bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thefnr-likemutants enhance isoxaben tolerance by initiating mitochondrial retrograde signalling
Authors: Broad Ronan , Ogden Michael , Dracatos Peter M , Whelan James , Persson Staffan , Khan Ghazanfar Abbas 
Published: January 2024

AbstractIsoxaben is a pre-emergent herbicide used to control broadleaf weeds. While the phytotoxic mechanism is not completely understood, isoxaben interferes with cellulose synthesis. Certain mutations in cellulose synthase complex proteins can confer isoxaben tolerance; however, these mutations cause compromised cellulose synthesis and perturbed plant growth, rendering them unsuitable as herbicide tolerance traits. We conducted a genetic screen to identify new genes associated with isoxaben tolerance by screening a selection ofArabidopsis thalianaT-DNA mutants. We found that mutations in aFERREDOXIN-NADP(+) OXIDOREDUCTASE-LIKE (FNRL)gene enhanced tolerance to isoxaben, exhibited as a reduction in primary root stunting, reactive oxygen species accumulation, and ectopic lignification. Thefnrlmutant did not exhibit a reduction in cellulose levels following exposure to isoxaben, indicating that FNRL operates upstream of isoxaben-induced cellulose inhibition. In line with these results, transcriptomic analysis revealed a highly reduced response to isoxaben treatment infnrlmutant roots. Thefnrlmutants displayed constitutively induced mitochondrial retrograde signalling, and the observed isoxaben tolerance is partially dependent on the transcription factor ANAC017, a key regulator of mitochondrial retrograde signalling. Moreover, FNRL is highly conserved across all plant lineages, implying conservation of its function. Notably,fnrlmutants did not show a growth penalty in shoots, making FNRL a promising target for biotechnological applications in breeding isoxaben tolerance in crops.
Gray Matters: An Efficient Vision Transformer GAN Framework for Predicting Functional Network Connectivity Biomarkers from Brain Structure
Authors: Bi Yuda , Abrol Anees , Jia Sihan , Fu Zening , Calhoun Vince D. 
Published: January 2024

AbstractThe field of brain connectivity research has under-gone revolutionary changes thanks to state-of-the-art advancements in neuroimaging, particularly regarding structural and functional magnetic resonance imaging (MRI). To navigate the intricate neural dynamics, one must possess a keen comprehension of the interdependent links between structure and function. Such relationships are understudied as they are complex and likely nonlinear. To address this, we created a new generative deep learning architecture using a conditional efficient vision transformer generative adversarial network (cEViTGAN) to capture the distinct information in structural and functional MRI of the human brain. Our model generates functional network connectivity (FNC) matrices directly from three-dimensional sMRI data. Two pioneering innovations are central to our approach. First, we use a novel linear embedding method for structural MRI (sMRI) data that retains the 3D spatial detail. This embedding is best for representative learning, and when used on a consistent dataset, and shows that it is good at upstream classification assignments. To estimate neural biomarkers, we need to process much smaller patches using ViT-based architectures, which usually makes the computations more difficult because of the self-attention operations. We present a new, lightweight self-attention mechanism to address this challenge. Our mechanism not only overcomes computational shortcomings of traditional softmax self-attention but also surpasses pure linear self-attention models in accuracy and performance. This optimization enables us to analyze even the tiniest neuroanatomical details with exceptional precision. Our model allows for the identification of functional network connectivity (FNC) with 74.2% accuracy and also predicts subject differences in FNC for schizophrenia patients versus controls. The results are intriguing and suggest the links between gray matter volume and brain function may be stronger than previously considered.
Mechanisms and implications of high depolarization baseline offsets in conductance-based neuronal models
Authors: Kumar Anal , Shahul Anzal K. , Bhalla Upinder S. 
Published: January 2024

