bluuebunny/crossref_metadata_2025 huggingface dataset:
“I Have to Do It in Secrecy”: Provider Perspectives on HIV Service Delivery and Quality of Care for Key Populations in Zambia
Authors: Mulenga Drosin M. , Rosen Joseph G. , Banda Lunda , Musheke Maurice , Mbizvo Michael T. , Raymond Henry F. , Keating Ryan , Witola Harold , Phiri Lyson , Geibel Scott , Tun Waimar , Pilgrim Nanlesta
Published: November 2023

Key populations (KPs) experience suboptimal outcomes along the HIV care and prevention continua, but there is limited study of the challenges service providers encounter delivering HIV services to KPs, particularly in settings like Zambia, where provision of these services remains legally ambiguous. Seventy-seven providers completed in-depth interviews exploring constraints to HIV service delivery for KPs and recommendations for improving access and care quality. Thematic analysis identified salient challenges and opportunities to service delivery and quality of care for KPs, spanning interpersonal, institutional, and structural domains. Limited provider training in KP-specific needs was perceived to influence KP disclosure patterns in clinical settings, impeding service quality. The criminalization of KP sexual and drug use behaviors, coupled with perceived institutional and legal ambiguities to providing HIV services to KPs, cultivated unwelcoming service delivery environments for KPs. Findings elucidate opportunities for improving HIV service delivery/quality, from decentralized care to expanded legal protections for KPs and service providers.
Cerebrospinal fluid cytology-assisted diagnosis of T-lymphoblastic lymphoma: A case report
Authors: Wang Hao-Chuan , Li Yanan , Li Dao-Jing , Li Hongfang
Published: November 2023

Background:

Lymphoblastic lymphoma is a rare form of highly aggressive non-Hodgkin lymphoma. The most common clinical manifestations are superficial lymphadenopathy and mediastinal mass. In a few cases, invasion of the central nervous system is the first manifestation. It is also difficult to diagnose patients using the central nervous system as the first manifestation. Here, we report the case of a 26-year-old man with central nervous system disease as the primary manifestation; we used cerebrospinal fluid cytology (CSF-C) for early diagnosis and shared the importance of CSF-C for early diagnosis of T-cell lymphoblastic lymphoma.

Case presentation:

The patient was admitted to the hospital because of “right eyelid closure weakness with headache for 1 month and exacerbation with sluggish response for 1 week.” Physical examination revealed a bilateral Kernig sign (+) and Lasgue sign (+). The Mini-Mental State Examination and Montreal Cognitive Assessment scores were 20 (out of 30). When there was no abnormality in the imaging examination, the patient was misdiagnosed with meningoencephalitis and received anti-inflammatory treatment because the initial symptom was a clinical manifestation of the central nervous system, and the imaging and blood tests showed no definite abnormality. Cerebrospinal fluid has been studied and second-generation sequencing detection, such as after CSF-C tip to abnormal lymphocytes, to open the breakthrough of the diagnosis of lymphoma.

Conclusions:

In the cases with central nervous system injury as the first manifestation, CSF-C was combined with immunohistochemistry and cerebrospinal fluid flow cytometry to provide a clear and effective method and evidence for the early diagnosis of T-cell lymphoblastic lymphoma.
Diurnal Variation in Accommodation, Binocular Vergence, and Pupil Size
Authors: Redondo Beatríz , Serramito María , Vera Jesús , Alguacil-Espejo Marina , Rubio-Martínez Mercedes , Molina Rubén , Jiménez Raimundo
Published: November 2023

SIGNIFICANCE

Our results show significant diurnal variations in accommodative function and the magnitude of the phoria. Therefore, when comparing visual measures in clinical or laboratory settings, performing the visual examination at the same time of day (±1 hour) is encouraged.

PURPOSE

The aim of this study was to evaluate the accommodation, binocular vergence, and pupil behavior on three different times during the day.

METHODS

Twenty collegiate students (22.8 ± 2.1 years) participated in this study. Participants visited the laboratory on three different days at 2-hourly intervals (morning, 9:00 to 11:00 am; afternoon, 2:00 to 4:00 pm; evening, 7:00 to 9:00 pm). The binocular vergence and accommodative function were measured using clinical optometric procedures, and the accommodative response and pupil function were evaluated in binocular conditions using the WAM-5500 autorefractometer.

RESULTS

The accommodative amplitude for the right and left eyes showed statistically significant differences for the time interval (P = .001 and P = .02, respectively), revealing higher accommodative amplitude in the morning and afternoon in comparison with the evening. Participants were more esophoric when assessed in the morning in comparison with the evening at far and near (P = .02 and P = .01, respectively) and when assessed in the afternoon in comparison with the evening at far distance (P = .02). The magnitude of accommodative response was higher in the morning, and it decreased throughout the day at 500 (P < .001), 40 (P = .05), and 20 cm (P < .001). No statistically significant differences were obtained for any other variable.

