“Even after weeks of staying home, my kids are just not interested in all the stuff we have. Let’s be honest. If a toy isn’t getting any action amid this distraction-free, stuck-at-home living, chances are it’s never getting touched again.” Liz Russell figures out what really engages and changes kids during the quarantine, and will […]

I realize that sounds kinda nuts — why are we asking PARENTS to show us their KIDS being independent? Who, after all, is better at making videos? Mom or little Ava (who’s 5)? But legally we can’t ask anyone under 13 to do anything. So go document your children doing something new on their own, […]

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...

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...

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...

The National Highway Traffic Safety Administration (NHTSA) finds Tesla's Autopilot cuts crashes by 40%. How cool is that? Autonomous vehicles are going to cause a huge decline in accidents and deaths. Even short of autonomous vehicles, when you get your next car try to get one that supports automatic braking on imminent collision detection. You could get a large fraction of the collision avoidance benefit at a much lower cost today. Check out Insurance Institute for Highway Safety ratings of collision avoidance systems in current cars. Watch a Tesla react to a crash in front of it: Watch a Tesla avoid hitting a reckless driver: A recent analysis finds that autonomous vehicles will allow 2 million disabled people to get...

Let your finger do the unlocking.

Ziggy, is that you?

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Contes de fées aux enfants - Frédéric la grenouille et Elias l'éléphant.

On accorde "The World of Art Award" (WAA) aux artistes, aux galeries et aux musées qui poursuivent les "meilleures pratiques" dans l'art et la culture. Cette concurrence cherche à attirer dies artistes, galeries, les musées qui redéfinissent des normes de l'excellence d'art. Ceux qui défie des trends et des tendances existantes dans l'art et la culture.

The bartender says “You can’t have that thing in here! Get out!” The guy says “It’s okay, this Alligator is highly trained. Just give me a few seconds and I’ll show you.” The bartender, intrigued, gives him the go-ahead. The man gingerly lifts the alligator up onto a table. By this point, everybody in the […]

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Date: April 27, 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!

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Our 2017 Doodle game celebrating 50 years of Kids Coding!

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Date: April 28, 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!

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Our 2017 Doodle game celebrating Cricket!

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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!

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Date: April 30, 2020

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Our 2016 Doodle game celebrating Clara Rockmore!
 

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Date: May 1, 2020

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Date: May 4, 2020

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Date: May 5, 2020

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Date: May 6, 2020

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Date: May 7, 2020

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Date: May 8, 2020

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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?

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.

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.

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).

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.

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.

Immunosuppression continues to be a necessary component of transplantation, despite its association with a multitude of adverse effects. Numerous efforts have been made to circumvent the need for immunosuppression by using various techniques to achieve donor hyporesponsiveness. In this issue of the JCI, Morath et al. take this endeavor forward. Prior to transplantation, the researchers infused recipients with donor-modified immune cells and achieved immunologic hyporesponsiveness. This successful phase I trial also provides a possible avenue for achieving transplantation without the requisite immunosuppression.

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).

