CPS1 augments hepatic glucagon response through CaMKII/FOXO1 pathway.

Introduction: Elevated glucagon levels are a characteristic feature of type 2 diabetes. This abnormal increase in glucagon can lead to an accelerated rate of gluconeogenesis. Glucagon also stimulates hepatic metabolism of amino acids, particularly promoting the formation of urea. The specific role of carbamoyl phosphate synthetase 1 (CPS1), a rate-limiting enzyme in the urea cycle, in the development versus the persistence of glucagon-induced hyperglycemia has not been previously established. Methods: The study employed both in vivo and in vitro approaches to assess the impact of CPS1 modulation on glucagon response. CPS1 was knockdown or overexpression to evaluate its influence on hepatic gluconeogenesis. In addition, an in-silico strategy was employed to identify a potential CPS1 inhibitor. Results: Knockdown of CPS1 significantly reduced the glucagon response both in vivo and in vitro. Conversely, overexpression of CPS1 resulted in an overactive hepatic gluconeogenic response. Mechanistically, CPS1 induced the release of calcium ions from the endoplasmic reticulum, which in turn triggered the phosphorylation of CaMKII. The activation of CaMKII then facilitated the dephosphorylation and nuclear translocation of FOXO1, culminating in the enhancement of hepatic gluconeogenesis. Furthermore, cynarin, a natural CPS1 inhibitor derived from the artichoke plant, had the capacity to attenuate the hepatic glucagon response in a CPS1-dependent manner. Discussion: CPS1 played a pivotal role in mediating glucagon-induced hepatic gluconeogenesis. The discovery of cynarin as a natural inhibitor of CPS1 suggested its potential as a therapeutic agent for diabetes treatment.

[Research Progress in Diagnosis and Treatment of Acute Leukemia Complicated with Pulmonary Infection--Review].

Acute leukaemia is a group of aggressive malignancies with a high mortality rate. The reduction in functional immune cells due to the disease itself and radiotherapy/chemotherapy makes the patients susceptible to co-infections, of which pulmonary infection is a major cause of death. Early accurate diagnosis and appropriate treatment may prevent the spread of infection in patients with acute leukaemia complicated with pulmonary infection, thus reduce serious complications such as sepsis, respiratory failure and multi-organ failure. However, there are still clinical difficulties in the diagnosis and treatment of pulmonary infections in acute leukemia patients. Therefore, the current research advances in the diagnosis and treatment of bacterial, fungal and viral infections in the lungs of patients with acute leukemia were briefly summarized in this review.

Unmasking the reactants inhomogeneity in gas diffusion layer and the performances of PEMFC induced by assembly pressure.

The gas diffusion layer (GDL), as the bridge to reactants and electrons in PEMFC, is a carbon-based porous component and would be deformed under compression to induce changes in the distributions of reactants and the corresponding performances of PEMFC; therefore, unmasking the impacts of assembly pressure on the distribution of the reactants in GDL is significant to improve the performance of PEMFC. In the present article, the structural response of GDL to assembly pressure was first studied; the variations in transport properties of GDL and the reactant distributions induced by assembly pressure were then discussed; the impacts on the dynamic performances of PEMFC were finally investigated. From the results, assembly pressure was found to have different effects on the regions of GDL under the rib and channel, significant gaps in GDL porosity and/or GDL permeability existed near the rib/channel transition region to worsen the inhomogeneity of reactants. Suffering assembly pressure, the distribution of current density became uneven, and the current density near the rib-channel border seriously rose to the aggravated risk of MEA thermal damage. Furthermore, the power density at specific efficiencies was raised under certain assembly pressures, which meant suitable assembly pressure(s) existed for better output performances of PEMFC.

A machine learning system for artificial ligaments with desired mechanical properties in ACL reconstruction applications.

