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Abstract Background Chronic Obstructive Pulmonary Disease (COPD) describes a group of progressive lung diseases causing breathing difficulties. While COPD development typically involves a complex interplay between genetic and environmental factors, genetics play a role in disease susceptibility. This study used genome-wide association studies (GWAS) and polygenic risk score (PRS) to elucidate the genetic basis for COPD in Taiwanese patients. Results GWAS was performed on a Taiwanese COPD case–control cohort with a sample size of 5,442 cases and 17,681 controls. Additionally, the PRS was calculated and assessed in our target groups. GWAS results indicate that although there were no single nucleotide polymorphisms (SNPs) of genome-wide significance, prominent COPD susceptibility loci on or nearby genes such as WWTR1, EXT1, INTU, MAP3K7CL, MAMDC2, BZW1/CLK1, LINC01197, LINC01894, and CFAP95 (C9orf135) were identified, which had not been reported in previous studies. Thirteen susceptibility loci, such as CHRNA4, AFAP1, and DTWD1, previously reported in other populations were replicated and confirmed to be associated with COPD in Taiwanese populations. The PRS was determined in the target groups using the summary statistics from our base group, yielding an effective association with COPD (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02–1.17, p = 0.011). Furthermore, replication a previous lung function trait PRS model in our target group, showed a significant association of COPD susceptibility with PRS of Forced Expiratory Volume in one second (FEV1)/Forced Vital Capacity (FCV) (OR 0.89, 95% CI 0.83–0.95, p = 0.001). Conclusions Novel COPD-related genes were identified in the studied Taiwanese population. The PRS model, based on COPD or lung function traits, enables disease risk estimation and enhances prediction before suffering. These results offer new perspectives on the genetics of COPD and serve as a basis for future research.

Abstract Breast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women worldwide. The 5-year survival rate is over 90% in BC patients, but once BC cells metastasis into distal organs, it is dramatically decreasing to less than 30%. Especially, triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. Understanding the underline mechanisms of TNBC metastasis is a critical issue. Non-coding RNAs, including of lncRNAs and microRNAs, are non-protein-coding transcripts and have been reported as important regulators in TNBC metastasis. However, the underline mechanisms for non-coding RNAs regulating TNBC metastasis remain largely unclear. Here, we found that lncRNA MIR4500HG003 was highly expressed in highly metastatic MDA-MB-231 TNBC cells and overexpression of MIR4500HG003 enhanced metastasis ability in vitro and in vivo and promoted MMP9 expression. Furthermore, we found MIR4500HG003 physically interacted with miR-483-3p and reporter assay showed miR-483-3p attenuated MMP9 expression. Importantly, endogenous high expressions of MIR4500HG003 were correlated with tumor recurrence in TNBC patients with tumor metastasis. Taken together, our findings suggested that MIR4500HG003 promotes metastasis of TNBC through miR-483-3p-MMP9 signaling axis and may be used as potential prognostic marker for TNBC patients.

Objective To identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE.Methods The study enrolled 2429 patients with SLE and 48 580 controls from China Medical University Hospital in Taiwan. A genome-wide association study (GWAS) and PRS analyses of SLE and other three SLE markers, namely ANA, anti-double-stranded DNA antibody (dsDNA) and anti-Smith antibody (Sm), were conducted.Results Genetic variants associated with SLE were identified through GWAS. Some novel genes, which have been previously reported, such as RCC1L and EGLN3, were revealed to be associated with SLE in Taiwan. Multiple PRS models were established, and optimal cut-off points for each PRS were determined using the Youden Index. Combining the PRSs for SLE, ANA, dsDNA and Sm yielded an area under the curve of 0.64 for the optimal cut-off points. An analysis of human leucocyte antigen (HLA) haplotypes in SLE indicated that individuals with HLA-DQA1*01:01 and HLA-DQB1*05:01 were at a higher risk of being classified into the SLE group.Conclusions The use of PRSs to predict SLE enables the identification of high-risk patients before abnormal laboratory data were obtained or symptoms were manifested. Our findings underscore the potential of using PRSs and GWAS in identifying SLE markers, offering promise for early diagnosis and prediction of SLE.

