CoFeSe2 @DMSA@FA Nanocatalyst for Amplification of Oxidative Stress to Achieve Multimodal Tumor Therapy.

Nanomedicine has significantly advanced precise tumor therapy, providing essential technical blessing for active drug accumulation, targeted consignment, and mitigation of noxious side effects. To enhance anti-tumor efficacy, the integration of multiple therapeutic modalities has garnered significant attention. Here, we designed an innovative CoFeSe2 @DMSA@FA nanocatalyst with Se vacancies (abbreviated as CFSDF), which exhibits synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT), leading to amplified tumor oxidative stress and enhanced photothermal effects. The multifunctional CFSDF nanocatalyst exhibits the remarkable ability to catalyze the Fenton reaction within the acidic tumor microenvironment, efficiently converting hydrogen peroxide (H2 O2 ) into highly harmful hydroxyl radicals (⋅OH). Moreover, the nanocatalyst effectively diminishes GSH levels and ameliorates intracellular oxidative stress. The incorporation of FA modification enables CFSDF to evade immune detection and selectively target tumor tissues. Numerous in vitro and in vivo investigations have consistently demonstrated that CFSDF optimizes its individual advantages and significantly enhances therapeutic efficiency through synergistic effects of multiple therapeutic modalities, offering a valuable and effective approach to cancer treatment.

Application of image super-resolution recognition and artificial intelligence system in repairing students' psychological education problems.

With the continuous development of society, people's life pressure is constantly increasing, and the mental health problems of college students are becoming increasingly prominent, bringing many challenges to their education and management. Universities should not only cultivate students' theoretical and professional knowledge and practical skills, but also attach importance to their mental health and effectively implement psychological education. Therefore, it is very necessary to develop and design a simple and effective student psychological evaluation system. As a new form of ideological and political transformation in universities in the era of big data, online ideological and political work has potential development space. It is necessary to carry out mental health education in universities, fully utilize online education forms, and improve ability of universities to repair mental health problems. Based on this, this system designs and implements software for typical image resolution based recognition and artificial intelligence. The use of B/S architecture in the development and use of. net technology and web server technology will enable more students to connect and use different terminals. In addition, an algorithm for image super-resolution recognition was proposed, which uses clustering convolution to improve residual blocks, improves modeling ability by extracting features on a larger scale, reduces the number of parameters to improve model calculation efficiency, and enables mental health educators and managers to work better. This article combines image super-resolution recognition technology with artificial intelligence technology to apply it to the process of psychological education in universities, thereby promoting the development of problem repair applications.

TRAIL inhibition by soluble death receptor 5 protects against acute myocardial infarction in rats.

Acute myocardial infarction (AMI) is associated with high morbidity and mortality. An effective therapeutic strategy is to rescue cardiomyocytes from death. Apoptosis is a key reason of cardiomyocyte death that can be prevented. In this study, we investigated the role of TNF-related apoptosis-inducing ligand (TRAIL) in initiating apoptosis by binding to death receptor 5 (DR5), and this procession is inhibited by soluble DR5 (sDR5) in rats after AMI. First, we found that the level of TRAIL in serum was down-regulated in AMI patients. Then, TRAIL and DR5 expression was analysed in the myocardium of rats after AMI, and their expression was up-regulated. sDR5 treatment reduced the myocardial infarct size and the levels of CK-MB and cTn-I in serum. The expression of caspase 3 and PARP is decreased, but the anti-apoptotic factor Bcl-2 was increased in sDR5 treatment rats after AMI. DR5 expression was also analysed after sDR5 treatment and it was down-regulated, and a low level of DR5 expression seemed to be beneficial for the myocardium. Overall, our findings indicated that sDR5 decreases myocardial damage by inhibiting apoptosis in rat after AMI. We expect to observe the potential therapeutic effects of sDR5 on AMI in the future.

Survival and analysis of prognostic factors for severe burn patients with inhalation injury: based on the respiratory SOFA score.

