HIF1/2-exerted control over glycolytic gene expression is not functionally relevant for glycolysis in human leukemic stem/progenitor cells

Background Hypoxia-inducible factors (HIF)1 and 2 are transcription factors that regulate the homeostatic response to low oxygen conditions. Since data related to the importance of HIF1 and 2 in hematopoietic stem and progenitors is conflicting, we investigated the chromatin binding profiles of HIF1 and HIF2 and linked that to transcriptional networks and the cellular metabolic state. Methods Genome-wide ChIPseq and ChIP-PCR experiments were performed to identify HIF1 and HIF2 binding sites in human acute myeloid leukemia (AML) cells and healthy CD34(+) hematopoietic stem/progenitor cells. Transcriptome studies were performed to identify gene expression changes induced by hypoxia or by overexpression of oxygen-insensitive HIF1 and HIF2 mutants. Metabolism studies were performed by 1D-NMR, and glucose consumption and lactate production levels were determined by spectrophotometric enzyme assays. CRISPR-CAS9-mediated HIF1, HIF2, and ARNT(-/-) lines were generated to study the functional consequences upon loss of HIF signaling, in vitro and in vivo upon transplantation of knockout lines in xenograft mice. Results Genome-wide ChIP-seq and transcriptome studies revealed that overlapping HIF1- and HIF2-controlled loci were highly enriched for various processes including metabolism, particularly glucose metabolism, but also for chromatin organization, cellular response to stress and G protein-coupled receptor signaling. ChIP-qPCR validation studies confirmed that glycolysis-related genes but not genes related to the TCA cycle or glutaminolysis were controlled by both HIF1 and HIF2 in leukemic cell lines and primary AMLs, while in healthy human CD34(+) cells these loci were predominantly controlled by HIF1 and not HIF2. However, and in contrast to our initial hypotheses, CRISPR/Cas9-mediated knockout of HIF signaling did not affect growth, internal metabolite concentrations, glucose consumption or lactate production under hypoxia, not even in vivo upon transplantation of knockout cells into xenograft mice. Conclusion These data indicate that, while HIFs exert control over glycolysis but not OxPHOS gene expression in human leukemic cells, this is not critically important for their metabolic state. In contrast, inhibition of BCR-ABL did impact on glucose consumption and lactate production regardless of the presence of HIFs. These data indicate that oncogene-mediated control over glycolysis can occur independently of hypoxic signaling modules.</p

Assessment of the requisites of microbiology based infectious disease training under the pressure of consultation needs

<p>Abstract</p> <p>Background</p> <p>Training of infectious disease (ID) specialists is structured on classical clinical microbiology training in Turkey and ID specialists work as clinical microbiologists at the same time. Hence, this study aimed to determine the clinical skills and knowledge required by clinical microbiologists.</p> <p>Methods</p> <p>A cross-sectional study was carried out between June 1, 2010 and September 15, 2010 in 32 ID departments in Turkey. Only patients hospitalized and followed up in the ID departments between January-June 2010 who required consultation with other disciplines were included.</p> <p>Results</p> <p>A total of 605 patients undergoing 1343 consultations were included, with pulmonology, neurology, cardiology, gastroenterology, nephrology, dermatology, haematology, and endocrinology being the most frequent consultation specialties. The consultation patterns were quite similar and were not affected by either the nature of infections or the critical clinical status of ID patients.</p> <p>Conclusions</p> <p>The results of our study show that certain internal medicine subdisciplines such as pulmonology, neurology and dermatology appear to be the principal clinical requisites in the training of ID specialists, rather than internal medicine as a whole.</p

Flame retardant effect of aluminum phytate in huntite–hydromagnesite filled plasticized poly(lactic acid) compounds

In the current study, aluminum phytate (AlPt) is used with huntite–hydromagnesite (HH) in plasticized poly(lactic acid) (PLA) in order to improve the fire-retardant performance of the composite. The flame retardant, thermal, and mechanical properties of the composites are investigated using the limiting oxygen index (LOI), horizontal and vertical burning test (UL-94), mass loss calorimeter, thermogravimetric analysis, tensile, and impact tests. According to the test results, the fire-retardant performance of the composite was improved when HH and AlPt were used together. The highest LOI value (33.8) and UL-94 rating of V0 were achieved with the addition of 5 mass% AlPt in the presence of 55 mass% HH. Further, the addition of AlPt did not change the flammability properties. AlPt showed its adjuvant effect predominantly in the condensed phase via improved char formation with enhanced barrier properties. Tensile and impact strength reduced as the added amount of AlPt increased due to the hydrolytic degradation of PLA during the extrusion process

