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This study aims to investigate the effect of adipose-derived stem cells (ADSCs) transplantation on progranulin (PGRN) expression and functional recovery in rats with spinal cord injury (SCI). ADSCs were isolated from the inguinal adipose tissue of rats. A SCI model was created, and ADSCs were injected into the injured area. Various techniques were used to assess the effects of ADSCs transplantation, including hematoxylin-eosin staining, Masson staining, immunofluorescence staining, electron microscopy, MRI, and motor function assessment. The potential mechanisms of ADSC transplantation were investigated using gene expression analysis and protein analysis. Finally, the safety of this therapy was evaluated through hematoxylin-eosin staining and indicators of liver and kidney damage in serum. PGRN expression increased in the injured spinal cord, and ADSCs transplantation further enhanced PGRN levels. The group that received ADSCs transplantation showed reduced inflammation, decreased scar formation, increased nerve regeneration, and faster recovery of bladder function. Importantly, motor function significantly improved in the ADSC transplantation group. ADSCs transplantation enhances functional regeneration in SCI by upregulating PGRN expression, reducing inflammation and scar formation, and promoting nerve regeneration and myelin repair. These findings suggest that ADSC transplantation is a potential therapy for SCI., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The introduction of anthropogenic inputs into natural systems may lead to enduring alterations in the innate characteristics of Rare Earth Elements (REEs). Against this backdrop, the evolutionary processes and environmental drivers of REEs in soil remain uncertain. A 3000-year soil chronosequence with uniform parent material was established in reclaimed farmland along the Yangtze River, reconstructing, for the first time, the dynamic processes of REE accumulation and fractionation over a long-time scale. Analysis of 122 soil samples showed REE concentrations ranging from 146.00 to 216.56 μg/g. Based on reclamation duration, three significant stages of REE evolution were identified: natural leaching, rapid accumulation, and stable accumulation with differentiation. Reclaimed soil after 3000 years exhibited a 14.1 % increase in REE concentrations compared to fresh sediments, attributed to anthro -pedogenic processes. Moreover, Heavy Rare Earth Elements (HREEs) accumulated faster than Light Rare Earth Elements (LREEs), particularly in deeper soils (60-100 cm), where HREE concentrations rose by 34.3 %, mainly due to acidic environments promoting HREE fixation. Additionally, the potential ecological risk posed by REEs heightened with reclamation duration, with HREEs exhibiting a sensitivity of 83 % to 94 %. Our findings stress the urgency of carefully monitoring exogenous REEs introduced through anthropogenic activities, particularly HREEs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Epidemiological studies on heavy metal exposure and liver injury are predominantly cross-sectional, lacking longitudinal data and exploration of potential mechanisms., Method: We conducted a repeated-measures study in Northeast China from 2016 to 2019, involving 322 participants. Linear mixed models (LMM) and Bayesian kernel machine regression (BKMR) were employed to explore the associations between individual and mixed blood metal concentrations [chromium (Cr), cadmium (Cd), vanadium (V), manganese (Mn), lead (Pb)] and liver function biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), globulin (GLB), total protein (TP)]. Mediation and enrichment analyses were used to determine whether the inflammatory response is a critical pathway for heavy metal-induced liver damage., Result: We obtained a total of 958 observations. The results from LMM and BKMR indicated significant associations between individual and mixed heavy metals and liver function biomarkers. Longitudinal analysis revealed associations between Cd and the annual increase rate of ALT (β = 2.61; 95% CI: 0.97, 4.26), the annual decrease rate of ALB (β = -0.21; 95% CI: -0.39, -0.03), Mn and the annual increase rate of GLB (β = 0.38; 95% CI: 0.05, 0.72), and V and the annual decrease rate of ALB/GLB (β = -1.15; 95% CI: -2.00, -0.31). Mediation analysis showed that high-sensitivity C-reactive protein (hsCRP) mediated the associations between Cd and AST, TP, with mediation effects of 27.7% and 13.4%, respectively. Additionally, results from Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses supported the role of inflammatory response pathways., Conclusion: Our findings indicate that heavy metal exposure leads to liver damage, with the inflammatory response potentially serving as a crucial pathway in this process. This study offers a novel perspective on understanding heavy metal-induced liver injury and provides insights for preventive measures against the health damage caused by heavy metals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background and Aims: Liver injury is one of the common complications of paraquat (PQ) poisoning, but whether the degree of liver injury is related to patient prognosis is still controversial. This study aimed to investigate whether liver injury was a risk factor for death in PQ-poisoned patients., Methods: We conducted a retrospective cohort study of PQ-poisoned patients from the past 10 years (2011-2020) from a large tertiary academic medical centre in China. PQ-poisoned patients were divided into a normal liver function group (n = 580) and a liver injury group (n = 60). Propensity score matching (PSM) analysis was then performed., Results: A total of 640 patients with PQ poisoning were included in this study. To reduce the impact of bias, dose of PQ, urinary PQ concentration and time from poisoning to hospital admission were matched between the two groups. A 3:1 PSM analysis was performed, ultimately including 240 patients. Compared with the normal liver function group, patients in the liver injury group were older, had a higher R value ([ALT/ULN]/[ALP/ULN]) (p < .001) and had a higher mortality rate. Cox regression analysis showed that there was no significant association between alanine aminotransferase, alkaline phosphatase, total bilirubin levels and hazard of death, but age, PQ dose, creatine kinase isoenzyme, creatine kinase, white blood cell count, neutrophil percentage and lymphocyte percentage were associated with mortality in patients with PQ poisoning., Conclusions: The occurrence of liver injury within 48 h after PQ poisoning was a risk factor for mortality, and such liver injury was likely of a hepatocellular nature. Age, PQ dose, creatine kinase isoenzyme and white blood cell count were positively correlated with mortality, while creatine kinase, percentage of neutrophils and lymphocytes were inversely correlated., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to analyze the intracerebral abnormalities of hemodynamics in patients with Parkinson's disease (PD) through arterial spin labelling (ASL) technique with multi-delay ASL (MDASL) and conventional single-delay ASL (SDASL) protocols and to verify the potential clinical application of these features for the diagnosis of PD., Materials and Methods: Perfusion data of the brain obtained using MDASL and SDASL in patients with PD were compared to those obtained in healthy control (HC) subjects. Intergroup comparisons of z-scored cerebral blood flow (zCBF), arterial transit time (zATT) and cerebral blood volume (zCBV) were performed via voxel-based analysis. Performance of these perfusion metrics were estimated using area under the receiver operating characteristic curve (AUC) and compared using Delong test., Results: A total of 47 patients with PD (29 men; 18 women; mean age, 69.0 ± 7.6 (standard deviation, [SD]) years; range: 50.0-84.0 years) and 50 HC subjects (28 men; 22 women; mean age, 70.1 ± 6.2 [SD] years; range: 50.0-93.0 years) were included. Relative to the uncorrected-zCBF map, the corrected-zCBF map further refined the distributed brain regions in the PD group versus the HC group, manifested as the extension of motor-related regions (P FWE < 0.001). Compared to the HC subjects, patients with PD had elevated zATT and zCBV in the right putamen, a shortened zATT in the superior frontal gyrus, and specific zCBV variations in the left precuneus and the right supplementary motor area (P FWE < 0.001). The corrected-zCBF (AUC, 0.90; 95% confidence interval [CI]: 0.84-0.96) showed better classification performance than uncorrected-zCBF (AUC, 0.84; 95% CI: 0.75-0.92) (P = 0.035). zCBV achieved an AUC of 0.89 (95% CI: 0.82-0.96) and zATT achieved an AUC of 0.66 (95% CI: 0.55-0.77). The integration model of hemodynamic features from MDASL provided improved performance (AUC, 0.97; 95% CI: 0.95-0.98) for the diagnosis of PD by comparison with each perfusion model (P < 0.001)., Conclusion: ASL identifies impaired hemodynamics in patients with PD including regional abnormalities of CBF, CBV and ATT, which can better be mapped with MDASL compared to SDASL. These findings provide complementary depictions of perfusion abnormalities in patients with PD and highlight the clinical feasibility of MDASL., Competing Interests: Disclosure of Interests The authors have no conflicts of interest to disclose in relation with this manuscript., (Copyright © 2024 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

