👤 Ethan Lee

Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care. Show less

Maternal separation (MS) is a widely used model of early-life stress that induces long-lasting behavioral and neurobiological alterations in offspring. Maternal exercise during pregnancy has been proposed as a non-pharmacological strategy to counteract these adverse effects. Pregnant Wistar rats were assigned to either a sedentary or exercise group, with the exercise group having free access to a running wheel throughout pregnancy. Offspring were divided into four experimental groups: offspring of sedentary mothers without MS (SedMS-), offspring of sedentary mothers with MS (SedMS+), offspring of exercised mothers without MS (ExMS-), and offspring of exercised mothers with MS (ExMS+). Behavioral assessments, conducted in adulthood starting at postnatal day 90 (P90), included the open field, elevated plus maze, forced swim test, and contextual fear conditioning. Morphological analysis of the hippocampus was performed using isotropic fractionation to quantify total neuronal and non-neuronal cells. Epigenetic changes were evaluated through chromatin immunoprecipitation (ChIP) using anti-acetylated histone H3 and H4, followed by amplification of bdnf exons IV and VI. Maternal separation increased depressive-like behavior and impaired hippocampus-dependent memory, effects that were attenuated by maternal exercise. MS also elevated non-neuronal cell numbers and reduced neuronal cells in the hippocampus, whereas prenatal exercise reversed these alterations. No significant group differences were found in histone acetylation at the Bdnf loci examined. Maternal exercise during pregnancy mitigates behavioral and morphological deficits induced by early-life stress, supporting its neuroprotective role in preserving hippocampal integrity and function. Although no significant epigenetic changes were detected, these findings suggest that maternal physical activity may be a promising intervention to mitigate the long-term neurobiological consequences of early-life adversity. Show less

High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK-ERK-CREB-BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline. Show less

Theogallin, a tea-derived polyphenol enriched in newly developed cultivars such as MK5601, has been shown to have cognitive benefits. However, its biological and mechanistic effects of theogallin remain unclear. Herein, we investigated the transcriptomic profiles of six mouse tissues after oral theogallin administration. Theogallin induced tissue-enriched transcriptional responses, particularly in the brain, where it activated memory-related and neuronal activity-related pathways through the upregulation of immediate-early genes (IEGs). These transcriptional changes closely resembled brain-derived neurotrophic factor (BDNF)-induced neuronal activation and contrasted with gene expression patterns associated with Alzheimer's disease. In aged mice, theogallin improved recognition memory and increased the expression of IEGs-associated proteins, while reducing neurodegeneration-linked markers. Theogallin also enhanced neuronal gene expression in SH-SY5Y cells, supporting a direct neuromodulatory role and further promoting neurite outgrowth. Therefore, theogallin is a functional enhancer of neuronal activation with potential therapeutic relevance for age-related cognitive decline and neurodegenerative disorders. Show less

Schisandrin C (SCC), a bioactive lignan compound derived from Schisandra chinensis (S. chinensis), has been demonstrated to promote intestinal health. However, the antidepressant activity of SCC and its impact on the gut‒brain axis have not been reported. This study aimed to investigate the antidepressant effects of SCC and elucidate its molecular mechanisms through modulation of the microbiota‒gut‒brain axis. Artificial intelligence (AI)-based target protein prediction, network pharmacology analysis, and experimental validation using intestinal cells, Caenorhabditis elegans, and mice models were conducted. Targeted metabolomics, gut microbiota analyses, and molecular biology techniques were employed for mechanistic elucidation. SCC treatment effectively suppressed depressive-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). SCC upregulated brain-derived neurotrophic factor (BDNF) expression in the brain by regulating the AKT/CREB/BDNF signaling pathway. Additionally, integrated network pharmacology, molecular docking, and metabolomics analyses revealed that SCC significantly increased brain serotonin levels by inhibiting monoamine oxidase (MAO) activity. Furthermore, SCC increased the abundance of Akkermansia and Bifidobacterium, as observed both in the synthetic microbial community in vitro and in the gut microbiota in vivo. Additionally, SCC effectively alleviated intestinal barrier dysfunction and reduced intestinal inflammation in vitro in intestinal cells, in vivo in C. elegans infected with Bacteroides fragilis, and in vivo in the CUMS-induced mice model. SCC improves depressive-like behaviors by modulating the microbiota‒gut‒brain axis. These findings underscore the potential of SCC as an effective therapeutic agent for depression. Show less

