An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain–containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti–PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti–PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4+ T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets in ex vivo CD4+ T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.

BACKGROUND The anti–programmed cell death 1 (anti–PD-1) antibody pembrolizumab is clinically active against non–small cell lung cancer (NSCLC). In addition to T cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of patients with advanced NSCLC, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC.METHODS In total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or higher were randomly allocated to group A (n = 55 patients given pembrolizumab plus NK cells) or group B (n = 54 patients given pembrolizumab alone). The patients received i.v. pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received 2 cycles of NK cell therapy as 1 course of treatment.RESULTS In our study, patients in group A had longer survival than did patients in group B (median overall survival [OS]: 15.5 months vs. 13.3 months; median progression-free survival [PFS]: 6.5 months vs. 4.3 months; P < 0.05). In group A patients with a TPS of 50% or higher, the median OS and PFS was significantly longer. Moreover, the patients in group A treated with multiple courses of NK cell infusion had better OS (18.5 months) than did those who received a single course of NK cell infusion (13.5 months).CONCLUSIONS Pembrolizumab plus NK cell therapy yielded improved survival benefits in patients with previously treated PD-L1+ advanced NSCLC.TRIAL REGISTRATION ClinicalTrials.gov NCT02843204.FUNDING This work was supported by grants from the National Natural Science Foundation of China (NSFC) – Guangdong Joint Foundation of China (no. U1601225); the NSFC (no. 81671965); the Guangdong Provincial Key Laboratory Construction Project of China (no. 2017B030314034); and the Key Scientific and Technological Program of Guangzhou City (no. 201607020016).

BACKGROUND Since December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODS In this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTS The median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSION The SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATION This is a retrospective observational study without a trial registration number.FUNDING This work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201).

Treating neuropathic pain is challenging and novel non–opioid-based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence, and in situ hybridization, we found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element–binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights into its signaling pathways. CARTp is involved in many diseases including depression and reward and addiction; de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

IL-17–producing RORγt+ γδ T cells (γδT17 cells) are innate lymphocytes that participate in type 3 immune responses during infection and inflammation. Herein, we show that γδT17 cells rapidly proliferate within neonatal lymph nodes and gut, where, upon entry, they upregulate T-bet and coexpress IL-17, IL-22, and IFN-γ in a STAT3- and retinoic acid–dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5, and its loss resulted in γδT17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homolog had a dominant role over STAT5B in promoting γδT17 cell expansion and downregulating gut-associated T-bet. In contrast, STAT5B preferentially expanded IFN-γ–producing γδ populations, implying a previously unknown differential role of STAT5 gene products in lymphocyte lineage regulation. Importantly, mice lacking γδT17 cells as a result of STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify that the neonatal microenvironment in combination with STAT5 is critical for post-thymic γδT17 development and tissue-specific imprinting, which is essential for infection and autoimmunity.

Colitis caused by Clostridium difficile infection is a growing cause of human morbidity and mortality, especially after antibiotic use in health care settings. The natural immunity of newborn infants and protective host immune mediators against C. difficile infection are not fully understood, with data suggesting that inflammation can be either protective or pathogenic. Here, we show an essential role for IL-17A produced by γδ T cells in host defense against C. difficile infection. Fecal extracts from children with C. difficile infection showed increased IL-17A and T cell receptor γ chain expression, and IL-17 production by intestinal γδ T cells was efficiently induced after infection in mice. C. difficile–induced tissue inflammation and mortality were markedly increased in mice deficient in IL-17A or γδ T cells. Neonatal mice, with naturally expanded RORγt+ γδ T cells poised for IL-17 production were resistant to C. difficile infection, whereas elimination of γδ T cells or IL-17A each efficiently overturned neonatal resistance against infection. These results reveal an expanded role for IL-17–producing γδ T cells in neonatal host defense against infection and provide a mechanistic explanation for the clinically observed resistance of infants to C. difficile colitis.

Regenerative pain medicine, which seeks to harness the body’s own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.

