Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase

Anti-apoptotic Bcl2 family proteins such as Bcl-x(L) protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-x(L) enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-x(L)interacts directly with the β-subunit of the F(1)F(O)?ATP synthase, decreasing an ion leak within the F(1)F(O) ATPase complex and thereby increasing net transport of H(+) by F(1)F(O) during F(1)F(O) ATPase activity. By patch clamping submitochondrial vesicles enriched in F(1)F(O) ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-x(L) activity increases the membrane leak conductance. In addition, recombinant Bcl-x(L) protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-x(L) decreases the level of F(1)F(O) enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x(L)-expressing?neurons.     

Surgical perspectives from a prospective, nonrandomized, multicenter study of breast conserving surgery and adjuvant electronic brachytherapy for the treatment of breast cancer

Background

The influence of viral hepatitis status on prognosis in patients undergoing hepatic resection for hepatocellular carcinoma (HCC) remains a matter of debate. This study is a meta-analysis of the available evidence.

Methods

A literature search was performed to identify comparative studies reporting postoperative survival of HCC in different types of viral hepatitis. Pooled odds ratios (OR) and weighted mean differences (WMD with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model.

Results

Twenty studies matched the selection criteria and reported on 4744 subjects, of whom 2008 in the HBV-positive (B-HCC) group, 2222 in the HCV-positive (C-HCC) group, and 514 in the hepatitis B- and C-negative (NBNC-HCC). Meta-analysis showed that patients with HBV or HCV infection had a worse 5-year disease-free survival when compared to patients with NBNC-HCC (respectively: OR: 0.39, 95% CI: 0.28 to 0.53, P < 0.001; WMD: 0.37, 95% CI: 0.22 to 0.64, P < 0.001). There was a tendency toward higher 5-year overall survival rates in the NBNC-HCC group compared to those in the other two groups, although these differences were not statistically significant. Both the 5-year overall survival and disease-free survival were not different among the B-HCC and C-HCC groups.

Conclusions

Patients with positive serology for hepatitis B or C undergoing resection for HCC had a poor prognosis compared to patients with negative serology.     

Who Needs Microtubules? Myogenic Reorganization of MTOC,Golgi Complex and ER Exit Sites Persists Despite Lack of Normal Microtubule Tracks

A wave of structural reorganization involving centrosomes, microtubules, Golgi complex and ER exit sites takes place early during skeletal muscle differentiation and completely remodels the secretory pathway. The mechanism of these changes and their functional implications are still poorly understood, in large part because all changes occur seemingly simultaneously. In an effort to uncouple the reorganizations, we have used taxol, nocodazole, and the specific GSK3-β inhibitor DW12, to disrupt the dynamic microtubule network of differentiating cultures of the mouse skeletal muscle cell line C2. Despite strong effects on microtubules, cell shape and cell fusion, none of the treatments prevented early differentiation. Redistribution of centrosomal proteins, conditional on differentiation, was in fact increased by taxol and nocodazole and normal in DW12. Redistributions of Golgi complex and ER exit sites were incomplete but remained tightly linked under all circumstances, and conditional on centrosomal reorganization. We were therefore able to uncouple microtubule reorganization from the other events and to determine that centrosomal proteins lead the reorganization hierarchy. In addition, we have gained new insight into structural and functional aspects of the reorganization of microtubule nucleation during myogenesis.     

Impact of Asthma on Educational Attainment in a Socioeconomically Deprived Population: A Study Linking Health,Education and Social Care Datasets

Background

Asthma has the potential to adversely affect children''s school examination performance, and hence longer term life chances. Asthma morbidity is especially high amongst UK ethnic minority children and those experiencing social adversity, populations which also have poor educational outcomes. We tested the hypothesis that asthma adversely affects performance in national school examinations in a large cohort from an area of ethnic diversity and social deprivation.

