At Let Grow, a wise mom named Kate Sundquist admits that while her kids were already good at playing, they certainly weren’t good at filling hours and hours of free time, playing by themselves. (Read the piece here.) So she her and boys created a schedule. “While these routines might seem restrictive or even the […]

“The most difficult part was persuading our children that they had the freedom to make anything they wanted,” writes mom Anam Ahmed at Let Grow. (Click here!) …Like most kids, my children live prescheduled lives (at least they did in “the time before”). At school, someone tells them when to play outside and when to […]

Parents, kids: Fear not the silica gel pack. Sure it says DO NOT EAT and THROW AWAY. But you should only follow one of those rules.    Instead, save the packs and use them a whole lot of ways: Place them on the car dashboard by the windshield to keep it from fogging up.   […]

1.8 million people in the United States drive heavy trucks for a living and are at risk of losing their jobs when trucks become autonomous. That number is from the BLS category heavy and tractor-trailer trucking with 1.8 million employees. A separate category Delivery Truck Drivers and Driver/Sales Workers has 1.3 million workers. The heavy duty truckers are more at risk than the local delivery drivers because it is easier to automate long haul driving on interstates than to automate driving on more complex (cross traffic, pedestrians, parked cars, etc) local roads. Plus, delivery drivers have to run up to houses and businesses to make most deliveries. Building robots to do that work will take longer. Railroad operation is easier...

The Miami Beach danger zone for mosquitoes carrying Zika virus is expanding. This isn't just about microcephaly in developing fetuses. Since Zika attacks neural progenitor cells it might cause lasting damage in adults too. A case of acute sensory polyneuropathy in an adult caused symptoms that lasted for months. It is suspected that Zika causes inflammation of sensory nerves and possibly an auto-immune response. So Zika is bad. What should we do about it? Wipe out the mosquitoes that carry it. Totally drive them to extinction. These mosquitoes are invasive in the Western Hemisphere. If a mosquito causes major health problems for the human species we should just wipe it out. Wiping out a mosquito species could be done with...

Elon Musk thinks a universal basic income is inevitable. Musk doesn't see plausible alternatives. I hope not. So here's the optimistic scenario: On the one hand, manual and low skilled work will mostly get automated out of existence. So one could imagine why demand for people at lower skill levels and lower levels of cognitive ability could just evaporate. On the other hand, automation will cut costs and boost the wealth of those still employed. Even if the pay of manual laborers is low the goods a manual laborer will need to survive should become very cheap. So any upper class people who can find a use for them might pay them enough to survive. But I see a stronger...

Nitrozac had to undergo an emergency endodontic procedure, *ouch*, so she is off for a few days to let her recover. We'll be back with a new smile soon, in the meantime, here's one of our fave retros...

The post Fishing Footwear Basics: Keeping Your Feet Neat and Safe appeared first on Ocean Blue Fishing Adventures.

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells’ inflammatory phenotype may impact obesity and its complications.

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow–derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress–triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.

Organ shortage continues to limit the lives of patients who require liver transplantation. While extending criteria for liver organs provides a needed resource, tissue damage from prolonged ischemic injury can result in early allograft dysfunction and consequent rejection. In this issue of the JCI, Nakamura et al. used a mouse transplantation model with prolonged ex vivo cold storage to explore liver graft protection. The authors found that liver grafts with absent carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) exhibited increased ischemia-reperfusion injury inflammation and decreased function in wild-type recipients. The authors went on to correlate CEACAM1 levels with postreperfusion damage in human liver transplant recipients. Notably, this study identified a potential biomarker for liver transplant donor graft quality.

Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.

Nerve growth factor (NGF) regulates many aspects of neuronal biology by retrogradely propagating signals along axons to the targets of those axons. How this occurs when axons contain a plethora of proteins that can silence those signals has long perplexed the neurotrophin field. In this issue of the JCI, Li et al. suggest an answer to this vexing problem, while exploring why the Elp1 gene that is mutated in familial dysautonomia (FD) causes peripheral neuropathy. They describe a distinctive function of Elp1 as a protein that is required to sustain NGF signaling by blocking the activity of its phosphatase that shuts off those signals. This finding helps explain the innervation deficits prominent in FD and reveals a unique role for Elp1 in the regulation of NGF-dependent TrkA activity.