CONCLUSIONS

This study shows small diurnal variations in some accommodative and binocular vergence parameters, but no effects were observed for the pupil response. These outcomes are of special relevance for eye care specialists when performing repeated accommodative or binocular vergence measures. However, the diurnal variations were modest and may not influence a routine orthoptic examination.
Demographics and Clinical Characteristics Assessment of Severe Acute Toxic Ingestions in Pediatric Patients
Authors: Sheng Chu-Qiao , Wang Wenzhen , Xue Yang , Li Yu-Mei
Published: November 2023

Objective

This study aimed to describe the demographic and clinical characteristics of severe acute toxic ingestions in children in Jilin Province and provide a reference for seeking effective measures to prevent poisoning accidents.

Methods

The clinical data of patients diagnosed with acute toxic ingestions and who presented with severe life-threatening symptoms or organ dysfunction at the Pediatric Intensive Care Unit of the First Hospital of Jilin University were retrospectively analyzed. Patients with incomplete clinical medical records, unclear toxic substance, and loss to follow-up within 6 months of discharge are excluded. We sorted out these children's demographic characteristics, types of poisoning, clinical manifestations, treatment process, and follow-up, etc.

Results

This study enrolled 141 cases with no significant differences in sex and region; adolescents accounted for 44.68%. The most common poisons were pesticides and insecticides for rural areas and internal medication for urban areas. With poisoning details as a grouping variable, there was no statistical difference between sex groupings (χ2 = 6.018, P = 0.198) and no difference between region groups (χ2 = 3.775, P = 0.289). However, there were statistical differences between age groups (χ2 = 28.22, P = 0.001). In this research, patients younger than 6 years are mainly unintentionally poisoned, whereas the suicide rate of the urban group (P < 0.05), adolescents (P < 0.01), and girls (P < 0.01) has increased significantly; moreover, the suicide group is more likely to take more overdose medication or pesticides and insecticides (P < 0.01). In addition, there was a statistical difference between suicide and length of intensive care unit stay (r = 0.268, P < 0.01). A total of 90.78% of the patients were successfully discharged after comprehensive treatment. Children aged younger than 12 years had good psychological and intellectual development during the follow-up period, whereas adolescents diagnosed with depression often required long-term psychological and medication intervention.

Conclusions

This study identified poisoning details in different ages, regions, and sex of acute severe oral poisoning in children from Jilin Province. The results presentation of different prevention priorities should vary among children of different ages and emphasize adolescent suicide being a reality in Jilin Province. There is an urgent need for further culture-specific research in this area.
First-Person Point-of-View Instructional Video on Lumbar Puncture Procedure
Authors: Hatt Danielle , Zimmerman Elise , Chang Elizabeth , Vane Jackson , Hollenbach Kathryn A. , Shah Ashish
Published: November 2023

Objectives

Tutorial videos filmed from a first-person point of view (FP-POV) are generally well received. Pediatric residents are expected to be competent in performing the lumbar puncture (LP). The educational effectiveness of a FP-POV in lumbar puncture procedure training for resident physicians has yet to be evaluated. We compared a FPPOV LP video with a standard in-person demonstration of the LP.

Methods

We designed an assigned cohort study to compare a FP-POV procedural instructional video of a simulated pediatric LP to the standard in-person procedure demonstration.

After the intervention, residents completed an LP observed by one of two blinded reviewers who assessed the procedure using a modified, published assessment tool.

Participants completed preintervention and postintervention surveys to rate self-confidence and usefulness of the FP-POV educational method. The data was analyzed using a Wilcoxon Rank sum test. z Scores were calculated on the raw assessment scores.

Results

Eighteen first year pediatric residents participated, nine in each group. The median modified assessment tool score was 17 in the FP-POV group (min, 14; max, 17; IQR:, 1.5) and 14 in the standard demonstration group (min, 6; max, 17; IQR, 4.5), with the higher score being more successful. There was a statistical difference between the assessment scores between the 2 groups (z score = 2.18, P = 0.04). Postintervention survey data demonstrated relative satisfaction with the FPPOV educational method.

Conclusions

This study supports the educational effectiveness of a FP-POV procedure tutorial.

Future studies with a larger sample size are needed.
Preparation, structure characterization, and in vitro bioactivity of yam starch-polyphenol complex
Authors: Zhang Weimei , Zhang Xueqian , Tian Hongyue , Wen Chunxiu , Liu Lingdi , Tian Wei , Gao Wenyuan , Li Xia
Published: November 2023

Background

Chinese yam (Dioscorea opposita Thunb.), with medicinal and edible properties, holds a significant position in both traditional medicine and food in China. It is rich in resistant starch (RS), which imparts various beneficial effects, including anticonstipation, regulation of blood lipids, and prevention of gastric ulcers. However, the resistance of native yam starch to digestion diminishes during cooking, necessitating suitable modifications.

Objective

In this article, yam starch was complexed with five different polyphenols to create RS5. The goal was to explore how these diverse polyphenols influence the physicochemical characteristics and bioactivities associated with yam RS.

Method

Yam starch-polyphenol complexes, involving five different polyphenols, namely, magnolol (MAG), ferulic acid (FA), resveratrol (RES), apple polyphenols (APs), and green tea polyphenols (GTPs), were prepared. The investigation encompassed the assessment of physicochemical properties, structural traits, in vitro cholate binding capacity, and in vitro antidigestive effects of these complexes.

