Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer’s disease phenotype in mice

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer’s disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age–related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs

Influence of Baseline Fluctuation Cancellation on Automatic Measurement of Motor Unit Action Potential Duration

The aim of this work is to analyze the influence of a method for baseline fluctuation (BLF) cancellation for electromyographic (EMG) signals on automatic methods for measurement of the motor unit action potential (MUAP) duration. These methods include four conventional automatic methods (CAMs) and a recently published wavelet transform method (WTM). A set of 182 MUAPs from 170 EMG recordings were studied. The CAMs and the WTM were applied to the MUAPs before and after applying BLF cancellation to the recordings. A gold standard of duration marker positions (GSP) ws manually established. The accuracy of each algorithm was estimated as the dfference between its positions and the GSP. Accuracies were compared for the 5 methods and for each method before and after BLF cancellation. A significant difference between accuracy pre- and post-BLF removal was found in two CAMs; markers were closer to the GSP after BLF removal. For all MUAPs, the differences between WTM markers and the GSP were the smallest, and significant differences were not found for the WTM before and after BLF cancellation. The management of BLF is an important issue in EMG signal processing and BLF removal must be considered in extraction and analyse of MUAP waveforms. The BLF removal method improved the performance of two CAMs for MUAP duration measurement. The WTM was the most accurate and was not affected by BLF.

Simultaneous detection of Mycobacterium bovis and M. tuberculosis in an apparentlyimmunocompetent patient

Mycobacterium tuberculosis remains the main cause of human tuberculosis (TB), with an unknown proportion of cases caused by M. bovis. Here we describe a case of pulmonary TB caused by mixed infection as studied from sequential sputum sampling and isolation of M. tuberculosis and M. bovis using a reverse dot blot (RDB) assay

Genetic characterization of Mycobacterium tuberculosis in the West Bank, Palestinian Territories

BACKGROUND: The World Health Organization (WHO) declared human tuberculosis (TB) a global health emergency and launched the “Global Plan to Stop Tuberculosis” which aims to save a million lives by 2015. Global control of TB is increasingly dependent on rapid and accurate genetic typing of species of the Mycobacterium tuberculosis (MTB) complex including M. tuberculosis. The aim of this study was to identify and genetically characterize the MTB isolates circulating in the West Bank, Palestinian Territories. Genotyping of the MTB isolates from patients with pulmonary TB was carried out using two molecular genetic techniques, spoligotyping and mycobacterial interspersed repetitive units-variable number of tandem repeat (MIRU-VNTR) supported by analysis of the MTB specific deletion 1 (TbD1). FINDINGS: A total of 17 MTB patterns were obtained from the 31 clinical isolates analyzed by spoligotyping; corresponding to 2 orphans and 15 shared-types (SITs). Fourteen SITs matched a preexisting shared-type in the SITVIT2 database, whereas a single shared-type SIT3348 was newly created. The most common spoligotyping profile was SIT53 (T1 variant), identified in 35.5 % of the TB cases studied. Genetic characterization of 22 clinical isolates via the 15 loci MIRU-VNTR typing distinguished 19 patterns. The 15-loci MIT144 and MIT145 were newly created within this study. Both methods determined the present of M. bovis strains among the isolates. CONCLUSIONS: Significant diversity among the MTB isolates circulating in the West Bank was identified with SIT53-T1 genotype being the most frequent strain. Our results are used as reference database of the strains circulating in our region and may facilitate the implementation of an efficient TB control program

Mitochondrial Phylogeography Illuminates the Origin of the Extinct Caspian Tiger and Its Relationship to the Amur Tiger

The Caspian tiger (Panthera tigris virgata) flourished in Central Asian riverine forest systems in a range disjunct from that of other tigers, but was driven to extinction in 1970 prior to a modern molecular evaluation. For over a century naturalists puzzled over the taxonomic validity, placement, and biogeographic origin of this enigmatic animal. Using ancient-DNA (aDNA) methodology, we generated composite mtDNA haplotypes from twenty wild Caspian tigers from throughout their historic range sampled from museum collections. We found that Caspian tigers carry a major mtDNA haplotype differing by only a single nucleotide from the monomorphic haplotype found across all contemporary Amur tigers (P. t. altaica). Phylogeographic analysis with extant tiger subspecies suggests that less than 10,000 years ago the Caspian/Amur tiger ancestor colonized Central Asia via the Gansu Corridor (Silk Road) from eastern China then subsequently traversed Siberia eastward to establish the Amur tiger in the Russian Far East. The conservation implications of these findings are far reaching, as the observed genetic depletion characteristic of modern Amur tigers likely reflects these founder migrations and therefore predates human influence. Also, due to their evolutionary propinquity, living Amur tigers offer an appropriate genetic source should reintroductions to the former range of the Caspian tiger be implemented

