Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metast Show more
Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport Show more
Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in Show less
Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remain Show more
Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic-related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders. Show less
Recently, FGFR4 has become a hot target for the treatment of cancer owing to its important role in cellular physiological processes. FGFR4 has been validated to be closely related to the occurrence of Show more
Recently, FGFR4 has become a hot target for the treatment of cancer owing to its important role in cellular physiological processes. FGFR4 has been validated to be closely related to the occurrence of cancers, such as hepatocellular carcinoma, rhabdomyosarcoma, breast cancer and colorectal cancer. Hence, the development of FGFR4 small-molecule inhibitors is essential to further understanding the functions of FGFR4 in cancer and the treatment of FGFR4-dependent diseases. Given the particular structures of FGFR1-4, the development of FGFR4 selective inhibitors presents significant challenges. The non-conserved Cys552 in the hinge region of the FGFR4 complex becomes the key to the selectivity of FGFR4 and FGFR1/2/3 inhibitors. In this review, we systematically introduce the close relationship between FGFR4 and cancer, and conduct an in-depth analysis of the developing methodology, binding mechanism, kinase selectivity, pharmacokinetic characteristics of FGFR4 selectivity inhibitors, and their application in clinical research. Show less
Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications (CNA). CNA are genetic alterations that are increasingly becoming relevant to breast oncology Show more
Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications (CNA). CNA are genetic alterations that are increasingly becoming relevant to breast oncology clinical practice. Here we identify CNA in metastatic breast tumor samples using publicly available datasets and characterize their expression and function using a metastatic mouse model of breast cancer. Our findings demonstrate that our organoid generation can be implemented to study clinically relevant features that reflect the genetic heterogeneity of individual tumors. Show less
The objective of this study was to investigate the effects of sex on meat quality and the composition of amino and fatty acids in the breast muscles of White King pigeon squabs. Untargeted metabolomic Show more
The objective of this study was to investigate the effects of sex on meat quality and the composition of amino and fatty acids in the breast muscles of White King pigeon squabs. Untargeted metabolomics was also conducted to distinguish the metabolic composition of plasma in different sexes. Compared with male squabs, female squabs had greater intramuscular fat (IMF) deposition and lower myofiber diameter and hydroxyproline content, leading to a lower shear force. Female squabs also had higher monounsaturated fatty acid and lower n-6 and n-3 polyunsaturated fatty acid proportions in the breast muscle, and had greater lipogenesis capacity via upregulation of PPARγ, FAS and LPL gene expression. Moreover, female squabs had lower inosine 5'-monophosphate, essential, free and sweet-tasting amino acid contents. Furthermore, Spearman's correlations between the differential plasma metabolites and key meat parameters were assessed, and putrescine, N-acetylglutamic acid, phophatidylcholine (18:0/P-16:0) and trimethylamine N-oxide were found to contribute to meat quality. In summary, the breast meat of male squabs may have better nutritional value than that of females, but it may inferior in terms of sensory properties, which can be attributed to the lower IMF content and higher shear force value. Our findings enhance our understanding of sex variation in squab meat quality, providing a basis for future research on pigeon breeding. Show less
Metal-organic frameworks (MOFs) with long persistent luminescence (LPL) have attracted extensive research attention from researchers due to their potential applications in information encryption, anti Show more
Metal-organic frameworks (MOFs) with long persistent luminescence (LPL) have attracted extensive research attention from researchers due to their potential applications in information encryption, anticounterfeiting technology, and security logic. In contrast to short-lived fluorescent materials, LPL materials offer a visible response that can be easily distinguished by the naked eye, thereby facilitating a much clearer visualization. However, there are few reports on functional LPL MOF materials as probes. In this article, two amino-functional LPL MOFs (VB4-2D and VB4-1D) were synthesized. They both exhibited adjustable fluorescence and phosphorescence from blue to green and from cyan to green, respectively. Notably, the MOFs emitted bright and adjustable LPL upon the removal of the different radiation sources. The basic amino functional groups in the MOFs exhibited acid and ammonia sensitivity, and fluorescence and phosphorescence emission intensities can be burst and restored in two atmospheres, respectively, which can be cycled multiple times. Furthermore, LPL intensity undergoes switching between two different conditions as well, which can be visually discerned by the naked eye, enabling visual sensing of volatiles by LPL. This combination of photoluminescence and the visual LPL switching behavior of acids and bases in functional MOFs may provide an effective avenue for stimulus response, anticounterfeiting, and encryption applications. Show less
