Fluorescent protein chromophores modified with aromatic heterocycles for photodynamic therapy and two-photon fluorescence imaging.

In this paper, three fluorescent protein chromophore analogs PFPAr (PFPP, PFPC, and PFPT) were synthesized and proved to be useful for photodynamic therapy and two-photon fluorescence imaging. By adding five- or six-membered aromatic heterocycles to the photosensitizer PFP, we obtained three fluorescent protein photosensitizers PFPAr with better performances. As a demonstration, compared with the reported photosensitizer PFP, photosensitizer PFPP exhibits larger emission wavelengths (701 nm) and achieves a slight enhancement in the efficiency of singlet oxygen (ΦΔ = 23%). Notably, PFPP can perform good two-photon fluorescence imaging with an 800 nm femtosecond laser in zebrafish. In in vitro cytotoxicity assays, PFPP shows good phototoxicity (IC50 = 4.12 µM) and acceptable dark toxicity (cell viability assay >90%). The reactive oxygen imaging experiments and AO/EB double staining assay indicate that PFPP can generate singlet oxygen to eliminate A-549 tumor cells effectively with photoexcitation of 460 nm blue light (20 mW cm-2). Furthermore, PFPP can label the lysosomes of tumor cells with high specificity for lysosomes (Pearson's correlation coefficient of 0.91). Thus, our study demonstrated that the rational introduction of aromatic heterocycles into fluorescent protein photosensitizers can effectively enhance the key parameters of photosensitivity and pave the way for further two-photon photodynamic therapy.

Circ ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 increases the stability of G9a and ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 messenger RNA through recruiting eukaryotic translation initiation factor 4A3, transcriptionally inhibiting PDZ and homeobox protein domain protein 1, and promotes the metastasis of hepatocellular carcinoma.

BACKGROUND AND AIM: Circular ubiquitin-like, containing PHD and ring finger domains 1 (circUHRF1) is aberrantly upregulated in human hepatocellular carcinoma (HCC) tissues. However, the underlying molecular mechanisms remain obscure. The present study aimed at elucidating the interactive function of circUHRF1-G9a-ubiquitin-like, containing PHD and ring finger domains 1 (UHRF1) mRNA-eukaryotic translation initiation factor 4A3 (EIF4A3)-PDZ and LIM domain 1 (PDLIM1) network in HCC. METHODS: Expression of circUHRF1, mRNAs of G9a, UHRF1, PDLIM1, epithelial-mesenchymal transition (EMT)-related proteins, and Hippo-Yap pathway components was determined by quantitative polymerase chain reaction (Q-PCR), immunofluorescence, or Western blot analysis. Tumorigenic and metastatic capacities of HCC cells were examined by cellular assays including Cell Counting Kit-8, colony formation, wound healing, and transwell assays. Molecular interactions between EIF4A3 and UHRF1 mRNA were detected by RNA pull-down experiment. Complex formation between UHRF1 and PDLIM1 promoter was detected by chromatin immunoprecipitation assay. Co-immunoprecipitation was performed to examine the binding between UHRF1 and G9a. RESULTS: Circular ubiquitin-like, containing PHD and ring finger domains 1, G9a, and UHRF1 were upregulated, while PDLIM1 was downregulated in HCC tissue samples and cell lines. Cellular silencing of circUHRF1 repressed HCC proliferation, invasion, migration, and EMT. G9a formed a complex with UHRF1 and inhibited PDLIM1 transcription. CONCLUSION: Eukaryotic translation initiation factor 4A3 regulated circUHRF1 expression by binding to UHRF1 mRNA promoter. circUHRF1 increased the stability of G9a and UHRF1 mRNAs through recruiting EIF4A3. Overexpression of circUHRF1 aggravated HCC progression through Hippo-Yap pathway and PDLIM1 inhibition. By elucidating the molecular function of circUHRF1-G9a-UHRF1 mRNA-EIF4A3-PDLIM1 network, our data shed light on the HCC pathogenesis and suggest a novel therapeutic strategy for future HCC treatment.

Visible-Light-Mediated Generation of Acyl Radicals from Triazine Esters.

Acyl radicals are significant synthetic active species in organic synthesis. However, their generation via green and compatible methods remains challenging. Herein, we report an unprecedented visible-light-mediated approach for generating aryl acyl radicals from readily available triazine esters. This protocol with mild and redox-neutral conditions affords a diverse array of oxindoles attached to alcohol groups in a single operation. The recycling of leaving groups and a range of visible-light-mediated reactions using triazine ester as an acyl radical precursor demonstrate the synthetic potential of this methodology.

Bergapten inhibits NLRP3 inflammasome activation and pyroptosis via promoting mitophagy.

Inhibition of NLRP3 inflammasome activation produces potent therapeutic effects in a wide array of inflammatory diseases. Bergapten (BeG), a furocoumarin phytohormone present in many herbal medicines and fruits, exibits anti-inflammatory activity. In this study we characterized the therapeutic potential of BeG against bacterial infection and inflammation-related disorders, and elucidated the underlying mechanisms. We showed that pre-treatment with BeG (20 µM) effectively inhibited NLRP3 inflammasome activation in both lipopolysaccharides (LPS)-primed J774A.1 cells and bone marrow-derived macrophages (BMDMs), evidenced by attenuated cleaved caspase-1 and mature IL-1ß release, as well as reduced ASC speck formation and subsequent gasdermin D (GSDMD)-mediated pyroptosis. Transcriptome analysis revealed that BeG regulated the expression of genes involved in mitochondrial and reactive oxygen species (ROS) metabolism in BMDMs. Moreover, BeG treatment reversed the diminished mitochondrial activity and ROS production after NLRP3 activation, and elevated the expression of LC3-II and enhanced the co-localization of LC3 with mitochondria. Treatment with 3-methyladenine (3-MA, 5 mM) reversed the inhibitory effects of BeG on IL-1ß, cleaved caspase-1 and LDH release, GSDMD-N formation as well as ROS production. In mouse model of Escherichia coli-induced sepsis and mouse model of Citrobacter rodentium-induced intestinal inflammation, pre-treatment with BeG (50 mg/kg) significantly ameliorated tissue inflammation and injury. In conclusion, BeG inhibits NLRP3 inflammasome activation and pyroptosis by promoting mitophagy and maintaining mitochondrial homeostasis. These results suggest BeG as a promising drug candidate for the treatment of bacterial infection and inflammation-related disorders.

Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases.

Recent evidence shows that targeting NLRP3 inflammasome activation is an important means to treat inflammasome-driven diseases. Scoparone, a natural compound isolated from the Chinese herb Artemisia capillaris Thunb, has anti-inflammatory activity. In this study we investigated the effect of scoparone on NLRP3 inflammasome activation in inflammatory diseases. In LPS-primed, ATP or nigericin-stimulated mouse macrophage J774A.1 cells and bone marrow-derived macrophages (BMDMs), pretreatment with scoparone (50 µM) markedly restrained canonical and noncanonical NLRP3 inflammasome activation, evidenced by suppressed caspase-1 cleavage, GSDMD-mediated pyroptosis, mature IL-1ß secretion and the formation of ASC specks. We then conducted a transcriptome analysis in scoparone-pretreated BMDMs, and found that the differentially expressed genes were significantly enriched in mitochondrial reactive oxygen species (ROS) metabolic process, mitochondrial translation and assembly process, as well as in inflammatory response. We demonstrated in J774A.1 cells and BMDMs that scoparone promoted mitophagy, a well-characterized mechanism to control mitochondrial quality and reduce ROS production and subsequent NLRP3 inflammasome activation. Mitophagy blockade by 3-methyladenine (3-MA, 5 mM) reversed the protective effects of scoparone on mitochondrial damage and inflammation in the murine macrophages. Moreover, administration of scoparone (50 mg/kg) exerted significant preventive effects via inhibition of NLRP3 activation in mouse models of bacterial enteritis and septic shock. Collectively, scoparone displays potent anti-inflammatory effects via blocking NLRP3 inflammasome activation through enhancing mitophagy, highlighting a potential action mechanism in treating inflammasome-related diseases for further clinical investigation.

C-reactive protein/albumin ratio and IL-6 are associated with disease activity in patients with ulcerative colitis.

