👤 Tiffany Dang

Gene-environment interactions play a critical role in shaping phenotypic heterogeneity in complex psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is a key genetic regulator of stress-sensitive neuroplasticity. Yet, how We conducted a case-control study including 93 patients with first-episode schizophrenia (SZ) and 64 healthy controls. Childhood trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ), and symptom dimensions were evaluated with the Positive and Negative Syndrome Scale (PANSS). Three Patients with SZ exhibited significantly higher CTQ scores across all trauma subtypes compared with controls (all These findings demonstrate that Show less

Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4 Show less

How extravillous trophoblast (EVT) invasion is regulated during placental development remains an important question in reproductive biology. This study demonstrates that growth differentiation factor-11 (GDF-11) promotes EVT invasion by upregulating angiopoietin-like 4 (ANGPTL4) via ALK4/ALK5-SMAD3 signaling, revealing a novel mechanism in placental biology. Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Growth differentiation factor 11 (GDF-11), a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to promote EVT cell invasion, yet the underlying molecular mechanisms remain largely unclear. In this study, RNA sequencing identified angiopoietin-like 4 (ANGPTL4), a multifunctional secreted protein, as a novel downstream target of GDF-11. In vitro experiments demonstrated that GDF-11 significantly upregulated ANGPTL4 expression in both HTR-8/SVneo cells and primary human EVT cells. Mechanistically, we found that the type I TGF-β receptors ALK4 and ALK5 were essential for mediating the stimulatory effect of GDF-11 on ANGPTL4 expression. Further analysis revealed that SMAD3, but not SMAD2, was the key transcription factor involved in this process. Using both loss- and gain-of-function approaches, we demonstrated that ANGPTL4 was required for GDF-11-induced EVT cell invasion. Importantly, serum levels of GDF-11 were markedly reduced in patients with preeclampsia (PE), a pregnancy disorder associated with shallow trophoblast invasion and poor placentation. Together, our findings uncover a previously unrecognized GDF-11-ANGPTL4 signaling axis that regulates EVT cell invasion and provides new insight into the pathophysiology of PE. Show less

Previous research has reported the efficacy of porcine brain hydrolysate (PBH) in improving Alzheimer's disease (AD). Nevertheless, the identification and screening of peptides with memory-enhancing effects within PBH remains ambiguous. The memory-enhancing effect of PBH was evaluated through animal and human experiments. Peptides with potential memory-enhancement effects were screened using molecular docking based on key target proteins (Keap1, BACE1, AChE, and p38α), and confirmed through cellular experiments. Results showed a significant reduction in behavioral errors of mice and marked improvements in the memory scores of humans. Five peptides with potential memory-enhancing effects were identified and screened. Cell experiments demonstrated that the cell activities were increased to 89.83 % and 78.14 % respectively for FPLHP and WGQKPW. Furthermore, the two peptides could reduce the contents of the four target proteins, thereby exhibiting the potential of memory enhancement. These findings offer a novel strategy for the discovery of peptides, which contribute to the development of memory-enhancing. Show less

This study aims to comprehensively analyze the intricate relationship between unsaturated fatty acids (UFAs, particularly omega-3 and omega-6 UFAs) and acne, from their clinical therapeutic effects to their underlying genetic regulatory mechanisms, to elucidate the role of UFAs in acne pathogenesis. Clinical evidence synthesis: we systematically reviewed randomized controlled trials (RCTs) to evaluate the impact of UFA supplementation on acne treatment outcomes. Genetic analysis: two-sample Mendelian randomization (MR) analysis we used to investigate causal relationships between serum UFA metabolites and acne, identifying potential key regulatory enzymes. The synthesis of these RCT studies confirmed that UFA supplementation improved acne conditions. MR analysis revealed causal links between three serum UFA metabolites and acne, with dihomo-gamma-linolenic acid (DGLA) (OR = 8.457; 95% CI: 2.367-30.214; P-value = 0.001) as a risk factor and arachidonic acid (AA) (OR = 0.209; 95% CI: 0.071-0.618; P-value = 0.005) and eicosapentaenoic acid (EPA) (OR = 0.318; 95% CI: 0.102-0.991; P-value = 0.048) as protective factors. Functional annotation suggested enzymes such as Δ5 desaturase (FADS1) and Δ6 desaturase (FADS2) may play a role in acne regulation. This study offers evidence that supports a connection between UFAs and acne, examining this relationship from both clinical and genetic angles. These findings highlight the role of specific UFAs and their associated metabolic enzymes in the development of acne. Omega-3 UFAs seem to have a protective effect against acne, whereas certain types and ratios of omega-6 UFAs might contribute to acne formation. The varied impacts of UFAs on acne could be attributed to disease processes mediated by specific enzymes. However, the study's limitations include its genetic analysis being primarily based on European populations, which limits the applicability of the findings to other groups. Future research should aim to include a more diverse range of participants to improve the generalizability of the results. Show less

