👤 Carissa Wong

(Sb,Bi)(S,Se)(Br,I) pnictogen chalcohalides constitute an emerging family of Van der Waals (VdW) semiconductors with remarkable potential for energy-related applications, including photovoltaics (PV), photocatalysis (PC), and photoelectrocatalysis (PEC). These ternary compounds exhibit a quasi-1D orthorhombic crystalline phase, and an electronic structure analogous to lead-halide perovskites, making them promising candidates for sustainable and high-performance energy devices. This study introduces a new versatile and adaptable synthesis methodology, which combines co-evaporation of binary chalcogenides with reactive annealing under high-pressure halide atmospheres, to fabricate the eight (Sb,Bi)(S,Se)(Br,I) chalcohalides. Comprehensive structural, compositional, and optoelectronic analyses reveal a wide bandgap range (1.2-2.2 eV), high absorption coefficients, and anisotropic properties driven by unique ribbon-like morphology. Theoretical and experimental results highlight their high stability, versatile chemical adaptability, and defect-tolerant characteristics. Moreover, the distinct differences in morphology and crystallization between Sb and Bi-based compounds, as well as the influence of chalcogen and halogen elements on the optical and structural properties are discussed. Demonstrations of functional devices, including photocatalytic systems, underscore the practical viability of these materials. This work establishes a foundation for the development of pnictogen chalcohalides as scalable and eco-friendly alternatives for advanced energy applications. Show less

FGFR1 genetic alterations are associated with brain malignancies, including FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the molecular mechanisms triggered by multiple concurrent FGFR1 mutations, we have mapped the proximal interactome of wild-type, single- and double-mutant FGFR1 proteins through a BioID-MS approach. Our data reveal novel oncogenic functionality for the two hotspot mutations N546K and K656E, linked to evasion of lysosomal degradation. Further, we identified a modulatory tumor-suppressive role for the susceptibility variant R661P, which hampers the oncogenic potential of both hotspot N546K and K656E mutations by rescuing receptor degradation and reducing N546K affinity for the downstream effector PLCγ. Introducing the R661P missense variant was sufficient to abolish self-renewal capacity of oligodendroglioma cells and downregulate genes involved in neurodevelopment and neuro-glial cell fate decisions, both aspects overcome in the double mutants. This study sheds light on contextual oncogenic effects associated with FGFR1 alterations and their recurrence in low-mutation burden and therapy naive tumors. Show less

Patients experiencing premature cardiovascular events (males: <55 years; females: <65 years) represent a high-risk subgroup within the atherosclerotic cardiovascular disease (ASCVD) population. Elevated lipoprotein(a) (Lp[a]) is an independent, genetic, causal risk factor for ASCVD. Lp(a) distribution among patients with premature ASCVD is poorly characterized. This study aimed to describe Lp(a) distribution and baseline characteristics in a large real-world sample of patients with premature ASCVD. We identified 17,594 patients with premature ASCVD who had Lp(a) values from US Medicare, Medicaid, and commercial plans between January 2016-September 2022. Mean age (SD) was 50.9 (10.1) years, most patients were female (68.9%), and half (52.2%) were not prescribed lipid-lowering therapy. Lp(a) levels ≥125, ≥175, and ≥225 nmol/L occurred in 26.8%, 18.8%, and 11.5%, respectively. Black patients had higher median (Q1-Q3) Lp(a) levels (111.0 [51.1-206.0] nmol/L) than Asian (35.0 [14.4-100.0] nmol/L), Hispanic (31.0 [10.9-95.0] nmol/L), or White patients (31.0 [10.7-110] nmol/L). In one of the largest studies in the US investigating Lp(a) distribution in premature ASCVD, we found over a quarter of patients had elevated Lp(a) (≥125 nmol/L). Show less

