bluuebunny/crossref_metadata_2025 huggingface dataset:
Larvicidal effect of some traditional Saudi Arabian herbs againstAedes aegyptilarvae, a vector of dengue fever
Authors: Sharawi Somia Eissa
Published: September 2023

Mosquitoes are effective disease vectors for human and veterinary health because they share a close environment with humans and represent a major public health problem. Saudi Arabia is home to the endemic dengue fever disease, carried by theAedes aegyptimosquito. Conventional insecticides based on organophosphates and insect growth regulators are the most effective short-term control methods for this vector. However, these insecticides are toxic to non-target organisms, the environment, and humans. This study, eight plant extracts (Ilex paraguariensis, Camellia sinensis, Cinnamomum zeylanicum, Elettaria cardamomum, Matricaria chamomilla, Allium sativum, Coffea arabica, andPiper nigrum) were assayed as an insecticide against the 3rdand 4thlarval stage ofAe. aegypti(L.), after 24 and 48 h of exposure in the duration between March and June 2023. After 48h, all plants extracted showed the highest mortality (100%), except forC. arabicawhich showed the lowest mortality rate (98.33%) at 30%.I. paraguariensisshowed the greatest effectiveness with an LC50=7.17 ppm, followed byP. nigrumwith an LC50= 5.66 ppm. Further investigation is needed to purify the active ingredients responsible for their toxicity to mosquito larvae and to investigate the mechanisms of action of plant extracts in water and other solvents.
Identifying the fungal diseases of African Yam Bean (Sphenostylis stenocarpa[Hochst ex. A. Rich.] Harms) and their occurrence in South-West Nigeria
Authors: Oyedele Temitope , Kehinde Iyabo , Atanda Habeeb Yinka , Oyelakin Abiodun , Popoola Tope , Mur Luis A. J.
Published: September 2023

Sphenostylis stenocarpa,commonly known as African yam bean (AYB), is an orphan crop with high nutritional properties but low yield production due to diseases. Hence, this study accessed the diversity and pathogenicity of fungi associated with AYB in Southwest (SW) Nigeria as a model area of cultivation. The incidence of fungi infecting AYB were surveyed in Oyo, Ondo, Ekiti, Osun, and Ogun states within SW Nigeria during 2018 planting season. The common field symptoms across all sites were tiny spot, brown spot, leaf blight, brown spot with yellow halo, necrotic lesion, and brown spot on pods. A total of 1005 fungi were isolated from leaf and pod samples, and identified morphologically on pure cultures asAspergillussp, Botrytissp, Colletotrichum gloeosporioides, Curvularia lunata, Trichoderma harzianum, Macrophomina phaseolina, Pestalotiasp, Phomasp,Fusarium verticillioides, F. oxysporum, F. solani,Botryodiplodia theobromae, andChoanephora curcubitarium and Nigrospora spp. Phomasp andC. gleosporoideshad highest frequency of occurrence 69.9% and 51.9% at early and mature stages, respectively. To conform to Koch’s postulates, the pathogenicities of 12 exemplar strains of the most abundant fungal species were confirmed in controlled glasshouse tests. The identities ofColletotrichumsp.,Aspergillussp., Didymellasp., Pestalopsissp,Lasiodiplodia theobromae,F. solaniandF. oxysporumwere confirmed based on internal transcribed spacer (ITS) sequencing and comparisons with the Genbank database. AYB germplasm from curated seed banks and farmer donated landraces were grown at the same site in 2020 and identical fungi were isolated. Further, genotypes with reduced disease incidences and incidences were identified. This first study to reveal the diversity of fungi associated with AYB in SW Nigeria that could inform disease management practices.
Dietary risk factors for monoclonal gammopathy of undetermined significance in a racially diverse population
Authors: Joseph Janine M. , Hillengass Jens , Tang Li , Lesokhin Alexander M. , Landgren Ola , Usmani Saad Z. , Moysich Kirsten B. , McCann Susan E. , Shah Urvi A.
Published: September 2023

Monoclonal gammopathy of undetermined significance (MGUS) – a precursor of multiple myeloma – is associated with shorter lifespan and cardiac, renal, neurologic, and immune-related comorbidities. There is little known about modifiable risk factors for this condition. To determine if risk of MGUS is associated with dietary factors in a racially diverse population, we conducted a United States population-based case-control study from the National Health and Nutrition Examination Survey (1988-2004), which included 373 individuals with MGUS and 1,406 matched controls. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. Unconditional multivariable logistic regressions were used to model associations between intake of several food groups and MGUS, with odds ratios (OR) and 95% confidence intervals (95% CI) reported for the highest relative to the lowest quantile of intake. Daily gram intake of several food and beverage groups were significantly associated with MGUS. MGUS was inversely associated with whole-grain bread, oats, and rice (OR 0.70; 95% CI 0.48-1.00;P<0.05), fruits (excluding juice) and vegetables (OR 0.69; 95% CI 0.52-0.93;P=0.02), vegetables (OR 0.75; 95% CI 0.56-0.99;P<0.05), tomatoes (OR 0.72; 95% CI 0.51-1.00;P<0.05), and cruciferous vegetables (OR 0.44; 95% CI 0.26-0.74;P<0.01). Direct associations were observed for sugar-sweetened beverages (OR 1.34; 95% CI 1.00-1.78;P<0.05), sugar-sweetened soft drinks (OR 1.41; 95% CI 1.01-1.96;P=0.04), and artificially sweetened soft drinks (OR 1.55; 95% CI 1.04-2.33;P=0.03). Our study shows that diet is potentially a modifiable risk factor for MGUS.
Non-invasive estimation of pressure drop across aortic coarctations: validation of 0D and 3D computational models within vivomeasurements
Authors: Nair Priya J. , Pfaller Martin R. , Dual Seraina A. , McElhinney Doff B. , Ennis Daniel B. , Marsden Alison L.
Published: September 2023

Purpose

Blood pressure gradient (ΔP) across an aortic coarctation (CoA) is an important measurement to diagnose CoA severity and gauge treatment efficacy. Invasive cardiac catheterization is currently the gold-standard method for measuring blood pressure. The objective of this study was to evaluate the accuracy ofΔP estimates derived non-invasively using patient-specific 0D and 3D deformable wall simulations.

