Publications by authors named "Kexin Chen"

257 Publications

Cortical motion perception emerges from dimensionality reduction with evolved spike-timing dependent plasticity rules.

J Neurosci 2022 Jun 21. Epub 2022 Jun 21.

Departments of Cognitive Sciences and.

The nervous system is under tight energy constraints and must represent information efficiently. This is particularly relevant in the dorsal part of the medial superior temporal area (MSTd) in primates where neurons encode complex motion patterns in order to support a variety of behaviors. A sparse decomposition model based on a dimensionality reduction principle known as Nonnegative Matrix Factorization (NMF) was previously shown to account for a wide range of monkey MSTd visual response properties. This model resulted in sparse, "parts-based" representations that could be regarded as basis flow fields, a linear superposition of which accurately reconstructed the input stimuli. This model provided evidence that the seemingly-complex response properties of MSTd may be a by-product of MSTd neurons performing dimensionality reduction on their input. However, an open question is how a neural circuit could carry out this function. In the current study, we propose a Spiking Neural Network (SNN) model of MSTd based on evolved spike-timing dependent plasticity and homeostatic synaptic scaling (STDP-H) learning rules. We demonstrate that the SNN model learns compressed and efficient representations of the input patterns similar to the patterns that emerge from NMF, resulting in MSTd-like receptive fields observed in monkeys. This SNN model suggests that STDP-H observed in the nervous system may be performing a similar function as NMF with sparsity constraints, which provides a test bed for mechanistic theories of how MSTd may efficiently encode complex patterns of visual motion to support robust self-motion perception.The brain may use dimensionality reduction and sparse coding to efficiently represent stimuli under metabolic constraints. Neurons in monkey area MSTd respond to complex optic flow patterns resulting from self-motion. We developed a spiking neural network model that showed MSTd-like response properties can emerge from evolving spike-timing dependent plasticity with homeostatic synaptic scaling (STDP-H) parameters of the connections between area MT and MSTd. Simulated MSTd neurons formed a sparse, reduced population code capable of encoding perceptual variables important for self-motion perception. This model demonstrates that complex neuronal responses observed in MSTd may emerge from efficient coding, and suggests that neurobiological plasticity, like STDP-H, may contribute to reducing the dimensions of input stimuli and allowing spiking neurons to learn sparse representations.
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http://dx.doi.org/10.1523/JNEUROSCI.0384-22.2022DOI Listing
June 2022

Evaluation of Financial Subsidy for Agriculture Based on Combined Algorithm.

Comput Intell Neurosci 2022 1;2022:6587460. Epub 2022 Jun 1.

College of Economics and Management, Shenyang Agricultural University, Shenyang 110866, Liaoning, China.

The stable development of agriculture is related to the national economy, and the fragility and foundation of agricultural production determine the inherent requirements of the government for financial support of agriculture. Based on China's policy of agricultural subsidy, in this study, the basic characteristics and classification methods of agricultural subsidies are analyzed, and an evaluation model of agricultural subsidies is established based on a combined algorithm, where the attributes of agricultural subsidies are screened by analytic hierarchy process, and the evaluation process of agricultural subsidies is constructed by data envelopment approach. Moreover, the development level of regional financial subsidies for agriculture is measured by relative efficiency value, and the implementation direction of financial subsidies is evaluated, to enhance the administrative benefits of government finance and deepen the supply-side reform of agricultural financial subsidies, which promote the sustainable development of agricultural insurance and agricultural production.
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http://dx.doi.org/10.1155/2022/6587460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177299PMC
June 2022

Adipose-Derived Stem Cells Exosomes Improve Fat Graft Survival by Promoting Prolipogenetic Abilities through Wnt/-Catenin Pathway.

Stem Cells Int 2022 6;2022:5014895. Epub 2022 May 6.

Department of Plastic Surgery, Changhai Hospital, Naval Military Medical University, Shanghai 200433, China.

Autologous fat grafting has been widely used in plastic surgery in recent years, but the unstable retention of fat graft has always been a key clinical problem. Adipose tissue has poor tolerant to ischemia, so the transplanted adipose tissue needs to rebuild blood supply at an early stage in order to survive stably. Our previous study has found that comparing to human foreskin fibroblast exosome (HFF-Exo), human adipose-derived stem cells exosome (hADSC-Exo) can significantly improve the proliferation of vascular endothelial cells and the angiogenic effect of artificial dermal preconstructed flaps. Therefore, the ability of hADSC-Exo to improve the retention of adipose grafts and its potential regenerative mechanism aroused our strong interest. In this study, we applied hADSC-Exo and HFF-Exo to adipose grafts and explored the potential regeneration mechanism through various means such as bioinformatics, immunofluorescence, immunohistochemistry, and adipogenic differentiation. The results showed that hADSC-Exo can significantly promote grafts angiogenesis and adipogenic differentiation of ADSC to improve the retention of fat grafts and may downregulate the Wnt/-catenin signaling pathway to promote the adipogenic differentiation. In summary, our results provide a theoretical basis for the clinical translation of hADSC-Exo in fat grafting.
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http://dx.doi.org/10.1155/2022/5014895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106480PMC
May 2022

Natural Product Library Screens Identify Sanguinarine Chloride as a Potent Inhibitor of Telomerase Expression and Activity.

Cells 2022 04 28;11(9). Epub 2022 Apr 28.

MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research and State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.

