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Wei Wang, Dong Xu, Xiaojun Wei, Kezheng Chen Lab of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology, Qingdao, People’s Republic of China Abstract: In this paper, magnetic and fluorescent bifunctional YbPO4:Er,Dy microspheres were synthesized via a simple solvothermal method. The prepared microspheres exposed to 980 nm near-infrared (NIR) laser light emitted bright upconversion fluorescence (450–570 nm) after calcination at high temperatures (>800°C). Results of magnetic resonance studies demonstrated that the YbPO4:Er,Dy microspheres are more suitable to be used as a transverse relaxation time (negative) contrast magnetic resonance imaging agent. The microspheres successfully entered the human hepatocellular carcinoma cells and presented low toxicity. A well-selected photodynamic therapy (PDT) drug, merocyanine 540 (MC540) with an ultraviolet–visible spectroscopy absorption maximum of 540 nm, was loaded onto the microspheres to obtain YbPO4:Er,Dy-MC540. Since the upconversion fluorescence emitting from the microspheres could be absorbed by MC540 with a small absorption/emission disparity, YbPO4:Er,Dy-MC540 could kill the hepatocellular carcinoma cells via PDT mechanism effectively. In other words, being upconverting particles, the prepared microspheres acted as light transducers in the NIR light-triggered PDT process. A chemotherapy drug, doxorubicin, was further loaded onto YbPO4:Er,Dy-MC540 to achieve enhanced antitumor effect based on synergistic therapeutic efficacy of PDT and chemotherapy. It is expected that the prepared YbPO4:Er,Dy microspheres have applications in tumor theranostics including magnetic-fluorescent bimodal imaging and NIR light-triggered PDT. Keywords: fluorescent, lanthanide, upconversion

MXene-based conductive hydrogels hold significant promise as epidermal sensors, yet their susceptibility to oxidation represents a formidable limitation. This study addresses this challenge by incorporating MXene into a tannic acid (TA) cross-linked silk fibroin matrix. The resulting conductive hydrogel (denoted as e-dive ) exhibits favorable characteristics such as adjustable mechanical properties, self-healing capabilities (both mechanically and electrically), and strong underwater adhesion. The existence of a percolation network of MXene within the nanocomposites guarantees good electrical conductivity. Importantly, the surface interaction of MXene nanosheets with the hydrophobic moiety from TA substantially reduced moisture and oxygen interactions with MXene, thereby effectively mitigating MXene oxidation within hydrogel matrices. This preservation of the electrical characteristics ensures prolonged functional stability. Furthermore, the e-dive demonstrates inherent antibacterial properties, making it suitable for use in underwater environments where bacterial contamination is a concern. The utilization of this advanced e-dive system extends to the correction of diving postures and the facilitation of underwater healthcare and security alerts. Our study presents a robust methodology for enhancing the stability of MXene-based conductive hydrogel electronics, thereby expanding their scope of potential applications.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons and the consequent decline in motor and cognitive functions. The primary therapeutic agent levodopa necessitates precise dosing due to its narrow therapeutic window and complex pharmacokinetics. This study presents the development of a novel CuCoFe-LDHzyme-based sweat sensor for real-time monitoring of levodopa concentration in PD patients. Employing differential pulse voltammetry (DPV) technique, the sensor demonstrates high sensitivity and selectivity, achieving a detection limit of 28.1 nM. The sensor's design allows for non-invasive, continuous monitoring, significantly enhancing patient convenience compared to traditional blood sampling methods. Through pH correction, precise quantification of levodopa in sweat is accomplished, and a strong correlation (Pearson coefficient = 0.833) with blood levodopa levels is established. The pharmacokinetic profile of levodopa is reconstructed in real-time, offering a promising tool for optimizing PD treatment regimens. This study highlights the potential of CuCoFe-LDHzyme sensors to advance personalized treatment strategies, aiming to improve the quality of life for PD patients by providing clinicians with real-time data for medication adjustments., 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.)

Multifunctional fibers represent a cornerstone of human civilization, playing a pivotal role in numerous aspects of societal development. Natural biomaterials, in contrast to synthetic alternatives, offer environmental sustainability, biocompatibility, and biodegradability. Among these biomaterials, natural silk is favored in biomedical applications and smart fiber technology due to its accessibility, superior mechanical properties, diverse functional groups, controllable structure, and exceptional biocompatibility. This review delves into the intricate structure and properties of natural silk fibers and their extensive applications in biomedicine and smart fiber technology. It highlights the critical significance of silk fibers in the development of multifunctional materials, emphasizing their mechanical strength, biocompatibility, and biodegradability. A detailed analysis of the hierarchical structure of silk fibers elucidates how these structural features contribute to their unique properties. The review also encompasses the biomedical applications of silk fibers, including surgical sutures, tissue engineering, and drug delivery systems, along with recent advancements in smart fiber applications such as sensing, optical technologies, and energy storage. The enhancement of functional properties of silk fibers through chemical or physical modifications is discussed, suggesting broader high-end applications. Additionally, the review addresses current challenges and future directions in the application of silk fibers in biomedicine and smart fiber technologies, underscoring silk's potential in driving contemporary technological innovations. The versatility and sustainability of silk fibers position them as pivotal elements in contemporary materials science and technology, fostering the development of next-generation smart materials.

Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8 + T cell infiltration and better prognoses in ICC patients. Mechanistically, β-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, β-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic β-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or β-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control., (© 2024. The Author(s).)

Layered double hydroxides (LDH) are a class of functional anionic clays that typically consist of orthorhombic arrays of metal hydroxides with anions sandwiched between the layers. Due to their unique properties, including high chemical stability, good biocompatibility, controlled drug loading, and enhanced drug bioavailability, LDHs have many potential applications in the medical field. Especially in the fields of bioimaging and tumor therapy. This paper reviews the research progress of LDHs and their nanocomposites in the field of tumor imaging and therapy. First, the structure and advantages of LDH are discussed. Then, several commonly used methods for the preparation of LDH are presented, including co-precipitation, hydrothermal and ion exchange methods. Subsequently, recent advances in layered hydroxides and their nanocomposites for cancer imaging and therapy are highlighted. Finally, based on current research, we summaries the prospects and challenges of layered hydroxides and nanocomposites for cancer diagnosis and therapy., (© 2024 The Chemical Society of Japan & Wiley‐VCH GmbH.)

Objective: The temporomandibular joint (TMJ) is anatomically comprised of the mandibular condylar cartilage (CC) lined with fibrocartilaginous superficial zone and is crucial for eating and dental occlusion. TMJ osteoarthritis (OA) leads to pain, joint dysfunction and permanent loss of cartilage tissue. However, there are no drugs clinically available that ameliorate OA and little is known about global profiles of genes that contribute to TMJ OA. Furthermore, animal models that recapitulate the complexity of signalling pathways contributing to OA pathogenesis are crucial for designing novel biologics that thwart OA progression. We have previously developed a New Zealand white rabbit TMJ injury model that demonstrates CC degeneration. Here, we performed genome-wide profiling to identify new signalling pathways critical for cellular functions during OA pathology., Materials and Methods: Temporomandibular joint OA was surgically induced in New Zealand white rabbits. Three months following injury, we performed global gene expression profiling of the TMJ condyle. RNA samples from TMJ condyles were subjected to sequencing. After raw RNA-seq data were mapped to relevant genomes, differential expression was analysed with DESeq2. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted., Results/conclusions: Our study revealed multiple pathways altered during TMJ OA induction including the Wnt, Notch and PI3K-Akt signalling pathways. We demonstrate an animal model that recapitulates the complexity of the cues and signals underlying TMJ OA pathogenesis, which is essential for developing and testing novel pharmacologic agents to treat OA., (© 2023 The Authors. Orthodontics & Craniofacial Research published by John Wiley & Sons Ltd.)

Vimentin is a major type III intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout (GFAP -/- VIM -/- ) mice. However, attenuated glial scar formation in post-stroke in GFAP -/- VIM -/- mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIM -/- mice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination., Competing Interests: None

Messenger RNA (mRNA) has become a key focus in the development of therapeutic agents, showing significant potential in preventing and treating a wide range of diseases. The COVID-19 pandemic in 2020 has accelerated the development of mRNA nucleic therapeutics and attracted significant investment from global biopharmaceutical companies. These therapeutics deliver genetic information into cells without altering the host genome, making them a promising treatment option. However, their clinical applications have been limited by issues such as instability, inefficient in vivo delivery, and low translational efficiency. Recent advances in molecular design and nanotechnology have helped overcome these challenges, and several mRNA formulations have demonstrated promising results in both animal and human testing against infectious diseases and cancer. This review provides an overview of the latest research progress in structural optimization strategies and delivery systems, and discusses key considerations for their future clinical use.