The anterior cruciate ligament is one of the important tissues to maintain the stability of the human knee joint, but it is difficult for this ligament to self-heal after injury. Consequently, transplantation of artificial ligaments (ALs) has gained widespread attention as an important alternative treatment method in recent years. However, accurately predicting the intricate mechanical properties of ALs remains a formidable challenge, particularly when employing theoretical frameworks such as braiding theory. This obstacle presents a significant impediment to achieving optimal AL design. Therefore, in this study, a high-precision machine learning model based on an artificial neural network was developed to rapidly and accurately predict the mechanical properties of ALs. The results showed that the proposed model achieved a reduction of 45.22% and 50.17% in the normalized root mean square error on the testing set when compared to traditional machine learning models (Random Forest and Support Vector Machine), demonstrating its higher accuracy. In addition, the design of ALs with desired mechanical properties was achieved by optimizing the braiding parameters, and its effectiveness was verified through experiments. The mechanical properties of the prepared ALs were able to fully meet the desired targets and were at least 2% higher. Finally, the influence weights of different braiding parameters on the mechanical properties of ALs were analyzed by feature importance.

Design, synthesis and cytotoxic activity of sulfonylated derivatives of camptothecin.

With the intention of advancing our research on diverse C-20 derivatives of camptothecin (CPT), 38 CPT derivatives bearing sulphonamide and sulfonylurea chemical scaffolds and different substituent groups have been designed, synthesised and evaluated in vitro for cytotoxicity against four tumour cell lines, A-549 (lung carcinoma), KB (nasopharyngeal carcinoma), MDA-MB-231 (triple-negative breast cancer) and KBvin (an MDR KB subiline). As a result, all the synthesised compounds showed promising in vitro cytotoxic activity against the four cancer cell lines tested, and were more potent than irinotecan. Importantly, compounds 12b, 12f, 12j and 13 l possessed better antiproliferative activity against all tested tumour cell lines with IC50 values of 0.0118 - 0.5478 µM, and resulted approximately 3 to 4 times more cytotoxic than topotecan against multidrug-resistant KBvin subline. Convincing evidences are achieved that incorporation of sulphonamide and sulfonylurea motifs into position-20 of camptothecin confers markedly enhanced cytotoxic activity against cancer cell lines.

A set of diagnostic tests for detection of active Babesia duncani infection.

OBJECTIVES: Human babesiosis is an emerging and potentially fatal tick-borne disease caused by intraerythrocytic parasites of the Babesia genus. Among these, Babesia duncani is particularly notable for causing severe and life-threatening illness in humans. Accurate diagnosis and effective disease management hinge on the detection of active B. duncani infections. While molecular assays are available to detect the parasite in blood, a reliable method for identifying biomarkers of active infection remains elusive. METHODS: We developed the first B. duncani antigen capture assays, targeting two immunodominant antigens, BdV234 and BdV38. These assays were validated using established in vitro and in vivo B. duncani infection models, and following drug treatment. RESULTS: The assays demonstrated no cross-reactivity with other species such as B. microti, B. divergens, Babesia MO1, or Plasmodium falciparum, and can detect as few as 115 infected erythrocytes/µl of blood. Screening of 1731 blood samples from various biorepositories, including samples previously identified as Lyme and/or B. microti-positive, as well as new specimens from wild mice, revealed no evidence of B. duncani infection or cross-reactivity. CONCLUSIONS: These assays hold significant promise for various applications, including point-of-care testing for the early detection of B. duncani in patients, field tests for screening reservoir hosts, and high-throughput screening of blood samples intended for transfusion.

4,5-Dimethoxycanthin-6-one Inhibits Glioblastoma Stem Cell and Tumor Growth by Inhibiting TSPAN1 Interaction with TM4SF1.

