Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice.

BACKGROUND: Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. METHODS: The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-ß1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-ß1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. RESULTS: CCl4 exposure or TGF-ß1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-ß1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-ß1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. CONCLUSION: GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

Efficacy and safety of SBRT combined with sintilimab and IBI305 in patients with advanced HCC and previously failed immunotherapy: study protocol of a phase 2 clinical trial.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors, has been recommended as first-line treatment for advanced HCC. However, two-thirds of patients did not benefit from this form of immunotherapy. Currently, data on the subsequent regimen for patients previously treated with ICIs are lacking. Studies have shown that the combination of radiotherapy (RT) and ICIs is a potentially effective second-line therapy for HCC. This study aims to assess the efficacy and safety of combined therapy with stereotactic body RT (SBRT), sintilimab and IBI305 (a biosimilar of bevacizumab) in patients with HCC following the progression of first-line ICI therapy. METHODS AND ANALYSIS: This study is an open-label, single-arm, single-centre, phase 2 trial of 21 patients with advanced HCC in whom previous ICI therapy has failed. Participants will receive approximately 30-40 Gy/5-8F SBRT, followed by 200 mg sintilimab and 15 mg/kg IBI305 intravenously every 3 weeks. Treatment will continue until the development of unacceptable toxicity or disease progression. We will use Simon's two-stage design, with the objective response rate (ORR) as the primary endpoint. Secondary endpoints include ORR of lesions without RT, disease control rate, progression-free survival, overall survival and safety. ETHICS AND DISSEMINATION: The study was authorised by the Medical Ethics Committee. Dissemination of results will occur via a peer-reviewed publication and other relevant media. TRIAL REGISTRATION NUMBER: ChiCTR2200056068.

The global distribution of the macrolide esterase EstX from the alpha/beta hydrolase superfamily.

Macrolide antibiotics, pivotal in clinical therapeutics, are confronting resistance challenges mediated by enzymes like macrolide esterases, which are classified into Ere-type and the less studied Est-type. In this study, we provide the biochemical confirmation of EstX, an Est-type macrolide esterase that initially identified as unknown protein in the 1980s. EstX is capable of hydrolyzing four 16-membered ring macrolides, encompassing both veterinary (tylosin, tidipirosin, and tilmicosin) and human-use (leucomycin A5) antibiotics. It uses typical catalytic triad (Asp233-His261-Ser102) from alpha/beta hydrolase superfamily for ester bond hydrolysis. Further genomic context analysis suggests that the dissemination of estX is likely facilitated by mobile genetic elements such as integrons and transposons. The global distribution study indicates that bacteria harboring the estX gene, predominantly pathogenic species like Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae, are prevalent in 74 countries across 6 continents. Additionally, the emergence timeline of the estX gene suggests its proliferation may be linked to the overuse of macrolide antibiotics. The widespread prevalence and dissemination of Est-type macrolide esterase highlight an urgent need for enhanced monitoring and in-depth research, underlining its significance as an escalating public health issue.

Phosphorus adsorption from aqueous solutions using different types of cement: kinetics, isotherms, and mechanisms.

Exploring low-cost and high-performance phosphorus (P) adsorbents is key to controlling P contamination in water. This study evaluated the P adsorption performance of three types of cement: Ordinary Portland cement (OPC), Portland slag cement (PSC), and Portland pozzolana cement (PPC). Furthermore, SEM-EDS, XRD, XPS, and FTIR were employed to reveal the adsorption mechanism. The results showed that the pseudo-second-order model exhibited higher regression coefficients than the pseudo-first-order model, indicating that chemisorption dominated the adsorption process. The Langmuir equation fitted the P adsorption data well, with maximum P adsorption capacities of 245.8, 226.1, and 210.0 mg g-1 for OPC, PSC, and PPC at 25 °C, respectively. P adsorption capacities decreased gradually with increasing initial pH and reached their maximum values at pH 3. The anions of F-, CO32-, and SO42- negatively affected P adsorption due to the competitive adsorption with Ca2+. The results of XPS, XRD, and FTIR confirmed that Ca-P precipitates (i.e., hydroxyapatite) were the main removal mechanism. A real domestic sewage experiment showed that 0.6 g L-1 OPC effectively reduced the P concentration from 2.4 to below 0.2 mg L-1, with a dosage cost of 0.034 $ per ton. This study indicated that cement, as a low-cost and efficient P adsorbent, has great potential for application in removing P from acidic and neutral wastewater.

USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase.

BACKGROUND: Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment. METHODS: The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1. RESULTS: Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism. CONCLUSION: USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.

Electric-field control of nonvolatile resistance state of perpendicular magnetic tunnel junction via magnetoelectric coupling.

Magnetic tunnel junctions (MTJs) are the core elements of spintronic devices. Now, the mainstream writing operation of MTJs mainly relies on electric current with high energy dissipation, which can be greatly reduced if an electric field is used instead. In this regard, strain-mediated multiferroic heterostructure composed of MTJ and ferroelectrics are promising with the advantages of room temperature and magnetic field-free as already demonstrated by MTJ with in-plane magnetic anisotropy. However, there is no such report on the perpendicular MTJs (p-MTJs), which have been commercialized. Here, we investigate electric-field control of resistance state of MgO-based p-MTJs in multiferroic heterostructures. A remarkable and nonvolatile manipulation of resistance is demonstrated at room temperature without magnetic field assistance. Through various characterizations and micromagnetic simulation, the manipulation mechanism is uncovered. Our work provides an effective avenue for manipulating p-MTJ resistance by electric fields and is notable for high density and ultralow power spintronic devices.

Experimental Study of the Mechanical Properties of Full-Scale Rubber Bearings at 23 °C, 0 °C, and -20 °C.

In this study, the effects of ambient temperature on the horizontal mechanical performance of isolated rubber bearings were investigated using high-speed reciprocating loading methods. A comprehensive series of 54 experimental trials are performed on the full-scale (900 mm-diameter) isolation rubber bearings, encompassing a range of temperatures (-20 °C, 0 °C, and 23 °C), shear pressures (50%, 100%, and 250%), and frequencies (0.20 Hz, 0.25 Hz, and 0.30 Hz). Because the compression-shear tests were conducted at high velocities and pressures (specifically, vertical compressive stress of 15 MPa), the equipment used in these tests was capable of generating substantial inertial and frictional forces. Appropriate correction methodologies for the precise determination of mechanical performance metrics for bearings are presented. Then, a comprehensive investigation of the effects of various loading conditions on the characteristic strength, post-yield stiffness, horizontal equivalent stiffness, and equivalent damping ratio of LRB900 (lead-core rubber bearings 900 mm-diameter) and LNR900 (linear natural rubber bearings 900 mm-diameter) is conducted. The empirical results show a discernible relationship between these characteristics and ambient temperature as the number of loading cycles increases, except for the equivalent damping ratio. Finally, empirical fitting formulations incorporating the influence of ambient temperature are presented for each performance indicator. These formulas are intended to assist designers in performing seismic design analyses by allowing them to take into consideration the effects of ambient temperature comprehensively.

Transcriptome analysis of Kluyveromyces marxianus under succinic acid stress and development of robust strains.

Kluyveromyces marxianus has become an attractive non-conventional yeast cell factory due to its advantageous properties such as high thermal tolerance and rapid growth. Succinic acid (SA) is an important platform molecule that has been applied in various industries such as food, material, cosmetics, and pharmaceuticals. SA bioproduction may be compromised by its toxicity. Besides, metabolite-responsive promoters are known to be important for dynamic control of gene transcription. Therefore, studies on global gene transcription under various SA concentrations are of great importance. Here, comparative transcriptome changes of K. marxianus exposed to various concentrations of SA were analyzed. Enrichment and analysis of gene clusters revealed repression of the tricarboxylic acid cycle and glyoxylate cycle, also activation of the glycolysis pathway and genes related to ergosterol synthesis. Based on the analyses, potential SA-responsive promoters were investigated, among which the promoter strength of IMTCP2 and KLMA_50231 increased 43.4% and 154.7% in response to 15 g/L SA. In addition, overexpression of the transcription factors Gcr1, Upc2, and Ndt80 significantly increased growth under SA stress. Our results benefit understanding SA toxicity mechanisms and the development of robust yeast for organic acid production. KEY POINTS: • Global gene transcription of K. marxianus is changed by succinic acid (SA) • Promoter activities of IMTCP2 and KLMA_50123 are regulated by SA • Overexpression of Gcr1, Upc2, and Ndt80 enhanced SA tolerance.