This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using pos Show more
This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using postnatal imaging. Unique to this study was the case series of CCD for prenatal diagnosis using prenatal ultrasound, as well as we found that AXIN1 and FOXC1 mutations may be related to CCD. Show less
We present a rare case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia (LPL/WM) diagnosed in a 65-year-old female initially presenting with recurrent bilateral epistaxis. Despite multiple Show more
We present a rare case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia (LPL/WM) diagnosed in a 65-year-old female initially presenting with recurrent bilateral epistaxis. Despite multiple cauterizations and a history of ineffective conventional treatments, comprehensive evaluations led to the diagnosis, underscoring the critical need for thorough investigation in persistent epistaxis cases, particularly when standard approaches fail. This case emphasizes the importance of considering indolent lymphomas in the differential diagnosis of recurrent epistaxis and showcases the diagnostic pathway leading to successful identification and treatment of a rare etiology. Laryngoscope, 134:3974-3976, 2024. Show less
Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with ag Show more
Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin-β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD. Show less
Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and Show more
Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM Show less
To evaluate the efficacy of subcutaneous specific immunotherapy (SCIT) for allergic rhinitis (AR) combined with asthma. A retrospective analysis of clinical data from 93 patients with AR combined with Show more
To evaluate the efficacy of subcutaneous specific immunotherapy (SCIT) for allergic rhinitis (AR) combined with asthma. A retrospective analysis of clinical data from 93 patients with AR combined with asthma admitted to our hospital from January 2022 to January 2023 was conducted. Based on the treatment interventions received, the patients were divided into a control group (n=46, receiving sublingual specific immunotherapy [SLIT]) and an observation group (n=47, receiving SCIT). Clinical treatment response, lung function, levels of immune indicators, levels of inflammatory indicators, and occurrence of adverse reactions were compared between the two groups. The total response rate was 95.74% in the observation group and 84.78% in the control group (P > 0.05). In terms of scores for symptom assessment, Total Nasal Symptom Score (TNSS), Depression Anxiety Stress Scale (DASS), and Nasal Allergy Symptom Score (NASS) scores in both groups decreased after treatment, with greater decreases in the observation group (P < 0.05). In addition, lung function was improved in both groups after treatment as reflected by increased Forced Expiratory Volume in one second to Forced Vital Capacity ratio (FEV1/FVC) and Peak Expiratory Flow (PEF) levels, with greater increases found in the observation group (P < 0.05). Among the immune and inflammatory indicators, Cluster of Differentiation 14 (CD14) and Interleukin-33 (IL-33) levels decreased, while Secretory Protein D-1 (SPD-1), serum Immunoglobulin G4 (sIgG4), Interferon-γ (INF-γ), and Interleukin-27 (IL-27) levels increased in both groups after treatment, with greater changes observed in the observation group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the observation group (14.89%) and the control group (21.74%) (P > 0.05). In the treatment of AR combined with asthma, SCIT can better alleviate clinical symptoms, improve lung function, regulate immune and inflammatory responses in patients, and does not increase the risk of adverse reactions compared to SLIT. Show less
Cancer is rarely the straightforward consequence of an abnormality in a single gene, but rather reflects a complex interplay of many genes, represented as gene modules. Here, we leverage the recent ad Show more