Methods

Medical imaging and routine clinical measurements were used to create patient-specific models of patients with CoA (N=17). 0D simulations were performed first and used to tune boundary conditions and initialize 3D simulations.ΔP across the CoA estimated using both 0D and 3D simulations were compared to invasive catheter-based pressure measurements for validation.

Results

The 0D simulations were extremely efficient (∼15 secs computation time) compared to 3D simulations (∼30 hrs computation time on a cluster). However, the 0DΔP estimates, unsurprisingly, had larger mean errors when compared to catheterization than 3D estimates (12.1±9.9 mmHg vs 5.3±5.4 mmHg). In particular, the 0D model performance degraded in cases where the CoA was adjacent to a bifurcation. The 0D model classified patients with severe CoA requiring intervention (defined asΔP≥20 mmHg) with 76% accuracy and 3D simulations improved this to 88%.

Conclusion

Overall, a combined approach, using 0D models to efficiently tune and launch 3D models, offers the best combination of speed and accuracy for non-invasive classification of CoA severity.
Cas9 is mostly orthogonal to human systems of DNA break sensing and repair
Authors: Maltseva Ekaterina A. , Vasil’eva Inna A. , Moor Nina A. , Kim Daria V. , Dyrkheeva Nadezhda S. , Kutuzov Mikhail M. , Vokhtantsev Ivan P. , Kulishova Lilya M. , Zharkov Dmitry O. , Lavrik Olga I.
Published: September 2023

CRISPR/Cas9 system is а powerful gene editing tool based on the RNA-guided cleavage of target DNA. The Cas9 activity can be modulated by proteins involved in DNA damage signalling and repair due to their interaction with double- and single-strand breaks (DSB and SSB, respectively) generated by wild-type Cas9 or Cas9 nickases. Here we address the interplay betweenStreptococcus pyogenesCas9 and key DNA repair factors, including poly(ADP-ribose) polymerase 1 (SSB/DSB sensor), its closest homolog poly(ADP-ribose) polymerase 2, Ku antigen (DSB sensor), DNA ligase I (SSB sensor), replication protein A (DNA duplex destabilizer), and Y-box binding protein 1 (RNA/DNA binding protein). None of those significantly affected Cas9 activity, while Cas9 efficiently shielded DSBs and SSBs from their sensors. Poly(ADP-ribosyl)ation of Cas9 detected for poly(ADP-ribose) polymerase 2 had no apparent effect on the activity.In cellulo, Cas9-dependent gene editing was independent of poly(ADP-ribose) polymerase 1. Thus, Cas9 can be regarded as an enzyme mostly orthogonal to the natural regulation of human systems of DNA break sensing and repair.
Autoantibodies against eukaryotic translation elongation factor 1 delta (EEF1D) in two patients with autoimmune cerebellar ataxia
Authors: Guo Liyuan , Ren Haitao , Fan Siyuan , Chao Xingchen , Liu Mange , Guan Hongzhi , Wang Jing
Published: September 2023

To report a novel autoantibody against eukaryotic translation elongation factor 1 delta (EEF1D) in two patients with autoimmune cerebellar ataxia (ACA). The patients on one center with cerebellar ataxia of unknown cause, who were tested positive with tissue-based indirect immunofluorescence assay (TBA) on rat cerebellum sections and negative for comprehensive anti-neural autoantibodies panel, were investigated for novel autoantibody identification. Tissue-immunoprecipitation (TIP) combined with mass spectrometric (MS) analysis was used to identify the target antigen. The EEF1D protein was identified from complex precipitated by serum and cerebrospinal fluid (CSF) of one patient, while the specific binding of autoantibodies and EEF1D were confirmed by subsequent neutralization experiment, recombinant cell-based indirect immunofluorescence assay (CBA) and western blot. In consequently test using CBA, another anti-EEF1D positive ACA patient was identified and confirmed by western blot. All enrolled 30 health doners and 15 connective tissue diseases patients without neurological disorders were anti-EEF1D negative. The two anti-EEF1D positive patients presented similar clinical manifestations, their outcomes supported the effectiveness of immunotherapy, but the cerebellar atrophy occurred before treatment may be irreversible. Symptoms of one patient worsened again after the weaning of pulse corticosteroid therapy. The identification of anti-EEF1D autoantibody provides a new potential biomarker for early diagnosis and recurrence prevention of ACA.
Myeloid A20 is critical for type-2 immune mediated helminth resistance
Authors: Petta Ioanna , Thorp Marie , Ciers Maarten , Blancke Gillian , Boon Louis , Meese Tim , Van Nieuwenburgh Filip , Wullaert Andy , Grencis Richard , Elewaut Dirk , van Loo Geert , Vereecke Lars
Published: September 2023