Lipoprotein (a) (Lp[a]) is an independent risk factor for cardiovascular disease (CVD). Structurally like low-density lipoprotein, Lp(a) is distinguished by the covalent attachment of apolipoprotein(a) to apolipoprotein B-100. Although its physiological role remains incompletely understood, evidence suggests that Lp(a) may facilitate wound healing and inhibit cancer growth and metastasis. In contrast, Lp(a) exhibits proatherogenic properties; it transports proinflammatory oxidized phospholipids, induces the secretion of proinflammatory cytokines, increases endothelial permeability, promotes smooth muscle cell migration and proliferation, and upregulates adhesion molecules that facilitate monocyte recruitment and retention. In addition, Lp(a) exerts prothrombotic activity by enhancing platelet aggregation, suppressing plasminogen activation, and inhibiting fibrinolysis. Although its clinical relevance in CVD is well established, the role of Lp(a) in peripheral arterial disease (PAD) remains unclear. This narrative review aimed to synthesize and critically examine the current evidence on the biological role of Lp(a) in PAD pathogenesis and identify knowledge gaps in PAD-specific outcomes. This review summarizes the epidemiology, pathophysiology, and management of elevated Lp(a) levels in patients with PAD and examines their association with post-treatment clinical outcomes. Elevated Lp(a) levels are associated with an increased PAD incidence and a higher risk of restenosis post-revascularization. Understanding the mechanisms by which Lp(a) contributes to PAD pathogenesis is essential for developing effective targeted therapeutic approaches and improving the identification and management of high-risk patients. Show less

Lipoprotein(a) [Lp(a)] is an independent, genetic, and causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are limited data on its impact on premature ASCVD, including in diverse populations and with family history. We examined Lp(a) in relation to premature ASCVD (male aged <55, female aged <65 years) compared to later onset ASCVD, and differences by family history, sex, and race/ethnicity in a large, multi-ethnic U.S. cohort. We analyzed data from 27,756 individuals without prior ASCVD at baseline from a pooled cohort consisting of five U.S. prospective studies. Lp(a) levels were stratified by cohort-specific percentiles. Multivariable Cox regression assessed the association of Lp(a) with composite incident premature and non-premature ASCVD events by sex, race, and family history. Among 5276 ASCVD events over a mean follow-up of 21.1 years, 773 (14.7 %) were premature ASCVD events. A higher proportion of women (65.2% vs. 38.3%) and Black individuals (45.8% vs. 27.7%) were observed in individuals with premature ASCVD compared to those with non-premature ASCVD events. For each 50 mg/dL increase in Lp(a), the risk of premature ASCVD increased by 30 % (HR: 1.30, 95% CI: 1.28-1.51), compared to a 24 % increase for non-premature ASCVD (HR: 1.24 [1.14-1.33]). Compared with Lp(a) levels <50th percentile, Lp(a) levels ≥ 90th percentile had adjusted HRs of 1.39 (1.10-1.75) and 1.39 (1.26-1.54) for premature and non-premature ASCVD events, respectively. We observed a trend for elevated Lp(a) levels predicting premature ASCVD events more strongly in those with a family history of ASCVD and in White individuals. Elevated Lp(a) is an important predictor of both premature and later onset ASCVD events. Show less

Accurate skin lesion classification is crucial for the early detection of malignant lesions, including melanoma, as well as improved patient outcomes. While convolutional neural networks (CNNs) excel at capturing local morphological features, they struggle with global context modeling essential for comprehensive lesion assessment. Vision transformers address this limitation but suffer from quadratic computational complexity O(n Show less

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a leading cause of hypertrophic cardiomyopathy (HCM). Although most cMyBP-C mutations produce truncated proteins and cause HCM via haploinsufficiency, the mechanisms by which missense mutations result in disease remain poorly understood. Here, we have evaluated three mutations in immunoglobulin-like domains C1 (P161S, Y237S) and C2 (P371R), predicted to be pathogenic for HCM, assessing their effects on cMyBP-C actin-binding function, protein thermal stability, and residue mobility. Using a fluorescence lifetime-based actin-binding assay, we found that N-terminal mutants P161S, Y237S, and P371R enhanced C0-C2 interactions with actin in both unphosphorylated and phosphorylated states, suggesting that the mutations strengthen actin binding and make the binding resistant to phosphorylation-mediated regulation. Differential scanning calorimetry revealed that mutants exhibit destabilized thermal melting profiles with reduced unfolding temperature, energy, and cooperativity. Molecular dynamics simulations indicated that these mutations induce allosteric effects, increasing fluctuations of unstructured loops in C1 or C2 that contain key actin-binding residues. These alterations in protein stability and residue mobility may promote domains to visit binding-competent conformations more frequently, reduce the energetic cost of complex formation, and/or expose actin-interacting interfaces, thereby enhancing C0-C2 binding and contributing to HCM pathogenesis. Show less