Helium beam shadowing for high spatial resolution patterning of antibodies on microstructured diagnostic surfaces

We have developed a technique for the high-resolution, self-aligning, and high-throughput patterning of antibody binding functionality on surfaces by selectively changing the reactivity of protein-coated surfaces in specific regions of a workpiece with a beam of energetic helium particles. The exposed areas are passivated with bovine serum albumin (BSA) and no longer bind the antigen. We demonstrate that patterns can be formed (1) by using a stencil mask with etched openings that forms a patterned exposure, or (2) by using angled exposure to cast shadows of existing raised microstructures on the surface to form self-aligned patterns. We demonstrate the efficacy of this process through the patterning of anti-lysozyme, anti-Norwalk virus, and anti-Escherichia coli antibodies and the subsequent detection of each of their targets by the enzyme-mediated formation of colored or silver deposits, and also by binding of gold nanoparticles. The process allows for the patterning of three-dimensional structures by inclining the sample relative to the beam so that the shadowed regions remain unaltered. We demonstrate that the resolution of the patterning process is of the order of hundreds of nanometers, and that the approach is well-suited for high throughput patterning

Evolutionary changes in the genome of Mycobacterium tuberculosis and the human genome from 9000 years BP until modern times

The demonstration of Mycobacterium tuberculosis DNA in ancient skeletons gives researchers an insight into its evolution. Findings of the last two decades sketched the biological relationships between the various species of tubercle bacilli, the time scale involved, their possible origin and dispersal. This paper includes the available evidence and on-going research. In the submerged Eastern Mediterranean Neolithic village of Atlit Yam (9000 BP), a human lineage of M. tuberculosis, defined by the TbD1 deletion in its genome, was demonstrated. An infected infant at the site provides an example of active tuberculosis in a human with a naïve immune system. Over 4000 years later tuberculosis was found in Jericho. Urbanization increases population density encouraging M. tuberculosis/human co-evolution. As susceptible humans die of tuberculosis, survivors develop genetic resistance to disease. Thus in 18th century Hungarian mummies from V ac, 65% were positive for tuberculosis yet a 95-year-old woman had clearly survived a childhood Ghon lesion. Whole genome studies are in progress, to detect changes over the millennia both in bacterial virulence and also host susceptibility/resistance genes that determine the NRAMP protein and Killer Cell Immunoglobulin-like Receptors (KIRs). This paper surveys present evidence and includes initial findings.The contribution made by our many collaborators, researchers and students is gratefully acknowledged. Special acknowledgement is due to Dr Angela Gernaey (deceased) who helped pioneer the early mycolic acid work on the bison bone

Sliding window averaging in normal and pathological motor unit action potential trains

Objective: To evaluate the performance of a recently proposed motor unit action potential (MUAP) averaging method based on a sliding window, and compare it with relevant published methods in normal and pathological muscles. Methods: Three versions of the method (with different window lengths) were compared to three relevant published methods in terms of signal analysis-based merit figures and MUAP waveform parameters used in the clinical practice. 218 MUAP trains recorded from normal, myopathic, subacute neurogenic and chronic neurogenic muscles were analysed. Percentage scores of the cases in which the methods obtained the best performance or a performance not significantly worse than the best were computed. Results: For signal processing figures of merit, the three versions of the new method performed better (with scores of 100, 86.6 and 66.7%) than the other three methods (66.7, 25 and 0%, respectively). In terms of MUAP waveform parameters, the new method also performed better (100, 95.8 and 91.7%) than the other methods (83.3, 37.5 and 25%). Conclusions: For the types of normal and pathological muscle studied, the sliding window approach extracted more accurate and reliable MUAP curves than other existing methods. Significance: The new method can be of service in quantitative EMG