We investigated the effect of individual, joint and fluctuating exposure to air pollution (PM 2.5 , BC, NO 3 - , NH 4 + , OM, SO 4 2- , PM 10 , NO 2 , SO 2 , O 3 ) on glucose metabolisms among prediabetes, and simultaneously explored the modifying effect of lifestyle. We conducted a longitudinal study among prediabetes during 2018-2022. Exposure windows within 60-days moving averages and their variabilities were calculated. FBG, insulin, HOMA-IR, HOMA-B, triglyceride glucose index (TyG), glucose insulin ratio (GI) and allostatic load of glucose homeostasis system (AL-GHS) was included. Linear mixed-effects model and BKMR were adopted to investigate the individual and overall effects, respectively. We also explored the preventive role of lifestyle. Individual air pollutant was associated with increased FBG, insulin, HOMA-IR, HOMA-B, TyG, and decreased GI. People with FBG ≥6.1 mmol/L were more susceptible. Air pollutants mixture were only associated with increased HOMA-B, and constituents have the highest group-PIP. Air pollutants variation also exert harmful effect. We observed similar diabetic effect on AL-GHS. Finally, the diabetic effect of air pollutants disappeared if participants adopt a favorable lifestyle. Our findings highlighted the importance of comprehensively assessing multiple air pollutants and their variations, focusing on metabolic health status in the early prevention of T2D, and adopting healthy lifestyle to mitigate such harmful effect., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A significant knowledge gap exists regarding the impact of soil organic matter on the bioavailability of Ag 2 S-NPs (environmentally relevant forms of Ag-NPs) in soil-earthworm-plant systems. This study used two soils with varying organic matter content, both with and without earthworms, to investigate the bioavailability of Ag 2 S-NPs. The findings revealed an 80 % increase in Ag bioaccessibility to soybeans in soils with high organic matter content compared to soils with low organic matter. Additionally, the presence of earthworms significantly increased Cl concentrations from 24.3-62.2 mg L -1 to 80.1-147.2 mg L -1 , triggering the elevated bioavailability of Ag. Interestingly, Ag 2 S-NPs eliminated the stimulative effects of earthworms on plant nutrient uptake. In the presence of earthworms, the high organic matter soil amended with Ag 2 S-NPs exhibited lower concentrations of essential elements (Ca, Cu, Fe, K, and P) in plant tissues compared to soils without earthworms. Our study presents evidence of the transformation of Ag 2 S-NPs into Ag-NPs across various soil solutions, resulting in the formation of Ag nanoparticle complexes. Particularly noteworthy is the significant reduction in particle sizes in soils incubated with earthworms and high organic matter content, from 85.0 nm to 40.2 nm. Notably, in the rhizosphere soil, a decrease in the relative abundance of nutrient cycling-related phyla was observed, with reductions of 18.5 % for Proteobacteria and 30.0 % for Actinobacteriota. These findings offer valuable insights into the biological and biochemical consequences of Ag 2 S-NP exposure on earthworm-mediated plant nutrient acquisition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Epidemiological studies have reported associations between heavy metals and renal function. However, longitudinal studies are required to further validate these associations and explore the interactive effects of heavy metals on renal function and their directional influence., Method: This study, conducted in Northeast China from 2016 to 2021, included a four-time repeated measures design involving 384 participants (1536 observations). Urinary concentrations of chromium (Cr), cadmium (Cd), manganese (Mn), and lead (Pb) were measured, along with renal biomarkers including urinary microalbumin (umAlb), urinary albumin-to-creatinine ratio (UACR), N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin (β2-MG) levels. Estimated glomerular filtration rate (eGFR) was calculated. A Linear Mixed Effects Model (LME) examined the association between individual metal exposure and renal biomarkers. Subsequently, Quantile g-computation and Bayesian Kernel Machine Regression (BKMR) models assessed the overall effects of heavy metal mixtures. Marginal Effect models examined the directional impact of metal interactions in the BKMR on renal function., Result: Results indicate significant impacts of individual and combined exposures of Cr, Cd, Pb, and Mn on renal biomarkers. Metal interactions in the BKMR model were observed, with synergistic effects of Cd-Cr on NAG, umAlb, UACR; Cd-Pb on NAG, UACR; Pb-Cr on umAlb, UACR, eGFR-MDRD, eGFR-EPI; and an antagonistic effect of Mn-Pb-Cr on UACR., Conclusion: Both individual and combined exposures to heavy metals are associated with renal biomarkers, with significant synergistic interactions leading to renal damage. Our findings elucidate potential interactions among these metals, offering valuable insights into the mechanisms linking multiple metal exposures to renal injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Endoplasmic reticulum stress (ERS) and apoptosis of nucleus pulposus (NP) cells are considered to be the main pathological factors of intervertebral disc degeneration (IDD). Fucoxanthin (FX), a marine carotenoid extracted from microalgae, has antioxidant, anti-inflammatory, and anticancer properties. The aim of this study was to investigate the effect of FX on NP cells induced by oxidative stress and its molecular mechanism. Primary NP cells of the lumbar vertebrae of rats were extracted and tested in vitro. qRT-PCR, western blot, immunofluorescence, and TUNEL staining were used to detect apoptosis, ERS, extracellular matrix (ECM), and Sirt1-related pathways. In vivo experiments, the recovery of IDD rats was determined by X-ray, hematoxylin and eosin, Safranin-O/Fast Green, Alcian staining, and immunohistochemistry. Our study showed that oxidative stress induced ERS, apoptosis, and ECM degradation in NP cells. After the use of FX, the expression of Sirt1 was up-regulated, the activation of PERK-eIF2α-ATF4-CHOP was decreased, and apoptosis and ECM degradation were decreased. At the same time, FX improved the degree of disc degeneration in rats in vivo. Our study demonstrates the effect of FX on improving IDD in vivo and in vitro, suggesting that FX may be a potential drug for the treatment of IDD., (© 2023 John Wiley & Sons Ltd.)

Microwave radiometry (MWR) is instrumental in detecting thermal variations in skin tissue before anatomical changes occur, proving particularly beneficial in the early diagnosis of cancer and inflammation. This study concisely traces the evolution of microwave radiometers within the medical sector. By analyzing a plethora of pertinent studies and contrasting their strengths, weaknesses, and performance metrics, this research identifies the primary factors limiting temperature measurement accuracy. The review establishes the critical technologies necessary to overcome these limitations, examines the current state and prospective advancements of each technology, and proposes comprehensive implementation strategies. The discussion elucidates that the precise measurement of human surface and subcutaneous tissue temperatures using an MWR system is a complex challenge, necessitating an integration of antenna directionality for temperature measurement, radiometer error correction, hardware configuration, and the calibration and precision of a multilayer tissue forward and inversion method. This study delves into the pivotal technologies for non-invasive human tissue temperature monitoring in the microwave frequency range, offering an effective approach for the precise assessment of human epidermal and subcutaneous temperatures, and develops a non-contact microwave protocol for gauging subcutaneous tissue temperature distribution. It is anticipated that mass-produced measurement systems will deliver substantial economic and societal benefits.

