Ru-P pair sites boost charge transport in hematite photoanodes for exceeding 1% efficient solar water splitting.

Fast transport of charge carriers in semiconductor photoelectrodes are a major determinant of the solar-to-hydrogen efficiency for photoelectrochemical (PEC) water slitting. While doping metal ions as single atoms/clusters in photoelectrodes has been popularly used to regulate their charge transport, PEC performances are often low due to the limited charge mobility and severe charge recombination. Here, we disperse Ru and P diatomic sites onto hematite (DASs Ru-P:Fe2O3) to construct an efficient photoelectrode inspired by the concept of correlated single-atom engineering. The resultant photoanode shows superior photocurrent densities of 4.55 and 6.5 mA cm-2 at 1.23 and 1.50 VRHE, a low-onset potential of 0.58 VRHE, and a high applied bias photon-to-current conversion efficiency of 1.00% under one sun illumination, which are much better than the pristine Fe2O3. A detailed dynamic analysis reveals that a remarkable synergetic ineraction of the reduced recombination by a low Ru doping concentration with substitution of Fe site as well as the construction of Ru-P bonds in the material increases the carrier separation and fast charge transportation dynamics. A systematic simulation study further proves the superiority of the Ru-P bonds compared to the Ru-O bonds, which allows more long-lived carriers to participate in the water oxidation reaction. This work offers an effective strategy for enhancing charge carrier transportation dynamics by constructing pair sites into semiconductors, which may be extended to other photoelectrodes for solar water splitting.

NEK2 contributes to radioresistance in esophageal squamous cell carcinoma by inducing protective autophagy via regulating TRIM21.

BACKGROUND: Radiotherapy (RT) has been identified as a vital treatment for esophageal squamous cell carcinoma (ESCC), while the development of radioresistance remains a major obstacle in ESCC management. The aim of this study was to investigate the effect of NIMA-related kinase 2 (NEK2) on radioresistance in ESCC cells and to reveal potential molecular mechanisms. METHODS: Human esophageal epithelial cells (HEEC) and human ESCC cell lines were obtained from the Research Center of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). Cell Counting Kit-8 (CCK-8) and flow cytometry assays were applied to assess the proliferation ability, cell cycle, apoptosis rates, and ROS production of ESCC cells. The colony-forming assay was used to estimate the effect of NEK2 on radiosensitivity. Autophagy was investigated by western blotting analysis, GFP-mRFP-LC3 fluorescence assay, and transmission electron microscopy (TEM). RESULTS: In the present study, our results showed that NEK2 was associated with radioresistance, cell cycle arrest, apoptosis, ROS production, and survival of ESCC. NEK2 knockdown could significantly inhibit growth while enhancing radiosensitivity and ROS production in ESCC cells. Interestingly, NEK2 knockdown inhibited ESCC cell autophagy and reduced autophagic flux, ultimately reversing NEK2-induced radioresistance. Mechanistically, NEK2 bound to and regulated the stability of tripartite motif-containing protein 21 (TRIM21). The accumulation of NEK2-induced light chain 3 beta 2 (LC3B II) can be reversed by the knockdown of TRIM21. CONCLUSION: These results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC.

Population pharmacokinetics of free and liposome-encapsulated mitoxantrone in patients with relapsed/refractory lymphoma or small cell lung cancer.

OBJECTIVE: This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or small cell lung cancer (SCLC) by constructing population pharmacokinetic (popPK) models for both liposome-encapsulated mitoxantrone and free mitoxantrone. METHODS: A total of 23 patients with relapsed/refractory lymphoma and 42 patients with SCLC were included. A popPK model was simultaneously developed utilizing a non-linear mixed effects model (NONMEM) to explore the PK profiles of liposome-encapsulated mitoxantrone and free mitoxantrone. Clearance (CL) and distribution volume (V) were calculated, and covariate analysis was employed to evaluate the influence of patient disease type, demographic information, and biochemical indicators of liver and kidney function on PK parameters. RESULTS: The concentration-time profiles for both liposome-encapsulated mitoxantrone and free mitoxantrone were described by a one-compartment model. The release (Rel) of liposome-encapsulated mitoxantrone to free mitoxantrone was determined to be 0.0191 L/h, and the V of liposome-encapsulated mitoxantrone was 2.32 L. The apparent CL of free mitoxantrone was estimated at 1.66 L/h. The apparent V of free mitoxantrone was 35.8 L in patients with relapsed/refractory lymphoma and 22.2 L for patients with SCLC. In patients with relapsed/refractory lymphoma, lower maximum concentration (Cmax) and higher apparent V of free mitoxantrone were observed compared with patients with SCLC. CONCLUSION: The popPK characteristics of both liposome-encapsulated and free mitoxantrone in patients with relapsed/refractory lymphoma or SCLC were effectively described by a one-compartment model.