Glioblastoma stem cells (GSCs) have been implicated in the self-renewal and treatment resistance of glioblastoma (GBM). Our previous study found that 4,5-dimethoxycanthin-6-one has the potential to inhibit GBM cell proliferation. This current study aims to elucidate the molecular mechanism underlying the effects of 4,5-dimethoxycanthin-6-one in GBM development. The effect of 4,5-dimethoxycanthin-6-one on GSC formation and differentiation was explored in human GBM cell lines U251 and U87. Subsequently, 4,5-dimethoxycanthin-6-one binding to tetraspanin 1 (TSPAN1) / transmembrane 4 L six family member 1 (TM4SF1) was analyzed by molecular simulation docking. Co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were used to assess the interactions between TSPAN1 and TM4SF1 in GSCs. Cell proliferation was detected by cell counting kit-8 (CCK-8) and colony formation assay. To evaluate cell migration, invasion and apoptosis, we employed wound healing assay, transwell and flow cytometry, respectively. Furthermore, subcutaneous xenograft tumor models in nude mice were constructed to evaluate the impact of 4,5-dimethoxycanthin-6-one on GSCs in vivo by examining tumor growth and histological characteristics. 4,5-Dimethoxycanthin-6-one inhibited GSC formation and promoted stem cell differentiation in a concentration-dependent manner. Molecular docking models of 4,5-dimethoxycanthin-6-one with TM4SF1 and TSPAN1 were constructed. Then, the interaction between TSPAN1 and TM4SF1 in GSC was clarified. Moreover, 4,5-dimethoxycanthin-6-one significantly inhibited the expressions of TM4SF1 and TSPAN1 in vitro and in vivo. Overexpression of TSPAN1 partially reversed the inhibitory effects of 4,5-dimethoxycanthin-6-one on GSC formation, proliferation, migration and invasion. 4,5-Dimethoxycanthin-6-one inhibited GBM progression by inhibiting TSPAN1/TM4SF1 axis. 4,5-Dimethoxycanthin-6-one might be a novel and effective drug for the treatment of GBM.

Lower plasma linoleic acids as a risk factor for gout: an integrated analysis of population-based cohort and genetic data.

Background: Gout is a nutrition-related, highly prevalent inflammatory arthritis with undesirable effects on the quality of life. The relationships between circulating fatty acids (FAs) and gout remain poorly understood. Method: We included 268 174 participants with plasma FAs measured using nuclear magnetic resonance at the baseline (2006-2010) from the UK Biobank, of which 15 194 participants had repeated measures of FAs between 2012 and 2013. Cox proportional hazards models were used to assess the association of the baseline and longitudinal changes in relative levels of plasma FAs (% total FAs) with incident gout. Mendelian randomization (MR) analyses were conducted to assess the potential causality of the examined association. Results: Over a median follow-up of 12.8 years, 5160 incident cases of gout occurred. Baseline polyunsaturated fatty acids (PUFAs), n-6 PUFAs, and linoleic acids (LAs) were inversely associated with incident gout (all P-trend values < 0.0001). Baseline monounsaturated fatty acids (MUFAs), n-3 PUFAs, and docosahexaenoic acids (DHAs) were positively associated with incident gout (all P-trend values < 0.0001). Longitudinal increments of n-6 PUFAs and LAs were associated with a lower risk of subsequent gout, whereas an increment of n-3 PUFAs was associated with a higher risk. In two-sample MR analyses, genetically determined higher levels of PUFAs, n-6 PUFAs, and LAs were associated with a decreased risk of gout (all P values < 0.05). Conclusions: Our findings consistently indicate a causal relationship of elevated levels of n-6 PUFAs, especially LAs, with a reduced risk of gout.

Discovery of novel CXCR4 inhibitors for the treatment of inflammation by virtual screening and biological evaluation.

C-X-C chemokine receptor type 4 (CXCR4) exerts considerable influence on the pathogenesis of inflammatory disorders and offers a potent avenue for drug intervention. This research utilizes a hybrid virtual screening methodology constructed using computer-aided drug design to discover novel CXCR4 inhibitors for the treatment of inflammation. First, a compound library was screened by Lipinski's five rules and adsorption, distribution, metabolism, excretion and toxicity properties. Second, the HypoGen algorithm was used in constructing a 3D-QSAR pharmacophore model and verify it layer by layer, and the obtained optimal pharmacophore 1 (Hypo 1) was used as a 3D query for compound screening. Then, hit compounds were obtained through molecular docking (Libdock and CDOCKER). The toxicity of the compounds to MDA-MB-231 cells was evaluated in vitro, and their binding affinity to the target was evaluated according to how they compete with 12G5 antibody for CXCR4 on the surfaces of the MDA-MB-231 cells. Compound Hit14 showed the strongest binding affinity among the hit compounds and inhibited cell migration and invasion in Matrigel invasion and wound healing assay at a concentration of 100 nM, demonstrating a better effect than AMD3100. Western Blot experiments further showed that Hit14 blocked the CXCR4/CXCL12-mediated phosphorylation of Akt. Meanwhile, cellular thermal displacement assay analysis showed that CXCR4 protein bound to Hit14 had high thermal stability. Finally, through in vivo experiments, we found that Hit14 inhibited mouse ear inflammation and reduced ear swelling and damage. Therefore, Hit14 is a promising drug for the further development of CXCR4 inhibitors for inflammation treatment.