Facioscapulohumeral muscular dystrophy (FSHD) results from expression of the full-length double homeobox 4 (DUX4-FL) retrogene in skeletal muscle. However, even in cases of severe FSHD the presence of DUX4 is barely detectable. In this issue of the JCI, Bosnakovski et al. used an inducible, muscle-specific human DUX4 to reproduce the low-level, sporadic DUX4 expression of human FSHD muscle as well the myopathology seen in human FSHD disease. Notably, dysregulated fibroadipogenic progenitors accumulated in affected muscles, thus providing a mechanism for the replacement of muscle by fibrosis and fat.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration–related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B–dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression.

Infection with the Gram-negative bacterium Helicobacter pylori remains the most important modifiable risk factor for the development of gastric cancer, a leading cause of cancer-related deaths worldwide. How the interactions between H. pylori and its host shape the gastric environment during chronic infection warrants further investigation. In this issue of the JCI, Palrasu et al. used human cell lines and mouse models to provide mechanistic insight into H. pylori’s ability to delay apoptosis in gastric epithelial cells by actively driving the degradation of a proapoptotic factor, SIVA1. Their findings suggest that promoting the survival of gastric epithelial cells has implications not only for H. pylori pathogenesis but for host tumorigenesis.

Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β–dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure. FSHD is also a chronic disease that progresses slowly over decades. We used the sporadic, low-level, muscle-specific expression of DUX4 enabled by the iDUX4pA-HSA mouse to develop a chronic long-term muscle disease model. After 6 months of extremely low sporadic DUX4 expression, dystrophic muscle presented hallmarks of FSHD histopathology, including muscle degeneration, capillary loss, fibrosis, and atrophy. We investigated the transcriptional profile of whole muscle as well as endothelial cells and fibroadiopogenic progenitors (FAPs). Strikingly, differential gene expression profiles of both whole muscle and, to a lesser extent, FAPs, showed significant overlap with transcriptional profiles of MRI-guided human FSHD muscle biopsies. These results demonstrate a pathophysiological similarity between disease in muscles of iDUX4pA-HSA mice and humans with FSHD, solidifying the value of chronic rare DUX4 expression in mice for modeling pathological mechanisms in FSHD and highlighting the importance FAPs in this disease.

Approximately half of the world’s population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori–infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR–expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.

BACKGROUND Glucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient donor RBCs would have inferior storage quality for transfusion as compared with G6PD-normal RBCs.METHODS Male volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed.RESULTS The mean 24-hour PTR for G6PD-deficient subjects was 78.5% ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways.CONCLUSION Based on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs.TRIAL REGISTRATION ClinicalTrials.gov NCT04081272.FUNDING The Harold Amos Medical Faculty Development Program, Robert Wood Johnson Foundation grant 71590, the National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career Award 2017 by the Boettcher Foundation, and National Heart, Lung, and Blood Institute grants R01HL14644 and R01HL148151.

Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1β, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1β. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.

BACKGROUND Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODS We treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTS Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSION These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATION Clinicaltrials.gov NCT03049462.FUNDING This work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.

The editors of JCI and JCI Insight are revisiting our editorial processes in light of the strain that the COVID-19 pandemic places on the worldwide scientific community. Here, we discuss adjustments to our decision framework in light of restrictions placed on laboratory working conditions for many of our authors.

Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability–enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.

Brown and beige adipose tissues contain thermogenic fat cells that can be activated by β3-adrenergic receptor agonists. In rodents, such drugs both diminish obesity and improve glucose homeostasis. In this issue of the JCI, O’Mara et al. and Finlin and Memetimin et al. report that chronic administration of the approved β3 agonist mirabegron to human subjects was without effect on body weight or fat mass, but improved several measures of glucose homeostasis. Though the mechanisms mediating these metabolic effects are uncertain, the data suggest that β3 agonists could have therapeutic utility in disorders of glucose homeostasis.