Results

The results highlight the pronounced affinity of MAG for yam starch, followed by FA. Fourier transform infrared spectroscopy reveals that starch-polyphenol binding primarily involves noncovalent interactions. X-ray diffraction analysis discloses V-type crystal structures in YS-MAG, YS-APs, and YS-GTPs complexes. The incorporation of polyphenols reduces the thermal stability of starch while enhancing its in vitro cholate binding capacity, restraining starch digestion, and elevating RS content. Notably, YS-FA exhibits an impressive RS content of up to 54.15%. In addition, YS-MAG and YS-FA significantly enhance the production of short-chain fatty acids. These findings deepen our comprehension of the interplay between yam starch and polyphenols, offering valuable insights for the development of novel food products with enhanced health benefits.
Eggshell colour differences in a classic example of coevolved eggshell mimicry
Authors: Villa Juliana , Wisocki Phillip A. , Dela Cruz Jacob E. , Hanley Daniel
Published: November 2023

Avian brood parasitism is a model system for understanding coevolutionary arms races, and the great reed warbler (
Acrocephalus arundinaceus
, hereafter ‘warbler’) and its parasite the common cuckoo (
Cuculus canorus
, hereafter ‘cuckoo’) are prime examples of this coevolutionary struggle. Here, warblers select for egg colour mimicry by rejecting poorly matched cuckoo eggs. Contrary to long-held assumptions, recent work showed that warblers tend to reject lighter and browner eggs but tended to accept darker and bluer eggs rather than basing rejection decisions solely on perceived colour differences (i.e. the degree of mimicry). This counterintuitive, colour-biased rejection behaviour would select for bluer and darker cuckoo eggs, but would only be adaptive if cuckoos were consistently lighter and browner than warbler eggs. Therefore, we tested whether warbler eggs were consistently bluer and darker than cuckoo eggs. To do so, we re-analysed eggshell reflectance spectra of warblers and the cuckoos that parasitized them in the Czech Republic. As expected, we found that warbler eggs were significantly bluer and darker than the cuckoo eggs at the population level. Thus, we demonstrate imperfect mimicry in a long-coevolved cuckoo host-race and provide insights for exploring the coevolutionary interactions among hosts and their brood parasites.
Identification of potential riboswitch elements inHomo SapiensmRNA 5’UTR sequences using Positive-Unlabeled machine learning
Authors: Raymond William S. , DeRoo Jacob , Munsky Brian
Published: November 2023

Riboswitches are a class of noncoding RNA structures that interact with target ligands to cause a conformational change that can then execute some regulatory purpose within the cell. Riboswitches are ubiquitous and well characterized in bacteria and prokaryotes, with additional examples also being found in fungi, plants, and yeast. To date, no purely RNA-small molecule riboswitch has been discovered inHomo Sapiens. Several analogous riboswitch-like mechanisms have been described within theH. Sapienstranslatome within the past decade, prompting the question: Is there aH. Sapiensriboswitch dependent on only small molecule ligands? In this work, we set out to train positive unlabeled machine learning classifiers on known riboswitch sequences and apply the classifiers toH. SapiensmRNA 5’UTR sequences found in the 5’UTR database, UTRdb, in the hope of identifying a set of mRNAs to investigate for riboswitch functionality. 67,683 riboswitch sequences were obtained from RNAcentral and sorted for ligand type and used as positive examples and 48,031 5’UTR sequences were used as unlabeled, unknown examples. Positive examples were sorted by ligand, and 20 positive-unlabeled classifiers were trained on sequence and secondary structure features while withholding one or two ligand classes. Cross validation was then performed on the withheld ligand sets to obtain a validation accuracy range of 75%-99%. The joint sets of 5’UTRs identified as potential riboswitches by the 20 classifiers were then analyzed. 15333 sequences were identified as a riboswitch by one or more classifier(s) and 436 of theH. Sapiens5’UTRs were labeled as harboring potential riboswitch elements by all 20 classifiers. These 436 sequences were mapped back to the most similar riboswitches within the positive data and examined. An online database of identified and ranked 5’UTRs, their features, and their most similar matches to known riboswitches, is provided to guide future experimental efforts to identifyH. Sapiensriboswitches.

Author summary

Riboswitches are an important regulatory element mostly found in bacteria that have not been described inHomo Sapiens. However, if human riboswitches exist and if they can be found, they could have vast implications on human disease. We apply positive-unlabeled machine learning to on known riboswitch sequences to searchH. Sapiens5’UTR sequences for potential riboswitches. We analyze our ensemble predictions for likelyH. Sapiens5’UTR riboswitches using GO analysis to determine their potential functional roles, and we rank and display our predicted sequences next to the most similar known riboswitches. We expect these analyses to be helpful to the scientific community in planning future experiments for laboratory discovery and validation.

