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Biodegradable metals offer significant advantages by reducing the need for additional surgeries following bone fixation. These materials, with their optimal mechanical and degradable properties, also mitigate stress-shielding effects while promoting biological processes essential for healing. This study investigated the in vitro and in vivo biocompatibility of ZK60 magnesium alloy coated with a micro-arc oxidative layer incorporated with cerium oxide nanoparticles in orthopedic implants. The results demonstrated that the magnesium substrate undergoes gradual degradation, effectively eliminating long-term inflammation during bone formation. The micro-arc oxidative coating forms a dense ceramic layer, acting as a protective barrier that reduces corrosion rates and enhances the biocompatibility of the magnesium substrate. The incorporation of cerium oxide nanoparticles improves the tribological properties of the coating, refining degradation patterns and improving osteogenic characteristics. Furthermore, cerium oxide nanoparticles enhance bone reconstruction by facilitating appropriate interconnections between newly formed bone and native bone tissue. Consequently, cerium oxide nanoparticles contribute to favorable biosafety outcomes and exceptional bone remodeling capabilities by supporting bone healing and sustaining a prolonged degradation process, ultimately achieving dynamic equilibrium in bone formation. STATEMENT OF SIGNIFICANCE: This study comprehensively examined the incorporation of cerium oxide nanoparticles into biodegradable magnesium through a micro-arc oxidative process for use in orthopedic implants. This study conducted a comprehensive analysis involving material characterization, biodegradability testing, in vitro osteogenesis assays, and in vivo implantation, highlighting the potential benefits of the distinctive properties of cerium oxide nanoparticles. This research emphasizes the ability of cerium oxide nanoparticles to enhance the biodegradability of magnesium and facilitate remarkable bone regeneration, suggesting promising advantages for additive materials in orthopedic implants., Competing Interests: Declaration of interests 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 Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ethnopharmacological Relevance: Alzheimer's disease (AD) is a common type of neurodegenerative disease with the β-amyloid plaques (Aβ) deposition. Previously, Dengzhan Shengmai capsule (DZSM) has been shown to reduce the pathology associated with AD, but the underlying mechanism is unclear., Aim of Study: This study investigated the potential mechanisms of DZSM against AD., Materials and Methods: The six-month-old wild-type male mice and APP/PS1 double transgenic male mice were administered 0.9 % saline or DZSM for 8 weeks by gavage. Open field test, new object recognition test, and Morris Water maze test were used to assess spatial learning and memory. Aβ plaques in brains were visualized using ThT staining. Nissl staining, TUNEL staining, and Western blot analyses were used to detect the neuronal function and apoptosis level. The superoxide dismutase (SOD), glutathione peroxidase assay kit (GSH-Px), and malondialdehyde (MDA) kits were performed to assess oxidative stress levels. Then, immunofluorescence and Western blot analysis were applied to evaluate ER stress pathway protein levels. Finally, HT22 cells were treated by Aβ 1-42 with or without DZSM medicated serum. Cell viability was assessed using the CCK-8 assay, and Western blot analysis was applied to evaluate ER stress pathway protein levels., Results: Open filed test, new object recognition test and Morris Water maze test showed that DZSM restored cognitive disorders in APP/PS1 mice. Immunohistochemistry and Thioflavin T staining results indicated that DZSM reduced Aβ plaques in the brain. Deeper and denser Nissl bodies were found in APP/PS1 mice after DZSM administration. Besides, APP/PS1 mice treated with DZSM showed a lower level of TUNEL and Bax/Bcl-2 ratio. DZSM improved the acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity while reducing acetylcholinesterase (AChE) and malondialdehyde (MDA) activity. In addition, the levels of ER stress pathway containing Phospho-PKR-like ER kinase (P-PERK), phosphorylate eukaryotic initiation factor 2 (P-eIF2α), activating transcription factor 4 (ATF4), glutamine-rich protein 1 (QRICH1), phosphorylate inositol-requiring protein 1α (P-IRE1α), the spliced form of X-box binding protein 1 (XBP1s), activating transcription factor-6 (ATF6) and C/EBP homologous binding protein (CHOP) were decreased by DZSM. CCK-8 results indicated that DZSM medicated serum played cytoprotective effects on Aβ 1-42 -induced HT22 cells. Western blot results suggested DZSM possibly inhibited ER stress pathways in Aβ 1-42 -induced HT22 cells., Conclusion: The potential protective mechanism of DZSM on cognitive impairment in AD might be related to ER stress pathways., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear., Aim of Study: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway., Materials and Methods: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression., Results: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins., Conclusion: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway., Competing Interests: Declaration of Competing interest There is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The need for wideband radio frequency front ends (RFFEs) with next-generation wireless protocols highlights the importance of electromechanical coupling [Formula: see text]. The hetero acoustic layered (HAL) surface acoustic wave (SAW) resonator with aluminum (Al) electrodes has shown superior performance compared to conventional SAW devices. Despite gold (Au) having excellent conductivity and stable properties, its high acoustic absorption and low phase velocity have made it less favorable for electrodes. This work demonstrates that high-performance shear horizontal (SH)-SAW resonators can be fabricated on the lithium niobate-on-insulator (LNOI) platform using a setup specifically designed for an Au electrodes. Experimental validation shows that the device achieves a high quality factor (Q) over 870, excellent [Formula: see text] up to 40%, and operates around 765 MHz. Unwanted transverse spurious modes are suppressed through adequate electrode design, and the temperature stability of LNOI SH-SAW with Au electrodes is discussed. This study highlights gold's potential as an electrode material for high [Formula: see text], clean spectrum, and wideband applications.

Background and Objectives: Circadian rhythms, the endogenous biological clocks that govern physiological processes, have emerged as pivotal regulators in the development and progression of breast cancer. This comprehensive review delves into the intricate interplay between circadian disruption and breast tumorigenesis from multifaceted perspectives, encompassing biological rhythms, circadian gene regulation, tumor microenvironment dynamics, and genetic polymorphisms., Methods and Results: Epidemiological evidence underscores the profound impact of external factors, such as night shift work, jet lag, dietary patterns, and exercise routines, on breast cancer risk and progression through the perturbation of circadian homeostasis. The review elucidates the distinct roles of key circadian genes, including CLOCK, BMAL1, PER, and CRY, in breast cancer biology, highlighting their therapeutic potential as molecular targets. Additionally, it investigates how circadian rhythm dysregulation shapes the tumor microenvironment, fostering epithelial-mesenchymal transition, chronic inflammation, and immunosuppression, thereby promoting tumor progression and metastasis. Furthermore, the review sheds light on the association between circadian gene polymorphisms and breast cancer susceptibility, paving the way for personalized risk assessment and tailored treatment strategies., Conclusions: Importantly, it explores innovative therapeutic modalities that harness circadian rhythms, including chronotherapy, melatonin administration, and traditional Chinese medicine interventions. Overall, this comprehensive review emphasizes the critical role of circadian rhythms in the pathogenesis of breast cancer and highlights the promising prospects for the development of circadian rhythm-based interventions to enhance treatment efficacy and improve patient outcomes., (© 2024. The Author(s).)

