Tumor burden affects the progression pattern on the prognosis in patients treated with sorafenib.

The progression pattern of tumors has an impact on the survival of patients with advanced hepatocellular carcinoma (HCC) and has been applied in the design of clinical trials for multiple second-line drugs. Previous research results have been contradictory, and the clinical impact of different progression patterns and their role in survival are still in question. Purpose: The study aims to analyze the impact of different progression patterns and tumor burden size on survival of HCC patients, as well as their interactions, through a retrospective cohort study. Patients and methods: The study involved 538 patients who had undergone treatment with sorafenib and had shown radiographic progression. The progression pattern was analyzed using Cox regression by including an interaction term between progression pattern and tumor burden, which was then visualized through a graphical analysis. Tumor burden was categorized into low, medium, and high subgroups based on the six-and-twelve criteria, allowing for an exploration of the effect of progression pattern on survival in different tumor burden situations. Results: Compared to patients with only intrahepatic progression (NIH/IHG) with an overall survival (OS) of 14.1/19.9 months and post-progression survival (PPS) of 8.1/13.1 months respectively, patients with extrahepatic lesions (NEH/EHG) had worse overall and postprogressive survival (OS: 9.3/9.2 months, PPS: 4.9/5.1 months). The hazard ratio for extrahepatic progression (NEH/EHG) compared to intrahepatic progression (NIH/IHG) at low, medium, and high tumor burden were [HR 2.729, 95%CI 1.189-6.263], [HR 1.755, 95%CI 1.269-2.427], and [HR 1.117, 95%CI 0.832-1.499], respectively. Conclusion: The study concluded that the interaction between the tumor progression patterns and tumor burden significantly affects the prognosis of HCC patients. As the tumor burden increases, the sensitivity of the patient's risk of death to the progression pattern decreases. These findings are valuable in personalized treatment and trial design.

Temperature and nutrients drive distinct successions between diatoms and dinoflagellates over the past 40 years: Implications for climate warming and eutrophication.

Diatoms and dinoflagellates are two typical functional groups of phytoplankton, playing important roles in ecosystem processes and biogeochemical cycles. Changes in diatoms and dinoflagellates are thought to be one of the possible mechanisms for the increase in harmful algal blooms (HABs), due to changing hydrological conditions associated with climate change and human activities. However, little is known about their ability to adapt to changing ocean environments, thus making it difficult to know whether and how they are adapting. By analyzing a 44-year monitoring dataset in the central Bohai Sea during 1978-2021, we found that the abundance ratio of diatoms to dinoflagellates showed a decreasing trend seasonally and ecologically, indicating that the phytoplankton community underwent distinct successional processes from diatom dominance to diatom-dinoflagellate co-dominance. These processes exhibited varying responses to temperature, nutrient concentrations and ratios, and their interactions, of which temperature primarily drove the seasonal succession whereas nutrients were responsible for the ecological succession. Specifically, diatoms showed a preference for lower temperatures and higher DIP concentrations, and were able to tolerate lower DIN at lower temperatures. In contrast, dinoflagellates tended to prevail at conditions of warming and high N/P ratios. These different traits of diatoms and dinoflagellates reflected the fact that warming as a result of rising temperature and eutrophication as a consequence of nutrient input would favor dinoflagellates over diatoms. Moreover, the increasing dominance of dinoflagellates indicated that dinoflagellate blooms were likely to become more frequent and intense in the central Bohai Sea.

Polyvinyl Chloride-Based Luminescent Downshifting Film with High Flame Retardancy and Excellent UV Resistance for Silicon Solar Cells.

Solar power generation, as a clean energy source, has significant potential for development. This work reports the recent efforts to address the challenge of low power conversion efficiency in photovoltaic devices by proposing the fabrication of a luminescence downshifting layer using polyvinyl chloride (PVC) with added fluorescent dots to enhance light utilization. A photoluminescent microsphere (HCPAM) is synthesized by cross-linking hexachlorocyclotriphosphazene, 2-iminobenzimidazoline, and polyethyleneimine. Low addition of HCPAM can improve the fire safety of PVC films, raising the limiting oxygen index of PVC to 32.4% and reducing the total heat release and smoke production rate values by 14.5% and 42.9%, respectively. Additionally, modified PVC film remains a transparency of 88% and shows down-conversion light properties. When the PVC+1%HCPAM film is applied to the solar cell, the short-circuit current density increases from 42.3 to 43.8 mA cm-2, resulting in a 7.0% enhancement in power conversion efficiency. HCPAM also effectively delays the photooxidative aging of PVC, particularly at a 3% content, maintaining the surface morphology and optical properties of PVC samples during ultraviolet aging. This study offers an innovative strategy to enhance the fire and UV-resistant performance of PVC films and expand their applications in protecting and efficiently utilizing photovoltaic devices.

