Immunophenotypic clustering in paediatric acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a highly heterogeneous disease, exhibiting diverse subtypes according to the characteristics of tumour cells. The immunophenotype is one of the aspects acquired routinely through flow cytometry in the diagnosis of AML. Here, we characterized the antigen expression in paediatric AML cases across both morphological and molecular genetic subgroups. We discovered a subgroup of patients with unfavourable prognosis that can be immunologically characterized, irrespective of morphological FAB results or genetic aberrations. Cox regression analysis unveiled key antigens influencing the prognosis of AML patients. In terms of underlying genotypes, we observed that the antigenic profiles and outcomes of one specific group, primarily composed of CBFA2T3::GLIS2 and FUS::ERG, were analogous to the reported RAM phenotype. Overall, our data highlight the significance of immunophenotype to tailor treatment for paediatric AML.

Identifying sensors-based parameters associated with fall risk in community-dwelling older adults: an investigation and interpretation of discriminatory parameters.

BACKGROUND: Falls pose a severe threat to the health of older adults worldwide. Determining gait and kinematic parameters that are related to an increased risk of falls is essential for developing effective intervention and fall prevention strategies. This study aimed to investigate the discriminatory parameter, which lay an important basis for developing effective clinical screening tools for identifying high-fall-risk older adults. METHODS: Forty-one individuals aged 65 years and above living in the community participated in this study. The older adults were classified as high-fall-risk and low-fall-risk individuals based on their BBS scores. The participants wore an inertial measurement unit (IMU) while conducting the Timed Up and Go (TUG) test. Simultaneously, a depth camera acquired images of the participants' movements during the experiment. After segmenting the data according to subtasks, 142 parameters were extracted from the sensor-based data. A t-test or Mann-Whitney U test was performed on the parameters for distinguishing older adults at high risk of falling. The logistic regression was used to further quantify the role of different parameters in identifying high-fall-risk individuals. Furthermore, we conducted an ablation experiment to explore the complementary information offered by the two sensors. RESULTS: Fifteen participants were defined as high-fall-risk individuals, while twenty-six were defined as low-fall-risk individuals. 17 parameters were tested for significance with p-values less than 0.05. Some of these parameters, such as the usage of walking assistance, maximum angular velocity around the yaw axis during turn-to-sit, and step length, exhibit the greatest discriminatory abilities in identifying high-fall-risk individuals. Additionally, combining features from both devices for fall risk assessment resulted in a higher AUC of 0.882 compared to using each device separately. CONCLUSIONS: Utilizing different types of sensors can offer more comprehensive information. Interpreting parameters to physiology provides deeper insights into the identification of high-fall-risk individuals. High-fall-risk individuals typically exhibited a cautious gait, such as larger step width and shorter step length during walking. Besides, we identified some abnormal gait patterns of high-fall-risk individuals compared to low-fall-risk individuals, such as less knee flexion and a tendency to tilt the pelvis forward during turning.

