bluuebunny/crossref_metadata_2025 huggingface dataset:
20-20-20 Rule: Are These Numbers Justified?
Authors: Johnson Sophia , Rosenfield Mark
Published: December 2022

SIGNIFICANCE

The use of digital devices has increased substantially in recent years across all age groups for both vocational and avocational purposes. There are a wide range of proposed therapeutic and management options for this condition, including optical, medical, and ergonomic interventions.

PURPOSE

Regular breaks are frequently recommended by clinicians to minimize digital eye strain. The so-called 20-20-20 rule, whereby individuals are advised to fixate on an object at least 20 feet (6 m) away for at least 20 seconds every 20 minutes is widely cited. Unfortunately, there is relatively little peer-reviewed evidence to support this rule. The aim of this investigation was to determine whether scheduled breaks are effective in reducing the adverse effects of digital device usage.

METHODS

The study was carried out on 30 young subjects who performed a 40-minute, cognitively demanding reading task from a tablet computer. The task required them to read random words and to identify which ones began with a specific letter chosen by the experimenter. The task was undertaken on four separate occasions, with 20-second breaks being allowed every 5, 10, 20, or 40 minutes (i.e., no break), respectively. Both before and after each trial, subjects completed a questionnaire regarding ocular and visual symptoms experienced during the session. In addition, both reading speed and task accuracy were quantified during each trial.

RESULTS

A significant increase in post-task symptoms (with respective to the pre-task value) was observed for all four trials (P < .001). However, there was no significant effect of scheduled breaks on reported symptoms (P = .70), reading speed (P = .93), or task accuracy (P = .55).

CONCLUSIONS

Although widely cited as a treatment option, these results do not support the proposal of using 20-second scheduled breaks as a therapeutic intervention for digital eye strain.
Relatively Stable Prevalence of Myopia among Swedish Children Aged 4 to 7 Years between 2015 and 2020
Authors: Bro Tomas , Löfgren Stefan
Published: December 2022

SIGNIFICANCE

The global increase of myopia has caused a lot of debate the last years. Previous research of myopia in the Nordic population has shown diverse results, and only a few Swedish studies have been published in the subject the last two decades.

PURPOSE

This study aimed to analyze trends in the prevalence of myopia in a population of Swedish children.

METHODS

A retrospective analysis of medical records for children between 4 and 7 years of age in a region in Sweden was performed. The inclusion criterion was a first glasses prescription for myopia between 2012 and 2020. Children with other eye diseases or syndromes affecting the eye and vision were excluded. Age, sex, uncorrected visual acuity, and cycloplegic refractive values were extracted. The number of myopic children was compared with population data to calculate incidence and estimate prevalence.

RESULTS

During the study period, 427 children between 4 and 7 years old in an average population of 17,200 children were prescribed glasses for myopia. The incidence for myopia increased from 0.11% in 2012 to 0.39% in 2020 (P < .05). In 2015 to 2020, the prevalence of myopia for the same age group increased from 0.5 to 1.2% (P < .05). Linear regression of the prevalence of myopia showed a significant increase in the age group of 7 years (β = 0.2%, R
2 = 0.82, P ≤ .05).

CONCLUSIONS

This study found a relatively stable prevalence of myopia among Swedish children aged 4 to 7 years between 2015 and 2020. The prevalence of 1.6% among 7-year-old children is not higher than in previous Scandinavian studies.
Human galectin-9 promotes the expansion of HIV reservoirs in vivo in humanized mice
Authors: Yuan Zhe , Giron Leila B. , Hart Colin , Gyampoh Akwasi , Koshy Jane , Hong Kai Ying , Niki Toshiro , Premeaux Thomas A. , Ndhlovu Lishomwa C. , Deleage Claire , Montaner Luis J. , Abdel-Mohsen Mohamed
Published: December 2022

Objective:

The human endogenous protein galectin-9 (Gal-9) reactivates latently HIV-infected cells in vitro and ex vivo, which may allow for immune-mediated clearance of these cells. However, Gal-9 also activates several immune cells, which could negatively affect HIV persistence by promoting chronic activation/exhaustion. This potential ‘double-edged sword’ effect of Gal-9 raises the question of the overall impact of Gal-9 on HIV persistence in vivo.

Design:

We used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART).

Methods:

Two independent cohorts of ART-suppressed HIV-infected BLT mice were treated with either recombinant Gal-9 or phosphate-buffered saline control. Plasma viral loads and levels of tissue-associated HIV DNA and RNA were measured by qPCR. Immunohistochemistry and HIV RNAscope were used to quantify CD4+ T, myeloid, and HIV RNA+ cells in tissues. T cell activation and exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays.

Results:

Gal-9 did not induce plasma markers of inflammation or T cell markers of activation/exhaustion in vivo. However, the treatment significantly increased levels of tissue-associated HIV DNA and RNA compared to controls (P = 0.0007 and P = 0.011, respectively, for cohort I and P = 0.002 and P = 0.005, respectively, for cohort II). RNAscope validated the Gal-9 mediated induction of HIV RNA in tissue-associated myeloid cells, but not T cells.