AbstractSomatic step-current injection is commonly used to characterize the electrophysiological properties of neurons. Many neuronal types show a large depolarization baseline offset (DBLO), which is defined as the positive difference between the minimum membrane potential during action potential trains and resting. We used stochastic parameter search in experimentally constrained conductance-based models to show that four key factors together account for high DBLO: Liquid Junction Potential correction, high backpropagating passive charges during the repolarization phase of an action potential, fast potassium delayed rectifier kinetics, and appropriate transient sodium current kinetics. Several plausible mechanisms for DBLO, such as Ohmic depolarization due to current input or low-pass filtering by the membrane, fail to explain the effect, and many published conductance-based models do not correctly manifest high DBLO. Finally, physiological levels of DBLO constrain ion channel levels and kinetics, and are linked to cellular processes such as bistable firing, spikelets, and calcium influx.Abstract Figure
Estimating Disorder Probability Based on Polygenic Prediction Using the BPC Approach
Authors: Uffelmann Emil ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, Price Alkes L. , Posthuma Danielle , Peyrot Wouter J. 
Published: January 2024

AbstractPolygenic Scores (PGSs) summarize an individual’s genetic propensity for a given trait in a single value, based on SNP effect sizes derived from Genome-Wide Association Study (GWAS) results. Methods have been developed that apply Bayesian approaches to improve the prediction accuracy of PGSs through optimization of estimated effect sizes. While these methods are generally well-calibrated for continuous traits (implying the predicted values are on average equal to the true trait values), they are not well-calibrated for binary disorder traits in ascertained samples. This is a problem because well-calibrated PGSs are needed to reliably compute the absolute disorder probability for an individual to facilitate future clinical implementation. Here we introduce the Bayesian polygenic score Probability Conversion (BPC) approach, which computes an individual’s predicted disorder probability using GWAS summary statistics, an existing Bayesian PGS method (e.g. PRScs, SBayesR), the individual’s genotype data, and a prior disorder probability. The BPC approach transforms the PGS to its underlyingliabilityscale, computes the variances of the PGS in cases and controls, and applies Bayes’ Theorem to compute the absolute disorder probability; it is practical in its application as it does not require a tuning dataset with both genotype and phenotype data. We applied the BPC approach to extensive simulated data and empirical data of nine disorders. The BPC approach yielded well-calibrated results that were consistently better than the results of another recently published approach.
Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys
Authors: Wu Yixuan , Sawano Mitsuaki , Wu Yilun , Shah Rishi M. , Bishop Pamela , Iwasaki Akiko , Krumholz Harlan M. 
Published: January 2024

AbstractBackgroundLong COVID (LC) is a complex and multisystemic condition marked by a diverse range of symptoms, yet its associated risk factors remain poorly defined.MethodsLeveraging data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and National Health Interview Survey (NHIS), both representative of the United States population, this study aimed to identify demographic characteristics associated with LC. The sample was restricted to individuals aged 18 years and older who reported a positive COVID-19 test or doctor’s diagnosis. We performed a descriptive analysis comparing characteristics between participants with and without LC. Furthermore, we developed multivariate logistic regression models on demographic covariates that would have been valid at the time of the COVID-19 infection.ResultsAmong the 124,313 individuals in BRFSS and 10,131 in the NHIS reporting either a positive test or doctor’s diagnosis for COVID-19 (Table), 26,783 (21.5%) in BRFSS and 1,797 (17.1%) in NHIS reported LC. In the multivariate logistic regression model, we found middle age, female gender, Hispanic ethnicity, lack of a college degree, and residence in non-metropolitan areas associated with higher risk of LC. Notably, the initial severity of acute COVID-19 was strongly associated with LC risk. In contrast, significantly lower ORs were reported for Non-Hispanic Asian and Black Americans compared to Non-Hispanic White.ConclusionsIn the United States, there is marked variation in the risk of LC by demographic factors and initial infection severity. Further research is needed to understand the underlying cause of these observations.
Efficacy and safety of praziquantel plus Artemisinin-based combinations in the treatment of Kenyan children withSchistosoma mansoniinfection: an open-label, randomized, head-to-head, non-inferiority (SCHISTOACT) trial
Authors: Obonyo Charles O. , Were Vincent O. , Wamae Peter , Muok Erick M.O. 
Published: January 2024