Effectiveness of sensor-based interventions in improving gait and balance performance in older adults: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Sensor-based interventions (SI) have been suggested as an alternative rehabilitation treatment to improve older adults' functional performance. However, the effectiveness of different sensor technologies in improving gait and balance remains unclear and requires further investigation. METHODS: Ten databases (Academic Search Premier; Cumulative Index to Nursing and Allied Health Literature, Complete; Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Web of Science; OpenDissertations; Open grey; ProQuest; and Grey literature report) were searched for relevant articles published up to December 20, 2022. Conventional functional assessments, including the Timed Up and Go (TUG) test, normal gait speed, Berg Balance Scale (BBS), 6-Minute Walk Test (6MWT), and Falling Efficacy Scale-International (FES-I), were used as the evaluation outcomes reflecting gait and balance performance. We first meta-analyzed the effectiveness of SI, which included optical sensors (OPTS), perception sensors (PCPS), and wearable sensors (WS), compared with control groups, which included non-treatment intervention (NTI) and traditional physical exercise intervention (TPEI). We further conducted sub-group analysis to compare the effectiveness of SI (OPTS, PCPS, and WS) with TPEI groups and compared each SI subtype with control (NTI and TPEI) and TPEI groups. RESULTS: We scanned 6255 articles and performed meta-analyses of 58 selected trials (sample size = 2713). The results showed that SI groups were significantly more effective than control or TPEI groups (p < 0.000) in improving gait and balance performance. The subgroup meta-analyses between OPTS groups and TPEI groups revealed clear statistically significant differences in effectiveness for TUG test (mean difference (MD) = - 0.681 s; p < 0.000), normal gait speed (MD = 4.244 cm/s; p < 0.000), BBS (MD = 2.325; p = 0.001), 6MWT (MD = 25.166 m; p < 0.000), and FES-I scores (MD = - 2.036; p = 0.036). PCPS groups also presented statistically significant differences with TPEI groups in gait and balance assessments for normal gait speed (MD = 4.382 cm/s; p = 0.034), BBS (MD = 1.874; p < 0.000), 6MWT (MD = 21.904 m; p < 0.000), and FES-I scores (MD = - 1.161; p < 0.000), except for the TUG test (MD = - 0.226 s; p = 0.106). There were no statistically significant differences in TUG test (MD = - 1.255 s; p = 0.101) or normal gait speed (MD = 6.682 cm/s; p = 0.109) between WS groups and control groups. CONCLUSIONS: SI with biofeedback has a positive effect on gait and balance improvement among a mixed population of older adults. Specifically, OPTS and PCPS groups were statistically better than TPEI groups at improving gait and balance performance, whereas only the group comparison in BBS and 6MWT can reach the minimal clinically important difference. Moreover, WS groups showed no statistically or clinically significant positive effect on gait and balance improvement compared with control groups. More studies are recommended to verify the effectiveness of specific SI. Research registration PROSPERO platform: CRD42022362817. Registered on 7/10/2022.

Germline Neurofibromin 1 mutation enhances the anti-tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity.

Juvenile myelomonocytic leukaemia (JMML) is an aggressive paediatric leukaemia characterized by mutations in five canonical RAS pathway genes, including the NF1 gene. JMML is driven by germline NF1 gene mutations, with additional somatic aberrations resulting in the NF1 biallelic inactivation, leading to disease progression. Germline mutations in the NF1 gene alone primarily cause benign neurofibromatosis type 1 (NF1) tumours rather than malignant JMML, yet the underlying mechanism remains unclear. Here, we demonstrate that with reduced NF1 gene dose, immune cells are promoted in anti-tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by NF1 mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that NF1 mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced NF1 gene dose. NF1 mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, NF1-mutated iNKs had a high capacity to kill NF1-KO iMacs. NF1-mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline NF1 mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.

Prognostic significance of HLA-G in patients with colorectal cancer: a meta-analysis and bioinformatics analysis.

PURPOSE: Human leukocyte antigen-G (HLA-G) has been reported to be aberrantly expressed in colorectal cancer (CRC); however, its prognostic value remains controversial. Hence, our meta-analysis aims to assess the prognostic value of HLA-G in CRC patients based on published literature and The Cancer Genome Atlas (TCGA) datasets. METHODS: A systematic search was conducted on relevant studies retrieved from four electronic databases including PubMed, Embase, Web of Science and Cochrane Library. Hazard ratios (HRs) with 95% confidence intervals (CIs) were recorded to be applied as effective values. Fixed-effects models or random-effects models were applied on the basis of the value of heterogeneity (I 2). Publication bias was analyzed by Begg's and Egger's tests. In addition, the results were validated by using TCGA datasets. RESULTS: Thirteen studies comprising 3896 patients were incorporated into this meta-analysis. The pooled results showed that HLA-G expression was significantly associated with poor overall survival (OS) in both the univariate analysis (HR = 1.44, 95% CI: 1.14-1.83, P = 0.002) and the multivariate analysis (HR = 1.55, 95% CI: 1.23-1.95, P < 0.001). Nevertheless, the expression of HLA-G is not related to age, sex, tumor type, tumor differentiation, TNM stage, or distant metastasis but lymph node metastasis. Notably, the prognosis of colorectal cancer was not consistent with the analysis result from TCGA data. CONCLUSION: HLA-G expression was significantly related to poor OS in CRC according to the results of our meta-analysis. However, we found that the prognostic significance was inconsistent with our results according to the TCGA data in CRC. Hence, more research is still needed to further illustrate the prognostic role of HLA-G in CRC.