BACKGROUND: Cytokines are key mediators of the inflammation in ulcerative colitis (UC); there are inconsistent data on cytokines profile in patients with UC. C-reactive protein/albumin ratio (CRP/ALB) has also been found as an inflammatory indicator. However, the role of CRP/ALB in UC remains unclear. We aimed to evaluate the CRP/ALB ratio and cytokines profile in patients with UC. We further explore the association between CRP/ALB and inflammatory markers, such as erythrocyte sedimentation rate (ESR), fecal calprotectin (FC) and cytokines. METHODS: One hundred thirty UC patients and 65 controls were included in the study. Clinical and laboratory findings were retrospectively reviewed; differences in variables between two groups were examined using the Mann-Whitney U-test. The association between CRP/ALB, cytokines, and clinical parameters was determined by Spearman's correlation test. RESULTS: CRP/ALB levels were significantly elevated in active UC patients. The optimal cutoff level of the CRP/ALB was 0.083. The patients with active UC had a median interleukin-6 (IL-6) level of 7.715 pg/ml (interquartile ranges, IQR 3.475-14.63), which was significantly higher than those in remission (2.95 pg/ml, IQR 2.17-5.44) (p < 0.001). Positive correlations between CRP/ALB and inflammatory markers were also observed. CONCLUSIONS: Our results suggest that CRP/ALB and IL-6 could be potential biomarkers for assessment of clinical activity in Chinese patients with UC.

CircUBE2Q2 promotes differentiation of cattle muscle stem cells and is a potential regulatory molecule of skeletal muscle development.

BACKGROUND: The growth and development of muscle stem cells (MuSCs) are significant events known to affect muscle plasticity, disease, meat production, and meat quality, which involves the types and functions of mRNA and non-coding RNA. Here, MuSCs were cultured from Guangxi fetal cattle. RNA sequencing was used to analyze the RNA expression of mRNA and non-coding RNAs during the cell proliferation and differentiation phases. RESULTS: Two thousand one hundred forty-eight mRNAs and 888 non-coding RNAs were differentially expressed between cell proliferation and differentiation phases, including 113 miRNAs, 662 lncRNAs, and 113 circRNAs. RT-qPCR verified the differential expression levels of mRNAs and non-coding RNAs, and the differentially expressed circUBE2Q2 was subsequently characterized. Expression profile analysis revealed that circUBE2Q2 was abundant in muscle tissues and intramuscular fat. The expression of cricUBE2Q2 was also significantly upregulated during MuSCs myogenic differentiation and SVFs adipogenic differentiation and decreased with age in cattle muscle tissue. Finally, the molecular mechanism of circUBE2Q2 regulating MuSCs function that affects skeletal muscle development was investigated. The results showed that circUBE2Q2 could serve as a sponge for miR-133a, significantly promoting differentiation and apoptosis of cultured MuSCs, and inhibiting proliferation of MuSCs. CONCLUSIONS: CircUBE2Q2 is associated with muscle growth and development and induces MuSCs myogenic differentiation through sponging miR-133a. This study will provide new clues for the mechanisms by which mRNAs and non-coding RNAs regulate skeletal muscle growth and development, affecting muscle quality and diseases.

In Situ Anodic Oxidation Tuning of NiFeV Diselenide to the Core-Shell Heterojunction for Boosting Oxygen Evolution.

Developing non-noble metal-based core-shell heterojunction electrocatalysts with high catalytic activity and long-lasting stability is crucial for the oxygen evolution reaction (OER). Here, we prepared novel core-shell Fe,V-NiSe2@NiFe(OH)x heterostructured nanoparticles on hydrophilic-treated carbon paper with high electronic transport and large surface area for accelerating the oxygen evolution rate via high-temperature selenization and electrochemical anodic oxidation procedures. Performance testing shows that Fe,V-NiSe2@NiFe(OH)x possesses the highest performance for OER compared to as-prepared diselenide core-derived heterojunctions, which only require an overpotential of 243 mV at 10 mA cm-2 and a low Tafel slope of 91.6 mV decade-1 under basic conditions. Furthermore, X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) confirm the morphology and elementary stabilities of Fe,V-NiSe2@NiFe(OH)x after long-term chronopotentiometric testing. These advantages are largely because of the strong synergistic effect between the Fe,V-NiSe2 core with high conductivity and the amorphous NiFe(OH)x shell with enriched defects and vacancies. This study also presents a general approach to designing and synthesizing more active core-shell heterojunction electrocatalysts for OER.

Evaluation of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential markers for ulcerative colitis: a retrospective study.