Reverse transcriptase hTERT is essential to telomerase function in stem cells, as well as in 85-90% of human cancers. Its high expression in stem cells or cancer cells has made telomerase/hTERT an attractive therapeutic target for anti-aging and anti-tumor applications. In this study, we screened a natural product library containing 800 compounds using an endogenous hTERT reporter. Eight candidates have been identified, in which sanguinarine chloride (SC) and brazilin (Braz) were selected due to their leading inhibition. SC could induce an acute and strong suppressive effect on the expression of and telomerase activity in multiple cancer cells, whereas Braz selectively inhibited telomerase in certain types of cancer cells. Remarkably, SC long-term treatment could cause telomere attrition and cell growth retardation, which lead to senescence features in cancer cells, such as the accumulation of senescence-associated β-galactosidase (SA-β-gal)-positive cells, the upregulation of p16/p21/p53 pathways and telomere dysfunction-induced foci (TIFs). Additionally, SC exhibited excellent capabilities of anti-tumorigenesis, both in vitro and in vivo. In the mechanism, the compound down-regulated several active transcription factors including p65, a subunit of NF-κB complex, and reintroducing p65 could alleviate its suppression of the hTERT/telomerase. Moreover, SC could directly bind hTERT and inhibit telomerase activity in vitro. In conclusion, we identified that SC not only down-regulates the gene's expression, but also directly affects telomerase/hTERT. The dual function makes this compound an attractive drug candidate for anti-tumor therapy.
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http://dx.doi.org/10.3390/cells11091485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104802PMC
April 2022

Effect of estradiol as a continuous variable on breast cancer survival by menopausal status: a cohort study in China.

Breast Cancer Res Treat 2022 Jul 25;194(1):103-111. Epub 2022 Apr 25.

Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology in Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China.

High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR 1.79, 95% CI 1.17-2.75, P = 0.008) and OS in post-menopausal women (HR 1.35, 95% CI 1.04-1.74, P = 0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation ("L-shaped" and "U-shaped", respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a "U-shaped" relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.
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http://dx.doi.org/10.1007/s10549-022-06593-5DOI Listing
July 2022

Partially fluorinated nanoemulsions for F MRI-fluorescence dual imaging cell tracking.

Colloids Surf B Biointerfaces 2022 Jul 11;215:112493. Epub 2022 Apr 11.

Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430071, China. Electronic address:

Fluorine-19 magnetic resonance imaging (F MRI) has been a technology of choice for in vivo cell tracking, in which perfluorocarbons (PFCs) nanoemulsions are the most used F MRI agents. However, the peculiar physicochemical properties of PFCs may lead to poor cell uptake and misleading cell tracking results. Herein, we employed partially fluorinated aromatic agents to formulate paramagnetic nanoemulsions as novel F MRI-fluorescence (FL) dual imaging agents for cell tracking. With the intramolecular π-π interaction, low density and fluorine content, the partially fluorinated agents enable considerable solubilities of functional agents and short relaxation times, which facilitates convenient preparation of stable, biocompatible, and multifunctional nanoemulsions with high F MRI sensitivity. Replacing PFCs in F MRI nanoemulsions with readily available partially fluorinated aromatic agents may address many issues associated with PFCs and provide a novel strategy for high-performance F MRI agents of broad biomedical applications.
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http://dx.doi.org/10.1016/j.colsurfb.2022.112493DOI Listing
July 2022

Enterogenous Microbiotic Markers in the Differential Diagnosis of Crohn's Disease and Intestinal Tuberculosis.

Front Immunol 2022 16;13:820891. Epub 2022 Mar 16.

Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.

Crohn's disease (CD) is a chronic intestinal disorder characterized by refractory gastrointestinal ulcerations. Intestinal tuberculosis (ITB) is one common intestinal disease in east Asia. The two diseases share similar clinical manifestations and endoscopic characteristics. Thus, it is difficult to establish a definite diagnosis of CD, CD concomitant with ITB (CD-ITB), and ITB in practice. Some enterogeneous microbiotic markers have been applied to differentiate CD and ITB, but it remains unknown how they work for the three groups of patients. The aim of our study was to explore the diagnostic values of these enterogeneous microbiotic markers (ASCA IgG, ASCA IgA, ACCA, Anti-I2 and AMCA) among CD, CD-ITB, and ITB patients. A total of 124 individuals were retrospectively enrolled in this study, namely, 103 CD patients, 10 CD-ITB patients, 9 ITB patients, and 68 healthy controls. The demographic and clinical characteristics of these patients were collected and analyzed. The values of these individual or combined enterogeneous microbiotic markers in diagnosis and classification were assessed in CD, CD-ITB, and ITB patients. ASCA IgG, ASCA IgA, and AMCA could accurately differentiate CD patients from healthy controls with an area under curve (AUC) of 0.688, 0.601, and 0.638, respectively. ASCA IgG was significantly higher in CD patients than in CD-ITB patients (P = 0.0003). The Anti-I2 antibody was appropriate for distinguishing CD-ITB from ITB patients (P = 0.039). In CD patients, ASCA IgG was higher in severe patients than in mild (P <0.0001) and inactive patients (P <0.0001), respectively. AMCA was significantly elevated in severe and moderate patients compared to inactive patients (P = 0.001, P = 0.003, respectively). AMCA was associated with a higher risk of CD-related surgery with a significant P-value of 0.0038. In our cohort, ASCAs and AMCA could accurately distinguish CD from healthy controls with an acceptable AUC. A combination of elevated ASCA IgG and AMCA antibodies established a higher sensitivity in differentiating CD from healthy controls. Elevated ASCA IgG demonstrated a differential diagnostic value between CD and CD-ITB. Anti-I2 could also distinguish CD-ITB from ITB. The level of AMCA was associated with both disease severity and CD-related surgery. Likewise, the level of ASCA IgG was also related to disease severity.
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http://dx.doi.org/10.3389/fimmu.2022.820891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966387PMC
April 2022

Characterization of nitrilases from Variovorax boronicumulans that functions in insecticide flonicamid degradation and β-cyano-L-alanine detoxification.

J Appl Microbiol 2022 Apr 2. Epub 2022 Apr 2.

Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Center for Industrialization of Microbial Resources, College of Life Science, Nanjing Normal University, Nanjing, China.