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

Lung adenocarcinoma (LUAD) is a leading cause of cancer‑related death due to its aggressive nature and metastatic potential. The present study aimed to explore the expression of phospholipid phosphatase 2 (PPAP2C) in LUAD, and its effect on cell migration and invasion, with a particular focus on its association with the ERK/JNK signaling pathway and epithelial‑mesenchymal transition (EMT). The expression of PPAP2C in LUAD was analyzed using data from The Cancer Genome Atlas database. Pearson's correlation coefficient analysis was used to assess the correlation between PPAP2C and genes such as MAPK1, MAPK3, MAPK8, CDH1, CDH2 and SNAI1. Subsequently, the PPAP2C gene was silenced in A549 and H1299 LUAD cell lines using siRNA vectors, followed by assessments of gene expression, cell migration, invasion and protein interaction using reverse transcription‑quantitative PCR, western blotting, wound healing assay, Transwell invasion assay, molecular docking analysis, co‑immunoprecipitation and immunofluorescence staining. The results showed that PPAP2C was significantly upregulated in LUAD tissues compared with that in normal tissues. In addition, high levels of PPAP2C were significantly correlated with MAPK3, MAPK8, CDH1 and SNAI1. Notably, PPAP2C silencing significantly inhibited cell migration and invasion. Additionally, it reduced the phosphorylation levels of ERK and JNK proteins. PPAP2C showed specific binding sites with ERK1, and co‑precipitated with ERK1 in both A549 and H1299 cells. Furthermore, PPAP2C silencing decreased the expression levels of N‑cadherin and Snail, while increasing E‑cadherin expression, thereby inhibiting EMT. In conclusion, PPAP2C may be highly expressed in LUAD tissues, and could promote cell migration and invasion by activating the ERK/JNK signaling pathway and inducing EMT. These findings provide a novel potential target for the diagnosis and treatment of LUAD. Show less

Sichuan donkeys are small-statured donkeys native to the plateau and mountainous regions of southwestern China. They are well-suited for transportation tasks in mountainous terrain and exhibit remarkable adaptability to the harsh environment, characterized by low temperatures and hypoxia. Adaptation to the local environment has shaped their unique genomic characteristics and is an important source of genetic variation. However, the genome-wide landscape of Sichuan donkeys remains undescribed. In this study, we obtained whole-genome sequencing data from 17 Sichuan donkeys and combined this data with published data of 99 donkeys from 9 other donkey breeds. We aimed to elucidate the population structure, genetic diversity, genetic differentiation, and selection pressure of Sichuan donkeys at the whole-genome level. Population structure and genetic diversity analysis showed that Sichuan donkeys were less influenced by the hybridization of foreign donkey breeds. They maintained a relatively pure lineage of Chinese native donkeys and exhibited higher genetic diversity. The study also found that Sichuan donkeys were genetically closest to Tibetan and Yunnan donkeys. Although their effective population size around 1000 years ago was smaller compared to Tibetan and Yunnan donkeys, it was still larger than that of other donkey breeds. Moreover, selective signature analysis (θπ, CLR, F This study clarified the genetic diversity, genetic differentiation, and effective population size of Sichuan donkeys by comparing them with other donkey breeds. Our findings contribute to deeper understanding of the high-altitude adaptability of Sichuan donkeys, and provide valuable information for the conservation and breeding of the breed. Show less