IntroductionAngiopoietin 1 (angpt1) is essential for angiogenesis. However, its role in neurogenesis is largely undiscovered. This study aimed to identify the role of angpt1 in brain development, the mode of action of angpt1, and its prime targets in the zebrafish brain.MethodsWe investigated the effects of embryonic brain angiogenesis and neural development using qPCR, in situ hybridization, microangiography, retrograde labeling, and immunostaining in the angpt1sa14264, itgb1bmi371, tekhu1667 mutant fish and transgenic overexpression of angpt1 in the zebrafish larval brains.ResultsWe showed the co-localization of angpt1 with notch, delta, and nestin in the proliferation zone in the larval brain. Additionally, lack of angpt1 was associated with downregulation of TEK tyrosine kinase, endothelial (tek), and several neurogenic factors despite upregulation of integrin beta 1b (itgb1b), angpt2a, vascular endothelial growth factor aa (vegfaa), and glial markers. We further demonstrated that the targeted angpt1sa14264 and itgb1bmi371 mutant fish showed severely irregular cerebrovascular development, aberrant hindbrain patterning, expansion of the radial glial progenitors, downregulation of cell proliferation, deficiencies of dopaminergic, histaminergic, and GABAergic populations in the caudal hypothalamus. In contrast to angpt1sa14264 and itgb1bmi371 mutants, the tekhu1667 mutant fish regularly grew with no apparent phenotypes. Notably, the neural-specific angpt1 overexpression driven by the elavl3 (HuC) promoter significantly increased cell proliferation and neuronal progenitor cells but decreased GABAergic neurons, and this neurogenic activity was independent of its typical receptor tek.DiscussionOur results prove that angpt1 and itgb1b, besides regulating vascular development, act as a neurogenic factor via notch and wnt signaling pathways in the neural proliferation zone in the developing brain, indicating a novel role of dual regulation of angpt1 in embryonic neurogenesis that supports the concept of angiopoietin-based therapeutics in neurological disorders.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. The prevalence and phenotypes of AMD differ among populations, including between people in Taiwan and other regions. We performed a genome-wide association study to identify genetic variants and to develop genetic models to predict the risk of AMD development and progression in the Taiwanese population. In total, 4039 patients with AMD and 16,488 non-AMD controls (aged ≥ 65 years) were included. We identified 31 AMD-associated variants (p < 5 × 10−8) on chromosome 10q26, surrounding PLEKHA1-ARMS2-HTRA1. Two genetic models were constructed using the clump and threshold method. Model 1 included the single nucleotide polymorphism rs11200630 and showed a 1.31-fold increase in the risk of AMD per risk allele (95% confidence interval (CI) = 1.20–1.43, p < 0.001). In model 2, 1412 single-nucleotide polymorphisms were selected to construct a polygenic risk score (PRS). Individuals with the top 5% PRS had a 1.40-fold higher AMD risk compared with that of individuals with a PRS in the bottom quartile (95% CI = 1.04–1.89, p = 0.025). Moreover, the PRS in the upper quartile was related to a decreased age at AMD diagnosis by 0.62 years (95% CI = −1.15, −0.09, p = 0.023). Both genetic models provide useful predictive power for populations at high risk of AMD, affording a basis for identifying patients requiring close follow-up and early intervention.

Abstract Cell subpopulations in the blood and joint fluid of patients with gout are poorly understood. Single-cell RNA sequencing and bioinformatic tools were used to identify cell subsets and their gene signatures in blood and synovial fluid (SF) cells, determine their relationships, characterize the diversity, and evaluate interactions among specific cell types. We identified 34 subpopulations (5 types of B cells, 16 types of T and natural killer cells, 9 types of monocytes, and 4 other cell types) in the blood of five healthy subjects and seven patients with acute gouty, and the SF of three patients with acute gout. We found that naïve CD4 T cells and classical monocytes cell populations were enriched in patients with gout, whereas plasmacytoid dendritic cells and intermediate monocytes were more abundant in healthy subjects. SF was enriched in Th1/Th17 cells, effector memory CD8 T cells, mucosal-associated invariant T cells, and macrophages. Subclusters of these cell subpopulations showed different compositions between healthy subjects and those with acute gout, according to blood and SF samples. At the cellular level, the inflammation score of a subpopulation or subcluster was highest in SF, following by the blood of acute gout patients and healthy person, whereas energy score showed the opposite trend. We also detected specific cell–cell interactions for interleukin-1, tumor necrosis factor-α, and transforming growth factor-β1 expression in the cells of patients with acute gout. Our study reveals cellular and molecular insights on inflammatory responses to hyperuricemia or uric crystal and may provide therapeutic guidance to improve treatments for gout.