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 Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.METHODS In this phase I trial, patients received either 1.5 × 106 MICs per kg BW on day –2 (n = 3, group A), or 1.5 × 108 MICs per kg BW on day –2 (n = 3, group B) or day –7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.RESULTS MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 1010 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19+CD24hiCD38hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.CONCLUSION MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATION EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220FUNDING Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.

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.

The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti–CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.

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.

Lamin A is a component of the inner nuclear membrane that, together with epigenetic factors, organizes the genome in higher order structures required for transcriptional control. Mutations in the lamin A/C gene cause several diseases belonging to the class of laminopathies, including muscular dystrophies. Nevertheless, molecular mechanisms involved in the pathogenesis of lamin A–dependent dystrophies are still largely unknown. The polycomb group (PcG) of proteins are epigenetic repressors and lamin A interactors, primarily involved in the maintenance of cell identity. Using a murine model of Emery-Dreifuss muscular dystrophy (EDMD), we show here that lamin A loss deregulated PcG positioning in muscle satellite stem cells, leading to derepression of non–muscle-specific genes and p16INK4a, a senescence driver encoded in the Cdkn2a locus. This aberrant transcriptional program caused impairment in self-renewal, loss of cell identity, and premature exhaustion of the quiescent satellite cell pool. Genetic ablation of the Cdkn2a locus restored muscle stem cell properties in lamin A/C–null dystrophic mice. Our findings establish a direct link between lamin A and PcG epigenetic silencing and indicate that lamin A–dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells.

Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor–driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.

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.

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).

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.

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 The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1.METHODS We performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified.RESULTS All BPZE1 vaccinees showed robust B. pertussis–specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1–specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1.CONCLUSION The breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission.TRIAL REGISTRATION ClinicalTrials.gov NCT02453048, NCT00870350.FUNDING ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.

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.

