Signalling by senescent melanocytes hyperactivates hair growth.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

Growth inhibition of subcutaneous tumor with glioma cells in nude mice by silencing TLR4.

This study investigated the regulatory impact of Toll-like receptor 4 (TLR4) gene on glioma cell proliferation and apoptosis, elucidating the molecular mechanisms underlying TLR4-induced growth inhibition in vivo. U-87MG-Sh and U-87MG-NC cells, with silenced TLR4 and negative control plasmid respectively, were established. Eighteen nude mice, divided into transfection, negative control, and blank control groups, were inoculated with corresponding cells. Over four weeks, the transfection group exhibited significantly reduced tumor growth rates, smaller mass and volume, and lower growth activity compared to controls. Histological analysis revealed sparse tumor cells, increased fibrous connective tissue, and slower angiogenesis in the transfection group. Flow cytometry demonstrated a lower proliferation index and increased G0/1 cell count in the transfection group. mRNA levels of TLR4, NF-κB, and CyclinD1 were significantly lower in the transfection group. TLR4 silencing correlated with U-87MG cell proliferation regulation, growth inhibition, NF-κB and CyclinD1 modulation, and induction of cell cycle arrest and apoptosis. These findings suggest TLR4 as a potential gene therapy target for glioma.

Current status and influencing factors of policy identification in health impact assessment: a case study of Zhejiang Province.

BACKGROUND: Health impact assessment (HIA) is a procedure, method and tool for evaluating the potential health impacts of policies, plans and construction projects, as well as the distribution of these impacts on population. Majority of international studies on health impact assessment have focussed on conceptual papers or case evaluations, neglecting participants' views on policies. METHODS: A semi-structured interview with 30 health impact assessment experts was employed in this study, and the Nvivo software was utilized to analyse factors that influence policy identification. Subsequently, a multi-stage stratified random sampling method was adopted to survey 655 pilot staff members involved in health impact assessment in Zhejiang Province. Descriptive statistics were used to describe the current status and identify the factors influencing policy identification. In addition, hierarchical linear regression analysis and structural equation modelling were employed to determine the relationship between policy identification and influencing factors. RESULTS: Statistically significant differences were found among participants in the level of identification of policies across three dimensions. The policy sentiment dimension had the highest score (4.137 ± 0.664), followed by policy cognition (4.075 ± 0.632) and policy evaluation (3.631 ± 0.797) dimensions. Subject trust had a positive impact on policy cognition (ß = 0.503, P < 0.001), policy sentiment (ß = 0.504, P < 0.001) and policy evaluation (ß = 0.465, P < 0.001). Procedural justice had a positive impact on policy sentiment (ß = 0.085, P < 0.01) and policy evaluation (ß = 0.084, P < 0.05), but not policy cognition (ß = 0.056, P > 0.05). Policy identification is influenced by age and average monthly salary among other factors. CONCLUSION: These results highlight the importance of subjective trust and procedural justice in policy identification of health impact assessment. They provide valuable insights to developing interventions to overcome barriers to the implementation and enhancement of global identification of policies. Going forward, cross-sectoral synergies, enhanced international communication and training to increase participants' trust in the policy should be optimized to improve health impact assessment. Additional measures should be taken, such as ensuring seamless communication channels, embedding health impact assessment in administrative mechanisms, and establishing strong oversight and grievance mechanisms to improve fairness and transparency in the implementation and results of health impact assessment.

Genetics of progressive supranuclear palsy in a Chinese population.

BACKGROUND: Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled. METHODS: Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP. RESULTS: A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10-3, p = 4.98 × 10-4). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group. CONCLUSIONS: The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.

Research progress of omics technology in the field of tumor resistance: From single-omics to multi-omics combination application. / ç»„å­¦æŠ€æœ¯åœ¨è‚¿ç˜¤è€è¯é¢†åŸŸçš„ç ”ç©¶è¿›å±•ï¼šä»Žå•ç»„å­¦åˆ°å¤šç»„å­¦è”åˆåº”ç”¨.

Drug resistance is the main obstacle in the treatment of many cancers. It is of great clinical significance to study the mechanism of drug resistance and find new targets. Multi-omics mainly includes genomics, epigenomics, transcriptomics, proteomics, metabolomics, and radiomics. In recent years, the research of tumor resistance has made rapid development, which has significantly accelerated the discovery of new targets.

Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence.

Glioma is a common brain malignancy for which new drug development is urgently needed because of radiotherapy and drug resistance. Recent studies have demonstrated that artemisinin (ARS) compounds can display antiglioma activity, but the mechanisms are poorly understood. Using cell lines and mouse models, we investigated the effects of the most soluble ARS analogue artesunate (ART) on glioma cell growth, migration, distant seeding and senescence and elucidated the underlying mechanisms. Artemisinin effectively inhibited glioma cell growth, migration and distant seeding. Further investigation of the mechanisms showed that ART can influence glioma cell metabolism by affecting the nuclear localization of SREBP2 (sterol regulatory element-binding protein 2) and the expression of its target gene HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), the rate-limiting enzyme of the mevalonate (MVA) pathway. Moreover, ART affected the interaction between SREBP2 and P53 and restored the expression of P21 in cells expressing wild-type P53, thus playing a key role in cell senescence induction. In conclusion, our study demonstrated the new therapeutic potential of ART in glioma cells and showed the novel anticancer mechanisms of ARS compounds of regulating MVA metabolism and cell senescence.

Nitrogen-containing flavonoid and their analogs with diverse B-ring in acetylcholinesterase and butyrylcholinesterase inhibition.

In this study, a series of new flavones (2-phenyl-chromone), 2-naphthyl chromone, 2-anthryl-chromone, or 2-biphenyl-chromone derivatives containing 6 or 7-substituted tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results indicated that the alteration of aromatic ring connecting to chromone scaffold brings about a significant impact on biological activity. Compared with flavones, the inhibitory activity of 2-naphthyl chromone, 2-anthryl-chromone derivatives against AChE significantly decreased, while that of 2-biphenyl chromone derivatives with 7-substituted tertiary amine side chain is better than relative flavones derivatives. For all new synthesized compounds, the position of tertiary amine side chain obviously influenced the activity of inhibiting AChE. The results above provide great worthy information for the further development of new AChE inhibitors. Among the newly synthesized compounds, compound 5a is potent in AChE inhibition (IC50 = 1.29 ± 0.10 µmol/L) with high selectivity for AChE over BChE (selectivity ratio: 27.96). An enzyme kinetic study of compound 5a suggests that it produces a mixed-type inhibitory effect against AChE.

Structure-activity study of fluorine or chlorine-substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition.

In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results show that almost all the derivatives containing tertiary amine side chain (compounds 4a-9d) exhibit moderate or potent activity in AChE inhibition. By contrast, their parent compounds (compounds 3a-3f) in the absence of tertiary amine moitery exhibit poor inhibitory activity against AChE. For the compounds containing pyrroline or piperidine side chain, the bioactivity in AChE inhibition is much intense than those containing N,N-diethylamino side chain. The chlorine or fluorine substituted position produces a significant effect on the bioactivity and selectivity in AChE inhibition. Most of the compounds that contain para-substituted fluorine or chlorine exhibit potent activity against AChE and poor activity against BChE, while ortho-substituted analogs show the opposite effect. It is worth noticing that the compounds containing N,N-diethylamino side chain are exceptions to this pattern. Among the newly synthesized compounds, compounds 6d are the most potent in AChE inhibition (IC50 = 1.11 ± 0.08 µmol/L) with high selectivity for AChE over BChE (selectivity ratio: 46.58). An enzyme kinetic study of compounds 6d suggests it produces a mixed-type inhibitory effect in AChE.

In vivo measurement of bone manganese and association with manual dexterity: A pilot study.

We used neutron activation analysis (NAA) to measure hand bone manganese (BnMn) in 19 adult males. Median BnMn was 0.89µg/g dry bone (interquartile range = 1.07). After adjustment for age and occupation, higher ln(BnMn) was significantly associated with lower manual dexterity based on the Purdue Pegboard assembly task: ß = -1.77, standard error = 0.79, p = 0.04. Due to the small sample size, these results should be interpreted cautiously. BnMn appears to be a promising biomarker, and should be further studied.

[Research progress of copper transporter 1 in platinum-based chemotherapy].

Platinum drugs are widely used in the treatment of various solid tumors, but their resistance to platinum is the most significant obstacle to successful treatment. Copper transporter 1 (CTR1) is the specific transporter for copper, and it mainly locates at the plasma membrane and plays a role in pumping copper into the cell. CTR1 is also the major platinum influx transporter and plays a key role in platinum resistance. The expression, polymorphism, and degradation of CTR1 affect platinum resistance in tumors. Therefore, CTR1 may be a potential predictive biomarker of platinum resistance and a therapeutic target for overcoming platinum resistance.

