bluuebunny/crossref_metadata_2025 huggingface dataset:
Seroprevalence, correlates and kinetics of SARS-CoV-2 Nucleocapsid IgG antibody in healthcare workers at a tertiary hospital: A prevaccine census study
Authors: Maina Daniel , Omuse Geoffrey , Ong’ete George , Mugaine Patrick , Sayed Shahin , Moloo Zahir , Shah Reena , Etyang Anthony , Adam Rodney
Published: April 2022

Background

Healthcare workers are perceived to be a high-risk group for acquiring SAR-CoV-2 infection, and more so in countries where COVID-19 vaccination uptake is low. Serosurveillance may best determine the true extent of SARS-CoV-2 infection since most infected HCWs may be asymptomatic or present with only mild symptoms. Over time, determining the true extent of SARS-CoV-2 infection could inform hospital management and staff whether the preventive measures instituted are effective and valuable in developing targeted solutions.

Methods

This was a census survey study conducted at the Aga Khan University Hospital, Nairobi, between November 2020 and February 2021 before the implementation of the COVID-19 vaccination. The SARS-CoV-2 nucleocapsid IgG test was performed using a chemiluminescent assay.

Results

One thousand six hundred thirty-one (1631) staff enrolled, totalling 60% of the workforce. The overall crude seroprevalence was 18.4% and the adjusted value (for assay sensitivity of 86%) was 21.4% (95% CI; 19.2-23.7). The HCW groups with higher prevalence included pharmacy (25.6%), outreach (24%), hospital-based nursing (22.2%) and catering staff (22.6%). Independent predictors of a positive IgG result included prior COVID-19 like symptoms, odds ratio (OR) 1.9 [95% confidence interval (CI) 1.3-2.9, p=0.002], and a prior positive SARS-CoV-2 PCR result OR 11.0 (CI: 7.2-18.0, p<0.001). Age, sex, comorbidities or working in a COVID-19 designated area were not associated with seropositivity. The odds of testing positive for IgG after a positive PCR test were lowest if the antibody test was performed more than 2 months later; OR 0.7 (CI: 0.48-0.95, p= 0.025).

Conclusions

The prevalence of anti-SARS-CoV-2 nucleocapsid IgG among HCWs was lower than in the general population. Staff working in clinical areas were not at increased risk when compared to staff working in non-clinical areas.
Longitudinal change in cognition in older adults in Uganda: a prospective population study
Authors: Prynn Josephine E , Davey Calum , Davis Daniel , Kuper Hannah , Mugisha Joseph , Seeley Janet
Published: April 2022

Introduction

Dementia is an important and growing issue in sub-Saharan Africa, but epidemiological data are lacking. Risk factors may differ from other regions due to high stroke incidence and HIV prevalence. Understanding the epidemiology of cognition in older adults in Africa is crucial for informing public health strategies to improve the lives of people with dementia and their carers.

Methods

The Wellbeing of Older People Study in Uganda is an open cohort of adults aged 50+ with and without HIV, established in 2009. Detailed socio-demographic and health data have been collected at four waves spanning 10 years, including cognitive assessment using internationally validated WHO-recommended tests: verbal recall, digit span, and verbal fluency. Mortality data was collected until the end of the fourth wave (2019). We examined associations of low baseline cognition scores and cognitive decline over time, care needs of people with lower cognition, and the relationship between cognition and mortality.

Results

Data were collected on 811 participants. Older age, lower educational attainment, lower socio-economic position, and extremes of BMI were associated with lower cognition scores. Cognition declined faster at older ages, but rate of decline was not associated with cardiovascular disease or HIV. People with lower cognition required more assistance with Activities of Daily Living, but mortality rates were similar across the range of cognition.

Conclusions

The crucial next step will be investigating the determinants of low cognition scores and clinical dementia, to better understand the clinical relevance of these findings to inform public health planning in sub-Saharan Africa.
qPCR in a suitcase for rapid Plasmodium falciparum and Plasmodium vivax surveillance in Ethiopia
Authors: Carlier Lise , Baker Sarah Cate , Huwe Tiffany , Yewhalaw Delenasaw , Haileselassie Werissaw , Koepfli Cristian
Published: April 2022

Many Plasmodium spp. infections, both in clinical and asymptomatic patients, are below the limit of detection of light microscopy or rapid diagnostic test (RDT). Molecular diagnosis by qPCR can be valuable for surveillance, but is often hampered by absence of laboratory capacity in endemic countries. To overcome this limitation, we optimized and tested a mobile qPCR laboratory for molecular diagnosis in Ziway, Ethiopia, where transmission intensity is low. Protocols were optimized to achieve high throughput and minimize costs and weight for easy transport. 899 samples from febrile patients and 1021 samples from asymptomatic individuals were screened by local microscopy, RDT, and qPCR within a period of six weeks. 34/52 clinical Plasmodium falciparum infections were missed by microscopy and RDT. Only 4 asymptomatic infections were detected. No hrp2 deletions were observed among 25 samples typed, but 19/24 samples carried hrp3 deletions. The majority (25/41) of Plasmodium vivax infections (1371 samples screened) were found among asymptomatic individuals. All asymptomatic P. vivax infections were negative by microscopy and RDT. In conclusion, the mobile laboratory described here can identify hidden parasite reservoirs within a short period of time, and thus inform malaria control activities.
Protective efficacy of holed and aging PBO-pyrethroid synergist-treated nets on malaria infection prevalence in north-western Tanzania
Authors: Lukole Eliud , Cook Jackie , Mosha Jacklin F. , Messenger Louisa A , Rowland Mark , Kleinschmidt Immo , Charlwood Jacques D , Mosha Franklin W , Manjurano Alphaxard , Wright Alexandra , Protopopoff Natacha
Published: April 2022