Effective nitrogen doping of TiO2 polymorphs at mild temperatures for visible-light-responsive hydrogen evolution.

Herein, a mild-temperature nitrogen doping route with the urea-derived gaseous species as the active doping agent is proposed to realize visible-light-responsive photocatalytic hydrogen evolution both for the anatase and rutile TiO2. DFT simulations reveal that the cyanic acid (HOCN), derived from the decomposition of urea, plays a curial role in the effective doping of nitrogen in TiO2 at mild temperatures. Photocatalytic performance demonstrates that both the anatase and rutile TiO2 doped at mild temperatures exhibit the highest hydrogen evolution rates, although the ones prepared at high temperatures possess higher absorbance in the visible range. Steady-state and transient surface photovoltage characterizations of these doped TiO2 polymorphs prepared at different temperatures reveal that harsh conditions (high temperature reaction) typically result in the formation of intrinsic defects that are detrimental to the transport of the low-energy visible-light-induced electrons, while the mild-temperature nitrogen-doping could flatten the pristine upward band bending without triggering the formation of Ti3+, thus achieving enhanced visible-light-responsive hydrogen evolution rates. We anticipate that our findings will provide inspiring information for shrinking the gap between the visible-light-absorbance and the visible-light-responsiveness in the band engineering of wide-bandgap metal-oxide photocatalysts.

Agrimol B alleviates cisplatin-induced acute kidney injury by activating the Sirt1/Nrf2 signaling pathway in mice.

Cisplatin (CDDP) is a widely used chemotherapeutic agent that has remarkable antineoplastic effects. However, CDDP can cause severe acute kidney injury (AKI), which limits its clinical application. Agrimol B is the main active ingredient found in Agrimonia pilosa Ledeb and has a variety of pharmacological activities. The effect of agrimol B on CDDP-induced renal toxicity has not been determined. To investigate whether agrimol B has a protective effect against CDDP-induced AKI, we first identify Sirtuin 1 (Sirt1) as a critical target protein of agrimol B in regulating AKI through network pharmacology analysis. Subsequently, the AKI mouse model is induced by administering a single dose of CDDP via intraperitoneal injection. By detecting the serum urea nitrogen and creatinine levels, as well as the histopathological changes, we confirm that agrimol B effectively reduces CDDP-induced AKI. In addition, treatment with agrimol B counteracts the increase in renal malondialdehyde level and the decrease in superoxide dismutase (SOD), catalase and glutathione levels induced by CDDP. Moreover, western blot results reveal that agrimol B upregulates the expressions of Sirt1, SOD2, nuclear factor erythroid2-related factor 2, and downstream molecules, including heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1. However, administration of the Sirt1 inhibitor EX527 abolishes the effects of agrimol B. Finally, we establish a tumor-bearing mouse model and find that agrimol B has a synergistic antitumor effect with CDDP. Overall, agrimol B attenuates CDDP-induced AKI by activating the Sirt1/Nrf2 signaling pathway to counteract oxidative stress, suggesting that this compound is a potential therapeutic agent for the treatment of CDDP-induced AKI.

Calcium silicate/gelatin composite scaffolds with controllable degradation behavior: Fabrication and evaluation.

Calcium silicate can be used as an excellent material for biodegradable bone scaffolds because it can provide bioactive ions to promote bone regeneration. However, the brittleness and rapid degradation of calcium silicate scaffolds have significantly limited their clinical application. In this work, the calcium silicate scaffolds printed by DLP technology were immersed in a gelatin solution under high vacuum condition to obtain calcium silicate/gelatin composite scaffolds with good mechanical and biological properties. Then, genipin was used as a cross-linker for gelatin to control the degradation properties of the composite scaffolds. The initial compressive strength and toughness of the composite scaffolds were 5.0 times and one order of magnitude higher than those of the pure calcium silicate scaffolds, respectively. The gelatin on the surface of the scaffolds could effectively act as a protective layer to regulate the degradation behaviors of the calcium silicate substrate through controlling the crosslinking degree of the gelatin. After degrading for 14 days, the composite scaffolds at 1.0 % genipin concentration exhibited the highest compressive strength of 8.6 ± 0.8 MPa, much higher than that of the pure ceramic scaffold (1.5 ± 0.3 MPa). It can be found that the toughness of the composite scaffolds were almost over 13.2 times higher than that of the pure ceramic scaffold during degradation, despite the higher toughness loss for the former. Furthermore, the composite scaffolds showed enhanced cell biocompatibility and viability. These results demonstrate that the calcium silicate/gelatin composite scaffolds can be a promising candidate in bone tissue regeneration.