Background: The impact of heavy metals on liver function has been examined in numerous epidemiological studies. However, these findings lack consistency and longitudinal validation., Methods: In this study, we conducted three follow-up surveys with 426 participants from Northeast China. Blood and urine samples were collected, along with questionnaire information. Urine samples were analyzed for concentrations of four metals (chromium [Cr], cadmium [Cd], lead [Pb], and manganese [Mn]), while blood samples were used to measure five liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin [ALB], globulin [GLB], and total protein [TP]). We utilized a linear mixed-effects model (LME) to explore the association between individual heavy metal exposure and liver function. Joint effects of metal mixtures were investigated using quantile g-computation and Bayesian kernel machine regression (BKMR). Furthermore, we employed BKMR and Marginal Effect models to examine the interaction effects between metals on liver function., Results: The LME results demonstrated a significant association between urinary heavy metals (Cr, Cd, Pb, and Mn) and liver function markers. BKMR results indicated positive associations between heavy metal mixtures and ALT, AST, and GLB, and negative associations with ALB and TP, which were consistent with the g-comp results. Synergistic effects were observed between Cd-Cr on ALT, Mn-Cr and Cr-Pb on ALB, while an antagonistic effect was found between Mn-Pb and Mn-Cd on ALB. Additionally, synergistic effects were observed between Mn-Cr on GLB and Cd-Cr on TP. Furthermore, a three-way antagonistic effect of Mn-Pb-Cr on ALB was identified., Conclusion: Exposure to heavy metals (Cr, Cd, Mn, Pb) is associated with liver function markers, potentially leading to liver damage. Moreover, there are joint and interaction effects among these metals, which warrant further investigation at both the population and mechanistic levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The overuse of pefloxacin (PEF) leaves residues in foods. Therefore, the development of robust analytical techniques for the selective detection of PEF is of great importance. In this study, a highly stable electrochemical sensing platform has been constructed, using molecularly imprinted polymer (MIP)-coated gold nanoparticle/black phosphorus nanocomposites (BPNS-AuNPs), for the selective detection of PEF. BPNS-AuNPs significantly enhance the black phosphorus (BP) stability and electrochemical activity and offer a larger surface area to accommodate more imprinted sites for selective PEF binding. MIP/BPNS-AuNPs exhibit a broad linear detection range (0.005-10 μM), low detection limit (0.80 nM), and high sensitivity (3.199 μA μM -1 ). The MIP/BPNS-AuNPs show a high binding affinity for PEF, even in the presence of structural analogs, and maintain stable voltammetric signals for at least 35 d. The MIP sensor exhibits consistent high sensitivity in the detection of PEF in real milk and orange juice samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Osteoporosis is a prevalent systemic skeletal disorder, particularly affecting postmenopausal women, primarily due to excessive production and activation of osteoclasts. However, the current anti-osteoporotic drugs utilized in clinical practice may lead to certain side effects. Therefore, it is necessary to further unravel the potential mechanisms regulating the osteoclast differentiation and to identify novel targets for osteoporosis treatment. This study revealed the most significant decline in VSIG4 expression among the VSIG family members. VSIG4 overexpression significantly inhibited RANKL-induced osteoclastogenesis and bone resorption function. Mechanistically, both western blot and immunofluorescence assay results demonstrated that VSIG4 overexpression attenuated the expression of osteoclast marker genes and dampened the activation of MAPK and NF-κB signaling pathways. Furthermore, VSIG4 overexpression could inhibit the generation of reactive oxygen species (ROS) and stimulate the expression of Nrf2 along with its downstream antioxidant enzymes via interaction with Keap1. Notably, a potent Nrf2 inhibitor, ML385, could reverse the inhibitory effect of VSIG4 on osteoclast differentiation. In line with these findings, VSIG4 overexpression also mitigated bone loss induced by OVX and attenuated the activation of osteoclasts in vivo. In conclusion, our results suggest that VSIG4 holds promise as a novel target for addressing postmenopausal osteoporosis. This is achieved by suppressing osteoclast formation via enhancing Nrf2-dependent antioxidant response against reactive oxygen species production., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Aging is a key risk factor in cognitive diseases. Recently, metal exposures were found associated with both biological aging and cognitive function. Here, we aim to evaluate the associations of blood metals with cognitive function and the mediated effect of biological aging. Fourteen metals were detected and biological age was calculated through Klemera and Doubal method among 514 adults in Beijing, China. The generalized linear models indicated that the copper (Cu), molybdenum (Mo), and strontium (Sr) were positively associated with biological aging [β Cu (95% CI): 12.76 (9.26, 16.27); β Mo (95% CI): 1.50 (0.15, 2.85)], and β Sr (95% CI): 1.86 (0.68, 3.03)], while vanadium (V) was inversely related to biological aging [β V (95% CI): -0.76 (-1.48, -0.05)]. Subsequently, Cu, lead (Pb), selenium (Se), and biological aging were associated with cognitive function and further mediation analyses confirmed that biological aging partially mediated (33.98%, P = 0.019) the association of Cu and cognitive function. Additionally, we constructed a lifestyle index that implied the modifiable healthy lifestyle could slow aging to attenuate the detrimental effect of metals on cognition. Our findings provide insights into the potential pathways linking multiple metals exposure to aging and cognition and underscore the importance of adopting healthy lifestyles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Dementia is a significant cause of elderly disability and Alzheimer's disease (AD) is the most prevalent form of dementia. As an early stage of AD, the mechanism related to mild cognitive impairment (MCI) and heavy metals is still unclear. This study utilized a cross-sectional design and enrolled 514 older adults in Bejing, China. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) and fourteen blood metals were measured by inductively coupled plasma mass spectrometry (ICP-MS). In the adjusted single-metal models, we observed that copper [Cu, β (95% CI): 3.73 (-6.42, -1.03)] and lead [Pb, β (95% CI): 0.79 (-1.26, -0.32)] demonstrated negative associations with cognitive function, while selenium [Se, β (95% CI): 2.97 (1.23, 4.70)] was beneficial to cognition. Our findings were robust in secondary analysis using multi-metal models, which included generalized linear models (GLM), Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp). Moreover, the toxic metal mixture (Cu and Pb) exhibited a significant negative association with MMSE scores and the inclusion of Se in the metal mixture attenuated the neurotoxicity of Cu-Pb mixture. The in silico analysis was used to examine the potential molecular mechanisms (genes, biological processes, pathways, and illnesses) of interaction among metal mixtures. We identified 20 cognition-related genes that are associated with both Cu-Pb and Se. Among these genes, eight (APOE, APP, BAX, BDNF, CASP3, HMOX1, TF, and TPP1) exhibited opposite effects on protein activity, mRNA expression, or protein expression in response to Se and Cu/Pb exposure, which could be the key genes accounting for the anti-neurotoxic effects of Se. Our findings support that Se can attenuate the neurotoxicity of exposure to single Cu or Pb, and Cu-Pb mixture. More research is needed to confirm our findings and gain knowledge about the molecular mechanisms of combined metal exposure on cognitive function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The musculoskeletal toxicity of immune checkpoint inhibitors (ICIs) is receiving increasing attention with clinical experience. Nevertheless, the absence of a systematic investigation into the musculoskeletal toxicity profile of ICIs currently results in the under-recognition of associated adverse events. Further and more comprehensive investigations are warranted to delineate the musculoskeletal toxicity profile of ICIs and characterize these adverse events. Material and methods: The present study employed the FDA Adverse Event Reporting System database to collect adverse events between January 2010 and March 2021. We utilized both the reporting odds ratio and the Bayesian confidence propagation neural network algorithms to identify suspected musculoskeletal adverse events induced by ICIs. Subsequently, the clinical characteristics and comorbidities of the major musculoskeletal adverse events were analyzed. The risk of causing these events with combination therapy versus monotherapy was compared using logistic regression model and Ω shrinkage measure model. Results: The musculoskeletal toxicity induced by ICIs primarily involves muscle tissue, including neuromuscular junctions, fascia, tendons, and tendon sheaths, as well as joints, spine, and bones, including cartilage. The toxicity profile of PD-1/PD-L1 and CTLA-4 inhibitors varies, wherein the PD-1 inhibitor pembrolizumab exhibits a heightened overall risk of inducing musculoskeletal adverse events. The major ICIs-induce musculoskeletal adverse events, encompassing conditions such as myositis, neuromyopathy (including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Guillain-Barré syndrome, and Chronic inflammatory demyelinating polyradiculoneuropathy), arthritis, fractures, myelitis, spinal stenosis, Sjogren's syndrome, fasciitis, tenosynovitis, rhabdomyolysis, rheumatoid myalgia, and chondrocalcinosis. Our study provides clinical characteristics and comorbidities of the major ICIs-induced musculoskeletal adverse events. Furthermore, the combination therapy of nivolumab and ipilimumab does not result in a statistically significant escalation of the risk associated with the major musculoskeletal adverse events. Conclusion: Immune checkpoint inhibitors administration triggers a range of musculoskeletal adverse events, warranting the optimization of their management during clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Li, Li, Zhang, Wu, Li, Meng, Cao and Li.)

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg -1 , and p < 0.001 at 1 mg kg -1 and 10 mg kg -1 ) and cynomolgus monkeys (p ≤ 0.05 at 1 mg kg -1 and 3 mg kg -1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase., (© 2023 Takeda Pharmaceutical Company Limited. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Objective: To quantitatively compare the diagnostic values of conventional diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) analysis of microstructural differences for clear cell renal cell carcinoma (CRCC)., Methods: A total of 108 patients with pathologically confirmed CRCC, including 38 Grade I, 37 Grade II, 18 Grade III and 15 Grade IV, were enrolled and divided into groups according to tumor grade [low grade (Ⅰ+Ⅱ, n = 75) and high grade (Ⅲ+Ⅳ, n = 33)]. Apparent diffusion coefficient (ADC), mean diffusivity (MD), mean kurtosis (MK), kurtosis anisotropy (KA) and radial kurtosis (RK) were performed., Results: Both the ADC ( r = -0.803) and MD (-0.867) values showed a negative correlation with tumor grading ( p < 0.05) and MK ( r = 0.812), KA (0.816) and RK (0.853) values a positive correlation with tumor grading ( p < 0.05). Mean FA values showed no significant differences among CRCC grades ( p > 0.05). ROC curve analyses showed that MD values had the highest diagnostic efficacy in differentiating low/high and Ⅱ/Ⅲ tumor grading. MD values gave AUC: 0.937 (0.896); sensitivity: 92.0% (86.5%); specificity: 78.8% (77.8%) and accuracy: 90.7% (87.3%). ADC performed worse than MD, MK, KA or RK (all p < 0.05) during pair-wise comparisons of ROC curves to show diagnostic efficacy., Conclusion: DKI analysis performs better than ADC in differentiating CRCC grading., Advances in Knowledge: Both the ADC and MD values correlated negatively with CRCC grading.The MK, KA and RK values correlated positively with CRCC grading.MD values had the highest diagnostic efficacy in differentiating low/high and Ⅱ/Ⅲ CRCC grading., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: Osteoarthritis (OA), a degenerative disease with a high global prevalence, is characterized by the degradation of the extracellular matrix (ECM) and the apoptosis of chondrocytes. Ajugol, a extract derived from the herb Rehmannia glutinosa, has not yet been investigated for its potential in modulating the development of OA., Methods: We employed techniques such as western blotting, immunofluorescence, immunohistochemistry, X-ray imaging, HE staining, and SO staining to provide biological evidence supporting the role of Ajugol as a potential therapeutic agent for modulating OA. Furthermore, in an in vivo experiment, intra-peritoneal injection of 50 mg/kg Ajugol effectively mitigated the progression of OA following destabilization of the medial meniscus (DMM) surgery., Results: Our findings revealed that treatment with 50 μM Ajugol activated TFEB-mediated autophagy, alleviating ER stress-induced chondrocyte apoptosis and ECM degradation caused by TBHP. Furthermore, in an in vivo experiment, intra-peritoneal injection of 50 mg/kg Ajugol effectively mitigated the progression of OA following destabilization of the medial meniscus (DMM) surgery., Conclusion: These results provide compelling biological evidence supporting the role of Ajugol as a potential therapeutic agent for modulating OA by activating autophagy and attenuating ER stress-induced cell death and ECM degradation. The promising in vivo results further suggest the potential of Ajugol as a treatment strategy for OA progression., (© 2023. International Society for Chinese Medicine and BioMed Central Ltd.)

