p Net: A toolbox for personalized functional networks modeling.

Personalized functional networks (FNs) derived from functional magnetic resonance imaging (fMRI) data are useful for characterizing individual variations in the brain functional topography associated with the brain development, aging, and disorders. To facilitate applications of the personalized FNs with enhanced reliability and reproducibility, we develop an open-source toolbox that is user-friendly, extendable, and includes rigorous quality control (QC), featuring multiple user interfaces (graphics, command line, and a step-by-step guideline) and job-scheduling for high performance computing (HPC) clusters. Particularly, the toolbox, named personalized functional network modeling (pNet), takes fMRI inputs in either volumetric or surface type, ensuring compatibility with multiple fMRI data formats, and computes personalized FNs using two distinct modeling methods: one method optimizes the functional coherence of FNs, while the other enhances their independence. Additionally, the toolbox provides HTML-based reports for QC and visualization of personalized FNs. The toolbox is developed in both MATLAB and Python platforms with a modular design to facilitate extension and modification by users familiar with either programming language. We have evaluated the toolbox on two fMRI datasets and demonstrated its effectiveness and user-friendliness with interactive and scripting examples. pNet is publicly available at https://github.com/MLDataAnalytics/pNet .

A general exposome factor explains individual differences in functional brain network topography and cognition in youth.

Childhood environments are critical in shaping cognitive neurodevelopment. With the increasing availability of large-scale neuroimaging datasets with deep phenotyping of childhood environments, we can now build upon prior studies that have considered relationships between one or a handful of environmental and neuroimaging features at a time. Here, we characterize the combined effects of hundreds of inter-connected and co-occurring features of a child's environment ("exposome") and investigate associations with each child's unique, multidimensional pattern of functional brain network organization ("functional topography") and cognition. We apply data-driven computational models to measure the exposome and define personalized functional brain networks in pre-registered analyses. Across matched discovery (n=5139, 48.5% female) and replication (n=5137, 47.1% female) samples from the Adolescent Brain Cognitive Development study, the exposome was associated with current (ages 9-10) and future (ages 11-12) cognition. Changes in the exposome were also associated with changes in cognition after accounting for baseline scores. Cross-validated ridge regressions revealed that the exposome is reflected in functional topography and can predict performance across cognitive domains. Importantly, a single measure capturing a child's exposome could more accurately and parsimoniously predict cognition than a wealth of personalized neuroimaging data, highlighting the importance of children's complex, multidimensional environments in cognitive neurodevelopment.

Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.

Ethylene/Polar Monomer Copolymerization by [N, P] Ti Complexes: Polar Copolymers with Ultrahigh-Molecular Weight.

A series of novel titanium complexes (2a-2e) bearing [N, P] aniline-chlorodiphenylphosphine ligands (1a-1e) featuring CH3 and F substituents have been synthesized and characterized. Surprisingly, in the presence of polar additive, the complexes (2a-2e) all displayed high catalytic activities (up to 1.04 × 106 gPolymer (mol·Ti)-1·h-1 and produced copolymer with the ultrahigh molecular weight up to 1.37 × 106 g/mol. The catalytic activities are significantly enhanced by introducing electron-withdrawing group (F) into the aniline aromatic ring. Especially, the increase in activity based on different complexes followed the order of 2e > 2d > 2c > 2b > 2a. Simultaneously, density functional theory (DFT) calculations have been performed to probe the polymerization mechanism as well as the electronic and steric effects of various substituents on the catalyst backbone. DFT computation revealed that the polymerization behaviors could be adjusted by the electronic effect of ligand substituents; however, it has little to do with the steric hindrance of the substituents. Furthermore, theoretical calculation results keep well in accordance with experimental measurement results. The article provided an appealing design method that the employment of fluorine atom as electron-withdrawing to be studied is the promotive effect of transition-metal coordination polymerization.

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1.

Aging increases the risks of various diseases and the vulnerability to death. Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases. This study demonstrates that extracellular vesicles from human urine-derived stem cells (USC-EVs) efficiently inhibit cellular senescence in vitro and in vivo. The intravenous injection of USC-EVs improves cognitive function, increases physical fitness and bone quality, and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice. The anti-aging effects of USC-EVs are not obviously affected by the USC donors' ages, genders, or health status. Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase (PLAU) and tissue inhibitor of metalloproteinases 1 (TIMP1). These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases, cyclin-dependent kinase inhibitor 2A (P16INK4a), and cyclin-dependent kinase inhibitor 1A (P21cip1). These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.

