Benzo[a]pyrene (BaP), a ubiquitous pollutant, raises environmental health concerns due to induction of bone toxicity in the unexposed offspring. Exposure of F0 ancestor medaka (Oryzias latipes) to 1 μg/L BaP for 21 days causes reduced vertebral bone thickness in the unexposed F3 male offspring. To reveal the inherited modifications, osteoblast (OB) abundance and molecular signaling pathways of transgenerational BaP-induced bone thinning were assessed. Histomorphometric analysis showed a reduction in OB abundance. Analyses of the miRNA and mRNA transcriptomes revealed the dysregulation of Wnt signaling (frzb/ola-miR-1–3p, sfrp5/ola-miR-96–5p/miR-455–5p) and bone morphogenetic protein (Bmp) signaling (bmp3/ola-miR-96–5p/miR-181b-5p/miR-199a-5p/miR-205–5p/miR-455–5p). Both pathways are major indicators of impaired bone formation, while the altered Rank signaling in osteoclasts (c-fos/miR-205–5p) suggests a potentially augmented bone resorption. Interestingly, a typical BaP-responsive pathway, the Nrf2-mediated oxidative stress response (gst/ola-miR-181b-5p/miR-199a-5p/miR-205), was also affected. Moreover, mRNA levels of epigenetic modification enzymes (e.g., hdac6, hdac7, kdm5b) were found dysregulated. The findings indicated that epigenetic factors (e.g., miRNAs, histone modifications) may directly regulate the expression of genes associated with transgenerational BaP bone toxicity and warrants further studies. The identified candidate genes and miRNAs may serve as potential biomarkers for BaP-induced bone disease and as indicators of historic exposures in wild fish for conservation purposes.
With inherent mechanical compliance and programmable force controllability, the Series Elastic Actuator (SEA) has been a popular choice for modern mechanical systems. It is crucial to realize accurate and robust force control for a SEA, especially in a physical human–robot interaction condition. In this paper, a model-free force controller (MFFC) for the SEA is developed, which relies only on the input–output measurement. Firstly, based on the ultra-local model concept, the SEA force dynamics is reformulated in a simpler way, and all unknown terms are grouped as one term called lumped total disturbance. Secondly, an enhanced extended stated observer (EESO) is designed to simultaneously estimate the lumped total disturbance, the force velocity, and the control input gain. Thirdly, a disturbance rejective intelligent PD (iPD) control scheme is established. In addition, the effects of the control input gain are analyzed and the close-loop stability is demonstrated with Lyapunov method. The control accuracy and robustness of the MFFC are verified in a physical human–robot interaction environment.
The limited clinical response and serious side effect have been challenging in cancer immunotherapy resulting from immunosuppressive tumor microenvironment (TME) and inferior drug targeting. Herein, an active targeting TME nanoplatform capable of revising the immunosuppressive TME microenvironment is designed. Briefly, gold nanorods (GNRs) are covered with silica dioxide (SiO2) and then coated manganese dioxide (MnO2) to obtain [email protected]2@MnO2 (GSM). Myeloid-derived suppressor cells (MDSCs) membrane is further camouflaged on the surface of GSM to obtain [email protected]2@MnO2@MDSCs (GSMM). In this system, GSMM inherits active targeting TME capacity of MDSCs. The localized surface plasmon resonance of GNRs is developed in near-infrared II window by MnO2 layer coating, realizing NIR-II window photothermal imaging and photoacoustic imaging of GSMM. Based on the release of Mn²⁺ in acidic TME, GSMM can be also used for magnetic resonance imaging. In cancer cells, Mn²⁺ catalyzes H2O2 into ·OH for (chemodynamic therapy) CDT leading to activate cGAS-STING, but also directly acts on STING inducing secretion of type I interferons, pro-inflammatory cytokines and chemokines. Additionally, photothermal therapy and CDT-mediated immunogenic cell death of tumor cells can further enhance anti-tumor immunity via exposure of CRT, HMGB1 and ATP. In summary, our nanoplatform realizes multimodal cancer imaging and dual immunotherapy.
The human gut microbiome is a complex ecosystem that is closely related to the aging process. However, there is currently no reliable method to make full use of the metagenomics data of the gut microbiome to determine the age of the host. In this study, we considered the influence of geographical factors on the gut microbiome, and a total of 2604 filtered metagenomics data from the gut microbiome were used to construct an age prediction model. Then, we developed an ensemble model with multiple heterogeneous algorithms and combined species and pathway profiles for multi-view learning. By integrating gut microbiome metagenomics data and adjusting host confounding factors, the model showed high accuracy (R² = 0.599, mean absolute error = 8.33 years). Besides, we further interpreted the model and identify potential biomarkers for the aging process. Among these identified biomarkers, we found that Finegoldia magna, Bifidobacterium dentium, and Clostridium clostridioforme had increased abundance in the elderly. Moreover, the utilization of amino acids by the gut microbiome undergoes substantial changes with increasing age which have been reported as the risk factors for age-associated malnutrition and inflammation. This model will be helpful for the comprehensive utilization of multiple omics data, and will allow greater understanding of the interaction between microorganisms and age to realize the targeted intervention of aging.