Sensory neurotoxicity involves damage to the sensory nerves, often resulting from exposure to chemicals, medications, toxins, infections, or neurological disorders. Benzalkonium chloride (BKC) is a widely used quaternary ammonium compound with antiseptic properties, commonly present in pharmaceuticals, household products, and cosmetics. While the potential neurotoxicity of BKC has been previously explored in ocular and nasal epithelia, its impact on other sensory systems and the underlying mechanisms remain largely unclear. In this study, we used zebrafish (Danio rerio) embryos to assess the developmental neurotoxicity of BKC. Embryonic exposure to 0.72, 1.28, and 2.24 mg/L BKC led to dose-dependent impairments in mechanosensory hair cells, reduced startle responses, and heightened nociceptive sensitivity upon noxious stimulation. BKC exposure induced pronounced oxidative stress, evidenced by increased reactive oxygen species levels, reduced antioxidant enzyme activity, and altered expression of redox-regulating genes. Moreover, BKC significantly upregulated inflammatory and pain-associated genes, including tnfa, il1b, cox2, bdnf, and trpa1b. Expression profiling of hair cell differentiation markers revealed increased pou4f3 and decreased tmc2a/tmc2b, suggesting that BKC disrupts both terminal differentiation and mechanotransduction processes in sensory hair cells. Collectively, these findings uncover a novel mechanistic link between oxidative stress, impaired hair-cell maturation, and sensory dysfunction, offering new insights into the mechanisms underlying BKC-induced sensory neurotoxicity. This study emphasizes the ecological and toxicological relevance of quaternary ammonium compounds in aquatic environments. Show less

Pathological neuroinflammation is a critical factor that disrupts neuronal activity and, when sustained, ultimately contributes to neuronal death. Among the primary mediators of neuroinflammation, microglia play a central role in modulating brain immunity. However, their overactivation is closely associated with neuronal damage and structural remodeling of brain tissue, leading to the onset and progression of various neurodegenerative diseases. We investigated the neuroprotective effects of avarol, a marine-derived sesquiterpenoid, focusing on its ability to inhibit lipopolysaccharide (LPS)-induced overactivation of BV2 microglial cells and its subsequent impact on neuronal activity in HT-22 hippocampal neuronal cells. Pretreatment with avarol significantly attenuated the LPS-induced release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), as well as oxidative stress markers such as reactive oxygen species (ROS) and nitric oxide (NO). These inhibitory effects were further substantiated by a dose-dependent reduction in nuclear translocation of nuclear factor-kappa B (NF-κB), a key transcription factor involved in the inflammatory signaling cascade. Regarding the interaction between microglia and neurons, both conditioned medium and co-culture systems demonstrated that avarol significantly attenuated alterations in neuronal plasticity-related molecules-such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)-induced by activated microglia. Overall, these findings suggest that avarol exerts neuroprotective effects through the modulation of microglia-mediated neuroinflammation. Importantly, avarol's capacity to traverse the blood-brain barrier highlights its potential as an effective pharmacological agent in mitigating neuroinflammation-associated neurological disorders. Show less

Food allergy (FA) arises from a complex interplay between an individual's genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been hindered by small sample sizes and varying FA definitions. We sought to identify novel FA risk loci by conducting a genome-wide association study meta-analysis in children and adults by using a multiphenotype approach to ensure a good trade-off between sufficient sample size and valid FA definitions. Analyses were conducted separately in children and adults on the basis of the following FA phenotypes: self-report, doctor diagnosis, food-specific sensitization, and doctor diagnosis plus food-specific sensitization. A meta-analysis was performed of genome-wide association studies from up to 16 cohorts of people of European ancestry including 229,426 adults and 14,234 children. Models were adjusted for sex, age, principal components, and, if applicable, further study-specific confounders. Sensitivity models were additionally adjusted for hay fever. Replication was conducted in additional external cohorts and a validation in oral food challenge-defined FA cases. Thirty-seven single nucleotide polymorphisms met suggestive significance (P < 1 × 10 This study identified 37 single nucleotide polymorphisms suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on FA's shared genetic architecture with allergies. Show less

Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence. Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry. Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6 INTS6 The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival. Show less

