Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains

Bromodomains have been pursued intensively over the past several years as emerging targets for the development of anticancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected polypharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selective target profile is desired. Here, we report that benzo[e]pyrimido-[5,4- b]diazepine-6(11H)-ones, versatile ATP-site directed kinase pharmacophores utilized in the development of inhibitors of multiple kinases, including several previously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity, as well as how to direct selectivity toward inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first reported kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 μM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers recognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid docking studies.</p

A genealogy of hacking

Hacking is now a widely discussed and known phenomenon, but remains difficult to define and empirically identify because it has come to refer to many different, sometimes incompatible, material practices. This paper proposes genealogy as a framework for understanding hacking by briefly revisiting Foucault’s concept of genealogy and interpreting its perspectival stance through the feminist materialist concept of the situated observer. Using genealogy as a theoretical frame a history of hacking will be proposed in four phases. The first phase is the ‘pre-history’ of hacking in which four core practices were developed. The second phase is the ‘golden age of cracking’ in which hacking becomes a self-conscious identity and community and is for many identified with breaking into computers, even while non-cracking practices such as free software mature. The third phase sees hacking divide into a number of new practices even while old practices continue, including the rise of serious cybercrime, hacktivism, the division of Open Source and Free Software and hacking as an ethic of business and work. The final phase sees broad consciousness of state-sponsored hacking, the re-rise of hardware hacking in maker labs and hack spaces and the diffusion of hacking into a broad ‘clever’ practice. In conclusion it will be argued that hacking consists across all the practices surveyed of an interrogation of the rationality of information techno-cultures enacted by each hacker practice situating itself within a particular techno-culture and then using that techno-culture to change itself, both in changing potential actions that can be taken and changing the nature of the techno-culture itself

Growth form and leaf habit drive contrasting effects of Arctic amplification in long-lived woody species

Current global change is inducing heterogeneous warming trends worldwide, with faster rates at higher latitudes in the Northern Hemisphere. Consequently, tundra vegetation is experiencing an increase in growth rate and uneven but expanding distribution. Yet, the drivers of this heterogeneity in woody species responses are still unclear. Here, applying a retrospective approach and focusing on long-term responses, we aim to get insight into growth trends and climate sensitivity of long-lived woody species belonging to different functional types with contrasting growth forms and leaf habits (shrub vs. tree and deciduous vs. evergreen). A total of 530 samples from 7 species (common juniper, dwarf birch, woolly willow, Norway spruce, lodgepole pine, rowan, and downy birch) were collected in 10 sites across Iceland. We modelled growth trends and contrasted yearly ring-width measurements, filtering in high- and low-frequency components, with precipitation, land- and sea-surface temperature records (1967-2018). Shrubs and trees showed divergent growth trends, with shrubs closely tracking the recent warming, whereas trees, especially broadleaved, showed strong fluctuations but no long-term growth trends. Secondary growth, particularly the high-frequency component, was positively correlated with summer temperatures for most of the species. On the contrary, growth responses to sea surface temperature, especially in the low frequency, were highly diverging between growth forms, with a strong positive association for shrubs and a negative for trees. Within comparable vegetation assemblage, long-lived woody species could show contrasting responses to similar climatic conditions. Given the predominant role of oceanic masses in shaping climate patterns in the Arctic and Low Arctic, further investigations are needed to deepen the knowledge on the complex interplay between coastal tundra ecosystems and land-sea surface temperature dynamics

Transient Effects of Snow Cover Duration on Primary Growth and Leaf Traits in a Tundra Shrub

With the recent climate warming, tundra ecotones are facing a progressive acceleration of spring snowpack melting and extension of the growing season, with evident consequences to vegetation. Along with summer temperature, winter precipitation has been recently recognised as a crucial factor for tundra shrub growth and physiology. However, gaps of knowledge still exist on long-living plant responses to different snowpack duration, especially on how intra-specific and year-to-year variability together with multiple functional trait adjustments could influence the long-term responses. To fill this gap, we conducted a 3 years snow manipulation experiment above the Alpine treeline on the typical tundra species Juniperus communis, the conifer with the widest distributional range in the north emisphere. We tested shoot elongation, leaf area, stomatal density, leaf dry weight and leaf non-structural carbohydrate content of plants subjected to anticipated, natural and postponed snowpack duration. Anticipated snowpack melting enhanced new shoot elongation and increased stomatal density. However, plants under prolonged snow cover seemed to compensate for the shorter growing period, likely increasing carbon allocation to growth. In fact, these latter showed larger needles and low starch content at the beginning of the growing season. Variability between treatments slightly decreased over time, suggesting a progressive acclimation of juniper to new conditions. In the context of future warming scenarios, our results support the hypothesis of shrub biomass increase within the tundra biome. Yet, the picture is still far from being complete and further research should focus on transient and fading effects of changing conditions in the long term

Renal Denervation Update From the International Sympathetic Nervous System Summit:JACC State-of-the-Art Review

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications

Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy

Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of &gt;70-year patients who completed intensive therapy (induction + &gt;3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age &gt;70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=&lt;.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies