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 […]

At least for some kids, yes, being flung from the stress of a super-structured, super-supervised existence is having a calming, life-expanding effect. I discuss this amazing phenom in this Big Think article, including six short essays by kids themselves, and also in this interview with Bored Panda,  the  pop culture site, where I note that […]

In a nutshell: editing offspring DNA at the embryo stage will eventually offer so many advantages that lots of people will cave in on some advantage. Don't want to make your kid smarter? Make him or her better looking? Don't want that? How about a throwing arm competitive in major league baseball? Opposed to that? How about avoiding passing along your terrible allergies, need for braces, terrible eyesight, tendency to get depressed or perhaps anxiety attacks or eating disorders? Lots of ways to be persuaded to step over the line once the tech becomes safe. If asked whether one would genetically engineer one's offspring today many people would answer "No" to the hypothetical question. But today choosing genes for your...

Check out: The FDA Is Cracking Down On Rogue Genetic Engineers. Apparently the US Food and Drug Administration wants to classify genetically altered dogs as drugs. When this is done to humans will they become drugs too? I think Huey Lewis has foreseen this possibility. A substantial part of the population is going to continue to insist on owning highly inbred genetically messed up dog breeds with serious health issues (e.g. bulldogs and pugs). If you do not want to me like them then avoid the unhealthiest dog breeds. But given that these breeds will continue to exist it certainly makes sense to genetically fix the fixable ones (some are, by breed standard, probably not fixable). So genetic engineers who...

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Contes de fées aux enfants - Bonne route, les amis !.

Contes de fées aux enfants - L'histoire de Jack le fermier.

It’s not everyday we regurgitate a few old (and new!) chemistry jokes. How often do we tell them? Periodically. We told one the other day, but there was no reaction. Hahaha! Wait? How come nobody else is laughing? Ehem… well, anyways, here are a few more: When I first heard oxygen and magnesium got together […]

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Date: April 29, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2017 Doodle game celebrating Oskar Fischinger!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

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Date: April 29, 2020

On the fifth day of the Hebrew month of Iyar, Israeli communities worldwide celebrate their Independence Day, known locally as Yom Ha’atzmaut. Today’s Doodle pays tribute to this annual holiday in recognition of the day in 1948 when the State of Israel declared its independence. 

Depicted in the Doodle artwork, the flag of Israel features two blue stripes running horizontally over the white background with the Star of David at its center. Officially adopted in 1948, the same year as independence, the flag will be waved proudly wherever Israeli’s call home. 

Happy Yom Ha’atzmaut, Israel!​

Location: Israel

Tags: national day, National Holiday, independence, history, Israel

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---------------------------------------------------[Sat Nov 26 15:25:44 2016]--
From: (S) ease of well-being  (steph)

Subject: Optimism or denial as mental self-defence

A few things recently have given me cause to consider my response to bad things
happening, and my reactions to other people's responses.  First, there's
Trump's election in the US which is undesirable and directly or indirectly
likely to cause some people harm (although I doubt it'll have any effect on me
personally).  I agree that he's not the best or even a good candidate and I
agree that he has incited prejudiced people to show and act on their
prejudices: people are being hurt.  However, I do not like the stream of
articles saying he's a white supremacist or a Nazi or California should secede
or the Electoral College should choose Clinton, or whatever.  Part of this is
doubtless my contrary streak, but part of it is something different.  I observe
that I am semi-consciously adopting a position that `things will turn out all
right' or `it won't be that bad' because countenancing the opposite is not good
for my mental health.

The other thing is some changes in the wider organisation for which I work;
basically there has been a botched reorganisation which has left most people
unhappy and from what I hear from numerous sources with good reason.  This
doesn't currently affect me much and I don't expect it to because of political
realities.  However, even just having the argument with someone closer to the
failing department (and more likely to feel its direct effects) seems to be
followed by my feeling anxious and depressed.  Again, adopting a constructive
positive attitude (which may appear to others pollyannaish, naive, optimistic,
or just in denial) seems to be a defence I've learned here and I suspect it
helps.  But there's more obviously a risk when I'm more involved than I am in
the US case, namely that my optimism will blind me to dangers that will be to
my detriment.

Does my ornery nature come to the rescue, though?  Perhaps because I'm at heart
a bit of a grumpy sod and only respect authorities when I think they deserve it
my tendency to want to probe and prod and query and dig my heels in may
counteract the defensive optimism.  Or alternatively, I'm optimistic in a
different sense: perhaps I just have confidence that I'll win?

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.

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.

Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients including those with hereditary and idiopathic CP undergoing total pancreatectomy with islet autotransplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP samples showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in the CP and control groups. TCRβ sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreases indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanisms of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis, providing insights into immune responses associated with human CP.

Elevated pressure in the pancreatic gland is the central cause of pancreatitis following abdominal trauma, surgery, endoscopic retrograde cholangiopancreatography, and gallstones. In the pancreas, excessive intracellular calcium causes mitochondrial dysfunction, premature zymogen activation, and necrosis, ultimately leading to pancreatitis. Although stimulation of the mechanically activated, calcium-permeable ion channel Piezo1 in the pancreatic acinar cell is the initial step in pressure-induced pancreatitis, activation of Piezo1 produces only transient elevation in intracellular calcium that is insufficient to cause pancreatitis. Therefore, how pressure produces a prolonged calcium elevation necessary to induce pancreatitis is unknown. We demonstrate that Piezo1 activation in pancreatic acinar cells caused a prolonged elevation in intracellular calcium levels, mitochondrial depolarization, intracellular trypsin activation, and cell death. Notably, these effects were dependent on the degree and duration of force applied to the cell. Low or transient force was insufficient to activate these pathological changes, whereas higher and prolonged application of force triggered sustained elevation in intracellular calcium, leading to enzyme activation and cell death. All of these pathological events were rescued in acinar cells treated with a Piezo1 antagonist and in acinar cells from mice with genetic deletion of Piezo1. We discovered that Piezo1 stimulation triggered transient receptor potential vanilloid subfamily 4 (TRPV4) channel opening, which was responsible for the sustained elevation in intracellular calcium that caused intracellular organelle dysfunction. Moreover, TRPV4 gene–KO mice were protected from Piezo1 agonist– and pressure-induced pancreatitis. These studies unveil a calcium signaling pathway in which a Piezo1-induced TRPV4 channel opening causes pancreatitis.

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 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).

The pandemic coronavirus infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. In this issue of the JCI, Chen and colleagues compared the clinical and immunological characteristics between moderate and severe COVID-19. The authors found that respiratory distress on admission is associated with unfavorable outcomes. Increased cytokine levels (IL-6, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFN-γ expression in CD4+ T cells are associated with severe COVID-19. Overall, this study characterized the cytokine storm in severe COVID-19 and provides insights into immune therapeutics and vaccine design.

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.

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.

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.

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.

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.

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.

Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.

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