Production and Characterization of Green Flame Retardant Poly(lactic acid) Composites

In the current study, huntite hydromagnesite (HH) was used as flame retardant additive in poly (lactic acid) (PLA) to produce green flame retardant composites. The effects of HH amount, particle size and surface modifications on the flame retardant, thermal and mechanical properties were investigated. The properties of the composites were investigated using limiting oxygen index (LOI), horizontal and vertical burning test (UL 94), mass loss calorimeter, thermogravimetric analysis, tensile test, impact test and dynamic mechanical analysis. According to results, the flame retardant PLA composites with different UL-94 ratings (HB, V2, V0) were produced. The LOI value increased as the added amount of HH increased. The highest LOI value of 34.2 was achieved with the addition of 60 wt% HH. Surface modifications had no remarkable effect on the flammability properties of the composites. The addition of HH reduced the tensile and impact strengths and improved the elastic modulus of the composites as the added amount of HH increased. The addition of HH with large particle size deteriorated the flammability properties and tensile strength despite of the increase in impact strength. Surface modifications improved the mechanical properties of the composites due to the improvement in interfacial adhesion between HH and PLA

Potential Use of Melamine Phytate as a Flame-Retardant Additive in Chicken Feather-Containing Thermoplastic Polyurethane Biocomposites

Using waste materials such as chicken feathers (CF) and biobased flame-retardant additives including melamine phytate (MPht) has become an effective approach for environmentally friendly and sustainable production in recent years. This study explores the flame retardant effectiveness of MPht in thermoplastic polyurethane (TPU)-based biocomposites containing CF. The characterizations of the composites are performed through thermal gravimetric analysis (TGA), limiting oxygen index (LOI), vertical UL-94 (UL-94 V), and mass loss calorimetry (MLC) tests. According to the test results, the highest UL-94 V rating of V0, a LOI value of 29.4%, and the lowest peak heat release rate (pHRR) (110 Kw/m2) and total heat evolved (THE) (39 MJ/m2) values are obtained with the use of 20 wt % MPht. It is demonstrated that MPht acts as an effective flame-retardant filler through the formation of intumescent char in the condensed phase and flame dilution in the gas phase

The relation between thrombus burden and early mortality risk in inpatients diagnosed with COVID-19-related acute pulmonary embolism: a retrospective cohort study

Abstract Background COVID-19-related acute pulmonary thromboembolism (APE) is associated with poor outcomes in patients with COVID-19. There are studies investigating the association between thrombus burden and high risk of early mortality in the pre-COVID-19 period. This study aimed to evaluate the relationship between clot burden and early mortality risk in COVID-19-related APE patients. Methods In this single-center retrospective cohort study, the data of hospitalized adult patients followed up for COVID-19-related APE between April 1, 2020, and April 1, 2021, were electronically collected. A radiologist evaluated the computed tomography (CT) findings and calculated the Mastora scores to determine clot burden. The early mortality risk group of each patient was determined using 2019 the European Society of Cardiology guidelines. Results Of the 87 patients included in the study, 58 (66.7%) were male, and the mean age was 62.5±16.2 years. There were 53 (60.9%) patients with a low risk of mortality, 18 (20.7%) with an intermediate-low risk, and 16(18.4%) with an intermediate-high/high risk. The median total simplified Mastora scores were 11.0, 18.5, and 31.5 in the low, the intermediate-low, and the intermediate-high/high-risk groups, respectively (p = 0.002). With the 80.61% of post-hoc power of the study, intermediate-high/high early mortality risk was associated statistically significantly with the total simplified Mastora score (adj OR = 1.06, 95%CI = 1.02–1.11,p = 0.009). Total simplified Mastora score was found to predict intermediate-high/high early mortality risk with a probability of 0.740 (95% CI = 0.603–0.877): At the optimal cut-off value of 18.5, it had 75.0% sensitivity, 66.2% specificity, 33.3% positive predictive value, and 92.2% negative predictive value. Conclusions The total simplified Mastora score was found to be positively associated with early mortality risk and could be useful as decision support for the risk assessment in hospitalized COVID-19 patients. Evaluation of thrombus burden on CT angiography performed for diagnostic purposes can accelerate the decision of close monitoring and thrombolytic treatment of patients with moderate/high risk of early mortality