Background: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides., Methods: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate., Results: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients., Conclusions: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.)., (Copyright © 2023 Massachusetts Medical Society.)

To achieve the Paris Agreement, China pledged to become "Carbon Neutral" by the 2060s. In addition to massive decarbonization, this would require significant changes in ecosystems toward negative CO 2 emissions. The ability of coastal blue carbon ecosystems (BCEs), including mangrove, salt marsh, and seagrass meadows, to sequester large amounts of CO 2 makes their conservation and restoration an important "nature-based solution (NbS)" for climate adaptation and mitigation. In this review, we examine how BCEs in China can contribute to climate mitigation. On the national scale, the BCEs in China store up to 118 Tg C across a total area of 1,440,377 ha, including over 75% as unvegetated tidal flats. The annual sedimental C burial of these BCEs reaches up to 2.06 Tg C year -1 , of which most occurs in salt marshes and tidal flats. The lateral C flux of mangroves and salt marshes contributes to 1.17 Tg C year -1 along the Chinese coastline. Conservation and restoration of BCEs benefit climate change mitigation and provide other ecological services with a value of $32,000 ha -1 year -1 . The potential practices and technologies that can be implemented in China to improve BCE C sequestration, including their constraints and feasibility, are also outlined. Future directions are suggested to improve blue carbon estimates on aerial extent, carbon stocks, sequestration, and mitigation potential. Restoring and preserving BCEs would be a cost-effective step to achieve Carbon Neutral by 2060 in China despite various barriers that should be removed., Competing Interests: The authors declare no competing interests., (© 2023.)

Chronic kidney disease (CKD) is a public health concern worldwide, and chromium exposure may be a risk factor due to its potential nephrotoxicity. However, research on the association between chromium exposure and kidney function especially the potential threshold effect of chromium exposure is limited. A repeated-measures study involving 183 adults (641 observations) was conducted from 2017 to 2021 in Jinzhou, China. Urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were measured as kidney function biomarkers. Generalized mixed models and two-piecewise linear spline mixed models were used to assess the dose-response relationship and potential threshold effect of chromium on kidney function, respectively. Temporal analysis was conducted by the latent process mixed model to depict the longitudinal change of kidney function over age. Urinary chromium was associated with CKD (odds ratio [OR] = 1.29; 95 % confidence interval [CI], 6.41, 14.06) and UACR (Percent change = 10.16 %; 95 % CI, 6.41 %, 14.06 %), and we did not find significant association between urinary chromium and eGFR (Percent change = 0.06 %; 95 % CI, -0.80 %, 0.95 %). The threshold analyses suggested the existence of threshold effects of urinary chromium, with inflection points at 2.74 μg/L for UACR and 3.95 μg/L for eGFR. Furthermore, we found that chromium exposure exhibited stronger kidney damage over age. Our study provided evidence for the threshold effects of chromium exposure on kidney function biomarkers and the heightened nephrotoxicity of chromium in older adults. More attention should be paid to the supervision of chromium exposure concentrations for preventing kidney damage, especially in older adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study explored the mediating role of glucose homeostasis indicators in the relationship between serum cystatin C and mild cognitive impairment (MCI)., Methods: The present study used a cross-sectional design and included 514 participants aged ≥50 years in Beijing, China. The Mini-Mental State Examination was used to assess cognitive function. Serum cystatin C and a comprehensive set of glucose homeostasis indicators were detected, including fasting blood glucose (FBG), glycosylated albumin percentage (GAP), glycated hemoglobin (HbAlc), insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), and beta cell function (HOMA-β). Generalized linear models were used to investigate the associations among cystatin C, glucose homeostasis indicators, and cognitive function. Mediation analysis was conducted to explore potential mediator variables., Results: In this study of 514 participants, 76 (14.8%) had MCI. Those with cystatin C levels ≥1.09 mg/L had a 1.98-fold higher risk of MCI than those with levels <1.09 mg/L (95% CI, 1.05-3.69). FBG, GAP, and HbA1c increased the risk of MCI, while HOMA-β decreased the risk. Notably, the associations between MCI risk and cystatin C or glucose homeostasis were only founded in diabetes patients. Serum cystatin C was found to be positively associated with HOMA-β (beta (95% CI): 0.20 [0.06, 0.34]), HOMA-IR (0.23 [0.09, 0.36]), and insulin (0.22 [0.09, 0.34]) levels. Moreover, HOMA-β was identified as playing a negative mediating role (proportion mediated: -16%) in the relationship between cystatin C and MCI., Conclusion: Elevated levels of cystatin C are associated with an increased risk of MCI. The glucose homeostasis indicator, HOMA-β, plays a negative mediating role in the relationship between cystatin C and MCI risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Xu, Zhao, Wu, Mei, Zhou, Zhao, Li, Yang and Xu.)

