bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insights into human health from phenome- and genome-wide analyses of UK Biobank retinal optical coherence tomography phenotypes
Authors: Zekavat Seyedeh Maryam , Jorshery Saman Doroodgar , Shweikh Yusrah , Horn Katrin , Rauscher Franziska G. , Sekimitsu Sayuri , Kayoma Satoshi , Ye Yixuan , Raghu Vineet , Zhao Hongyu , Ghassemi Marzyeh , Elze Tobias , Segrè Ayellet V. , Wiggs Janey L. , Scholz Markus , Del Priore Lucian , Wang Jay C. , Natarajan Pradeep , Zebardast Nazlee 
Published: May 2023

AbstractThe human retina is a complex multi-layered tissue which offers a unique window into systemic health and disease. Optical coherence tomography (OCT) is widely used in eye care and allows the non-invasive, rapid capture of retinal measurements in exquisite detail. We conducted genome- and phenome-wide analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed phenome-wide association analyses, associating retinal thicknesses with 1,866 incident ICD-based conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association analyses, identifying inherited genetic markers which influence the retina, and replicated our associations among 6,313 individuals from the LIFE-Adult Study. And lastly, we performed comparative association of phenome- and genome-wide associations to identify putative causal links between systemic conditions, retinal layer thicknesses, and ocular disease.Independent associations with incident mortality were detected for photoreceptor thinning and ganglion cell complex thinning. Significant phenotypic associations were detected between retinal layer thinning and ocular, neuropsychiatric, cardiometabolic and pulmonary conditions. Genome-wide association of retinal layer thicknesses yielded 259 loci. Consistency between epidemiologic and genetic associations suggested putative causal links between thinning of the retinal nerve fiber layer with glaucoma, photoreceptor segment with AMD, as well as poor cardiometabolic and pulmonary function with PS thinning, among other findings.In conclusion, retinal layer thinning predicts risk of future ocular and systemic disease. Furthermore, systemic cardio-metabolic-pulmonary conditions promote retinal thinning. Retinal imaging biomarkers, integrated into electronic health records, may inform risk prediction and potential therapeutic strategies.One Sentence SummaryPhenome- and genome-wide associations of retinal OCT images across nearly 50,000 individuals identifies ocular and systemic phenotypes linked to retinal layer thinning, inherited genetic variants linked to retinal layer thickness, and putative causal links between systemic conditions, retinal layer thickness, and ocular disease.
A comparison between a Random Forest model and the Kidney Failure Risk Equation to predict progression to kidney failure
Authors: Wainstein Marina , Rahimi Amir Kamel , Katz Ivor , Healy Helen , Pirabhahar Saiyini , Turner Kylie , Shrapnel Sally 
Published: May 2023

AbstractBackgroundMachine learning may offer a superior alternative to traditional prediction tools when used to model complicated, nonlinear interactions between variables. While modern machine learning methods are tagged as “black boxes”, the random forest (RF) classifier can be interrogated to understand the contribution of input variables (feature importance), thereby improving the interpretability of its predictions. We hypothesized that a random forest (RF) classifier would have equivalent, if not superior, performance to the 4-variable Kidney Failure Risk Equation (KFRE) in predicting progression to end stage kidney disease (ESKD) in a chronic kidney disease (CKD) population and explored the impact of serum creatinine and primary renal disease on prediction accuracy.MethodsA 2-year risk of ESKD was calculated using the 4-variable KFRE and compared to a RF model using the same four variables (age, gender, eGFR and urine albumin creatinine ratio). Four more RF models were developed using a combination of these as well as serum creatinine and primary renal disease. Performance of the KFRE and RF models was assessed by area under a receiver operating (AUC ROC) curve and feature importance was evaluated for each RF model.ResultsOf 1365 patients with CKD from two renal units included in the analysis, 208 progressed to ESKD in the 2-year follow-up period. The AUC ROC for KFRE was 0.95 (95% confidence interval, 0.93 – 0.96) and for the RF model using the same 4 variables 0.97. The remaining four RF models had similar performance (AUC ROC 0.97 – 0.98). In the RF models, eGFR and serum creatinine had the largest effect on risk prediction while gender had the smallest.ConclusionsOur findings suggest that RF models provide a potential tool to predict CKD progression with competing accuracy and interpretability to the current benchmark equation. They therefore warrant validation in larger and more diverse populations
Prehospital activation of the cardiac catheterisation laboratory in ST-segment elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI)
Authors: Savage Michael L , Hay Karen , Volbon William , Doan Tan , Murdoch J Dale , Hammett Christopher , Poulter Rohan , Walters Darren L , Denman Russell , Ranasinghe Isuru , Raffel Owen Christopher 
Published: May 2023