Correlation between metabolic syndrome and periurethral prostatic fibrosis: results of a prospective study.

BACKGROUND: Prostatic fibrosis, characterized by the accumulation of myofibroblasts and collagen deposition, is closely associated with LUTS and may lead to mechanical obstruction of the urethra. Additionally, Metabolic Syndrome (MetS), characterized by central obesity, high blood sugar, lipid metabolism disorders, and hypertension, is increasingly recognized as a proinflammatory condition linked to prostate inflammation. METHODS: Clinical data from 108 subjects who underwent transurethral resection of the prostate or bipolar plasmakinetic enucleation of the prostate were prospectively collected between June 2021 and August 2022. Patients were divided in two groups according to whether or not they had a diagnosis of MetS. Specimens were stained with Masson trichrome and the periurethral prostatic fibrosis extent was evaluated using quantitative morphometry. RESULTS: Forty-three patients (39.8%) were diagnosed with MetS. Patients with MetS showed a significantly greater extent of prostatic fibrosis than the others (68.1 ± 17.1% vs. 42.5 ± 18.2%, P < 0.001), and there was a positive correlation between the number of positive MetS parameters and the extent of prostatic fibrosis (R2 = 0.4436, P < 0.001). Multivariate regression analysis revealed that central obesity (B = 2.941, 95% confidence interval, 1.700-3.283), elevated fasting glucose (B = 1.036, 95% confidence interval, 0.293-1.780), reduced HDL cholesterol (B = 0.910, 95% confidence interval, 0.183-1.636) and elevated triglycerides (B = 1.666, 95% confidence interval, 0.824-2.508) were positively correlated to prostatic fibrosis. Elevated blood pressure, however, was unrelated to prostatic fibrosis (B = 0.009, 95% confidence interval, -0.664-0.683). CONCLUSIONS: The present findings suggest that prostatic fibrosis is positively correlated with MetS and its components including central obesity, elevated fasting glucose, reduced high density lipoprotein cholesterol and elevated triglycerides.

A deep learning approach to the diagnosis of atelectasis and attic retraction pocket in otitis media with effusion using otoscopic images.

BACKGROUND: This study aimed to develop and validate a deep learning (DL) model to identify atelectasis and attic retraction pocket in cases of otitis media with effusion (OME) using multi-center otoscopic images. METHOD: A total of 6393 OME otoscopic images from three centers were used to develop and validate a DL model for detecting atelectasis and attic retraction pocket. A threefold random cross-validation procedure was adopted to divide the dataset into training validation sets on a patient level. A team of otologists was assigned to diagnose and characterize atelectasis and attic retraction pocket in otoscopic images. Receiver operating characteristic (ROC) curves, including area under the ROC curve (AUC), accuracy, sensitivity, and specificity were used to assess the performance of the DL model. Class Activation Mapping (CAM) illustrated the discriminative regions in the otoscopic images. RESULTS: Among all OME otoscopic images, 3564 (55.74%) were identified with attic retraction pocket, and 2460 (38.48%) with atelectasis. The diagnostic DL model of attic retraction pocket and atelectasis achieved a threefold cross-validation accuracy of 89% and 79%, AUC of 0.89 and 0.87, a sensitivity of 0.93 and 0.71, and a specificity of 0.62 and 0.84, respectively. Larger and deeper cases of atelectasis and attic retraction pocket showed greater weight, based on the red color depicted in the heat map of CAM. CONCLUSION: The DL algorithm could be employed to identify atelectasis and attic retraction pocket in otoscopic images of OME, and as a tool to assist in the accurate diagnosis of OME.

Irradiation-induced exosomal HMGB1 to confer radioresistance via the PI3K/AKT/FOXO3A signaling pathway in ESCC.