No-till (NT) as a conservation practice aims to minimize soil disturbance and enhance soil sustainability. However, how NT practice affects soil physicochemical and biological properties in soybean areas remains unclear. This study selected 65 high-yielding soybean farms under a long-term NT system in the Brazilian Cerrado and collected soil samples at 0.0-0.10 m (L1), 0.10-0.20 m (L2) and 0.20-0.40 m (L3) depths. The effect of NT on soil properties and interactions with soybean productivities were assessed. Results showed that the average soybean yield of the study areas in the last three years was 4.13 Mg ha -1 , with 26 areas presenting yields over 4.20 Mg ha -1 . Most studied soil properties showed a depth stratification and were strongly concentrated in L1, except for S, Al 3+ and aluminum saturation, which displayed lower surface and higher subsurface concentrations. Moreover, a high proportion of SOM is composed of light SOM fraction in areas of high soybean yield, with the average SOM values of 39.9, 27.8 and 19.6 g kg -1 in L1, L2 and L3, respectively. Soils under long-term NT present moderate values of enzyme activity compared with the relatively low values under conventional tillage system, especially 94 % of the plots have moderate values of activity of arylsulfatase enzymes. The data presented support the conclusion that NT system can enhance soil fertility and biological quality in soybean cultivation. Our results suggest that it is necessary to adopt NT practice because it allows increasing soybean productivity in Brazil without the need to increase the sown area, in addition to increasing productivity associated with an improvement in the agroecosystem quality, thus moving toward a more sustainable agriculture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Improper application of phosphorus (P) fertilizer during soil cadmium (Cd) immobilization reduces the efficiency of fertilizer and Cd remediation. In this study, we synthesized three types of nano-hydroxyapatite (NHAP) with different surface charges as slow-release P fertilizers during Cd immobilization. We also evaluated the effects of wollastonite application with or without NHAP addition, in comparison with triple superphosphate (TSP) or bulk hydroxyapatite, on Cd accumulation in Amaranthus tricolor L. The results showed that adding wollastonite significantly reduced P availability (23.5%) in the soil, but it did not inhibit plant P uptake. In wollastonite-amended soil, the application of negatively/positively charged NHAP significantly increased plant biomass by 643-865% and decreased Cd uptake by 74.8-75.1% compared to the unamended soil as well as showed greater efficiency than those with TSP. This was ascribed to the increased soil pH (from 3.94 to 6.52-6.63) and increased abundance of organic acids (including citric acid, malic acid, lactic acid, and acetic acid) secreted by plants. In addition, the P-preferring bacterial class Bacteroidia was specific to soils amended with both wollastonite and NHAP-. These results suggest that NHAP- may be an appropriate P fertilizer for soil Cd immobilization using wollastonite., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: This study aimed to characterize the topological alterations and classification performance of high-order functional connectivity (HOFC) networks in cognitively preserved patients with Parkinson's disease (PD), relative to low-order FC (LOFC) networks., Methods: The topological metrics of the constructed networks (LOFC and HOFC) obtained from fifty-one cognitively normal patients with PD and 60 matched healthy control subjects were analyzed. The discriminative abilities were evaluated using machine learning approach., Results: The HOFC networks in the PD group showed decreased segregation and integration. The normalized clustering coefficient and small-worldness in the HOFC networks were correlated to motor performance. The altered nodal centralities (distributed in the precuneus, putamen, lingual gyrus, supramarginal gyrus, motor area, postcentral gyrus and inferior occipital gyrus) and intermodular FC (frontoparietal and visual networks, sensorimotor and subcortical networks) were specific to HOFC networks. Several highly connected nodes (thalamus, paracentral lobule, calcarine fissure and precuneus) and improved classification performance were found based on HOFC profiles., Conclusion: This study identified disrupted topology of functional interactions at a high level with extensive alterations in topological properties and improved differentiation ability in patients with PD prior to clinical symptoms of cognitive impairment, providing complementary insights into complex neurodegeneration in PD., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Dyslipidemia is a common disease in the older population and represents a considerable disease burden worldwide. Epidemiological and experimental studies have indicated associations between heavy metal exposure and dyslipidemia; few studies have investigated the effects of heavy metal mixture and interactions between metals on dyslipidemia. We recruited 1121 participants living in heavy metal-contaminated and control areas in northeast China from a cross-sectional survey (2017-2019). Urinary metals including chromium (Cr), cadmium (Cd), lead (Pb), and manganese (Mn) and dyslipidemia biomarkers, namely triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, were measured. The generalized linear model (GLM) was used to explore the association of a single metal with dyslipidemia biomarkers. Bayesian kernel machine regression (BKMR) and multivariable linear regression were performed to explore the overall effect of metal mixture and the interaction between metals on dyslipidemia. Heavy metal mixture was positively associated with LDL-C, TC, and TG and negatively with HDL-C. In multivariable linear regression, Pb and Cd exhibited a synergistic association with LDL-C in the participants without hyperlipemia. Mn-Cd and Pb-Cr also showed a synergistic association with increasing the level of LDL-C in subjects without hyperlipemia. Cd-Cr showed an antagonistic association with HDL-C, respectively. Cr-Mn exhibited an antagonistic association with decreased HDL-C and TG levels. No significant interaction was noted among the three metals. Our study indicated that exposure to heavy metals is associated with dyslipidemia biomarkers and the presence of potential synergistic or antagonistic interactions between the heavy metals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To systematically review the clinical value of three imaging examinations (Magnetic Resonance Imaging, Computed Tomography, and myelography) in the diagnosis of Lumbar Disc Herniation., Methods: Databases including PubMed, Embase, The Cochrane Library, Web of Science, CBM, CNKI, WanFang Data, and VIP were electronically searched to collect relevant studies on three imaging examinations in the diagnosis of Lumbar Disc Herniation from inception to July 1, 2021. Two reviewers using the Quality Assessment of Diagnostic Accuracy Studies-2 tool independently screened the literature, extracted the data, and assessed the risk of bias of included studies. Then, meta-analysis was performed by using Meta-DiSc 1.4 software and Stata 15.0 software., Results: A total of 38 studies from 19 articles were included, involving 1,875 patients. The results showed that the pooled Sensitivity, pooled Specificity, pooled Positive Likelihood Ratio, pooled Negative Likelihood Ratio, pooled Diagnostic Odds Ratio, Area Under the Curve of Summary Receiver Operating Characteristic, and Q* were 0.89 (95%CI: 0.87-0.91), 0.83 (95%CI: 0.78-0.87), 4.57 (95%CI: 2.95-7.08), 0.14 (95%CI: 0.09-0.22), 39.80 (95%CI: 18.35-86.32), 0.934, and 0.870, respectively, for Magnetic Resonance Imaging. The pooled Sensitivity, pooled Specificity, pooled Positive Likelihood Ratio, pooled Negative Likelihood Ratio, pooled Diagnostic Odds Ratio, Area Under the Curve of Summary Receiver Operating Characteristic, and Q* were 0.82 (95%CI: 0.79-0.85), 0.78 (95%CI: 0.73-0.82), 3.54 (95%CI: 2.86-4.39), 0.19 (95%CI: 0.12-0.30), 20.47 (95%CI: 10.31-40.65), 0.835, and 0.792, respectively, for Computed Tomography. The pooled Sensitivity, pooled Specificity, pooled Positive Likelihood Ratio, pooled Negative Likelihood Ratio, pooled Diagnostic Odds Ratio, Area Under the Curve of Summary Receiver Operating Characteristic, and Q* were 0.79 (95%CI: 0.75-0.82), 0.75 (95%CI: 0.70-0.80), 2.94 (95%CI: 2.43-3.56), 0.29 (95%CI: 0.21-0.42), 9.59 (95%CI: 7.05-13.04), 0.834, and 0.767 respectively, for myelography., Conclusion: Three imaging examinations had high diagnostic value. In addition, compared with myelography, Magnetic Resonance Imaging had a higher diagnostic value., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Huang, Zhao, Zhang, Wu and Liu.)

Introduction: Previous studies have reported that chromium (Cr)-induced epigenetic alterations and DNA methylation play a vital role in the pathogenesis of diseases induced by chromium exposure. Epigenomic analyses have been limited and mainly focused on occupational chromium exposure; their findings are not generalizable to populations with environmental Cr exposure. Methods: We identified the differential methylation of genes and regions to elucidate the mechanisms of toxicity related to environmental chromium exposure. DNA methylation was measured in blood samples collected from individuals in Cr-contaminated ( n = 10) and unexposed areas ( n = 10) by using the Illumina Infinium HumanMethylation850K array. To evaluate the relationship between chromium levels in urine and CpG methylation at 850 thousand sites, we investigated differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by using linear models and DMRcate method, respectively. The model was adjusted for biologically relevant variables and estimated cell-type compositions. Results: At the epigenome-wide level, we identified five CpGs [cg20690919 ( p FDR = 0.006), cg00704664 ( p FDR = 0.024), cg10809143 ( p FDR = 0.043), cg27057652 ( p FDR = 0.047), cg05390480 ( p FDR = 0.024)] and one DMR (chr17: 19,648,718-19,648,972), annotated to ALDH3A1 genes ( p < 0.05) as being significantly associated with log 2 transformed urinary chromium levels. Discussion: Environmental chromium exposure is associated with DNA methylation, and the significant DMPs and DMR being annotated to cause DNA damage and genomic instability were found in this work. Research involving larger samples is required to further explore the epigenetic effect of environmental chromium exposure on health outcomes through DNA methylation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Wu, Xu, Li, Mei, Ge, Yin, Liu, Wei and Xu.)

Background: Athletic fatigue is an inescapable issue in competitive sports. It belongs to a physiological response that is triggered when competitive athletes are trained to a critical point., Objective: The study aims to explore the relationships involving boxers' social support, mental fatigue, coach leadership behaviors and psychological resilience., Methods: 1050 boxers were selected in several provinces across China and investigated on the basis of the Social Support Questionnaire for Athletes, Mental Fatigue Scale, Psychological Resilience Scale, and Leadership Scale for Sport., Results: Boxers' social support was negatively correlated with mental fatigue and psychological resilience, while it was positively correlated with coach leadership behaviors. Apart from direct effects on mental fatigue, other impacts are imposed by boxers' social support via mediating effects such as coach leadership behaviors and psychological resilience. The total effect value was -0.18, the direct effect value was -0.08, and the indirect effect value was -0.12; furthermore, coach leadership behaviors and psychological resilience play a mediating role, accounting for 65.57% of the total., Conclusion: In order to alleviate the stress from intense competitive training and abate mental fatigue, competitive athletes may be encouraged in subsequent training to seek all-sided social support for social interpersonal relationships. While clarifying the mechanism how the external environment affects individuals, this paper explains the principle of social support on athletes' psychological fatigue and identifies mutual influences between coaches and athletes.

Background: TOMM40 '523 has been associated with cognitive performance and risk for developing Alzheimer's disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time., Objective: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 '523 for genetic risk for conversion to mild cognitive impairment., Methods: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months., Results: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = -0.088, p = 0.034) and for the executive function domain score (B = -0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration., Conclusions: Our results add to the growing body of evidence that TOMM40, in the absence of APOEɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer's disease risk.

