bluuebunny/crossref_metadata_2025 huggingface dataset:
Public Health Strategies: A Pathway for Public Health Practice to Leverage Law in Advancing Equity
Authors: Weber Samantha Bent , Penn Matthew
Published: November 2021

This article outlines a pathway for public health departments and practitioners to incorporate law into their efforts to advance equity in health outcomes. We assert that examining and applying law can accelerate public health efforts to mitigate structural and systemic inequities, including racism. Recent events such as the COVID-19 pandemic and the community impacts of policing have brought into sharp relief the inequities faced by many populations. These stark and explosive examples arise out of long-standing, persistent, and sometimes hidden structural and systemic inequities that are difficult to trace because they are embedded in laws and accompanying policies and practices. We emphasize this point with a case study involving a small, majority Black community in semirural Appalachia that spent almost 50 years attempting to gain access to the local public water system, despite being surrounded by water lines. We suggest that public health practitioners have a role to play in addressing these kinds of public health problems, which are so clearly tied to the ways laws and policies are developed and executed. We further suggest that public health practitioners, invoking the 10 Essential Public Health Services, can employ law as a tool to increase their capacity to craft and implement evidence-based interventions.
Community-Informed Mobile COVID-19 Testing Model to Addressing Health Inequities
Authors: Jiménez Jonathan , Parra Yury J. , Murphy Katherine , Chen Alexandra Nixxi , Cook Andrew , Watkins Jacob , Baker Melissa D. , Sung Semi , Kaur Guneet , Kress Marielle , Kurien Sarah Joseph , Keeley Chris , Long Theodore
Published: November 2021

Context:

The New York City (NYC) Test & Trace Corps (Test & Trace), under New York City Health + Hospitals (NYC H+H), set out to provide universal access to COVID-19 testing. Test & Trace partnered with numerous organizations to direct mobile COVID-19 testing from concept through implementation to reduce COVID-19-related health inequities.

Program:

Test & Trace employs a community-informed mobile COVID-19 testing model to deliver testing to the hardest-hit, underserved communities. Community partners, uniquely knowledgeable of the residents they serve, are engaged as decision makers and operational partners in mobile COVID-19 testing delivery.

Implementation:

Through several mobile testing methods, community partners choose testing locations and tailor outreach to their community. Test & Trace assumes logistical responsibility for mobile testing but defers critical programmatic decisions and community engagement to partners. Integral to the success of this program is responsive, bidirectional communication.

Evaluation:

During the reporting period of December 1, 2020, to April 30, 2021, Test & Trace's community-informed mobile COVID-19 testing model provided testing to 150351 unique patients and processed 274083 tests in total. The available outcomes data and qualitative feedback provided by community partners illustrate that this intervention, combined with robust governmental investment, successfully ensured that NYC-identified, low-resource neighborhoods had greater access to COVID-19 testing.

Discussion:

Making community partners decision makers reduced inequities in access to testing for communities of color. In addition, the model has served as the framework for Test & Trace's community-informed mobile COVID-19 vaccination program, operated in concert with NYC's Vaccine Command Center, and is a foundation for addressing health inequities at scale, including during public health crises.
Using Public Deliberation to Set Priorities: The Case of COVID-19 Vaccine Access in New York City
Authors: Scherer Maya , Kamler Alexandra , Weiss Linda , Blacksher Erika , Jeavons Jessica , Gold Marthe R.
Published: November 2021

Context:

The COVID-19 pandemic has resulted in a record number of deaths in the United States and tremendous economic and personal strain. During 2020, in anticipation of a vaccine to slow the spread of disease, local and state governments in the United States developed plans for vaccine prioritization, given a limited initial supply. Recognizing the challenges inherent in prioritization, the New York City (NYC) health department sought guidance from members of the public about the fairest approach to early-stage vaccine distribution.

Objective:

To solicit recommendations from NYC residents on priorities regarding vaccine access for essential worker occupations, considering risk factors and preferred approaches to fairness.

Implementation:

Five public deliberations were conducted with NYC residents (N = 91). Participants heard presentations on the COVID-19 vaccine, the local distribution of illness and death, and approaches to fairness in the context of deliberating on priorities for 6 essential worker occupations and 4 risk factors. Discussions were transcribed, and transcriptions were coded and analyzed using preidentified and emergent themes. Pre- and post-surveys, focused on factors relevant to prioritization, were administered during each public deliberation.

Results:

Recommendations for prioritization emphasized risk of severe morbidity and mortality, and work and neighborhood conditions with fewer protections (eg, in-person work, exposure to many people). Participants prioritized elementary schoolteachers, grocery store workers, and bus drivers, underlying health conditions, and neighborhood of residence. Participants focused on equity, recognizing that those at highest risk were largely low-income populations of color and individuals living in low-resourced neighborhoods.

Conclusions:

Participants' focus on equity, and acknowledgment of racial and ethnic disparities, revealed a nuanced understanding of the broader determinants of health. Recommendations reinforced the NYC health department's approach to vaccine distribution.