BACKGROUND Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODS Before and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTS The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSION Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATION Clinicaltrials.gov NCT02919176.FUNDING NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

You read that right. Joanne and I visited a Masonic Cemetary. Alone. It was one of the most calming experiences of my life. We were kind of invited, by the town, and when we arrived, we were definitely welcomed by the residents. This all started when, in the brochure listing the “town attractions” that we received in St. Helens, were two cemeteries. The addresses as well as short descriptions were listed, as well as a short missive asking us to please be respectful and not make loud noises. It sounded really creepy and really interesting, so both of us jumped at the chance to drive out there right before sunset. They weren’t what I expected at all… Well, the first one was actually roped off with a “no trespassing” sign hanging from it, so we didn’t go inside. It was right alongside the highway in Oregon, across some old train tracks, visible from the road, and named and marked on a tourist map, yet they didn’t want visitors. I wonder what happened there. In any case, we headed for the other cemetery. This one was removed from the main road, and rumored to be a lot larger. It was also known to be haunted, but visitors were welcome as long as they were respectful. Off the map it was, but when we arrived, it was also gated off. A sad Joanne looks through the gate at the second destination that was cut off from us. Ah, but unlike the other cemetery, this one didn’t have a “no tresspassing” sign. There was a clear path around the sides of the gate, the ground bare of grass and obviously well-traversed. Apparently a lot of people walked around the gate. Maybe they just didn’t want us to drive. We decided to walk. There was even a sign. And a long, winding, steep road through the forest.  It was quite a hike to reach the top of the large hill where the cemetery was supposedly located, but the view was breathtaking. It took us a good ten or fifteen minutes to reach the top, and the road was quite steep. For some reason, to the immediate right of the trail, someone had been excavating land for quite some time, and there was a deep quarry. Why someone would dig a quarry next to a burial ground is beside me. I don’t doubt that the residents were unhappy about it. I wondered if maybe I would feel some spirits, but I didn’t expect what really happened to me. As soon as I stepped off of the road and onto the grass, a calm unlike anything I’ve ever felt descended upon me. It enveloped me in a warm cocoon, and Joanne and I immediately separated and wandered quietly alone between the gravestones. I know, 100%, that not only was I welcomed, but that the residents were happy to have me there. I talked a bit with some of the gravestones, but mostly wandered about, amazed at how much serenity I felt. We must have spent around a half hour wandering quietly alone, together, before we left in order to return to the festivities in town. But I’ll never forget the experience. It was something really, really special. I took some video footage too, but I’m not sure yet whether I want to use it. We’ll see! Someday, I’ll set up a tripod and get a shot of me walking like this. But for now, have Joanne instead. ???? <3

iFixit hasn't yet done a full teardown of the new Magic Keyboard designed for the new iPad Pro models, but the repair site today partnered with x-ray company Creative Electron to create Magic Keyboard x-rays that give us a view of just what's inside.


The Magic Keyboard uses scissor switch keys instead of butterfly keys, which have now been effectively eliminated from Apple's product lineup. The scissor switch mechanism is clearly visible in the x-ray view, and iFixit calls it the simplest mechanism in the accessory, but the biggest improvement compared to the Smart Keyboard.

Below the keyboard, there are metal plates that iFixit believes are for reinforcing the keyboard's body against bending, and the trackpad is a new design that's different from MacBook trackpads.

There appear to be multiple buttons under the trackpad to capture presses, while the MacBook Trackpads have no buttons and simulate presses with haptic feedback.


There are at least two spring loaded hinge designs at the folding point, featuring both a small coil and a larger coil, plus there are two cables for connecting the Smart Connector to the keyboard for power and data transfer.

Lots and lots of magnets are visible in the x-ray, with the magnets used to hold the Magic Keyboard on the ‌iPad Pro‌. There's a whole ring of tiny magnets around the camera cutout, which iFixit said was a "lot of little polarized bits" to line up, space out, and configure with the ‌iPad Pro‌ components.

According to iFixit, there's more going on in the Magic Keyboard than there is in many laptops, which could explain its price point. Apple charges $299 for the 11-inch Magic Keyboard and $349 for the 12.9-inch version.

This article, "An X-Ray View of Apple's Magic Keyboard for iPad Pro" first appeared on MacRumors.com

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Apple has launched a new web page that brings together links and information about its online services for customers shopping from home during the global health crisis.