BACKGROUND: It is important to determine the severity of inhalation injury in severely burned patients. The oxygenation index PaO2/FiO2(PF) ratio is a key clinical indicator of inhalation injury. Sequential organ failure assessment (SOFA) is developed to assess the acute incidence of critical illness in the population. We hope to provide an assessment of survival or prognostic factor for severely burned patients with inhalation injury based on the respiratory SOFA score. METHODS: This is a retrospective cohort study of all admissions to Department of Burn and Plastic Surgery at West China Hospital of Sichuan University from July 2010 to March 2021. Data was analyzed using Cox regression models to determine significant predictors of mortality. Survival analysis with time to death event was performed using the Kaplan-Meier survival curve with the log-rank test. All potential risk factors were considered independent variables, while survival was considered the risk dependent variable. RESULTS: One hundred eighteen severe burn patients with inhalation injury who met the inclusion and exclusion criteria were admitted, including men accounted for 76.3%. The mean age and length of stay were 45.9 (14.8) years and 44.3 (38.4) days. Flame burns are the main etiology of burn (74.6%). Patients with the respiratory SOFA score greater than 2 have undergone mechanical ventilation. Univariate Kaplan-Meier analysis identified age, total body surface area burned (TBSA), ICU admission and the respiratory SOFA score as significant factors on survival. Cox regression analysis showed that TBSA and the respiratory SOFA score were associated with patient survival (p < 0.001). In some patients with severe burns and inhalation damage, the survival probability drops to less than 10% (TBSA greater than 80%: 8.9% and respiratory SOFA score greater than 2: 5.6%). This study statistically found that the TBSA with the respiratory SOFA score model (AUROC: 0.955) and the rBaux score (AUROC: 0.927) had similar predictive value (p = 0.175). CONCLUSION: The study indicates that a high respiratory system SOFA score was identified as a strong and independent predictor of severely burned patients with inhalation injury during hospitalization. When combined with TBSA, the respiratory SOFA scores can dynamically assess the severity of the patient's lung injury and improve the predictive level.

Realizing Scalable Nano-SiO2-Aerogel-Reinforced Composite Polymer Electrolytes with High Ionic Conductivity via Rheology-Tuning UV Polymerization.

Polymer electrolytes for lithium metal batteries have aroused widespread interest because of their flexibility and excellent processability. However, the low ambient ionic conductivity and conventional fabrication process hinder their large-scale application. Herein, a novel polyethylene-oxide-based composite polymer electrolyte is designed and fabricated by introducing nano-SiO2 aerogel as an inorganic filler. The Lewis acid-base interaction between SiO2 and anions from Li salts facilitates the dissociation of Li+. Moreover, the SiO2 interacts with ether oxygen (EO) groups, which weakens the interaction between Li+ and EO groups. This synergistic effect produces more free Li+ in the electrolyte. Additionally, the facile rheology-tuning UV polymerization method achieves continuous coating and has potential for scalable fabrication. The composite polymer electrolyte exhibits high ambient ionic conductivity (0.68 mS cm-1) and mechanical properties (e.g., the elastic modulus of 150 MPa). Stable lithium plating/stripping for 1400 h in Li//Li symmetrical cells at 0.1 mA cm-2 is achieved. Furthermore, LiFePO4//Li full cells deliver superior discharge capacity (153 mAh g-1 at 0.5 C) and cycling stability (with a retention rate of 92.3% at 0.5 C after 250 cycles) at ambient temperature. This work provides a promising strategy for polymer-based lithium metal batteries.

Enabling Scalable Polymer Electrolyte with Synergetic Ion Conductive Channels via a Two Stage Rheology Tuning UV Polymerization Strategy.

Lithium metal batteries with polyethylene oxide (PEO) electrolytes are considered as one of the ideal candidates for next generation power sources. However, the low ambient operation capability and conventional solvent-based fabrication process of PEO limit their large-scale application. In this work, a comb-like quasi-solid polymer electrolyte (QPE) reinforced with polyethylene glycol terephthalate nonwoven is fabricated. Combining the density functional theory calculation analysis and polymer structure design, optimized and synergized ion conductive channels are established by copolymerization of tetrahydrofurfuryl acrylate and introduction of plasticizer tetramethyl urea. Additionally, a unique two-stage solventless UV polymerization strategy is utilized for rheology tuning and electrolyte fabrication. Compared with the conventional one-step UV process, this strategy is ideally suited for the roll-to-roll continuous coating fabrication process with environmental friendliness. The fabricated QPE exhibits high ionic conductivity of 0.40 mS cm-1 and Li+ transference number (t = 0.77) at room temperature. LiFePO4 //Li batteries are assembled to evaluate battery performance, which deliver excellent discharge capacity (144.9 mAh g-1 at 0.5 C) and cycling stability (with the retention rate 94.5% at 0.5 C after 200 cycles) at room temperature. The results demonstrate that it has high potential for solid-state lithium metal batteries.

