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Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the first to explore the role and molecular mechanism of stress granules (SGs) in MAFLD. A gene knock-down model of G3BP1, a core SG molecule in mice and HepG2 cells, was constructed to explore the role of SGs in MAFLD induced in vivo by a high-fat diet or in vitro by palmitic acid (PA). Methods included metabolic phenotyping; western blotting; qPCR; and immunofluorescence, haematoxylin/eosin and masson staining. The downstream molecules of G3BP1 and its specific molecular mechanism were screened using RNA sequencing (RNA-seq). G3BP1 and TIA1 expression were upregulated in high-fat diet-fed mouse liver tissues and PA-induced HepG2 cells, and the two molecules showed significantly increased colocalisation. G3BP1 knock-down slightly increased TIA1 expression in the livers of obese mice but not in lean mice. G3BP1 deficiency aggravated liver lipid deposition and insulin resistance in obese mice, and this phenotype was confirmed in vitro in PA-induced hepatocytes. RNA-seq demonstrated that G3BP1 slowed down MAFLD progression by inhibiting APOC3, possibly through a mechanistic suppression of APOC3 entry into the nucleus. This study reveals for the first time a protective role for SGs in MAFLD. Specifically, knocking down the core G3BP1 molecule in SGs aggravated the progression of fatty acid-induced MAFLD through a mechanism that may involve the nuclear entry of APOC3. These findings provide a new therapeutic direction for MAFLD. Show less

The objective of this study was to investigate head circumference (HC) in patients with melanocortin 4 receptor (MC4R) deficiency, the most common cause of monogenetic obesity. Patients with (likely) pathogenic MC4R variants were included. HC, height, and weight were measured, and BMI and standard deviation score (SDS) were calculated. HC SDS was compared to the Dutch reference population. Children were matched 1:1 to a control group with common obesity. Children with MC4R deficiency (n = 63, mean age, 10.32 years) had significantly larger HC (mean, +1.73 SDS) compared to the reference population (0 SDS; p < 0.001) and controls (+1.22 SDS; p = 0.009). In adults (n = 13), HC (median, + 0.86 SDS) did not differ from the reference population (0 SDS; p = 0.152). Macrocephaly (HC ≥ 2 SDS) was present in 43%, 25%, and 23% of pediatric patients with MC4R deficiency, controls, and adult patients, respectively. Children with MC4R deficiency were taller than controls (+1.00 SDS vs. +0.42 SDS; p = 0.016), with similar BMI (+3.99 SDS vs. +3.75 SDS; p = 0.157). HC SDS was associated with height SDS (R Macrocephaly is a common feature of patients with MC4R deficiency. We recommend measuring HC in patients suspected for genetic obesity, as it can be a clue for MC4R deficiency. Show less

Cholangiocarcinoma (CCA) is a diverse group of aggressive liver tumors with up to 20% being intrahepatic CCA (iCCA). Up to 15% of patients with iCCA have fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. Here we evaluated iCCA treatment with pemigatinib, a selective inhibitor of FGFR1-3, in two patients from Denmark and Finland. We identified a total of two Nordic patients with iCCA in our clinics, who received first-line cisplatin/gemcitabine before initiating pemigatinib. Case 1 was a 34-year-old woman with aggressive, metastatic iCCA upon presentation, who progressed on cisplatin/gemcitabine. Pemigatinib was initiated after FGFR2 fusion detection by genomic testing. She had a partial response after three cycles (9 weeks) of pemigatinib but experienced disease progression after three more pemigatinib cycles. Adverse events were primarily managed by supportive care and dose reduction, except hyperphosphatemia, which was complicated by food allergies and required medication. She received subsequent chemotherapy but deteriorated rapidly and died 1 month later. Case 2 was an 81-year-old man with unresectable iCCA who achieved stable disease with first-line chemotherapy. He switched to pemigatinib after FGFR2 fusion detection by next-generation sequencing. The tumor shrank by 20% after three pemigatinib cycles and completely calcified with continued treatment. Adverse events were managed by two dose adjustments. Treatment has continued for 57 months and is ongoing. CCA is an aggressive disease that requires early molecular testing of abundant biopsy tissue so not to delay second-line therapies, such as pemigatinib. Variability in treatment outcomes is expected. Show less