PHGDH knockdown increases sensitivity to SR1, an aryl hydrocarbon receptor antagonist, in colorectal cancer by activating the autophagy pathway.

Colorectal cancer (CRC) has emerged as the third most prevalent and second deadliest cancer worldwide. Metabolic reprogramming is a key hallmark of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) is over-expressed in multiple cancers, including CRC. Although the role of PHGDH in metabolism has been extensively investigated, its effects on CRC development remains to be elucidated. In the present study, it was demonstrated that PHGDH expression was significantly up-regulated in colorectal cancer. PHGDH expression was positively correlated with that of the aryl hydrocarbon receptor (AhR) and its target genes, CYP1A1 and CYP1B1, in CRC cells. Knockdown of PHGDH reduced AhR levels and activity, as well as the ratio of reduced to oxidized glutathione. The selective AhR antagonist stemregenin 1 induced cell death through reactive oxygen species-dependent autophagy in CRC cells. PHGDH knockdown induced CRC cell sensitivity to stemregenin 1 via the autophagy pathway. Our findings suggest that PHGDH modulates AhR signaling and the redox-dependent autophagy pathway in CRC, and that the combination of inhibition of both PHGDH and AhR may be a novel therapeutic strategy for CRC.

Microbiome analysis reveals the inducing effect of Pseudomonas on prostatic hyperplasia via activating NF-κB signalling.

Benign prostatic hyperplasia (BPH) is a prevalent disease among middle-aged and elderly males, but its pathogenesis remains unclear. Dysbiosis of the microbiome is increasingly recognized as a significant factor in various human diseases. Prostate tissue also contains a unique microbiome, and its dysbiosis has been proposed to contribute to prostate diseases. Here, we obtained prostate tissues and preoperative catheterized urine from 24 BPH individuals, and 8 normal prostate samples as controls, which followed strict aseptic measures. Using metagenomic next-generation sequencing (mNGS), we found the disparities in the microbiome composition between normal and BPH tissues, with Pseudomonas significantly enriched in BPH tissues, as confirmed by fluorescence in situ hybridization (FISH). Additionally, we showed that the prostate microbiome differed from the urine microbiome. In vitro experiments revealed that lipopolysaccharide (LPS) of Pseudomonas activated NF-κB signalling, leading to inflammation, proliferation, and EMT processes, while inhibiting apoptosis in prostatic cells. Overall, our research determines the presence of microbiome dysbiosis in BPH, and suggests that Pseudomonas, as the dominant microflora, may promote the progression of BPH through LPS activation of NF-κB signalling.

Multimedia Mercury Recovery from Coal-Fired Power Plants Utilizing N-Containing Conjugated Polymer Functionalized Fly Ash.

To recover multimedia mercury from coal-fired power plants, a novel N-containing conjugated polymer (polyaniline and polypyrrole) functionalized fly ash was prepared, which could continuously adsorb 99.2% of gaseous Hg0 at a high space velocity of 368,500 h-1 and nearly 100% of aqueous Hg2+ in the solution pH range of 2-12. The adsorption capacities of Hg0 and Hg2+ reach 1.62 and 101.36 mg/g, respectively. Such a kind of adsorbent has good environmental applicability, i.e. good resistance to coexisting O2/NO/SO2 and coexisting Na+/K+/Ca2+/Mg2+/SO42-. This adsorbent has very low specific resistances (6 × 106-5 × 109 Ω·cm) and thus can be easily collected by an electrostatic precipitator under low-voltage (0.1-0.8 kV). The Hg-saturated adsorbent can desorb almost 100% Hg under relatively low temperature (<250 °C). Characterization and theoretical calculations reveal that conjugated-N is the critical site for adsorbing both Hg0 and Hg2+ as well as activating chlorine. Gaseous Hg0 is oxidized and adsorbed in the form of HgXClX(ad), while aqueous Hg2+ is adsorbed to form a complex with conjugated-N, and parts of Hg2+ are reduced to Hg+ by conjugated-N. This adsorbent can be easily large-scale manufactured; thus, this novel solid waste functionalization method is promising to be applied in coal-fired power plants and other Hg-involving industrial scenes.

KDM4B down-regulation facilitated breast cancer cell stemness via PHGDH upregulation in H3K36me3-dependent manner.