Cancer is rarely the straightforward consequence of an abnormality in a single gene, but rather reflects a complex interplay of many genes, represented as gene modules. Here, we leverage the recent advances of model-agnostic interpretation approach and develop CGMega, an explainable and graph attention-based deep learning framework to perform cancer gene module dissection. CGMega outperforms current approaches in cancer gene prediction, and it provides a promising approach to integrate multi-omics information. We apply CGMega to breast cancer cell line and acute myeloid leukemia (AML) patients, and we uncover the high-order gene module formed by ErbB family and tumor factors NRG1, PPM1A and DLG2. We identify 396 candidate AML genes, and observe the enrichment of either known AML genes or candidate AML genes in a single gene module. We also identify patient-specific AML genes and associated gene modules. Together, these results indicate that CGMega can be used to dissect cancer gene modules, and provide high-order mechanistic insights into cancer development and heterogeneity. Show less
More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. Show more
More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS. Here, we generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. We investigated NS-associated phenotypes in these Nup160podKO mice. We verified efficient abrogation of Nup160 in Nup160podKO mice at both the DNA and protein levels. We showed that Nup160podKO mice develop typical signs of NS. Nup160podKO mice exhibited progression of proteinuria to average albumin/creatinine ratio (ACR) levels of 15.06 ± 2.71 mg/mg at 26 weeks, and had lower serum albumin levels of 13.13 ± 1.34 g/l at 30 weeks. Littermate control mice had urinary ACR mean values of 0.03 mg/mg and serum albumin values of 22.89 ± 0.34 g/l at the corresponding ages. Further, Nup160podKO mice exhibited glomerulosclerosis compared with littermate control mice. Podocyte-specific Nup160 knockout in mice led to NS and glomerulosclerosis. Thus, our findings strongly support that mutations in NUP160 cause SRNS. The newly generated Nup160podKO mice are a reliable mammalian model for future study of the pathogenesis of NUP160-associated SRNS. Show less
The purpose of this study was to identify biomarkers associated with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and to develop a new combination with good diagnostic performance. Show more
The purpose of this study was to identify biomarkers associated with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and to develop a new combination with good diagnostic performance. This study was divided into four phases: discovery, verification, validation, and modeling. A total of four candidate tumor-associated autoantibodies (TAAb; anti-ZIC2, anti-PCNA, anti-CDC37L1, and anti-DUSP6) were identified by human proteome microarray (52 samples) and bioinformatics analysis. Subsequently, these candidate TAAbs were further confirmed by indirect ELISA with two testing cohorts (120 samples for verification and 663 samples for validation). The AUC for these four TAAbs to identify patients with HBV-HCC from chronic hepatitis B (CHB) patients ranged from 0.693 to 0.739. Finally, a diagnostic panel with three TAAbs (anti-ZIC2, anti-CDC37L1, and anti-DUSP6) was developed. This panel showed superior diagnostic efficiency in identifying early HBV-HCC compared with alpha-fetoprotein (AFP), with an AUC of 0.834 [95% confidence interval (CI), 0.772-0.897] for this panel and 0.727 (95% CI, 0.642-0.812) for AFP (P = 0.0359). In addition, the AUC for this panel to identify AFP-negative patients with HBV-HCC was 0.796 (95% CI, 0.734-0.858), with a sensitivity of 52.4% and a specificity of 89.0%. Importantly, the panel in combination with AFP significantly increased the positive rate for early HBV-HCC to 84.1% (P = 0.005) and for late HBV-HCC to 96.3% (P < 0.001). Our findings suggest that AFP and the autoantibody panel may be independent but complementary serologic biomarkers for HBV-HCC detection. We developed a robust diagnostic panel for identifying patients with HBV-HCC from patients with CHB. This autoantibody panel provided superior diagnostic performance for HBV-HCC at an early stage and/or with negative AFP results. Our findings suggest that AFP and the autoantibody panel may be independent but complementary biomarkers for HBV-HCC detection. Show less
Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the managemen Show more
Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the management of hyperparathyroidism, radical options to halt underlying disease progression remain lacking. Identifying putative genetic drivers and exploring novel drug targets that can impede HPT progression remain critical unmet needs. A Mendelian randomization (MR) analysis was performed to uncover putative therapeutic targets implicated in hyperparathyroidism pathology. Cis-expression quantitative trait loci (cis-eQTL) data serving as genetic instrumental variables were obtained from the eQTLGen Consortium and Genotype-Tissue Expression (GTEx) portal. Hyperparathyroidism summary statistics for single nucleotide polymorphism (SNP) associations were sourced from the FinnGen study (5590 cases; 361,988 controls). Colocalization analysis was performed to determine the probability of shared causal variants underlying SNP-hyperparathyroidism and SNP-eQTL links. Five drug targets (CMKLR1, FSTL1, IGSF11, PIK3C3 and SLC40A1) showed significant causation with hyperparathyroidism in both eQTLGen and GTEx cohorts by MR analysis. Specifically, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and solute carrier