AbstractBackgroundPrehospital activation of the cardiac catheter laboratory is associated with significant improvements in ST-segment elevation myocardial infarction (STEMI) performance measures. However, there is equivocal data, particularly within Australia regarding its influence on mortality. We assessed the association of prehospital activation on performance measures and mortality in STEMI patients treated with primary percutaneous coronary intervention (PCI) from the Queensland Cardiac Outcomes Registry (QCOR).MethodsConsecutive ambulance transported STEMI patients treated with primary PCI were analysed from 1stJanuary 2017 to 31stDecember 2020 from the QCOR. The total and direct effects of prehospital activation on the primary outcomes (30-day and 1-year cardiovascular mortality) were estimated using logistic regression analyses. Secondary outcomes were STEMI performance measures.ResultsAmong 2498 patients (mean age: 62.2 ± 12.4 years; 79.2% male), 73% underwent prehospital activation. Median door-to-balloon (DTB) time (34mins [26-46] vs 86 mins [68-113]; p<0.001), first-electrocardiograph-to-balloon (ECGTB) time (83.5 mins [72-98] vs 109 mins [81-139]; p<0.001), and proportion of patients meeting STEMI targets (DTB<60mins 90% vs 16%; p<0.001), ECGTB<90mins (62% vs 33%; p<0.001) were significantly improved with prehospital activation. Prehospital activation was associated with significantly lower 30-day (1.6% vs 6.6%; p<0.001) and 1-year cardiovascular mortality (2.9% vs 9.5%; p<0.001). After adjustment, no prehospital activation was strongly associated with increased 30-day (OR: 3.6; 95%CI: 2.2-6.0, p<0.001) and 1-year cardiovascular mortality (OR: 3.0 (95%CI:2.0-4.6; p<0.001).ConclusionsPrehospital activation of cardiac catheterisation laboratory for primary PCI was associated with significantly shorter time to reperfusion, achievement of STEMI performance measures and lower 30-day and 1-year cardiovascular mortality.Clinical PerspectiveIn patients who suffer STEMI, prehospital activation of the cardiac catheter laboratory and initiation of medical therapy is associated with shorter time to reperfusion, greater achievement of performance measures and lower cardiovascular mortalityThis study adds to the existing literature and demonstrates that a standardised prehospital activation strategy can be implemented on a large scaleWidespread implementation of standardised prehospital activation strategies may offer opportunity to expedite STEMI care and improve outcomes
Endovascular treatment of ruptured very small intracranial aneurysms: a systematic review and meta-analysis
Authors: Matsukawa Hidetoshi , Elawady Sameh Samir , Sowlat Mohammad Mahdi , Al Kasab Sami , Uchida Kazutaka , Yoshimura Shinichi , Spiotta Alejandro M 
Published: May 2023

AbstractBackgroundEndovascular treatment (EVT) is widely accepted for intracranial aneurysms due to its safety and efficacy. However, EVT of ruptured very small intracranial aneurysms (RVSIA) (≤3 mm) is still challenging and the risk-benefit ratio of EVT remains unclear. The aim of this study was to evaluate the safety and efficacy of EVT of RVSIA.MethodsWe performed a systematic review and meta-analysis of the studies on EVT of RVSIA. Pooled prevalence rates were calculated for initial and follow-up complete occlusion rates (Raymond Roy Grade 1), recanalization, retreatment, long-term favorable outcome (modified Rankins scale score 0 to 2 or Glasgow Outcome Scale 4 or 5), procedure-related complications (coil herniation, thromboembolism, and intraprocedural re-rupture), and procedure-related mortality. Pooled odds ratios were calculated to compare these outcomes between simple coiling and stent-assisted coiling (SAC).ResultsOf the 600 studies screened, 24 studies with a total of 1355 RVSIAs treated with EVT were included. The initial and follow-up complete aneurysm occlusion rates were 64% (95% confidence interval [CI]: 52–74%) and 85% (95% CI: 74–92%). The rates of recanalization and retreatment were 6% (95% CI: 3–10%) and 3% (95% CI: 2–4%). The favorable long-term follow-up outcome was observed in 91% (95% CI: 89– 93%) of patients. The rates of coil herniation, thromboembolism, and intraprocedural rupture were 2% (95% CI: 1–8%), 4% (95% CI: 3–6%), and 4% (95% CI: 2–7%), respectively. Mortality was 3% (95% CI: 2–4%). Comparison of outcomes between simple coiling and SAC revealed no significant difference, except for a higher likelihood of recanalization in the coiling group (Odds ratio, 3.51 [95% CI, 1.31–9.45]).ConclusionsOur meta-analysis demonstrates that EVT for RVSIA is a feasible, effective, and safe approach that is associated with favorable clinical outcomes in both the short and long term.
Prevalence of untreated prediabetes and glucose metabolism disturbances in Mexico: An analysis of nationally representative surveys spanning 2016-2021
Authors: Fermín-Martínez Carlos A. , Paz-Cabrera César Daniel , Basile-Alvarez Martín Roberto , Castro Paulina Sánchez , Núñez-Luna Alejandra , Perezalonso-Espinosa Jerónimo , Ramírez-García Daniel , Antonio-Villa Neftali Eduardo , Vargas-Vázquez Arsenio , Fernández-Chirino Luisa , Carrillo-Herrera Karime Berenice , Cabrera-Quintana Leslie Alitzel , Rojas-Martínez Rosalba , Seiglie Jacqueline A. , Bello-Chavolla Omar Yaxmehen 
Published: May 2023

