijuan Teresa , dos Santos Camila da Silva , Vitória Gabriela , Higa Luiza M. , Tanuri Amilcar , Guimarães Marília Zaluar P. , Rehen Stevens Kastrup
Published: May 2023

The Zika virus (ZIKV) outbreak in Brazil between 2015 and 2016 was associated with an increased prevalence of severe congenital malformations, including microcephaly. Notably, the distribution of microcephaly cases was not uniform across the country, with a disproportionately higher incidence recorded in the Northeast region (NE). Our previous work demonstrated that saxitoxin (STX), a toxin ubiquitously present in the drinking water reservoirs of the NE, exacerbated the damaging effects of ZIKV on the developing brain. In the present study, we hypothesized that STX’s impact might vary among different neural cell types. Our experimental observations suggest that exposure to STX potentiates the neurotoxic effect of Zika Virus (ZIKV) on human neuronal cells. However, while ZIKV infection demonstrated severe impacts on astrocytes and neural stem cells (NSCs), the addition of STX did not exacerbate these effects. We observed that neurons subjected to STX exposure were more prone to apoptosis and displayed a higher number of ZIKV-infected cells. These findings suggest that STX exacerbates the harmful effects of ZIKV on neurons, thereby providing a plausible explanation for the heightened severity of ZIKV-induced congenital malformations observed in Brazil’s NE. This study underscores the importance of understanding the interactive effects of environmental toxins and infectious pathogens on neural development, with potential implications for public health policies and interventions.
Disease associated human TCR characterization by deep-learning framework TCR-DeepInsight
Authors: Xue Ziwei , Wu Lize , Tian Ruonan , Liu Zuozhu , Bai Yadan , Sun Di , Guo Yixin , Chen Pengwei , Zhao Yu , He Bing , Wang Lie , Yao Jianhua , Lu Linrong , Liu Wanlu
Published: May 2023

T cell function is defined by both T cell receptors (TCR) and T cell gene expression (GEX). Although single-cell technology enables the simultaneous capture of TCR and GEX information, the lack of a reference atlas and computational tools hinders our ability to uncover the fundamental TCR usage rules and to efficiently characterize disease-associated TCRs (dTCR). Here, through the collection of million-scale single-cell GEX-TCR reference atlas comprising 20 diverse disease conditions, we revealed the intrinsic features of TCR-MHC (Major Histocompatibility Complex) restriction in CD4/CD8 lineages. We observed the higher coherence for TCRα/β chains in memory T cells, and detected widely-existing public TCRα/β pairs across individuals. Building upon the reference atlas, we introduced TCR- DeepInsight, a deep-learning framework featuring a disease specificity scoring system that enables the characterization of dTCR clusters with similar GEX-TCR. Our study provides a valuable tool for researchers to analyze single-cell GEX-TCR data and identify dTCRs comprehensively and robustly.
Rational screening for cooperativity in small-molecule inducers of protein–protein associations
Authors: Liu Shuang , Tong Bingqi , Mason Jeremy W. , Ostrem Jonathan M. , Tutter Antonin , Hua Bruce K. , Tang Sunny A. , Bonazzi Simone , Briner Karin , Berst Frédéric , Zécri Frédéric J. , Schreiber Stuart L.
Published: May 2023

The hallmark of a molecular glue is its ability to induce cooperative protein–protein interactions, leading to the formation of a ternary complex, despite weaker binding towards one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, a second class of inducers of protein–protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues. Here, we propose a binding-based screen of DNA-barcoded compounds on a target protein in the presence and absence of a presenter protein, using the “presenter ratio”, the ratio of ternary enrichment to binary enrichment, as a predictive measure of cooperativity. Through this approach, we identified a range of cooperative, noncooperative, and uncooperative compounds in a single DNA-encoded library screen with bromodomain (BRD)9 and the VHL–elongin C–elongin B (VCB) complex. Our most cooperative hit compound,13-7, exhibits micromolar binding affinity to BRD9 but nanomolar affinity for the ternary complex with BRD9 and VCB, with cooperativity comparable to classical molecular glues. This approach may enable the discovery of molecular glues for pre-selected proteins and thus facilitate the transition to a new paradigm of molecular therapeutics.
p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor suppressor function mediated by p190A RhoGAP
Authors: Ouyang Hanyue , Li Wangji , Hansen Steen H.
Published: May 2023