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Graphical Abstract
Unveiling the Genetic Tapestry: Rare Disease Genomics of Spinal Muscular Atrophy and Phenylketonuria Proteins
Authors: Nawn Debaleena , Hassan Sk. Sarif , Redwan Elrashdy M. , Bhattacharya Tanishta , Basu Pallab , Lundstrom Kenneth , Uversky Vladimir N.
Published: November 2023

Rare diseases, defined by their low prevalence, present significant challenges, including delayed detection, expensive treatments, and limited research. This study delves into the genetic basis of two noteworthy rare diseases in Saudi Arabia: Phenylketonuria (PKU) and Spinal Muscular Atrophy (SMA). PKU, resulting from mutations in the phenylalanine hydroxylase (PAH) gene, exhibits geographical variability and impacts intellectual abilities. SMA, characterized by motor neuron loss, is linked to mutations in the survival of motor neuron 1 (SMN1) gene. Recognizing the importance of unveiling signature genomics in rare diseases, we conducted a quantitative study on PAH and SMN1 proteins of multiple organisms by employing various quantitative techniques to assess genetic variations. The derived signature-genomics contributes to a deeper understanding of these critical genes, paving the way for enhanced diagnostics and treatments for disorders associated with PAH and SMN1.
Visualizing tomato spotted wilt virus protein localization: Cross-kingdom comparisons of protein-protein interactions
Authors: Martin K.M. , Chen Y. , Mayfield M.A. , Montero-Astúa M. , Whitfield A.E.
Published: November 2023

Tomato spotted wilt virus (TSWV) is an orthotospovirus that infects both plant and insect cells. Understanding the protein localization and interactions in these cells is crucial for unraveling the infection cycle and host-virus interactions. In this study, we investigated the localization of TSWV proteins in cells of plants and insects. Furthermore, we identified the protein-protein interactions among TSWV proteins using bimolecular fluorescence complementation (BiFC) and yeast two-hybrid (MbY2H) assays. Our results revealed distinct localization patterns for TSWV proteins in plant and insect cells. The nucleocapsid protein (N), essential for genome encapsidation, was found in the cytoplasm of both cell types. The non-structural movement protein (NSm) localized to the cytoplasm in insect cells, different from the localization in plant cells’ plasmodesmata. The non-structural silencing protein (NSs) exhibited peripheral localization in plant cells and cytoplasmic localization in insect cells. Additionally, glycoproteins GNand GCshowed cytoplasmic localization in both cell types. Moreover, protein-protein interaction analyses revealed self-interactions of NSm, N, GN, GC, and NSs. These interactions are crucial for viral genome encapsidation, virion assembly, and RNA silencing suppression. We also identified interactions between different TSWV proteins, indicating their roles and host interactions. Comparisons with other orthotospovirus interaction maps highlighted the uniqueness of TSWV protein-protein interaction networks. Despite sharing genome organization and putative gene annotations, each orthotospovirus exhibited distinct interaction maps. Overall, this research expands our knowledge of TSWV infection and elaborates on the intricate relationships between viral proteins, cellular dynamics, and host responses. These findings lay the groundwork for future studies on the molecular mechanisms of TSWV infection and may facilitate the development of effective control strategies.
Discovering Novel Prognostic Biomarkers of Hepatocellular Carcinoma using eXplainable Artificial Intelligence
Authors: Gutierrez-Chakraborty Elizabeth , Chakraborty Debaditya , Das Debodipta , Bai Yidong
Published: November 2023

Hepatocellular carcinoma (HCC) remains a global health challenge with high mortality rates, largely due to late diagnosis and suboptimal efficacy of current therapies. With the imperative need for more reliable, non-invasive diagnostic tools and novel therapeutic strategies, this study focuses on the discovery and application of novel genetic biomarkers for HCC using explainable artificial intelligence (XAI). Despite advances in HCC research, current biomarkers like Alpha-fetoprotein (AFP) exhibit limitations in sensitivity and specificity, necessitating a shift towards more precise and reliable markers. This paper presents an innovative XAI framework to identify and validate key genetic biomarkers for HCC prognosis. Our methodology involved analyzing clinical and gene expression data to identify potential biomarkers with prognostic significance. The study utilized robust AI models validated against extensive gene expression datasets, demonstrating not only the predictive accuracy but also the clinical relevance of the identified biomarkers through explainable metrics. The findings highlight the importance of biomarkers such as TOP3B, SSBP3, and COX7A2L, which were consistently influential across multiple models, suggesting their role in improving the predictive accuracy for HCC prognosis beyond AFP. Notably, the study also emphasizes the relevance of these biomarkers to the Hispanic population, aligning with the larger goal of demographic-specific research. The application of XAI in biomarker discovery represents a significant advancement in HCC research, offering a more nuanced understanding of the disease and laying the groundwork for improved diagnostic and therapeutic strategies.
A Bayesian Approach to Correcting the Attenuation Bias of Regression Using Polygenic Risk Score
Authors: Zhou Geyu , Qie Xinyue , Zhao Hongyu
Published: November 2023

Polygenic risk score (PRS) has become increasingly popular for predicting the value of complex traits. In many settings, PRS is used as a covariate in regression analysis to study the association between different phenotypes. However, measurement error in PRS causes attenuation bias in the estimation of regression coefficients. In this paper, we employ a Bayesian approach to accounting for the measurement error of PRS and correcting the attenuation bias in linear and logistic regression. Through simulation, we show that our approach is able to obtain approximately unbiased estimation of coefficients and credible intervals with correct coverage probability. We also empirically compare our Bayesian measurement error model to the conventional regression model by analyzing real traits in the UK Biobank. The results demonstrate the effectiveness of our approach as it significantly reduces the error in coefficient estimates.
Understanding epistatic networks in the B1 β-lactamases through coevolutionary statistical modeling and deep mutational scanning
Authors: Chen JZ , Bisardi M , Lee D , Cotogno S , Zamponi F , Weigt M , Tokuriki N
Published: November 2023