Although considered as a major contributor to low back pain (LBP), intervertebral disc degeneration (IVDD) has poor medical and surgical treatments. Various studies have revealed that endoplasmic reticulum (ER) stress and extracellular matrix (ECM) degeneration play a vital role in initiating and developing the progression of IVDD. Moreover, restoration of SIRT1/AMPK was confirmed to prevent IVDD and damage via maintaining ER and extracellular homeostasis. In addition, orientin (Ori) has been shown to upregulate SIRT1. However, the effect of Ori in nucleus pulposus cells (NPCs) is not determined. Hence, in this study we aim to explore the function of Ori in IVDD pathological model. The results demonstrate that Ori treatment in vitro increased SIRT1/AMPK in NPCs, maintained ECM and ER balance and decreased oxidative stress (OS) response. Ori rescued the disordered homeostasis stimulated by tert-butyl hydroperoxide (TBHP), and its function can be inhibited by thapsigargin (TG). Compound C and EX-527, inhibitors of AMPK and SIRT1 counteracted the Ori-mediated ER stress elimination. These results confirm that Ori exerts its effects by upregulating AMPK and SIRT1. Puncture-stimulated IVDD rats were used to show that Ori attenuates the pathological development in vivo. In all, we partly unveil the underlying mechanisms of Ori in IVDD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pfaffia glomerata is a candidate for phytoremediation due to its high biomass and high bioaccumulation efficiency of multiple heavy metals. It is essential to further evaluate its tolerance, absorption, transfer, and distribution to multiple heavy metals. In the current study, we evaluated the tolerance, absorption, transfer, and distribution of P. glomerata in a Cd/Pb/Cu/Zn combined-contaminated environment by two hydroponic experiments. The results demonstrated that P. glomerata was not affected by Cd/Pb/Cu/Zn exposure, except for the 50 μM Cd/Pb/Cu/Zn treatment, which significantly decreased the stem biomass. In a single Cd, Pb, Cu, and Zn exposure, the root of P. glomerata absorbed Cd/Pb/Cu/Zn in the order of Cd > Zn > Pb > Cu. Almost all Pb and Cu accumulated in the plant roots and were hardly transferred to the aboveground parts. Therefore, the order of total Cd/Pb/Cu/Zn extraction of a single plant in multiple Cd/Pb/Cu/Zn exposures at the same concentration was Cd > Zn > Pb > Cu. The bioconcentration factor (BCF) of Cd and Zn in roots, stems, and leaves increased with the concentration of Cd and Zn in the solution, and was > 1. In contrast with Cd and Zn, the BCFs of Cu and Pb in the stems and leaves were < 1. The element distribution of Pb, Cu, Zn, and Mn in the stem of P. glomerata was dispersed, indicating that the stem of P. glomerata does not have a detoxification mechanism for distributing metals to the area of low biological activity. The total amount of tartaric acid, critic acid, and DOC secreted by P. glomerata roots decreased with the increase in Cd/Pb/Cu/Zn exposure. However, further investigation is needed to unravel the interaction between the LMWOAs secreted by the root of P. glomerata and heavy metals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Herein we present a facile synthesis of the graphene oxide-decorated binary transition metal oxides of Bi 2 O 3 and MnO 2 nanocomposites (Bi 2 O 3 /MnO 2 /GO) and their applications in the voltammetric detection of lead ions (Pb 2+ ) in water samples. The surface morphologies, crystal structures, electroactive surface area, and charge transferred resistance of the Bi 2 O 3 /MnO 2 /GO nanocomposites were investigated through the scanning electron microscopy (SEM), power X-ray diffraction (XRD), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) techniques, respectively. The Bi 2 O 3 /MnO 2 /GO nanocomposites were further decorated onto the surface of a glassy carbon electrode (GCE), and Pb 2+ was quantitatively analyzed by using square-wave anodic stripping voltammetry (SWASV). We explored the effect of the analytical parameters, including deposition potential, deposition time, and solution pH, on the stripping peak current of Pb 2+ . The Bi 2 O 3 /MnO 2 /GO nanocomposites enlarged the electroactive surface area and reduced the charge transferred resistance by significant amounts. Moreover, the synergistic enhancement effect of MnO 2 , Bi 2 O 3 and GO endowed Bi 2 O 3 /MnO 2 /GO/GCE with extraordinary electrocatalytic activity toward Pb 2+ stripping. Under optimal conditions, the Bi 2 O 3 /MnO 2 /GO/GCE showed a broad linear detection range (0.01-10 μM) toward Pb 2+ detection, with a low limit of detection (LOD, 2.0 nM). The proposed Bi 2 O 3 /MnO 2 /GO/GCE electrode achieved an accurate detection of Pb 2+ in water with good recoveries (95.5-105%).

Pathological process in Parkinson's disease (PD) is accompanied with functional and metabolic alterations. The time-varying properties of functional coherence and their coupling to regional perfusion are still rarely elucidated. To investigate early disruption of dynamic regional homogeneity (dReho) and neurovascular coupling in cognitively normal PD patients, dynamic neuronal synchronization and regional perfusion were measured using dReho and cerebral blood flow (CBF), respectively. Neurovascular coupling was assessed by CBF-ReHo correlation coefficient and CBF/ReHo ratio. Multivariate pattern analysis was conducted for the differentiating ability of each feature. Relative to healthy controls (HC) subjects, PD patients demonstrated increased dReho in middle temporal gyrus (MTG), rectus gyrus, middle occipital gyrus, and precuneus, whereas reduced dReho in putamen and supplementary motor area (SMA); while higher CBF/dReho ratio was located in putamen, SMA, paracentral lobule, and postcentral gyrus, whereas lower CBF/dReho ratio in superior temporal gyrus, MTG, precuneus, and angular gyrus (AG). Global and regional CBF-Reho decoupling were both observed in PD groups. The CBF/Reho ratio features achieved more powerful classification performance than other features. From the view of dynamic neural synchronization and neurovascular coupling, this study reinforced the insights into neural basis underlying PD and the potential role in the disease diagnosis and differentiation.

Norfloxacin (NOR) is an antibiotic commonly used to treat humans and food-producing animals. Owing to NOR abuse, its residues are frequently found in animal-derived food products and the surrounding environment. Therefore, development of an efficient analytical technique for the selective determination of trace NOR is greatly significant for food safety and environmental protection. Here, we fabricated an ultrasensitive, label-free molecularly imprinted polymer (MIP) voltammetric sensor for the selective determination of NOR, based on an Au nanoparticle-functionalized black phosphorus nanosheet nanocomposite (BPNS-AuNP) covered by a polypyrrole-imprinted film. BPNS-AuNP nanocomposites were prepared via an in-situ one-step method without the use of reducing agents. The imprinted polypyrrole film was formed on the surface of the BPNS-AuNPs in the presence of NOR. The physical properties and electrochemical behavior of the MIP/BPNS-AuNPs were investigated using various characterization techniques, and the analytical parameters were optimized. We found that BPNS-AuNPs improve the ambient stability and electrocatalytic activity, providing a large surface area for locating a higher number of specific recognition sites. Consequently, the MIP/BPNS-AuNP/GCE showed excellent sensing performance toward NOR, with a wide linear response range (0.1 nM - 10 μM), an extremely low limit of detection (0.012 nM), and extraordinary selectivity. Moreover, the MIP/BPNS-AuNP/GCE was used to determine NOR in various experimental samples with satisfactory results., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is an age-related degenerative disease. Oxidative stress (OS) modulates OA pathogenesis by enhancing chondrocyte apoptosis and extracellular matrix (ECM) degeneration via activation of the endoplasmic reticulum (ER) stress. Prior studies revealed that safranal plays a critical role in multiple diseases treatments, but there are no reports on its effect on OA. Therefore, investigating the effect of safranal on OA is needed. As a compound that can lead excessive reactive oxygen species (ROS) accumulation, tert -butyl hydroperoxide (TBHP) was used to induce OS and OS-mediated endoplasmic reticulum (ER) stress for imitating OA in vitro. Besides, the bilateral medial meniscus was removed to induce joint instability and excessive friction of the joint surface to establish destabilization of medial meniscus for imitating the initiation and progression of OA in vivo. We, next, conducted Western blot and RT-PCR analyses to identify biomarkers of the underlying signaling pathway. Our results demonstrated that 30 μM safranal strongly upregulated Sirt1 expression, suppressed TBHP-mediated ER stress, and, in turn, prevented chondrocyte apoptosis and ECM degeneration. Furthermore, compared with the other two classic signaling pathways of ER stress, safranal can inhibit the PERK-eIF2α-CHOP axis at the lower concentration (5 and 15 μM). In vivo, using Safranin O staining, X-ray, immunofluorescence (IF), and immunohistochemical (IHC) staining, we demonstrated that OA progression can be postponed with intraperitoneal injection of 90 and 180 mg/kg safranal in an OA mouse model. Taken together, our analyses revealed that safranal can potentially prevent OA development.