Two billion pyrethroid long-lasting insecticidal nets (LLINs) have been distributed since 2010 for malaria prevention in Sub-Saharan Africa. Current malaria control strategies rely on an assumed effective 3-year lifespan for LLINs. PBO synergist LLINs are a newly recommended class but there is limited information on their life span and long-term protective efficacy in communities. To assess their operational survival, a cohort of 390 PBO LLINs (Olyset Plus) and 367 standard pyrethroid LLIN (Olyset net) from 396 households were followed for 36 months in Western Tanzania. To assess the association between the condition of the LLIN and malaria infection, nets from at least 480 randomly selected households were assessed during malaria prevalence cross-sectional surveys at 4, 9, 16, 21, 28, and 33 months post-distribution. Information on the presence and condition of nets, and demographic information from the household, were collected to evaluate factors influencing net durability. After 3 years less than 17% of nets distributed were available for sleeping. The fabric condition was not associated with malaria infection in either type of net. The difference between the net types was highest when nets were between 1-2 years old, when PBO nets appeared to be similarly protective as nets less than a year old, whereas standard nets were considerably less protective as they aged, regardless of fabric condition. There was no statistical difference in the estimated median functional survival time between net types with 1.6 years (95% CI 1.38-1.87) for PBO LLIN and 1.9 years (95% CI 1.67-2.06) for standard LLINs. After 3 years, there was a loss of 55% of permethrin content for both nets, and 97% of PBO content was lost in PBO LLIN. These results highlight that functional survival is less than the recommended 3 years for both net types. However, even as the nets age, the PBO nets remained more protective than standard nets, regardless of their condition.
Elucidating the genetic architecture of DNA methylation to identify promising molecular mechanisms of disease
Authors: Ma Jiantao , Joehanes Roby , Liu Chunyu , Keshawarz Amena , Shih-Jen Hwang , Bui Helena , Tejada Brandon , Sooda Meera , Munson Peter J. , Cumhur Demirkale Y. , Courchesne Paul , Heard-Costa Nancy L. , Pitsillides Achilleas N. , Feolo Mike , Sharopova Nataliya , Vasan Ramachandran S. , Huan Tianxiao , Levy Daniel
Published: April 2022

DNA methylation commonly occurs at cytosine-phosphate-guanine sites (CpGs) that can serve as biomarkers for many diseases. We analyzed whole genome sequencing data to identify DNA methylation quantitative trait loci (mQTLs) in 4,126 Framingham Heart Study participants. Our mQTL mapping identified 94,362,817 cis-mQTLvariant-CpG pairs (for 210,156 unique autosomal CpGs) at P<1e-7 and 33,572,145 trans-mQTL variant-CpG pairs (for 213,606 unique autosomal CpGs) at P<1e-14. Using cis-mQTL variants for 1,258 CpGs associated with seven cardiovascular disease risk factors, we found 104 unique CpGs that colocalized with at least one cardiovascular disease trait. For example, cg11554650 (PPP1R18) colocalized with type 2 diabetes, driven by a single nucleotide polymorphism (rs2516396). We performed Mendelian randomization (MR) analysis and demonstrated 58 putatively causal relations of CVD risk factor-associated CpGs to one or more risk factors (e.g., cg05337441 [APOB] with LDL; MR P=1.2e-99, and 17 causal associations with coronary artery disease (e.g. cg08129017 [SREBF1] with coronary artery disease; MR P=5e-13). We also showed that three CpGs, e.g., cg14893161 (PM20D1), are putatively causally associated with COVID-19 severity. To assist in future analyses of the role of DNA methylation in disease pathogenesis, we have posted a comprehensive summary data set in the National Heart, Lung, and Blood Institute’s BioData Catalyst.
Unlocking the multiphasic nature of intracellular calcium signatures triggered by fungal signals inLotus japonicusroots
Authors: Binci Filippo , Offer Elisabetta , Crosino Andrea , Sciascia Ivan , Kleine-Vehn Jürgen , Genre Andrea , Giovannetti Marco , Navazio Lorella
Published: April 2022

The recognition of different microbe-associated molecular patterns in the rhizosphere triggers in the plant root the activation of either an immune response or an accommodation program. In both types of responses, Ca2+is a crucial intracellular messenger, mediating the early stages of the respective signalling pathways. In this work, we analysed the cytosolic and nuclear Ca2+changes activated by a set of chitin-related oligomers in different genetic backgrounds ofLotus japonicusroots by using specifically targeted aequorin-based Ca2+reporters. By means of pharmacological and genetic approaches, we dissected the Ca2+signal into two temporally distinct components: a rapid initial transient, followed by a longer and milder elevation in Ca2+concentration. Taking advantage of a complementary analysis using a cameleon-based bioassay inMedicago truncatularoot organ cultures, we showed that the second phase can be interpreted as the Ca2+spiking that is widely described in response to the perception of symbiotic signals. By contrast, the rapid first phase, critically dependent on elicitor concentration, was found to correlate with the activation of plant immunity marker genes. Overall, our study provides novel clues to a better understanding of the subtle boundaries between symbiotic and immunity responses in root-fungus interactions.