Public Health Implications:

Results from these public deliberations confirmed community support for approaches prioritizing health equity, recognizing both societal and personal factors affecting vulnerability to poor health.
ALM Fluid Therapy Shifts Sympathetic Hyperactivity to Parasympathetic Dominance in the Rat Model of Non-Compressible Hemorrhagic Shock
Authors: Letson Hayley L. , Biros Erik , Morris Jodie L. , Dobson Geoffrey P.
Published: November 2021

Excessive sympathetic outflow following trauma can lead to cardiac dysfunction, inflammation, coagulopathy, and poor outcomes. We previously reported that buprenorphine analgesia decreased survival after hemorrhagic trauma. Our aim is to examine the underlying mechanisms of mortality in a non-compressible hemorrhage rat model resuscitated with saline or adenosine, lidocaine, magnesium (ALM). Anesthetized adult male Sprague-Dawley rats were randomly assigned to Saline control group or ALM therapy group (both n = 10). Hemorrhage was induced by 50% liver resection. After 15 min, 0.7 mL/kg 3% NaCl ± ALM intravenous bolus was administered, and after 60 min, 0.9% NaCl ± ALM was infused for 4 h (0.5 mL/kg/h) with 72 h monitoring. Animals received 6–12-hourly buprenorphine for analgesia. Hemodynamics, heart rate variability, echocardiography, and adiponectin were measured. Cardiac tissue was analyzed for adrenergic/cholinergic receptor expression, inflammation, and histopathology. Four ALM animals and one Saline control survived to 72 h. Mortality was associated with up to 97% decreases in adrenergic (β-1, α-1A) and cholinergic (M2) receptor expression, cardiac inflammation, myocyte Ca2+ loading, and histopathology, indicating heart ischemia/failure. ALM survivors had higher cardiac output and stroke volume, a 30-fold increase in parasympathetic/sympathetic receptor expression ratio, and higher circulating adiponectin compared to Saline controls. Paradoxically, Saline cardiac adiponectin hormone levels were higher than ALM, with no change in receptor expression, indicating intra-cardiac synthesis. Mortality appears to be a “systems failure” associated with CNS dysregulation of cardiac function. Survival involves an increased parasympathetic dominance to support cardiac pump function with reduced myocardial inflammation. Increased cardiac α-1A adrenergic receptor in ALM survivors may be significant, as this receptor is highly protective during heart dysfunction/failure.
Intravenous administration of mesenchymal stromal cells leads to a dose-dependent coagulopathy and is unable to attenuate acute traumatic coagulopathy in rats
Authors: Wu Xiaowu , Darlington Daniel N. , Christy Barbara A. , Liu Bin , Keesee Jeffrey D. , Salgado Christi L. , Bynum James A. , Cap Andrew P.
Published: November 2021

BACKGROUND

Mesenchymal stromal cells (MSCs) express surface tissue factor (TF), which may affect hemostasis and detract from therapeutic outcomes of MSCs if administered intravenously. In this study, we determine a safe dose of MSCs for intravenous (IV) administration and further demonstrate the impact of IV-MSC on acute traumatic coagulopathy (ATC) in rats.

METHODS

Tissue factor expression of rat bone marrow–derived mesenchymal stromal cell (BMSC) or adipose-derived mesenchymal stromal cell (AMSC) was detected by immunohistochemistry and enzyme-linked immunosorbent assay. The coagulation properties were measured in MSC-treated rat whole blood, and blood samples were collected from rats after IV administration of MSCs. Acute traumatic coagulopathy rats underwent polytrauma and 40% hemorrhage, followed by IV administration of 5 or 10 million/kg BMSCs (BMSC-5, BMSC-10), or vehicle at 1 hour after trauma.

RESULTS

Rat MSCs expressed TF, and incubation of rat BMSCs or AMSCs with whole blood in vitro led to a significantly shortened clotting time. However, a dose-dependent prolongation of prothrombin time with reduction in platelet counts and fibrinogen was found in healthy rat treated with IV-MSCs. Bone marrow–derived mesenchymal stromal cells at 5 million/kg or less led to minimal effect on hemostasis. Mesenchymal stromal cells were not found in circulation but in the lungs after IV administration regardless of the dosage. Acute traumatic coagulopathy with prolonged prothrombin time was not significantly affected by 5 or 10 million/kg BMSCs. Intravenous administration of 10 million/kg BMSCs led to significantly lower fibrinogen and platelet counts, while significantly higher levels of lactate, wet/dry weight ratio, and leukocyte infiltration in the lung were present compared with BMSC-5 or vehicle. No differences were seen in immune or inflammatory profiles with BMSC treatment in ATC rats, at least in the acute timeframe.