Design, synthesis, and biological evaluation of novel molecules as potent inhibitors of PLK1.

Polo-like kinase 1 (PLK1) is an attractive therapeutic target for the treatment of tumors, as it is an essential cell-cycle regulator frequently overexpressed in tumor tissues. PLK1 can promote tumor invasion and metastasis, and is often associated with poor prognosis in cancer patients. However, no PLK1 inhibitor has been granted marketing approval until now. Therefore, more potentially promising PLK1 inhibitors need to be investigated. In this study, a series of novel inhibitors targeting PLK1 was designed and optimized derived from a new scaffold. After synthesis and characterization, we obtained the structure-activity relationship and led to the discovery of the most promising compound 30e for PLK1. The antiproliferative activity against HCT116 cells (IC50 = 5 nM versus 45 nM for onvansertib) and the cellular permeability and efflux ratio were significantly improved (PappA→B = 2.03 versus 0.345 and efflux ratio = 1.65 versus 94.7 for 30e and onvansertib, respectively). Further in vivo studies indicated that 30e had favorable antitumor activity with 116.2% tumor growth inhibition (TGI) in comparison with TGI of 43.0% for onvansertib. Furthermore, 30e improved volume of tumor tissue distribution in mice as compared to onvansertib. This initial study on 30e holds promise for further development of an antitumor agent.

Temporal relationship between sleep duration and obesity among Chinese Han people and ethnic minorities.

BACKGROUND: No studies have assessed the association between sleep duration and obesity in Chinese ethnic minorities. Whether the relationship between sleep duration and obesity is different between Chinese Han people and Chinese ethnic minorities remains unclear. The study aimed to explore the relationship between sleep duration and obesity among Chinese Han people and Chinese ethnic minorities. METHODS: We applied data from the Guizhou Population Health Cohort Study (GPHCS), which 9,280 participants were recruited in the baseline survey from 2010 to 2012, and 8,163 completed the follow-up survey from 2016 to 2020. A total of 5,096 participants (3,188 Han Chinese and 1,908 ethnic minorities) were included in the ultimate analysis. Information on sleep duration (total 24-hour sleep time), body mass index (BMI), and waist circumference (WC) was collected at the baseline and follow-up survey, respectively. Cross-lagged panel analyses were conducted to explore the temporal relationship between sleep duration and obesity for Han people and ethnic minorities. RESULTS: For Han people, the results from cross-lagged panel analyses indicated that baseline sleep duration was significantly associated with follow-up BMI (ßBMI = -0.041, 95% CIBMI: -0.072 ~ -0.009) and follow-up WC (ßWC = -0.070, 95%CIWC: -0.103 ~ -0.038), but baseline BMI (ßBMI = -0.016, 95% CIBMI: -0.050 ~ 0.018) and baseline WC (ßWC = -0.019, 95% CIWC: -0.053 ~ 0.016) were not associated with follow-up sleep duration. In addition, the relationship between baseline sleep duration and follow-up BMI was gender-specific and significant only in the Han people female (ßBMI = -0.047, 95% CIBMI: -0.090 ~ -0.003) but not in the Han people male (ßBMI = -0.029, 95% CIBMI: -0.075 ~ 0.016). For ethnic minorities, the results indicated that there was no relationship between sleep duration and obesity at all, either from sleep duration to obesity (ßBMI = 0.028, 95%CIBMI: -0.012 ~ 0.068; ßWC = 0.020, 95%CIWC: -0.022 ~ 0.062), or from obesity to sleep duration (ßBMI = -0.022, 95%CIBMI: -0.067 ~ 0.022; ßWC = -0.042, 95%CIWC: -0.087 ~ 0.003). CONCLUSION: The relationship pattern between sleep duration and obesity across Han people and ethnic minorities is different. Future sleep-aimed overweight and obesity intervention should be conducted according to population characteristics.