family 40 member 1 (SLC40A1) showed strong evidence of colocalization with HPT. Multivariable MR and Phenome-Wide Association Study analyses indicated these two targets were not associated with other traits. Additionally, drug prediction analysis implies the potential of these two targets for future clinical applications. This study identifies PIK3C3 and SLC40A1 as potential genetically proxied druggable genes and promising therapeutic targets for hyperparathyroidism. Targeting PIK3C3 and SLC40A1 may offer effective novel pharmacotherapies for impeding hyperparathyroidism progression and reducing disease risk. These findings provide preliminary genetic insight into underlying drivers amenable to therapeutic manipulation, though further investigation is imperative to validate translational potential from preclinical models through clinical applications. Show less
Paroxysmal nocturnal haemoglobinuria (PNH) is a disorder resulting from erythrocyte membrane deficiencies caused by PIG-A gene mutations. While current treatments alleviate symptoms, they fail to addr Show more
Paroxysmal nocturnal haemoglobinuria (PNH) is a disorder resulting from erythrocyte membrane deficiencies caused by PIG-A gene mutations. While current treatments alleviate symptoms, they fail to address the underlying cause of the disease-the pathogenic PNH clones. In this study, we found that the expression of carbamoyl phosphate synthetase 1 (CPS1) was downregulated in PNH clones, and the level of CPS1 was negatively correlated with the proportion of PNH clones. Using PIG-A knockout K562 (K562 KO) cells, we demonstrated that CPS1 knockdown increased cell proliferation and altered cell metabolism, suggesting that CPS1 participates in PNH clonal proliferation through metabolic reprogramming. Furthermore, we observed an increase in the expression levels of the histone demethylase JMJD1C in PNH clones, and JMJD1C expression was negatively correlated with CPS1 expression. Knocking down JMJD1C in K562 KO cells upregulated CPS1 and H3K36me3 expression, decreased cell proliferation and increased cell apoptosis. Chromatin immunoprecipitation analysis further demonstrated that H3K36me3 regulated CPS1 expression. Finally, we demonstrated that histone demethylase inhibitor JIB-04 can suppressed K562 KO cell proliferation and reduced the proportion of PNH clones in PNH mice. In conclusion, aberrant regulation of the JMJD1C-H3K36me3-CPS1 axis contributes to PNH clonal proliferation. Targeting JMJD1C with a specific inhibitor unveils a potential strategy for treating PNH patients. Show less
Globally, Parkinson's disease (PD) is one of the common neurodegenerative diseases in the elderly with increasing morbidity and disability, and its clinical pathogenesis is not clear. To compare the d Show more
Globally, Parkinson's disease (PD) is one of the common neurodegenerative diseases in the elderly with increasing morbidity and disability, and its clinical pathogenesis is not clear. To compare the differences in disease severity and blood biomarkers levels and their correlation between patients with early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD). A total of 342 patients diagnosed with PD were retrospectively collected. PD patients were categorized into EOPD (24 patients) and LOPD (318 patients) according to the age of onset of the disease. The Hoehn-Yahr (HY) staging was used to assess the severity of the disease in PD patients. Subjective rating scales such as the Mini-mental State Examination (MMSE) were used to assess the motor and non-motor functions of the patients. The differences of objective blood biomarkers such as triglyceride (TG) between the two groups were investigated. The correlation between them and PD was explored by logistic analysis. Percentage of EOPD group with HY staged as intermediate to late and Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Movement Disorder Society-Unified Parkinson's disease Rating Scale-III (MDS-UPDRS-III), Montreal Cognitive Assessment (MoCA) score and TG, non-high-density lipoprotein-cholesterol (N-HDL-C), homocysteine (HCY), apolipoprotein B (Apo-B), free triiodothyronine (FT3), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP) levels were lower than those in the LOPD group (P < 0.05); and the proportion of HY staged as early stage, Hamilton Anxiety Scale (HAMA) and Fatigue severity scale (FSS) scores and the levels of vitamin B12 were higher than those in the LOPD group (P < 0.05). The results of Multifactorial Logistic regression analysis showed that N-HDL-C [OR = 1.409, 95 % CI (1.063, 1.868)], Apo-B [OR = 0.797, 95 % CI (0.638, 0.997)], Vitamin B12 [OR = 0.992, 95 % CI (0.987, 0.998)] and hs-CRP [OR = 1.124, 95 % CI (1.070, 1.182)] were independent factors affecting the severity of PD, with significant differences between groups (P < 0.05). N-HDL-C, Apo-B, Vitamin B12, and hs-CRP levels play an important role in the progression of PD. Show less
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is Show more
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role. Show less