Climate change creates major challenges in livestock industry, making chickens vulnerable to heat stress because they can tolerate a narrow range of temperatures. Heat stress disrupts metabolic and physiological homeostasis, leading to reduced growth, productivity, reproduction, and immune function, thereby threatening the economic viability of poultry farming. This review explores the multifaceted impacts of heat stress on poultry, including physiological responses, production performance, and immune function. Recent advances in transcriptomic and genomic research have shed light on the molecular mechanisms underlying heat stress resilience in poultry. Key genes such as HSP70, HSP90, HSP27, and HSP47 are significantly upregulated under heat stress, playing vital roles in protein folding, preventing aggregation, and protecting cellular integrity. Additionally, genes like SOD and CAT enhance antioxidant defenses, mitigating oxidative damage. Genes such as RB1CC1, BAG3, and TRMT1L regulate apoptosis and oxidative stress, promoting cell survival. In the liver, CCK, DIO3, and ANGPTL4 improve energy homeostasis and reduce metabolism-related heat production, while BMP10 and MYH7 in the heart contribute to cardiac adaptation during thermal stress. Genetic adaptations such as the Naked neck, Frizzle, and Dwarf gene provide intrinsic thermotolerance by reducing feather mass, altering feather structure, and minimizing body size, thereby improving heat dissipation. These genetic traits, combined with transcriptomic insights into heat resilience genes, offer opportunities for developing heat-tolerant chicken breeds. By integrating molecular genetics, transcriptomics, and management strategies, this review highlights the importance of selective breeding programs to enhance poultry thermotolerance. Future research should focus on leveraging indigenous breeds, advanced molecular tools, and nutritional interventions to mitigate the effects of rising global temperatures. Enhancing heat stress resilience in poultry is imperative to ensure sustainable production and global food security in this climate change. Show less

Reliable prediction of reproductive toxicity remains a critical challenge in drug development and environmental safety. Here, a biomarker-integrated, fluorescent reporter-based reproductive organ-on-a-chip platform that recapitulates the multicellular composition, 3D architecture, endocrine signaling, and cyclic dynamics of the human menstrual cycle, is presented. The system is constructed using primary human theca, granulosa, endometrial stromal and stem cells, vascular endothelial cells, uterine macrophages, and myometrial smooth muscle cells, compartmentalized within collagen-hyaluronic acid hydrogels. Early-response toxicity biomarkers-ANGPTL4 (ovary) and SERPINB2 (endometrium)-are genetically linked to mCherry or GFP fluorescent reporters, enabling real-time, cell-type-specific visualization of toxicant-induced stress. Transcriptomic profiling, KEGG pathway enrichment, and gene knockdown studies confirm ANGPTL4 and SERPINB2 as functional mediators of toxic injury, not just passive indicators. Upon exposure to dioxin and other reproductive toxicants, the platform shows strong, region-specific fluorescent responses that preceded changes detected by conventional cytotoxicity assays. This system demonstrates high sensitivity, temporal precision, and mechanistic insight, offering a scalable and physiologically relevant tool for high-content reproductive toxicology screening. Furthermore, it supports endocrine crosstalk between the ovary and uterus, and dynamic responses across the menstrual cycle, enabling future applications in personalized toxicity prediction and preclinical safety evaluation. Show less

Tinnitus is a complex neurological condition affecting 10-15% of adults worldwide, characterized by phantom auditory perception without external sound sources. While traditional investigations have focused on discrete auditory structures, emerging evidence suggests tinnitus involves broader alterations across central auditory regions. This study employed transcriptomic analysis to investigate molecular mechanisms underlying salicylate-induced tinnitus across multiple brain regions simultaneously. Male C57BL/6 N mice received daily intraperitoneal injections of sodium salicylate (350 mg/kg) for five consecutive days to induce tinnitus-like behavior, assessed using gap-prepulse inhibition of acoustic startle reflex. RNA sequencing was performed on auditory cortex, inferior colliculus, and cochlear nucleus tissues. Differential gene expression analysis, weighted gene co-expression network analysis, and functional annotation were conducted to identify shared molecular signatures and pathways across auditory centers. Principal component analysis revealed region-specific transcriptomic changes following salicylate treatment. Differential gene expression analysis identified Depp1 and Angptl4 as consistently upregulated genes across multiple brain regions, particularly within the inferior colliculus and cochlear nucleus. Weighted gene co-expression network analysis revealed a 215-gene module increased across all auditory regions in tinnitus mice, with functional annotation indicating enrichment for vasculature-related biological processes. Depp1 emerged as a central hub gene linking oxidative stress responses to autophagy mechanisms. This study shows that tinnitus pathology involves not only neuronal hyperactivity but also oxidative stress, neuroinflammation, and autophagy in the central auditory pathway. Depp1 acts as a molecular hub linking redox imbalance to cellular clearance, highlighting its potential as a therapeutic target and offering new insights for intervention. Show less

