Dynamin 1xA interacts with Endophilin A1 via its spliced long C-terminus for ultrafast endocytosis.

Dynamin 1 mediates fission of endocytic synaptic vesicles in the brain and has two major splice variants, Dyn1xA and Dyn1xB, which are nearly identical apart from the extended C-terminal region of Dyn1xA. Despite a similar set of binding partners, only Dyn1xA is enriched at endocytic zones and accelerates vesicle fission during ultrafast endocytosis. Here, we report that Dyn1xA achieves this localization by preferentially binding to Endophilin A1 through a newly defined binding site within its long C-terminal tail extension. Endophilin A1 binds this site at higher affinity than the previously reported site, and the affinity is determined by amino acids within the Dyn1xA tail but outside the binding site. This interaction is regulated by the phosphorylation state of two serine residues specific to the Dyn1xA variant. Dyn1xA and Endophilin A1 colocalize in patches near the active zone, and mutations disrupting Endophilin A binding to the long tail cause Dyn1xA mislocalization and stalled endocytic pits on the plasma membrane during ultrafast endocytosis. Together, these data suggest that the specificity for ultrafast endocytosis is defined by the phosphorylation-regulated interaction of Endophilin A1 with the C-terminal extension of Dyn1xA.

Electrosynthesis of H2O2 Promoted by π-π Interaction on a Metal-Free Carbon Catalyst.

The synthesis of hydrogen peroxide (H2O2) through electrocatalytic oxygen reduction reaction is an ideal alternative to the current energy-intensive anthraquinone process, but developing cost-effective and high-efficiency electrocatalysts is still challenging. Herein, a metal-free graphitic carbon nitride/carbon nanotube (g-C3N4/CNT) hybrid catalyst can enhance H2O2 production via π-π interaction is reported, achieving almost unity (97%) H2O2 production at 0.57 V with high selectivity of over 92% across the wide potential range from 0.6 to 0 V. Other carbon materials with weak interaction with g-C3N4, such as acetylene black and super P, show markedly weakened H2O2 production, indicating the importance of π-π interaction. Electron transfer kinetic analysis combined with density functional theory calculations indicates that the synergistic effect between g-C3N4 and CNT enhances electron transfer and O2 activation between g-C3N4 and CNT, leading to enhanced H2O2 production performance. This work provides a complementary approach for H2O2 production from oxygen reduction besides introducing oxygenated groups or heteroatom doping into carbon materials.

Vacancy Engineering in 2D Transition Metal Chalcogenide Photocatalyst: Structure Modulation, Function and Synergy Application.

Transition metal chalcogenides (TMCs) are widely used in photocatalytic fields such as hydrogen evolution, nitrogen fixation, and pollutant degradation due to their suitable bandgaps, tunable electronic and optical properties, and strong reducing ability. The unique 2D malleability structure provides a pre-designed platform for customizable structures. The introduction of vacancy engineering makes up for the shortcomings of photocorrosion and limited light response and provides the greatest support for TMCs in terms of kinetics and thermodynamics in photocatalysis. This work reviews the effect of vacancy engineering on photocatalytic performance based on 2D semiconductor TMCs. The characteristics of vacancy introduction strategies are summarized, and the development of photocatalysis of vacancy engineering TMCs materials in energy conversion, degradation, and biological applications is reviewed. The contribution of vacancies in the optical range and charge transfer kinetics is also discussed from the perspective of structure manipulation. Vacancy engineering not only controls and optimizes the structure of the TMCs, but also improves the optical properties, charge transfer, and surface properties. The synergies between TMCs vacancy engineering and atomic doping, other vacancies, and heterojunction composite techniques are discussed in detail, followed by a summary of current trends and potential for expansion.

Long-term immunogenicity and safety of heterologous boosting with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants who had received two or three doses of inactivated vaccine.

The emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs booster vaccination. We evaluated the long-term safety and immunogenicity of heterologous boosting with a SARS-CoV-2 messenger RNA vaccine SYS6006. A total of 1000 participants aged 18 years or more who had received two (Group A) or three (Group B) doses of SARS-CoV-2 inactivated vaccine were enrolled and vaccinated with one dose of SYS6006 which was designed based on the prototype spike protein and introduced mutation sites. Adverse events (AEs) through 30 days and serious AEs during the study were collected. Live-virus and pseudovirus neutralizing antibody (Nab), binding antibody (immunoglobulin G [IgG]) and cellular immunity were tested through 180 days. Solicited all, injection-site and systemic AEs were reported by 618 (61.8%), 498 (49.8%), and 386 (38.6%) participants, respectively. Most AEs were grade 1. The two groups had similar safety profile. No vaccination-related SAEs were reported. Robust wild-type (WT) live-virus Nab response was elicited with peak geometric mean titers (GMTs) of 3769.5 (Group A) and 5994.7 (Group B) on day 14, corresponding to 1602.5- and 290.8-fold increase versus baseline, respectively. The BA.5 live-virus Nab GMTs were 87.7 (Group A) and 93.2 (Group B) on day 14. All participants seroconverted for WT live-virus Nab. Robust pseudovirus Nab and IgG responses to wild type and BA.5 were also elicited. ELISpot assay showed robust cellular immune response, which was not obviously affected by virus variation. In conclusion, SYS6006 heterologous boosting demonstrated long-term good safety and immunogenicity in participants who had received two or three doses of SARS-CoV-2 inactivated vaccine.

The clinical efficacy of a daratumumab-based regimen in relapsed/refractory acute leukemia: a single-center experience.

Relapsed/refractory acute leukemia (R/R-AL) is associated with a low remission rate, short survival rate, and poor prognosis. Treating R/R-AL remains challenging as there is no standardized effective regimen; hence, there is a need for efficient therapies. CD38 expression has been observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Daratumumab is a humanized anti-CD38 monoclonal antibody used to treat multiple myeloma and has been reported to treat R/R-AL safely and effectively. The clinical data of 10 adult patients with R/R-AL who were treated with a daratumumab-based salvage regimen between July 2018 and May 2023 at our center were analyzed retrospectively. Seven AML and three ALL cases were included in the analysis. Seven (70%) patients showed responses to the treatments (complete response [CR], 60%; partial response [PR], 10%). Of the seven responders, three underwent allogenic stem cell transplantation (ASCT), including one who underwent a second ASCT. Among the five patients with R/R AML who had prior exposure to venetoclax, three achieved a therapeutic response (two CR and one PR) when re-treated with venetoclax in combination with daratumumab. The median follow-up time was 6.15 months (0.9-21 months). Overall survival and event-free survival rates at 12 months were 68.6% and 40.0%, respectively. The main adverse events included grade 3 febrile neutropenia (20%) and grade 3 hematological toxicities (60%). The daratumumab-based salvage regimen offers patients with R/R-AL the opportunity of remission with acceptable tolerability, creating the possibility of bridging ASCT.

PFASs in Cerebrospinal Fluids and Blood-CSF Barrier Permeability in Patients with Cognitive Impairment.

Attention has been drawn to the associations between PFASs and human cognitive decline. However, knowledge on the occurrence and permeability of PFASs in the brains of patients with cognitive impairment has not been reported. Here, we determined 30 PFASs in paired sera and cerebrospinal fluids (CSFs) from patients with cognitive impairment (n = 41) and controls without cognitive decline (n = 18). We revealed similar serum PFAS levels but different CSF PFAS levels, with lower CSF PFOA (median: 0.125 vs 0.303 ng/mL, p < 0.05), yet higher CSF PFOS (0.100 vs 0.052 ng/mL, p < 0.05) in patients than in controls. Blood-brain transfer rates also showed lower RCSF/Serum values for PFOA and higher RCSF/Serum values for PFOS in patients, implying potential heterogeneous associations with cognitive function. The RCSF/Serum values for C4-C14 perfluoroalkyl carboxylates exhibited a U-shape trend with increasing chain length. Logistic regression analyses demonstrated that CSF PFOS levels were linked to the heightened risk of cognitive impairment [odds ratio: 3.22 (1.18-11.8)] but not for serum PFOS. Toxicity inference results based on the Comparative Toxicogenomics Database suggested that PFOS in CSF may have a greater potential to impair human cognition than other PFASs. Our results contribute to a better understanding of brain PFAS exposure and its potential impact on cognitive function.

Engineering an enzyme-like catalytic sensor for on-site dual-mode evaluation of total antioxidant capacity.