Background: As highly-conserved types of lipid flippases among fungi, P4-ATPases play a significant role in various cellular processes. Cdc50 acts as the regulatory subunit of flippases, forming heterodimers with Drs2 to translocate aminophospholipids. Cdc50 homologs have been reported to be implicated in protein trafficking, drug susceptibility, and virulence in Saccharomyces cerevisiae, Candida albicans and Cryptococcus neoformans. It is likely that Cdc50 has an extensive influence on fungal cellular processes. The present study aimed to determine the function of Cdc50 in Candida glabrata by constructing a Δcdc50 null mutant and its complemented strain., Results: In Candida glabrata, the loss of Cdc50 led to difficulty in yeast budding, probably caused by actin depolarization. The Δcdc50 mutant also showed hypersensitivity to azoles, caspofungin, and cell wall stressors. Further experiments indicated hyperactivation of the cell wall integrity pathway in the Δcdc50 mutant, which elevated the major cell wall contents. An increase in exposure of β-(1,3)-glucan and chitin on the cell surface was also observed through flow cytometry. Interestingly, we observed a decrease in the phagocytosis rate when the Δcdc50 mutant was co-incubated with THP-1 macrophages. The Δcdc50 mutant also exhibited weakened virulence in nematode survival tests., Conclusion: The results suggested that the lipid flippase subunit Cdc50 is implicated in yeast budding and cell wall integrity in C. glabrata, and thus have a broad influence on drug susceptibility and virulence. This work highlights the importance of lipid flippase, and offers potential targets for new drug research., (© 2023. The Author(s).)

Inadequate bioavailability is one of the most critical reasons for the failure of oral drug development. However, the way that substructures affect bioavailability remains largely unknown. Serotonin transporter (SERT) inhibitors are first-line drugs for major depression disorder, and improving their bioavailability may be able to decrease side-effects by reducing daily dose. Thus, it is an excellent model to probe the relationship between substructures and bioavailability. Here, we proposed the concept of "nonbioavailable substructures", referring to substructures that are unfavorable to bioavailability. A machine learning model was developed to identify nonbioavailable substructures based on their molecular properties and shows the accuracy of 83.5%. A more potent SERT inhibitor DH4 was discovered with a bioavailability of 83.28% in rats by replacing the nonbioavailable substructure of approved drug vilazodone. DH4 exhibits promising anti-depression efficacy in animal experiments. The concept of nonbioavailable substructures may open up a new venue for the improvement of drug bioavailability.

Accurate and non-invasive monitoring of allograft posttransplant is essential for early detection of acute cellular rejection and determines the long-term survival of the graft. Clinically, tissue biopsy is the most effective approach for diagnosing transplant rejection. Nonetheless, the procedure is invasive and potentially triggers organ failure. This work aims to design and apply GzmB-responsive nanosensors (GBRNs) that can readily size-change in graft tissues. Subsequently, we investigate the activity of serine protease granzyme B by generating a direct colorimetric urinary readout for non-invasive detection of transplant rejection in under 1 h. In preclinical heart graft mice models of transplant rejection, GBRNs were cleaved by GzmB and excreted by the kidneys via accurate nanometre-size glomerular filtration. By exploiting the catalytic activity of ultrasmall gold nanoclusters, GBRNs urinalysis promotes ultrasensitive surveillance of rejection episodes with a receiver operator characteristic curve area under the curve of 0.896 as well as a 95% confidence interval of about 0.7701-1.000. Besides, the catalytic activity of gold nanoclusters in urine can be detected at point-of-care testing to predict the immunity responses in mice with insufficient immunosuppressive therapy. Therefore, this non-invasive, sensitive, and quantitative method is a robust and informative approach for rapid and routine monitoring of transplant allografts without invasive biopsy., 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.)

The Chinese food system has undergone a transition of unprecedented speed, leading to complex interactions with China's economy, health and environment. Structural changes experienced by the country over the past few decades have boosted economic development but have worsened the mismatch between food supply and demand, deteriorated the environment, driven obesity and overnutrition levels up, and increased the risk for pathogen spread. Here we propose a strategy for slimming and greening the Chinese food system towards sustainability targets. This strategy takes into account the interlinkages between agricultural production and food consumption across the food system, going beyond agriculture-focused perspectives. We call for a food-system approach with integrated analysis of potential triple benefits for the economy, health and the environment, as well as multisector collaboration in support of evidence-based policymaking., (© 2022. Springer Nature Limited.)

Despite the frequent occurrence of γ-branched amines in bioactive molecules, the direct catalytic asymmetric synthesis of this structural motif containing a remote stereocenter remains an important synthetic challenge. Here, we report an amide-directed, rhodium-catalyzed highly diastereo- and enantioselective hydroboration of unactivated internal alkenes. This method provided facile access to enantioenriched amines containing β,γ-vicinal stereocenters. The application of this strategy to the synthesis of bioactive molecules was demonstrated. Computational studies indicated that migratory insertion of the alkene into rhodium hydride controls the enantioselectivity.

Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications., (© 2022. The Author(s).)

