Differential effects of UCHL1 modulation on alpha-synuclein in PD-like models of alpha-synucleinopathy

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Abnormal accumulation and aggregation of alpha-synuclein (a-syn) within neurons, and mutations in the a-syn and UCH-L1 genes have been shown to play a role in the pathogenesis of PD. In light of recent reports suggesting an interaction between a-synuclein and UCH-L1, we investigated the effects of UCH-L1 inhibition on a-syn distribution and expression levels in primary neurons and hippocampal tissues derived from non transgenic (non tg) and a-syn over expressing tg mice. We show that suppression of UCH-L1 activity increased a-syn levels in control, non tg neurons, and resulted in a concomitant accumulation of presynaptic a-syn in these neurons. In contrast, blocking UCH-L1 activity in a-syn over expressing neurons decreased a-syn levels, and enhanced its synaptic clearance. In vitro studies verified the LDN-induced inhibition of UCH-L1 had minimal effect on LC3 (a marker of autophagy) in control cells, in cells over expressing a-syn UCH-L1 inhibition resulted in increased LC3 activity. These findings suggest a possible differential role of UCH-L1 function under normal and pathological conditions. Furthermore, in the context of a-syn-induced pathology, modulation of UCH-L1 activity could serve as a therapeutic tool to enhance the autophagy pathway and induce clearance of the observed accumulated/aggregated a-syn species in the PD brain.     

Phylogenetic diversity and mutational analysis of New Delhi Metallo-β-lactamase (NDM) producing E. coli strains from pediatric patients in Pakistan

The evolution of NDM genes (bla_NDM) in E. coli is accounted for expansive multidrug resistance (MDR), causing severe infections and morbidities in the pediatric population. This study aimed to analyze the phylogeny and mutations in NDM variants of E. coli recovered from the pediatric population. Carbapenem-resistant clinical strains of E. coli were identified using microbiological phenotypic techniques. PCR technique used to amplify the bla_NDM genes, identified on agarose gel, and analyzed by DNA sequencing. The amino acid substitutions were examined for mutations after aligning with wild types. Mutational and phylogenetic analysis was performed using Lasergene, NCBI blastn, Clustal Omega, and MEGA software, whereas PHYRE2 software was used for the protein structure predictions. PCR amplification of the bla_NDM genes detected 113 clinical strains of E. coli with the contribution of bla_NDM-1 (46%), bla_NDM-4 (3.5%), and bla_NDM-5 (50%) variants. DNA sequencing of bla_NDM variants showed homology to the previously described bla_NDM-1, bla_NDM-4, and bla_NDM-5 genes available at GenBank and NCBI database. In addition, the mutational analysis revealed in frame substitutions of Pro60Ala and Pro59Ala in bla_NDM-4 and bla_NDM-5, respectively. The bla_NDM-1 was ortholog with related sequences of E. coli available at GenBank. The phylogenetic analysis indicated that the NDM gene variants resemble other microbes reported globally with some new mutational sites.     

On Three-Dimensional Flow and Heat Transfer over a Non-Linearly Stretching Sheet: Analytical and Numerical Solutions

This article studies the viscous flow and heat transfer over a plane horizontal surface stretched non-linearly in two lateral directions. Appropriate wall conditions characterizing the non-linear variation in the velocity and temperature of the sheet are employed for the first time. A new set of similarity variables is introduced to reduce the boundary layer equations into self-similar forms. The velocity and temperature distributions are determined by two methods, namely (i) optimal homotopy analysis method (OHAM) and (ii) fourth-fifth-order Runge-Kutta integration based shooting technique. The analytic and numerical solutions are compared and these are found in excellent agreement. Influences of embedded parameters on momentum and thermal boundary layers are sketched and discussed.     

Differences in Reporting of Violence and Deliberate Self Harm Related Injuries to Health and Police Authorities,Rawalpindi, Pakistan

Background

The aim of study was to assess differences in reporting of violence and deliberate self harm (DSH) related injuries to police and emergency department (ED) in an urban town of Pakistan.

Methods/Principal Findings

Study setting was Rawalpindi city of 1.6 million inhabitants. Incidences of violence and DSH related injuries and deaths were estimated from record linkage of police and ED data. These were then compared to reported figures in both datasets. All persons reporting violence and DSH related injury to the police station, the public hospital''s ED, or both in Rawalpindi city from July 1, 2007 to June 30, 2008 were included. In Rawalpindi city, 1 016 intentional injury victims reported to police whereas 3 012 reported to ED. Comparing violence related fatality estimates (N = 56, 95% CI: 46–64), police reported 75.0% and ED reported 42.8% of them. Comparing violence related injury estimates (N = 7 990, 95% CI: 7 322–8 565), police reported 12.1% and ED reported 33.2% of them. Comparing DSH related fatality estimates (N = 17, 95% CI: 4–30), police reported 17.7% and ED reported 47.1% of them. Comparing DSH related injury estimates (N = 809, 95% CI: 101–1 516), police reported 0.5% and ED reported 39.9% of them.

