Rationale: Microbiome studies typically focus on bacteria, but fungal species are common in many body sites and can have profound effects on the host. Wide gaps exist in the understanding of the fungal microbiome (mycobiome) and its relationship to lung disease.Objectives: To characterize the mycobiome at different respiratory tract levels in persons with and without HIV infection and in HIVinfected individuals with chronic obstructive pulmonary disease (COPD).Methods: Oral washes (OW), induced sputa (IS), and bronchoalveolar lavages (BAL) were collected from 56 participants. We performed 18S and internal transcribed spacer sequencing and used the neutral model to identify fungal species that are likely residents of the lung. We used ubiquity-ubiquity plots, random forest, logistic regression, and metastats to compare fungal communities by HIV status and presence of COPD.

These data provide evidence that compositionally and structurally distinct lower airway microbiomes are associated with discrete local host immune responses, peripheral metabolic reprogramming, and different rates of mortality.

Prions are viewed as enigmatic infectious entities whose genetic properties are enciphered solely in an array of self-propagating protein aggregate conformations. Rnq1, a yeast protein with yet unknown function, forms a prion named [PIN+] for its ability to facilitate the de novo induction of another prion, [PSI+]. Here we investigate a set of RNQ1 truncations that were designed to cover major Rnq1 sequence elements similar to those important for the propagation of other yeast prions: a region rich in asparagines and glutamines and several types of oligopeptide repeats. Proteins encoded by these RNQ1 truncations were tested for their ability to (a) join (decorate) pre-existing [PIN+] aggregates made of wild-type Rnq1 and (b) maintain the heritable aggregated state in the absence of wild-type RNQ1. While the possible involvement of particular sequence elements in the propagation of [PIN+] is discussed, the major result is that the efficiency of transmission of [PIN+] from wild-type Rnq1 to a fragment decreased with the fragment's length.

Background: Wolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration.Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial. Methods:Based on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic -cell functions, visual acuity, quality of life measures related to vision, and neurological functions. Results:The results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Overall, -cell functions were not significantly improved by dantrolene, but there was a significant correlation between baseline -cell functions and the change in -cell responsiveness (R 2 , p=0.004) after 6 months of dantrolene therapy. Other outcome measures, including visual acuity and neurological functions, were not improved by dantrolene sodium treatment within 6 months. As previously reported, markers of inflammatory cytokines and oxidative stress, such as IFN, IL-1, TNF, and isoprostane, were elevated in subjects with Wolfram syndrome. Conclusion:This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome. Abreu & Stone et. al. 3 Trial registration ClinicalTrials.gov Identifier NCT02829268 Conflict of interest statement F. Urano received research funding from Eli Lilly, Ono Pharmaceuticals, and Amarantus BioScience for the development of MANF-based regenerative therapy for Wolfram syndrome, optic nerve atrophy, and diabetes. F. Urano received chemical compounds from Amylyx Pharmaceuticals, Mitochon Pharmaceuticals, Aetas Pharma, and National Center for Advancing Translational Sciences for the development of small molecule-based therapies for ER stress-related disorders, including Wolfram syndrome. F. Urano is an inventor of two patents related to the treatment of Wolfram syndrome, US 9,891,231 SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS and US 10,441,574 and US 10,695,324 TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS. F. Urano is a Founder and President of CURE4WOLFRAM, INC.

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