Aims: To characterize the functions of nitrilases of Variovorax boronicumulans CGMCC 4969 and evaluate flonicamid (FLO) degradation and β-cyano-L-alanine (Ala(CN)) detoxification by this bacterium.

Methods And Results: Variovorax boronicumulans CGMCC 4969 nitrilases (NitA and NitB) were purified, and substrate specificity assay indicated that both of them degraded insecticide FLO to N-(4-trifluoromethylnicotinoyl)glycinamide (TFNG-AM) and 4-(trifluoromethyl)nicotinol glycine (TFNG). Ala(CN), a plant detoxification intermediate, was hydrolysed by NitB. Escherichia coli overexpressing NitA and NitB degraded 41.2 and 93.8% of FLO (0.87 mmol·L ) within 1 h, with half-lives of 1.30 and 0.25 h, respectively. NitB exhibited the highest nitrilase activity towards FLO. FLO was used as a substrate to compare their enzymatic properties. NitB was more tolerant to acidic conditions and organic solvents than NitA. Conversely, NitA was more tolerant to metal ions than NitB. CGMCC 4969 facilitated FLO degradation in soil and surface water and utilized Ala(CN) as a sole nitrogen source for growth.

Conclusions: CGMCC 4969 efficiently degraded FLO mediated by NitA and NitB; NitB was involved in Ala(CN) detoxification.

Significance And Impact Of The Study: This study promotes our understanding of versatile functions of nitrilases from CGMCC 4969 that is promising for environmental remediation.
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http://dx.doi.org/10.1111/jam.15561DOI Listing
April 2022

Synthesis of trifluoromethylated aza-BODIPYs as fluorescence-F MRI dual imaging and photodynamic agents.

Org Biomol Chem 2022 04 20;20(16):3335-3341. Epub 2022 Apr 20.

Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.

Dual-imaging agents with highly sensitive fluorescence (FL) imaging and highly selective fluorine-19 magnetic resonance imaging (F MRI) are valuable for biomedical research. At the same time, photosensitizers with a high reactive oxygen species (ROS) generating capability are crucial for photodynamic therapy (PDT) of cancer. Herein, a series of tetra-trifluoromethylated aza-boron dipyrromethenes (aza-BODIPYs) were conveniently synthesized from readily available building blocks and their physicochemical properties, including ultraviolet-visible (UV-Vis) absorption, FL emission, photothermal efficacy, ROS generating efficacy, and F MRI sensitivity, were systematically investigated. An aza-BODIPY with 12 symmetrical fluorines was identified as a potent FL-F MRI dual-imaging traceable photodynamic agent. It was found that the selective introduction of trifluoromethyl (CF) groups into aza-BODIPYs may considerably improve their UV absorption, FL emission, photothermal efficacy, and ROS generating properties, which lays the foundation for the rational design of trifluoromethylated aza-BODIPYs in biomedical applications.
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http://dx.doi.org/10.1039/d2ob00297cDOI Listing
April 2022

Comparative Study on Synergistic Toxicity of Enrofloxacin Combined with Three Antibiotics on Proliferation of THLE-2 Cell.

Antibiotics (Basel) 2022 Mar 16;11(3). Epub 2022 Mar 16.

College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.

Little attention has been paid to the problem of the combined toxicity of accumulated antibiotics on humans from food and clinical treatments. Therefore, we used human hepatocytes to study the joint toxicity of four common antibiotics. The cytotoxicity of enrofloxacin (ENR), combined with ciprofloxacin (CFX), florfenicol (FFC), or sulfadimidine (SMD) on THLE-2 cells was determined by CCK-8 assays; then their joint toxicity was evaluated using CalcuSyn 2.0. Dose-effect curves and median-effect plots established on large amounts of data and CI values were calculated to judge the nature of the combination's interaction. ED50, ED75, and ED90 were predicted to elucidate the changing trend of the concentration on the toxicity of each drug pair. The ENR-CFX and ENR-FFC pairs exhibited synergistic toxicity only at special concentration rates, while ENR and SMD synergistically induced cytotoxicity at almost all the concentration rates studied. The mixed ratio was a significant factor for synergistic toxicity and should be evaluated in all combined effect studies. These results suggested that the combined toxicity of these four drugs should be taken into account in their risk assessment.
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http://dx.doi.org/10.3390/antibiotics11030394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8944827PMC
March 2022

Intense Luminescence and Good Thermal Stability in a Mn-Activated Mg-Based Phosphor with Self-Reduction.

Inorg Chem 2022 Apr 15;61(14):5495-5501. Epub 2022 Mar 15.

Key Laboratory of Weak-Light Nonlinear Photonics, Ministry of Education, School of Physics, Nankai University, Tianjin 300071, China.

White light-emitting diodes provide widespread applications in lighting, electronic equipment, and high-tech displays. However, thermal quenching effect severely limits their practical application. Here, we developed an orange-red phosphor β-KMg(PO):Mn, which emits bright orange-red light when excited by ultraviolet light without the energy transfer of sensitizer, owing to the strong crystal field provided by β-KMg(PO) for Mn. The self-reduction of Mn → Mn and good thermal stability have been realized in an ambient atmosphere. The defect types were verified by X-ray photoelectron spectroscopy, and cationic vacancy plays a significant role in the self-reduction of Mn → Mn. Furthermore, the properties of the trap energy levels were studied by thermoluminescence. The recombination luminescence of the detrapped carriers released from the deep trap levels at high temperatures suppresses the luminescence loss of thermal quenching. Moreover, the trap energy levels play an important role in the mechanoluminescence of β-KMg(PO):Mn. This work emphasizes the significance of the defects in the luminescent characteristics and opens up a new approach for the development of advanced optical functional materials.
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http://dx.doi.org/10.1021/acs.inorgchem.1c03741DOI Listing
April 2022

Poor oral health and risks of total and site-specific cancers in China: A prospective cohort study of 0.5 million adults.