Genetic Screening of Patients with Sporadic Alzheimer's Disease and Frontotemporal Lobar Degeneration in the Chinese Population.

Background: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.

Distinct virtual histology of grey matter atrophy in four neuroinflammatory diseases.

Gray matter (GM) atrophies were observed in multiple sclerosis, neuromyelitis optica spectrum disorders (both anti-aquaporin-4 antibody-positive [AQP4+], and -negative [AQP4-] subtypes NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicenter cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD, and 2,169 healthy controls (HCs). First, interregional GM atrophy profiles across the cortical and subcortical regions were determined by Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, MOGAD and HCs. Then, the GM atrophy profiles were spatially correlated with the gene expressions extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical feature relevant GM atrophy by subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden, and cognitive function. Multiple sclerosis showed severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed obvious widespread GM atrophy pattern, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes, and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD had spatial correlations with GM atrophy profiles were observed, while no atrophy profile related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature relevant GM atrophy mainly pointed to the shared neuronal and endothelial cells among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes, and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings might help their differential diagnosis and optimal therapeutic strategies.

Expression of genes related to gonadal development and construction of gonadal DNA methylation maps of Trachinotus blochii under hypoxia.

Chronic hypoxia can affect the growth and metabolism of fish and potentially impact gonadal development through epigenetic regulation. Trachinotus blochii (Golden pompano) is widely cultured near the coast and is sensitive to low oxygen conditions. We found that hypoxia and reoxygenation processes acted on multiple targets on the HPG axis, leading to endocrine disorders. Changes in the expression of key genes in the brain (gnrh), pituitary (fsh and lh), ovaries (cyp19a1a, foxl2, and er), and testes (dmrt1, ar, sox9, and gsdf) were associated with significant decreases in estrogen and testosterone levels. Hypoxia and reoxygenation lead to changes in DNA methylation levels in the gonads. Hypoxia upregulated the expression of dnmt1, dnmt3a, dnmt3b, tet1, and tet2 in females and dnmt3a and dnmt3b in males, while reoxygenation down-regulated the expression of dnmt1, dnmt3a, dnmt3b, tet1, and tet2 in males. Whole genome methylation sequencing showed that the number of differentially methylated regions was highest on chromosome 10 (5192) and lowest on chromosome 24 (275). Differentially methylated genes in females and males, as well as between males and females, were enriched in the oxytocin signaling pathway, fatty acid metabolism pathway, and HIF-1a pathway. In summary, hypoxia and reoxygenation can induce endocrine disorders, affect the expression of HPG axis genes, change the methylation pattern and modification pattern of gonad DNA, and then have potential effects on gonad development.

The role of NF-κB in carcinogenesis of cervical cancer: opportunities and challenges.

The nuclear factor-κB (NF-κB) family, consisting of several transcription factors, has been implicated in the regulation of cell proliferation and invasion, as well as inflammatory reactions and tumor development. Cervical cancer (CC) results from long-term interactions of multiple factors, among which persistent high-risk human papillomavirus (hrHPV) infection is necessary. During different stages from early to late after HPV infection, the activity of NF-κB varies and plays various roles in carcinogenesis and progress of CC. As the center of the cell signaling transduction network, NF-κB can be activated through classical and non-classical pathways, and regulate the expression of downstream target genes involved in regulating the tumor microenvironment and acquiring hallmark traits of CC cells. Targeting NF-κB may help treat CC and overcome the resistance to radiation and chemotherapy. Even though NF-κB inhibitors have not been applied in clinical treatment as yet, due to limitations such as dose-restrictive toxicity and poor tumor-specificity, it is still considered to have significant therapeutic potential and application prospects. In this review, we focus on the role of NF-κB in the process of CC occurrence and hallmark capabilities acquisition. Finally, we summarize relevant NF-κB-targeted treatments, providing ideas for the prevention and treatment of CC.