Biomimetic Mineralization of Gold Nanoclusters as Multifunctional Thin Films for Glass Nanopore Modification, Characterization, and Sensing.

Hurdles of nanopore modification and characterization restrain the development of glass capillary-based nanopore sensing platforms. In this article, a simple but effective biomimetic mineralization method was developed to decorate glass nanopore with a thin film of bovine serum albumin-protected Au nanocluster (BSA-Au NC). The BSA-Au NC film emitted a strong red fluorescence whereby nondestructive characterization of Au film decorated at the inner surface of glass nanopore can be facilely achieved by a fluorescence microscopy. Besides, the BSA molecules played dual roles in the fabrication of functionalized Au thin film in glass nanopore: they not only directed the synthesis of fluorescent Au thin film but also provided binding sites for recognition, thus achieving synthesis-modification integration. This occurred due to the ionized carboxyl groups (-COO-) of a BSA coating layer on Au NCs which can interacted with arginine (Arg) via guanidinium groups. The added Arg selectively led to the change in the charge and ionic current of BSA-Au NC film-decorated glass nanopore. Such ionic current responses can be used for quantifying Arg with a detection limit down to 1 fM, which was more sensitive than that of previous sensing systems. Together, the designed method exhibited great promise in providing a facile and controllable solution for glass nanopore modification, characterization, and sensing.

Association between polymorphisms in CTR1, CTR2, ATP7A, and ATP7B and platinum resistance in epithelial ovarian cancer.

The copper transporters CTR1, CTR2, ATP7A, and ATP7B regulate intracellular concentration of platinum by mediating its uptake and efflux in cells. We sought to explore the effect of genetic polymorphisms in CTR1, CTR2, ATP7A, and ATP7B on platinum resistance in patients suffering from epithelial ovarian cancer (EOC). A total of 152 Chinese EOC patients were enrolled in this study, all of whom underwent adjuvant chemotherapy using platinum and taxane after maximal debulking surgery. In total, 11 single-nucleotide polymorphisms (SNPs) in CTR1, CTR2, ATP7A, and ATP7B were genotyped in these patients. The CTR1 rs10981694 polymorphism was observed to be associated with carboplatin resistance, while patients with the rs10981694 G allele showed a significantly higher rate of carboplatin resistance (OR = 4.00, 95% CI 1.309 - 12.23, p < 0.01). In addition, we found that ATP7A rs2227291 was associated with cisplatin resistance and that carriers of the C allele were more sensitive to cisplatin (OR = 0.40, 95% CI: 0.17 - 0.94, p = 0.03). Our findings suggest that the CTR1 and ATP7A genetic polymorphisms could affect platinum resistance. The CTR1 and ATP7A genes might be considered a predictive marker for carboplatin and cisplatin resistance, respectively.
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Transcriptomics Analysis on Excellent Meat Quality Traits of Skeletal Muscles of the Chinese Indigenous Min Pig Compared with the Large White Breed.

The Min pig (Sus scrofa) is a well-known indigenous breed in China. One of its main advantages over European breeds is its high meat quality. Additionally, different cuts of pig also show some different traits of meat quality. To explore the underlying mechanism responsible for the differences of meat quality between different breeds or cuts, the longissimus dorsi muscle (LM) and the biceps femoris muscle (BF) from Min and Large White pigs were investigated using transcriptome analysis. The gene expression profiling identified 1371 differentially expressed genes (DEGs) between LM muscles from Min and Large White pigs, and 114 DEGs between LM and BF muscles from the same Min pigs. Gene Ontology (GO) enrichment of biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the gene products were mainly involved in the IRS1/Akt/FoxO1 signaling pathway, adenosine 5'-monophosphate-activated protein kinase (AMPK) cascade effects, lipid metabolism and amino acid metabolism pathway. Such pathways contributed to fatty acid metabolism, intramuscular fat deposition, and skeletal muscle growth in Min pig. These results give an insight into the mechanisms underlying the formation of skeletal muscle and provide candidate genes for improving meat quality. It will contribute to improving meat quality of pigs through molecular breeding.

