Starving leukemia to induce differentiation

A new study shows that fasting induces the differentiation and elimination of some types of leukemia in mice, which implicates fasting or its mimetics as a novel strategy for the treatment of this disease

The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver

Air quality assessment along China-Pakistan economic corridor at the confluence of Himalaya-Karakoram-Hindukush

Recently, analyses of the air quality in Pakistan have received significant interest, especially regarding the impact of air pollutant concentrations on human health. The Atlas of Baseline Environmental Profiling along the China-Pakistan Economic Corridor (CPEC) at five locations in Gilgit-Baltistan (GB) is a major landmark in this regard due to the presence of massive glaciers in the region, which are considered as water reserves for the country. Using various statistical measurements, the air quality was analyzed at the studied geographic locations. Further, air quality was evaluated based on air pollutant data acquired from ambient air monitoring laboratories. For example, 24 h concentrations of particulate matter (PM2.5) were found to range from 25.4 to 60.1 µg/m3, with peaks in the winter season at Gilgit. It was found that PM2.5 values were 1.7 and 1.3 times greater than National Environmental Quality Standards (NEQS) standards only at Gilgit and Chilas, respectively, and 1.5 to 4 times greater than the World Health Organization (WHO) standards at all locations. Similarly, PM2.5 concentrations were found to range from 31.4 to 63.9 µg/m3, peaking at Chilas in summer 2020. The observed values were 1.1 to 1.8 times and 2 to 4.2 times greater than the NEQS and WHO standards, respectively, at all locations. In addition, the average peaks of black carbon (BC) were measured at Gilgit, both in winter (16.21 µg/m3) and summer (7.83 µg/m3). These elevated levels could be attributed to the use of heavy diesel vehicles, various road activities and different meteorological conditions. Pollutants such as carbon monoxide (CO), sulfur dioxide (SO2), nitrogen oxides (NOX) and ozone (O3) were found to be within NEQS and WHO limits. Based on air quality metrics, the effect of PM2.5 on air quality was found to be moderate in Sost, Hunza and Jaglot, while it was at unhealthy levels at Gilgit and Chilas in the winter of 2019; moderate levels were observed at Sost while unhealthy levels were detected at the remaining locations in the summer of 2020. There are no specific guidelines for BC. However, it is associated with PM2.5, which was found to be a major pollutant at all locations. The concentrations of CO, SO2 and O3 were found to be at safe levels at all locations. The major fraction of air masses is received either locally or from transboundary emissions. This study demonstrates that PM2.5 and BC are the major and prevailing air pollutants within the study region, while other air pollutants were found to be within the permissible limits of the WHO and NEQS

Insights into surface chemistry down to nanoscale: an accessible colour hyperspectral imaging approach for scanning electron microscopy

Chemical imaging (CI) is the spatial identification of molecular chemical composition and is critical to characterising the (in-) homogeneity of functional material surfaces. Nanoscale CI on bulk functional material surfaces is a longstanding challenge in materials science and is addressed here. We demonstrate the feasibility of surface sensitive CI in the scanning electron microscope (SEM) using colour enriched secondary electron hyperspectral imaging (CSEHI). CSEHI is a new concept in the SEM, where secondary electron emissions in up to three energy ranges are assigned to RGB (red, green, blue) image colour channels. The energy ranges are applied to a hyperspectral image volume which is collected in as little as 50 s. The energy ranges can be defined manually or automatically. Manual application requires additional information from the user as first explained and demonstrated for a lithium metal anode (LMA) material, followed by manual CSEHI for a range of materials from art history to zoology. We introduce automated CSEHI, eliminating the need for additional user information, by finding energy ranges using a non-negative matrix factorization (NNMF) based method. Automated CSEHI is evaluated threefold: (1) benchmarking to manual CSEHI on LMA; (2) tracking controlled changes to LMA surfaces; (3) comparing automated CSEHI and manual CI results published in the past to reveal nanostructures in peacock feather and spider silk. Based on the evaluation, CSEHI is well placed to differentiate/track several lithium compounds formed through a solution reaction mechanism on a LMA surface (eg. lithium carbonate, lithium hydroxide and lithium nitride). CSEHI was used to provide insights into the surface chemical distribution on the surface of samples from art history (mineral phases) to zoology (di-sulphide bridge localisation) that are hidden from existing surface analysis techniques. Hence, the CSEHI approach has the potential to impact the way materials are analysed for scientific and industrial purposes

Low Rates of Both Lipid-Lowering Therapy Use and Achievement of Low-Density Lipoprotein Cholesterol Targets in Individuals at High-Risk for Cardiovascular Disease across Europe

Aims To analyse the treatment and control of dyslipidaemia in patients at high and very high cardiovascular risk being treated for the primary prevention of cardiovascular disease (CVD) in Europe. Methods and Results Data were assessed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials.gov identifier: NCT00882336), which included a randomly sampled population of primary CVD prevention patients from 12 European countries (n = 7641). Patients’ 10-year risk of CVD-related mortality was calculated using the Systematic Coronary Risk Evaluation (SCORE) algorithm, identifying 5019 patients at high cardiovascular risk (SCORE 5% and/or receiving lipid-lowering therapy), and 2970 patients at very high cardiovascular risk (SCORE 10% or with diabetes mellitus). Among high-risk individuals, 65.3% were receiving lipid-lowering therapy, and 61.3% of treated patients had uncontrolled low-density lipoprotein cholesterol (LDL-C) levels ( 2.5 mmol/L). For very-high-risk patients (uncontrolled LDL-C levels defined as 1.8 mmol/L) these figures were 49.5% and 82.9%, respectively. Excess 10-year risk of CVD-related mortality (according to SCORE) attributable to lack of control of dyslipidaemia was estimated to be 0.72%and 1.61% among high-risk and very-high-risk patients, respectively. Among high-risk individuals with uncontrolled LDL-C levels, only 8.7% were receiving a high-intensity statin (atorvastatin 40 mg/day or rosuvastatin 20 mg/day). Among veryhigh- risk patients, this figure was 8.4%. Conclusions There is a considerable opportunity for improvement in rates of lipid-lowering therapy use and achievement of lipid-level targets in high-risk and very-high-risk patients being treated for primary CVD prevention in EuropeWriting support was provided by Oxford PharmaGenesis Ltd, Oxford, UK, and was funded by AstraZenec