Attention Deficit and Hyperactivity Disorder (ADHD) is a disease that cannot be overcome only by clinical diagnosis and treatment. It is a complex problem that affects both society and medicine. This article first analyzes the societal causes and disease status of ADHD. Then, introduces the Shared Action Model proposed by Prof. Vincent Chen of the Department of Psychiatry at Chiayi Chang Gung Memorial is introduced. The model is based on the interaction between the medical professionals and the families, It provides comprehensive care for ADHD children and helps them resolve difficulties It provides in their care. Through the oral history interview method, we find that each party empathizes with The others through listening, from the doctors to the caregivers and eventually to the patients themselves. As the trust-based, empowerment-oriented partnership to emerges, it gives a new meaning to the condition and encourages ADHD patients to develop their strengths. In the process of joint, the medical professionals and caregivers develop solutions, accumulate knowledge, create a sustainable learning environment with mutual respect, improve quality of life, work together to create a new life and cultural values, and establish a new medical paradigm.

Abstract Background Gout is a highly hereditary disease, but not all those carrying well-known risk variants have developing gout attack even in hyperuricemia status. We performed a genome-wide association study (GWAS) and polygenic risk score (PRS) analysis to illustrate the new genetic architectures of gout and asymptomatic hyperuricemia (AH). Methods GWAS was performed to identify variants associated with gout/AH compared with normouricemia. The participants were males, enrolled from the Taiwan Biobank and China Medical University, and divided into discovery (n=39,594) and replication (n=891) cohorts for GWAS. For PRS analysis, the discovery cohort was grouped as base (n=21,814) and target (n=17,780) cohorts, and the score was estimated by grouping the polymorphisms into protective or not for the phenotypes in the base cohort. Results The genes ABCG2 and SLC2A9 were found as the major genetic factors governing gouty and AH, and even in those carrying the rs2231142 (ABCG2) wild-genotype. Surprisingly, variants on chromosome 1, such as rs7546668 (DNAJC16), rs10927807 (AGMAT), rs9286836 (NUDT17), rs4971100 (TRIM46), rs4072037 (MUC1), and rs2974935 (MTX1), showed significant associations with gout in both discovery and replication cohorts (all p-values < 1e−8). Concerning the PRS, the rates of gout and AH increased with increased quartile PRS in those SNPs having risk effects on the phenotypes; on the contrary, gout/AH rates decreased with increased quartile PRS in those protective SNPs. Conclusions We found new variants on chromosome 1 significantly relating to gout, and PRS predicts the risk of developing gout/AH more robustly based on the SNPs’ effect types on the trait.

Liver cancer is caused by complex interactions among genetic factors, viral infection, alcohol abuse, and metabolic diseases. We conducted a genome-wide association study and polygenic risk score (PRS) model in Taiwan, employing a nonspecific etiology approach, to identify genetic risk factors for hepatocellular carcinoma (HCC). Our analysis of 2836 HCC cases and 134,549 controls revealed 13 novel associated loci such as the FAM66C gene, noncoding genes, liver-fibrosis-related genes, metabolism-related genes, and HCC-related pathway genes. We incorporated the results from the UK Biobank and Japanese database into our study for meta-analysis to validate our findings. We also identified specific subtypes of the major histocompatibility complex that influence both viral infection and HCC progression. Using this data, we developed a PRS to predict HCC risk in the general population, patients with HCC, and HCC-affected families. The PRS demonstrated higher risk scores in families with multiple HCCs and other cancer cases. This study presents a novel approach to HCC risk analysis, identifies seven new genes associated with HCC development, and introduces a reproducible PRS model for risk assessment.

