Research summary: U- and inverted U-shaped relationships are increasingly explored in strategy research, with 11 percent of all articles published in Strategic Management Journal (SMJ) in 2008-2012 ...investigating such quadratic relationships. Moreover, a movement towards introducing moderation to quadratic relationships has emerged. By reviewing 110 articles published in SMJ from 1980 to 2012, we identify several critical issues in theorizing and testing of these relationships for which current practice falls short. These include insufficient causal argumentation, incorrect testing, mixing up two different types of moderation, and not realizing that the curve can flip completely. For these and other issues, a guideline is provided which, when followed, may bring clarity to theoretical motivation and rigor to empirical testing. Managerial summary: Too much can be as bad as too little. Many relationships in strategic management follow an inverted U-shaped pattern, where moderate levels of a strategy lead to optimal performance. To gain deeper insights into the conventional wisdom that too much of a good thing can be harmful to performance, we discuss how such relationships can be better theorized and tested based on a review of articles exploring U-shaped relationships in Strategic Management Journal during 1980-2012. We identify several critical issues that require close attention and provide a guideline to further develop and validate this important managerial intuition.
Dissipationless currents from topologically protected states are promising for disorder-tolerant electronics and quantum computation. Here, we photogenerate giant anisotropic terahertz nonlinear ...currents with vanishing scattering, driven by laser-induced coherent phonons of broken inversion symmetry in a centrosymmetric Dirac material ZrTe5. Our work suggests that this phononic terahertz symmetry switching leads to formation of Weyl points, whose chirality manifests in a transverse, helicity-dependent current, orthogonal to the dynamical inversion symmetry breaking axis, via circular photogalvanic effect. The temperature-dependent topological photocurrent exhibits several distinct features: Berry curvature dominance, particle–hole reversal near conical points and chirality protection that is responsible for an exceptional ballistic transport length of ~10 μm. These results, together with first-principles modelling, indicate two pairs of Weyl points dynamically created by B1u phonons of broken inversion symmetry. Such phononic terahertz control breaks ground for coherent manipulation of Weyl nodes and robust quantum transport without application of static electric or magnetic fields.Femtosecond optical pulses are used to generate coherent phonons that break inversion symmetry and drive anisotropic terahertz photocurrents in the topological material ZrTe5.
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET ...inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between ...platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.
Flight of the dragonflies and damselflies Bomphrey, Richard J.; Nakata, Toshiyuki; Henningsson, Per ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
09/2016, Letnik:
371, Številka:
1704
Journal Article
Recenzirano
Odprti dostop
This work is a synthesis of our current understanding of the mechanics, aerodynamics and visually mediated control of dragonfly and damselfly flight, with the addition of new experimental and ...computational data in several key areas. These are: the diversity of dragonfly wing morphologies, the aerodynamics of gliding flight, force generation in flapping flight, aerodynamic efficiency, comparative flight performance and pursuit strategies during predatory and territorial flights. New data are set in context by brief reviews covering anatomy at several scales, insect aerodynamics, neuromechanics and behaviour. We achieve a new perspective by means of a diverse range of techniques, including laser-line mapping of wing topographies, computational fluid dynamics simulations of finely detailed wing geometries, quantitative imaging using particle image velocimetry of on-wing and wake flow patterns, classical aerodynamic theory, photography in the field, infrared motion capture and multi-camera optical tracking of free flight trajectories in laboratory environments. Our comprehensive approach enables a novel synthesis of datasets and subfields that integrates many aspects of flight from the neurobiology of the compound eye, through the aeromechanical interface with the surrounding fluid, to flight performance under cruising and higher-energy behavioural modes.
This article is part of the themed issue ‘Moving in a moving medium: new perspectives on flight’.
Respiratory syncytial virus is a common cause of illness and hospitalization, especially among infants and immunocompromised persons, but there are no accepted antiviral therapies. In this RSV ...challenge study, GS-5806, a new compound, showed activity against RSV.
Respiratory syncytial virus (RSV) infection accounts for substantial morbidity and mortality among infants
1
–
7
and is the most common reason for hospitalization of infants in the United States,
8
with an even greater outpatient burden of disease. Estimates indicate that among children younger than 2 years of age, the annual rate of RSV-related hospitalization is 5.2 per 1000, the rate of emergency department encounters is 32 to 57 per 1000, and the rate of outpatient visits is 66 to 177 per 1000.
2
Among infants younger than 1 year of age, the risk of death from respiratory causes is increased by a . . .
