👤 Jing Jin

Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases: (i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and Show less

Low physical activity (LPA) is associated with cardiovascular and cerebrovascular pathologies. This study aimed to assess the prevalence of several noncommunicable diseases relating to LPA. Using the 2021 Global Burden of Disease data set, we modelled LPA-related disease burdens across 204 countries and territories, quantifying mortality counts, age-standardised mortality rates, and disability-adjusted life years (DALYs) for five noncommunicable diseases. We conducted multivariable stratification analyses to assess variations by gender, age, and sociodemographic index (SDI) quintiles. We used age-period-cohort modelling to project burden trajectories, while applying counterfactual decomposition frameworks to delineate synergistic interactions between LPA and risk factors. We found that LPA accounted for 555 101 related deaths globally in 2021 across the five studied pathologies, mostly among individuals aged 60-94 years. Association between LPA-related disease burden and SDI followed a U-shaped distribution across regions and diseases. Among individuals aged 60-89 years, LPA-related deaths were significantly higher in women than in men, indicating a disproportionate burden on elderly females. Ischaemic heart disease (IHD) trends stabilised in low- and middle-SDI regions but declined significantly in high-SDI regions, underscoring global health disparities. From 2007 to 2011, LPA DALYs and mortality risk ratios for IHD, stroke, and lower extremity peripheral arterial disease declined from >1 to <1, whereas diabetes mellitus exhibited an opposite trend, highlighting LPA's persistent and significant impact on diabetes-related morbidity. Demographic shifts and epidemiological transitions were primary drivers of LPA-related disease burden across five pathologies. In high-SDI regions, epidemiological changes predominated, whereas population growth was a key factor in low- and middle-SDI regions. Synergistic interaction of these factors with LPA is projected to substantially amplify future disease burden. Physical activity should be increased among elderly women to address health risks associated with LPA. Likewise, urgent public health interventions are needed for LPA-related diabetes. As IHD burden rises in low- and middle-SDI regions, vascular disease care strategies require optimisation. Moreover, high-SDI regions should strengthen nationwide physical activity promotion, while low- and middle-SDI areas must enhance healthcare infrastructure and manage population growth to reduce LPA-related disease burdens. Show less

We investigated the association between lipoprotein(a) [Lp(a)] levels and stroke recurrence in type 2 diabetes mellitus (T2DM) patients with recent acute ischemic stroke or transient ischemic attack (TIA). This study included 3,311 T2DM patients with recent acute ischemic stroke or TIA and complete Lp(a) data from the Third China National Stroke Registry. The patients were categorized into three groups based on the 40th and 70th percentiles of the Lp(a): ≤13.1, 13.1 to 29.2 and ≥ 29.2 mg/dL. The primary outcome was stroke recurrence within one year, with incident cases further classified as either ischemic or hemorrhagic. Cox proportional hazards regression and restricted cubic splines were used to evaluate these associations. A total of 3311 patients (2142 men, 64.69%, median age 63) were analyzed. Restricted cubic spline analysis revealed a U-shaped relationship between Lp(a) levels and the risk of stroke recurrence. After adjusting for cardiovascular risk factors, patients with Lp(a) levels ≤ 13.1 mg/dL or ≥ 29.2 mg/dL had hazard ratios of 1.34 (95% confidence interval (CI), 1.02-1.76) and 1.35 (95% CI, 1.01-1.79), respectively, for total stroke compared to those with Lp(a) levels between 13.1 and 29.2 mg/dL. The corresponding hazard ratios were 1.36 (95% CI, 1.02-1.81) and 1.36 (95% CI, 1.01-1.83) for ischemic stroke and 0.88 (95% CI, 0.37-2.09) and 0.77 (95% CI, 0.31-1.94) for hemorrhagic stroke, respectively. Both low and high levels of Lp(a) are associated with an increased risk of stroke recurrence in T2DM patients with a recent history of acute ischemic stroke or TIA, demonstrating a U-shaped relationship. Show less

