👤 Agnieszka Michael

Movement behaviours, including moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), sedentary behaviour (SB), and sleep, influence childhood adiposity. However, their collective impact on adiposity from a sex-specific perspective remains underexplored. Our research examined the sex-specific longitudinal associations of 24-h movement behaviours with body mass index (BMI) and abdominal adiposity among children. In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study, we repeatedly measured 24-h movement behaviours using wrist-worn accelerometers (ActiGraph GT3x) and assessed adiposity (BMI, abdominal circumference, and MRI-based abdominal fat volumes) at three time points (ages 5.5-6, 7.5-8, and 10-10.5 years) within the same children in a longitudinal design. Compositional multivariable linear mixed-effect modelling and isotemporal substitution were used to estimate the associations. 531 children (49.5% girls) were included in the analysis. Significant interactions between movement behaviours and sex were observed across all outcomes. In girls, higher MVPA relative to other behaviours was linked to lower BMI [-0.8 (-1.5, -0.1) kg/m²] and total abdominal adiposity [-225.5 (-451.6, -2.5) mL], while in boys, longer sleep duration was associated with lower BMI [-1.6 (-3.2, -0.1) kg/m²] and total abdominal adiposity [-624.2 (-1225.6, -31.3) mL]. The isotemporal substitution model showed that replacing 30 min of LPA/SB with MVPA reduced BMI and abdominal circumference by 1-2% and MRI-measured abdominal adiposity by 6-9% in both sexes. However, replacing LPA/SB with sleep reduced BMI and abdominal circumference by 1% and MRI-measured adiposity by 3-6% only in boys, with no changes in girls. These associations were pronounced on visceral adiposity. This study highlights sex-specific associations of movement behaviours with adiposity in school-aged children, with stronger associations observed in MRI-derived measures compared to conventional adiposity indices. Replacing LPA/SB with MVPA reduced BMI and abdominal adiposity in both sexes, with particularly pronounced effects on visceral adiposity. However, sleep replacement benefits were observed only in boys, suggesting the need for gender-sensitive approaches in lifestyle interventions. Show less

Muvalaplin inhibits lipoprotein(a) formation. A 14-day phase 1 study demonstrated that muvalaplin was well tolerated and reduced lipoprotein(a) levels up to 65%. The effect of longer administration of muvalaplin on lipoprotein(a) levels in individuals at high cardiovascular risk remains uncertain. To determine the effect of muvalaplin on lipoprotein(a) levels and to assess safety and tolerability. Phase 2, placebo-controlled, randomized, double-blind trial enrolling 233 participants with lipoprotein(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia at 43 sites in Asia, Europe, Australia, Brazil, and the United States between December 10, 2022, and November 22, 2023. Participants were randomized to receive orally administered muvalaplin at dosages of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68) or placebo (n = 67) for 12 weeks. The primary end point was the placebo-adjusted percentage change from baseline in lipoprotein(a) molar concentration at week 12, using an assay to measure intact lipoprotein(a) and a traditional apolipoprotein(a)-based assay. Secondary end points included the percentage change in apolipoprotein B and high-sensitivity C-reactive protein. The median age of study participants was 66 years; 33% were female; and 27% identified as Asian, 4% as Black, and 66% as White. Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay. Dose-dependent reductions in apolipoprotein B were observed at 8.9% (95% CI, -2.2% to 18.8%), 13.1% (95% CI, 4.4%-20.9%), and 16.1% (95% CI, 7.8%-23.7%) at 10 mg/d, 60 mg/d, and 240 mg/d, respectively. No change in high-sensitivity C-reactive protein was observed. No safety or tolerability concerns were observed at any dosage. Muvalaplin reduced lipoprotein(a) measured using intact lipoprotein(a) and apolipoprotein(a)-based assays and was well tolerated. The effect of muvalaplin on cardiovascular events requires further investigation. ClinicalTrials.gov Identifier: NCT05563246. Show less

To review the development of oral agents to lower Lp(a) levels as an approach to reducing cardiovascular risk, with a focus on recent advances in the field. Extensive evidence implicates Lp(a) in the causal pathway of atherosclerotic cardiovascular disease and calcific aortic stenosis. There are currently no therapies approved for lowering of Lp(a). The majority of recent therapeutic advances have focused on development of injectable agents that target RNA and inhibit synthesis of apo(a). Muvalaplin is the first, orally administered, small molecule inhibitor of Lp(a), which acts by disrupting binding of apo(a) and apoB, in clinical development. Nonhuman primate and early human studies have demonstrated the ability of muvalaplin to produce dose-dependent lowering of Lp(a). Ongoing clinical trials will evaluate the impact of muvalaplin in high cardiovascular risk and will ultimately need to determine whether this strategy lowers the rate of cardiovascular events. Muvalaplin is the first oral agent, developed to lower Lp(a) levels. The ability of muvalaplin to reduce cardiovascular risk remains to be investigated, in order to determine whether it will be a useful agent for the prevention of cardiovascular disease. Show less