CONCLUSION

Intravenous administration of MSCs leads to a risk of coagulopathy associated with a dose-dependent reduction in platelet counts and fibrinogen and is incapable of restoring hemostasis of rats with ATC after polytrauma and hemorrhagic shock.
Extending and using anatomical vocabularies in the Stimulating Peripheral Activity to Relieve Conditions (SPARC) program
Authors: Surles-Zeigler Monique C. , Sincomb Troy , Gillespie Thomas H. , de Bono Bernard , Bresnahan Jacqueline , Mawe Gary M. , Grethe Jeffrey S. , Tappan Susan , Heal Maci , Martone Maryann E.
Published: November 2021

The Stimulating Peripheral Activity to Relieve Conditions (SPARC) program is a US National Institutes of Health-funded effort to improve our understanding of the neural circuitry of the autonomic nervous system in support of bioelectronic medicine. As part of this effort, the SPARC program is generating multi-species, multimodal data, models, simulations, and anatomical maps supported by a comprehensive knowledge base of autonomic circuitry. To facilitate the organization of and integration across multi-faceted SPARC data and models, SPARC is implementing the FAIR data principles to ensure that all SPARC products are findable, accessible, interoperable, and reusable. We are therefore annotating and describing all products with a common FAIR vocabulary. The SPARC Vocabulary is built from a set of community ontologies covering major domains relevant to SPARC, including anatomy, physiology, experimental techniques, and molecules. The SPARC Vocabulary is incorporated into tools researchers use to segment and annotate their data, facilitating the application of these ontologies for annotation of research data. However, since investigators perform deep annotations on experimental data, not all terms and relationships are available in community ontologies. We therefore implemented a term management and vocabulary extension pipeline where SPARC researchers may extend the SPARC Vocabulary using InterLex, an online vocabulary management system. To ensure the quality of contributed terms, we have set up a curated term request and review pipeline specifically for anatomical terms involving expert review. Accepted terms are added to the SPARC Vocabulary and, when appropriate, contributed back to community ontologies to enhance autonomic nervous system coverage. Here, we provide an overview of the SPARC Vocabulary, the infrastructure and process for implementing the term management and review pipeline. In an analysis of > 300 anatomical contributed terms, the majority represented composite terms that necessitated combining terms within and across existing ontologies. Although these terms are not good candidates for community ontologies, they can be linked to structures contained within these ontologies. We conclude that the term request pipeline serves as a useful adjunct to community ontologies for annotating experimental data and increases the FAIRness of SPARC data.
The landscape of metabolic brain alterations in Alzheimer’s disease
Authors: Batra Richa , Arnold Matthias , Wörheide Maria A. , Allen Mariet , Wang Xue , Blach Colette , Levey Allan I. , Seyfried Nicholas T. , Ertekin-Taner Nilüfer , Bennett David A. , Kastenmüller Gabi , Kaddurah-Daouk Rima F. , Krumsiek Jan ,   Alzheimer’s Disease Metabolomics Consortium (ADMC)
Published: November 2021

INTRODUCTION

Alzheimer’s disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in brain has been missing.

METHODS

We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures.

RESULTS

We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than β-amyloid pathology.

DISCUSSION

This work provides a comprehensive reference map of metabolic brain changes in AD which lays the foundation for future mechanistic follow-up studies.
Lateral Line Ablation by Ototoxic Compounds Results in Distinct Rheotaxis Profiles in Larval Zebrafish
Authors: Newton Kyle C , Kacev Dovi , Nilsson Simon R O , Saettele Allison L , Golden Sam A , Sheets Lavinia
Published: November 2021

The zebrafish lateral line is an established model for hair cell organ damage, yet few studies link mechanistic disruptions to changes in biologically relevant behavior. We used larval zebrafish to determine how damage via ototoxic compounds impact rheotaxis. Larvae were treated with CuSO4 or neomycin to disrupt lateral line function then exposed to water flow stimuli. Their swimming behavior was recorded on video then DeepLabCut and SimBA software were used to track movements and classify rheotaxis behavior, respectively. Lateral line-disrupted fish performed rheotaxis, but they swam greater distances, for shorter durations, and with greater angular variance than controls. Furthermore, spectral decomposition analyses confirmed that lesioned fish exhibited ototoxic compound-specific behavioral profiles with distinct changes in the magnitude, frequency, and cross-correlation between fluctuations in linear and angular movements. Our observations demonstrate that lateral line input is needed for fish to hold their station in flow efficiently and reveals that commonly used lesion methods have unique effects on rheotaxis behavior.
Family-Assisted Severity of Illness Monitoring for Hospitalized Children in Low-resource settings – a two-arm interventional pilot study
Authors: von Saint Andre-von Arnim Amelie O. , Kumar Rashmi K. , Clark Jonna D. , Wilfond Benjamin S. , Nguyen Quynh-Uyen P. , Mutonga Daniel M. , Zimmerman Jerry , Oron Assaf P. , Walson Judd L.
Published: November 2021

Introduction

Pediatric mortality remains unacceptably high in many low-resource settings, with inpatient deaths often associated with delayed recognition of clinical deterioration. The Family-Assisted Severe Febrile Illness ThERapy (FASTER) tool has been developed for caregivers to assist in monitoring their hospitalized children and alert clinicians. While utilization of the tool is feasible, the impact on outcomes in low-resource settings has not been studied.

Methods

Randomized controlled pilot study at Kenyatta National Hospital, Kenya. Children hospitalized with acute febrile illness with a caregiver at the bedside for 24 hours were enrolled. Caregivers were trained using the FASTER tool (monitors work of breathing, mental status, perfusion, producing color-coded flags to signal illness severity). The primary outcome was the frequency of clinician reassessments between intervention (FASTER) and control (standard care) arms. Secondary outcomes included survey assessments of clinician and caregiver experiences with the tool. The study was registered with ClinicalTrials.govNCT03513861.