Observational studies have investigated the association between lipid-lowering drugs and breast cancer (BC) and endometrial cancer (EC), but some controversy remains. This paper aims to explore the causal relationship between genetic proxies for lipid-lowering drugs and breast and endometrial cancers using drug-target Mendelian randomization (MR). Analyses were mainly performed using inverse variance weighted (IVW), heterogeneity and horizontal pleiotropy tests, and sensitivity analysis to assess the robustness of the results and causal relationship. HMGCR, APOB, and NPC1L1 increased the risk of breast cancer, LPL increased the risk of endometrial cancer, and APOC3 decreased the risk of breast and endometrial cancer. No heterogeneity or horizontal pleiotropy was detected, and nor was there any evidence of an association between other lipid-lowering drugs and breast and endometrial cancer. Our study demonstrated genetically that HMGCR inhibition, APOB inhibition, and NPC1L1 inhibition decrease the risk of breast cancer, LPL agonist increases the risk of endometrial cancer, and APOC3 inhibition decreases the risk of breast cancer and endometrial cancer, and these findings provide genetic insights into the potential risks of lipid-lowering drug therapy. Show less

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) in the blood from an incredibly early age. This condition leads to the early development of atherosclerotic arterial diseases, which can manifest even in the first few decades of life. Mutations in genes related to the LDL receptor (LDL-R), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) are the main molecular mechanisms causing familial hypercholesterolemia. This case involves a 44-year-old Vietnamese female who presented at the emergency department with chest pain and was diagnosed with acute myocardial infarction (AMI) complicated by cardiogenic shock. Clinical signs and an elevated LDL-C level pointed to prolonged exposure to high cholesterol. A Dutch Lipid Clinic Network (DLCN) score of 10 further supported the diagnosis of FH. The reverse T-stenting and small protrusion (TAP) technique was selected and successfully employed to stent the LMCA, left anterior descending artery (LAD) and left circumflex artery (LCx). This technique was chosen due to its simplicity and rapid execution, making it particularly suitable in situations of cardiogenic shock where time-consuming procedures should be avoided. Genetic testing confirmed a heterozygous pathogenic mutation in the LDL-R gene, corroborating the clinical diagnosis of FH. The patient's condition has gradually stabilized, and they have been discharged from the hospital. The patient is currently being monitored as an outpatient at the cardiology clinic. This case emphasizes the importance of considering FH in patients with premature cardiovascular events by applying the clinical diagnostic criteria and confirming by genetic analysis. It also highlights advanced interventional techniques for managing complex coronary lesions, such as reverse TAP. Show less

Due to the large size and high flexibility of the catalytic active site of BACE1 enzyme, the development of nonpeptide inhibitors with optimal pharmacological properties is still highly demanding. In this work, we have discovered 2-aminobenzimidazole-containg ether scaffolds having potent and selective inhibitory potentials against BACE1 enzyme. We have synthesized novel 29 compounds and optimization of aryl linker region resulted in highly potent BACE1 inhibitory activities with EC Show less

It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 )] relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes [ CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 )] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies. These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD. Show less

Lipid metabolism disorders are frequently noted in atopic dermatitis (AD) patients, prompting the long-term use of lipid-lowering drugs. However, the causal effects of circulating lipids and different lipid-lowering drugs on the risk of AD are not thoroughly understood. Using publicly available genome-wide association studies (GWAS) summary data from two different cohorts, a series of Mendelian randomization (MR) analyses were conducted to explore the causal effects of genetically proxied circulating lipids and lipid-lowering drugs on the risk of AD. Statistically, the random-effects inverse-variance-weighted (IVW) model was used as main analysis and several methods were conducted for sensitivity analysis to test the robustness of our results. Our findings revealed reduced risks of AD related to genetically proxied subtilisin/kexin type 9 (PCSK9) inhibition and lipoprotein lipase (LPL) agonist, while an increased AD risk associated with Niemann-Pick C1-like 1 (NPC1L1) inhibition. Circulating lipids and other drug targets did not show significant associations with AD risk. These results were replicated in the validation cohort; sensitivity analyses confirmed the robustness. This MR study suggests that, independent of circulating lipids, the use of PCSK9 inhibitors and LPL agonists may be associated with a decreased risk of AD, while inhibition of NPC1L1 is implicated in an increased risk. These findings may help optimize personalized selection of lipid-lowering drugs for AD patients and those at risk of AD. Show less

Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that the intestinal clock has major impacts on shaping peripheral rhythms via diurnal nutritional signals. Here, we investigate the role of the intestinal clock in controlling liver rhythmicity and metabolism. Transcriptomic analysis, metabolomics, metabolic assays, histology, quantitative (q)PCR, and immunoblotting were performed with Bmal1-intestine-specific knockout (iKO), Rev-erba-iKO, and control mice. Bmal1 iKO caused large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, the liver clock was resistant to entrainment by inverted feeding and a high-fat diet. Importantly, Bmal1 iKO remodelled diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis during the dark phase, leading to elevated glucose production (hyperglycaemia) and insulin insensitivity. Conversely, Rev-erba iKO caused a diversion to lipogenesis from gluconeogenesis during the light phase, resulting in enhanced lipogenesis and an increased susceptibility to alcohol-related liver injury. These temporal diversions were attributed to disruption of hepatic SREBP-1c rhythmicity, which was maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of a local clock. Our findings establish a pivotal role for the intestinal clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health. Our findings establish the centrality of the intestinal clock among peripheral tissue clocks, and associate liver-related pathologies with its malfunction. Clock modifiers in the intestine are shown to modulate liver metabolism with improved metabolic parameters. Such knowledge will help clinicians improve the diagnosis and treatment of metabolic diseases by incorporating intestinal circadian factors. Show less

Interleukin (IL) 27 is a member of the IL-12 family and is a heterodimeric cytokine composed of IL-27A and Epstein-Barr virus-induced 3 (EBI3). It plays an important role in regulating inflammation and cancer progression. IL-27A not only functions by dimerizing with EBI3 but also acts alone. Here, we report that IL-27A and EBI3 suppress spring viremia of carp virus (SVCV) replication in zebrafish. Expression analysis reveals that il-27a and ebi3 were significantly upregulated in the ZF4 cells by SVCV and poly(I:C), and in the zebrafish caudal fin (ZFIN) cells overexpressed with SVCV genes. Interestingly, il-27a and ebi3 were not modulated by IFNφ1, indicating that they are not IFN stimulated genes (ISGs). Furthermore, overexpression of IL-27A and EBI3 alone inhibited SVCV replication in the EPC cells, but less potent than co-expression of IL-27A and EBI3. Intriguingly, IL-27A could not induce the expression of irf3, ifn, isg15 and mx1. Taken together, our results demonstrate that IL-27A and EBI3 activate innate antiviral response in an IFN independent manner in zebrafish. Show less

Acute myeloid leukemia (AML) with megakaryocytic differentiation (AMkL) is a rare subtype of AML more common in children. Recent literature has identified multiple fusions associated with this type of leukemia. Morphology, cytogenetics, and genomic sequencing were assessed in patients from Children's Oncology Group trials AAML0531 and AAML1031 with central-pathology review confirmed non-Down syndrome AMkL. The 5-year event-free survival (EFS), overall survival (OS), and RR were evaluated in these AMkL subcategories. A total of 107 cases of AMkL (5.5%) were included. Distinct fusions were identified in the majority: RBM15::MRTFA (20%), CBFA2T3::GLIS2 (16%), NUP98 (10%), KMT2A (7%), TEC::MLLT10 (2%), MECOM (1%), and FUS::ERG (1%); many of the remaining cases were classified as AMkL with (other) myelodysplasia-related changes (MRC). Very few cases had AML-associated somatic mutations. Cases with CBFA2T3::GLIS2 were enriched in trisomy 3 (p = .015) and the RAM phenotype, with associated high CD56 expression (p < .001). Cases with NUP98 fusions were enriched in trisomy 6 (p < .001), monosomy 13/del(13q) (p < .001), trisomy 21 (p = .026), and/or complex karyotypes (p = .026). While different 5-year EFS and OS were observed in AMkL in each trial, in general, those with CBFA2T3::GLIS2 or KMT2A rearrangements had worse outcomes compared to other AMkL, while those with RBM15::MRTFA or classified as AMkl-MRC fared better. AMkL with NUP98 fusions also had poor outcomes in the AAML1031 trial. Given the differences in outcomes, AMkL classification by fusions, cytogenetics, and morphology may be warranted to help in risk stratification and therapeutic options. Show less