Chronic inflammation has been closely linked to the development and progression of various cancers. The epithelial-mesenchymal transition (EMT) is a process involving the acquisition of mesenchymal features by carcinoma cells and is an important link between inflammation and cancer development. Inflammatory mediators in the tumour micro-environment, such as cytokines and chemokines, can promote EMT changes in cancer cells. The aim of this systematic review is to analyse the effect of cytokines on EMT in gynaecological cancers and discuss their possible therapeutic implications. A search of the databases CINAHL, Cochrane, Embase, Medline, PubMed, TRIP, and Web of Science was performed using the keywords: "cytokines" AND "epithelial mesenchymal transition OR transformation" AND "gynaecological cancer". Seventy-one articles reported that various cytokines, such as TGF-β, TNF-α, IL-6, etc., promoted EMT changes in ovarian, cervical, and endometrial cancers. The EMT changes included from epithelial to mesenchymal morphological change, downregulation of the epithelial markers E-cadherin/β-catenin, upregulation of the mesenchymal markers N-cadherin/vimentin/fibronectin, and upregulation of the EMT-transformation factors (EMT-TF) Show less

Histaminergic neurons of the tuberomammillary nucleus (TMN) are wake-promoting and contribute to the regulation of energy homeostasis. Evidence indicates that melanocortin 4 receptors (MC4R) are expressed within the TMN. However, whether the melanocortin system influences the activity and function of TMN neurons expressing histidine decarboxylase (HDC), the enzyme required for histamine synthesis, remains undefined. We utilized Hdc-Cre mice in combination with whole-cell patch-clamp electrophysiology and in vivo chemogenetic techniques to determine whether HDC neurons receive metabolically relevant information via the melanocortin system. We found that subsets of HDC-expressing neurons were excited by melanotan II (MTII), a non-selective melanocortin receptor agonist. Use of melanocortin receptor selective agonists (THIQ, [D-Trp These experiments identify a functional interaction between the melanocortin and histaminergic systems and suggest that HDC neurons act naturally to restrain the anorexigenic effect of melanocortin system activation. These findings may have implications for the control of arousal and metabolic homeostasis, especially in the context of obesity, in which both processes are subjected to alterations. Show less

Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" (∼50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor ( Show less

Agrobacterium tumefaciens infects its plant hosts by a mechanism of horizontal gene transfer. This capability has led to its widespread use in artificial genetic transformation. In addition to DNA, the bacterium delivers an abundant ssDNA binding protein, VirE2, whose roles in the host include protection from cytoplasmic nucleases and adaptation for nuclear import. In Agrobacterium, VirE2 is bound to its acidic chaperone VirE1. When expressed in vitro in the absence of VirE1, VirE2 is prone to oligomerization and forms disordered filamentous aggregates. These filaments adopt an ordered solenoidal form in the presence of ssDNA, which was characterized previously by electron microscopy and three-dimensional image processing. VirE2 coexpressed in vitro with VirE1 forms a soluble heterodimer. VirE1 thus prevents VirE2 oligomerization and competes with its binding to ssDNA. We present here a crystal structure of VirE2 in complex with VirE1, showing that VirE2 is composed of two independent domains presenting a novel fold, joined by a flexible linker. Electrostatic interactions with VirE1 cement the two domains of VirE2 into a locked form. Comparison with the electron microscopy structure indicates that the VirE2 domains adopt different relative orientations. We suggest that the flexible linker between the domains enables VirE2 to accommodate its different binding partners. Show less

Changes in fatty acid metabolism associated with insulin resistance have been described in rats and humans but have not been well characterized in the frequently used mouse model of diet-induced obesity. To analyse the early phase as well as established insulin resistance, C57BL/6 mice were placed for 1 or 16 weeks on a high fat diet (1w-HFD, 16w-HFD). Endocrine and metabolic parameters indicated that 1w-HFD mice showed a moderate but significant induction of insulin resistance while 16w-HFD mice exhibited profound obesity-associated insulin resistance and dyslipidemias. Significant alterations in fatty acid composition were observed in plasma and liver in both groups. Liver phospholipid-associated arachidonate and docosahexaenoate were increased in both 1w-HFD and 16w-HFD mice, possibly due to increased expression of the desaturases Fads1 and Fads2. Unexpectedly, SCD1 activity and gene expression in liver were decreased in the 1w-HFD group accompanied by diminished total hepatic lipid levels, while they were increased in chronically fed mice. Our data indicate that the early phase of HFD-induced insulin resistance is not associated with elevated liver lipid concentration. Furthermore, the early and persistent rise of arachidonate and docosahexaenoate indicates that insulin resistance is not due to insufficient availability (or concentrations) of polyunsaturated fatty acids as postulated previously. Show less

The principal goal of the Israel Structural Proteomics Center (ISPC) is to determine the structures of proteins related to human health in their functional context. Emphasis is on the solution of structures of proteins complexed with their natural partner proteins and/or with DNA. To date, the ISPC has solved the structures of 14 proteins, including two protein complexes. It has adopted automated high-throughput (HTP) cloning and expression techniques and is now expressing in Escherichia coli, Pichia pastoris and baculovirus, and in a cell-free E. coli system. Protein expression in E. coli is the primary system of choice in which different parameters are tested in parallel. Much effort is being devoted to development of automated refolding of proteins expressed as inclusion bodies in E. coli. The current procedure utilizes tagged proteins from which the tag can subsequently be removed by TEV protease, thus permitting streamlined purification of a large number of samples. Robotic protein crystallization screens and optimization utilize both the batch method under oil and vapour diffusion. In order to record and organize the data accumulated by the ISPC, a laboratory information-management system (LIMS) has been developed which facilitates data monitoring and analysis. This permits optimization of conditions at all stages of protein production and structure determination. A set of bioinformatics tools, which are implemented in our LIMS, is utilized to analyze each target. Show less