EClinicalMedicine 2022 Mar 5;45:101330. Epub 2022 Mar 5.

Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Huanhuxi Road, Hexi District, Tianjin 300060, China.

Background: There is a strong connection between oral health and overall wellness. We aim to examine the association between poor oral health and the risk of developing or dying of cancer, and whether the association differs by residential area.

Methods: Between 2004 and 2008, a total of 510,148 adults free of cancer were included from the China Kadoorie Biobank study and thereafter followed up to 2015. Poor oral health was assessed from a self-reported baseline questionnaire and defined as a combination of rarely brushing teeth and always gum bleeding. We used Cox proportional hazards models to estimate the hazard ratio (HR) of cancer risk and its associated 95% confidence interval (CI) according to oral health status.

Findings: Overall, 14.9% of participants (19.7% in rural areas and 8.8% in urban areas) reported poor oral health at baseline. After 4,602,743 person-years of follow-up, we identified 23,805 new cancer cases and 11,973 cancer deaths, respectively. Poor oral health was associated with higher risks of total cancer incidence (HR: 1.08, 95% CI: 1.04-1.12) and death (HR: 1.10, 95% CI: 1.05-1.16). For the site-specific cancers, poor oral health was significantly associated with higher risk of stomach cancer incidence (cases: 2964, HR: 1.10, 95% CI: 1.00-1.22), esophageal cancer incidence (cases: 2119, HR: 1.19, 95% CI: 1.07-1.33), esophageal cancer death (cases: 1238, HR: 1.29, 95% CI: 1.12-1.49), liver cancer incidence (cases: 2565, HR: 1.18, 95% CI: 1.06-1.32), and liver cancer death (cases: 1826, HR: 1.20, 95% CI: 1.05-1.36). This positive association was stronger among rural residents compared to urban residents (interaction test < 0.01).

Interpretation: Our findings indicate that poor oral health is associated with higher risk for cancers, especially digestive system cancers. Promotion of oral health in the general population, especially for rural residents, could have valuable public health significance in preventing major systemic diseases.

Funding: Supported by grants (2021YFC2500400, 2016YFC0900500, 2016YFC0900501, 2016YFC0900504) from the National Key Research and Development Program of China, grants from the Kadoorie Charitable Foundation in Hong Kong and grants grants (088158/Z/09/Z, 104085/Z/14/Z, 202922/Z/16/Z) from Wellcome Trust in the UK. CKB is supported by the Kadoorie Charitable Foundation (KCF) in Hong Kong.
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http://dx.doi.org/10.1016/j.eclinm.2022.101330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902628PMC
March 2022

Identification of key genes associated with polycystic ovary syndrome (PCOS) and ovarian cancer using an integrated bioinformatics analysis.

J Ovarian Res 2022 Feb 28;15(1):30. Epub 2022 Feb 28.

Institute of Basic Medical Sciences, College of Basic Medicine, Guilin Medical University, Guilin, Guangxi, China.

Background: Accumulating evidence suggests a strong association between polycystic ovary syndrome (PCOS) and ovarian cancer (OC), but the potential molecular mechanism remains unclear. In this study, we identified previously unrecognized genes that are significantly correlated with PCOS and OC via bioinformatics.

Materials And Methods: Multiple bioinformatic analyses, such as differential expression analysis, univariate Cox analysis, functional and pathway enrichment analysis, protein-protein interaction (PPI) network construction, survival analysis, and immune infiltration analysis, were utilized. We further evaluated the effect of OGN on FSHR expression via immunofluorescence.

Results: TCGA-OC, GSE140082 (for OC) and GSE34526 (for PCOS) datasets were downloaded. Twelve genes, including RNF144B, LPAR3, CRISPLD2, JCHAIN, OR7E14P, IL27RA, PTPRD, STAT1, NR4A1, OGN, GALNT6 and CXCL11, were identified as signature genes. Drug sensitivity analysis showed that OGN might represent a hub gene in the progression of PCOS and OC. Experimental analysis found that OGN could increase FSHR expression, indicating that OGN could regulate the hormonal response in PCOS and OC. Furthermore, correlation analysis indicated that OGN function might be closely related to m6A and ferroptosis.

Conclusions: Our study identified a 12-gene signature that might be involved in the prognostic significance of OC. Furthermore, the hub gene OGN represent a significant gene involved in OC and PCOS progression by regulating the hormonal response.
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http://dx.doi.org/10.1186/s13048-022-00962-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886837PMC
February 2022

Dry Eye Disease in Patients With Schizophrenia: A Case-Control Study.

Front Med (Lausanne) 2022 9;9:831337. Epub 2022 Feb 9.

Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, China.

Objective: To evaluate the clinical features and inflammatory cytokines of dry eye disease (DED) in patients with schizophrenia.

Methods: This is a case-control study. The modified self-rating depression scale (M-SDS) and the ocular surface disease index (OSDI) were used to evaluate the symptoms of depression and DED, respectively. Lipid layer thickness (LLT), partial blink rate (PBR), meibomian gland loss (MGL), tear break-up time (TBUT), corneal fluorescein staining, Schirmer I-test, and eyelid margin abnormalities were also measured. A multiplex ELISA Quantibody array was used to detect the inflammatory cytokines in the tears of all participants.

