Identification of oxidative phosphorylation-related genes in moyamoya disease by combining bulk RNA-sequencing analysis and machine learning.

Introduction: Moyamoya disease (MMD) is a chronic cerebrovascular disease that can lead to ischemia and hemorrhagic stroke. The relationship between oxidative phosphorylation (OXPHOS) and MMD pathogenesis remains unknown. Methods: The gene expression data of 60 participants were acquired from three Gene Expression Omnibus (GEO) datasets, including 36 and 24 in the MMD and control groups. Differentially expressed genes (DEGs) between MMD patients MMD and control groups were identified. Machine learning was used to select the key OXPHOS-related genes associated with MMD from the intersection of DEGs and OXPHOS-related gene sets. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), gene set enrichment analysis (GSEA), Immune infiltration and microenvironments analysis were used to analyze the function of key genes. Machine learning selected four key OXPHOS-related genes associated with MMD: CSK, NARS2, PTPN6 and SMAD2 (PTPN6 was upregulated and the other three were downregulated). Results: Functional enrichment analysis showed that these genes were mainly enriched in the Notch signaling pathway, GAP junction, and RNA degradation, which are related to several biological processes, including angiogenesis, proliferation of vascular smooth muscle and endothelial cells, and cytoskeleton regulation. Immune analysis revealed immune infiltration and microenvironment in these MMD samples and their relationships with four key OXPHOS-related genes. APC co-inhibition (p = 0.032), HLA (p = 0.001), MHC I (p = 0.013), T cellco- inhibition (p = 0.032) and Type I IFN responses (p < 0.001) were significantly higher in the MMD groups than those in the control groups. The CSK positively correlated with APC co-inhibition and T cell-co-inhibition. The NARS2 negatively correlated with Type I IFN response. The SMAD2 negatively correlated with APC co-inhibition and Type I IFN response. The PTPN6 positively correlated with HLA, MHC I and Type I IFN responses. Discussion: This study provides a comprehensive understanding of the role of OXPHOS in MMD and will contribute to the development of new treatment methods and exploration of MMD pathogenesis.

Bioinformatic analysis of chromatin organization and biased expression of duplicated genes between two poplars with a common whole-genome duplication.

The nonrandom three-dimensional organization of chromatin plays an important role in the regulation of gene expression. However, it remains unclear whether this organization is conserved and whether it is involved in regulating gene expression during speciation after whole-genome duplication (WGD) in plants. In this study, high-resolution interaction maps were generated using high-throughput chromatin conformation capture (Hi-C) techniques for two poplar species, Populus euphratica and Populus alba var. pyramidalis, which diverged ~14 Mya after a common WGD. We examined the similarities and differences in the hierarchical chromatin organization between the two species, including A/B compartment regions and topologically associating domains (TADs), as well as in their DNA methylation and gene expression patterns. We found that chromatin status was strongly associated with epigenetic modifications and gene transcriptional activity, yet the conservation of hierarchical chromatin organization across the two species was low. The divergence of gene expression between WGD-derived paralogs was associated with the strength of chromatin interactions, and colocalized paralogs exhibited strong similarities in epigenetic modifications and expression levels. Thus, the spatial localization of duplicated genes is highly correlated with biased expression during the diploidization process. This study provides new insights into the evolution of chromatin organization and transcriptional regulation during the speciation process of poplars after WGD.

Intraoperative transit-time ultrasonography combined with FLOW800 predicts the occurrence of cerebral hyperperfusion syndrome after direct revascularization of Moyamoya disease: a preliminary study.

BACKGROUND: Cerebral hyperperfusion syndrome (CHS) is a common complication after direct bypass surgery in patients with Moyamoya disease (MMD). Since preventive measures may be inadequate, we assessed whether the blood flow difference between the superficial temporal artery (STA) and recipient vessels (△BF) and the direct perfusion range (DPR) are related to CHS. METHODS: We measured blood flow in the STA and recipient blood vessels before bypass surgery by transit-time probe to calculate △BF. Perfusion changes around the anastomosis before and after bypass were analyzed with FLOW800 to obtain DPR. Multiple factors, such as △BF, DPR, and postoperative CHS, were analyzed using binary logistic regression. RESULTS: Forty-one patients with MMD who underwent direct bypass surgery were included in the study. Postoperative CHS symptoms occurred in 13/41 patients. △BF and DPR significantly differed between the CHS and non-CHS groups. The optimal receiver operating characteristic (ROC) curve cut-off value was 31.4 ml/min for ΔBF, and the area under the ROC curve (AUC) was 0.695 (sensitivity 0.846, specificity 0.500). The optimal cut-off value was 3.5 cm for DPR, and the AUC was 0.702 (sensitivity 0.615, specificity 0.750). CONCLUSION: Postoperative CHS is caused by multiple factors. △BF is a risk factor for CHS while DPR is a protective factor against CHS.

FGF20-FGFR1 signaling through MAPK and PI3K controls sensory progenitor differentiation in the organ of Corti.

