Exploring Subsite Selectivity within -Myristoyltransferase Using Pyrazole-Derived Inhibitors.

-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report NMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity.

The endoplasmic reticulum plays a key role in α-cell intracellular Ca dynamics and glucose-regulated glucagon secretion in mouse islets.

Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied the role of transmembrane and endoplasmic reticulum (ER) Ca on intrinsic α-cell glucagon secretion.

The significance of managers' knowledge of common mental disorders on managerial stigma towards employee depression: a cross-sectional study in Sweden.

Background: Common mental disorders (CMD) such as depression, anxiety and stress-related disorders have increased in the working-age population in many countries but are still often associated with social stigma in workplaces. Managers have a key role in supporting employees with impaired health. Identifying factors that can improve stigmatizing attitudes among managers towards CMD is crucial.

Associations of dietary choline and betaine with all-cause mortality: a prospective study in a large Swedish cohort.

Purpose: Investigate the association between choline and betaine intake and all-cause mortality in a large Swedish cohort.

Methods: Women (52,246) and men (50,485) attending the Västerbotten Intervention Programme 1990-2016 were included. Cox proportional hazard regression models adjusted for energy intake, age, BMI, smoking, education, and physical activity were used to estimate mortality risk according to betaine, total choline, phosphatidylcholine, glycerophosphocholine, phosphocholine, sphingomyelin, and free choline intakes [continuous (per 50 mg increase) and in quintiles].

Mechanisms behind changes of neurodegeneration biomarkers in plasma induced by sleep deprivation.

Acute sleep deprivation has been shown to affect cerebrospinal fluid and plasma concentrations of biomarkers associated with neurodegeneration, though the mechanistic underpinnings remain unknown. This study compared individuals who, for one night, were either subject to total sleep deprivation or free sleep, (i) examining plasma concentrations of neurodegeneration biomarkers the morning after sleep deprivation or free sleep and (ii) determining how overnight changes in biomarkers plasma concentrations correlate with indices of meningeal lymphatic and glymphatic clearance functions. Plasma concentrations of amyloid-β 40 and 42, phosphorylated tau peptide 181, glial fibrillary acid protein and neurofilament light were measured longitudinally in subjects who from Day 1 to Day 2 either underwent total sleep deprivation ( = 7) or were allowed free sleep ( = 21).

Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts.

Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs.

Designing an automatic pollen monitoring network for direct usage of observations to reconstruct the concentration fields.

We consider several approaches to a design of a regional-to-continent-scale automatic pollen monitoring network in Europe. Practical challenges related to the arrangement of such a network limit the range of possible solutions. A hierarchical network is discussed, highlighting the necessity of a few reference sites that follow an extended observations protocol and have corresponding capabilities.

Chemical-genomic profiling identifies genes that protect yeast from aluminium, gallium, and indium toxicity.

Aluminium, gallium, and indium are group 13 metals with similar chemical and physical properties. While aluminium is one of the most abundant elements in the Earth's crust, gallium and indium are present only in trace amounts. However, the increased use of the latter metals in novel technologies may result in increased human and environmental exposure.

Trends in the Prevalence of Hypertension and Type 2 Diabetes in Bangladesh (2010-2020): A Systematic Review and Meta-Analysis.

Background: The prevalence of cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) has increased in Bangladesh. This paper has reviewed published studies on hypertension and T2DM from 2010 to 2020 in Bangladesh and conducted a meta-analysis.

Methods: The PubMed database was used for systematic search.

Domino effect of a natural cascade alpine lake system on the Third Pole.

Third Pole natural cascade alpine lakes (NCALs) are exceptionally sensitive to climate change, yet the underlying cryosphere-hydrological processes and associated societal impacts are largely unknown. Here, with a state-of-the-art cryosphere-hydrology-lake-dam model, we quantified the notable high-mountain Hoh-Xil NCALs basin (including Lakes Zonag, Kusai, Hedin Noel, and Yanhu, from upstream to downstream) formed by the Lake Zonag outburst in September 2011. We demonstrate that long-term increased precipitation and accelerated ice and snow melting as well as short-term heavy precipitation and earthquake events were responsible for the Lake Zonag outburst; while the permafrost degradation only had a marginal impact on the lake inflows but was crucial to lakeshore stability.

Systematic Review of Human and Animal Evidence on the Role of Buckwheat Consumption on Gastrointestinal Health.

