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

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

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.

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

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.

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

SANDERS: ... there is more coverage about the political gossip of a campaign, about raising money, about polling, about somebody saying something dumb, or some kid works for a campaign sends out something stupid on Facebook, right? We can expect that to be a major story. But what your job is, what the media's job is, is to say, look, these are the major issues facing the country. We're a democracy. People have different points of view. Let's argue it. Continue reading →

Have you ever observed the mating dance of the birds of paradise? The male moves dramatically, and in response, the female inches away, but ultimately the male conquers the female, and achieves the purpose of this ritualistic, instinctive dance. Well, … Continue reading →

Berlin needs an independent candidate on its Town Council to counter and prevent the dominance of a major political party from unilaterally imposing its agenda and will on the citizens of Berlin. Our Town Council has been voting along strict party lines on key issues even though members pledged to reach across the aisle. It has dismissed or circumvented the results of referendums, reducing them to mere dog-and-pony shows. Berlin has more unaffiliated voters than those of the two major parties. Let's petition, nominate, and place on the ballot an independent candidate to represent these citizens and prevent the control of our Town by the dominant party on the Town Council. If interested, please contact us: berlinctpropertyownersassn@gmail.com. Continue reading →

we know how politics works in the United States. Whoever—whatever political party gets into government is going to merge with the bureaucracy pretty damn fast. It will be in a position where it has some levers in its hand. And so, as a result, corporate lobbyists will move in to help control those levers. So it doesn’t make much difference in the end. What does make a difference is political accountability, a general deterrence set to stop political organizations behaving in a corrupt manner. Continue reading →

Gentle Readers, here is another treat for us while we are confined to our homes. We may even be able to lure Dorothy away from her garret for this one. Streaming Musicals will present a free streaming event of Paul Gordon’s musical adaptation of Pride and Prejudice on Friday, April 10, 2020 at 6:30 p.m.…

IBM today announced its Health Cloud and Watson cognitive computing capabilities will support health data entered by customers in iOS apps using Apple's ResearchKit and HealthKit frameworks. The move, which complements IBM’s new Watson Health business unit, will arm medical researchers with a secure, open data storage solution, as well as access to IBM’s most sophisticated data analytics capabilities.

3D printers can be loud and hot, but they don't actually use a ton of electricity.

[Image: An example of gravitational lens effects, via Wikipedia.] Over at WIRED, Daniel Oberhaus, author of the recent book Extraterrestrial Languages, takes a look at some proposals from NASA’s Innovative Advanced Concept (NIAC) program. “Among this year’s NIAC grants,” Oberhaus writes, “are proposals to turn a lunar crater into a giant radio dish, to develop … Continue reading "Gravitational Lensing, Interstellar Cinematography, and the Future of Magical Warfare in Space"

IBM today announced it is building an industry-first insurance platform on the IBM Cloud that aims to improve the processes and economics for new product development, underwriting, and benefits delivery.

Mayo Clinic and IBM Watson Health today unveiled results from early use of the Watson for Clinical Trial Matching, an IBM cognitive computing system. Use of this system in the Mayo Clinic oncology practice has been associated with more patients enrolled in Mayo’s breast cancer clinical trials.

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.

A Peter MacCallum Cancer Centre study has demonstrated the potential for artificial intelligence to help reduce the time for clinicians to match lung cancer patients to relevant clinical trials.

INPEX selects IBM to manage operation critical apps in Australia

Just a short note that the memorial article “Analysis and applications: The mathematical work of Elias Stein” has just been published in the Bulletin of the American Mathematical Society.  This article was a collective effort led by Charlie Fefferman, Alex Ionescu, Steve Wainger and myself to describe the various mathematical contributions of Elias Stein, who […]

Next quarter, starting March 30, I will be teaching “Math 247B: Classical Fourier Analysis” here at UCLA.  (The course should more accurately be named “Modern real-variable harmonic analysis”, but we have not gotten around to implementing such a name change.) This class (a continuation of Math 247A from previous quarter, taught by my colleague, Monica […]

The actor behind Luke Skywalker takes StarWars.com on a journey through filming the Star Wars sequel in time for the 40th anniversary of its release.

Emmy Nominee Leslye Headland to write, produce, and serve as showrunner for new untitled Star Wars series for Disney+.