Conclusions:

Our study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.
Factors Associated with the Development of Thrombosis in Pediatric Behçet Disease
Authors: Güngörer Vildan , Polat Merve Cansu , Çelikel Elif , Ekici Tekin Zahide , Kurt Tuba , Tekgöz Nilüfer , Sezer Müge , Karagöl Cüneyt , Coşkun Serkan , Kaplan Melike Mehveş , Öner Nimet , Yarali H. Neşe , Çelikel Acar Banu
Published: December 2022

Objective

The present study aimed to compare the demographic, clinical, and laboratory characteristics of patients with pediatric Behçet disease (BD) with and without thrombosis to elucidate the factors that may contribute to the development of thrombosis.

Methods

This observational, descriptive, medical records review study included patients with BD (n = 85) who were diagnosed at age younger than 16 years at our clinic between 2010 and 2022. The demographic, clinical, and available laboratory data of patients with and without thrombosis were compared. The potential risk factors for the development of thrombosis were evaluated with multivariable logistic regression analysis.

Results

Central venous sinus thrombosis was the most common type of thrombosis. Thrombosis was significantly more common in male patients (p = 0.002), and regression analysis revealed that being male was a risk factor for developing thrombosis. Genital ulcers were less common in patients with thromboses. Patients with thrombosis had higher erythrocyte sedimentation rates, C-reactive protein, leukocyte, and neutrophil counts, as well as antinuclear antibody positivity. In contrast, mean platelet volume and lymphocyte counts were significantly lower in patients with thrombosis. According to the logistic regression analysis, erythrocyte sedimentation rate value >17 mm/h was a risk factor for developing thrombosis (odds ratio, 1; confidence interval, 1.1–1.8; p = 0.012).

Conclusions

Male sex has been associated with an increased risk of thrombosis in children with BD. Inflammatory parameters may serve as predictive factors for thrombosis in pediatric BD.
Surgical Procedures at Critical Access Hospitals Within Hospital Networks
Authors: Mullens Cody L. , Scott John W. , Mead Mitchell , Kunnath Nicholas , Dimick Justin B. , Ibrahim Andrew M.
Published: December 2022

Objective:

To compare surgical outcomes and expenditures at critical access hospitals that do versus do not participate in a hospital network among Medicare beneficiaries.

Background:

Critical access hospitals provide essential care to more than 80 million Americans. These hospitals, often rural, are located more than 35 miles away from another hospital and are required to maintain patient transfer agreements with other facilities capable of providing higher levels of care. Some critical access hospitals have gone further to formally participate in a hospital network.

Methods:

This was a cross-sectional retrospective study from 2014 to 2018 comparing 16,128 Medicare beneficiary admissions for appendectomy, cholecystectomy, colectomy, or hernia repair at critical access hospitals that do versus do not participate in a hospital network. Thirty-day mortality and readmissions were risk adjusted using multivariable logistic regression accounting for patient and hospital factors. Price-standardized, risk-adjusted Medicare expenditures were compared for the 30-day total episode payments consisting of index hospitalization, physician services, readmissions, and postacute care payments.

Results:

Beneficiaries (average age = 75.7 years, SD = 7.4) who obtained care at critical access hospitals in a hospital network were more likely to carry ≥2 Elixhauser comorbidities (68.7% vs. 62.8%, P < 0.001). Rates of 30-day mortality were higher at critical access hospitals in a hospital network (4.30% vs. 3.81%, OR = 1.11, P < 0.001). Similarly, readmission rates were higher at critical access hospitals that were in a hospital network (15.13% vs. 14.34%, OR = 1.06, P < 0.001). Additionally, total episode payments were found to be $960 higher per patient at critical access hospitals that were in a hospital network ($23,878 vs. $22,918, P < 0.001).

Conclusions:

Critical access hospitals within hospital networks provided care to more medically complex patients and were associated with worse clinical outcomes and higher costs among Medicare beneficiaries undergoing common general surgery operations.
Genomic characterization of viruses associated with the parasitoid Anagyrus vladimiri (Hymenoptera: Encyrtidae)
Authors: Izraeli Yehuda , Lepetit David , Atias Shir , Mozes-Daube Netta , Wodowski Gal , Lachman Oded , Luria Neta , Steinberg Shimon , Varaldi Julien , Zchori-Fein Einat , Chiel Elad
Published: December 2022

Knowledge on symbiotic microorganisms of insects has increased dramatically in recent years, yet relatively little data are available regarding non-pathogenic viruses. Here we studied the virome of the parasitoid wasp Anagyrus vladimiri Triapitsyn (Hymenoptera: Encyrtidae), a biocontrol agent of mealybugs. By high-throughput sequencing of viral nucleic acids, we revealed three novel viruses, belonging to the families Reoviridae [provisionally termed AnvRV (Anagyrus vladimiri reovirus)], Iflaviridae (AnvIFV) and Dicistroviridae (AnvDV). Phylogenetic analysis further classified AnvRV in the genus Idnoreovirus, and AnvDV in the genus Triatovirus. The genome of AnvRV comprises 10 distinct genomic segments ranging in length from 1.5 to 4.2 kb, but only two out of the 10 ORFs have a known function. AnvIFV and AnvDV each have one polypeptide ORF, which is typical of iflaviruses but very un-common among dicistroviruses. Five conserved domains were found along both the ORFs of those two viruses. AnvRV was found to be fixed in an A. vladimiri population that was obtained from a mass rearing facility, whereas its prevalence in field-collected A. vladimiri was ~15 %. Similarly, the prevalence of AnvIFV and AnvDV was much higher in the mass rearing population than in the field population. The presence of AnvDV was positively correlated with the presence of

