Symmetric stability of compressible zonal flows on a generalized equatorial β plane

Sufficient conditions are derived for the linear stability with respect to zonally symmetric perturbations of a steady zonal solution to the nonhydrostatic compressible Euler equations on an equatorial � plane, including a leading order representation of the Coriolis force terms due to the poleward component of the planetary rotation vector. A version of the energy–Casimir method of stability proof is applied: an invariant functional of the Euler equations linearized about the equilibrium zonal flow is found, and positive definiteness of the functional is shown to imply linear stability of the equilibrium. It is shown that an equilibrium is stable if the potential vorticity has the same sign as latitude and the Rayleigh centrifugal stability condition that absolute angular momentum increase toward the equator on surfaces of constant pressure is satisfied. The result generalizes earlier results for hydrostatic and incompressible systems and for systems that do not account for the nontraditional Coriolis force terms. The stability of particular equilibrium zonal velocity, entropy, and density fields is assessed. A notable case in which the effect of the nontraditional Coriolis force is decisive is the instability of an angular momentum profile that decreases away from the equator but is flatter than quadratic in latitude, despite its satisfying both the centrifugal and convective stability conditions

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

A cross-institutional analysis of the effects of broadening trainee professional development on research productivity

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Brandt, P. D., Sturzenegger Varvayanis, S., Baas, T., Bolgioni, A. F., Alder, J., Petrie, K. A., Dominguez, I., Brown, A. M., Stayart, C. A., Singh, H., Van Wart, A., Chow, C. S., Mathur, A., Schreiber, B. M., Fruman, D. A., Bowden, B., Wiesen, C. A., Golightly, Y. M., Holmquist, C. E., Arneman, D., Hall, J. D., Hyman, L. E., Gould, K. L., Chalkley, R., Brennwald, P. J., Layton, R. L. A cross-institutional analysis of the effects of broadening trainee professional development on research productivity. Plos Biology, 19(7), (2021): e3000956, https://doi.org/10.1371/journal.pbio.3000956.PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and nonprofit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health (NIH) funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the NIH BEST awardee institutions included career panels, skill-building workshops, job search workshops, site visits, and internships. Because doctoral training is lengthy and requires focused attention on dissertation research, an initial concern was that students participating in additional complementary training activities might exhibit an increased time to degree or diminished research productivity. Metrics were analyzed from 10 NIH BEST awardee institutions to address this concern, using time to degree and publication records as measures of efficiency and productivity. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Our findings support the policy that doctoral students should participate in career and professional development opportunities that are intended to prepare them for a variety of diverse and important careers in the workforce.Funding sources included the Common Fund NIH Director’s Biomedical Research Workforce Innovation Broadening Experiences in Scientific Training (BEST) Award. The following institutional NIH BEST awards (alphabetical by institution) included: DP7OD020322 (Boston University; AFB, ID, BMS, LEH); DP7OD020316 (University of Chicago; CAS); DP7OD018425 (Cornell University; SSV); DP7OD018428 (Virginia Polytechnic Institute; AVW, BB); DP7OD020314 (Rutgers University; JA); DP7OD020315 (University of Rochester; TB); DP7OD018423 (Vanderbilt University; KAP, AMB, KLG, RC); DP7OD020321 (University of California, Irvine; HS, DAF); DP7OD020317 (University of North Carolina, Chapel Hill; PDB, PJB, RLL); DP7 OD018427 (Wayne State University; CSC, AM). National Institutes of Health (NIH) General Medical Sciences - Science of Science Policy Approach to Analyzing and Innovating the Biomedical Research Enterprise (SCISIPBIO) Award (GM-19-011) - 1R01GM140282-01 (University of North Carolina at Chapel Hill; RLL, PDB, PJB)

Phosphoinositide-3 Kinase-Akt Pathway Controls Cellular Entry of Ebola Virus

The phosphoinositide-3 kinase (PI3K) pathway regulates diverse cellular activities related to cell growth, migration, survival, and vesicular trafficking. It is known that Ebola virus requires endocytosis to establish an infection. However, the cellular signals that mediate this uptake were unknown for Ebola virus as well as many other viruses. Here, the involvement of PI3K in Ebola virus entry was studied. A novel and critical role of the PI3K signaling pathway was demonstrated in cell entry of Zaire Ebola virus (ZEBOV). Inhibitors of PI3K and Akt significantly reduced infection by ZEBOV at an early step during the replication cycle. Furthermore, phosphorylation of Akt-1 was induced shortly after exposure of cells to radiation-inactivated ZEBOV, indicating that the virus actively induces the PI3K pathway and that replication was not required for this induction. Subsequent use of pseudotyped Ebola virus and/or Ebola virus-like particles, in a novel virus entry assay, provided evidence that activity of PI3K/Akt is required at the virus entry step. Class 1A PI3Ks appear to play a predominant role in regulating ZEBOV entry, and Rac1 is a key downstream effector in this regulatory cascade. Confocal imaging of fluorescently labeled ZEBOV indicated that inhibition of PI3K, Akt, or Rac1 disrupted normal uptake of virus particles into cells and resulted in aberrant accumulation of virus into a cytosolic compartment that was non-permissive for membrane fusion. We conclude that PI3K-mediated signaling plays an important role in regulating vesicular trafficking of ZEBOV necessary for cell entry. Disruption of this signaling leads to inappropriate trafficking within the cell and a block in steps leading to membrane fusion. These findings extend our current understanding of Ebola virus entry mechanism and may help in devising useful new strategies for treatment of Ebola virus infection

PI3Kδ and primary immunodeficiencies.

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy