bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Pathway-specific Polygenic Risk Scores for Alzheimer’s Disease (AD) on Rate of Change in Cognitive Function and AD-related Biomarkers among Asymptomatic Individuals
Authors: Xu Yuexuan , Vasiljevic Eva , Deming Yuetiva K. , Jonaitis Erin M. , Koscik Rebecca L. , Van Hulle Carol A. , Lu Qiongshi , Carboni Margherita , Kollmorgen Gwendlyn , Wild Norbert , Carlsson Cynthia M. , Johnson Sterling C. , Zetterberg Henrik , Blennow Kaj , Engelman Corinne D.
Published: February 2023

Background

Genetic scores for late-onset Alzheimer’s disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan.

Objective

In this study, we leveraged 10 years of longitudinal data from initially cognitively unimpaired individuals in the Wisconsin Registry for Alzheimer’s Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways.

Methods

PRS and p-PRSs with and without apolipoprotein E (APOE) were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared toAPOEalone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and global/domain-specific cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers for beta-amyloid 42 (Aβ42), Aβ42/40 ratio, total tau, and phosphorylated tau in a subset. Replication analyses were performed in an independent sample.

Results

We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of p-PRSs/PRS on rate of change in cognition, beta-amyloid, and tau outcomes are dependent on age and appear earlier in the lifespan whenAPOEis included in these risk scores compared to whenAPOEis excluded.

Conclusion

In addition toAPOE, the p-PRSs can predict age-dependent changes in beta-amyloid, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating beta-amyloid and tau, long before the onset of clinical symptoms.
Evaluation of a Commercially Available Rapid RT-PCR Assay’s Detection of SARS-CoV-2 Novel Variants
Authors: Back Lewis , Logue Jennifer K. , Wolf Caitlin R. , Han Peter D. , Starita Lea M. , Chu Helen Y.
Published: February 2023

Rapid molecular diagnostic tests have been critical in the response to the COVID-19 pandemic. It is important to evaluate the ability of these assays to identify variants of concern, particularly across varying collection and storage conditions. Nasal swabs positive for Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.167.2), Gamma (P.1), or Omicron (B.1.1.529) variants of concern (VOCs) were stored in TE buffer and viral transport media (VTM). We evaluated the sensitivity of the Cepheid Xpert® Xpress SARS-CoV-2 assay in detecting VOC samples and validated TE buffer for use with the assay. Testing of known VOC positives revealed no substantial reduction of PCR sensitivity. Comparison of TE and VTM samples also revealed no reduction in performance when using TE buffer, validating the use of TE buffer to store SARS-CoV-2 samples. SARS-CoV-2 VOCs collected and stored across various conditions can be detected by the Cepheid Xpert® Xpress SARS-CoV-2 assay.
Molecular Epidemiology and Diversity of SARS-CoV-2 in Ethiopia, 2020-2022
Authors: Sisay Abay , Tshiabuila Derek , Tesfaye Abraham , Mboowa Gerald , Oyola Samuel O. , Tesema Sofonias Kifle , Baxter Cheryl , Martin Darren , Lessells Richard , Tegally Houriiyah , van Wyk Stephanie , Moir Monika , Giandhari Jennifer , Pillay Sureshnee , Singh Lavanya , Ramphal Yajna , Maharaj Arisha , Pillay Yusasha , Maharaj Akhil , Naidoo Yeshnee , Ramphal Upasana , Chabuka Lucious , Wilkinson Eduan , de Oliveira Tulio , Desta Adey Feleke , San James E.
Published: January 2023

Ethiopia is the second most populous country in Africa and the sixth most affected by COVID-19 on the continent. Despite having experienced five infection waves, >499 000 cases, and ∼7 500 COVID-19-related deaths as of January 2023, there is still no detailed genomic epidemiological report on the introduction and spread of SARS-CoV-2 in Ethiopia. In this study, we reconstructed and elucidated the COVID-19 epidemic dynamics. Specifically, we investigated the introduction, local transmission, ongoing evolution, and spread of SARS-CoV-2 during the first four infection waves using 353 high-quality near-whole genomes sampled in Ethiopia. Our results show that whereas viral introductions seeded the first wave, subsequent waves were seeded by local transmission. The B.1.480 lineage emerged in the first wave and notably remained in circulation even after the emergence of the Alpha variant. The B.1.480 was out-competed by the Delta variant. Notably, Ethiopia’s lack of local sequencing capacity was further limited by sporadic, uneven, and insufficient sampling that limited the incorporation of genomic epidemiology in the epidemic public health response in Ethiopia. These results highlight Ethiopia’s role in SARS-CoV-2 dissemination and the urgent need for balanced, near-real-time genomic sequencing.
Measures of socioeconomic advantage are not independent predictors of support for healthcare AI: subgroup analysis of a national Australian survey
Authors: Frost Emma , O’Shaughnessy Pauline , Steel David , Braunack-Mayer Annette , James Aquino Yves Saint , Carter Stacy M.
Published: February 2023

Applications of AI (artificial intelligence) have the potential to improve aspects of healthcare. However, studies have shown that healthcare AI algorithms also have the potential to perpetuate existing inequities in healthcare, performing less effectively for marginalised populations. Studies on public attitudes toward AI outside of the healthcare field have tended to show higher levels of support for AI amongst socioeconomically advantaged groups that are less likely to be sufferers of algorithmic harms. We aimed to examine the sociodemographic predictors of support for scenarios related to healthcare AI.