Weight loss medications are emerging candidates for pharmacotherapy of sleep-disordered breathing (SDB). A melanocortin 4 receptor (MC4R) agonist, setmelanotide (Set), is used to treat obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that Set can treat SDB in mice with diet-induced obesity. We performed a proof-of-concept randomized crossover trial of a single dose of Set versus vehicle and a 2-week daily Set versus vehicle trial, examined colocalization of Mc4r mRNAs with the markers of CO2-sensing neurons Phox2b and neuromedin B in the brainstem, and expressed Cre-dependent designer receptors exclusively activated by designer drugs (DREADDs) or caspase in obese Mc4r-Cre mice. Set increased minute ventilation across sleep/wake states, enhanced the hypercapnic ventilatory response (HCVR), and abolished apneas during sleep. Phox2b+ neurons in the nucleus of the solitary tract (NTS) and the parafacial region expressed Mc4r. Chemogenetic stimulation of the MC4R+ neurons in the parafacial region, but not in the NTS, augmented HCVR without any changes in metabolism. Caspase elimination of the parafacial MC4R+ neurons abolished effects of Set on HCVR. Parafacial MC4R+ neurons projected to the respiratory premotor neurons retrogradely labeled from C3-C4. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R+ neurons. Show less

Familial chylomicronemia syndrome (FCS) is a rare Mendelian autosomal recessive disorder (MIM 238600) characterized by extreme and sustained hypertriglyceridemia due to profound reduction of lipoprotein lipase (LPL) activity. This expert opinion statement synthesizes current knowledge on the definition, pathophysiology, genetics, prevalence, diagnosis, and management of FCS. FCS typically manifests at a young age with persistent severe hypertriglyceridemia-defined as ≥10 mmol/L (≥885 mg/dL), or ≥1000 mg/dL (≥11.2 mmol/L) depending on region and whether Systeme International (SI) units are utilized-in the absence of secondary factors, resistance to conventional lipid-lowering therapies, and a high lifetime risk of acute pancreatitis. It is caused by biallelic pathogenic variants in the LPL gene encoding LPL, or 1 of 4 other related genes that encode proteins that interact with LPL. Affected individuals require a strict, lifelong very low-fat diet with <15% of energy from fat. Emerging therapies inhibiting apolipoprotein C-III show promise in reducing serum triglycerides and pancreatitis risk in patients with FCS. A multidisciplinary approach, encompassing dietary management, pharmacotherapy, and patient education, is pivotal in mitigating the significant morbidity associated with FCS. Show less

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence and limited treatment options. To identify actionable therapeutic targets, we developed a patient-derived xenograft (PDX) model using a metastatic ASCC sample and performed single-cell RNA sequencing. Our analysis confirmed previously reported genetic mutations highly expressed in the sample, along with copy number alterations, and revealed epithelial cancer cell heterogeneity. Notably, epithelial cells exhibited a low hybrid epithelial-mesenchymal transition (hEMT) signature compared to stromal cells. Among epithelial subpopulations, the most abundant cluster displayed high expression of FGFR1-2 and FGF ligands. Treatment with AZD4547, an FGFR1-3 inhibitor, resulted in a significant reduction in tumor volume over time (p = 0.0036). Immunohistochemistry staining for proliferative Ki67 and cleaved caspase 3 suggested ongoing proliferation in residual cells. Fourier-transform infrared (FTIR) spectroscopy of post-treatment residual tumors revealed significant differences in the Amide I and Amide II regions between AZD4547-treated and control groups. These findings demonstrate that FGFR inhibition effectively attenuates ASCC tumor growth and highlights the promise of precision medicine in managing this rare cancer. Show less

Esophageal cancer (ESCA) poses a significant challenge in oncology because of the limited treatment options and poor prognosis. Therefore, enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients. To define the role of the transcription factor Snail family transcriptional repressor 1 (SNAI1) in ESCA, particularly its regulation of radiosensitivity. A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA. Survival curves correlated SNAI1 levels with radiotherapy outcomes. Colony formation assays, flow cytometry, and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis. Western blot validated protein expression, while Chromatin immunoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition (EMT). SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease. Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy. Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation (IR), resulting in remarkable tumor regression upon IR treatment This study highlights SNAI1's role in ESCA radiosensitivity, offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes. Show less