A deep learning framework for joint image restoration and recognition

Image restoration and recognition are important computer vision tasks representing an inherent part of autonomous systems. These two tasks are often implemented in a sequential manner, in which the restoration process is followed by a recognition. In contrast, this paper proposes a joint framework that simultaneously performs both tasks within a shared deep neural network architecture. This joint framework integrates the restoration and recognition tasks by incorporating: i) common layers, ii) restoration layers and iii) classification layers. The total loss function combines the restoration and classification losses. The proposed joint framework, based on capsules, provides an efficient solution that can cope with challenges due to noise, image rotations and occlusions. The developed framework has been validated and evaluated on a public vehicle logo dataset under various degradation conditions, including Gaussian noise, rotation and occlusion. The results show that the joint framework improves the accuracy compared with the single task networks

Supported online self-management versus care as usual for symptoms of fatigue, pain and urgency/incontinence in adults with inflammatory bowel disease (IBD-BOOST): study protocol for a randomised controlled trial.

BACKGROUND: Despite being in clinical remission, many people with inflammatory bowel disease (IBD) live with fatigue, chronic abdominal pain and bowel urgency or incontinence that limit their quality of life. We aim to test the effectiveness of an online self-management programme (BOOST), developed using cognitive behavioural principles and a theoretically informed logic model, and delivered with facilitator support. PRIMARY RESEARCH QUESTION: In people with IBD who report symptoms of fatigue, pain or urgency and express a desire for intervention, does a facilitator-supported tailored (to patient needs) online self-management programme for fatigue, pain and faecal urgency/incontinence improve IBD-related quality of life (measured using the UK-IBDQ) and global rating of symptom relief (0-10 scale) compared with care as usual? METHODS: A pragmatic two-arm, parallel group randomised controlled trial (RCT), of a 12-session facilitator-supported online cognitive behavioural self-management programme versus care as usual to manage symptoms of fatigue, pain and faecal urgency/incontinence in IBD. Patients will be recruited through a previous large-scale survey of unselected people with inflammatory bowel disease. The UK Inflammatory Bowel Disease Questionnaire and global rating of symptom relief at 6 months are the co-primary outcomes, with multiple secondary outcomes measured also at 6 and 12 months post randomisation to assess maintenance. The RCT has an embedded pilot study, health economics evaluation and process evaluation. We will randomise 680 patients, 340 in each group. Demographic characteristics and outcome measures will be presented for both study groups at baseline. The UK-IBDQ and global rating of symptom relief at 6 and 12 months post randomisation will be compared between the study groups. DISCUSSION: The BOOST online self-management programme for people with IBD-related symptoms of fatigue, pain and urgency has been designed to be easily scalable and implemented. If it is shown to improve patients' quality of life, this trial will enable clinicians and patients to make informed management decisions. This is the first trial, to our knowledge, focused on multiple symptoms prioritised by both people with IBD and health professionals. TRIAL REGISTRATION: ISRCTN71618461 . Registered on 9 September 2019

Modelling survival : exposure pattern, species sensitivity and uncertainty

The General Unified Threshold model for Survival (GUTS) integrates previously published toxicokinetic-toxicodynamic models and estimates survival with explicitly defined assumptions. Importantly, GUTS accounts for time-variable exposure to the stressor. We performed three studies to test the ability of GUTS to predict survival of aquatic organisms across different pesticide exposure patterns, time scales and species. Firstly, using synthetic data, we identified experimental data requirements which allow for the estimation of all parameters of the GUTS proper model. Secondly, we assessed how well GUTS, calibrated with short-term survival data of Gammarus pulex exposed to four pesticides, can forecast effects of longer-term pulsed exposures. Thirdly, we tested the ability of GUTS to estimate 14-day median effect concentrations of malathion for a range of species and use these estimates to build species sensitivity distributions for different exposure patterns. We find that GUTS adequately predicts survival across exposure patterns that vary over time. When toxicity is assessed for time-variable concentrations species may differ in their responses depending on the exposure profile. This can result in different species sensitivity rankings and safe levels. The interplay of exposure pattern and species sensitivity deserves systematic investigation in order to better understand how organisms respond to stress, including humans

Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc

<p>Abstract</p> <p>Background</p> <p>Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer.</p> <p>Methods</p> <p>Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Cell cycle distribution was determined by flow cytometry. Apoptosis was examined by analyzing subdiploid population and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Senescent cells were determined by senescence-associated β-galactosidase activity analysis. Semi-quantitative RT-PCR was used to examine the changes of mRNA of p16, p21, p27 and c-myc. The concomitant changes of protein expression were analyzed with Western blot. Expression of AcH3 and AcH4 were examined by immunofluorescence staining and Western blots. Effects of oridonin on colony formation of SW1116 were examined by Soft Agar assay. The in vivo efficacy of oridonin was detected using a xenograft colorectal cancer model in nude mice.</p> <p>Results</p> <p>Oridonin induced potent growth inhibition, cell cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice. With western blot and reverse transcription-PCR, we further showed that the antitumor activities of oridonin correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, p27 and p16, and suppression of c-myc expression.</p> <p>Conclusion</p> <p>Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment.</p