The AVA-AI survey was conducted in March 2020 to assess Australians’ attitudes toward artificial intelligence in healthcare. An innovative weighting methodology involved weighting a non-probability web-based panel against results from a shorter omnibus survey distributed to a representative sample of Australians. We used multinomial logistic regression to examine the relationship between support for AI and a suite of sociodemographic variables in various healthcare scenarios.

Where support for AI was predicted by measures of socioeconomic advantage such as education, household income, and SEIFA index, the same variables were not predictors of support for the scenarios presented. Variables associated with support for healthcare AI across all three scenarios included being male, having computer science or programming experience, and being aged between 18 and 34 years. Other Australian studies suggest that this group have a higher level of perceived familiarity with AI. Our findings suggest that while support for AI in general is predicted by indicators of social advantage, these same indicators do not predict support for healthcare AI.

WHAT IS ALREADY KNOWN ON THIS TOPIC

Artificial intelligence has the potential to perpetuate existing biases in healthcare datasets, which may be more harmful for marginalised populations. Support for the development of artificial intelligence tends to be higher amongst more socioeconomically privileged groups.

WHAT THIS STUDY ADDS

Whilst general support for the development of artificial intelligence was higher amongst socioeconomically privileged groups, support for the development of healthcare artificial intelligence was not. Groups that were more likely to support healthcare artificial intelligence were males, those with computer science experience, and younger people.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY

Healthcare artificial intelligence is becoming more relevant for the public as new applications are developed and implemented. Understanding how public attitudes differ amongst sociodemographic subgroups is important for future governance of healthcare AI.
midiaPASEF maximizes information content in data-independent acquisition proteomics
Authors: Distler Ute , Łącki Mateusz Krzysztof , Startek Michał Piotr , Teschner David , Brehmer Sven , Decker Jens , Schild Thilo , Krieger Jonathan , Krohs Florian , Raether Oliver , Hildebrandt Andreas , Tenzer Stefan
Published: February 2023

Data-independent acquisition (DIA) approaches provide comprehensive records of all detectable pre-cursor and fragment ions. Here we introduce midiaPASEF, a novel DIA scan mode using mobility-specific micro-encoding of overlapping quadrupole windows to optimally cover the ion population in the ion mobility-mass to charge plane. Using overlapping ion mobility-encoded quadrupole windows, midiaPASEF maximizes information content in DIA acquisitions which enables the determination of the precursor m/z of each fragment ion with a precision of less than 2 Th. The Snakemake-based MIDIAID pipeline integrates algorithms for multidimensional peak detection and for machine-learning-based classification of precursor-fragment relationships. The MIDIAID pipeline enables fully automated processing and multidimensional deconvolution of midia-PASEF files and exports highly specific DDA-like MSMS spectra which are suitable forde novosequencing and can be searched directly with established tools including PEAKS, FragPipe and Mascot. midiaPASEF acquisition identifies over 40 unique peptides per second and provides powerful library-free DIA analyses including phosphopeptidome and immunopeptidome samples.
When do longer reads matter? A benchmark of long read de novo assembly tools for eukaryotic genomes
Authors: Cosma Bianca-Maria , Zade Ramin Shirali Hossein , Jordan Erin Noel , van Lent Paul , Peng Chengyao , Pillay Stephanie , Abeel Thomas
Published: February 2023

Background

Assembly algorithm choice should be a deliberate, well-justified decision when researchers create genome assemblies for eukaryotic organisms from third-generation sequencing technologies. While third-generation sequencing by Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio) have overcome the disadvantages of short read lengths specific to next-generation sequencing (NGS), third-generation sequencers are known to produce more error-prone reads, thereby generating a new set of challenges for assembly algorithms and pipelines. Since the introduction of third-generation sequencing technologies, many tools have been developed that aim to take advantage of the longer reads, and researchers need to choose the correct assembler for their projects.

Results

We benchmarked state-of-the-art long-readde novoassemblers, to help readers make a balanced choice for the assembly of eukaryotes. To this end, we used 13 real and 72 simulated datasets from different eukaryotic genomes, with different read length distributions, imitating PacBio CLR, PacBio HiFi, and ONT sequencing to evaluate the assemblers. We include five commonly used long read assemblers in our benchmark: Canu, Flye, Miniasm, Raven and Redbean. Evaluation categories address the following metrics: reference-based metrics, assembly statistics, misassembly count, BUSCO completeness, runtime, and RAM usage. Additionally, we investigated the effect of increased read length on the quality of the assemblies, and report that read length can, but does not always, positively impact assembly quality.