Glucosamine (GlcN) is one of the dietary supplements used in the treatment of osteoarthritis. Endogenously, GlcN is synthesized from glucose through the hexosamine pathway. In addition to ameliorating arthritis, several biological functions of GlcN have been reported, including insulin resistance in skeletal muscle. However, the regulatory role of GlcN in skeletal muscle development is not clear. We therefore investigated the effect of GlcN on myoblast proliferation, differentiation, and myotube development and their underlying mechanisms in C2C12 cells. Myoblast proliferation was measured by MTT assay. The expressions of MyoD, myogenin (MyoG), and myosin heavy chain (MyHC) were identified as determinants of myoblast differentiation. Expressions of atrogin-1 and muscle RING-finger protein-1 (MuRF-1) were identified as markers of myotube atrophy. The results show that treatment with GlcN significantly reduced myoblast proliferation and phosphorylation of Stat3 and S6K. These findings suggest that GlcN can inhibit growth of myoblasts through inhibiting phosphorylation of Stat3 and S6K. In addition, GlcN significantly suppressed the expression of MyoD, MyoG, and MyHC, as well as myotube formation. Pretreatment of C2C12 myoblast cells with ER stress inhibitors significantly blocked GlcN-inhibited MyHC expression and myotube formation. It can be concluded that GlcN suppressed myogenic differentiation via a pathway that involved ER stress. Moreover, GlcN decreased myotube diameter and expression of MyHC, as well as increased MuRF-1 in C2C12 myotubes. Meanwhile, GlcN also reduced the expressions of phosphorylated Akt and mTOR were stimulated after GlcN treatment in C2C12 myotubes. Thus, GlcN induced skeletal muscle atrophy by inhibiting the protein synthesis pathway. Chronic GlcN infusion also caused skeletal muscle atrophy in mice. In conclusion, GlcN regulated important stages of skeletal muscle development through different signaling pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neutrophil extracellular traps (NETs) are novel inflammatory cell death in neutrophils. Emerging studies demonstrated NETs contributed to cancer progression and metastases in multiple ways. This study intends to provide a prognostic NETs signature and therapeutic target for lung adenocarcinoma (LUAD) patients. Consensus cluster analysis performed by 38 reported NET-related genes in TCGA-LUAD cohorts. Then, WGCNA network was conducted to investigate characteristics genes in clusters. Seven machine learning algorithms were assessed for training of the model, the optimal model was picked by C-index and 1-, 3-, 5-year ROC value. Then, we constructed a NETs signature to predict the overall survival of LUAD patients. Moreover, multi-omics validation was performed based on NETs signature. Finally, we constructed stable knockdown critical gene LUAD cell lines to verify biological functions of Phospholipid Scramblase 1 (PLSCR1) in vitro and in vivo. Two NETs-related clusters were identified in LUAD patients. Among them, C2 cluster was provided as "hot" tumor phenotype and exhibited a better prognosis. Then, WGCNA network identified 643 characteristic genes in C2 cluster. Then, Coxboost algorithm proved its optimal performance and provided a prognostic NETs signature. Multi-omics revealed that NETs signature was involved in an immunosuppressive microenvironment and predicted immunotherapy efficacy. In vitro and in vivo experiments demonstrated that knockdown of PLSCR1 inhibited tumor growth and EMT ability. Besides, cocultural assay indicated that the knockdown of PLSCR1 impaired the ability of neutrophils to generate NETs. Finally, tissue microarray (TMA) for LUAD patients verified the prognostic value of PLSCR1 expression. In this study, we focus on emerging hot topic NETs in LUAD. We provide a prognostic NETs signature and identify PLSCR1 with multiple roles in LUAD. This work can contribute to risk stratification and screen novel therapeutic targets for LUAD patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Currently, clinical therapeutic strategies for nasopharyngeal carcinoma (NPC) confront insurmountable dilemmas in which surgical resection is incomplete and chemotherapy/radiotherapy has significant side effects. Phototherapy offers a maneuverable, effective, and noninvasive pattern for NPC therapy. Herein, we developed a lysosome-targeted and pH-responsive nanophototheranostic for near-infrared II (NIR-II) fluorescence imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) of NPC. A lysosome-targeted S-D-A-D-S-type NIR-II phototheranostic molecule (IRFEM) is encapsulated within the acid-sensitive amphiphilic DSPE-Hyd-PEG2k to form IRFEM@DHP nanoparticles (NPs). The prepared IRFEM@DHP exhibits a good accumulation in the acidic lysosomes for facilitating the release of IRFEM, which could disrupt lysosomal function by generating an amount of heat and ROS under laser irradiation. Moreover, the guidelines of NIR-II fluorescence enhance the accuracy of PTT/PDT for NPC and avoid damage to normal tissues. Remarkably, IRFEM@DHP enable efficient antitumor effects both in vitro and in vivo , opening up a new avenue for precise NPC theranostics.

Introduction: Allergic rhinitis (AR) is a respiratory immune system disorder characterized by dysregulation of immune responses. Within the context of AR, gut microbiota and its metabolites have been identified as contributors to immune modulation. These microorganisms intricately connect the respiratory and gut immune systems, forming what is commonly referred to as the gut-lung axis. Xiaoqinglong Decoction (XQLD), a traditional Chinese herbal remedy, is widely utilized in traditional Chinese medicine for the clinical treatment of AR. In this study, it is hypothesized that the restoration of symbiotic microbiota balance within the gut-lung axis plays a pivotal role in supporting the superior long-term efficacy of XQLD in AR therapy. Therefore, the primary objective of this research is to investigate the impact of XQLD on the composition and functionality of the gut microbiota in a murine model of AR., Methods: An ovalbumin-sensitized mouse model to simulate AR was utilized, the improvement of AR symptoms after medication was investigated, and high-throughput sequencing was employed to analyze the gut microbiota composition., Results: XQLD exhibited substantial therapeutic effects in AR mice, notably characterized by a significant reduction in allergic inflammatory responses, considerable alleviation of nasal symptoms, and the restoration of normal nasal function. Additionally, following XQLD treatment, the disrupted gut microbiota in AR mice displayed a tendency toward restoration, showing significant differences compared to the Western medicine (loratadine) group., Discussion: This results revealed that XQLD may enhance AR allergic inflammatory responses through the regulation of intestinal microbiota dysbiosis in mice, thus influencing the dynamics of the gut-lung axis. The proposal of this mechanism provides a foundation for future research in this area., 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 © 2024 Liu, Chen, Yun-Dang, Yan, He, Li, Ruan and Wu.)

Plant diversity can significantly affect the grassland productivity and its stability. However, it remains unclear how plant diversity affects the spatial stability of natural grassland productivity, especially in alpine regions that are sensitive to climate change. We analyzed the interaction between plant (species richness and productivity, etc.) and climatic factors (precipitation, temperature, and moisture index, etc.) of alpine natural grassland on the Qinghai-Tibetan Plateau. In addition, we tested the relationship between plant diversity and spatial stability of grassland productivity. Results showed that an increase in plant diversity significantly enhanced community productivity and its standard deviation, while reducing the coefficient of variation in productivity. The influence of plant diversity on productivity and the reciprocal of productivity variability coefficient was not affected by vegetation types. The absolute values of the regression slopes between climate factors and productivity in alpine meadow communities with higher plant diversity were smaller than those in alpine meadow communities with lower plant diversity. In other words, alpine meadow communities with higher plant diversity exhibited a weaker response to climatic factors in terms of productivity, whereas those with lower plant diversity showed a stronger response. Our results indicate that high plant diversity buffers the impact of ambient pressure (e.g., precipitation, temperature) on alpine meadow productivity, and significantly enhanced the spatial stability of grassland productivity. This finding provides a theoretical basis for maintaining the stability of grassland ecosystems and scientifically managing alpine grasslands under the continuous climate change., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chemodynamic therapy (CDT) is a particular oncological therapeutic strategy by generates the highly toxic hydroxyl radical (•OH) from the dismutation of endogenous hydrogen peroxide (H 2 O 2 ) via Fenton or Fenton-like reactions. However, single CDT therapies have been limited by unsatisfactory efficacy. Enhanced chemodynamic therapy (ECDT) triggered by near-infrared (NIR) is a novel therapeutic modality based on light energy to improve the efficiency of Fenton or Fenton-like reactions. However, the limited penetration and imaging capability of the visible (400-650 nm) and traditional NIR-I region (650-900 nm) light-amplified CDT restrict the prospects for its clinical application. Combined with the high penetration/high precision imaging characteristics of the second near-infrared (NIR-II,) nanoplatform, it is expected to kill deep tumors efficiently while imaging the treatment process in real-time, and more notably, the NIR-II region radiation with wavelengths above 1000 nm can minimize the irradiation damage to normal tissues. Such NIR-II ECDT nanoplatforms have greatly improved the effectiveness of CDT therapy and demonstrated extraordinary potential for clinical applications. Accordingly, various strategies have been explored in the past years to improve the efficiency of NIR-II Enhanced CDT. In this review, the mechanisms and strategies used to improve the performance of NIR-II-enhanced CDT are outlined., (© 2023 Wiley‐VCH GmbH.)

Background: Shoulder disorders, particularly rotator cuff tears, are prevalent musculoskeletal conditions related to aging. Although the widely used suture anchor technique provides strong mechanical support to the tendon, it is associated with a risk of postoperative tendon retearing. The conventionally used titanium alloys can affect the interpretation of magnetic resonance imaging. Degradable magnesium alloys possess excellent biocompatibility, similar mechanical property to the bone, and stimulating bone formation ability from Mg 2+ . The purpose of this experiment was to develop innovative magnesium-based suture anchors to enhance rotator cuff repair by improving fixation materials, and to evaluate their feasibility in a goat model., Methods: We developed fluoridized ZK60 suture anchors as the implantation material for two goats, who underwent rotator cuff repair surgery on both shoulders. Computed tomography (CT) and histological analysis were performed at 12 weeks postoperatively, and the results were compared between the magnesium and titanium alloy groups. Additionally, a hematological examination was conducted, which included assessments of red blood cells, white blood cells, platelets, coagulation function, liver function, kidney function, and magnesium ion concentration., Results: The 12-week postoperative CT images showed intact MgF 2 ZK60 suture anchors, effectively reconnecting the infraspinatus tendon to the humeral head. The anchors became less visible on CT scans, indicating absorption by surrounding tissues. New bone formation in the MgF 2 group surpassed that in the Ti group, demonstrating superior osseointegration. The similarity between cortical bone and magnesium reduced stress-shielding and promoted bone regeneration. Histological analysis revealed successful tendon healing with MgF 2 anchors, while the Ti group showed discontinuous interfaces and reduced collagen secretion. Hematological examination showed stable liver, renal function, and magnesium ion levels., Conclusions: The findings indicate that MgF 2 -coated suture anchors are feasible for rotator cuff repair and potentially other orthopedic applications. We hope that magnesium alloy anchors can become the solution for rotator cuff tendon repair surgery., (© 2024. The Author(s).)