Background The clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma. Methods In this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios. Findings Of 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9–18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p<0·0001), had higher BMI (p<0·0001), and were more likely to present with metabolic comorbidities (diabetes [p<0·0001], hypertension [p<0·0001], and hyperlipidaemia [p<0·0001]) or cardiovascular disease at presentation (p=0·0055) than patients with hepatocellular carcinoma due to other causes. They were also more likely to be non-cirrhotic (38·5%, 27·9–50·2 vs 14·6%, 8·7–23·4 for hepatocellular carcinoma due to other causes; p<0·0001). Patients with NAFLD-related hepatocellular carcinoma had larger tumour diameters (p=0·0087), were more likely to have uninodular lesions (p=0·0003), and had similar odds of Barcelona Clinic Liver Cancer stages, TNM stages, alpha fetoprotein concentration, and Eastern Cooperative Oncology Group (ECOG) performance status to patients with non-NAFLD-related hepatocellular carcinoma. A lower proportion of patients with NAFLD-related hepatocellular carcinoma underwent surveillance (32·8%, 12·0–63·7) than did patients with hepatocellular carcinoma due to other causes (55·7%, 24·0–83·3; p<0·0001). There were no significant differences in treatment allocation (curative therapy, palliative therapy, and best supportive care) between patients with NAFLD-related hepatocellular carcinoma and those with hepatocellular carcinoma due to other causes. Overall survival did not differ between the two groups (hazard ratio 1·05, 95% CI 0·92–1·20, p=0·43), but disease-free survival was longer for patients with NAFLD-related hepatocellular carcinoma (0·79, 0·63–0·99; p=0·044). There was substantial heterogeneity in most analyses (I²>75%), and all articles had low-to-moderate risk of bias. Interpretation NAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma. Funding None.
It is well-established that appropriate hydration practices are essential in promoting health and optimizing performance and recovery. However, evidence-based hydration guidelines may not be adopted due to cultural differences across countries, such as religious beliefs, traditions, preferences, and beverage availability. Examples of hydration practices influenced by culture include beer consumption after sports in Western countries, consumption of sugarcane juice in India and Ramadan fasting among Muslims. For most cultural hydration practices, there is limited scientific evidence on their effects on rehydration, exercise performance, and recovery. Despite possible benefits of various hydration practices on exercise performance and recovery, they are inconsistent with current evidence-based hydration recommendations. More research on the impacts of cultural hydration differences on physiology, performance, and recovery is warranted to allow evidence-based guidelines and advisories. Abbreviations: ABV: alcohol by volume, ACSM: American College of Sports Medicine, NATA: National Athletic Trainers' Association, ROS: reactive oxygen species, TCM: Traditional Chinese Medicine.
Particles and condensing vapors contribute to the contamination of optical components of solar thermochemical reactors including windows and secondary concentrators and result in severe reactor performance deterioration. We propose an impinging-jet solar reactor in a distinctive topology to enhance aerodynamic-aided window protection. The vector fields on the two-dimensional inner surfaces of the impinging-jet reactor and four conventional reactors are analyzed for the first time using differential topology. The topological analysis demonstrates that the application of an impinging jet in the reactor leads to the prevention of the stagnation point in the vicinity of the window, which is inevitable in any axisymmetric flow field of the conventional reactors. The transient two-dimensional flow fields of all reactors are numerically investigated using the finite volume method to understand the effects of the reactor geometry, aspect ratio, and sweep gas mass flow rate on the window protection performance characterized by the contaminant residence time and peak volumetric concentration near the window. The impinging-jet reactors with aspect ratios of one and two are found to be the most effective designs in aerodynamic-aided window protection among all investigated configurations.
Interleukin-1α (IL-1α) plays an important role in inflammation and hematopoiesis. Many tumors have increased IL-1α expression. However, the immune regulatory role of secreted IL-1α in tumor development and whether it can be targeted for cancer therapy are still unclear. Here, we found that tumoral-secreted IL-1α significantly promoted hepatocellular carcinoma (HCC) development in vivo. Tumoral-released IL-1α were found to inhibit T and NK cell activation, and the killing capacity of CD8+ T cells. Moreover, MDSCs were dramatically increased by tumoral-released IL-1α in both spleens and tumors. Indeed, higher tumoral IL-1α expression is associated with increased tumoral infiltration of MDSCs in HCC patients. Further studies showed that tumoral-released IL-1α promoted MDSC recruitment to the tumor microenvironment through a CXCR2-dependent mechanism. Depletion of MDSCs could diminish the tumor-promoting effect of tumoral-released IL-1α. On the contrary, systemic administration of recombinant IL-1α protein significantly inhibited tumor development by activating T cells. In fact, IL-1α protein could promote T cell activation and enhance the cytotoxicity of CD8+ T cells in vitro. Thus, our study demonstrated that tumoral-released IL-1α promoted tumor development through recruiting MDSCs to inhibit T cell activation, while systemic IL-1α directly promoted anti-tumor T cell responses. We further identified calpain 1 as the major intracellular protease mediating tumoral IL-1α secretion. Calpain 1 KO tumors had diminished IL-1α release and reduced tumor development. Thus, our findings provide new insights into the functions of secreted IL-1α in tumor immunity and its implications for immunotherapy.
Background We aimed to investigate the association between time from admission to appendectomy on perioperative outcomes in order to determine optimal time-to-surgery windows. Methods We performed a retrospective review of all the appendectomies performed between July 2018 to May 2020. We first compared the perioperative outcomes using preselected time-to-surgery cut-offs, then determined optimal safe windows for surgery, and finally identified subgroups of patients who may require early intervention. Results Six hundred twenty-one appendectomies were performed in the time period. The patients with a time-to-surgery of ≥12 hours had a significantly longer length of stay (median 2 days [interquartile range 1–3] vs 3 days [interquartile range 2–4], mean difference = 0.74 [95% confidence interval 0.32–1.17, P = .0006]) and higher 30-day readmission risk (odds ratio 2.58, 95% confidence interval 1.12–5.96, P = .0266) versus those with a time-to-surgery of <12 hours. These differences persisted when the time-to-surgery was dichotomized by <24 or ≥24 hours. A time-to-surgery beyond 25 hours was associated with a 3.34-fold increased odds of open conversion (P = .040), longer operation time (mean difference 15.8 mins, 95% confidence interval 3.4–28.3, P = .013) and longer postoperative length of stay (mean difference 10.3 hours, 95% confidence interval 3.4–20.2, P = .042) versus a time-to-surgery of <25 hours. The patients with time-to-surgery beyond 11 hours had a 1.35-fold increased odds of 30-day readmission (95% confidence interval 1.02–5.43, P = .046) compared with those who underwent appendectomy before 11 hours. Older patients, patients with American Society of Anesthesiologist score II to III, and individuals with long duration of preadmission symptoms had higher risk of prolonged operation time, open conversion, increased length of stay, and postoperative morbidity with increasing time-to-surgery. Conclusion This study identified the safe windows for appendectomy to be 11 to 25 hours from admission for most perioperative outcomes. However, certain patient subgroups may be less tolerant of surgical delays.
Background and Aims The evaluation of the natural history of non-alcoholic steatohepatitis (NASH) has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomised controlled trials (RCT) to examine the natural history of NASH. Methods A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (i) the resolution of NASH without worsening of fibrosis, (ii) 2-point reduction in NAFLD activity score (NAS) without worsening of fibrosis and (iii) at least 1-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. Results This meta-analysis of 43 RCTs included 2,649 placebo-treated patients. The pooled estimate of NASH resolution and 2-point NAS reduction without worsening of fibrosis was 11.65% (95% CI: 7.98 - 16.71) and 21.11% (95% CI: 17.24 - 25.57). The rate of ≥1 stage reduction and progression of fibrosis was and 18.82% (95% CI: 15.65 - 22.47) and 22.74% (CI: 19.63 to 26.17) respectively. Older age and African-American ethnicity was associated with lower NASH resolution rate in placebo-treated patients. Conclusion Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of Phase 2B and Phase 3 trials.
Severe toxicity of heavy metal ions and their adverse effects on the ecosystem and health of living species raised a requirement to develop practical detection configurations capable of simultaneous and differentiable detection of toxic metal ions in aquatic samples. In this regard, we have fabricated a high-performance sensor configuration based on the integrated reduced graphene oxide (rGO) flakes with brominated white polyaniline (PANi) flakes toward the prompt and accurate detection of Pb (II) and Cd (II) in biological and non-biological specimens. The as-developed configuration simultaneously identified both Pb (II) and Cd (II) through a differentiable manner with a limit of detection (LOD)/quantification limit (QL) of 7.3 nM/85 nM and 6.5 nM/92 nM, respectively. The sensor also showed superior sensitivity of about 4547.77 and 3914.01 µA.µM⁻¹.cm⁻² toward Pb (II) and Cd (II), respectively, along with a favorable recovery rate in actual human blood plasma and wastewater samples. The as-developed complex proved to be an ideal platform for simultaneous detection/recovery of heavy metal ions in various aquatic samples.