Despite recent advances have been made in clinical treatments of breast cancer, the general prognosis of patients remains poor. Therefore, it is imperative to develop a more effective therapeutic strategy. Lysine demethylase 4B (KDM4B) has been reported to participate in breast cancer development recently, but its exact biological role in breast cancer remains unclear. Here, we observed that KDM4B was down-regulated in human primary BRCA tissues and the low levels of KDM4B expression were correlated with poor survival. Gain- and loss-of-function experiments showed that KDM4B inhibited the proliferation and metastasis of breast cancer cells. Besides, knockdown of KDM4B promoted the epithelial-mesenchymal transition (EMT) and cell stemness in breast cancer cells. Mechanistically, KDM4B down-regulates PHGDH by decreasing the enrichment of H3K36me3 on the promoter region of PHGDH. Knockdown of PHGDH could significantly reversed proliferation, migration, EMT, and cell stemness induced by KDM4B silencing in breast cancer cells. Collectively, we propose a model for a KDM4B/PHGDH axis that provides novel insight into breast cancer development, which may serve as a potential factor for predicting prognosis and a therapeutic target for breast cancer.

Reassessing endothelial-to-mesenchymal transition in mouse bone marrow: insights from lineage tracing models.

Endothelial cells (ECs) and bone marrow stromal cells (BMSCs) play crucial roles in supporting hematopoiesis and hematopoietic regeneration. However, whether ECs are a source of BMSCs remains unclear. Here, we evaluate the contribution of endothelial-to-mesenchymal transition to BMSC generation in postnatal mice. Single-cell RNA sequencing identifies ECs expressing BMSC markers Prrx1 and Lepr; however, this could not be validated using Prrx1-Cre and Lepr-Cre transgenic mice. Additionally, only a minority of BMSCs are marked by EC lineage tracing models using Cdh5-rtTA-tetO-Cre or Tek-CreERT2. Moreover, Cdh5+ BMSCs and Tek+ BMSCs show distinct spatial distributions and characteristic mesenchymal markers, suggestive of their origination from different progenitors rather than CDH5+ TEK+ ECs. Furthermore, myeloablation induced by 5-fluorouracil treatment does not increase Cdh5+ BMSCs. Our findings indicate that ECs hardly convert to BMSCs during homeostasis and myeloablation-induced hematopoietic regeneration, highlighting the importance of using appropriate genetic models and conducting careful data interpretation in studies concerning endothelial-to-mesenchymal transition.

Personalized functional brain network topography is associated with individual differences in youth cognition.

Individual differences in cognition during childhood are associated with important social, physical, and mental health outcomes in adolescence and adulthood. Given that cortical surface arealization during development reflects the brain's functional prioritization, quantifying variation in the topography of functional brain networks across the developing cortex may provide insight regarding individual differences in cognition. We test this idea by defining personalized functional networks (PFNs) that account for interindividual heterogeneity in functional brain network topography in 9-10 year olds from the Adolescent Brain Cognitive Development℠ Study. Across matched discovery (n = 3525) and replication (n = 3447) samples, the total cortical representation of fronto-parietal PFNs positively correlates with general cognition. Cross-validated ridge regressions trained on PFN topography predict cognition in unseen data across domains, with prediction accuracy increasing along the cortex's sensorimotor-association organizational axis. These results establish that functional network topography heterogeneity is associated with individual differences in cognition before the critical transition into adolescence.

The value of ICG-guided left colon vascular variation and anatomical rules for the radical resection of proctosigmoid colon cancer.

Objective: During laparoscopic radical resection for proctosigmoid colon cancer (PCC), surgeons could inadvertently damage the arteries when following the operation path.This study investigated the variations in left colon blood vessels in order to guide the scientific protection of the marginal artery (MA) during laparoscopic surgery for PCC. Methods: Data from seven patients who underwent inferior mesenteric artery (IMA) angiography were included as imaging references to preliminarily explore the vascular structure and variation in the left colon. The clinical video data of 183 PCC patients were retrospectively analyzed to observe intraoperative MA injury. Meanwhile, a prospective cohort of 96 patients with the same disease underwent intraoperative indocyanine green (ICG) fluorescence imaging of the peripheral sigmoid artery network, the variation of marginal arteries was summarized, and the distance between vessels and the bowel was measured at different levels. Patients were divided into 'ICG group' and 'non-ICG group' according to whether ICG guidance was performed, and perioperative conditions were compared between the two groups. Taking the integrity of lymph node dissection into consideration, 18 patients underwent carbon nanonode tracing. This study was conducted under the standard consent and ethical approval of the Ethics Committee of our center. Results: 7 patients with IMA angiography shared some vascular structures, defined as 'Dangerous Triangle' and 'Secure Window'. Through intraoperative observation, the primary arch was typically located 4.2 (2.3-6.0) cm away from the intestinal canal, and 5.21% (5/96) patients had poor anastomosis at the primary arch. Moreover, secondary vascular arches (6.4 (4.6-10.0) cm from the intestinal wall) were observed in 38.54% of patients. MA injury was identified in 2 of 183 cases, and the ischemic bowel was timely dissected, whereas no such injury occurred during ICG fluorescenceguided surgery. Guided by carbon nanoparticles, the integrity of lymph node dissection can be maintained while preserving the secondary arch in all patients. Conclusions: This study demonstrated the benefits of ICG guidance in protecting the intestinal blood supply in laparoscopic PCC surgery. By enhancing the understanding of primary and secondary vascular arches, secure windows, and dangerous triangles, surgeons can safely optimize the surgical path during surgery.