While anticounterfeiting systems based on long persistent luminescence (LPL) materials demonstrate a mature trend, the integration of tunable luminescent lifetimes and emission colors in LPL-based anticounterfeiting systems remains a challenge. Herein, we propose a temporal and spatial anticounterfeiting strategy utilizing novel zero dimensional (0D) metal halides, specifically (PBA) Show less

Insulin secretory granule (ISG) maturation is a crucial aspect of insulin secretion and glucose homeostasis. The regulation of this maturation remains poorly understood, especially how secretory stimuli affect ISG maturity and subcellular localization. In this study, we used soft X-tomography (SXT) to quantitatively map ISG morphology, density, and location in single INS-1E and mouse pancreatic β-cells under the effect of various secretory stimuli. We found that the activation of glucokinase (GK), gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and G-protein coupled receptor 40 (GPR40) promote ISG maturation. Each stimulus induces unique structural remodeling in ISGs, by altering size and density, depending on the specific signaling cascades activated. These distinct ISG subpopulations mobilize and redistribute in the cell altering overall cellular structural organization. Our results provide insight into how current diabetes and obesity therapies impact ISG maturation and may inform the development of future treatments that target maturation specifically. Show less

The rs12970134 variant near the melanocortin receptor 4 (MC4-R) has gained relevance suggesting an age dependent phenotypic effect in the induction of obesity in young age. A previous study evaluating 740 Caucasian children has shown this association in prepubertal children older than 8 years. The aim of this study was to assess whether the obesogenic effect of M4CR gene contributed to obesity also in adolescence. After 8 years participants of the original study were contacted and invited to perform an anthropometric evaluation. Out of 35 carriers of the AA risk allele of MC4-R, 12 subjects accepted to participate. Adolescent subjects with the AA risk allele of MC4-R were matched with 24 and 48 subjects, respectively for AG and GG variants. Differences between the three MC4-R genotypes for anthropometric data, for percentage of overweight and obesity and for changes in BMI-SDS over visit have been assessed. At Visit 1 (baseline examination study), the AA risk genotype was confirmed to be associated with higher BMI-SDS (1.3 ± 0.4 vs 0.4 ± 0.1) and waist circumference (66.5 ± 5.8 vs 60.9 ± 7.1) when compared to the GG genotype (p < 0.016 both). At Visit 2 the AA genotype not only was associated with a higher BMI-SDS (1.07 ± 0.5 vs 0.02 ± 0.8) and WC (95.6 ± 13.3 vs 64.9 ± 13.5) when compared to GG genotype, but also when compared to AG genotype (vs 0.5 ± 0.1 and 62.9 ± 10.0, p < 0.016). Whereas AA genotype demonstrated no change of BMI-SDS between visit 1 and visit 2 (p00.32), AG and GG genotype showed a significant reduction (p = 0.01 and 0.001 respectively). Furthermore, a higher percentage of patients were affected by overweight/obesity in the AA genotype compared to AG and GG genotypes (50% vs 20.8% vs 16.5% p = 0.03). This study demonstrates that the rs12970134 variant not only exerts an obesogenic influence in the prepubertal age but remains a major risk factor also during adolescence. Show less

Little is known, how life-long hyperlipidaemia affects vascular ageing, before atherosclerosis. Here, we characterise effects of mild, life-long hyperlipidaemia on age-dependent endothelial dysfunction (ED) in humanised dyslipidaemia model of E3L.CETP mice. Vascular function was characterised using magnetic resonance imaging in vivo and wire myograph ex vivo. Plasma endothelial biomarkers and non-targeted proteomics in plasma and aorta were analysed. Early atherosclerosis lesions were occasionally present only in 40-week-old or older E3L.CETP mice. However, age-dependent ED developed earlier, in 14-week-old male and 22-week-old female E3L.CETP mice as compared with 40-week-old female and male C57BL/6J mice. Acetylcholine-induced vasodilation in 8-week-old E3L.CETP, especially female mice, was blocked by catalase and attributed to H Show less