Results

150 patient/caregiver pairs were enrolled, 139 included in the analysis, 74 in the intervention, 65 in the control arm. Patients’ median age was 0.9 (range 0.2-10) and 1.1 years (range 0.2-12) in intervention versus control arms. The most common diagnoses were pneumonia (80[58%]), meningitis (58[38%]) and malaria (34[24%]). 134(96%) caregivers were patients’ mothers. Clinician visits/hour increased with patients’ illness severity in both arms, but without difference in frequency between arms (point estimate for the difference -0.2%, p=0.99). Of the 16 deaths, 8 (four/arm) occurred within 2 days of enrollment. Forty clinicians were surveyed, 33(82%) reporting that FASTER could improve outcomes of very sick children in low-resource settings; 26(65%) rating caregivers as able to adequately capture patients’ severity of illness. Of 70 caregivers surveyed, 63(90%) reported that FASTER training was easy to understand; all(100%) agreed that the intervention would improve care of hospitalized children and help identify sick children in their community.

Discussion

Although we observed no difference in recorded frequency of clinician visits with FASTER monitoring, the tool was rated positively by caregivers and clinicians. Further research to refine implementation with additional input from all stakeholders might increase the effectiveness of FASTER in detecting and responding to clinical deterioration in low-resource settings.
Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells
Authors: Okahashi Nobuyuki , Shima Tomoki , Kondo Yuya , Araki Chie , Tsuji Shuma , Sawai Akane , Uehara Hikaru , Kohno Susumu , Shimizu Hiroshi , Takahashi Chiaki , Matsuda Fumio
Published: November 2021

Adenosine triphosphate (ATP) regeneration by substrate-level phosphorylation is a general feature of cancer metabolism, even under normoxic conditions (aerobic glycolysis). However, it is unclear why cancer cells prefer inefficient aerobic glycolysis over the highly efficient process of oxidative phosphorylation for ATP regeneration. To investigate the metabolic principles underlying aerobic glycolysis, we performed13C-metabolic flux analysis of 12 cultured cancer cell lines and explored the metabolic constraints required to reproduce the results usingin silicometabolic simulations. We found that the measured flux distribution can be reproduced by maximizing the ATP consumption in the flux balance analysis considering a limitation of metabolic heat dissipation (enthalpy change). It suggests that aerobic glycolysis may be preferable because metabolic heat production during one mol of ATP regeneration by aerobic glycolysis was less than that produced by oxidative phosphorylation (OXPHOS). Consistent with the simulation, OXPHOS inhibition induced metabolic redirection to aerobic glycolysis while maintaining the intracellular temperature. Furthermore, the dependency on aerobic glycolysis was partly alleviated upon culturing at low temperatures. Our data suggest that metabolic thermogenesis is an important factor in understanding aerobic glycolysis in cancer cells and that an advantage of aerobic glycolysis is the reduction in metabolic heat generation during ATP regeneration.
Validation of cervical lesion proportion measure using a gridded imaging technique to assess cervical pathology in women with genital schistosomiasis
Authors: Aaroe Katrina Kaestel , Schmidt Arenholt Louise Thomsen , Norderud Kanutte , Lumholdt Mads , Randrianasolo Bodo Sahondra , Ramarokoto Charles Emile , Rabozakandraina Oliva , Broennum Dorthe , Feldmeier Hermann , Christian Leutscher Peter Derek
Published: November 2021

Female genital schistosomiasis (FGS) is characterized by a pattern of lesions which manifest at the cervix and the vagina, such as homogeneous and grainy sandy patches, rubbery papules in addition to neovascularization. A tool for quantification of the lesions is needed to improve FGS research and control programs. Hitherto, no tools are available to quantify clinical pathology at the cervix in a standardized and reproducible manner. This study aimed to develop and validate a cervical lesion proportion (CLP) measure for quantification of cervical pathology in FGS. A digital imaging technique was applied in which a grid containing 424 identical squares was positioned on high resolution digital images from the cervix of 70 women with FGS. A CLP was made for each image by counting the total number of squares containing at least one type of pathognomonic lesions. For validation of inter- and intra-observer reliability, three different observers estimated CLP independently. In addition, a rubbery papule count (RPC) was determined in a similar manner. The intraclass correlation coefficient was 0.94 (excellent) for the CLP inter-rater reliability and 0.90 (good) for intra-rater reliability and the coefficients for the RPC were 0.88 and 0.80 (good), respectively. The CLP facilitated a reliable and reproducible quantification of the surface of the cervix affected by FGS pathognomonic lesions. Grading of cervical pathology by CLP can provide insight into the natural course of schistosome egg-induced pathology of the cervix. Moreover, CLP provides a measure for the efficacy of treatment.