With the dramatically increasing detection rate of ground-glass nodules (GGN), exact understanding and treatment strategy of them has become the hottest issue currently. More and more studies have begun to explore the underlying mechanisms of their indolent characteristics and favorable prognosis from the perspectives of molecular evolution and immune microenvironment. GGN has different dominating gene mutations at different evolutional stages. The pure GGN has a lower tumor mutation burden and genomic instability, while a gradually evolutionary feature of genomic mutation along with the pathological progression can be observed. GGN has less infiltration of immune cells, and they are under the pressure of immune surveillance with weakened immune escape. With the increase of solid components, an inhibitory immune microenvironment is gradually established and immune escape is gradually enhanced, leading to rapid tumor growth. Further exploration of the molecular characteristics of GGN will help to more precisely distinguish these highly heterogeneous lesions, which could be helpful to make personalized treatment plans.

Objective: To examine the efficiacy of a machine learning diagnostic model specifically for solid nodules in multiple pulmonary nodules constructed by combining patient clinical information and CT features. Methods: Totally 446 solid nodules resected from 287 patients with multiple pulmonary nodules in Department of Thoracic Surgery, Peking University People's Hospital from January 2010 to December 2018 were included. There were 117 males and 170 females, aging (61.4±9.9) yeras (range: 33 to 84 years). The nodules were randomly divided into training set (228 patients with 357 nodules) and test set (59 patients with 89 nodules) by a ratio of 4∶1. The extreme gradient boosting (XGBoost) algorithm was used to generate a predictive model (PKU-ML model) on the training set. The accuracy was verified on the test set and compared with previous published models. Finally, an independent single solid nodule set (155 patients, 95 males, aging (62.3±8.3) years (range: 37 to 77 years)) was used to evaluate the accuracy of the model for predictive value of single solid nodules. Area of receiver operating characteristic curve (AUC) was used to evaluate diagnostic values of models. Results: In the training set, the AUC of the PKU-ML model was 0.883 (95% CI : 0.849 to 0.917). In the test set, the performance of the PKU-ML model (AUC=0.838, 95% CI : 0.754 to 0.921) was better than the models designed for single pulmonary nodules (Brock model: AUC=0.709, 95% CI : 0.603 to 0.816, P= 0.04; Mayo model: AUC=0.756, 95% CI : 0.656 to 0.856, P= 0.01; VA model: AUC=0.674, 95% CI : 0.561 to 0.787, P< 0.01), similar with PKUPH model (AUC=0.750, 95% CI : 0.649 to 0.851, P= 0.07). In the independent single solid nodules set, the PKU-ML model also achieved good performance (AUC=0.786, 95% CI : 0.701 to 0.872). Conclusion: The machine learning based PKU-ML model can better predict the malignancy of solid nodules in multiple pulmonary nodules, and also achieved a good performance in predicting the malignancy of single solid pulmonary nodules compared to mathematical models.

Background: The Candida glabrata does not develop into a pathogenic hiphal form; however, it has become the second most common pathogen of fungal infections in humans, partly because of its adhesion ability and virulence., Objectives: The present study aimed to determine whether Flo8, a transcription factor that plays an important role in the virulence and drug resistance in Candida albicans, has a similar role in C. glabrata., Methods: We constructed FLO8 null strains of a C. glabrata standard strain and eight clinical strains from different sources, and a FLO8 complemented strain. Real-time quantitative PCR, biofilm formation assays, hydrophobicity tests, adhesion tests, Caenorhabditis elegans survival assay, and drug-susceptibility were then performed., Results: Compared with the wild-type strains, the biofilm formation, hydrophobicity, adhesion, and virulence of the FLO8-deficient strains decreased, accompanied by decreased expression of EPA1, EPA6, and EPA7. On the other hand, it showed no changes in antifungal drug resistance, although the expression levels of CDR1, CDR2, and SNQ2 increased after FLO8 deletion., Conclusions: These results indicated that Flo8 is involved in the adhesion and virulence of C. glabrata, with FLO8 deletion leading to decreased expression of EPA1, EPA6, and EPA7 and decreased biofilm formation, hydrophobicity, adhesion, and virulence., (© 2022. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Perturbations in mitochondrial membrane stability lead to cytochrome c release and induce caspase-dependent apoptosis. Using synthetic smart chemicals with changeable physicochemical properties to interfere the mitochondrial membrane stability has not yet been reported. Here we show that a thermosensitive anchor-polymer-peptide conjugate (anchor-PPC) destabilizes mitochondrial membranes upon in situ molecule changes from hydrophilic to hydrophobic, which consequently induces apoptosis in a spatiotemporally controlled manner and acts as an antitumor pharmaceutical. The anchor-PPC is composed of a thermosensitive copolymer, a photolabile linker, a hydrophilic HIV Tat-derived peptide both for cell penetration and polymer phase transition temperature (Tt) modulation, and an anchor peptide for intercalating into mitochondrial membranes. The photocontrollable anchor-PPC dehydrates and changes from being hydrophilic to hydrophobic upon photoactivation at body temperature. This cell-penetrable anchor-PPC specifically targets mitochondria and destabilizes mitochondrial membranes upon irradiation, and consequently initiates apoptosis in cells and a complex 3D tumor model. This study provides the first experimental evidence that the synthetic smart chemical can spatiotemporally control the stability of organelle membranes based on its in situ physicochemical property change.