Conclusion

In Rawalpindi city, police records were more likely to be complete for violence related deaths as compared to injuries due to same mechanism. As compared to ED, police reported DSH related injuries and deaths far less than those due to other types of violence.     

A unified framework for the restoration of Southeast Asian mangroves—bridging ecology, society and economics

The effect of intensive human intervention, poor socio-economic conditions and little knowledge on mangrove ecology pose enormous challenges for mangrove restoration in Southeast Asia. We present a framework for tropical mangrove restoration. Our proposed restoration framework addresses the ecology, economy and social issues simultaneously by considering the causes of mangrove degradation. We provide a step by step guideline for its restoration. We argue that although, ecological issues are of prime importance, economic and social issues must be considered in the restoration plan in order for it to be successful. Since mangrove ecology is not adequately studied in this region, local ecological knowledge can be used to fill the baseline information gaps. Unwanted human disturbance can be minimized by encouraging community participation. This can be ensured and sustained by facilitating the livelihood of the coastal community. We translated the restoration paradigm into a readily available practical guideline for the executors of the plans. We provide an example of mangrove restoration project that is closely related to our proposed framework. We are optimistic that this framework has the potential for universal application with necessary adjustments.     

A new tool for prioritization of sequence variants from whole exome sequencing data

Background

Whole exome sequencing (WES) has provided a means for researchers to gain access to a highly enriched subset of the human genome in which to search for variants that are likely to be pathogenic and possibly provide important insights into disease mechanisms. In developing countries, bioinformatics capacity and expertise is severely limited and wet bench scientists are required to take on the challenging task of understanding and implementing the barrage of bioinformatics tools that are available to them.

Results

We designed a novel method for the filtration of WES data called TAPER? (Tool for Automated selection and Prioritization for Efficient Retrieval of sequence variants).

Conclusions

TAPER? implements a set of logical steps by which to prioritize candidate variants that could be associated with disease and this is aimed for implementation in biomedical laboratories with limited bioinformatics capacity. TAPER? is free, can be setup on a Windows operating system (from Windows 7 and above) and does not require any programming knowledge. In summary, we have developed a freely available tool that simplifies variant prioritization from WES data in order to facilitate discovery of disease-causing genes.

     

Recent advances in production of succinic acid from lignocellulosic biomass

Production of succinic acid via separate enzymatic hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF) are alternatives and are environmentally friendly processes. These processes have attained considerable positions in the industry with their own share of challenges and problems. The high-value succinic acid is extensively used in chemical, food, pharmaceutical, leather and textile industries and can be efficiently produced via several methods. Previously, succinic acid production via chemical synthesis from petrochemical or refined sugar has been the focus of interest of most reviewers. However, these expensive substrates have been recently replaced by alternative sustainable raw materials such as lignocellulosic biomass, which is cheap and abundantly available. Thus, this review focuses on succinic acid production utilizing lignocellulosic material as a potential substrate for SSF and SHF. SSF is an economical single-step process which can be a substitute for SHF — a two-step process where biomass is hydrolyzed in the first step and fermented in the second step. SSF of lignocellulosic biomass under optimum temperature and pH conditions results in the controlled release of sugar and simultaneous conversion into succinic acid by specific microorganisms, reducing reaction time and costs and increasing productivity. In addition, main process parameters which influence SHF and SSF processes such as batch and fed-batch fermentation conditions using different microbial strains are discussed in detail.     

Pediatricians’ Own Weight: Self‐perception,Misclassification, and Ease of Counseling

Objectives: Pediatricians underdiagnose overweight and feel ineffective at counseling. Given the relationship between physicians’ health and health habits and counseling behaviors, we sought to determine the 1) percentage of pediatricians who are overweight; 2) accuracy of pediatricians’ own weight status classification; and 3) relationship between weight self‐perception and perceived ease of obesity counseling. Research Methods and Procedures: This study was a cross‐sectional, mail survey of North Carolina pediatricians that queried about their weight status and ease of counseling. Accuracy of pediatricians’ self‐classification of weight status was compared with BMIs derived from self‐reported height and weight. Using logistic regression, controlling for potential confounding variables, we examined the association between weight perception and ease of counseling. Results: The unadjusted response rate was 62%, and the adjusted response rate was 71% (n = 355). Nearly one‐half (49%) of overweight pediatricians did not identify themselves as such. Men had greater adjusted odds of misclassifying overweight than women [odds ratio (OR), 3.61; 95% confidence interval (CI) = 1.81, 7.21]. Self‐classified “thin” pediatricians had nearly six times the odds of reporting more counseling difficulty as a result of their weight than “average” weight pediatricians (OR = 5.69; 95% CI = 2.30, 14.1), and self‐identified “overweight” pediatricians reported nearly four times as great counseling difficulty as “average” weight physicians (OR = 3.84; 95% CI = 1.11, 13.3), after adjustment for self‐reported BMI weight status and other potential confounders. Discussion: The roles that physician weight misclassification and self‐perception potentially play in influencing rates of obesity counseling warrant further research.