Highlight

Intracellular calcium changes induced inLotus japonicusroots by fungal signals were dissected in two separate phases, relying on distinct genetic programs and differentially mediating plant symbiotic or immunity responses.
Effects of local versus global competition on reproductive skew and sex differences in social dominance behaviour
Authors: Leimar Olof , Bshary Redouan
Published: April 2022

Social hierarchies are often found in group-living animals. The hierarchy position can influence reproductive success (RS), with a skew towards high-ranking individuals. The amount of aggression in social dominance varies greatly, both between species and between males and females within species. Using game theory we study this variation by taking into account the degree to which reproductive competition in a social group is mainly local to the group, emphasising within-group relative RS, or global to a larger population, emphasising an individual’s absolute RS. Our model is similar to recent approaches in that reinforcement learning is used as a behavioural mechanism allowing social-hierarchy formation. We test two hypotheses. The first is that local competition should favour the evolution of mating or foraging interference, and thus of reproductive skew. Second, decreases in reproductive output caused by an individual’s accumulated fighting damage, such as reduced parenting ability, will favour less intense aggression but should have little influence on reproductive skew. From individual-based simulations of the evolution of social dominance and interference, we find support for both hypotheses. We discuss to what extent our results can explain observed sex differences in reproductive skew and social dominance behaviour.
The cilia enriched oxysterol 7β,27-DHC is required for polycystin activation
Authors: Ha Kotdaji , Mundt Nadine , Bisignano Paola , Pinedo Aide , Cao Erhu , Reiter Jeremy F. , Raleigh David R. , Delling Markus
Published: April 2022

PC-1 and PC-2 form a heteromeric ion channel complex (hereafter called the Polycystin complex) that is abundantly expressed on primary cilia of renal epithelial cells. Mutations within the polycystin complex cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). The Polycystin complex forms a non-selective cation channel, yet the spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood, partially due to technical limitations posed by the tiny ciliary compartment. Here, we employ our novel assays to functionally reconstitute the polycystin complex in the plasma membrane. Using whole-cell and ciliary patch-clamp recordings we identified a ciliary enriched oxysterol, 7β,27-DHC, as a critical component required for activation of the polycystin complex. We identified a novel oxysterol binding pocket in PC-2 using molecular docking simulation. We also identified two amino acids within the PC-2 oxysterol binding pocket, E208 and R581, to be critical for 7β,27-DHC dependent polycystin activation in both the plasma membrane and ciliary compartment. Further, we can show that the pharmacological and genetic inhibition of oxysterol synthesis by carbenoxolone (CNX) reduces channel activity in primary cilia. Our findings identified a unique second messenger that regulates the polycystin complex. We hypothesize that cilia-enriched lipids license the polycystin complex to be functional only in the ciliary organelle, thus providing novel insights into the spatial regulation of the polycystin complex. Our results also establish a framework to target the same allosteric regulatory site in the polycystin complex to identify activators of the polycystin channels as novel therapeutic strategies for ADPKD.
A quantitative and spatial analysis of cell cycle regulators during the fission yeast cycle
Authors: Curran Scott , Dey Gautam , Rees Paul , Nurse Paul
Published: April 2022

We have carried out a systems-level analysis of the spatial and temporal dynamics of cell cycle regulators in the fission yeastSchizosaccharomyces pombe. In a comprehensive single cell analysis we have precisely quantified the levels of 38 proteins previously identified as regulators of the G2 to mitosis transition, and of 7 proteins acting at the G1 to S-phase transition. Only two of the 38 mitotic regulators exhibit changes in concentration at the whole cell level, the mitotic B-type cyclin Cdc13 which accumulates continually throughout the cell cycle, and the regulatory phosphatase Cdc25 which exhibits a complex cell cycle pattern. Both proteins show similar patterns of change within the nucleus as in the whole cell but at higher concentrations. In addition, the concentrations of the major fission yeast cyclin dependent kinase (CDK) Cdc2, the CDK regulator Suc1 and the inhibitory kinase Wee1 also increase in the nucleus peaking at mitotic onset but are constant in the whole cell. The significant increase in concentration with size for Cdc13 supports the model that mitotic B-type cyclin accumulation acts as a cell size sensor. We propose a two-step process for the control of mitosis. First, Cdc13 accumulates in a size-dependent manner which drives increasing CDK activity. Second, from mid G2 the increasing nuclear accumulation of Cdc25 and the counteracting Wee1 introduces a bistability switch that results in a rapid rise of CDK activity at the end of G2 and thus brings about an orderly progression into mitosis.

