Tillandsia-Inspired Ultra-Efficient Thermo-Responsive Hygroscopic Nanofibers for Solar-Driven Atmospheric Water Harvesting.

Sorption-based atmospheric water harvesting (SAWH) is a promising approach for supplying water in off-grid arid regions. However, it is difficult to improve the SAWH efficiency because water undergoes multiple phase transformations, such as water vapor-water (desorption and condensation) in the desorption phase. To address this issue, an ultrahygroscopic temperature-responsive hydrogel nanofiber inspired by Tillandsia is developed, comprising poly N-isopropylacrylamide, poly N-dimethylacetamide, and carbon nanotubes and impregnated with lithium chloride (PCP@LiCl). The hydrophobicity of the nanofiber membrane is enhanced with increasing temperature, facilitating water separation from the hydrogel in liquid form. Moreover, PCP@LiCl exhibits unique kinetics at 25 °C and 15%-30% relative humidity, capable of adsorbing moisture to saturation within 2 h, and oozing liquid water within 5 min under sunlight. Through global potential modeling, it is demonstrated that PCP@LiCl has potential applications in arid and semiarid regions. This study provides new insights into the design of high-performance composites for solar-powered atmospheric water harvesting.

SALL2 regulates neural differentiation of mouse embryonic stem cells through Tuba1a.

The spalt (Sal) gene family has four members (Sall1-4) in vertebrates, all of which play pivotal roles in various biological processes and diseases. However, the expression and function of SALL2 in development are still less clear. Here, we first charted SALL2 protein expression pattern during mouse embryo development by immunofluorescence, which revealed its dominant expression in the developing nervous system. With the establishment of Sall2 deficient mouse embryonic stem cells (ESCs), the in vitro neural differentiation system was leveraged to interrogate the function of SALL2, which showed impaired neural differentiation of Sall2 knockout (KO) ESCs. Furthermore, neural stem cells (NSCs) could not be derived from Sall2 KO ESCs and the generation of neural tube organoids (NTOs) was greatly inhibited in the absence of SALL2. Meanwhile, transgenic expression of E1 isoform of SALL2 restored the defects of neural differentiation in Sall2 KO ESCs. By chromatin immunoprecipitation sequencing (ChIP-seq), Tuba1a was identified as downstream target of SALL2, whose function in neural differentiation was confirmed by rescuing neural phenotypes of Sall2 KO ESCs when overexpressed. In sum, by elucidating SALL2 expression dynamics during early mouse development and mechanistically characterizing its indispensable role in neural differentiation, this study offers insights into SALL2's function in human nervous system development, associated pathologies stemming from its mutations and relevant therapeutic strategy.

Overexpression of NUDT16L1 sustains proper function of mitochondria and leads to ferroptosis insensitivity in colorectal cancer.

Cancer research is continuously exploring new avenues to improve treatments, and ferroptosis induction has emerged as a promising approach. However, the lack of comprehensive analysis of the ferroptosis sensitivity in different cancer types has limited its clinical application. Moreover, identifying the key regulator that influences the ferroptosis sensitivity during cancer progression remains a major challenge. In this study, we shed light on the role of ferroptosis in colorectal cancer and identified a novel ferroptosis repressor, NUDT16L1, that contributes to the ferroptosis insensitivity in this cancer type. Mechanistically, NUDT16L1 promotes ferroptosis insensitivity in colon cancer by enhancing the expression of key ferroptosis repressor and mitochondrial genes through direct binding to NAD-capped RNAs and the indirect action of MALAT1. Our findings also reveal that NUDT16L1 localizes to the mitochondria to maintain its proper function by preventing mitochondrial DNA leakage after treatment of ferroptosis inducer in colon cancer cells. Importantly, our orthotopic injection and Nudt16l1 transgenic mouse models of colon cancer demonstrated the critical role of NUDT16L1 in promoting tumor growth. Moreover, clinical specimens revealed that NUDT16L1 was overexpressed in colorectal cancer, indicating its potential as a therapeutic target. Finally, our study shows the therapeutic potential of a NUDT16L1 inhibitor in vitro, in vivo and ex vivo. Taken together, these findings provide new insights into the crucial role of NUDT16L1 in colorectal cancer and highlight its potential as a promising therapeutic target.