Glyphosate and 2,4-D are among the most widely used herbicides globally, leading to environmental presence, food contamination, and human contact. Investigations based on current toxicological limits or populational-based herbicide exposures are warranted, and in vitro bioassays provide useful tools for toxicological screening. Thus, this study evaluated the transcriptomic implications of non-cytotoxic exposures to glyphosate, its metabolite aminomethylphosphonic acid (AMPA), or 2,4-D - or to their mixes - on hepatic cells. The half maximal effective concentration (IC50) of each herbicide was calculated (cell viability) in human hepatic C3A cells and 1000-fold lower concentrations were used for transcriptomic analysis (RNA-Seq) after 48 h exposure, resembling current toxicological limits and considering herbicide water levels (glyphosate: 0.95 µg/mL; AMPA: 3.7 µg/mL; 2,4-D: 0.56 µg/mL). Glyphosate exposure enriched MAPK-related biological processes (upregulated TNF, FOS, IGF1, and PDGFB), and downregulated genes associated with lipid metabolism (CD36 and PPARA). Many AMPA exposure-related differentially expressed genes (DEGs, such as PFKFB3, HK2, and ALDOA) were associated with glucose metabolic pathways. Glyphosate and its metabolite yielded a common molecular signature, as illustrated by principal component analysis and the function of 212 shared DEGs. The exposure to 2,4-D was associated with the JNK cascade and the solute carrier family annotations. The herbicide mixtures had a discrete effect on enhancing the impact of individual herbicides, although important epithelial-mesenchymal transition genes were exclusively modified by the mixes (COL11A2, LOXL3, SNAI1). Altogether, our data reveals new perspectives on the short-term molecular effects of herbicide exposure in liver cells, emphasizing potential avenues for further exploration. Show less

Many drug targets in ongoing Parkinson's disease (PD) clinical trials have strong genetic links. While genome-wide association studies (GWAS) nominate regions associated with disease, pinpointing causal genes is challenging. Our aim was to prioritize additional druggable genes underlying PD GWAS signals. The polygenic priority score (PoPS) integrates genome-wide information from MAGMA gene-level associations and over 57,000 gene-level features. We applied PoPS to East Asian and European PD GWAS data and prioritized genes based on PoPS, distance to the GWAS signal, and non-synonymous credible set variants. We prioritized 46 genes, including well-established PD genes (SNCA, LRRK2, GBA1, TMEM175, VPS13C), genes with strong literature evidence supporting a mechanistic link to PD (RIT2, BAG3, SCARB2, FYN, DYRK1A, NOD2, CTSB, SV2C, ITPKB), and genes relatively unexplored in PD. Many hold potential for drug repurposing or development. We prioritized high-confidence genes with strong links to PD pathogenesis that may represent our next-best candidates for developing disease-modifying therapeutics. Show less

Foamy macrophages are pivotal contributors to the development and progression of atherosclerotic plaques, posing a substantial threat to human health. Presently, there is no pharmaceutical intervention available to effectively eliminate foamy macrophages. In this study, we demonstrate that probiotic membrane vesicles (MVs) can induce atherosclerotic plaque regression by modulating foamy macrophages. MVs isolated from Lactobacillus rhamnosus exhibited a specific uptake by foamy macrophages. Near-infrared fluorescence (NIRF) imaging, aortic oil red O staining, and hematoxylin and eosin staining showed reductions in the plaque area following MVs treatment. Mechanistically, bioinformatics analysis provided insights into how MVs exert their effects, revealing that they promote lipid efflux and macrophage polarization. Notably, MVs treatment upregulated NR1H3, which in turn increased ABCA1 expression, facilitating lipid efflux from foamy macrophages. Moreover, MVs shifted macrophage polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, highlighting their potential to create a more protective environment against plaque progression. This study is significant as it introduces MVs as a novel therapeutic platform for the targeted delivery of anti-inflammatory agents to atherosclerotic sites. By specifically modulating macrophage function, MVs hold considerable potential for the treatment of atherosclerosis and related cardiovascular diseases, addressing an unmet need in current therapeutic strategies. Show less

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-driven B-cell lymphoproliferative disease that often progresses to high-grade lymphoma. We describe a case of high-grade LYG causing Pancoast syndrome, diagnosed via transbronchial biopsy after a failed incisional biopsy. Complete remission was achieved with R-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone), but 2.5 years later, the patient developed lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Despite bendamustine-rituximab improving LPL/WM, LYG recurred, underscoring its treatment challenges. This case highlights LYG's diagnostic complexity, its potential link with other hematologic malignancies, and therapeutic limitations. Further research is needed to elucidate LYG's pathogenesis and develop effective treatments for relapsed cases. Show less

