Miracle-dz/UniFAR-FTUs huggingface dataset:
Mito-nuclear variation in transgenerational and reproductive effects of amino acid and lipid nutrition

Animals vary genetically in responses to dietary change. Both mitochondrial and nuclear genomes contribute to this variation, but the role of combinatorial “mito-nuclear” genetic variation is understudied. We do not know whether specific nutrients modify patterns of mito-nuclear variation, nor whether putative epigenetic mechanisms play a role. Here, we show that enriching dietary essential amino acids or lipids modifies patterns of mito-nuclear variation in Drosophila life-history, including transgenerational effects of lipids. Systematically evaluating alternative statistical models revealed that diet-mito-nuclear interactions were a leading driver of phenotypic variation. Mito-nuclear genotype repeatably predicted phenotypic impacts of nutritional changes, but genotypes bearing naturally co-occurring pairs of mitochondria and nuclei did not necessarily outperform novel pairings, suggesting that nutrition-dependent phenotypes cannot easily be optimised by matching mitochondria to coincident nuclear genotypes. These results enhance understanding of how nutrition and genetics sculpt phenotype, with potential implications for human mitochondrial transfer therapies.
Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

More than two decades have elapsed since the publication of the first genome sequence of Mycobacterium tuberculosis (Mtb) which, shortly thereafter, enabled methods to determine gene essentiality in the pathogen. Despite this, target-based approaches have not yielded drugs that have progressed to clinical testing. Whole-cell screening followed by elucidation of mechanism of action has to date been the most fruitful approach to progressing inhibitors into the tuberculosis drug discovery pipeline although target-based approaches are gaining momentum. This review discusses scaffolds that have been identified over the last decade from screens of small molecule libraries against Mtb or defined targets where mechanism of action investigation has defined target-hit couples and structure-activity relationship studies have described the pharmacophore.
Phase Angle Cut-Off Points and Their Association With Sarcopenia and Frailty in Adults of 50–64 Years Old and Older Adults in Mexico City

Background: In recent studies, the usefulness of the phase angle (PA) to assess geriatric conditions such as sarcopenia and frailty has been evaluated. However, there are no useful cut-off points for clinical research and/or practice. Objective: To analyze PA cut-off points associated with sarcopenia and frailty in adults of 50-64 years old and older adults in Mexico City. Design: Cross-sectional analysis of the FraDySMex cohort study (Frailty, Dynapenia, and Sarcopenia in Mexican Adults). Setting and Participants: 498 people were included, 78.7% women, aged 71.1 ± 9.5 years. Methods: The sarcopenia measurements were made according to the European Working Group on Sarcopenia in Older People (EWGSOP) (2019) (by dynamometer to evaluate hand grip strength and dual energy X-ray absorptiometry (DXA) for appendicular muscle mass), and the frailty through the physical frailty phenotype with cut-off points adjusted to the Mexican population. The PA was evaluated by bioelectrical impedance analysis (BIA), tetrapolar to 50 Hz, other variables such as socio-demographic, comorbidity, cognitive status, and functional dependence were evaluated. Results: The prevalence of frailty was 10.6% and sarcopenia 10.0%. The mean of the PA was 4.6° ± 0.70°. The PA cut-off point for frailty in adults 50 to 64 years was ≤4.3° [sensitivity (S) = 91.95%, specificity (Sp) 66.77%, AUROC (Area Under the Receiver Operating Characteristic) curve = 0.9273 95% CI (0.8720-0.9825)]; the PA cut-off point for sarcopenia was ≤4.3 [S = 91.95%, Sp = 66.77%, AUROC = 0.9306 95% CI (0.8508-1.000)]. The PA cut-off for frailty in adults ≥ 65 years was ≤4.1° [S = 72.37%, Sp 71.43%, AUROC = 0.7925 95%, CI (0.7280-0.8568)] for sarcopenia was ≤4.1° [S = 72.76%, Sp 73.81%, AUROC = 0.7930 95% CI (0.7272-0.8587)]. These cut-off points showed a significant association between PA with frailty (OR 4.84; 95% CI 2.61-8.99) and sarcopenia (OR 8.44; 95% CI 3.85-18.4) after adjusted by age, sex, BMI, comorbidity index and cognitive impairment. Conclusions and Implications: These cut-off points of PA could be useful for the screening of sarcopenia and frailty in Mexican adults of 50 years and older in centers that have BIA.
Antagonistic Activity of Trichoderma spp. Against Fusarium oxysporum in Rhizosphere of Radix pseudostellariae Triggers the Expression of Host Defense Genes and Improves Its Growth Under Long-Term Monoculture System