Angiopoietin-like 4 (Angptl4) is a secreted glycoprotein involved in the regulation of various homeostatic and disease processes. In the intestine, prior studies have suggested protective roles for Angptl4 in inflammation using Angptl4 knockout mouse models; however, phenotypic variability-such as perinatal lethality and intestinal inflammation accompanied by lymphatic defects in only a subset of animals-has complicated the interpretation of its role in intestinal pathogenesis. In this study, the impact of Angptl4 deficiency was examined using a subset of Angptl4 knockout mice that survive postnatally without overt abnormalities. It was found that loss of Angptl4 confers protection against colitis and colitis-associated colorectal tumorigenesis. These protective effects were associated with the alternative activation of anti-inflammatory M2-like macrophages. Similarly, in a genetic model of intestinal tumorigenesis, Angptl4 deficiency resulted in reduced tumor burden and attenuated inflammation, accompanied by increased M2-like macrophages. Analysis of human colorectal cancer data sets further revealed that low ANGPTL4 expression is associated with improved survival outcomes as well as reduced expression of inflammation-related marker genes. Collectively, the findings uncover a previously unrecognized protective effect of Angptl4 deficiency against intestinal pathogenesis via anti-inflammatory mechanisms, suggesting Angptl4 as a potential therapeutic target and prognostic biomarker for colorectal cancer and inflammatory bowel disease. Show less

Skin aging arises from intrinsic processes and extrinsic insults (e.g., ultraviolet exposure and oxidative stress). Mesenchymal stromal cell (MSC)-derived secretome offers a cell-free approach to skin regeneration. Wharton's jelly-derived MSCs (WJ-MSCs) may outperform adipose-derived (AD-MSCs) and bone marrow-derived MSCs (BM-MSCs). Secretomes from WJ-MSCs, AD-MSCs, and BM-MSCs were compared in vitro for human dermal fibroblast proliferation, scratch-wound closure, extracellular-matrix (ECM) remodeling, and type I procollagen secretion. Anti-inflammatory and antioxidant activities were assessed by IL-6, IL-1β, TNF-α, COX-2 and intracellular reactive oxygen species (ROS). Antibody arrays profiled secreted factors. An exploratory, single-arm human pilot ( The WJ-MSC secretome increased fibroblast proliferation, ECM remodeling, and type I procollagen, and reduced cytokines and ROS, exceeding the effects of AD-MSC and BM-MSC secretomes. Profiling highlighted apolipoprotein A4 (ApoA4) and SERPINH1 as enriched, functionally active mediators; recombinant ApoA4 and SERPINH1 enhanced fibroblast activity, collagen-related readouts, and accelerated in vitro wound closure. In the pilot study, within-subject increases in instrument-derived hydration and elasticity were observed over one week (paired tests). No treatment-related adverse events were noted. Patch testing showed no irritation (ICDRG scores all 0; non-irritant classification). The WJ-MSC secretome demonstrated consistent in-vitro pro-regenerative, anti-inflammatory, and antioxidant activities, with ApoA4 and SERPINH1 as candidate mediators. Human findings are preliminary/exploratory and suggest potential short-term benefits that require confirmation in adequately powered, controlled trials. Show less