Rapid climate warming is altering multiple ecosystem functions of alpine grasslands. However, the responses of the above- and belowground ecosystem multifunctionality (EMF) to climate warming might exhibit difference in semi-arid alpine grasslands. Based on manipulative field experiments at an alpine meadow and an alpine steppe, we explored warming effects on the functioning of alpine grassland ecosystems on the Tibetan Plateau. Warming significantly decreased plant diversity and aboveground biomass, but tended to increase belowground biomass, soil carbon, and soil nutrient contents. Experimental warming generally had neutral effects on the EMF of both alpine grasslands. Nevertheless, warming differentially affects the above- and belowground ecosystem functioning of Tibetan semi-arid alpine grasslands, with the aboveground EMF (AEMF) deceased but the belowground EMF (BEMF) increased under warmer conditions. Our results further showed that the negative effect of experimental warming on AEMF was mainly regulated by the changes of plant and soil biodiversity. However, plant productivity had a pivotal role in propelling the positive effect of warming on BEMF. Our results emphasized the potential impacts of plant and soil biodiversity, productivity, and soil nutrients in maintaining the EMF of alpine grasslands, which could offer novel views for sustainable management of Tibetan semi-arid alpine ecosystems., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Limonin is one of the most abundant active ingredients of Tetradium ruticarpum . It exerts antitumor effects on several kinds of cancer cells. However, whether limonin exerts antitumor effects on colorectal cancer (CRC) cells and cancer stem-like cells (CSCs), a subpopulation responsible for a poor prognosis, is unclear., Aim: To evaluate the effects of limonin on CSCs derived from CRC cells., Methods: CSCs were collected by culturing CRC cells in serum-free medium. The cytotoxicity of limonin against CSCs and parental cells (PCs) was determined by cholecystokinin octapeptide-8 assay. The effects of limonin on stemness were detected by measuring stemness hallmarks and sphere formation ability., Results: As expected, limonin exerted inhibitory effects on CRC cell behaviors, including cell proliferation, migration, invasion, colony formation and tumor formation in soft agar. A relatively low concentration of limonin decreased the expression stemness hallmarks, including Nanog and β-catenin, the proportion of aldehyde dehydrogenase 1-positive CSCs, and the sphere formation rate, indicating that limonin inhibits stemness without presenting cytotoxicity. Additionally, limonin treatment inhibited invasion and tumor formation in soft agar and in nude mice. Moreover, limonin treatment significantly inhibited the phosphorylation of STAT3 at Y705 but not S727 and did not affect total STAT3 expression. Inhibition of Nanog and β-catenin expression and sphere formation by limonin was obviously reversed by pretreatment with 2 μmol/L colievlin., Conclusion: Taken together, these results indicate that limonin is a promising compound that targets CSCs and could be used to combat CRC recurrence and metastasis., Competing Interests: Conflict-of-interest statement: No conflicts of interest was declared., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Malignant tumors seriously threaten human life and well-being. Emerging Near-infrared II (NIR-II, 1000-1700 nm) phototheranostic nanotechnology integrates diagnostic and treatment modalities, offering merits including improved tissue penetration and enhanced spatiotemporal resolution. This remarkable progress has opened promising avenues for advancing tumor theranostic research. The tumor microenvironment (TME) differs from normal tissues, exhibiting distinct attributes such as hypoxia, acidosis, overexpressed hydrogen peroxide, excess glutathione, and other factors. Capitalizing on these attributes, researchers have developed TME-activatable NIR-II phototheranostic agents with diagnostic and therapeutic attributes concurrently. Therefore, developing TME-activatable NIR-II phototheranostic agents with diagnostic and therapeutic activation holds significant research importance. Currently, research on TME-activatable NIR-II phototheranostic agents is still in its preliminary stages. This review examines the recent advances in developing dual-functional NIR-II activatable phototheranostic agents over the past years. It systematically presents NIR-II phototheranostic agents activated by various TME factors such as acidity (pH), hydrogen peroxide (H 2 O 2 ), glutathione (GSH), hydrogen sulfide (H 2 S), enzymes, and their hybrid. This encompasses NIR-II fluorescence and photoacoustic imaging diagnostics, along with therapeutic modalities, including photothermal, photodynamic, chemodynamic, and gas therapies triggered by these TME factors. Lastly, the difficulties and opportunities confronting NIR-II activatable phototheranostic agents in the simultaneous diagnosis and treatment field are highlighted., (© 2024 Wiley-VCH GmbH.)

Background: About 25% of pregnant women experience bleeding in the early stage, and half of them eventually progress to pregnancy loss. Progesterone serves as a useful biomarker to predict miscarriage in threatened miscarriage, yet its performance is still debated., Aim: To evaluate the performance of single serum progesterone predicting miscarriage in early pregnant patients with threatened miscarriage., Method: The online database was searched to yield the literature using the terms of 'Abortion', 'Miscarriage', and 'serum Progesterone', including PubMed, Scopus, Embase, Cochrane library, and China national knowledge infrastructure. Receiver operating characteristic (ROC) curve, likelihood ratio (LLR) and diagnostic odds ratio (DOR) and 95% confidence interval (CI) were computed. Publication bias was assessed by the deeks funnel plot asymmetry test. Subgroup analyses were conducted according to the progesterone level (< 12 ng/mL), recruited location and region, progesterone measurement method, exogenous progesterone supplement and follow up., Results: In total, 12 studies were eligible to be included in this study, with sample sizes ranging from 76 to 1087. The included patients' gestational age was between 4 and 12 weeks. No significant publication bias was detected from all included studies. The threshold of progesterone reported ranged from 8 to 30 ng/ml. The synthesized area under the ROC curve (0.85, 95% CI 0.81 to 0.88), positive LLR (6.2, 4.0 to 9.7) and DOR (18, 12 to 27) of single progesterone measurement distinguishing miscarriage were relatively good in early pregnant patients with threatened miscarriage. When the threshold of < 12 ng/mL was adapted, the progesterone provided a higher area under the ROC curve (0.90 vs. 0.78), positive LLR (8.3 vs. 3.8) and DOR (22 vs.12) than its counterpart (12 to 30 ng/mL)., Conclusion: Single progesterone measurement can act as a biomarker of miscarriage in early pregnant patients with threatened miscarriage, and it has a better performance when the concentration is <12 ng/mL., Trial Registration: PROSPERO (CRD42021255382)., (© 2024. The Author(s).)

As an inflammatory bowel disease, ulcerative colitis (UC) does not respond well to current treatments. It is of positive clinical significance to further study the pathogenesis of UC and find new therapeutic targets. B lymphocytes play an important role in the pathogenesis of UC. The effect of anti-CD20 therapy on UC also provides new evidence for the involvement of B cells in UC process additionally, suggesting the important role and potential therapeutic value of B cells in UC. In this study, we screened the most critical immune cell-related gene modules associated with UC and found that activated B cells were closely related to the gene modules. Subsequently, key activated B cell-associated gene (BRG) signatures were obtained based on WGCNA and differential expression analysis, and three overlapping BRG-associated genes were obtained by RF and LASSO algorithms as BRG-related diagnostic biomarkers for UC. Nomogram model was further performed to evaluate the diagnostic ability of BRG-related diagnostic biomarkers, subsequently followed by UC molecular subsets identification and immunoinfiltration analysis. We also further verified the expressions of the three screened BRGs in vitro by using an LPS-induced NCM460 cell line model. Our results provide new evidence and potential intervention targets for the role of B cells in UC from a new perspective.

