Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis

Blood vessels are part of the stem cell niche in the developing cerebral cortex, but their in vivo role in controlling the expansion and differentiation of neural stem cells (NSCs) in development has not been studied. Here, we report that relief of hypoxia in the developing cerebral cortex by ingrowth of blood vessels temporo‐spatially coincided with NSC differentiation. Selective perturbation of brain angiogenesis in vessel‐specific Gpr124 null embryos, which prevented the relief from hypoxia, increased NSC expansion at the expense of differentiation. Conversely, exposure to increased oxygen levels rescued NSC differentiation in Gpr124 null embryos and increased it further in WT embryos, suggesting that niche blood vessels regulate NSC differentiation at least in part by providing oxygen. Consistent herewith, hypoxia‐inducible factor (HIF)‐1α levels controlled the switch of NSC expansion to differentiation. Finally, we provide evidence that high glycolytic activity of NSCs is required to prevent their precocious differentiation in vivo. Thus, blood vessel function is required for efficient NSC differentiation in the developing cerebral cortex by providing oxygen and possibly regulating NSC metabolism.     

12种短命植物叶解剖结构及其对荒漠环境的适应性

以分布于新疆北部古尔班通古特沙漠南缘的12种短命植物为研究材料,采用常规石蜡切片法,对其叶的解剖结构进行了观察分析,探讨12种短命植物的叶解剖结构对荒漠生态环境的适应性关系。结果显示:(1)12种短命植物中,有8种植物的叶肉栅栏组织发达,表现出等面叶特征;有7种植物侧脉维管束具有花环状结构,表现出C4植物特点。(2)12种植物叶片均具有气孔下室,其中,小花荆芥等7种植物叶片具有发达的气孔下室。(3)12种植物叶肉及叶脉中常有晶体存在,晶体数量及大小在不同植物中有差异。研究认为,12种短命植物从总体上呈现出旱生结构特征,从个体角度看这些特征是不同类群的植物以不同方式适应沙漠干旱环境的结果,但不足以改变该类植物的中生性质。     

OSAHS风险对患者静脉麻醉术后认知功能障碍的影响

目的:探讨OSAHS风险与静脉麻醉手术患者术后发生认知功能障碍的关系。方法:采用No SAS评分对55例静脉麻醉手术患者进行OSAHS风险评估,并将其分为对照组23例(NoSAS 8分)和OSAHS组32例(No SAS≥8分),以蒙特利尔认知评估量表(MoCA)对两组患者在术前和术后第一天进行认知功能评估,计算每位患者手术前后Mo CA评分的差值△Mo CA(术前MoCA-术后MoCA),比较两组患者手术前后的MoCA评分及△MoCA。结果:OSAHS组术前MoCA评分(25.83±1.80)明显低于对照组术前MoCA评分(28.05±1.31)(P0.05)。OSAHS组术后MoCA评分(25.13±1.64)较术前无明显变化(P0.05),对照组术后Mo CA评分(26.73±1.17)明显低于术前(P0.05)。OSAHS组△MoCA(0.39±1.03)明显低于对照组(1.32±1.08),主要表现为视空间与执行功能[(0.09±0.29) vs.(0.30±0.32)]、注意力[(0.09±0.60) vs.(0.47±0.70)]和延时回忆力[(0.17±0.39) vs.(0.47±0.51)]两方面(P0.05)。结论:OSAHS高风险患者静脉麻醉术后认知功能障碍的程度较OSAHS低风险人群显著降低。     

Nerve growth factor regulates endothelial cell survival and pathological retinal angiogenesis

The mechanism underlying vasoproliferative retinopathies like retinopathy of prematurity (ROP) is hypoxia‐triggered neovascularisation. Nerve growth factor (NGF), a neurotrophin supporting survival and differentiation of neuronal cells may also regulate endothelial cell functions. Here we studied the role of NGF in pathological retinal angiogenesis in the course of the ROP mouse model. Topical application of NGF enhanced while intraocular injections of anti‐NGF neutralizing antibody reduced pathological retinal vascularization in mice subjected to the ROP model. The pro‐angiogenic effect of NGF in the retina was mediated by inhibition of retinal endothelial cell apoptosis. In vitro, NGF decreased the intrinsic (mitochondria‐dependent) apoptosis in hypoxia‐treated human retinal microvascular endothelial cells and preserved the mitochondrial membrane potential. The anti‐apoptotic effect of NGF was associated with increased BCL2 and reduced BAX, as well as with enhanced ERK and AKT phosphorylation, and was abolished by inhibition of the AKT pathway. Our findings reveal an anti‐apoptotic role of NGF in the hypoxic retinal endothelium, which is involved in promoting pathological retinal vascularization, thereby pointing to NGF as a potential target for proliferative retinopathies.     