ARHGAP35, which encodes p190A RhoGAP (p190A), is a major cancer gene. p190A is a tumor suppressor that activates the Hippo pathway. p190A was originally cloned via direct binding to p120 RasGAP (RasGAP). Here, we determine that a novel interaction of p190A with the tight junction-associated protein ZO-2 is dependent on RasGAP. We establish that both RasGAP and ZO-2 are necessary for p190A to activate LATS kinases, elicit mesenchymal-to-epithelial transition, promote contact inhibition of cell proliferation and suppress tumorigenesis. Moreover, RasGAP and ZO-2 are required for transcriptional modulation by p190A. Finally, we demonstrate that lowARHGAP35expression is associated with shorter survival in patients with high, but not low, transcript levels ofTJP2encoding ZO-2. Hence, we define a tumor suppressor interactome of p190A that includes ZO-2, an established constituent of the Hippo pathway, and RasGAP, which despite strong association with Ras signaling, is essential for p190A to activate LATS kinases.
Multiple mechanisms contribute to isolation-by-environment in the redheaded pine sawfly,Neodiprion lecontei
Authors: Bagley Robin K. , Hurst Melanie N. , Frederick Jeremy , Wolfe Jordan , Terbot John W. , Frost Christopher J. , Linnen Catherine R.
Published: May 2023

Isolation by environment (IBE) is a population genomic pattern that arises when ecological barriers reduce gene flow between populations. Although current evidence suggests IBE is common in nature, few studies have evaluated the underlying mechanisms that generate IBE patterns. In this study, we evaluate five proposed mechanisms of IBE (natural selection against immigrants, sexual selection against immigrants, selection against hybrids, biased dispersal, environment-based phenological differences) that may give rise to host-associated differentiation within a sympatric population of the redheaded pine sawfly,Neodiprion lecontei, a species for which IBE has previously been detected. We first characterize the three pine species used byN. leconteiat the site, finding morphological and chemical differences among the hosts that could generate divergent selection on sawfly host-use traits. Next, using morphometrics and ddRAD sequencing, we detect modest phenotypic and genetic differentiation among sawflies originating from different pines that is consistent with recent,in situdivergence. Finally, via a series of laboratory assays – including assessments of larval performance on different hosts, adult mate and host preferences, hybrid fitness, and adult eclosion timing – we find evidence that multiple mechanisms contribute to IBE inN. lecontei. Overall, our results suggest IBE can emerge quickly, possibly due to multiple mechanisms acting in concert to reduce migration between different environments.
One size does not fit all: Family specific differences in seasonal patterns of abundance and behavior in butterfly communities
Authors: Hirzel Grace E. , Anderson Ashlyn E. , Westerman Erica L.
Published: May 2023

Animal communities can undergo seasonal shifts in assemblage, responding to changes in their environment. Animal behavior can also shift due to seasonal environmental variation, with the potential to shape ecosystems. However, it is unclear if similar environmental factors and time scales affect both abundance and behavior. We examined how butterfly abundance and behavior change seasonally in temperate prairies and a butterfly garden, and if the factors driving variation differ between taxonomic families. We conducted monthly abundance surveys year-round and biweekly abundance and behavior surveys during the summer and fall, in 2017-2021 and 2018-2020 respectively. We also determined how ambient light, temperature, precipitation, and time of year interact to affect butterfly abundance and behavior. We found increased temperature and light levels correlate with increases in general butterfly abundance. Unlike the greater community, Lycaenidae abundance decreased as weekly precipitation increased, and Papilionidae abundance did not respond to changes in environmental factors. Only Nymphalidae changed behavior in response to environmental factors, increasing thermoregulatory behaviors as temperature and light levels decreased. These results indicate that lineages may differ in their sensitivity to environmental factors, which could result in disproportionate changes in their abundances in response to future climate change and anthropogenic-driven disturbance.
Conflict between short-and long-term experiences affects visual perception by modulating sensory or motor response system: evidence from Bayesian inference models
Authors: Wang Jing-Yi , Gong Xiu-Mei , Sun Qi
Published: May 2023