Evodia lepta Merr. (Evodia lepta) is a well-known traditional Chinese medicine, which has been widely used in herbal tea. We previously reported that the coumarin compounds from the root of Evodia lepta exhibited neuroprotective effects. However, whether Evodia lepta could inhibit NLRP3 inflammasome in dementia was still unknown. In this study, the components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. We employed a scopolamine-treated mouse model. Evodia lepta extract (10 or 20 mg/kg) and donepezil were treated by gavage once a day for 14 consecutive days. Following the behavioral tests, oxidative stress levels were measured. Then, Western blot and immunofluorescence analysis were used to evaluate the expressions of NLRP3 inflammasome. 14 major components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. The results of Morris water maze, object recognition task and open field test indicated that Evodia lepta extract could ameliorate cognitive impairment in scopolamine-treated mice. Evodia lepta extract improved cholinergic system. Moreover, Evodia lepta extract improved the expressions of PSD95 and BDNF. Evodia lepta extract suppressed neuronal oxidative stress and apoptosis. In addition, Evodia lepta extract inhibited NLRP3 inflammasome in the hippocampus of scopolamine-treated mice. Evodia lepta extract could protect against cognitive impairment by inhibiting NLRP3 inflammasome in scopolamine-treated mice.

In Alzheimer's disease (AD), amyloid-beta (Aβ) plays a crucial role in pathogenesis. Clearing Aβ from the brain is considered as a key therapeutic strategy. Previous studies indicated that Salvia miltiorrhiza (Danshen) could protect against AD. However, the main anti-AD components in Danshen and their specific mechanisms are not clear. In this study, pharmacological network analysis indicated that Tanshinone IIA (Tan IIA) was identified as the key active compound in Danshen contributing to protect against AD. Then, APP/PS1 double transgenic mice were employed to examine the neuroprotective effect of Tan IIA. APP/PS1 mice (age, 6 months) were administered (10 and 20 mg/kg) for 8 weeks. Tan IIA improved learning and anxiety behaviors in APP/PS1 mice. Furthermore, Tan IIA reduced oxidative stress, inhibited neuronal apoptosis, improved cholinergic nervous system and decreased endoplasmic reticulum stress in the brain of APP/PS1 mice. Moreover, Tan IIA treatment reduced the level of Aβ. Molecular docking result showed that Tan IIA might block AD by upregulating Aβ-degrading enzymes. Western blot results confirmed that the expressions of insulin degrading enzymes (IDE) and neprilysin (NEP) were significantly increased after Tan IIA treatment, which demonstrated that Tan IIA improved AD by increasing Aβ-degrading enzymes., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

On-going climate warming is threatening the ecological function of grassland ecosystems. However, whether warming has positive effects on community microhabitats and appearance, especially in degraded grasslands, remains elusive. To address this issue, we conducted a 2-year field experiment on the severely degraded alpine meadow and undegraded alpine meadow with no warming and warming treatments. Community coverage and height in degraded meadow significantly increased under warming, while these changes were not significant in undegraded meadow. Two-year warming increased the community height of degraded meadow and undegraded meadow by 56.55% and 10.99%, respectively. Warming also increased community coverage by 41.88% in degraded meadow and decreased community coverage by 3.01% in undegraded meadow. Moreover, the response of topsoil temperature to warming was stronger in degraded meadow (6.89%) than in undegraded meadow (- 0.26%), while the negative response of topsoil moisture to warming was weaker in degraded meadow (- 13.95%) than in undegraded meadow (- 20.00%). The SEMs further demonstrated that warming had positive effects on topsoil temperature and community height, while had negative effects on topsoil moisture both in degraded and undegraded meadows. Our results confirm that warming-induced soil drying is an important pathway affecting the community appearance in alpine meadows. These findings highlight that warming has positive effects on community height and coverage and is particularly effective in improving community coverage appearance in severely degraded alpine meadow with topsoil drying., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Tumor microenvironment (TME)-triggered phototheranostic platform offers a feasible strategy to improve cancer diagnosis accuracy and minimize treatment side effects. Developing a stable and biocompatible molecular phototheranostic platform for TME-activated second near-infrared (NIR-II) fluorescence imaging-guided multimodal cascade therapy is a promising strategy for creating desirable anticancer agents. Herein, a new NIR-II fluorescence imaging-guided activatable molecular phototheranostic platform (IR-FEP-RGD-S-S-S-Fc) is presented for actively targeted tumor imaging and hydrogen sulfide (H 2 S) gas-enhanced chemodynamic-hypothermal photothermal combined therapy (CDT/HPTT). It is revealed for the first time that the coupling distance between IR-FE and ferrocene is proportional to the photoinduced electron transfer (PET), and the aqueous environment is favorable for PET generation. The part of Cyclic-RGDfK (cRGDfk) peptides can target the tumor and benefit the endocytosis of nanoparticles. The high-concentration glutathione (GSH) in the TME will separate the fluorescence molecule and ferrocene by the GSH-sensitive trisulfide bond, realizing light-up NIR-II fluorescence imaging and a cascade of trimodal synergistic CDT/HPTT/gas therapy (GT). In addition, the accumulation of hydroxyl radicals (•OH) and down-regulation of glutathione peroxidase 4 (GPX4) can produce excessive harmful lipid hydroperoxides, ultimately leading to ferroptosis., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The activable NIR-based phototheranostic nanoplatform (NP) is considered an efficient and reliable tumor treatment due to its strong targeting ability, flexible controllability, minimal side effects, and ideal therapeutic effect. This work describes the rational design of a second near-infrared (NIR-II) fluorescence imaging-guided organic phototheranostic NP (FTEP-TBFc NP). The molecular-engineered phototheranostic NP has a sensitive response to glutathione (GSH), generating hydrogen sulfide (H 2 S) gas, and delivering ferrocene molecules in the tumor microenvironment (TME). Under 808 nm irradiation, FTEP-TBFc could not only simultaneously generate fluorescence, heat, and singlet oxygen but also greatly enhance the generation of reactive oxygen species to improve chemodynamic therapy (CDT) and photodynamic therapy (PDT) at a biosafe laser power of 0.33 W/cm 2 . H 2 S inhibits the activity of catalase and cytochrome c oxidase (COX IV) to cause the enhancement of CDT and hypothermal photothermal therapy (HPTT). Moreover, the decreased intracellular GSH concentration further increases CDT's efficacy and downregulates glutathione peroxidase 4 (GPX4) for the accumulation of lipid hydroperoxides, thus causing the ferroptosis process. Collectively, FTEP-TBFc NPs show great potential as a versatile and efficient NP for specific tumor imaging-guided multimodal cancer therapy. This unique strategy provides new perspectives and methods for designing and applying activable biomedical phototheranostics.

Objective: Cardiovascular diseases (CVD) are prevalent among those with obstructive sleep apnea (OSA) and are the leading cause of death in these individuals. However, due to clinical confounders, the mechanism by which OSA induces CVD is still unclear. Previous studies have shown that chronic intermittent hypoxia (CIH) and high cholesterol diet (HCD) induce distinct characteristics of atherosclerotic plaques, highlighting the specific mechanisms involved in CIH-induced vascular endothelial injury., Materials and Methods: This study aims to investigate whether nicotinamide adenine dinucleotide (NAD+) biosynthesis reduction-mediated mitochondrial dysfunction is responsible for vascular endothelial injury induced by CIH and to elucidate its specific role in this process. Models were established to stimulate human umbilical vein endothelial cells (HUVECs) with CIH and oxidized low-density lipoprotein (ox-LDL), and the NAD+ biosynthesis-related indicators, such as NAD+ levels and nicotinamide phosphoribosyltransferase (NAMPT) enzyme activity, were measured in this model. Additionally, interventions were performed by supplementing NAD+ levels with nicotinamide mononucleotide (NMN), inhibiting NAD+ synthesis with FK866, and evaluating mitochondrial function, oxidative stress status, vascular constriction and dilation function, and endothelial adhesion function in these models. A comparative study was conducted to assess the effects of these interventions., Results: We found that under CIH conditions, NAMPT enzyme activity was inhibited, leading to a reduction in NAD+ biosynthesis and a decrease in NAD+/NADH ratio. At the same time, CIH caused mitochondrial dysfunction in HUVECs, including a decrease in adenosine triphosphate (ATP) content and mitochondrial membrane potential, as well as the activity of respiratory chain complex I and III, induced an increase in oxidative stress levels in endothelial cells, impaired vascular constriction and dilation function, and significantly increased expression of adhesion factors. The impact of CIH on endothelial cell-related mitochondrial function and endothelial function was restored by supplementing NMN. Although ox-LDL also causes multi-level endothelial injury, it does not involve the NAD+ pathway, as there were no significant changes in the related indicators, and the impaired endothelial function under ox-LDL conditions was not restored by supplementing NMN., Conclusions: CIH-induced vascular endothelial injury may be associated with NAD+ biosynthesis reduction-mediated mitochondrial dysfunction. Supplementing NAD+ precursors to increase its levels may be a potential intervention to ameliorate CIH-induced vascular endothelial injury, while it does not have a significant effect on endothelial injury caused by ox-LDL.