Wolbachia

in the same individuals. Transmission electron micrographs of females’ ovaries revealed clusters and viroplasms of reovirus-like particles in follicle cells, suggesting that AnvRV is vertically transmitted from mother to offspring. AnvRV was not detected in the mealybugs, supporting the assumption that this virus is truly associated with the wasps. The possible effects of these viruses on A. vladimiri’s biology, and on biocontrol agents in general, are discussed. Our findings identify RNA viruses as potentially involved in the multitrophic system of mealybugs, their parasitoids and other members of the holobiont.
Adaptive collective motions: a hybrid method to improve conformational sampling with molecular dynamics and normal modes
Authors: Resende-Lara Pedro T. , Costa Maurício G. S. , Dudas Balint , Perahia David
Published: December 2022

Protein function is closely related to its structure and dynamics. Due to its large number of degrees of freedom, proteins adopt a large number of conformations, which describe a highly complex potential energy landscape. Considering the huge ensemble of conformations in dynamic equilibrium in solution, detailed investigation of proteins dynamics is extremely costly. Therefore, a significant number of different methods have emerged in order to improve the conformational sampling of biomolecules. One of these methods is Molecular Dynamics with excited Normal Modes (MDeNM) in which normal modes are used as collective variables in molecular dynamics. Here, we present a new implementation of the MDeNM method that allows a continuously controlled kinetic excitation energy in the normal mode space, while taking into account the natural constraints imposed either by the structure or the environment. These implementations prevent unphysical structural distortions. We tested the new approach on bacteriophage’s T4 lysozyme, Gallus gallus hen egg-white lysozyme and Staphylococcus aureus membrane-bound transglycosylase. Our results showed that the new approach outperformed free MD sampling and preserved the structural features comparatively to the original MDeNM approach. We also observed that by adaptively changing the excitation direction during calculations, proteins follow new transition paths preventing structural distortions.
ABHD4 regulates adipocyte differentiation in vitro but does not affect adipose tissue lipid metabolism in mice
Authors: Seramur Mary , Sink Sandy , Cox Anderson O’Brien , Furdui Cristina M. , Key Chia-Chi Chuang
Published: December 2022

Alpha/beta hydrolase domain-containing protein 4 (ABHD4) catalyzes the deacylation ofN-acyl phosphatidyl-ethanolamine (NAPE) and Lyso-NAPE to produce Glycerophospho-N-acyl ethanolamine (GP-NAE). Through a variety of metabolic enzymes, NAPE, Lyso-NAPE, and GP-NAE are ultimately converted into NAE, a group of bioactive lipids that control many physiological processes including inflammation, cognition, and food intake (i.e., oleoylethanolamide or OEA). In a diet-induced obese mouse model, adipose ABHD4 gene expression positively correlated with adiposity. However, it is unknown whether ABHD4 is a causal or a reactive gene to obesity. To fill this knowledge gap, we generated an ABHD4 knockout (KO) 3T3-L1 pre-adipocyte. During adipogenic stimulation, ABHD4 KO pre-adipocytes had increased adipogenesis and lipid accumulation, suggesting ABHD4 is responding to (a reactive gene), not contributing to (not a causal gene), adiposity and may serve as a mechanism for protecting against obesity. However, we did not observe any differences in adiposity and metabolic outcomes between adipocyte specific ABHD4 KO mice or whole body ABHD4 KO mice and their littermate control mice on chow or a high fat diet. This might be because we found that deletion of ABHD4 did not affect NAE such as OEA production, even though ABHD4 was highly expressed in adipose tissue and correlated with fasting adipose OEA levels and lipolysis. These data suggest that ABHD4 plays a role in adipocyte differentiation in vitro but not in adipose tissue lipid metabolism in mice despite nutrient overload, possibly due to compensation from other NAPE and NAE metabolic enzymes.
Tamoxifen exacerbates morbidity and mortality in mice receiving medetomidine anaesthesia
Authors: Rashbrook Victoria S. , Denti Laura , Ruhrberg Christiana
Published: December 2022