A laccase catalyzed colorimetric biosensing approach is promising for the detection of pheochromocytoma biomarkers, yet suffers from the poor stability of enzymes and high cost for production. Here we report for the first time an easy to produce, cheap, stable and reliable laccase-mimicking CuCoFe-LDHzyme, which can catalyze the oxidation of pheochromocytoma biomarkers to form a chromogenic product for smartphone-based colorimetric detection.

Overweight induced by high-fat diet (HFD) represents one of the major health concerns in modern societies, which can cause lasting peripheral and central metabolic disorders in all age groups. Specifically, childhood obesity could lead to life-long impact on brain development and functioning. On the other hand, environmental enrichment (EE) has been demonstrated to be beneficial for learning and memory. Here, we explored the impact of high-fat diet on olfaction and organization of olfactory bulb cells in adolescent mice, and the effect of EE intervention thereon. Puberty mice (3-week-old) fed with HFD for 10 weeks exhibited poorer odor sensitivity and olfactory memory relative to controls consuming standard chows. The behavioral deficits were rescued in the HFD group with EE intervention. Neuroanatomically, parvalbumin (PV) interneurons in the olfactory bulb (OB) were reduced in the HFD-fed animals relative to control, while EE intervention also normalized this alteration. In contrast, cells expressing calbindin (CB), doublecortin (DCX) in the OB were not altered. Our findings suggest that PV interneurons may play a crucial role in mediating the HFD-induced olfactory deficit in adolescent mice, and can also serve a protective effect of EE against the functional deficit., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ inhibition normalized CD4/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo., (© 2022 by The American Society of Hematology.)

Our previous RNA sequencing study showed that the long non-coding RNA ischemia-related factor Vof-16 (lncRNA Vof-16) was upregulated after spinal cord injury, but its precise role in spinal cord injury remains unclear. Bioinformatics predictions have indicated that lncRNA Vof-16 may participate in the pathophysiological processes of inflammation and apoptosis. PC12 cells were transfected with a pHBLV-U6-MCS-CMV-ZsGreen-PGK-PURO vector to express an lncRNA Vof-16 knockdown lentivirus and a pHLV-CMVIE-ZsGree-Puro vector to express an lncRNA Vof-16 overexpression lentivirus. The overexpression of lncRNA Vof-16 inhibited PC12 cell survival, proliferation, migration, and neurite extension, whereas lncRNA Vof-16 knockdown lentiviral vector resulted in the opposite effects in PC12 cells. Western blot assay results showed that the overexpression of lncRNA Vof-16 increased the protein expression levels of interleukin 6, tumor necrosis factor-α, and Caspase-3 and decreased Bcl-2 expression levels in PC12 cells. Furthermore, we established rat models of spinal cord injury using the complete transection at T10. Spinal cord injury model rats were injected with the lncRNA Vof-16 knockdown or overexpression lentiviral vectors immediately after injury. At 7 days after spinal cord injury, rats treated with lncRNA Vof-16 knockdown displayed increased neuronal survival and enhanced axonal extension. At 8 weeks after spinal cord injury, rats treated with the lncRNA Vof-16 knockdown lentiviral vector displayed improved neurological function in the hind limb. Notably, lncRNA Vof-16 knockdown injection increased Bcl-2 expression and decreased tumor necrosis factor-α and Caspase-3 expression in treated animals. Rats treated with the lncRNA Vof-16 overexpression lentiviral vector displayed opposite trends. These findings suggested that lncRNA Vof-16 is associated with the regulation of inflammation and apoptosis. The inhibition of lncRNA Vof-16 may be useful for promoting nerve regeneration and functional recovery after spinal cord injury. The experiments were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China., Competing Interests: None