Current climate models systematically underestimate the strength of oceanic fronts associated with strong western boundary currents, such as the Kuroshio and Gulf Stream Extensions, and have ...difficulty simulating their positions at the mid-latitude ocean's western boundaries. Even with an enhanced grid resolution to resolve ocean mesoscale eddies-energetic circulations with horizontal scales of about a hundred kilometres that strongly interact with the fronts and currents-the bias problem can still persist; to improve climate models we need a better understanding of the dynamics governing these oceanic frontal regimes. Yet prevailing theories about the western boundary fronts are based on ocean internal dynamics without taking into consideration the intense air-sea feedbacks in these oceanic frontal regions. Here, by focusing on the Kuroshio Extension Jet east of Japan as the direct continuation of the Kuroshio, we show that feedback between ocean mesoscale eddies and the atmosphere (OME-A) is fundamental to the dynamics and control of these energetic currents. Suppressing OME-A feedback in eddy-resolving coupled climate model simulations results in a 20-40 per cent weakening in the Kuroshio Extension Jet. This is because OME-A feedback dominates eddy potential energy destruction, which dissipates more than 70 per cent of the eddy potential energy extracted from the Kuroshio Extension Jet. The absence of OME-A feedback inevitably leads to a reduction in eddy potential energy production in order to balance the energy budget, which results in a weakened mean current. The finding has important implications for improving climate models' representation of major oceanic fronts, which are essential components in the simulation and prediction of extratropical storms and other extreme events, as well as in the projection of the effect on these events of climate change.
We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer.
Seven cell lines originating from three pathologic types of thyroid ...cancer (papillary, follicular and anaplastic) were studied. The cytotoxicity of dinaciclib was measured using a lactate dehydrogenase assay. The expression of proteins associated with cell cycle and apoptosis was assessed using Western blot analysis and immunofluorescence microscopy. Cell cycle distribution was measured by flow cytometry and immunofluorescence microscopy. Apoptosis and caspase-3 activity were measured by flow cytometry and fluorometric assay. Mice bearing flank anaplastic thyroid cancer (ATC) were treated with intraperitoneal injections of dinaciclib.
Dinaciclib inhibited thyroid cancer cell proliferation in a dose-dependent manner. Dinaciclib had a low median-effect dose (≤ 16.0 nM) to inhibit cell proliferation in seven thyroid cancer cell lines. Dinaciclib decreased CDK1, cyclin B1, and Aurora A expression, induced cell cycle arrest in the G2/M phase, and induced accumulation of prophase mitotic cells. Dinaciclib decreased Mcl-1, Bcl-xL and survivin expression, activated caspase-3 and induced apoptosis. In vivo, the growth of ATC xenograft tumors was retarded in a dose-dependent fashion with daily dinaciclib treatment. Higher-dose dinaciclib (50 mg/kg) caused slight, but significant weight loss, which was absent with lower-dose dinaciclib (40 mg/kg) treatment.
Dinaciclib inhibited thyroid cancer proliferation both in vitro and in vivo. These findings support dinaciclib as a potential drug for further studies in clinical trials for the treatment of patients with refractory thyroid cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Methylation of histone H3 lysine 4 (H3K4me) is an evolutionarily conserved modification whose role in the regulation of gene expression has been extensively studied. In contrast, the function of H3K4 ...acetylation (H3K4ac) has received little attention because of a lack of tools to separate its function from that of H3K4me. Here we show that, in addition to being methylated, H3K4 is also acetylated in budding yeast. Genetic studies reveal that the histone acetyltransferases (HATs) Gcn5 and Rtt109 contribute to H3K4 acetylation in vivo. Whilst removal of H3K4ac from euchromatin mainly requires the histone deacetylase (HDAC) Hst1, Sir2 is needed for H3K4 deacetylation in heterochomatin. Using genome-wide chromatin immunoprecipitation (ChIP), we show that H3K4ac is enriched at promoters of actively transcribed genes and located just upstream of H3K4 tri-methylation (H3K4me3), a pattern that has been conserved in human cells. We find that the Set1-containing complex (COMPASS), which promotes H3K4me2 and -me3, also serves to limit the abundance of H3K4ac at gene promoters. In addition, we identify a group of genes that have high levels of H3K4ac in their promoters and are inadequately expressed in H3-K4R, but not in set1Δ mutant strains, suggesting that H3K4ac plays a positive role in transcription. Our results reveal a novel regulatory feature of promoter-proximal chromatin, involving mutually exclusive histone modifications of the same histone residue (H3K4ac and H3K4me).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor ...(CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.
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