The predictors of short and long term urinary continence recovery after laparoscopic radical prostatectomy: a single cancer center report in China.

PURPOSE: To evaluate the predictors for short and long term urinary continence (UC) recovery after laparoscopic radical prostatectomy (LRP) from clinical and oncological variables. METHODS: We retrospectively collected data from 142 prostate cancer patients who underwent LRP between September 2014 and June 2021 at a tumor specialist diagnosis and treatment center in China. The rate of post-prostatectomy incontinence (PPI) was evaluated from immediate and at 3, 6 and 12 mo after LRP, and UC was defined as the use of no or one safety pad. Sixteen clinical and oncological variables were analyzed by univariate and multivariate regression analysis to determine whether they were associated with short (3 mo) or long term (12 mo) UC recovery after LRP. RESULTS: After eliminating patients who were lost to follow-up, 129 patients were eventually included. The mean ± SD age was 68 ± 6.3 years. The UC rates of immediate, 3, 6 and 12 mo after the operation were 27.9%, 54.3%, 75.2% and 88.4%, respectively. Multivariate analyses revealed that membranous urethral length (MUL) was a protective predictor of UC after catheter extraction(P < 0.001), and at 3 mo (P < 0.001), 6 mo (P < 0.001) and 12 mo (P = 0.009) after surgery. CONCLUSION: MUL is a significant independent factor that can contribute to short and long term UC recovery post-LRP, which may assist clinicians and their patients in counseling of treatment.

Efficacy of chidamide maintenance therapy versus autologous stem cell transplantation versus observation as a post-remission choice in the survival of adult patients with peripheral T-cell lymphoma: Post hoc analysis of a prospective, multicenter, phase 2 study in China.

In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .

Sorting Out the Latest Advances in Separators and Pilot-Scale Microbial Electrochemical Systems for Wastewater Treatment: Concomitant Development, Practical Application, and Future Perspective.

To date, dozens of pilot-scale microbial fuel cell (MFC) devices have been successfully developed worldwide for treating various types of wastewater. The availability and configurations of separators are determining factors for the economic feasibility, efficiency, sustainability, and operability of these devices. Thus, the concomitant advances between the separators and pilot-scale MFC configurations deserve further clarification. The analysis of separator configurations has shown that their evolution proceeds as follows: from ion-selective to ion-non-selective, from nonpermeable to permeable, and from abiotic to biotic. Meanwhile, their cost is decreasing and their availability is increasing. Notably, the novel MFCs configured with biotic separators are superior to those configured with abiotic separators in terms of wastewater treatment efficiency and capital cost. Herein, a highly comprehensive review of pilot-scale MFCs (>100 L) has been conducted, and we conclude that the intensive stack of the liquid cathode configuration is more advantageous when wastewater treatment is the highest priority. The use of permeable biotic separators ensures hydrodynamic continuity within the MFCs and simplifies reactor configuration and operation. In addition, a systemic comparison is conducted between pilot-scale MFC devices and conventional decentralized wastewater treatment processes. MFCs showed comparable cost, higher efficiency, long-term stability, and significant superiority in carbon emission reduction. The development of separators has greatly contributed to the availability and usability of MFCs, which will play an important role in various wastewater treatment scenarios in the future.

A Set of Diagnostic Tests for Detection of Active Babesia duncani Infection.