Titled "Everything you love about our stores is online," the new catch-all page links from the Apple.com home page and includes details about no-contact delivery options, Apple Specialist help, financing and credit options, Apple Trade In, Apple Card, order status checking, service and support.

The page also links out to "Today at Apple - At home," a series of fun how-to videos to help users get creative during the ongoing stay-at-home measures, and there's a series of category links for customers to explore products on Apple's online store.

Apple has been gradually re-opening its retail stores in countries where lockdowns have eased, although some are operating on limited hours.

Apple CEO Tim Cook last week said that Apple was going to reopen stores in Austria and Australia this week, and Apple's sole Apple Store in Vienna will be reopening on Tuesday, May 5.

We're still waiting to hear exactly when stores in North America will reopen, but Cook also said that Apple is planning to reopen a few stores in the U.S. starting in May. Store openings will be staggered, with Apple evaluating data that includes local guidelines and recommendations before reopening.
This article, "New Apple Web Page Directs Customers to Its Online Shopping Services" first appeared on MacRumors.com

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Microsoft plans to add trackpad and mouse support to its Word, Excel, and PowerPoint apps for iPad by the fall, according to TechCrunch and The Verge.

iPadOS 13.4 introduced trackpad and mouse support on all iPad models released in the past four to five years. Keyboards with trackpads include Apple's Magic Keyboard and Brydge's Pro+ for the iPad Pro and Logitech's Combo for the 10.2-inch iPad and the 10.5-inch iPad Air.

When using a trackpad, the cursor displays as a circle on the screen, popping up only when you have a finger on the trackpad. The circle then morphs into various other shapes when hovering over app icons, text fields, or other on-screen elements.

This article, "Microsoft to Add Trackpad Support to Word, Excel, and PowerPoint Apps on iPad" first appeared on MacRumors.com

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A new NFC specification announced this week by the NFC Froum will allow future NFC enabled devices to offer wireless charging capabilities, which means a smartphone could be used to charge a small accessory like headphones.


According to the NFC Forum, the Wireless Charging Specification (WLC) will allow smartphones or other NFC charging devices to wirelessly charge small, battery-powered consumer and IoT devices at a power transfer rate of up to one watt.

The 1W rating is much slower than the Qi-based standard used by iPhones and other smartphones. Qi-based wireless charging on the iPhone maxes out at 7.5W, but is even faster on some Android devices.

Charging over NFC would require new hardware, and it's not a feature that can be added to existing devices. The NFC Forum believes the WLC specification could be used to complement Qi-based wireless charging.

It works using a single antenna to manage communications and charging, which is convenient for low-power devices like smart watches, fitness trackers, and earbuds that already use NFC for connectivity because there's no need to build in Qi support.

"The NFC Forum's Wireless Charging Technical Specification allows for wireless charging of small battery-powered devices like those found in many of the estimated 36 billion IoT devices in use today," said Koichi Tagawa, chair, NFC Forum. "NFC wireless charging is truly transformative because it changes the way we design and interact with small, battery-powered devices as the elimination of plugs and cords enables the creation of smaller, hermetically-sealed devices."

Apple in 2015 joined the NFC Forum and participates in the approval of new NFC specifications and developments.

Rumors in 2019 suggested that Apple was working on bilateral wireless charging that would allow its iPhones to charge the AirPods and the Apple Watch, but the feature was ultimately nixed. At the time, Apple analyst Ming-Chi Kuo said that the two-way wireless charging feature Apple was exploring did not meet Apple's requirements.

Samsung has implemented bilateral wireless charging in its smartphones, but the Wireless PowerShare option does not use NFC and is powered by the Qi-based charging coils in the device. Samsung's smartphones can charge other smartphones or accessories like headphones that support Qi wireless chargers.
This article, "New NFC Specification Will Let Smartphones Charge Small Devices" first appeared on MacRumors.com

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Apple's next-generation Apple Watch and watchOS 7 will focus on new mental health capabilities, according to leaker Jon Prosser who recently spoke on the Geared Up podcast. The mention of new ‌Apple Watch‌ features comes towards the end of the podcast.


The next-generation version of the ‌Apple Watch‌, the ‌Apple Watch‌ Series 6, has been rumored to include a blood oxygen sensor, which Prosser says Apple will take advantage of to implement new mental health-related features, such as detecting panic attacks.

