Comparative toxicity of pyrethroid insecticides to two estuarine crustacean species,Americamysis bahia and Palaemonetes pugio

Pyrethroid insecticides are widely used on agricultural crops, as well as for nurseries, golf courses, urban structural and landscaping sites, residential home and garden pest control, and mosquito abatement. Evaluation of sensitive marine and estuarine species is essential for the development of toxicity testing and risk‐assessment protocols. Two estuarine crustacean species, Americamysis bahia (mysids) and Palaemonetes pugio (grass shrimp), were tested with the commonly used pyrethroid compounds, lambda‐cyhalothrin, permethrin, cypermethrin, deltamethrin, and phenothrin. Sensitivities of adult and larval grass shrimp and 7‐day‐old mysids were compared using standard 96‐h LC₅₀ bioassay protocols. Adult and larval grass shrimp were more sensitive than the mysids to all the pyrethroids tested. Larval grass shrimp were approximately 18‐fold more sensitive to lambda‐cyhalothrin than the mysids. Larval grass shrimp were similar in sensitivity to adult grass shrimp for cypermethrin, deltamethrin, and phenothrin, but larvae were approximately twice as sensitive to lambda‐cyhalothrin and permethrin as adult shrimp. Acute toxicity to estuarine crustaceans occurred at low nanogram per liter concentrations of some pyrethroids, illustrating the need for careful regulation of the use of pyrethroid compounds in the coastal zone. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1099–1106, 2014.     

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure–activity relationship studies

Extremely potent, new hepatitis C virus (HCV) nonstructural 5A (NS5A) featuring substituted biaryl sulfate core structures was designed and synthesized. Based on the previously reported novel HCV NS5A inhibitors featuring biaryl sulfate core structures which exhibit two-digit picomolar half-maximal effective concentration (EC₅₀) values against HCV genotype 1b and 2a, the new inhibitors equipped with the sulfate core structures containing diversely substituted aryl groups were explored. In this study, highly efficient, chemoselective coupling reactions between an arylsulfonyl fluoride and an aryl silyl ether, known as the sulfur(vi) fluoride exchange (SuFEx) reaction, were utilized. Among the inhibitors prepared based on the SuFEx chemistry, compounds 14, 15 and 29 exhibited two-digit picomolar EC₅₀ values against GT-1b and single digit or sub nanomolar activities against the HCV GT-2a strain. Nonsymmetrical inhibitors containing an imidazole and amide moieties on each side of the sulfate core structures were also synthesized. In addition, a biotinylated probe targeting NS5A protein was prepared for labeling using the same synthetic methodology.

SuFEx chemistry was utilized for the design and synthesis of potent HCV NS5A inhibitors featuring a biaryl sulfate core.     

Dexras1/AGS-1, a steroid hormone-induced guanosine triphosphate-binding protein, inhibits 3',5'-cyclic adenosine monophosphate-stimulated secretion in AtT-20 corticotroph cells

Dexras1 is a novel GTP-binding protein that shares structural similarity with the Ras family of small molecular weight GTPases and is strongly and rapidly induced during treatment with dexamethasone. The function of Dexras1 and its contribution to glucocorticoid-dependent signaling in the corticotroph cell are unknown. The present study was undertaken to examine the potential role of Dexras1 in the regulation of peptide hormone secretion in the AtT-20 corticotroph cell line. To determine the effects of Dexras1 expressed independently of glucocorticoid treatment, expression plasmids for wild-type and constitutively active mutant Dexras1 proteins were cotransfected with human GH (hGH), which provides an ectopic marker for the stimulus-coupled secretory pathway. GTP binding properties and the GTP to GDP ratio of wild-type and mutant Dexras1 proteins were examined in transiently transfected AtT-20 and COS-7 cells. Stimulated and constitutive components of secretion were assessed after 2-h incubations with 5 mM 8-Br-cAMP or control. cAMP treatment led to a 2-fold increase in hGH secretion relative to control. Cotransfection of wild-type Dexras1 had no effect on cAMP-stimulated hGH secretion, but a constitutively active mutant, Dexras[A178V], attenuated stimulated secretion by 86% (P < 0.01). A double-mutant containing a deletion of the carboxyl terminus isoprenylation site, Dexras[A178V/C277term], did not inhibit cAMP-stimulated hGH secretion, indicating that the effect is prenylation dependent. These findings suggest that activation of Dexras1 has important functional consequences leading to inhibition of stimulus-secretion coupling in corticotroph cells. Because Dexras1 messenger RNA is strongly and rapidly induced during glucocorticoid treatment, these results raise the possibility that Dexras1 may participate in the signal transduction pathways that govern the rapid regulatory effects of glucocorticoids on peptide hormone secretion in corticotroph cells.     