Human babesiosis is a rapidly emerging and potentially fatal tick-borne disease caused by intraerythrocytic apicomplexan parasites of the Babesia genus. Among the various species of Babesia that infect humans, B. duncani has been found to cause severe and life-threatening infections. Detection of active B. duncani infection is critical for accurate diagnosis and effective management of the disease. While molecular assays for the detection of B. duncani infection in blood are available, a reliable strategy to detect biomarkers of active infection has not yet been developed. Here, we report the development of the first B. duncani antigen capture assays that rely on the detection of two B. duncani -exported immunodominant antigens, BdV234 and BdV38. The assays were validated using blood samples from cultured parasites in human erythrocytes and B. duncani -infected laboratory mice at different parasitemia levels and following therapy. The assays display high specificity with no cross-reactivity with B. microti , B. divergens , Babesia MO1, or P. falciparum. The assay also demonstrates high sensitivity, detecting as low as 115 infected erythrocytes/µl of blood. Screening of 1,731 blood samples from diverse biorepositories, including previously identified Lyme and/or B. microti positive human samples and new specimens from field mice, showed no evidence of B. duncani infection in these samples. The assays could be useful in diverse diagnostic scenarios, including point-of-care testing for early B. duncani infection detection in patients, field tests for screening reservoir hosts, and high-throughput screening such as blood collected for transfusion. Short summary: We developed two ELISA-based assays, BdACA38 and BdACA234, for detecting B. duncani , a potentially fatal tick-borne parasite causing human babesiosis. The assays target two immunodominant antigens, BdV234 and BdV38, demonstrating high specificity (no cross-reactivity with other Babesia species or Plasmodium falciparum ) and sensitivity (detecting as low as 115 infected erythrocytes/µl). The assays were validated using in vitro-cultured parasites and infected mice. Screening diverse blood samples showed no evidence of B. duncani active infection among 1,731 human and field mice blood samples collected from the north-eastern, midwestern, and western US. These assays offer potential in diverse diagnostic scenarios, including early patient detection, reservoir animal screening, and transfusion-transmitted babesiosis prevention.

Severe adenovirus infection outbreak in Colombia: Experience from a tertiary pediatric hospital in 2022. / Brote de adenovirus grave en Colombia: experiencia de un hospital pediátrico de tercer nivel en 2022

Introduction. During the SARS-CoV-2 pandemic, many countries experienced decreased respiratory virus circulation, followed by an out-of-season outbreak. In a pediatric hospital in Colombia, we observed a surge in severe adenovirus infections, leading to concerns about the impact of eased public health restrictions and immune debt in children under five years old. Objective. To describe the clinical characteristics of patients with severe adenovirus infection in a pediatric hospital in Colombia. Materials and methods. We reviewed the data of 227 patients with severe adenovirus infection at the Fundación Hospital Pediátrico La Misericordia. Results. A total of 196 patients were included in this study. The median age was two years, and 62% were male. Adenoviruses were isolated from all patients' samples. Ninetyseven percent were admitted to the pediatric intensive care unit, 94% required respiratory support, and the in-hospital lethality rate was 11%. Conclusion. In 2022, there was an outbreak of severe adenovirus infections, affecting mainly children under five years of age, with higher-than-usual mortality.

Introducción. Durante la pandemia por SARS-CoV-2, muchos países evidenciaron una disminución en la circulación de virus respiratorios, seguida por un brote fuera de la temporada esperada. En un hospital de Colombia, se observó un aumento en los casos de infección grave por adenovirus, lo cual generó preocupación sobre el impacto que tuvo la disminución de los cuidados establecidos durante pandemia y la posible deuda inmunológica en niños menores de cinco años. Objetivo. Describir las características clínicas de los pacientes con infección grave por adenovirus en un hospital pediátrico de Colombia. Materiales y métodos. Se revisaron 227 pacientes con infección grave por adenovirus en la Fundación Hospital Pediátrico La Misericordia, desde el 1° de enero hasta el 31 de diciembre de 2022. Resultados. El estudio incluyó 196 casos. La edad media de los pacientes fue de dos años y el 62 % eran de sexo masculino. Los adenovirus se aislaron a partir de las muestras de todos los pacientes. El 97 % de los pacientes ingresó a la unidad de cuidados intensivos, el 94 % requirió soporte ventilatorio y la tasa de mortalidad fue del 11 %. Conclusiones. En el 2022 hubo un brote de adenovirus que afectó principalmente a los niños menores de cinco años, con una mortalidad mayor a lo reportado con anterioridad en Colombia.