Purpose: Young age is associated with poor prognosis in ductal carcinoma in situ (DCIS) of female breast and controversy exists regarding the optimal treatment modality for young patients. We aimed to compare treatment outcomes among breast conserving surgery (BCS), BCS with adjuvant radiotherapy (BCS + RT), and total mastectomy (MT) for young DCIS women. Methods: PubMed, Cochrane, and Embase were searched for studies reporting comparative results among BCS, BCS + RT, or MT in ≤50 years old (y/o) DCIS females. Study quality was assessed and meta-analysis with subgroup analysis was performed to pool the effect sizes of the outcomes-of-interest. Results: We included 3 randomized control trials and 18 observational studies. For DCIS women ≤50 y/o, RT following BCS significantly reduced the risk for ipsilateral breast tumor recurrence (IBTR) (HR = 0.66, 95% CI 0.50–0.87). However, the benefit was less robust in extremely young patients and with long follow-ups. RT revealed no statistically significant preventive effect on ipsilateral invasive recurrence (HR = 1.38, 95% CI 0.98–1.94). On the other hand, MT yielded the lowest IBTR (BCS + RT vs MT: HR = 4.4, 95% CI 2.06–9.40), both in ipsilateral DCIS recurrence and ipsilateral invasive recurrence. There was great heterogeneity and could not reach an evident conclusion concerning survival outcomes. Conclusion: This study highlighted the varying effect of RT for young DCIS females. The local control benefit of MT was definite without survival differences observed. Our study provided a moderate certainty of evidence to guide the treatment for young DCIS women. Further age-specific prospective trial is warranted.

Background: Intralesional steroid treatment for alopecia areata (AA) has been developed for decades, yet the optimal concentration of triamcinolone acetonide (TrA) is not well-established. Objectives: This review aims to determine the optimal concentration of intralesional TrA in treating patchy AA. Methods: We conducted a systematic review and meta-analysis, and searched the Cochrane Library, Embase, and PubMed databases on July 4, 2021, to identify randomized or nonrandomized comparative studies reporting the response rates and/or adverse events among AA patients treated with various concentrations of TrA. The meta-analysis of proportions and odds ratios was analyzed using random-effects modeling. Results: Nineteen studies and a total of 783 participants were included. The estimated response rate of 5 mg/dl (74.82%, 95% confidence interval [CI] 64.99%–83.50%) was shown to be more efficacious than 2.5/3.33 mg/dl (38.64%, 95% CI 16.98%–62.99%) but similar to 10 mg/dl (71.06%, 95% CI 59.72%–81.20%), while pooled estimate of odds ratios revealed higher efficacy with 10 mg/dl than 5 mg/dl (odds ratio = 1.64, 95% CI 1.05–2.58, P = 0.031). The rates of skin atrophy were 18.05% (95% CI, 10.32%–27.38%), 11.49% (95% CI, 2.86%–24.84%), and 3.85% (95% CI, 1.27%–14.01%) in groups 10, 5, and 2.5/3.33 mg/dl, respectively. Higher concentration is associated with more skin atrophy in a dose-dependent fashion (P = 0.012). Heterogeneity among studies in the meta-analyses was high. Conclusion: The optimal intralesional concentration of TrA for patchy AA is probably 10 mg/dl with acceptable adverse events.

Hyperuricemia and gout are two of the most common metabolic disorders worldwide; their incidence is increasing with changes in lifestyle, and they are correlated with many diseases, including renal and cardiovascular diseases. The majority of studies on hyperuricemia and gout have focused on the discovery of the associated genes and their functions and on the roles of monocytes and neutrophils in the development of gout. Virtually no studies investigating the epigenomics of gout disease or exploring the clinical significance of such research have been conducted. In this study, we observed that the expression of enzymes involved in RNA modifications or RNA editing was affected in uric acid (UA)- or monosodium urate (MSU)-treated cell lines. RNA alternative splicing and splicing factors were also affected by UA or MSU treatment. We used transcriptome sequencing to analyze genome-wide RNA splicing and RNA editing and found significant changes in RNA splicing and RNA editing in MSU- or UA-treated THP-1 and HEK293 cells. We further found significant changes of RNA modifications, editing, and splicing in patients with gout. The data indicate that RNA modifications, editing, and splicing play roles in gout. The findings of this study may help to understand the mechanism of RNA splicing and modifications in gout, facilitating the development of new diagnostic and therapeutic strategies.

