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 […]

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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.

Alterations in calcium signaling in pancreatic acinar cells can result in pancreatitis. Although pressure changes in the pancreas can elevate cytosolic calcium (Ca2+) levels, it is not known how transient pressure-activated elevations in calcium can cause prolonged calcium changes and consequent pancreatitis. In this issue of the JCI, Swain et al. describe roles for the mechanically activated plasma membrane calcium channels Piezo1 and transient receptor potential vanilloid subfamily 4 (TRPV4) in acinar cells. The authors used genetic deletion models and cell culture systems to investigate calcium signaling. Notably, activation of the Piezo1-dependent TRPV4 pathway was independent of the cholecystokinin (CCK) stimulation pathway. These results elegantly resolve an apparent discrepancy in calcium signaling and the pathogenesis of pancreatitis in pancreatic acinar cells.

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.

BACKGROUND Neurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking.METHODS We used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs.RESULTS Whole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns.CONCLUSION These findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications.FUNDING This work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.

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).

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 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).

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Democratic presidential candidate Sen. Bernie Sanders explains why he thinks he thinks his record of “strong and bold leadership” could help him best candidate Hillary Clinton in the Democratic primary. Continue reading →

Claudia Stauber provides a perfect metaphor of how she felt listening to Bernie Sanders today in Vermont, telling us how much he still fights for us against the 1% and the oligarchs. Continue reading →

The indie cinema chain is going digital.

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The publisher is adding videos of their creators entertaining themselves while sheltering in place.

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DARK NIGHTS: DEATH METAL #1 is due out June 16, and we've got early unlettered pages.

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What's the Beat staff reading this weekend? Let's find out!

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As the 2015 Atlantic hurricane season gets underway, communities in severe weather-prone regions are anxiously tracking pending storms and working to create effective disaster response plans. IBM, through its strategic alliance with The Weather Company and its global B2B division WSI, today announced a new emergency management solution that features sophisticated analytics and the use of real-time weather data to help communities predict and plan for natural disasters far more accurately and deploy the right resources in advance.

The Weather Company, an IBM Business announced today that it is enhancing its global flight operations solution WSI Fusion, with live flight tracking data from FlightAware. WSI Fusion provides early insight into changing flight, airport and airspace conditions, enabling aviation providers to carefully plan and track flights, optimize operations and reduce the impacts of disruptive events. With the addition of FlightAware’s data, including its private network of over 12,000 Automatic Dependent Surveillance – Broadcast (ADS-B) ground stations in over 160 countries, WSI Fusion customers will have access to enhanced flight following capabilities worldwide.

Each year, weather-related power outages cost the U.S. economy as much as $33 billion a year. Additionally, one severe weather event has the potential to impact the daily lives and routines of millions of people. As 2017 marks the fifth anniversary of Superstorm Sandy, The Weather Company, an IBM Business (NYSE: IBM) and Zpryme are releasing the results of a survey that found that U.S. utility companies still feel underprepared for weather-related outages and that their reactive approach to outage prediction leads to lost time and resources.

IBM Security, Packet Clearing House (PCH) and The Global Cyber Alliance (GCA) today launched a free service designed to give consumers and businesses added privacy and security protection as they access the internet. The new Quad9 Domain Name System (DNS) service helps protect users from accessing millions of malicious internet sites known to steal personal information, infect users with ransomware and malware, or conduct fraudulent activity.

At the International Supercomputing Conference in Frankfurt, The Weather Company, an IBM Business, today announced a plan to help improve weather prediction globally via a new collaboration with the University Corporation for Atmospheric Research (UCAR) and the National Center for Atmospheric Research (NCAR), a federally funded research and development center for the atmosphere and Earth’s geospace systems.

IBM today announced that according to results from International Data Corporation (IDC) Worldwide Quarterly Server Tracker®(June, 2017) IBM has achieved market growth by 3x compared with the total Linux server market which grew at +6 percent. The improved performance are the result of success across IBM Power Systems including IBM’s OpenPOWER LC servers and IBM Power Systems running SAP HANA as well as the OpenPOWER-Ready servers developed through the OpenPOWER Foundation.