Conclusions

Our benchmark concludes that there is no assembler that performs the best in all the evaluation categories. However, our results shows that overall Flye is the best-performing assembler, both on real and simulated data. Next, the benchmarking using longer reads shows that the increased read length improves assembly quality, but the extent to which that can be achieved depends on the size and complexity of the reference genome.
Jointly looking to the past and the future in visual working memory
Authors: Liu Baiwei , Alexopoulou Zampeta-Sofia , van Ede Freek
Published: February 2023

Working memory enables us to bridge past sensory information to upcoming future behaviour. Accordingly, by its very nature, working memory is concerned with two components: the past and the future. Yet, in conventional laboratory tasks, these two components are often conflated, such as when sensory information in working memory is encoded and tested at the same location. We developed a task in which we dissociated the past (encoded location) and future (to-be-tested location) attributes of visual contents in working memory. This enabled us to independently track the utilisation of past and future memory attributes through gaze, as observed during mnemonic selection. Our results reveal the joint consideration of past and future locations. This was prevalent even at the single-trial level of individual saccades that were jointly biased to the past and future. This uncovers the rich nature of working memory representations, whereby both past and future memory attributes are retained and can be accessed together when memory contents become relevant for behaviour.
How cells wrap around virus-like particles using extracellular filamentous protein structures
Authors: Gupta Sarthak , Santangelo Christian D. , Patteson Alison E. , Schwarz J. M.
Published: January 2023

Nanoparticles, such as viruses, can enter cells via endocytosis. During endocytosis, the cell surface wraps around the nanoparticle to effectively eat it. Prior focus has been on how nanoparticle size and shape impacts endocytosis. However, inspired by the noted presence of extracellular vimentin affecting viral and bacteria uptake, as well as the structure of coronaviruses, we construct a computational model in whichboththe cell-like construct and the virus-like construct contain filamentous protein structures protruding from their surfaces. We then study the impact of these additional degrees of freedom on viral wrapping. We find that cells with an optimal density of filamentous extracellular components (ECCs) are more likely to be infected as they uptake the virus faster and use relatively less cell surface area per individual virus. At the optimal density, the cell surface folds around the virus, and folds are faster and more efficient at wrapping the virus than crumple-like wrapping. We also find that cell surface bending rigidity helps generate folds, as bending rigidity enhances force transmission across the surface. However, changing other mechanical parameters, such as the stretching stiffness of filamentous ECCs or virus spikes, can drive crumple-like formation of the cell surface. We conclude with the implications of our study on the evolutionary pressures of virus-like particles, with a particular focus on the cellular microenvironment that may include filamentous ECCs.
Power analysis for human melatonin suppression experiments
Authors: Spitschan Manuel , Vidafar Parisa , Cain Sean W. , Phillips Andrew , Lambert Ben C.
Published: February 2023

In humans, the nocturnal secretion of melatonin by the pineal gland is suppressed by ocular exposure to light. In the laboratory, melatonin suppression is a convenient biomarker for this neural pathway. Recent work has found that individuals differ substantially in their melatonin-suppressive response to light, with the most sensitive individuals being up to 60 times more sensitive than the least sensitive individuals. Planning experiments with melatonin suppression as an outcome needs to incorporate these individual differences, particularly in common resource-limited scenarios where running within-subjects studies at multiple light levels is expensive and not feasible with respect to participant compliance. Here, we present a novel framework for virtual laboratory melatonin suppression experiments, incorporating a Bayesian statistical model. We provide a Shiny web app for power analyses that allows users to modify various experimental parameters (sample size, individual-level heterogeneity, statistical significance threshold, light levels), and simulate a systematic shift in sensitivity (e.g., due to a pharmacological or other intervention). Our framework helps experimenters to design compelling and robust studies, offering novel insights into the underlying biological variability relevant for practical applications.
Soil legacies of extreme droughts enhance the performance of invading plants
Authors: Thakur Madhav P. , van der Sloot Maartje A. , Wilschut Rutger A. , Hannula S. Emilia , Hooven Freddy ten , Geisen Stefan , Quist Casper W. , Steinauer Katja , van der Putten Wim H.
Published: February 2023

Extreme droughts can weaken the biotic resistance of native plant communities against the establishment of invading plants. However, we know little about the underlying mechanisms. Using a plant-soil feedback approach, we tested how an extreme drought event alters the soil-mediated biotic resistance of resident native plant communities against invading plant species from native and non-native ranges, namely non-resident natives, native range-expanders, and alien plants. We show that all three types of invading plants performed better in soils with a legacy of extreme drought independent of resident native plant diversity. Path models revealed that extreme drought effects on non-resident natives were mediated by the root biomass of resident native plants and endophytic fungal pathogens during drought, whereas alien plant performance was mediated onlyviathe root biomass of resident native plants also during drought. Our results highlight that the performance of resident native plants during extreme drought and subsequent effects on soil fungi determine the performance of invading plants from native and non-native origins after extreme droughts.
Individual differences in time-varying and stationary brain connectivity during movie watching from childhood to early adulthood: age, sex, and behavioral associations
Authors: Di Xin , Xu Ting , Uddin Lucina Q. , Biswal Bharat B.
Published: February 2023