Methods and Findings

With a novel method (using patient and address-matching algorithms) we linked administrative and clinical data for 2002–2005 for children in east London aged 5–14 years to contemporaneous education and social care datasets. We modelled children''s performance in school examinations in relation to socio-demographic and clinical variables.The dataset captured examination performance for 12,136 children who sat at least one national examination at Key Stages 1–3. For illustration, estimates are presented as percentage changes in Key Stage 2 results. Having asthma was associated with a 1.1% increase in examination scores (95%CI 0.4 to 1.7)%,p = 0.02. Worse scores were associated with Bangladeshi ethnicity −1.3%(−2.5 to −0.1)%,p = 0.03; special educational need −14.6%(−15.7 to −13.5)%,p = 0.02; mental health problems −2.5%(−4.1 to −0.9)%,p = 0.003, and social adversity: living in a smoking household −1.2(−1.7 to −0.6)%,p<0.001; living in social housing −0.8%(−1.3 to −0.2)% p = 0.01, and entitlement to free school meals −0.8%(−1.5 to −0.1)%,p<0.001.

Conclusions

Social adversity and ethnicity, but not asthma, are associated with poorer performance in national school examinations. Policies to improve educational attainment in socially deprived areas should focus on these factors.     

Effect of the fluid-structure interactions on low-density lipoprotein transport within a multi-layered arterial wall

The effects of fluid-structure interactions (FSI) and pulsation on the transport of low-density lipoprotein (LDL) through an arterial wall are analyzed in this work. To this end, a comprehensive multi-layer model for both LDL transport as well as fluid-structure interaction (FSI) is introduced. The constructed model is analyzed and compared with the existing results in the limiting cases. Excellent agreement is found between the presented model and the existing results in the limiting cases. The presented model takes into account the complete multi-layered LDL transport while incorporating the FSI aspects to enable a comprehensive study of the deformation effect on the pertinent parameters of the transport processes within an artery. Since the flow inside an artery is time-dependent, the impact of pulsatile flow is also analyzed with and without FSI. A detailed analysis is presented to illustrate the consequence of different factors on the LDL transport in an artery.     

Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury

Background

Minocycline prevents the development of neuropathic and inflammatory pain by inhibiting microglial activation and postsynaptic currents. But, how minocycline obviates acute visceral pain is unclear. The present study investigated whether minocycline had an any antinociceptive effect on acetic acid-induced acute abdominal pain after intraperitoneal (i.p.) administration of saline or minocycline 1 hour before acetic acid injection (1.0%, 250 ??l, i.p.).

Results

Minocycline (4, 10, or 40 mg/kg) significantly decreased acetic acid-induced nociception (0-60 minutes post-injection) and the enhancement in the number of c-Fos positive cells in the T5-L2 spinal cord induced by acetic acid injection. Also, the expression of spinal phosphorylated extracellular signal-regulated kinase (p-ERK) induced by acetic acid was reduced by minocycline pre-administration. Interestingly, intrathecal introduction of PD98059, an ERK upstream kinase inhibitor, markedly blocked the acetic acid-stimulated pain responses.

Conclusions

These results demonstrate that minocycline effectively inhibits acetic acid-induced acute abdominal nociception via the inhibition of neuronal p-ERK expression in the spinal cord, and that minocycline may have therapeutic potential in suppressing acute abdominal pain.     

Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury

ABSTRACT: The epidermis is innervated by fine nerve endings that are important in mediating nociceptive stimuli. However, their precise role in neuropathic pain is still controversial. Here, we have studied the role of epidermal peptidergic nociceptive fibers that are located adjacent to injured fibers in a rat model of neuropathic pain. Using the Spared Nerve Injury (SNI) model, which involves complete transections of the tibial and common peroneal nerve while sparing the sural and saphenous branches, mechanical hypersensitivity was induced of the uninjured lateral (sural) and medial (saphenous) area of the foot sole. At different time points, a complete foot sole biopsy was taken from the injured paw and processed for Calcitonin Gene-Related Peptide (CGRP) immunohistochemistry. Subsequently, a novel 2D-reconstruction model depicting the density of CGRP fibers was made to evaluate the course of denervation and re-innervation by uninjured CGRP fibers. The results show an increased density of uninjured CGRP-IR epidermal fibers on the lateral and medial side after a SNI procedure at 5 and 10 weeks. Furthermore, although in control animals the density of epidermal CGRP-IR fibers in the footpads was lower compared to the surrounding skin of the foot, 10 weeks after the SNI procedure, the initially denervated footpads displayed a hyper-innervation. These data support the idea that uninjured fibers may play a considerable role in development and maintenance of neuropathic pain and that it is important to take larger biopsies to test the relationship between innervation of injured and uninjured nerve areas.