PURPOSE: Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder affecting the large intestine. Inflammatory biomarkers in UC are nonspecific, simple and cheap biomarker is needed. Our study aimed to explore the possible relationship of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) with the disease activity in UC. Furthermore, the correlation of PLR or NLR with other clinical indicators was evaluated. METHODS: We retrospectively reviewed the clinical data of UC patients presented to the Affiliated Hospital of Nanjing TCM University. A total of 306 UC patients were included in the study. Clinical characteristics, NLR, PLR, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC) and other data were collected. RESULTS: PLR and NLR were elevated in active UC patients than those in remission. The receiver-operating characteristic (ROC) analysis revealed the optimal cutoff of NLR for active UC was 2.19, with sensitivity and specificity of 78.8 and 65%, respectively. For PLR, the best cut-off value was 147.96, with sensitivity and specificity of 58.3 and 75%, respectively. Both NLR and PLR were positively correlated with CRP, ESR and FC. CONCLUSIONS: PLR and NLR were elevated in patients with active UC as compared with patients in remission. NLR and PLR could be used in patients with UC as noninvasive markers of disease activity.

[Chronic psychological stress exacerbates aortic medial calcification via glucocorticoids].

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D3 (VitD3) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD3, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11ß-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD3, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.

Eosinophilic ascites: an unusual manifestation of eosinophilic gastroenteritis.

INTRODUCTION: Eosinophilic gastroenteritis is an uncommon disorder, characterized by eosinophilic infiltration of the gastrointestinal tract. Clinical presentations are variable. It depends on the involvement of GI layer. Eosinophilic ascites is a rare presentation of eosinophilic gastroenteritis and is often associated with the serosal form. CASE PRESENTATION: In this paper, we present a 26-year-old male with EGE who presented with massive hemorrhagic ascites and was successfully treated with steroids. CONCLUSION: The diagnosis of eosinophilic gastroenteritis requires histopathological examination and is often made after the exclusion of other possible causes of eosinophilia. EGE should be considered in a patient with unexplained hemorrhagic ascites.

Emerging role of zinc finger protein A20 as a suppressor of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the third leading cause of cancer-associated mortality worldwide, is a major public health problem. Zinc finger protein A20 (A20), an acute phase response gene, is a potent inhibitor of NF-κB signaling. A20 serves a critical role in liver protection, including limiting inflammation following hepatic injury, stimulating hepatocyte growth, and preventing hepatic ischemia-reperfusion injury. A20 is also involved in different processes, including tumorigenesis, progression, and metastasis through multiple mechanisms. Accumulated studies have reported the clinical implications and biological relevance of A20 in the development and progression of HCC. The underlying mechanisms of A20 in HCC include inhibition of epithelial-mesenchymal transition, protein tyrosine kinase 2 activation and Rac family GTPase 1 activity. Combining liver protection with tumor inhibition is a unique advantage of A20, which has the potential to be a novel treatment for promoting liver regeneration following liver resection in patients with HCC with liver cirrhosis. This review discusses the hepato-protective effect of A20 on hepatocytes and its potential role in cancer development, particularly its suppressor effect on HCC.

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation.

Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 ± 3.8 years (range 1.1-16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT.

CRISPR/dCas9-mediated transcriptional improvement of the biosynthetic gene cluster for the epothilone production in Myxococcus xanthus.

BACKGROUND: The CRISPR/dCas9 system is a powerful tool to activate the transcription of target genes in eukaryotic or prokaryotic cells, but lacks assays in complex conditions, such as the biosynthesis of secondary metabolites. RESULTS: In this study, to improve the transcription of the heterologously expressed biosynthetic genes for the production of epothilones, we established the CRISPR/dCas9-mediated activation technique in Myxococcus xanthus and analyzed some key factors involving in the CRISPR/dCas9 activation. We firstly optimized the cas9 codon to fit the M. xanthus cells, mutated the gene to inactivate the nuclease activity, and constructed the dCas9-activator system in an epothilone producer. We compared the improvement efficiency of different sgRNAs on the production of epothilones and the expression of the biosynthetic genes. We also compared the improvement effects of different activator proteins, the ω and α subunits of RNA polymerase, and the sigma factors σ54 and CarQ. By using a copper-inducible promoter, we determined that higher expressions of dCas9-activator improved the activation effects. CONCLUSIONS: Our results showed that the CRISPR/dCas-mediated transcription activation is a simple and broadly applicable technique to improve the transcriptional efficiency for the production of secondary metabolites in microorganisms. This is the first time to construct the CRISPR/dCas9 activation system in myxobacteria and the first time to assay the CRISPR/dCas9 activations for the biosynthesis of microbial secondary metabolites.