ABSTRACTBackgroundPraziquantel alone is insufficient for the control of schistosomiasis. Unlike praziquantel, artemisinin derivatives are effective for treating juvenile schistosome worms but not adult worms. Few studies have assessed the role of combination therapy, including praziquantel and artemisinin-based combinations, in treating schistosomiasis.MethodsA randomized, open-label, noninferiority trial was conducted in central Kenya to assess the efficacy and safety of praziquantel plus one of four artemisinin-based combination therapies in treating intestinal schistosomiasis. 540 children aged 9-15 years withSchistosoma mansoniinfection were randomly assigned (1:1:1:1:1) to receive a single oral dose of praziquantel (40mg/kg/day) alone or in combination with a 3-day course of artesunate plus sulfalene/pyrimethamine or artesunate plus amodiaquine or artesunate plus mefloquine or dihydroartemisinin-piperaquine. The primary endpoint was the cure rate assessed at six weeks in a per-protocol population. The noninferiority margin was defined as the lower limit of 95%CI of the risk difference in cure rates less than -10%.ResultsCure rates were available for 523 children. Overall, 82.5%, 81.7%, 76.2%, 88.7% and 85.7% of patients on praziquantel, praziquantel-artesunate-sulfalene/pyrimethamine, praziquantel-artesunate-amodiaquine, praziquantel-artesunate-mefloquine, and praziquantel-dihydroartemisinin-piperaquine, respectively, were cured. Non-inferiority was declared for praziquantel-artesunate-mefloquine (difference 6.2 [95%CI -3.3 to 15.6]) and praziquantel-dihydroartemisinin-piperaquine (3.2 [-6.7 to 13.1]) but not for praziquantel-artesunate-sulfalene/pyrimethamine (-0.8 [-11.2 to 9.6]) or praziquantel-artesunate-amodiaquine (-6.3 [-17.3 to 4.6]). A significantly lower number of adverse events were reported in the praziquantel arm than in the combined treatment arm. No serious adverse events were observed.ConclusionsPraziquantel-dihydroartemisinin-piperaquine and praziquantel-artesunate-mefloquine are suitable alternatives to praziquantel monotherapy. The role of artemisinin-based combinations in the treatment of intestinal schistosomiasis remains unclear.Clinical trials registrationPan-African Clinical Trials Registry, PACTR202001919442161.
Breaking down causes, consequences, and mediating effects of age-related telomere shortening on human health
Authors: Moix Samuel , Sadler Marie , Kutalik Zoltán , Auwerx Chiara 
Published: January 2024

AbstractTelomeres represent repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry and used linear regression and bidirectional univariable and multivariable Mendelian randomization (MR and MVMR) to elucidate the relationships between leukocyte telomere length (LTL) and 141 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, which cannot be explained by hormonal or lifestyle differences. MR revealed 23 traits modulating LTL; e.g., smoking cessation and high educational attainment associated with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associated with shorter LTL. We also identified 26 traits affected by LTL, with risk for cardiovascular, pulmonary, renal, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through MVMR, we show that LTL partially mediates the impact of educational attainment, body mass index, and female age at childbirth on lifespan. These results provide new insights into the biology of telomere regulation by shedding light on the modulators, consequences, and the mediatory role of telomere shortening, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.
Antibody signatures against viruses and microbiome reflect past and chronic exposures and associate with aging and inflammation
Authors: Andreu-Sánchez Sergio , Ripoll-Cladellas Aida , Culinscaia Anna , Bulut Ozlem , Bourgonje Arno R. , Netea Mihai G. , Lansdorp Peter , Aubert Geraldine , Bonder Marc Jan , Franke Lude , Vogl Thomas , van der Wijst Monique G.P. , Melé Marta , Van Baarle Debbie , Fu Jingyuan , Zhernakova Alexandra 
Published: January 2024