A 'touch' of the White platelet syndrome

Investigations into structural defects in platelets from a large family with the White platelet syndrome (WPS) separated the members into three groups. The first group of 22 members was the subject of our first report (White JG, Key NS, King RA, Vercellotti GM. The white platelet syndrome: A new autosomal dominant platelet disorder. Platelets 2004;15:173-184). A third group of 13 members had no abnormalities of platelet ultrastructure. The second group of 17 members, the focus of the present study, had a 'touch' of the WPS. Platelet counts, mean platelet volumes (MPVs) and platelet responses to aggregating agents were normal in 'touch' patients in contrast to platelets of those with the full WPS in whom these parameters were abnormal. Up to 13% of the full WPS platelets contained large, fully developed Golgi complexes, up to seven in number, extruding innumerable vesicles from the trans-Golgi face and filling the cytoplasm of many platelets. Many Golgi complexes had centrioles associated with them. 'Touch' platelets had one or two Golgi complexes of intermediate size in 3-5% of their platelets. Golgi vesicles were uncommon and centrioles absent. Gray platelets and hypogranular cells were infrequent in patients with a 'touch' of the WPS, whereas up to 44% of the platelets from those with the WPS were gray or hypogranular. Elements of the dense tubular system were prominent in full WPS platelets, together with their formation into areas of cytoplasmic sequestration and autodigestion. These features were absent in 'touch' platelets. As commonly observed in full WPS platelets, mitochondria were larger and more numerous than alpha granules in some 'touch' cells. Both 'touch' and full WPS platelets frequently contained giant and rod-shaped granules. Dense bodies, however, were normal in size and number in 'touch' platelets, and half normal size in full WPS platelets. The separation of ultrastructural abnormalities in the two varieties of the WPS suggests that genetic defects involve more than a single gene and the genes are variable in their penetrance. Genetic studies to determine if this is the case are currently in progress.     

Hemoglobin levels and coronary heart disease risk by age,race, and sex in the reasons for geographic and racial differences in stroke study (REGARDS)

Higher and lower hemoglobin concentrations are associated with coronary heart disease (CHD), but whether this risk is consistent across age, sex, and race is unclear. The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study is an observational cohort study of 30 239 black, and white, adults aged 45 and older recruited 2003-7. Participants were included if they had hemoglobin measures, were CHD-free at baseline, and had all baseline variables. The primary outcome was incident CHD. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for incident CHD by hemoglobin concentration. This was expressed as a continuous variable and divided into age-, sex-, and race-specific quintiles. The 16 332 participants were included, contributing 114 362 person-years of follow-up and 915 incident CHD events. The mean age was 63 years, 35% were male, 41% were black, and the mean baseline hemoglobin was 13.6 g/dL (SD 1.4). A significant non-linear association between hemoglobin and CHD was identified (P < .001). This association differed significantly by race (P = .025) but not by sex or age. In whites, the risk for incident CHD was higher in the lowest (HR 2.28, 95% CI 1.61, 3.33) and highest (HR 1.94, 95% CI 1.35, 2.79) hemoglobin quintiles relative to the third quintile. For blacks, only those in the lowest hemoglobin quintile had an increased risk for incident CHD events (HR 1.70, 95% CI 1.20, 2.41). Hemoglobin is an independent risk factor for CHD in whites and blacks but with different hemoglobin concentrations conferring different risks.     

Maximizing the benefits of antiretroviral therapy for key affected populations

Introduction

Scientific research has demonstrated the clinical benefits of earlier initiation of antiretroviral treatment (ART), and that ART can markedly reduce HIV transmission to sexual partners. Ensuring universal access to ART for those who need it has long been a core principle of the HIV response, and extending the benefits of ART to key populations is critical to increasing the impact of ART and the overall effectiveness of the HIV response. However, this can only be achieved through coordinated efforts to address political, social, legal and economic barriers that key populations face in accessing HIV services.

Discussion

Recent analyses show that HIV prevalence levels among key populations are far higher than among the general population, and they experience a range of biological and behavioural factors, and social, legal and economic barriers that increase their vulnerability to HIV and have resulted in alarmingly low ART coverage. World Health Organization 2014 consolidated guidance on HIV among key populations offers the potential for increased access to ART by key populations, following the same principles as for the general adult population. However, it should not be assumed that key populations will achieve greater access to ART unless stigma, discrimination and punitive laws, policies and practices that limit access to ART and other HIV interventions in many countries are addressed.

Conclusions

Rights-based approaches and investments in critical enablers, such as supportive legal and policy environments, are essential to enable wider access to ART and other HIV interventions for key populations. The primary objective of ART should always be to treat the person living with HIV; prevention is an important, additional benefit. ART should be provided only with informed consent. The preventive benefits of treatment must not be used as a pretext for failure to provide other necessary HIV programming for key populations, including comprehensive harm reduction and other prevention interventions tailored to meet the needs of key populations. An end to AIDS is only possible if we overcome the barriers of criminalization, stigma and discrimination that remain key drivers of the HIV epidemics among key populations.     

微电极阵列细胞传感器芯片技术的研究进展

综述了目前国际上基于微电极阵列技术的细胞传感器芯片的研究状况。介绍了微电极阵列的工艺设计、界面模型以及在细胞电生理研究中的应用,同时分析了细胞胞外记录技术在实现组织-细胞以及细胞间信号传导过程的实时动态检测的特点和目前存在的问题。在此基础上,介绍了单细胞以及细胞传感器网络芯片技术的发展。最后,提出微电极阵列细胞传感器研究的发展方向。     

屠鹏飞/曾克武团队在肉苁蓉抗脑缺血靶点研究中取得进展

近日,北京大学药学院天然药物及仿生药物国家重点实验室屠鹏飞/曾克武团队在学术期刊《Signal Transduction and Targeted Therapy》发表了题为:"Small molecule induces mitochondrial fusion for neuroprotection via tar...