Enhanced ammonia removal in tidal flow constructed wetland by incorporating steel slag: Performance, microbial community, and heavy metal release.

Utilizing alkaline solid wastes, such as steel slag, as substrates in tidal flow constructed wetlands (TFCWs) can effectively neutralize the acidity generated by nitrification. However, the impacts of steel slag on microbial communities and the potential risk of heavy metal release remain poorly understood. To address these knowledge gaps, this study compared the performance and microbial community structure of TFCWs filled with a mixture of steel slag and zeolite (TFCW-S) to those filled with zeolite alone (TFCW-Z). TFCW-S exhibited a much higher NH4+-N removal efficiency (98.35 %) than TFCW-Z (55.26 %). Additionally, TFCW-S also achieved better TN and TP removal. The steel slag addition helped maintain the TFCW-S effluent pH at around 7.5, while the TFCW-Z effluent pH varied from 3.74 to 6.25. The nitrification and denitrification intensities in TFCW-S substrates were significantly higher than those in TFCW-Z, consistent with the observed removal performance. Moreover, steel slag did not cause excessive heavy metal release, as the effluent concentrations were below the standard limits. Microbial community analysis revealed that ammonia-oxidizing bacteria, ammonia-oxidizing archaea, and complete ammonia-oxidizing bacteria coexisted in both TFCWs, albeit with different compositions. Furthermore, the enrichment of heterotrophic nitrification-aerobic denitrification bacteria in TFCW-S likely contributed to the high NH4+-N removal. In summary, these findings demonstrate that the combined use of steel slag and zeolite in TFCWs creates favorable pH conditions for ammonia-oxidizing microorganisms, leading to efficient ammonia removal in an environmentally friendly manner.

Magnetic Field Enhanced Oxygen Reduction Reaction via Oxygen Diffusion Speedup.

The mass-transfer of oxygen in liquid phases (including in the bulk electrolyte and near the electrode surface) is a critical step to deliver oxygen to catalyst sites (especially immersed catalyst sites) and use the full capacity of oxygen reduction reaction (ORR). Despite the extensive efforts of optimizing the complex three-phase reaction interfaces to enhance the gaseous oxygen transfer, strong limitations remain due to oxygen's poor solubility and slow diffusion in electrolytes. Herein, a magnetic method for boosting the directional hydrodynamic pumping of oxygen toward immersed catalyst sites is demonstrated which allows the ORR to reach otherwise inaccessible catalytic regions where high currents normally would have depleted oxygen. For Pt foil electrodes without forced oxygen saturation in KOH electrolytes, the mass-transfer-limited current densities can be improved by 60% under an external magnetic field of 435 mT due to the synergistic effect between bulk- and surface-magnetohydrodynamic (MHD) flows induced by Lorentz forces. The residual magnetic fields are further used at the surface of magnetic materials (such as CoPt alloys and Pt/FeCo heterostructures) to enhance the surface-MHD effect, which helps to retain part of the ORR enhancement permanently without applying external magnetic fields.

Near-infrared â ¡ light-assisted Cu-containing porous TiO2 coating for combating implant-associated infection.

Treatment implant-associated infections remains a severe challenge in the clinical practice. This work focuses on the fabrication of Cu-containing porous TiO2 coatings on titanium (Ti) by a combination of magnetron sputtering and dealloying techniques. Additionally, photothermal therapy is employed to enhance the effect of Cu ions in preventing bacterial infection. After the dealloying, most of Cu element was removed from the magnetron sputtered Cu-containing films, and porous TiO2 coatings were prepared on Ti. The formation of porous nanostructures significantly enhanced the photothermal conversion performance under NIR-II light irradiation. The combined effect of hyperthermia and Cu ions demonstrated enhanced antibacterial activity in both in vitro and in vivo experiments, and the antibacterial efficiency can reach 99% against Streptococcus mutans. Moreover, the porous TiO2 coatings also exhibited excellent biocompatibility. This modification of the titanium surface structure through dealloying changes may offer a novel approach to enhance the antimicrobial properties of titanium implants.