Spatially remote brain regions exhibit dynamic functional interactions across various task conditions. While time-varying functional connectivity during movie watching shows sensitivity to movie content, stationary functional connectivity remains relatively stable across videos. These findings suggest that dynamic and stationary functional interactions may represent different aspects of brain function. However, the relationship between individual differences in time-varying and stationary connectivity and behavioral phenotypes remains elusive. To address this gap, we analyzed an open-access functional MRI dataset comprising participants aged 5 to 22 years, who watched two cartoon movie clips. We calculated regional brain activity, time-varying connectivity, and stationary connectivity, examining associations with age, sex, and behavioral assessments. Model comparison revealed that time-varying connectivity was more sensitive to age and sex effects compared with stationary connectivity. The preferred age models exhibited quadratic log age or quadratic age effects, indicative of inverted-U shaped developmental patterns. In addition, females showed higher consistency in regional brain activity and time-varying connectivity than males. However, in terms of behavioral predictions, only stationary connectivity demonstrated the ability to predict full-scale intelligence quotient. These findings suggest that individual differences in time-varying and stationary connectivity may capture distinct aspects of behavioral phenotypes.
Multichannel Modulation of Depolarizing and Repolarizing Ion Currents Increases the Positive Rate Dependence of Action Potential Prolongation
Authors: Cabo Candido
Published: February 2023

A pharmacological approach to prevent reentrant tachycardias is to prolong the action potential duration (APD) of the myocytes that provide the substrate for the arrhythmia. For such an anti-arrhythmic approach to be effective, APD prolongation should be positive rate dependent, that is, it should maximize APD prolongation at the fast excitation rates of tachycardia and minimize APD prolongation at slow excitation rates. APD prolongation by current anti-arrhythmic agents is either reverse (larger APD prolongation at slow rates than at fast rates) or neutral (similar APD prolongation at slow and fast rates), which may not result in an effective anti-arrhythmic action. In this report we show that, in computer models of the human ventricular action potential, the combined modulation of both depolarizing and repolarizing ion currents (INaL, ICaL, IKs, IKrand IK1) results in a stronger positive rate dependent APD prolongation than modulation of just repolarizing potassium currents (IKs, IKrand IK1); modulation of a single repolarizing current (IKr) results in reverse rate dependence. A robust positive rate dependent APD prolongation correlates with an acceleration of phase 2 repolarization and a deceleration of phase 3 repolarization, which leads to a triangulation of the action potential shape. A positive rate dependent APD prolongation decreases the repolarization reserve with respect to control at slow excitation rates, which can be managed by interventions that prolong APD at fast excitation rates and shorten APD at slow excitation rates. Feature importance analysis shows that, for both computer models of the action potential, ICaLand IK1are the most important ion currents to achieve a positive rate dependent APD prolongation. In conclusion, multichannel modulation of depolarizing and repolarizing ion currents, with ion channel activators and blockers, results in a robust APD prolongation at fast excitation rates, which should be anti-arrhythmic, while minimizing APD prolongation at slow heart rates, which should reduce potential pro-arrhythmic risks.
The defects of the hippocampal ripples and theta rhythm in depression, and the effects of physical exercise on their amelioration
Authors: Koketsu Shinnosuke , Matsubara Kohki , Ueki Yoshino , Shinohara Yoshiaki , Inoue Koichi , Murakami Satona , Ueki Takatoshi
Published: February 2023

Accumulated evidence demonstrate that environmental stress affects the hippocampus, functioning in cognition and sociality, and causes various depressive symptoms. In addition, recent findings showed that environmental stress influenced the hippocampal activity correlated with neuroinflammation, and impaired the hippocampal sharp wave ripples (SWRs), pattens of spike sequences, and the theta rhythms, a strong oscillation observed in the hippocampus. The involvement of the electrophysiological alterations in the etiology of depression has not been appreciated especially in the hippocampus. Furthermore, the pathological markers associated with such alterations have not been identified. In the present study, therefore, the impairment of the SWRs and the theta rhythms in the hippocampus of the restraint stress-induced depression model of mice was analyzed. In the model mice the hippocampal SWRs and theta rhythms were impaired in depression, while physical exercise significantly reverted them. As previously reported, chronic stress induced inflammation in the affected hippocampus in parallel with defects of adult neurogenesis, on the other hand physical exercise ameliorated those pathological conditions of the bran in depression. In conclusion, this study demonstrated the implications of impairment of the hippocampal SWRs and theta rhythms in the etiology of depression and their usefulness as diagnostic markers of depression.
Mass Spectrometry Imaging of Hair Identifies Daily Maraviroc Adherence in HPTN 069/ACTG A5305
Authors: Rosen Elias P. , White Nicole , Gilliland William M. , Gerona Roy R. , Gandhi Monica , Amico K. Rivet , Mayer Kenneth H. , Gulick Roy M. , Kashuba Angela DM
Published: February 2023