Protective immunity against intestinal helminths requires induction of robust Type-2 immunity orchestrated by various cellular and soluble effectors which promote goblet cell hyperplasia, mucus production, epithelial proliferation and smooth muscle contractions to expel worms and reestablish immune homeostasis. Conversely, defects in type-2 immunity result in ineffective helminth clearance, persistent infection and chronic inflammation. We identify A20 as an essential myeloid factor for the induction of type-2 immune responses against the intestinal parasiteTrichuris muris. Myeloid cell-specific loss of A20 in mice (A20myel-KO) results in chronicTrichuris murisinfection and intestinal inflammation. Myeloid A20 deficient mice are not able to induce anti-helmith type-2 immune responses while instead mount detrimental Th1/Th17 polarized immune responses. Antibody-mediated neutralization of the type-1 cytokines IFNγ, IL18 and IL12 prevents Th1/Th17 polarization and reestablishes Type-2 mediated protective immunity againstTrichuris murisin A20myel-KOmice. In contrast, the strong Th1/Th17 biased immunity in A20myel-KOmice offers protection againstSalmonellainfection. We hereby identify A20 as an essential myeloid factor to initiate approriate adaptive immunity in response to infection, and to induce a balanced type-2 immune response against the intestinal parasiteTrichuris muris.

Graphical abstract

The clearance of gastrointestinal helmiths depends on type-2 immunity. Helminths interact with and damage intestinal tissue, which leads to the release of intracellular DAMPs and cytokines such as TSLP and IL33, and IL25 produced by epithelial cells. These factors may activate myeloid cells and ILC’s, which further activate T and B cells to mount effective Th2 responses and the secretion of IL4, IL5 and IL13 cytokines, as well as helminth-specific IgG1 immunoglobulins, leading to effective expulsion of the helminths. Deletion of A20 in the myeloid cells leads to enhanced secretion of type-1 cytokines, including IL12, IL18 and IFNγ, which impede type-2 immune-mediated helminth clearance and promotes chronic intestinal inflammation.
Parental dietary vitamin B12 causes intergenerational growth acceleration and protects offspring from pathogenic microsporidia and bacteria
Authors: Willis Alexandra R. , Zhao Winnie , Sukhdeo Ronesh , Burton Nicholas O. , Reinke Aaron W.
Published: September 2023

The parental environment ofC. eleganscan have lasting effects on progeny development and immunity. Vitamin B12 exposure inC. eleganshas been shown to accelerate development and to reduce killing caused by pathogenicPseudomonas aeruginosa. Vitamin B12 is also maternally transferred to offspring, suggesting a potential role in progeny development. However, the intergenerational effects of vitamin B12 inC. elegansremain uncharacterized. Here, we show that parental exposure to dietary vitamin B12 or vitamin B12-producing bacteria results in offspring with accelerated growth. We find that this inherited acceleration phenotype is vitamin B12 dose-dependent and persists for a single generation. Progeny from vitamin B12 treated parents display reduced levels of the acdh-1 dietary sensor in the earliest larval stages, with expression of this protein recovering into adulthood. During infection withNematocida parisii, a natural microsporidian pathogen, the offspring of worms fed vitamin B12 diets have better reproductive fitness. However, vitamin B12 diet does not affect offspring infection levels, suggesting that accelerated development provides tolerance to microsporidian infection. Offspring from parents exposed to vitamin B12 are also protected from killing by pathogenicPseudomonas vranovensis. Vitamin B12-induced intergenerational growth acceleration andN. parisiitolerance is dependent upon the methionine biosynthesis pathway. However, protection fromP. vranovensiskilling is mediated through both the methionine biosynthesis and the propionyl-CoA breakdown pathways. Our results show how parental microbial diet impacts progeny development through the transfer of vitamin B12 which results in accelerated growth and pathogen tolerance.
Focal control of non-invasive deep brain stimulation using multipolar temporal interference
Authors: Botzanowski Boris , Acerbo Emma , Lehmann Sebastian , Kearsley Sarah L. , Steiner Melanie , Neufeld Esra , Missey Florian , Muller Lyle , Jirsa Viktor , Corneil Brian D. , Williamson Adam
Published: September 2023

Temporal interference (TI) is a method of non-invasive brain stimulation using transcutaneous electrodes that allows the targeting and modulation of deeper brain structures, not normally associated with non-invasive simulation, while avoiding unwanted stimulation of shallower cortical structures. The properties of TI have been previously demonstrated, however, the problem of decoupling stimulation focality from stimulation intensity has not been addressed. In this paper, we provide a possible novel solution, multipolar TI (mTI), which allows increased independent control over both the size of the stimulated region and the stimulation intensity. The mTI method uses multiple carrier frequencies to create multiple overlapping amplitude-modulated envelopes, rather than using one envelope as in standard TI. The study presents an explanation of the concept of mTI along with experimental data gathered from Rhesus macaques and mice. We improved the focality at depth in anesthetized mice and monkeys, and using the new focality in awake monkeys, evoked targeted activity at depth in the superior colliculus. The mTI method could be an interesting and potentially useful new tool alongside other forms of non-invasive brain stimulation.