Background: The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood., Objective: The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory., Methods: Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed., Results: ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall., Conclusion: The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The rats were exposed to chronic unpredictable mild stress(CUMS) and kept in separate cages for inducing depressive disorder, which was judged by behavioral indicators. The number and morphology of neurons in hippocampal CA3 area and prefrontal cortex were observed by hematoxylin-eosin(HE) staining. The levels of brain-derived neurotrophic factor(BDNF), 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), norepinephrine(NE), glutamic acid(GLU), interleukin-1β(IL-1β), interleukin-18(IL-18), and tumor necrosis factor-α(TNF-α) were detected by enzyme-linked immunosorbent assay(ELISA). Real-time polymerase chain reaction(RT-PCR) and Western blot were conducted to determine the mRNA and protein expression levels of related molecules in NLRP3 pathway. The results showed that compared with the model group, acidic polysaccharides from Poria at the low-, medium-, and high-doses(0.1, 0.3 and 0.5 g·kg~(-1)·d~(-1)) all improved the depression-like behavior of rats, increased the number of neurons and the levels of BDNF, 5-HT, 5-HIAA, DA, and NE in the hippocampus, and reduced GLU and serum IL-1β, IL-18, and TNF-α levels. The mRNA expression levels of ASC, caspase-1, IL-1β, and IL-18 and the protein expression levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in each medication group were down-regulated, whereas the protein expression levels of pro-caspase-1, pro-IL-1β, and pro-IL-18 were up-regulated. All these have indicated that acidic polysaccharides from Poria exerted the antidepressant effect possibly by regulating neurotransmitters and NLRP3 inflammasome signaling pathway.

Context: The COVID-19 pandemic continues to spread over the world and has heightened concerns over global food security risks. As the first country hit by COVID-19, China has adopted a series of stringent mitigation policies to contain the spread of virus. This has led to food system disruptions due to restrictions on labor and interruption of transport, processing, retailing, and input distribution., Objective: The objective of this contribution is to report evidence for initial impacts and resilience of China's food system amid the COVID-19 pandemic and to discuss government's responses as well as long-term efforts that promoted resilience., Methods: We reviewed a range of publications, government released reports and official information, blogs, and media articles, and whenever possible, we complemented this qualitative information with quantitative data from China's National Bureau of Statistics and finally empirical data obtained from a simulation study., Results and Conclusions: We identified China's earlier responses in each key food system activities including ensuring effective logistics of agricultural products and inputs, supporting production and processing, matching supply with demand, and mitigating consumer's income loss. In particular, innovative information and communications technology (ICT) applications along the food system had been highlighted. Coupled with China's long-term efforts in investing in agriculture, building emergency response systems, and adopting governor's responsibility mechanisms, there has been little panic in the food system with largely sufficient supplies and stable prices. In the second quarter of 2020, after registered negative growth in the first quarter, primary agriculture grew by 3.4% and the negative growth of livestock production was narrowed significantly by 8.7 percentage points. Food prices rose by a modest 0.6% and returned to normal after a surge in February 2020., Significance: We expect that China's experiences on building resilient food systems could improve understanding of the challenges posed by COVID-19 from a retrospective perspective and provide lessons to other countries that are experiencing disruptions in the food systems worldwide. The lessons are also important for strengthening the resilience of food systems over longer time horizons., Competing 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., (© 2021 Elsevier Ltd. All rights reserved.)

The outbreak and wide spread of COVID-19 poses a new threat to global food security. This paper aims to address two important policy related issues, that is which agricultural subsector suffers more under zoonotic diseases and how do zoonotic diseases affect these subsectors. Using provincial panel data of 24 main farm commodities in China from 2002 to 2017, this paper identifies the impacts of zoonotic diseases and projects the potential disruption of COVID-19 to agricultural output in China under three scenarios. The main findings are as follows. First, zoonotic diseases have adverse impacts on almost all the farm commodities, while livestock on average suffers more than crops. Second, zoonotic diseases affect these subsectors mainly through the channel of adverse shocks on total factor productivity (TFP). Third, while a few subsectors can find a way to offset part of the TFP loss by applying more input, most subsectors suffer from both input reduction and TFP loss. Fourth, the spread of COVID-19 is projected to lower the growth rates of China's crop and livestock sector by 1.1%-2.3% and 1.3%-2.6%, with TFP loss by 1.1%-2.0% and 1.4%-2.7%, respectively, in 2020. This paper then discusses several policy implications for mitigating the negative impacts of COVID-19 on agricultural production in China and elsewhere., Competing 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., (© 2020 Elsevier B.V. All rights reserved.)

Substantial evidence has revealed that abnormalities in synaptic plasticity play important roles during the process of depression. LASP1 (LIM and SH3 domain protein 1), a member of actin-binding proteins, has been shown to be associated with the regulation of synaptic plasticity. However, the role of LASP1 in the regulation of mood is still unclear. Here, using an unpredictable chronic mild stress (UCMS) paradigm, we found that the mRNA and protein levels of LASP1 were decreased in the hippocampus of stressed mice and that UCMS-induced down-regulation of LASP1 was abolished by chronic administration of fluoxetine. Adenosine-associated virus-mediated hippocampal LASP1 overexpression alleviated the UCMS-induced behavioral results of forced swimming test and sucrose preference test in stressed mice. It also restored the dendritic spine density, elevated the levels of AKT (a serine/threonine protein kinase), phosphorylated-AKT, insulin-like growth factor 2, and postsynaptic density protein 95. These findings suggest that LASP1 alleviates UCMS-provoked behavioral defects, which may be mediated by an enhanced dendritic spine density and more activated AKT-dependent LASP1 signaling, pointing to the antidepressant role of LASP1., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of ( S )-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that ( S )-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide ( C3 ) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.