Objective measures of adherence for antiretrovirals used as pre-exposure prophylaxis (PrEP) are critical for improving preventative efficacy in both clinical trials and real-world application. Current objective adherence measures either reflect only recent behavior (eg days for plasma or urine) or cumulative behavior (eg months for dried blood spots). We measured the accumulation of the antiretroviral drug maraviroc (MVC) in hair strands by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) to evaluate adherence behavior longitudinally at high temporal resolution. An MSI threshold for classifying daily adherence was established using clinical samples from healthy volunteers following directly observed dosing of 1 to 7 doses MVC/week. We then used the benchmarked MSI assay to classify adherence to MVC-based PrEP regimens in hair samples collected throughout the 49-week HPTN069/ACTGA5305 study. We found that only ~32% of investigated hair samples collected during the study’s active dosing period showed consistent daily PrEP adherence throughout a retrospective period of 30 days, and also found that profiles of daily individual adherence from MSI hair analysis could identify when patients were and were not taking study drug. The assessment of adherence from MSI hair strand analysis was 62% lower than adherence classified using paired plasma samples, the latter of which may be influenced by white-coat adherence. These findings demonstrate the ability of MSI hair analysis to examine daily variability of adherence behavior over a longer-term measurement and offer the potential for longitudinal comparison with risk behavior to target patient-specific adherence interventions and improve outcomes.
EstroGene database reveals diverse temporal, context-dependent and directional estrogen receptor regulomes in breast cancer
Authors: Li Zheqi , Li Tianqin , Yates Megan E. , Wu Yang , Ferber Amanda , Chen Lyuqin , Brown Daniel D. , Carroll Jason S. , Sikora Matthew J. , Tseng George C. , Oesterreich Steffi , Lee Adrian V.
Published: February 2023

As one of the most successful cancer therapeutic targets, estrogen receptor-α (ER/ESR1) has been extensively studied in decade-long. Sequencing technological advances have enabled genome-wide analysis of ER action. However, reproducibility is limited by different experimental design. Here, we established the EstroGene database through centralizing 246 experiments from 136 transcriptomic, cistromic and epigenetic datasets focusing on estradiol-treated ER activation across 19 breast cancer cell lines. We generated a user-friendly browser (https://estrogene.org/) for data visualization and gene inquiry under user-defined experimental conditions and statistical thresholds. Notably, documentation-based meta-analysis revealed a considerable lack of experimental details. Comparison of independent RNA-seq or ER ChIP-seq data with the same design showed large variability and only strong effects could be consistently detected. We defined temporal estrogen response metasignatures and showed the association with specific transcriptional factors, chromatin accessibility and ER heterogeneity. Unexpectedly, harmonizing 146 transcriptomic analyses uncovered a subset of E2-bidirectionally regulated genes, which linked to immune surveillance in the clinical setting. Furthermore, we defined context dependent E2 response programs in MCF7 and T47D cell lines, the two most frequently used models in the field. Collectively, the EstroGene database provides an informative resource to the cancer research community and reveals a diverse mode of ER signaling.
A k-mer based transcriptomics analysis for NPM1-mutated AML
Authors: Silva Raíssa , Riedel Cédric , Guibert Benoit , Ruffle Florence , Boureux Anthony , Commes Thérèse
Published: February 2023

Motivation

Acute Myeloid Leukemia is a highly heterogeneous disease. Although current classifications are well-known and widely adopted, many patients experience drug resistance and disease relapse. New biomarkers are needed to make classifications more reliable and propose personalized treatment.

Results

We performed tests on a large scale in 3 AML cohorts, 1112 RNAseq samples. The accuracy to distinguish NPM1 mutant and non-mutant patients using machine learning models achieved more than 95% in three different scenarios. Using our approach, we found already described genes associated with NPM1 mutations and new genes to be investigated. Furthermore, we provide a new view to search for signatures/biomarkers and explore diagnosis/prognosis, at the k-mer level.

Availability

Code available athttps://github.com/railorena/npm1amlandhttps://osf.io/4s9tc/. The cohorts used in this article were authorized for use.

Contact*

therese.commes@inserm.fr
Using publicly available data to identify priority communities for a SARS-CoV-2 testing intervention in a southern U.S. state
Authors: Matthews Lynn T , Long Dustin M , Pratt Madeline C , Yuan Ya , Heath Sonya L , Levitan Emily B , Grooms Sydney , Creger Thomas , Rana Aadia , Mugavero Michael J , Judd Suzanne E
Published: February 2023

Background

The U.S. Southeast has a high burden of SARS-CoV-2 infections and COVID-19 disease. We used public data sources and community engagement to prioritize county selections for a precision population health intervention to promote a SARS-CoV-2 testing intervention in rural Alabama during October 2020 and March 2021.

Methods

We modeled factors associated with county-level SARS-CoV-2 percent positivity using covariates thought to associate with SARS-CoV-2 acquisition risk, disease severity, and risk mitigation practices. Descriptive epidemiologic data were presented to scientific and community advisory boards to prioritize counties for a testing intervention.