Teaser: Multipolar Temporal Interference Stimulation can produce a more focal brain stimulation at depth compared to Temporal Interference.
Generative design approach to combine architected Voronoi foams with porous collagen scaffolds to create a tunable composite biomaterial
Authors: Dewey Marley J. , Chang Raul Sun Han , Nosatov Andrey V. , Janssen Katherine , Crotts Sarah J. , Hollister Scott J. , Harley Brendan A.C.
Published: September 2023

Regenerative biomaterials for musculoskeletal defects must address multi-scale mechanical challenges. We are developing biomaterials for craniomaxillofacial bone defects that are often large and irregularly shaped. These require close conformal contact between implant and defect margins to aid healing. While we have identified a mineralized collagen scaffold that promotes mesenchymal stem cell osteogenic differentiationin vitroand bone formationin vivo,its mechanical performance is insufficient for surgical translation. We report a generative design approach to create scaffold-mesh composites by embedding a macro-scale polymeric Voronoi mesh into the mineralized collagen scaffold. The mechanics of architected foam reinforced composites are defined by a rigorous predictive moduli equation. We show biphasic composites localize strain during loading. Further, planar and 3D mesh-scaffold composites can be rapidly shaped to aid conformal fitting. Voronoi-based composites overcome traditional porosity-mechanics relationship limits while enabling rapid shaping of regenerative implants to conformally fit complex defects unique for individual patients.
Evolutionary diversity of the control of the azole response by Tra1 across yeast species
Authors: Nunes Librais Gabriela Marsiglio , Jiang Yuwei , Razzaq Iqra , Brandl Christopher J. , Shapiro Rebecca S. , Lajoie Patrick
Published: September 2023

Tra1 is an essential co-activator protein of the yeast SAGA and NuA4 acetyltransferase complexes that regulate gene expression through multiple mechanisms including the acetylation of histone proteins. Tra1 is a pseudokinase of the PIKK family characterized by a C-terminal PI3K domain with no known kinase activity. However, mutations of specific arginine residues to glutamine in the PI3K domains (an allele termedtra1Q3) result in reduced growth and increased sensitivity to multiple stresses. In the opportunistic fungal pathogenCandida albicans, thetra1Q3allele reduces pathogenicity and increases sensitivity to the echinocandin antifungal drug caspofungin, which disrupts the fungal cell wall. Here, we found that loss of Tra1 function, in contrast to what is seen with caspofungin, increases tolerance to the azole class of antifungal drugs, which inhibits ergosterol synthesis. InC. albicans, tra1Q3increases expression of genes linked to azole resistance, such asERG11andCDR1. CDR1encodes a multidrug ABC transporter associated with efflux of multiple xenobiotics, including azoles. Consequently, cells carryingtra1Q3show reduced intracellular accumulation of fluconazole. In contrast, atra1Q3S. cerevisiaestrain displayed opposite phenotypes: decreased tolerance to azole, decreased expression of the efflux pumpPDR5and increased intracellular accumulation of fluconazole. Therefore, our data provide evidence that Tra1 differentially regulates the antifungal response across yeast species.
TO DETERMINE THE KNOWLEDGE OF MIDWIVES ON UTILIZATION OF PARTOGRAPH AT SELECTED HOSPITALS IN KENYA
Authors: kanyottu Mary wangeci , karonjo Jane , karani Anna
Published: September 2023

Partograph is graphical tool presentation of key data during the progress of labor. The observations of the mother are interpreted by a midwife or an obstetrician to make conclusions to whether the condition of the mother and fetus is fine. This tool alerts the skilled birth attendants of pending risk of the mother or fetus through the observations and action taken without delay. Worldwide the Maternal Mortality Rate is 400/ 100,000 live births. A woman from developing world is 100 times more probable to die during pregnancy or child birth than a woman from a developed country. The purpose of the study is to develop a model to promote partograph utilization by midwives during management of mothers in labour in selected hospitals in Kenya so as to reduce Maternal Mortality rate related to delivery.
Cognition, physical function, and life purpose in the rural elderly population: a systematic review protocol
Authors: Morais Campos Hércules Lázaro , De Leon Elisa Brosina , de Souza Ingred Merllin Batista , Quialheiro Anna , de Oliveira Elizabete Regina Araújo
Published: September 2023

Introduction

Aging in the rural setting world from the perspective of cognition, physical function, and life purpose, essential constructs for a prosperous old age, still needs to be better discussed. Thus, this systematic review protocol highlights the prevalence of cognitive decline, physical functioning, and life purpose in older adults aging in rural community settings. Methods and analysis: We will include cross-sectional studies published until April 2022 found in 8 databases: Embase, MEDLINE, LILACS, PsycINFO, Scopus, SciELO, and Web of Science. For the first selection of studies, the Ryyan software will be used, and to check the methodological quality and the risk of bias, we will use COSMIN. For the primary analysis, the titles and abstracts available in the search engine will be analyzed by the following MeSH descriptors “Physical functioning,”; “Cognition,”; “Cognitive function,”; “Life purpose,”; Personal satisfaction; Subjective well-being; “Elderly”; “Older”; “Rural aging”; “Rural population”; “Communities, rural”; “Distribution, rural spatial”; “Medium communities”; “Rural settlement”; “Small community”. If necessary, the secondary analysis will adopt a complete reading of the selected articles by two blinded reviewers and confirmed by a third person. Publication bias will be assessed using cross-sectional analytical study quality. Sensitivity analyses will be performed by retrieving one article at a time and analyzing their endpoints with the proposal to identify the manuscripts that significantly influenced the combined prevalence of the endpoints.

Strengths and limitations of this study

It will present worldwide epidemiological data on aging in rural settings from the perspective of cognition, physical functioning, and life purpose.

It is the first systematic review that involves the theme of life purpose worldwide in rural elderly.

