Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice

Hexokinase domain containing 1, a recently discovered putative fifth hexokinase, is hypothesized to play key roles in glucose metabolism. Specifically, during pregnancy in a recent genome wide association study (GWAS), a strong correlation between HKDC1 and 2-h plasma glucose in pregnant women from different ethnic backgrounds was shown. Our earlier work also reported diminished glucose tolerance during pregnancy in our whole body HKDC1 heterozygous mice. Therefore, we hypothesized that HKDC1 plays important roles in gestational metabolism, and designed this study to assess the role of hepatic HKDC1 in whole body glucose utilization and insulin action during pregnancy. We overexpressed human HKDC1 in mouse liver by injecting a human HKDC1 adenoviral construct; whereas, for the liver-specific HKDC1 knockout model, we used AAV-Cre constructs in our HKDC1^fl/fl mice. Both groups of mice were subjected to metabolic testing before and during pregnancy on gestation day 17–18. Our results indicate that hepatic HKDC1 overexpression during pregnancy leads to improved whole-body glucose tolerance and enhanced hepatic and peripheral insulin sensitivity while hepatic HKDC1 knockout results in diminished glucose tolerance. Further, we observed reduced gluconeogenesis with hepatic HKDC1 overexpression while HKDC1 knockout led to increased gluconeogenesis. These changes were associated with significantly enhanced ketone body production in HKDC1 overexpressing mice, indicating that these mice shift their metabolic needs from glucose reliance to greater fat oxidation and ketone utilization during fasting. Taken together, our results indicate that hepatic HKDC1 contributes to whole body glucose disposal, insulin sensitivity, and aspects of nutrient balance during pregnancy.     

Improving SWATH-MS analysis by deep-learning

Data-independent acquisition (DIA) of tandem mass spectrometry spectra has emerged as a promising technology to improve coverage and quantification of proteins in complex mixtures. The success of DIA experiments is dependent on the quality of spectral libraries used for data base searching. Frequently, these libraries need to be generated by labor and time intensive data dependent acquisition (DDA) experiments. Recently, several algorithms have been published that allow the generation of theoretical libraries by an efficient prediction of retention time and intensity of the fragment ions. Sequential windowed acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) is a DIA method that can be applied at an unprecedented speed, but the fragmentation spectra suffer from a lower quality than data acquired on Orbitrap instruments. To reliably generate theoretical libraries that can be used in SWATH experiments, we developed deep-learning for SWATH analysis (dpSWATH), to improve the sensitivity and specificity of data generated by Q-TOF mass spectrometers. The theoretical library built by dpSWATH allowed us to increase the identification rate of proteins compared to traditional or library-free methods. Based on our analysis we conclude that dpSWATH is a superior prediction framework for SWATH-MS measurements than other algorithms based on Orbitrap data.     

Exogenous Nitric Oxide Delays Ripening and Maintains Postharvest Quality of Pointed Gourd During Storage

This study was aimed to assess the effect of nitric oxide (NO; 1 and 2 mM) on shelf life and quality of pointed gourd. Fruits were stored at 12 °C for 14 days with simulated ambient storage for 3 days (7 + 3 and 14 + 3) to mimic the marketing period. NO treatment significantly improved the postharvest shelf life as compared to control samples. The fruits underwent to the application of NO (2 mM) effectively maintained the chlorophyll, phenolics, antioxidant activity and membrane integrity. It suppressed weight loss, yellow color development, lignin formation, and electrolytic leakage. Activity of enzymes (PAL and LOX) was also influenced positively by NO application. Postharvest treatment of NO (2 mM) could be suggested as an eco-safe and effective technique for enhancing the shelf life without hampering quality of pointed gourd.

     

Cultivable bacteria in the supraglacial lake formed after a glacial lake outburst flood in northern Pakistan

International Microbiology - Recently, a supraglacial lake formed as a result of a glacial lake outburst flood (GLOF) in the Dook Pal Glacier. Lake debris and meltwater samples were collected from...     

Superactive analogs of the atrial natriuretic peptide (ANP)

Three analogs of the atrial natriuretic peptide ANP(105-126), lacking the N-terminal exocyclic peptide segment and containing 2-mercaptoacetic acid, 3-mercaptopropionic acid or 4-mercaptobutyric acid in place of the cysteine residue in position 105 of the peptide sequence, were synthesized by the solid-phase method. The resulting des-amino analogs showed 2 to 4 times higher diuretic/natriuretic activity than the most active natural ANP and displayed a potent hypotensive effect as well. All three analogs were relatively less potent in various in vitro bioassays and in a binding assay, indicating that their high activities in vivo may be due to resistance to enzymatic degradation and to reduced non-specific tissue adsorption. These compounds not only will serve as useful pharmacologic tools but also represent prototypes for the development of further reduced-size ANP analogs.     

Frequency of poor quality of life and predictors of health related quality of life in cirrhosis at a tertiary care hospital Pakistan

ABSTRACT: BACKGROUND: Cirrhosis produces variety of symptoms which eventually lead to a negative impact on Health Related Quality of Life (HRQOL). The general aim of this study was to evaluate the magnitude of poor HRQOL and to assess factors related with HRQOL in patients with CLD in Pakistan. FINDINGS: This was a cross sectional study conducted in gastroenterology outpatient clinics of Aga Khan University Hospital, Karachi on adult patients with cirrhosis. In this study chronic liver disease questionnaire (CLDQ) was used to assess HRQOL of these patients and CLDQ score was used as an outcome measure to determine factors related with HRQOL. 273 participants were recruited in the study; 155 (57%) were males. Mean age of participants was 49 [PLUS-MINUS SIGN] 11 years. The most common cause for cirrhosis was viral infection 247(91.5%). Mean Model for End Stage Liver Disease (MELD) score was 12.6 [PLUS-MINUS SIGN] 6.8 and 2/3 of patients 209 (76.6%) had advanced cirrhosis in Child Turcot Pugh (CTP) B or C stage. Poor HRQOL was seen in 187(69%; 95% C.I.: 63%, 74%) of the participants. Mean CLDQ score was 4.36 [PLUS-MINUS SIGN]1.1. Amongst all of the domains, fatigue domain had lower CLDQ score. Hemoglobin (beta = 0.09 [SE = 0.04]), Albumin (beta = 0.32[SE = 0.09]), Diastolic Blood Pressure (DBP) (beta = 0.01[0.005) prior history of decompensation (beta = 0.98[SE = 0.39] were significant factors associated with HRQOL in patients with liver cirrhosis. CONCLUSION: Frequency of poor health related quality of life determined by CLDQ score is high in patients with liver cirrhosis. Hemoglobin, serum albumen, prior history of decompensation (like encephalopathy and upper gastro intestinal bleed), are associated with health related quality of life.