Rheumatoid arthritis (RA) is a systemic disease characterized by non-infectious inflammation of the joints and surrounding tissues, which can cause severe health problems, affect the patient’s daily life, and even cause death. RA can be clinically diagnosed by the occurrence of blood serological markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP). However, about 20% of RA patients exhibit negative results for both markers, which makes RA diagnosis difficult and, therefore, may delay the effective treatment. Previous studies found some evidence that human leukocyte antigen (HLA)-related genes might be the susceptibility genes for RA and their polymorphisms might contribute to varieties of susceptibility and disease severity. This study aimed for the genetic polymorphisms of the RA patient genome and their effects on the RA patient’s serological makers, RF and anti-CCP. A total of 4580 patients’ electronic medical records from 1992 to 2020 were retrieved from the China Medical University Hospital database. The most representative single-nucleotide polymorphisms (SNPs) were identified through a genome-wide association study (GWAS) followed by enzyme-linked immunosorbent assay (ELISA) validation using the blood from 30 additional RA patients. The results showed significant changes at the position of chromosome 6 with rs9270481 being the most significant locus, which indicated the location of the HLA-DRB1 gene. Further, patients with the CC genotype at this locus were more likely to exhibit negative results for RF and anti-CCP than those with the TT genotype. The C allele was also more likely to be associated with negative results for RF and anti-CCP. The results demonstrated that a genetic polymorphism at rs9270481 affected the expression of RF and anti-CCP in RA patients, which might indicate the necessity to develop a personalized treatment plan for each individual patient based on the genetic profile.

Excess thyroid hormones have complex metabolic effects, particularly hyperthyroidism, and are associated with various cardiovascular risk factors. Previous candidate gene studies have indicated that genetic variants may contribute to this variable response. Electronic medical record (EMR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform the disease comorbidity development. In this study, we combined electronic medical record (EMR) -derived phenotypes and genotype information to conduct a genome-wide analysis of hyperthyroidism in a 35,009-patient cohort in Taiwan. Diagnostic codes were used to identify 2,767 patients with hyperthyroidism. Our genome-wide association study (GWAS) identified 44 novel genomic risk markers in 10 loci on chromosomes 2, 6, and 14 (P < 5 × 10–14), including CTLA4, HCP5, HLA-B, POU5F1, CCHCR1, HLA-DRA, HLA-DRB9, TSHR, RPL17P3, and CEP128. We further conducted a comorbidity analysis of our results, and the data revealed a strong correlation between hyperthyroidism patients with thyroid storm and stroke. In this study, we demonstrated application of the PheWAS using large EMR biobanks to inform the comorbidity development in hyperthyroidism patients. Our data suggest significant common genetic risk factors in patients with hyperthyroidism. Additionally, our results show that sex, body mass index (BMI), and thyroid storm are associated with an increased risk of stroke in subjects with hyperthyroidism.