The genetic etiology of hypertrophic cardiomyopathy (HCM) and the critical role of sarcomeric variants in its pathogenesis are well recognized (1). Among these, loss-of-function variants in the myosin binding protein C gene ( This was a prospective, cross-sectional study of 100 adults (aged 18-65 years) with symptomatic Pre-existing anti-AAV9 NAb were undetectable in 50% of patients. Among those with detectable titers (range: 1:10-1:720), only 16% exceeded 1:40. TAb were undetectable in 53%; titers ranged from 1:10 to 1:65,600. A strong correlation was observed between NAb and TAb titers (r = 0.671, Pre-existing immunity to AAV9 was absent or low in most Show less

Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM, with the majority of mutations resulting in haploinsufficiency. To restore cardiac MYBPC3, we use an adeno-associated virus (AAV9) vector and engineer an optimized expression cassette with a minimal promoter and cis-regulatory elements (TN-201) to enhance packaging efficiency and cardiomyocyte expression. Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival. Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. These findings suggest that TN-201 may offer therapeutic benefits in MYBPC3-associated cardiomyopathy, pending further validation in clinical settings. Show less

The STAT3 pathway promotes epithelial-mesenchymal transition, migration, invasion and metastasis in cancer. STAT3 upregulates the transcription of the key epithelial-mesenchymal transition transcription factor SNAIL in a DNA binding-independent manner. However, the mechanism by which STAT3 is recruited to the SNAIL promoter to upregulate its expression is still elusive. In our study, the lysine methylation binding protein L3MBTL3 is positively associated with metastasis and poor prognosis in female patients with breast cancer. L3MBTL3 also promotes epithelial-mesenchymal transition and metastasis in breast cancer. Mechanistic analysis reveals that L3MBTL3 interacts with STAT3 and recruits STAT3 to the SNAIL promoter to increase SNAIL transcription levels. The interaction between L3MBTL3 and STAT3 is required for SNAIL transcription upregulation and metastasis in breast cancer, while the methylated lysine binding activity of L3MBTL3 is not required for these functions. In conclusion, L3MBTL3 and STAT3 synergistically upregulate SNAIL expression to promote breast cancer metastasis. Show less

Strategies in genetic and pharmacological modulation of innate immunity to enhance oncolytic virotherapy (OV) efficacy are being explored. We have recently characterized the ability for vanadium-based compounds, a class of pan-phosphatase (PP) inhibitors, to potentiate OVs. We next sought to identify PPs that could be targeted to enhance OVs, akin to vanadium. By conducting a high-throughput screen of a library of silencing RNA (siRNA) targeting human PPs, we uncovered several PPs that robustly enhanced infectivity and oncolysis of the oncolytic vesicular stomatitis virus (VSV∆51). Knockdown of our top validated hit, lysosomal acid phosphatase 2 (ACP2), increased VSV∆51 viral titers by over 20-fold. In silico analysis by RNA sequencing revealed ACP2 to regulate antiviral type I interferon (IFN-1) signaling pathways, similar to vanadium. To further exploit this mechanism for therapeutic gain, we encoded a short-hairpin RNA (shRNA) against ACP2 into oncolytic vesicular stomatitis virus (VSV∆51) under a miR-30 promoter. This bioengineered OV demonstrated expression of the miR-30 promoter, knockdown of ACP2, repression and ultimately, showed markedly enhanced viral VSV∆51 particle production compared to its non-targeting control counterpart. Altogether, this study identifies IFN-1 regulating PP targets, namely ACP2, that may prove instrumental in increasing the therapeutic efficacy of OVs. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor-GLP-1 receptor (GIPR-GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist-GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil-induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity. Show less