Diabetic retinopathy (DR) is a severe microangiopathy of diabetes. Müller cells play an important role in the development of DR. Acteoside (ACT) has been reported to be effective in the treatment of D Show more
Diabetic retinopathy (DR) is a severe microangiopathy of diabetes. Müller cells play an important role in the development of DR. Acteoside (ACT) has been reported to be effective in the treatment of DR. In this study, we explored the molecular mechanism of ACT in the treatment of DR from the perspective of the reactive proliferation of Müller cells. The effect of ACT on DR was investigated via high-glucose (HG) treatment of Müller RMC-1 cells and an injection of streptozotocin (STZ) in constructed DR cells and animal models. The results showed that after ACT treatment, damage to the retinal structure in DR rats was alleviated, the number of hemangiomas was reduced, and the penetration of blood vessels was weakened. In addition, ACT treatment improved the hypertrophy and gliogenesis of Müller cells during DR, promoted the expression of Kir4.1 and activated the PI3K/Akt signaling pathway. ACT treatment inhibited the proliferation and migration of RMC-1 cells and promoted the expression of Kir4.1. TXNIP overexpression effectively reversed the inhibitory effect of ACT on the proliferation and migration of Müller cells and its induction of Kir4.1 expression. In addition, TXNIP knockdown effectively reversed the inhibitory effect of HG on the expression of p-PI3K and p-Akt, whereas TXNIP overexpression had the opposite effect, and treatment with the PI3K/AKT pathway inhibitor LY294002 effectively reversed the effect of TXNIP knockdown. Animal experiments also confirmed that the therapeutic effect of ACT on DR rats could be reversed by the overexpression of TXNIP or LY294002. In conclusion, ACT inhibits Müller cell reactive proliferation and alleviates diabetic retinopathy by regulating TXNIP and mediating the expression of Kir4.1 channels in a PI3K/Akt-dependent manner. Show less
Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index Show more
Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity. Show less
Psoriasis is an inflammatory skin disease, there is no radical cure. Traditional Chinese medicine has accumulated a lot of clinical experience in the treatment of psoriasis and developed a variety of Show more
Psoriasis is an inflammatory skin disease, there is no radical cure. Traditional Chinese medicine has accumulated a lot of clinical experience in the treatment of psoriasis and developed a variety of treatment methods, among which Yinxieling optimization formula (PSORI-CM01) have a definite clinical effect in the treatment of psoriasis, but their mechanism of action is still unclear. To investigate the molecular mechanism of the PSORI-CM01 in the treatment of psoriasis. Firstly, potential active compounds and key signaling pathways of PSORI-CM01 were explored by the systems pharmacology method. Then MTT assay was used to screen the potentially active compounds of PSORI-CM01, and explore the combined effects of potentially active compounds. The regulation of potentially active compounds on inflammatory factors were evaluated by a Human Th17 Magnetic Bead Panel. The regulation of PSORI-CM01 on key targets in the key signaling pathways were explored by qRT-PCR method. Finally, the molecular mechanism of PSORI-CM01 in the treatment of psoriasis was explained by the systems pharmacology method. The potentially active compounds of PSORI-CM01 included gallic acid, liquiritigenin, rosmarinic acid, syringic acid, isoliquiritin apioside, caffeic acid, naringenin, cryptochlorogenic acid, (+)-taxifolin, p-coumaric acid, chlorogenic acid, fraxin, 5-hydroxymethylfurfural, lithospermic acid, isoliquiritigenin, salviandic acid B, octahydrocurcumin, catechin, syringaldehyde, methyl rosmarinate, paeonol, protocatechuic acid, astilbin, isoastilbin, isofraxidin and zederone. Both antagonistic and synergistic effects were determined in the combinations of active compounds. Most of the active compounds up-regulated IL-2, IL-6, IL-9 and TNF-α, and down-regulated IFN-γ, IL-1β, IL-2, IL-9, IL-10, IL-13, IL-15, IL-17F, IL-21, IL-22 and IL-27. The PI3K-Akt signaling pathway would be the key signaling pathway of PSORI-CM01. The qRT-PCR results showed that its compounds can effectively regulate the expression of key targets in this pathway. The molecular mechanism of PSORI-CM01 for treating psoriasis would be mediated by regulating the network of inflammatory factors through the PI3K-Akt signaling pathway. Show less
We investigate the role of the black-phosphorus-based n-p (BP-np) junction modulated by linearly polarized light (LPL) in governing the quantum transport behaviors. Following the analysis of the band Show more