Design of a Sensor-Technology-Augmented Gait and Balance Monitoring System for Community-Dwelling Older Adults in Hong Kong: A Pilot Feasibility Study.

Routine assessments of gait and balance have been recognized as an effective approach for preventing falls by issuing early warnings and implementing appropriate interventions. However, current limited public healthcare resources cannot meet the demand for continuous monitoring of deteriorations in gait and balance. The objective of this study was to develop and evaluate the feasibility of a prototype surrogate system driven by sensor technology and multi-sourced heterogeneous data analytics, for gait and balance assessment and monitoring. The system was designed to analyze users' multi-mode data streams collected via inertial sensors and a depth camera while performing a 3-m timed up and go test, a five-times-sit-to-stand test, and a Romberg test, for predicting scores on clinical measurements by physiotherapists. Generalized regression of sensor data was conducted to build prediction models for gait and balance estimations. Demographic correlations with user acceptance behaviors were analyzed using ordinal logistic regression. Forty-four older adults (38 females) were recruited in this pilot study (mean age = 78.5 years, standard deviation [SD] = 6.2 years). The participants perceived that using the system for their gait and balance monitoring was a good idea (mean = 5.45, SD = 0.76) and easy (mean = 4.95, SD = 1.09), and that the system is useful in improving their health (mean = 5.32, SD = 0.83), is trustworthy (mean = 5.04, SD = 0.88), and has a good fit between task and technology (mean = 4.97, SD = 0.84). In general, the participants showed a positive intention to use the proposed system in their gait and balance management (mean = 5.22, SD = 1.10). Demographic correlations with user acceptance are discussed. This study provides preliminary evidence supporting the feasibility of using a sensor-technology-augmented system to manage the gait and balance of community-dwelling older adults. The intervention is validated as being acceptable, viable, and valuable.

A Systematic Review of Wearable Sensor-Based Technologies for Fall Risk Assessment in Older Adults.

Falls have been recognized as the major cause of accidental death and injury in people aged 65 and above. The timely prediction of fall risks can help identify older adults prone to falls and implement preventive interventions. Recent advancements in wearable sensor-based technologies and big data analysis have spurred the development of accurate, affordable, and easy-to-use approaches to fall risk assessment. The objective of this study was to systematically assess the current state of wearable sensor-based technologies for fall risk assessment among community-dwelling older adults. Twenty-five of 614 identified research articles were included in this review. A comprehensive comparison was conducted to evaluate these approaches from several perspectives. In general, these approaches provide an accurate and effective surrogate for fall risk assessment. The accuracy of fall risk prediction can be influenced by various factors such as sensor location, sensor type, features utilized, and data processing and modeling techniques. Features constructed from the raw signals are essential for predictive model development. However, more investigations are needed to identify distinct, clinically interpretable features and develop a general framework for fall risk assessment based on the integration of sensor technologies and data modeling.

Assessing elderly's functional balance and mobility via analyzing data from waist-mounted tri-axial wearable accelerometers in timed up and go tests.

BACKGROUND: Poor balance has been cited as one of the key causal factors of falls. Timely detection of balance impairment can help identify the elderly prone to falls and also trigger early interventions to prevent them. The goal of this study was to develop a surrogate approach for assessing elderly's functional balance based on Short Form Berg Balance Scale (SFBBS) score. METHODS: Data were collected from a waist-mounted tri-axial accelerometer while participants performed a timed up and go test. Clinically relevant variables were extracted from the segmented accelerometer signals for fitting SFBBS predictive models. Regularized regression together with random-shuffle-split cross-validation was used to facilitate the development of the predictive models for automatic balance estimation. RESULTS: Eighty-five community-dwelling older adults (72.12 ± 6.99 year) participated in our study. Our results demonstrated that combined clinical and sensor-based variables, together with regularized regression and cross-validation, achieved moderate-high predictive accuracy of SFBBS scores (mean MAE = 2.01 and mean RMSE = 2.55). Step length, gender, gait speed and linear acceleration variables describe the motor coordination were identified as significantly contributed variables of balance estimation. The predictive model also showed moderate-high discriminations in classifying the risk levels in the performance of three balance assessment motions in terms of AUC values of 0.72, 0.79 and 0.76 respectively. CONCLUSIONS: The study presented a feasible option for quantitatively accurate, objectively measured, and unobtrusively collected functional balance assessment at the point-of-care or home environment. It also provided clinicians and elderly with stable and sensitive biomarkers for long-term monitoring of functional balance.