Glioblastoma (GBM) is one of the most progressive and prevalent cancers of the central nervous system. Identifying genetic markers is therefore crucial to predict prognosis and enhance treatment effectiveness in GBM. To this end, we obtained gene expression data of GBM from TCGA and GEO datasets and identified differentially expressed genes (DEGs), which were overlapped and used for survival analysis with univariate Cox regression. Next, the genes' biological significance and potential as immunotherapy candidates were examined using functional enrichment and immune infiltration analysis. Eight prognostic-related DEGs in GBM were identified, namely Show less

Previous studies have shown that microtubule actin crosslinking factor 1 (MACF1) can regulate osteoblast proliferation and differentiation through non-coding RNA (ncRNA) in bone-forming osteoblasts. However, the role of MACF1 in targeting the competing endogenous RNA (ceRNA) network to regulate osteoblast differentiation remains poorly understood. Here, we profiled messenger RNA (mRNA), microRNA (miRNA), and long ncRNA (lncRNA) expression in MACF1 knockdown MC3TC‑E1 pre‑osteoblast cells. In total, 547 lncRNAs, 107 miRNAs, and 376 mRNAs were differentially expressed. Significantly altered lncRNAs, miRNAs, and mRNAs were primarily found on chromosome 2. A lncRNA-miRNA-mRNA network was constructed using a bioinformatics computational approach. The network indicated that mir-7063 and mir-7646 were the most potent ncRNA regulators and mef2c was the most potent target gene. Pathway enrichment analysis showed that the fluid shear stress and atherosclerosis, p53 signaling, and focal adhesion pathways were highly enriched and contributed to osteoblast proliferation. Importantly, the fluid shear stress and atherosclerosis pathway was co-regulated by lncRNAs and miRNAs. In this pathway, Dusp1 was regulated by AK079370, while Arhgef2 was regulated by mir-5101. Furthermore, Map3k5 was regulated by AK154638 and mir-466q simultaneously. AK003142 and mir-3082-5p as well as Ak141402 and mir-446 m-3p were identified as interacting pairs that regulate target genes. This study revealed the global expression profile of ceRNAs involved in the differentiation of MC3TC‑E1 osteoblasts induced by MACF1 deletion. These results indicate that loss of MACF1 activates a comprehensive ceRNA network to regulate osteoblast proliferation. Show less

The high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto α5-containing GABA Show less

Angiopoietin like 4 (ANGPTL4) has been proved to play an important role in lipid and glucose metabolism disorders and related cardiovascular diseases, but its role in the formation of cirrhosis still needs to be further explored. Therefore, the aim of this study was to investigate the role of ANGPTL4 in the development of liver cirrhosis and its mechanism, as well as its effect on Kupffer cell polarization and hepatic stellate cell activation. The ELISA and RT-qPCR assay were used to detect the content of ANGPTL4 in serum and mRNA expression in cells and tissues respectively. The expression of ANGPTL4, Arg1 and Mrc2 in Kupffer cells was measured by Western blot. The percentage of CD163 Show less