It is a cross-sectional study that although it cannot describe clinical outcomes, presents sociodemographic, cognition, physical functioning, and life purpose data that can help in public health decision-making for this population.
Deep learning on electronic medical records identifies distinct subphenotypes of diabetic kidney disease driven by genetic variations in theRhopathway
Authors: Paranjpe Ishan , Wang Xuan , Anandakrishnan Nanditha , Haydak Jonathan C. , Van Vleck Tielman , DeFronzo Stefanie , Li Zhengzhe , Mendoza Anthony , Liu Ruijie , Fu Jia , Forrest Iain , Zhou Weibin , Lee Kyung , O’Hagan Ross , Dellepiane Sergio , Menon Kartikeya M. , Gulamali Faris , Kamat Samir , Gusella Gabriele Luca , Charney Alexander W. , Hofer Ira , Cho Judy H. , Do Ron , Glicksberg Benjamin S , He John C. , Nadkarni Girish N. , Azeloglu Evren U.
Published: September 2023

Abstract

Kidney disease affects 50% of all diabetic patients; however, prediction of disease progression has been challenging due to inherent disease heterogeneity. We use deep learning to identify novel genetic signatures prognostically associated with outcomes. Using autoencoders and unsupervised clustering of electronic health record data on 1,372 diabetic kidney disease patients, we establish two clusters with differential prevalence of end-stage kidney disease. Exome-wide associations identify a novel variant inARHGEF18,a Rho guanine exchange factor specifically expressed in glomeruli. Overexpression ofARHGEF18in human podocytes leads to impairments in focal adhesion architecture, cytoskeletal dynamics, cellular motility, and RhoA/Rac1 activation. Mutant GEF18 is resistant to ubiquitin mediated degradation leading to pathologically increased protein levels. Our findings uncover the first known disease-causing genetic variant that affects protein stability of a cytoskeletal regulator through impaired degradation, a potentially novel class of expression quantitative trait loci that can be therapeutically targeted.
Genome-wide association study and genomic risk prediction of age-related macular degeneration in Israel
Authors: Grunin Michelle , Triffon Daria , Beykin Gala , Rahmani Elior , Schweiger Regev , Tiosano Liran , Khateb Samer , Hagbi-Levi Shira , Rinsky Batya , Munitz Refael , Winkler Thomas W , Heid Iris M , Halperin Eran , Carmi Shai , Chowers Itay
Published: September 2023

Purpose

The risk of developing age-related macular degeneration(AMD) is influenced by genetic background. In 2016, International AMD Genomics Consortium(IAMDGC) identified 52 risk variants in 34 loci, and a polygenic risk score(PRS) based on these variants was associated with AMD. The Israeli population has a unique genetic composition: Ashkenazi Jewish(AJ), Jewish non-Ashkenazi, and Arab sub-populations. We aimed to perform a genome-wide association study(GWAS) for AMD in Israel, and to evaluate PRSs for AMD.

Methods

For our discovery set, we recruited 403 AMD patients and 256 controls at Hadassah Medical Center. We genotyped all individuals via custom exome chip. We imputed non-typed variants using cosmopolitan and AJ reference panels. We recruited additional 155 cases and 69 controls for validation. To evaluate predictive power of PRSs for AMD, we used IAMDGC summary statistics excluding our study and developed PRSs via either clumping/thresholding or LDpred2.

Results

In our discovery set, 31/34 loci previously reported by the IAMDGC were AMD associated with P<0.05. Of those, all effects were directionally consistent with the IAMDGC and 11 loci had a p-value under Bonferroni-corrected threshold(0.05/34=0.0015). At a threshold of 5x10-5, we discovered four suggestive associations inFAM189A1,IGDCC4,C7orf50, andCNTNAP4. However, only theFAM189A1variant was AMD associated in the replication cohort after Bonferroni-correction. A prediction model including LDpred2-based PRS and other covariates had an AUC of 0.82(95%CI:0.79-0.85) and performed better than a covariates-only model(P=5.1x10-9).

Conclusions

Previously reported AMD-associated loci were nominally associated with AMD in Israel. A PRS developed based on a large international study is predictive in Israeli populations.
Exploring the diversity of participants with dementia taking part in research: a mixed methods study
Authors: Bajwa Rupinder Kaur , Howe Louise , Agbonmwandolor Joy O. , Cowley Alison , Adams Emma J. , Goldberg Sarah , Harwood Rowan H.
Published: September 2023

Introduction

Dementia is becoming increasingly prevalent in the UK. Older adults from black and south Asian communities have a higher risk for dementia due to an increased prevalence of dementia specific risk factors such as hypertension, diabetes, and heart disease. Deprivation has also been linked to an increased risk of dementia. Ethnic minority and lower socioeconomic groups are underrepresented in dementia research. The aim of this study was to explore factors influencing diversity in dementia and rehabilitation research within the context of the Promoting Activity, Independence, and Stability in Early Dementia (PrAISED) randomised controlled trial (RCT).

Methods

We conducted an exploratory sequential mixed methods study to explore disparities in socioeconomic and ethnic diversity between the PrAISED RCT population and recruitment pathways used in one study site (Nottinghamshire) and compared these with regional and national data. We aimed to collate and summarise data available on ethnicity and deprivation for recruitment/referral pathways (Nottinghamshire site) and the PrAISED cohort (all sites). Additionally, we interviewed healthcare professionals (n=2), researchers (n=2) and members of black and south Asian communities (n=4) to explore barriers to participating in research for people with dementia.