Co4 N-Decorated 3D Wood-Derived Carbon Host Enables Enhanced Cathodic Electrocatalysis and Homogeneous Lithium Deposition for Lithium-Sulfur Full Cells.

The sluggish kinetics of sulfur conversion in the cathode and the nonuniform deposition of lithium metal at the anode result in severe capacity decay and poor cycle life for lithium-sulfur (Li-S) batteries. Resolving these deficiencies is the most direct route toward achieving practical cells of this chemistry. Herein, a vertically aligned wood-derived carbon plate decorated with Co4 N nanoparticles host (Co4 N/WCP) is proposed that can serve as a host for both the sulfur cathode and the metallic lithium anode. This Co4 N/WCP electrode host drastically enhances the reaction kinetics in the sulfur cathode and homogenizes the electric field at the anode for the uniform lithium plating. Density functional theory calculations confirm the experimental observations that Co4 N/WCP provides a lower energy barrier for the polysulfide redox reaction in the cathode and a low adsorption energy for lithium deposition at the anode. Employing the Co4 N/WCP host at both electrodes in a S@Co4 N/WCP||Li@Co4 N/WCP full cell delivers a specific capacity of 807.9 mAh g-1 after 500 cycles at a 1 C rate. Additional experiments are performed with high areal sulfur loading of 4 mg cm-2 to demonstrate the viability of this strategy for producing practical Li-S cells.

Inhibition of hepatocyte nuclear factor 1ß contributes to cisplatin nephrotoxicity via regulation of nf-κb pathway.

Cisplatin nephrotoxicity has been considered as serious side effect caused by cisplatin-based chemotherapy. Recent evidence indicates that renal tubular cell apoptosis and inflammation contribute to the progression of cisplatin-induced acute kidney injury (AKI). Hepatocyte nuclear factor 1ß (HNF1ß) has been reported to regulate the development of kidney cystogenesis, diabetic nephrotoxicity, etc However, the regulatory mechanism of HNF1ß in cisplatin nephrotoxicity is largely unknown. In the present study, we examined the effects of HNF1ß deficiency on the development of cisplatin-induced AKI in vitro and in vivo. HNF1ß down-regulation exacerbated cisplatin-induced RPTC apoptosis by indirectly inducing NF-κB p65 phosphorylation and nuclear translocation. HNF1ß knockdown C57BL/6 mice were constructed by injecting intravenously with HNF1ß-interfering shRNA and PEI. The HNF1ß scramble and knockdown mice were treated with 30 mg/kg cisplatin for 3 days to induce acute kidney injury. Cisplatin treatment caused increased caspase 3 cleavage and p65 phosphorylation, elevated serum urea nitrogen and creatinine, and obvious histological damage of kidney such as fractured tubules in control mice, which were enhanced in HNF1ß knockdown mice. These results suggest that HNF1ß may ameliorate cisplatin nephrotoxicity in vitro and in vivo, probably through regulating NF-κB signalling pathway.

Recent Advances and Perspectives in Lithium-Sulfur Pouch Cells.

Lithium-sulfur batteries (LSBs) are considered one of the most promising candidates for next-generation energy storage owing to their large energy capacity. Tremendous effort has been devoted to overcoming the inherent problems of LSBs to facilitate their commercialization, such as polysulfide shuttling and dendritic lithium growth. Pouch cells present additional challenges for LSBs as they require greater electrode active material utilization, a lower electrolyte-sulfur ratio, and more mechanically robust electrode architectures to ensure long-term cycling stability. In this review, the critical challenges facing practical Li-S pouch cells that dictate their energy density and long-term cyclability are summarized. Strategies and perspectives for every major pouch cell component-cathode/anode active materials and electrode construction, separator design, and electrolyte-are discussed with emphasis placed on approaches aimed at improving the reversible electrochemical conversion of sulfur and lithium anode protection for high-energy Li-S pouch cells.