BACKGROUND: Radioresistance is a major cause of treatment failure in esophageal squamous cell carcinoma (ESCC) radiotherapy, and the underlying mechanisms of radioresistance are still unclear. Irradiation (IR) stimulates changes in tumor-derived exosome contents, which can be taken up by recipient cells, playing an important role in the proliferation, cell cycle and apoptosis of recipient cells. This study investigated the effect of IR-induced exosomal high mobility group box 1 (HMGB1) on radioresistance in ESCC cells. METHODS: Plasma exosomes were isolated from 21 ESCC patients and 24 healthy volunteers, and the expression of HMGB1 was examined. Then, the therapeutic effect of radiotherapy was analyzed according to the different expression levels of plasma exosomal HMGB1 in ESCC patients. The uptake of exosomes by recipient cells was verified by immunofluorescence staining, and the localization of exosomes and HMGB1 in cells before and after IR was evaluated. The effects of IR-induced exosomes on cell proliferation, invasion, apoptosis, cell cycle distribution and radioresistance after HMGB1 knockdown were verified. Moreover, western blotting was used to measure changes in the expression of cyclin B1, CDK1, Bax, Bcl2, phosphorylated histone H2AX and the PI3K/AKT/FOXO3A pathway in the HMGB1-knockdown exosome group and the negative control group. RESULTS: The expression of HMGB1 in ESCC plasma exosomes was significantly increased compared with that in healthy volunteers, and high expression of HMGB1 in plasma exosomes was associated with radioresistance (P = 0.016). IR-induced the release of exosomal HMGB1 and promoted proliferation and radioresistance in recipient cells, with a sensitization enhancement ratio (SER) of 0.906 and 0.919, respectively. In addition, IR-induced exosomal HMGB1 promotes G2/M phase arrest by regulating the proteins cyclin B1 and CDK1, cooperating with the proteins Bax and Bcl2 to reduce the apoptosis rate through the PI3K/AKT/FOXO3A signaling pathway, and participated in IR-induced DNA damage repair through γH2AX. CONCLUSION: These findings indicate that high expression of plasma exosomal HMGB1 is associated with an adverse radiotherapy response. IR-induced exosomal HMGB1 enhances the radioresistance of ESCC cells.

HMGB1 induces radioresistance through PI3K/AKT/ATM pathway in esophageal squamous cell carcinoma.

BACKGROUND: To explore the effect of HMGB1 on the radio-sensitivity of esophageal cancer cells through regulating the PI3K/Akt/ATM pathway. METHODS AND RESULTS: We observed the expression of HMGB1 and p-ATM in biopsies of esophageal cancer patients with immunohistochemical staining. Western blot and RT-qPCR were applied to detect the protein and RNA related to PI3K/Akt/ATM pathway, respectively. In addition, we inhibited the PI3K/Akt pathway with ly294002 and activated it with IGF1, then we explored the invasion, proliferation ability, and apoptosis of esophageal cancer cells in vitro by transwell, CCK8 assay, and flow cytometry respectively. In vivo, xenograft tumor model was established in nude mice to study the effect of HMGB1 on radioresistance via PI3K/AKT/ATM Signaling Pathway. The survival rate in patients with single positive/double negative expression of HMGB1 and p-ATM was significantly higher than in those with both positive expression of HMGB1 and p-ATM, the depletion of HMGB1 combined with ly294002 significantly inhibited cell proliferation and invasion ability, meanwhile, the addition of IGF1 reversed it. Meanwhile, depletion of HMGB1 and ly294002 promoted apoptosis and arrested the cancer cells in G0/G1 cell cycle with the decreased expression of Cyclin D1 and CDK4 and improved P16. We further validated these results in vivo, the application of HMGB1 silencing promoted apoptosis of xenograft tumors after radiation, especially combined with pathway inhibitor ly294002. CONCLUSIONS: Esophageal cancer patients with high expression of HMGB1 and p-ATM have a poor prognosis after chemo-radiotherapy. Down-regulation of HMGB1 may promote the radio-sensitivity of esophageal cancer cells through regulating PI3K/Akt/ATM pathway.

Treatment of Atherosclerotic Femoropopliteal Artery Disease with Supera Interwoven Nitinol Stent: A Real-World Study in China.

