Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK)

Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.     

High Altitude Bird Migration at Temperate Latitudes: A Synoptic Perspective on Wind Assistance

At temperate latitudes the synoptic patterns of bird migration are strongly structured by the presence of cyclones and anticyclones, both in the horizontal and altitudinal dimensions. In certain synoptic conditions, birds may efficiently cross regions with opposing surface wind by choosing a higher flight altitude with more favourable wind. We observed migratory passerines at mid-latitudes that selected high altitude wind optima on particular nights, leading to the formation of structured migration layers at varying altitude up to 3 km. Using long-term vertical profiling of bird migration by C-band Doppler radar in the Netherlands, we find that such migration layers occur nearly exclusively during spring migration in the presence of a high-pressure system. A conceptual analytic framework providing insight into the synoptic patterns of wind assistance for migrants that includes the altitudinal dimension has so far been lacking. We present a simple model for a baroclinic atmosphere that relates vertical profiles of wind assistance to the pressure and temperature patterns occurring at temperate latitudes. We show how the magnitude and direction of the large scale horizontal temperature gradient affects the relative gain in wind assistance that migrants obtain through ascending. Temperature gradients typical for northerly high-pressure systems in spring are shown to cause high altitude wind optima in the easterly sectors of anticyclones, thereby explaining the frequent observations of high altitude migration in these synoptic conditions. Given the recurring synoptic arrangements of pressure systems across temperate continents, the opportunities for exploiting high altitude wind will differ between flyways, for example between easterly and westerly oceanic coasts.     

Millennial Climatic Fluctuations Are Key to the Structure of Last Glacial Ecosystems

Whereas fossil evidence indicates extensive treeless vegetation and diverse grazing megafauna in Europe and northern Asia during the last glacial, experiments combining vegetation models and climate models have to-date simulated widespread persistence of trees. Resolving this conflict is key to understanding both last glacial ecosystems and extinction of most of the mega-herbivores. Using a dynamic vegetation model (DVM) we explored the implications of the differing climatic conditions generated by a general circulation model (GCM) in “normal” and “hosing” experiments. Whilst the former approximate interstadial conditions, the latter, designed to mimic Heinrich Events, approximate stadial conditions. The “hosing” experiments gave simulated European vegetation much closer in composition to that inferred from fossil evidence than did the “normal” experiments. Given the short duration of interstadials, and the rate at which forest cover expanded during the late-glacial and early Holocene, our results demonstrate the importance of millennial variability in determining the character of last glacial ecosystems.     

Impairment of Endothelial-Myocardial Interaction Increases the Susceptibility of Cardiomyocytes to Ischemia/Reperfusion Injury

Endothelial-myocardial interactions may be critically important for ischemia/reperfusion injury. Tetrahydrobiopterin (BH₄) is a required cofactor for nitric oxide (NO) production by endothelial NO synthase (eNOS). Hyperglycemia (HG) leads to significant increases in oxidative stress, oxidizing BH₄ to enzymatically incompetent dihydrobiopterin. How alterations in endothelial BH₄ content impact myocardial ischemia/reperfusion injury remains elusive. The aim of this study was to examine the effect of endothelial-myocardial interaction on ischemia/reperfusion injury, with an emphasis on the role of endothelial BH₄ content. Langendorff-perfused mouse hearts were treated by triton X-100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion. The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X-100 treated hearts compared with vehicle-treated hearts. Cardiomyocytes (CMs) were co-cultured with endothelial cells (ECs) and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation. Addition of ECs to CMs at a ratio of 1∶3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone. This EC-derived protection was abolished by HG. The addition of 100 µM sepiapterin (a BH₄ precursor) or overexpression of GTP cyclohydrolase 1 (the rate-limiting enzyme for BH₄ biosynthesis) in ECs by gene trasfer enhanced endothelial BH₄ levels, the ratio of eNOS dimer/monomer, eNOS phosphorylation, and NO production and decreased lactate dehydrogenase activity in the presence of HG. These results demonstrate that increased BH₄ content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia/reoxygenation in the presence of HG. Maintaining sufficient endothelial BH₄ is crucial for cardioprotection against hypoxia/reoxygenation injury.     

Emotional dysregulation in children with attention-deficit/hyperactivity disorder

Emotional dysregulation is increasingly recognized as a core feature of attention-deficit/hyperactivity disorder (ADHD). The purpose of the present systematic literature review was to identify published data related to the neuropsychology of emotional dysregulation in children with ADHD. The literature obtained is discussed in the contexts of deficits in emotional control, impairments in executive function, the emotional components of comorbidities, neurophysiological and autonomic correlates of emotional dysregulation, and the significance of multiple neuropsychological pathways of ADHD on emotional dysregulation. These various lines of evidence are used to create a patient-oriented conceptual model framework of the pathway from stimulus to inappropriate internalized (sadness, moodiness) or externalized (anger, aggressiveness) emotional responses. The article concludes by calling for continued research into the development of reliable and universally accepted measures of emotional dysregulation in order to provide children affected with ADHD, and their caregivers, some explanation for their emotional lability and, ultimately, to be used as tools to evaluate potential treatments.