Soluble uric acid induces myocardial damage through activating the NLRP3 inflammasome.

Uric acid crystal is known to activate the NLRP3 inflammasome and to cause tissue damages, which can result in many diseases, such as gout, chronic renal injury and myocardial damage. Meanwhile, soluble uric acid (sUA), before forming crystals, is also related to these diseases. This study was carried out to investigate whether sUA could also activate NLRP3 inflammasome in cardiomyocytes and to analyse the mechanisms. The cardiomyocyte activity was monitored, along with the levels of mature IL-1ß and caspase-1 from H9c2 cells following sUA stimulus. We found that sUA was able to activate NLRP3 inflammasome, which was responsible for H9c2 cell apoptosis induced by sUA. By elevating TLR6 levels and then activating NF-κB/p65 signal pathway, sUA promoted NLRP3, pro-caspase 1 and pro-IL-1ß production and provided the first signal of NLRP3 inflammasome activation. Meanwhile, ROS production regulated by UCP2 levels also contributed to NLRP3 inflammasome assembly and subsequent caspase 1 activation and mature IL-1ß secretion. In addition, the tlr6 knockdown rats suffering from hyperuricemia showed the lower level of IL-1ß and an ameliorative cardiac function. These findings suggest that sUA activates NLRP3 inflammasome in cardiomyocytes and they may provide one therapeutic strategy for myocardial damage induced by sUA.

A chemiluminescence immunoassay for the detection of NT-proBNP.

BACKGROUND: The aim of the study was to assess the analytical performance of the HISCL NT-proBNP assay, a newly developed chemiluminescence immunoassay, for the detection of NT-proBNP. METHODS: The within-run and total imprecision of the NT-proBNP assay were determined with HISCL cardiac marker controls. The linear ranges of the NT-proBNP assays were evaluated based on the CLSI EP6-A document using selected serum samples. Two hundred serum samples were evaluated to compare the HISCL NT-proBNP and Elecsys NT-proBNP assays. Five additional high NT-proBNP concentrations serum samples were evaluated to assess if there was high-dose hook effect in the HISCL NT-proBNP assay. RESULTS: The total and within-run imprecision values of the HISCL NT-proBNP assay were 5.85%, 0.81%, 2.56% and 0.54% and 6.07%, 0.73%, 2.61% and 0.59% at 6.1, 129.83, 3732.84and39737.33 pg/ml, respectively. The assay was verified to be linear for NT-proBNP levels ranging between 6.1 and 39737.33 pg/ml. The assay comparison showed that HISCL NT-proBNP = 0.9803 × Elecsys NT-proBNP -4.383. The sensitivity of HISCL NT-proBNP was 87.23%, and the specificity was 85.61%. The AUC of HISCL NT-proBNP (0.90 (95% CI, 0.86-0.93)) did not differ from that of Elecsys NT-proBNP(0.89 (95% CI, 0.85-0.93)) (P = 0.638). The results of five high NT-proBNP concentrations samples (44448, 54206, 55634, 55728 and 109406 pg/ml, measured with the Elecsys NT-proBNP assay) tested with HISCL NT-proBNP assay were all displayed with ">40000 pg/ml". CONCLUSIONS: The HISCL NT-proBNP chemiluminescence immunoassay showed good analytical and diagnostic performance for the detection of NT-proBNP and could be used in routine clinical practice.

RACK1 deficiency synergizes with all-trans retinoic acid to induce apoptosis in human acute promyelocytic leukemia cells.

As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in the treatment of acute promyelocytic leukemia (APL). However, the clinical application of ATRA has strict limitations, for its severe side effects due to the accumulation of peripheral blood leukocytes. The scaffold protein RACK1 (Receptor for activated C kinase 1), which regulates multiple signaling pathways, has been proposed to contribute to the survival of leukemic progenitors. But it remains unclear whether it is also involved in the oncogenic growth of APL. In the present study, we demonstrate that silencing of endogenous RACK1 expression synergized with ATRA to promote the death of NB4 and HL-60 APL cells without effect on cell differentiation induced by ATRA. Interestingly, RACK1 knockdown combined with ATRA treatment mainly induces apoptosis. It is distinct to the necrotic cell death induced by idarubicin in combination with ATRA, a regimen extensively used in the clinic to prevent neutrophil accumulation. Further exploration revealed that the lysosome-autophagy pathway is likely to be responsible for the anti-apoptotic role of RACK1. Taken together, our findings indicate that RACK1 is essential in maintaining the malignant features of APL, and targeting RACK1 may have promising therapeutic implications in the treatment of APL.