Surgically assisted rapid palatal expansion (SARPE) was introduced to release bony resistance to facilitate skeletal expansion in skeletally mature patients. However, asymmetric expansion between the left and right sides has been reported in 7.52% of all SARPE patients, of which 12.90% had to undergo a second surgery for correction. The etiologies leading to asymmetric expansion remain unclear. Finite element analysis has been used to evaluate the stress associated with SARPE in the maxillofacial structures. However, as a collision of the bone at the LeFort I osteotomy sites occurs only after a certain amount of expansion, most of the existing models do not truly represent the force distribution, given that the expansion amount of these existing models rarely exceeds 1 mm. Therefore, there is a need to create a novel finite element model of SARPE that could perform a clinically required amount of expander activation for further analysis of the expansion patterns of the hemimaxillae in all three dimensions. A three-dimensional (3D) skull model from cone beam computed tomography (CBCT) was imported into Mimics and converted into mathematical entities to segment the maxillary complex, maxillary first premolars, and maxillary first molars. These structures were transferred into Geomagic for surface smoothing and cancellous bone and periodontal ligament creation. The right half of the maxillary complex was then retained and mirrored to create a perfectly symmetrical model in SolidWorks. A Haas expander was constructed and banded to the maxillary first premolars and first molars. Finite element analysis of various combinations of buccal osteotomies at different angles with 1 mm clearance was performed in Ansys. A convergence test was conducted until the desired amount of expansion on both sides (at least 6 mm in total) was achieved. This study lays the foundation for evaluating how buccal osteotomy angulation influences the expansion patterns of SARPE.

Ethnopharmacological Relevance: A growing number of people suffer from Alzheimer's disease (AD), but there is currently no effective treatment yet. Taohong Siwu Decoction (TSD) has been proved to take strong neuropharmacological activity on dementia, but the effect and mechanism of TSD against AD are still elusive., Aim of Study: To investigate whether TSD could be effective in ameliorating cognitive deficits through SIRT6/ER stress pathway., Materials and Methods: Herein, the APP/PS1 mice, an AD model, and HT-22 cell lines were utilized. Different dosages of TSD (4.25, 8.50 and 17.00 g/kg/d) were administered to the mice for 10 weeks by gavage. Following the behavioral tests, oxidative stress levels were measured using malondialdehyde (MDA) and superoxide dismutase (SOD) kits. Nissl staining and Western blot analyses were used to detect the neuronal function. Then, immunofluorescence and Western blot analysis were applied to evaluate silent information regulator 6 (SIRT6) and ER Stress related protein levels in APP/PS1 mice and HT-22 cells., Results: Behavioral tests revealed that APP/PS1 mice administered with TSD orally took more time in the target quadrant, crossed more times in the target quadrant, had a higher recognition coefficient, and spent more time in the central region. In addition, TSD could ameliorate oxidative stress and inhibit neuronal apoptosis in APP/PS1 mice. Furthermore, TSD could up-regulate the SIRT6 protein expression and inhibit ER sensing proteins expressions, such as p-PERK and ATF6, in APP/PS1 mice and Aβ 1-42 -treated HT22 cells., Conclusion: According to the abovementioned findings, TSD could alleviate cognitive dysfunction in AD by modulating the SIRT6/ER stress pathway., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Triadimefon is a typical systemic fungicide that is widely used in the management of powdery mildew, rust disease, and southern blight. In this study, we measured fungicide residue to profile its absorption, translocation, and accumulation in three representative vegetable crops (Pak choi, cucumber, and pepper) after over-application. The fungicides were applied through entire-plant spraying (EPS), root-irrigation (RI), and middle-leaf-daubing (MLD). The half-life of triadimefon depends on the application method and plant species. In EPS, the half-life was 5.42 days (Pak choi), 6.86 days (cucumber), and 6.73 days (pepper), while in RI it was 4.39 days (Pak choi), 6.30 days (cucumber), and 5.98 days (pepper). In the EPS treatment, triadimefon is translocated both upward/outside and downward/inner-side from the daubed leaves in all the three vegetable crops. The transfer amount to each organ reached a peak on the 2nd day after fungicide application. The mesophyll of Pak choi exhibited a higher fungicide deposition compared to the petiole. In cucumber and pepper, the leaves demonstrated the highest accumulation of triadimefon (approximately 0.3-0.5 mg·kg -1 ), followed by stems. Roots and fruits displayed the lowest levels of triadimefon accumulation. Furthermore, triadimefon was found to have an impact on chlorophyll content, root activity, as well as the activity of superoxide dismutase and catalase in Pak choi, indicating its potential as a plant growth regulator. These aforementioned studies provide novel insights for the safe and efficient application of triadimefon in the production of Pak choi, cucumber, and pepper., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We analyzed the variation patterns of growth and wood properties of 24 different provenances of 18-year-old Schima superba in Jian'ou, Fujian Province. A total of 11 growth and wood indices were measured, including tree height, diameter at breast height, wood basic density and anatomical structure. We analyzed the geographical variation patterns of growth and wood properties, and the provenance areas were divided. Further, the excellent timber provenances were selected according to different uses. The results showed that the variation of growth traits, which was 17.6%-27.3% with mean value of 22.4%, was larger than that of wood properties (7.0%-21.0%, mean 12.7%). Growth properties and some wood properties (fiber length, fiber lumen diameter and fiber cell wall thickness) had significant differences among provenances. Growth traits were not correlated with fiber traits, and they could be selected independently without emphasis on other traits. There was significant correlation between the longitudinal and radial growth indicators of wood properties, but they were not correlated with the wood basic density, which could be selected independently. In addition, the growth and wood properties were significantly influenced by temperature and precipitation, which showed a latitudinal variation pattern. According to Q-type clustering analysis, 24 provenances could be divided into four categories, of which southern provenances from distribution area of S. superba had vigorous growth and supper wood properties. They had smaller microfibril angle, higher maturity, longer fiber length, and thicker fiber cell wall. Finally, five excellent provenances were selected according to pulpwood and building use.

The community stability is the main ability to resist and be resilient to climate changes. In a world of climate warming and melting glaciers, alpine gravel encroachment was occurring universally and threatening hillside grassland ecosystem. Gravel encroachment caused by climate warming and glacial melting may alter community structure and community stability in alpine meadow. Yet, the effects of climate warming-induced gravel encroachment on grassland communities are unknown. Here, a 1-year short-term field experiment was conducted to explore the early stage drive process of gravel encroachment on community structure and stability at four different gravel encroachment levels 0%, 30%, 60%, and 90% gravel coverage at an alpine meadow on the Qinghai Tibetan Plateau, by analyzing the changes of dominant species stability and species asynchrony to the simulated gravel encroachment processes. Gravel encroachment rapidly changed the species composition and species ranking of alpine meadow plant community in a short period of time. Specifically, community stability of alpine meadow decreased by 61.78-79.48%, which may be due to the reduced dominant species stability and species asynchrony. Species asynchrony and dominant species stability were reduced by 2.65-17.39% and 46.51-67.97%, respectively. The results of this study demonstrate that gravel encroachment presents a severe negative impact on community structure and stability of alpine meadow in the short term, the longer term and comprehensive study should be conducted to accurate prediction of global warming-induced indirect effects on alpine grassland ecosystems., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy., (© 2023 Wiley-VCH GmbH.)