Author summary

Female genital schistosomiasis (FGS) is characterized by development of egg-induced chronic inflammatory lesions of the cervix and the vagina. FGS causes various symptoms such vaginal discharge, dyspareunia and post-coital bleeding, and the disease is further associated with reproductive complications such as ectopic pregnancy and infertility. Moreover, FGS is today considered as a major risk factor for transmission of HIV in Sub-Saharan Africa. General prevention directed against Schistosoma infection and use of praziquantel as anthelmintic drug therapy are cornerstones in the FGS control strategy. In that overall context, we have developed an important new digital image tool for quantitative assessment of FGS evoked cervical lesions, which enables evaluation of treatment outcome at individual as well as community level. The tool will also provide new information in understanding the natural history of FGS including development of clinical pathology.
Association of EBV (Type 1 and 2) with Histopathological Outcomes in Breast Cancer in Pakistani Women
Authors: Ilyas Yusra , Khan Sanaullah , Khan Naveed
Published: November 2021

Introduction

Breast cancer is one of the major and frequent tumors in the public health sector globally. The rising global prevalence of breast cancer has aroused attention in a viral etiology. Other than genetic and hormonal roles, viruses like Epstein - Barr virus (EBV) also participate in the development and advancement of breast cancer.

Aim

This study was conducted to detect the frequency of EBV genotypes in breast cancer patients and compare it with histopathological breast cancer changes.

Methods

Formalin-fixed paraffin-embedded samples of breast cancer (N=60) ages ranged from 22-70 years were collected. EBV DNA was isolated, amplified, typed through PCR, and correlated with histopathological outcomes of breast cancer using SPSS software version 26.

Results

Our findings suggest that among breast cancer factors, Invasive ductal carcinoma (IDC) was the most common pathological pattern found among patients (90%), observed statistically significant (p= 0.01275). In regards to clinical staging, 8 (13.3 %) patients diagnosed with stage I, 39 (65 %) with stage II, and 13 (21.6 %) with stage III reported statistically significant association (p=0.0003). EBV DNA was detected in 68.3% (41/60) breast cancer patients, reported a statistically significant difference between the prevalence of EBV in breast cancer patients and normal samples (p= 0.001). Of 41 EBV-positive samples, 40 were EBV-1, while only 1 had EBV-2 infection (p < 0.001). No influence on cancer histology was observed. Regarding the association of breast cancer with EBV, histological type (P =0.209), tumor stage (P = 0.48), tumor grade (0.356), tumor sizes (p= 0.976), age (p= 0.1055), tumor laterality (p= 0.533) and ER/PR status (p=0.773) showed no significant association.

Conclusion

EBV-1 is prevalent in breast cancer patients and associated with IDC in the study area. For conclusive evidence, more studies are required based on a large sample size and by using more sensitive techniques.
Investigating the structural changes due to adenosine methylation of the Kaposi’s sarcoma-associated herpes virus ORF50 transcript
Authors: Röder Konstantin , Barker Amy M. , Whitehouse Adrian , Pasquali Samuela
Published: November 2021

Kaposi’s sarcoma-associated herpes virus (KSHV) is a human oncovirus. KSHV relies on manipulating the host cell N6-methyl adenosine (m6A) RNA modification pathway. Methylation within a RNA stem loop of the open reading frame 50 (ORF50) enhances transcript stability via the recruitment of the m6A reader, SND1. In this contribution we explore the energy landscapes of the unmethylated and methylated RNA stem loops of ORF50 to investigate the effect of methylation on the structure of the stem loop. We observe a significant shift upon methylation between an open and closed configuration of the top of the stem loop. In the unmethylated stem loop the closed configuration is much lower in energy, and, as a result, exhibits higher occupancy.
Quantifying the Morphology and Mechanisms of Cancer Progression in 3D in-vitro environments: Integrating Experiments and Multiscale Models
Authors: Dimitriou Nikolaos M , Flores-Torres Salvador , Kinsella Joseph Matthew , Mitsis Georgios D
Published: November 2021

Mathematical models of cancer growth have become increasingly more accurate both in the space and time domains. However, the limited amount of data typically available has resulted in a larger number of qualitative rather than quantitative studies. In the present study, we provide an integrated experimental-computational framework for the quantification of the morphological characteristics and the mechanistic modelling of cancer progression in 3D environments. The proposed framework allows for the calibration of multiscale, spatiotemporal models of cancer growth using state-of-the-art 3D cell culture data, and their validation based on the resulting experimental morphological patterns using spatial point-pattern analysis techniques. We applied this framework to the study of the development of Triple Negative Breast Cancer cells cultured in Matrigel scaffolds, and validated the hypothesis of chemotactic migration using a multiscale, hybrid Keller-Segel model. The results revealed transient, non-random spatial distributions of cancer cells that consist of clustered, and dispersion patterns. The proposed model was able to describe the general characteristics of the experimental observations and suggests that cancer cells exhibited chemotactic migration and accumulation, as well as random motion during the examined time period of development. The developed framework enabled us to pursue two goals; first, the quantitative description of the morphology of cancer growth in 3D cultures using point-pattern analysis, and second, the relation of tumour morphology with underlying biophysical mechanisms that govern cancer growth and migration.
Recapitulation of patient-specific 3D chromatin conformation using machine learning and validation of identified enhancer-gene targets
Authors: Xu Duo , Forbes Andre Neil , Cohen Sandra , Palladino Ann , Karadimitriou Tatiana , Khurana Ekta
Published: November 2021

