The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development

Conserved metallo β‐Lactamase and β‐CASP (CPSF‐Artemis‐Snm1‐Pso2) domain nuclease family member SNM1B/Apollo is a shelterin‐associated protein that localizes to telomeres through its interaction with TRF2. To study its in vivo role, we generated a knockout of SNM1B/Apollo in a mouse model. Snm1B/Apollo homozygous null mice die at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Snm1B/Apollo mutant mouse embryonic fibroblasts (MEFs) owing to high levels of telomeric end‐to‐end fusions. Deficiency of the nonhomologous end‐joining (NHEJ) factor Ku70, but not p53, rescued the developmental defects and lethality observed in Snm1B/Apollo mutant mice as well as the impaired proliferation of Snm1B/Apollo‐deficient MEFs. These findings demonstrate that SNM1B/Apollo is required to protect telomeres against NHEJ‐mediated repair, which results in genomic instability and the consequent multi‐organ developmental failure. Although Snm1B/Apollo‐deficient MEFs exhibited high levels of apoptosis, abrogation of p53‐dependent programmed cell death did not rescue the multi‐organ developmental failure in the mice.     

Receptor-based targeting of engineered nanocarrier against solid tumors: Recent progress and challenges ahead

BackgroundIn past few decades, the research on engineered nanocarriers (NCs) has gained significant attention in cancer therapy due to selective delivery of drug molecules on the diseased cells thereby preventing unwanted uptake into healthy cells to cause toxicity.Scope of reviewThe applicability of enhanced permeability and retention (EPR) effect for the delivery of nanomedicines in cancer therapy has gained limited success due to poor accessibility of the drugs to the target cells where non-specific payload delivery to the off target region lack substantial reward over the conventional therapeutic systems.Major conclusionsIn spite of the fact, nanomedicines fabricated from the biocompatible nanocarriers have reduced targeting potential for meaningful clinical benefits. However, over expression of receptors on the tumor cells provides opportunity to design functional nanomedicine to bind substantially and deliver therapeutics to the cells or tissues of interest by alleviating the bio-toxicity and unwanted effects. This critique will give insight into the over expressed receptor in various tumor and targeting potential of functional nanomedicine as new therapeutic avenues for effective treatment.General significanceThis review shortly shed light on EPR-based drug targeting using nanomedicinal strategies, their limitation, and advances in therapeutic targeting to the tumor cells.     

Squalamine, a novel cationic steroid, specifically inhibits the brush-border Na+/H+ exchanger isoform NHE3

Squalamine, anendogenous molecule found in the liver and other tissues ofSqualus acanthias, hasantibiotic properties and causes changes in endothelial cell shape. Thelatter suggested that its potential targets might include transportproteins that control cell volume or cell shape. The effect of purifiedsqualamine was examined on clonedNa⁺/H⁺exchanger isoforms NHE1, NHE2, and NHE3 stably transfected in PS120fibroblasts. Squalamine (1-h pretreatment) decreased the maximalvelocity of rabbit NHE3 in a concentration-dependent manner (13, 47, and 57% inhibition with 3, 5, and 7 µg/ml, respectively) and alsoincreasedK'[H⁺]_i.Squalamine did not affect rabbit NHE1 or NHE2 function. The inhibitoryeffect of squalamine was 1) timedependent, with no effect of immediate addition and maximum effect with1 h of exposure, and 2) fullyreversible. Squalamine pretreatment of the ileum for 60 min inhibitedbrush-border membrane vesicleNa⁺/H⁺activity by 51%. Further investigation into the mechanism of squalamine's effects showed that squalamine required the COOH-terminal 76 amino acids of NHE3. Squalamine had no cytotoxic effect at theconcentrations studied, as indicated by monitoring lactate dehydrogenase release. These results indicate that squalamine 1) is a specific inhibitor of thebrush-border NHE isoform NHE3 and not NHE1 or NHE2,2) acts in a nontoxic and fullyreversible manner, and 3) has adelayed effect, indicating that it may influence brush-borderNa⁺/H⁺exchanger function indirectly, through an intracellular signaling pathway or by acting as an intracellular modulator.

