Advances in understanding the molecular basis of the first steps in color vision

Serving as one of our primary environmental inputs, vision is the most sophisticated sensory system in humans. Here, we present recent findings derived from energetics, genetics and physiology that provide a more advanced understanding of color perception in mammals. Energetics of cis–trans isomerization of 11-cis-retinal accounts for color perception in the narrow region of the electromagnetic spectrum and how human eyes can absorb light in the near infrared (IR) range. Structural homology models of visual pigments reveal complex interactions of the protein moieties with the light sensitive chromophore 11-cis-retinal and that certain color blinding mutations impair secondary structural elements of these G protein-coupled receptors (GPCRs). Finally, we identify unsolved critical aspects of color tuning that require future investigation.     

Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells

c-Met, a cognate receptor tyrosine kinase of hepatocyte growth factor, is overexpressed and/or mutated in number of tumors. Therefore, abrogation of c-Met signaling may serve as potential therapeutic targets. In this study, we generated Ads expressing single shRNA specific to c-Met (shMet) (dl/shMet4 and dl/shMet5) or dual shRNAs specific to c-Met (dl/shMet4+5); and examined the therapeutic potential of these newly engineered Ads in targeting c-Met, and delineated their mechanism of action in vitro and in vivo. Ads expressing shMet induced knock-down in c-Met, and phenotypically resulted in autophagy-like features including appearance of membranousvacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein1 light chain 3 to autophagosomes. Ads expressing shMet also suppressed Akt phosphorylation and increased number of senescence-related gene products including SM22, TGase II, and PAI-1. These changes resulted in inhibition of cell proliferation and G₂/M arrest of U343 cells. In vivo, intratumoral injection with dl/shMet4+5 resulted in a significant reduction of tumor growth with corresponding increasing overall survival. Histopathological analysis of these treated tumors revealed that Atg5 was highly up-regulated, indicating the therapeutic induction of autophagy. In sum, these results reveal that autophagic cell death induced by shMet-expressing Ads provide a novel strategy for targeting c-Met-expressing tumors through non-apoptotic mechanism of cell death.     

Vitamin D Receptor Poly(A) Microsatellite Polymorphism and 25-Hydroxyvitamin D Serum Levels: Association with Susceptibility to Breast Cancer

Purpose

According to previous studies, vitamin D exhibits protective effects against breast cancer via the vitamin D receptor (VDR). There is growing evidence that breast cancer incidence is associated with various polymorphisms of the VDR gene. This study investigates the association of VDR poly(A) microsatellite variants with 25-hydroxyvitamin D (25(OH)D) serum levels and breast cancer risk.

Methods

Polymorphism analysis was performed on a total of 261 blood samples, which were collected from 134 women with breast cancer and 127 controls. Single strand conformation polymorphism was assessed by polymerase chain reaction in combination with sequencing to detect poly(A) lengths for each sample. The vitamin D levels of samples were determined by electrochemiluminescence.

Results

The poly(A) variant L allele frequency was significantly higher in cancer patients than in controls (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.16-2.57; p=0.006). Thus, carriers of the L allele (LS and LL genotypes) have a higher risk for breast cancer (OR, 1.86; 95% CI, 1.13-3.05; p=0.013). A larger increase in the risk for breast cancer was found in individuals with the L carrier genotype and lowered 25(OH)D levels.

Conclusion

The results primarily suggest that VDR gene polymorphism in the poly(A) microsatellite is associated with 25(OH)D levels and that it can affect the breast cancer risk in the female population from northern Iran.     

PentaD、PentaE基因座基因频率在军人主、被动攻击行为群体分布的比较

目的通过比较PentaD、PentaE基因座等位基因及基因型频率在军人主、被动攻击行为群体中的分布,来推测与主、被动攻击行为发生相关的遗传因素。方法采用PCR结合毛细管电泳的方法对华东地区273例男性军人主动攻击行为者与163例男性军人被动攻击行为者进行PentaD、PentaE基因座的基因型分析,观察两组在PentaD、PentaE基因座的等位基因及基因型分布差异。结果PentaD、PentaE基因座均符合Hardy-Weinberg平衡;PentaE基因座基因型频率在主、被动军人攻击行为群体分布差异有统计学意义（P〈0．01）;单因素分析显示两组在PentaE基因座的基因型16-18的频率分布差异有统计学意义（P=0．0001）;PentaE基因座等位基因频率及PentaD基因座等位基因频率和基因型频率在两个群体中分布差异均无统计学意义（P〉0．05）。结论PentaE基因座可能与攻击行为的发生有关;在人攻击行为群体中PentaE基因座的基因型16-18为被动攻击行为的易感因素。     

D6S1043、D12S391基因座与主动攻击行为的关联研究

目的 探讨主动攻击行为与D6S1043、D12S391基因座等位基因或基因型的关联情况.方法 采用PCR结合毛细管电泳的方法对江苏地区103例男性主动攻击行为者(研究组)和159例健康男性(对照组)的外周静脉血样进行D6S1043、D12S391基因座的基因型分析,观察两组在D6S1043、D12S391基因座的等位基因及基因型分布差异,以推测与主动攻击行为相关的易感因素和(或)抗性因素.结果 D6S1043、D12S391基因座均符合遗传平衡定律(Hardy-Weinberg定律)(P＞0.05);在两个群体中D6S1043基因座的基因型12-19的频率分布差异有统计学意义(P =0.000 4,OR=7.511,95％CI:2.084 ～ 27.066),但等位基因频率分布无差异(P ＞0.05/n);在D12S391基因座上未发现分布存在显著差异的等位基因及基因型(P ＞0.05/n).结论 D6S1043基因座的基因型12-19可能为主动攻击行为的易感因素.     