The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene. Show less

High fat diets overwhelm the physiological mechanisms for absorption, storage, and utilization of triglycerides (TG); consequently TG, TG-rich lipoproteins (TGRL), and TGRL remnants accumulate, circulate systemically, producing dyslipidemia. This associates with, or is causative for increased atherosclerotic cardiovascular risk, ischemic stroke, fatty liver disease, and pancreatitis. TGRL hydrolysis by endothelial surface-bound lipoprotein lipase (LPL) generates metabolites like free fatty acids which have proinflammatory properties. While osteoblasts utilize fatty acids as an energy source, dyslipidemia is associated with negative effects on the skeleton. In this study we investigated the effects of TGRL lipolysis products (TGRL-LP) on expression of a stress responsive transcription factor, termed activating transcription factor 3 (ATF3), reactive oxygen species (ROS), ATF3 target genes, and angiopoietin-like 4 (Angptl4) in osteoblasts. As ATF3 negatively associates with osteoblast differentiation, we also investigated the skeletal effects of global ATF3 deletion in mice. TGRL-LP increased expression of Atf3, proinflammatory proteins Ptgs2 and IL-6, and induced ROS in MC3T3-E1 osteoblastic cells. Angptl4 is an endogenous inhibitor of LPL which was transcriptionally induced by TGRL-LP, while recombinant Angptl4 prevented TG-driven Atf3 induction. Atf3 global knockout male mice demonstrated increased trabecular and cortical microarchitectural parameters. In summary, we find that TGRL-LP induce osteoblastic cell stress as evidenced by expression of ATF3, which may contribute to the negative impact of dyslipidemia in the skeleton. Further, concomitant induction of Angptl4 in osteoblasts might play a protective role by reducing local lipolysis. Show less

Serum low density lipoprotein (LDL) cholesterol shows marked interindividual variation in response to the replacement of saturated fatty acids (SFAs) with unsaturated fatty acids (UFAs). To demonstrate the efficacy of United Kingdom guidelines for exchanging dietary SFAs for UFAs, to reduce serum LDL cholesterol and other cardiovascular disease (CVD) risk factors, and to identify determinants of the variability in LDL cholesterol response. Healthy males (n = 109, mean ± SD age 48 ± 11 y; BMI 25.1 ± 3.3 kg/m Transition from a higher-SFA/lower-UFA to a lower-SFA/higher-UFA diet significantly reduced fasting blood lipids: LDL cholesterol (-0.50 mmol/L; 95% confidence interval [CI]: -0.58, -0.42), high-density lipoprotein (HDL) cholesterol (-0.11 mmol/L; 95% CI: -0.14, -0.08), and total cholesterol (TC) (-0.65 mmol/L; 95% CI:-0.75, -0.55). The dietary exchange also reduced apolipoprotein (apo)B, TC:HDL cholesterol ratio, non-HDL cholesterol, E-selectin (P < 0.0001), and LDL subfraction composition (cholesterol [LDL-I and LDL-II], apoB100 [LDL-I and LDL-II], and TAG [LDL-II]) (P < 0.01). There was also an increase in plasma biomarkers of cholesterol intestinal absorption (β-sitosterol, campesterol, cholestanol), and synthesis (desmosterol) (P < 0.0001) and fold change in PBMC LDL-receptor mRNA expression relative to the higher-SFA/lower-UFA diet (P = 0.035). Marked interindividual variation in the change in serum LDL cholesterol response (-1.39 to +0.77 mmol/L) to this dietary exchange was observed, with 33.7% of this variation explained by serum LDL cholesterol before the lower-SFA/higher-UFA diet and reduction in dietary SFA intake (adjusted R These findings support the efficacy of United Kingdom SFA dietary guidelines for the overall lowering of serum LDL cholesterol but showed marked variation in LDL cholesterol response. Further identification of the determinants of this variation will facilitate targeting and increasing the efficacy of these guidelines. The RISSCI-1 study was registered with ClinicalTrials.Gov (No. NCT03270527). Show less

