Clocking out and letting go to unleash green biotech applications in a photosynthetic host.

Cyanobacteria are photosynthetic bacteria whose gene expression patterns are globally regulated by their circadian (daily) clocks. Due to their ability to use sunlight as their energy source, they are also attractive hosts for "green" production of pharmaceuticals, renewable fuels, and chemicals. However, despite the application of traditional genetic tools such as the identification of strong promoters to enhance the expression of heterologous genes, cyanobacteria have lagged behind other microorganisms such as Escherichia coli and yeast as economically efficient cell factories. The previous approaches have ignored large-scale constraints within cyanobacterial metabolic networks on transcription, predominantly the pervasive control of gene expression by the circadian (daily) clock. Here, we show that reprogramming gene expression by releasing circadian repressor elements in the transcriptional regulatory pathways coupled with inactivation of the central oscillating mechanism enables a dramatic enhancement of expression in cyanobacteria of heterologous genes encoding both catalytically active enzymes and polypeptides of biomedical significance.

Kielin/chordin-like protein deficiency aggravates pressure overload-induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice.

Targeting cardiac remodeling is regarded as a key therapeutic strategy for heart failure. Kielin/chordin-like protein (KCP) is a secretory protein with 18 cysteine-rich domains and associated with kidney and liver fibrosis. However, the relationship between KCP and cardiac remodeling remains unclear. Here, we aimed to investigate the role of KCP in cardiac remodeling induced by pressure overload and explore its potential mechanisms. Left ventricular (LV) KCP expression was measured with real-time quantitative PCR, western blotting, and immunofluorescence staining in pressure overload-induced cardiac remodeling in mice. Cardiac function and remodeling were evaluated in wide-type (WT) mice and KCP knockout (KO) mice by echocardiography, which were further confirmed by histological analysis with hematoxylin and eosin and Masson staining. RNA sequence was performed with LV tissue from WT and KO mice to identify differentially expressed genes and related signaling pathways. Primary cardiac fibroblasts (CFs) were used to validate the regulatory role and potential mechanisms of KCP during fibrosis. KCP was down-regulated in the progression of cardiac remodeling induced by pressure overload, and was mainly expressed in fibroblasts. KCP deficiency significantly aggravated pressure overload-induced cardiac dysfunction and remodeling. RNA sequence revealed that the role of KCP deficiency in cardiac remodeling was associated with cell division, cell cycle, and P53 signaling pathway, while cyclin B1 (CCNB1) was the most significantly up-regulated gene. Further investigation in vivo and in vitro suggested that KCP deficiency promoted the proliferation of CFs via P53/P21/CCNB1 pathway. Taken together, these results suggested that KCP deficiency aggravates cardiac dysfunction and remodeling induced by pressure overload via P53/P21/CCNB1 signaling in mice.

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats.

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.

Immunomagnetic microscopy of tumor tissues using quantum sensors in diamond.

Histological imaging is essential for the biomedical research and clinical diagnosis of human cancer. Although optical microscopy provides a standard method, it is a persistent goal to develop new imaging methods for more precise histological examination. Here, we use nitrogen-vacancy centers in diamond as quantum sensors and demonstrate micrometer-resolution immunomagnetic microscopy (IMM) for human tumor tissues. We immunomagnetically labeled cancer biomarkers in tumor tissues with magnetic nanoparticles and imaged them in a 400-nm resolution diamond-based magnetic microscope. There is barely magnetic background in tissues, and the IMM can resist the impact of a light background. The distribution of biomarkers in the high-contrast magnetic images was reconstructed as that of the magnetic moment of magnetic nanoparticles by employing deep-learning algorithms. In the reconstructed magnetic images, the expression intensity of the biomarkers was quantified with the absolute magnetic signal. The IMM has excellent signal stability, and the magnetic signal in our samples had not changed after more than 1.5 y under ambient conditions. Furthermore, we realized multimodal imaging of tumor tissues by combining IMM with hematoxylin-eosin staining, immunohistochemistry, or immunofluorescence microscopy in the same tissue section. Overall, our study provides a different histological method for both molecular mechanism research and accurate diagnosis of human cancer.