The effects of catalpol on lung cancer cell proliferation, apoptosis, migration, and oxidative stress via the Nrf2/ARE signaling pathway are investigated in this work. Catalpol-12 g/mL group, catalpol-24 g/mL group, catalpol-48 g/mL group, catalpol - 48 g/mL + vector group, catalpol - 48 g/mL + Nrf2 group, si-NC group, and si-Nrf2 group were used to split lung cancer cells A549 into control groups. Proliferation was detected using the CCK-8 assay; apoptosis was detected using flow cytometry; migration was detected using the transwell chamber; ROS was distinguished using the DCFHDA method; MDA, SOD, and GSH were detected using the microvolume method; and Cleaved Caspase-3, Cleaved Caspase-9, Nrf2, HO-1, MMP-9, and MMP-2 were detected using the Western blot method. Catalpol 12 g/mL and 24 g/mL-48 g/mL treatment decreased the proliferation activity, migration number, and Nrf2, HO-1, MMP-9, and MMP-2 protein levels of lung cancer cells when compared to the control group. SOD and GSH levels of lung cancer cells were decreased, and MDA and ROS levels were increased. Cleaved caspase-3, cleaved caspase-9 protein expression levels, and apoptosis were boosted ( P < 0.05). The proliferation activity, migration number, and protein levels of Nrf2, HO-1, MMP-9, and MMP-2 in the catalpol - 48 g/mL + Nrf2 group were raised compared to the catalpol - 48 g/mL + vector group, whereas there was an apparent drop in the Cleaved Caspase-3, Cleaved Caspase-9, and apoptosis rate. Similarly, SOD and GSH contents increased, whereas MDA and ROS decreased ( P < 0.05). The proliferation activity, migration number, and Nrf2, HO-1, MMP-9, and MMP-2 protein levels of lung cancer cells in the si-Nrf2 group were all decreased when compared to the si-NC and control groups. Cleaved Caspase-3 and Cleaved Caspase-9 protein expression, on the other hand, increased as MDA and ROS levels were raised while SOD and GSH levels dropped ( P < 0.05). It reveals that catalpol inhibits the Nrf2/ARE signaling pathway, which causes antiproliferation, migration, apoptosis, and oxidative stress in cancer cells of lungs. The rate of apoptosis was also lowered., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Huanyuan Wang et al.)

Objective: To quantitatively compare the diagnostic values of conventional region of interest (ROI)-based and volumetric histogram analysis derived from CT enhancement in differentiating malignant and benign renal tumors., Methods: A total of 230 patients with pathologically confirmed renal tumors who had undergone CT enhancement were classified into clear cell renal cell carcinoma (ccRCC) ( n = 133), non-ccRCC ( n = 56), and benign renal tumor( n = 41) group. Parametric CT enhancement of each tumor from volumetric histogram were obtained using in-house software, including 10th percentile, 25th percentile, median, 75th percentile, 90th percentile, mean, standard deviation, as well as skewness, kurtosis and entropy, and histogram metrics among these groups were analyzed. ROI-based enhancement density was also analyzed., Results: The entropy and SD values of ccRCCs were higher than those of non-ccRCCs and benign renal tumors ( p < 0.05). The 10th percentile, 25th percentile, median, 75th percentile, 90th percentile and mean values of ccRCCs were lower than those of benign renal tumors, however, higher than those of non-ccRCCs ( p < 0.05). The ROI-based enhancement density of non-ccRCCs were lower than those of ccRCCs and benign renal tumors( p < 0.05). Receiver operating characteristic (ROC) curve analyses showed that entropy and mean values had the highest diagnostic efficacy in differentiating ccRCCs/non-ccRCCs and benign renal tumors. ROC curve analyses showed that mean values had the highest diagnostic efficacy in differentiating ccRCCs and non-ccRCCs. In terms of pairwise comparisons of ROC curves and diagnostic efficacy, ROI-based CT enhancement density was worse than volumetric histogram analysis ( p < 0.05)., Conclusion: Volumetric histogram analysis parameters can effectively distinguish malignant and benign renal tumors., Advances in Knowledge: 1. Entropy and mean values had the highest diagnostic efficacy in differentiating ccRCCs/ non-ccRCCs and benign renal tumors.2. Mean values had the highest diagnostic efficacy in differentiating ccRCCs and non-ccRCCs.3.Volumetric histogram analysis had better performance than ROI-based enhancement density.

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [ 11 C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [ 11 C]PHNO binding potential relative to the non-displaceable component (BP ND ) in all regions examined (16-28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BP ND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BP ND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [ 11 C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development., (© 2021. The Author(s).)

A major reason for the high mortality of patients with bladder cancer (BC) is that chemotherapy and surgery are only effective for very limited patients. Thus, developing novel treatment options becomes an urgent need for improving clinical outcomes and the quality of life for BC patients. Here, we demonstrated that proguanil significantly inhibited the growth of BC in vitro and in vivo. Importantly, our results indicated that the sensitivity of BC cells to proguanil is positively correlated with the expression of epidermal growth factor receptor (EGFR). Mechanistically, proguanil specifically targeted EGFR and promoted EGFR binding to Caveolin-1, enhanced its endocytosis in a Clathrin-independent manner, and then recruited c-Cbl to promote EGFR ubiquitination and degradation through the lysosomal pathway. Further studies suggested that proguanil induced autophagy by destabilizing EGFR and inhibiting its downstream signaling pathway. Thus, this study reveals the novel mechanism of proguanil on anticancer activity and implies the potential benefits of this drug in the treatment of BC., (© 2022. The Author(s).)

In-situ soil cadmium (Cd) immobilization helps to reduce Cd accumulation in rice grain, while its effects on bioaccessibility of Cd in rice during digestion and the associated health risk from rice consumption remain unclear. Here, we combined in-situ soil Cd immobilization and bioaccessibility-corrected health risk assessment (HRA) to minimize both the risk and uncertainty of Cd exposure from rice consumption. Wollastonite with or without four different phosphates (P) were applied to immobilize soil Cd at paddy fields, and their influences on Cd, essential elements, and amino acids in rice grain were analyzed. Moreover, a bioaccessibility-corrected HRA was conducted to accurately reflect the Cd exposure risk from ingesting these rices. The results showed the co-application of wollastonite and four different P reduced Cd concentrations in rice grain equally, while their impacts on bioaccessibility of Cd in rice during simulated human digestion were inconsistent (53-71%). The HRA based on bioaccessibility of Cd in rice revealed that Cd exposure risk from rice consumption was lowest with the application of wollastonite, followed by the co-application of wollastonite and sodium hexametaphosphate. This work highlights the value of bioaccessibility-corrected HRA for screening the optimal Cd immobilization strategy to achieve safer rice consumption., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To quantitatively compare the diagnostic values of conventional diffusion-weighted imaging (DWI) and introvoxel incoherent motion (IVIM) analysis of microstructural differences for clear cell renal cell carcinoma (ccRCC)., Methods: Multiple b value DWIs and IVIMs were performed in patients with 146 ccRCCs, 42 with Grade Ⅰ, 46 with Grade Ⅱ, 28 with Grade Ⅲ and 30 with Grade Ⅳ. These tumours were divided into low (Ⅰ+Ⅱ, n = 88) and high grades (Ⅲ+Ⅳ, n = 58). The diagnostic efficacy of various diffusion parameters for predicting ccRCC grades was compared., Results: The mean signal-to-noise ratios (SNRs) of IVIM images at b = 0, 800 and 1500 s/mm 2 were 31.9, 12.3 and 8.4, respectively. The apparent diffusion coefficient (ADC), D and D* values correlated negatively with ccRCC grading ( r = -0.786,-0.913, -0879, p < 0.05). f values correlated positively with ccRCC grading ( r = 0.811, p < 0.05). The ADC, D and D* values were higher for Grade Ⅱ ccRCC than that of Grade Ⅲ ccRCC ( p < 005), however, f values were higher for Grade Ⅲ ccRCC than that of Grade Ⅱ ccRCC ( p < 005). Receiver operating characteristic curve analyses showed that D values had the highest diagnostic efficacy in differentiating low/high and Ⅱ/Ⅲ ccRCC grading. The area under the curve, sensitivity, specificity and accuracy of the D values were 0.963, 0.960; 90.9%, 89.1%; 81.0%,78.6 and 89.0%, 87.8%, respectively. For pairwise comparisons of receiver operating characteristic curves and diagnostic efficacy, ADC was worse than IVIM (all p < 0.05)., Conclusion: IVIM parameters have better performance than ADC in differentiating ccRCC grading, given an adequate SNR of IVIM images., Advances in Knowledge: 1. D values had the highest diagnostic efficacy in differentiating low/high and Ⅱ/Ⅲ ccRCC grading. 2. IVIM parameters have better performance than ADC in differentiating ccRCC grading, given an adequate SNR of IVIM images. 3. The ADC, D and D* values correlated negatively with ccRCC grading, however, f values correlated positively with ccRCC grading.

