An accessible and comprehensive history of terrorism from ancient times to the present In the years since 9/11, there has been a massive surge in interest surrounding the study of terrorism. This ...volume applies distinguished military historian John Lynn's lifetime of research and teaching experience to this difficult topic. As a form of violence that implies the threat of future violence, terrorism breeds insecurity, vulnerability, and a desire for retribution that has far-reaching consequences. Lynn distinguishes between the paralyzing effect of fear and the potentially dangerous and chaotic effects of moral outrage and righteous retaliation guiding counterterrorism efforts. In this accessible and comprehensive text, Lynn traces the evolution of terrorism over time, exposing its constants and contrasts. In doing so, he contextualizes this violence and argues that a knowledge of the history and nature of terrorism can temper its psychological effects, and can help us more accurately and carefully assess threats as well as develop informed and measured responses.
Defining the molecular targets of insecticides is crucial for assessing their selectivity and potential impact on environment and health. Two commercial insecticides are now shown to target a ...transient receptor potential (TRP) ion channel complex that is unique to insect stretch receptor cells. Pymetrozine and pyrifluquinazon disturbed Drosophila coordination and hearing by acting on chordotonal stretch receptor neurons. This action required the two TRPs Nanchung (Nan) and Inactive (Iav), which co-occur exclusively within these cells. Nan and Iav together sufficed to confer cellular insecticide responses in vivo and in vitro, and the two insecticides were identified as specific agonists of Nan-Iav complexes that, by promoting cellular calcium influx, silence the stretch receptor cells. This establishes TRPs as insecticide targets and defines specific agonists of insect TRPs. It also shows that TRPs can render insecticides cell-type selective and puts forward TRP targets to reduce side effects on non-target species.
Fatigue and its management in the workplace Caldwell, John A.; Caldwell, J. Lynn; Thompson, Lauren A. ...
Neuroscience & biobehavioral reviews/Neuroscience and biobehavioral reviews,
01/2019, Letnik:
96, Številka:
C
Journal Article
Recenzirano
Odprti dostop
•Fatigue, or workplace sleepiness, is a consequence of modern industrial society.•Excessive sleepiness in the workplace and on highways is a serious safety hazard.•The greatest cause of fatigue is ...insufficient or disrupted sleep.•Validated sleep-enhancement and alertness-management strategies can mitigate fatigue.
Fatigue and workplace sleepiness are consequences of modern industrial society. Fatigue is a complex biological phenomenon that occurs as a function of time awake, time-of-day, workload, health, and off-duty lifestyle. Fatigue is a function of two major biological factors – the homeostatic drive for sleep and circadian rhythm of sleepiness. The greatest cause of fatigue is insufficient or disrupted sleep. Excessive sleepiness in the workplace and on highways is a serious safety hazard, and insufficient or disrupted sleep results in numerous accidents and adverse mental and physical health outcomes. Evidence-based strategies that promote better sleep and optimize work/rest schedules can mitigate the impact of fatigue and sleep loss. Proper nap and sleep scheduling, work breaks, modeling and monitoring tools, fatigue detection technologies, and pharmacological countermeasures can be implemented at home and/or in the workplace to reduce performance and safety hazards. Education about obtaining adequate sleep, the dangers of fatigue in terms of both health and cognitive consequences, and the availability of scientifically-proven sleep-enhancement and alertness-management strategies is essential.
The net ecosystem CO₂ exchange (NEE) between a Mojave Desert ecosystem and the atmosphere was measured over the course of 2 years at the Mojave Global Change Facility (MGCF, Nevada, USA) using the ...eddy covariance method. The investigated desert ecosystem was a sink for CO₂, taking up 102±67 and 110±70 g C m⁻² during 2005 and 2006, respectively. A comprehensive uncertainty analysis showed that most of the uncertainty of the inferred sink strength was due to the need to account for the effects of air density fluctuations on CO₂ densities measured with an open-path infrared gas analyser. In order to keep this uncertainty within acceptable bounds, highest standards with regard to maintenance of instrumentation and flux measurement postprocessing have to be met. Most of the variability in half-hourly NEE was explained by the amount of incident photosynthetically active radiation (PAR). On a seasonal scale, PAR and soil water content were the most important determinants of NEE. Precipitation events resulted in an initial pulse of CO₂ to the atmosphere, temporarily reducing NEE or even causing it to switch sign. During summer, when soil moisture was low, a lag of 3-4 days was observed before the correlation between NEE and precipitation switched from positive to negative, as opposed to conditions of high soil water availability in spring, when this transition occurred within the same day the rain took place. Our results indicate that desert ecosystem CO₂ exchange may be playing a much larger role in global carbon cycling and in modulating atmospheric CO₂ levels than previously assumed - especially since arid and semiarid biomes make up >30% of Earth's land surface.
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the ...kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson’s disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of familial and sporadic Parkinson's disease (PD). That the most prevalent mutation, G2019S, leads to ...increased kinase activity has led to a concerted effort to identify LRRK2 kinase inhibitors as a potential disease-modifying therapy for PD. An internal medicinal chemistry effort identified several potent and highly selective compounds with favorable drug-like properties. Here, we characterize the pharmacological properties of cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi-2), a structurally novel, highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels. Acute oral and subchronic dosing in MLi-2 mice resulted in dose-dependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 was well tolerated over a 15-week period at brain and plasma exposures >100× the in vivo plasma IC50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, were observed in MLi-2-treated MitoPark mice. These data demonstrate the suitability of MLi-2 as a compound to explore LRRK2 biology in cellular and animal models.
Merkel-cell carcinoma is an aggressive neuroendocrine tumor that is poorly responsive to chemotherapy. In a small series of patients, pembrolizumab produced responses in a majority of patients, ...including some complete responses.
The programmed death 1 (PD-1) immune checkpoint pathway, which comprises the PD-1 T-cell coinhibitory receptor and its ligands PD-L1 and PD-L2 expressed on tumor and immune cells in the tumor microenvironment, mediates local immune resistance.
1
Monoclonal antibodies blocking this pathway are active against advanced tumors of several different types, providing a “common denominator” for cancer therapy.
2
PD-L1 expression in pretreatment tumor specimens may identify patients and tumor types that are more likely to have a response to PD-1 pathway blockade, and PD-L1 immunohistochemical tests were recently approved by the Food and Drug Administration to guide clinical decision making for patients . . .
Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often ...unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the general population and in individuals with Brugada syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data. The ten previously studied controls had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wild-type-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 22 variants had partial loss of function (10%–50% normalized peak current). The previously unstudied variants were initially classified as likely benign (n = 2), likely pathogenic (n = 10), or VUSs (n = 61). After the patch clamp studies, 16 variants were benign/likely benign, 45 were pathogenic/likely pathogenic, and only 12 were still VUSs. Structural modeling identified likely mechanisms for loss of function including altered thermostability and disruptions to alpha helices, disulfide bonds, or the permeation pore. High-throughput patch clamping enabled reclassification of the majority of tested VUSs in SCN5A.
Molecular glues are an intriguing therapeutic modality that harness small molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have ...been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multicovalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells, and engage in molecular glue interactions with the neosubstrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal an anticancer mechanism of this natural product family, and highlight the potential for combining chemoproteomics and multicovalent natural products for the discovery of new molecular glues.
For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of ...indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme–heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor–enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.
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