Tamoxifen-induced CreER-LoxP recombination is often used to induce spatiotemporally controlled gene deletion in genetically modified mice. Prior work has shown that tamoxifen and tamoxifen-induced CreER activation can have off-target effects that should be controlled. However, it has not yet been reported whether tamoxifen administration, independently of CreER expression, interacts adversely with commonly used anaesthetic drugs such as medetomidine or its enantiomer dexmedetomidine in mice. Here we report a high incidence of urinary plug formation and morbidity in male mice on a mixed C57Bl6/J and 129/SvEv background when tamoxifen treatment was followed by ketamine-medetomidine anaesthesia. Medetomidine is therefore contra-indicated for male mice after tamoxifen treatment. As dexmedetomidine causes morbidity and mortality in male mice at higher rates than medetomidine even without tamoxifen treatment, our findings suggest that dexmedetomidine is not a suitable alternative for anaesthesia of male mice after tamoxifen treatment. We conclude that the choice of anaesthetic drug needs to be carefully evaluated in studies using male mice that have undergone tamoxifen treatment for inducing CreER-LoxP recombination.
Patterns of secondary invasion in the understory of exotic, invasive timber stands
Authors: Jobin Varughese , Das Arundhati , Harikrishnan C.P. , Chanda Ritobroto , Lawrence Swapna , Robin V.V.
Published: December 2022

Current climate and land cover change threaten global mountaintops with increased spread of invasive species. Long-established plantations of exotic and invasive trees on these mountaintops can alter their surroundings, further increasing invader-facilitated or secondary invasion. Identifying the ecological conditions that promote such specific associations can help develop better management interventions.

The Western Ghats’s Shola Sky Islands (>1400m MSL) host vast stretches of exotic and invasive tree plantations that sustain colonisation of other invasive woody, herbaceous and fern species in their understories. Here we analysed vegetation and landscape variables from 232 systematically-placed plots in randomly selected grids using NMDS and Phi Coefficient approaches, to examine patterns of association (positive interactions) between secondary understory invasive species with specific exotic and invasive overstory species. We also conducted GLMM with zero inflation to determine the influence of environmental variables where such associations occur.

We find that secondary invasion of multiple species under the canopy of other exotic invasives is widespread across the Shola Sky Islands. Stands of Eucalyptus host the colonisation of 70% of non-native invasive species surveyed across the Shola Sky Islands. In particular, Lantana camara invasion is strongly associated with Eucalyptus stands.

We also found that climatic variables affect the colonisation of understorey woody invasive species, while invasion by exotic herbaceous species is associated with the density of road networks.. Canopy cover impacts all invasives negatively, while incidence of fire was negatively associated with invasion byLantana sppand thePteridium spp. While the restoration of natural habitats largely targets the highly invasive Acacia, less invasive Eucalyptus and Pine are often not included. Our study suggests that retaining such exotic species in natural habitats, particularly protected areas, can hinder ongoing restoration efforts by facilitating further invasions by multiple woody and herbaceous species.
Comparing Genomic and Epigenomic Features across Species Using the WashU Comparative Epigenome Browser
Authors: Zhuo Xiaoyu , Hsu Silas , Purushotham Deepak , Chen Samuel , Li Daofeng , Wang Ting
Published: December 2022

Genome browsers have become an intuitive and critical tool to visualize and analyze genomic features and data. Conventional genome browsers display data/annotations on a single reference genome/assembly; there are also genomic alignment viewer/browsers that help users visualize alignment, mismatch, and rearrangement between syntenic regions. However, there is a growing need for a comparative epigenome browser that can display genomic and epigenomic datasets across different species and enable users to compare them between syntenic regions. Here, we present the WashU Comparative Epigenome Browser (http://comparativegateway.wustl.edu). It allows users to load functional genomic datasets/annotations mapped to different genomes and display them over syntenic regions simultaneously. The browser also displays genetic differences between the genomes from single nucleotide variants (SNVs) to structural variants (SVs) to visualize the association between epigenomic differences and genetic differences. Instead of anchoring all datasets to the reference genome coordinates, it creates independent coordinates of different genome assemblies to faithfully present features and data mapped to different genomes. It uses a simple, intuitive genome-align track to illustrate the syntenic relationship between different species. It extends the widely used WashU Epigenome Browser infrastructure and can be expanded to support multiple species. This new browser function will greatly facilitate comparative genomic/epigenomic research, as well as support the recent growing needs to directly compare and benchmark the T2T CHM13 assembly and other human genome assemblies.
High-throughput Approaches to Uncover Synergistic Drug Combinations in Leukemia
Authors: Chory Emma J. , Wang Meng , Ceribelli Michele , Michalowska Aleksandra M , Golas Stefan , Beck Erin , Klumpp-Thomas Carleen , Chen Lu , McKnight Crystal , Itkin Zina , Divakaran Sanjay , Bradner James , Khan Javed , Gryder Berkley E. , Thomas Craig J. , Stanton Benjamin Z.
Published: December 2022

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate 11 cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicteda priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Abstract Figure
KGML-xDTD: A Knowledge Graph-based Machine Learning Framework for Drug Treatment Prediction and Mechanism Description
Authors: Ma Chunyu , Zhou Zhihan , Liu Han , Koslicki David
Published: December 2022

Background

Computational drug repurposing is a cost- and time-efficient approach that aims to identify new therapeutic targets or diseases (indications) of existing drugs/compounds. It is especially critical for emerging and/or orphan diseases due to its cheaper investment and shorter research cycle compared with traditional wet-lab drug discovery approaches. However, the underlying mechanisms of action (MOAs) between repurposed drugs and their target diseases remain largely unknown, which is still a main obstacle for computational drug repurposing methods to be widely adopted in clinical settings.