Objectives: To quantify the effect of carnitine on glucose and lipid metabolic profiles and fertility outcomes in women with Polycystic ovary syndrome (PCOS)., Design: A systematic review and meta-analysis were conducted., Patients: Women with PCOS diagnosed by Rotterdam or Androgen Excess Society (AES) criteria and taking carnitine supplement were assessment., Measurements: Fertility outcomes (ovulation, clinical pregnancy, live birth, and miscarriage), lipid parameters (BMI, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein), fasting glucose and insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)., Results: In total, 839 participants were included in this analysis. The dosage of carnitine and treatment duration reported by studies varied from 250 mg to 3000 mg daily and 84 to 90 days, respectively. The publication bias was absent. Compared with placebo, carnitine significantly improved ovulation rates (RR 3.42, 95% CI 2.39 to 4.89, I2 = 0%) and pregnancy rates (RR 11.05, 95% CI 1.21 to 100.58, I2 = 79%). None of included studies reported live birth. After treatment, carnitine resulted in significant reductions relative to baseline in body mass index (BMI, MD -0.93 kg/m2, 95% CI -1.15 to -0.70, I2 = 55.0%), insulin levels (MD -2.47 mIU/L, 95% CI -4.49 to -0.45, I2 = 0%) and the Homeostasis Model Assessment index (MD -0.67, 95% CI -1.20 to -0.14, I2 = 0%) than placebo, but not for lipid profiles including triglyceride, total cholesterol, and low-density lipoprotein., Conclusion: With the available literature, carnitine seems to improve ovulation and clinical pregnancy and insulin resistance, BMI in women with PCOS. These effects are warranted to be further validated, due to insufficient statistical power., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

The aim of the present study was to investigate the effects of short-term ketogenic diet on the low temperature tolerance of mice and the involvement of peroxisome proliferator-activated receptor α (PPARα). C57BL/6J mice were divided into two groups: normal diet (WT+ND) group and ketogenic diet (WT+KD) group. After being fed with normal or ketogenic diet at room temperature for 2 d, the mice were exposed to 4 °C low temperature for 12 h. The changes in core temperature, blood glucose, blood pressure of mice under low temperature condition were detected, and the protein expression levels of PPARα and mitochondrial uncoupling protein 1 (UCP1) were detected by Western blot. PPARα knockout mice were divided into normal diet (PPARα -/- +ND) group and ketogenic diet (PPARα -/- +KD) group. After being fed with the normal or ketogenic diet at room temperature for 2 d, the mice were exposed to 4 °C low temperature for 12 h. The above indicators were also detected. The results showed that, at room temperature, the protein expression levels of PPARα and UCP1 in liver and brown adipose tissue of WT+KD group were significantly up-regulated, compared with those of WT+ND group. Under low temperature condition, compared with WT+ND, the core temperature and blood glucose of WT+KD group were increased, while mean arterial pressure was decreased; The ketogenic diet up-regulated PPARα protein expression in brown adipose tissue, as well as UCP1 protein expression in liver and brown adipose tissue of WT+KD group. Under low temperature condition, compared to WT+ND group, PPARα -/- +ND group exhibited decreased core temperature and down-regulated PPARα and UCP1 protein expression levels in liver, skeletal muscle, white and brown adipose tissue. Compared to the PPARα -/- +ND group, the PPARα -/- +KD group exhibited decreased core temperature and did not show any difference in the protein expression of UCP1 in liver, skeletal muscle, white and brown adipose tissue. These results suggest that the ketogenic diet promotes UCP1 expression by up-regulating PPARα, thus improving low temperature tolerance of mice. Therefore, short-term ketogenic diet can be used as a potential intervention to improve the low temperature tolerance.

Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 μM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-β peptides (Aβ) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aβ toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.

Secondary copper smelting is an important source of heavy metal emission. Flue gas samples were collected from different stages in secondary copper smelters to study the emission characteristics and control of particulate matters (PM) and heavy metals such as Cd, Cr, As, Pb, Sn, and Sb. The mass concentrations of heavy metals in flue gas and fly ash were determined using inductively coupled plasma-mass spectrometry. The emission factors of heavy metals were estimated. The results showed that the mass concentrations of heavy metals and PM in the flue gas were high in the cooling stage. After passing through a series of air pollution control devices, such as a bag filter and adsorption tower, the heavy metals and PM were simultaneously removed with a removal efficiency of 80%-99%. The concentration order of heavy metals in the stack gas from different anode furnace stages followed feeding-fusion>oxidation≈deoxidization. In general, the mass concentrations of heavy metals and PM in the stack gas could meet the industry emission standards. The average emission factors of As, Pb, Cr, Sn, Sb, and Cd were 2.6×10 3 , 2.4×10 3 , 2.7×10 3 , 5.6×10 2 , 34.1, and 9.8 mg·t -1 , respectively. This could provide data support for estimating the annual emission amounts of heavy metals from the secondary copper industry and establishing the emission inventories. The fly ash contained high concentrations of Cu and Zn, which can be recycled as raw materials for recycling the valuable metals.

Suitable biomechanical properties, good biocompatibility, and osteoconductivity of a degradable magnesium (Mg) alloy make it a potential material for orthopedic implants. The main limitation of Mg is its high corrosion rate in the human body. Surface modification is necessary to improve the Mg corrosion resistance. In this work, a polymeric layer of gelatin/nanohydroxyapatite (Gel/nHA) was coated on a ZK60 Mg alloy by dip coating and spin coating to test the corrosion resistance and biocompatibility in vitro and in vivo. The results from the in vitro test revealed that the coated groups reduced the corrosion rate with the corrosion current density by 59 and 81%, from 31.22 to 12.83 μA/cm 2 and 5.83 μA/cm 2 in the spin coating and dip coating groups, respectively. The dip coating group showed better corrosion resistance than the spin coating group with the lowest released hydrogen content (17.5 mL) and lowest pH value (8.23) and reducing the current density by 45%. In vitro, the relative growth rate was over 75% in all groups tested with MG63, demonstrating that the Mg substrate and coating materials were within the safety range. The dip coating and spin coating groups enhanced the cell proliferation with significantly higher OD values (3.3, 3.0, and 2.5, respectively) and had better antihemolysis and antiplatelet adhesion abilities than the uncoated group. The two coating methods showed no difference in the cellular response, cell migration, hemolysis, and platelet adhesion test. In in vivo tests in rats, the dip coating group also showed a higher corrosion resistance with a lower corrosion rate and mass loss than the spin coating group. In addition, the blood biochemistry and histopathology results indicated that all materials used in this study were biocompatible with living subjects. The present research confirmed that the two methods have no noticeable difference in cell and organ response but the corrosion resistance of dip coating was higher than that of spin coating either in vitro or in vivo.

Background: The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer's disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD., Methods: Aβ 1-42 -treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APP swe /PS dE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aβ deposition respectively., Results: Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells., Conclusion: Tan IIA could promote Aβ transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice., (© 2023. The Author(s).)

Metallic aerogels (MAs) are self-supported porous nanomaterials with excellent catalytic activity, which could be a promising candidate for high-performance nanozymes. The interface regulation by heteroatom and vacancies is an effective strategy for boosting the enzyme-mimicking activity. Herein, magnetic RuCo aerogels with doping of boron and oxygen vacancies were prepared by a one-pot spontaneous NaBH 4 gelation method under a low temperature. The three-dimensional network structure with high specific surface area and interlinked pores of RuCo aerogels afford abundant active sites to facilitate the interaction with substrates. Moreover, the monolithic structure avoided conventional aggregation, thus enhancing stability during catalysis. Introducing elemtal boron and oxygen vacancies adjusted the electronic structure of RuCo aerogels to achieve enhanced enzyme-like performances. It is found that the RuCo aerogel nanozyme can mimic nature peroxidase, demonstrating their viable applications in the bioassay of H 2 O 2 and glucose. The constructed glucose sensor possesses acceptable sensitivity and stability with a linear range of 0.002 ~ 5 mM and a low detection limit (1.66 μM). This work provides insights into the rational design of advanced nanozymes and paves the avenue for the applications of metallic aerogels in the bioassay field. A boron-doped RuCo bimetallic aerogel with rich oxygen vacancies was prepared by a facile self-assembly method under an ice bath. The unique physical and electronic structure of RuCo aerogel results in the improvement of the intrinsic peroxidaselike activity, and thus, a sensitive and robust colorimetric glucose sensor could be developed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Contrasting views exist on timing and mechanisms of Tertiary crustal uplift in the NE Tibetan Plateau based on different approaches, with many models attributing surface uplift to crustal shortening. We carry out a comprehensive investigation of mid-Tertiary stratigraphy, sedimentology, and volcanism in the West Qinling, Hoh Xil and Qaidam basin, and the results challenge previous views. It was held that the discordance between Oligocene and Miocene strata is an angular unconformity in the West Qinling, but our field observations show that it is actually a disconformity, indicative of vertical crustal uplifting rather than crustal shortening at the Oligocene to Miocene transition. Widespread occurrence of synsedimentary normal faults in mid-Tertiary successions implicates supracrustal stretching. Miocene potassic-ultrapassic and mafic-ultramafic volcanics in the Hoh Xil and West Qinling suggest a crucial role of deep thermomechanical processes in generating crust- and mantle-sourced magmatism. Also noticeable are the continuity of mid-Tertiary successions and absence of volcanics in the Qaidam basin. Based on a holistic assessment of stratigraphic-sedimentary processes, volcanic petrogenesis, and spatial variations of lithospheric thicknesses, we speculate that small-sale mantle convection might have been operating beneath northeast Tibet in the mid-Tertiary. It is assumed that northward asthenospheric flow was impeded by thicker cratonic lithosphere of the Qaidam and Alxa blocks, thereby leading to edge convection. The edge-driven convection could bring about surface uplift, induce supracrustal stretching, and trigger vigorous volcanism in the Hoh Xil and West Qinling in the mid-Tertiary period. This mechanism satisfactorily explains many key geologic phenomena that are hardly reconciled by previous models., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