BACKGROUND: To analyze the outcomes of Supera stent deployment in Chinese patients with atherosclerotic femoropopliteal artery (FPA) disease in a real-world setting. METHODS: This retrospective cohort study collected and analyzed the medical records of 246 consecutive patients who received Supera stents for FPA disease at the China Academy of Chinese Medical Sciences Xiyuan Hospital between February 2017 and December 2019. All study patients underwent balloon angioplasty and were treated with Supera stents (Abbott Vascular, Santa Clara, CA, USA). The primary outcome was the rate of primary patency 12 months after discharge. RESULTS: The analyses included 246 consecutive patients and 260 lesions. The mean ± SD age was 73.2 ± 9.9 years and most patients (60.2%) were males. Of the 260 treated lesions, Supera stents were deployed in eight (3.1%) cases after a previous stent fracture. Critical limb ischemia was diagnosed in 87.3% of the limbs, and 84 (32.3%) and 83 (31.5%) cases were classified as TransAtlantic Inter-Society Consensus (TASC) C and D, respectively. Most of the lesions were in situ (80.8%) and located in the superficial femoral artery (45.0%) or the FPA (45.8%). The mean lesion length was 147.7 mm. Nominal deployment (-10 to 10% compression) was the most common deployment scenario (84.1%). The 1-year primary patency rate was 80.6%. Lesions that occurred as restenosis (odds ratio [OR]: = 3.34, 95% confidence interval [CI]: 1.03-10.85, P = 0.045) or in-stent restenosis (OR: = 2.88, 95% CI: 1.03-8.07, P = 0.045) were independently associated with occlusion or stenosis after stent deployment. No stent fracture was observed in this study. CONCLUSIONS: Our study indicates that the use of Supera stents is feasible for the treatment of Chinese patients with FPA disease. The long-term results reveal high primary patency.

Evaluation of tofacitinib citrate bioequivalence based on pharmacokinetic parameters in healthy Chinese subjects.

OBJECTIVE: To evaluate the pharmacokinetics and bioequivalence of tofacitinib citrate using pharmacokinetic parameters, a single-dose, randomized-sequence, two-way crossover study of tofacitinib citrate test (T) and reference (R) formulations, with a 4-day washout period, was performed. MATERIALS AND METHODS: 72 healthy Chinese subjects were randomly divided into 4 groups: sequence A (TR) and B (RT) in a fasted state and sequence C (TR) and D (RT) in a fed state. Plasma tofacitinib citrate levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the pharmacokinetic parameter maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate bioequivalence. RESULTS: The geometric least-squares mean (GLSM) ratio and 90% confidence intervals for fasted state Cmax, AUC0-t, and AUC0-∞ were 93.90 - 108.17%, 100.41 - 103.95%, and 100.48 - 104.02% and at fed state were 99.45 - 119.52%, 100.05 - 104.23%, and 100.00 - 104.20%, respectively. The 90% CI of the two preparations, Cmax, AUC0-t, and AUC0-∞, all fell within the equivalent range of 80 - 125%. tmax was ~ 0.6 hours later, and Cmax was ~ 27% lower after a high-fat diet in the fasted state. CONCLUSION: Two types of tofacitinib citrate tablets were bioequivalent under both fasted and fed conditions, and both were generally well tolerated; moreover, food-drug interaction may affect drug pharmacokinetics.

Effects of Emotional Expressiveness of a Female Digital Human on Loneliness, Stress, Perceived Support, and Closeness Across Genders: Randomized Controlled Trial.

BACKGROUND: Loneliness is a growing public health problem that has been exacerbated in vulnerable groups during the COVID-19 pandemic. Social support interventions have been shown to reduce loneliness, including when delivered through technology. Digital humans are a new type of computer agent that show promise as supportive peers in health care. For digital humans to be effective and engaging support persons, it is important that they develop closeness with people. Closeness can be increased by emotional expressiveness, particularly in female relationships. However, it is unknown whether emotional expressiveness improves relationships with digital humans and affects physiological responses. OBJECTIVE: The aim of this study is to investigate whether emotional expression by a digital human can affect psychological and physiological outcomes and whether the effects are moderated by the user's gender. METHODS: A community sample of 198 adults (101 women, 95 men, and 2 gender-diverse individuals) was block-randomized by gender to complete a 15-minute self-disclosure conversation with a female digital human in 1 of 6 conditions. In these conditions, the digital human varied in modality richness and emotional expression on the face and in the voice (emotional, neutral, or no face; emotional or neutral voice). Perceived loneliness, closeness, social support, caring perceptions, and stress were measured after each interaction. Heart rate, skin temperature, and electrodermal activity were assessed during each interaction. 3-way factorial analyses of variance with post hoc tests were conducted. RESULTS: Emotional expression in the voice was associated with greater perceptions of caring and physiological arousal during the interaction, and unexpectedly, with lower feelings of support. User gender moderated the effect of emotional expressiveness on several outcomes. For women, an emotional voice was associated with increased closeness, social support, and caring perceptions, whereas for men, a neutral voice increased these outcomes. For women, interacting with a neutral face was associated with lower loneliness and subjective stress compared with no face. Interacting with no face (ie, a voice-only black screen) resulted in lower loneliness and subjective stress for men, compared with a neutral or emotional face. No significant results were found for heart rate or skin temperature. However, average electrodermal activity was significantly higher for men while interacting with an emotional voice. CONCLUSIONS: Emotional expressiveness in a female digital human has different effects on loneliness, social, and physiological outcomes for men and women. The results inform the design of digital human support persons and have theoretical implications. Further research is needed to evaluate how more pronounced emotional facial expressions in a digital human might affect the results. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000865819; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381816&isReview.