Significance Statement

Across eukaryotes the increasing level of cyclin dependent kinase (CDK) activity drives progression through the cell cycle. As most cells divide at specific sizes, information responding to the size of the cell must feed into the regulation of CDK activity. In this study, we use fission yeast to precisely measure how proteins that have been previously identified in genome wide screens as cell cycle regulators change in their levels with cell cycle progression. We identify the mitotic B-type cyclin Cdc13 and mitotic inhibitory phosphatase Cdc25 as the only two proteins that change in both whole cell and nuclear concentration through the cell cycle, making them candidates for universal cell size sensors at the onset of mitosis and cell division.
Resolving subcellular pH with a quantitative fluorescent lifetime biosensor
Authors: Rennick Joshua J. , Nowell Cameron J. , Pouton Colin W. , Johnston Angus P.R.
Published: April 2022

Changes in sub-cellular pH play a key role in metabolism, cell growth, membrane transport, and can also be exploited to control cargo release from therapeutic delivery systems. Most methods to measure pH rely on intensity changes of pH sensitive fluorophores, however these measurements are hampered by high uncertainty in the inferred pH and the need for multiple fluorophores. To address this, we have developed a method to accurately quantify sub-cellular pH in individual vesicles using fluorescent lifetime imaging microscopy (pHLIM). pHLIM exploits the linear pH dependant lifetime of the fluorescent protein mApple and uses deep learning models to automatically identify and measure the pH of subcellular compartments. We have engineered mApple fusion proteins to measure the pH of the cytosol, endosomes, lysosomes and demonstrated the utility of pHLIM by measuring pH changes induced by drugs (bafilomycin A1) and polyethylenimine (a common transfection reagent). pHLIM is a simple and quantitative method to measure sub-cellular pH that has the potential to help with the design of the next generation of controlled drug release systems and to understand drug action and disease progression.
The transcription factor RXRA regulates lipid metabolism in duck myoblasts by the CD36 network
Authors: Pan Ziyi , Li Guoyu , Du Guoqing , Wu Dongsheng , Li Xuewen , Wang Yu , Zhao Junxian , Zhang Xiran , Chen Xingyong , Zhang Chen , Jing Sihua , Geng Zhaoyu
Published: April 2022

Lipid metabolism is a highly complex metabolic process regulated at multiple levels. RXRA is a well-characterized factor that regulates lipid metabolism. To explore the function and mechanism of the transcription factor RXRA in myoblasts, and to further explore the key factors that RXRA regulates the target gene CD36 signaling network to regulate lipid metabolism. We found that the transcription factor RXRA inhibited the accumulation of triglycerides (TGs), cholesterol (CHOL) and non-esterified fatty acids (NEFA) in CS2 cells by regulating CD36 as well as the fatty acid beta oxidation pathway. CD36 functions similar to RXRA in myoblasts. CD36 overexpression reduced the levels of TGs, CHOL, NEFAs and saturated fatty acids (SFAs) in these cells, while CD36 knockout increased the levels of TGs, CHOL, NEFAs, SFAs and monounsaturated fatty acids (MUPAs) in these cells. GRB2, MAP1B, SLC38A1, SLC4A7, NCOA3, PKIA, MOB2, SAA2 and RXRA are involved in the CD36 promotion of lipid efflux through lipid metabolism, endocytosis and amino acid metabolism. Considering these results, we propose that RXRA regulates lipid metabolism in myoblasts by regulating the CD36 signaling network.
N-terminal helices and A domain of archaeal FtsY facilitate SRP54 binding and the association with cell membrane
Authors: Gupta Sayandeep , Sinha Souvik , Bhakta Koustav , Bhowmick Arghya , Ghosh Abhrajyoti
Published: April 2022

The process of protein translocation is essential to the maintenance of cellular life and has been critically addressed in eukaryotes and bacteria. However, little information is available regarding protein translocation across archaeal membranes. The signal recognition particle (SRP) plays an important role in this process. It binds the signal peptide at the N-terminus of the polypeptide chain and interacts with the cognate SRP receptor (FtsY) located on the target membrane to form a targeting complex (TC). Concomitant GTP hydrolysis by SRP and FtsY delivers the polypeptide to the adjacent protein-conducting channel. The present study aims to characterize the structural domains of FtsY contributing to the targeting complex (TC) formation in Sulfolobus acidocaldarius, a thermo-acidophilic crenarchaeon. The contacting residues between SRP54 and FtsY were mapped along the αN1-N3 helices. Interestingly, the previously reported crystal structure did not take the N-terminal A domain into account – a region rich in negatively charged residues. Such observation led us to investigate the contribution of each of the three participating helices (αN1-3) in terms of membrane association and functional TC formation. Through biophysical analyses of SRP-FtsY and FtsY-membrane interaction, and biochemical characterization of the reciprocal GTPase activity, this work sought to elucidate the minimal structural motif controlling the archaeal TC assembly.
BCL-xL antagonizes the deleterious effects of KRAS on mitochondrial scaffolding
Authors: Belaid NM , Basseville A , Andre-Gregoire G , Fetiveau A , Maillet L , Guillonneau F , Leduc M , Guette C , Desaubry L , Gavard J. , Gautier F , Juin PP
Published: April 2022