ABSTRACTOBJECTIVECharacterizing prediabetes phenotypes may be useful in guiding diabetes prevention efforts; however, heterogeneous criteria to define prediabetes have led to inconsistent prevalence estimates, particularly in low- and middle-income countries. We estimated trends in untreated prediabetes prevalence in Mexico across different definitions and its association with prevalent cardiometabolic conditions.METHODSWe conducted a serial cross-sectional analysis of National Health and Nutrition Surveys in Mexico (2016-2021), totaling 21,442 Mexican adults, excluding individuals with diagnosed or undiagnosed diabetes. Prediabetes was defined using ADA (impaired fasting glucose [IFG] 100-125 mg/dL and/or HbA1c 5.7-6.4%), WHO (IFG 110-125 mg/dL), and IEC criteria (HbA1c 6.0-6.4%). Prevalence trends of prediabetes over time were evaluated using Poisson regression and its association with prevalent cardiometabolic conditions with logistic regression.RESULTSPrevalence of prediabetes in Mexico in 2021 was 27.3%. Despite an overall downward trend in prediabetes (RR 0.960, 95%CI 0.940-0.979), this decrease was primarily driven by decreases in prediabetes by ADA-IFG (RR 0.883, 95%CI 0.861-0.907) and WHO-IFG criteria (RR 0.878, 95%CI 0.838-0.921), while prediabetes by ADA-HbA1c (RR 1.049, 95%CI 1.022-1.077) and IEC-HbA1C criteria (RR 1.064, 95%CI 1.014-1.115) increased over time. Prediabetes prevalence increased over time in adults >40 years, individuals with central obesity, self-identified as indigenous or living in urban areas. Regardless of the definition, prediabetes was associated with increased risk of cardiometabolic conditions.CONCLUSIONSPrediabetes rates in Mexico from 2016-2021 varied based on defining criteria but consistently increased for HbA1c-based definitions and high-risk subgroups. Regardless of the definition, prediabetes clusters subjects with high cardiometabolic risk.
Engineered bacteria titrate hydrogen sulfide and induce concentration-dependent effects on host in a gut microphysiological system
Authors: Hayes Justin A. , Lunger Anna W. , Sharma Aayushi S. , Fernez Matthew T. , Koppes Abigail N. , Koppes Ryan , Woolston Benjamin M. 
Published: May 2023

AbstractHydrogen sulfide (H2S) is a gaseous microbial metabolite whose role in gut diseases is debated, largely due to the difficulty in controlling its concentration and the use of non-representative model systems in previous work. Here, we engineeredE. colito titrate H2S controllably across the physiological range in a gut microphysiological system (chip) supportive of the co-culture of microbes and host cells. The chip was designed to maintain H2S gas tension and enable visualization of co-culture in real-time with confocal microscopy. Engineered strains colonized the chip and were metabolically active for two days, during which they produced H2S across a sixteen-fold range and induced changes in host gene expression and metabolism in an H2S concentration-dependent manner. These results validate a novel platform for studying the mechanisms underlying microbe-host interactions, by enabling experiments that are infeasible with current animal andin vitromodels.
Structural insights into human TFIIIC promoter recognition
Authors: Seifert-Davila Wolfram , Girbig Mathias , Hauptmann Luis , Hoffmann Thomas , Eustermann Sebastian , Müller Christoph W. 
Published: May 2023