The Printability, Microstructure, and Mechanical Properties of Fe80-xMnxCo10Cr10 High-Entropy Alloys Fabricated by Laser Powder Bed Fusion Additive Manufacturing.

This work investigated the effect of Fe/Mn ratio on the microstructure and mechanical properties of non-equimolar Fe80-xMnxCo10Cr10 (x = 30% and 50%) high-entropy alloys (HEAs) fabricated by laser powder bed fusion (LPBF) additive manufacturing. Process optimization was conducted to achieve fully dense Fe30Mn50Co10Cr10 and Fe50Mn30Co10Cr10 HEAs using a volumetric energy density of 105.82 J·mm-3. The LPBF-printed Fe30Mn50Co10Cr10 HEA exhibited a single face-centered cubic (FCC) phase, while the Fe50Mn30Co10Cr10 HEA featured a hexagonal close-packed (HCP) phase within the FCC matrix. Notably, the fraction of HCP phase in the Fe50Mn30Co10Cr10 HEAs increased from 0.94 to 28.10%, with the deformation strain ranging from 0 to 20%. The single-phase Fe30Mn50Co10Cr10 HEA demonstrated a remarkable combination of high yield strength (580.65 MPa) and elongation (32.5%), which surpassed those achieved in the FeMnCoCr HEA system. Comparatively, the dual-phase Fe50Mn30Co10Cr10 HEA exhibited inferior yield strength (487.60 MPa) and elongation (22.3%). However, it displayed superior ultimate tensile strength (744.90 MPa) compared to that in the Fe30Mn50Co10Cr10 HEA (687.70 MPa). The presence of FCC/HCP interfaces obtained in the Fe50Mn30Co10Cr10 HEA resulted in stress concentration and crack expansion, thereby leading to reduced ductility but enhanced resistance against grain slip deformation. Consequently, these interfaces facilitated an earlier attainment of yield limit point and contributed to increased ultimate tensile strength in the Fe50Mn30Co10Cr10 HEA. These findings provide valuable insights into the microstructure evolution and mechanical behavior of LPBF-printed metastable FeMnCoCr HEAs.

Targeting FBXO22 enhances radiosensitivity in non-small cell lung cancer by inhibiting the FOXM1/Rad51 axis.

Radioresistance is a major constraint on the efficacy of lung cancer radiotherapy, but its mechanism has not been fully elucidated. Here, we found that FBXO22 was aberrantly highly expressed in lung cancer and that FBXO22 knockdown increased the radiosensitivity of lung cancer cells. Mechanistically, FBXO22 promoted Rad51 gene transcription by increasing the level of FOXM1 at the Rad51 promoter, thereby inducing the formation of lung cancer radioresistance. Furthermore, we found that deguelin, a potential inhibitor of FBXO22, enhanced radiosensitivity in an FBXO22/Rad51-dependent manner and was safely tolerated in vivo. Collectively, our results illustrate that FBXO22 induces lung cancer radioresistance by activating the FOXM1/Rad51 axis and provide preclinical evidence for the clinical translation of this critical target.

Transforming aggression into creativity: Creative thinking training as a new strategy for aggression intervention.

Although reducing students' aggressive behaviors and improving their creativity are both important commitments of educators, they are usually treated independently as unrelated tasks. However, cumulative evidence suggests potential links between aggression and creativity, not only from the perspectives of personality traits and psychological development, but also from their shared cognitive mechanisms. This implies that there may be an approach to achieving these two goals through a single intervention. Moreover, this new approach may overcome the limitation of the usually adopted aggression intervention, which is limited in its regulatory effectiveness and might bring about some disadvantageous impacts on creativity that are closely associated with aggression. To test this possibility, the present study implemented a four-session, 2-week creative thinking training (CTT) intervention for students with high aggression scores to examine whether it could simultaneously downregulate aggression and increase creativity. Our results demonstrate that, compared to the control group, the intervention group experienced significant improvements in creativity and a reduction in aggression following the CTT intervention. Furthermore, our findings suggest that this regulatory effect can persist for up to 6 months. The CTT-induced creativity change (increase) could significantly correlate with and predict the CTT-induced aggression decrease, thus suggesting that the CTT could transform aggression into creativity.

