Regulation of Glycolysis by Pdk Functions as a Metabolic Checkpoint for Cell Cycle Quiescence in Hematopoietic Stem Cells

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Highlights? LT-HSCs activate glycolysis and generate ATP in a HIF-1α-dependent manner ? Pdk overexpression in HIF-1α^Δ/Δ HSCs restored glycolysis and stem cell capacity ? Pdk2^?/?: Pdk4^?/? LT-HSCs show defective glycolysis and cell cycle quiescence ? Pdk mimetic promotes the survival and transplantation capacity of LT-HSCs     

Pharmacoinformatics and molecular docking reveal potential drug candidates against Schizophrenia to target TAAR6

Schizophrenia (SZ) is a complex disabling disorder that leads to the mental disability and afflicts 1% of the world's total population and placed in top ten medical disorders. In current work, bioinformatics analyses were carried out on Trace amine (TA)-associated receptor 6 (TAAR6) to recognize the potential drugs and compounds against SZ. Comparative modeling and threading-based approaches were utilized for the structure prediction of TAAR6. Fifty-nine predicted structures were evaluated by various model assessment techniques and final model having only eight amino acids in the outlier region and 98.5% overall quality factor was chosen for further pharmacoinformatics and molecular docking analyses. From an extensive literature review, 11 Food and Drug Administration (FDA) approved drugs were analyzed by computational techniques and Aripiprazole was found as the most effective drug against SZ by targeting TAAR6. Here, we report five novel molecules which exhibited the highest binding affinity, effective drug properties, and interestingly, observed better results than the approved selected drugs against SZ by targeting TAAR6. The docking analyses revealed that Arg-92, Trp-98, Gln-191, Thr-192, Ala-290, Cys-291, Tyr-293, and Glu-294 residues were observed as critical interacting residues in receptor-ligand interactions. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, Lipinski rule of five, highest binding affinity coupled with virtual screening (VS), and pharmacophore modeling approach illustrated that aripiprazole (−8.6 kcal/mol) and TAAR6_0094 (−9.3 kcal/mol) are potential inhibitors for targeting TAAR6. It is suggested that schizophrenic patients have to use Aripiprazole for the medication of SZ by targeting TAAR6 and develop effective therapies by utilizing scrutinized novel compound.     

High Tuberculosis Prevalence in a South African Prison: The Need for Routine Tuberculosis Screening

Background

Tuberculosis is a major health concern in prisons, particularly where HIV prevalence is high. Our objective was to determine the undiagnosed pulmonary tuberculosis (“undiagnosed tuberculosis”) prevalence in a representative sample of prisoners in a South African prison. In addition we investigated risk factors for undiagnosed tuberculosis, to explore if screening strategies could be targeted to high risk groups, and, the performance of screening tools for tuberculosis.

Methods and Findings

In this cross-sectional survey, male prisoners were screened for tuberculosis using symptoms, chest radiograph (CXR) and two spot sputum specimens for microscopy and culture. Anonymised HIV antibody testing was performed on urine specimens. The sensitivity, specificity and predictive values of symptoms and investigations were calculated, using Mycobacterium tuberculosis isolated on sputum culture as the gold standard.From September 2009 to October 2010, 1046 male prisoners were offered enrolment to the study. A total of 981 (93.8%) consented (median age was 32 years; interquartile range [IQR] 27–37 years) and were screened for tuberculosis. Among 968 not taking tuberculosis treatment and with sputum culture results, 34 (3.5%; 95% confidence interval [CI] 2.4–4.9%) were culture positive for Mycobacterium tuberculosis. HIV prevalence was 25.3% (242/957; 95% CI 22.6–28.2%). Positive HIV status (adjusted odds ratio [aOR] 2.0; 95% CI 1.0–4.2) and being an ex-smoker (aOR 2.6; 95% CI 1.2–5.9) were independently associated with undiagnosed tuberculosis. Compared to the gold standard of positive sputum culture, cough of any duration had a sensitivity of 35.3% and specificity of 79.6%. CXR was the most sensitive single screening modality (sensitivity 70.6%, specificity 92.2%). Adding CXR to cough of any duration gave a tool with sensitivity of 79.4% and specificity of 73.8%.

Conclusions

Undiagnosed tuberculosis and HIV prevalence was high in this prison, justifying routine screening for tuberculosis at entry into the prison, and intensified case finding among existing prisoners.     