Over the course of evolution, proteins families undergo sequence diversification via mutation accumulation, with extant homologs often sharing less than 25% sequence identity. The resulting diversity presents a complex view of sequence-structure-function relationships, as epistasis is prevalent, and deleterious mutations in one protein can be tolerated in homologous sequences through networks of intramolecular, compensatory interactions. Understanding these epistatic networks is crucial for understanding and predicting protein function, yet comprehensive analysis of such networks across protein families is limited. In this study, we combine computational and experimental approaches to examine epistatic networks in the class B1 metallo-β-lactamases, a diverse family of antibiotic-degrading enzymes. Using Direct Coupling Analysis, we assess global coevolutionary signatures across the B1 family. We also obtain detailed experimental data from deep mutational scanning on two distant B1 homologs, NDM-1 and VIM-2. There is good agreement between the two approaches, revealing both family-wide and homolog specific patterns that can be associated with 3D structure. However, specific interactions remain complex, and strong epistasis in evolutionarily entrenched residues are not easily compensated for by changes in nearby interactions.
Virus-induced gene silencing (VIGS) as a tool for functional genetic analysis in passion fruit plants
Authors: Wang Xiaoqing , Shen Wentao , Cui Hongguang , Dai Zhaoji
Published: November 2023

Passion fruit (Passiflora edulis) is grown perennially in sub-tropical and tropical areas. Its fruits contain multiple vitamins and antioxidants, and thus are consumed increasingly in drinks and foods. However, the functions and regulations of genes that are engaged in the biosynthesis of the health-promoting compounds in passion fruits remain largely unknown. Its whole genome sequence has just been published recently. Virus-induced gene silencing (VIGS) is a reverse genetics tool for analyzing gene function. Here, we engineered telosma mosaic virus (TelMV), a potyvirus infecting passion fruit, into a VIGS vector by inserting the Gateway-compatible recombination sites. The newly constructed TelMV-VIGS virus successfully expressed foreign protein and induced systemic infection in bothNicotiana benthamianaandP. edulisplants. Intriguingly, TelMV-VIGS vector containing different fragments of green fluorescent protein (GFP) gene induced systemic gene silencing on the GFP-transgenicN. benthamianaplants (16c). When thephytoene desaturase(PDS) gene, an endogenous gene in passion fruit, was engineered into the vector, it triggered the silencing ofPePDS, as evidenced by the reduced mRNA levels and photobleached phenotype. We reported the first development of VIGS vector in passion fruit, as the first step in our endeavor of discovering horticulturally important genes for improving passion fruit production and quality.
Association between late-life air pollution exposure and medial temporal lobe atrophy in older women
Authors: Wang Xinhui , Salminen Lauren E. , Petkus Andrew J. , Driscoll Ira , Millstein Joshua , Beavers Daniel P. , Espeland Mark A. , Erus Guray , Braskie Meredith N. , Thompson Paul M. , Gatz Margaret , Chui Helena C. , Resnick Susan M , Kaufman Joel D. , Rapp Stephen R. , Shumaker Sally , Brown Mark , Younan Diana , Chen Jiu-Chiuan
Published: November 2023

Background

Ambient air pollution exposures increase risk for Alzheimer’s disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results.

Method

To determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Women’s Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mageat MRI-1=77.3±3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics.

Results

On average, MTL volume decreased by 0.53±1.00cm3over 5 years. For each interquartile increase of PM2.5(3.26µg/m3) and NO2(6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3(95%CI=[-0.43,-0.21]) and 0.12cm3(95%CI=[-0.22,-0.01]), respectively. The exposure effects did not differ byAPOEε4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5exposure. Greater PHG atrophy was associated with higher PM2.5(b=-0.24, 95%CI=[-0.29,-0.19]) and NO2exposures (b=-0.09, 95%CI=[-0.14,-0.04]). Higher exposure to PM2.5but not NO2was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy.

Conclusion

In summary, higher late-life PM2.5and NO2exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.

Highlights

First longitudinal study on air pollution and medial temporal lobe (MTL) volume.

Late-life PM2.5and NO2associated with MTL atrophy over time in older women.

Heterogeneous adverse effects were observed across different subregions of the MTL.

Results not differ byAPOEgenotype, age, education, or cardiovascular risk factors.