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

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

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

It’s no secret that I love Japan. I mean, I really, really love Japan. I felt more at home in Tokyo than I ever have anywhere else, and I think about going back all. the. time. I’m even thinking about it right now. You’re probably reading this right now because, at the very least, some tiny part of you is curious about whether you should do it. It might be the tiiiiiiiniest little part, but I’m sure it’s there. Maybe you don’t want to admit it because it seems pretty impossible, and yeah, I will admit that if you have a job that you don’t want to leave, strong family ties, kids, pets, or no money (among other things), it must seem like a distant what-if that will never happen. Here’s the thing. If you’re really, honestly interested, then make it happen. Because guess what? You freaking can make it happen, and don’t let anybody tell you no. If you’re coming up with a “But…” right now, I’ll stop you right there! “But I have kids/pets…” Figure out how to take them with you, because you can! “But I don’t want to leave my job…” Take a sabbatical for a year, look into transfers to a branch abroad, look for a better job in the same field in Japan, or look into whether this job is really worth giving up on this dream (maybe it isn’t). “But I can’t speak the language…” So? I moved to Japan and didn’t speak a word. Some people learn before they go, some people learn while they’re there (me), and some people never learn (I don’t recommend this). I could go on forever, but the whole world is at your fingers if you really want it! I seriously believe that. It’s not always easy, but if you want something badly enough, don’t you owe it to yourself to at least try? Anyways, let me give you the top reasons why I think that you should give living in Japan a try! 1. Living in a different culture opens your eyes. This especially is true if you immerse yourself in as much of the culture as you can. Make Japanese friends, learn about what people do on a daily basis and what they believe in. Try doing things in ways that are new to you. Try new foods! Mochi is the schiz, by the way! Once you’ve experienced doing new things, it will change how you do things even if you return back home. I will always have a no-shoes policy in my house (it’s so much cleaner!), I absolutely CRAVE a train system (if only!), and I have a newfound respect for walking and cycling. I never did this when I was little, but now, if I can, I walk! 2. You’ll have a fresh start. In your new home in Japan, you won’t have any of the drama that surrounded you in your old one. Thanks to the internet, we can still keep in touch with friends and family, but being a few thousand miles away from them will keep a lot of the drama to a minimum. Take a chance to stretch your wings and see what kind of person you are when you have the freedom to be you without their judgement. Trust me, it takes a weight off being in a new place where nobody knows who you used to be (or who they thought you used to be). Oh, and you know what? I bet that you will love yourself more than you ever did before. 3. Japan is a magical place! Seriously. Cherry blossoms, gorgeous temples and “castles” (I wouldn’t call them castles, but they’re called that nonetheless, and they’re really cool anyway), a rich history filled with Samurai and ninjas (who doesn’t love ninjas?), seasonal treats, and an entire culture that grew up reading manga. How does this not sound like an amazing place to live?!  And no offense to any other country, but Japanese trains come quickly, go almost everywhere, are extremely punctual, and pretty clean, which makes them (Tokyo especially) easily #1 in the world in public transportation. Now that sounds magical to me. 4. Universal Health Care. If you’re American like me, this will make a HUGE difference in your life. Trust me. If you come from pretty much any other 1st world nation, it probably won’t matter as much, though. But at least it’s good! 5. Japan is safer than where you came from. There’s no gun violence. There’s very low crime in general. You can walk in the dead of night in the seediest parts of town, as a woman, alone, and still feel perfectly safe from other people. From earthquakes is another matter, but you’ll get used to them really fast, and Japan is built to withstand all but the biggest. 6. Wa. There is a concept called wa in Japanese society, which essentially promotes practicing peace and harmony in your daily life. Wa is obvious in everything from traditional architecture and decor to the way that people act around each other– courteousness, quiet, and respect are what you expect most from your neighbors. You’re never going to wake up to your neighbors blaring music at 3am having a raucous party. Even drunken people wandering the street are more polite than not (although most of them just sort of stumble home or sit down where they are for the night– but remember, Japan is safe so they only thing they have to worry about is getting chilly). We could all use a little bit of harmony in our lives, and that’s something that Japan taught me to value. I’m surprised that yoga isn’t more popular, since they’re pretty in tune with each other. 7. All the new gadgets, and all of the old culture. Sure, Silicon Valley is where a lot of new apps are coming out, but if you want lots of little weird but useful gadgets to make your life easier (or more interesting), take a stroll through Akihabara. Plus, there are tons of cheap versions of what you’re used to, like large-capacity flash drives and SD cards. And I would be remiss in not mentioning the used electronics! Smartphones! Right next to small neighborhood temples, btw. It’s the only place to find Ayanami Rei in a kimono, wandering the street. The best of both worlds! 8. MANGA AND ANIME EVERYWHERE. This should be your main reason. This should be enough of a reason. Not only is it available everywhere, but events abound. If you wanted, you could go to an anime-related event every weekend of the year. Also, let’s not forget that it’s the only place to see all of the anime movies released in the theater, go to the official events (like Jump Festa, Comicket, World Cosplay Summit, and Anime Japan, among others), and see the musicals, seiyuu radio shows, and stage plays. If this isn’t reason enough, you’re probably in the wrong place. 9. It’s cheaper than you think. I lived in Tokyo, and then I moved back to the US, thinking that because I was living in a place often called “The Most Expensive City In The World,” it would be cheaper here. Nope.. Apartment rents, even in small cities, are at least the price that I was paying in Tokyo (~$600/mo). And try finding that in LA. So far I haven’t had any luck, and especially not in the areas that are actually sort-of-kind-of safe. Food is also about on-par with the US, especially domestic food. Considering that it’s an island, it’s actually really, really cheap. Food in Hawaii cost sometimes 3-4 times what I was able to get it for in Japan. Then, when you factor in healthcare, which is pretty cheap (what you pay for the insurance is based on your income, and then it covers 80% of all your bills — this is a simplification, but generally holds true), and transportation costs (you don’t need a car, therefore no gas, no insurance, no car maintenance fees), it’s downright cheap. Even living in Tokyo. 10. You will never run out of things to do. In nearly a decade, I never ran out of cool things to do. Can you say the same about the city that you live in now? Thought so. Ah man, I kinda feel ready to jump back on a plane and move across the ocean… three cats and all! Somebody hold me back… resistance is fading……………….  