The carcinogenicity of radon has been convincingly documented through epidemiological studies of underground miners. However, there is a lack of early warning indicators for radon radiation damage. In this study, mixed serum samples of 3 groups were collected from 27 underground uranium miners and seven aboveground miners according to the radiation exposure dose. The differentially expressed proteins in the serum were identified using the isobaric tags for the relative and absolute quantitation (iTRAQ)-based method. Some differentially expressed proteins were validated by enzyme-linked immunosorbent assay (ELISA) in 84 underground and 32 aboveground miners. A total of 25 co-differentially expressed proteins in 2 underground miner groups were screened, of which 9 were downregulated and 13 were upregulated. Biological process analysis of these proteins using Metascape showed that 5 GO terms were enriched, such as negative regulation of very-low-density lipoprotein particle clearance, endocytosis, and regulated exocytosis. The results of the ELISA for the expression levels of GCN1, CIP2A, and IGHV1-24 in the serum of 116 miners' serum showed that the levels of GCN1 and CIP2A were consistent with the iTRAQ results. In conclusion, APOC1, APOC2, APOC3, ORM1, ORM2, ANTXR1, GCN1, and CIP2A may be potential early markers of radon radiation damage. Show less

OBJECTIVE: Leveraging microRNA-Seq data and the 1000 Genomes imputed genotypes, we identified rs174561 as a strong microRNA quantitative trait loci for circulating microRNA-1908-5p with higher miR-1908-5p and reduced LDL (lowdensity lipoprotein)-cholesterol, fasting glucose and A1c concentrations in carriers of the rs-174561-C allele. Here, we have investigated the molecular mechanism(s) linking miR-1908-5p to LDL-C concentrations. APPROACH AND RESULTS: Transfection experiments demonstrate that the presence of the C allele significantly increases miR- 1908-5p abundance relative to the T allele. LDLR mRNA and low-density lipoprotein receptor (LDLR) total protein were unchanged in response to differential miR-1908-5p expression. However, the ratio of the cleaved to full-length form of LDLR decreased with miR-1908-5p mimic and increased with miR-1908-5p inhibitor treatment. BMP1 (bone morphogenetic protein 1) is a protease responsible for LDLR cleavage, and we show that miR-1908-5p mimic reduces BMP1 mRNA. Using a reporter array, we identified the TGF-β (transforming growth factor-beta) signaling pathway activity to be reduced by miR- 1908-5p mimic treatment, and this was associated with reduced TGFB1 expression. TGF-β signaling increases BMP1, and we further demonstrate that the effect of miR-1908-5p on LDLR cleavage is abolished by exogenous TGF-β treatment. CONCLUSIONS: These findings uncover a mechanism whereby miR-1908-5p reduces TGFB1 abundance resulting in lower expression of BMP1, ultimately leading to reduced LDLR cleavage. Cleavage of the mature LDLR is known to reduce cell surface affinity for LDL, thereby linking miR-1908-5p to lower circulating LDL-cholesterol levels. Show less

The ovarian surface epithelium (OSE) is a monolayer of epithelial cells surrounding the ovary that ruptures during each ovulation to allow release of the oocyte. This wound is quickly repaired, but mechanisms promoting repair are poorly understood. The contribution of tissue-resident stem cells in the homeostasis of several epithelial tissues is widely accepted, but their involvement in OSE is unclear. We show that traits associated with stem cells can be increased following exposure to the cytokine TGFB1, overexpression of the transcription factor Snai1, or deletion of Brca1. We find that stemness is often linked to mesenchymal-associated gene expression and higher activation of ERK signalling, but is not consistently dependent on their activation. Expression profiles of these populations are extremely context specific, suggesting that stemness may not be associated with a single, distinct population, but rather is a heterogeneous cell state that may emerge from diverse environmental cues. These findings support that the OSE may not require distinct stem cells for long-term maintenance, and may instead achieve this through transient dedifferentiation into a stem-like state. Show less