To explore the potential categories of fear of falling in elderly stroke patients and analyze the differences in characteristics and influencing factors among patients in different categories. AA total of 386 elderly stroke patients hospitalized in the Department of Neurology of a tertiary grade A general hospital in Jilin Province from March 2024 to June 2024 were selected as research subjects using the convenience sampling method. A general information questionnaire, Modified Falls Efficacy Scale (MFES), Simplified Coping Style Questionnaire (SCSQ), and Social Support Rating Scale (SSRS) were used for the survey. Mplus 8.3 software was applied to conduct latent profile analysis (LPA) on fear of falling in elderly stroke patients to identify potential categories, and multivariate logistic regression was used to further explore the influencing factors of each category. There were 3 potential categories of fear of falling in elderly stroke patients: the high fear of falling group (21.8%), moderate fear of falling group (38.3%), and low fear of falling group (39.9%). Multivariate logistic regression analysis showed that gender, age, type of stroke diagnosis, visual status, hearing status, limb strength, coping style, and social support were the influencing factors for the potential categories of fear of falling in elderly stroke patients. Fear of falling in elderly stroke patients has obvious categorical characteristics. Medical staff should implement targeted interventions based on the characteristics and influencing factors of different potential categories to reduce patients' fear of falling. Show less

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

Precise differential diagnosis between lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and marginal zone lymphoma (MZL) remains a challenging issue because of overlapping clinicopathological and immunophenotypic features. In the present study, the differential diagnostic potential of CD180 was assessed by determining its expression patterns in patients with MZL and LPL/WM through flow cytometry. The results indicated that LPL/WM cases exhibited a complete absence of CD180 expression on malignant B cells, whereas MZL cases showed robust CD180 expression (P < .001). Receiver operating characteristic analysis demonstrated that CD180 expression percentage showed optimal diagnostic accuracy in LPL/WM and MZL cases (area under the curve = 0.998, sensitivity = 100%, and specificity = 98.0%), with a further improvement in differentiation potential by the CD180 mean fluorescence intensity ratio (lymphocytes/monocytes) of ≤ 0.47 (area under the curve = 0.937). Moreover, although the MYD88 Show less

To reveal the molecular basis of knee osteoarthritis (KOA) with Yang deficiency and blood stasis syndrome by analyzing the gene expression profiles in synovial fluid and blood of KOA patients with this syndrome. A total of 80 KOA patients were recruited from October 2022 to June 2024, including 40 cases in the non- Logistic regression analysis showed that compared with KOA patients with non-Yang deficiency and blood stasis syndrome, those with Yang deficiency and blood stasis syndrome had increased BMI, LDL, fibrinogen, total cholesterol, and D-dimer, and decreased HDL, with a clear correlation between the two groups. There were 562 differential genes in the blood, among which 322 were up-regulated and 240 were down-regulated;755 differential genes were found in the synovial fluid, with 350 up-regulated and 405 down-regulated. KEGG signaling pathway analysis of synovial fluid revealed changes in lipid metabolism-related pathways, including cholesterol metabolism, fatty acid metabolism, and PPARG signaling pathway. Analysis of the involved differential genes identified 6 genes in synovial fluid that were closely related to lipid metabolism, namely LRP1, LPL, ACOT6, TM6SF2, DGKK, and PPARG. Subsequently, PCR and immunohistochemical verification were performed using synovial fluid and cartilage samples, and the results were consistent with those of microarray sequencing. This study explores the clinical and genomic correlation between traditional Chinese medicine syndromes and knee osteoarthritis from the perspective of lipid metabolism, and proves that abnormal lipid metabolism is closely related to KOA with Show less

This study focuses on the impacts of polystyrene/polylactic acid microplastics (PS/PLA-MPs) on ovarian reserve and oocyte maturation in female mice, along with the underlying mechanisms. 1 μm PS-MPs and PLA-MPs were prepared, with PLA-MPs having a rougher surface and broader size distribution. In vitro, PLA-MPs showed higher cytotoxicity to granulosa cells compared to PS-MPs. In vivo, MPs exposure disrupted the estrous cycle, and damaged ovarian reserve. Granulosa cell apoptosis and cytokine activation led to transzonal projection retraction, oocyte oxidative stress, meiotic abnormalities, and reduced oocyte retrieval and polar body extrusion rate, thus reducing litter size. PS-MPs induced more severe intestinal and ovarian impairment. Analysis of feces 16S rRNA, serum metabolomics, and ovarian RNA sequencing revealed that lipoprotein lipase (LPL) was suppressed by both MPs, linking gut microbiota, lipid metabolism, and ovarian injury. Fecal microbiota transplantation as a rescue strategy in MPs exposed mice upregulated LPL, alleviating ovarian reserve decline. In PLA-MPs exposed mice, ovarian reserve related indicators partially recovered after a two-week exposure cessation. These results clarify the similarities and differences in how PS-MPs and PLA-MPs impair ovarian function via gut-ovary axis and lipid metabolism dysregulation. Show less