Lung squamous cell carcinoma (LUSC) is one of the most common subtype of lung cancer and is associated with the poor prognoses. The fibroblast growth factor receptor (FGFR) family is known to be activated through fusions with various partners across multiple cancer types, including nonsmall cell lung cancer (NSCLC). FGFR inhibitors are currently undergoing clinical evaluation for the treatment of tumors harboring these fusions. While FGFR1 amplification has been well-documented in numerous NSCLC datasets, the characterization of specific FGFR fusion variants remains limited. In this study, we identified a novel PLPP5-FGFR1 fusion in a 65-year-old male patient with lung squamous cell carcinoma through targeted RNA sequencing. The fusion junction was located between exon 1 of PLPP5 and exon 5 of FGFR1, and the result was validated by Sanger sequencing. To our knowledge, this is the first reported case of a PLPP5-FGFR1 fusion coexisting with a TP53 mutation in LUSC. These findings broaden the spectrum of potential translocation partners in FGFR1 fusions, and the clinical implications of this novel fusion on treatment outcomes and prognosis warrant further investigation and long-term follow-up. Show less

Although it has been shown that the tumor extracellular matrix (ECM) may sustain the cancer stem cell (CSC) niche, its role in the modulation of CSC properties remains poorly characterized. To elucidate this, paired tumor and adjacent normal mucosa, derived from colon cancer patients' surgical resections, were decellularized and recellularized with two distinct colon cancer cells, HT-29 or HCT-15. Methods: The matrix impact on cancer stem cell marker expression was evaluated by flow cytometry and qRT-PCR, while transforming growth factor-β (TGF-β) secretion and matrix metalloprotease (MMP) activity were quantified by ELISA and zymography. Results: In contrast to their paired normal counterparts, the tumor decellularized matrices enhanced HT-29 expression of the pluripotency and stemness genes Show less

Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat. Milk-derived exosomes, particularly those from sheep milk (SM-Exo), have shown potential in treating gastrointestinal disorders, though their efficacy in Cd-induced colitis remains unclear. In this study, we investigated the therapeutic potential of SM-Exo in a Cd-induced colitis model. Hu sheep were exposed to Cd, and their fecal microbiota were collected to prepare bacterial solutions for fecal microbiota transplantation (FMT) in mice. The changes in gut microbiota and gene expression were analyzed through microbiome and transcriptomics. Our results showed that prior to treatment, harmful bacteria (e.g., Show less

The refrigeration (cold storage) of platelet components provides several benefits over room-temperature (RT) storage, extending the shelf-life up to 21 days. However, the effect of storage conditions on platelet activation in response to stimulation remains unclear. A paired study was conducted where buffy-coat platelet concentrates were pooled, split, and allocated to RT or cold storage (n = 6 in each group). Platelet samples were taken on days 1, 7, 14, and 21, which were tested without stimulation or following activation with TRAP-6, A23187, lipopolysaccharides, or Histone-H4. Imaging flow cytometry was used to assess the surface characteristics of platelets and extracellular vesicles (EVs). The supernatant concentration of EGF, RANTES, PF4, CD62P, IL-27, CD40L, TNF-α, and OX40L was examined using ELISA. Cold-stored platelets generated a greater proportion of procoagulant platelets and EVs than RT-stored platelets in response to stimulation. The supernatant of cold-stored components contained lower concentrations of soluble factors under basal conditions, suggesting that platelet granules were better retained. Cold-stored platelets released higher concentrations of soluble factors following stimulation with TRAP-6, A23187, or Histone-H4. Only cold-stored platelets responded to lipopolysaccharides. These data demonstrate that cold-stored platelets retain the capacity to respond to stimuli after 21 days of storage, which may facilitate improved functional post-transfusion. Show less