In addition to its canonical role as a regulator of mitochondrial outer membrane permeabilization, BCL-xL exerts diverse non canonical functions contributing to cancer cell aggressiveness. In particular it regulates KRAS intracellular activation levels. We herein explored the mechanistic basis for this effect by a spatially restricted biotin-labelling proteomic approach designed to characterize proteins whose proximity to KRAS, used as a bait, is BCL-xL dependant. BCL-xL loss relocalizes KRAS to the vicinity of mitochondrial proteins. Proximal proteins include the mitochondrial scaffold prohibitin 2 (PHB2), which also interacts with BCL-xL and the downregulation of which prevents BCL-xL sensitive effects of KRAS induced contacts between mitochondria and endosomes, and mitochondrial mass decrease. These results argue that BCL-xL prevents a negative feedback regulation of KRAS canonical signaling by KRAS interference with mitochondrial quality control.
A bug’s tale: revealing the history, biogeography and ecological patterns of 500 years of insect introductions
Authors: López Daniela N. , Fuentes-Contreras Eduardo , Ruiz Cecilia , Ide Sandra , Estay Sergio A.
Published: April 2022

The arrival of Europeans to the Americas triggered a massive exchange of organisms on a continental scale. This exchange was accelerated by the amazing increase in the movement of people and goods during the 20th century. In Chile, scientific and technical literature contains hundreds of records of exotic insect species in different parts of the territory, from the hyperarid Atacama Desert to the Magallanes Region. Here, we analyze the biological patterns obtained from the database of introductions of exotic insects to Chile from the European arrival to the present. Our task includes a review of old records in museums, libraries, collections, expedition records and catalogs. Almost 600 species of exotic insects have been reported in Chile. Introductions started at the very arrival of Europeans to the central valley of Chile and underwent a huge acceleration in the second half of the 20th century. The order Hemiptera was the most prevalent among introduced insects. Most species are linked to agriculture and forestry. Species are of Palearctic origin in more than 50% of the records. In terms of temporal trends, the rate of introduced species shows an abrupt increase at the beginning of the 1950s. This change may be associated with the strong development in agriculture and forestry in Chile after World War II and the increase in intercontinental air traffic. We believe that the understanding of past patterns of introductions is an important component in the design of current policies to minimize the impact of invasive insects.
Cycling for climate and public health: a missed opportunity for France
Authors: Schwarz Emilie , Leroutier Marion , Quirion Philippe , Jean Kévin
Published: April 2022

In addition to its potential contribution to reaching climate targets, cycling may generate substantial population-level health benefits through the physical activity it requires. Due to the lack of nationally representative mobility data, the health impact of current levels of cycling is still unknown for France. Relying on a health impact assessment framework and using recent nationally-representative data on mobility, we assessed the health and related economic benefits of cycling in 2018-2019 in France. We show that such benefits remain moderated and fall short when compared to those estimated in other countries with high cycling levels. We argue that cycling in France did not receive the attention and investments it deserves over the past decade and thus represents a missed opportunity for climate action and public health.
Art therapy as treatment modality for persons living with dementia- a protocol for a scoping review of systematic reviews
Authors: Guseva Elena , Wilchesky Machelle
Published: April 2022

Objective

To establish a robust understanding of the state of the evidence on the effectiveness and/or efficacy of art therapy (AT) as a non-pharmacological treatment (NPT) modality for persons living with dementia (PLWD).

Background

Over the past decade, AT has received increased attention from health care professionals and researchers as having a potential role to play within treatment plans for PLWD.(1-4)

Inclusion criteria

This scoping review will include systematic reviews from health-related disciplines conducted within the last 20 years that report the effectiveness and/or efficacy of AT as an NPT modality for PLWD and Mild Cognitive Impairment (MCI) as their main objective. Study outcomes must include cognition, quality of life, emotional and psychological well-being, and/or neuropsychiatric symptoms (NPS).

Methods

A scoping review of systematic reviews was selected to outline different types of evidence and to identify gaps in the literature. The proposed review will be guided by the methodological framework proposed by the Joanna Briggs Institute. We will therefore specify the research question, identify relevant studies, select eligible studies, extract, collate, and summarize our results. We will not conduct a quality appraisal of the included studies as this review aims to explore the general scope of research conducted that assesses AT effectiveness and efficacy in PLWD.
MOSAIC (MOthers’ AdvocateS In the Community) for Pregnant Women and Mothers of Children Under 5 with Experience of Intimate Partner Violence: A pilot randomized trial study protocol
Authors: Hailemariam Maji , Zlotnick Caron , Taft Angela , Johnson Jennifer E.
Published: April 2022

Background

Pregnancy and motherhood increase the risk for long-term exposure to physical, psychological and sexual intimate partner violence (IPV; sexual or physical violence by current or former partners). Pregnant women and mothers with children under 5 who have experienced IPV exhibit poor physical and mental health and obstetric outcomes. Depression and posttraumatic stress disorder (PTSD) are the two most common mental health consequences of IPV. There is good evidence that women with good social support have better mental health and IPV outcomes.