Dose-response relationship between 15 weeks of running and aerobic fitness: a retrospective analysis based on the fun running program.

BACKGROUND: Students' physical fitness, particularly aerobic fitness, has seriously declined during the COVID-19 epidemic. However, in the post-epidemic era, there are few studies on the methods of improving aerobic fitness. Understanding the dose-response relationship between physical activity and aerobic fitness is crucial for developing effective exercise prescriptions. METHOD: This retrospective study reviewed the Fun Running program at Wannan Medical College in China. We conducted a pre-post study design to analyze the impact of 15 weeks of Fun Running training on aerobic fitness. Middle and long-distance running pace (MLDR-P) was used as the primary indicator of aerobic fitness. A paired sample T-test was used to analyze the differences between the two MLDR-Ps. Pearson's correlation was used to examine the correlation between variables. Multiple linear regression was used to determine the extent to which Fun Running components explain the variance in MLDR-P. RESULTS: A total of 3244 college students participated in this study. 15 weeks of Fun Running training can significantly improve the MLDR-P in both females (P < 0.001, ES = 0.68) and males (P < 0.001, ES = 0.72). The MLDR-P was significantly correlated with Fun Running (R2 = 0.95, p < 0.05, for females; R2 = 0.96, p < 0.05, for males). The component that had the greatest impact on MLDR-P was pace (ß = 1.39, for females; ß = 1.09, for males), followed by distance (ß = 0.49, for females; ß = 0.15, for males), and last frequency (ß = -0.03, for all). CONCLUSION: This study fills the gap in research on the dose-response relationship between running and aerobic fitness among college students in the post-epidemic era. The results show that 15 weeks of Fun Running training can significantly improve aerobic fitness. Examination of the dose-response relationship between Fun Running and MLDR-P provides practitioners with valuable insights into prescribing aerobic fitness training, allowing them to develop more effective training programs. Future research should focus on how to implement a hierarchical Fun Running program effectively.

Cryo-EM structures of adenosine receptor A3AR bound to selective agonists.

The adenosine A3 receptor (A3AR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective A3AR agonists, CF101 and CF102, are clinically significant, yet their recognition mechanisms remained elusive. Here we report the cryogenic electron microscopy structures of the full-length human A3AR bound to CF101 and CF102 with heterotrimeric Gi protein in complex at 3.3-3.2 Å resolution. These agonists reside in the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal the critical role of extracellular loop 3 in A3AR's ligand selectivity and receptor activation. Key mutations, including His3.37, Ser5.42, and Ser6.52, in a unique sub-pocket of A3AR, significantly impact receptor activation. Comparative analysis with the inactive A2AAR structure highlights a conserved receptor activation mechanism. Our findings provide comprehensive insights into the molecular recognition and signaling of A3AR, paving the way for designing subtype-selective adenosine receptor ligands.

Effect of Histamine H2 Receptor Antagonists on All-Cause Mortality in Critically Ill Patients With Essential Hypertension: A Retrospective Cohort Study.

Previous studies found that histamine H2 receptor antagonists (H2RAs) had blood pressure lowering and cardioprotective effects, but the impact of H2RAs on the survival outcomes of critically ill patients with essential hypertension is still unclear. The aim of this study was to investigate the association of H2RAs exposure with all-cause mortality in patients with essential hypertension based on Medical Information Mart for Intensive Care III database. A total of 17,739 patients were included, involving 8482 H2RAs users and 9257 non-H2RAs users. Propensity score matching (PSM) was performed to improve balance between 2 groups that were exposed to H2RAs or not. Kaplan-Meier survival curves were used to compare the cumulative survival rates and multivariable Cox regression models were performed to evaluate the association between H2RAs exposure and all-cause mortality. After 1:1 PSM, 4416 pairs of patients were enrolled. The results revealed potentially significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortalities in multivariate analyses (HR = 0.783, 95% CI: 0.696-0.882 for 30-day; HR = 0.860, 95% CI: 0.778-0.950 for 90-day; and HR = 0.883, 95% CI: 0.811-0.961 for 1-year mortality, respectively). Covariate effect analyses showed that the use of H2RAs was more beneficial in essential hypertension patients with age ≥ 60, BMI ≥ 25 kg/m2, coronary arteriosclerosis, stroke, and acute kidney failure, respectively. In conclusion, H2RAs exposure was related to lower mortalities in critically ill patients with essential hypertension, which provided novel potential strategy for the use of H2RAs in essential hypertension patients.