Fear extinction is an important preclinical model for behavior therapy in human anxiety disorders, such as post-traumatic stress disorder (PTSD). Histone acetylation is involved in the extinction of fear memory. As the "readers" of histone acetylation markers, the role of the bromodomain and extraterminal domain (BET) proteins in fear extinction is still unclear. In the present study, we found that suppression of BET proteins using small molecule JQ-1 had no effects on the acquisition of auditory fear or on the extinction of recent auditory fear, but it impaired the extinction of remote auditory fear. We found that insulin like growth factor 2 (IGF-2) mRNA and protein were up-regulated in the anterior cingulate cortex (ACC) after the extinction training of remote fear memory, and that this effect was inhibited by JQ-1 administration. Further, the local delivery of IGF-2 protein to the ACC region rescued the impaired extinction of remote memory caused by JQ-1 administration, which suggesting IGF-2 mediates the effects of JQ-1 on remote memory extinction. Gene expression profiling analysis demonstrated that JQ-1 treatment inhibited the up-regulated expression of a key set of neuroplasticity-related genes following remote memory extinction. Together, these findings establish BET proteins as epigenetic mediator for the extinction of remote fear memory. In particular, the findings of this study imply that as a prospective preclinical cancer drug, JQ-1 (or other BET bromodomain inhibitors) should be modified to prevent it from crossing the blood brain barrier and causing neurological side effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Long non-coding RNAs (lncRNAs) are abundantly expressed in the central nervous system and exert a critical role in gene regulation via multiple biological processes. To uncover the functional significance and molecular mechanisms of lncRNAs in spinal cord injury (SCI), the expression signatures of lncRNAs were profiled using RNA sequencing (RNA-seq) technology in a Sprague-Dawley rat model of the 10 th thoracic vertebra complete transection SCI. Results showed that 116 of 14,802 detected lncRNAs were differentially expressed, among which 16-including eight up-regulated (H19, Vof16, Hmox2-ps1, LOC100910973, Ybx1-ps3, Nnat, Gcgr, LOC680254) and eight down-regulated (Rmrp, Terc, Ngrn, Ppp2r2b, Cox6a2, Rpl37a-ps1, LOC360231, Rpph1)-demonstrated fold changes > 2 in response to transection SCI. A subset of these RNA-seq results was validated by quantitative real-time PCR. The levels of 821 mRNAs were also significantly altered post-SCI; 592 mRNAs were up-regulated and 229 mRNAs were down-regulated by more than 2-fold. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that differentially expressed mRNAs were related to GO biological processes and molecular functions such as injury and inflammation response, wound repair, and apoptosis, and were significantly enriched in 15 KEGG pathways, including cell phagocytosis, tumor necrosis factor alpha pathway, and leukocyte migration. Our results reveal the expression profiles of lncRNAs and mRNAs in the rat spinal cord of a complete transection model, and these differentially expressed lncRNAs and mRNAs represent potential novel targets for SCI treatment. We suggest that lncRNAs may play an important role in the early immuno-inflammatory response after spinal cord injury. This study was approved by the Administration Committee of Experimental Animals, Guangdong Province, China., Competing Interests: None

Purpose of Review: The purpose of this review is to summarize the current understanding of germline mutations as they contribute to leukemia development and progression. We also discuss how these new insights may help improve clinical management of germline mutations associated with leukemia., Recent Findings: Germline mutations may represent important initial mutations in the development of leukemia where interaction with somatic mutations provide further hits in leukemic progression. In addition, germline mutations may also contribute to leukemogenesis by impacting bone marrow stem-cell microenvironment and immune cell development and function., Summary: Leukemia is characterized by the clonal expansion of malignant cells secondary to somatic or germline mutations in a variety of genes. Understanding somatic mutations that drive leukemogenesis has drastically improved our knowledge of leukemia biology and led to novel therapeutic strategies. Advances have also been made in identifying germline mutations that may affect leukemic development and progression. This review will discuss the biological and clinical relationship of germline mutations with clonal hematopoiesis, bone marrow microenvironment, and immunity in the progression of leukemia.