Anlotinib in Chinese patients aged ≥70 years with advanced non-squamous non-small cell lung cancer without prior chemotherapy: a multicenter, single-arm pilot trial.

Background: Based on pharmacoeconomics, drug availability and actual treatment, optimal treatment regimens for Chinese non-small-cell lung carcinoma (NSCLC) patients over 70 years old are needed. Methods: This multicenter, single-arm pilot trial enrolled patients with advanced non-squamous NSCLC who refused systemic chemotherapy. Eligible patients received anlotinib (12 mg/day, d1-14, Q3W) until disease progression, intolerant toxicities, or withdrawal from the study. The primary endpoint was progression-free survival (PFS). Results: Forty-nine patients were screened between January 2019 and September 2021, of whom 40 patients were eligible. The median age was 76 years. With a median follow-up period of 16.20 (95% CI: 8.77, 25.10) months, the median PFS was 5.45 months (95% CI: 3.52-9.23) and the median overall survival was 10.32 months (95% CI: 6.44-12.78). Three patients achieved a partial response and 34 had stable disease, with an objective response rate of 7.5% and a disease control rate of 92.5%. Thirty-three (82.5%; 33/40) patients reported treatment-related adverse events (TRAEs) of any grade, and the incidence rate of grade ≥3 TRAEs was 35% (14/40). The most common grade ≥3 TRAEs were hypertension (4/40; 10.0%), hand-foot syndrome (3/40; 7.5%), and proteinuria (2/40; 5.0%). Conclusion: Anlotinib treatment was feasible and safe in Chinese elderly patients with advanced non-squamous NSCLC who did not receive any systemic chemotherapy.

Ecological filter walls for efficient pollutant removal from urban surface water.

Urban surface water pollution poses significant threats to aquatic ecosystems and human health. Conventional nitrogen removal technologies used in urban surface water exhibit drawbacks such as high consumption of carbon sources, high sludge production, and focus on dissolved oxygen (DO) concentration while neglecting the impact of DO gradients. Here, we show an ecological filter walls (EFW) that removes pollutants from urban surface water. We utilized a polymer-based three-dimensional matrix to enhance water permeability, and emergent plants were integrated into the EFW to facilitate biofilm formation. We observed that varying aeration intensities within the EFW's aerobic zone resulted in distinct DO gradients, with an optimal DO control at 3.19 ± 0.2 mg L-1 achieving superior nitrogen removal efficiencies. Specifically, the removal efficiencies of total organic carbon, total nitrogen, ammonia, and nitrate were 79.4%, 81.3%, 99.6%, and 79.1%, respectively. Microbial community analysis under a 3 mg L-1 DO condition revealed a shift in microbial composition and abundance, with genera such as Dechloromonas, Acinetobacter, unclassified_f__Comamonadaceae, SM1A02 and Pseudomonas playing pivotal roles in carbon and nitrogen elimination. Notably, the EFW facilitated shortcut nitrification-denitrification processes, predominantly contributing to nitrogen removal. Considering low manufacturing cost, flexible application, small artificial trace, and good pollutant removal ability, EFW has promising potential as an innovative approach to urban surface water treatment.

A novel GSK3ß inhibitor 5n attenuates acute kidney injury.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality caused by various factor. The specific strategies for AKI are still lacking. GSK3ß is widely expressed in the kidneys. In acute models of injury, GSK3ß promotes the systemic inflammatory response, increases the proinflammatory release of cytokines, induces apoptosis, and alters cell proliferation. We screened a series of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives which are recognized as new GSK3ß inhibitors, and found that 5n had the least toxicity and the best cell protection. We then tested the anti-inflammatory and reno-protective effect of 5n in cisplatin-treated tubular epithelial cells. 5n had anti-inflammation effect indicated by phosphor-NF-κB detection. Finally, we found that 5n ameliorated renal injury and inflammation in cisplatin-induced AKI mouse model. Silencing GSK3ß inhibited cell injury and inflammation induced by cisplatin. We found that GSK3ß interacted with PP2Ac to modulate the activity of NF-κB. In conclusion, 5n, the novel GSK3ß inhibitor, protects against AKI via PP2Ac-dependent mechanisms which may provide a potential strategy for the treatment of AKI in clinic.