The melanocortin receptor accessory protein 2 (MRAP2), which is abundantly expressed in the brain including the hypothalamus, has emerged as a key regulator of melanocortin-4 receptor (MC4R) activity. We sought to delineate the physiological significance of MRAP2 in MC4R neurons, with a particular focus on metabolic, autonomic and cardiovascular functions. Selective deletion of MRAP2 in MC4R neurons causes obesity that was associated with hyperphagia and impairment in glucose homeostasis and insulin sensitivity. MC4R agonist Melatonan II (MTII)-induced anorectic effects were blunted in mice lacking MRAP2 in MC4R neurons, whereas Celastrol retained its efficacy in reducing food intake and body weight. MRAP2 deletion also reduced baseline sympathetic nerve activity (SNA), particularly the SNA subserving the kidney. This was associated with reduced innervation of the kidney. In addition, MTII-induced increases in renal and brown adipose tissue (BAT) SNA as well as hepatic vagal nerve activity were significantly attenuated in MC4R neuron MRAP2-deficient mice. Transynaptic tracing revealed that MC4R neurons projecting to BAT and kidneys were localized to specific brain nuclei including the paraventricular nucleus of the hypothalamus, providing anatomical substrate for MRAP2 regulation of sympathetic outflow. Although the loss of MRAP2 in MC4R neurons did not affect arterial pressure, it caused a significant decrease in heart rate and baroreflex sensitivity. Finally, MRAP2 deficiency in MC4R neurons attenuated MTII-induced increase in arterial pressure and heart rate. These findings demonstrate that in addition to its role in energy balance and glucose homeostasis MRAP2 in MC4R neurons is crucial for cardiovascular autonomic regulation and is required for the development of obesity-associated hypertension and autonomic dysfunction. Show less

Monogenic defects in the leptin-melanocortin pathway are associated with hyperphagia and severe, early-onset obesity. Early childhood growth patterns in height, weight, and BMI, might serve as phenotypic markers for specific genetic disorders; however, reliable data are scarce. This study aimed to evaluate the natural history of height, weight, and BMI in early childhood in a large European group of individuals with monogenic obesity. This multicentre observational study analysed height, weight, and BMI from birth to age 5 years in individuals diagnosed with biallelic (likely) pathogenic LEP, LEPR, POMC, PCSK1, or MC4R variants or monoallelic (likely) pathogenic MC4R variants from six European centres (Berlin and Ulm, Germany; Cambridge, UK; Madrid, Spain; Paris, France; Rotterdam, Netherlands). All patient data up to May 31, 2022 were included in this analysis. All individuals had at least two height or weight measurements between birth and age 5 years. Early childhood growth trajectories were compared with those of control children with obesity without a known genetic cause, following a negative next-generation sequencing panel. Diagnostic performance of BMI as a predictor test for monogenic obesity was also evaluated. We included 147 individuals with monogenic obesity. From the age of 6 months onwards, children with biallelic variants (n=88, 55% female vs 45% male) had substantially higher BMIs than those with monoallelic MC4R variants (n=59, 53% female vs 47% male) and control children (n=113, 59% female vs 41% male). Children with biallelic LEP, LEPR, and MC4R variants showed a steep BMI increase during the first year of life, followed by a plateau until age 5 years, whereas those with biallelic POMC variants did not plateau. Accelerated linear growth was only observed in children with biallelic MC4R variants starting from age 1 year. The optimal BMI cut-off for distinguishing individuals with biallelic variants from control individuals was identified at age 2 years, with a test positivity cutoff of 24·0 kg/m This study identified characteristic early childhood BMI trajectories for different forms of monogenic obesity. From age 6 months onwards, individuals with biallelic variants can be distinguished from those with monoallelic variants and common obesity. A BMI ≥24 kg/m Federal Ministry of Education and Research as part of the German Center for Child and Adolescent Health, German Research Foundation, Spanish Ministry of Health, The Wellcome Trust, Botnar Fondation, Leducq Foundation, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, and NIHR Senior Investigator Award. Show less

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic or likely pathogenic variants, of which 30-50 % involve a variant in the gene encoding cardiac myosin-binding protein-C (MYBPC3). We generated human induced pluripotent stem cell lines from five individuals from two families carrying a pathogenic Dutch MYBPC3 founder variant: c.2373insG (n = 2) and c.2827C > T (n = 3), with highly variable disease expression. Peripheral blood mononuclear cells were reprogrammed using episomal plasmids. All cell lines express pluripotent markers, exhibit a normal karyotype, and could differentiate into derivatives of each germ layers in vitro. These cell lines can serve as disease model to investigate HCM pathogenesis. Show less

Human single nucleotide variants in peroxisome proliferator-activated receptor-ɑ (PPARɑ) have been associated with beneficial metabolic phenotypes, yet their specific effects on metabolic gene expression are not well defined. Here, we developed a mouse model of a human PPARɑ variant encoding a substitution of valine for alanine at position 227 (V227A) to explore the role of this variant on systemic metabolism. Substitution with this variant in mice reduced plasma triglycerides, without altering body mass or liver lipid accumulation, consistent with phenotypes observed in human cohorts. Gene expression analysis revealed that the V227A variant enhances Ppara target gene expression in mouse liver, consistent with the effects of synthetic PPARɑ agonist treatment. Notably, V227A increased hepatic expression of Lpl, the predominant enzyme responsible for circulating triglyceride hydrolysis. Further characterization revealed that heart tissue from variant mice exhibited increased Lpl expression and triglyceride hydrolysis activity, suggesting that V227A enhances cardiac triglyceride clearance. These findings validate human observational studies and clarify the physiological impact of the V227A PPARɑ variant on plasma triglycerides. Show less

Alzheimer's disease (AD) remains a formidable challenge, necessitating the discovery of effective therapeutic agents targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1). This study investigates the inhibitory potential of phytochemicals derived from Bacopa monnieri, a plant renowned for its cognitive-enhancing properties, in comparison to established synthetic inhibitors such as Atabecestat, Lanabecestat, and Verubecestat. Utilizing molecular docking and advanced computational simulations, we demonstrate that Bacopaside I exhibits superior binding affinity and a unique interaction profile with BACE1, suggesting a more nuanced inhibitory mechanism. Our findings highlight the promising role of Bacopa monnieri phytochemicals as viable alternatives to synthetic drugs, emphasizing their potential to overcome limitations faced in clinical settings. Furthermore, the development of the SIMANA ( https://simana.streamlit.app/ ) platform enhances the visualization and analysis of protein-ligand interactions, facilitating a deeper understanding of the dynamics involved. This research not only underscores the therapeutic promise of natural compounds in AD treatment but also advocates for a paradigm shift towards integrating traditional medicinal knowledge into contemporary drug discovery efforts. Show less

To investigate the role of adipokines in primary open angle glaucoma (POAG) by comparing the levels of these molecules in the aqueous humor among POAG patients and cataract patients with or without metabolic disorders. In this cross-sectional study, aqueous humor samples of 22 eyes of POAG patients (POAG group), 24 eyes of cataract patients without metabolic disorders (cataract group), and 24 eyes of cataract patients with metabolic disorders (cataract+metabolic disorders group) were assessed for 15 adipokines by Luminex bead-based multiplex array. The correlation between aqueous humor adipokines and clinical indicators of POAG was analyzed and compared across the groups. The analysis revealed that the levels of adiponectin, leptin, adipsin, retinol-binding protein 4 (RBP4), angiopoietin-2, angiopoietin-like protein 4 (ANGPTL4), chemokine (C-C motif) ligand 2 (CCL2), interleukin-8 (IL-8), and interleukin-18 (IL-18) in the aqueous humor of the POAG group were significantly higher than those in the cataract group. Additionally, the level of angiopoietin-2 in the POAG group was higher than in the cataract+metabolic disorders group. However, no significant correlation was found between the levels of adipokines in the POAG group and intraocular pressure (IOP), severity of POAG, or the use of glaucoma medications. This study demonstrates significant differences in aqueous humor adipokine levels between POAG and cataract patients. The findings suggest that the levels of aqueous humor adipokines may reflect the inflammatory states in POAG and systemic metabolic abnormalities. Show less

We aimed to study the role of Apolipoprotein B (Apo-B) polymorphisms (Ins/Del and EcoRI) and genotype interaction on lipid profiles and atherogenic indices in response to changes in dietary total antioxidant capacity (DTAC) of diet. This cross-sectional study consisted of 700 diabetic patients. Biochemical markers including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), superoxide dismutase (SOD), C-reactive protein (CRP), total antioxidant capacity (TAC), interlukin-18 (IL-18), and Prostaglandin F2α (PGF2α) were measured based on standard protocols. Genotyping of the Apo-B polymorphisms was conducted by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Subjects with Ins/Ins genotype with higher DTAC intake had lower TG, AIP, and AC compared to Del-allele carriers. Moreover, A-allele carriers (EcoRI) with a higher median intake of DTAC had lower body mass index (BMI) and waist circumference (WC) compared to GG homozygotes. For combined genotypes, the EcoRI only variant (Ins/Ins and AA + AG) with higher DTAC intake had lower BMI and WC. Moreover, Ins/Del only variant (Ins/del + del/del and GG) with more adherence to DTAC had higher TG and AIP. Our study showed that Apo-B polymorphisms interact with the antioxidant capacity of diet to ameliorate the risk of cardio-metabolic diseases, especially atherosclerosis in the A carriers of EcoR1 and Ins/Ins homozygous of Ins/Del polymorphism. Show less