Results: Forty schizophrenic patients and 20 control subjects were included. The mean age was 45.0 ± 9.5 years (range, 22-63 years) in schizophrenic patients and 45.4 ± 16.2 years (range, 23-76 years) in controls ( = 0.914). The ratio of male to female was 1.1 in schizophrenic patients and 1.0 in controls ( = 0.914). Ten women (52.6%) with schizophrenia and 2 (20%) in the control group (P = 0.096) were menopausal or post-menopausal. The OSDI [0.0 (0.0-4.2) vs. 7.3 (2.1-14.6)] and TBUT [4.5 (3.0-6.0) vs. 10.0 (3.5-11.0)] were significantly lower in patients with schizophrenia than in controls ( = 0.003 and = 0.009, respectively). The rate of MGL [36.5 (17.5-47.5) vs. 8.5 (0.0-17.5)] increased in schizophrenic patients ( < 0.001). Among pro-inflammatory cytokines, the levels of interleukin (IL)-1α, IL-6, IL-11, IL-12A, IL-15, IL-17A, and granulocyte colony-stimulating factor (G-CSF) in tears were elevated in the schizophrenia group (all < 0.01). Most of the chemokines examined were at increased levels in the tears of schizophrenics (all < 0.05). The levels of matrix metalloproteinases-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) were also higher in the schizophrenic patients (all < 0.001). The concentrations of IL-1Ra, tissue-inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in the schizophrenia group were decreased (all < 0.001). In schizophrenic patients, the level of CCL2 in tears was positively correlated with OSDI (R = 0.34, = 0.03). The increasing TIMP-1 and decreasing IL-5 were correlated with increasing LLT ( = 0.33, = 0.035; = -0.35, = 0.027, respectively). The level of ICAM-1 was then positively correlated with partial blink rate (PBR) ( = 0.33, = 0.035). There was a negative correlation between IL-8 and the Schirmer -test ( = -0.41, = 0.009).

Conclusions: Patients with schizophrenia were more likely to experience asymptomatic DED, with mild symptoms and obvious signs. The inflammatory cytokines in the tears of schizophrenic patients differed greatly from that of non-schizophrenic patients.
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http://dx.doi.org/10.3389/fmed.2022.831337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864171PMC
February 2022

Targeted Phototherapy by Niobium Carbide for Mammalian Tumor Models Similar to Humans.

Front Oncol 2022 10;12:827171. Epub 2022 Feb 10.

Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.

Background: In the past few decades, nanomaterial-mediated phototherapy has gained significant attention as an alternative antitumor strategy. However, its antitumor success is majorly limited to the treatment of subcutaneous tumors in nude mice. In fact, no studies have been previously conducted in this area/field on clinically-relevant big animal models. Therefore, there is an urgent need to conduct further investigation in a typical big animal model, which is more closely related to the human body.

Results: In this study, niobium carbide (NbC) was selected as a photoactive substance owing to the presence of outstanding near-infrared (NIR) absorption properties, which are responsible for the generation of NIR-triggered hyperthermia and reactive oxygen species that contribute towards synergetic photothermal and photodynamic effect. Moreover, the present study utilized macrophages as bio-carrier for the targeted delivery of NbC, wherein phagocytosis by macrophages retained the photothermal/photodynamic effect of NbC. Consequently, macrophage-loaded NbC ensured/allowed complete removal of solid tumors both in nude mice and big animal models involving rabbits. Meanwhile, two-dimensional ultrasound, shave wave elastography (SWE), and contrast-enhanced ultrasound (CEUS) were used to monitor physiological evolution in tumor post-treatment, which clearly revealed the occurrence of the photoablation process in tumor and provided a new strategy for the surveillance of tumor in big animal models.

Conclusion: Altogether, the use of a large animal model in this study presented higher clinical significance as compared to previous studies.
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http://dx.doi.org/10.3389/fonc.2022.827171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866440PMC
February 2022

A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study.

Eur Heart J 2022 May;43(18):1702-1711

Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Aims: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations.

Methods And Results: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43-3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20-80%) PRS.

Conclusion: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.
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http://dx.doi.org/10.1093/eurheartj/ehac093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076396PMC
May 2022

Tough and self-healing hydrogels based on transient crosslinking by nanoparticles.

Soft Matter 2022 Mar 2;18(9):1885-1895. Epub 2022 Mar 2.

Endoscopy Center, First Clinical Hospital of Bethune Medical, Jilin University, Changchun 130021, P. R. China.

In this investigation, transient crosslinking was constructed to obtain a hydrogel with excellent mechanical and self-healing properties. Firstly, core-shell particles with hydrophilic amino groups were prepared by emulsion polymerization and subsequently dispersed into hydrophobic association polyacrylamide hydrogels. Transient crosslinking was constructed through hydrogen bonding between core-shell particles and polyacrylamide. As a result, the hydrogels exhibited a tensile strength of 1.4 MPa and self-healing efficiency of 98% at 24 h. Furthermore, reconstruction of the transient crosslinking was confirmed from rheological measurements. Therefore, the essential reinforcement principle based on transient crosslinking would open a novel strategy to obtain hydrogels with superior toughness and self-healing properties.
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http://dx.doi.org/10.1039/d1sm01439kDOI Listing
March 2022

The Migration and Deposition Behaviors of Montmorillonite and Kaolinite Particles in a Two-Dimensional Micromodel.

Materials (Basel) 2022 Jan 23;15(3). Epub 2022 Jan 23.

MOE Key Laboratory of Soft Soils and Geoenvironmental Engineering, Institute of Geotechnical Engineering, College of Civil Engineering and Architecture, Zhejiang University, Hangzhou 310058, China.

The pick-up, migration, deposition, and clogging behaviors of fine particles are ubiquitous in many engineering applications, including contaminant remediation. Deposition and clogging are detrimental to the efficiency of environmental remediation, and their mechanisms are yet to be elucidated. Two-dimensional microfluidic models were developed to simulate the pore structure of porous media with unified particle sizes in this study. Kaolin and bentonite suspensions were introduced to microfluidic chips to observe their particle deposition and clogging behaviors. Interactions between interparticle forces and particle velocity profiles were investigated via computational fluid dynamics and discrete element method simulations. The results showed that (1) only the velocity vector toward the micropillars and drag forces in the reverse direction were prone to deposition; (2) due to the negligible weight of particles, the Stokes number implied that inertia was not the controlling factor causing deposition; and (3) the salinity of the carrying fluid increased the bentonite deposition because of the shrinkage of the diffused electrical double layer and an increase in aggregation force, whereas it had little effect on kaolin deposition.
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http://dx.doi.org/10.3390/ma15030855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8838163PMC
January 2022

Prediction of Two Molecular Subtypes of Gastric Cancer Based on Immune Signature.