Spatial heterogeneity of climatic and edaphic gradients can substantially affect the grassland productivity function. However, few studies have tested the importance of species richness and evenness on regulating grassland productivity across spatial-scale climatic and edaphic changes. This study examines the complex mechanisms by which species richness and evenness regulate productivity in alpine meadow and steppe. We used field survey data to explore above-ground productivity formation and sensitivity to spatial-scale climatic and edaphic response of alpine grassland based on species richness and evenness. Results showed that the growing season solar radiation was the main driving factor of above-ground biomass and was strongly negatively correlated with above-ground biomass. Furthermore, compared with alpine steppe, above-ground biomass in alpine meadow was more responsive to climatic variables, but less responsive to soil variables. Unexpectedly, we found that the regulation patterns of species richness and evenness on above-ground biomass were different in both habitats by a structural equation model analysis. Our study demonstrated that species evenness and richness were both important in co-regulating above-ground biomass in alpine meadow, whereas species richness mattered more than species evenness in regulating above-ground biomass in alpine steppe. Our results offer further support for species richness and evenness co-regulating grassland productivity across spatial-scale climatic and edaphic gradients, which helps maintain the benefits of plant diversity and alpine grassland ecosystems., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Near-infrared-II (NIR-II) bioimaging gradually becomes a vital visualization modality in the real-time investigation for fundamental biological research and clinical applications. The favorable NIR-II contrast agents are vital in NIR-II imaging technology for clinical translation, which demands good optical properties and biocompatibility. Nevertheless, most NIR-II contrast agents cannot be applied to clinical translation due to the acute or chronic toxicity caused by organ retention in vivo imaging. Therefore, it is critical to understand the pharmacokinetic properties and optimize the clearance pathways of NIR-II contrast agents in vivo to minimize toxicity by decreasing organ retention. In this review, the clearance mechanisms of biomaterials, including renal clearance, hepatobiliary clearance, and mononuclear phagocytic system (MPS) clearance, are synthetically discussed. The clearance pathways of NIR-II contrast agents (classified as inorganic, organic, and other complex materials) are highlighted. Successively analyzing each contrast agent barrier, this review guides further development of the clearable and biocompatible NIR-II contrast agents., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Phototherapy is a conducive and non-invasive strategy for cancer therapy under light irradiation. Inspiringly, fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) holds a great promise for imaging-guided phototherapy with deep penetration and high spatiotemporal resolution. However, most phototherapeutics still face great challenges, including complicated synthesis of agents, potential biotoxicity and unsatisfied therapeutic outcomes. Herein, a near-infrared laser triggered molecular photosensitizer FEPT, modified with triphenylphosphine PEGylation (PEG2000-TPP), is developed for NIR-II imaging-guided mitochondria-targeting synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/immune therapy (IMT). The mitochondria-targeting photosensitizer FEPT can produce reactive oxygen species (ROS) and hyperpyrexia upon 808 nm laser irradiation, resulting in mitochondrial dysfunction and photo-induced apoptosis via caspase-3 pathway. Phototherapy-induced hyperthermia or ROS triggers the release of immunogenic intracellular substrates from dying tumor cells, thereby promoting the activation of antitumor immunity. Herein, this work provides a practicable strategy to develop a molecular phototheranostic platform for imaging-guided cancer therapy via mitochondria-targeting., (© 2022. The Author(s).)

Background: As an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the common signs of coronavirus disease 2019 (COVID-19) are respiratory symptoms, fever, cough, shortness of breath, and dyspnea, with multiple organ injuries in severe cases. Therefore, finding drugs to prevent and treat COVID-19 is urgently needed and expected by the public. Several studies suggested beneficial effects of melatonin for the relevant prevention and treatment. To explore the effect and safety of melatonin in the treatment and provide theoretical support and reference for seeking the most suitable drug for COVID-19, the meta-analysis was carried out accordingly., Methods: It included randomized clinical trials of patients with COVID-19 treated with melatonin. Total effective rate was the primary outcome, while C-reactive protein (CRP), arterial oxygen saturation (SaO2), white blood cell count (WBC) were the secondary measures. Random-effect and fixed-effect models were used to evaluate the effect size of some indicators in this meta-analysis., Results: Six eligible studies with 338 participants were included. One hundred seventy subjects were treated with melatonin adjuvant therapy and 168 subjects were assigned to the control group, with total excellent effective rate in subjects treated with melatonin [odds ratio = 3.05, 95 % confidence interval (CI) = 1.47, 6.31, P = .003]. Homogeneity was analyzed by fixed effect model (I2 = 0%). There was no significant difference in CRP between the melatonin group and the control group (weighted mean difference [WMD] = -0.36, 95% CI = -3.65, 2.92, P = .83). Significant difference was not existed in SaO2 between the melatonin treatment group and the control group (WMD = 1, 95% CI = -1.21, 3.22, P = .37). In terms of WBC, there was no significant difference between the 2 groups (WMD = -1.07, 95% CI = -2.44, 0.30, P = .13)., Conclusions: The meta-analysis showed that melatonin had the beneficial effects for COVID-19 prevention and treatment as an adjunctive agent in combination with basic treatment for the treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

In this study, we investigated the functional roles of Asp40, Asp57, and C-terminal Asn60 in Naja atra cardiotoxin 3 (CTX3) structure and function by modifying these three carboxyl groups with semicarbazide. The conjugation of the carboxyl groups with semicarbazide produced two conformational isomers whose gross and fine structures were different from those of CTX3. The blocking of the carboxyl groups increased the structural flexibility of CTX3 in response to trifluoroethanol-induced effect. Despite presenting modest to no effect on decreasing the induction of permeability in zwitterionic phospholipid vesicles, the carboxyl group-modified CTX3 showed a marked reduction in its permeabilizing effect on anionic phospholipid vesicles in comparison to that of the native protein. Compared with native CTX3, carboxyl group-modified CTX3 exhibited lower activity in inducing membrane leakage in U937 cells. The CD spectra of lipid-bound toxins and the color transition of polydiacetylene/lipid assay showed that the membrane interaction mode of CTX3 was distinctly changed by the modification in the carboxyl groups. Given that the selective modification of Asp40 does not cause the conformational isomerization of CTX3, our data indicate that the carboxyl groups in Asp57 and Asn60 are essential in maintaining the structural topology of CTX3. Furthermore, modification of carboxyl groups changes the interdependence between the infrastructure and the global conformation of CTX3 in modulating membrane permeabilizing activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Castanea henryi is a monoecious plant with a low female-to-male ratio, which limits its yield. The phytohormone cytokinin (CK) plays a crucial role in flower development, especially gynoecium development. Here, the feminizing effect of CK on the development of C. henryi was confirmed by the exogenous spraying of N-(2-chloro-4-pyridyl)-N'-phenylurea (CPPU). Spraying CPPU at 125 mg·L -1 thrice changed the male catkin into a pure female catkin, whereas at 5 mg·L -1 and 25 mg·L -1 , only a part of the male catkin was transformed into a female catkin. A comparative transcriptome analysis of male catkins subjected to CPPU was performed to study the mechanism of the role of CKs in sex differentiation. Using Pearson's correlation analysis between hormone content and hormone synthesis gene expression, four key genes, LOG1 , LOG3 , LOG7 and KO , were identified in the CK and GA synthesis pathways. Moreover, a hub gene in the crosstalk between JA and the other hormone signaling pathways, MYC2 , was identified, and 15 flowering-related genes were significantly differentially expressed after CPPU treatment. These results suggest that CK interacts with other phytohormones to determine the sex of C. henryi , and CK may directly target floral organ recognition genes to control flower sex.