Adverse effects remained at low-level exposure compliant with regulatory standards.
Neuronal-specific methylome and hydroxymethylome analysis reveal replicated and novel loci associated with alcohol use disorder
Authors: Andrade-Brito Diego E. , Núñez-Ríos Diana L. , Martínez-Magaña José Jaime , Nagamatsu Sheila T. , Rompala Gregory , Zillich Lea , Witt Stephanie H. , Clark Shaunna L. , Latig Maria C. ,   Traumatic Stress Brain Research Group,   PGC SUD Epigenetics Working Group, Montalvo-Ortiz Janitza L.
Published: November 2023

1

Alcohol use disorder (AUD) is a complex condition associated with adverse health consequences that affect millions of individuals worldwide. Epigenetic modifications, including DNA methylation (5mC), have been associated with AUD and other alcohol-related traits. Epigenome-wide association studies (EWAS) have identified differentially methylated genes associated with AUD in human peripheral and brain tissue. More recently, epigenetic studies of AUD have also evaluated DNA hydroxymethylation (5hmC) in the human brain. However, most of the epigenetic work in postmortem brain tissue has examined bulk tissue. In this study, we investigated neuronal-specific 5mC and 5hmC alterations at CpG sites associated with AUD in the human orbitofrontal cortex (OFC). Neuronal nuclei from the OFC were evaluated in 34 human postmortem brain samples (10 AUD, 24 non-AUD). Reduced representation oxidative bisulfite sequencing was used to assess 5mC and 5hmC at the genome-wide level. Differential 5mC and 5hmC were evaluated using the methylKit R package and significance was set at false discovery rate <0.05 and differential methylation >2. Functional enrichment analyses were performed and replication was evaluated replication in an independent dataset that assessed 5mC and 5hmC of AUD in bulk cortical tissue. We identified 417 5mC and 363 5hmC genome-wide significant differential CpG sites associated with AUD, with 59% in gene promoters. We also identified genes previously implicated in alcohol consumption, such asSYK,CHRM2,DNMT3A, andGATA4, for 5mC andGATA4, andGAD1,GATA4,DLX1for 5hmC. Replication was observed for 28 CpG sites from a previous AUD 5mC and 5hmC study, includingFOXP1. Lastly, GWAS enrichment analysis showed an association with AUD for differential 5mC genes. This study reveals neuronal-specific methylome and hydroxymethylome dysregulation associated with AUD. We replicated previous findings and identified novel associations with AUD for both 5mC and 5hmC marks within the OFC. Our findings provide new insights into the epigenomic dysregulation of AUD in the human brain.
Hepatitis E in Kathmandu Valley: Insights from a Representative Longitudinal Serosurvey
Authors: Katuwal Nishan , Thapa Melina , Shrestha Sony , Vaidya Krista , Bogoch Isaac I , Andrews Jason , Shrestha Rajeev , Tamrakar Dipesh , Aiemjoy Kristen
Published: November 2023

Hepatitis-E virus (HEV), an etiologic agent of acute inflammatory liver disease, is a significant cause of morbidity and mortality in South Asia. HEV is considered endemic in Nepal; but data on population-level infection transmission is sparse. We conducted a representative longitudinal serologic study between February 2019 and April 2021 in urban and peri-urban areas of central Nepal to characterize community-level HEV transmission. Individuals were followed up to four times, during which capillary blood samples were collected on dried blood spots and tested for anti-HEV immunoglobulin-G antibodies. Analyzing 2513 dried blood samples from 923 participants aged 0-25 years, we found a seroprevalence of 4.8% and a seroincidence rate of 10.9 per 1000 person-years. Notably, young adults, including women of childbearing age, faced the highest incidence of infection. Geospatial analysis identified potential HEV clusters in Kavre and Kathmandu districts, emphasizing the need for targeted interventions. Water source played a crucial role in HEV transmission, with individuals consuming surface water facing the highest risk of seroconversion. Our findings underscore the endemic nature of HEV in Nepal, emphasizing the importance of safe water practices and potential vaccination strategies for high-risk groups.
The Development, Optimization, and Validation of Four Different Machine Learning Algorithms to Identify Ventilator Dyssynchrony
Authors: Sottile Peter D , Smith Bradford , Moss Marc , Albers David J
Published: November 2023

Objective

Invasive mechanical ventilation can worsen lung injury. Ventilator dyssynchrony (VD) may propagate ventilator-induced lung injury (VILI) and is challenging to detect and systematically monitor because each patient takes approximately 25,000 breaths a day yet some types of VD are rare, accounting for less than 1% of all breaths. Therefore, we sought to develop and validate accurate machine learning (ML) algorithms to detect multiple types of VD by leveraging esophageal pressure waveform data to quantify patient effort with airway pressure, flow, and volume data generated during mechanical ventilation, building a computational pipeline to facilitate the study of VD.

Materials and Methods

We collected ventilator waveform and esophageal pressure data from 30 patients admitted to the ICU. Esophageal pressure allows the measurement of transpulmonary pressure and patient effort. Waveform data were cleaned, features considered essential to VD detection were calculated, and a set of 10,000 breaths were manually labeled. Four ML algorithms were trained to classify each type of VD: logistic regression, support vector classification, random forest, and XGBoost.

Results

We trained ML models to detect different families and seven types of VD with high sensitivity (>90% and >80%, respectively). Three types of VD remained difficult for ML to classify because of their rarity and lack of sample size. XGBoost classified breaths with increased specificity compared to other ML algorithms.

Discussion

We developed ML models to detect multiple types of VD accurately. The ability to accurately detect multiple VD types addresses one of the significant limitations in understanding the role of VD in affecting patient outcomes.