Revealing Na+-coordination Induced Failure Mechanism of Metal Sulfide Anode for Sodium Ion Batteries.

Metal sulfide (MS) is regarded as a promising candidate of the anode materials for sodium-ion battery (SIB) with ideal capacity and low cost, yet still suffers from the inferior cycling stability and voltage degradation. Herein, the coordination relationship between the discharge product Na2S with the Na+ (NaPF6) in the electrolyte, is revealed as the root cause for the cycling failure of MS. Na+-coordination effect assistants the dissolution of Na2S, further delocalizing Na2S from the reaction interface under the function of electric field, which leads to the solo oxidation of the discharge product element metal without the participation of Na2S. Besides, the higher highest occupied molecular orbital of Na2S suggest the facilitated Na2S solo oxidation to produce sodium polysulfides (NaPSs). Based on these, lowering the Na+ concentration of the electrolyte is proposed as a potential improvement strategy to change the coordination environment of Na2S, suppressing the side reactions of the solo-oxidation of element metal and Na2S. Consequently, the enhanced conversion reaction reversibility and prolonged cycle life are achieved. This work renders in-depth perception of failure mechanism and inspiration for realizing advanced conversion-type anode.

Comparative effects of three different physical education teaching modes on college students' physical fitness during the COVID-19 pandemic: A longitudinal study.

Background: An appropriate teaching mode in physical education is crucial for ensuring effective education outcomes. Given the dynamic nature of the COVID-19 pandemic, teaching modes are often adjusted. However, there is a lack of in-depth research on the impact of different teaching modes on the outcomes of physical education. Our study aims to address this gap by conducting a comparative analysis of the teaching effectiveness of three different physical education modes among Chinese college students, with a focus on evaluating their impact on physical fitness. Method: This study adopted a longitudinal retrospective observational design. We systematically examined the three stages of the COVID-19 pandemic (stage 1: September 2020 to January 2021; stage 2: September 2021 to January 2022 and stage 3: February 2022 to July 2022), along with the three corresponding physical education teaching modes (classroom teaching, online teaching and blended teaching) and administered three physical fitness tests (T1, T2 and T3). The physical fitness test included 7 indicators: body mass index, vital capacity, 50-m run, standing long jump, sit-and-reach, pull-ups (male), 1000-m run (male), sit-ups (female) and 800-m run (female). A mixed ANOVA model was used to analyse the physical fitness test indicators across the three different teaching modes. Results: A total of 3363 college students (1616 males and 1747 females) enrolled in 2020 completed the three physical fitness tests. Most students were aged between 17 and 20 years old, and the BMI criteria indicated a normal distribution. The results indicated that there were significant differences in the overall training effectiveness for all students across vital capacity (p < 0.001, η2 = 0.077), sit-and-reach (p < 0.001, η2 = 0.027), and middle and long-distance running (p < 0.001, η2 = 0.031). Post-hoc multiple comparison analyses further revealed that the blended teaching was the most effective in improving these fitness indicators, whereas the online teaching performed poorly on the training effects of middle and long-distance running. Significant training effects were also shown for sit-ups (p < 0.001, η2 = 0.192) for females and pull-ups (p < 0.001, η2 = 0.020) for males in gender-specific physical fitness indicators. Similarly, blended teaching showed superior results to other teaching modes. Conclusion: These findings emphasize the importance of conducting online physical education during unforeseen public health events and highlight the comprehensive effects of blended physical education in the post-pandemic era. Future initiatives should prioritize targeted interventions to address the observed variations in various physical fitness indicators under different physical education teaching models.

The 'Candidatus phytoplasma ziziphi' effectors SJP1 and SJP2 destabilise the bifunctional regulator ZjTCP7 to modulate floral transition and shoot branching.