SUMMARYTranscription factor IIIC (TFIIIC) recruits RNA polymerase (Pol) III to most of its target genes. Recognition of intragenic A- and B-box motifs in tRNA genes by TFIIIC modules τA and τB is the first critical step for tRNA synthesis but is mechanistically poorly understood. Here, we report cryo-EM structures of the human 624 kDa TFIIIC complex unbound and bound to a tRNA gene. The τB module recognizes the B-box via DNA shape and sequence readout through the assembly of multiple winged-helix domains. TFIIIC220 forms an integral part of both τA and τB connecting the two subcomplexes via a ∼550 amino acid residue flexible linker. Our data provide a structural mechanism by which high-affinity B-box recognition anchors TFIIIC to promoter DNA and permits scanning for low-affinity A-boxes and TFIIIB for Pol III activation.
Amino acid supplementation confers protection to red blood cells prior to Plasmodium falciparum bystander stress
Authors: Binns Heather Colvin , Alipour Elmira , Nahid Dinah S. , Whitesides John F. , Cox Anderson O’Brien , Furdui Cristina M. , Marrs Glen S. , Kim-Shapiro Daniel B. , Cordy Regina Joice 
Published: May 2023

AbstractMalaria is a highly oxidative parasitic disease in which anemia is the most common clinical symptom. A major contributor to malarial anemia pathogenesis is the destruction of bystander, uninfected red blood cells. Metabolic fluctuations are known to occur in the plasma of individuals with acute malaria, emphasizing the role of metabolic changes in disease progression and severity. Here, we report that conditioned media fromPlasmodium falciparumculture induces oxidative stress in healthy uninfected RBCs. Additionally, we show the benefit of amino acid pre-exposure for RBCs and how this pre-treatment intrinsically prepares RBCs to mitigate oxidative stress.Key pointsIntracellular ROS is acquired in red blood cells incubated withPlasmodium falciparumconditioned mediaGlutamine, cysteine, and glycine amino acid supplementation increased glutathione biosynthesis and reduced ROS levels in stressed RBCs
Structural basis of TFIIIC-dependent RNA Polymerase III transcription initiation
Authors: Talyzina Anna , Han Yan , Banerjee Chiranjib , Fishbain Susan , Reyes Alexis , Vafabakhsh Reza , He Yuan 
Published: May 2023

SUMMARYRNA Polymerase III (Pol III) is responsible for transcribing 5S ribosomal RNA (5S rRNA), tRNAs, and other short non-coding RNAs. Its recruitment to the 5S rRNA promoter requires transcription factors TFIIIA, TFIIIC, and TFIIIB. Here we use cryo-electron microscopy to visualize theS. cerevisiaecomplex of TFIIIA and TFIIIC bound to the promoter. Brf1-TBP binding further stabilizes the DNA, resulting in the full-length 5S rRNA gene wrapping around the complex. Our smFRET study reveals that the DNA undergoes both sharp bending and partial dissociation on a slow timescale, consistent with the model predicted from our cryo-EM results. Our findings provide new insights into the mechanism of how the transcription initiation complex assembles on the 5S rRNA promoter, a crucial step in Pol III transcription regulation.
Serine proteinase inhibitors fromNicotiana benthamiana, a non-preferred host plant, inhibit the growth ofMyzus persicae(green peach aphid)
Authors: Feng Honglin , Jander Georg 
Published: May 2023

AbstractThe green peach aphid (Myzus persicae) is a severe agricultural crop pest that has developed resistance to most current control methods, requiring the urgent development of novel strategies. Plant proteinase inhibitors (PINs) are small proteins that protect plants against pathogens and/or herbivores, likely by preventing efficient protein digestion. We identified 67 protease genes in the transcriptomes of threeM. persicaelineages (USDA-Red, G002, and G006). Comparison of gene expression levels in aphid guts and whole aphids showed that several proteases, including a highly expressed serine protease, are significantly overexpressed in the guts. Furthermore, we identified three genes encoding serine protease inhibitors (SerPIN-II1,2, and3) inNicotiana benthamiana, which is a non-preferred host forM. persicae. Using virus-induced gene silencing (VIGS) with a tobacco rattle virus (TRV) vector and overexpression with a turnip mosaic virus (TuMV) vector, we demonstrated thatN. benthamiana SerPIN-II1andSerPIN-II2cause reduced survival and growth, but do not affect aphid protein content. Similarly,SerPIN-II3overexpression reduced survival and growth, andserpin-II3knockout mutations, which we generated using CRISPR/Cas9, increased survival and growth. Whereas protein content was significantly increased in aphids fed onSerPIN-II3overexpressing plants, it was decreased in aphids fed onserpin-II3mutants. Together, our results show that three PIN-IIs fromN. benthamiana, a non-preferred host plant, effectively inhibitM. persicaesurvival and growth, thereby representing a new resource for the development of aphid-resistant crop plants.
Small cationic cysteine-rich defensin-derived antifungal peptide controls white mold in soybean
Authors: Djami-Tchatchou Arnaud Thierry , Tetorya Meenakshi , Codjoe Jennette M. , Shah Dilip M. 
Published: May 2023