Photo-driven Oxygen Vacancies Extends Charge Carrier Lifetime for Efficient Solar Water Splitting.

A photocharge/discharge strategy is proposed to initiate the WO3 photoelectrode and suppress the main charge recombination, which remarkably improves the photoelectrochemical (PEC) performance. The photocharged WO3 surrounded by a 8-10 nm overlayer and oxygen vacancies could be operated more than 25 cycles with 50 h durability without significant decay on PEC activity. A photocharged WO3 /CuO photoanode exhibits an outstanding photocurrent of 3.2 mA cm-2 at 1.23 VRHE with a low onset potential of 0.6 VRHE , which is one of the best performances of p-n heterojunction structure. Using nonadiabatic molecular dynamics combined with time-domain DFT, we clarify the prolonged charge carrier lifetime of photocharged WO3 , as well as how electronic systems of photocharged WO3 /CuO semiconductors enable the effective photoinduced electrons transfer from WO3 into CuO. This work provides a feasible route to address excessive defects existed in photoelectrodes without causing extra recombination.

Bencycloquidium bromide nasal spray is effective and safe for persistent allergic rhinitis: a phase III, multicenter, randomized, double-blinded, placebo-controlled clinical trial.

PURPOSE: To investigate the efficacy and safety of bencycloquidium bromide nasal spray (BCQB) in patients with persistent allergic rhinitis (PAR). METHODS: We enrolled 720 patients from 15 hospitals across China and randomly assigned them into BCQB group or placebo group (90 µg per nostril qid) to receive a 4-week treatment. Visual analog scale (VAS) for rhinorrhea, sneezing, nasal congestion, itching and overall symptoms were recorded by patients every day. Anterior rhinoscopy scoring was completed by doctors on every visit. Adverse events were recorded in detail. RESULTS: A total of 354 and 351 patients were included in BCQB group and in placebo group. Baseline information was comparable. At the end of the trial, the decrease of VAS for rhinorrhea from baseline was 4.83 ± 2.35 and 2.46 ± 2.34 in BCQB group and placebo group, respectively (P < 0.001). The change ratio from baseline of VAS for rhinorrhea in BCQB group was 72.32%, higher than 31.03% in placebo group (P < 0.001). VAS for other symptoms and overall symptoms also improved significantly in the BCQB group, while no inter-group difference was found in anterior rhinoscopy scoring. The incidence of adverse reaction was similar between the two groups. Most reactions were mild and no severe reactions happened. CONCLUSION: 90 µg BCQB per nostril four times daily is effective and safe in the treatment of rhinorrhea as well as sneezing, nasal congestion and itching for patients with PAR. RETROSPECTIVELY REGISTERED: ChiCTR2000030924, 2020/3/17.

Eco-innovation and energy productivity: New determinants of renewable energy consumption.

This study provides new empirical evidence on the determinants of renewable energy consumption in the case of OECD economies over the period from 1990 to 2017. To examine the long run relationship among variables of renewable energy consumption and its determinants, this study uses the Durbin Hausman group mean cointegration test. The long-run and short-run coefficients are estimated via the cross-sectional Autoregressive Distributive Lag (CS-ARDL) method. The significant cointegration vector confirms the long-run equilibrium among the variables presented in the model. The results show that income, human capital, energy productivity, energy prices, and eco-innovation are important factors in explaining renewable energy consumption. This study adopts the Augmented Mean Group (AMG) method to check the robustness of the model. The results are found to be consistent with the estimates of the cross-sectional Autoregressive Distributive Lag Model method. To offer viable solutions to environmental problems and to achieve the targets set in the Paris Climate Agreement, policies and strategies should be devised to increase the share of renewable energy in the overall energy mix.

Long noncoding RNAs as diagnostic biomarkers for the early detection of digestive tract cancers: a systematic review and meta-analysis.