Hypertriglyceridaemia-induced pancreatitis in pregnancy (HTG-IPP) is a rare but serious condition. There is a paucity of evidence-based guidelines and recommendations for screening and management of HTG-IPP. Individual genomics can predispose certain populations to a higher risk of developing HTG-IPP. To report on a case series of the management of four individual pregnancies complicated by HTG-IPP, subsequently found to be associated with pathogenic genetic variants involved in triglyceride (TG) metabolism. The medical records of four individual pregnancies from two metropolitan hospitals in Australia were reviewed regarding the management of their HTG-IPP and genetic testing for hypertriglyceridaemia (HTG). A literature review of previous cases of HTG-IPP with an identified pathogenic variant was performed. The identified genetic variants resulting in a diagnosis of HTG and HTG-IPP were within glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1), lipoprotein lipase (LPL) and apolipoprotein A5 (APOA-5). All patients had co-morbid gestational diabetes mellitus (GDM) and were of South Asian or Asian ethnicity. All four patients were effectively managed with fasting, intravenous insulin, omega-3 fatty acids (O3FAs) and very low-fat diet (VLFD) with supplementation with medium-chain TG (MCT) oil. Further genomics research is needed to increase our understanding for its use in predicting risk of severe gestational HTG. With additional case identification, particular variants of pathogenic interest can be identified and screened for antenatally in patients with a moderate fasting HTG of more than 200 mg/dL (11.1 mmol/L) in the absence of other causative factors. Pre-conception optimisation of TGs and regular monitoring in pregnancy can reduce the incidence and disease burden associated with HTG-IPP and HTG. Show less

Apolipoprotein B (APOB) containing lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB, comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1 mediated uptake of APOB100 containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease. Show less

This study aimed to identify novel key targets and mechanisms for repurposing strategies and mitigating sorafenib (SFB) resistance using the GEO transcriptomic dataset GSE94550 within a systems pharmacology framework. Potential counteracting molecules against SFB were retrieved from chemical repositories, followed by molecular docking tests (MDT), Kaplan-Meier survival analysis, and density functional theory (DFT) assessments to evaluate therapeutic potential. PPI networks were constructed using STRING and R to characterize the relationships between upregulated and downregulated genes. The most relevant signalling pathways associated with major targets were determined to elucidate the upstream regulatory mechanisms. Among the differentially expressed genes, APOB emerged as a pivotal regulator (log Show less

Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder with an extremely elevated level of low-density lipoprotein (LDL) cholesterol (LDL-C) and accelerated premature coronary artery disease (PCAD). It is primarily caused by a single pathogenic variant of the LDL receptor (LDLR) gene. This report presents 2 rare and unrelated cases of HoFH with compound LDLR mutations. These 2 individuals presented with atypical clinical features and demonstrated variable degrees of hypercholesterolemia. Case 1 is a 36-year-old Malay woman identified during family cascade screening with a pretreated LDL-C of 8.5 mmol/L and a strong family history of PCAD. Case 2 is a 58-year-old Indian woman discovered to have a pretreated LDL-C of 5.2 mmol/L during routine health screening, without a significant family history of hypercholesterolemia or PCAD. Neither patient demonstrated tendon xanthomas or other lipid stigmata. Both patients underwent lipid profiling and targeted next-generation sequencing of FH-related genes (LDLR, APOB, PCSK9, ABCG5, and ABCG8). Two novel LDLR variants were identified in exon 18: c.2548-1₂₅₄₈delGAinsTC (pathogenic) and c.2556₂₅₅₇insTCAGTCTGG (p.Leu853Serfs*12; likely pathogenic) and classified according to American College of Medical Genetics and Genomics guidelines. Case 1 was homozygous for both variants, while Case 2 was homozygous for the splice-site variant and heterozygous for the frameshift variant. Both patients received guideline-directed lipid-lowering therapy and ongoing cardiovascular risk management. Despite biallelic LDLR variants, both patients demonstrated relatively milder hypercholesterolemia and absence of classical HoFH stigmata. The LDLR variants located in exon 18 affecting the cytoplasmic tail domain may be associated with attenuated clinical expression. Recognition of genotype-phenotype variability is crucial for accurate diagnosis, risk stratification, and individualized management of HoFH. Show less

The hemolymph of crustaceans (decapods, isopods, amphipods, copepods, branchiopods, cirripedes) and chelicerates (ticks, mites, spiders, scorpions, horseshoe crabs) contain female-specific and sex-independent lipoproteins in the high-density lipoprotein (HDL, density: 1.063-1.21 g/ml) and very high-density lipoprotein (VHDL, density>1.21 g/ml) classes. The first part of this review includes the history of the important developments in the study of hemolymph lipoproteins, synthesis by different tissues, important functions and synthesis/utilization by developing embryos. The sex-independent and female-specific lipoprotein have very different functions. The sex-independent lipoprotein functions include clotting, pattern recognition and transport of lipids, hormones, vitamins, heme and pheromones. Female-specific lipoproteins primarily serve as a source of energy and nutrition for developing embryos. Female-specific lipoproteins are assembled in the ovary, hepatopancreas, fat body or mid-gut and after the peptide is cleaved into subunits the lipoproteins are secreted into the hemolymph with subsequent uptake into the developing oocytes by receptor-mediated endocytosis. The second part of the review covers the past two decades of work which focused on the genes that encode the lipoproteins and determination of their amino acid sequences. Most crustacean and chelicerate lipoproteins are in the apolipoprotein B-like (apoB-like) or the vitellogenin-like (Vg-like) families of the superfamily of large lipid transfer proteins involved in the assembly, secretion and metabolism of lipoproteins. Decapod female-specific lipoproteins, vitellogenin/apocrustacein (Vg/apoCr), are in the apoB-like family while the female-specific lipoproteins in other crustacean groups and chelicerates are in the Vg-like family. Each family is characterized by certain major structural domains which are responsible for lipid binding, carbohydrate attachment and receptor binding. Show less