A novel Fe-MoOx nanozyme, engineered with enhanced peroxidase (POD)-like activity through strategic doping and the creation of oxygen vacancies, is introduced to catalyze the oxidation of TMB with high efficiency. Furthermore, Fe-MoOx is responsive to single electron transfer (SET) and hydrogen atom transfer (HAT) mechanisms related to antioxidants and can serve as a desirable nanozyme for total antioxidant capacity (TAC) determination. The TAC colorimetric platform can reach a low LOD of 0.512 µM in solution and 24.316 µM in the smartphone-mediated RGB hydrogel (AA as the standard). As proof of concept, the practical application in real samples was explored. The work paves a promising avenue to design diverse nanozymes for visual on-site inspection of food quality.

Improved YOLOv8-Based Target Precision Detection Algorithm for Train Wheel Tread Defects.

Train wheels are crucial components for ensuring the safety of trains. The accurate and fast identification of wheel tread defects is necessary for the timely maintenance of wheels, which is essential for achieving the premise of conditional repair. Image-based detection methods are commonly used for detecting tread defects, but they still have issues with the misdetection of water stains and the leaking of small defects. In this paper, we address the challenges posed by the detection of wheel tread defects by proposing improvements to the YOLOv8 model. Firstly, the impact of water stains on tread defect detection is avoided by optimising the structure of the detection layer. Secondly, an improved SPPCSPC module is introduced to enhance the detection of small targets. Finally, the SIoU loss function is used to accelerate the convergence speed of the network, which ensures defect recognition accuracy with high operational efficiency. Validation was performed on the constructed tread defect dataset. The results demonstrate that the enhanced YOLOv8 model in this paper outperforms the original network and significantly improves the tread defect detection indexes. The average precision, accuracy, and recall reached 96.95%, 96.30%, and 95.31%.

Recurrence and Complications of Peri-operative Steroid Injection of Keloids: A Systematic Review and Meta-analysis.

Keloid scars are a particularly challenging fibroproliferative wound healing disorder with a variety of proposed management approaches including concurrent surgery and intralesional steroid injection. We aimed to identify the optimum time for triamcinolone injection of keloids, by comparing the recurrence and complication occurrence in patients who received pre-, intra- or post-operative injection. Studies reporting on the rate of recurrence and complication occurrence following treatment of keloid scarring with concurrent surgical excision and intralesional steroid injection were identified from the PubMed, Web of science and Embase databases. The I-squared (I2) statistic was used to quantify the variability in study estimates due to heterogeneity and to determine whether the fixed or random effect models will be employed. Publication bias was visualized through funnel plots and tested with the Egger's test. We found that the recurrence rate was significantly lower with post-operative injection compared to intra-operative injection (p < 0.001) and pre-operative injection (p = 0.009). A significant difference between intra-operative and pre-operative injection was not found (p = 0.46). In conclusion, post-operative steroid injection after surgical excision results in lower keloid recurrence compared to pre- and intra-operative injection.Level of Evidence IV "This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ."

Exploring the Evolutionary History and Phylogenetic Relationships of Giant Reed (Arundo donax) through Comprehensive Analysis of Its Chloroplast Genome.

Giant reed (Arundo donax) is widely distributed across the globe and is considered an important energy crop. This study presents the first comprehensive analysis of the chloroplast genome of giant reed, revealing detailed characteristics of this species' chloroplast genome. The chloroplast genome has a total length of 137,153 bp, containing 84 protein-coding genes, 38 tRNA genes, and 8 rRNA genes, with a GC content of 39%. Functional analysis indicates that a total of 45 photosynthesis-related genes and 78 self-replication-related genes were identified, which may be closely associated with its adaptability and growth characteristics. Phylogenetic analysis confirmed that Arundo donax cv. Lvzhou No.1 belongs to the Arundionideae clade and occupies a distinct evolutionary position compared to other Arundo species. The findings of this study not only enhance our understanding of the giant reed genome but also provide valuable genetic resources for its application in biotechnology, bioenergy crop development, and ecological restoration.

Greenhouse gas emission characteristics and influencing factors of agricultural waste composting process: A review.

China, being a major agricultural nation, employs aerobic composting as an efficient approach to handle agricultural solid waste. Nevertheless, the composting process is often accompanied by greenhouse gas emissions, which are known contributors to global warming. Therefore, it is urgent to control the formation and emission of greenhouse gases from composting. This study provides a comprehensive analysis of the mechanisms underlying the production of nitrous oxide, methane, and carbon dioxide during the composting process of agricultural wastes. Additionally, it proposes an overview of the variables that affect greenhouse gas emissions, including the types of agricultural wastes (straw, livestock manure), the specifications for compost (pile size, aeration). The key factors of greenhouse gas emissions during composting process like physicochemical parameters, additives, and specific composting techniques (reuse of mature compost products, ultra-high-temperature composting, and electric-field-assisted composting) are summarized. Finally, it suggests directions and perspectives for future research. This study establishes a theoretical foundation for achieving carbon neutrality and promoting environmentally-friendly composting practices.

Effectiveness of teriparatide in in improving healing rates and bone-turnover markers of osteoporotic hip fracture: a meta-analysis.

Objective: To evaluate the effect of subcutaneous teriparatide therapy on fracture healing rate and change in bone mass density in osteoporotic hip fractures. METHODS: The meta-analysis was done from September to December 2022, and comprised literature search on Wanfang, CNKI, VIP, PubMed, Embase, Cochrane Library, and Web of Science databases from the establishment of the respective database till December 2022. The relevant journals of the library of Macao University of Science and Technology, China, were manually searched for randomised controlled trials of teriparatide in the treatment of osteoporotic hip fractures. The shortlisted studies were subjectd to Cochrane Risk of Bias tool and the Jadad Rating Scale. Meta-analysis was done using the RevMan 5.4 software provided by the Cochrane Collaboration Network. Fracture healing rate and bone mineral density were the primary outcome measures, while mortality, adverse events, malformations, complications, subsequent fractures, timed-up-and-go test, visual analogue scale score, and procollagen type I N-terminal propeptide were the secondary outcome measures. RESULTS: Of the 1,094 articles retrieved, 8(0.7%) randomised controlled trials were analysed. There were 744 patients; 372(50%) in the teriparatide group and 372(50%) in the control group. Fracture healing rate was not significantly different (p=0.82), while bone mineral density was significantly different between the groups (p<0.001). Mortality, adverse events, deformity, and complications were not significantly different (p>0.05), while subsequent fractures, timed-up-and-go score, visual analogue scale score and procollagen type I N-terminal propeptide were significantly different between the groups (p<0.05). Conclusion: The literature did not support teriparatide's ability to improve the healing rate of osteoporotic hip fractures, or to reduce mortality, adverse events, malformations, and complications. In addition, teriparatide could increase bone mineral density of osteoporotic hip fractures and the procollagen type I N-terminal propeptide value, alleviate hip pain, and reduce subsequent fracture rates. This trial is registered with PROSPERO with registration number CRD42022379832.

24-H movement behaviors and visual impairment among Chinese adolescents with and without obesity.

BACKGROUND: Previous studies have identified obesity, sleep patterns, screen time, and physical activity as independent risk factors for the visual health of adolescents. However, our understanding of how these factors interact and contribute to visual impairment remains limited. This study aimed to investigate the relationship between adherence to the 24-h movement guidelines (24-HMG) and visual impairment in adolescents with and without obesity. METHODS: We analyzed data from the 2014-2015 China Education Panel Survey. Participants provided self-reported information on their screen time, sleep duration, and physical activity levels. The data on weight, height, and visual acuity were obtained from school health examination reports. Logistic regression analysis was conducted to assess the association between 24-h movement behaviors and visual impairment, reported as odds ratios (ORs) with a 95 % confidence interval (CI). RESULTS: After controlling for covariates such as sex and age, it was found that adolescents with obesity who adhered to the sleep guidelines had a lower risk of visual impairment compared with adolescents without obesity who did not adhere to the 24-HMG (OR = 0.84, 95 % CI: 0.75-0.94, P = 0.003). Additionally, adolescents who adhered to both the physical activity and sleep guidelines had an even lower risk of visual impairment (OR = 0.58, 95 % CI: 0.42-0.79, P = 0.001). CONCLUSIONS: Adhering to the Sleep and physical activity + Sleep recommendations in the 24-HMG could significantly reduce the risk of visual impairment in adolescents without obesity. No significant relationship was observed between adherence to 24-HMG and the risk of visual impairment in adolescents with obesity.