Under consecutive monoculture, the abundance of pathogenic fungi, such as Fusarium oxysporum in the rhizosphere of Radix pseudostellariae, negatively affects the yield and quality of the plant. Therefore, it is pertinent to explore the role of antagonistic fungi for the management of fungal pathogens such as F. oxysporum. Our PCR-denatured gradient gel electrophoresis (DGGE) results revealed that the diversity of Trichoderma spp. was significantly declined due to extended monoculture. Similarly, quantitative PCR analysis showed a decline in Trichoderma spp. , whereas a significant increase was observed in F. oxysporum. Furthermore, seven Trichoderma isolates from the R. pseudostellariae rhizosphere were identified and evaluated in vitro for their potentiality to antagonize F. oxysporum. The highest and lowest percentage of inhibition (PI) observed among these isolates were 47.91 and 16.67%, respectively. In in vivo assays, the R. pseudostellariae treated with four Trichoderma isolates, having PI > 30%, was used to evaluate the biocontrol efficiency against F. oxysporum in which T. harzianum ZC51 enhanced the growth of the plant without displaying any disease symptoms. Furthermore, the expression of eight defense-related genes of R. pseudostellariae in response to a combination of F. oxysporum and T. harzianum ZC51 treatment was checked, and most of these defense genes were found to be upregulated. In conclusion, this study reveals that the extended monoculture of R. pseudostellariae could alter the Trichoderma communities in the plant rhizosphere leading to relatively low level of antagonistic microorganisms. However, T. harzianum ZC51 could inhibit the pathogenic F. oxysporum and induce the expression of R. pseudostellariae defense genes. Hence, T. harzianum ZC51 improves the plant resistance and reduces the growth inhibitory effect of consecutive monoculture problem.
Optimal Seismic Design of Stiffness and Gap of Hysteretic-Viscous Hybrid Damper System in Nonlinear Building Frames for Simultaneous Reduction of Interstory Drift and Acceleration

The viscous-hysteretic hybrid (HVH) damper system recently introduced by one of the authors has a clear property that, when the hysteretic dampers with gap mechanism become active (stiffness element starts working), the acceleration of building frames with this damper system as a stopper attains large values in spite of the advantageous feature to prevent excessive deformation. It is therefore desired that both the maximum interstory drift and the maximum acceleration exhibit an acceptable value with appropriate compromise. The double impulse as a simplified version of one-cycle sine wave as a representative of the main part of near-fault ground motions can simulate the maximum interstory drifts properly. However, it cannot simulate the maximum accelerations due to its impulsive nature. In this case, the sine wave corresponding to the double impulse can play an important role in the reliable simulation of the maximum accelerations. Even in such circumstance, the analysis using the double impulse is important because it enables to obtain the critical timing of the input, i.e. the nonlinear resonant frequency of the sine wave without repetition. The investigations on the criticality of the sine wave corresponding to the critical double impulse show that the critical timing of the double impulse leads to the nonlinear resonant frequency of the sine wave in view of the maximum interstory drift, the maximum top acceleration and the maximum relative acceleration for the constant input acceleration and the constant input velocity except for some cases. It is demonstrated finally that the index in terms of the maximum interstory drift and the maximum acceleration can be introduced as an appropriate parameter for deriving the optimally compromised gap quantity of hysteretic dampers with gap mechanism for various input velocity levels and various hysteretic damper stiffness ratios.
Dark-Induced Barley Leaf Senescence – A Crop System for Studying Senescence and Autophagy Mechanisms

This review synthesizes knowledge on dark-induced barley, attached, leaf senescence (DILS) as a model and discusses the possibility of using this crop system for studying senescence and autophagy mechanisms. It addresses the recent progress made in our understanding of DILS. The following aspects are discussed: the importance of chloroplasts as early targets of DILS, the role of Rubisco as the largest repository of recoverable nitrogen in leaves senescing in darkness, morphological changes of these leaves other than those described for chloroplasts and metabolic modifications associated with them, DILS versus developmental leaf senescence transcriptomic differences, and finally the observation that in DILS autophagy participates in the circulation of cell components and acts as a quality control mechanism during senescence. Despite the progression of macroautophagy, the symptoms of degradation can be reversed. In the review, the question also arises how plant cells regulate stress-induced senescence via autophagy and how the function of autophagy switches between cell survival and cell death.
G6PD Variants and Haemolytic Sensitivity to Primaquine and Other Drugs