A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells.

Cardiac biological pacing (BP) is one of the future directions for bradyarrhythmias intervention. Currently, cardiac pacemaker cells (PCs) used for cardiac BP are mainly derived from pluripotent stem cells (PSCs). However, the production of high-quality cardiac PCs from PSCs remains a challenge. Here, we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs. First, two PC markers, Shox2 and Hcn4, were selected to establish Shox2:EGFP; Hcn4:mCherry mouse PSC reporter line. Then, by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation, we designed the FSK method that increased the yield of SHOX2+; HCN4+ cells with typical PC characteristics, which was 12 and 42 folds higher than that of the embryoid body (EB) and the monolayer M10 methods respectively. In addition, the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing (scRNA-seq), which resembled in vivo PCs development, and ZFP503 was verified as a key regulator of cardiac PCs differentiation. These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology, help with the understanding of PCs (patho)physiology, and benefit drug discovery for PC-related diseases as well.

TEAM: Triangular-mEsh Adaptive and Multiscale proton spot generation method.

BACKGROUND: Proton therapy is preferred for its dose conformality to spare normal tissues and organs-at-risk (OAR) via Bragg peaks with negligible exit dose. However, proton dose conformality can be further optimized: (1) the spot placement is based on the structured (e.g., Cartesian) grid, which may not offer conformal shaping to complex tumor targets; (2) the spot sampling pattern is uniform, which may be insufficient at the tumor boundary to provide the sharp dose falloff, and at the same time may be redundant at the tumor interior to provide the uniform dose coverage, for example, due to multiple Coulomb scattering (MCS); and (3) the lateral spot penumbra increases with respect to the depth due to MCS, which blurs the lateral dose falloff. On the other hand, while (1) the deliverable spots are subject to the minimum-monitor-unit (MMU) constraint, and (2) the dose rate is proportional to the MMU threshold, the current spot sampling method is sensitive to the MMU threshold and can fail to provide satisfactory plan quality for a large MMU threshold (i.e., high-dose-rate delivery). PURPOSE: This work will develop a novel Triangular-mEsh-based Adaptive and Multiscale (TEAM) proton spot generation method to address these issues for optimizing proton dose conformality and plan delivery efficiency. METHODS: Compared to the standard clinically-used spot placement method, three key elements of TEAM are as follows: (1) a triangular mesh instead of a structured grid: the triangular mesh is geometrically more conformal to complex target shapes and therefore more efficient and accurate for dose shaping inside and around the target; (2) adaptive sampling instead of uniform sampling: the adaptive sampling consists of relatively dense sampling at the tumor boundary to create the sharp dose falloff, which is more accurate, and coarse sampling at the tumor interior to uniformly cover the target, which is more efficient; and (3) depth-dependent sampling instead of depth-independent sampling: the depth-dependent sampling is used to compensate for MCS, that is, with increasingly dense sampling at the tumor boundary to improve dose shaping accuracy, and increasingly coarse sampling at the tumor interior to improve dose shaping efficiency, as the depth increases. In the TEAM method the spot locations are generated for each energy layer and layer-by-layer in the multiscale fashion; and then the spot weights are derived by solving the IMPT problem of dose-volume planning objectives, MMU constraints, and robustness optimization with respect to range and setup uncertainties. RESULTS: Compared to the standard clinically-used spot placement method UNIFORM, TEAM achieved (1) better plan quality using <60% number of spots of UNIFORM; (2) better robustness to the number of spots; (3) better robustness to a large MMU threshold. Furthermore, TEAM provided better plan quality with fewer spots than other adaptive methods (Cartesian-grid or triangular-mesh). CONCLUSIONS: A novel triangular-mesh-based proton spot placement method called TEAM is proposed, and it is demonstrated to improve plan quality, robustness to the number of spots, and robustness to the MMU threshold, compared to the clinically-used spot placement method and other adaptive methods.

Cardinality-constrained plan-quality and delivery-time optimization method for proton therapy.

