Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery

Associations between preschool attendance and developmental impairments in pre-school children in a six-year retrospective survey

BACKGROUND: Many school-aged children suffer physical and mental impairments which can adversely affect their development and result in significant morbidity. A high proportion of children in western countries attend pre-school, and it is likely that the preschool environment influences the prevalence and severity of these impairments. Currently there is insufficient data available on the prevalence of these impairments and their causal associations. The influence that location of a pre-school and the duration of preschool attendance have on the prevalence of these impairments is not known. METHODS: In a retrospective survey spanning six years (1997–2002) we reviewed the records of 6,230 preschool children who had undergone routine school entry assessments. These children had been assessed utilising a modified manual of the "Bavarian Model" for school entry examinations. This model outlines specific criteria for impairments of motor, cognitive, behavioural and psychosocial functioning. Prevalence rates for physical and behavioural impairments were based on the results of these assessments. The relationship between the prevalence of impairments and the duration of preschool attendance and the location of the preschool attended was estimated utilizing logistic regression models. RESULTS: We found that 20.7% of children met the criteria for at least one type of impairment. Highest prevalence rates (11.5%) were seen for speech impairments and lowest (3.5%) for arithmetic impairments. Boys were disproportionately over represented, with 25.5% meeting the criteria for impairment, compared to 13.0% for girls. Children who had attended preschool for less than one year demonstrated higher rates of impairment (up to 19.1% for difficulties with memory, concentration or perseverance) compared to those who had attended for a longer duration (up to 11.6% for difficulties with pronouncation). Children attending preschool in an urban location had slightly elevated rates of impairment (up to 12.7%), compared to their rural counterparts (up to 11.1%). CONCLUSION: Our results demonstrate that there are high prevalence rates for physical and mental impairments among preschool children. Furthermore, children without preschool experience are a risk group for struggling with educational successes. The associations between the duration of preschool attendance and location of preschool attended and rates of impairment need replication and further exploration. Larger prospective studies are needed to examine if these relationships are causal and may therefore lend themselves to specific intervention strategies

Different Effect of Proteasome Inhibition on Vesicular Stomatitis Virus and Poliovirus Replication

Proteasome activity is an important part of viral replication. In this study, we examined the effect of proteasome inhibitors on the replication of vesicular stomatitis virus (VSV) and poliovirus. We found that the proteasome inhibitors significantly suppressed VSV protein synthesis, virus accumulation, and protected infected cells from toxic effect of VSV replication. In contrast, poliovirus replication was delayed, but not diminished in the presence of the proteasome inhibitors MG132 and Bortezomib. We also found that inhibition of proteasomes stimulated stress-related processes, such as accumulation of chaperone hsp70, phosphorylation of eIF2α, and overall inhibition of translation. VSV replication was sensitive to this stress with significant decline in replication process. Poliovirus growth was less sensitive with only delay in replication. Inhibition of proteasome activity suppressed cellular and VSV protein synthesis, but did not reduce poliovirus protein synthesis. Protein kinase GCN2 supported the ability of proteasome inhibitors to attenuate general translation and to suppress VSV replication. We propose that different mechanisms of translational initiation by VSV and poliovirus determine their sensitivity to stress induced by the inhibition of proteasomes. To our knowledge, this is the first study that connects the effect of stress induced by proteasome inhibition with the efficiency of viral infection

Spectroscopic ellipsometry and polarimetry for materials and systems analysis at the nanometer scale: state-of-the-art, potential, and perspectives

This paper discusses the fundamentals, applications, potential, limitations, and future perspectives of polarized light reflection techniques for the characterization of materials and related systems and devices at the nanoscale. These techniques include spectroscopic ellipsometry, polarimetry, and reflectance anisotropy. We give an overview of the various ellipsometry strategies for the measurement and analysis of nanometric films, metal nanoparticles and nanowires, semiconductor nanocrystals, and submicron periodic structures. We show that ellipsometry is capable of more than the determination of thickness and optical properties, and it can be exploited to gain information about process control, geometry factors, anisotropy, defects, and quantum confinement effects of nanostructures

HLA-C and HIV-1: friends or foes?

The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins

Accelerating Neutron Tomography experiments through Artificial Neural Network based reconstruction

Neutron Tomography (NT) is a non-destructive technique to investigate the inner structure of a wide range of objects and, in some cases, provides valuable results in comparison to the more common X-ray imaging techniques. However, NT is time consuming and scanning a set of similar objects during a beamtime leads to data redundancy and long acquisition times. Nowadays NT is unfeasible for quality checking study of large quantities of similar objects. One way to decrease the total scan time is to reduce the number of projections. Analytical reconstruction methods are very fast but under this condition generate streaking artifacts in the reconstructed images. Iterative algorithms generally provide better reconstruction for limited data problems, but at the expense of longer reconstruction time. In this study, we propose the recently introduced Neural Network Filtered Back-Projection (NN-FBP) method to optimize the time usage in NT experiments. Simulated and real neutron data were used to assess the performance of the NN-FBP method as a function of the number of projections. For the first time a machine learning based algorithm is applied and tested for NT image reconstruction problem. We demonstrate that the NN-FBP method can reliably reduce acquisition and reconstruction times and it outperforms conventional reconstruction methods used in NT, providing high image quality for limited datasets

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology