👤 Jin Kim

Fibroblast growth factor (FGF) is a broad class of secretory chemicals that act via FGF receptors (FGFR). The study aims to explore the role of a novel peptide, FAP1 (FGFR-agonistic peptide 1), in tissue regeneration and repair. It investigates whether FAP1 mimics basic fibroblast growth factor (bFGF) and accelerates wound healing both in vitro and in vivo. In this study, a novel peptide was designed and its ability to mimic bFGF was assessed through different in vitro experiments including its effect on cell proliferation, wound healing, cell signaling including FGFR1 phosphorylation and activation of mitogen-activated protein kinases (MAPKs). Specificity was confirmed through surface plasmon resonance (SPR) analysis and co-treatment with FGFR inhibitor, erdafitinib. In vivo, the effect of FAP1 on diabetic wound healing was tested in a mouse model, examining collagen production and the migration and proliferation of keratinocytes and fibroblasts. FAP1 specifically phosphorylated FGFR and activated MAPKs similar to bFGF. In vitro, it induced cell proliferation and accelerated wound healing. In vivo, FAP1 improved diabetic wound healing by increasing collagen production and promoting keratinocyte and fibroblast migration and proliferation. The specificity of FAP1 was confirmed through SPR. FAP1 shows potential as a novel pharmacological alternative to natural bFGF for skin tissue regeneration and repair. Its ability to accelerate wound healing and its specificity for FGFR suggest that FAP1 could serve as a cost-effective substitute for bFGF protein in therapeutic applications. Show less

Our previous studies indicate that NFI-C is essential for tooth root development and endochondral ossification. However, its exact role in calvarial intramembranous bone formation remains unclear. In this study, we demonstrate that the disruption of the Show less

The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC Show less

Colorectal cancers (CRCs) are traditionally divided into those with either chromosomal instability (CIN) or microsatellite instability (MSI). By utilizing TCGA data, the Laird team found a subset of CRCs, namely, genome-stable CRCs (GS CRCs), which lack both CIN and MSI. Although the molecular features of GS CRCs have been described in detail, the clinicopathological features are not well defined. A total of 437 CRCs were analyzed for copy number variation (CNV) statuses in eight genes ( Show less

Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-κB signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-κB, and inflammasome (NLRP3/or NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-κB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART-treated macaque revealed macrophage-rich plaques with p21 Show less

Malignant gliomas (MGs) are the most common primary brain malignancies and are considered universally fatal. Oncolytic herpes simplex viruses (oHSVs) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting antitumor immunity, and providing local delivery of immune-activating transgenes. Interleukin 27 (IL-27) is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T lymphocyte (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve antiglioma therapeutic activity. We developed an oHSV that expresses IL-27 (C027). The antiglioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed in vivo cell-specific depletion and IL-27 blockade alongside in vitro T cell stimulation assays. Local and systemic antitumor memory was evaluated by both orthotopic and flank tumor rechallenge of C027-treated long-term survivors. C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector CTLs and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit in vivo and IL-27 enhanced CTL function in vitro. C027-treated mice that survived their initial tumors had local and systemic antiglioma memory rejecting tumors on rechallenge. Our findings demonstrate that IL-27 expression by oHSV significantly improves antiglioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for MGs. Show less

Malignant gliomas (MG) are the most common primary brain malignancies and are considered universally fatal. Oncolytic HSVs (oHSV) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting anti-tumor immunity, and providing local delivery of immune-activating transgenes. IL-27 is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T cell (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve anti-glioma therapeutic activity. We developed an oncolytic herpes simplex virus (oHSV) that expresses IL-27 (C027). The anti-glioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector cytotoxic T lymphocytes (CTL) and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit Our findings demonstrate that IL-27 expression by oHSV significantly improves anti-glioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for malignant gliomas. Show less

Jeju native pig (JNP) is an indigenous breed originating from Korea, characterized by short black hair, small stature, and superior meat quality compared with commercial breeds. This study investigated meat quality and transcriptome differences in the Show less

A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2C We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD. Show less

A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2C We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD. Show less

Lipoprotein(a) (Lp[a]) is an independent cardiovascular risk factor. Although current guidelines recommend Lp(a) testing, physicians are seldom screened, even though they remain at risk and often overlook their own health. In Vietnam, data on Lp(a) remain unclear. To address this, the Vietnam Atherosclerosis Society launched a pilot study to assess elevated Lp(a) among Vietnamese cardiologists, aiming to generate initial data, encourage physician screening, and raise medical and public awareness. A cross-sectional study was conducted at the 2024 Vietnam Atherosclerosis Society Congress, inviting 800 cardiologists. After exclusions, 165 without cardiovascular disease were analyzed. Demographic, biochemical, and lipid profiles were collected, and Lp(a) was measured using the Tina-quant Lp(a) Gen 2 assay. Elevated Lp(a) levels (≥ 125 nmol/L) were observed in 12.12% of the participants. There were no significant differences in median age ( At the Vietnam Atherosclerosis Society Congress, elevated Lp(a) levels were detected in several cardiologists without prior cardiovascular disease, including those with well-controlled lipid profiles according to current guideline targets. Show less

We assessed the coverage of molecular drug susceptibility testing (mDST) among patients with pulmonary multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in South Korea and identified factors influencing the lack of mDST implementation. This retrospective study included patients with pulmonary MDR/RR-TB who initiated tuberculosis (TB) treatment between January 2015 and September 2021. Data were obtained from the K-TB-N cohort, an integrated national TB database linking three datasets. We assessed mDST coverage, temporal trends and factors associated with the lack of mDST implementation. mDST was defined as the use of the Xpert MTB/RIF assay or line probe assay (LPA) for isoniazid and rifampicin (first-line LPA). In total, 4637 patients were included in the analysis. Of the 4637 patients, 1342 (28.9%) did not undergo mDST; whereas, 3295 (71.1%) underwent mDST. Over the study period, a statistically significant annual increase in mDST coverage was observed, escalating from 49.1% in 2015 to 96.9% in 2021 (p<0.001). Throughout the study, the coverage of the Xpert MTB/RIF assay remained lower than that of LPA (22.1% vs 64.2%, p<0.001). Multivariable logistic regression analysis identified several factors independently associated with a decreased likelihood of mDST being conducted, including TB treatment initiation in secondary general hospitals, small hospitals or primary clinics, as well as in non-public-private mix (PPM) participating institutions. In addition, transfers between PPM-participating and non-participating institutions during the treatment period and sputum acid-fast bacilli smear-negative status were significantly associated with lower mDST uptake. Although the increasing mDST coverage is a positive development, further efforts are needed to achieve nationwide and universal implementation, particularly for the Xpert MTB/RIF assay, in South Korea. Show less

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, for the cell invasion assay experiments shown in Fig. 4B, the 'Con' and 'LPA+HF' data panels contained an overlapping section, such that data which were intended to show the results of differently performed experiments appeared to have been derived from the same original source. The authors were contacted by the Editorial Office to offer an explanation for this possible anomaly in the presentation of the data in this paper, although up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further.  [International Journal of Oncology 44: 309‑318, 2014; DOI: 10.3892/ijo.2013.2157]. Show less

Fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis of arthritis. However, the impact of small extracellular vesicles (sEVs) secreted by FLSs on osteoclastogenesis remains incompletely understood. In this study, we aimed to investigate the role of tumor necrosis factor (TNF)- and lysophosphatidic acid (LPA)-activated FLSs in sEV-mediated release of osteoclastogenic miRNAs and elucidate their functional contribution to osteoclastogenesis. Stimulation of SW982 cells with LPA or TNF significantly increased sEV secretion. TNF upregulated autotaxin expression and promoted sEV release; however, small interfering RNA (siRNA)-mediated knockdown (KD) of LPAR1 attenuated the increase in sEV release induced by the TNF-autotaxin-LPA axis. Notably, stimulation with TNF or LPA elevated syntenin-1 expression without altering its mRNA level. Furthermore, KD of the syntenin-1 gene (SDCBP) suppressed the LPA-induced increase in sEV release, indicating that syntenin-1 may mediate sEV secretion induced by the TNF-autotaxin-LPA-LPAR1 axis. sEVs derived from TNF- or LPA-treated SW982 cells stimulated osteoclastogenesis. We identified miR-31-5p as an osteoclastogenic miRNA enriched in sEVs. Expression levels of miR-31-5p in sEVs from TNF- and LPA-stimulated rheumatoid arthritis (RA) FLSs were significantly higher than in those from unstimulated RA FLSs. Treatment with a miR-31-5p mimic enhanced osteoclastogenesis by targeting large tumor suppressor kinase 2 (LATS2), whereas treatment with its inhibitor suppressed the sEV-mediated promotion of osteoclastogenesis. These findings reveal a mechanism by which TNF- and LPA-activated FLSs may facilitate sEV-mediated delivery of osteoclastogenic miRNAs, such as miR-31-5p, to osteoclast precursors, thereby contributing to osteoclast formation and bone destruction. Show less

Paraneoplastic syndromes arise when tumor-derived cytokines reprogram distant organs. Although mediators such as Interleukin-6 have been implicated, how these signals impair host organ function remains incompletely defined. Here, we identify a cytokine-lipid axis that drives hepatic autophagy dysfunction. Specifically, in Show less

Sex is a critical determinant of health and disease, yet it remains underrepresented in biomedical research. The identification of blood-based biomarkers facilitates early diagnosis and intervention for various diseases; however, sex-differential differences in the plasma proteome have not been sufficiently explored in mouse models. Understanding the molecular features associated with sex is essential for enhancing the translational potential of clinical research. We utilized Olink technology to analyze sex- and strain-differential plasma protein expression in two widely used mouse strains, C57BL/6 and BALB/c. A total of 36 mice (n = 9 per strain and sex) were analyzed using the 'Olink Target 48 Mouse Cytokine' and 'Olink Target 96 Mouse Exploratory' panels. Differences in normalized protein expression (NPX) were compared between groups, and proteins with a P-value < 0.05 were considered significantly different. Our analysis identified 55 strain-differential proteins and 33 sex-differential proteins among the 87 proteins analyzed in mouse plasma. Importantly, LPL (Lipoprotein lipase) and GHRL (Appetite-regulating hormone) were also more highly expressed in females in human datasets, suggesting a conserved sex-biased expression pattern across species. This study characterized sex- and strain-differential differences in the plasma proteomes of C57BL/6 and BALB/c mice. Among the identified proteins, LPL and GHRL were significantly elevated in females, consistent with human gene and plasma protein expression trends. These findings highlight the presence of sex-based molecular differences in energy and lipid metabolism and provide a valuable foundation for future mechanistic studies. Show less

In peripheral tissues, an endothelial cell (EC) protein, GPIHBP1, captures lipoprotein lipase (LPL) from the interstitial spaces and transports it to the capillary lumen. LPL mediates the margination of triglyceride-rich (TG-rich) lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. TRL-derived fatty acids are used for fuel in oxidative tissues or stored in adipose tissue. In mice, GPIHBP1 is absent from capillary ECs of the brain (which uses glucose for fuel); consequently, LPL and TRL margination are absent in mouse brain capillaries. However, because fatty acids were reported to play signaling roles in the brain, we hypothesized that LPL-mediated TRL processing might occur within specialized vascular beds within the central nervous system. Here, we show that GPIHBP1 is expressed in capillary ECs of human and mouse choroid plexus (ChP) and that GPIHBP1 transports LPL (produced by adjacent ChP cells) to the capillary lumen. The LPL in ChP capillaries mediates both TRL margination and processing. Intracapillary LPL and TRL margination are absent in the ChP of Gpihbp1-/- mice. GPIHBP1 expression, intracapillary LPL, and TRL margination were also observed in the median eminence and subfornical organ, circumventricular organs implicated in the regulation of food intake. Show less

Bacteroides-centric gut dysbiosis reported to exacerbates liver cirrhosis via inflammation and fibrosis, therefore utilizing Bacteroides species as microbiome-based therapeutic logical to mitigate disease progression. Feces were collected from 52 Healthy and 144 Liver cirrhosis individuals for V3-V4 dependent 16rRNA-bsed comparative metagenomics analysis, followed a by microbiome depleted and non-depleted DDC mice model to explain the role of Bacteroidetes phylum classified microbial species P. plebeius in liver fibrosis pathophysiological pathways. Bacteroides presented cirrhosis-dependent decrease in human and animal microbiome, and negatively correlated to key molecular pattern associated with cirrhosis. P. plebeius significantly reduced in abundance and identified as a microbial biomarker for cirrhosis (AUC = 0.73) and treatment with P. plebeius significantly improved the levels of cirrhosis-related phenotypical and biochemical markers in the microbiome-depleted cirrhosis group. P. plebeius decrease the expression of S100a9, CCR1, ADAM8, TREM2, ITGAM, and MYO5A which are primarily responsible for inducing inflammation in liver cirrhosis. P. plebeius downregulated the fibrosis related genes expression including CD51, PLAT, ITGA3, CXCR4, and TGFBR1 and gene related to extracellular matrix formation including COL1A1, LTBP2, S100A6, and SMCO2. Additionally, P. plebeius treatment decreased the expression of hepatotoxicity-related genes including LPL, KRT18, ALDOA, and MCM10, and increased the expression of FABP1 and RDX. Additionally, P. plebeius normalized the expression of genes connected to two pathophysiological process including TIMP4, TGFB3, S100A8, PLSCR1, MMP8, CXCL4, and BMP. Our study revealed P. plebeius as a multifaceted bio-therapeutic candidate that normalized dysregulated gene expression and reversed hepatic inflammation, fibrogenesis, and hepatotoxicity. Show less

This study used whole-genome sequence data on 406 beef cattle (203 Hanwoo and 203 Angus) to detect signatures of selection using four different methods; integrated haplotype score (iHS), Rsb, XP-EHH, and runs of homozygosity (ROH). Based on Rsb and XP-EHH analysis, 36 and 21 genomic regions differed significantly between Angus and Hanwoo breeds. Within breeds, we identified 108 regions (76 in Hanwoo and 32 in Angus) with the ROH analysis and 331 regions with the iHS method (298 in Hanwoo and 33 in Angus). The candidate genes related to meat quality, such as HSPA9 and LPL, were found within Hanwoo, while genes associated with growth and meat quantity traits, including ACTC1 and TMEM68, were identified within Angus. This study can assist in understanding the selection history of these breeds and identifying the genomic regions associated with the traits selected for in the breeding programs for these cattle breeds. Show less

Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcription factor carbohydrate-responsive element-binding protein (ChREBP), which regulates the Show less

Activation of cell cycle regulatory pathways has been detected during pathological cardiomyocyte growth. However, it has remained unclear whether DNA synthesis pathways play a direct role in cardiomyocyte hypertrophy. We previously discovered in a mouse model of hypertrophic cardiomyopathy that there was increased DNA synthesis, which led to cardiomyocyte endoreplication and replication stress-induced DNA damage. We hypothesized that targeting cardiomyocyte endoreplication pathways could reduce pathological myocardial hypertrophy. We utilized murine models of hypertrophic cardiomyopathy secondary to mutations in cardiac Mybpc3 (myosin-binding protein C3) We discovered that p21 protein peaked during the early stages of hypertrophic growth in both murine hypertrophic cardiomyopathy models and a pressure overload hypertrophy model. Using genetic manipulation of p21 expression, we discovered that cardiomyocyte endoreplication and hypertrophic growth were negatively correlated with p21 expression. Mechanistically, we discovered that p21 bound to PCNA (proliferating cell nuclear antigen), which led to a reduction of PCNA binding to POLD1 (DNA polymerase delta 1). Directly targeting PCNA or POLD1 prevented cardiomyocyte DNA synthesis and hypertrophic cardiomyocyte growth. Cardiomyocyte-selective overexpression of p21 using an adeno-associated virus vector reduced long-term pathological left ventricular hypertrophy and improved diastolic function in a preclinical murine model of hypertrophic cardiomyopathy (Myh6 Our results demonstrate that PCNA-POLD1-mediated cardiomyocyte endoreplication drives hypertrophic cardiomyocyte growth, and p21 serves as a negative regulator of this process. Targeting these pathways demonstrates therapeutic potential in preventing pathological myocardial hypertrophy. Show less

Apical hypertrophic cardiomyopathy (HCM) is a rare variant of HCM, often considered to have a benign prognosis. This study aimed to compare the clinical characteristics and genetic predisposition of apical HCM with non-apical HCM. We included 195 patients with HCM who underwent next-generation sequencing at two tertiary centres in South Korea (2017-2024). The primary outcome was a composite of lethal arrhythmic events (LAE), including death, ventricular arrhythmia, implantable cardioverter defibrillator (ICD) implantation and appropriate ICD shock. Secondary outcomes included major adverse cardiovascular events (MACE), such as new-onset atrial fibrillation, ischaemic stroke, heart failure hospitalisation, septal reduction therapy or heart transplant. Of the 195 patients, 67 (34.4%) had apical HCM. Patients with apical HCM were older at diagnosis and had lower maximal left ventricular wall thickness compared with non-apical HCM. Disease-causing variants were less frequent in apical HCM (20.9% vs 46.9%, p<0.001). Although apical HCM is associated with less hypertrophy and lower genetic yield, it is not entirely benign. The presence of disease-causing variants is an important predictor of arrhythmic risk, underscoring the value of genetic testing in all HCM patients, regardless of phenotype. Show less

Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in Show less

Pediatric hypertrophic cardiomyopathy (HCM) is a rare condition, particularly in neonates, and is characterized by rapid and extensive myocardial hypertrophy, often leading to severe clinical outcomes. HCM can arise from variants in sarcomeric genes, which are essential for myocardial contractions, as well as non-sarcomeric gene variants. Although genetic modifiers and oligogenic inheritance have been implicated in congenital heart disease and cardiomyopathy, their complexity in HCM has not been fully elucidated, especially in familial cases with variable phenotypes. Hence, this study aims to investigate the genetic architecture in a family with a history of cardiac disease and neonatal HCM, focusing on oligogenic inheritance of non-sarcomeric variants. Clinical data and blood samples were collected for genetic analysis. Whole genome sequencing (WGS) and bioinformatic analyses identified compound heterozygous variants in the MYO19 gene. Maternally inherited variants were analyzed because the proband's mother was also diagnosed with HCM. WGS was performed on the patient's maternal grandfather and aunt, who have cardiac disease, revealing candidate genetic variants that may contribute to the cardiac phenotype. Compound heterozygous MYO19 variants were identified in the neonatal patient. Missense c.203C > G (p.A68G) and frameshift c.275₂₇₆del (p.E92Vfs*19) variants were identified, which were located in the myosin motor domain, a functionally crucial region of the MYO19 protein. Maternally inherited missense variants were identified in SURF1 and ETFDH. All three genes are associated with mitochondrial function, and in silico prediction tools suggest that these variants are likely damaging. Other candidate genetic variants possibly contributing to the cardiac phenotype were also detected in the extended maternal family. To the best of our knowledge, this study represents the first report proposing MYO19 as a candidate gene for HCM and highlights the potential role of oligogenic inheritance in the etiology of the disease. Furthermore, plausible candidate variants of other mitochondria-related genes, such as MYO19, SURF1, and ETFDH, were identified, and other family members were investigated to support the pathogenesis of HCM further. Given the limited understanding of the genetics of pediatric HCM, these findings contribute valuable insights into its genetic basis in pediatric patients. Show less