Conclusion

ML models identify multiple types of VD by utilizing esophageal pressure data and airway pressure, flow, and volume waveforms. The development of such computational pipelines will facilitate the identification of VD in a scalable fashion, allowing for the systematic study of VD and its impact on patient outcomes.
Age and type of task-based impact of mental fatigue on balance: Systematic review and meta-analysis
Authors: Salihu Abubakar Tijjani , Hill Keith D. , Jaberzadeh Shapour
Published: November 2023

The role of cognition in balance control suggests that mental fatigue may negatively affect balance. However, cognitive involvement in balance control varies with the type or difficulty of the balance task and age. Steady-state balance tasks, such as quiet standing, are well learned tasks executed automatically through reflex activities controlled by the brainstem and spinal cord. In contrast, novel, and challenging balance tasks, such as proactively controlling balance while walking over rugged terrain or reacting to unexpected external perturbations, may require cognitive processing. Furthermore, individuals with pre-existing balance impairments due to aging or pathology may rely on cognitive processes to control balance in most circumstances. This systematic review and meta-analysis investigated the effect of mental fatigue on different types of balance control tasks in young and older adults. A literature search was conducted in seven electronic databases and 12 studies met eligibility criteria. The results indicated that mental fatigue had a negative impact on both proactive (under increased cognitive load) and reactive balance in young adults. In older adults, mental fatigue affected steady-state and proactive balance. Therefore, mentally fatigued older individuals may be at increased risk of a loss of balance during steady-state balance task compared to their younger counterparts.
Urban-use pesticides in stormwater ponds and their accumulation in biofilms
Authors: Izma Gab , Raby Melanie , Prosser Ryan , Rooney Rebecca
Published: November 2023

Stormwater ponds frequently receive urban runoff, increasing the likelihood of pesticide contamination. Biofilms growing in surface waters of these ponds are known to accumulate a range of aquatic contaminants, paradoxically providing both water purification services and potentially posing a threat to urban wildlife. Thus, sampling biofilms in stormwater ponds may be a critical and biologically relevant tool for characterizing pesticide contamination and toxicity in urban environments. Here, we aimed to investigate pesticide occurrences at 21 stormwater ponds in Brampton, ON, one of Canada’s fastest growing municipalities, and quantify their accumulation in biofilm. Over nine weeks, we collected time-integrated composite water and biofilm samples for analysis of ∼500 current-use and legacy pesticides. Thirty-two pesticide compounds were detected across both matrices, with 2,4-D, MCPA, MCPP, azoxystrobin, bentazon, triclopyr, and diuron having near-ubiquitous occurrences. Several compounds not typically monitored in pesticide suites (e.g., melamine and nicotine) were also detected, but only in biofilms. Overall, 56% of analytes detected in biofilms were not found in water samples, indicating traditional pesticide monitoring practices fail to capture all exposure routes, as even when pesticides are below detection levels in water, organisms may still be exposed via dietary pathways. Calculated bioconcentration factors ranged from 4.2 – 1275 and were not predicted by standard pesticide physicochemical properties. Monitoring biofilms provides a sensitive and comprehensive supplement to water sampling for pesticide quantification in urban areas, and identifying pesticide occurrences in stormwater could improve source-tracking efforts in the future. Further research is needed to understand the mechanisms driving pesticide accumulation, to investigate toxicity risks associated with pesticide-contaminated biofilm, and to evaluate whether pesticide accumulation in stormwater pond biofilms represents a route through which contaminants are mobilized into the surrounding terrestrial and downstream aquatic environments.
Visual to default network pathways: A double dissociation between semantic and spatial cognition
Authors: Gonzalez Alam Tirso RJ , Krieger-Redwood Katya , Varga Dominika , Gao Zhiyao , Horner Aidan , Hartley Tom , Thiebaut de Schotten Michel , Sliwinska Magdalena W , Pitcher David , Margulies Daniel S. , Smallwood Jonathan , Jefferies Elizabeth
Published: November 2023

Processing pathways between sensory and default mode network (DMN) regions support recognition, navigation, and memory but their organisation is not well understood. We show that functional subdivisions of visual cortex and DMN sit at opposing ends of parallel streams of information processing that support visually-mediated semantic and spatial cognition, providing convergent evidence from univariate and multivariate task responses, intrinsic functional and structural connectivity. Participants learned virtual environments consisting of buildings populated with objects, drawn from either a single semantic category or multiple categories. Later, they made semantic and spatial context decisions about these objects and buildings during functional magnetic resonance imaging. A lateral ventral occipital to frontotemporal DMN pathway was primarily engaged by semantic judgements, while a medial visual to medial temporal DMN pathway supported spatial context judgements. These pathways had distinctive locations in functional connectivity space: the semantic pathway was both further from unimodal systems and more balanced between visual and auditory-motor regions compared with the spatial pathway. When semantic and spatial context information could be integrated (in buildings containing objects from a single category), regions at the intersection of these pathways responded, suggesting that parallel processing streams interact at multiple levels of the cortical hierarchy to produce coherent memory-guided cognition.
Bi-parental graph strategy to represent and analyze hybrid plant genomes
Authors: Kong Qianqian , Jiang Yi , Wang Zhiheng , Wang Zijie , Liu Yuting , Gan Yuanxian , Liu Han , Gao Xiang , Yang Xuerong , Song Xinyuan , Liu Hongjun , Shi Junpeng
Published: November 2023