Toward the Improvement of the Mechanical and Tribological Properties of Braided Ligament for ACL Reconstruction: A "Carrot and Stick" Strategy.

Bone tunnel enlargement has been troubling the clinical adoption of braided artificial ligaments for decades, to which mechanical and tribological performance promotion shall be an effective and promising approach. Herein, a "carrot and stick" strategy has been introduced with two types of polyethylene terephthalate (PET) fibers to fabricate hybrid textures, which is expected to advance fatigue and tribological performance without yielding essential mechanical strength and biocompatibility. Owing to advancements in such a "carrot and stick" strategy, the obtained grafts present three promising properties: i) enhancement of mechanical strength; ii) coefficient of friction (COF) reduction of 25% at the greatest extent, thus lowering the risk of bone tunnel enlargement; iii) final displacement shrinkage of graft length after cyclic loadings, favored in the clinic for isometric reconstruction. The results obtained in this study show that the "carrot and stick" strategy can be a creative and convenient method to optimize the service life, saving the complication rate of artificial ligaments for clinical applications.

Evaluation of Bioequivalence for Avapritinib Tablets in Chinese Participants Under Fasting Conditions Using a Reference-Scaled Average Bioequivalence Method.

This study aimed to assess the bioequivalence of 2 avapritinib tablets formulations. A randomized, open-label, single-center trial was conducted on fasting, healthy Chinese participants. The study utilized a partial replicated design with 3 sequences and 3 periods. Participants were assigned to 1 of 3 sequences, with each sequence receiving the reference formulation twice and the test formulation once. Plasma samples were collected and analyzed to determine pharmacokinetic parameters. The bioequivalence of the 2 avapritinib formulations was assessed using reference-scaled average bioequivalence for the maximum plasma concentration (Cmax) and the average bioequivalence analysis for the area under the concentration-time curve (AUC). Out of 39 participants, 38 completed the study. For Cmax, the 1-sided 95% upper confidence interval (CI) bound from the scaled approach was -0.035 (<0) and the point estimate value was 0.958, falling inside the acceptance range of 0.8-1.25. For both the AUC over all concentrations measured (AUC0-t) and the AUC from time 0 to infinity (AUC0-inf), the 90% CIs of geometric mean ratios (0.87-1.01) also met the bioequivalence criteria of 0.8-1.25. Consequently, the study demonstrated that the 2 avapritinib formulations were bioequivalent under fasting conditions.

Plant-based diets, mediating biomarkers, and mortality risk among adults with diabetes or prediabetes.

Background: A healthy eating pattern characterized by a higher intake of healthy plant foods has been associated with a lower risk of premature mortality, but whether this applies to individuals with varying glycemic status remains unclear. Methods: This study included 4621 participants with diabetes and 8061 participants with prediabetes from the US National Health and Nutrition Examination Survey (2007-2016). Using the dietary data assessed by two 24 h dietary recalls, a healthful plant-based diet index (hPDI) and an unhealthful plant-based diet index (uPDI) were created based on 15 food groups and were assessed for their relationships with mortality risk. Results: Over a median follow-up of 7.2 years, there were 1021 deaths in diabetes and 896 deaths in prediabetes. A higher hPDI (highest vs. lowest quartile) was associated with a 41% (HR = 0.59, 95% CI: 0.49-0.72; P-trend < 0.001) lower risk of all-cause mortality in diabetes and a 31% (HR = 0.69, 95% CI: 0.55-0.85; P-trend < 0.001) lower risk in prediabetes. A higher uPDI was associated with an 88% (HR = 1.88, 95% CI: 1.55-2.28; P-trend < 0.001) higher risk of mortality in diabetes and a 63% (HR = 1.63, 95% CI: 1.33-1.99; P-trend < 0.001) higher risk in prediabetes. Mediation analysis suggested that C-reactive protein and γ-glutamine transaminase explained 6.0% to 10.9% of the relationships between hPDI or uPDI and all-cause mortality among participants with diabetes. Conclusions: For adults with diabetes as well as those with prediabetes, adhering to a plant-based diet rich in healthier plant foods is associated with a lower mortality risk, whereas a diet that incorporates less healthy plant foods is associated with a higher mortality risk.