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS-mediated NLRP3 inflammasome activation.

NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti-hyperglycaemia and anti-inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL-1ß and IL-18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down-regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C-reactive proteins (CRPs), IL-1ß and IL-18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS-mediated NLRP3 inflammasome activation.

Treponema pallidum promotes macrophage polarization and activates the NLRP3 inflammasome pathway to induce interleukin-1ß production.

BACKGROUND: The involvement of inflammasome activation and macrophage polarization during the process of syphilis infection remains unknown. In this study, A series of experiments were performed using human macrophages to research the role of NLRP3 inflammasome regulation in interleukin (IL)-1ß production and its influence on macrophage polarization triggered by T. pallidum. RESULTS: The results showed that in M0 macrophages treated with T. pallidum, the M1-associated markers inducible nitric oxide synthase (iNOS), IL-1ß and TNF-α were upregulated, and the M2-associated markers CD206 and IL-10 were downregulated. In addition, we observed NLRP3 inflammasome activation and IL-1ß secretion in T. pallidum-treated macrophages, and the observed production of IL-1ß occurred in a dose- and time-dependent manner. Moreover, the secretion of IL-1ß by macrophages after T. pallidum treatment was notably reduced by anti-NLRP3 siRNA and caspase-1 inhibitor treatment. NAC, KCl, and CA074-ME treatment also suppressed IL-1ß release from T. pallidum-treated macrophages. CONCLUSIONS: These findings showed that T. pallidum induces M0 macrophages to undergo M1 macrophage polarization and elevate IL-1ß secretion through NLRP3. Moreover, the process of NLRP3 inflammasome activation and IL-1ß production in macrophages in response to T. pallidum infection involves K+ efflux, mitochondrial ROS production and cathepsin release. This study provides a new insight into the innate immune response to T. pallidum infection.

Correlation between polymorphisms in toll-like receptor genes and the activity of hepatitis B virus among treatment-naïve patients: a case-control study in a Han Chinese population.

BACKGROUND: Because of the high prevalence and absence of cure for infection, chronic hepatitis B virus (HBV) infection has been acknowledged as a pressing public health issue. Toll-like receptors (TLRs) activate the human innate immune system and the polymorphisms in TLRs may alter their function. The present study aimed to investigate the association between TLR polymorphisms and disease progression of chronic HBV infection. METHODS: During the study period, 211 treatment-naïve patients with chronic HBV infection were recruited, and blood samples were collected from each individual. Matrix-assisted laser desorption/ionization time of flight mass spectrometry was employed to genotype the selected TLR polymorphisms after human genome extraction. In addition, HbsAg, TNF-α, and IL-6 levels were quantified using enzyme linked immunosorbent assay (ELISA). Statistical analyses were conducted to investigate the association between TLR polymorphisms and hepatitis activity, liver function parameters, HbsAg level, and cytokine level. RESULTS: We did not observe any mutations in rs4986790, rs4986791, and rs5743708 among all study subjects. A logistic regression revealed that mutations in rs3804099 and rs4696480 were associated with milder hepatitis activity. Consistent with the logistic regression, improved liver function parameters and reduced level of both HbsAg and cytokines were also correlated with the mutant carriers of rs3804099 and rs4696480. CONCLUSIONS: TLR mutations were significantly associated with milder hepatitis activity among patients with chronic HBV infection. Therefore, we conclude that the activation of TLR pathways may further intensify the inflammation of hepatocytes, and leads to progression of disease.

Development of tissue inflammation accompanied by NLRP3 inflammasome activation in rabbits infected with Treponema pallidum strain Nichols.