Physiologically-Based Pharmacokinetic Modeling of Blood Clearance of Liver Fluorescent Markers for the Assessment of the Degree of Hepatic Ischemia-Reperfusion Injury.

During liver transplantation, ischemia-reperfusion injury (IRI) is inevitable and decreases the overall success of the surgery. While guidelines exist, there is no reliable way to quantitatively assess the degree of IRI present in the liver. Our recent study has shown a correlation between the bile-to-plasma ratio of FDA-approved sodium fluorescein (SF) and the degree of hepatic IRI, presumably due to IRI-induced decrease in the activity of the hepatic multidrug resistance-associated protein 2 (MRP2); however, the contribution of SF blood clearance via the bile is still convoluted with other factors, such as renal clearance. In this work, we sought to computationally model SF blood clearance via the bile. First, we converted extant SF fluorescence data from rat whole blood, plasma, and bile to concentrations using calibration curves. Next, based on these SF concentration data, we generated a "liver-centric", physiologically-based pharmacokinetic (PBPK) model of SF liver uptake and clearance via the bile. Model simulations show that SF bile concentration is highly sensitive to change in the activity of hepatic MPR2. These simulations suggest that SF bile clearance along with the PBPK model can be used to quantify the effect of IRI on the activity of MRP2.Clinical Relevance- This study establishes the theory necessary to generate a model for predicting the degree of IRI during liver transplantation.

P4HA1 expression and function in esophageal squamous cell carcinoma.

This study aimed to explore the effect of P4HA1 (prolyl 4-hydroxylase subunit α1) and its ratio on the prognosis of esophageal squamous cell carcinoma. The expression data of P4HA1 in esophageal cancer in The Cancer Genome Atlas and Genotype-Tissue Expression were collected using the public database gene expression profiling interactive analysis. The expression levels of P4HA1 were examined by immunohistochemistry. The relationship between P4HA1 expression and clinicopathological parameters was analyzed the χ2 test. Survival analysis was performed to investigate the effect of P4HA1 and its ratio on prognosis. Compared with normal esophageal mucosal epithelium, there was higher P4HA1 gene mRNA in esophageal cancer tissue. Regarding the expression level, no significant difference was observed in patients with stage I-IV esophageal cancer. Immunohistochemistry showed that P4HA1 was highly expressed in esophageal squamous cell carcinoma (68.7%), while it was negatively expressed in paracancerous tissues. There was a significant difference in expression between cancer and adjacent tissues. The expression of P4HA1 associated with the degree of tumor differentiation, site, lymph node metastasis, and tumor node metastasis stage. The prognostic factors that affected the OS (overall survival) of esophageal cancer patients were the degree of differentiation, lymph node metastasis, and P4HA1 expression. Multivariate analysis of the OS results of patients showed that lymph node metastases and P4HA1 expression were independent prognostic factors that affected the OS of esophageal cancer patients. The prognostic factors affecting the PFS (progression-free survival) of esophageal cancer patients in the univariate survival analysis were as follows: degree of differentiation, lymph node metastasis, and P4HA1 expression. In addition, multivariate analysis of the PFS results of patients showed that lymph node metastasis and P4HA1 expression were independent prognostic factors that affected the PFS of esophageal cancer patients. P4HA1 may be a novel potential biomarker for the early diagnosis, prognosis, and targeted therapy of esophageal cancer.

The impact of three carbapenems at a single-day dose on intestinal colonization resistance against carbapenem-resistant Klebsiella pneumoniae.

IMPORTANCE: The intestinal colonization of carbapenem-resistant Klebsiella pneumoniae (CRKP) is an important source of clinical infection. Our research showed that even single-day dose use of carbapenems caused CRKP colonization and continuous bacterial shedding, which reminds clinical doctors to prescribe carbapenems cautiously. Whenever possible, ertapenem should be the preferred choice over other carbapenems especially when the identified or highly suspected pathogens can be effectively targeted by ertapenem.