Results

Under 2% of the overall PrAISED RCT sample (across all sites) were from a non-white ethnic minority background and a third of participants lived in areas with the least deprivation. Referrals to memory assessment services in Nottinghamshire included people from diverse socioeconomic backgrounds, with 7.3% being from non-white ethnic minority communities. Through interviews, several barriers to healthcare, research and rehabilitation were identified. Healthcare barriers included lack of awareness of dementia, mistrust, stigma, fear, and lack of culturally appropriate services. Research barriers included recruitment routes, awareness of research, language, and recruiter beliefs. Barriers to rehabilitation research included a lack of use of culturally appropriate language, more culturally specific barriers, and lack of representation.

Conclusion

Participants recruited to the PrAISED RCT were mainly white and socioeconomically privileged. Data recording and access around ethnicity is still inconsistent, making it difficult to ascertain at which point services and research become inaccessible for people from underserved communities. Future research needs to work with these communities to develop innovative solutions to overcome the barriers identified in this study and to put recommendations made into practice.
Designing a Library of Lived Experience for Mental Health: integrated realist synthesis and experience-based co-design study
Authors: Marshall Paul , Lobban Fiona , Barbrook John , Collins Grace , Foster Sheena , Glossop Zoe , Inkster Clare , Jebb Paul , Johnston Rose , Khan Hameed , Lodge Christopher , Machin Karen , Michalak Erin E. , Powell Sarah , Russell Samantha , Rycroft-Malone Jo , Slade Mike , Whittaker Lesley , Jones Steven
Published: September 2023

Objective

Living Library ‘Readers’ can learn about experiences of others through conversations with living ‘Books’. This study sought to generate a realist programme theory and a theory-informed implementation guide for a Library of Lived Experience for Mental Health (LoLEM).

Design

Integrated realist synthesis and experience-based co-design.

Setting

Ten online workshops with participants based in the North of England.

Participants

Thirty-one participants with a combination of personal experience of using mental health services, caring for someone with mental health difficulties, and/or working in mental health support roles.

Results

Database searches identified 30 published and grey literature evidence sources which were integrated with data from 10 online co-design workshops. The analysis generated a programme theory comprising five context-mechanism-outcome (CMO) configurations. For Readers, direct conversations humanise others’ experiences (CMO 2) and provide the opportunity to flexibly explore new ways of living (CMO 3). Through participation in a Living Library, Books may experience personal empowerment (CMO 4), while the process of self-authoring and co-editing their story (CMO 5) can contribute to personal development. This programme theory informed the co-design of an implementation guide highlighting the importance of tailoring event design and participant support to the contexts in which LoLEM events are held.

Conclusions

The LoLEM has appeal across stakeholder groups and can be applied flexibly in a range of mental health-related settings. Implementation and evaluation are required to better understand the positive and negative impacts on Books and Readers.

Registration

PROSPERO CRD42022312789

Strengths and limitations of this study

This study used a novel, iterative, and creative approach to integrating theory development and intervention co-design.

The programme theory provides a conceptual basis for further evaluation of a LoLEM, including outcomes for those participating in events as ‘Books’ and ‘Readers’.

This study informed detailed, co-designed implementation guidance for use by LoLEM organisers.

However, the LoLEM is yet to be delivered as a sustained programme of events, so long-term impacts require further investigation.
Fast clinical trial identification using fuzzy-search elastic searches: retrospective validation with high-quality Cochrane benchmark
Authors: Otte Willem M , van IJzendoorn David G P , Habets Philippe C , Vinkers Christiaan H
Published: September 2023

The synthesis of treatment effects relies on systematic reviews of intervention trials. This process is often laborious due to the need for precise search queries and manual study identification. Recent advancements in database architecture and natural language processing (NLP) offer a potential solution by enabling faster, more flexible searches and automated extraction of information from unstructured texts.

Our study assesses the effectiveness of NLP-based literature searches within a novel database structure in comparison to the Cochrane Database of Systematic Reviews. We created a user-friendly elastic search database containing 36 million PubMed-indexed entries. We developed reliable filters for identifying randomized clinical trials and clinical intervention studies, as well as extracting relevant subtext related to population and intervention.

Our results indicate a high precision of 0.74, recall of 0.81, and F1-score of 0.77 for population subtext, and a precision of 0.70, recall of 0.71, and an F1-score of 0.70 for intervention subtext. Our approach efficiently identified included studies in 90% of systematic reviews, missing no more than two trials compared to Cochrane. Furthermore, it produced fewer total hits than a comparable PubMed keyword search, demonstrating the potential of the new database structure to enhance the efficiency and effectiveness of aggregating clinical evidence.
Quantity of SARS-CoV-2 RNA copies exhaled per minute during natural breathing over the course of COVID-19 infection
Authors: Lane Gregory , Zhou Guangyu , Hultquist Judd F. , Simons Lacy M. , Redondo Ramon Lorenzo- , Ozer Egon A. , McCarthy Danielle M. , Ison Michael G. , Achenbach Chad J. , Wang Xinkun , Wai Ching Man , Wyatt Eugene , Aalsburg Alan , Yang Qiaohan , Noto Torben , Alisoltani Arghavan , Ysselstein Daniel , Awatramani Rajeshwar , Murphy Robert , Theron Grant , Zelano Christina
Published: September 2023