BACKGROUND: While minimizing plan delivery time is beneficial for proton therapy in terms of motion management, patient comfort, and treatment throughput, it often poses a tradeoff with optimizing plan quality. A key component of plan delivery time is the energy switching time, which is approximately proportional to the number of energy layers, that is, the cardinality. PURPOSE: This work aims to develop a novel optimization method that can efficiently compute the pareto surface between plan quality and energy layer cardinality, for the planner to navigate through this quality-and-efficiency tradeoff and select the appropriate plan of a balanced tradeoff. METHODS: A new IMPT method CARD is proposed that (1) explicitly incorporates the minimization of energy layer cardinality as an optimization objective, and (2) automatically generates a set of plans sequentially with a descending order in number of energy layers. The energy layer cardinality is penalized through the l1,0-norm regularization with an upper bound, and the upper bound is monotonically decreased to compute a series of treatment plans with gradually decreased energy layer cardinality on the quality-and-efficiency pareto surface. For any given treatment plan, the plan optimality is enforced using dose-volume planning objectives and the plan deliverability is imposed through minimum-monitor-unit (MMU) constraints, with optimization solution algorithm based on iterative convex relaxation. RESULTS: The new method CARD was validated in comparison with the benchmark plan of all energy layers (P0), and a state-of-the-art method called MMSEL, using prostate, head-and-neck (HN), lung, pancreas, liver and brain cases. While labor-intensive and time-consuming manual parameter tuning was needed for MMSEL to generate plans of predefined energy layer cardinality, CARD automatically and efficiently computed all plans with sequentially decreasing predefined energy layer cardinality all at once. With the acceptable plan quality (i.e., no more than 110% of total optimization objective value from P0), CARD achieved the reduction of number of energy layers to 52% (from 77 to 40), 48% (from 135 to 65), 59% (from 85 to 50), 67% (from 52 to 35), 80% (from 50 to 40), and 30% (from 66 to 20), for prostate, HN, lung, pancreas, liver, and brain cases, respectively, compared to P0, with overall better plan quality than MMSEL. Moreover, due to the nonconvexity of the MMU constraint, CARD provided the similar or even smaller optimization objective than P0, at the same time with fewer number of energy layers, that is, 55 versus 77, 85 versus 135, 45 versus 52, and 25 versus 66 for prostate, HN, pancreas, and brain cases, respectively. CONCLUSIONS: We have developed a novel optimization algorithm CARD that can efficiently and automatically compute a series of treatment plans of any given energy layer sequentially, which allows the planner to navigate through the plan-quality and energy-layer-cardinality tradeoff and select the appropriate plan of a balanced tradeoff.

CDC-like kinase 3 deficiency aggravates hypoxia-induced cardiomyocyte apoptosis through AKT signaling pathway.

Hypoxia-induced cardiomyocyte apoptosis is one major pathological change of acute myocardial infarction (AMI), but the underlying mechanism remains unexplored. CDC-like kinase 3 (CLK3) plays crucial roles in cell proliferation, migration and invasion, and nucleotide metabolism, however, the role of CLK3 in AMI, especially hypoxia-induced apoptosis, is largely unknown. The expression of CLK3 was elevated in mouse myocardial infarction (MI) models and neonatal rat ventricular myocytes (NRVMs) under hypoxia. Furthermore, CLK3 knockdown significantly promoted apoptosis and inhibited NRVM survival, while CLK3 overexpression promoted NRVM survival and inhibited apoptosis under hypoxic conditions. Mechanistically, CLK3 regulated the phosphorylation status of AKT, a key player in the regulation of apoptosis. Furthermore, overexpression of AKT rescued hypoxia-induced apoptosis in NRVMs caused by CLK3 deficiency. Taken together, CLK3 deficiency promotes hypoxia-induced cardiomyocyte apoptosis through AKT signaling pathway.

HAND factors regulate cardiac lineage commitment and differentiation from human pluripotent stem cells.

