Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process

Parkinson disease (PD) is known as a common progressive neurodegenerative disease which is clinically diagnosed by the manifestation of numerous motor and nonmotor symptoms. PD is a genetically heterogeneous disorder with both familial and sporadic forms. To date, researches in the field of Parkinsonism have identified 23 genes or loci linked to rare monogenic familial forms of PD with Mendelian inheritance. Biochemical studies revealed that the products of these genes usually play key roles in the proper protein and mitochondrial quality control processes, as well as synaptic transmission and vesicular recycling pathways within neurons. Despite this, large number of patients affected with PD typically tends to show sporadic forms of disease with lack of a clear family history. Recent genome-wide association studies (GWAS) meta-analyses on the large sporadic PD case–control samples from European populations have identified over 12 genetic risk factors. However, the genetic etiology that underlies pathogenesis of PD is also discussed, since it remains unidentified in 40% of all PD-affected cases. Nowadays, with the emergence of new genetic techniques, international PD genomics consortiums and public online resources such as PDGene, there are many hopes that future large-scale genetics projects provide further insights into the genetic etiology of PD and improve diagnostic accuracy and therapeutic clinical trial designs.     

Association between CASP3 polymorphisms and overall cancer risk: A meta-analysis of case-control studies

Several studies inspected the relationship between caspase-3 (CASP3) polymorphisms and the risk of several human cancers, but the findings remain controversial. We conducted a meta-analysis aiming to inspect the association between CASP3 rs1049216 T>C, rs12108497 C>T, rs4647603 G>A, rs4647602 C>A, rs6948 T>G, rs2705897 A>C, and rs113420705 G>A polymorphisms and cancer risk. Eligible studies were recognized by searching the Web of Science, PubMed, Scopus, and Google Scholar databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to quantitatively evaluate the association between each polymorphism of CASP3 and cancer risk. The rs4647603 variant significantly increased the risk of cancer in an overdominant (OR, 1.44; 95% CI, 1.03-2.01; P = 0.03; AG vs AA+GG) inheritance model. Regarding the rs4647602 variant, the findings revealed that this variant was associated with protection against cancer in homozygous codominant (OR, 0.67; 95% CI, 0.56-0.80; P < 0.00001; AA vs CC), dominant (OR, 0.84; 95% CI, 0.73-0.96; P = 0.009; AC+AA vs CC), recessive (OR, 0.70; 95% CI, 0.61-0.79; P < 0.00001; AA vs AC+CC), and allele (OR, 0.81; 95% CI, 0.75-0.88; P = 0.00001; A vs C) models. The findings suggested that the rs2705897 variant significantly decreased the risk of cancer in heterozygous codominant (OR, 0.80; 95% CI, 0.67-0.94; P = 0.009; AC vs AA), dominant (OR, 0.81; 95% CI, 0.69-0.95; P = 0.009; AC+CC vs AA), overdominant (OR, 0.80; 95% CI, 0.68-0.95; P = 0.01; AC vs CC+AA), and allele (OR, 0.85; 95% CI, 0.74-0.97; P = 0.02; C vs A) models. The results did not support an association between CASP3 rs1049216 and rs6948 polymorphisms and cancer risk. In summary, the findings of this meta-analysis support an association between CASP3 polymorphisms and cancer risk. Larger and well-designed studies are desired to evaluate these associations in detail.     

Nanoconfined polymers: modelling and simulation approaches

In this article, application of molecular simulation methods for studying molecular pictures of nanoconfined polymers is reviewed and discussed. The simulation methods, covering a range from atomistic to systematically parameterised coarse-grained models, employed in the literature to study nanoconfined polymers are reviewed and their results are compared together. The effect of polymer–surface interactions, surface curvature and surface area on the alteration of polymer structure and dynamics from the unperturbed (bulk) polymer properties are discussed. The length scales over which the surface influences the polymer structure and dynamics and the magnitude of surface effect on dynamics deceleration in the interphase are addressed in terms of different local and global chain properties.     

Trophic flexibility of Eurasian otter (Lutra lutra) in Anzali Wetland,Iran, assessed by fecal and stable isotope analysis

Aquatic Ecology - Information on the feeding habits of species is essential to develop appropriate conservation actions. This study aimed to assess spatial and temporal variation in the diet of the...     

In Silico Design of a Poly-epitope Vaccine for Urinary Tract Infection Based on Conserved Antigens by Modern Vaccinology

International Journal of Peptide Research and Therapeutics - Immunoinformatics or vaccine informatics focuses on applying computational approaches to advance vaccine research and development...     

Chemical disinfection of high-consequence transboundary animal disease viruses on nonporous surfaces

Disinfection is a critical part of the response to transboundary animal disease virus (TADV) outbreaks by inactivating viruses on fomites to help control infection. To model the inactivation of TADV on fomites, we tested selected chemicals to inactivate Foot and Mouth Disease virus (FMDV), African Swine Fever virus (ASFV), and Classical Swine Fever virus (CSFV) dried on steel and plastic surfaces. For each of these viruses, we observed a 2 to 3 log reduction of infectivity due to drying alone. We applied a modified surface disinfection method to determine the efficacy of selected disinfectants to inactivate surface-dried high-titer stocks of these three structurally different TADV. ASFV and FMDV were susceptible to sodium hypochlorite (500 and 1000 ppm, respectively) and citric acid (1%) resulting in complete disinfection. Sodium carbonate (4%), while able to reduce FMDV infectivity by greater than 4-log units, only reduced ASFV by 3 logs. Citric acid (2%) did not totally inactivate dried CSFV, suggesting it may not be completely effective for disinfection in the field. Based on these data we recommend disinfectants be formulated with a minimum of 1000 ppm sodium hypochlorite for ASFV and CSFV disinfection, and a minimum of 1% citric acid for FMDV disinfection.     

