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High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium. Editor's summary: Endothelial cell function is enhanced by bioactive lipids such as prostacyclin and sphingosine 1-phosphate (S1P) when bound to its chaperone apolipoprotein M (ApoM). Lin et al. generated a fusion protein called A1M to promote both S1P and prostacyclin signaling. A1M consisted of ApoM and ApoA1, a structural component of high-density lipoprotein (HDL) that stabilizes prostacyclin. When bound to S1P or a prostacyclin analog, A1M suppressed inflammation and increased the barrier function of cultured endothelial cells. In mouse models of acute or systemic inflammation, S1P-loaded A1M suppressed neutrophil infiltration, increases in circulating proinflammatory factors, and cytokine storm. The ApoA1 moiety of A1M therefore provides additional benefits over previously engineered S1P chaperones. —Wei Wong [ABSTRACT FROM AUTHOR]

Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation or elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected from the cardiometabolic impact of circadian misalignment on a high-fat diet seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice, biasing toward increased potential for diabetogenic branched chain amino acid production. Antibiotic ablation of the gut microbiota diminished the impact of misalignment. In the United Kingdom Biobank, females showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males among job-matched shiftworkers. Thus, we show that female mice are more resilient than males to chronic circadian misalignment and that these differences are conserved in humans. Cardiometabolic sex differences in circadian stress: Working night shifts increases risk of cardiometabolic dysfunction. Anderson et al. report that among mice on a high-fat diet and an altered circadian schedule similar to that of shiftwork, females were more resilient to the cardiometabolic consequences of the regimen compared with male mice, which showed stress-related changes at both the tissue and microbiome levels. Sexual dimorphism in cardiometabolic dysfunction was replicated in a human cohort of shiftworkers and might in part explain why males are more prone to developing metabolic disease. —Catherine A. Charneski [ABSTRACT FROM AUTHOR]

Female gender affords relative protection from cardiovascular disease until the menopause. We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacydin, PG[I.sub.2], by activation of cyclooxygenase 2 (COX-2). This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice. Deletion of the PG[I.sub.2] receptor removed the atheroprotective effect of estrogen in ovariectomized female mice. This suggests that chronic treatment of patients with selective inhibitors of COX-2 could undermine protection from cardiovascular disease in premenopausal females., Age-dependent increases in cardiovascular disease are less pronounced in women than in men, but this difference narrows after the menopause (1). Estrogen (E2) retards atherogenesis in models (2) and improves [...]

Thromboxane (Tx) [A.sub.2] is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of Tx[A.sub.2] formation by platelet cyclooxygenase (COX-l). Prostacydin (PG[I.sub.2]) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PG[I.sub.2] receptor (IP) but are depressed in mice genetically deficient in the Tx[A.sub.2] receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PG[I.sub.2] modulates platelet-vascular interactions in vivo and specifically limits the response to Tx[A.sub.2]. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PG[I.sub.2] but not Tx[A.sub.2]., Prostacyclin (PG[I.sub.2]) is the major product of cyclooxygenase (COX) catalyzed metabolism of arachidonic acid in macrovascular endothelium (1, 2). It is a potent inhibitor of platelet activation by all recognized [...]

The article discusses the study on the importance of circadian rhythms in the process of aging. The study reportedly involved a conditional Bmal1 knockout mice which did not have the Bmal1 protein as an adult. The results revealed that the timing of the expression of Bmal1 protein affect its effects on the aging process and longevity.

The article focuses on therapies that modulate bioactive lipids that regulate the host immune response to respiratory viral infections may be beneficial. It mentions spike (S) glycoprotein on the surface of SARS-CoV-2 tightly binds the free fatty acid linoleic acid, stabilizing it and reducing its interaction with the host angiotensin-converting enzyme 2 (ACE2) receptor. It also mentions S1P signaling in the lung decreases dendritic cell (DC) migration.

The article presents a study which reveals that sexual dimorphism in chronobiology extends into oscillations of transcriptome, metabolome, and microbiome. It mentions that males tend to be more evening oriented than females after puberty; and estrogen and androgen receptors are expressed in a sexually dimorphic pattern along the central neuronal circuitry regulating circadian rhythms and show rhythmic expression in peripheral tissues.

The article discusses the use of dimethyl Prostaglandin E2 (PGE2) as a supplement to hematopoietic stem cell transplantation to promote tissue regeneration. Topics include the suppression of prostaglandin (PG) formation by nonsteroidal anti-inflammatory drugs (NSAIDs), risks associated with the use of prostaglandin inhibitors to treat inflammatory disease, and increased hematopoiesis, liver regeneration, and resistance to colitis in mice from elevated PGE2 and reduced 15-PGHD by Zhang et al.