Recent advances in CAR-T cell therapy for acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a fatal and refractory haematologic cancer that primarily affects adults. It interferes with bone marrow cell proliferation. Patients have a 5 years survival rate of less than 30% despite the availability of several treatments, including chemotherapy, allogeneic haematopoietic stem cell transplantation (Allo-HSCT), and receptor antagonist drugs. Allo-HSCT is the mainstay of acute myeloid leukaemia treatment. Although it does work, there are severe side effects, such as graft-versus-host disease (GVHD). In recent years, chimeric antigen receptor (CAR)-T cell therapies have made significant progress in the treatment of cancer. These engineered T cells can locate and recognize tumour cells in vivo and release a large number of effectors through immune action to effectively kill tumour cells. CAR-T cells are among the most effective cancer treatments because of this property. CAR-T cells have demonstrated positive therapeutic results in the treatment of acute myeloid leukaemia, according to numerous clinical investigations. This review highlights recent progress in new targets for AML immunotherapy, and the limitations, and difficulties of CAR-T therapy for AML.

Anisotropic Charge Migration on Perovskite Oxysulfide for Boosting Photocatalytic Overall Water Splitting.

The synthesis of photocatalysts with both broad light absorption and efficient charge separation is significant for a high solar energy conversion, which still remains to be a challenge. Herein, a narrow-bandgap Y2Ti2O5S2 (YTOS) oxysulfide nanosheet coexposed with defined {101} and {001} facets synthesized by a flux-assisted solid-state reaction was revealed to display the character of an anisotropic charge migration. The selective photodeposition of cocatalysts demonstrated that the {101} and {001} surfaces of YTOS nanosheets were the reduction and oxidation regions during photocatalysis, respectively. Density functional theory (DFT) calculations indicated a band energy level difference between the {101} and {001} facets of YTOS, which contributes to the anisotropic charge migration between them. The exposed Ti atoms on the {101} surface and S atoms on the {001} surface were identified, respectively, as reducing and oxidizing centers of YTOS nanosheets. This anisotropic charge migration generated a built-in electric field between these two facets, quantified by spatially resolved surface photovoltage microscopy, the intensity of which was found to be highly correlated with photocatalytic H2 production activity of YTOS, especially exhibiting a high apparent quantum yield of 18.2% (420 nm) after on-site modification of a Pt@Au cocatalyst assisted by Na2S-Na2SO3 hole scavengers. In conjunction with an oxygen-production photocatalyst and a [Co(bpy)3]2+/3+ redox shuttle, the YTOS nanosheets achieved a solar-to-hydrogen conversion efficiency of 0.15% via a Z-scheme overall water splitting. Our work is the first to confirm anisotropic charge migration in a perovskite oxysulfide photocatalyst, which is crucial for enhancing charge separation and surface catalytic efficiency in this material.

Prediction of Epidermal Growth Factor Receptor Mutation Subtypes in Non-Small Cell Lung Cancer From Hematoxylin and Eosin-Stained Slides Using Deep Learning.

Accurate assessment of epidermal growth factor receptor (EGFR) mutation status and subtype is critical for the treatment of non-small cell lung cancer patients. Conventional molecular testing methods for detecting EGFR mutations have limitations. In this study, an artificial intelligence-powered deep learning framework was developed for the weakly supervised prediction of EGFR mutations in non-small cell lung cancer from hematoxylin and eosin-stained histopathology whole-slide images. The study cohort was partitioned into training and validation subsets. Foreground regions containing tumor tissue were extracted from whole-slide images. A convolutional neural network employing a contrastive learning paradigm was implemented to extract patch-level morphologic features. These features were aggregated using a vision transformer-based model to predict EGFR mutation status and classify patient cases. The established prediction model was validated on unseen data sets. In internal validation with a cohort from the University of Science and Technology of China (n = 172), the model achieved patient-level areas under the receiver-operating characteristic curve (AUCs) of 0.927 and 0.907, sensitivities of 81.6% and 83.3%, and specificities of 93.0% and 92.3%, for surgical resection and biopsy specimens, respectively, in EGFR mutation subtype prediction. External validation with cohorts from the Second Affiliated Hospital of Anhui Medical University and the First Affiliated Hospital of Wannan Medical College (n = 193) yielded patient-level AUCs of 0.849 and 0.867, sensitivities of 79.2% and 80.7%, and specificities of 91.7% and 90.7% for surgical and biopsy specimens, respectively. Further validation with the Cancer Genome Atlas data set (n = 81) showed an AUC of 0.861, a sensitivity of 84.6%, and a specificity of 90.5%. Deep learning solutions demonstrate potential advantages for automated, noninvasive, fast, cost-effective, and accurate inference of EGFR alterations from histomorphology. Integration of such artificial intelligence frameworks into routine digital pathology workflows could augment existing molecular testing pipelines.

CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer.

BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs). METHODS: We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE. RESULTS: AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures. CONCLUSIONS: Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.

Gene and Photothermal Combination Therapy: Principle, Materials, and Amplified Anticancer Intervention.

Gene therapy (GT) and photothermal therapy (PTT) have emerged as promising alternatives to chemotherapy and radiotherapy for cancer treatment, offering noninvasiveness and reduced side effects. However, their efficacy as standalone treatments is limited. GT exhibits slow response rates, while PTT is confined to local tumor ablation. The convergence of GT and PTT, known as GT-PTT, facilitated by photothermal gene nanocarriers, has attracted considerable attention across various disciplines. In this integrated approach, GT reciprocates PTT by sensitizing cellular response to heat, while PTT benefits GT by improving gene translocation, unpacking, and expression. Consequently, this integration presents a unique opportunity for cancer therapy with rapid response and improved effectiveness. Extensive efforts over the past few years have been dedicated to the development of GT-PTT, resulting in notable achievements and rapid progress from the laboratory to potential clinical applications. This comprehensive review outlines recent advances in GT-PTT, including synergistic mechanisms, material systems, imaging-guided therapy, and anticancer applications. It also explores the challenges and future prospects in this nascent field. By presenting innovative ideas and insights into the implementation of GT-PTT for enhanced cancer therapy, this review aims to inspire further progress in this promising area of research.

Gestational diabetes mellitus and risk of long-term all-cause and cardiac mortality: a prospective cohort study.

BACKGROUND: To investigate the association between gestational diabetes mellitus (GDM) without subsequent overt diabetes and long-term all-cause and cardiac mortality. METHODS: This prospective cohort study included 10,327 women (weighted population: 132,332,187) with a pregnancy history from the National Health and Nutrition Examination Survey (2007 to 2018). Participants were divided into three groups (GDM alone, overt diabetes, and no diabetes). Mortality data was linked from the National Death Index up to December 31, 2019. Multivariable Cox regression analysis was performed to examine the association between GDM alone and overt diabetes with all-cause mortality and cardiac mortality. Data analysis was performed from October 2022 to April 2023. RESULTS: Among the participants, 510 (weighted 5.3%) had GDM alone and 1862 (weighted 14.1%) had overt diabetes. Over a median follow-up period of 6.7 years (69,063 person-years), there were 758 deaths. The GDM group did not show an increased risk of all-cause mortality (hazard ratio [HR] 0.67; 95% CI, 0.25-1.84), while the overt diabetes group had a significantly higher risk (HR 1.95; 95% CI, 1.62-2.35). Similarly, the GDM group did not exhibit an elevated risk of cardiac mortality (HR 1.48; 95% CI, 0.50-4.39), whereas the overt diabetes group had a significantly higher risk (HR 2.37; 95% CI, 1.69-3.32). Furthermore, sensitivity analysis focusing on women aged 50 or above showed that the HR of GDM history for all-cause mortality was 1.14 (95% CI, 0.33-3.95) and the HR for cardiac mortality was 1.74 (95% CI, 0.49-6.20). CONCLUSIONS: GDM alone was not associated with an increased risk of all-cause and cardiac mortality, while overt diabetes was significantly associated with both types of mortality.