Front Genet 2021 17;12:793494. Epub 2022 Jan 17.

National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.

Gastric cancer is the fifth most common type of human cancer and the third leading cause of cancer-related death. The purpose of this study is to investigate the immune infiltration signatures of gastric cancer and their relation to prognosis. We identified two distinct subtypes of gastric cancer (C1/C2) characterized by different immune infiltration signatures. C1 is featured by immune resting, epithelial-mesenchymal transition, and angiogenesis pathways, while C2 is featured by enrichment of the MYC target, oxidative phosphorylation, and E2F target pathways. The C2 subtype has a better prognosis than the C1 subtype (HR = 0.61, 95% CI: 0.44-0.85; log-rank test, = 0.0029). The association of C1/C2 with prognosis remained statistically significant (HR = 0.62, 95% CI: 0.44-0.87; = 0.006) after controlling for age, gender, and stage. The prognosis prediction of C1/C2 was verified in four independent cohorts (including an internal cohort). In summary, our study is helpful for better understanding of the association between immune infiltration and the prognosis of gastric cancer.
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http://dx.doi.org/10.3389/fgene.2021.793494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802764PMC
January 2022

Hydrofluorocarbon nanoparticles for F MRI-fluorescence dual imaging and chemo-photodynamic therapy.

Org Biomol Chem 2022 02 9;20(6):1299-1305. Epub 2022 Feb 9.

Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.

The synergistic chemotherapy and photodynamic therapy (PDT) may significantly improve the cancer therapeutic efficacy, in which fluorinated nanoemulsions are highly advantageous for their ability to deliver oxygen to hypoxic tumors and provide fluorine-19 magnetic resonance imaging (F MRI). The low solubility of chemotherapy drugs and photosensitizers in current perfluorocarbon (PFC)-based F MRI agents usually leads to complicated formulations or chemical modifications and low nanoemulsion stability and performance. Herein, we employ readily available partially fluorinated ethyl 2-(3,5-bis(trifluoromethyl)phenyl)acetate as the F MRI agent and the solvent to dissolve the cancer stem cell inhibitor salinomycin and the photosensitizer ICG for the convenient preparation of F MRI-fluorescence dual imaging and synergistic chemotherapy, photothermal and photodynamic therapy nanoemulsions. The chemotherapy drug salinomycin has a high solubility in the partially fluorinated reagent, facilitating its high loading and efficient delivery. Paramagnetic iron(III) (Fe) is incorporated into the nanoemulsion through the dissolved chelator to significantly improve the F MRI sensitivity. Furthermore, the dissolved fluorinated 2-pyridone enables the efficient capture and sustained release of singlet oxygen in the dark for high PDT efficacy. The multifunctional nanoemulsions show sensitive F MRI and fluorescence dual imaging capability and high synergistic chemotherapy, photothermal and photodynamic therapy efficacy in cancer cells, which may be valuable oxygen delivery, sustained ROS generating and release, dual imaging and multimodal therapy agents for hypoxic tumors. This study provided a convenient co-solubilization strategy for the rapid construction of multifunctional theranostics for hypoxic tumors.
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http://dx.doi.org/10.1039/d1ob02392fDOI Listing
February 2022

A universal approach for integrating super large-scale single-cell transcriptomes by exploring gene rankings.

Brief Bioinform 2022 03;23(2)

Tianjin Cancer Institute, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.

Advancement in single-cell RNA sequencing leads to exponential accumulation of single-cell expression data. However, there is still lack of tools that could integrate these unlimited accumulations of single-cell expression data. Here, we presented a universal approach iSEEEK for integrating super large-scale single-cell expression via exploring expression rankings of top-expressing genes. We developed iSEEEK with 11.9 million single cells. We demonstrated the efficiency of iSEEEK with canonical single-cell downstream tasks on five heterogenous datasets encompassing human and mouse samples. iSEEEK achieved good clustering performance benchmarked against well-annotated cell labels. In addition, iSEEEK could transfer its knowledge learned from large-scale expression data on new dataset that was not involved in its development. iSEEEK enables identification of gene-gene interaction networks that are characteristic of specific cell types. Our study presents a simple and yet effective method to integrate super large-scale single-cell transcriptomes and would facilitate translational single-cell research from bench to bedside.
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http://dx.doi.org/10.1093/bib/bbab573DOI Listing
March 2022

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Eur J Hum Genet 2022 03 14;30(3):349-362. Epub 2022 Jan 14.

Maria Sklodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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http://dx.doi.org/10.1038/s41431-021-00987-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904525PMC
March 2022

RSL3 Drives Ferroptosis through NF-B Pathway Activation and GPX4 Depletion in Glioblastoma.

Oxid Med Cell Longev 2021 26;2021:2915019. Epub 2021 Dec 26.

School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China.