Phytoplasmic SAP11 effectors alter host plant architecture and flowering time. However, the exact mechanisms have yet to be elucidated. Two SAP11-like effectors, SJP1 and SJP2, from 'Candidatus Phytoplasma ziziphi' induce shoot branching proliferation. Here, the transcription factor ZjTCP7 was identified as a central target of these two effectors to regulate floral transition and shoot branching. Ectopic expression of ZjTCP7 resulted in enhanced bolting and earlier flowering than did the control. Interaction and expression assays demonstrated that ZjTCP7 interacted with the ZjFT-ZjFD module, thereby enhancing the ability of these genes to directly bind to the ZjAP1 promoter. The effectors SJP1 and SJP2 unravelled the florigen activation complex by specifically destabilising ZjTCP7 and ZjFD to delay floral initiation. Moreover, the shoot branching of the ZjTCP7-SRDX transgenic Arabidopsis lines were comparable to those of the SJP1/2 lines, suggesting the involvement of ZjTCP7 in the regulation of shoot branching. ZjTCP7 interacted with the branching repressor ZjBRC1 to enhance suppression of the auxin efflux carrier ZjPIN3 expression. ZjTCP7 also directly bound to and upregulated the auxin biosynthesis gene ZjYUCCA2, thereby promoting auxin accumulation. Our findings confirm that ZjTCP7 serves as a bifunctional regulator destabilised by the effectors SJP1 and SJP2 to modulate plant development.

Multilocular thymic cysts can be easily misdiagnosed as malignant tumor on computer tomography: A case report.

BACKGROUND: Multilocular thymic cyst (MTC) is a rare mediastinal lesion which is considered to occur in the process of acquired inflammation. It is usually characterized by well-defined cystic density and is filled with transparent liquid. CASE SUMMARY: We report on a 39-year-old male with a cystic-solid mass in the anterior mediastinum. Computer tomography (CT) imaging showed that the mass was irregular with unclear boundaries. After injection of contrast agent, there was a slight enhancement of stripes and nodules. According to CT findings, it was diagnosed as thymic cancer. CONCLUSION: After surgery, MTC accompanied by bleeding and infection was confirmed by pathological examination. The main lesson of this case was that malignant thymic tumor and MTC of the anterior mediastinum sometimes exhibit similar CT findings. Caution is necessary in clinical work to avoid misdiagnosis.

The PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation.

CCCTC-binding factor (CTCF), a ubiquitously expressed and highly conserved protein, is known to play a critical role in chromatin structure. Post-translational modifications (PTMs) diversify the functions of protein to regulate numerous cellular processes. However, the effects of PTMs on the genome-wide binding of CTCF and the organization of three-dimensional (3D) chromatin structure have not been fully understood. In this study, we uncovered the PTM profiling of CTCF and demonstrated that CTCF can be O-GlcNAcylated and arginine methylated. Functionally, we demonstrated that O-GlcNAcylation inhibits CTCF binding to chromatin. Meanwhile, deficiency of CTCF O-GlcNAcylation results in the disruption of loop domains and the alteration of chromatin loops associated with cellular development. Furthermore, the deficiency of CTCF O-GlcNAcylation increases the expression of developmental genes and negatively regulates maintenance and establishment of stem cell pluripotency. In conclusion, these results provide key insights into the role of PTMs for the 3D chromatin structure.

Design and Synthesis of C4-Symmetric Axially Chiral ß-Aryl Porphyrins and Application for Supporting Ir(III)-Catalyzed Enantioselective C-H Alkylation.

A hitherto unknown class of C4-symmetric Caryl-Cß (C3, C8, C13, C18) axially chiral porphyrins has been synthesized and the application of their iridium (Ir) complexes in catalytic asymmetric C(sp3)-H functionalization is documented. Cyclotetramerization of enantioenriched axially chiral 2-hydroxymethyl-3-naphthyl pyrroles under mild acidic conditions affords, after oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the C4-symmetric α,α,α,α-atropenantiomer as an only isolable diastereomer. Both regioisomeric Ir(Por*)(CO)(Cl) complexes catalyze the carbene C-H insertion reaction affording the same enantiomer, albeit with slight difference in enantioselectivity. With the optimum Ir-complex 3e, the 2-substituted arylacetic acid derivatives were generated from diazo compounds and cyclohexadiene in excellent yields and enantioselectivities.