Results

In October 2020, SARS-CoV-2 percent positivity was not associated with any modeled factors. In March 2021, premature death rate (aRR 1.16, 95% CI 1.07, 1.25), percent Black residents (aRR 1.00, 95% CI 1.00, 1.01), preventable hospitalizations (aRR 1.03, 95% CI 1.00, 1.06), and proportion of smokers (aRR 0.231, 95% CI 0.10, 0.55) were associated with average SARS-CoV-2 percent positivity. We then ranked counties based on percent positivity, case fatality, case rates, and number of testing sites using individual variables and factor scores. Top ranking counties identified through factor analysis and univariate associations were provided to community partners who considered ongoing efforts and strength of community partnerships to promote testing to inform intervention.

Conclusions

The dynamic nature of SARS-CoV-2 proved challenging for a modelling approach to inform a precision population health intervention at the county level. Epidemiological data allowed for engagement of community stakeholders implementing testing. As data sources and analytic capacities expand, engaging communities in data interpretation is vital to address diseases locally.
Factors influencing modern contraceptive use in Kinshasa, Democratic Republic of Congo
Authors: Mokeke Reagan Ingoma , Han Whiejong M. , Kang Hee Cheol , Kim Han Nah
Published: February 2023

Family planning allows individuals and couples to schedule and regulate births at the appropriate time and number. Women who carry unplanned pregnancies are susceptible to postnatal complications, which directly impact their well-being, making them a burden to society. There are 27600 adolescent abortions in the Democratic Republic of the Congo (DRC), accounting for about 19 percent of abortion cases in Kinshasa in 2021 while the reproduction rate remains one of the highest in the world at 5.7 and a low contraceptive prevalence across all methods (28%) in 2022. This study aims to determine the factors that influence modern contraceptive use among women in Kinshasa city in the Democratic Republic of Congo by using data from the PMA 2020 cross-sectional survey to assess the association between predictors and modern contraceptive use through logistic regression analysis (OR and 95% CI).

Findings show that older women are more likely to use modern contraceptive than younger (15-22) and their sensitivity diminishes as they age. This likelihood is also high when women do not discuss this topic with their partner. As household size increases, women’s use of modern contraceptives is positively affected (OR: 4.993). The same is true for women who have given birth at least compared to those who have never given birth (OR: 2.313). Wanting fewer children makes her more likely to use these contraceptives than when she wants more (OR: 1.244). Male condoms, emergency contraceptives and pills were used more by women aged 15-31 while the most common contraceptive method used only by older women is female sterilization.

In a country with rapid population growth such as the DRC, the strategy should focus on raising awareness among young women through school programs, health facilities, community outreach, and other means to achieve optimal use of modern contraceptives based on commonly used methods and involving adult men and women.
The fading of the mpox outbreak among men who have sex with men: a mathematical modelling study
Authors: Xiridou Maria , Miura Fuminari , Adam Philippe , Op de Coul Eline , de Wit John , Wallinga Jacco
Published: February 2023

Background

In the Netherlands, the number of mpox cases started declining before mpox vaccination was initiated. Most cases were men who have sex with men (MSM). We investigated whether the decline in mpox could be attributed to infection-induced immunity or behavioural adaptations.

Methods

We developed a transmission model and accounted for possible behavioural adaptations: less casual partners and shorter time until MSM with mpox refrain from sexual contacts.

Results

Without behavioural adaptations, the peak in modelled cases matched observations, but the decline was less steep than observed. With behavioural adaptations in the model, we found a decline of 16-18% in numbers of casual partners in June and 13-22% in July 2022. Model results showed a halving of the time before refraining from sex. When mpox vaccination started, 57% of MSM with very high sexual activity in the model had been infected. Model scenarios revealed that the outbreak could have waned by November 2022 even without vaccination.

Conclusions

The limited duration of the mpox outbreak in the Netherlands can be ascribed primarily to infection-induced immunity among MSM with high sexual activity levels. The decline was accelerated by behavioural adaptations. Immunity among those most sexually active is essential to impede mpox resurgence.

Short summary

Modelling study shows that the decline in mpox cases among MSM in the Netherlands was primarily due to infection-induced immunity among those with high sexual activity levels and accelerated by behavioural adaptions. The outbreak could have faded even without vaccination.
Influence of root cortical aerenchyma on the rhizosphere microbiome of field-grown maize
Authors: Galindo-Castañeda Tania , Rojas Claudia , Karaöz Ulas , Brodie Eoin L. , Brown Kathleen M. , Lynch Jonathan P.
Published: February 2023