Huge studies have explored the effects of short-and long-term experiences on visual perception, respectively. However, no study investigated whether and how the conflict between the two types of experiences affected our visual perception. To address this question, we adopted a task of estimating simulated self-motion directions (i.e., headings) from optic flow, in which a long-term experience – straight-forward motion is more often than lateral motion – plays an important role. The long-term experience is learned daily or encoded in our brains from birth. The heading directions in the experiment were selected from three different distributions, generating different conflicts between short-and long-term experiences. The results showed that both estimation errors and sizes of serial dependence of previously seen headings on current heading estimates varied when the experience conflict changed. Finally, we developed two Bayesian inference models, assuming that the experience conflict affected visual perception by influencing the sensory representation’s likelihood distribution or motor decision process. We found that both models captured participants’ estimation errors and serial dependences well in three distributions. In conclusion, the current study revealed the effects of the conflict between short-and long-term experiences on visual perception and preliminarily uncovered that Bayesian inference theory could explain the effects. Moreover, the study implied that the experience conflict affected visual perception by modulating our sensory or motor response systems.
Mixed-Feedback Architectures for Precise Event Timing Through Stochastic Accumulation of Biomolecules
Authors: Rezaee Sayeh , Nieto César , Singh Abhyudai
Published: May 2023

The timing of biochemical events is often determined by the accumulation of a protein or chemical species to a critical threshold level. In a stochastic model, we define event timing as the first-passage time for the level to cross the threshold from zero or random initial conditions. This first-passage time can be modulated by implementing feedback in synthesis, that is, making the production rate an arbitrary function of the current species level. We aim to find the optimal feedback strategy that reduces the timing noise around a given mean first-passage time. Previous results have shown that while a no-feedback strategy (i.e., an independent constant production rate) is optimal in the absence of degradation and zero-molecules initial condition, a negative feedback is optimal when the process starts at random initial conditions. We show that when the species can be degraded and the synthesis rates are set to depend linearly on the number of molecules, a positive feedback strategy (the production rate increases with the level of the molecule) minimizes timing noise. However, if no constraints on the feedback are imposed, the optimal strategy involves a mixed feedback approach, which consists of an initial positive feedback followed by a sharp negative feedback (the production rate decreases with the level) near the threshold. Finally, we quantify the fundamental limits of timing noise reduction with and without feedback control when time-keeping species are subject to degradation.
EEG resting state alpha dynamics predict individual proneness to auditory hallucinations
Authors: Honcamp H. , Duggirala S.X. , Rodino Climent J. , Astudillo A. , Trujillo-Barreto N.J. , Schwartze M. , Linden D.E.J. , van Amelsvoort T.A.M.J. , El-Deredy W. , Kotz S.A.
Published: May 2023

Introduction

Auditory verbal hallucinations (AVH) are a transdiagnostic phenomenon but also occur in the general population. The disposition to experience AVH is considered a continuous expression from non-clinical to clinical hallucination proneness (HP). Currently, little is known about the neurophysiology of the non-clinical HP part of the continuum. AVH might result from a heightened sensitivity to sensory inputs and a decreased ability to differentiate between externally and internally generated input. Resting state (RS) alpha band activity is associated with perceptual sensitivity, attentional shifts, and cognitive control. Accordingly, spontaneous alpha fluctuations might present as a HP correlate. To investigate the time-varying dynamics of alpha band activity, we deployed a novel method for brain state allocation.

Methods

We recorded RS electroencephalography (EEG) data from 33 individuals with varying levels of HP but without clinically relevant hallucinations and used a Hidden Semi-Markov Model (HsMM) to identify five recurrent alpha states with unique temporal dynamics and topographies. The states’ mean duration and occupancy were analyzed as a function of HP. The sources of each state were reconstructed to identify the most active brain areas and their correspondence with known resting state networks.

Results

Occupancy and mean duration of a state corresponding to sensorimotor, auditory, and default-mode network (DMN) areas significantly predicted auditory and auditory-verbal HP, but not general HP. The temporal dynamics of all other states did not relate to HP.