Light-responsive porous liquids (LPLs) attract significant attention for their controllable gas uptake under light irradiation, while their preparation has remained a great challenge. Here we report the fabrication of type II LPLs with enhanced light-responsive efficiency by tailoring the host's functionality for the first time. The functionality of light-responsive metal-organic cage (MOC-RL, constructed from dicopper and responsive ligands) is modified by introducing the second long-chain alkyl ligand, producing MOC-RL-AL as a new host. A spatially hindered solvent based on polyethylene glycol, IL-NTf Show less

Dysregulated lipid metabolism promotes the progression of various cancer types, including breast cancer. The present study aimed to explore the lipidomic profiles of patients with breast cancer, providing insights into the correlation between lipid compositions and tumor subtypes characterized by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Briefly, 30 patients with breast cancer were categorized into four groups based on their HR and HER2 status: HR+ no HER2 expression (HER2-0), HR+ HER2-low; HR+ HER2-positive (pos) and HR- HER2-pos. The lipidomic profiles of these patients were analyzed using high-throughput liquid chromatography-mass spectrometry. The data were processed through principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and random forest (RF) classification to assess the lipidomic variations and significant lipid features among these groups. The profiles of the lipids, particularly triglycerides (TG) such as TG(16:0-18:1-18:1)+NH Show less

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. Show less

The association between obesity and cholelithiasis has been identified. However, the causal relationship between age-specific childhood obesity and adult cholelithiasis remains unclear. In addition, the biological basis for the association between childhood obesity and adult cholelithiasis is poorly understood, which poses a challenge for preventing adult cholelithiasis in specific biological pathways. Summary statistics of genome-wide association studies (GWASs) of childhood age-specific body mass index (BMI) at 12 time points and adult cholelithiasis derived from FinnGen were used in this study, with the former covering data from birth to 8 years. Linkage disequilibrium score regression (LDSC) analyses were used to assess the genetic correlations of age-specific childhood BMI to cholelithiasis. Two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) analyses were utilized to explore the causal associations. As downstream analyses, summary-based Mendelian randomization (SMR) analyses, transcriptome-wide association studies (TWAS), and Bayesian colocalization were conducted to discover the shared transcriptomic signals. The GWAS summary statistics of cholelithiasis from the UK Biobank were used for sensitivity analyses. LDSC analyses revealed significant genetic correlations between 11 age-specific childhood BMIs and adult cholelithiasis (except for birth BMI). Two-sample MR and MVMR analyses indicated causal relationships between birth BMI and BMI at 8 months, 1.5 years, 7 years, and 8 years after birth and adult cholelithiasis. SMR, TWAS, and colocalization analyses identified MLXIPL as the strongest overlapping signal between age-specific BMI and adult cholelithiasis. This study provides new evidence on the relationships between childhood obesity and adult cholelithiasis, highlighting the role of early intervention for obesity in childhood at key time points. MLXIPL gene expression was identified as a potential biological pathway, suggesting potential therapeutic targets and precise intervention strategies for childhood obesity and adult cholelithiasis. Show less

Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less

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

Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Fritillariae Thunbergii Bulbus, Leonuri Herba, and Forsythiae Fructus, has shown efficacy in treating cardiovascular diseases, although its mechanisms are unclear. This study aimed to explore the protective effects of QRSJF against atherosclerosis and the mechanisms involved. The composition of QRSJF was analyzed using Ultra Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. An 8-week high-fat diet (HFD)-induced atherosclerosis model was established in ApoE Both low- and high-dose QRSJF effectively attenuated dyslipidemia and decreased serum inflammatory cytokine levels in HFD-fed ApoE QRSJF improves dyslipidemia and reduces atherosclerotic plaque in ApoE Show less

