Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src@

Background  

Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and altered EGFR signaling contributes to human cancer. EGFR kinase domain mutants found in non-small cell lung cancer (NSCLC) are constitutively active, a trait critical for cell transformation through activation of downstream pathways. Endocytic trafficking of EGFR is a major regulatory mechanism as ligand-induced lysosomal degradation results in termination of signaling. While numerous studies have examined mutant EGFR signaling, the endocytic traffic of mutant EGFR within the NSCLC milieu remains less clear.     

Effect of marriage on duration of chest pain associated with acute myocardial infarction before seeking care

Background:

Coronary artery disease is the most common cause of death in the Western world, and being married decreases the risk of death from cardiovascular causes. We aimed to determine whether marital status was a predictor of the duration of chest pain endured by patients with acute myocardial infarction before they sought care and whether the patient’s sex modified the effect.

Methods:

We conducted a retrospective, population-based cohort analysis of patients with acute myocardial infarction admitted to 96 acute care hospitals in Ontario, Canada, from April 2004 to March 2005. We excluded patients who did not experience chest pain. Using multivariable regression analyses, we assessed marital status in relation to delayed presentation to hospital (more than six hours from onset of pain), both overall and stratified by sex. In patients who reported the exact duration of chest pain, we assessed the effect of marital status on the delay in seeking care.

Results:

Among 4403 eligible patients with acute myocardial infarction, the mean age was 67.3 (standard deviation 13.6) years, and 1486 (33.7%) were women. Almost half (2037 or 46.3%) presented to a hospital within two hours, and 3240 (73.6%) presented within six hours. Overall, 75.3% (2317/3079) of married patients, 67.9% (188/277) of single patients, 68.5% (189/276) of divorced patients and 70.8% (546/771) of widowed patients presented within six hours of the onset of chest pain. Being married was associated with lower odds of delayed presentation (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.30–0.71, p < 0.001) relative to being single. Among men, the OR was 0.35 (95% CI 0.21–0.59, p < 0.001), whereas among women the effect of marital status was not significant (OR 1.36, 95% CI 0.49–3.73, p = 0.55).

Interpretation:

Among men experiencing acute myocardial infarction with chest pain, being married was associated with significantly earlier presentation for care, a benefit that was not observed for married women. Earlier presentation for medical care appears to be one reason for the observed lower risk of cardiovascular death among married men, relative to their single counterparts.Marriage has long been known to offer health benefits^1,2 and is associated with a lower risk of death^3,4 relative to people who are not married. The effect is more pronounced among men than among women.^5,6 However, the specific mechanisms responsible for the lower rate of cardiovascular deaths in married persons⁷ are not known.Effective, time-sensitive therapy for acute myocardial infarction is available,^8,9 and delays in the emergency department and for in-hospital components of care have been substantially reduced over the past few decades.^10,11 In contrast, patients’ delay in seeking care for acute myocardial infarction has shown little improvement over time,^12,13 despite intensive campaigns to raise public awareness.^14,15 Patients’ delay remains by far the largest component of the overall delay between onset of symptoms and receipt of therapy.¹⁶ No study has examined the effect of marital status on patients’ delay, and only a few small studies have examined predictors of this component of delay by sex.^17,18We examined the effect of marital status, a social factor, on the time from onset of chest pain to arrival in an emergency department or hospital, in a population-based cohort of patients with acute myocardial infarction. We hypothesized that being married or in a common-law relationship would be associated with less delay, because we surmised that a spouse would encourage earlier pursuit of medical care, either directly or indirectly (i.e., even if the spouse was not physically present during the symptoms, his or her existence might spur the patient to seek care earlier). We hypothesized that wives would be more likely than husbands to assume the caregiver role and that the beneficial effect of marriage would therefore be stronger among men than among women.     