Combining hybrid polymeric platforms with laser-assisted reduced graphene oxide (LArGO) could bridge the gap between a battery and supercapacitor device, overshadow the drawbacks of polymeric configurations, and boost the cyclic stability, specific capacitance (SC), and energy density of the resulting configurations. Herein, drawbacks of polymeric configurations such as polypyrrole (PPy) and polyindole (PIN) are modified via reinforcement with silver nanowires (Ag-PPy and Ag-PIN), and their performances are compared via in-depth fundamental analyses to select the superior one. Accordingly, the SC of PPy and PIN increased from 282 and 324 F.g-1 to 452 and 587 F.g-1 at the current density of 1 A.g-1 upon reinforcement with silver nanowires, respectively. The Ag-PIN configuration as the superior modified polymeric platform is assembled in an asymmetric supercapacitor along with LArGO. The as-developed electrodes show an ideal synergic effect and reveal favorable SC retention (94.2%) after 5000 cycles, high specific capacitance of 368.8 F.g-1, and energy density of 41.5 W.h.Kg-1 at the power density of 450 W.Kg-1. The obtained data illuminate the great capability of the hybrid package that bridges the gap between a high-performance battery and supercapacitor.
Background: Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows quantification of biventricular blood flow by flow components and kinetic energy (KE) analyses. However, it remains unclear whether 4D flow parameters can predict cardiopulmonary exercise testing (CPET) as a clinical outcome in repaired tetralogy of Fallot (rTOF). Current study aimed to (1) compare 4D flow CMR parameters in rTOF with age- and gender-matched healthy controls, (2) investigate associations of 4D flow parameters with functional and volumetric right ventricular (RV) remodelling markers, and CPET outcome. Methods: Sixty-three rTOF patients (14 paediatric, 49 adult; 30 ± 15 years; 29 M) and 63 age- and gender-matched healthy controls (14 paediatric, 49 adult; 31 ± 15 years) were prospectively recruited at four centers. All underwent cine and 4D flow CMR, and all adults performed standardized CPET same day or within one week of CMR. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes. Four flow components were analyzed: direct flow, retained inflow, delayed ejection flow and residual volume. Additionally, three phasic KE parameters normalized to end-diastolic volume (KEiEDV), were analyzed for both LV and RV: peak systolic, average systolic and peak E-wave. Results: In comparisons of rTOF vs. healthy controls, median LV retained inflow (18% vs. 16%, P = 0.005) and median peak E-wave KEiEDV (34.9 µJ/ml vs. 29.2 µJ/ml, P = 0.006) were higher in rTOF; median RV direct flow was lower in rTOF (25% vs. 35%, P < 0.001); median RV delayed ejection flow (21% vs. 17%, P < 0.001) and residual volume (39% vs. 31%, P < 0.001) were both greater in rTOF. RV KEiEDV parameters were all higher in rTOF than healthy controls (all P < 0.001). On multivariate analysis, RV direct flow was an independent predictor of RV function and CPET outcome. RV direct flow and RV peak E-wave KEiEDV were independent predictors of RV remodelling index. Conclusions: In this multi-scanner multicenter 4D flow CMR study, reduced RV direct flow was independently associated with RV dysfunction, remodelling and, to a lesser extent, exercise intolerance in rTOF patients. This supports its utility as an imaging parameter for monitoring disease progression and therapeutic response in rTOF. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifier: NCT03217240.
There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.
The discovery of two-dimensional (2D) magnetic van der Waals (vdW) materials has flourished an endeavor for fundamental problems as well as potential applications in computing, sensing and storage technologies. Of particular interest are antiferromagnets, which due to their intrinsic exchange coupling show several advantages in relation to ferromagnets such as robustness against external magnetic perturbations. Here we show that, despite of this cornerstone, the magnetic domains of recently discovered 2D vdW MnPS 3 antiferromagnet can be controlled via magnetic fields and electric currents. We achieve ultrafast domain-wall dynamics with velocities up to ~3000 m s ⁻¹ within a relativistic kinematic. Lorentz contraction and emission of spin-waves in the terahertz gap are observed with dependence on the edge termination of the layers. Our results indicate that the implementation of 2D antiferromagnets in real applications can be further controlled through edge engineering which sets functional characteristics for ultrathin device platforms with relativistic features.
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