Methods

This study will develop MOthers’ AdvocateS In the Community (MOSAIC) Plus intervention for pregnant women and mothers with children under the age of 5. MOSAIC uses trained mentor mothers and has been found to reduce subsequent IPV. This study will blend the original MOSAIC intervention with principles of interpersonal psychotherapy (IPT) to address symptoms of depression, PTSD, and prevent subsequent risk of IPV. We will conduct a pilot randomized trial of the MOSAIC Plus intervention compared to the traditional MOSAIC intervention to determine its feasibility and acceptability. Study samples include focus groups (n=36), open trial (n=15), and a randomized pilot trial including 40 pregnant women and mothers with children under 5 who report current/recent of IPV and elevated symptoms of maternal depression and/or PTSD. The study’s primary outcome will be changes in maternal depressive and PTSD symptoms. Secondary outcomes will include reduction in subsequent IPV, improvement in functioning, changes in social support and effectiveness in obtaining resources.

Discussion

This is a formative study evaluating the feasibility and acceptability of a mentor mother intervention for pregnant women and mothers with children under 5. Promising results of this study will be used for a larger, fully-powered randomized trial evaluating the effectiveness of a mentor mother intervention in preventing subsequent IPV and reducing depressive and PTSD symptoms in this population.

Strengths and limitations of this study

The study is informed by a robust qualitative approach to intervention development that involves a series of focus group discussions.

This study aims to develop an intervention that reduces future intimate partner violence, while also addressing related maternal mental health outcomes.

A rigorous and reproducible design includes randomization, clear inclusion criteria, manualized treatment protocols and fidelity assessments.

The study will use reliable and validated measures.

Given the small sample size, results from the pilot randomized trial are underpowered to draw firm conclusions about effectiveness.
Medical Exemptions to Vaccination — Riverside County, California, 2016–2019
Authors: Kaiser Cameron , Geiger Tonya , Lynch Cassandra , Rivera Anna
Published: April 2022

Objectives

To review the nature and clinical reasoning of medical exemptions to vaccination received in Riverside County, CA after California Senate Bill 277 eliminated personal belief exemptions statewide.

Methods

614 deduplicated medical exemptions to vaccination from 156 providers were reviewed from August 2016 to August 2019. Exemptions covering all vaccines were additionally coded for number and category of medical justification.

Results

81.3% of reviewed exemptions were for all vaccines, 91.0% were permanent or indefinite, and 74.9% were for all vaccines and permanent or indefinite. Of the 490 evaluated all-vaccine exemptions, a median of two and maximum of ten justifications were cited per exemption, most often a family history of autoimmune disease other than allergy. Three providers wrote more than 70 exemptions each.

Conclusions

The number and nature of the exemptions reviewed here raise concerns over their impact on immunization rates, and future policies may need to ensure additional oversight.
How does target lesion selection affect RECIST? A computer simulation study
Authors: Bucho Teresa T. , Tissier Renaud , Lipman Kevin Groot , Bodalal Zuhir , Pizzi Andrea Delli , Nguyen-Kim Thi Dan Linh , Beets-Tan Regina , Trebeschi Stefano
Published: April 2022

RECIST is grounded on the assumption that target lesion selection is objective and representative of the change in total tumor burden during therapy. A computer simulation model was designed to challenge this assumption, focusing on a particular aspect of subjectivity: target lesion selection. Disagreement among readers, and between readers and total tumor burden was analyzed, as a function of the total number of lesions, affected organs, and lesion growth. Disagreement aggravates when the number of lesions increases, when lesions are concentrated on few organs, and when lesion growth borders the thresholds of progressive disease and partial response. An intrinsic methodological error is observed in the estimation of total tumor burden (TTB) via RECIST. In a metastatic setting, RECIST displays a non-linear, unpredictable behavior. Our results demonstrate that RECIST can deliver an accurate estimate of total tumor burden in localized disease, but fails in cases of distal metastases and multiple organ involvement. This is worsened by the “selection of the largest lesions”, which introduce a bias that makes it hardly possible to perform an accurate estimate of the total tumor burden. Including more (if not all) lesions in the quantitative analysis of tumor burden is desirable.
Top-down modulation and cortical-AMG/HPC interaction in familiar face processing
Authors: Fan Xiaoxu , Guo Qiang , Zhang Xinxin , Fei lingxia , He Sheng , Weng Xuchu
Published: April 2022

Humans can accurately recognize familiar faces in only a few hundred milliseconds, but the underlying neural mechanism remains unclear. Here we recorded intracranial electrophysiological signals from ventral temporal cortex (VTC), superior/middle temporal cortex (STC/MTC), medial parietal cortex (MPC) and amygdala/hippocampus (AMG/HPC) in 20 epilepsy patients while they viewed faces of famous people and strangers as well as common objects. In posterior VTC and MPC, familiarity-sensitive responses emerged significantly later than initial face-selective responses, suggesting that familiarity enhances face representations after they are first being extracted. Moreover, viewing famous faces increased the coupling between cortical areas and AMG/HPC in multiple frequency bands. These findings imply that the top-down modulation in local face-selective response and interactions between cortical face areas and AMG/HPC contribute to the superior recognition of familiar faces.