BACKGROUND: The inflammasome responses in Treponema pallidum infection have been poorly understood to date. This study aimed to investigate the expression of the nucleotide-binding leucine-rich receptor protein 3 (NLRP3) inflammasome in the development of tissue inflammation in rabbits infected with T. pallidum. METHODS: Forty-five rabbits were randomly assigned to a blank group or an infection group, and the latter was divided into no benzathine penicillin G (BPG) and BPG treatment subgroups. Rabbits in the infection group were injected intradermally with 0.1 mL of a 107/mL T. pallidum suspension at 10 marked sites along the back, and the blank group was treated with normal saline. The BPG treatment subgroup received 200,000 U of BPG administered intramuscularly twice, at 14 d and 21 d post-infection. The development of lesions was observed, and biopsies of the injection site and various organs, including the kidney, liver, spleen, lung, and testis, were obtained for NLRP3, caspase-1, and interleukin-1ß (IL-1ß) mRNA analysis during infection. Blood was also collected for the determination of IL-1ß concentration. RESULTS: Rabbits infected with T. pallidum (both the BPG treatment and no BPG treatment subgroups), exhibited NLRP3 inflammasome activation and IL-1ß secretion in cutaneous lesions, showing a trend in elevation to decline; NLRP3 mRNA expression reached a peak at 18 d in the BPG treatment subgroup and 21 d in the no BPG treatment subgroup and returned to "normal" levels [vs. the blank group (P > 0.05)] at 42 d post-infection. The trend was similar to the change in cutaneous lesions in the infected rabbits, which reached a peak at 16 d in the BPG treatment subgroup and 18 d in the no BPG treatment subgroup. NLRP3, caspase-1, and IL-1ß mRNA expression levels were slightly different in different organs. NLRP3 inflammasome activation was also observed in the kidney, liver, lung, spleen and testis. IL-1ß expression was observed in the kidney, liver, lung and spleen; however, there was no detectable level of IL-1ß in the testes of the infected rabbits. CONCLUSIONS: This study established a clear link between NLRP3 inflammasome activation and the development of tissue inflammation in rabbits infected with T. pallidum. BPG therapy imperceptibly adjusted syphilitic inflammation.

Novel predictors of neurosyphilis among HIV-negative syphilis patients with neurological symptoms: an observational study.

BACKGROUND: Known predictors of neurosyphilis were mainly drawn from human immunodeficiency virus (HIV)-infected syphilis patients, which may not be applicable to HIV-negative populations as they have different characteristics, particularly those with neurological symptoms. This study aimed to identify novel predictors of HIV-negative symptomatic neurosyphilis (S-NS). METHODS: From June 2005 to June 2015, 370 HIV-negative syphilis patients with neurological symptoms were recruited, consisting of 191 S-NS patients (including 123 confirmed neurosyphilis and 68 probable neurosyphilis patients) and 179 syphilis/non-neurosyphilis (N-NS) patients. Clinical and laboratory characteristics of S-NS were compared with N-NS to identify factors predictive of S-NS. Serum rapid plasma reagin (RPR), Treponema pallidum particle agglutination (TPPA), and their parallel testing format for screening S-NS were evaluated. RESULTS: The likelihood of S-NS was positively associated with the serum RPR and TPPA titers. The serum TPPA titers performed better than the serum RPR titers in screening S-NS. The optimal cut-off points to recognize S-NS were serum RPR titer ≥1:4 and serum TPPA titer ≥1:2560 respectively. A parallel testing format of a serum RPR titer ≥1:2 and serum TPPA titer ≥1:1280 screened out 95.8% of S-NS and all confirmed cases of neurosyphilis. S-NS was independently associated with male sex, serum RPR titer ≥1:4, serum TPPA titer ≥1:2560, and elevated serum creatine kinase. Concurrence of these factors increased the likelihood of S-NS. CONCLUSIONS: Quantitation of serum TPPA is worthwhile and performs better than serum RPR in screening S-NS. Serum RPR, serum TPPA, male sex, and serum creatine kinase can predict S-NS. Moreover, patients with both a serum RPR titer <1:2 and a serum TPPA titer <1:1280 have a low probability of S-NS, suggesting that it is reasonable to reduce lumbar punctures in such individuals.

Hsf4 counteracts Hsf1 transcription activities and increases lens epithelial cell survival in vitro.

