Global Gene Expression Analysis Reveals a Link between NDRG1 and Vesicle Transport

N-myc downstream-regulated gene 1 (NDRG1) is induced by cellular stress such as hypoxia and DNA damage, and in humans, germ line mutations cause Charcot-Marie-Tooth disease. However, the cellular roles of NDRG1 are not fully understood. Previously, NDRG1 was shown to mediate doxorubicin resistance under hypoxia, suggesting a role for NDRG1 in cell survival under these conditions. We found decreased apoptosis in doxorubicin-treated cells expressing NDRG1 shRNAs under normoxia, demonstrating a requirement for NDRG1 in apoptosis in breast epithelial cells under normal oxygen pressure. Also, different cellular stress regimens, such as hypoxia and doxorubicin treatment, induced NDRG1 through different stress signalling pathways. We further compared expression profiles in human breast epithelial cells ectopically over-expressing NDRG1 with cells expressing NDRG1 shRNAs in order to identify biological pathways where NDRG1 is involved. The results suggest that NDRG1 may have roles connected to vesicle transport.     

Increased exercise capacity after surgically induced weight loss in morbid obesity

Objective: To investigate the effects of surgically induced weight loss on exercise capacity in patients with morbid obesity (MO). Research Methods and Procedures: A prospective 1‐year follow‐up study was carried out, with patients being their own controls. A symptom‐limited cardiopulmonary exercise stress test was performed in 31 MO patients (BMI > 40 kg/m²) before and 1 year after undergoing bariatric surgery. Results: At 1 year after surgery, weight was reduced from 146 ± 33 to 95 ± 19 kg (p < 0.001), and BMI went from 51 ± 4 to 33 ± 6 kg/m² (p < 0.001). After weight loss, obese patients performed each workload with lower oxygen consumption, heart rate, systolic arterial pressure, and ventilatory volume (p < 0.001). This reduced energy expenditure allowed them to increase the duration of their effort test from 13.8 ± 3.8 to 21 ± 4.2 minutes (p < 0.001). Upon finishing the exercise, MO patients before surgery were able to reach only 83% of their age‐predicted maximal heart rate, and their respiratory exchange ratio was 0.87 ± 0.06. After weight loss, those values were 90% and 1 ± 0.08, respectively (p < 0.01). When we compared the peak O₂ pulse corrected by fat free mass before and after surgery, no significant differences between the groups were found. Discussion: After surgically induced weight loss, MO patients markedly improved their exercise capacity. This is due to the fact that they were able to perform the external work with lower energy expenditure and also to increase cardiovascular stress, optimizing the use of cardiac reserve. There were no differences in cardiac function before and after surgery.     

The AP-1/CJUN signaling cascade is involved in muscle differentiation: implications in muscle wasting during cancer cachexia

The aim of the present study was to investigate a possible role of the AP-1 signaling cascade in the process of wasting associated with cancer cachexia at the level of skeletal muscle. The injection of virus containing the TAM67 protein (a blocker of the AP-1 protein) to the gastrocnemius muscle of tumour-bearing rats resulted in a significant recovery of the muscle mass (which is dramatically reduced as a result of tumour burden), therefore suggesting that AP-1 is certainly involved in the signaling associated with muscle protein accretion. In conclusion, the gene therapy approach presented here clearly suggests an important role for AP-1 in muscle signaling during catabolic states.     

Neuregulins mediate calcium-induced glucose transport during muscle contraction

Neuregulin, a growth factor involved in myogenesis, has rapid effects on muscle metabolism. In a manner analogous to insulin and exercise, neuregulins stimulate glucose transport through recruitment of glucose transporters to surface membranes in skeletal muscle. Like muscle contraction, neuregulins have additive effects with insulin on glucose uptake. Therefore, we examined whether neuregulins are involved in the mechanism by which muscle contraction regulates glucose transport. We show that caffeine-induced increases in cytosolic Ca2+ mediate a metalloproteinase-dependent release of neuregulins, which stimulates tyrosine phosphorylation of ErbB4 receptors. Activation of ErbB4 is necessary for Ca2+-derived effects on glucose transport. Furthermore, blockage of ErbB4 abruptly impairs contraction-induced glucose uptake in slow twitch muscle fibers, and to a lesser extent, in fast twitch muscle fibers. In conclusion, we provide evidence that contraction-induced activation of neuregulin receptors is necessary for the stimulation of glucose transport and a key element of energetic metabolism during muscle contraction.     

Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites

Background  

The apicomplexan parasite Plasmodium falciparum causes the most severe form of malaria in humans. After invasion into erythrocytes, asexual parasite stages drastically alter their host cell and export remodeling and virulence proteins. Previously, we have reported identification and functional analysis of a short motif necessary for export of proteins out of the parasite and into the red blood cell.     

Detailed architecture of a DNA translocating machine: the high-resolution structure of the bacteriophage phi29 connector particle.

The three-dimensional crystal structure of the bacteriophage phi29 connector has been solved and refined to 2.1A resolution. This 422 kDa oligomeric protein connects the head of the phage to its tail and translocates the DNA into the prohead during packaging. Each monomer has an elongated shape and is composed of a central, mainly alpha-helical domain that includes a three-helix bundle, a distal alpha/beta domain and a proximal six-stranded SH3-like domain. The protomers assemble into a 12-mer, propeller-like, super-structure with a 35 A wide central channel. The surface of the channel is mainly electronegative, but it includes two lysine rings 20 A apart. On the external surface of the particle a hydrophobic belt extends to the concave area below the SH3-like domain, which forms a crown that retains the particle in the head. The lipophilic belt contacts the non-matching symmetry vertex of the capsid and forms a bearing for the connector rotation. The structure suggests a translocation mechanism in which the longitudinal displacement of the DNA along its axis is coupled to connector spinning.