Systematic analysis of protein pools, isoforms, and modifications affecting turnover and subcellular localization

In higher eukaryotes many genes encode protein isoforms whose properties and biological roles are often poorly characterized. Here we describe systematic approaches for detection of either distinct isoforms, or separate pools of the same isoform, with differential biological properties. Using information from ion intensities we have estimated protein abundance levels and using rates of change in stable isotope labeling with amino acids in cell culture isotope ratios we measured turnover rates and subcellular distribution for the HeLa cell proteome. Protein isoforms were detected using three data analysis strategies that evaluate differences between stable isotope labeling with amino acids in cell culture isotope ratios for specific groups of peptides within the total set of peptides assigned to a protein. The candidate approach compares stable isotope labeling with amino acids in cell culture isotope ratios for predicted isoform-specific peptides, with ratio values for peptides shared by all the isoforms. The rule of thirds approach compares the mean isotope ratio values for all peptides in each of three equal segments along the linear length of the protein, assessing differences between segment values. The three in a row approach compares mean isotope ratio values for each sequential group of three adjacent peptides, assessing differences with the mean value for all peptides assigned to the protein. Protein isoforms were also detected and their properties evaluated by fractionating cell extracts on one-dimensional SDS-PAGE prior to trypsin digestion and MS analysis and independently evaluating isotope ratio values for the same peptides isolated from different gel slices. The effect of protein phosphorylation on turnover rates was analyzed by comparing mean turnover values calculated for all peptides assigned to a protein, either including, or excluding, values for cognate phosphopeptides. Collectively, these experimental and analytical approaches provide a framework for expanding the functional annotation of the genome.     

Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 peptide for potential use in Alzheimer's disease

Alzheimer's disease is a growing concern in the modern world. As the currently available medications are not very promising, there is an increased need for the fabrication of newer drugs. Curcumin is a plant derived compound which has potential activities beneficial for the treatment of Alzheimer's disease. Anti-amyloid activity and anti-oxidant activity of curcumin is highly beneficial for the treatment of Alzheimer's disease. The insolubility of curcumin in water restricts its use to a great extend, which can be overcome by the synthesis of curcumin nanoparticles. In our work, we have successfully synthesized water-soluble PLGA coated- curcumin nanoparticles and characterized it using different techniques. As drug targeting to diseases of cerebral origin are difficult due to the stringency of blood-brain barrier, we have coupled the nanoparticle with Tet-1 peptide, which has the affinity to neurons and possess retrograde transportation properties. Our results suggest that curcumin encapsulated-PLGA nanoparticles are able to destroy amyloid aggregates, exhibit anti-oxidative property and are non-cytotoxic. The encapsulation of the curcumin in PLGA does not destroy its inherent properties and so, the PLGA-curcumin nanoparticles can be used as a drug with multiple functions in treating Alzheimer's disease proving it to be a potential therapeutic tool against this dreaded disease.     

Blood clot formation under flow: the importance of factor XI depends strongly on platelet count

A previously validated mathematical model of intravascular platelet deposition and tissue factor (TF)-initiated coagulation under flow is extended and used to assess the influence on thrombin production of the activation of factor XI (fXI) by thrombin and of the activation of factor IX (fIX) by fXIa. It is found that the importance of the thrombin-fXIa-fIXa feedback loop to robust thrombin production depends on the concentration of platelets in the blood near the injury. At a near-wall platelet concentration of ~250,000/μL, typical in vessels in which the shear rate is <200 s(-1), thrombin activation of fXI makes a significant difference only at low densities of exposed TF. If the near-wall platelet concentration is significantly higher than this, either because of a higher systemic platelet count or because of the redistribution of platelets toward the vessel walls at high shear rates, then thrombin activation of fXI makes a major difference even for relatively high densities of exposed TF. The model predicts that the effect of a severe fXI deficiency depends on the platelet count, and that fXI becomes more important at high platelet counts.     

Flow cytometric determination of genome size for eight commercially important fish species in China

The genome size (C value) of eight commercially important fish species in China was measured using flow cytometry. Chicken (Gallus domesticus) erythrocytes were used as reference cells. When using propidium iodide (PI) as the fluorescent dye, genome sizes were 1.09?±?0.08, 2.75?±?0.12, 1.05?±?0.05, 1.35?±?0.11, 0.99?±?0.05, 0.90?±?0.08, 0.90?±?0.07, and 0.88?±?0.07?pg for Japanese eel (Anguilla japonica), mullet (Myxocyprinus asiaticus), yellowcheek carp (Elopichthys bambusa), blunt snout bream (Megalobrama amblycephala), yellow catfish (Pelteobagrus fulvidraco), ricefield eel (Monopterus albus), mandarin fish (Siniperca chuatsi), and snakehead (Ophicephalus argus), respectively. However, genome sizes were 1.25?±?0.00, 3.08?±?0.02, 1.25?±?0.00, 1.57?±?0.01, 0.96?±?0.01, 1.00?±?0.01, 0.91?±?0.01, and 0.89?±?0.01?pg for these fishes, respectively, when 4??, 6-diamidino-2-phenylindole (DAPI) was used as the fluorescent dye. Regardless of the dye used, the more evolutionarily advanced species had a smaller genome size than those with a lower evolutionary status. For each species, we also measured the size of erythrocytes and their nucleus and evaluated the relationships between erythrocyte size, nucleus size, chromosome number, and genome size. Genome size was positively correlated with erythrocyte nucleus size and chromosome number when using PI as the fluorescent dye, but it was only correlated with erythrocyte nucleus size when DAPI was used.