Glioblastoma, the most aggressive form of malignant glioma, is very difficult to treat because of its aggressively invasive nature and high recurrence rates. RAS-selective lethal 3 (RSL3), a well-known inhibitor of glutathione peroxidase 4 (GPX4), could effectively induce oxidative cell death in glioblastoma cells through ferroptosis, and several signaling pathways are involved in this process. However, the role of the nuclear factor kappa-B (NF-B) pathway in glioblastoma cell ferroptosis has not yet been investigated. Therefore, we aimed to clarify the underlying mechanism of the NF-B pathway in RSL3-induced ferroptosis in glioblastoma cells. We found that RSL3 led to an increase in lipid ROS concentration and downregulation of ferroptosis-related proteins such as GPX4, ATF4, and SLC7A11 (xCT) in glioblastoma cells. Additionally, the NF-B pathway was activated by RSL3, and its inhibition by BAY 11-7082 could alleviate ferroptosis. The murine xenograft tumor model indicated that NF-B pathway inhibition could mitigate the antitumor effects of RSL3 . Furthermore, we found that GPX4 knockdown could not effectively induce ferroptosis. However, NF-B pathway activation coupled with GPX4 silencing induced ferroptosis. Additionally, ATF4 and xCT expression might be regulated by the NF-B pathway. Collectively, our results revealed that the NF-B pathway plays a novel role in RSL3-induced ferroptosis in glioblastoma cells and provides a new therapeutic strategy for glioblastoma treatment.
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http://dx.doi.org/10.1155/2021/2915019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720588PMC
March 2022

Characterization of Two Ferroptosis Subtypes With Distinct Immune Infiltration and Gender Difference in Gastric Cancer.

Front Nutr 2021 16;8:756193. Epub 2021 Dec 16.

Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Iron is an essential nutrient involved in the redox cycle and the formation of free radicals. The reprogramming of iron metabolism is the main link to tumor cell survival. Ferroptosis is an iron-dependent form of regulated cell death associated with cancer; the characteristics of ferroptosis in cancers are still uncertain. This study aimed to explore the application value and gender difference of ferroptosis in prognosis and immune prediction to provide clues for targeted therapy of gastric cancer. We comprehensively evaluated the ferroptosis levels of 1,404 gastric cancer samples from six independent GC cohorts based on ferroptosis-related specific genes and systematically correlated ferroptosis with immune cell infiltrating and gender characteristics. The ferroptosis score was constructed to quantify the ferroptosis levels of individual tumors using principal component analysis (PCA) algorithms. We identified two distinct ferroptosis subtypes in gastric cancer, namely Subtype-A and Subtype-B. We found that male patients in Subtype-B had the worst prognosis in contrast with the other groups. Three sex hormone receptors (AR, ER, and PR) in Subtype-B tumor patients were higher than in Subtype-A tumor patients in GC, while the HER2 displayed an opposite trend. We developed a risk model termed ferroptosis score to evaluate ferroptosis levels within individual tumors. The low-ferroptosis score group was characterized by activation of immune cells and increased mutation burden, which is also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. The patients with a low-ferroptosis score showed a high microsatellite instability status (MSI-H) and had a higher response to immunotherapy. Furthermore, the patients with low-ferroptosis scores have a lower estimated IC50 in the several chemotherapy drugs, including paclitaxel, gemcitabine, and methotrexate. We revealed that sex hormone receptors and immune cell infiltration were markedly different between ferroptosis subtypes in GC patients. The results suggested that gender difference may be critical when the ferroptosis-related strategy is applied in GC treatment. Further, ferroptosis levels were identified with an extreme variety of prognosis and tumor immune characteristics, which might benefit GC individualized treatment.
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http://dx.doi.org/10.3389/fnut.2021.756193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716917PMC
December 2021

RNA-Seq Identification of Cd Responsive Transporters Provides Insights into the Association of Oxidation Resistance and Cd Accumulation in L.

Antioxidants (Basel) 2021 Dec 10;10(12). Epub 2021 Dec 10.

Collaborative Innovation Center for Efficient and Green Production of Agriculture in Mountainous Areas of Zhejiang Province, College of Horticulture Science, Zhejiang Agriculture and Forestry University, Hangzhou 311300, China.

Greenhouse vegetable production (GVP) has grown rapidly and has become a major force for cucumber production in China. In highly intensive GVP systems, excessive fertilization results in soil acidification, increasing Cd accumulation and oxidative stress damage in vegetables as well as increasing health risk of vegetable consumers. Therefore, enhancing antioxidant capacity and activating the expression level of Cd transporter genes seem to be feasible solutions to promote plant resistance to Cd stress and to reduce accumulated Cd concentration. Here, we used transcriptomics to identify five cucumber transporter genes (CsNRAMP1, CsNRAMP4, CsHMA1, CsZIP1, and CsZIP8) in response to cadmium stress, which were involved in Cd transport activity in yeast. Ionomics, gene expression, and REDOX reaction level association analyses have shown that the transcript of CsNRAMP4 was positively correlated with Cd accumulation and antioxidant capacity of cucumber roots. The expression level of CsHMA1 was negatively correlated with Cd-induced antioxidant capacity. The overexpression of CsHMA1 significantly relieved Cd stress-induced antioxidant activities. In addition, shoots with high CsHMA2 expression remarkably presented Cd bioaccumulation. Grafting experiments confirmed that CsHMA1 contributed to the high antioxidant capacity of cucumber, while CsHMA2 was responsible for the transport of Cd from the roots to the shoots. Our study elucidated a novel regulatory mechanism for Cd transport and oxidative damage removal in horticultural melons and provided a perspective to regulate Cd transport artificially by modulating Cd accumulation and resistance in plants.
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http://dx.doi.org/10.3390/antiox10121973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750378PMC
December 2021

Genome-wide association and functional interrogation identified a variant at 3p26.1 modulating ovarian cancer survival among Chinese women.

Cell Discov 2021 Dec 21;7(1):121. Epub 2021 Dec 21.

Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.