Results

In this work, we proposeKGML-xDTD: aKnowledgeGraph-basedMachineLearning framework for explainably predictingDrugsTreatingDiseases. It is a two-module framework that not only predicts the treatment probabilities between drugs/compounds and diseases but also biologically explains them via knowledge graph (KG) path-based, testable mechanisms of action (MOAs). We leverage knowledge-and-publication based information to extract biologically meaningful “demonstration paths” as the intermediate guidance in the Graph-based Reinforcement Learning (GRL) path-finding process. Comprehensive experiments and case study analyses show that the proposed framework can achieve state-of-the-art performance in both predictions of drug repurposing and recapitulation of human-curated drug MOA paths.

Conclusions

KGML-xDTDis the first model framework that can offer KG-path explanations for drug repurposing predictions by leveraging the combination of prediction outcomes and existing biological knowledge and publications. We believe it can effectively reduce “black-box” concerns and increase prediction confidence for drug repurposing based on predicted path-based explanations, and further accelerate the process of drug discovery for emerging diseases.
Battle of Polio eradication in the Western Pacific Region in the transition to COVID-19 endemicity
Authors: Mei Ruobing , Kwok Shirley L. L. , Lau Eric H. Y. , Lo Tiffany H. K. , Wu Joseph T. , Lin Leesa K. , Leung Kathy
Published: December 2022

The Polio eradication campaign has been set back substantially since 2020 due to the COVID-19 pandemic. Recent detections of poliovirus transmission in multiple high-income countries suggest suboptimal population immunity in many parts of the world even though polio vaccination has been included in routine childhood immunization for decades. We reviewed polio vaccination schedules and vaccine uptake in the Western Pacific Region countries and assessed the potential shortfall in population immunity against polio resurgence across these populations. In addition, we conducted a repeated cross-sectional study between 2021 and 2022 in the Western Pacific Region to understand factors contributing to polio vaccine hesitancy. Our results reveal potential shortfalls in population immunity against polio in Western Pacific Region and provide insights into how vaccination programs and campaigns can be strengthened to ensure continual progress towards polio eradication.
GOThresher: a program to remove annotation biases from protein function annotation datasets
Authors: Joshi Parnal , Banerjee Sagnik , Hu Xiao , Khade Pranav M. , Friedberg Iddo
Published: December 2022

Motivation

Advances in sequencing technologies have led to a surge in genomic data, although the functions of many gene products coded by these genes remain unknown. While in-depth, targeted experiments that determine the functions of these gene products are crucial and routinely performed, they fail to keep up with the inflow of novel genomic data. In an attempt to address this gap, high-throughput experiments are being conducted in which a large number of genes are investigated in a single study. The annotations generated as a result of these experiments are generally biased towards a small subset of less informative Gene Ontology (GO) terms. Identifying and removing biases from protein function annotation databases is important since biases impact our understanding of protein function by providing a poor picture of the annotation landscape. Additionally, as machine learning methods for predicting protein function are becoming increasingly prevalent, it is essential that they are trained on unbiased datasets. Therefore, it is not only crucial to be aware of biases, but also to judiciously remove them from annotation datasets.

Results

We introduce GOThresher, a Python tool that identifies and removes biases in function annotations from protein function annotation databases.

Implementation and Availability

GOThresher is written in Python and released via PyPIhttps://pypi.org/project/gothresher/and on the Bioconda Anaconda channelhttps://anaconda.org/bioconda/gothresher. The source code is hosted on GitHubhttps://github.com/FriedbergLab/GOThresherand distributed under the GPL 3.0 license.

Contact

{idoerg@iastate.edu|parnal@iastate.edu}
Multiplexed microfluidic screening of bacterial chemotaxis
Authors: Stehnach Michael R. , Henshaw Richard J. , Floge Sheri A. , Guasto Jeffrey S.
Published: December 2022

Microorganism sensing of and responding to ambient chemical gradients regulates a myriad of microbial processes that are fundamental to ecosystem function and human health and disease. The development of efficient, high-throughput screening tools for microbial chemotaxis is essential to disentangling the roles of diverse chemical compounds and concentrations that control cell nutrient uptake, chemorepulsion from toxins, and microbial pathogenesis. Here, we present a novel microfluidic multiplexed chemotaxis device (MCD) which uses serial dilution to simultaneously perform six parallel bacterial chemotaxis assays that span five orders of magnitude in chemostimulant concentration on a single chip. We first validated the dilution and gradient generation performance of the MCD, and then compared the measured chemotactic response of an established bacterial chemotaxis system (Vibrio alginolyticus) to a standard microfluidic assay. Next, the MCD’s versatility was assessed by quantifying the chemotactic responses of different bacteria (Psuedoalteromonas haloplanktis, Escherichia coli) to different chemoattractants and chemorepellents. The MCD vastly accelerates the chemotactic screening process, which is critical to deciphering the complex sea of chemical stimuli underlying microbial responses.
Convergent remodeling of the gut microbiome is associated with host energetic condition over long-distance migration
Authors: Trevelline Brian K. , Sprockett Daniel , DeLuca William V. , Andreadis Catherine R. , Moeller Andrew H. , Tonra Christopher
Published: December 2022