It is crucial to grasp the characteristics of tumour immune microenvironment to improve effects of immunotherapy. In this study, the immune and stromal scores of 371 cases were calculated for quantitative analysis of immune and stromal cell infiltration in the tumour microenvironment of hepatocellular carcinoma (HCC). The weighted gene co-expression network analysis and protein-protein interaction network were analysed to identify immune microenvironment-related genes. The results showed that patients with high immune scores had a higher 4-year recurrence-free rate. TP53, CTNNB1, and AXIN1 mutations significantly varied with immune scores. In immune score-related modules analysis, Kyoto encyclopaedia of genes and genomes pathways and gene ontology terms were closely related to immune processes, tumorigenesis, and metastasis. Twelve new immune microenvironment-related genes were identified and had significantly positive correlations with seven immune checkpoint genes. In prognostic analysis, eleven immune microenvironment-related genes exhibited high expression, nine of which were validated in the GSE62232 dataset and were significantly associated with a good prognosis. Our findings suggest that calculating immune score and stromal score could help to determine tumour purity and immune cell infiltration in the tumour microenvironment. Nine immune microenvironment-related genes identified in this study had potential as prognostic markers for HCC. Show less

Microtubule actin cross-linking factor 1 (Macf1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of Macf1 inhibited the differentiation of MC3T3-E1 cell line. However, whether Macf1 could regulate bone formation in vivo is unclear. To study the function and mechanism of Macf1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven Macf1 conditional knockout mice (Macf1 Show less

Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to show metastasis-promoting property in LUAD. However, whether miR-24-3p could regulate LUAD metastasis by targeting KLF8 remains unclear. This study explored the functions and mechanisms of miR-24-3p/KLF8 signaling in advanced LUAD. The expression level of miR-24-3p and KLF8 were tested in LUAD patients, and the corelation of miR-24-3p and KLF8 was evaluated. The interaction of miR-24-3p and KLF8 was demonstrated by luciferase reporter activity assay, Show less

Nitidine chloride (NC) has been demonstrated to have an anticancer effect in hepatocellular carcinoma (HCC). However, the mechanism of action of NC against HCC remains largely unclear. In this study, three pairs of NC-treated and NC-untreated HCC xenograft tumour tissues were collected for circRNA sequencing analysis. In total, 297 circRNAs were differently expressed between the two groups, with 188 upregulated and 109 downregulated, among which hsa_circ₀₀₈₈₃₆₄ and hsa_circ₀₀₉₀₀₄₉ were validated by real-time quantitative polymerase chain reaction. The in vitro experiments showed that the two circRNAs inhibited the malignant biological behaviour of HCC, suggesting that they may play important roles in the development of HCC. To elucidate whether the two circRNAs function as "miRNA sponges" in HCC, we identified circRNA-miRNA and miRNA-mRNA interactions by using the CircInteractome and miRwalk, respectively. Subsequently, 857 miRNA-associated differently expressed genes in HCC were selected for weighted gene co-expression network analysis. Module Eigengene turquoise with 423 genes was found to be significantly related to the survival time, pathology grade and TNM stage of HCC patients. Gene functional enrichment analysis showed that the 423 genes mainly functioned in DNA replication- and cell cycle-related biological processes and signalling cascades. Eighteen hubgenes (SMARCD1, CBX1, HCFC1, RBM12B, RCC2, NUP205, ECT2, PRIM2, RBM28, COPS7B, PRRC2A, GPR107, ANKRD52, TUBA1B, ATXN7L3, FUS, MCM8 and RACGAP1) associated with clinical outcomes of HCC patients were then identified. These findings showed that the crosstalk between hsa_circ₀₀₈₈₃₆₄ and hsa_circ₀₀₉₀₀₄₉ and their competing mRNAs may play important roles in HCC, providing interesting clues into the potential of circRNAs as therapeutic targets of NC in HCC. Show less

We developed a ribonuclease for site-specific targeting and cleavage of single-stranded RNA. The engineered RNase protein was constructed by incorporating two independent functional domains, an RNase HI domain that could cleave the RNA strand in a DNA-RNA hybrid, and a domain of the RHAU protein that could selectively recognize a parallel DNA G-quadruplex (G4). The newly designed RNase first recruits a DNA guide oligonucleotide containing both a parallel G4 motif and a template sequence complementary to the target RNA. This RNase:DNA complex targets and efficiently cleaves the single-stranded RNA in a site-specific manner. A major cleavage site occurs at the RNA region that is complementary to the DNA template sequence. The newly designed RNase can serve as a simple tool for RNA manipulation and probing RNA structure. Show less