Sometime over the summer, I saw a video on Facebook about a little town in Oregon where it’s Halloween all year long. Halloween? OMG YES, I LOVE HALLOWEEN! You’re not the only one dressing up for once, so it really doesn’t feel awkward to let your geek shine! Especially now that “sexy” halloween costumes aren’t the only “cool” option. I mean, as if nerdy costumes were ever less than cool, but I digress. History has been hard to us nerds. Anyways! So, I saw a video for this Halloweentown that made it look really, really cool, and I thought, hey, I have to go!  Guess what? I did! ???? Here is my report.  First off, did you know that this isn’t a Halloween thing, as much as it is a movie set thing?? I had never even heard of the Halloweentown movie until a week before I went, much less that there was an entire series of movies that I guess kids my age grew up with! I was more of an It’s the Great Pumpkin, Charlie Brown and The Worst Witch kid. Side note: holy cow, why is that movie so expensive now?! Maybe because it’s awesome, but still… So, in order to get myself into the mood, I watched Halloweentown the night before. It was cute, but it’ll still never mean to me what it means to people that grew up watching it. Here’s me and Joanne (my traveling companion — she and my cousin used to be an item, but she’s too cool for him now) at the “famous” gates! We let our Ravenclaw banner fly high all weekend! So, we drove from western Washington for about two hours to get to St. Helens, where all of the festivities take place. From the video, which I had bookmarked and is no longer available(!), it looked like this place would be huge and chock-full of Halloween everywhere we looked. Yay! There were events listed including coin hunts and rides in hearses, and because we went on a weekend in October, some of the movie cast would even be there taking photos (for a price)! It sounded really neat, and we planned to stay the night in the closest drivable town, which was 40 minutes away. There were only a few hotels in town and they were all booked up, boo. So, here’s where I want to mention something… St. Helens is a small town on the bank of the Columbia River. Right across from St. Helens, on the opposite bank of the river, is a town called Kalama. You can stand on the riverbank in St. Helens and look at Kalama on the other side. But there is no bridge. Nada. Nothing! So if you want to drive to that town that you can see happening over yonder, you have to either drive all the way up to Longview,  or all the way down to Portland, and then back. So it’s an hour’s DRIVE to cross the river, and you have to go through other cities to do it. WTF. I don’t understand this at all. Who planned these cities?!?! I just had to say something because it still boggles my mind! Alright, whew! Let’s look at some cute photos to feel better. ???? There was a band performing in Town Square, the center of all activity Halloweentown. Here’s the taxi from the movie. And this big steel pumpkin. It didn’t get crowded until night, but it was still hard to get a shot without people all over the place. I didn’t feel like waiting around, so this was the best that I could do. There was one huge parking lot, and this guy was there to welcome us in… Looks like he’d been waiting for quite a while! City Hall was at the front of the Town Square, and in the movie. This woman is apparently the ideal resident. Someone had a drone, and I thought it made for a cool shot. Looking at Mt. Hood in the distance! I’d love to go hiking there in the spring! Well… to be honest, there wasnt’ actually much to do. There were a few food trucks next to town hall selling noms and running charity drives, a haunted house around the corner, a street full of consignment/used goods shops, and a hair salon selling t-shirts and mugs of the event. During the day, there was also a shuttle to take you uptown where you could do a scavenger hunt and win a commemorative coin. It took Joanne and I over an hour to figure out where the shuttle came, even though you could walk the entire downtown area in 5 minutes, because it wasnt’ on any map and none of the shopkeepers or staff that we asked knew where it came to pick up people! Organization points: 0 We did find it, though, around the corner from all of the fuss, and boarded to do the scavenger hunt. I wasn’t really expecting anything, and it basically was a piece of paper asking us to go into 10 of 15 or so listed shops on the street and find a plaque with numbers on it. If we collected ten numbers and then took them to a certain gas station on the way out of town, we’d receive our coin. Alright, well it wasn’t super imaginative, but I get what they were going for. We did get to see some cute local shops (and I saw my second pot store in a town that takes 1-2 minutes to drive through… I’m not sure I could ever live in Oregon, as I despise any kind of smoking). I also found, of all things, local vegan caramel, so I bought it fully aware that I would try not to eat the entire bag, but would probably fail (I finished them all before I went to bed). It was delicious, though! Soft and chewy and so, so buttery….. yum! Well, after the scavenger hunt, we decided to get the car and drive around a little bit because we had run out of things to do and, guess what? According to a map that we picked up in town, apparently the Twilight series was also filmed there, and all of the locations were mapped! Forget Halloweentown (sorry!), I am a sucker for Edward and Bella’s tale of fated love. I’ve visited Forks and La Push, the real towns that the books are set in, but never the actual movie filming locations. This sort of made my weekend! There were also some old cemetaries marked on the map as places to visit. Both of those things will be in my next posts! After having a bit of an adventure, we returned to the town square to check out the nightly festivities. I think, honestly, that just coming at night to St. Helens would have been enough, because when we returned to Town Square it was starting to get packed. Apparently, at night is when the real town comes alive! Although there still wasn’t a lot to do, the atmosphere was really eerie and the throngs were thick enough that we had trouble getting through. There was a pumpkin-lighting ceremony at 7:30, but it started really late, so we abandoned it to go to the adults-only haunted house. I’m on a perpetual quest to find a haunted house that is actually scary, and this one turns adults-only after 7pm, so I was hoping for something great! Here’s the coin that we got for our scavenger hunt. It was plastic, not metal as I’d been hoping for, but it had been a nice afternoon looking in shops that we otherwise would have probably passed by. Jack was hanging out. You can see how thick the crowd was after dark! These girls had on mermaid-sparkle witch hats. I approve! I wonder whether they attended Ilvermorny. I had to have one of these necklaces. Can’t wait to rock them on halloween! I wore it into the haunted house, which was… well, it was very well done. It was probably the best put-together haunted house that I’ve ever visited in America, but I wasn’t scared at all. So, in terms of usual haunted houses, it gets an A+ rating! But on the honestly-scared-o-meter, it doesn’t register at all. This is probably what most people want, so give it a go when you visit, though! I just have really, really high expectations! Oh, and we did get a photo with Marnie’s actress. She was a real sweetie! Sure, I had just watched Halloweentown for the first time the night before, but why not! So that’s our little visit to Halloweentown! Final Verdict: If you’re nearby and a fan of Halloween, it’s definitely worth a stop! It’s only a half-hour’s drive from Portland, so it’s easy to take a little nip up and check out the festivities! It’s definitely kid-appropriate, and probably actually the most fun for the little ones. If you’re a fan of the movies, this place should definitely be on your bucketlist! Don’t plan for a whole day, though. It’s mostly a nighttime thing. See you tomorrow to share my photos from Bella’s!