Revision of serum ALT upper limits of normal facilitates assessment of mild liver injury in obese children with non-alcoholic fatty liver disease.

BACKGROUND: The serum alanine aminotransferase (ALT) level is a critical parameter for evaluating liver injury in non-alcoholic fatty liver disease (NAFLD). However, the currently accepted upper limits of normal (ULN) for serum ALT (ULN-ALT) are debated, as they may be excessively high. METHODS: A total of 1638 children aged 6-16 years, comprising 507 children with normal BMI (500 healthy children and 7 children with NAFLD), 199 overweight children, and 932 obese children, were included in the analysis. We re-evaluated the ULN-ALT in 500 healthy Chinese children using the 95th percentiles of serum ALT levels as revised ULN-ALT. Fatty liver was identified by ultrasound examination. RESULTS: Significant positive correlations between serum ALT levels and body mass index (BMI) were detected in overweight boys (r = .399, P < .001), obese boys (r = .398, P < .001), and obese girls (r = .392, P < .001). The prevalence percentages of NAFLD were 93.6%, 75.8%, and 37.9% in obese boys with serum ALT levels of >50, 25-50, and ≤25 U/L and were 81.6%, 67.9%, and 20.6% in obese girls with serum ALT levels of >40, 20-40, and ≤20 U/L, respectively. CONCLUSION: Serum ALT levels significantly correlated with abnormal BMI values in children, suggesting a rigorous BMI threshold is needed to establish the cutoffs for serum ULN-ALT in children. Besides, the revised serum ULN-ALT can uncover mild liver injury in obese children with NAFLD.

A Personalized Health Monitoring System for Community-Dwelling Elderly People in Hong Kong: Design, Implementation, and Evaluation Study.

BACKGROUND: Telehealth is an effective means to assist existing health care systems, particularly for the current aging society. However, most extant telehealth systems employ individual data sources by offline data processing, which may not recognize health deterioration in a timely way. OBJECTIVE: Our study objective was two-fold: to design and implement an integrated, personalized telehealth system on a community-based level; and to evaluate the system from the perspective of user acceptance. METHODS: The system was designed to capture and record older adults' health-related information (eg, daily activities, continuous vital signs, and gait behaviors) through multiple measuring tools. State-of-the-art data mining techniques can be integrated to detect statistically significant changes in daily records, based on which a decision support system could emit warnings to older adults, their family members, and their caregivers for appropriate interventions to prevent further health deterioration. A total of 45 older adults recruited from 3 elderly care centers in Hong Kong were instructed to use the system for 3 months. Exploratory data analysis was conducted to summarize the collected datasets. For system evaluation, we used a customized acceptance questionnaire to examine users' attitudes, self-efficacy, perceived usefulness, perceived ease of use, and behavioral intention on the system. RESULTS: A total of 179 follow-up sessions were conducted in the 3 elderly care centers. The results of exploratory data analysis showed some significant differences in the participants' daily records and vital signs (eg, steps, body temperature, and systolic blood pressure) among the 3 centers. The participants perceived that using the system is a good idea (ie, attitude: mean 5.67, SD 1.06), comfortable (ie, self-efficacy: mean 4.92, SD 1.11), useful to improve their health (ie, perceived usefulness: mean 4.99, SD 0.91), and easy to use (ie, perceived ease of use: mean 4.99, SD 1.00). In general, the participants showed a positive intention to use the first version of our personalized telehealth system in their future health management (ie, behavioral intention: mean 4.45, SD 1.78). CONCLUSIONS: The proposed health monitoring system provides an example design for monitoring older adults' health status based on multiple data sources, which can help develop reliable and accurate predictive analytics. The results can serve as a guideline for researchers and stakeholders (eg, policymakers, elderly care centers, and health care providers) who provide care for older adults through such a telehealth system.