BACKGROUND: long noncoding RNAs (lncRNAs) have attracted attention recently. However, many inconsistencies frequently appeared for the early diagnosis of digestive tract cancers (DTCs). We performed this meta-analysis to describe the diagnostic performance of lncRNAs in the discrimination of DTCs. METHODS: data were extracted from PubMed, Web of Science, Embase, and Cochrane Library. Their quality was evaluated using the revised Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Such parameters as sensitivity and specificity were included for pooled analyses. The STATA 12.0 and Meta-Disc 1.4 software packages were used to perform the statistical analysis. RESULTS: sixty-nine papers were included in this meta-analysis. The pooled analysis of DTCs showed that lncRNAs had a sensitivity of 0.78 and a specificity of 0.80. The area under the summary ROC curve (AUC) was 0.86. For gastric cancer (GC), the pooled sensitivity and specificity were 0.77 (95 % CI: 0.72-0.81) and 0.75 (95 % CI: 0.71-0.79), respectively, and the AUC was 0.83. For colorectal cancer (CRC), these three parameters were 0.82 (95 % CI: 0.76-0.86), 0.84 (95 % CI: 0.79-0.88), and 0.90, respectively. For esophageal cancer (EC) sensitivity was 0.74 (95 % CI: 0.67-0.80) and specificity reached 0.86 (95 % CI: 0.72-0.93), with an AUC of 0.82. CONCLUSIONS: LncRNAs show potential diagnostic value for discrimination between DTCs.

Auditory and speech function after cochlear implantation in prelingually deaf children with white matter lesions.

AIM: To explore how auditory and speech function developed post-cochlear implantation (pCI) in prelingually deaf children with white matter lesions (WML). METHOD: Patients (41 males, 29 females; mean age at implantation 2y 11mo [SD 7.5mo], range 1y 8mo-5y) were divided into the following groups according to preoperative brain magnetic resonance imaging evaluation: mild WML, moderate WML, severe WML, and control. We assessed auditory and speech performance at baseline, 6 months, 12 months, and 24 months pCI. As well as auditory event-related potentials, topographic maps and electroencephalography source imaging were recorded and analysed at 24 months pCI. RESULTS: For children with WML (any level), postoperative auditory or speech performance at 6 months was significantly below that of control participants. After stratification, auditory and speech performance was highly related to WML grading. Auditory or speech performance in mild WML or control groups was comparatively better than the moderate WML and severe WML groups. The recovery rate of speech performance fell behind that of the auditory perception. With the increasing severity of WML, N1 amplitude was significantly smaller with a consistent presentation in the topographic map, which was similar in the mild WML and control group. The dominant auditory centre was activated in the control or mild WML groups, but not in the moderate WML and severe WML groups. INTERPRETATION: WML gradually affect auditory and speech development, and electrophysiological performance pCI in prelingually deaf children. WHAT THIS PAPER ADDS: Auditory and speech performance in prelingually deaf children with white matter lesions (WML) was significantly worse than those without WML. Postoperative auditory and speech performance in children with WML was highly related to WML grading. Grand N1 amplitude in auditory event-related potentials was negatively related to the severity of WML. Non-dominant areas close to the auditory cortex were potentially activated in severe WML.

FUNCIÓN AUDITIVA Y DEL HABLA DESPUÉS DE LA IMPLANTACIÓN COCLEAR EN NIÑOS SORDOS PRE VERBALES CON LESIONES DE MATERIA BLANCA: OBJETIVO: Explorar cómo se desarrolla la función auditiva y del habla post implante coclear (pIC) en niños sordos pre verbales con lesiones de sustancia blanca (LSB) METODO: Los pacientes (41 varones, 29 mujeres; edad media de implantación 2y 11m [DS 7.5m], rango 1y 8m - 5 años) se dividieron en los siguientes grupos de acuerdo con la evaluación de imagen de resonancia magnética cerebral preoperatoria: LSB leve, LSB moderada, LSB grave y control. Evaluamos el rendimiento auditivo y del habla al inicio del estudio, a los 6 meses, a los 12 meses y a los 24 meses, pIC. Además de los potenciales evocados auditivos, se registraron y analizaron los mapas topográficos y las imágenes de fuentes de electroencefalografía a los 24 meses pIC. RESULTADOS: Para los niños con LSB (cualquier nivel), el rendimiento auditivo o del habla postoperatorio a los 6 meses fue significativamente inferior al de los participantes de control. Después de la estratificación, el desempeño auditivo y del habla estuvo altamente relacionado con la calificación de la LSB. El rendimiento auditivo o del habla en LSB leve o en el grupo control fue comparativamente mejor que en los grupos de LSB moderada y de LSB grave. La tasa de recuperación del rendimiento del habla quedó por detrás de la percepción auditiva. Con el aumento de la gravedad de LSB, la amplitud de N1 fue significativamente menor con una presentación consistente en el mapa topográfico, que fue similar en el grupo control y de LSB leve. El centro auditivo dominante se activó en el grupo control o de LSB leve, pero no lo hizo en los grupos de LSB moderada y severa. INTERPRETACION: La LSB afecta gradualmente el desarrollo del habla auditiva y el rendimiento electrofisiológico pIC en niños sordos pre verbales.