The Kirgiz, a Turkic-speaking ethnic group with a rich nomadic heritage, represent a pivotal population for understanding human migration and adaptation in Central Asia. However, their genetic origins and admixture history remain largely unexplored. Here, we present the first comprehensive genomic study of Kirgiz populations from Xinjiang, China (XJ.KGZ, n = 36) and their counterparts in Kyrgyzstan (KRG), integrating genome-wide data of 2,406 global individuals. Our analyses reveal four primary ancestry components in XJ.KGZ: East Asian (41.7%), Siberian (25.6%), West Eurasian (25.2%), and South Asian (7.6%). Despite close genetic affinity (FST = 0.13%), XJ.KGZ and KRG diverged ∼447 years ago, with limited gene flow post-split. A two-wave admixture model elucidates their demographic history: an initial East-West Eurasian mixture ∼2,225 years ago, likely reflecting west-east contacts during the period of the Warring States and the Qin Dynasty, followed by secondary admixture events (∼875 to 425 years ago) linked to historical migrations under Mongol and post-Mongol rule. Local adaptation signatures implicate genes critical for cellular tight junction (e.g. PATJ), pathogen invasion (e.g. OR14I1), and cardiac functions (e.g. RYR2) with allele frequency deviations suggesting ancestry-specific selection. While no classical high-altitude adaptation genes (e.g. EPAS1) showed selection signals, RYR2 and C10orf67-implicated in hypoxia response in Tibetan fauna-displayed Western ancestry bias, hinting at convergent adaptation mechanisms. This study advances our understanding of the genetic makeup and admixture history of the Kirgiz people and provides novel insights into human dispersal in Central Asia. Show less

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a substantial global threat. SARS-CoV-2 nonstructural proteins (NSPs) are essential for impeding the host replication mechanism while also assisting in the production and organization of new viral components. However, NSPs are not incorporated into viral particles, and their subsequent fate within host cells remains poorly understood. Additionally, their role in viral pathogenesis requires further investigation. This study aimed to discover the ultimate fate of NSP6 in host cells and to elucidate its role in viral pathogenesis. We investigated the effects of NSP6 on cell death and explored the underlying mechanism; moreover, we examined the degradation mechanism of NSP6 in human cells, along with analysing its correlation with coronavirus disease 2019 (COVID-19) severity in patient peripheral blood mononuclear cells (PBMCs). NSP6 was demonstrated to induce cell death. Specifically, NSP6 interacted with EI24 autophagy-associated transmembrane protein (EI24) to increase intracellular Ca This study reveals that KLHL22-mediated ubiquitination controls NSP6 stability and that NSP6 induces autophagic cell death via calcium overload, highlighting its cytotoxic role and suggesting therapeutic strategies that target calcium signaling or promote NSP6 degradation as potential interventions against COVID-19. Show less

This study aimed to investigate the role of SIRT4 in retinal protection, specifically its ability to mitigate excitotoxic damage to Müller glial cells through the regulation of mitochondrial dynamics and glutamate transporters (GLASTs). A model of retinal excitatory neurotoxicity was established in mice. Proteins related to mitochondrial dynamics, GLAST, and SIRT4 were analyzed on days 0, 1, 3, and 5 following toxic injury. The influence of SIRT4 on mitochondrial dynamics-related proteins and GLAST was examined by inducing SIRT4 overexpression through intraperitoneal injection of resveratrol or by using SIRT4 knockout (KO) mice. Additionally, the effects of upregulating and downregulating SIRT4 expression in rat Müller glial cell lines (rMC-1) were explored via lentiviral vector transfection to assess changes in mitochondrial morphology and GLAST expression. After excitotoxic injury to the mouse retina, the retinal thickness and structure were disrupted, the number of retinal ganglion cells (RGCs) decreased, and Müller glial cells were activated by day 1. The levels of OPA1, GLAST, and SIRT4 proteins peaked on the first day after injury and then gradually decreased, indicating a synchronized dynamic trend. The upregulation of SIRT4 expression promoted OPA1 and GLAST protein expression, thereby alleviating retinal excitotoxic injury. Furthermore, the upregulation of SIRT4 expression promoted mitochondrial fusion and increased GLAST expression in rMC-1 cells, reducing cellular excitotoxic damage. Conversely, downregulation of SIRT4 had the opposite effect. SIRT4 plays a significant role in mitigating excitotoxic damage in the retina, modulating Müller glial cell injury by regulating mitochondrial dynamics and glutamate transporter expression, ultimately influencing retinal health. Show less