     

Does service accessibility reduce socioeconomic differentials in maternity care seeking? Evidence from rural Bangladesh

Maternal mortality is a serious public health concern in Bangladesh. However, most deaths could be prevented through proper and timely care seeking and adequate management. Unfortunately, fewer than half of pregnant women in Bangladesh seek antenatal care, and only one in eight receive delivery care from medically trained providers. The specific objectives of this research are to examine the socioeconomic differentials of maternity care seeking, and to determine whether accessibility of health services reduces the socioeconomic differentials in maternity care seeking. A multi-level logistic regression method is employed to analyse longitudinal data collected from a sample of 1019 women from all over Bangladesh. The study finds significant socioeconomic disparities in both antenatal and delivery care seeking. Service accessibility, however, significantly reduces the socioeconomic differentials in delivery care seeking. Services need to be made accessible to reduce the inequality in maternity care seeking between rich and poor, empowered and non-empowered.     

FANCI is a negative regulator of Akt activation

Akt is a critical mediator of the oncogenic PI3K pathway, and its activation is regulated by kinases and phosphatases acting in opposition. We report here the existence of a novel protein complex that is composed minimally of Akt, PHLPP1, PHLPP2, FANCI, FANCD2, USP1 and UAF1. Our studies show that depletion of FANCI, but not FANCD2 or USP1, results in increased phosphorylation and activation of Akt. This activation is due to a reduction in the interaction between PHLPP1 and Akt in the absence of FANCI. In response to DNA damage or growth factor treatment, the interactions between Akt, PHLPP1 and FANCI are reduced consistent with the known phosphorylation of Akt in response to these stimuli. Furthermore, depletion of FANCI results in reduced apoptosis after DNA damage in accord with its role as a negative regular of Akt. Our findings describe an unexpected function for FANCI in the regulation of Akt and define a previously unrecognized intersection between the PI3K-Akt and FA pathways.     

Neuro-fuzzy structural classification of proteins for improved protein secondary structure prediction

Fourier transform infrared (FTIR) spectroscopy is a very flexible technique for characterization of protein secondary structure. Measurements can be carried out rapidly in a number of different environments based on only small quantities of proteins. For this technique to become more widely used for protein secondary structure characterization, however, further developments in methods to accurately quantify protein secondary structure are necessary. Here we propose a structural classification of proteins (SCOP) class specialized neural networks architecture combining an adaptive neuro-fuzzy inference system (ANFIS) with SCOP class specialized backpropagation neural networks for improved protein secondary structure prediction. Our study shows that proteins can be accurately classified into two main classes "all alpha proteins" and "all beta proteins" merely based on the amide I band maximum position of their FTIR spectra. ANFIS is employed to perform the classification task to demonstrate the potential of this architecture with moderately complex problems. Based on studies using a reference set of 17 proteins and an evaluation set of 4 proteins, improved predictions were achieved compared to a conventional neural network approach, where structure specialized neural networks are trained based on protein spectra of both "all alpha" and "all beta" proteins. The standard errors of prediction (SEPs) in % structure were improved by 4.05% for helix structure, by 5.91% for sheet structure, by 2.68% for turn structure, and by 2.15% for bend structure. For other structure, an increase of SEP by 2.43% was observed. Those results were confirmed by a "leave-one-out" run with the combined set of 21 FTIR spectra of proteins.     

Patent ductus arteriosus endarteritis in a 40-year old woman, diagnosed with Transesophageal Echocardiography. A case report and a brief review of the literature

Background

It has been suggested that an extensive contractile reserve identified recognised by means of dobutamine stress echocardiography may predict a better prognosis in patients with severe left ventricular dysfunction at rest. However, the clinical use of dobutamine stress echocardiography may be limited in patients with chronic heart failure by the substantial proportion of such patients treated with beta-blockers, since the inotropic response to adrenergic stimulation is known to be attenuated in patients receiving beta-adrenoceptor blockers. Enoximone is a positive inotropic agent that inhibits cyclic adenosine monophosphate-specific phosphosdiesterase. We therefore tested the hypothesis that enoximone may be an alternative to dobutamine in evaluating left ventricular contractile reserve in patients with systolic dysfunction on chronic beta-blocker therapy.