The gut microbiome can be thought of as a ‘forgotten organ’, owing to its profound effects on host phenotypes. Long-distance migratory birds are capable of adaptively modulating their physiology, raising the hypothesis that the microbiome of migratory birds may undergo a parallel remodeling process that helps to meet the energetic demands of long-distance migration. To test this hypothesis, we investigated changes in gut microbiome composition and function over the fall migration of a Neotropical-Nearctic migratory Blackpoll Warbler (Setophaga striata), which exhibits one of the longest known autumnal migratory routes of any songbird and rapidly undergoes extensive physiological remodeling during migration. Overall, our results showed that the Blackpoll warbler microbiome differed significantly across phases of fall migration. This pattern was driven by a dramatic increase in the relative abundance of Proteobacteria, and more specifically a single ASV belonging to the family Enterobacteriaceae. Further, blackpolls exhibited a progressive reduction in microbiome phylogenetic diversity and within-group variances over migration, indicating convergence of microbiome composition among individuals during long-distance migration. Metagenomic analysis revealed that the gut microbiome of staging blackpolls was enriched in bacterial pathways involved in vitamin, amino acid, and fatty acid biosynthesis, as well as carbohydrate metabolism, and that these pathways were in turn positively associated with host body mass and subcutaneous fat deposits. Together, these results provide evidence that the gut microbiome of migratory birds may undergo adaptive remodeling to meet the physiological and energetic demands of long-distance migration.
Secure and Federated Genome-Wide Association Studies for Biobank-Scale Datasets
Authors: Cho Hyunghoon , Froelicher David , Chen Jeffrey , Edupalli Manaswitha , Pyrgelis Apostolos , Troncoso-Pastoriza Juan R. , Hubaux Jean-Pierre , Berger Bonnie
Published: December 2022

Sharing data across institutions for genome-wide association studies (GWAS) would enhance the discovery of genetic variants linked to health and disease1, 2. However, existing data sharing regulations limit the scope of such collaborations3. Although cryptographic tools for secure computation promise to enable collaborative analysis with formal privacy guarantees, existing approaches either are computationally impractical or support only simplified analyses4–7. We introduce secure federated genome-wide association studies (SF-GWAS), a novel combination of secure computation frameworks and distributed algorithms that empowers efficient and accurate GWAS on private data held by multiple entities while ensuring data confidentiality. SF-GWAS supports the most widely-used GWAS pipelines based on principal component analysis (PCA) or linear mixed models (LMMs). We demonstrate the accuracy and practical runtimes of SF-GWAS on five datasets, including a large UK Biobank cohort of 410K individuals, showcasing an order-of-magnitude improvement in runtime compared to previous work. Our work realizes the power of secure collaborative genomic studies at unprecedented scale.
Plasmonic Stimulation of Gold Nanorods for the Photothermal Control of Engineered Living Materials
Authors: Basaran Selim , Dey Sourik , Bhusari Shardul , Sankaran Shrikrishnan , Kraus Tobias
Published: December 2022

Engineered living materials (ELMs) use encapsulated microorganisms within polymeric matrices for biosensing, drug delivery, capturing viruses, and bioremediation. It is often desirable to control their function remotely and in real time. Suitable, genetically engineered microorganisms respond to changes of their environment. Here, we combine this local sensitivity with a nanostructured encapsulation material to sensitize the ELM for infrared light. Previously, blue light has been used to stimulate microorganisms that contain optogenetic modules responsive to those wavelengths without the need for exogenous cofactors. Here, we use plasmonic gold nanorods (AuNR) that have a strong absorption maximum at 808 nm, a wavelength where human tissue is relatively transparent. Biocompatible composites of a Pluronic-based hydrogel and AuNR are prepared without agglomeration; they react to illumination by local heating. We measure a photothermal conversion efficiency of 47 % in transient temperature measurements. Steady-state temperature profiles from local photothermal heating are quantified using infrared photothermal imaging, correlated with measurements inside the gel, and applied to stimulate thermoresponsive bacteria. Using a bilayer ELM construct with the thermoresponsive bacteria and the thermoplasmonic composite gel in two separate but connected hydrogel layers, it is shown that the bacteria can be stimulated to produce a fluorescent protein using infrared light in a spatially controlled manner.
Kinetic co-evolutionary models predict the temporal emergence of HIV resistance mutations under drug selection pressure
Authors: Biswas Avik , Choudhuri Indrani , Arnold Eddy , Lyumkis Dmitry , Haldane Allan , Levy Ronald M.
Published: December 2022

Drug resistance in human immunodeficiency virus (HIV) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interactions between a DRM and other residues in HIV protein sequences, is found to be key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naïve patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, reverse transcriptase, and integrase, the primary targets of antiretroviral therapy (ART). The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV and other infectious agents.