The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPLs) in the development and progression of coronary disease is known, but their influence on extracoronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extracoronary vascular disease and incident major adverse limb events (MALEs). Four hundred forty-six participants who underwent coronary and/or peripheral angiography were followed up for a median of 3.7 years. Lp(a) and OxPLs were measured before angiography. Elevated Lp(a) was defined as ≥150 nmol/L. Elevated OxPL-apoB and OxPL-apo(a) were defined as greater than or equal to the 75th percentile (OxPL-apoB ≥8.2 nmol/L and OxPL-apo(a) ≥35.8 nmol/L, respectively). Elevated Lp(a) had a stronger association with the presence of extracoronary vascular disease compared to OxPLs and was minimally improved with the addition of OxPLs in multivariable models. Compared to participants with normal Lp(a) and OxPL concentrations, participants with elevated Lp(a) levels were twice as likely to experience a MALE (odds ratio: 2.14, 95% confidence interval: 1.03, 4.44), and the strength of the association as well as the C statistic of 0.82 was largely unchanged with the addition of OxPL-apoB and OxPL-apo(a). Elevated Lp(a) and OxPLs are risk factors for progression and complications of extracoronary vascular disease. However, the addition of OxPLs to Lp(a) does not provide additional information about risk of extracoronary vascular disease. Therefore, Lp(a) alone captures the risk profile of Lp(a), OxPL-apoB, and OxPL-apo(a) in the development and progression of atherosclerotic plaque in peripheral arteries. Show less

Raddeanin A is a triterpenoid isolated from Anemone raddeana Regel. It exhibits a broad spectrum of biological activities such as anti-tumor and anti-inflammatory, however, its neuroprotective effect in targeting Alzheimer's disease (AD) remains uninvestigated. To provide scientific base for the development of novel AD drug by clarifying the neuroprotective effect and molecular mechanisms of raddeanin A in both in vitro and in vivo AD model. To confirm the neuroprotective role of raddeanin A in the treatment of AD, its mechanisms and effects on β-amyloidosis and Aβ fibrillation was studied in U87 cells. Besides, the improvement on cognitive deficit, pathological defects, reactive astrocyte clusters, inhibition on neuronal inflammation and apoptosis were further studied in 3 x Tg-AD mice model of AD. Real-time PCR, western blot, dot blot, biolayer interferometry and bioinformatics analysis were used to confirm the in vitro effect and targets of raddeanin A on β-amyloidosis and its associated protein network. A series of experiments including Morris water maze, H&E staining, nissl staining and immunofluorescence analysis were conducted to confirm the protective behavioral effect of raddeanin A in the in vivo AD mice model. Raddeanin A was identified to reduce β-amyloidosis in U87 cells and 3 x Tg-AD mice model of AD by decreasing level of BACE1, APP, APP-β and Aβ. Raddeanin A improved behavioral, spatial memory and learning ability in the AD mice. In the cortex and hippocampus, raddeanin A improved the morphology and arrangement of neurons, lower the level of reactive astrocyte marker GFAP and apoptotic marker proteins Bax/Bcl2 ratio. Moreover, raddeanin A upregulated the mRNA and protein level of Prkcα in the hippocampus of AD mice whose neuroprotective effect was exerted possibly via the activation of protein kinase C. As a novel natural agent targeting β-amyloidosis, our results provide the first evidence of the multiple in vitro and in vivo neuroprotective effect of raddeanin A, suggesting its potential therapeutic application in preventing or alleviating the symptoms of AD. Show less

Neuroblastoma is the most common extracranial solid tumour in children, comprising close to 10% of childhood cancer-related deaths. We have demonstrated that activation of NTRK1 by TP53 repression of PTPN6 expression is significantly associated with favourable survival in neuroblastoma. The molecular mechanisms by which this activation elicits cell molecular changes need to be determined. This is critical to identify dependable biomarkers for the early detection and prognosis of tumours, and for the development of personalised treatment. In this investigation we have identified and validated a gene signature for the prognosis of neuroblastoma using genes differentially expressed upon activation of the NTRK1-PTPN6-TP53 module. A random survival forest model was used to construct a gene signature, which was then assessed across validation datasets using Kaplan-Meier analysis and ROC curves. The analysis demonstrated that high Show less

Some contemporary articulator systems claim to be highly precise in their interchangeability, with tolerances below 10 μm in vertical error; however, the claims have not been independently verified. The purpose of this study was to investigate the interchangeability of calibrated semiadjustable articulators in service over time. A calibrated mounting articulator served as the master articulator, while the test groups were used articulators with a minimum of 1-year use by predoctoral dental students (n=10); used articulators with a minimum of 1-year use by prosthodontic residents (n=10); and new articulators (n=10). One set of mounted maxillary and mandibular master models was positioned in the master and test articulators. High-precision reference markers on the master models were used to determine interarch 3D distance distortions (dR For interarch 3D distance distortion, the mean dR The new and used articulators tested did not fulfill the manufacturer's claim of accuracy of up to 10 μm in the vertical dimension. Up to 1 year of time in service, none of the investigated test groups fulfilled the criterion for articulator interchangeability, even if the more lenient threshold of 166 μm were accepted. Show less