New treatment of free-radical scavenger in adrenoleukodystrophy

What is known and Objective: Adrenoleukodystrophy (ALD) is an X‐linked disorder and characterized by the accumulation of saturated very long‐chain fatty acids. Treatment is still unsatisfactory. Our objective is to report on the effect of the free‐radical scavenger, edaravone, in a patient with ALD. Case summary: The patient was given edaravone intravenously twice. D‐ROM in cerebral spinal fluid decreased dramatically, and a shortening of neuronal transmission time as estimated on somatosensory evoked potential was observed. After terminating the treatment, his symptoms progressively reappeared. What is new and Conclusion: This is the first report of the use of edaravone in ALD. The drug is apparently effective in improving symptoms of ALD and should be evaluated more formally.     

Excessive release of endogenous neuropeptide Y into cerebrospinal fluid after treatment of spontaneous subarachnoid haemorrhage and its possible impact on self-reported neuropsychological performance – results of a prospective clinical pilot study on good-grade patients

ABSTRACT

Objectives: Neuropsychological dysfunction after treatment of spontaneous subarachnoid haemorrhage (sSAH) is common but underreported. The vasoconstrictor neuropeptide Y (NPY) is excessively released after sSAH and in psychiatric disorders. We prospectively analysed the treatment-specific differences in the secretion of endogenous cerebrospinal fluid (CSF) NPY during the acute stage after sSAH and its impact on cognitive processing.

Methods: A total of 26 consecutive patients (f:m = 13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out n = 5): n = 9 underwent endovascular aneurysm occlusion, n = 6 microsurgery, and n = 6 patients with perimesencephalic SAH received standardized intensive medical care. Ventricular CSF was drawn daily from day 1–10. CSF NPY levels were determined with competitive enzyme immunoassay. All patients underwent neuropsychological self-report assessment [36-Item Short Form Health Survey (SF-36) and ICD-10-Symptom-Rating questionnaire (ISR)] after the onset of sSAH (day 11–35; t₁) and at the 6-month follow-up (t₂).

Results: At t₁, increased mean levels of NPY in CSF significantly correlated with impaired performance in most ISR scores (ISR total p = .018, depression p = .035, anxiety p = .008, nutrition disorder p = .047, supplementary items p = .038) and in several psychological SF-36 items (vitality p = .019, general mental health p = .001, mental component summary p = .025).

Discussion: To the best of our knowledge, this study is the first to correlate the levels of endogenous NPY in supratentorial CSF with cognitive outcome in good-grade sSAH patients. Excessive NPY release into CSF may have a short-term influence on the pathogenesis of neuropsychological deficits. The impact of cerebrovascular manipulation on NPY release has to be further elucidated.

Abbreviations: ANOVA: analysis of variance; aSAH: aneurysmal subarachnoid haemorrhage; AUC: area under the curve; CBF: cerebral blood flow; CSF: cerebrospinal fluid; CT (scan): computed tomography (scan); CV: cerebral vasospasm; DIND: delayed ischemic neurological deficit; DSA: digital subtraction angiography; EIA: enzyme immunoassay; EV: endovascular aneurysm occlusion; EVD: external ventricular drainage; FU: 6-month follow-up; GCS: Glasgow Coma Scale; Ghp: general health perceptions; GOS: Glasgow Outcome Scale; h: hour/s; HH: Hunt and Hess; ICU: intensive care unit; ISR: ICD-10-Symptom-Rating questionnaire; MCS: mental component summary; Mhi: general mental health; min: minute/s; min-max: minimum – maximum; ml: millilitre; mRS: modified Ranking Scale; MS: microsurgical clipping, microsurgical aneurysm occlusion; ng: nanograms; no. [n]: number; NPY: Neuropeptide Y; p: p value; Pain: bodily pain; PCS: physical component summary; Pfi: physical functioning; pSAH: perimesencephalic subarachnoid haemorrhage; PTSD: posttraumatic stress disorder; QoL: quality of life; Rawhtran: health transition item; Rolem: role limitations because of emotional problems; Rolph: role limitations due to physical health problems; SAH: subarachnoid haemorrhage; SD: standard deviation; SF-36: 36-Item Short Form Health Survey; Social: social functioning; sSAH: spontaneous subarachnoid haemorrhage; TCD: trans-cranial Doppler ultrasound; (test) t₁: test in the sub-acute phase after the onset of bleeding (between day 11 and 35 after subarachnoid haemorrhage); (test) t₂: test in the short-term (chronic phase) after treatment at 6-month follow-up; test t₁ - t₂: intergroup development from t₁ to t₂; Vital: vitality; vs: versus.