Influenza A virus (IAV) has caused recurrent epidemics and severe pandemics. In this study, we adapted an MS2-MCP live-cell imaging system to visualize IAV replication. A reporter plasmid, pHH-PB2-vMSL, was constructed by replacing a part of the PB2-coding sequence in pHH-PB2 with a sequence encoding 24 copies of a stem-loop structure from bacteriophage MS2 (MSL). Binding of MS2 coat protein (MCP) fused to green fluorescent protein (GFP) to MSL enabled the detection of vRNA as fluorescent punctate signals in live-cell imaging. The introduction of pHH-PB2-vMSL into A549 cells transduced to express an MCP-GFP fusion protein lacking the nuclear localization signal (MCP-GFPdN), subsequently allowed tracking of the distribution and replication of PB2-vMSL vRNA after IAV PR8 infection. Spatial and temporal measurements revealed exponential increases in vRNA punctate signal intensity, which was only observed after membrane blebbing in apoptotic cells. Similar signal intensity increases in apoptotic cells were also observed after MDCK cells, transduced to express MCP-GFPdN, were infected with IAV carrying PB2-vMSL vRNA. Notably, PB2-vMSL vRNA replication was observed to occur only in apoptotic cells, at a consistent time after apoptosis initiation. There was a lack of observable PB2-vMSL vRNA replication in non-apoptotic cells, and vRNA replication was suppressed in the presence of apoptosis inhibitors. These findings point to an important role for apoptosis in IAV vRNA replication. The utility of the MS2-imaging system for visualizing time-sensitive processes such as viral replication in live host cells is also demonstrated in this study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Known as COVID-19, it has affected billions of people worldwide, claiming millions of lives and posing a continuing threat to humanity. This is considered one of the most extensive pandemics ever recorded in human history, causing significant losses to both life and economies globally. However, the available evidence is currently insufficient to establish the effectiveness and safety of antiviral drugs or vaccines. The entry of the virus into host cells involves binding to angiotensin-converting enzyme 2 (ACE2), a cell surface receptor, via its spike protein. Meanwhile, transmembrane protease serine 2 (TMPRSS2), a host surface protease, cleaves and activates the virus's S protein, thus promoting viral infection. Plant protease inhibitors play a crucial role in protecting plants against insects and/or microorganisms. The major storage proteins in sweet potato roots include sweet potato trypsin inhibitor (SWTI), which accounts for approximately 60% of the total water-soluble protein and has been found to possess a variety of health-promoting properties, including antioxidant, anti-inflammatory, ACE-inhibitory, and anticancer functions. Our study found that SWTI caused a significant reduction in the expression of the ACE2 and TMPRSS2 proteins, without any adverse effects on cells. Therefore, our findings suggest that the ACE2 and TMPRSS2 axis can be targeted via SWTI to potentially inhibit SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Abstract Background Precision therapy for lung cancer requires comprehensive genomic analyses. Specific effects of targeted therapies have been reported in Asia populations, including Taiwanese, but genomic studies have rarely been performed in these populations. Method We enrolled 72 patients with non-small cell lung cancer, of whom 61 had adenocarcinoma, 10 had squamous cell carcinoma, and 1 had combined adenocarcinoma and squamous cell carcinoma. Whole-exome or targeted gene sequencing was performed. To identify trunk mutations, we performed whole-exome sequencing in two tumor regions in four patients. Results Nineteen known driver mutations in EGFR, PIK3CA, KRAS, CTNNB1, and MET were identified in 34 of the 72 tumors evaluated (47.22%). A comparison with the Cancer Genome Atlas dataset showed that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS and TP53 mutations were found in only 5.56% and 25% of our Taiwanese patients, respectively. We also identified new mutations in ARID1A, ARID2, CDK12, CHEK2, GNAS, H3F3A, KDM6A, KMT2C, NOTCH1, RB1, RBM10, RUNX1, SETD2, SF3B1, SMARCA4, THRAP3, TP53, and ZMYM2. Moreover, all ClinVar pathogenic variants were trunk mutations present in two regions of a tumor. RNA sequencing revealed that the trunk or branch genes were expressed at similar levels among different tumor regions. Conclusions We identified novel variants potentially associated with lung cancer tumorigenesis. The specific mutation pattern in Taiwanese patients with non-small cell lung cancer may influence targeted therapies.

Monoamine oxidase (MAO) deficiency and imbalanced levels of brain monoamines have been associated with developmental delay, neuropsychiatric disorders and aggressive behavior. Animal models are valuable tools to gain mechanistic insight into outcomes associated with MAO deficiency. Here, we report a novel genetic model to study the effects of mao loss of function in zebrafish. Quantitative PCR, in situ hybridization and immunocytochemistry were used to study neurotransmitter systems and expression of relevant genes for brain development in zebrafish mao mutants. Larval and adult fish behavior was evaluated through different tests. Stronger serotonin immunoreactivity was detected in mao+/− and mao−/− larvae compared with their mao+/+ siblings. mao−/− larvae were hypoactive, and presented decreased reactions to visual and acoustic stimuli. They also had impaired histaminergic and dopaminergic systems, abnormal expression of developmental markers and died within 20 days post-fertilization. mao+/− fish were viable, grew until adulthood, and demonstrated anxiety-like behavior and impaired social interactions compared with adult mao+/+ siblings. Our results indicate that mao−/− and mao+/− mutants could be promising tools to study the roles of MAO in brain development and behavior. This article has an associated First Person interview with the first author of the paper.

Mammalian STE20‐like kinase 1 (MST1/STK4/KRS2) encodes a serine/threonine kinase that is the mammalian homolog of Drosophila Hippo. STK4 plays an important role in controlling cell growth, apoptosis, and organ size. STK4 has been studied in many cancers with previous studies indicating an involvement in colon cancer lymph node metastasis and highlighting its potential as a diagnostic marker for colon cancer. However, the role of STK4 defect in promoting colon cancer progression is still understudied. Here, we found that STK4 was significantly downregulated in colon cancer and was associated with distal metastasis and poor survival. Furthermore, STK4 knockdown enhanced sphere formation and metastasis in vitro and promoted tumor development in vivo. We found that STK4 colocalized with β‐catenin and directly phosphorylated β‐catenin resulting in its degradation via the ubiquitin‐mediated pathway. This may suggest that STK4 knockdown causes β‐catenin phosphorylation failure and subsequently β‐catenin accumulation, consequently leading to anchorage‐independent growth and metastasis in colon cancer. Our results support that STK4 may act as a potential candidate for the assessment of β‐catenin‐mediated colon cancer prognosis.

Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/β-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/β-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/β-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.

AbstractDuring oogenesis, a group of specialized follicle cells, known as stretched cells (StCs), flatten drastically from cuboidal to squamous shape. While morphogenesis of epithelia is critical for organogenesis, genes and signaling pathways involved in this process remain to be revealed. In addition to formation of gap junctions for intercellular exchange of small molecules, gap junction proteins form channels or act as adaptor proteins to regulate various cellular behaviors. In invertebrates, gap junction proteins are Innexins. Knockdown of Innexin 2InnexinmyospheroidInnexin 2Innexin 2myospheroidInnexin 2

Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL‐X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine‐rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor‐bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.

Head and neck cancer has poor overall survival. Patients with head and neck cancer more frequently develop second primary tumors than do patients with other cancers, leading to a poor prognosis. In this study, we used next-generation sequencing to analyze and compare mutations between first tumors and second tumors in oral cancer. We retrieved tumor tissues collected from 13 patients who were diagnosed twice as having cancer. We used driver gene and trunk mutations to distinguish between recurrent cancer and primary cancer in oral cancer. We observed unique driver gene mutations in three patients with an initial clinical diagnosis of recurrent cancer; hence, we believe that the corresponding patients had primary cancer. Four patients with an initial clinical diagnosis of primary cancer were found to actually have recurrent cancer according to our results. Genetic testing can be used to enhance the accuracy of clinical diagnosis.

Abstract Background Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20–30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients. Methods The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student’s t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction. Results miR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/β-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease. Conclusions miR-105/93-3p activates Wnt/β-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC.

Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56δ (encoded by PPP2R5D) is a regulatory subunit of protein phosphatase 2A (PP2A) with long IDRs that harbor a substrate-mimicking SLiM and multiple phosphorylation sites. De novo missense mutations in PPP2R5D cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Our single-particle cryo-EM structures of the PP2A-B56δ holoenzyme reveal that the long, disordered arms at the B56δ termini fold against each other and the holoenzyme core. This architecture suppresses both the phosphatase active site and the substrate-binding protein groove, thereby stabilizing the enzyme in a closed latent form with dual autoinhibition. The resulting interface spans over 190 Å and harbors unfavorable contacts, activation phosphorylation sites, and nearly all residues with ID-associated mutations. Our studies suggest that this dynamic interface is coupled to an allosteric network responsive to phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations increase the holoenzyme activity and perturb the phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the normal variant. [ABSTRACT FROM AUTHOR]

Abstract Alternative splicing is a mechanism for increasing protein diversity from a limited number of genes. Studies have demonstrated that aberrant regulation in the alternative splicing of apoptotic gene transcripts may contribute to the development of cancer. In this study, we isolated 4β-Hydroxywithanolide E (4bHWE) from the traditional herb Physalis peruviana and investigated its biological effect in cancer cells. The results demonstrated that 4bHWE modulates the alternative splicing of various apoptotic genes, including HIPK3, SMAC/DIABLO, and SURVIVIN. We also discovered that the levels of SRSF1 phospho-isoform were decreased and the levels of H3K36me3 were increased in 4bHWE treatment. Knockdown experiments revealed that the splicing site selection of SMAC/DIABLO could be mediated by changes in the level of H3K36me3 in 4bHWE-treated cells. Furthermore, we extended our study to apoptosis-associated molecules, and detected increased levels of poly ADP-ribose polymerase cleavage and the active form of CASPASE-3 in 4bHWE-induced apoptosis. In vivo experiments indicated that the treatment of tumor-bearing mice with 4bHWE resulted in a marked decrease in tumor size. This study is the first to demonstrate that 4bHWE affects alternative splicing by modulating splicing factors and histone modifications, and provides a novel view of the antitumor mechanism of 4bHWE.