BACKGROUND: Transcription factors HAND1 and HAND2 (HAND1/2) play significant roles in cardiac organogenesis. Abnormal expression and deficiency of HAND1/2 result in severe cardiac defects. However, the function and mechanism of HAND1/2 in regulating human early cardiac lineage commitment and differentiation are still unclear. METHODS: With NKX2.5eGFP H9 human embryonic stem cells (hESCs), we established single and double knockout cell lines for HAND1 and HAND2, respectively, whose cardiomyocyte differentiation efficiency could be monitored by assessing NKX2.5-eGFP+ cells with flow cytometry. The expression of specific markers for heart fields and cardiomyocyte subtypes was examined by quantitative PCR, western blot and immunofluorescence staining. Microelectrode array and whole-cell patch clamp were performed to determine the electrophysiological characteristics of differentiated cardiomyocytes. The transcriptomic changes of HAND knockout cells were revealed by RNA sequencing. The HAND1/2 target genes were identified and validated experimentally by integrating with HAND1/2 chromatin immunoprecipitation sequencing data. RESULTS: Either HAND1 or HAND2 knockout did not affect the cardiomyocyte differentiation kinetics, whereas depletion of HAND1/2 resulted in delayed differentiation onset. HAND1 knockout biased cardiac mesoderm toward second heart field progenitors at the expense of first heart field progenitors, leading to increased expression of atrial and outflow tract cardiomyocyte markers, which was further confirmed by the appearance of atrial-like action potentials. By contrast, HAND2 knockout cardiomyocytes had reduced expression of atrial cardiomyocyte markers and displayed ventricular-like action potentials. HAND1/2-deficient hESCs were more inclined to second heart field lineage and its derived cardiomyocytes with atrial-like action potentials than HAND1 single knockout during differentiation. Further mechanistic investigations suggested TBX5 as one of the downstream targets of HAND1/2, whose overexpression partially restored the abnormal cardiomyocyte differentiation in HAND1/2-deficient hESCs. CONCLUSIONS: HAND1/2 have specific and redundant roles in cardiac lineage commitment and differentiation. These findings not only reveal the essential function of HAND1/2 in cardiac organogenesis, but also provide important information on the pathogenesis of HAND1/2 deficiency-related congenital heart diseases, which could potentially lead to new therapeutic strategies.

Neutralizing IL-16 enhances the efficacy of targeting Aurora-A therapy in colorectal cancer with high lymphocyte infiltration through restoring anti-tumor immunity.

Cancer cells can evade immune elimination by activating immunosuppressive signaling pathways in the tumor microenvironment (TME). Targeting immunosuppressive signaling pathways to promote antitumor immunity has become an attractive strategy for cancer therapy. Aurora-A is a well-known oncoprotein that plays a critical role in tumor progression, and its inhibition is considered a promising strategy for treating cancers. However, targeting Aurora-A has not yet got a breakthrough in clinical trials. Recent reports have indicated that inhibition of oncoproteins may reduce antitumor immunity, but the role of tumor-intrinsic Aurora-A in regulating antitumor immunity remains unclear. In this study, we demonstrated that in tumors with high lymphocyte infiltration (hot tumors), higher tumor-intrinsic Aurora-A expression is associated with a better prognosis in CRC patients. Mechanically, tumor-intrinsic Aurora-A promotes the cytotoxic activity of CD8+ T cells in immune hot CRC via negatively regulating interleukin-16 (IL-16), and the upregulation of IL-16 may impair the therapeutic effect of Aurora-A inhibition. Consequently, combination treatment with IL-16 neutralization improves the therapeutic response to Aurora-A inhibitors in immune hot CRC tumors. Our study provides evidence that tumor-intrinsic Aurora-A contributes to anti-tumor immunity depending on the status of lymphocyte infiltration, highlighting the importance of considering this aspect in cancer therapy targeting Aurora-A. Importantly, our results suggest that combining Aurora-A inhibitors with IL-16-neutralizing antibodies may represent a novel and effective approach for cancer therapy, particularly in tumors with high levels of lymphocyte infiltration.

An overview of scholarly literature on navigation hazards in Arctic shipping routes.

