The Intrinsic Substrate Specificity of the Human Tyrosine Kinome

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Decade long upsurge in mutations associated with pyrethroid resistance in bed bug populations in the USA

Over the past three decades, the bed bug Cimex lectularius has resurged as a prominent indoor pest on a global scale. Knockdown-associated insecticide resistance (kdr) involving the voltage-gated sodium channel, targeted by organochlorine and pyrethroid insecticides, was first reported in C. lectularius within a few years of the widespread use of dichlorodiphenyltrichloroethane (DDT) and has been implicated as a significant factor contributing to the species’ recent resurgence. Since then, selection with pyrethroid insecticides has intensified, yet little is known regarding its short-term impacts on the frequency of kdr-associated mutations. Here, we report temporal changes in the frequencies of three kdr-associated mutations in C. lectularius populations collected across the USA from two time periods, sampled approximately a decade apart. The results reveal a significant increase in the frequencies of kdr-associated mutations over this period and the absence of the insecticide-susceptible genotype in recent collections. Furthermore, a significant transition was observed toward infestations possessing multiple kdr-associated mutations. These findings suggest that the persistent use of pyrethroid insecticides over the past decade continues to impose strong selection pressure on C. lectularius populations, driving the proliferation of kdr-associated mutations. They demonstrate that, if unabated, strong anthropogenic selection can drive the rapid evolution of adaptive traits

Sexual exploitability: Observable cues and their link to sexual attraction

Abstract Although antiexploitation adaptations, such as cheater-detection mechanisms, have been well explored, comparatively little research has focused on identifying adaptations for exploitation. The present study had two purposes: (1) to identify observable cues that afford information about which women are sexually exploitable and (2) to test the hypothesis that men find cues to sexual exploitability sexually attractive, an adaptation that functions to motivate pursuit of accessible women. Male participants rated photographs of women who displayed varying levels of hypothesized cues to exploitability. We identified 22 cues indicative of sexual exploitability. Nineteen of these cues were correlated significantly with sexual attractiveness, supporting the central hypothesis. Results suggest that sexual attraction to exploitability cues functions to motivate men to employ exploitative strategies towards accessible targets, and contribute foundational knowledge to the diverse classes of cues that afford information about which women are and are not sexually exploitable

Evolutionary psychology: Controversies, questions, prospects, and limitations

Evolutionary psychology has emerged over the past 15 years as a major theoretical perspective, generating an increasing volume of empirical studies and assuming a larger presence within psychological science. At the same time, it has generated critiques and remains controversial among some psychologists. Some of the controversy stems from hypotheses that go against traditional psychological theories; some from empirical findings that may have disturbing implications; some from misunderstandings about the logic of evolutionary psychology; and some from reasonable scientific concerns about its underlying framework. This article identifies some of the most common concerns and attempts to elucidate evolutionary psychology’s stance pertaining to them. These include issues of testability and falsifiability; the domain specificity versus domain generality of psychological mechanisms; the role of novel environments as they interact with evolved psychological circuits; the role of genes in the conceptual structure of evolutionary psychology; the roles of learning, socialization, and culture in evolutionary psychology; and the practical value of applied evolutionary psychology. The article concludes with a discussion of the limitations of current evolutionary psychology

Arsenic Exposure in Relation to Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study

BACKGROUND AND PURPOSE The purpose of this case-cohort study was to examine urinary arsenic levels in relation to incident ischemic stroke in the United States. METHODS We performed a case-cohort study nested within the REasons for Geographic and Racial Differences in Stroke(REGARDS) cohort. A subcohort(n=2,486) of controls was randomly sampled within region-race-sex strata, while all incident ischemic stroke cases from the full REGARDS cohort(n=671) were included. Baseline urinary arsenic was measured by inductively coupled plasma mass spectrometry. Arsenic species, including urinary inorganic arsenic(iAs) and its metabolites monomethylarsonic acid(MMA) and dimethylarsinic acid(DMA), were measured in a random subset(n=199). Weighted Cox’s proportional hazards models were used to calculate hazard ratios(HRs) and 95% confidence intervals(CIs) of ischemic stroke by arsenic and its species. RESULTS The average follow-up was 6.7 years. While incident ischemic stroke showed no association with total arsenic or total iAs, for each unit higher level of urinary MMA on a log-scale, after adjustment for potential confounders, ischemic stroke risk increased nearly 2-fold(HR=1.98; 95%CI: 1.12–3.50). Effect modification by age, race, sex, or geographic region was not evident. CONCLUSIONS A metabolite of arsenic was positively associated with incident ischemic stroke in this case-cohort study of the U.S. general population, a low-to-moderate exposure area. Overall, these findings suggest a potential role for arsenic methylation in the etiology of stroke, having important implications for future cerebrovascular research

Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial

Abstract Objective To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). Background Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. Methods This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16–64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. Results Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (− 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes. Conclusion Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048