Significance

HIV affects the lives of millions of patients worldwide; cases of pan-resistant HIV are emerging. We use kinetic Monte-Carlo methods to simulate the evolution of drug resistance based on HIV patient-derived sequence data available on public databases. Our simulations capture the timeline for the evolution of DRMs reported in the literature across the major drug-target enzymes – PR, RT, and IN. The network of epistatic interactions with the primary DRMs determines the rate at which DRMs are acquired. The timeline is not explained by the overall fitness of the DRMs or features of the genetic code. This work provides a framework for the development of computational methods that forecast the time course over which drug resistance to antivirals develops in patients.
Personalised medicine for Crohn’s disease is a cost-effective strategy
Authors: Buchanan Vanessa , Griffin Susan , Tahir Warda , Hills Karen , Parkes Miles , Smith Kenneth GC , Lyons Paul A , Lee James C , McKinney Eoin F
Published: December 2022

Objective

To evaluate the cost-effectiveness of a personalised medicine strategy for Crohn’s disease in the UK, using early targeted top-down therapy compared to standard of care.

Materials & Methods

A decision tree leading into a Markov state-transition model was constructed, allowing comparison of two treatment approaches: 1) standard of care therapy following established UK clinical guidelines (‘step-up’ treatment) and 2) a personalised medicine strategy in which patients identified as high-risk of subsequent relapse using a prognostic biomarker receive ‘top-down’ anti-TNF treatment at diagnosis. The model facilitated comparison of both costs and Quality Adjusted Life Years (QALYs) in a hypothetical cohort of newly diagnosed Crohn’s disease patients with sensitivity analyses undertaken to model the impact of key assumptions.

Results

Early personalised treatment with anti-TNF based combination therapy resulted in an incremental cost-effectiveness ratio (ICER) of £2,176 per quality-adjusted life year (QALY), with £717 incremental costs and 0.330 incremental QALYs, substantially below the NICE cost-effectiveness threshold of between £20,000 and £30,000 per QALY. Additional costs relating to earlier biologic use were offset by incremental QALYS and reductions in costs driven by fewer disease flares and hospitalisations. Sensitivity analysis across a wide range of parameter assumptions did not impact on the model’s conclusion.

Conclusion

A personalised medicine strategy using anti-TNF therapy at diagnosis in Crohn’s disease to patients at high risk of subsequent relapse is highly likely to be a cost-effective use of resources in the UK National Health Service.

KEY SUMMARY

Established Knowledge

Currently there are no validated prognostic test that can stratify IBD patients based on long term outcomes at the point of diagnosis used routinely in the UK

It therefore remains unclear which patients with Crohn’s disease should be treated with early anti-TNF based therapy as part of a ‘top-down’ regimen.

As a consequence, the majority of IBD patients in the UK are currently treated with an accelerated step-up approach

Significant new findings

We show here that the use of biomarkers at diagnosis to guide personalised use of such treatment is a cost-effective approach for treatment of Crohn’s disease.

Use of a prognostic test to deliver personalised medicine for Crohn’s disease results in positive QALY of 0.330

The approach is cost effective with an incremental cost of £717 and an ICER of 2,176

The model’s conclusions were unaffected by a wide range of sensitivity analyses
Aortic valve stenosis induced occult hemoglobin release promotes endothelial dysfunction
Authors: Quast Christine , Bönner Florian , Polzin Amin , Veulemans Verena , Poku Isabella Gyamfi , Chennupati Ramesh , Nankinova Magdalena , Staub Nicole , Jokiel Juliane , Keyser Fabian , Hoffe Jasmina , Becker Katrin , Leuders Pia , Zako Saif , Erkens Ralf , Jung Christian , Flögel Ulrich , Neidlin Michael , Steinseifer Ulrich , Niepmann Sven Thomas , Zimmer Sebastian , Feelisch Martin , Zeus Tobias , Kelm Malte
Published: December 2022

Rationale

The impact of aortic valve stenosis (AS) on systemic endothelial function independent of standard modifiable risk factors (SMuRFs) is unknown.

Objective

We hypothesized that AS induces subclinical hemoglobin release from red blood cells (RBCs) following transvalvular passage due to post-stenotic aberrant blood flow and that cell-free hemoglobin (fHb) may limit endothelial NO bioavailability, affecting vascular function.

Methods and Results

AS induces swirling blood flow in the ascending aorta which impairs RBC integrity with consecutive release of fHb. Indeed, swirl flow magnitude assessed by 4D flow cardiac magnetic resonance correlates with fHb levels. Elevated systemic fHb reduces NO bioavailability and thus impairs endothelial cell function as evidenced by impaired flow mediated dilation (FMD). In addition, we here demonstrate impaired FMD in an experimental model of AS utilising C57BL/6 mice with preserved left ventricular function and without cardiovascular risk factors. In this model, endothelial dysfunction is accompanied by significantly increased fHb, exaggerated NO consumption and increased plasma levels of nitroso species and the final NO oxidation product, nitrate. Scavenging of fHb by infusion of haptoglobin reversed these deleterious effects. There observations were verified by transfer experiments with human plasma (sampled from patients with AS sheduled for TAVR) using a murine aortic ring bioassay system where the plasma from AS patients induced endothelial dysfunction when compared to plasma from control individuals without AS. Importantly, these deleterious effects were reversed by successful aortic valve replacement via TAVR independent of SMuRFs.