BACKGROUND: Fibroblast Growth Factor 20 (FGF20)-FGF receptor 1 (FGFR1) signaling is essential for cochlear hair cell (HC) and supporting cell (SC) differentiation. In other organ systems, FGFR1 signals through several intracellular pathways including MAPK (ERK), PI3K, phospholipase C ɣ (PLCɣ), and p38. Previous studies implicated MAPK and PI3K pathways in HC and SC development. We hypothesized that one or both would be important downstream mediators of FGF20-FGFR1 signaling for HC differentiation. RESULTS: By inhibiting pathways downstream of FGFR1 in cochlea explant cultures, we established that both MAPK and PI3K pathways are required for HC differentiation while PLCɣ and p38 pathways are not. Examining the canonical PI3K pathway, we found that while AKT is necessary for HC differentiation, it is not sufficient to rescue the Fgf20-/- phenotype. To determine whether PI3K functions downstream of FGF20, we inhibited Phosphatase and Tensin Homolog (PTEN) in Fgf20-/- explants. Overactivation of PI3K resulted in a partial rescue of the Fgf20-/- phenotype, demonstrating a requirement for PI3K downstream of FGF20. Consistent with a requirement for the MAPK pathway for FGF20-regulated HC differentiation, we show that treating Fgf20-/- explants with FGF9 increased levels of dpERK. CONCLUSIONS: Together, these data provide evidence that both MAPK and PI3K are important downstream mediators of FGF20-FGFR1 signaling during HC and SC differentiation.

Survival in the Tropics despite isolation, inbreeding and asexual reproduction: insights from the genome of the world's southernmost poplar (Populus ilicifolia).

Species are becoming extinct at unprecedented rates as a consequence of human activity. Hence it is important to understand the evolutionary dynamics of species with already small population sizes. Populus ilicifolia is a vulnerable poplar species that is isolated from other poplar species and is uniquely adapted to the Tropics. It has a very limited size, reproduces partly clonally and is therefore an excellent case study for conservation genomics. We present here the first annotated draft genome of P. ilicifolia, characterize genome-wide patterns of polymorphisms and compare those to other poplar species with larger natural ranges. P. ilicifolia experienced a more prolonged and severe decline of effective population size (Ne ) and signs of genetic erosion than any other poplar species with which it was compared. At present, the species has the lowest genome-wide genetic diversity, the highest abundance of long runs of homozygosity, high inbreeding levels as well as a high overall accumulation of deleterious variants. However, more effective purging of severely deleterious variants and adaptation to the Tropics may have contributed to its survival. Hence, in spite of its limited genetic variation, it is certainly worth pursuing the conservation efforts of this unique species.

Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent.

Cell fate transitions are essential for specification of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we identify, with 3D and 4D microscopy, unclustered precursors of dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes. With population-based and single-cell transcriptomics, we define a molecular time-lapse from pre-DC fate specification through DC niche formation and establish the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then coincide with DC formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for pre-DC specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.

Resistance to zinc and cadmium in Staphylococcus aureus of human and animal origin.

OBJECTIVE: Studies conducted in Europe have observed resistance to trace metals such as zinc chloride and copper sulfate in livestock-associated Staphylococcus aureus. This study was conducted to determine the prevalence of zinc and cadmium resistance in S. aureus isolated in the United States. DESIGN: Cross-sectional study of convenience sample of S. aureus isolates. PARTICIPANTS: Three hundred forty-nine S. aureus isolates, including methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) obtained from human, swine, and retail meat were included in the sample set. METHODS: Polymerase chain reaction was used to test for the presence of genes for zinc and cadmium resistance (czrC), methicillin resistance (mecA), and staphylococcal complement inhibitor (scn). Antibiotic susceptibility of isolates was tested using the broth microdilution method. Data were analyzed using the multivariable logistic regression method. RESULTS: Twenty-nine percent (102/349) of S. aureus isolates were czrC positive. MRSA isolates were more likely to be czrC positive compared to MSSA (MRSA czrC positive: 12/61, 19.6%; MSSA czrC positive: 12/183, 6.6%). After adjustment for oxacillin and clindamycin susceptibility in analysis, multidrug-resistant S. aureus was observed to have low odds of being czrC positive (P = .03). The odds of being czrC positive were observed to be significantly high in tetracycline-resistant S. aureus isolated from noninfection samples (P = .009) and swine (P < .0001). CONCLUSIONS: Resistance to zinc and cadmium was observed to be associated with MRSA, a finding consistently observed in European studies. Prolonged exposure to zinc in livestock feeds and fertilizers could propagate resistance to the metal ion, thereby hindering use of zinc-based topical agents in treating S. aureus infections.

Effect of TRIF on permeability and apoptosis in bovine microvascular endothelial cells exposed to lipopolysaccharide.

Bovine respiratory disease complex (BRDC) can be caused by several Gram negative bacteria. Lung endothelial cells may be damaged by the release of lipopolysaccharide (LPS) from these organisms. Toll-like receptor (TLR-4) signaling pathways include the myeloid differentiation primary response gene 88 (MyD88) and the Toll/interleukin (IL)-1 receptor (TIR) domain-containing adapter-inducing interferon-ß (TRIF) pathways. The aim of this study was to determine which of these pathways is responsible for permeability changes, apoptosis and cytokine production in bovine lung microvascular cells exposed to LPS. Bovine lung endothelial cells were treated with a peptide to inhibit MyD88 signaling or small interfering RNA (siRNA) to inhibit TRIF signaling. Effects were measured using trans-well endothelial electrical resistance to determine cell monolayer permeability, annexin staining to estimate apoptosis and real-time PCR to measure levels of expression of IL-1ß and tumor necrosis factor (TNF)-α mRNA. Inhibition of TRIF signaling reduced permeability changes and apoptosis in endothelial cells exposed to LPS. In contrast, MyD88 inhibition reduced expression of IL-1ß and TNF-α mRNA in LPS treated cells, but had no effect on permeability. It was concluded that TRIF signaling in LPS-stimulated lung endothelial cells results in permeability changes and apoptosis.