The root anatomical phenotype root cortical aerenchyma (RCA) decreases the metabolic cost of soil exploration and improves plant growth under drought and low soil fertility. RCA may also change the microenvironment of rhizosphere microorganisms by increasing oxygen availability or by reducing carbon rhizodeposition. We tested the hypothesis that plants with contrasting expression of RCA have different rhizosphere prokaryotic communities. Maize inbreds were grown in two field sites, Limpopo Province, South Africa and Pennsylvania, USA, and their rhizosphere soil sampled at flowering. High- and low-nitrogen fertilization was imposed as separate treatments in the experiment in South Africa. The rhizosphere microbial composition of plants with contrasting RCA was characterized by metabarcoding of the 16S rRNA genes. Geographic location was the most important factor related to the composition of rhizosphere microbial communities. In the site in South Africa, RCA explained greater percent of variance (9%) in the composition of microbial communities than genotype (7%). Although other root anatomical and architectural phenotypes were studied as possible cofactors affecting the microbial composition, RCA was among the best significant explanatory variables for the South African site although it was neutral in the Pennsylvania site. High-RCA rhizospheres significantly enriched OTUs of the familiesBurkholderiaceae(in South Africa) andBacillaceae(in USA), compared to low-RCA plants, and OTUs of the familiesBeijerinckiaceaeandSphingomonadaceaewere enriched at the two nitrogen levels in high RCA plants in South Africa. Our results are consistent with the hypothesis that RCA is an important factor for rhizosphere microbial communities, especially under suboptimal nitrogen conditions.
Perturb-tracing enables high-content screening of multiscale 3D genome regulators
Authors: Cheng Yubao , Hu Mengwei , Yang Bing , Jensen Tyler B , Yang Tianqi , Yu Ruihuan , Ma Zhaoxia , Radda Jonathan S D , Jin Shengyan , Zang Chongzhi , Wang Siyuan
Published: February 2023

Three-dimensional (3D) genome organization becomes altered during development, aging, and disease1–23, but the factors regulating chromatin topology are incompletely understood and currently no technology can efficiently screen for new regulators of multiscale chromatin organization. Here, we developed an image-based high-content screening platform (Perturb-tracing) that combines pooled CRISPR screen, a new cellular barcode readout method (BARC-FISH), and chromatin tracing. We performed a loss-of-function screen in human cells, and visualized alterations to their genome organization from 13,000 imaging target-perturbation combinations, alongside perturbation-paired barcode readout in the same single cells. Using 1.4 million 3D positions along chromosome traces, we discovered tens of new regulators of chromatin folding at different length scales, ranging from chromatin domains and compartments to chromosome territory. A subset of the regulators exhibited 3D genome effects associated with loop-extrusion and A-B compartmentalization mechanisms, while others were largely unrelated to these known 3D genome mechanisms. We found that the ATP-dependent helicase CHD7, the loss of which causes the congenital neural crest syndrome CHARGE24and a chromatin remodeler previously shown to promote local chromatin openness25–27, counter-intuitively compacts chromatin over long range in different genomic contexts and cell backgrounds including neural crest cells, and globally represses gene expression. The DNA compaction effect of CHD7 is independent of its chromatin remodeling activity and does not require other protein partners. Finally, we identified new regulators of nuclear architectures and found a functional link between chromatin compaction and nuclear shape. Altogether, our method enables scalable, high-content identification of chromatin and nuclear topology regulators that will stimulate new insights into the 3D genome functions, such as global gene and nuclear regulation, in health and disease.
AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in a neurodevelopmental disorder
Authors: Lewis Sara A. , Bakhtiari Somayeh , Forstrom Jacob , Bayat Allan , Bilan Frédéric , Le Guyader Gwenaël , Alkhunaizi Ebba , Vernon Hilary , Padilla-Lopez Sergio R. , Kruer Michael C.
Published: February 2023

AGAP1is an Arf1 GAP that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report 3 new individuals with microdeletion variants inAGAP1. Affected individuals have intellectual disability (3/3), autism (3/3), dystonia with axial hypotonia (1/3), abnormalities of brain maturation (1/3), growth impairment (2/3) and facial dysmorphism (2/3). We investigated mechanisms potentially underlyingAGAP1neurodevelopmental impairments using theDrosophilaortholog,CenG1a. We discovered reduced axon terminal size, increased neuronal endosome abundance, and elevated autophagy at baseline. Given potential incomplete penetrance, we assessed gene-environment interactions. We found basal elevation in phosphorylation of the integrated stress-response protein eIF2α and inability to further increase eIF2α-P with subsequent cytotoxic stressors.CenG1a-mutant flies have increased lethality from exposure to environmental insults. We propose a model wherein disruption ofAGAP1function impairs endolysosomal trafficking, chronically activating the integrated stress response, and leaving AGAP1-deficient cells susceptible to a variety of second hit cytotoxic stressors. This model may have broader applicability beyondAGAP1in instances where both genetic and environmental insults co-occur in individuals with neurodevelopmental disorders.

Summary statement

We describe 3 additional patients with heterozygous AGAP1 deletion variants and use a loss of functionDrosophilamodel to identify defects in synaptic morphology with increased endosomal sequestration, chronic autophagy induction, basal activation of eIF2α-P, and sensitivity to environmental stressors.
Integrase-associated niche differentiation of endogenous large DNA viruses in crustaceans
Authors: Kawato Satoshi , Nozaki Reiko , Kondo Hidehiro , Hirono Ikuo
Published: February 2023