Congenital anomalies of the kidney and urinary tract (CAKUT) represent a major health burden in humans. Phenotypes range from renal hypoplasia or renal agenesis, cystic renal dysplasia, duplicated or horseshoe kidneys to obstruction of the ureteropelvic junction, megaureters, duplicated ureters, urethral valves or bladder malformations. Over the past decade, next-generation sequencing has identified numerous causative genes; however, the genetic basis of most cases remains unexplained. It is assumed that environmental factors have a significant impact on the phenotype, but, overall, the pathogenesis has remained poorly understood. Interestingly however, CAKUT is a common phenotypic feature in two human syndromes, Kabuki and Koolen-de Vries syndrome, caused by dysfunction of genes encoding for KMT2D and KANSL1, both members of protein complexes playing an important role in histone modifications. In this chapter, we discuss current knowledge regarding epigenetic modulation in renal development and a putatively under-recognized role of epigenetics in CAKUT. Show less

Gastric cancer (GC) is an aggressive and heterogeneous disease with poor survival outcomes. The progression of GC involves complex, multi-step processes. Endothelial cells (ECs) play a crucial role in tumor angiogenesis, proliferation, invasion, and metastasis, particularly through the process of endothelial-to-mesenchymal transition (EndoMT). However, the specific role and mechanisms of EndoMT in gastric cancer remain unclear. Based on 6 GC single-cell RNA-sequencing (scRNA-seq) cohorts (samples = 97), we established an EndoMT-related gene signature, termed EdMTS. Leveraging this gene signature, ssGSEA was applied to calculate sample scores across multiple bulk RNA-seq datasets, which include information on immunotherapy, metastasis, GC progression, and survival. Moreover, we applied the Monocle2 method to calculate cell pseudotime and used CellChat to analyze interactions between malignant and EC cells. We verified the molecular mechanism by multiple immunofluorescence and cell function experiments. Findings In this study, we established a single-cell atlas of ECs in GC and identified a subpopulation of COL1A1 Show less

Approximately 95% of lymphoplasmacytic lymphomas (LPL) are IgM secreting and are characterized as Waldenstrom Macroglobulinemia (WM). Conversely, non-IgM secreting LPL are rare. As part of the 12th International Workshop on WM (IWWM-12), a consensus panel of experts was tasked to develop recommendations for the management and response assessment of non-IgM LPL. The panel considered that in view of available molecular, pathological and clinical data, non-IgM LPL should be considered as a separate sub-entity of LPL. The panel further recommended that the IWWM-2 consensus criteria used for IgM LPL (WM) treatment initiation, should also be used for non-IgM LPL and be independent of IgG or IgA paraprotein level unless symptomatic hyperviscosity is present. The panel agreed that based on current evidence, there is insufficient data to support a different clinical management for non-IgM vs IgM (WM) LPL. Moreover, the panel advised that patients with non-IgM LPL should be treated in a similar manner to patients with IgM LPL independent of MYD88 mutation status until more is known about its impact on treatment outcomes for non-IgM LPL patients. The panel therefore recommends the use of the IWWM-11 IgM LPL (WM) response criteria for cases of non-IgM LPL with a monoclonal IgA or IgG paraprotein component, but creating a specific panel to develop formal response criteria for this LPL subset was also recommended. Show less

Breast cancer, a major threat to women's health worldwide, has mechanisms of onset that remain unclear. Within the human lysosomal system, a class of enzymes known as cathepsins exhibit elevated expression levels in various malignant tumors, suggesting that they may play key roles in cancer progression. This study employed the two-sample Mendelian randomization (MR) approach to investigate the potential causal relationship between cathepsin levels and the risk of developing breast cancer. Furthermore, we conducted MR analysis using eQTL data to investigate how gene expression, mediated by cathepsins, affects the occurrence of different types of breast cancer and assessed the regulatory effects of cathepsins. MR analysis revealed that increased levels of cathepsin E are associated with a greater risk of malignant breast tumors (IVW: p = 0.006, OR = 1.103, 95% CI = 1.028-1.184), and increased levels of cathepsin F are associated with an increased risk of These findings highlight the dual roles of cathepsins as potential risk and protective factors for breast cancer, underscoring their potential in diagnostic and therapeutic strategies. Show less