AbstractWhite mold disease caused by a necrotrophic ascomycete pathogenSclerotinia sclerotiorumresults in serious economic losses of soybean yield in the USA. Lack of effective genetic resistance to this disease in soybean germplasm and increasing pathogen resistance to fungicides makes white mold difficult to manage. Small cysteine-rich antifungal peptides with multi-faceted modes of action hold potential for development as sustainable spray-on bio-fungicides. We have previously reported that GMA4CG_V6 peptide, a 17-amino acid variant of the MtDef4 defensin-derived peptide GMA4CG containing the active γ-core motif, exhibits potent antifungal activity against the gray mold fungal pathogenBotrytis cinerea in vitroandin planta. This peptide exhibited antifungal activity against an aggressive field isolate ofS. sclerotiorum 555 in vitro.It markedly reduced white mold disease symptoms when applied to detached soybean leaves, pods, and stems. Spray-application on soybean plants provided robust control of the white mold disease. GMA4CG_V6 at sub-lethal concentrations reduced sclerotia production. It was also non-phytotoxic to soybean plants. Our results demonstrate that GMA4CG_V6 peptide has high potential for development as a bio-fungicide for white mold control in soybean.
CyuR is a Dual Regulator for L-Cysteine Dependent Antimicrobial Resistance inEscherichia coli
Authors: Rodionova Irina A. , Lim Hyun Gyu , Rodionov Dmitry A , Hutchison Ying , Dalldorf Christopher , Gao Ye , Monk Jonathan , Palsson Bernhard O. 
Published: May 2023

ABSTRACTHydrogen sulfide (H2S), mainly produced from L-cysteine (Cys), renders bacteria highly resistant to oxidative stress. This mitigation of oxidative stress was suggested to be an important survival mechanism to achieve antimicrobial resistance (AMR) in many pathogenic bacteria. CyuR (known as DecR or YbaO) is a recently characterized Cys-dependent transcription regulator, responsible for the activation of thecyuAPoperon and generation of hydrogen sulfide from Cys. Despite its potential importance, the regulatory network of CyuR remains poorly understood. In this study, we investigated the roles of the CyuR regulon in a Cys-dependent AMR mechanism inE. colistrains. We found: 1) Cys metabolism has a significant role in AMR and its effect is conserved in manyE. colistrains, including clinical isolates; 2) CyuR negatively controls the expression ofmdlABencoding a transporter that exports antibiotics such as cefazolin and vancomycin; 3) CyuR binds to a DNA sequence motif ‘GAAwAAATTGTxGxxATTTsyCC’ in the absence of Cys, confirmed by anin vitrobinding assay; and 4) CyuR may regulate 25 additional genes as suggested byin silicomotif scanning and transcriptome sequencing. Collectively, our findings expanded the understanding of the biological roles of CyuR relevant to antibiotic resistance associated with Cys.
Pangenome analysis reveals the genetic basis for taxonomic classification of the Lactobacillaceae family
Authors: Rajput Akanksha , Chauhan Siddharth M. , Mohite Omkar S. , Hyun Jason C. , Ardalani Omid , Jahn Leonie J. , Sommer Morten OA , Palsson Bernhard O. 
Published: May 2023

AbstractLactobacillaceaerepresent a large family of important microbes that are foundational to the food industry. Many genome sequences ofLactobacillaceaestrains are now available, enabling us to conduct a comprehensive pangenome analysis of this family. We collected 3,591 high-quality genomes from public sources and found that: 1) they contained enough genomes for 26 species to perform a pangenomic analysis, 2) the normalized Heap’s coefficient λ (a measure of pangenome openness) was found to have an average value of 0.27 (ranging from 0.07-0.37), 3) the pangenome openness was correlated with the abundance and genomic location of transposons and mobilomes, 4) the pangenome for each species was divided into core, accessory, and rare genomes, that highlight the species-specific properties (such as motility and restriction-modification systems), 5) the pangenome ofLactiplantibacillus plantarum(which contained the highest number of genomes found amongst the 26 species studied) contained nine distinct phylogroups, and 6) genome mining revealed a richness of detected biosynthetic gene clusters, with functions ranging from antimicrobial and probiotic to food preservation, but ∼93% were of unknown function. This study provides the first in-depth comparative pangenomics analysis of theLactobacillaceaefamily.