Maritime transport plays a crucial role in international trade. As the number and tonnage of ships continue to increase, traditional shipping routes are becoming progressively congested. The development of Arctic shipping routes has the potential to significantly improve trade efficiency and decrease reliance on traditional shipping routes. At the same time, the harsh navigation conditions in the Arctic pose a huge challenge to ships crossing the Arctic shipping routes. To address the above issues, this paper reviews the natural, navigational environment and unique navigational modes of ships in the Arctic shipping routes. Furthermore, the navigational risks caused by factors including low temperature, sea ice, poor visibility, communication, lack of infrastructure, lack of navigational experience, lack of historical data, high collision risk, and complex navigational environment are summarized and analyzed, providing a reference for researchers and policymakers to conduct research related to Arctic shipping routes.

Oleic acid-induced metastasis of KRAS/p53-mutant colorectal cancer relies on concurrent KRAS activation and IL-8 expression bypassing EGFR activation.

Background: Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding the molecular mechanisms regulating anti-EGFR-resistant CRC metastasis can improve CRC therapy. This study aimed to investigate the effects of IL-8 and the activation of KRAS on reactive oxygen species (ROS) production and metastasis of hyperlipidemia-associated CRC harboring mutations of KRAS and p53. Methods: The cytokine array analysis determined the up-expression of secreted factors, including IL-8. The clinical relevance of the relationship between IL-8 and angiopoietin-like 4 (ANGPTL4) was examined in CRC patients from National Cheng Kung University Hospital and TCGA dataset. Expressions of IL-8, ANGPTL4, NADPH oxidase 4 (NOX4), and epithelial-mesenchymal transition (EMT) markers in free fatty acids (FFAs)-treated KRAS/p53 mutant CRC cells were determined. The hyperlipidemia-triggered metastatic ability of CRC cells under treatments of antioxidants, statin, and cetuximab or knockdown of IL-8, KRAS, and EGFR was evaluated in vitro and in vivo. In addition, the effects of antioxidants and depletion of IL-8 and KRAS on the correlation between ROS production and hyperlipidemia-promoted CRC metastasis were also clarified. Results: In this study, we found that free fatty acids promoted KRAS/p53-mutant but not single-mutant or non-mutant CRC cell metastasis. IL-8, the most abundant secreted factor in KRAS/p53-mutant cells, was correlated with the upregulation of NOX4 expression and ROS production under oleic acid (OA)-treated conditions. In addition, the metastasis of KRAS/p53-mutant CRC relies on the ANGPTL4/IL-8/NOX4 axis and the activation of KRAS. The antioxidants and inactivation of KRAS also inhibited OA-induced EMT and metastasis. Although KRAS mediated EGF- and OA-promoted CRC cell invasion, the inhibition of EGFR did not affect OA-induced ANGPTL4/IL-8/NOX4 axis and CRC metastasis. The high-fat diet mice fed with vitamin E and statin or in IL-8-depleted cells significantly inhibited tumor extravasation and metastatic lung growth of CRC. Conclusion: The antioxidants, statins, and targeting IL-8 may provide better outcomes for treating metastatic CRC that harbors multigene mutations and anti-EGFR resistance.

Efficacy and Safety of a Parenteral Nutrition Program for Patients with RAS Wild-Type Metastatic Colorectal Cancer Administered First-Line Cetuximab Plus Chemotherapy: A Propensity Score Matching Study.

Malnutrition is a common problem in patients with metastatic colorectal cancer (mCRC) receiving targeted therapy plus chemotherapy, resulting in severe toxicity and decreased survival rates. This retrospective study employing propensity score matching (PSM) examined the efficacy and safety of a supplemental home parenteral nutrition (HPN) program for patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy. This retrospective nationwide registry study included data from 14 medical centers/hospitals across Taiwan, and the data period ranged from November 2016 to December 2020. Patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy as their first-line therapy were included and divided into HPN and non-HPN program groups. HPN was initiated based on patient-specific factors, such as baseline nutritional status, treatment-related toxicities, and comorbidities. Clinical outcomes were evaluated using response to therapy, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). This study recruited 758 patients, of whom 110 and 648 were included in the HPN and non-HPN program groups, respectively. After 1:3 PSM, the data of 109 and 327 patients from the HPN and non-HPN program groups were analyzed, respectively. The HPN program group had a higher metastasectomy rate (33.9% vs. 20.2%, p = 0.005), and longer duration of treatment and DoR than the non-HPN program group (13.6 vs. 10.3 and 13.6 vs. 9.9 months, p = 0.001 and < 0.001, respectively). The HPN program group tended to have a longer median PFS (18.2 vs. 13.9 months, p = 0.102). Moreover, we noted a significant improvement in the median OS in the same group (53.4 vs. 34.6 months, p = 0.002). Supplemental HPN programs may be recommended for select patients with mCRC receiving targeted therapy plus chemotherapy to improve oncological outcomes.