High YBX1 expression indicates poor prognosis and promotes cell migration and invasion in nasopharyngeal carcinoma.

Y-box binding protein-1 (YBX1) is a multifunctional protein and often acts as an indicator of poor prognosis in cancers. Increasing evidence has shown that the levels of YBX1 protein were closely associated with multidrug resistance, relapse, metastasis and poor prognosis in cancers. However, its role in nasopharyngeal carcinoma (NPC) metastasis remains unknown. In our study, we discovered that the expression of YBX1 was increased in nasopharyngeal carcinoma tissues. YBX1 protein levels positively correlated with T stage and metastasis of NPC patients. Moreover, expression of YBX1 was negatively correlated with membrane E-cadherin levels and positively correlated with Vimentin expression. In vitro, the expression of YBX1 was closely related to the invasive and migratory ability of nasopharyngeal carcinoma cells. Knockdown of YBX1 inhibited migration and invasion in 5-8F cells, and over-expression of YBX1 promoted CNE1 cells migration and invasion. Transforming growth factor-ß1 (TGF-ß1) treatment led to epithelial-to-mesenchymal transition (EMT) in CNE1 cells accompanied by elevated YBX1 expression. On the contrary, knockdown of YBX1 partially inhibited the TGF-ß1-induced CNE1 cell migration, together with changes of EMT-associated markers. Our study revealed that TGF-ß1/YBX1 signaling might be one of novel mechanisms mediating EMT in NPC, providing a new target for the treatment of nasopharyngeal carcinoma.

Accuracy of iohexol plasma clearance for GFR-determination: a comparison between single and dual sampling.

BACKGROUND: Current guidelines regarding plasma-sampling techniques for glomerular filtration rate (GFR) determination are inconsistent. Single-sample methods are commonly believed not to be precise enough to meet clinical demands. The present study compared the agreement between single- and dual- plasma sampling methods with a three-point plasma clearance of iohexol. METHODS: A total of 46 healthy volunteers and 124 chronic kidney disease (CKD) patients with varying degrees of renal dysfunction received 5 ml iohexol (300 mgI/ml) i.v. and plasma samples were drawn at 2-, 3- and 4-h post-injection. Plasma-iodine concentrations were detected by high-performance liquid chromatography (HPLC). RESULTS: Bias was similar among single-plasma sampling methods (SPSM) and dual-plasma sampling methods (DPSM). The best correlation was obtained from the 2- and 4-h DPSM (concordance correlation coefficient [CCC]: 0.9988) with none of the estimates differed by more than 30% from the reference GFR and only one (0.06%) estimate differed by more than 10% (P30, 100%; P10, 99.4%). SPSM using samples around 3- or 4-h demonstrated acceptable accuracy at a GFR level of ≥60 ml/min/1.73m2 (P30 = 100% and P10 > 75% for both measurements). CONCLUSION: 4-h SPSM is advantageous in clinical practice in subjects with GFR ≥ 60 ml/min/1.73m2. For patients with an expected GFR < 60 ml/min/1.73m2, a prolonged sampling time is more reliable.

Conservative and surgical treatment of pediatric asymptomatic lumbosacral lipoma: a meta-analysis.

The aim of this study is to compare the outcomes of surgical and conservative treatments of pediatric asymptomatic lumbosacral lipomas, and to address whether the patients can benefit from prophylactic surgeries. The literature reports of surgical and conservative treatments of child asymptomatic lumbosacral lipomas were reviewed and collected, and a meta-analysis of the reports regarding the incidence of sphincter and lower limb dysfunctions was performed. A total of five literatures were collected, containing a total of 403 patients, among which 124 patients received conservative treatments with 32 (25.81%) cases developing neurological dysfunctions during follow-up, and 279 received prophylactic surgical treatments with 30 (10.75%) patients developing neurological dysfunctions in follow-up, the difference being statistically significant (P ≤ 0.05). For pediatric asymptomatic lumbosacral lipomas of the three major subtypes, the limited source of literature so far suggests that prophylactic surgery is superior to conservative strategy in preventing the patients from neurological deterioration. Larger patient cohorts, randomized studies, and longer length of follow-ups are needed for further corroboration.