Hybrid plants are universally existed in wild and often exhibit greater performance of complex traits compared with their parents and other selfing plants. This phenomenon, known as heterosis, has been extensively applied in plant breeding for decades. However, the process of decoding hybrid plant genomes has seriously lagged due to the challenges in their genome assembling and the lack of proper methods to further represent and analyze them. Here we report the assembly and analysis of two hybrids: an intraspecific hybrid between two maize inbred lines and an interspecific hybrid between maize and its wild relative teosinte, based on the combination of PacBio High Fidelity (HiFi) sequencing and chromatin conformation capture sequencing data. The haplotypic assemblies are well-phased at chromosomal scale, successfully resolving the complex loci with extensive parental structural variations (SVs). By integrating into a bi-parental genome graph, the haplotypic assemblies can facilitate downstream short-reads based SV calling and allele-specific gene expression analysis, demonstrating outstanding advantages over one single linear genome. Our work provides an entire workflow which hopefully can promote the deciphering of the large numbers of hybrid plant genomes, especially those whose parents are unknown or unavailable and help to understand genome evolution and heterosis.
DomainFit: Identification of Protein Domains in cryo-EM maps at Intermediate Resolution using AlphaFold2-predicted Models
Authors: Gao Jerry , Tong Max , Lee Chinkyu , Gaertig Jacek , Legal Thibault , Bui Khanh Huy
Published: November 2023

Cryo-electron microscopy (cryo-EM) has revolutionized our understanding of macromolecular complexes, enabling high-resolution structure determination. With the paradigm shift toin situstructural biology recently driven by the ground-breaking development of cryo-focused ion beam milling and cryo-electron tomography, there are an increasing number of structures at sub-nanometer resolution of complexes solved directly within their cellular environment. These cellular complexes often contain unidentified proteins, related to different cellular states or processes. Identifying proteins at resolutions lower than 4 Å remains challenging because the side chains cannot be visualized reliably. Here, we present DomainFit, a program for automated domain-level protein identification from cryo-EM maps at resolutions lower than 4 Å. By fitting domains from artificial intelligence-predicted models such as AlphaFold2-predicted models into cryo-EM maps, the program performs statistical analyses and attempts to identify the proteins forming the density. Using DomainFit, we identified two microtubule inner proteins, one of them, a CCDC81 domain-containing protein, is exclusively localized in the proximal region of the doublet microtubule from the ciliateTetrahymena thermophila. The flexibility and capability of DomainFit makes it a valuable tool for analyzingin situstructures.
A simple methods for obtaining a multivalent protein with a variable number of binding sites and estimating its binding parameters
Authors: Mikhaylina Alisa , Lekontseva Natalia , Khairetdinova Albina , Ilyina Nelly , Balobanov Vitalii
Published: November 2023

The study of natural and the design of artificial multivalent proteins is a promising field of molecular biology. Working with such proteins is much more difficult than with their monovalent analogues. In this paper, we show how using a ring of heptameric Sm-like protein as a scaffold, it is possible to create a multivalent protein with a different number of binding sites. This is an urgent task for the study of multivalent and multicenter protein-protein interactions. The method of analysis used in the work allows us to evaluate the stoichiometry and the dissociation constant of complexes of artificial chaperone with a non-native protein. It is shown that for reliable binding of non-native αLA, its interaction with several apical domains of GroEL is necessary. At the same time, the dissociation constant of such a complex does not significantly change with an increase in the number of binding domains in the oligomer. Up to 4 αLA molecules can be attached to the complete heptameric ring of apical domains. The proposed methods have a good cost-to-result ratio and can be applied to the study and design of other new proteins.
Examining chromatin heterogeneity through PacBio long-read sequencing of M.EcoGII methylated genomes: an m6A detection efficiency and calling bias correcting pipeline
Authors: Dennis Allison F. , Xu Zhuwei , Clark David J.
Published: November 2023

Recent studies have combined DNA methyltransferase footprinting of genomic DNA in nuclei with long-read sequencing, resulting in detailed chromatin maps for multi-kilobase stretches of genomic DNA from one cell. Theoretically, nucleosome footprints and nucleosome-depleted regions can be identified using M.EcoGII, which methylates adenines in any sequence context, providing a high-resolution map of accessible regions in each DNA molecule. Here we report PacBio long-read sequence data for budding yeast nuclei treated with M.EcoGII and a bioinformatic pipeline which corrects for three key challenges undermining this promising method. First, detection of m6A in individual DNA molecules by the PacBio software is inefficient, resulting in false footprints predicted by random gaps of seemingly unmethylated adenines. Second, there is a strong bias against m6A base calling as AT content increases. Third, occasional methylation occurs within nucleosomes, breaking up their footprints. After correcting for these issues, our pipeline calculates a correlation coefficient-based score indicating the extent of chromatin heterogeneity within the cell population for every gene. Although the population average is consistent with that derived using other techniques, we observe a wide range of heterogeneity in nucleosome positions at the single-molecule level, probably reflecting cellular chromatin dynamics.