Cats. Cats are the best, and I can’t seem to settle down in any one place for too long, so my cats (possibly to their dismay) have had to move around with my silly butt. I don’t own a boat that can cross the Pacific Ocean, so that means taking them on a plane. BUT! While it’s no fun for anyone, it’s not really as hard as you think! Really really! My cats are my family, and if you’re here then you probably also have furry family members, and you are worried about flying with them. I’ve both taken my cats in the cabin and had to check them into the pet cargo hold (to my terror), but they not only survived, they are all flourishing wonderfully. While things do happen (and if something happens, raise a ruckus and make sure that whomever hurt your baby knows it), for the most part, flying is actually pretty safe for cats. Not that you want to take them. It’s just that sometimes you have to. So read on for my personal tips on how to make the flight go as smoothly as possible for all of you! Trust me, you’ll want it to be this way. My cats at the vet for their checkups and vaccinations. 1. Do Your Homework. This might seem obvious, but that being said, let’s put it out there anyway. Know your stuff! There are two things that you’re going to need to find out as soon as you decide to fly with your pets:      a) What paperwork does the airline require for me to bring my cat on the plane?      b) What does my arrival location require for me to bring my cat into the country/state? Usually, a) is the easiest part. It’s usually just a health certificate from your vet, issued less than a week before travel. Just book an appointment at your vet for less than a week before departure, and tell them that you’re flying to (wherever). All of my vets, even my one in Japan, either knew what they needed, or looked it up beforehand. Check your airline’s webpage (my absolute favorite for flying with pets is Alaska Air, btw. You can take two in the cabin by yourself, and it’s the only airline I know of that allows this!), and follow the instructions. I keep all of my paperwork with my passport while flying, so that I can show it to the ticketing agent or anyone else that asks (sometimes, nobody has, but at least I had it). In all of the cases where I’ve flown, my plane required a current health certificate to board, and when I left Japan, they required an inspection from the on-site team, which I just asked for when I arrived in Narita. b) can be easy, or it can be hard. In order to enter the US from Japan, I had to check the US Customs website for the country’s official regulations, and Washington State for its regulations.  The US didn’t have any regulations at the time, but Washington state required a health certificate (same as the plane), and current rabies vaccination, both of which I had done within the week before I left. Funny enough, nobody checked my paperwork after I landed, since it was the 4th of July and the Agricultural Inspections office was closed. When I went to Hawaii, it was another story. It was a long, long, long process (more than 6 months) to get all of my testing and paperwork done for Sansa to enter the state, but I did it, kept all of my paperwork in order, and was able to leave the airport in Hawaii with her in my arms without any fuss! There was a lot to do, but I just made sure that I knew what I needed, did it, and had the documentation, and things were pretty smooth sailing afterward! You should always check the official government pages to make sure that you have the correct information. In Hawaii’s case, it can be found here. All of my cats reacted differently to being examined. 2. Get your stuff in order! Once you have your list of things that you need (vaccinations, health checks, etc), then CALL the airline to make your reservations (you always need to call them in order to add pets to your tickets. They usually cost a little bit extra, and try to get them in the cabin if you can). Then, check your airline’s website to find out what kind of carrier you will need, and whether you will need anything else. When I flew to Washington the first time, and to Hawaii, I only had one cat, so I didn’t need any food (I brought some anyway, and a little bowl in my carryon just in case), and a soft-sided carrier that would fit in the dimensions they specified on their websites (it’s usually in the pet section or the carry-on section, and every airline is different). When I flew to Washington again, it was with three cats, so I needed two large hard carriers that met certain criteria for my babies flying underneath, and one soft-sided one for the baby going in the cabin. The website for the airline was very specific, but it was easy to find what I needed at Petco. Check, check, and check. I had my carriers, my paperwork, and I was ready! When your cat isn’t too happy about getting her shots. 