Use of a dose-response model to guide future clinical trial of benvitimod cream to treat mild and moderate psoriasis.

OBJECTIVE: To investigate the time-dose-response relationship of benvitimod cream after topical administration in patients with mild and moderate psoriasis vulgaris for dosage regimen exploring. METHODS: 36 patients with mild and moderate psoriasis vulgaris were randomly assigned to receive 0.5%, 1.0%, 1.5%, and 0% (placebo) benvitimod cream of 30 g/1.7 m2 twice daily for 6 weeks. The primary efficacy outcome was the proportion of patients achieving more than 75% change of the psoriasis area and severity index (PASI 75) from baseline. A longitudinal Emax model was established using the NONMEM method, and then applied to try to find an appropriate dose for following trials. RESULTS: In the final time-dose-response model, the primary outcome at week 6 of PASI 75 of the 0.5%, 1.0%, and 1.5% benvitimod cream was 31%, 63%, and 75%, respectively, demonstrating that the 1.0% benvitimod cream was an appropriate dose for the next trial. The time parameters of ET50 and ET90 were 15 and 69 days for 1.0% benvitimod cream, indicating that the maximum efficacy of PASI change rate was obtained at approximately week 10. The accuracy of PASI change rate by extrapolation prediction was limited at week 10, so the treatment period should be longer in future trials. CONCLUSIONS: The established dose-response model could well describe the relationship between PASI change rate and doses of benvitimod cream in patients with mild and moderate psoriasis vulgaris. This modeling approach may help choose 1.0% benvitimod cream twice daily as a dosage regimen in following clinical trials.

Probing hidden sectors with Stückelberg U(1) gauge fields.

We propose a framework in which visible matter interacts with matter from a hidden sector through mass mixings of Stückelberg U(1) gauge fields. In contrast to other Z(') mediation scenarios, our setup has the added appealing features that (i) the choice of Z(')'s can be significantly broadened without necessarily introducing unwanted exotic matter and (ii) there can be sizable tree-level interactions between the visible and hidden sectors. String theory embeddings of this scenario and their phenomenological features are briefly discussed.

Water-soluble red fluorescent protein dimers for hypoxic two-photon photodynamic therapy.

In this study, two water-soluble red fluorescent protein (RFP) dimers, FP2R' and FP2R'', were synthesized by linking two phenothiazine-based RFP chromophore analogues through alkyl chains or alkoxy chains for hypoxic two-photon photodynamic therapy. RFP dimers are heavy-atom-free two-photon photosensitizers in which the intersystem crossing process is boosted by S and N heteroatoms. In terms of the aqueous solubility, the saturation concentration of FP2R'' was 3.5 mM, the emission wavelength was 677 nm, the singlet oxygen yield was 18%, and the two-photon absorption coefficient (ß) was 2.1 × 10-11 cm W-1. Further, the RFP dimer FP2R'' showed excellent biocompatibility, negligible dark toxicity, and could produce 1O2 and O2˙- simultaneously. Under 460 nm illumination, the photosensitizer FP2R'' showed high phototoxicity with an IC50 value of 4.08 µM in an hypoxia environment, indicating that the photosensitizer FP2R'' has an excellent anti-hypoxia ability. In addition, the photosensitizer FP2R'' demonstrated a precise localization ability to lysosomes and its Pearson's colocalization coefficient was 0.94, which could guide the aggregation of photosensitizers in the lysosomes of tumor cells to effectively improve its photodynamic therapy (PDT) effect. In particular, when exposed to 800 nm two-photon excitation, FP2R'' effectively produced 1O2 and O2˙- in zebrafish and exhibited a bright two-photon fluorescence imaging capability. At the same time, the efficacy of two-photon photodynamic therapy mediated by the photosensitizer FP2R'' was verified in the tumor zebrafish model, and the growth of tumor cells in zebrafish was significantly inhibited under a two-photon laser irradiation. The water-soluble two-photon photosensitizer FP2R'' that was reasonably constructed in this study can be used as a high-efficiency hypoxic two-photon photosensitizer to inhibit deep tumor tissues.