Protein-level fluctuation correlation at the microcolony level and its application to the Vibrio harveyi quorum-sensing circuit

Gene expression is stochastic, and noise that arises from the stochastic nature of biochemical reactions propagates through active regulatory links. Thus, correlations in gene-expression noise can provide information about regulatory links. We present what to our knowledge is a new approach to measure and interpret such correlated fluctuations at the level of single microcolonies, which derive from single cells. We demonstrated this approach mathematically using stochastic modeling, and applied it to experimental time-lapse fluorescence microscopy data. Specifically, we investigated the relationships among LuxO, LuxR, and the small regulatory RNA qrr4 in the model quorum-sensing bacterium Vibrio harveyi. Our results show that LuxR positively regulates the qrr4 promoter. Under our conditions, we find that qrr regulation weakly depends on total LuxO levels and that LuxO autorepression is saturated. We also find evidence that the fluctuations in LuxO levels are dominated by intrinsic noise. We furthermore propose LuxO and LuxR interact at all autoinducer levels via an unknown mechanism. Of importance, our new method of evaluating correlations at the microcolony level is unaffected by partition noise at cell division. Moreover, the method is first-order accurate and requires less effort for data analysis than single-cell-based approaches. This new correlation approach can be applied to other systems to aid analysis of gene regulatory circuits.     

Triptolide derivatives as potential multifunctional anti-Alzheimer agents: Synthesis and structure–activity relationship studies

Owning to the promising neuroprotective profile and the ability to cross the blood–brain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structure–activity relationship studies for Alzheimer’s disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model. Among the triptolide derivatives tested, a memantine conjugate, compound 8, showed a remarkable neuroprotective effect against Aβ_1–42 toxicity in primary cortical neuron cultures as well as an inhibitory effect against LPS-induced TNF-α production in BV2 cells at a subnanomolar concentration. Our findings provide insight into the different pharmacophores that are responsible for the multifunctional effects of triptolide in the central nervous system. Our study should help in the development of triptolide-based multifunctional anti-Alzheimer drugs.     

NADH-Linked Ferricyanide and Cytochrome c Reduction Activities in Corn Root Plasma Membrane

Corn root plasma membrane catalyzed NADH reduction of ferricyanideand cytochrome c over a wide pH range. At pH 7.5, apparent K_msof NADH-cytochrome c pair were significantly lower than thoseof NADH-ferricyanide pair. FMN and polylysine respectively enhancedthe reduction of ferricyanide and cytochrome c. Yet, polyaspartatedecreased the ferricyanide reduction. NADH oxidation observedin the presence of both ferricyanide and cytochrome c was significantlyslower than the sum of rates obtained with individual acceptors.The results suggest that the membrane may contain differentbut not totally independent reduction sites for cytochrome cand ferricyanide. (Received April 13, 1993; Accepted August 23, 1993)     

Purification and properties of lysophospholipase from the venom of the giant hornet Vespa orientalis

Using biospecific chromatography on polylysocephamide, a toxic phospholipase possessing a presynaptic effect on neuromuscular preparations was isolated from the venom of the giant hornet Vespa orientalis. The enzyme was shown to possess a high hydrolytic activity towards 1-acyllysophosphatidylcholine within a narrow pH range (pH optimum 7.5). The enzyme activity was suppressed by detergents of various chemical composition. Lysophospholipase caused an intensive hemolysis of washed human erythrocytes. The catalytic and hemolytic functions of the enzyme were sensitive to metal ions, however, in a different degree. Ca2+ and Mn2+ activated, while Cu2+ and Zn2+ inhibited the enzyme. Mg2+ and Sr2+ had no effect on the enzyme activity.     

Learnability-based further prediction of gene functions in Gene Ontology

Currently the functional annotations of many genes are not specific enough, limiting their further application in biology and medicine. It is necessary to push the gene functional annotations deeper in Gene Ontology (GO), or to predict further annotated genes with more specific GO terms. A framework of learnability-based further prediction of gene functions in GO is proposed in this paper. Local classifiers are constructed in local classification spaces rooted at qualified parent nodes in GO, and their classification performances are evaluated with the averaged Tanimoto index (ATI). Classification spaces with higher ATIs are selected out, and genes annotated only to the parent classes are predicted to child classes. Through learnability-based further predicting, the functional annotations of annotated genes are made more specific. Experiments on the fibroblast serum response dataset reported further functional predictions for several human genes and also gave interesting clues to the varied learnability between classes of different GO ontologies, different levels, and different numbers of child classes.