Regioselective synthesis of isoquinolinonediones through remote unactivated C(sp3)-H bonds.

Herein, a general strategy for the remote-site-selective cascade addition/cyclization of unactivated C(sp3)-H bonds in free alcohols and sulfonamides to build isoquinolinonedione skeletons is developed. The site selectivity occurs predominantly via a 1,5-hydrogen atom transfer (HAT) process, triggered by heteroatom-centred radicals generated directly under silver catalysis. A broad substrate scope and excellent regio-/chemo-selective control are demonstrated in this method.

Establishment and characterization of a golden pompano (Trachinotus blochii) fin cell line for applications in marine fish pathogen immunology.

Pompano fishes have been widely farmed worldwide. As a representative commercial marine species of the Carangidae family, the golden pompano (Trachinotus blochii) has gained significant popularity in China and worldwide. However, because of rapid growth and high-density aquaculture, the golden pompano has become seriously threatened by various diseases. Cell lines are the most cost-effective resource for in vitro studies and are widely used for physiological and pathological research owing to their accessibility and convenience. In this study, we established a novel immortal cell line, GPF (Golden pompano fin cells). GPF has been passaged over 69 generations for 10 months. The morphology, adhesion and extension processes of GPF were evaluated using light and electron microscopy. GPF cells were passaged every 3 days with L-15 containing 20 % fetal bovine serum (FBS) at 1:3. The optimum conditions for GPF growth were 28 °C and a 20 % FBS concentration. DNA sequencing of 18S rRNA and mitochondrial 16S rRNA confirmed that GPF was derived from the golden pompano. Chromosomal analysis revealed that the number pattern of GPF was 48 chromosomes. Transfection experiments demonstrated that GPF could be utilized to express foreign genes. Furthermore, heavy metals (Cd, Cu, and Fe) exhibited dose-dependent cytotoxicity against GPF. After polyinosinic-polycytidylic acid (poly I:C) treatment, transcription of the retinoic acid-inducible gene I-like receptor (RLR) pathway genes, including mda5, mita, tbk1, irf3, and irf7 increased, inducing the expression of interferon (IFN) and anti-viral proteins in GPF cells. In addition, lipopolysaccharide (LPS) stimulation up-regulated the expression of inflammation-related factors, including myd88, irak1, nfκb, il1ß, il6, and cxcl10 expression. To the best of our knowledge, this is the first study on the immune response signaling pathways of the golden pompano using an established fin cell line. In this study, we describe a preliminary investigation of the GPF cell line immune response to poly I:C and LPS, and provide a more rapid and efficient experimental material for research on marine fish immunology.

Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity.

An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells.

TIN2-mediated reduction of mitophagy induces RPE senescence under high glucose.

The telomere-associated protein TIN2 localizes to both telomeres and mitochondria. Nevertheless, the impact of TIN2 on retinal pigment epithelial (RPE) cells in diabetic retinopathy (DR) remains unclear. This research aims to examine the role of TIN2 in the senescence of RPE and its potential as a therapeutic target. Western blotting and immunofluorescence staining were utilized to identify TIN2 expression and mitophagy. RT-qPCR was employed to identify senescent associated secretory phenotype (SASP) in ARPE-19 cells infected with TIN2 overexpression. To examine mitochondria and the cellular senescence of RPE, TEM, SA-ß-gal staining, and cell cycle analysis were used. The impact of TIN2 was examined using OCT and immunohistochemistry in mice. DHE staining and ZO-1 immunofluorescence were applied to detect RPE oxidative stress and tight junctions. Our research revealed that increased mitochondria-localized TIN2 aggravated the cellular senescence of RPE cells both in vivo and in vitro under hyperglycemia. TIN2 overexpression stimulated the mTOR signaling pathway in ARPE-19 cells and exacerbated the inhibition of mitophagy levels under high glucose, which can be remedied through the mTOR inhibitor, rapamycin. Knockdown of TIN2 significantly reduced senescence and mitochondrial oxidative stress in ARPE-19 cells under high glucose and restored retinal thickness and RPE cell tight junctions in DR mice. Our study indicates that increased mitochondria-localized TIN2 induced cellular senescence in RPE via compromised mitophagy and activated mTOR signaling. These results propose that targeting TIN2 could potentially serve as a therapeutic strategy in the treatment of DR.