SIRT4 is a member of the sirtuin family, which is related to mitochondrial function and possesses antioxidant and regulatory redox effects. Currently, the roles of SIRT4 in retinal Müller glial cells, oxidative stress, and mitochondrial function are still unclear. We confirmed, by immunofluorescence staining, that SIRT4 is located mainly in the mitochondria of retinal Müller glial cells. Using flow cytometry and Western blotting, we analyzed cell apoptosis, intracellular reactive oxygen species (ROS) levels, apoptotic and proapoptotic proteins, mitochondrial dynamics-related proteins, and mitochondrial morphology and number after the overexpression and downregulation of SIRT4 in rMC-1 cells. Neither the upregulation nor the downregulation of SIRT4 alone affected apoptosis. SIRT4 overexpression reduced intracellular ROS, reduced the BAX/BCL2 protein ratio, and increased the L-OPA/S-OPA1 ratio and the levels of the mitochondrial fusion protein MFN2 and the mitochondrial cleavage protein FIS1, increasing mitochondrial fusion. SIRT4 downregulation had the opposite effect. Mitochondria tend to divide after serum starvation for 24 h, and SIRT4 downregulation increases mitochondrial fragmentation and oxidative stress, leading to aggravated cell damage. The mitochondrial division inhibitor Mdivi-1 reduced oxidative stress levels and thus reduced cell damage caused by serum starvation. The overexpression of SIRT4 in rMC-1 cells reduced mitochondrial fragmentation caused by serum starvation, leading to mitochondrial fusion and reduced expression of cleaved caspase-3, thus alleviating the cellular damage caused by oxidative stress. Thus, we speculate that SIRT4 may protect retinal Müller glial cells against apoptosis by mediating mitochondrial dynamics and oxidative stress. Show less

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate clinical characteristics and therapeutic targets concerning FOXO1 fusion status. 65 pediatric RMS patients were enrolled. Clinical data were analyzed using Kaplan-Meier estimates and Cox regression. Surgically resected tumor tissues were subject to single-cell RNA sequencing (scRNA-seq). Patient-derived xenograft (PDX) was establish and dissociated to cells for high-throughput drug screening. Among the 65 patinets (36 patients with embryonal RMSs (ERMSs), 15 patients with alveolar RMSs (ARMSs) and 14 patients with other types of RMSs), 73.3% of ARMSs were defined as fusion positive (FP) while 6 ERMS (ERMS)s were also FP. Cox regression analysis identified FOXO1 fusion as a risk factor alone and combined with pathologic subtype, sex and age or metastasis status. scRNA-seq revealed distinct transcription factor networks between FP and FN RMS, showing up-regulated activity of OLIG2, NHLH1, SNAI1, TFF3 and other TFs related to neural development and differentiation. MAPK, PI3K-Akt, and mTOR pathways were enriched in FP-RMS tumor cells. High-throughput drug screening of PDX-derived cells identified sensitive drugs targeting FP-RMS specific signatures. AMG-337 was selected and validated for its anti-tumor effect. FOXO1 fusion status influences RMS clinical outcomes, including rare FP-ERMS cases. scRNA-seq combined with drug screening identified MET as a promising therapeutic target in FP-RMS. Show less

Distant metastasis and immune evasion are the major obstacles for successful colorectal cancer (CRC) treatment. The link between metastasis and immune evasion, as well as their therapeutic significance, remains unclear. Long non-coding RNAs from six paired CRC and normal tissues were screened by RNA sequencing (RNA-seq). LncRNA-CTD (CTD-2568A17.8) expression levels were determined using in situ hybridization and quantitative PCR analysis. In vitro and in vivo assays were performed to confirm the function of lncRNA-CTD. Flow cytometry was used to analyze the impact of lncRNA-CTD on immune cell infiltration and T-cell function. RNA-seq combined with RNA pull-down and RNA immunoprecipitation assay was used to identify the changes in downstream molecules induced by lncRNA-CTD. The therapeutic value of the combination of lncRNA-CTD and immune checkpoint inhibitors has been evaluated. In this study, we identified a novel long non-coding RNA, lncRNA-CTD, which is downregulated in CRC and correlates with both metastasis and immunotherapy response. Mechanistically, the interaction of lncRNA and smad2 prevented the phosphorylation and nuclear translocation of smad2, which inhibited the expression of snail1, thereby inhibiting the metastasis of CRC. LncRNA-CTD enhances major histocompatibility complex class I (MHC-I) expression on the cancer cell membrane by interacting with STUB1 to disrupt the interaction of STUB1 with the MHC-I activator NLRC5 and subsequent NLRC5 ubiquitination-mediated degradation, increasing the susceptibility of CRC cells to being killed by CD8 Collectively, our study reveals the role and mechanism of lncRNA-CTD in CRC metastasis and immune evasion. Overexpression of lncRNA-CTD suppresses CRC metastasis and improves the efficacy of immune checkpoint inhibitors.Cite Now. Show less