Tendinosis develops from age‐ and oxygen tension‐dependent modulation of Rac1 activity

Age‐related tendon degeneration (tendinosis) is characterized by a phenotypic change in which tenocytes display characteristics of fibrochondrocytes and mineralized fibrochondrocytes. As tendon degeneration has been noted in vivo in areas of decreased tendon vascularity, we hypothesized that hypoxia is responsible for the development of the tendinosis phenotype, and that these effects are more pronounced in aged tenocytes. Hypoxic (1% O₂) culture of aged, tendinotic, and young human tenocytes resulted in a mineralized fibrochondrocyte phenotype in aged tenocytes, and a fibrochondrocyte phenotype in young and tendinotic tenocytes. Investigation of the molecular mechanism responsible for this phenotype change revealed that the fibrochondrocyte phenotype in aged tenocytes occurs with decreased Rac1 activity in response to hypoxia. In young hypoxic tenocytes, however, the fibrochondrocyte phenotype occurs with concomitant decreased Rac1 activity coupled with increased RhoA activity. Using pharmacologic and adenoviral manipulation, we confirmed that these hypoxic effects on the tenocyte phenotype are linked directly to the activity of RhoA/Rac1 GTPase in in vitro human cell culture and tendon explants. These results demonstrate that hypoxia drives tenocyte phenotypic changes, and provide a molecular insight into the development of human tendinosis that occurs with aging.     

Adaptation capacity of Boer goats to saline drinking water

Due to global climatic changes, water and soil salinization is an increasing worldwide phenomenon, thus creating new threats for farm animal production. The present study was designed to investigate the adaptation capacity of goats towards sodium chloride (NaCl) in drinking water. Twelve non-pregnant Boer goats with an average body weight of 50.5 ± 9.0 kg were kept in individual pens. The study was conducted in four phases applying a two-choice preference test. In the control phase (phase 1) only fresh water was supplied in two containers. In phase 2, water with different salt concentrations (0.25%, 0.5%, 0.75%, 1.0%, 1.25% and 1.5%) was offered in one container and tap water in the other (sensitivity test). During the third phase (adaptation), goats were stepwise habituated to saline water by offering only saline water with different increasing concentrations (between 0% and 1.5% NaCl) in both containers. Subsequently, in phase 4 (sensitivity re-test) the same treatment as in phase 2 was repeated. Goats had ad libitum access to hay, water and a mineral licking block. Individual water and feed intake were recorded daily, while body weight and body condition score were measured every 2^nd week. Body weight was not affected by saline water intake, whereas dry matter intake and body condition scores decreased significantly during the experiment. Water intake was significantly (P<0.001) higher in phase 2 (sensitivity test) and phase 3 (adaptation), compared to phase 1 (control) and phase 4 (sensitivity re-test). Total sodium intake followed the same pattern. In phase 2, when goats had the choice between fresh and saline water for the first time they preferred higher salt concentrations and consumed significantly (P<0.001) higher amounts of saline water (75.4 ± 53.2 g/kg BW^0.82 per day) than in the re-test (40.4 ± 34.0 g/kg BW^0.82 per day) after the habituation period. Thus, salt discrimination rejection thresholds were lowered to 1.25% in phase 4 compared to 1.5% in phase 2. The results suggest that a stepwise adaptation to saline drinking water in goats is an effective method to habituate the animals to saline water intake when concentrations were below 1.5%. Goats reacted more sensitively to the salinity of drinking water after prolonged exposure to saline water indicating flexible regulation mechanisms depending on the total sodium balance of the animal.     

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

This review will focus on the role of the tumor microenvironment (TME) in the development of drug resistance in melanoma. Resistance to mitogen‐activated protein kinase inhibitors (MAPKi) in melanoma is observed months after treatment, a phenomenon that is often attributed to the incredible plasticity of melanoma cells but may also depend on the TME. The TME is unique in its cellular composition—it contains fibroblasts, immune cells, endothelial cells, adipocytes, and among others. In addition, the TME provides “non‐homeostatic” levels of oxygen, nutrients (hypoxia and metabolic stress), and extracellular matrix proteins, creating a pro‐tumorigenic niche that drives resistance to MAPKi treatment. In this review, we will focus on how changes in the tumor microenvironment regulate MAPKi resistance.