Augmented cardiac growth hormone signaling contributes to cardiomyopathy following genetic disruption of the cardiomyocyte circadian clock

Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the hypothesis that the cardiomyopathy observed following cardiomyocyte circadian clock disruption may be secondary to chronic activation of cardiac GH/IGF1 signaling. Here, we report that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit increased cardiac GH sensitivity, as evidenced by augmented GH-induced STAT5 phosphorylation (relative to littermate controls) in the heart (but not in the liver). Moreover

Overcoming the roadblocks to cardiac cell therapy using tissue engineering

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart’s contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality. [Display omitted

Sitting at the edge: How biomolecules use hydrophobicity to tune their interactions and function

Water near hydrophobic surfaces is like that at a liquid-vapor interface, where fluctuations in water density are substantially enhanced compared to that in bulk water. Here we use molecular simulations with specialized sampling techniques to show that water density fluctuations are similarly enhanced, even near hydrophobic surfaces of complex biomolecules, situating them at the edge of a dewetting transition. Consequently, water near these surfaces is sensitive to subtle changes in surface conformation, topology, and chemistry, any of which can tip the balance towards or away from the wet state, and thus significantly alter biomolecular interactions and function. Our work also resolves the long-standing puzzle of why some biological surfaces dewet and other seemingly similar surfaces do not.Comment: 12 pages, 4 figure

Applicant perspectives during selection

We provide a comprehensive but critical review of research on applicant reactions to selection procedures published since 2000 (n = 145), when the last major review article on applicant reactions appeared in the Journal of Management. We start by addressing the main criticisms levied against the field to determine whether applicant reactions matter to individuals and employers (“So what?”). This is followed by a consideration of “What’s new?” by conducting a comprehensive and detailed review of applicant reaction research centered upon four areas of growth: expansion of the theoretical lens, incorporation of new technology in the selection arena, internationalization of applicant reactions research, and emerging boundary conditions. Our final section focuses on “Where to next?” and offers an updated and integrated conceptual model of applicant reactions, four key challenges, and eight specific future research questions. Our conclusion is that the field demonstrates stronger research designs, with studies incorporating greater control, broader constructs, and multiple time points. There is also solid evidence that applicant reactions have significant and meaningful effects on attitudes, intentions, and behaviors. At the same time, we identify some remaining gaps in the literature and a number of critical questions that remain to be explored, particularly in light of technological and societal changes

Optics and Quantum Electronics

Contains table of contents for Section 2 and reports on twenty research projects.Charles S. Draper Laboratory Contract DL-H-404179Joint Services Electronics Program Contract DAALO3-89-C-0001National Sciences Foundation Grant EET 87-00474National Science Foundation Grant EET 88-15834U.S. Air Force - Office of Scientific Research Contract F49620-88-C-0089National Science Foundation Grant ECS 85-52701International Business Machines CorporationMassachusetts General Hospital Contract N00014-86K-0117National Institutes of Health Grant 2-RO1-GM35459U.S. Department of Energy Grant DE-FG02-89-ER14012Lawrence Livermore National Laboratory Subcontract B04870

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992

On ethically solvent leaders : the roles of pride and moral identity in predicting leader ethical behavior.

The popular media has repeatedly pointed to pride as one of the key factors motivating leaders to behave unethically. However, given the devastating consequences that leader unethical behavior may have, a more scientific account of the role of pride is warranted. The present study differentiates between authentic and hubristic pride and assesses its impact on leader ethical behavior, while taking into consideration the extent to which leaders find it important to their self-concept to be a moral person. In two experiments we found that with higher levels of moral identity, authentically proud leaders are more likely to engage in ethical behavior than hubristically proud leaders, and that this effect is mediated by leaders’ motivation to act selflessly. A field survey among organizational leaders corroborated that moral identity may bring the positive effect of authentic pride and the negative effect of hubristic pride on leader ethical behavior to the forefront

Optics and Quantum Electronics

Contains table of contents for Section 2 and reports on eighteen research projects.National Science Foundation (Grant EET 87-00474)Joint Services Electronics Program (Contract DAAL03-86-K-0002)Joint Services Electronics Program (Contract DAALO3-89-C-0001)Charles Stark Draper Laboratory (Grant DL-H-285408)Charles Stark Draper Laboratory (Grant DL-H-2854018)National Science Foundation (Grant EET 87-03404)National Science Foundation (Grant ECS 84-06290)U.S. Air Force - Office of Scientific Research (Contract F49620-88-C-0089)AT&T Bell FoundationNational Science Foundation (Grant ECS 85-52701)National Institutes of Health (Grant 5-RO1-GM35459)Massachusetts General Hospital (Office of Naval Research Contract N00014-86-K-0117)Lawrence Livermore National Laboratory (Subcontract B048704

Optics and Quantum Electronics

Contains reports on eleven research projects.National Science Foundation (Grant EET 87-00474)Joint Services Electronics Program (Contract DAALO03-86-K-O002)Charles Stark Draper Laboratory, Inc. (Grant DL-H-2854018)National Science Foundation (Grant DMR 84-18718)National Science Foundation (Grant EET 87-03404)National Science Foundation (ECS 85-52701)US Air Force - Office of Scientific Research (Contract AFOSR-85-0213)National Institutes of Health (Contract 5-RO1-GM35459)US Navy - Office of Naval Research (Contract N00014-86-K-0117