Relationship between Left Ventricular Outflow Tract Pressure Gradient and Hemoglobin in Patients with Hypertrophic Cardiomyopathy.

BACKGROUND: Anemia caused by left ventricular outflow tract obstruction in patients with hypertrophic obstructive cardiomyopathy (HOCM) has been reported, however, large clinical studies confirming this association are lacking. The objective of the present study was to investigate the relationship between left ventricular outflow tract (LVOT) pressure gradient and hemoglobin in patients with hypertrophic cardiomyopathy (HCM). METHODS: Patient demographics, laboratory and echocardiography data from 310 patients diagnosed with HCM from our hospital who had undergone echocardiography from July 2014 to March 2019 were collected from medical records. Patients were classified into HOCM and non-HOCM groups. RESULTS: Compared to the non-HOCM group, patients in the HOCM group had a lower hemoglobin level (112.2 ± 16.7 vs. 132.9 ± 22.2 g/L, p < 0.001). In addition, significant negative correlations between hemoglobin and LVOT pressure gradient were found in males (r = -0.568, p < 0.001) and females (r = -0.589, p < 0.001). Receiver operating characteristic curve analysis revealed that the best cut-off value for hemoglobin to predict HOCM in male patients was 128 g/L with 74.19% sensitivity and 75.51% specificity (area under the curve: 0.763, p < 0.001). For female patients, the cut-off value was 125 g/L, with a sensitivity and specificity of 89.39% and 48.48%, respectively (area under the curve: 0.718, p < 0.001). CONCLUSIONS: Our results indicate that hemoglobin level is inversely proportional to the LVOT gradient pressure and has value for predicting outflow tract obstruction in patients with HCM.

Scaling Laws in Directional Spreading of Droplets on Wettability-Confined Diverging Tracks.

Spontaneous pumpless transport of droplets on wettability-confined tracks is important for various applications, such as rapid transport and mixing of fluid droplets, enhanced dropwise condensation, biomedical devices, and so forth. Recent studies have shown that on an open surface, a superhydrophilic track of diverging width, laid on a superhydrophobic background, facilitates the transport of water from the narrower end to the wider end at unprecedented rates (up to 40 cm/s) without external actuation. The spreading behavior on such surfaces, however, has only been characterized for water. Keeping in mind that such designs play a key role for a diverse range of applications, such as handling organic liquids and in point-of-care devices, the importance of characterizing the spreading behavior of viscous liquids on such surfaces cannot be overemphasized. In the present work, the spreading behavior on the aforementioned wettability-patterned diverging tracks was observed for fluids of different viscosities. Two dimensionless variables were identified, and a comprehensive relationship was obtained. Three distinct temporal regimes of droplet spreading were established: I), a Washburn-type slow spreading, II) a much faster Laplace pressure-driven spreading, and III), a sluggish density-augmented Tanner-type film spreading. The results offer design guidance for tracks that can pumplessly manage fluids of various viscosities and surface tensions.

Precise Liquid Transport on and through Thin Porous Materials.

Porous substrates have the ability to transport liquids not only laterally on their open surfaces but also transversally through their thickness. Directionality of the fluid transport can be achieved through spatial wettability patterning of these substrates. Different designs of wettability patterns are implemented herein to attain different schemes (modes) of three-dimensional transport in a high-density paper towel, which acts as a thin porous matrix directing the fluid. All schemes facilitate precise transport of metered liquid microvolumes (dispensed as droplets) on the surface and through the substrate. One selected mode features lateral fluid transport along the bottom surface of the substrate, with the top surface remaining dry, except at the initial droplet dispension point. This configuration is investigated in further detail, and an analytical model is developed to predict the temporal variation of the penetrating drop shape. The analysis and respective measurements agree within the experimental error limits, thus confirming the model's ability to account for the main transport mechanisms.

Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response.

Triptolide (TP), an oxygenated diterpene, has a variety of beneficial pharmacodynamic activities but its clinical applications are restricted due to severe testicular injury. This study aimed to delineate the molecular mechanisms of TP-induced testicular injury in vitro and in vivo. TP (5-50000 nmol/L) dose-dependently decreased the viability of TM4 Sertoli cells with an IC50 value of 669.5-269.45 nmol/L at 24 h. TP (125, 250, and 500 nmol/L) dose-dependently increased the accumulation of ROS, the phosphorylation of JNK, mitochondrial dysfunction and activation of the intrinsic apoptosis pathway in TM4 cells. These processes were attenuated by co-treatment with the antioxidant N-acetyl cysteine (NAC, 1 mmol/L). Furthermore, TP treatment inhibited the translocation of Nrf2 from cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), catalase (CAT) and hemeoxygenase 1 (HO-1), thus abrogating Nrf2-mediated defense mechanisms against oxidative stress. Moreover, siRNA knockdown of Nrf2 significantly potentiated TP-induced apoptosis of TM4 cells. The above results from in vitro experiments were further validated in male mice after oral administration of TP (30, 60, and 120 mg·kg-1·d-1, for 14 d), as evidenced by the detected indexes, including dose-dependently decreased SDH activity, increased MDA concentration, altered testicle histomorphology, elevated caspase-3 activation, apoptosis induction, increased phosphorylation of JNK, and decreased gene expression of NQO1, CAT and HO-1 as well as nuclear protein expression of Nrf2 in testicular tissue. Our results demonstrate that TP activates apoptosis of Sertoli cells and injury of the testis via the ROS/JNK-mediated mitochondrial-dependent apoptosis pathway and down-regulates Nrf2 activation.

Bacteria/Nanozyme Composites: New Therapeutics for Disease Treatment.

Bacterial therapy is recognized as a cost-effective treatment for several diseases. However, its development is hindered by limited functionality, weak inherent therapeutic effects, and vulnerability to harsh microenvironmental conditions, leading to suboptimal treatment activity. Enhancing bacterial activity and therapeutic outcomes emerges as a pivotal challenge. Nanozymes have garnered significant attention due to their enzyme-mimic activities and high stability. They enable bacteria to mimic the functions of gene-edited bacteria expressing the same functional enzymes, thereby improving bacterial activity and therapeutic efficacy. This review delineates the therapeutic mechanisms of bacteria and nanozymes, followed by a summary of strategies for preparing bacteria/nanozyme composites. Additionally, the synergistic effects of such composites in biomedical applications such as gastrointestinal diseases and tumors are highlighted. Finally, the challenges of bacteria/nanozyme composites are discussed and propose potential solutions. This study aims to provide valuable insights to offer theoretical guidance for the advancement of nanomaterial-assisted bacterial therapy.

Hemostatic and antibacterial calcium-copper zeolite gauze for infected wound healing.

The design and development of wound dressings with excellent procoagulant and antibacterial activity to achieve high wound healing effectiveness are highly desirable in clinical applications. In this work, we develop a calcium-copper zeolite gauze (CaCu-ZG) by a two-step process involving calcium and copper ion exchange in a zeolite gauze. The CaCu-ZG exhibits remarkable procoagulant and antibacterial abilities, as well as good biocompatibility. Compared with the medical gauze, the blood clotting time of CaCu-ZG significantly decreases and the antibacterial activity increases in both in vivo and in vitro experiments. The remarkable ability of wound healing has been verified using a mouse dorsal skin-infected wound model, demonstrating its great potential for wound treatment in clinical applications.

Tetrahydrocurcumin Protects Against GSK3ß/PTEN/PI3K/Akt-Mediated Neuroinflammatory Responses and Microglial Polarization Following Traumatic Brain Injury.