Teaser

Top-down modulation and cortical-AMG/HPC interactions contribute to the superior processing of familiar faces.
Exact polynomial-time graph canonisation and isomorphism testing through comparison of ordered vertex eigenprojections
Authors: O’Shea Robert John
Published: April 2022

Motivation

Graph canonisation and isomorphism testing representation are fundamental computational problems, whose complexity has remained unsolved to date. This study examines graph eigenprojections, demonstrating that linear-ordering transformations induce canonical properties therein to yield polynomial-time canonisation and isomorphism testing in all undirected graphs.

Results

This study presents an exact method to identify analogous vertices in isomorphic graphs, through comparison of vertices’ eigenprojection matrices, which are shown to be related by a linear permutation. Systematic perturbation strategies are developed to reduce degeneracy whilst conserving isomorphism, through the addition of characteristically weighted self-loops to analogous vertices. Repeated iterations of analogy testing and perturbation deliver canonical vertex labelling and recovery of isomorphic mappings in time in all graphs. Analytical proofs are provided to support claims and experimental performance is demonstrated in biological and synthetic data, with comparison to a commonly used heuristic algorithm.

Availability and Implementation

Source code is provided at github.com/robertoshea/graph_isomorphism.

Contact

robert.1.oshea@kcl.ac.uk

Supplementary Data.

Not applicable.
Bidirectional alterations in brain temperature profoundly modulate spatiotemporal neurovascular responses in-vivo: Implications for theragnostics
Authors: Boorman Luke W. , Harris Samuel S. , Shabir Osman , Lee Llywelyn , Eyre Beth , Howarth Clare , Berwick Jason
Published: April 2022

Neurovascular coupling (NVC) is a mechanism that, amongst other known and latent critical functions, ensures activated brain regions are adequately supplied with oxygen and glucose. This biological phenomenon underpins non-invasive perfusion-related neuroimaging techniques and recent reports have implicated NVC impairment in several neurodegenerative disorders. Yet, much remains unknown regarding NVC in health and disease, and only recently has there been burgeoning recognition of a close interplay with brain thermodynamics. Accordingly, we developed a novel multi-modal approach to systematically modulate cortical temperature and interrogate the spatiotemporal dynamics of sensory-evoked NVC. We show that changes in cortical temperature profoundly and intricately modulate NVC, with low temperatures associated with diminished oxygen delivery, and high temperatures inducing a distinct vascular oscillation. These observations provide novel insights into the relationship between NVC and brain thermodynamics, with important implications for brain-temperature related therapies, functional biomarkers of elevated brain temperature, and in-vivo methods to study neurovascular coupling.
Cooperative ectodomain interaction among TCRαβ, CD3γε, and CD3δε enhances TCR mechanotransduction
Authors: Yuan Zhou , Cong Peiwen , Natarajan Aswin , Ge Chenghao , Travaglino Stefano , Beesam Saikiran , Grazette Danielle , Krogsgaard Michelle , Zhu Cheng
Published: April 2022

The T-cell receptor (TCR) complex comprises TCRαβ, CD3γε, CD3δε, and CD3ζζ. TCRαβ engagement with peptide-bound major histocompatibility complex (pMHC) triggers CD3 phosphorylation, which is regulated by mechanical force. However, the inner workings of the TCR mechanotransduction machinery remains unclear. TCR ectodomain (ECD) interactions have been inferred from structural and mutagenesis studies. Due to their extreme weakness, however, direct measurements of affinity had failed and of force regulation have never been attempted. Here we measured two-dimensional affinities and force-dependent lifetimes of interactions among TCRαβ, CD3γε, and CD3δε ECDs, showing a cooperative CD3δε–TCRαβ–CD3γε catch bond with longer- lasting lifetime that exceeds the TCR–pMHC bond lifetime. Molecular dynamics stimulations revealed a central interacting region surrounded by TCR ECDs and identified critical interacting residues at their interfaces. Interfering TCR ECD interactions by antibodies impaired TCR–pMHC interaction and T cell function. Mutating residues that mediate TCR ECD cis-interactions with CD3s altered the catch bond of TCR–pMHC trans-interaction, which correlates with changed T cell cytokine production. Thus, TCR mechanotransduction is supported by cooperative TCR ECD interactions, which regulates T cell function. Our results provide a missing link between pMHC ligation and CD3 signaling and may guide future TCR engineering design for immunotherapies.
WNT5A-RHOA axis is a new vulnerability in small-cell lung cancer
Authors: Kim Kee-Beom , Kim Dong-Wook , Kim Youngchul , Tang Jun , Kirk Nicole , Gan Yongyu , Fang Bingliang , Park Jae-Il , Zheng Yi , Park Kwon-Sik
Published: April 2022

WNT signaling presents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers including small-cell lung cancer (SCLC). Here we show that beta-catenin, a master mediator of canonical WNT signaling, is not required for SCLC development in genetically engineered mouse models (GEMMs) and its transcriptional program is largely silenced during tumor development. Instead, inactivation of p130 in SCLC cells induces expression of WNT5A, a ligand for beta-catenin-independent WNT pathways. WNT5A is both sufficient and required for SCLC development and cell proliferation and selectively induces Rhoa transcription and activates RHOA protein to drive SCLC. Rhoa knockout suppresses SCLC development in vivo, and chemical perturbation of RHOA selectively inhibits SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A-RHOA axis in SCLC that is distinct from other noncanonical WNT pathways. This vulnerability of p130-WNT5A-RHOA pathway provides critical insight into the development of novel therapeutic strategies for the recalcitrant cancer, as well as the stratification of patients who may benefit from them. This study also sheds new light on the heterogeneity of WNT signaling and the molecular determinants of its cell-type specificity.
Integrative chromatin domain annotation through graph embedding of Hi-C data
Authors: Shokraneh Neda , Arab Mariam , Libbrecht Maxwell
Published: April 2022

