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Increasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction and that this effect might be exacerbated in conditions of increased vulnerability in affected brain regions, such as the amygdala.We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment, which models non-motor symptoms of Parkinson’s disease and affects amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in malathies. These results may explain why, in the hands of many research groups, this model does not elicit pronounced Parkinson’s disease-like symptoms in the absence of mitochondrial dysfunction. This despite the presence of significant α-synuclein pathology in brain regions involved in non-motor (amygdala) and motor (striatum) disease symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, particularly in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.Recurrent implantation failure (RIF) refers to repeated failure to become pregnant after transferring embryos with normal morphology. However, the pathogenesis of RIF remains unrevealed, especially for those without any pathological features. In this study, we characterized the vaginal microbiota and metabolomes of patients with unexplained RIF, while patients who achieved clinical pregnancy in the first frozen embryo transfer (FET) cycle were used as controls. Based on 16S rRNA gene sequencing of the vaginal microbiota, the vaginal Lactobacillus showed a significant positive correlation with the pregnancy rate, and the RIF group presented higher microbial α-diversity than the control group (P value = 0.016). The metabolomic profile identified 2,507 metabolites, of which 37 were significantly different between the two groups (P value 1). Among them, 2′,3-cyclic UMP and inositol phosphate were the top two metabolites that were higher in the RIF group, while glycerophospholipids and benzopyran were important md to many female reproductive diseases. In this study, we characterized the vaginal microbiota and metabolomes of patients with unexplained RIF, while patients who achieved clinical pregnancy in the first IVF cycle were set as controls. In general, significant differences were discovered in the vaginal microbiota and metabolomes between the two groups. see more This study is the first detailed elaboration of the vaginal microbiota and metabolites associated with RIF. We believe that our findings will inspire researchers to consider the dynamics of microbiomes related to the microenvironment as a critical feature for future studies of nosogenesis not only for RIF but also for other reproductive diseases.The heterochromatin environment plays a central role in silencing genes associated with the malaria parasite’s development, survival in the host, and transmission to the mosquito vector. However, the underlying mechanism regulating the dynamic chromatin structure is not understood yet. Here, we have uncovered that Plasmodium falciparum Rrp6, an orthologue of eukaryotic RNA exosome-associated RNase, controls the silencing of heterochromatic genes. PfRrp6 knockdown disrupted the singular expression of the GC-rich ncRNA RUF6 family, a known critical regulator of virulence gene expression, through the stabilization of the nascent transcripts. Mechanistic investigation showed that the accumulation of the multiple RUF6 ncRNAs triggered local chromatin remodeling in situ, which activated their adjacent var genes. Strikingly, chromatin isolation by RNA purification analysis (ChIRP-seq) revealed that a remarkable RUF6 ncRNA had interacted with distal heterochromatin regions directly and stimulated a global derepressiocal chromatin alteration, thereby activating most heterochromatic genes via direct interaction of RUF6 and distal gene loci. This finding not only uncovered the in-depth mechanism of RUF6-mediated regulation of heterochromatic genes but also identified Rrp6 as a novel regulator of gene expression in human malaria parasites, which provides a new target for developing intervention strategies against malaria.Mucormycosis, caused by Rhizopus species, is a life-threatening fungal infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), cytotoxic chemotherapy, immunosuppressive therapy, hematologic malignancies, or severe trauma. Inhaled Rhizopus spores cause pulmonary infections in patients with hematologic malignancies, while patients with DKA are much more prone to rhinoorbital/cerebral mucormycosis. Here, we show that Rhizopus delemar interacts with glucose-regulated protein 78 (GRP78) on nasal epithelial cells via its spore coat protein CotH3 to invade and damage the nasal epithelial cells. Expression of the two proteins is significantly enhanced by high glucose, iron, and ketone body levels (hallmark features of DKA), potentially leading to frequently lethal rhinoorbital/cerebral mucormycosis. In contrast, R. delemar CotH7 recognizes integrin β1 as a receptor on alveolar epithelial cells, causing the activation of epidermal growth factor receptor (EGFR) and leading to host cell invases or those undergoing cytotoxic chemotherapy, Rhizopus causes pulmonary infections. On the other hand, DKA patients predominantly suffer from rhinoorbital/cerebral mucormycosis. The reason for such disparity in disease types by the same fungus is not known. Here, we show that the unique susceptibility of DKA subjects to rhinoorbital/cerebral mucormycosis is likely due to specific interaction between nasal epithelial cell GRP78 and fungal CotH3, the expression of which increases in the presence of host factors present in DKA. In contrast, pulmonary mucormycosis is initiated via interaction of inhaled spores expressing CotH7 with integrin β1 receptor, which activates EGFR to induce fungal invasion of host cells. These results introduce a plausible explanation for disparate disease manifestations in DKA versus those in hematologic malignancy patients and provide a foundation for development of therapeutic interventions against these lethal forms of mucormycosis.