Tetrahydrocurcumin (THC) and microglial polarization play crucial roles in neuroprotection during traumatic brain injury (TBI). However, whether THC regulates microglial polarization in TBI is unknown. Thus, we intended to analyze the functions and mechanism of THC in nerve injury after TBI via the regulation of microglial polarization. A TBI rat model was established, and modified neurological function score (mNSS), brain water content, Nissl staining, and Fluoro-Jade B (FJB) staining were used to evaluate neurological function. The expression of the M1-linked markers CD16 and CD86, as well as the M2-associated markers CD206 and YM-1, was analyzed via qRT-PCR, western blotting, and immunofluorescence. The levels of inflammatory cytokines were assessed via ELISA. Primary microglia were isolated from the brain and treated with lipopolysaccharide (LPS) to induce injury. TUNEL staining was used to measure primary microglial apoptosis. The expression of GSK3ß, PTEN, and PI3K/Akt pathway proteins was detected via western blotting. TBI induced nerve injury, while THC improved neurological function recovery after TBI. Further analysis indicated that THC enhanced M2 microglial polarization and attenuated the inflammatory reaction mediated by microglia both in vitro and in vivo. Moreover, we found that THC promoted the M2 microglial phenotype through upregulating GSK3ß expression. Additionally, we proved that GSK3ß activated the PI3K/Akt pathway by phosphorylating PTEN. In conclusion, we demonstrated that THC protected against nerve injury after TBI via microglial polarization via the GSK3B/PTEN/PI3K/Akt signaling axis, suggesting the potential of THC for TBI treatment by promoting microglial M2 polarization.

Cross-talk between the gut microbiota and hypothyroidism: a bidirectional two-sample Mendelian randomization study.

Background: Multiple observational studies suggest a connection between the composition of the gut microbiota and hypothyroidism. However, it has yet to be determined whether the gut microbiota has a causal effect on hypothyroidism. Methods: To investigate the connection between the gut microbiota and hypothyroidism, two-sample Mendelian randomization was performed using data from a genome-wide association study meta-analysis (n = 18,430) conducted by the MiBioGen consortium. Summary statistics for hypothyroidism (26,342 cases and 59,827 controls) were obtained using the data from the FinnGen consortium R8 release data. To investigate the causal link between the gut microbiota and hypothyroidism, various methods, including MR-Egger, weighted median, weighted model, simple model, MR-PRESSO, and inverse variance weighted (IVW), were employed. The bacteria that were causally linked to hypothyroidism in forward Mendelian randomization analysis were subjected to reverse Mendelian randomization analysis. Cochran's Q statistics were utilized to gauge the heterogeneity of the instrumental variables. Results: The results indicated that Akkermansia had a positive impact on hypothyroidism, with an odds ratio of 0.84 (95% CI 0.74-0.95, p = 0.01) based on the inverse variance-weighted estimates. Additionally, Anaerostipes (OR = 1.17, 95% CI 1.01-1.36, p = 0.04), Butyrivibrio (OR = 0.93, 95% CI 0.88-0.99, p = 0.02), Holdemania (OR = 0.89, 95% CI 0.81-0.99, p = 0.03), Intestinimonas (OR = 1.13, 95% CI 1.02-1.26, p = 0.03), Ruminiclostridium5 (OR = 1.19, 95% CI 1.01-1.41, p = 0.04), and Ruminococcaceae UCG-011 (OR = 0.91, 95% CI 0.84-0.99, p = 0.03) were identified. The gut microbiota was not significantly affected by hypothyroidism, as indicated by the results of the reverse MR analysis. There was no significant variation in the instrumental variables or horizontal pleiotropy. Conclusion: The findings of this study using two-sample Mendelian randomization indicate a causal relationship between Akkermansia and hypothyroidism. Increased Akkermansia inhibits the onset and progression of hypothyroidism. Additional randomized controlled experiments are necessary to elucidate the beneficial impact of probiotics on hypothyroidism and their distinct protective mechanisms.