Y-box binding protein 1 promotes chromatin accessibility to aggravate liver fibrosis.

Y-box binding protein 1 (YBX1) has been reported to be involved in the transcriptional regulation of various pathophysiological processes, such as inflammation, oxidative stress, and epithelial-mesenchymal transformation. However, its precise role and mechanism in regulating hepatic fibrosis remain unclear. In this study, we aimed to investigate the effects of YBX1 on liver fibrosis and its potential mechanism. The expression of YBX1 in human liver microarray, mice tissues and primary mouse hepatic stellate cells (HSCs) was validated to be upregulated in several hepatic fibrosis models (CCl4 injection, TAA injection, and BDL). Hepatic-specific Ybx1 overexpression exacerbated the liver fibrosis phenotypes in vivo and in vitro. Moreover, the knockdown of YBX1 significantly improved TGF-ß-induced fibrosis in the LX2 cell (a hepatic stellate cell line). Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq) of hepatic-specific Ybx1 overexpression (Ybx1-OE) mice with CCl4 injection showed increasing chromatin accessibility than CCl4 only group. Functional enrichments of open regions in the Ybx1-OE group indicated that extracellular matrix (ECM) accumulation, lipid purine metabolism, and oxytocin-related pathways were more accessible in the Ybx1-OE group. Accessible regions of the Ybx1-OE group in the promoter also suggested significant activation of genes related to liver fibrogenesis, such as response to oxidative stress and ROS, lipid localization, angiogenesis and vascular development, and inflammatory regulation. Moreover, we screened and validated the expression of candidate genes (Fyn, Axl, Acsl1, Plin2, Angptl3, Pdgfb, Ccl24, and Arg2), which might be potential targets of Ybx1 in the pathogenesis of liver fibrosis.

Prognostic role of tissue plasminogen activator in coronary artery disease with or without aortic valve sclerosis.

AIMS: We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients with or without aortic valve sclerosis (AVSc). METHODS AND RESULTS: Serum levels of t-PA were determined in 347 consecutive stable angina patients with (n = 183) or without (n = 164) AVSc. Outcomes were prospectively recorded as planned clinic evaluations every 6 months up to 7 years. The primary endpoint was a composite of cardiovascular death and rehospitalization due to heart failure. The secondary endpoint included all-cause mortality, cardiovascular death, and rehospitalization due to heart failure. Serum t-PA was significantly higher in AVSc than in non-AVSc patients (2131.22 pg/mL vs. 1495.85 pg/mL, P < 0.001). For patients with AVSc, those with t-PA level above the median (>1840.68 pg/mL) were more likely to meet the primary and secondary endpoints (all P < 0.001). After adjusting for potential confounding factors, serum t-PA level remained significantly predictive for each endpoint in the Cox proportional hazard models. The prognostic value of t-PA was good, with an AUC-ROC of 0.753 (P < 0.001). The combination of t-PA with traditional risk factors improved the risk reclassification of AVSc patients, with a net reclassification index of 0.857 and an integrated discrimination improvement of 0.217 (all P < 0.001). However, for patients without AVSc, both primary and secondary endpoints were similar, irrespective of t-PA levels. CONCLUSIONS: Elevated circulating t-PA confers an increased risk for poor long-term clinical outcomes in stable coronary artery disease patients with AVSc.

Integrated analysis of genome-wide gene expression and DNA methylation profiles reveals candidate genes in ovary endometriosis.