SARS-CoV-2 is spread through exhaled breath of infected individuals. A fundamental question in understanding transmission of SARS-CoV-2 is how much virus an individual is exhaling into the environment while they breathe, over the course of their infection. Research on viral load dynamics during COVID-19 infection has focused on internal swab specimens, which provide a measure of viral loads inside the respiratory tract, but not on breath. Therefore, the dynamics of viral shedding on exhaled breath over the course of infection are poorly understood. Here, we collected exhaled breath specimens from COVID-19 patients and used RTq-PCR to show that numbers of exhaled SARS-CoV-2 RNA copies during COVID-19 infection do not decrease significantly until day 8 from symptom-onset. COVID-19-positive participants exhaled an average of 80 SARS-CoV-2 viral RNA copies per minute during the first 8 days of infection, with significant variability both between and within individuals, including spikes over 800 copies a minute in some patients. After day 8, there was a steep drop to levels nearing the limit of detection, persisting for up to 20 days. We further found that levels of exhaled viral RNA increased with self-rated symptom-severity, though individual variation was high. Levels of exhaled viral RNA did not differ across age, sex, time of day, vaccination status or viral variant. Our data provide a fine-grained, direct measure of the number of SARS-CoV-2 viral copies exhaled per minute during natural breathing—including 312 breath specimens collected multiple times daily over the course of infection—in order to fill an important gap in our understanding of the time course of exhaled viral loads in COVID-19.
Standardisation of cell-free DNA measurements: An International Study on Comparability of Low Concentration DNA Measurements using cancer variants
Authors: Burke Daniel , Devonshire Alison S. , Pinheiro Leonardo B. , Jones Gerwyn M. , Griffiths Kate R. , Fernandez Gonzalez Ana , Forbes-Smith Michael , McLaughlin Jacob , Emslie Kerry R. , Weidner Christopher , Mankertz Joachim , Leguizamon John E. , Medeiros Marcelo Neves de , Flatschart Roberto Becht , Saraiva Antonio M. , Beltrao Paulo Jose Iwakami , Divieto Carla , Revel Laura , Bae Young-Kyung , Dong Lianhua , Niu Chunyan , Wang Xia , Temisak Sasithon , Shibayama Sachie , Yalcinkaya Burhanettin , Akgoz Muslum , Macdonald Rainer , Plauth Annabell , Huggett Jim
Published: September 2023

For the impact of genomic testing from liquid biopsies to be maximized, mechanisms to ensure reproducible and comparable test performance will be required. This can be established and maintained through reference measurement procedures and materials with property values that are internationally comparable through traceability to a common standard. To achieve this objective, an interlaboratory study was organised to explore digital PCR (dPCR) for standardisation of cell-free DNA (cfDNA) quantification.

Blinded samples of wild-type/variant mixtures of two DNA sequences (BRAFp.V600E single nucleotide variant orEGFRexon 19 deletion) were provided to 12 laboratories. Laboratories independently designed and applied dPCR assays to determine absolute and relative quantities, with no guidance provided to harmonise the approach.

The mean and coefficient of variation (CV) of copy number concentrations for variant sequences were 18 copies/μL (CV 7.2%) (BRAFvariant sample) and 9 copies/μL (CV 25%) (EGFRvariant sample) while the mean variant allele frequencies (vAF) were 8.0% (CV 5.3%) and 0.080% (CV 29%) respectively.

This study demonstrated that dPCR was capable of exceptional technical accuracy for variant copy number concentration and vAF, even when different assays and platforms were used. This implies that dPCR offers a unique analytical methodology that can be deployed globally in supporting comparability for cfDNA testing based on the existing framework of the International System of units of measurement.
MAFB drives differentiation by permitting WT1 binding to podocyte specific promoters
Authors: Massa Filippo M. , Jian-Motamedi Fariba , Šerys Marijus , Tison Amelie , Loubat Agnès , Lacas-Gervais Sandra , Martin Luc , Belahbib Hassiba , Sarrazin Sandrine , Sieweke Michael H. , Schedl Andreas
Published: September 2023

Podocytes are highly specialized cells, but their chromatin status and the precise molecular events leading to their differentiation remain poorly defined. Here we used ChIP-Seq analysis for H3K4me3, H3K4me1 and H3K27me3 to establish the histone methylation map in adult mouse podocytes. Our data demonstrate open chromatin across podocyte specific genes and reveals that genes expressed in the mesoderm lineage become actively repressed upon podocyte differentiation. To better understand the transcriptional control of podocyte differentiation, we studied the role of transcription factor MAFB. ChIP-Seq experiments and functional analysis in conditional knockout mice identified a set of direct MAFB targets includingNphs1,Nphs2, VegfaandTcf21. Loss ofMafBled to the deposition of extracellular matrix, progressive foot process effacement, and kidney disease. ChIP experiments in knockout animals revealed that during development MAFB is essential for H3K4me3 methylation and the recruitment of WT1 to the promoters of the podocyte specific genesNphs1andNphs2. Taken together our data reveal the crucial function of MAFB by permitting chromatin accessibility at podocyte-specific genes during development and maintaining terminal differentiation in adults.
PUFFFIN: A novel, ultra-bright, customisable, single-plasmid system for labelling cell neighbourhoods
Authors: Lebek Tamina , Malaguti Mattias , Elfick Alistair , Lowell Sally
Published: September 2023