Aptamer-functionalized hydrogels promote bone healing by selectively recruiting endogenous bone marrow mesenchymal stem cells.

Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.

Predicting Alzheimer's Disease and Quantifying Asymmetric Degeneration of the Hippocampus Using Deep Learning of Magnetic Resonance Imaging Data.

In order to quantify lateral asymmetric degeneration of the hippocampus for early predicting Alzheimer's disease (AD), we develop a deep learning (DL) model to learn informative features from the hippocampal magnetic resonance imaging (MRI) data for predicting AD conversion in a time-to-event prediction modeling framework. The DL model is trained on unilateral hippocampal data with an autoencoder based regularizer, facilitating quantification of lateral asymmetry in the hippocampal prediction power of AD conversion and identification of the optimal strategy to integrate the bilateral hippocampal MRI data for predicting AD. Experimental results on MRI scans of 1307 subjects (817 for training and 490 for validation) have demonstrated that the left hippocampus can better predict AD than the right hippocampus, and an integration of the bilateral hippocampal data with the instance based DL method improved AD prediction, compared with alternative predictive modeling strategies.

Deep Clustering Survival Machines with Interpretable Expert Distributions.

We develop deep clustering survival machines to simultaneously predict survival information and characterize data heterogeneity that is not typically modeled by conventional survival analysis methods. By modeling timing information of survival data generatively with a mixture of parametric distributions, referred to as expert distributions, our method learns weights of the expert distributions for individual instances based on their features discriminatively such that each instance's survival information can be characterized by a weighted combination of the learned expert distributions. Extensive experiments on both real and synthetic datasets have demonstrated that our method is capable of obtaining promising clustering results and competitive time-to-event predicting performance.

SurfNN: Joint Reconstruction of Multiple Cortical Surfaces from Magnetic Resonance Images.

To achieve fast, robust, and accurate reconstruction of the human cortical surfaces from 3D magnetic resonance images (MRIs), we develop a novel deep learning-based framework, referred to as SurfNN, to reconstruct simultaneously both inner (between white matter and gray matter) and outer (pial) surfaces from MRIs. Different from existing deep learning-based cortical surface reconstruction methods that either reconstruct the cortical surfaces separately or neglect the interdependence between the inner and outer surfaces, SurfNN reconstructs both the inner and outer cortical surfaces jointly by training a single network to predict a midthickness surface that lies at the center of the inner and outer cortical surfaces. The input of SurfNN consists of a 3D MRI and an initialization of the midthickness surface that is represented both implicitly as a 3D distance map and explicitly as a triangular mesh with spherical topology, and its output includes both the inner and outer cortical surfaces, as well as the midthickness surface. The method has been evaluated on a large-scale MRI dataset and demonstrated competitive cortical surface reconstruction performance.

Ångstrom-scale silver particles ameliorate collagen-induced and K/BxN-transfer arthritis in mice via the suppression of inflammation and osteoclastogenesis.