What their biggest focus on is right now and I hope it comes this year, it might come next year, but I hope it's coming to WWDC is mental health capabilities. Where they can take the oxygen levels in your blood with your heart rate and determine if you're hyperventilating.

They can identify a panic attack before it happens and warn you on your watch. Especially if you're driving, they'll ask you to pull over and they'll offer breathing exercises once you get pulled over.

Prosser says that while he hopes the feature is released this year, "it might come next year." He also says he hopes for a WWDC unveiling, but if the new feature relies on a blood oxygen sensor in an unreleased version of the ‌Apple Watch‌, it's not likely Apple will unveil the capability until the fall when new ‌Apple Watch‌ models that support it are released.

There is, however, a possibility that it will be revealed at WWDC if older ‌Apple Watch‌ models have a latent ability to detect blood oxygen level, which is not clear at this time, or if the feature does not involve blood oxygen monitoring.

The panic attack detecting rumor was first shared by EverythingApplePro and leaker Max Weinbach back in April, who said that the ‌Apple Watch‌ will also be able to determine when a user is experiencing high levels of stress. Weinbach and EverythingApplePro did not suggest the feature would rely on blood oxygen monitoring, however, and said that it would be available on the ‌Apple Watch‌ Series 4 or later.

Hints that blood oxygen tracking capabilities are coming to a future version of the ‌Apple Watch‌ were found in a leaked version of iOS 14. Blood oxygen monitoring is an important feature because a drop in blood oxygen levels can suggest a serious respiratory or cardiac problem that requires immediate medical attention.

Multiple prior rumors from Bloomberg and other sources have also indicated that the next-generation ‌Apple Watch‌ and watchOS 7 will include sleep tracking features, allowing the ‌Apple Watch‌ to measure sleep quality, length, and other metrics.
This article, "Rumor Claims watchOS 7 Will Have 'Mental Health Capabilities' to Detect Panic Attacks" first appeared on MacRumors.com

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On Wednesday, May 1, 2019, Flayrah contributor 2cross2affliction wrote in the article 'Sonic the Hedgehog' ... the movie ... the trailer:

Fun fact: no movie directly adapted from a video game has ever scored as "fresh" on the review aggregate site Rotten Tomatoes. [...] But, a new challenger approaches! [...] The question of whether this movie is going to be any good, perhaps unfairly, has mostly already been answered by the Internet. The answer so far has been no. No. Just no. Okay, maybe Jim Carrey? But otherwise, why? Why the human teeth? Why ten times?

Whoops. Turns out Sonic the Hedgehog somehow, against the odds, is rated Fresh by Rotten Tomatoes, with a score of 64% positive reviews from 175 professional opinions, as of this writing.

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The Ursa Majors are ready for votes and the nominees have been revealed. Voting can be found at their website and is open throughout the month of March. Two categories, however, received no nominees due to being an insufficient number of nominations and will not be put up to vote for a winner. Those two categories being Fursuits and Non-Fiction.

If you enjoy film, fiction, art, or any other of the many items that are up for selection as the best of the best for the year of 2019 be sure to vote this month. If you like non-fiction or fursuits, well, you can always be sure to nominate next year.

The nominees are:

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Dan Avidan, after years of dancing around topic of being a furry and which he would be, seems to have settled on his fursona of a cyberpunk wolf in a recently released music video. The video features animal characters with trans-humanist enhancements. The coloration has a signature bleed of 80s style animation.

The story portrays a pack of wolves seeking vengeance against a stag mogul after having their kin slaughtered at his hand. The style of animation and situation has some striking similarities to that of Caravan Palace's music video for Lone Digger.

This was brought to my attention by Majira Strawberry who asked why know one was talking about it. The answer to that in my case is object pertinence.

For those who are fans of cyberpunk and animation this is certainly worth the watch.