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

Recently, I’ve found myself thinking more often than not about the past – mistakes I’ve made, where I could have done better, things like that. I think that’s a symptom of unhappiness, really, so yeah… I’m putting a stop to that. It’s a hard and imperfect stop, but I’m not willing to continue to think about things that I can’t change. Instead, I am going to look forward — to my next step and how to make it count! That’s how I’ve been trending, anyway, I hope you can tell! I guess that makes it funny that I roped people into going fossil-hunting with me! Get it? THE PAST. But, I LOVE ANCIENT HISTORY! It’s my first time finding a fossil, and my first time hunting, so I count it as a giant leap forward in this travelogue I call life. :3 Anyways, I found a book in the library about gem hunting in Washington and there was a listing for a site where you could find fossils (!!!!) nearby (!!!!!!!!!!). It’s called Lincoln Creek (there does appear to be a creek somewhere nearby, but it’s not right at the site), and let’s just say that I’ve learned a lot from it, both about fossil hunters (STINGY WITH LOCATIONS) and about fossil hunting itself (by blundering right into it without knowing anything). Thank god there were GPS coordinates in the book, because although I found a lot of reviews on fossil hunting at Lincoln Creek online, as well as a few blurry photos, I couldn’t find any information on how to actually get there or what exactly it looked like. All I had was the GPS coordinates from the book. I know that people want to protect their “stash,” and it comes across as pretty selfish to me, but it really makes it hard to start out as a beginner with only passion to rely on, and I don’t think that being “protective” or “exclusive” is a good way to behave in general. That said, let me help you if you decide to go yourself: – GPS coordinates in Google Maps. – A screencap of the map and the turns I walked to get there. I don’t recommend it, unless you want a really great walk in nature that is also technically trespassing and won’t be disappointed if you find nothing, but if you want to go, go for it and enjoy it all you can! It was only supposed to be a half hour drive or so from my sister’s house to the little logging road that led to the site. But I learned something new that had seriously never once crossed my mind: logging roads can be closed off! There was a gate blocking the main road, so we tried driving for miles in every direction to get in another way, but ALL of those were blocked off, too. There were “no tresspassing, this land belongs to Weyerhaeuser” signs, but we eventually just decided to walk it. I am not sorry at all to say that I have zero respect for companies that clearcut or attempt to think that land can “belong” to them for that purpose. Oh, and they have tried to sue the government to be able to log on lands that contain endangered species. Now, I love paper, but f you, Weyerhaeuser. I’m not at all sorry, and I’d walk these lands again a hundred times if I wanted to. So, we ignored the signs, and walked past the gate all the way to our destination. ALLLLLLLL the two hours. It might not seem like a lot, but we honestly thought that we’d be able to drive right up to the site as it said in the book. Welp, it was an unexpected walk, but super awesome to get back among the trees. Being in the forest and a slow walker anyways, I spent a lot of the time by myself contemplating life and sacred rituals. You know, the usual. Come look at some photos with me, and I’ll tell you a little bit about the journey. ???? When we realized that the road was blocked off, we drove around searching for another way into the deep forest and saw this. You know you’re… oh, wait. It looked like their neighbors a little further down were more my kind of people, though! Here’s my niece, all ready for adventure! I’m pretty sure that these were bear droppings, as they were full of berries. They were also somewhat fresh. There are a lot of bears up here in Western Washington, since there aren’t many settled areas. I never thought for a moment that I’d need to bring bear spray, but I definitely am going to have to buy some for my adventures. :/ It was quite lovely. One of the very few blue, sunny days that we’ve had so far this summer. I won’t be sorry to leave the cold behind, as I’m a desert sprite and being in the cold depletes my magic! But this… it was lovely. There were two clearcut clearings. They made for gorgeous views of the valley, but it was also quite sad. I could feel the souls of all of those trees calling out to me… ???? We delved onto a very overgrown road after over an hour of walking. And there was a huge, recent-looking landslide blocking the path! We weren’t about to turn back, so we picked our way across it. And just a little ways farther, down another overgrown road, this one much more primitive, the fossil site was evident. It was also really, really disappointing. It was exactly where the GPS coordinates said it would be (funny enough, I got better cell signal in the middle of the forest than I do in town), and there was basically a slope of discarded rocks that led up to a little overhang. Oops, I mean a lot overhang. People had dug deep into the cliff, and it looked like the forest above was one hit shy of collapsing in on you. I like adventuring, but I don’t like playing with death. And yet, I still picked for about half an hour, looking for concretions (fossilized crabs in the center of rock balls trapped within the rock, if that makes sense). Supposedly this site was full of them, and there were people online saying that they found 80 within an hour. But we found nothing at all, except for some shells that were indeed trapped in the rock, but looked like any old shell. Fossils, yes, but not really cool. This was supposed to be my “I’m tired and disappointed” face. I guess I shouldn’t have smiled, haha! Guess what, though???? We felt so empty-handed that we decided to see if there was anything in the rock slide, and that’s where I found the concretion!! In the middle of this giant rock that I slowly whittled away at. We must have spent about two hours picking through the debris, and we found a ton more shells, but just that one crab. Still, it’s cool, right? I considered it a win for the day after all, and we decided to get out of there as the sun started to go down. Here’s the slightly-overgrown trail we were on (the panorama makes it look like a circle, but it was a straight path XD). Passed the clearcut areas with the sun much lower in the sky. The fairies started to come out as we entered the wooded paths again in the late afternoon sunlight. We made it home while it was still light out, exhausted and quite sore. Here is my concretion, though! Isn’t it cool? You can barely tell that there was a crab inside when it was formed. I didn’t really know what I was doing, so I think that I didn’t preserve it as well as I could when I cracked it open, but I’m still really proud to have found it. ????   My first fossil. Of many. ????  