Development of Au Disk Nanoelectrode Down to 3 nm in Radius for Detection of Dopamine Release from a Single Cell.

A Au disk nanoelectrode down to 3 nm in radius was developed by a facile and reliable method and successfully applied for monitoring dopamine release from single living vesicles. A fine etched Au wire was coated with cathodic electrophoretic paint followed by polyimide, which retracted from the tip end during curing to expose the Au nanotip. By cyclic voltammetric scanning the above tip in 0.5 M KCl, the transformation of a core-shaped apex into a geometrically well-defined Au disk nanoelectrode with different dimensions can be controllably and reproducibly achieved. Scanning electron microscopy, transmission electron microscopy, and steady-state voltammetry were used to determine the size of nanoelectrodes. The results showed that the specific etching and insulation method not only avoids the use of toxic etching solution and the uncontrollable treatment to expose the tip but also makes possible the controllable and reproducible fabrication of Au disk nanoelectrode down to 3 nm in radius. The nanoelectrodes with well-demonstrated analytical performance were further applied for amperometrically monitoring dopamine release from single rat pheochromacytoma cells with high spatial resolution.

Immunomodulatory effects of epicatechin-(2ß→O→7, 4ß→8)-ent-epicatechin isolated from Rhododendron spiciferum in vitro.

CONTEXT: Many traditional Chinese medicines (TCMs) can act as either immunosuppresants or immunostimulants, properties that have lead to their increasing use as immunomodulators in the treatment of disease. Recently, our lab successfully identified a dimer epicatechin-(2ß→O → 7, 4ß→8)-ent-epicatechin (EEE) from the chloroform extract of Rhododendron spiciferum. OBJECTIVE: To evaluate the immunomodulatory effects of EEE in vitro. MATERIALS AND METHODS: Splenocytes, peritoneal macrophages and peripheral blood mononuclear cells from BALB/c mice were incubated with different concentrations of EEE. RESULTS: EEE significantly stimulates splenocyte proliferation when administered either alone or in combination with concanavalin A (Con A), lipopolysaccharide (LPS), and Anti-CD3. EEE enhances the cytotoxicity of natural killer (NK) cells markedly and phagocytic function of macrophage. Moreover, we found that the levels of several helper T1 (Th1) cytokines, including interleukin-2 (IL-2), IL-12, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are significantly increased after EEE treatment, while the levels of Th2 cytokine IL-4 and IL-10 are significantly decreased. As a result, the ratio of Th1/Th2 is significantly increased in the presence of EEE. EEE also increased CD4 and CD8 cell populations. CONCLUSION: These results indicate that EEE exhibits immunomodulatory activity and suggests that this compound could be developed as a novel immunotherapeutic agent for treating cancer and other immune-mediated diseases.

Production, purification, and antibiofilm activity of a novel exopolysaccharide from Arthrobacter sp. B4.

A novel exopolysaccharide (EPS), namely, B4-EPS, is produced by Arthrobacter sp. B4. Response surface methodology (RSM) was employed to optimize the fermentation medium for increasing B4-EPS production. Based on Plackett-Burman design (PBD), glucose, yeast extract, and KH2PO4 were selected as significant variables, which were further optimized by a central composite design (CCD). According to response surface and canonical analysis, the optimal medium was composed of 16.94 g/L glucose, 2.33 g/L yeast extract, and 5.32 g/L KH2PO4. Under this condition, the maximum yield of B4-EPS reached about 8.54 g/L after 72 hr of batch fermentation, which was pretty close to the predicted value (8.52 g/L). Furthermore, B4-EPS was refined by column chromatography. The main homogeneous fraction (B4-EPS1) was collected and applied to assay of antibiofilm activity. B4-EPS1 exhibited a dose-dependent inhibitory effect on biofilm formation of Pseudomonas aeruginosa PAO1 without antibacterial activity. About 86.1% of biofilm formation of P. aeruginosa PAO1 was inhibited in the presence of 50 µg/mL B4-EPS1, which was more effective than the peer published data. Moreover, B4-EPS1 could prevent biofilm formation of other strains. These data suggest B4-EPS may represent a promising strategy to combat bacterial biofilms in the future.

[eIF3a gene polymorphism and chemo-sensitivity to platinum-based drugs in ovarian cancer].