Motivation

The organization of the genome into domains plays a central role in gene expression and other cellular activities. Researchers identify genomic domains mainly through two views: 1D functional assays such as ChIP-seq, and chromatin conformation assays such as Hi-C. Fully understanding domains requires integrative modeling that combines these two views. However, the predominant form of integrative modeling uses segmentation and genome annotation (SAGA) along with the rigid assumption that loci in contact are more likely to share the same domain type, which is not necessarily true for epigenomic domain types and genome-wide chromatin interactions.

Results

Here, we present an integrative approach that annotates domains using both 1D functional genomic signals and Hi-C measurements of genome-wide 3D interactions without the use of a pairwise prior. We do so by using a graph embedding to learn structural features corresponding to each genomic region, then inputting learned structural features along with functional genomic signals to a SAGA algorithm. We show that our domain types recapitulate well-known subcompartments with an additional granularity that distinguishes a combination of the spatial and functional states of the genomic regions. In particular, we identified a division of the previously-identified A2 subcompartment such that the divided domain types have significantly varying expression levels.

Availability

https://github.com/nedashokraneh/IChDA

Contact

maxwl@sfu.ca

Supplementary information
Infected I. scapularis nymphs maintained in prolonged questing under optimal environmental conditions for one year can transmit B. burgdorferi to uninfected hosts
Authors: Samanta Kamalika , Azevedo Jose F. , Nair Nisha , Kundu Suman , Gomes-Solecki Maria
Published: April 2022

In recent decades, Lyme disease has been expanding to previous non-endemic areas. We hypothesized that infected I. scapularis nymphs that retain host-seeking behavior under optimal environmental conditions are fit to fulfil their transmission role in the enzootic cycle of B. burgdorferi. To test this hypothesis, we produced nymphal ticks in the laboratory under controlled temperature (22-25°C), humidity (80-90%) and natural daylight cycle conditions to allow them to retain host-seeking/questing behavior for 1 year. We then analyzed differences in B. burgdorferi infection prevalence in questing and diapause nymphs at 6 weeks post-molting (prime questing) as well as differences in infection prevalence of questing nymphs maintained under prolonged environmental induced questing over 12 months (prolonged questing). Lastly, we analyzed the fitness of nymphal ticks subjected to prolonged questing in transmission of B. burgdorferi to naïve mice over the course of the year. Our study shows that B. burgdorferi infected unfed I. scapularis nymphal ticks maintained under optimal environmental conditions in the laboratory not only survived for a year in a developmental state of prolonged questing (host-seeking), as they retained an infection prevalence sufficient to effectively fulfil transmission of B. burgdorferi to uninfected mice after tick challenge. Our study is important for understanding and possibly modeling Lyme disease expansion into former non-endemic regions due to global warming.

IMPORTANCE

Lyme disease is rapidly spreading from its usual endemic areas in the Northeast, Midwest and Midatlantic states into neighboring areas which could be due to changing climate patterns. Our study shows that unfed I. scapularis nymphal ticks kept under optimal environmental conditions in the laboratory survived for a year while exhibiting aggressive host-seeking behavior and they maintained a B. burgdorferi infection prevalence which was sufficient to infect naïve reservoir hosts after tick challenge. Our study raises important questions regarding prolonged survival of B. burgdorferi infected host-seeking nymphal I. scapularis ticks that can potentially increase the risk of Lyme disease incidence, if conditions of temperature and humidity become amenable to the enzootic cycle of B. burgdorferi in regions currently classified as non-endemic.
Roseoflavin, a natural riboflavin analogue, possesses in vitro and in vivo antiplasmodial activity
Authors: Hemasa Ayman , Mack Matthias , Saliba Kevin J.
Published: April 2022

The ability of the human malaria parasite Plasmodium falciparum to access and utilise vital nutrients is critical to its growth and proliferation. Molecules that interfere with these process could potentially serve as antimalarials. We found that two riboflavin analogues, roseoflavin and 8-aminoriboflavin, inhibit malaria parasite proliferation by targeting riboflavin metabolism and/or the utilisation of the riboflavin metabolites flavin mononucleotide and flavin adenine dinucleotide. An additional eight riboflavin analogues were evaluated, but none were found to be more potent than roseoflavin, nor was their activity on target. Focussing on roseoflavin, we tested its antimalarial activity in vivo against Plasmodium vinckei vinckei in mice. We found that roseoflavin decreased the parasitemia by 46-fold following a 4 day suppression test and, on average, increased the survival of mice by 4-5 days. Our data are consistent with riboflavin metabolism and/or the utilisation of riboflavin-derived cofactors being viable drug targets for the development of new antimalarials and that roseoflavin could serve as a potential starting point.