Ovarian cancer survival varies considerably among patients, to which germline variation may also contribute in addition to mutational signatures. To identify genetic markers modulating ovarian cancer outcome, we performed a genome-wide association study in 2130 Chinese ovarian cancer patients and found a hitherto unrecognized locus at 3p26.1 to be associated with the overall survival (P = 8.90 × 10). Subsequent statistical fine-mapping, functional annotation, and eQTL mapping prioritized a likely casual SNP rs9311399 in the non-coding regulatory region. Mechanistically, rs9311399 altered its enhancer activity through an allele-specific transcription factor binding and a long-range interaction with the promoter of a lncRNA BHLHE40-AS1. Deletion of the rs9311399-associated enhancer resulted in expression changes in several oncogenic signaling pathway genes and a decrease in tumor growth. Thus, we have identified a novel genetic locus that is associated with ovarian cancer survival possibly through a long-range gene regulation of oncogenic pathways.
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http://dx.doi.org/10.1038/s41421-021-00342-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688503PMC
December 2021

Hyperconnectivity Associated with Anosognosia Accelerating Clinical Progression in Amnestic Mild Cognitive Impairment.

ACS Chem Neurosci 2022 01 18;13(1):120-133. Epub 2021 Dec 18.

Institute of Neuropsychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.

The incidence and prevalence of anosognosia are highly variable in amnestic mild cognitive impairment (aMCI) patients. The study aims to explore the neuropathological mechanism of anosognosia in aMCI patients using two different but complementary technologies, including F-flortaucipir positron emission tomography and resting state functional magnetic resonance imaging. The study found that anosognosia was related to higher tau accumulation in the left medial orbitofrontal cortex (OFC), left posterior cingulate cortex, and right precuneus in aMCI patients. Intrinsic functional connectivity analyses found significant correlations between anosognosia index and hypoconnectivity between the left medial OFC and left middle temporal gyrus (MTG), right precuneus and left lingual gyrus. Longitudinally, the connectivity of these brain regions as well as the right precuneus and right cuneus showed hyperconnectivity in aMCI patients with anosognosia. The anosognosia index was also correlated with AD pathological markers (i.e., Aβ, t-tau, and p-tau) and brain glucose metabolism in aMCI patients. In conclusion, anosognosia in aMCI patients is associated with the dysfunction of medial OFC-MTG circuit and the precuneus-visual cortex circuit and accelerates clinical progression to AD dementia.
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http://dx.doi.org/10.1021/acschemneuro.1c00595DOI Listing
January 2022

Identification of an m6A Regulators-Mediated Prognosis Signature For Survival Prediction and Its Relevance to Immune Infiltration in Melanoma.

Front Cell Dev Biol 2021 25;9:718912. Epub 2021 Nov 25.

Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Key Laboratory of Molecular Cancer Epidemiology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Despite robust evidence for the role of m6A in cancer development and progression, its association with immune infiltration and survival outcomes in melanoma remains obscure. Here, we aimed to develop an m6A-related risk signature to improve prognostic and immunotherapy responder prediction performance in the context of melanoma. We comprehensively analyzed the m6A cluster and immune infiltration phenotypes of public datasets. The TCGA ( = 457) and eleven independent melanoma cohorts ( = 758) were used as the training and validation datasets, respectively. We identified two m6A clusters (m6A-clusterA and m6A-clusterB) based on the expression pattern of m6A regulators unsupervised consensus clustering. (7.49%), (7.06%), and (4.28%) were the three most frequently mutated genes. There was a correlation between driver genes mutation statuses and the expression of m6A regulators. A significant difference in tumor-associated immune infiltration between two m6A clusters was detected. Compared with m6A-clusterA, the m6A-clusterB was characterized by a lower immune score and immune cell infiltration but higher mRNA expression-based stemness index (mRNAsi). An m6A-related risk signature consisting of 12 genes was determined via Cox regression analysis and divided the patients into low- and high-risk groups (). A nomogram was developed for the prediction of the survival rate. Compared with the high-risk group, the low-risk group was characterized by high expression of immune checkpoints and immunophenoscore (IPS), activation of immune-related pathways, and more enriched in immune cell infiltrations. The low-risk group had a favorable prognosis and contained the potential beneficiaries of the immune checkpoint blockade therapy and verified by the IMvigor210 cohort ( = 298). The m6A-related signature we have determined in melanoma highlights the relationships between m6A regulators and immune cell infiltration. The established risk signature was identified as a promising clinical biomarker of melanoma.
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http://dx.doi.org/10.3389/fcell.2021.718912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656227PMC
November 2021

A receptor-like cytoplasmic kinase PCRK2 undergoes ubiquitination and proteasomal degradation.

Biochem Biophys Res Commun 2022 01 27;587:113-118. Epub 2021 Nov 27.

Center for Agricultural Resources Research, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Shijiazhuang, Hebei, 050021, China. Electronic address:

Receptor-like cytoplasmic kinase (RLCK) subfamily VII members are involved in diverse biological processes, like reproduction, immunity, growth and development. Ubiquitination and proteasomal degradation of a RLCK VII member, BOTRYTIS-INDUCED KINASE1 (BIK1) play important roles in regulating immune signaling. It remains largely unknown whether most other RLCK VII members undergo ubiquitination and proteasomal degradation. Here, we select the 6-member RLCK VII-4 to examine the potential proteasomal degradation of its members. We find that three closely related RLCK VII-4 members, PBL38 (AvrPphB SUSCEPTIBLE1-LIKE38), PCRK1 (PTI-COMPROMISED RECEPTOR-LIKE CYTOPLASMIC KINASE1), and PCRK2 are under proteasomal control, while the other members in this group are not. Moreover, we demonstrate that PCRK2 undergoes ubiquitination and proteasomal in a kinase activity-dependent manner. However, the plasma membrane (PM) localization of PCRK2 is not required for its degradation. Our work suggests that many other RLCK VII members may undergo ubiquitination and proteasomal degradation to modulate their homeostasis and cellular functions.
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http://dx.doi.org/10.1016/j.bbrc.2021.11.094DOI Listing
January 2022
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