Conclusions

In aortic valve stenosis, increases in post-valvular swirl blood flow in the ascending aorta induces subclinical hemolysis that impairs NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement limits NO scavenging by realigning of postvalvular blood flow to normal physiological patterns.
Effects of breast fibroepithelial tumor associated retinoic acid receptor alpha ligand binding domain mutations on receptor function and retinoid signaling
Authors: Huang Xi Xiao , Ng Ley Moy , Lee Po-Hsien , Guan Peiyong , Chow Mun Juinn , Mohamed Bashir Aisyah Binte , Lau Meina , Shu Tan Kenric Yi , Li Zhimei , Chan Jason Yongsheng , Hong Jing Han , Ng Sheng Rong , Teo Hsiang Ling , Rhodes Daniela , Tan Patrick , Tan Puay Hoon , McDonnell Donald P. , Teh Bin Tean
Published: December 2022

Point mutations in the ligand binding domain of retinoic acid receptor alpha (RARα) have been implicated in breast fibroepithelial tumors development. However, their role in the tumorigenesis of solid tumors is currently unknown. In this study, using a combination of biochemical and cellular assays, we evaluated the functional consequences of known tumor associated RARα mutations on retinoic acid signaling. All of the clinically associated mutants tested showed diminished transcriptional activities compared to wild type RARα. These mutants also exhibited a dominant negative effect, an activity which has previously been linked to developmental defects and tumor formation in mice. X-ray crystallography showed that mutants remain relatively intact structurally and the loss of transcriptional activity is due to altered co-activator recruitment. In agreement with our biochemical analyses, transcriptomics and cell growth analysis showed that the mutant RARα proteins confer resistance to growth inhibition in the presence of its ligand in phyllodes tumor cells. Although the mutations impair the receptor responses to retinoic acid, certain mutant RARα are partially reactivatable with alternative synthetic agonists. Our data provide insights into the mechanisms by which RARα mutations impact tumorigenesis.
Investigation of whether oxytocin and trust play a role in placebo effects of marketing actions
Authors: Schelski Daniela S. , Scheele Dirk , Schmidt Liane , Hurlemann René , Weber Bernd , Plassmann Hilke
Published: December 2022

Expectations about the quality of a medical treatment influence how much an inert treatment helps to improve patient well-being. Similarly, expectations about the quality of products influence how identical goods and services are evaluated differently after their consumption. One driver for such “placebo effects” in medical treatments is social cognition in the form of trust, which may be influenced by the hormone oxytocin. An open question is whether trust and oxytocin play similar roles in marketing placebo effects. To answer this question, we combined oxytocin administration (24 IU) and trust questionnaires in a pre-registered double-blind randomized between-subjects study design (Nfoodtastingtask= 223;Ncognitiveperformancetask= 202). We could not find evidence that oxytocin and trust play a role in placebo effects of marketing actions. Together with other recent null findings from oxytocin administration studies, these findings question the role trust might play in different types of placebo effects.
Parabens Promote Pro-Tumorigenic Effects in Luminal Breast Cancer Cell Lines with Diverse Genetic Ancestry
Authors: Tapia Jazma L. , McDonough Jillian C. , Cauble Emily L. , Gonzalez Cesar G. , Teteh Dede K. , Treviño Lindsey S.
Published: December 2022

One in 8 women will develop breast cancer in their lifetime. Yet, the burden of disease is greater in Black women. Black women have a 40% higher mortality rate compared to White women, and a higher incidence of breast cancer at age 40 and younger. While the underlying cause of this disparity is multifactorial, exposure to endocrine disrupting chemicals (EDCs) in hair and other personal care products has been associated with an increased risk of breast cancer. Parabens are known EDCs that are commonly used as preservatives in hair and other personal care products, and Black women are disproportionately exposed to products containing EDCs. Studies have shown that parabens impact breast cancer cell proliferation, death, migration/invasion, and metabolism, as well as gene expressionin vitro. However, these studies were conducted using cell lines of European ancestry; to date, no studies have utilized breast cancer cell lines of West African ancestry to examine the effects of parabens on breast cancer progression. Like breast cancer cell lines with European ancestry, we hypothesize that parabens promote pro-tumorigenic effects in breast cancer cell lines of West African ancestry. Luminal breast cancer cell lines with West African ancestry (HCC1500) and European ancestry (MCF-7) were treated with biologically relevant doses of methylparaben, propylparaben, and butylparaben. Following treatment, estrogen receptor target gene expression and cell viability were examined. We observed altered estrogen receptor target gene expression and cell viability that was paraben- and cell-line specific. This study provides greater insight into the tumorigenic role of parabens in the progression of breast cancer in Black women.