The interplay between Hsf4 and Hsf1 plays an important role in the regulation of lens homeostasis. However, the mechanism of the intermolecular association involved is still unclear. In this paper, we find that reconstitution of Hsf4b into Hsf4-/- lens epithelial (mLEC/Hsf4-/-) cells can simultaneously downregulate Hsp70 expression and upregulate the expression of small heat shock proteins Hsp25 and αB-crystallin at both RNA and protein levels. ChIP assay results indicate Hsf4b, which binds to the promoters of Hsp90α, Hsp70.3, Hsp25 and αB-crystallin but not Hsp70.1, can inhibit Hsf1 binding to Hsp70.3 promoter and the heat shock mediated Hsp70 promoter activity by reducing Hsf1 protein expression. Hsf4b N-terminal hydrophobic region can interact with Hsf1 N-terminal hydrophobic region. Their interaction impairs Hsf1's intramolecular interaction between the N- and C-terminal hydrophobic regions, leading to Hsf1's cytosolic retention and protein degradation. Both lysosome inhibitors (chloroquine, pepstatin A plus E64d) and proteasome inhibitor MG132 can inhibit Hsf4-mediated Hsf1 protein degradation, but MG132 can induce Hsf1 activation as well. Upregulation of Hsf4b can significantly inhibit cisplatin and staurosporine induced lens epithelial cell apoptosis through direct upregulation of Hsp25 and αB-crystallin expression. Taken together, our results imply that upregulation of Hsf4b modulates the expression pattern of heat shock proteins in lens tissue by either directly binding to their promoters or promoting Hsf1 protein degradation. Moreover, upregulation of Hsf4b protects lens cell survival by upregulating anti-apoptotic pathways. These studies reveal a novel regulatory mechanism between Hsf1 and Hsf4b in modulating lens epithelial cell homeostasis.

Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472.

Hsf4b, a key regulator of postnatal lens development, is subjected to posttranslational modifications including phosphorylation. However, the phosphorylation sites in Hsf4b and their biological effects on the transcription activity of Hsf4b are poorly understood. Here we examined 17 potential phosphorylation residues in Hsf4b with alanine-scanning assays and found that a T472A mutation diminished Hsf4b-mediated expression of Hsp25 and alphaB-crystallin. In contrast, the phosphomimetic mutation of T472D enhanced their expression. Further investigation demonstrated that Hsf4b could interact with nuclear-transporter importin beta-1 and Hsc70 via amino acids 246-320 and 320-493, respectively. T472A mutation reduced Hsf4bs interaction with importin beta-1, while enhancing its interaction with Hsc7O, resulting in Hsf4b cytosolic re-localization, protein instability and transcription activity attenuation. At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI(6 regulates Hsf4b interaction with the importin V I -Hsc7O complex, resulting in blockade of its nuclear translocation and transcriptional activity of Hsf4b.

Glucose regulates heat shock factor 1 transcription activity via mTOR pathway in HCC cell lines.

HSF1-mediated heat shock response is activated in most tumors and plays important roles in regulating tumor homeostasis. However, the signals underlying HSF1 activation is still not completely understood. In this paper, we find that glucose, the dominant tumor energy supplement, participates in regulating HSF1's activation in HCC cell lines. The immunoblotting results indicate that the phosphorylation of HSF1/S326, a hallmark of HSF1 activation, varies between the HCC cell lines (e.g., SMMC7721, HapG2, plc/prf5, and Chang-liver). Glucose, but not 2D-glucose, can induce the phosphorylation of HSF1 at S326 and upregulate the expression of HSF1's downstream alpha B-crystallin and Hsp70 as well as the none-heat shock proteins CSK2 and RBM23 in two tested hepatocellular carcinoma cell lines (prl/prf5 and SMMC7721). Rapamycin, an inhibitor of mTOR, can suppress the glucose-induced phosphorylation of HSF1/S326 and the expression of alpha B-crystallin. Knockdown of HSF1 with shRNA enhances the glucose-depletion-mediated inhibition of plc/prf5 cell proliferation. Our data reveal that HSF1 can be activated by glucose-mTOR pathway, providing an alternative pathway for targeting HSF1 in tumor therapy.