Propionate alleviates itch in murine models of atopic dermatitis by modulating sensory TRP channels of dorsal root ganglion.

BACKGROUND: Itch is the most common symptom of atopic dermatitis (AD) and significantly decreases the quality of life. Skin microbiome is involved in AD pathogenesis, whereas its role in the regulation of itch remains elusive. In this study, we aimed to investigate the effects of skin microbial metabolite propionate on acute and chronic pruritus and to explore the mechanism. METHODS: Using various mouse models of itch, the roles of propionate were explored by behavioral tests and histopathology/immunofluorescent analysis. Primary-cultured dorsal root ganglion neurons and HEK293 cells expressing recombinant human TRP channels were utilized for in vitro calcium imaging/in vivo miniature two-photon imaging in combination with electrophysiology and molecular docking approaches for investigation of the mechanism. RESULTS: Propionate significantly alleviated itch and alloknesis in various mouse models of pruritus and AD and decreased the density of intraepidermal nerve fibers. Propionate reduced the responsiveness of dorsal root ganglion neurons to pruritogens in vitro, attenuated the hyper-excitability in sensory neurons in MC903-induced AD model, and inhibited capsaicin-evoked hTRPV1 currents (IC50 = 20.08 ± 1.11 µM) via interacting with the vanilloid binding site. Propionate also decreased the secretion of calcitonin gene-related peptide by nerves in MC903-induced AD mouse model, which further attenuated itch and skin inflammation. CONCLUSION: Our study revealed a protective effect of propionate against persistent itch through direct modulation of sensory TRP channels and neuropeptide production in neurons. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD.

TRPA1 deficiency aggravates dilated cardiomyopathy by promoting S100A8 expression to induce M1 macrophage polarization in rats.

Transient receptor potential ankyrin 1 (TRPA1) plays an important role in different cardiovascular diseases. However, the role of TRPA1 in dilated cardiomyopathy (DCM) remains unclear. Here, we aimed to investigate the role of TRPA1 in DCM induced by doxorubicin (DOX) and explore its possible mechanisms. GEO data were used to explore the expression of TRPA1 in DCM patients. DOX (2.5 mg/kg/week, 6 weeks, i.p.) was used to induce DCM. Bone marrow-derived macrophages (BMDMs) and neonatal rat cardiomyocytes (NRCMs) were isolated to explore the role of TRPA1 in macrophage polarization, cardiomyocyte apoptosis, and pyroptosis. In addition, DCM rats were treated with the TRPA1 activator, cinnamaldehyde to explore the possibility of clinical translation. TRPA1 expression was increased in left ventricular (LV) tissue in DCM patients and rats. TRPA1 deficiency aggravated the cardiac dysfunction, cardiac injury, and LV remodeling in DCM rats. In addition, TRPA1 deficiency promoted the M1 macrophage polarization, oxidative stress, cardiac apoptosis, and pyroptosis induced by DOX. RNA-seq results showed that TRPA1 knockout promoted the expression of S100A8, an inflammatory molecule that belongs to the family of Ca2+ -binding S100 proteins, in DCM rats. Furthermore, S100A8 inhibition attenuated M1 macrophage polarization in BMDMs isolated from TRPA1 deficiency rats. Recombinant S100A8 promoted the apoptosis, pyroptosis, and oxidative stress in primary cardiomyocytes stimulated with DOX. Finally, TRPA1 activation via cinnamaldehyde alleviated the cardiac dysfunction and reduced S100A8 expression in DCM rats. Taken together, these results suggested that TRPA1 deficiency aggravates DCM by promoting S100A8 expression to induce M1 macrophage polarization and cardiac apoptosis.

Progress on Copper-Based Anode Materials for Sodium-Ion Batteries.