After the bumper here, the review will get into spoiler territory. I will say that if you are a Sonic fan this movie will give you a sense of pride as it is far better than it should have had any right in being. Taking the franchise’s lore and resetting it to tell its own story, but retaining the strong characterization and quip heavy personalities of Sonic and Robotnik that makes their rivalry such a strong one. It also keeps the first entry simple with the hedgehog and doctor being the only two characters from the universe being in the film. This makes the story stronger since it can develop those two far more and not have to worry about any other kind of side character fan service for now.

Hey, at least now Sonic fans can brag to Mario ones that Mario may still be the king of games, but Sonic blew the plumber’s cinematic pieces out of the water. Not that that was a high bar I suppose. Then again, having better quality games than Sonic these days isn’t one either (the author quips while using a quote from Sonic Forces for his review’s headline).

In the video game Sonic the Hedgehog, timing is everything. While at the heart of the game is a fast paced platformer, its foundation has always been learning the layout of a level and timing your actions appropriately. In a twist, the timing of this film and its release had quite a bit of impact on my view of it.

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Rick May, best known to furries and non-furries alike as the voice of Peppy Hare in the English version of the game Star Fox 64 passed away April 13, 2020 due to COVID-19. May was born September 21, 1940 (with the full name of Richard J. May), meaning he would have turned 80 later this year. May had also recently suffered a stroke in February, making him even more vulnerable to the disease caused by the novel coronavirus.

May will forever be known as the man who originally uttered the memetic line "Do a barrel roll! (Z or R twice.)" in Star Fox 64, explaining to players how to perform what is technically an aileron roll in order to deflect enemy attacks. May also played the villain of Star Fox 64, Andross. Outside of furry video games, May is probably best known for voicing the Soldier of Team Fortress 2; furries might also recognize his voice behind the villainous Dr. M from the third Sly Cooper game. In addition to voice work for video games, May has had a long history of working both on and for the stage as both a director and actor, beginning with USO shows while stationed in Japan. His part in a Renton, Washington production of Cotton Patch Gospel featured a combination of his voice and stage work, as he used different voices to portray 21 characters in what was reportedly his favorite stage role.

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Bonesy the Dog

Camo the Chameleon

Dodger the Fox

Empress the Cat

Gunner the Dog

Hamirez the Hamster

Kitsune the Fox

Kyo the Robot Cat

Remus the Wolf

Scales the Dragon

Woodsy the Puppet Dog

As governments restrict gatherings of people, furry conventions are being postponed or canceled. Here's a quick run down of events in April, May, and June and their status as of May 5 17:28 EDT (UTC-4) in response to the COVID-19 pandemic - updates to come.

A new section has been added for past events impacted for historical purposes.

Links go to statements if available, or to their Twitter feed or site. See also: Furry Fandom and the Internet forced back to roots by viral outbreak

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….for the three of you who still read blogs! Album of the Year: Janelle Monae, Dirty Computer. Really no question about this one. I enjoyed her previous albums, but this one is really a whole additional quantum level of amazing. Honorable Mentions: K.I.D, Tired All the Time — the early contender before Janelle’s album came … Continue reading Music Picks for 2018

Tough choices this year! Charly Bliss got surprisingly (and impressively) sophisticated on their sophomore effort, K.Flay took one step further away from indie-rap towards indie-rock, and her girlfriend Miya Folick put forth a deeply rich and powerful album. Album of the Year: Maddie Ross, Never Have I Ever. I was already digging this a lot … Continue reading Music Picks for 2019

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On the Young Turks, Cenk Uygur quotes passages from Bob Woodward's book, "The Price of Politics", quoting statements made by President Obama proving that he intends to cut entitlements like social security, medicare, and medicaid. Continue reading →

Linda McMahon is running for the US Senate in Connecticut. For twenty (20) years, she ran World Wrestling Entertainment (WWE) with her husband, Vince McMahon. A few years ago, a documentary film examined the WWE's celebration of violence against women. Her campaign doesn't want Connecticut voters to see that film. Watch these excerpts from the film to see why. Continue reading →

Glenn Greenwald predicts over the next four years that "it's all going to get much worse", with President Obama shifting politically more to the right while the Democratic base continues to support him. Continue reading →

Have you ever noticed that the Internal Revenue Service's regulations often are illogical? Does anyone at the IRS think through its regulations? Continue reading →