OBJECTIVE: Nanoparticles (NPs) hold a great promise in combating rheumatoid arthritis, but are often compromised by their toxicities because the currently used NPs are usually synthesized by chemical methods. Our group has previously fabricated Ångstrom-scale silver particles (AgÅPs) and demonstrated the anti-tumor and anti-sepsis efficacy of fructose-coated AgÅPs (F-AgÅPs). This study aimed to uncover the efficacy and mechanisms of F-AgÅPs for arthritis therapy. METHODS: We evaluated the efficacy of F-AgÅPs in collagen-induced arthritis (CIA) mice. We also compared the capacities of F-AgÅPs, the commercial AgNPs, and the clinical drug methotrexate (MTX) in protecting against K/BxN serum-transfer arthritis (STA) mice. Moreover, we evaluated the effects of F-AgÅPs and AgNPs on inflammation, osteoclast formation, synoviocytes migration, and matrix metalloproteinases (MMPs) production in vitro and in vivo. Meanwhile, the toxicities of F-AgÅPs and AgNPs in vitro and in vivo were also tested. RESULTS: F-AgÅPs significantly prevented bone erosion, synovitis, and cartilage damage, attenuated rheumatic pain, and improved the impaired motor function in mouse models of CIA or STA, the anti-rheumatic effects of which were comparable or stronger than AgNPs and MTX. Further studies revealed that F-AgÅPs exhibited similar or greater inhibitory abilities than AgNPs to suppress inflammation, osteoclast formation, synoviocytes migration, and MMPs production. No obvious toxicities were observed in vitro and in vivo after F-AgÅPs treatment. CONCLUSIONS: F-AgÅPs can effectively alleviate arthritis without notable toxicities and their anti-arthritic effects are associated with the inhibition of inflammation, osteoclastogenesis, synoviocytes migration, and MMPs production. Our study suggests the prospect of F-AgÅPs as an efficient and low-toxicity agent for arthritis therapy.

The dynamic impact mechanism of China's financial conditions on real economy and international crude oil market.

As financial conditions become more complex and variable, capturing economic patterns becomes harder. The Financial Conditions Index (FCI) has gained traction as a tool to assess the performance of financial markets in nations or regions. This paragraph has created the China FCI using various financial indicators from 2002 to 2022. And with the use of statistical models like DMA-TVP-FAVAR, mixed-frequency Granger causality test, TVP-SV-VAR, and MS-VAR to analyze the relationship between China's financial condition, real economy, and the crude oil market. Different impacts were observed over time and in response to economic shocks, Results show that the fluctuation of international oil price has a negative impact on our financial condition. Therefore, the government should consider the impact of external shock factors such as international crude oil price when formulating financial policies to prevent financial risks.

Preparation of Biomass Carbon Composites MgO@ZnO@BC and Its Adsorption and Removal of Cu(II) and Pb(II) in Wastewater.

The ternary composite MgO@ZnO@BC was synthesized and characterized for the adsorption of Cu2+, Pb2+ heavy metal ions from wastewater. The results show that the addition of the MgO@ZnO@BC composite results in higher adsorption properties for Cu2+ and Pb2+, with a molar ratio of 5% 0.1 g, and maximum adsorption capacity (50.63 mg/g for Cu2+ and 61.46 mg/g for Pb2+). The Langmuir adsorption isotherm of the adsorption complex and the kinetics of adsorption are secondary kinetics. The adsorption of Cu2+ and Pb2+ was mainly chemisorption, accompanied by physical adsorption. This adsorption method fully conforms to the concepts of clean production and efficient waste utilization, providing a reference for the removal of heavy metal ions from wastewater and waste recycling using ternary composite materials.

SIK1 suppresses colorectal cancer metastasis and chemoresistance via the TGF-ß signaling pathway.

In the present study, we investigated the role of salt-induced kinase 1 (SIK1), a serine/threonine kinase protein, in colorectal cancer (CRC). Despite the reported association of SIK1 with tumor malignancy suppression in various cancers, limited research has been conducted on its function in CRC. Our findings revealed that SIK1 expression was low in CRC cells. The results of a KEGG pathway analysis showed a strong association between SIK1 and the TGF-ß signaling pathway. In addition, a coimmunoprecipitation assay validated the interaction between SIK1 and Smad7. Our data indicate that SIK1 inhibited the phosphorylation of Smad2, a critical molecule in the Smad-related TGF-ß pathway, and downstream target genes of the TGF-ß pathway. Furthermore, SIK1 was found to inhibit indicators of epithelial-mesenchymal transition (EMT) and reverse oxaliplatin resistance in CRC. Additionally, SIK1 reduced cell migration and invasion. Our results suggest that the inhibitory effect of SIK1 on the TGF-ß pathway contributes to the suppression of metastasis and oxaliplatin chemoresistance in CRC. However, this effect was reversed by galunisertib (LY2157299). In conclusion, our findings provide novel insights into the role of SIK1 in the regulation of the TGF-ß pathway in CRC, suggesting its potential as a therapeutic target for the treatment of CRC. Further studies are required to fully characterize the mechanism underlying these observations and to validate these findings in animal models.