OBJECTIVE: To investigate the relationship between the eukaryotic initiation factor 3a (eIF3a)polymorphisms and chemo-sensitivity to platinum-based drug in ovarian cancer.
 METHODS: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis was performed to detect 57 cases of eIF3a polymorphic genotypes (rs3824830, rs77382849, rs10787899 and rs3740556) after platinum-based chemotherapy drugs up to 6 cycles in primary ovarian cancer. The association between these gene sites was analyzed.
 RESULTS: There were 3 genotypes for eIF3a rs3824830, named AA, GA and GG. The frequency distribution for them was 43.86%, 36.84% and 15.79% (2 cases did not detect the genotype, 3.51%), respectively. There were 2 genotypes for eIF3a rs77382849, named CC and TC. The frequency distribution for them was 85.96% and 12.28%(1 case did not detect the genotype, 1.76%), respectively. There were 3 genotypes for eIF3a rs10787899, named GG, GA and AA, respectively. The frequency distribution for them was 26.32%, 47.36% and 26.32%, respectively. There were significant difference in different genotypes between age group and FIGO stage (P<0.05). The genotype of eIF3a rs10787899 GA was easier to resist platinum drug compared with the GG genotype and the odds ratio could be increased by 2.676 (95%CI: 0.544-13.159). The genotype of eIF3a rs10787899 AA was easier to resist platinum drug compared with the GG genotype and the odds ratio could be increased by 5.419(95%CI: 0.964-30.471). Rebalanced by age and FIGO stage, there was no significant difference (P>0.05) among these genotype groups. In all blood samples, there was only one genotype for eIF3a rs3740556, named GG.
 CONCLUSION: There is no mutation genotype in eIF3a rs3740556 loci. Polymorphism in the eIF3a rs3824830, rs77382849 and rs10787899 doesn't affect the response of ovarian cancer to platinum-based chemotherapy.

In situ synthesis of poly(ionic liquid)-Pt nanoparticle composite in glass capillary for the electrocatalytic reduction of oxygen.

A novel approach for in situ synthesizing poly(ionic liquid)-Pt nanoparticle (PIL-Pt) composite in a glass capillary for fabricating filling-type electrode is reported in this work. XRD and TEM were used to characterize the as-synthesized PIL-Pt composite. Because of the modification of poly(ionic liquid)s (PILs), the PIL-Pt composite can not only be dispersed well to form a homogeneous suspension of Pt nanoparticles, but also be synthesized directly in a glass capillary with a tip radius ranging from 250 nm to 2.5 µm. By simple heating at 130 °C, the PIL-Pt composite capillary electrode was fabricated under mild conditions. With the advantages of both PILs and glass capillary, a PIL-Pt capillary electrode can provide a favourable microenvironment for the encapsulated Pt nanoparticles and promote the mass transfer rate; thus, showing a high electrocatalytic activity and stability for an oxygen reduction reaction (ORR). The present study provided a novel method for the development of high performance electrocatalysts based on the construction of PIL-Pt composite in a glass capillary for fuel cell or electrochemical sensors.

Integrated Single-Cell Analysis Reveals Spatially and Temporally Dynamic Heterogeneity in Fibroblast States during Wound Healing.

Wound healing is a dynamic process over temporal and spatial scales. Key to repair outcomes are fibroblasts; yet, how they modulate healing across time and in different wound regions remains incompletely understood. By integrating single-cell RNA-sequencing datasets of mouse skin and wounds, we infer that fibroblasts are the most transcriptionally dynamic skin-resident cells, evolving during postnatal skin maturation and rapidly after injury toward distinct late scar states. We show that transcriptional dynamics in fibroblasts are largely driven by genes encoding extracellular matrix and signaling factors. Lineage trajectory inference and spatial gene mapping reveal that Prg4-expressing fibroblasts transiently emerge along early wound edges. Within days, they become replaced by long-lasting and likely noninterconverting fibroblast populations, including Col25a1-expressing and Pamr1-expressing fibroblasts that occupy subepidermal and deep scar regions, respectively, where they engage in reciprocal signaling with immune cells. Signaling inference shows that fibroblast-immune crosstalk repeatedly uses some signaling pathways across wound healing time, whereas use of other signaling pathways is time and space limited. Collectively, we uncovered high transcriptional plasticity by wound fibroblasts, with early states transiently forming distinct microniches along wound edges and in the fascia, followed by stable states that stratify scar tissue into molecularly dissimilar upper and lower layers.