Background: The incidence of endometriosis (EMs), a common disease in gynecology, has increased over the years. Women suffer from the symptoms caused by EMs, such as chronic pelvic pain, dysmenorrhea, and infertility. However, the etiology and pathophysiology of EMs remain unclear. This study aimed to identify candidate genes of endometriosis through integrated analysis of genome-wide gene expression and DNA methylation profiles. Results: Eutopic and ectopic endometrial tissues were collected from patients who were diagnosed as ovarian EMs. Genome-wide methylation profiling identified 17551 differentially methylated loci, with 9777 hypermethylated and 7774 hypomethylated loci. Differentially methylated loci were mainly concentrated in the gene body and intergenic regions. Genome-wide gene expression profiling identified 1837 differentially expressed genes (DEGs), with 1079 genes upregulated and 758 downregulated in ectopic groups. Integrated analysis revealed that DNA methylation was negatively correlated to gene expression in most genomic regions, such as exon, 3'UTR, 5'UTR, and promoter. We also identified promoter-related (53 downregulated and 113 upregulated) and enhancer-related DMGs (212 downregulated and 232 upregulated), which were significantly correlated to the gene expression. Further validation of the top-ranked genes belonging to differentially methylated genes (DMGs) and DEGs revealed that TMEM184A, GREM2, SFN, KIR3DX1, HPGD, ESR1, BST2, PIK3CG and RNASE1 were significant candidate genes in ovarian endometriosis. Conclusion: Our study revealed the significance of DNA methylation in the gene expression in ovary endometriosis, which provides new insights and a molecular foundation for understanding the underlying mechanisms of endometriosis.

Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis.

Metastasis is the main cause of death in many cancers including colorectal cancer (CRC); however, the underlying mechanisms responsible for metastatic progression remain largely unknown. We found that nuclear TYRO3 receptor tyrosine kinase is a strong predictor of poor overall survival in patients with CRC. The metastasis-promoting function of nuclear TYRO3 requires its kinase activity and matrix metalloproteinase-2 (MMP-2)-mediated cleavage but is independent of ligand binding. Using proteomic analysis, we identified bromodomain-containing protein 3 (BRD3), an acetyl-lysine reading epigenetic regulator, as one of nuclear TYRO3's substrates. Chromatin immunoprecipitation-sequencing data reveal that TYRO3-phosphorylated BRD3 regulates genes involved in anti-apoptosis and epithelial-mesenchymal transition. Inhibition of MMP-2 or BRD3 activity by selective inhibitors abrogates nuclear TYRO3-induced drug resistance and metastasis in organoid culture and in orthotopic mouse models. These data demonstrate that MMP-2/TYRO3/BRD3 axis promotes the metastasis of CRC, and blocking this signaling cascade is a promising approach to ameliorate CRC malignancy.

Dual role of sprouty2 as an inhibitor of RAS/ERK-driven proliferation and a promoter of cancer invasion in KRAS wild-type colorectal cancer.

Sprouty2 (SPRY2) is known to inhibit the RAS/MAPK/ERK pathway, and is a potential study target for cancer. The effect of SPRY2 in colorectal cancer (CRC) and whether it is influenced by KRAS mutation are not known. We manipulated SPRY2 gene expression and used an activating KRAS-mutant plasmid to determine its effect on CRC cell function in vitro and/or in vivo. We performed SPRY2 immunohistochemical staining in 143 CRC specimens and analyzed the staining results with various clinicopathological characteristics in relation to KRAS mutation status. SPRY2 knockdown in Caco-2 cells carrying the wild-type (WT) KRAS gene upregulated phosphorylated ERK (p-ERK) levels and increased cell proliferation in vitro, but inhibited cell invasion. However, SPRY2 knockdown in SW480 cells (activating KRAS mutant) or Caco-2 cells transfected with KRAS-mutant plasmid did not significantly alter p-ERK levels, cell proliferation, or invasion. The xenografts of SPRY2-knockdown Caco-2 cells were larger with less deep muscle invasion than those of control cells. The clinical cohort study revealed a positive association of SPRY2 protein expression with pT status, lymphovascular invasion, and perineural invasion in KRAS-WT CRCs. However, the associations were not observed in KRAS-mutant CRCs. Interestingly, high SPRY2 expression was related to shorter cancer-specific survival in both KRAS-WT and KRAS-mutant CRC patients. Our study demonstrated the dual role of SPRY2 as an inhibitor of RAS/ERK-driven proliferation and as a promoter of cancer invasion in KRAS-WT CRC. SPRY2 may promote the invasion and progression of KRAS-WT CRC, and might also enhance KRAS-mutant CRC progression through pathways other than invasion.