Idiopathic frozen shoulder (FS) can lead to difficulties in daily activities and significantly impact the quality of life. Early diagnosis and treatment can help alleviate symptoms and restore shoulder function. Therefore, we aimed to explore the diagnostic biomarkers and potential mechanisms of FS from a transcriptomics perspective. Total RNA was extracted from tissue samples of 15 FS and 11 controls. At the outset, we conducted differential expression analysis, weighted gene co-expression network analysis (WGCNA), and utilized the cytoHubba plugin, complemented by two machine learning algorithms, receiver operating characteristic (ROC) analysis, and expression level evaluation to identify biomarkers for FS. Subsequently, a nomogram was constructed based on the biomarkers. Additionally, we conducted enrichment and immune infiltration analyses to explore the mechanisms associated with these biomarkers. Finally, we confirmed the expression patterns of the biomarkers at the clinical level through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). This study established a link between FS biomarkers that have strong diagnostic potential and specific immune responses, highlighting possible targets for diagnosing and treating FS. Show less

This study aimed to investigate the role of the Midline1 gene in secondary palate development by analyzing its expression and function in palatal shelf fusion and morphology. Initially, twenty mouse embryos were collected for each of the embryonic stages E13.5, E13.75, and E14.5. Whole-mount in situ hybridization was performed approximately ten times to optimize the experimental protocol and to analyze the expression pattern of Midline1 (MID1) in the palatal tissues at these developmental stages. Subsequently, palatal tissues from E13.5 embryos were treated with varying concentrations of Midline1 small interfering RNA (MID1 siRNA), and the knockdown efficiency was evaluated using Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), with each concentration tested in triplicate. Based on the results, the most effective concentration, 100 nM MID1 siRNA, was selected for further experiments. Subsequently, twelve E13.5 palatal explants were allocated into two groups: six explants were treated with 100 nM MID1 siRNA (experimental group), and six with scrambled small interfering RNA(Scramble siRNA; control group). After 48 h of in vitro culture, hematoxylin and eosin (HE) staining was performed to evaluate the morphology of palatal shelf fusion. To evaluate apoptotic activity, Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) staining was performed on both experimental and control groups. Finally, immunohistochemistry and Western blot analyses were conducted to examine the expression levels of Matrix Metalloproteinase 8 (MMP8) and Snail Family Transcription Factors (Snail) proteins in three biological replicates from each group. Midline1 deficiency resulted in incomplete palatal shelf fusion and significantly reduced apoptosis. Additionally, the knockdown of Midline1 led to the upregulation of Snail and MMP8 gene expression, indicating that Midline1 plays a critical role in regulating epithelial-to-mesenchymal transition and maintaining cytoskeletal stability during palate development. Midline1 is essential for normal secondary palate development. Its dysregulation disrupts palatal shelf fusion and morphology, potentially contributing to craniofacial abnormalities such as cleft palate. These findings provide new insights into the molecular mechanisms underlying palate development and suggest that Midline1 could be a therapeutic target for addressing cleft palate and related defects. Show less

Ovarian cancer is the third most common gynecological cancer worldwide. Due to the high recurrence rate of advanced-stage ovarian cancer, often resulting from drug-resistant and refractory disease, various treatment strategies are under investigation. Genome editing of therapeutic target genes holds promise in enhancing cancer treatment efficacy by elucidating gene functions and mechanisms involved in cancer progression. The CRISPR/Cas9 system, in particular, shows great potential in ovarian cancer gene therapy and drug development. Targeting therapeutic genes such as BRCA1/2, P53, Snai1 etc, could improve the therapeutic strategy in ovarian cancer. CRISPR/Cas9 is a powerful gene-editing tool that there are many on-going clinical trials to treat various diseases including cancer. Nano-based delivery systems for CRISPR/Cas9 offer further therapeutic benefits, leveraging the unique properties of nanoparticles to improve delivery efficiency. Nano-based delivery systems could enhance the stability of CRISPR/Cas9 delivery formats (such as plasmid, mRNA, etc) and improve the delivery precision of delivery to target tumors. Additionally, combining CRISPR/Cas9 with targeted drug treatments, especially those aimed at genes associated with drug resistance, may significantly improve therapeutic outcomes in ovarian cancer. In this review, we discuss therapeutic target genes and their mechanisms in ovarian cancer, advances in nano-based CRISPR/Cas9 delivery, and the therapeutic potential of combining CRISPR/Cas9 with drug treatments for ovarian cancer. Show less