Fossil fuels have clearly failed to meet people's growing energy needs due to their limited reserves, potential pollution of the environment, and high costs. The development of cleaner, renewable energy sources as well as secondary batteries for energy storage is imminent, in a modern society where energy demand is soaring. Sodium-ion batteries (SIBs) have become the focus of large-scale energy storage systems as a promising alternative to lithium-ion batteries. The development of SIBs relies on the construction of high performance electrode materials. The design of low cost and high performance anode materials is a key link in this regard. Copper-based anodes are characterised by high theoretical capacity, abundant reserves, low cost and environmental friendliness. A variety of copper-based anode materials, which include cobalt oxides, sulfides, selenides and phosphides, have been synthesised and evaluated in the scientific literature for sodium storage. In detail, the preparation methods, response mechanisms, strengths and weaknesses, the relationship between morphology structure and electrochemical performance are discussed, as well as highlighting strategies to improve the  electrochemical performance of copper-based anode materials. Finally, we offer our perspective on the challenges and potential for the development of copper-based anodes as a means of developing practical and high performing SIBs.

KIF4A promotes epithelial-mesenchymal transition by activating the TGF-ß/SMAD signaling pathway in glioma cells.

Gliomas are the most prevalent type of primary brain tumor, with poor prognosis reported in patients with high-grade glioma. Kinesin family member 4 A (KIF4A) stimulates the proliferation, migration, and invasion of tumor cells. However, its function in gliomas has not been clearly established. Therefore, this study aimed to investigate the effects of KIF4A on the epithelial-mesenchymal transition and invasion of glioma cells. We searched The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases to identify KIF4A-related signaling pathways and downstream genes. We further validated them using western blotting, transwell migration and invasion, wound-healing scratch, and dual-luciferase reporter assays in U251 and U87 human glioblastoma cells. Our analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas data showed elevated KIF4A expression in patients with gliomas and was associated with clinical grade. Here, KIF4A overexpression promoted the migration, invasion, and proliferation of glioma cells, whereas KIF4A knockdown showed contrasting results. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) analyses demonstrated that KIF4A positively controls TGF-ß/SMAD signaling in glioma cells. Additionally, genetic correlation analysis revealed that KIF4A transcriptionally controls benzimidazoles-1 expression in glioma cells. KIF4A promotes the epithelial-mesenchymal transition by regulating the TGF-ß/SMAD signaling pathway via benzimidazoles-1 in glioma cells.

Recyclable V2O5/g-C3N4 Heterojunction-Catalyzed Visible-Light-Promoted C3-H Trifluoromethylation of Quinoxalin-2-(1H)-ones.

A visible-light-initiated C-H trifluoromethylation of quinoxalin-2(1H)-ones was established using a Z-scheme V2O5/g-C3N4 heterojunction as a recyclable photocatalyst in an inert atmosphere at room temperature under additive-free and mild conditions. A variety of trifluoromethylated quinoxalin-2-(1H)-one derivatives were heterogeneously generated in moderate to high yields, exhibiting good functional group tolerance. Remarkably, the recyclable V2O5/g-C3N4 catalyst could be reused five times with a slight loss of catalytic activity.

Fluorescence biosensor to detect microRNAs via integrating DNA hairpins transition mediated strand displacement amplification with primer exchange reaction.

Herein, we constructed a fluorescence biosensor for the ultra-sensitive analysis of microRNAs (miRNAs) by combining DNA hairpins transition triggered strand displacement amplification (DHT-SDA) with primer exchange reaction (PER). Target miRNA initiated DHT-SDA to facilitate the generation of multiple single-stranded DNA (ssDNA) as PER primer, which was extended into a long ssDNA. The biosensor is successfully utilized in detecting miRNAs with high sensitivity (limit of detection for miRNA-21 was 58 fM) and a good linear relationship between 100 nM and 100 fM. By simply changing the DNA hairpin sequence, the constructed biosensor can be extended to analyze another miRNAs. Moreover, the biosensor has the feasibility of detecting miRNAs in real samples with satisfactory accuracy and reliability. Therefore, the fluorescent biosensor has great application potential in clinical diagnosis.

A sensitive fluorescence biosensor based on ligation-transcription and CRISPR/Cas13a-assisted cascade amplification strategies to detect the H1N1 virus.