In arid and semi-arid areas, unsuitable afforestation programs may cause soil water deficit and even, in some cases, deep-soil desiccation and the subsequent death of part of the vegetation. However, the benefits of preferential flow through decayed root channels for supplying water in the dried soil layers are rarely evaluated. This study examines the effects of root channels on soil water content (SWC) and infiltration (initial and steady-state) in two planted species with high drought tolerance, namely: Korshinsk peashrub (Caragana korshinskii Kom.), and red plum apricot (Armeniaca vulgaris Lam.), using bare land as control site and published data from alfalfa (Medicago sativa L.) plots to refine results analysis. The infiltration rates were measured using a double-ring infiltrometer in areas with alive and decayed roots; and methylene blue was used to trace the pathways of water flow. The highest SWC appeared in the Korshinsk peashrub land, whereas the alfalfa grassland had the lowest SWC; and the differences of SWC among treatments were significant at all soil layers. Korshinsk peashrub had the highest steady infiltration rates, which were about 23% and 83% higher than those rates measured in the fruit tree plantation and alfalfa grasslands, respectively. The steady infiltration rates were significantly and positively correlated with the average root diameter and area. Within the same species, the decayed root plots significantly increased the soil water infiltration capacity compared to the alive root plots. Considering the water scarcity conditions of the study area, the preferential flow formed through decomposed roots was conducive to soil water supplement, appearing as a natural compensation mechanism caused by dead vegetation. Our findings contribute to a better understanding of soil water infiltration during root decay of the plants in water-limited ecosystems, and how this dynamic replenishes soil moisture and alleviates soil desiccation., 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 © 2021 Elsevier B.V. All rights reserved.)

This paper studies whether containing COVID-19 pandemic by stringent strategies deteriorates or saves economic growth. Since there are country-specific factors that could affect both economic growth and deaths due to COVID-19, we first start with a cross-country analysis on identifying risk and protective factors on the COVID-19 deaths using large across-country variation. Using data on 100 countries from 3 January to 27 November 2020 and taking into account the possibility of underreporting, we find that for deaths per million population, GDP per capita, population density, and income inequality are the three most important risk factors; government effectiveness, temperature, and hospital beds are the three most important protective factors. Second, inspired by the stochastic frontier literature, we construct a measure of pandemic containment effectiveness (PCE) after controlling for country-specific factors and rank countries by their PCE scores for deaths. Finally, by linking the PCE score with GDP growth data in Quarters 2 and 3 of 2020, we find that PCE is positively associated with economic growth in major economies. Countries with average PCE scores, such as Malaysia, would gain more GDP growth by 3.47 percentage points if they could improve their PCE scores for deaths to South Korea's level in Q2 of 2020. Therefore, there is not a trade-off between lives and livelihood facing by governments. Instead, to save economy, it is important to contain the pandemic first. Our conclusion is also mainly valid for infections due to COVID-19., Competing Interests: None., (© 2022 Elsevier B.V. All rights reserved.)

In this study, ultra-high performance liquid chromatography-linear ion trap/electrostatic field orbit trap combined-type mass spectrometry(UPLC-LTQ-Orbitrap-MS) was used to analyze the main active components of Huangqi Guizhi Wuwu Decoction(HQGZ). A total of 50 active components were identified from HQGZ and 108 potential targets of the components related to the treatment of rheumatoid arthritis were retrieved based on network pharmacology, including 87 key targets, followed by Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment of the targets. The result indicated that HQGZ may exert therapeutic effects mainly through the sphingolipid signaling pathway, tumor necrosis factor(TNF) signaling pathway, as well as the positive regulation of ribonucleic acid(RNA) polymerase Ⅱ promoter transcription, inflammatory response and other biological processes. At the same time, cell experiment was performed to verify the key proteins in the TNF signaling pathway. The results demonstrated that HQGZ significantly reduced the expression of caspase-3(CASP3), TNF, relaxed(RELA) protein, and IkappaB kinase beta(IKBKB) in fibroblast-like synoviocytes induced by TNF-α. The results of UPLC-LTQ-Orbitrap-MS, network pharmacology and cell experiment showed that the active components in HQGZ may inhibit inflammatory response and regulate immune function and cell apoptosis by modulating key proteins in TNF signaling pathway to treat rheumatoid arthritis.

Based on the textual research on literature, the key information of Wenjing Decoction were tested and identified, and 15 batches of lyophilized powder samples of Wenjing Decoction were prepared. The specific components, including paeoniflorin, glycyrrhizin, ginsenosides(Rg&#95;1, Re and Rb&#95;1), glycyrrhizic acid, and paeonol, were used as indexes to establish the HPLC method for quantitative evaluation, and the content ranges and transfer rates of these components were determined. The results showed that the contents of paeoniflorin, glycyrrhizin, ginsenosides Rg&#95;1 + Re, ginsenoside Rb&#95;1, glycyrrhizic acid, and paeonol in the 15 batches of samples were 0.62%-0.86%, 0.25%-0.76%, 0.14%-0.30%, 0.07%-0.21%, 0.63%-1.16%, and 0.09%-0.25%, respectively, and their transfer rates from the decoction pieces to the reference materials were 14.99%-19.42%, 28.11%-40.93%, 25.92%-61.88%, 25.03%-64.06%, 23.43%-35.53%, and 5.34%-10.44%, respectively. The consistency of the transfer rates between batches indicated that the preparation process was stable. It is suggested that the contents of paeoniflorin, glycyrrhizin, ginsenosides Rg&#95;1 + Re, ginsenoside Rb&#95;1, glycyrrhizic acid, and paeonol in Wenjing Decoction should not be less than 0.52%, 0.35%, 0.15%, 0.10%, 0.63%, and 0.12%, respectively. In this study, we determined the contents and analyzed the quantity transfer process of the index components in Wenjing Decoction, which can provide a basis for the follow-up development of Wenjing Decoction and the quality control of related preparations.

Objective: To evaluate the efficacy and safety profile of ixazomib/lenalidomide/dexamethasone (IRd) in Chinese patients with relapsed/refractory multiple myeloma (MM) . Methods: This study comprising 14 medical centers in China included patients with relapsed/refractory MM who received at least. Ixazomib at an initial oral dose of 4 mg was administered. Seven patients had dose adjustment to 3 mg at the time of first dose. The lenalidomide doses were adjusted according to creatinine clearance rate. The efficacy and safety were evaluated every cycle. Results: In the study cohort of 74 patients, the median age was 65 years and 11 (14.9% ) patients received over three lines of therapy. Overall response rate (ORR) was 54.1% (40/74) , and 7 (9.5% ) , 14 (18.9% ) , and 19 (25.7% ) patients achieved stringent complete response or complete response, very good partial response, and partial response, respectively. The median progression-free survival and overall survival were 9.9 and 20 months, respectively. The median time to response was 1 month. The efficacy and survival outcome were similar to those reported in the Tourmaline-MM1 China Continuous Study. The ORR of patients refractory to bortezomib, lenalidomide, and bortezomib plus lenalidomide were 52.0% (13/25) , 57.1% (4/7) , and 33.3% (6/18) , respectively. The rate of grade 3-4 adverse events was 36.5% (27/74) . Common hematological toxicities were anemia, thrombocytopenia, lymphopenia, and neutropenia. Common non-hematological toxicities were fatigue, gastrointestinal symptoms, and infections. Two cases of grade 3 peripheral neuropathy were reported. The patients eligible for the Tourmaline-MM1 China Continuous Study had a higher ORR than the ineligible patients [77.8% (14/18) vs 46.4% (26/56) , P =0.020]. There was no difference in the rate of grade 3-4 adverse events [33.3% (6/18) vs 37.5% (21/56) , P =0.749]. Conclusion: The IRd regimen had good efficacy and acceptable toxicity in Chinese patients with relapsed/refractory MM.

Exposure to low concentrations of antibiotics links to multiple health hazards, such as drug resistance of bacteria, and childhood obesity. In this study, seven antibiotics were measured in the urine of 107 children and 126 pregnant women in Jiangsu Province by ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). The overall urinary antibiotics detection rate was 38.6%. Most (98.3%) of the participants' antibiotics concentrations were no more than 10 ng/mL. Children had a significantly higher detection rate than pregnant women (47.7% vs. 31.0%, P = 0.009), as well as the concentration (95th percentile: 6.49 vs. 4.08 ng/mL, P = 0.002). The detection rates of individual antibiotics ranged from 0.4% to 15.0%, and the concentrations ranged from lower than the limit of detection (LOD) through up to 31.96 ng/mL individually. Two or more antibiotics were detected in 11.2% of the urines. Tetracyclines were more frequently detected than phenicols (30.9% vs.12.4%). Oxytetracycline was the most frequently detected (15.0%). Multivariate logistic regression showed that consuming puffed food every day was associated with a significantly increased likelihood of detection, and higher concentration of overall antibiotics, and of doxycycline. Children were more likely to be detected of doxycycline and florfenicol, and to have elevated concentration of doxycycline, compared with pregnant women. This study highlights the relatively heavier antibiotics exposure in children, and a possible impact of puffed food on it, which needs to be warranted in future studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)