The influence of perceived teacher support on online English learning engagement among Chinese university students: a cross-sectional study on the mediating effects of self-regulation.

Objectives: This study examines the association between perceived teacher support and self-regulation in learning, and their combined relationship with online English learning engagement among university students in China. The objective is to uncover the underlying mechanisms of this relationship, with a particular focus on the role of self-regulation in learning as a mediator. Methods: The study involved 1,361 university students from Southwest China, predominantly female (73.84%) with an average age of 18.94 years (SD = 1.07). Refined measurement tools were employed to assess perceived teacher support, online English learning engagement, and self-regulation in learning. Results: The findings indicate that components of self-regulation, such as goal setting, environmental structuring, and time management, act as full mediators in the relationship between perceived teacher support and online English learning engagement. Conclusion: This research underscores the importance of self-regulation in learning in linking perceived teacher support with online English learning engagement. The insights gained are crucial for enhancing teaching strategies in online English language education.

The physical activity and social support scale: a translation and psychometric validation study in a Chinese college student sample.

Objective: This study aims to evaluate the reliability and validity of the Chinese version of the Physical Activity Social Support Scale (PASSS-C) and its measurement invariance across different gender groups in a Chinese college student sample. Methods: A total of 1,689 Chinese college students participated in the study. We assessed the internal consistency of PASSS-C using Cronbach's alpha and McDonald's omega. A Confirmatory Factor Analysis (CFA) was conducted to test its five-factor model. Multi-group CFA was used to examine measurement equivalence between male and female groups. Convergent and criterion-related validity were assessed using Pearson correlation coefficients. Results: The overall internal consistency of PASSS-C was good with a Cronbach's alpha of 0.952, and the subscales showed acceptable consistency. The CFA results supported the five-factor structure of PASSS-C in the college student sample, with values of CFI = 0.932, TLI = 0.917, RMSEA = 0.048, 90% CI [0.043 0.053], SRMR = 0.047. Scalar invariance was also supported across different gender groups, with ΔCFI = -0.003, ΔTLI = 0, ΔRMSEA = 0. PASSS-C demonstrated good convergent and criterion-related validity. Conclusion: PASSS-C exhibits satisfactory psychometric properties and is a valid and reliable tool for assessing the perceived level of social support for physical activity among college students.

Validity evaluation of the Health Information Preferences Questionnaire among college students.

Objective: This study aims to explore the association between health information preferences and specific health behaviors and outcomes, such as preventive measures and chronic disease management among college students. It assesses how different levels of health information preference influence individuals' utilization, perception, and self-efficacy within healthcare and health information contexts. Given the rising prevalence of non-communicable chronic diseases among younger populations in China, this research seeks to understand how tailored health information preferences can support effective health education and behavioral interventions. The development of the Health Information Preference Questionnaire (HIPQ) aims to bridge the existing gap in tools for assessing health information preferences among Chinese college students, with a focus on collecting validity evidence to confirm the HIPQ's applicability in this group. Methods: The study employed a mixed-methods approach, beginning with an initial item pool derived from a comprehensive review of existing research tools, literature, and expert inputs. An expert review panel conducted item evaluations, leading to item reduction for clarity and relevance. The validation process utilized two independent samples of college students, detailing the sample size (n = 446 for preliminary testing, n = 1,593 for validation) and characteristics (age, major, urban vs. rural background) to enhance the understanding of the study's generalizability. Results: The HIPQ, comprising 25 items across five dimensions-prevention-oriented approaches, relationship with healthcare providers, self-efficacy in obtaining health information, perception of the importance of health information, and health information behavior-demonstrated excellent content validity (ICVI ranged from 0.72 to 0.86). Factor analysis confirmed significant loadings for each item across the anticipated factors, with fit indices (RMSEA = 0.065, CFI = 0.942) supporting good model fit. The HIPQ's reliability was underscored by Cronbach's alpha coefficients (>0.8) for each subscale, with significant correlations across all subscales, indicating strong internal consistency and construct validity. Conclusion: The HIPQ proves to be a reliable and valid instrument for assessing health information preferences among Chinese college students, highlighting its potential for broader application in health education and intervention strategies. Recognizing the study's focus on a specific demographic, future research should investigate the HIPQ's adaptability and utility in broader populations and different cultural settings. The study's limitations, including its concentrated demographic and context, invite further exploration into the HIPQ's applicability across diverse groups. Additionally, potential future research directions could include longitudinal studies to assess the impact of tailored health information on actual health outcomes and behaviors.

