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Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), one of the leading hereditary kidney diseases, and Alzheimer’s disease etc. There are no targeted therapies. ADTKD is also a genetic form of renal fibrosis and chronic kidney disease, which affects 500 million people worldwide. For the first time, in our newly generated mouse model recapitulating human ADTKD-UMODcarrying a leadingUMODdeletion mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are severely impaired, leading to cGAS- STING activation and tubular injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel endoplasmic reticulum stress-regulated secreted protein. We provide the first study that inducible tubular overexpression of MANF after the onset of disease stimulates autophagy/mitophagy and clearance of the misfolded UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, resulting in protection of kidney function. Conversely, genetic ablation of endogenous MANF upregulated in the mutant mouse and human tubular cells worsens autophagy suppression and kidney fibrosis. Together, we discover MANF as a novel biotherapeutic protein and elucidate previously unknown mechanisms of MANF in regulating organelle homeostasis to treat ADTKD, which may have broad therapeutic application to treat various proteinopathies.

Obesity and diabetes modulate macrophage activation often leading to prolonged inflammation and dysfunctional tissue repair. Increasing evidence suggests that the NLRP3 inflammasome plays an important role in obesity-associated inflammation. We have previously shown that activation of the lipotoxic inflammasome by excess fatty acids in macrophages occurs via a lysosomal dependent pathway. However, the mechanisms that link cellular lipid metabolism to altered inflammation remain poorly understood. PPARγ is a nuclear receptor transcription factor expressed by macrophages that is known to alter lipid handling, mitochondrial function, and inflammatory cytokine expression. To undercover novels links between metabolic signaling and lipotoxic inflammasome activation we investigated mouse primary macrophages deficient in PPARγ. Contrary to our expectation, PPARγ knock out (KO) macrophages released significantly less IL-1β and IL-1α in response to lipotoxic stimulation. The suppression occurred at the transcriptional level and was apparent for multiple activators of the NLRP3 inflammasome. RNA sequencing revealed upregulation of IFNβ in activated PPARγ KO macrophages and this was confirmed at the protein level. A blocking antibody against the type 1 interferon receptor restored the release of IL-1β to wild type levels in PPARγ KO cells confirming the mechanistic link between these events. Conversely, PPARγ activation with rosiglitazone selectively suppressed IFNβ expression in activated macrophages. Loss of PPARγ also resulted in diminished expression of genes involved in sterol biosynthesis, a pathway known to influence interferon production. Together these findings demonstrate a crosstalk pathway that influences the interplay between metabolism and inflammation in macrophages.

Supplemental material, Supplemental_Table_4_R1_6.19.18 for A Microarray Study of Articular Cartilage in Relation to Obesity and Severity of Knee Osteoarthritis by Muhammad Farooq Rai, Linda J. Sandell, Toby N. Barrack, Lei Cai, Eric D. Tycksen, Simon Y. Tang, Matthew J. Silva and Robert L. Barrack in CARTILAGE

Supplemental material, Supplemental_Table_3_R1_6.19.18 for A Microarray Study of Articular Cartilage in Relation to Obesity and Severity of Knee Osteoarthritis by Muhammad Farooq Rai, Linda J. Sandell, Toby N. Barrack, Lei Cai, Eric D. Tycksen, Simon Y. Tang, Matthew J. Silva and Robert L. Barrack in CARTILAGE

Supplemental material, Supplemental_Table_1_R1_6.19.18 for A Microarray Study of Articular Cartilage in Relation to Obesity and Severity of Knee Osteoarthritis by Muhammad Farooq Rai, Linda J. Sandell, Toby N. Barrack, Lei Cai, Eric D. Tycksen, Simon Y. Tang, Matthew J. Silva and Robert L. Barrack in CARTILAGE

Supplemental material, Supplemental_Table_2_R1_6.19.18 for A Microarray Study of Articular Cartilage in Relation to Obesity and Severity of Knee Osteoarthritis by Muhammad Farooq Rai, Linda J. Sandell, Toby N. Barrack, Lei Cai, Eric D. Tycksen, Simon Y. Tang, Matthew J. Silva and Robert L. Barrack in CARTILAGE

Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.