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less

Amblyopia is characterized by decreased visual acuity due to abnormal visual experience during development. It affects approximately 3% of the population and is associated with abnormal development of the visual cortex. Despite treatment, many patients have residual visual acuity deficits. This study aimed to explore the genetic contributions to amblyopia. Case-control. The All of Us Research Program includes genotypic and phenotypic data from a diverse population of adults (age ≥ 18 years) across the United States. A total of 764 subjects with amblyopia (based on International Classification of Diseases and Systematized Nomenclature of Medicine codes) and 122 305 controls with no record of amblyopia and with whole genome sequencing data were compared. Only participants of European genetic ancestry were included because of small numbers of affected participants in other ancestral groups. Genome-wide association study (GWAS) of common variants (minor allele frequency > 1%) and rare variant association study (RVAS) at the gene level for amblyopia of participants in the All of Us Research Program. Individual single nucleotide polymorphisms (SNPs) significantly associated with amblyopia and genes with significant burden of rare variants in amblyopia. The GWAS revealed 4 loci that approached statistical significance defined as P < 5e-8: rs56105618, rs1349660, rs7958343, and rs138693522. Each of the variants is an expression quantitative trait locus (eQTL) for a gene expressed in the brain or related to neural development. This RVAS revealed 15 genes with a statistically significant (P < 5e-05) different burden of variants: DCP1B, OR12D2, PCDHA4, ALKBH8, NMUR2, OR52P1P, NEU1, CACNB2, PSMA7, LRR1, ZNF831, FSIP2, ZNF654, CES5A, and MPV17, several of which have known roles in neurodevelopment. The identification of genes linked to amblyopia with roles in neurodevelopment suggests that the neurodevelopmental changes in amblyopia are not only secondary to abnormal visual experience but also may result from the interaction of primary neurodevelopmental deficits with abnormal experience. This potentially explains why some children develop amblyopia and others do not with the same ocular risk factors, may explain differences in treatment outcomes, and suggests new avenues for amblyopia treatment. Proprietary or commercial disclosure may be found after the references. Show less

In the context of head-and-neck squamous cell carcinoma (HNSCC), dendritic cells (DCs) assume pivotal responsibilities, acting as architects of antigen presentation and conductors of immune checkpoint modulation. In this study, we aimed to identify hub genes associated with DCs in HNSCC and explore their prognostic significance and implications for immunotherapy. Integrated clinical datasets from The Cancer Genome Atlas (TCGA)-HNSCC and GSE65858 cohorts underwent meticulous analysis. Employing weighted gene co-expression network analysis (WGCNA), we delineated candidate genes pertinent to DCs. Through the application of random survival forest and least absolute shrinkage and selection operator (LASSO) Cox's regression, we derived key genes of significance. Lisa (epigenetic Landscape In Silico deletion Analysis and the second descendent of MARGE) highlighted transcription factors, with Dual-luciferase assays confirming their regulatory role. Furthermore, immunotherapeutic sensitivity was assessed utilizing the Tumor Immune Dysfunction and Exclusion online tool. This study illuminated the functional intricacies of HNSCC DC subsets to tailor innovative therapeutic strategies. We leveraged clinical data from the TCGA-HNSCC and GSE65858 cohorts. We subjected the data to advanced analysis, including WGCNA, which revealed 222 DC-related candidate genes. Following this, a discerning approach utilizing random survival forest analysis and LASSO Cox's regression unveiled seven genes associated with the prognostic impact of DCs, notably Our research may yield a robust DC-based prognostic system for HNSCC; this will aid personalized treatment and improve clinical outcomes as the battle against this challenging cancer continues. Show less

The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline. This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD. The ICR mice intracerebroventricularly injected with Aβ Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis. Show less

The objective of this study was to investigate the potential of salidroside (SAL) (a major active compound in The expression of HIF-1 SAL enhanced the expression of HIF-1 SAL promotes osteoclast proliferation, differentiation and bone resorption through HIF-1 Show less