Endothelial deletion of PTBP1 disrupts ventricular chamber development.

The growth and maturation of the ventricular chamber require spatiotemporally precise synergy between diverse cell types. Alternative splicing deeply affects the processes. However, the functional properties of alternative splicing in cardiac development are largely unknown. Our study reveals that an alternative splicing factor polypyrimidine tract-binding protein 1 (PTBP1) plays a key role in ventricular chamber morphogenesis. During heart development, PTBP1 colocalizes with endothelial cells but is almost undetectable in cardiomyocytes. The endothelial-specific knockout of Ptbp1, in either endocardial cells or pan-endothelial cells, leads to a typical phenotype of left ventricular noncompaction (LVNC). Mechanistically, the deletion of Ptbp1 reduces the migration of endothelial cells, disrupting cardiomyocyte proliferation and ultimately leading to the LVNC. Further study shows that Ptbp1 deficiency changes the alternative splicing of ß-arrestin-1 (Arrb1), which affects endothelial cell migration. In conclusion, as an alternative splicing factor, PTBP1 is essential during ventricular chamber development, and its deficiency can lead to congenital heart disease.

Recent Progress on Nanomaterial-Facilitated Electrochemical Strategies for Cancer Diagnosis.

Cancer is a malignant disease that endangers human life, especially owing to its high fatality rate; therefore, rapid and accurate early screening is needed to effectively improve the survival rate. Compared with traditional cancer detection methods, electrochemical biosensors that recognize cancer biomarkers in blood have the advantages of low invasiveness, fast diagnosis, and low cost. However, there is always a trade-off between sensitivity and selectivity, which limits the detection of trace amounts of biomarkers produced in the early stages. To address this issue, an increasing number of nanomaterials with simultaneous improvements in both sensitivity and selectivity have recently been reported. In this review, different categories of state-of-the-art electrochemical biosensors and their operating principles are introduced, and their respective advantages and disadvantages are described. Furthermore, the review discusses the existing detection strategies and performance of nanomaterial-based cancer biosensors for biomarker recognition, providing overall guidance for the material selection of different biomarkers. Finally, the main challenges involving existing electrochemical cancer biosensors are evaluated to present the future development prospects of nanomaterials and detection strategies.

The effect of femoral component valgus/varus angle on the mid-term efficacy of unicondylar knee arthroplasty.

OBJECTIVE: To investigate the effect of femoral component valgus/varus angle (FCVA) on the mid-term outcome after unicondylar knee arthroplasty. METHODS: Patients who underwent unicompartmental knee replacement in the Department of Bone and Joint Surgery, were retrospectively analyzed. According to the postoperative femoral prosthesis internal and external rotation angle, patients were divided into six groups the postoperative femoral prosthesis internal and external rotation angle: standard group, mildly abnormal group. The patients were followed up for 12 months, and complications were recorded during the follow-up period. The Range of motion (ROM), visual analog scale (VAS), and Knee society score (KSS) were compared between the six groups. RESULTS: One hundred twenty-four patients with 124 knees were included in this study. There were no statistical differences in age, gender, body mass index, preoperative ROM, or preoperative VAS, KSS-C, and KSS-F scores among the six groups. Comparison of postoperative outcomes and efficacy grades showed that: (1) the differences in ROM grades, as well as VAS, KSS-C, and KSS-F efficacy at 12 months postoperatively were statistically significant in all six groups by rank sum test; and patients in the normal group had better ROM grades and KSS-F grades than those in the mild and severe abnormality groups; (2) During the follow-up, no patient records had other serious complications such as periprosthetic infection, prosthetic loosening, periprosthetic fracture, and spacer dislocation. CONCLUSION: Controlling the femoral prosthetic internal rotation angle between 6° and 0° in unicompartmental knee replacements can lead to better mid-term outcomes for patients.