Regulatory networks containing enhancer to gene edges define cellular state and their rewiring is a hallmark of cancer. While efforts, such as ENCODE, have revealed these networks for reference tissues and cell-lines by integrating multi-omics data, the same methods cannot be applied for large patient cohorts due to the constraints on generating ChIP-seq and three-dimensional data from limited material in patient biopsies. We trained a supervised machine learning model using genomic 3D signatures of physical enhancer-gene connections that can predict accurate connections using data from ATAC-seq and RNA-seq assays only, which can be easily generated from patient biopsies. Our method overcomes the major limitations of correlation-based approaches that cannot distinguish between distinct target genes of given enhancers in different samples, which is a hallmark of network rewiring in cancer. Our model achieved an AUROC (area under receiver operating characteristic curve) of 0.91 and, importantly, can distinguish between active regulatory elements with connections to target genes and poised elements with no connections to target genes. Our predicted regulatory elements are validated by multi-omics data, including histone modification marks from ENCODE, with an average specificity of 0.92. Application of our model on chromatin accessibility and transcriptomic data from 400 cancer patients across 22 cancer types revealed novel cancer-type and subtype-specific enhancer-gene connections for known cancer genes. In one example, we identified two enhancers that regulate the expression of ESR1 in only ER+ breast cancer (BRCA) samples but not in ER-samples. These enhancers are predicted to contribute to the high expression of ESR1 in 93% of ER+ BRCA samples. Functional validation using CRISPRi confirms that inhibition of these enhancers decreases the expression of ESR1 in ER+ samples.
Reconstructing mutational lineages in breast cancer by multi-patient-targeted single cell DNA sequencing
Authors: Leighton Jake , Hu Min , Sei Emi , Meric-Bernstam Funda , Navin Nicholas E.
Published: November 2021

Single cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells, however most genomic regions characterized in single cells are non-informative. To overcome this issue, we developed a Multi-Patient-Targeted (MPT) scDNA-seq sequencing method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 TNBC patients, which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From this data, we reconstructed mutational lineages and identified early mutational and copy number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggests that MPT can overcome technical obstacles for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.
DNA methylation of Nuclear Factor of Activated T Cells 1 mediates the prospective relation between exposure to different traumatic event types and post-traumatic stress disorder
Authors: Occean James R. , Wani Agaz H. , Donglasan Janelle , Aiello Allison E. , Galea Sandro , Koenen Karestan C. , Qu Annie , Wildman Derek E. , Uddin Monica
Published: November 2021

Background

The mechanisms through which exposure to differing trauma types become biologically embedded to shape the risk for subsequent post-traumatic stress disorder (PTSD) is unclear. DNA methylation (5-mC), particularly in stress-relevant genes, may play a role in this relationship.

Methods

We conducted path analysis using generalized structural equation modeling to investigate whether blood-derived 5-mC in Nuclear Factor of Activated T Cells 1 (NFATC1) mediated the prospective association between each of five different trauma types (“assaultive violence”, “other injury or shocking experience”, “learning of trauma to loved one”, “sudden, unexpected death of a close friend or relative”, and “other”) and lifetime PTSD assessed prospectively in the Detroit Neighborhood Health Study (n=183).

Results

All five trauma types were significantly associated with reduced methylation atNFATC1CpG site, cg17057218. Three of the five trauma types were significantly associated with increased methylation atNFATC1CpG site, cg22324981. Moreover, methylation at cg17057218 significantly mediated 23-34% of the total effect for three of the five trauma types (assaultive violence, other injury or shocking experience, and learning of trauma to a loved one), while methylation at cg22324981 mediated 36-53% of the total effect for two of the five trauma types (other injury or shocking experience and other). These CpG sites were differentially associated with transcription factor binding sites and chromatin state signatures.

Limitations

Prospective assessment of lifetime PTSD, rather than PTSD onset.

Conclusions

NFATC15-mC may be a potential mechanism in the relationship between some trauma types and prospective risk for PTSD. This finding may help inform treatment for trauma-specific PTSD.
How do avian embryos resume development following diapause? A new role for TGF-β in regulating pluripotency-related genes
Authors: Pokhrel Narayan , Genin Olga , Sela-Donenfeld Dalit , Cinnamon Yuval
Published: November 2021

Avian embryos can halt their development for long periods at low temperature in a process called diapause and successfully resume development when reincubated at maternal body temperature. Successful resumption of development depends on different factors, including temperature. We have recently shown that embryos that enter diapause at 18 °C present a significant reduction in their ability to develop normally when put back into incubation, compared to embryos entering diapause at 12 °C. However, the mechanisms underlying these differences are unknown. To address this question, transcriptome analysis was performed to compare the effect of diapause temperature on gene expression, and to identify pathways involved in the process. Genetic comparison and pathway-enrichment analysis revealed that TGF-β and pluripotency-related pathways are differentially regulated at the two temperatures, with higher expression at 12 °C compared to 18 °C. Investigating the involvement of the TGF-β pathway revealed an essential role for BMP4 in regulating the expression of the transcription factors Nanog and Id2, which are known to regulate pluripotency and self-renewal in embryonic stem cells. BMP4 gain- and loss-of-function experiments in embryos in diapause at the different temperatures revealed the main role of BMP4 in enabling resumption of normal development following diapause. Collectively, these findings identify molecular regulators that facilitate embryos’ ability to undergo diapause at different temperatures and resume a normal developmental program.
Cooperative protein allosteric transition mediated by a fluctuating transmission network
Authors: Post Matthias , Lickert Benjamin , Diez Georg , Wolf Steffen , Stock Gerhard
Published: November 2021