Cell communication orchestrates development, homeostasis, and disease. Understanding these processes depends on effective methods to study how cells influence their neighbours. Here, we present Positive Ultra-bright Fluorescent Fusion For Identifying Neighbours (PUFFFIN), a novel cell neighbour-labelling system based upon secretion and uptake of a positively supercharged fluorescent protein s36GFP. To achieve sensitive labelling, we amplified the fluorescent signal by fusing s36GFP to the ultra-bright protein mNeonGreen. Secretor cells transfer s36GFP-mNeonGreen to neighbours while retaining a nuclear mCherry, making it straightforward to unambiguously identify, isolate, and profile neighbours of secretor cells. Transfer of the s36GFP-mNeonGreen fusion occurs within minutes, enabling even relatively transient interactions to be captured or tracked over time with live-imaging or flow cytometry. To enhance flexibility of use, we incorporated HaloTag technology to facilitate colour-of-choice labelling. To further increase the range of applications, we engineered a customisable single-plasmid construct composed of interchangeable components with option to incorporate any additional transgene. This allows users to manipulate the properties of a cell, while at the same time applying a fluorescent label to the surrounding cells. PUFFFIN offers a simple, sensitive, customisable approach to profile non-cell-autonomous responses to natural or induced changes in cell identity or behaviour in mammalian cells.

Graphical abstract
Overnight fasting facilitates safety learning by changing the neurophysiological response to relief from threat omission
Authors: Papalini Silvia , Beckers Tom , Van Oudenhove Lukas , Vervliet Bram
Published: September 2023

Excessive avoidance and slow extinction of fear are hallmarks of anxiety disorders. We have previously found that overnight fasting diminishes excessive avoidance and speeds up fear extinction by decreasing subjective relief during threat omissions. Since relief tracks the reward prediction error signal that governs safety learning, we hypothesized that these effects of fasting might be linked to a decreased activation in brain regions related to reward prediction error processing. Hence, we replicated our previous study in a 3T-MRI scanner. Overnight fasting increased effective avoidance and sped up fear extinction learning. During extinction, the fasting group showed lower activations in the ventromedial prefrontal cortex and nucleus accumbens in response to threat omissions signaled by a safe cue. Nucleus accumbens activations were modulated by relief in the control group. This study provides support for overnight fasting as an adjunct to treatments for anxiety, but the effects should be investigated in anxious patients.
Using methyl bromide for interspecies cell-cell signaling and as a reporter in a model soil consortium
Authors: Kim Jiwoo , Lu Li Chieh , Gao Xiaodong , Hofmockel Kirsten S. , Masiello Caroline A. , Silberg Jonathan J.
Published: September 2023

Soil microbial communities with reduced complexity are emerging as model systems for studying consortia-scale phenotypes. To establish synthetic biology tools for studying these communities in hard-to-image environmental materials, we evaluated whether a single member of a model soil consortium (MSC) can be programmed to report on gene expression without requiring matrix disruption. For these studies, we targeted a five member MSC that includesDyadobacter fermentans,Ensifer adhaerens,Rhodococcussp003130705, Streptomycessp001905665, andVariovorax beijingensis. By coupling the expression of a methyl halide transferase to a constitutive promoter, we show thatVariovorax beijingensiscan be programmed to synthesize methyl halides that accumulate in the soil headspace at levels that are ≥24-fold higher than all other MSC members across a range of environmentally-relevant hydration conditions. We find that methyl halide production can report on a MSC promoter that is activated by changes in water potential, and we demonstrate that a synthetic gas signal can be read out directly using gas chromatography and indirectly using a soil-derivedMethylorubrumthat is programmed to produce a visual output in response to methyl halides. These tools will be useful for future studies that investigate how MSC respond to dynamic hydration conditions, such as drought and flood events induced by climate change, which can alter soil water potential and induce the release of stored carbon.
A study of genetic variants associated with skin traits in the Vietnamese population
Authors: Hoang Tham Hong , Vu Duc Minh , Vu Giang Minh , Nguyen Thien Khac , Do Nguyet Minh , Duong Vinh Chi , Pham Thang Luong , Tran Mai Hoang , Nguyen Ly Thi Khanh , Han Han Thi Tuong , Can Thuy Thu , Pham Thai Hong , Pham Tho Duc , Nguyen Thanh Hong , Do Huy Phuoc , Vo Nam S. , Nguyen Xuan-Hung
Published: September 2023

Background

Most skin-related traits have been studied from Caucasian genetic background. A comprehensive study on skin-associated genetic effects on under-represented populations like Vietnam is needed to fill the gaps in the field.

Objectives

To develop a computational pipeline to predict the effect of genetic factors on skin traits using public data (GWAS catalogs and whole genome sequencing (WGS) data of 1000 genomes project-1KGP) and in-house Vietnamese data (WGS and genotyping by SNP array). By using this information we may have a better understanding of the susceptibility of Vietnamese people.

Methods

Vietnamese cohorts of whole genome sequencing (WGS) of 1008 healthy individuals for the reference and 96 genotyping samples (which do not have any skin cutaneous issues) by Infinium Asian Screening Array-24 v1.0 BeadChip were employed to predict skin-associated genetic variants of 25 skin-related and micronutrients requirement traits in population analysis and correlation analysis. Simultaneously, we compared the landscape of cutaneous issues of Vietnamese people with other populations by assessing their genetic profiles.

Results

The skin-related genetic profile of Vietnamese cohorts is similar at most with East Asian (JPT: Fst=0.036, CHB: Fst=0.031, CHS: Fst=0.027, CDX: Fst=0.025) in the population study. In addition, we identified pairs of skin traits being at high risk of frequent co-occurrence (such as skin aging and wrinkles (r = 0.45, p =1.50e-5) or collagen degradation and moisturizing (r = 0.35, p = 1.1e-3).

Conclusion

This is the first investigation in Vietnam to explore genetic variants of facial skin. These findings could improve inadequate skin-related genetic diversity in the currently published database.