AbstractPrior encounters with pathogens and other molecules can imprint long-lasting effects on our immune system, potentially influencing future physiological outcomes. However, given the wide range of pathogens and commensal microbes to which humans are exposed, their collective impact on the health and aging processes in the general population is still not fully understood. In this study, we aimed to explore relations between exposures, including to pathogens, microbiome and common allergens, and biological aging and inflammation. We capitalized on an extensive repository of the antibody-binding repertoire against 2,815 microbial, viral, and environmental peptides in a deeply-phenotyped population cohort of 1,443 participants. Utilizing antibody-binding as a proxy for past exposures, we investigated their impact on biological aging markers, immune cell composition and systemic inflammation. This identified that immune response against cytomegalovirus (CMV), rhinovirus and specific gut bacterial species influences the telomere length of different immune cell types. Using blood single-cell RNA-seq measurements, we identified a large effect of CMV infection on the transcriptional landscape of specific immune cells, in particular subpopulations of CD8 and CD4 T-cells. Our work provides a broad examination of the role of past and chronic exposures in biological aging and inflammation, highlighting a role for chronic infections (CMV and Epstein-Barr Virus) and common pathogens (rhinoviruses and adenovirus C).HighlightsThe study provides a broad association of antibody reactivity with biomarkers of aging and inflammationIt shows that anti-CMV, rhinovirus and gut antimicrobial antibody reactivity relate to telomere lengthCMV infection associates to the telomere length of CD45RA+CD57+ cells in a sex-dependent mannerCMV influences the transcriptomic landscape of CD8+ T effector memory and cytotoxic CD4+ cell populationsAnti-Epstein-Barr-Virus and anti-adenoviral responses are associated with higher circulating IL-18BP concentrations
Hydroxyurea Therapy for Neurological and Cognitive Protection in Pediatric Sickle Cell Anemia in Uganda (BRAIN SAFE II): Protocol for a single-arm open label trial
Authors: Mboizi Vincent , Nabaggala Catherine , Munube Deogratias , Ssenkusu John M. , Kasirye Phillip , Kamya Samson , Kawooya Michael G. , Boehme Amelia , Minja Frank , Mupere Ezekiel , Opoka Robert , Rosano Caterina , Green Nancy S. , Idro Richard 
Published: January 2024

AbstractBackgroundChildren with sickle cell anemia (SCA) in Sub-Saharan Africa are at high risk of sickle cerebrovascular injury (SCVI). Hydroxyurea, a commonly used disease-modifying therapy, may prevent or decrease SCVI for reduced incident stroke, stroke risk and potentially cognitive dysfunction. We aim to test the impact of daily hydroxyurea therapy on these outcomes in Ugandan children with SCA. We hypothesize that hydroxyurea therapy over 36 months will prevent, stabilize or improve these complications of SCA.MethodsThe BRAIN SAFE II study is an open-label, single-arm trial of daily hydroxyurea for 270 children with SCA (HbSS) in Uganda, ages 3-9 years. Following baseline assessments, participants began hydroxyurea therapy and clinically followed per local guidelines. Standard hydroxyurea dose is escalated to maximum tolerated dose (MTD). SCVI is assessed by cerebral arterial velocity using Doppler ultrasound, with cognitive function determined by formal neurocognitive testing (primary outcomes). Structural SCVI is assessed by magnetic resonance imaging (MRI) and angiography (MRA) in a sub-sample of 90 participants ages ≥5 years, along with biomarkers of anemia, inflammation and malnutrition (secondary outcomes). At trial midpoint (18 months) and completion (36 months), primary outcomes will be compared to participants’ baseline to determine hydroxyurea impact and relationships to secondary outcomes.ConclusionThis open-label, single-arm trial will examine the impact of hydroxyurea on preventing or ameliorating SCA SCVI in children, assessed by reducing incident stroke, stroke risk and neurocognitive dysfunction. Trial results will provide important insight into the role of hydroxyurea therapy on critical manifestations of SCVI in children with SCA.
Psychotic symptoms are associated with elevated tau PET signal in the amygdala independent of Alzheimer’s disease clinical severity and amyloid burden
Authors: Johnson Aubrey S. , Ziaggi Galen , Smith Anna C. , Houlihan Hannah , Heuer Lauren B. , Guzmán Diana S. , Okafor Amarachukwu , Huey Edward D. , Talmasov Daniel , Provenzano Frank , Kreisl William C. , Lao Patrick J. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2024