To evaluate the lipid-lowering efficacy, safety, and adherence of switching from moderate- or low-intensity statin monotherapy to ezetimibe 10 mg/rosuvastatin 2.5 mg in Korean patients with type 2 diabetes mellitus (T2DM) and dyslipidaemia. This multicentre, open-label, single-arm, prospective study enrolled adults with T2DM and LDL-C ≥70 mg/dL despite ≥12 weeks of moderate or low-intensity statin therapy. Participants received ezetimibe 10 mg/rosuvastatin 2.5 mg once daily for 12 weeks. The primary endpoint was the proportion achieving LDL-C <70 mg/dL at Week 12. Secondary endpoints included changes in lipid and glycaemic parameters, subgroup analyses, and safety outcomes. Of 639 screened patients, 586 were included in the full analysis set (FAS). At Week 12, 62.3% (95% CI 58.4-66.2) achieved LDL-C <70 mg/dL. Mean LDL-C decreased by 26.0% from 90.9 ± 17.2 to 67.3 ± 19.3 mg/dL (p < 0.001). Total cholesterol, non-HDL-C, and apoB decreased significantly (all p < 0.001); HDL-C and triglycerides were unchanged (p = 0.914 and p = 0.393, respectively). HbA1c increased by 0.15 ± 0.53% and fasting glucose by 3.6 ± 24.7 mg/dL (both p < 0.001). HOMA-IR decreased by -0.22 ± 3.09, not significant (p = 0.085). Subgroup analyses showed greater LDL-C reductions in patients with BMI <23 kg/m Switching to ezetimibe 10 mg/rosuvastatin 2.5 mg achieved substantial LDL-C reductions, high goal attainment, excellent adherence, and good tolerability in Korean T2DM patients with dyslipidaemia. Show less

This study developed and validated a continuous metabolic syndrome (MetS) risk score (msRS) for adolescents and evaluated its clinical utility in identifying multiple clinical cardiovascular markers (CCMs) using dual adolescent populations. Adolescents aged 12‒18 from two stratified random samples were used: the nationwide Nutrition and Health Survey in Taiwan (NAHSIT, n = 1920) for development and the Adiposity‒Cardiovascular Disease Axis study in Southern Taiwan (adiCards, n = 3295) for validation. Four sex-and-age-specific msRS were developed through confirmatory factor analysis (CFA) utilizing five MetS components-waist circumference, high-density lipoprotein cholesterol, triglycerides, fasting glucose, and mean arterial pressure. Their discriminatory ability for clinical outcomes was validated using the area under receiver operating characteristic (AU-ROC) curve. The msRS demonstrated exceptional capability in detecting MetS in NAHSIT and adiCards cohorts (AU-ROCs: 0.954‒0.969). Adjusted for covariates, msRS explained higher variability in body-fat percentage, apolipoproteins B/A1, and homeostatic model assessment of insulin resistance (HOMA-IR) than binary MetS and abnormal components count (partial R The CFA-derived sex-and-age-adjusted msRS scheme provides an improving measure to assess and manage adolescent cardiometabolic health. Adolescent MetS components share a latent metabolic construct. A scoring system through confirmatory factor analysis captures sex-and-age specific metabolic heterogeneity. Continuous risk score accurately discriminates pediatric MetS. MetS risk score effectively detects pediatric cardiovascular risk. Consideration of population characteristics is essential when developing a continuous MetS score. Show less