Methods

We studied 26 patients (21 males and five females) with a mean age of 58 ± 10 years: 11 were not receiving beta-blockers (noBB group); 15 were receiving carvedilol at a mean dose of 34 mg/day (BB group). Dobutamine was infused at doses of 5 and 10 micrograms/kg/min, and enoximone at a dose of 1.5 mg/kg.

Results

The ejection fraction in the noBB group increased by 9% with dobutamine and 8.73% with enoximone (p = 0.86); in the BB group, it increased by 6% with dobutamine and 8.94% with enoximone (p = 0.03). Regional peak systolic velocities were evaluated by means of tissue Doppler imaging in four basal and four medium level segments. In the noBB group, they increased more with dobutamine than with enoximone in three of the eight segments; no significant differences were found in the BB group. Dobutamine induced non-sustained ventricular tachycardia in three patients and supraventricular tachycardia in one, whereas enoximone did not induce any repetitive arrhythmias.

Conclusions

Enoximone might be preferable to low-dose dobutamine for evaluating left ventricular contractile reserve in chronically beta-blocked heart failure patients as it is slightly more potent and has a better safety profile.     

Evaluating the Association between p53 Codon 72 Arg>Pro Polymorphism and Risk of Ovary Cancer: A Meta-Analysis

Aim

Allelic polymorphism in codon 72 of the p53 tumor suppressor gene causes imbalance of p53 protein expression. Earlier studies have shown association between allelic polymorphism in codon 72 of the p53 gene with risk of ovary cancer (OC); however the results are inconclusive and conflicting. Therefore, we performed this meta-analysis to investigate the relation between p53 codon 72 Arg>Pro polymorphism and overall OC susceptibility.

Methods

We searched all eligible published studies based on the association between codon 72 of the p53 Arg>Pro polymorphism and risk of OC. Data were pooled together from individual studies and meta-analysis was performed. Pooled odds ratios (ORs) and 95% CI were calculated for allele contrast, homozygous, heterozygous, dominant and recessive genetic models.

Results

A total of twelve studies comprising of 993 OC cases and 1264 healthy controls were included in this meta-analysis. Overall, no significant association was detected for Pro allele carrier (Pro vs. Arg: p = 0.916; OR = 0.980, 95% CI = 0.677 to 1.419), homozygous (Pro/Pro vs. Arg/Arg: p = 0.419; OR = 0.731, 95% CI = 0.341 to 1.564), heterozygous (Arg/Pro vs. Arg/Arg: p = 0.248; OR = 1.237, 95% CI = 0.862 to 1.773), dominant (Pro/Pro+Arg/Pro vsArg/Arg: p = 0.699; OR = 1.089, 95% CI = 0.706 to 1.681), and recessive (Pro/Pro vs Arg/Arg+Arg/Pro: p = 0.329; OR = 0.754, 95% CI = 0.428 to 1.329) genetic models, respectively. Also, in the stratified analysis by ethnicity, no significant association of this polymorphism with risk of OC was found in the Caucasian population.

Conclusions

This meta-analysis suggested that codon 72 of the p53 Arg>Pro polymorphism may not significantly contribute in ovary cancer susceptibility. However, future large studies with gene-gene and gene-environment interactions are needed to validate these findings.     

Magnetic resonance imaging of glutamate

Glutamate, a major neurotransmitter in the brain, shows a pH- and concentration-dependent chemical exchange saturation transfer effect (GluCEST) between its amine group and bulk water, with potential for in vivo imaging by nuclear magnetic resonance. GluCEST asymmetry is observed ～3 p.p.m. downfield from bulk water. Middle cerebral artery occlusion in the rat brain resulted in an ～100% elevation of GluCEST in the ipsilateral side compared with the contralateral side, predominantly owing to pH changes. In a rat brain tumor model with blood-brain barrier disruption, intravenous glutamate injection resulted in a clear elevation of GluCEST and a similar increase in the proton magnetic resonance spectroscopy signal of glutamate. GluCEST maps from healthy human brain were also obtained. These results demonstrate the feasibility of using GluCEST for mapping relative changes in glutamate concentration, as well as pH, in vivo. Contributions from other brain metabolites to the GluCEST effect are also discussed.