FUNÇÃO AUDITIVA E DE FALA APÓS IMPLANTE COCLEAR EM CRIANÇAS SURDAS PRÉ-LINGUAGEM COM LESÕES DA SUBSTÂNCIA BRANCA: OBJETIVO: Explorar como a função auditiva e da fala se desenvolveu pós implante coclear (pIC) em crianças surdas pré-linguagem com lesões da substância branca (LSB). MÉTODO: Pacientes (41 do sexo masculino, 29 do sexo feminino; média de idade no implante 2a 11m [DP 7,5m], variação 1a 8m-5a) foram divididos nose seguintes grupos de acordo com a avaliação da imagem de ressonância magnética pré-operatória: LSB leve, LSB moderada, LSB severa, e controle. Avaliamos o desempenho auditivo e de fala na linha de base, 6 meses, 12 meses, e 24 meses, pCI. Também foram registrados e analisados potenciais auditivos relacionados a eventos, mapas topográficos e imagem de fontes de eletroencefalorafia 24 meses pIC. RESULTADOS: Para crianças com LSB (qualquer nível), o desempenho auditivo e de fala pós-operatório aos 6 meses foi significantemente abaixo dos participantes controle. Após estratificação, o desempenho se relaciou fortemente com o grau de LSB. O desempenho auditivo e de fala nos grupos com LSB leve e controle foi comparativamente melhor do que nos grupos LSB moderado e severo. A taxa de recuperação do desempenho da fala ficou atrás da percepção auditiva. Com a maior severidade da LSB, a amplitude N1 foi significativamente menor, com apresentação consistente no mapa topográfico, que foi similar nos grupos LSB leve e controle. O centro auditivo dominante estava ativado nos grupos controle e LSB leve, mas não nos grupos com LSB moderada e grave. INTERPRETAÇÃO: A LSB gradualmente afeta o desenvolvimento auditivo e de fala, e o desempenho eletrofisiológico pIC em crianças surdas pré-linguagem.

Preclinical Pharmacokinetics of C118P, a Novel Prodrug of Microtubules Inhibitor and Its Metabolite C118 in Mice, Rats, and Dogs.

C118P, a phosphate prodrug of C118, which is a novel microtubule protein inhibitor, is currently under Phase I clinical development in China for treating ovarian cancer and lung cancer. The preclinical pharmacokinetics of prodrug C118P and its metabolite C118 were extensively characterized in vivo in mice, rats, and dogs and in vitro to support the further development of C118P. The preclinical tissue distribution and excretion were investigated in rats. Plasma protein binding in mice, rat, and human, and hepatic microsomal metabolic stability in mice, rat, dog, monkey, and human, were also evaluated. The (AUC0-inf) and C30s of C118P at 50 mg/kg in rats and 6 mg/kg in dogs, and the C2min of C118 at 6 mg/kg in dogs increased less than the dosage increase, suggested nonlinear pharmacokinetic occurred at high dose. As a prodrug, C118P can be quickly hydrolyzed into C118 after an intravenous administration. The unbound C118 in plasma is slightly higher than C118P. C118P can hardly penetrate the tissue, while C118 can distribute widely into tissues. In tumor-bearing nude mice, the concentration of C118 is high in lung, ovary, and tumor, with an extended half-life in tumor. C118P is a promising candidate prodrug for further clinical development.

Atypical Kinetics and Albumin Effect of Glucuronidation of 5-n-Butyl-4-{4-[2-(1H-tetrazole-5- yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6- dichlorophenyl)-3H-1,2,4-triazol-3-one, a Novel Nonpeptide Angiotensin Type 1 Receptor Antagonist, in Liver Microsomes and UDP-Glucuronosyl-transferase.