Restrictions on the cultivation and ingestion of fava beans were first reported as early as the fifth century BC. Not until the late 19th century were clinical descriptions of fava-induced disease reported and soon after characterised as “favism” in the early 20th century. It is now well known that favism as well as drug-induced haemolysis is caused by a deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme, one of the most common enzyme deficiency in humans. Interest about the interaction between G6PD deficiency and therapeutics has increased recently because mass treatment with oxidative 8-aminoquinolines is necessary for malaria elimination. Historically, assessments of haemolytic risk have focused on the clinical outcomes (e.g., haemolysis) associated with either a simplified phenotypic G6PD characterisation (deficient or normal) or an ill-fitting classification of G6PD genetic variants. It is increasingly apparent that detailed knowledge of both aspects is required for a complete understanding of haemolytic risk. While more attention has been devoted recently to better phenotypic characterisation of G6PD activity (including the development of new point-of care tests), the classification of G6PD variants should be revised to be clinically useful in malaria eliminating countries and in populations with prevalent G6PD deficiency. The scope of this work is to summarize available literature on drug-induced haemolysis among individuals with different G6PD variants and to highlight knowledge gaps that could be filled with further clinical and laboratory research.
Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies

Therapeutic advances for neurological disorders are challenging due to limited accessibility of the human central nervous system and incomplete understanding of disease mechanisms. Many neurological diseases lack precision treatments, leading to significant disease burden and poor outcome for affected patients. Induced pluripotent stem cell (iPSC) technology provides human neuronal cells that facilitate disease modeling and development of therapies. The use of genome editing, in particular CRISPR-Cas9 technology, has extended the potential of iPSCs, generating new models for a number of disorders, including Alzheimers and Parkinson Disease. Editing of iPSCs, in particular with CRISPR-Cas9, allows generation of isogenic pairs, which differ only in the disease-causing mutation and share the same genetic background, for assessment of phenotypic differences and downstream effects. Moreover, genome-wide CRISPR screens allow high-throughput interrogation for genetic modifiers in neuronal phenotypes, leading to discovery of novel pathways, and identification of new therapeutic targets. CRISPR-Cas9 has now evolved beyond altering gene expression. Indeed, fusion of a defective Cas9 (dCas9) nuclease with transcriptional repressors or activation domains allows down-regulation or activation of gene expression (CRISPR interference, CRISPRi; CRISPR activation, CRISPRa). These new tools will improve disease modeling and facilitate CRISPR and cell-based therapies, as seen for epilepsy and Duchenne muscular dystrophy. Genome engineering holds huge promise for the future understanding and treatment of neurological disorders, but there are numerous barriers to overcome. The synergy of iPSC-based model systems and gene editing will play a vital role in the route to precision medicine and the clinical translation of genome editing-based therapies.
The Adjustment of Membrane Lipid Metabolism Pathways in Maize Roots Under Saline–Alkaline Stress

Plants are frequently confronted by diverse environmental stress, and the membrane lipids remodeling and signaling are essential for modulating the stress responses. Saline–alkaline stress is a major osmotic stress affecting the growth and development of crops. In this study, an integrated transcriptomic and lipidomic analysis was performed, and the metabolic changes of membrane lipid metabolism in maize (Zea mays) roots under saline–alkaline stress were investigated. The results revealed that phospholipids were major membrane lipids in maize roots, and phosphatidylcholine (PC) accounts for approximately 40% of the total lipids. Under 100 mmol NaHCO3 treatment, the level of PC decreased significantly (11–16%) and the parallel transcriptomic analysis showed an increased expression of genes encoding phospholipase A and phospholipase D/non-specific phospholipase C, which suggested an activated PC turnover under saline–alkaline stress. The plastidic galactolipid synthesis was also activated, and an abnormal generation of C34:6 galactolipids in 18:3 plants maize implied a plausible contribution from the prokaryotic pathway, which could be partially supported by the up-regulated expression of three putative plastid-localized phosphatidic acid phosphatase/lipid phosphate phosphatase. A comprehensive gene–metabolite network was constructed, and the regulation of membrane lipid metabolism under saline–alkaline stress in maize was discussed.
Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine. Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program. Results: The data (n = 36) from 20 infants (age range, 0.35–1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09–0.29) L/h/kg and 0.34 (0.24–0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively. Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model.
A neural progenitor mitotic wave is required for asynchronous axon outgrowth and morphology

Spatiotemporal mechanisms generating neural diversity are fundamental for understanding neural processes. Here, we investigated how neural diversity arises from neurons coming from identical progenitors. In the dorsal thorax of Drosophila, rows of mechanosensory organs originate from the division of sensory organ progenitor (SOPs). We show that in each row of the notum, a central SOP divides first, then neighboring SOPs divide, and so on. This centrifugal wave of mitoses depends on cell-cell inhibitory interactions mediated by SOP cytoplasmic protrusions and Scabrous, a secreted protein interacting with the Delta/Notch complex. Furthermore, when the mitotic wave was abolished, axonal growth was more synchronous, axonal terminals had a complex branching pattern and fly behavior was impaired. We show that the temporal order of progenitor divisions influences the birth order of sensory neurons, axon branching and impact on grooming behavior. These data support the idea that developmental timing controls axon wiring neural diversity.
The role of copper resistance in Mycobacterium tuberculosis pathogenesis