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Ribonuclease P (RNase P) is an essential metallonuclease found in all three domains of life. However, the structural basis for the ancient RNase P RNA component acting alone as a ribozyme and catalytic metal-ion chemistry remains unknown. We report a series of cryo-EM structures, at resolutions of 2.8-3.5 Å, of the Geobacillus stearothermophilus RNase P aporibozyme (apoE) in various states of the catalytic cycle. The formation of both the tetraloop/tetraloop-receptor interaction and the interdigitated double T-loop motif in the substrate-specificity domain facilitates substrate binding. The apoE uses two metal ions for catalysis, suggesting a catalytic mechanism and evolutionary importance of the RNase P ribozyme to function without its protein component. Together, our data portray the regulatory RNA-RNA interfaces, dynamic structures, and cation traffic that confer function to a trans-acting ribozyme. Show less

Alzheimer's disease prediction using genomic data remains challenging due to the high dimensionality of whole-genome sequencing data and the complex relationships between genetic variants. We developed DuAL-Net (Dual Approach Local-global Network), a hybrid framework that integrates local genomic window analysis with global annotation-based modeling to prioritize disease-associated single-nucleotide polymorphisms (SNPs). As a proof of concept, we applied DuAL-Net to 14,094 SNPs within the Show less

This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status. Show less

The rare APOE3-Christchurch (APOE3Ch) variant is linked to resistance against PSEN1 p.E280A-driven autosomal dominant Alzheimer's disease (AD). Recent studies in AD mouse models have demonstrated an effect of APOE3Ch in reducing tau pathology and tau propagation, yet its effects on amyloid pathology and related toxicity are not fully understood. While prior studies have reported reduced amyloid pathology with APOE3Ch, we extended this knowledge by investigating how astrocyte-specific expression of APOE3Ch impacts amyloid pathology and related responses in 5xFAD mice, an amyloid mouse model. Using adeno-associated virus (AAV)-mediated gene delivery, we overexpressed APOE3 or APOE3Ch in astrocytes of 5xFAD mice at the neonatal stage, then analyzed their effects during the advanced stage of amyloid pathology. Astrocytic APOE expression significantly reduced amyloid burden, neuritic dystrophy, and gliosis compared to GFP controls. Notably, astrocytic APOE3Ch expression, relative to APOE3, markedly lowered oligomeric Aβ levels and promoted the formation of more compact, fibrillar plaques, suggesting a shift toward a less toxic aggregation profile. Transcriptomic profiling of cortical tissue revealed broad downregulation of immune-related and proteostatic pathways. These findings indicate that astrocytic APOE3Ch sufficiently attenuates Aβ pathology and related toxicity, supporting its potential as a therapeutic modifier for AD. Show less

This study evaluates the clinical validity of the Korean Computerized Cognitive Function Test (CFT-S) by comparing its domain-specific scores with those of the Seoul Neuropsychological Screening Battery-II (SNSB-II) in patients with Mild Cognitive Impairment (MCI) or Alzheimer's Disease (AD). A total of 300 participants (MCI: n = 163; AD: n = 137) from Severance Hospital completed both CFT-S and SNSB-II assessments within a two-week interval, along with brain MRI and APOE genotyping. Pearson correlations and multiple regression analyses examined relationships between cognitive scores and biomarker variables. Receiver operating characteristic curves assessed diagnostic accuracy. Bland-Altman plots evaluated agreement across five shared cognitive domains. CFT-S index scores showed significant positive correlations with SNSB-II in attention, language, visuospatial, and executive domains (r = 0.59-0.71, p < 0.001). The memory domain showed a lower correlation in AD patients (r = 0.28), reflecting limitations under severe impairment. Hippocampal volume was positively associated with MMSE (r = 0.54), CFT-S memory (r = 0.50), and SNSB memory scores (r = 0.52). Education correlated with MMSE (r = 0.32) but not with CFT-S or SNSB, suggesting minimal education bias. APOE-ε4 carriers had smaller hippocampal volumes, higher FBB-PET BAPL scores, and poorer cognitive outcomes. The Bland-Altman plots demonstrated acceptable agreement at the group level between CFT-S and SNSB-II across all cognitive domains, with small mean biases and symmetric distributions despite relatively wide limits of agreement. CFT-S index scores and Bland-Altman plot analysis demonstrated validity relative to SNSB-II, with significant associations to hippocampal atrophy and genetic risk factors. The findings support CFT-S as a viable and efficient cognitive assessment tool for diagnosing MCI and AD. Show less