Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress

Aging degrades hematopoietic stem cell (HSC) functions, including stress response; however, the involved molecular pathways are incompletely defined. Murine BM conditionally deleted for One-Twenty-Two-1 (Ott1), is able to maintain lifelong hematopoiesis and has preserved numbers of long-term HSCs, yet cannot repopulate nor sustain itself after transplantation against a competitor even when Ott1 is excised after engraftment. We show, specifically under replicative stress, that Ott1-deleted HSCs have a significant reduction of the G(0) cell-cycle fraction associated with self-renewal and undergo early failure. Therefore, Ott1 is required to preserve HSC quiescence during stress but not steady-state hematopoiesis. Reduced tolerance of replicative stress, increased myeloid potential, and greater absolute numbers are mutual characteristics of both Ott1-deleted and aged HSCs, and comparison of their gene expression profiles reveals a shared signature. Ott1-deleted HSCs share multiple aging-associated physiologic changes, including increases in NF-κB activation and DNA damage. Loss of Ott1 causes increased reactive oxygen species; however, antioxidant treatment does not rescue the competitive defect, indicating the existence of additional essential Ott1-dependent HSC pathways. In conclusion, our data establish a requirement for Ott1 in stress hematopoiesis and suggest that Ott1-dependent processes may converge with those affected by aging.     

Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like Peptide 1-dependent mechanism

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endothelium-dependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.     

The effects of stimulus timing features on P300 speller performance

ObjectiveDespite numerous examinations of factors affecting P300 speller performance, the impact of stimulus presentation parameters remains incompletely understood. This study examines the effects of four distinct stimulus presentation parameters (stimulus-off time [ISI¹], interstimulus interval [ISI], flash duration, and flash-duration:ISI ratio) on the accuracy and efficiency of the P300 speller performance.MethodsEEG data from a 32-electrode set were recorded from six subjects using a row–column paradigm of the speller task and analyzed offline.ResultsP300 speller accuracy is affected by the number of trial repetitions (F(14,354) = 69.002, p < 0.0001), as expected. In addition, longer ISI and ISI¹ times resulted in higher accuracy and characters per minute [CPM] rates. Subsets of the entire group (i.e. good vs. poor performers) were compared to show consistency of performance trends despite great variance among subjects. Moreover, the same significant effects were observed whether using the entire 32-electrode dataset or the reduced 8-channel set described by Sharbrough et al. (1991).ConclusionsDespite variability in user performance, both ISI¹ and ISI can affect P300 speller performance.SignificanceP300 system optimization must consider critical stimulus timing features including ISI¹ and ISI. Further characterization of the impact of these timing features in online experiments is warranted and the differential effect on accuracy and CPM should be more comprehensively explored.     

缺血性卒中患者血清同型半胱氨酸与脑白质病变体积相关性研究

目的本文顾性横断面研究旨在探讨脑卒中患者脑白质病变体积与血清同型半胱氨酸(Hcy)水平的关系。方法回顾性收集87例急性脑梗死患者的人口学、临床、实验室及器械检查资料。Hcy的测定采用荧光偏振免疫分析法。应用半自动测量软件对所有患者颅脑MRI冠状位液体衰减反转回复序列(FLAIR)上脑白质病变进行体积测量。应用多元线性回归法对脑白质病变的体积(平方根值)进行相关因素的分析。结果共87例患者纳入研究,男54例(62.1%),平均年龄(62.2±11.2)岁,76例(87.4%)有高血压,18例(20.7%)有糖尿病,18例(20.7%)既往有脑卒中史。在多元线性回归显示,年龄、既往卒中史、腔隙性梗死数目、血清Hcy水平及颅内动脉狭窄均为脑白质病变体积(平方根值)的独立相关因素。结论脑卒中患者的血清Hcy水平是其脑白质病变体积的独立危险因素。血清Hcy可作为脑部小血管病变的生物学标记。