Despite the development of new drugs and social interventions, tuberculosis remains a leading cause of mortality. This burden falls disproportionately on developing countries, particularly those where the incidence of HIV is high. In the Western Cape, South Africa, we have identified and isolated two Beijing family strains of Mycobacterium tuberculosis that, despite few differences at a genomic level, differ greatly in their severity of disease caused, providing an opportunity to study virulence in this organism. The aim of this study was to identify differences at a genomic and transcriptomic level that may identify the cause of the different virulence levels observed in the two isolates. The isolates were compared at the transcriptome level under four different growth conditions including oxidative stress. In comparing the transcriptome of the two isolates, an operon containing genes involved in the production of molybdenum cofactor that showed consistently lower levels of expression in the hypervirulent isolate was identified. A copper sensing transcriptional regulator was identified as the most probable regulator, and we found that the Cso operon which it is known to regulate was similarly differentially expressed in the strains. The production of molybdenum cofactor is effected in two ways by copper levels. Through the independent insertion of copper into molybdopterin (MPT), and destabilisation of Fe-S clusters. As MoaA3 contains a Fe-S cluster that is known to be destabilised by copper, and a number of copper sensitive genes are likewise found differentially expressed, it is likely that the strains differ in terms of their levels of resistance to copper. It is therefore hypothesised that the differences in virulence are as a result of different levels of resistance to phagosome copper overload, and the mechanism by which copper levels are linked to the production of molybdenum cofactor is described. Author summary In this article, we describe the differences in gene expression of two closely related strains of Mycobacterium tuberculosis isolated in the Western Cape of South Africa that differ in the severity of disease that they cause. We compared the strains at a genomic and transcriptomic level, and in doing so, we discovered a set of molybdenum cofactor genes regulated by a copper sensing transcription factor that came up in all datasets. Further genes linked to copper response were identified, providing greater evidence that the difference between the two strains was the manner in which they responded to copper stress. Phagocytes are known to exploit high levels of copper to kill intracellular bacteria, suggesting an important link between copper and disease. We conclude that resistance to copper toxicity is the most probable reason for the relative increase in virulence, and describe the regulatory relationship between copper levels and molybdenum cofactor synthesis.
The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood-brain barrier formation and maturation

The blood-brain barrier (BBB) of Drosophila is comprised of a thin epithelial layer of subperineural glia (SPG), which ensheath the nerve cord and insulate it against the potassium-rich hemolymph by forming intercellular septate junctions (SJs). Previously, we identified a novel Gi/Go protein-coupled receptor (GPCR), Moody, as a key factor in BBB formation at the embryonic stage. However, the molecular and cellular mechanisms of Moody signaling in BBB formation and maturation remain unclear. Here, we identify cAMP-dependent protein kinase A (PKA) as a crucial antagonistic Moody effector that is required for the formation, as well as for the continued SPG growth and BBB maintenance in the larva and adult stage. We show that PKA is enriched at the basal side of the SPG cell and that this polarized Moody/PKA pathway finely tunes the enormous cell growth and BBB integrity, by precisely regulating the actomyosin contractility, vesicle trafficking, and the proper SJ organization in a highly coordinated spatiotemporal manner. These effects are mediated in part by PKA’s molecular targets MLCK and Rho1. Moreover, 3D reconstruction of SJ ultrastructure demonstrates that the continuity of individual SJ segments and not their total length is crucial for generating a proper paracellular seal. Based on these findings, we propose a model that polarized Moody/PKA signaling plays a central role in controlling the cell growth and maintaining BBB integrity during the continuous morphogenesis of the SPG secondary epithelium, which is critical for maintain tissue size and brain homeostasis during organogenesis.
Efficient Genomic Control for Mixed Model Associations in Large-scale Population

Among linear mixed model-based association methods, GRAMMAR has the lowest computing complexity for association tests, but it produces a high false-negative rate due to the deflation of test statistics for complex population structure. Here, we present an optimized GRAMMAR method by efficient genomic control, Optim-GRAMMAR, that estimates the phenotype residuals by regulating downward genomic heritability in the genomic best linear unbiased prediction. Even though using the fewer sampling markers to evaluate genomic relationship matrices and genomic controls, Optim-GRAMMAR retains a similar statistical power to the exact mixed model association analysis, which infers an extremely efficient approach to handle large-scale data. Moreover, joint association analysis significantly improved statistical power over existing methods.