Foliar zinc (Zn) fertilization is an important approach for overcoming crop Zn deficiency, yet little is known regarding the subsequent translocation of this foliar-applied Zn. Using synchrotron-based X-ray fluorescence microscopy (XFM) and transcriptome analysis, the present study examined the translocation of foliar absorbed Zn in sunflower ( Helianthus annuus ) leaves. Although bulk analyses showed that there had been minimal translocation of the absorbed Zn out of the leaf within 7 days, in situ analyses showed that the distribution of Zn in the leaf had changed with time. Specifically, when Zn was applied to the leaf for 0.5 h and then removed, Zn primarily accumulated within the upper and lower epidermal layers (when examined after 3 h), but when examined after 24 h, the Zn had moved to the vascular tissues. Transcriptome analyses identified a range of genes involved in stress response, cell wall reinforcement, and binding that were initially upregulated following foliar Zn application, whereas they were downregulated after 24 h. These observations suggest that foliar Zn application caused rapid stress to the leaf, with the initial Zn accumulation in the epidermis as a detoxification strategy, but once this stress decreased, Zn was then moved to the vascular tissues. Overall, this study has shown that despite foliar Zn application causing rapid stress to the leaf and that most of the Zn stayed within the leaf over 7 days, the distribution of Zn in the leaf had changed, with Zn mostly located in the vascular tissues 24 h after the Zn had been applied. Not only do the data presented herein provide new insight for improving the efficiency of foliar Zn fertilizers, but our approach of combining XFM with a transcriptome methodological system provides a novel approach for the study of element translocation in plants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Wang, Wu, Blamey, Wang, Chen, Ye, Wang, Paterson, Read, Wang, Lombi, Wang and Kopittke.)

Few studies have estimated the nonlinear association of ambient temperature with the risk of influenza. We therefore applied a time-series analysis to explore the short-term effect of ambient temperature on the incidence of influenza in Wuhan, China. Daily influenza cases were collected from Hubei Provincial Center for Disease Control and Prevention (Hubei CDC) from January 1, 2014, to December 31, 2017. The meteorological and daily pollutant data was obtained from the Hubei Meteorological Service Center and National Air Quality Monitoring Stations, respectively. We used a generalized additive model (GAM) coupled with the distributed lag nonlinear model (DLNM) to explore the exposure-lag-response relationship between the short-term risk of influenza and daily average ambient temperature. Analyses were also performed to assess the extreme cold and hot temperature effects. We observed that the ambient temperature was statistically significant, and the exposure-response curve is approximately S-shaped, with a peak observed at 23.57 ℃. The single-day lag curve showed that extreme hot and cold temperatures were both significantly associated with influenza. The extreme hot temperature has an acute effect on influenza, with the most significant effect observed at lag 0-1. The extreme cold temperature has a relatively smaller effect but lasts longer, with the effect exerted continuously during a lag of 2-4 days. Our study found significant nonlinear and delayed associations between ambient temperature and the incidence of influenza. Our finding contributes to the establishment of an early warning system for airborne infectious diseases., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: After heavy metals enter the body, they affect a variety of organs, particularly the main metabolic organ, the liver. Moreover, people are more likely to be exposed to multiple metals than to a single metal. We explored the associations between exposure to a heavy metal mixture and liver function biomarkers., Methods: This study involved 1171 residents living in areas with or without heavy metal exposure in northeast China. Urine concentrations of chromium (Cr), cadmium (Cd), lead (Pb), and manganese (Mn) were measured. Total protein (TP), albumin (ALB), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were used as biomarkers of liver function. A generalized linear model (GLM), quantile g-computation, and Bayesian kernel machine regression (BKMR) were used to explore the associations between the four metals and liver function., Results: GLM analysis revealed that Cr level was negatively associated with TP (β = - 0.57; 95% CI: - 0.89, - 0.26) and ALB (β = - 0.27; 95% CI: - 0.47, - 0.07) levels, and Cd level was positively associated with AST (β = 1.04; 95% CI: 0.43, 1.65) and ALT (β = 0.94; 95% CI: 0.08, 1.79) levels. ALB (β = 0.26; 95% CI: 0.10, 0.41) and ALT (β = 0.52; 95% CI: 0.02, 1.02) levels were positively associated with urine Mn concentration. The quantile g-computation indicated that exposure to a mixture of the four metals was significantly associated with TP (β = - 0.56; 95% CI: - 0.94, - 0.18) and ALT (β = 0.84; 95% CI: 0.04, 1.63) levels. Among the metals, Cr had the strongest effect on TP and Cd had that on AST. The BKMR model indicated that mixed metal exposure was negatively associated with TP and ALB levels and positively associated with ALT and AST levels., Conclusion: Exposure to mixtures of heavy metals may influence liver function. Cr and Cd may be the largest contributors., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Poly (ADP-ribose) polymerase inhibitors (PARPi) have showed clinical benefit as maintenance therapy in advanced ovarian cancer by impairing the homologous recombination (HR) pathway. Pyruvate kinase M2 (PKM2), the significant cancer metabolic biomarker, integrates with DNA damage to directly promote HR. We aimed to investigate the role and molecular mechanism of PKM2 downregulation on sensitization of ovarian cancer cells to PARPi. Inhibitory effects in vitro were assessed by cell viability, clone formation, transwell assay, and flow cytometry. Downregulation of PKM2 by siRNA or small molecular inhibitor shikonin (Sk) enhanced anti-tumour activity of olaparib (Ola) in ovarian cancer cells. Silencing PKM2 or Sk synergized with Ola and reduced cell growth, colony formation and migration, and induced apoptosis. Western blot and immunofluorescence demonstrated that inhibition of PKM2 amplified Ola-induced γH2AX and phospho-ATM (p-ATM) activation and interfered with BRCA1 accumulation in the nucleus. A xenograft animal model demonstrated in vivo antitumor combination effect of Sk and Ola. Furthermore, Western blot and immunofluorenscent analyses of tissue samples revealed that treatment of Sk increased DNA damage, reduced expression of BRCA1 and PKM2. Therefore, this study identified that PKM2 downregulation is a novel therapeutic strategy to enhance Ola effectiveness in treating ovarian cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ovarian cancer is the second leading cause of cancer-related deaths in women, with low five-year survival rates. Therefore, it is essential to seek new treatment options. Olaparib, a PARP inhibitor, has benefited many ovarian cancer patients, but olaparib is much less effective as a single agent in 50% of patients with high grade severe tumors. Proguanil, which was originally developed as an anti-malarial drug, has gained attention due to its anti-tumor effects. Here, we evaluated the anti-tumor effect of the combination of olaparib and proguanil on ovarian cancer cells, aimed to develop a potential medical option for treating ovarian cancer patients. We examined the effect on proliferation by MTT and colony formation assays, while cell migration was measured by the transwell assay. The effect on apoptosis was measured by flow cytometry and AO/EB staining assays. Western blotting was used to detect protein expression levels in cells treated with olaparib and/or proguanil. In addition, the synergistic effect of these two drugs is calculated by CompuSyn software. The combination of olaparib and proguanil significantly increased growth suppression and apoptosis in ovarian cancer cells, compared to either single agent alone. Furthermore, results showed that the combination of olaparib and proguanil synergistically increased olaparib-induced apoptosis and DNA damage and reduced the efficiency of DNA homologous recombination repair. Our findings indicate that combination of olaparib with proguanil will be a novel potential administration route for treating ovarian cancer patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The heavy metal accumulated biomass after phytoremediation needs to be decontaminated before disposal. Liquid extraction is commonly used to remove and recycle toxic heavy metals from contaminated biomass. In this study, we examined the cadmium (Cd) removal efficiency using different chemical reagents (hydrochloric acid, nitric acid, sulfuric acid, and ethylenediaminetetraacetic acid disodium) of the post-harvest Amaranthus hypochondriacus L. biomass. The purifications for the extracted liquids and ecological risk assessments for the extracted residues were also investigated. We have found that 77.8% of Cd in stems and 62.1% of Cd in leaves were removed by 0.25 M HCl after 24 h. In addition, K 2 CO 3 , KOH, and 4 Å molecular sieve could remove ≥89.0% of Cd in the extracted liquids. Finally, after we returned the extracted residues to the earthworm-incubated soil, the extracted biomass negatively affected the growth (weight loss ≥ 11.0%) and survival (mortality ≥ 33.3%) of Eisenia fetida. It should be noted that earthworms decreased soil available Cd concentrations from 0.14-0.05 mg kg -1 to 0.11-0.04 mg kg -1 and offset the negative effects of the Cd-contaminated biomass on soil microbes. Overall, given the cost of reagents, the Cd removal efficiency, and the ecological risks of the extracted biomass, using 0.25 M HCl for liquid extraction and K 2 CO 3 for purification should be recommended. This work highlights the potential of liquid extraction for immediately and directly removing the Cd from fresh contaminated accumulator biomass and the resource cycling potential of the extracted liquids and biomass after purification., (Copyright © 2021 Elsevier Ltd. All rights reserved.)