In silico analysis of six known Leishmania major antigens and in vitro evaluation of specific epitopes eliciting HLA-A2 restricted CD8 T cell response

Background

As a potent CD8⁺ T cell activator, peptide vaccine has found its way in vaccine development against intracellular infections and cancer, but not against leishmaniasis. The first step toward a peptide vaccine is epitope mapping of different proteins according to the most frequent HLA types in a population.

Methods and Findings

Six Leishmania (L.) major-related candidate antigens (CPB,CPC,LmsTI-1,TSA,LeIF and LPG-3) were screened for potential CD8⁺ T cell activating 9-mer epitopes presented by HLA-A*0201 (the most frequent HLA-A allele). Online software including SYFPEITHI, BIMAS, EpiJen, Rankpep, nHLApred, NetCTL and Multipred were used. Peptides were selected only if predicted by almost all programs, according to their predictive scores. Pan-A2 presentation of selected peptides was confirmed by NetMHCPan1.1. Selected peptides were pooled in four peptide groups and the immunogenicity was evaluated by in vitro stimulation and intracellular cytokine assay of PBMCs from HLA-A2⁺ individuals recovered from L. major. HLA-A2⁻ individuals recovered from L. major and HLA-A2⁺ healthy donors were included as control groups. Individual response of HLA-A2⁺ recovered volunteers as percent of CD8⁺/IFN-γ⁺ T cells after in vitro stimulation against peptide pools II and IV was notably higher than that of HLA-A2⁻ recovered individuals. Based on cutoff scores calculated from the response of HLA-A2⁻ recovered individuals, 31.6% and 13.3% of HLA-A2⁺ recovered persons responded above cutoff in pools II and IV, respectively. ELISpot and ELISA results confirmed flow cytometry analysis. The response of HLA-A2⁻ recovered individuals against peptide pools I and III was detected similar and even higher than HLA-A2⁺ recovered individuals.

Conclusion

Using in silico prediction we demonstrated specific response to LmsTI-1 (pool II) and LPG-3- (pool IV) related peptides specifically presented in HLA-A*0201 context. This is among the very few reports mapping L. major epitopes for human HLA types. Studies like this will speed up polytope vaccine idea towards leishmaniasis.     

A Theoretical Study of Single-Cell Electroporation in a Microchannel

Electroporation of a single cell in a microchannel was studied. The effects of electrical (e.g., strength of the electric pulse) and geometrical (e.g., microchannel height, electrode size and position) parameters on cell membrane permeabilization were investigated. The electrodes were assumed to be embedded in the walls of the microchannel; the cell was suspended between these two electrodes. By keeping the electric pulse constant, increasing the microchannel height reduces the number and the radius of the biggest nanopores, as well as the electroporated area of the cell membrane. If the width of the electrodes is bigger than the cell diameter, the transmembrane potential will be centralized and have a sinusoidal distribution around the cell if nanopores are not generated. As the width of the electrode decreases and becomes smaller than the cell diameter, the local transmembrane potential decreases; in the nonelectroporative area, the transmembrane potential distribution deviates from the sinusoidal behavior; the induced transmembrane potential also concentrates around the poles of the cell membrane (the nearest points of the cell membrane to the electrodes). During cell membrane permeabilization, the biggest nanopores are initially created at the poles and then the nanopore population expands toward the equator. The number of the created nanopores reaches its maximal value within a few microseconds; further presence of the electric pulse may not influence the number and location of the created nanopores anymore but will develop the generated nanopores. Strengthening the electric pulse intensifies the size and number of the created nanopores as well as the electroporated area on the cell membrane.     

General esterases of Bemisia tabaci (Hemiptera: Aleyrodidae) change in response to feed on cotton varieties

The esterase enzymes are a major component of insect detoxification systems and play a crucial role in hydrolyzing lots of xenobiotic compounds. Among insect, generalist herbivores can exhibit developed biochemical defences as a result of exposing to a wide range of plant chemical compounds. To overcome this ability, host plants may affect the level of hydrolases in herbivore insects feeding on. To examine this hypothesis, in the present study total esterase activity was investigated in a highly polyphagous whitefly, Bemisia tabaci, reared on six different varieties of cotton, Gossypium hirsutum. Results showed significant differences in esterase activity of B. tabaci feeding on the host plant varieties. The highest esterase activities were detected in whiteflies feeding on Sk-Tb and Siokra varieties, whereas those whiteflies that feed on Hopicala variety exhibited the least esterase activities. Our findings highlight the important role of host plants in detoxification ability of herbivore insects. The importance of these findings in biology of insect pests and their applications in integrated pest management programmes of B. tabaci have been discussed in detail.