Aralia continentalis Kitag roots (ACKRs) have been regarded as a nutritional natural resource for treating different diseases, including type 2 diabetes mellitus (T2DM), and its complications (heart attack; HA, diabetic nephropathy; DN). Nonetheless, an extensive investigation of T2DM-derived complications has yet to be performed. Accordingly, we adopted gas chromatography-mass spectrometry (GC-MS) to identify the molecules of ACKRs, followed by the use of cheminformatics (Similarity Ensemble Approach; SEA, SwissTargetPrediction; STP), bioinformatics (STRING, DisGeNET, and OMIM), and computer screening tools to investigate its corresponding targets, in T2DM diseases and its complications. The primary targets (PPARG, and IL6) were confirmed via a protein-protein interaction (PPI) network, suggesting that IL6- Andrographolide, PPARA-Germacrene D, PPARD- Kaurenoic acid, PPARG- Kaurenoic acid, NR1H3- 1-Naphthalenepropanol, α-ethenyldecahydro-5-(hydroxymethyl)-α,2,5,5,8a-pentamethyl-, and FABP4- Kaurenoic acid conformers on PPAR signaling pathway might exert agonistic mode. These findings underline that ACKRs' bioactives filtered by the devised platform could prevent T2DM-derived complications through multiple-target. Show less

Virus-induced trabeculitis is considered a significant cause of uveitic glaucoma, being marked by a sudden increase in intraocular pressure and relatively mild inflammation in the anterior chamber of the eye. In previous proteome analyses of aqueous humor (AH) derived from Cytomegalovirus (CMV) uveitic glaucoma patients, we observed the liver X receptor (LXR) pathway to be among the most prominently activated canonical pathways. In the present study, we explored the role of the LXR pathway in the etiology of glaucoma in association with ocular inflammation. LXRα/β and ABCA1, the downstream targets of LXR, were distributed throughout the conventional AH outflow pathway of the human eye, and their increased levels in human trabecular meshwork cells in response to CMV infection and -lipopolysaccharide (LPS) treatment. Treatment with an LXR agonist (T091317) suppressed LPS-induced inflammation and this response was reversed under the deficiency of LXRα/LXRβ. Furthermore, in the rat endotoxin uveitis model, the LXR agonist significantly reduced infiltrating cells and expression of proinflammatory cytokines in the iris and retina. These results reveal upregulation of LXR-ABCA1 under inflammatory insult in the conventional AH outflow pathway, and activation of LXR exhibiting an anti-inflammatory effect, implying its essential physiological protective role in glaucoma associated with ocular inflammation. Show less

Common variants in the FKBP5 gene have been implicated in recurrence of major depressive disorder (MDD) and response to antidepressant treatment. Although the relationship between FKBP5 and MDD has been revealed through several studies, the detailed molecular mechanisms by which FKBP5 regulates responsiveness to antidepressants have not been fully understood. Here, we aimed to elucidate the molecular mechanisms of FKBP5 in autophagy initiation and its potential role in the antidepressant response. We found that FKBP5 deficiency impaired the initiation of basal and stress-induced autophagy, accompanied by reduced protein levels of the PIK3C3/VPS34 complex, which is essential for autophagy initiation. Mechanistically, we demonstrated that FKBP5 physically binds to the VPS34 complex components, facilitating their assembly and subsequent autophagy initiation. Particularly, our study revealed that FKBP5 mediates antidepressant-induced autophagy by promoting the VPS34 complex assembly. These findings were consistent in neuronal cells, where FKBP5 depletion resulted in decreased autophagy and impaired the VPS34 complex assembly. Understanding the interplay between FKBP5, autophagy, and MDD may provide new insights into more effective treatments for MDD and related disorders. Show less

Hypoxic retinopathies, including diabetic retinopathy, are major contributors to vision impairment, mainly due to accelerated angiogenesis and inflammation. Previously, we demonstrated that AAV2-shmTOR, effective across distinct species, holds therapeutic promise by modulating the activated mTOR pathway, yet its mechanisms for reducing inflammation remain largely unexplored. To investigate AAV2-shmTOR's impact on atypical inflammation in these conditions, we employed an Show less