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In stepped wedge (SW) designs, differing cluster-level characteristics or individual-level covariate distributions that differ by cluster can lead to imbalance by treatment arm and potential confounding of the treatment effect. check details Adapting a method used in cluster-randomized trials, we propose a covariate-constrained randomization method to be used in SW designs. First, we define a balance metric to be calculated for all possible randomizations of cluster order for a given SW design. The resulting distribution of this balance metric across all possible randomizations is used to select a candidate set of randomizations with acceptable covariate balance. One cluster order is selected at random from this candidate set to be used as the cluster order for treatment implementation. In a simulation study, we implement the covariate-constrained randomization procedure and compare treatment effect estimation, type I error, and power under varying SW design and confounding settings, and using multiple analysis methods. We observed optimal statistical properties when the balance metric was used to exclude a small set of potential randomizations with the highest level of imbalance, and when analysis methods were adjusted for the potential confounders. The covariate-constrained randomization was most beneficial in settings with a small number of clusters and in the presence of cluster-level confounding.Molecular mechanisms underlying wing evolution and development have been a point of scientific inquiry for decades. Phloem-feeding aphids are one of the most devastating global insect pests, where dispersal of winged morphs lead to annual movements, migrations, and range expansions. Aphids show a polyphenic wing dimorphism trait, and offer a model to study the role of environment in determining morphological plasticity of a single genotype. Despite recent progresses in the genetic understanding of wing polyphenism, the influence of environmental cues remains unclear. To investigate the involvement of miRNAs in wing development, we sequenced small RNA libraries of the English grain aphid, Sitobion avenae (F.), across six different developmental stages. As a result, we identified 113 conserved and 193 S. avenae-specific miRNAs. Gene Ontology and KEGG pathway analyses of putative target mRNAs for the six differentially expressed miRNAs are enriched for wing development processes. Dietary uptake of miR-263a, miR-316, and miR-184a agomirs and antagomirs led to significantly higher mortality (>70%) and a lower proportion of winged morphs ( less then 5%). On the other hand, wing malformation was observed in miR-2 and miR-306 agomirs and miR-2 and miR-14 antagomirs, respectively, suggesting their involvement in S. avenae wing morphogenesis. Theses combined results not only shed light on the regulatory role of miRNAs in wing dimorphism, but also provide potential novel targets for the long-term sustainable management of S. avenae, a devastating global grain pest.Leigh syndrome is a progressive neurodegenerative syndrome caused by multiple mitochondrial DNA and nuclear DNA pathological variants. Patients with Leigh syndrome consistently have distinct brain lesions found on MRI scanning involving abnormal signal in the basal ganglia, brainstem and/or cerebellum. Other clinical findings vary depending on the genetic etiology and epigenetic factors. Mitochondrial DNA-derived Leigh syndrome phenotype is thought to be modulated by heteroplasmy level. The classic example is the clinical expression of the pathological variant, m. 8993 T>G. At heteroplasmy levels above 90%, the resulting phenotype is Leigh syndrome, but at levels 70-90% patients present with a syndrome of neuropathy, ataxia and retinitis pigmentosa. We describe a 15-year old girl with homoplasmic variant in m.8993 T>G and clinical and biochemical findings consistent with Leigh syndrome but with normal brain MRI findings and without retinal abnormalities or ataxia.Sepsis is a systemic inflammatory disease with an unacceptably high mortality rate caused by an infection or trauma that involves both innate and adaptive immune systems. Inflammatory events activate different downstream pathways leading to tissue damage and ultimately multi-organ failure. Mitochondria are responsible for cellular energy, thermoregulation, metabolite biosynthesis, intracellular calcium regulation, and cell death. Damaged mitochondria induce the high Ca2+ influx through mitochondrial calcium uniporter (MCU). It also generates excessive Reactive oxygen species (ROS) and releases mtDNA into the cytoplasm, which causes induction of NLRP3 inflammasome and apoptosis. Mitophagy (Autophagy of damaged mitochondria) controls mitochondrial dynamics and function. It also maintains cellular homeostasis. This review is about how pulmonary sepsis affects the body. What is the aftermath of sepsis, and how mitophagy affects Acute Lung Injury and macrophage polarisation to overcome the damages.Our laboratory has demonstrated that functional N-methyl-d-aspartate-like receptors are present on neuronal mitochondria (NMDAm). This novel site gates the influx of Ca2+ and causes a several-fold increase in ATP levels. Although elevations in ATP in other cell types have been linked to increases in mitochondrial Ca2+, it has not been established whether the same holds true for calcium uptake via NMDAm. In this study, we have investigated the effect of NMDAm activation on a variety of bioenergetic parameters. Our findings suggest that mitochondrial bioenergetics are not only modulated by NMDAm activation in a Ca2+-dependent but also in a Ca2+-independent manner.The hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are dioxygenases using oxygen and 2-oxoglutarate as co-substrates. Under normoxia, PHDs hydroxylate the conserved prolyl residues of HIFα, leading to HIFα degradation. In hypoxia PHDs are inactivated, which results in HIFα accumulation. The accumulated HIFα enters nucleus and initiates gene transcription. Many studies have shown that PHDs have substrates other than HIFα, implying that they have HIF-independent non-canonical functions. Besides modulating protein stability, the PHDs-mediated prolyl hydroxylation affects protein-protein interaction and protein activity for alternative substrates. Increasing evidence indicates that PHDs also have hydroxylase-independent functions. They influence protein stability, enzyme activity, and protein-protein interaction in a hydroxylase-independent manner. These findings highlight the functional diversity and complexity of PHDs. Due to having inhibitory activity on HIFα, PHDs are proposed to act as tumor suppressors.

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