Background: Buckwheat is a commonly cultivated crop with growing evidence that it is beneficial to gastrointestinal (GI) health. This systematic review summarizes the role of buckwheat in modifying GI health outcomes and microbiomes.

Methods: Four medical databases and Google Scholar were systematically searched.

Development of Dicationic Bisguanidine-Arylfuran Derivatives as Potent Agents against Gram-Negative Bacteria.

Antibiotic resistance among bacteria is a growing global challenge. A major reason for this is the limited progress in developing new classes of antibiotics active against Gram-negative bacteria. Here, we investigate the antibacterial activity of a dicationic bisguanidine-arylfuran, originally developed as an antitrypanosomal agent, and new derivatives thereof.

Genome-enabled discovery of candidate virulence loci in Striga hermonthica, a devastating parasite of African cereal crops.

Parasites have evolved proteins, virulence factors (VFs), that facilitate plant colonisation, however VFs mediating parasitic plant-host interactions are poorly understood. Striga hermonthica is an obligate, root-parasitic plant of cereal hosts in sub-Saharan Africa, causing devastating yield losses. Understanding the molecular nature and allelic variation of VFs in S.

Regulation of α-cell glucagon secretion: The role of second messengers.

Glucagon is a potent glucose-elevating hormone that is secreted by pancreatic α-cells. While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia, it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes. It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes.

Teleconnections between large-scale oceanic-atmospheric patterns and interannual surface wind speed variability across China: Regional and seasonal patterns.

Great attention has been paid to the long-term decline in terrestrial near-surface wind speed (SWS) in China. However, how the SWS varies with regions and seasons and what modulates these changes remain unclear. Based on quality-controlled and homogenized terrestrial SWS data from 596 stations, the covarying SWS patterns during the Asian Summer Monsoon (ASM) and the Asian Winter Monsoon (AWM) seasons are defined for China using empirical orthogonal function (EOF) analysis for 1961-2016.

A small molecule screen for paqr-2 suppressors identifies Tyloxapol as a membrane fluidizer for C. elegans and mammalian cells.

Defects in cell membrane homeostasis are implicated in numerous disorders, including cancer, neurodegeneration and diabetes. There is therefore a need for a powerful model to study membrane homeostasis and to identify eventual therapeutic routes. The C.

Post-transcriptional regulation during stress.

To remain competitive, cells exposed to stress of varying duration, rapidity of onset, and intensity, have to balance their expenditure on growth and proliferation versus stress protection. To a large degree dependent on the time scale of stress exposure, the different levels of gene expression control: transcriptional, post-transcriptional, and post-translational, will be engaged in stress responses. The post-transcriptional level is appropriate for minute-scale responses to transient stress, and for recovery upon return to normal conditions.

Population Pharmacodynamic Modeling of Eflornithine-Based Treatments Against Late-Stage Gambiense Human African Trypanosomiasis and Efficacy Predictions of L-eflornithine-Based Therapy.

Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers.

Etp1 confers arsenite resistance by affecting ACR3 expression.

In a high-throughput yeast two-hybrid screen of predicted coiled-coil motif interactions in the Saccharomyces cerevisiae proteome, the protein Etp1 was found to interact with the yeast AP-1-like transcription factors Yap8, Yap1 and Yap6. Yap8 plays a crucial role during arsenic stress since it regulates expression of the resistance genes ACR2 and ACR3. The function of Etp1 is not well understood but the protein has been implicated in transcription and protein turnover during ethanol stress, and the etp1∆ mutant is sensitive to ethanol.

Global SLAM-seq for accurate mRNA decay determination and identification of NMD targets.

Gene expression analysis requires accurate measurements of global RNA degradation rates, earlier problematic with methods disruptive to cell physiology. Recently, metabolic RNA labeling emerged as an efficient and minimally invasive technique applied in mammalian cells. Here, we have adapted SH-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) for a global mRNA stability study in yeast using 4-thiouracil pulse-chase labeling.

Impact of Fat Intake on Blood Glucose Control and Cardiovascular Risk Factors in Children and Adolescents with Type 1 Diabetes.

Nutrition therapy is a cornerstone of type 1 diabetes (T1D) management. Glycemic control is affected by diet composition, which can contribute to the development of diabetes complications. However, the specific role of macronutrients is still debated, particularly fat intake.