Conclusion

Alpha brain state sources align with prior results on the role of the alpha in the DMN. The temporal dynamics of alpha might reflect individual differences for attentional biases to internally generated sensory events and altered auditory perceptual sensitivity. Thus, changes in the temporal brain state dynamics of RS alpha oscillations could present as a neural marker of increased vulnerability to auditory hallucinatory experiences.
Morpho-physiobiochemical dissection reveals insight into salt-induced differential responses in genetically modified Solanum melongena L. (Bt Brinjal) varieties using an indigenous hydroponic system
Authors: Hasan Md. Nahid , Hasan Md. Nazmul , Siddiqui Md. Nurealam , Arifuzzaman Md. , Hossain Mohammad Anwar , Prodhan Shamsul H. , Ashrafuzzaman Md.
Published: May 2023

Salinity is a major abiotic constraint of crop production in many countries, including Bangladesh, where a significant amount of cultivable areas are diversely affected by rising salt concentrations. Therefore, it is of paramount importance to figure out the possible solutions to cope with this abiotic stress. So, the development of tolerant genotypes of various crop species can be the best alternative to enhance crop production as well as to improve the livelihoods of poor marginal farmers. With this in mind, the impact of different NaCl levels (50 mM, 100 mM, and 150 mM) on four different Bt Brinjal (Bacillus thuringiensis) genotypes (BARI Bt Begun-1, BARI Bt Begun-2, BARI Bt Begun-3, and BARI Bt Begun-4) was evaluated using morpho-physicochemical analyses at growth, harvesting, and postharvest stages by establishing a new indigenous cost-effective hydroponic system. Our results show that excess salt (> 100 mM) has a detrimental effect on plant growth and development and most of the traits measured across different growth stages. Based on the different measured traits, BARI Bt Begun-1 and BARI Bt Begun-2 varieties outperformed in terms of better morpho-physiological, biochemical, photosynthetic, and antioxidant capacity under salt stress when compared to BARI Bt Begun-3 and BARI Bt Begun-4. Therefore, we conclude that BARI Bt Begun-1 and BARI Bt Begun-2 are moderately tolerant varieties, while BARI Bt Begun-3 and Begun-4 were susceptible varieties to salinity stress. The identified salt-responsive contrasting varieties can serve as valuable genetic materials in comparative genomics for breeding salt-tolerant Brinjal varieties and the newly established hydroponic system could be utilized in translational research programs.
Temporal genomics help in deciphering neutral and adaptive patterns in the contemporary evolution of kelp populations
Authors: Reynes Lauric , Fouqueau Louise , Aurelle Didier , Mauger Stéphane , Destombe Christophe , Valero Myriam
Published: May 2023

The long-term persistence of species in the face of climate change can be evaluated by examining the interplay between selection and genetic drift in the contemporary evolution of populations. In this study, we focused on spatial and temporal genetic variation in four populations of the cold-water kelpLaminaria digitatausing thousands of SNPs (ddRAD-seq). These populations were sampled from the center to the south margin in the North Atlantic at two different time points, spanning at least two generations. By conducting genome scans for local adaptation from a single time point, we successfully identified candidate loci that exhibited clinal variation, closely aligned with the latitudinal changes in temperature. This finding suggests that temperature may drive the adaptive response of kelp populations, although other factors, such as the species’ demographic history should be considered. Furthermore, we provided compelling evidence of positive selection through the examination of allele frequency changes over time, offering additional insights into the impact of genetic drift. Specifically, we detected candidate loci exhibiting temporal differentiation that surpassed the levels typically attributed to genetic drift at the south margin, confirmed through simulations. This finding was in sharp contrast with the lack of detection of outlier loci based on temporal differentiation in a population from the North Sea, exhibiting low levels of genetic diversity, that further decreased over time. These contrasting evolutionary scenarios among populations can be primarily attributed to the differential prevalence of selection relative to genetic drift. In conclusion, our study highlights the potential of temporal genomics to gain deeper insights into the contemporary evolution of marine foundation species in response to rapid environmental changes.