The sparse estimation of the semiparametric linear transformation model with dependent current status data.

In this paper, we study the sparse estimation under the semiparametric linear transformation models for the current status data, also called type I interval-censored data. For the problem, the failure time of interest may be dependent on the censoring time and the association parameter between them is left unspecified. To address this, we employ the copula model to describe the dependence between them and a two-stage estimation procedure to estimate both the association parameter and the regression parameter. In addition, we propose a penalized maximum likelihood estimation procedure based on the broken adaptive ridge regression, and Bernstein polynomials are used to approximate the nonparametric functions involved. The oracle property of the proposed method is established and the numerical studies suggest that the method works well for practical situations. Finally, the method is applied to an Alzheimer's disease study that motivated this investigation.

Validation of the Chinese version of the exercise empowerment scale among college students (EES-C).

Objective: The escalating prevalence of physical inactivity among college students represents a significant public health challenge, particularly in light of its correlation with detrimental health outcomes. A growing body of evidence underscores the necessity of adhering to recommended levels of regular physical activity to thwart the onset of chronic diseases. One primary aim of school physical education initiatives is to elevate physical activity levels and bolster student motivation toward engaging in physical exercise. Engagement in sports activities has demonstrated efficacy in augmenting students' motor skills, elevating their self-efficacy, and enhancing cognitive competencies related to physical prowess, while also promoting sustained participation in physical activities. The Exercise Empowerment Scale (EES) has been formulated to quantitatively assess the degree of exercise empowerment. To date, no validated Chinese version of the EES has been reported in the literature. To address this, this present study developed and validated a Chinese version of the EES in a large sample of Chinese college students. Methods: A sample of Chinese college students (n = 885) was analyzed using Rasch analysis to examine the validity of the Exercise Empowerment Scale. In addition, physical activity and psychological resilience were used to investigate the potential associations with exercise empowerment. Results: The EES-C was found to be a unidimensional scale, and the distribution of item difficulty was relatively even. The scale had good reliability (individual reliability of 0.87, and item reliability of 0.99). No differential item functioning (DIF) was observed across genders for any of the 13 EES-C items, suggesting equitable and unbiased applicability for both male and female respondents. The five-point scoring method of the EES scale was consistent with the overall distribution of the items and subjects. Exercise empowerment was positively correlated with autonomous physical activity and psychological resilience. Conclusion: The results of the study indicate that the EES-C possesses robust psychometric properties, rendering it suitable for application among Chinese college student populations. The adapted version of the EES-C provides a basis for further exploration of the predictive factors of physical activity in Chinese samples. The generalizability of our findings should be further verified in other populations in the future.

Knockdown of NUF2-derived exosomes can inhibit the migration and autophagy of BC cells and improve resistance to doxorubicin.

Breast cancer (BC) is the most common type of fatal cancer in women. New therapeutic strategies need to be explored to enhance the efficacy of doxorubicin by overcoming the resistance of BC cells. NUF2 is a component of the Ndc80 centromere complex and is a key substance in mediating mitosis and affects the progression of multiple tumors. However, the role as well as mechanisms of NUF2 resistance in BC remain unclear. This study aims to reveal the role of NUF2 in drug resistance in BC. We here revealed that NUF2 was highly expressed in human BC. NUF2 depletion-derived exosomes blocked the growth of BC cells. Further, NUF2 ablation-derived exosomes inhibited autophagy in BC cells. Also, NUF2 ablation-derived exosomes improved doxorubicin resistance in BC cells. Mechanically, NUF2 ablation-derived exosomes blocked PI3K/AKT/mTOR axis in BC cells. In summary, NUF2 ablation-derived exosomes blocked the autophagy of BC cells and improved doxorubicin resistance via mediating PI3K/AKT/mTOR axis.