Video from Thabo Meerkat, transcribed

Welcome to another edition of Digging Up Positivity! This episode is dedicated to the many volunteers that make all those amazing conventions and charities possible. But besides them, we are covering some animation news and other (maybe otter?) tidbits!

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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.

While the pandemic has been chipping away at the furry convention scene, other furs have stepped forward to try and give those in the community events to look forward to over the now dormant weekends. This had started with a group of Furnal Equinox members creating a digital replacement for their late March convention called Keep Calm and Carry Con - Furnal Isolation. More have started to spring up this spring.

They can have internet dealers dens, streaming dance competitions, and other staples that conventions are known for. Accessible from the safety of your own home.

Below is a comprehensive list of conventions. Last updated May 2nd, 2020 12:18 ET.

Please feel free to place any not listed here in the comments below and we will look into adding it if it appears legitimate.

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Video from Thabo Meerkat, transcribed

Hey there, and welcome to the April 2020 edition of Digging Up Positivity from a rapidly changing world. But even in these weird times, there are still a lot of positive things to be found!

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As of today, my current job is now the longest one I’ve ever held.

….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

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 →

After being elected in 2008 on "hope and change", "change you can believe in", and "change the way Washington works", President Obama now says that he cannot change Washington from the inside? Then why should we re-elect him in 2012? Continue reading →

Barack Obama promised to change the way things work in Washington, and after four years, nothing has changed: Corporate money controls President Obama and Congress. We need real change: vote for Rocky Anderson. 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 →

Cornel West and Tavis Smiley criticize President Barack Obama for being to the right of even President Richard Nixon. Continue reading →