IBM and SAP SE have teamed up to provide a co-innovated solution for the retail and consumer packaged goods industries to help both increase profitability and improve the consumer experience.

The Weather Company, an IBM Business, and PRISA Noticias, one of the world’s leading Spanish-language media groups and owner of EL PAÍS newspaper, announced today a collaboration to combine the most accurate forecasts with one of the Spanish-speaking world’s largest media groups. The Weather Company will provide in-depth weather data and forecasts, as well as tailored content across PRISA properties. In turn, PRISA Noticias will provide locally relevant articles, photos and video content within the Spanish versions of The Weather Channel app and website (weather.com). The collaboration will also enable local marketers to access advanced data-driven advertising solutions from IBM Watson Advertising (formerly The Weather Company’s ad sales business) across both companies’ properties.

Pets at Home, the UK’s leading pet specialist retailer and IBM today announced the launch of Sales Assist, an IBM MobileFirst for iOS app for iPad which will be used across 440 stores nationwide to make it easier and simpler for customers to purchase the products they need.

IBM today announced the opening of IBM Studio Groningen, where IBM design, digital and industry experts will work with clients to help them engage with their customers using big data, mobile, cloud and social innovations.

The Weather Company, an IBM Business announced today that The Weather Channel has launched a cognitive weather bot for Facebook Messenger – powered by IBM Watson. Around the world, Messenger is used to stay in touch with friends and family. Now with The Weather Channel bot, it offers a way to view and share personalized weather-related news content, current conditions, forecasts, severe weather notifications, and other relevant weather information.

Millions of consumers depend on The Weather Channel and weather.com for their daily forecasts, breaking weather news, and the latest in health and travel. And, on August 21, they will be able to experience a solar eclipse like never before. The Weather Channel digital properties and Twitter have teamed up for a live stream of this once-in-a lifetime celestial event, which will allow consumers to chase the total solar eclipse in real time as it moves from coast-to-coast.

The Weather Company, an IBM Business and Rogers Media announced today an agreement to provide weather information and content customized specifically for the Canadian market. With this agreement, The Weather Company will provide in-depth weather data and forecasts, as well as curated content, across Rogers Media properties. In turn, Rogers Media will provide locally relevant articles, photos and video content across the Canadian versions of The Weather Channel app and website (weather.com) to provide residents with the most pertinent information possible. The Weather Company and Rogers Media will also align to enhance advertising across both companies’ properties, with Rogers leveraging its ad sales capabilities to monetize The Weather Channel properties in Canada.

IBM today announced that Fast Company has named IBM’s Harriet Green one of its 100 Most Creative People in Business for 2017. The annual list honors an influential and diverse group of leading thinkers from a vast range of global industries.

A few people don't want to own one of these intriguing red cement balls. I'm not one of those people.

3D printing is a slow process. A hot nozzle heats up and squirts molten hot plastic in a carefully determined pattern to form a three dimentional object. It's like using a hot glue gun to squirt out an entire sculpture. It takes time.

NASCAR and The Weather Company, an IBM Busines, announced today a multi-year agreement that will optimize the weather-related decision process for NASCAR as it incorporates hyper-local weather data and forecasts into their races to improve race-day operations and fan engagement. As part of the agreement, The Weather Company, via The Weather Channel brand, becomes the Official Weather Partner of NASCAR.

At the Smarter Cities Forum in Shanghai today, IBM announced a collaboration with South China's largest hospital, Guang Dong Hospital of Traditional Chinese Medicine, to apply new analytics technology to help doctors uncover trends and new knowledge about disease treatment from thousands of anonymous Electronic Medical Records (EMR)The tool will also enable clinicians to perform empirical studies on the efficacy of certain traditional Chinese treatments.