We propose a sensitive H1N1 virus fluorescence biosensor based on ligation-transcription and CRISPR/Cas13a-assisted cascade amplification strategies. Products are generated via the hybridization of single-stranded DNA (ssDNA) probes containing T7 promoter and crRNA templates to a target RNA sequence using SplintR ligase. This generates large crRNA quantities in the presence of T7 RNA polymerase. At such crRNA quantities, ternary Cas13a, crRNA, and activator complexes are successfully constructed and activate Cas13a to enhance fluorescence signal outputs. The biosensor sensitively and specifically monitored H1N1 viral RNA levels down to 3.23 pM and showed good linearity when H1N1 RNA concentrations were 100 pM-1 µM. Biosensor specificity was also excellent. Importantly, our biosensor may be used to detect other viral RNAs by altering the sequences of the two probe junctions, with potential applications for the clinical diagnosis of viruses and other biomedical studies.

Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations. METHODS AND RESULTS: Whole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875 C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as "Pathogenic", while the N625K variant as "VUS". CONCLUSIONS: Our results provide novel experimental evidence of functional alteration by LDLR variants identified in our study and expand the mutational spectrum of LDLR mutation induced FH.

Genome Mining Leads to Diverse Sesquiterpenes with Anti-inflammatory Activity from an Arctic-Derived Fungus.

With the advancement of bioinformatics, the integration of genome mining with efficient separation technology enables the discovery of a greater number of novel bioactive compounds. The deletion of the key gene responsible for triterpene cyclase biosynthesis in the polar strain Eutypella sp. D-1 instigated metabolic shunting, resulting in the activation of dormant genes and the subsequent production of detectable, new compounds. Fifteen sesquiterpenes were isolated from the mutant strain, with eight being new compounds. The structural elucidation of these compounds was obtained through a combination of HRESIMS, NMR spectroscopy, and ECD calculations, revealing six distinct skeleton types. Compound 7 possessed a unique skeleton of 5/10 macrocyclic ether structure. Based on the gene functions and newly acquired secondary metabolites, the metabolic shunting pathway in the mutant strain was inferred. Compounds 6, 8, 11, 14, and 15 exhibited anti-inflammatory effects without cytotoxicity through the release of nitric oxide from lipopolysaccharide-stimulated RAW264.7 cells. Notably, acorane-type sesquiterpene 8 inhibited nitric oxide production and modulated the MAPK and NLRP3/caspase-1 signaling pathways. Compound 8 also alleviated the CuSO4-induced systemic neurological inflammation symptoms in a transgenic fluorescent zebrafish model.

Effects of triglyceride glucose (TyG) and TyG-body mass index on sex-based differences in the early-onset heart failure of ST-elevation myocardial infarction.

BACKGROUND AND AIM: Heart failure (HF) is an important complication of ST-elevation myocardial infarction (STEMI), including early- and late-onset HF. This study aimed to investigate the association between insulin resistance (IR)-related parameters triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) index and early-onset HF in STEMI between sexes. METHODS AND RESULTS: This cross-sectional study included patients with STEMI who underwent primary percutaneous coronary intervention (PCI) between January 2016 and September 2022. Patients were divided into tertiles according to TyG/TyG-BMI index levels in males and females. The presence of early-onset HF was compared between tertiles in both sexes. Moreover, patients were stratified according to the tertiles of TyG/Tyg-BMI index. Differences in early-onset HF of STEMI were compared between males and females in each tertile group. 1118 patients were included in this study, 20.3% of whom were females. The incidence rate of early-onset HF was significantly higher in females than in males (29% vs. 14.8%). TyG-BMI index was negatively correlated with early-onset HF. In both females and males, there was no difference in the occurrence of early-onset HF between the highest and lowest TyG/TyG-BMI index groups. Sex disparity was observed in females who had a significantly higher prevalence of early-onset HF than males in each TyG/TyG-BMI index tertile group; however, after adjustment, the differences disappeared. CONCLUSIONS: For patients with STEMI who undergo primary PCI, the incidence of early-onset HF is higher in females than in males. The TyG/TyG-BMI index do not contribute to the difference in early-onset HF between sexes.