Noonan Syndrome (NS) is associated with an increased risk of low-grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case was a diagnostic and treatment dilemma, prior to whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile matched strongly with HGAP and sequencing identified somatic FGFR1 and NF1 variants and a PTPN11 germline pathogenic variant. Therapeutic targets were identified but also alterations novel to HGAP such as differential expression of VEGFA and PD-L1. The germline PTPN11 finding has not been previously described in individuals with HGAP. This case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported. Show less

The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5- Show less

Leukaemia of various subtypes are driven by distinct chromosomal rearrangement or genetic abnormalities. The leukaemogenic fusion transcripts or genetic mutations serve as molecular markers for minimal residual disease (MRD) monitoring. The current study evaluated the applicability of several droplet digital PCR assays for the detection of these targets at RNA and DNA levels (atypical BCR::ABL1 e19a2, e23a2ins52, e13a2ins74, rare types of CBFB::MYH11 (G and I), PCM1::JAK2, KMT2A::ELL2, PICALM::MLLT10 fusion transcripts and CEBPA frame-shift and insertion/duplication mutations) with high sensitivity. The analytical performances were assessed by the limit of blanks, limit of detection, limit of quantification and linear regression. Our data demonstrated serial MRD monitoring for patients at molecular level could become "digitalized", which was deemed important to guide clinicians in treatment decision for better patient care. Show less

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Show less

Glioma is a highly invasive brain cancer that is difficult to treat due to its complex molecular characteristics and poor prognosis. The COVID-19 pandemic has introduced additional clinical challenges for cancer patients, especially those with glioma. This study explored the molecular interactions between glioma and COVID-19 using integrated bioinformatics methods, including enrichment analysis, survival analysis, and molecular docking, focusing on the PI3K-Akt signaling pathway and the immunomodulatory role of vitamin D. From gene expression data of glioma and COVID-19, 203 common differentially expressed genes were identified, and six prognostic key genes-MYBL2, RBM6, VEPH1, AHNAK2, GNG10, and DUSP14-were further determined. After intersecting with vitamin D targets five prognostic key genes were determined-MYBL2, RBM6, VEPH1, AHNAK2 and GNG10. These genes play significant roles in the PI3K-Akt pathway and potentially interact with vitamin D. Molecular docking and single-cell RNA sequencing analyses suggest that vitamin D may improve the prognosis of glioma patients infected with COVID-19 by regulating these key genes and the PI3K-Akt pathway. The findings reveal molecular links between glioma and COVID-19, thereby providing new insights for developing targeted therapeutic strategies. Show less

Loss-of-function mutations in VPS13C are linked to early-onset Parkinson's disease (PD). While VPS13C has been previously studied in non-neuronal cells, the neuronal role of VPS13C in disease-relevant human dopaminergic neurons has not been elucidated. Using live-cell microscopy, we investigated the role of VPS13C in regulating lysosomal dynamics and function in human iPSC-derived dopaminergic neurons. Loss of VPS13C in dopaminergic neurons disrupts lysosomal morphology and dynamics with increased inter-lysosomal contacts, leading to impaired lysosomal motility and cellular distribution, as well as defective lysosomal hydrolytic activity and acidification. We identified Rab10 as a phospho-dependent interactor of VPS13C on lysosomes and observed a decreased phospho-Rab10-mediated lysosomal stress response upon loss of VPS13C. These findings highlight an important role of VPS13C in regulating lysosomal homeostasis in human dopaminergic neurons and suggest that disruptions in Rab10-mediated lysosomal stress response contribute to disease pathogenesis in VPS13C-linked PD. Show less