3. Getting ready for the flight. A week or so before my flight (or days in my last case), I set all of my pet carriers out in the living room and set them up how I was going to have them for the flight — I lined the bottoms with puppy training pads (in case there was an accident in-flight), then a towel for absorbency (in the large hard carriers only), and finally, on top of that, a blanket that I had been using a lot (so that it had our scents on it, and would comfort the cats). I sprayed the interior of all of the carriers with Feliway, and left them out for the cats to get used to them. The carriers sitting out for the curious kitties to explore. They all took turns exploring the carriers, and after a few days, got comfortable with them and would lounge around inside, play with them, and rub up against the sides. This was all in order to reduce the stress of travel on them as much as possible. I continued to spray them with Feliway at least once a day until we left. There is no hard and fast rule on this, but I took away my cats’ food and water the morning of the trip, and waited until just before we left to toss out the litter boxes. There was some satisfaction in being able to stuff those nasty things in a giant garbage bag and haul them to the trash without scooping! Hey, take pleasure while you can– you’re about to undertake something pretty stressful! After I called my Uber, I rounded up the cats one by one and deposited them in their carriers. Nobody was particularly happy about this, but just be patient. Two of my babies at the airport waiting for inspection. All of them were champs! 4. The Flight Be calm, patient, and as rational as possible. I know that it’s pretty scary (terrifying, to me) to let your precious babies our of your sight, but once the porter had helped me to the ticket counters (I actually needed two the last time, and I tipped them very well), I just reminded myself that it would all be over soon, and that the calmer I was, the better the kitties would feel. In order to pass through security, you will need to remove the cats one-by-one from their carriers and hold them while the crew puts your carrier through the scanner, or manually scans by hand (two of mine were too large to fit). Sometimes, they will let you do all of this in a separate room so that the cats are calmer, but there isn’t always one available (it will say that you can do this on most websites, but I wasn’t allowed a separate room the last time and had to hold three wiggly cats in the middle of the airport). BRING A HARNESS FOR THIS. I can’t stress this enough. My cats don’t like harnesses, but I fastened one to them before I brought them out of the carrier, and removed it right after, and it brought me a lot of peace of mind. None of my cats tried to run, but I have heard that some cats do, and you don’t want to take that chance. Look for a harness like this one— thick and really hard to pull out of. Better safe than sorry. I only brought one harness for three cats, since I would only need to take out one cat at a time. By the next morning, everyone was already claiming “our” new bed as their own. And that’s it!  Once you’re on the flight, it’s mostly a waiting game. I honestly am not sure whether the cats or I were more stressed about the trip, and they were certainly shaken and scared when they arrived at our new home. However, within a few days, my cats were all behaving as if they’d never lived anywhere else. They rebound quickly as long as you shower them with love and affection. ???? Well, those are my tips for making the smoothest ride possible! It helps to have litter and litter pans, food, etc, sent to your new place before you arrive, as well, so that everything will be easy to set up for you. Make sure that your kitties are confined to one room for at least a few hours, and let them hide for as long as they need to. They’ll get curious and hungry and come out on their own. I hope this helps someone! If I did it, anyone can! Remember, I took three cats on a flight overseas BY MYSELF! Nobody to even drop my off at the airport but an UberXL driver! =^-^=

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