Allosteric communication between distant protein sites represents a key mechanism of biomolecular regulation and signal transduction. Compared to other processes such as protein folding, however, the dynamical evolution of allosteric transitions is still not well understood. As example of allosteric coupling between distant protein regions, we consider the global open-closed motion of the two domains of T4 lysozyme, which is triggered by local motion in the hinge region. Combining extensive molecular dynamics simulations with a correlation analysis of interresidue contacts, we identify a network of interresidue distances that move in a concerted manner. The cooperative process originates from a cogwheel-like motion of the hydrophobic core in the hinge region, which constitutes a flexible transmission network. Through rigid contacts and the protein backbone, the small local changes of the hydrophobic core are passed on to the distant terminal domains and lead to the emergence of a rare global conformational transition. As in an Ising-type model, the cooperativity of the allosteric transition can be explained via the interaction of local fluctuations.
Sequence-dependent model of genes with dual σ factor preference
Authors: Baptista Ines S. C. , Kandavalli Vinodh , Chauhan Vatsala , Bahrudeen Mohammed N. M. , Almeida Bilena L. B. , Palma Cristina , Dash Suchintak , Ribeiro Andre S.
Published: November 2021

Escherichia coli uses σ factors to quickly control large gene cohorts during stress conditions. While most of its genes respond to a single σ factor, approximately 5% of them have dual σ factor preference. The most common are those responsive to both σ70, which controls housekeeping genes, and σ38, which activates genes during stationary growth and stresses. Using RNA-seq and flow-cytometry measurements, we show that ‘σ70+38 genes’ are nearly as upregulated in stationary growth as ‘σ38 genes’. Moreover, we find a clear quantitative relationship between their promoter sequence and their response strength to changes in σ38 levels. We then propose and validate a sequence dependent model of σ70+38 genes, with dual sensitivity to σ38 and σ70, that is applicable in the exponential and stationary growth phases, as well in the transient period in between. We further propose a general model, applicable to other stresses and σ factor combinations. Given this, promoters controlling σ70+38 genes (and variants) could become important building blocks of synthetic circuits with predictable, sequence-dependent sensitivity to transitions between the exponential and stationary growth phases.
Ribosome profiling of porcine reproductive and respiratory syndrome virus reveals novel features of viral gene expression
Authors: Cook Georgia M. , Brown Katherine , Shang Pengcheng , Li Yanhua , Soday Lior , Dinan Adam M. , Tumescheit Charlotte , Adrian Mockett A. P. , Fang Ying , Firth Andrew E. , Brierley Ian
Published: November 2021

Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus which causes significant economic losses to the swine industry worldwide. Here, we use ribosome profiling (RiboSeq) and parallel RNA sequencing (RNASeq) to characterise the transcriptome and translatome of both species of PRRSV and analyse the host response to infection. We quantified viral gene expression over a timecourse of infection, and calculated the efficiency of programmed ribosomal frameshifting (PRF) at both sites on the viral genome. At the nsp2 frameshift site (a rare example of protein-stimulated frameshifting), −2 PRF efficiency increases over time, likely facilitated by accumulation of the PRF- stimulatory viral protein (nsp1β) during infection. This marks arteriviruses as the second example of temporally regulated PRF. Surprisingly, we also found PRF efficiency at the canonical ORF1ab frameshift site increases over time, in apparent contradiction of the common assumption that RNA structure-directed frameshift sites operate at a fixed efficiency. This has potential implications for the numerous other viruses with canonical PRF sites. Furthermore, we discovered several highly translated additional viral ORFs, the translation of which may be facilitated by multiple novel viral transcripts. For example, we found a 125-codon ORF overlapping nsp12, which is expressed as highly as nsp12 itself at late stages of replication, and is likely translated from novel subgenomic (sg) RNA transcripts that overlap the 3′ end of ORF1b. Similar transcripts were discovered for both PRRSV-1 and PRRSV- 2, suggesting a potential conserved mechanism for temporal regulation of expression of the 3′-proximal region of ORF1b. In addition, we identified a highly translated, short upstream ORF (uORF) in the 5′ UTR, the presence of which is highly conserved amongst PRRSV-2 isolates. This is the first application of RiboSeq to arterivirus-infected cells, and reveals new features which add to the complexity of gene expression programmes in this important family of nidoviruses.
Body shape as a visual feature: evidence from spatially-global attentional modulation in human visual cortex
Authors: Thorat Sushrut , Peelen Marius V.
Published: November 2021