AbstractBackgroundPsychosis in Alzheimer’s disease (AD) is associated with worse outcomes, yet no established biomarkers exist for early diagnosis and intervention. We compared tau PET burden across older individuals with and without psychotic symptoms.Methods[18F]AV1451 tau PET binding was compared between 26 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects with psychotic symptoms (delusions and/or hallucinations) and 26 ADNI subjects without psychotic symptoms, matched for age, sex, race/ethnicity, and clinical severity. Tau was assessed on a region-of-interest and voxel level, corrected for amyloid PET burden.ResultsTau was greater in individuals with psychotic symptoms in the amygdala in region-of-interest analyses, and in amygdala, thalamus, putamen, right hippocampus, right entorhinal cortex, and right frontal cortex in voxel-based analyses. When considering different onset and type of psychotic symptoms, tau binding was greatest in those with concurrent delusions.ConclusionElevated tau in limbic regions may be relevant for psychotic symptoms in aging and AD.
Tar Spot Disease Severity Influences Phyllosphere-Associated Bacterial and Fungal Microbiomes
Authors: Singh Raksha , Crane Charles F. , Shim Sujoung , Telenko Darcy E. P. , Goodwin Stephen B. 
Published: January 2024

ABSTRACTTar spot, caused by the obligate fungal pathogenPhyllachora maydis, is a foliar disease of corn that has become a major economic concern in the United States. To test the hypothesis thatP. maydiscan interact with other foliar microorganisms, we investigated phyllosphere microbiomes in relation to corn inbreds with differential tar spot symptoms under natural infestation in the field. Leaf samples from sixteen inbred lines were assessed for tar spot symptoms, and bacterial and fungal microbiomes were characterized by paired-end sequencing on the Illumina MiSeq platform. Comparison of the phyllosphere microbiomes revealed distinct bacterial and fungal communities between resistant and susceptible lines. Bacterial and fungal species richness was significantly higher in resistant compared to susceptible inbred lines in a sample-specific manner. In contrast, there were no clear differences in diversity when including evenness of bacterial communities between the resistant and susceptible lines. Diversity of fungal communities differed significantly, particularly between twelve of the fourteen susceptible lines versus resistant lines. Plant-beneficial bacterial genera such asMethylorubrumandQuadrisphaerawere associated with resistant lines, whilePantoea, DeinococcusandPseudomonaswere the least abundant. The second-most commonly detected fungus likely was aConiothyrium, but whether it is the same species that was identified as a possible mycoparasite ofP. maydisin Central and South America is not known. Fungal generaCladosporium, Papiliotrema, Cryptococcus, TilletiopsisandAlternariawere associated with resistant lines whileSphaerellopsiswas the least-abundant genus. In contrast,Puccinia, SphaerellopsisandPhyllachorawere the dominant fungal genera in susceptible lines. Our findings imply thatP. maydisinfection may result in a distinct microbiota with lower diversity. Further analyses of these distinct microbiota between resistant and susceptible lines could lead to a better understanding of the potential role of foliar microbiomes in causing or resistingP. maydisinfection.