Multiple factors can contribute to sub-fecundity, including genetics, lifestyle, and environmental contaminants. PFASs are characterized as "forever chemicals" due to their ubiquitous contamination and their persistence in the environment, wildlife, and humans. Numerous studies have demonstrated that PFAS exposure adversely affects multiple bodily functions, including liver metabolism and gonadal function. It is unclear, however, how the disruption of hepatic fatty acid metabolism affects testicular function. In this study, male mice were administered 0.3 and 3 μg/g body weight of PFOS for 21 days. Our data showed that PFOS exposure caused hepatic steatosis, as evidenced by significant increases in triglyceride levels, expression of ATP-citrate lyase, and fatty acid synthase, as well as fasting insulin levels. PFOS perturbed the expression levels of hepatokines, of which fibroblast growth factor-21 ( This study revealed potential links between PFOS-elicited changes in hepatic metabolism and their impacts on testicular biology. This study provides insights into alternative targets elicited by PFOS that can be used to develop diagnostic and therapeutic strategies for improving testicular dysfunction. Show less

Prenatal exposure to perfluorooctanesulfonate (PFOS) increases fetus' metabolic risk; however, the investigation of the underlying mechanism is limited. In this study, pregnant mice in the gestational days (GD, 4.5-17.5) were exposed to PFOS (0.3 and 3 μg/g of body weight). At GD 17.5, PFOS perturbed maternal lipid metabolism and upregulated metabolism-regulating hepatokines ( Show less

As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not clearly understood, and underlying biomarkers that can affect the long-term consequences of COVID-19 are paramount to be identified. Participants for the current study were from a cohort study of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. We profiled the proteomic of plasma samples from hospitalised COVID-19 survivors at 6-month, 1-year, and 2-year after symptom onset and age and sex matched healthy controls. Fold-change of >2 or <0.5, and false-discovery rate adjusted P value of 0.05 were used to filter differentially expressed proteins (DEPs). In-genuity pathway analysis was performed to explore the down-stream effects in the dataset of significantly up- or down-regulated proteins. Proteins were integrated with long-term consequences of COVID-19 survivors to explore potential biomarkers of long COVID. The proteomic of 709 plasma samples from 181 COVID-19 survivors and 181 matched healthy controls was profiled. In both COVID-19 and control group, 114 (63%) were male. The results indicated four major recovery modes of biological processes. Pathways related to cell-matrix interactions and cytoskeletal remodeling and hypertrophic cardiomyopathy and dilated cardiomyopathy pathways recovered relatively earlier which was before 1-year after infection. Majority of immune response pathways, complement and coagulation cascade, and cholesterol metabolism returned to similar status of matched healthy controls later but before 2-year after infection. Fc receptor signaling pathway still did not return to status similar to healthy controls at 2-year follow-up. Pathways related to neuron generation and differentiation showed persistent suppression across 2-year after infection. Among 98 DEPs from the above pathways, evidence was found for association of 11 proteins with lung function recovery, with the associations consistent at two consecutive or all three follow-ups. These proteins were mainly enriched in complement and coagulation (COMP, PLG, SERPINE1, SRGN, COL1A1, FLNA, and APOE) and hypertrophic/dilated cardiomyopathy (TPM2, TPM1, and AGT) pathways. Two DEPs (APOA4 and LRP1) involved in both neuron and cholesterol pathways showed associations with smell disorder. The study findings provided molecular insights into potential mechanism of long COVID, and put forward biomarkers for more precise intervention to reduce burden of long COVID. National Natural Science Foundation of China; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences; Clinical Research Operating Fund of Central High Level Hospitals; the Talent Program of the Chinese Academy of Medical Science; Training Program of the Big Science Strategy Plan; Ministry of Science and Technology of the People's Republic of China; New Cornerstone Science Foundation; Peking Union Medical College Education Foundation; Research Funds from Health@InnoHK Program. Show less

The beta-site amyloid precursor protein cleaving enzyme (BACE1) is responsible for initiating the generation of beta-amyloid, the major constituent of amyloid plaques in Alzheimer's disease (AD). The purpose of this study was to develop a specific BACE1 radioligand for visualization of the distribution pattern and quantification of the BACE1 protein in the rodent and monkey brain both in vitro by autoradiography and in vivo by positron emission tomography (PET). The BACE1 inhibitor RO6807936 originating from an in-house chemical drug optimization program was selected based on its PET tracer-like physicochemical properties and a favorable pharmacokinetic profile. Saturation binding analysis of [ Show less