Crustacean genomes harbor sequences originating from nimaviruses, a family of large double-stranded DNA viruses infecting crustaceans. In this study, we recovered metagenome-assembled genomes of 25 endogenous nimaviruses from crustacean genome data. Phylogenetic analysis revealed four major lineages withinNimaviridae, and for three of these lineages, we propose novel genera of endogenous nimaviruses: “Majanivirus” and “Pemonivirus” identified from penaeid shrimp genomes, and “Clopovirus” identified from terrestrial isopods. Majanivirus genomes contain multiple eukaryotic-like genes such as baculoviral inhibitor of apoptosis repeat-containing genes, innexins, and heat shock protein 70-like genes, some of which contain introns. An alignment of long reads revealed that that each endogenous nimavirus species specifically inserts into host microsatellites or within 28S rDNA. This insertion preference was associated with the type of virus-encoded DNA recombination enzymes, the integrases. Majaniviruses, pemoniviruses, some whispoviruses, and possibly clopoviruses specifically insert into the arthropod telomere repeat motif (TAACC/GGTTA)n and all possessed a specific tyrosine recombinase family. Pasiphaea japonica whipovirus and Portunus trituberculatus whispovirus, the closest relatives of white spot syndrome virus, integrate into the host 28S rDNA and are equipped with members of another family of tyrosine recombinases that are distantly related to telomere-specific tyrosine recombinases. Endogenous nimavirus genomes identified from sesarmid crabs, which lack tyrosine recombinases and are flanked by a 46-bp inverted terminal repeat, integrate into (AT/TA)n microsatellites through the acquisition of a Ginger2-like cut- and-paste DDE transposase. These results suggest that endogenous nimaviruses are giant transposable elements that occupy different sequence niches through the acquisition of different integrase families.

Importance

Crustacean genomes harbor sequences originating from a family of large DNA viruses called nimaviruses, but it is unclear why they are present. We show that endogenous nimaviruses selectively insert into repetitive sequences within the host genome, and this insertion specificity was correlated with different types of integrases, which are DNA recombination enzymes encoded by the nimaviruses themselves. This suggests that endogenous nimaviruses have colonized various genomic niches through the acquisition of integrases with different insertion specificities. Our results point to a novel survival strategy of endogenous large DNA viruses colonizing the host genomes. These findings may clarify the evolution and spread of nimaviruses in crustaceans and lead to measures to control and prevent the spread of pathogenic nimaviruses in aquaculture settings.
Dopamine increases accuracy and lengthens deliberation time in explicit motor skill learning
Authors: Leow Li-Ann , Bernheine Lena , Carroll Timothy J , Dux Paul E , Filmer Hannah L
Published: February 2023

Although animal research implicates a central role for dopamine in motor skill learning, a direct causal link has yet to be established in neurotypical humans. Here, we tested if a pharmacological manipulation of dopamine alters motor learning, using a paradigm which engaged explicit, goal-directed strategies. Participants (27 females, 11 males, aged 18-29 years) first consumed either 100mg of Levodopa (n=19), a dopamine precursor that increases dopamine availability, or placebo (n=19). Then, during training, participants learnt the explicit strategy of aiming away from presented targets by instructed angles of varying sizes. Targets shifted mid-movement by the instructed aiming angle. Task success was thus contingent upon aiming accuracy. The effect of the dopamine manipulations on skill learning was assessed during training, and at an overnight follow-up. Increasing dopamine availability improved aiming accuracy and lengthened reaction times, particularly for larger, more difficult aiming angles, both at training, and at follow-up. Results support the proposal that dopamine is important in decisions to engage instrumental motivation to optimise performance, particularly when learning to execute goal-directed strategies in motor skill learning.
Evaluation of Fecal Occult Blood Testing Kits for Rapid Point-of-Care Diagnosis of Invasive Diarrhea in Young Children
Authors: Kwasi David A. , Adewole Pelumi D. , Akinlabi Olabisi C. , Ekpo Stella E. , Okeke Iruka N.
Published: February 2023

Background

Antimicrobials are only indicated in acute childhood diarrhea when the infection is invasive (and therefore often bloody), or persistent. Rapid and cost-effective screening for invasive diarrhea at the point of care can therefore inform treatment decisions. Multiple rapid fecal occult blood testing (FOBT) kit brands are widely available in Nigeria. This study aimed to compare the diagnostic utility of locally procurable FOBT kits in invasive infantile diarrhea to the innovators product, using fecal microscopy as the gold standard.

Materials and Methods

Fecal specimens from 46 children under 5 years old with diarrhea, being collected as part of ongoing case-control studies, were tested according to manufacturers’ instructions for each of five FOBT kits. Fecal microscopy for occult blood, and culture for bacterial pathogens were also performed concomitantly using standard procedures.

Results

Stool microscopy confirmed almost ubiquitous presence of white blood cells in stool from children with diarrhea, whereas red blood cells were less commonly detected. A positive FOBT reaction was only seen when red blood cells were present at more than trace levels and was partially correlated with the presence of a potentially invasive pathogen. Each of the five FOBT kits tested showed 54-61% sensitivity, 87-90% specificity, and acceptable positive- and negative-predictive values for invasive diarrhea.

Conclusions

Four inexpensive, locally available kits identified invasive pediatric diarrheas showed reasonable performance for detecting likely invasive diarrhea and performed similarly to the more difficult-to-procure innovator’s product. FOBT kits are a rapid option for presumptive diagnosis of invasive diarrhea, are a viable alternative to stool microscopy for paediatric specimens at the point-of-care, and could serve as early warning indicators for dysentery outbreaks.