Ib is a new nonpeptide AT1 receptor antagonist, which plays an active role in cardiovascular protection. Ib monoglucuronide has been identified as its main metabolite. A detailed study of Ib glucuronidation is important for predicting potential DDI. Besides, the elucidation of the "BSA effect" in Ib glucuronidation would make obtained kinetic parameters more predictive in IVIVE. "BSA effect" means that there is a significant change in in vitro kinetic parameters when generated from incubations performed in the presence of bovine serum albumin (BSA). Five UGTs (UGT1A3, UGT2B4, UGT2B7, UGT1A9 and UGT1A8) were identified that produced abundant Ib monoglucuronide, especially UGT1A3. We investigated Ib glucuronidation in liver microsomes from different species (rat, dog, human) and in five identified major human UGTs. Ib glucuronidation in liver microsomes and recombinant human UGTs all showed substrate inhibition kinetics. DLM showed the strongest affinity and activity, HLM showed the lowest affinity, and RLM showed the weakest activity. The addition of BSA did not alter the enzyme kinetics, but significantly altered enzyme kinetic parameters resulting in a reduction in Km value and an increase in CLint value. However, high concentrations of BSA could significantly attenuate this positive effect on enzyme affinity and activity, and the effect of BSA on the Vmax of Ib glucuronidation was opposite in different enzyme sources. In conclusion, this study demonstrated the substrate inhibition kinetics of Ib glucuronidation in the liver metabolism and the effect of BSA on its kinetic parameters, in order to provide more accurate in vitro data for in vivo prediction.

Differential Role of Rapamycin in Epidermis-Induced IL-15-IGF-1 Secretion via Activation of Akt/mTORC2.

Backgroud/Aims: The effects of rapamycin (RPM) on wound healing have been previously studied. However, reciprocal contradictory data have been reported, and the underlying mechanism remains unclear. This study aims to uncover differential role of RPM in regulation of wound healing and explore the possible mechanism. METHODS: C57BL/6J mice and epidermal cells were treated with different doses of RPM. The wound re-epithelialization was observed by hematoxylin and eosin (HE) staining. The expression of IL-15 and IGF-1 were detected by immunohistochemistry and quantitative real-time PCR. Epidermal cell survival was determined by CCK-8 assays. Moreover, the mTORC1 and mTORC2 pathway were examined by western blot analysis. RESULTS: This study showed that differential doses of RPM could lead to separate consequences in epidermis. Histological analyses showed that low-dose RPM promoted wound healing, and enhanced the expression of IL-15 and IGF-1. Furthermore, western blot analysis showed that the effect of low-dose RPM in epidermis were not through mTORC1 pathway. Instead, activation of the Akt/mTORC2 pathway was involved in low-dose RPM-induced IL-15 and IGF-1 production in epidermis, while high-dose RPM inhibited the expression of IL-15 and IGF-1 and the activity of mTORC1 and mTORC2 pathway. CONCLUSION: This study for the first time demonstrated that RPM-mediated wound healing was dose-dependent.

The effect of symmetrical and asymmetrical hearing impairment on music quality perception.

The purpose of this study was to investigate the effect of symmetrical, asymmetrical and unilateral hearing impairment on music quality perception. Six validated music pieces in the categories of classical music, folk music and pop music were used to assess music quality in terms of its 'pleasantness', 'naturalness', 'fullness', 'roughness' and 'sharpness'. 58 participants with sensorineural hearing loss [20 with unilateral hearing loss (UHL), 20 with bilateral symmetrical hearing loss (BSHL) and 18 with bilateral asymmetrical hearing loss (BAHL)] and 29 normal hearing (NH) subjects participated in the present study. Hearing impaired (HI) participants had greater difficulty in overall music quality perception than NH participants. Participants with BSHL rated music pleasantness and naturalness to be higher than participants with BAHL. Moreover, the hearing thresholds of the better ears from BSHL and BAHL participants as well as the hearing thresholds of the worse ears from BSHL participants were negatively correlated to the pleasantness and naturalness perception. HI participants rated the familiar music pieces higher than unfamiliar music pieces in the three music categories. Music quality perception in participants with hearing impairment appeared to be affected by symmetry of hearing loss, degree of hearing loss and music familiarity when they were assessed using the music quality rating test (MQRT). This indicates that binaural symmetrical hearing is important to achieve a high level of music quality perception in HI listeners. This emphasizes the importance of provision of bilateral hearing assistive devices for people with asymmetrical hearing impairment.