We investigate the role of the black-phosphorus-based n-p (BP-np) junction modulated by linearly polarized light (LPL) in governing the quantum transport behaviors. Following the analysis of the band structures, we find that the LPL can adjust the gap between the conduction and valence bands by reducing the impact of momentum mismatch caused by the band gap. In addition, LPL can also eliminate the angle dependence of transmission. This means that for BP with a fixed band gap, the transmission-forbidden region can be reduced and the transmission probability can be increased by applying LPL modulation of the band gap to achieve all-angle perfect transmission, i.e., super-Klein tunneling (SKT). Our investigation also found that the SKT is robust to different incident energies, resulting in a larger conductance platform. These findings could be useful for the development and application of optical-like electronic devices. Show less
The present study explored the effects of inositol on growth performance, body composition, antioxidant performance, and lipid metabolism of largemouth bass (
Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the Through integrated analy Show more
Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA. Show less
Organic afterglow materials have drawn increasing attention for their great potential in practical applications. Until now, most of them just show the lifetimes in milliseconds or seconds, while the r Show more
Organic afterglow materials have drawn increasing attention for their great potential in practical applications. Until now, most of them just show the lifetimes in milliseconds or seconds, while the realization of long persistent luminescence (LPL) lasting for minutes or even hours is difficult. In 2017, Adachi and Kabe successfully realize the LPL with a duration longer than 1 hour in a purely organic system, which can be even comparable to some excellent inorganic materials. However, partially for the unclear structure-property relationship, organic LPL materials are still rather scarce, especially for the stable ones in air or aqueous solution. In this review, we present the recent progress in organic LPL, mainly focusing on the material design strategy and internal mechanism. It is anticipated that the deep understanding can be beneficial for the further development of organic LPL materials with good stability in air and even aqueous phase. Show less
Lung squamous cell carcinoma (LUSC) is the second most common pathological type of non-small cell lung cancer (NSCLC). However, compared with lung adenocarcinoma (LUAD), the incidence of driver gene m Show more
Lung squamous cell carcinoma (LUSC) is the second most common pathological type of non-small cell lung cancer (NSCLC). However, compared with lung adenocarcinoma (LUAD), the incidence of driver gene mutations in LUSC is relatively lower and treatment options for LUSC patients are very limited. We described a LUSC patient with a novel FGFR3-IER5L fusion revealed by next generation sequencing in this report. The patient refused surgery, radiotherapy or chemotherapy and received anlotinib treatment. Anlotinib is a small molecular multi-target tyrosine kinase inhibitor, which can inhibit the activity of kinases including vascular endothelial growth factor receptor 2/3 (VEGFR2/3), fibroblast growth factor receptor 1-4 (FGFR1-4), platelet-derived growth factor receptor α/β (PDGFRα/β), and c-Kit. The patient achieved partial response and the progression-free survival was 3.8 months. Show less
Organic afterglow with long-persistent luminescence (LPL) after photoexcitation is highly attractive, but the realization of narrowband afterglow with small full-width at half-maximum (FWHM) is a huge Show more
Organic afterglow with long-persistent luminescence (LPL) after photoexcitation is highly attractive, but the realization of narrowband afterglow with small full-width at half-maximum (FWHM) is a huge challenge since it is intrinsically contradictory to the triplet- and solid-state emission nature of organic afterglow. Here, narrow-band, long-lived, and full-color organic LPL is realized by isolating multi-resonant thermally activated delayed fluorescent (MR-TADF) fluorophores in a glassy steroid-type host through a facile melt-cooling treatment. Such prepared host becomes capable of exciton dissociation and recombination (EDR) upon photoirradiation for both long-lived fluorescence and phosphorescence; and, the efficient Förster resonance energy transfer (FRET) from the host to various MR-TADF emitters leads to high-performance LPL, exhibiting small FWHM of 33 nm, long persistent time over 10 s, and facile color-tuning in a wide range from deep-blue to orange (414-600 nm). Moreover, with the extraordinary narrowband LPL and easy processability of the material, centimeter-scale flexible optical waveguide fibers and integrated FWHM/color/lifetime-resolved multilevel encryption/decryption devices have been designed and fabricated. This novel EDR and singlet/triplet-to-singlet FRET strategy to achieve excellent LPL performances illustrates a promising way for constructing flexible organic afterglow with easy preparation methods, shedding valuable scientific insights into the design of narrow-band emission in organic afterglow. Show less
Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens. Hi Show more
Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens. Histopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB. We successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure. Show less