Feature-based attention modulates visual processing beyond the focus of spatial attention. Previous work has reported such spatially-global effects for low-level features such as color and orientation, as well as for faces. Here, using fMRI, we provide evidence for spatially-global attentional modulation for human bodies. Participants were cued to search for one of six object categories in two vertically-aligned images. Two additional, horizontally-aligned, images were simultaneously presented but were never task-relevant across three experimental sessions. Analyses time-locked to the objects presented in these task-irrelevant images revealed that responses evoked by body silhouettes were modulated by the participants’ top-down attentional set, becoming more body-selective when participants searched for bodies in the task-relevant images. These effects were observed both in univariate analyses of the body-selective cortex and in multivariate analyses of the object-selective visual cortex. Additional analyses showed that this modulation reflected response gain rather than a bias induced by the cues, and that it reflected enhancement of body responses rather than suppression of non-body responses. These findings provide evidence for a spatially-global attention mechanism for body shapes, supporting the rapid and parallel detection of conspecifics in our environment.
Micro-state-based neural decoding of speech categorization using Bayesian non-parametrics
Authors: Al-Fahad Rakib , Yeasin Mohammed , Moinuddin Kazi Ashraf , Bidelman Gavin M
Published: November 2021

Understanding the many-to-many mapping between patterns of functional brain connectivity and discrete behavioral responses is critical for speech-language processing. We present a microstate-based analysis of EEG recordings to characterize spatio-temporal dynamics of neural activities that underly rapid speech categorization decisions. We implemented a data driven approach using Bayesian non-parametrics to capture the mapping between EEG and the speed of listeners’ phoneme identification [i.e., response time (RT)] during speech labeling tasks. Based on our empirical analyses, we show task-relevant events such as resting-state, stimulus coding, auditory-perceptual object (category) formation, and response selection can be explained using patterns of micro-state dwell-time and are decodable as unique time segments during speech perception. State-dependent activities localize to a fronto-temporo-parietal circuit (superior temporal, supramarginal, inferior frontal gyri) exposing a core decision brain network (DN) underlying rapid speech categorization. Furthermore, RTs were inversely proportional to the frequency of state transitions, such that the rate of change between brain microstates was higher for trials with slower compared to faster RTs. Our findings imply that during rapid speech perception, higher uncertainty producing prolonged RTs (slower decision-making) is associated with staying in the DN longer compared lower RTs (faster decisions). We also show that listeners’ perceptual RTs are highly sensitive to individual differences. Our computational method opens a new avenue in segmentation and dynamic brain connectivity for modeling neuroimaging data and understanding task-related cognitive events.
Effects of crude oil on juvenile threespine stickleback somatic and immune development
Authors: Ireland Kelly S. , Milligan-Myhre Kathryn
Published: November 2021

Aquatic oil spills have resounding effects on surrounding ecosystems, and thus significant resources are committed to oil spill responses to remove the oil from the environment as quickly as possible. Oil has immunotoxic effects and may be particularly harmful to larval and juvenile fish as it can cause a number of developmental defects and stunt growth. In spite of significant efforts to clean oil, it is unclear whether larval and juvenile fish can recover from the effects of oil and no work has been done on the effect crude oil has on developing threespine stickleback (Gasterosteus aculeatus) fish. Threespine stickleback are a ubiquitous sentinel species in the northern hemisphere and are an important food source for many larger, economically valuable fish. As fish with fully marine, anadromous, and freshwater populations, stickleback are exposed to oil in a variety of aquatic environments. We hypothesized that oil exposure would suppress both growth and immunity of developing stickleback, but that fish health could be recovered by removal of the crude oil. Fish were exposed to Alaska North Slope crude oil and then were moved to water without crude oil for two weeks (depuration). Measurements of growth and immunity were taken before and after the depuration. We found that crude oil effected different developmental pathways independently, significantly impacting some but not others. This is the first study to examine the effect crude oil has on early stages of stickleback development, and that stickleback fish are unable to recover from exposure after being transferred to clean water for two-weeks, suggesting larval/juvenile stickleback exposed to crude oil need longer than two-weeks to recover if they are able to recover at all.
A novel growth and isolation medium for exoelectrogenic bacteria
Authors: Nazeer Zumaira , Fernando Eustace Y.
Published: November 2021

A microbiological isolation and growth medium that can effectively discriminate electrochemically active exoelectrogenic bacteria from other non-exoelectrogenic bacteria, is currently unavailable. In this study, we developed a novel chromogenic growth and isolation solid medium based on MnO2 that can selectively allow the growth of exoelectrogenic bacteria and change the medium colour in the process. Known exoelectrogenic bacteria such as Shewanella oneidensis MR1 and other such bacteria from functional microbial fuel cell (MFC) anodes were capable of growing and changing colour in the novel growth medium. On the contrary, non-exoelectrogenic bacteria such as Escherichia coli ATCC 25922 were incapable of growing and inducing a colour change in the novel medium. Further biochemical characterisation of these isolated exoelectrogenic bacteria by Raman micro-spectroscopy demonstrated that these bacteria over express cytochrome proteins that are vital in extracellular electron transfer events. This medium is a convenient method to isolate exoelectrogenic bacteria from complex environmental samples.