The article discusses role of U.S. National Institutes of Health (NIH) Clinical and Translational Science Awards (CTSAs) in fostering research on human phenotyping. It states that program was designed to encourage the integration of basic and clinical science, and mentions that recent CTSA funding opportunity announcement has reflected a budgetary and programmatic shift. It notes the need of maintaining flexibility around the nature of the collaborations under the program.

In this article, the author talks about several aspects of opening schools during the Covid-19 pandemic. It mentions larger school outbreaks are associated with increased community transmission, insufficient physical distancing, and lack of masking. It mentions masks reduce spread by droplets and aerosols by limiting release and inhalation; and scientific understanding of severe acute respiratory syndrome coronavirus 2 SARS-CoV-2, cause of COVID-19 should inform how schools reopen.

The article discusses the drugs for the pandemic coronavirus disease 2019 (COVID-19) including cortisone, that can aggravate the infection and mentions acetaminophen that is an NSAID.

The article focuses on human phenotypic data and its uses in animal studies, drug research, and medical research. It comments on how mouse models can fail to properly predict the human condition and considers how using large human cohorts in deep genotypic and phenotypic evaluation. It considers the creation of algorithms to forecast rare adverse drug effects and subgroups that favorably respond to specific medicines. It talks about drug approval and examining drugs for unanticipated efficacies.

Science Translational Medicine's co-Chief Scientific Advisors discuss challenges and opportunities for the next decade of translational research. In this Editorial, co-Chief Scientific Advisors of Science Translational Medicine, Elazer Edelman and Garret FitzGerald, discuss challenges and opportunities for the next decade of translational research. [ABSTRACT FROM AUTHOR]

The article focuses on the measurement of the biomarker transparency and standards in the U.S. Topics discussed include an overview of biomarkers, the common evidentiary standards of biomarkers, and the significance of laboratory information system and electronic health record manufacturers in biomarker data resource development.

The article discusses findings by researcher R. Zhang and colleagues on the role of circadian gene expression and timing of drug administration, focusing on the development of a circadian gene expression atlas. Topics include oscillation in biological clocks, bimodal human heart and lung cluster gene expression, and implications for therapeutic practice.

The author argues that intellectual property (IP) reform is required for more cost effective and productive drug development research, particularly in cooperative research between the drug industry and academia. He advocates for a modular approach that promotes collaboration between different countries and discipline, which would necessitate changes in IP and licensing laws to allow the sharing of data. Topics discussed include patent and IP issues in the mobile electronic device industry, IP of the composition of matter of a drug under development versus the final approved drug, and incentivization of clinical trials.

The article announces that pharmacologists Garret FitzGerald of the University of Pennsylvania and Carlo Patrono of the Catholic University in Rome, Italy won the 2013 Grand Prix Scientifique from the Institut de France for their work in cardiovascular health.

The author reflects on the significant role of industry and academic cooperation in the development of innovative biotechnological drugs. He relates that the ensuing economic trend and government funding are threatening to hamper the development of new drugs as evident in the low number of drugs developed and approved in 2007. Moreover, he stresses that the academia, industry and regulatory agencies should be financially empowered and strengthened to identify opportunities in biotechnology.

Thromboxane (Tx) A² is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA² formation by platelet cyclooxy-genase (COX-1). Prostacyclin (PGI[sub 2]) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI[sub 2] receptor (IP) but are depressed in mice genetically deficient in the TxA[sub 2] receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI[sub 2] modulates platelet-vascular interactions in vivo and specifically limits the response to TxA[sub 2]. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI[sub 2] but not TxA[sub 2]. [ABSTRACT FROM AUTHOR]

The article discusses the use of computational modeling to enable personalized, precision medicine under the U.S. National Institutes of Health’s Precision Medicine Initiative, including its role in discovering drug therapies. An overview of the use of data collection in precision medicine is provided.

The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock., (Copyright © 2016, American Association for the Advancement of Science.)

This Review is based on the Franklin Epstein Lecture delivered at Beth Israel Deaconess Hospital on 25 April 2013. We discuss recent advances in our understanding of molecular clocks and highlight their relevance to human physiology and disease.

Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D(2) synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D(2) (PGD(2)), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD(2) levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD(2) receptor G protein (heterotrimeric guanine nucleotide)-coupled receptor 44 (GPR44), but not the PGD(2) receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD(2) in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD(2) as an inhibitor of hair growth in AGA and suggest the PGD(2)-GPR44 pathway as a potential target for treatment.