In this opinion piece, we highlight that trade barriers established during COVID-19 as "fire lines" to prevent cross-border transmission of the pandemic could become "fault lines" that demolish the global food system. We review restrictions on both international agricultural exports and imports, especially unilateral border controls such as import refusals and alerts, in previous epidemics and arising with two novel features amid COVID-19. Institutional causes to pervasive trade barriers in epidemics that are embedded in the WHO-WTO coordination scheme have been discussed. In the meantime, discussions on potential economic outcomes and policy recommendations have been provided., Competing Interests: Conflicts of interest/competing interestsThe authors declared that they have no conflict of interest., (© International Society for Plant Pathology and Springer Nature B.V. 2020.)

Recent studies indicate that circular ribonucleic acids (circRNAs) are involved in a variety of human diseases. The roles of circRNAs in traumatic spinal cord injury (SCI) remain unknown, however. We performed RNA-seq to analyze the circRNA expression profile in rat spinal cord after SCI and to investigate the relevant mechanisms. In all, 150 circRNAs were significantly differentially expressed in rat spinal cord after SCI by a fold-change ≥2 and p value ≤0.05. Among these, 99 circRNAs were upregulated, while 51 were downregulated. Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway analyses, and circRNA/miocroRNA (miRNA) interaction networks were conducted to predict the potential roles of circRNAs in the process of SCI. In addition, the expression levels of six selected circRNAs were verified successfully by quantitative real-time polymerase chain reaction. Further study identified circRNA&#95;07079 and circRNA&#95;01282 as being associated with SCI, and they may participate in the pathophysiology of SCI through circRNA-targeted miRNA-messenger RNA axis. In summary, the results of our study revealed the expression profiles and potential functions of differentially expressed circRNAs in traumatic SCI in rats; this may provide new clues for studying the mechanisms underlying SCI and also present novel molecular targets for clinical therapy of SCI.

Lung cancer is one of the most common cancers and the predominant cause of cancer-related death in the world. The low accuracy of early detection techniques and high risk of relapse greatly contribute to poor prognosis. An accurate clinical tool that can assist in diagnosis and surveillance is urgently needed. Circulating tumor DNA (ctDNA) is free DNA shed from tumor cells and isolated from peripheral blood. The genomic profiles of ctDNA have been shown to closely match those of the corresponding tumors. With the development of approaches with high sensitivity and specificity, ctDNA plays a vital role in the management of lung cancer as a result of its reproducible, non-invasive, and easy-to-obtain characteristics. However, most previous studies have focused on advanced lung cancer. Few studies have investigated ctDNA in the early stages of the disease. In this review, we focus on ctDNA obtained from patients in the early stage of lung cancer, provide a summary of the related literature to date, and describe the main approaches to ctDNA and the clinical applications., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application., Methods: A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort., Results: A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018)., Conclusions: Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.

In the clinical treatment of lung cancer, therapy failure is mainly caused by cancer metastasis and drug resistance. Here, we investigated whether the tyrosine phosphatase Shp2 is involved in the development of metastasis and drug resistance in non-small cell lung cancer (NSCLC). Shp2 was overexpressed in a subset of lung cancer tissues, and Shp2 knockdown in lung cancer cells inhibited cell proliferation and migration, downregulated c-Myc and fibronectin expression, and upregulated E-cadherin expression. In H1975 cells, which carry double mutations (L858R + T790M) in epidermal growth factor receptor (EGFR) that confers resistance toward the tyrosine kinase inhibitor gefitinib, Shp2 knockdown increased cellular sensitivity to gefitinib; conversely, in H292 cells, which express wild-type EGFR and are sensitive to gefitinib, Shp2 overexpression increased cellular resistance to gefitinib. Moreover, by overexpressing Shp2 or using U0126, a small-molecule inhibitor of extracellular signal-regulated kinase 1/2 (ERK1/2), we demonstrated that Shp2 inhibited E-cadherin expression and enhanced the expression of fibronectin and c-Myc through activation of the ERK1/2 pathway. Our findings reveal that Shp2 is overexpressed in clinical samples of NSCLC and that Shp2 knockdown reduces the proliferation and migration of lung cancer cells, and further suggest that co-inhibition of EGFR and Shp2 is an effective approach for overcoming EGFR T790M mutation acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Thus, we propose that Shp2 could serve as a new biomarker in the treatment of NSCLC., Competing Interests: CONFLICTS OF INTEREST There are no conflicts interest to declare.

Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have focused on advanced stage cancers, and few have evaluated ctDNA detection in early-stage lung cancer. In the present study, blood and tumor samples were collected prospectively from 58 early-stage non-small lung cancer (NSCLC) patients (stages IA, IB, and IIA) and a targeted sequencing approach was used to detect somatic driver mutations in matched tumor DNA (tDNA) and plasma ctDNA. We identified frequent driver mutations in plasma ctDNA and tDNA in EGFR, KRAS, PIK3CA, and TP53, and less frequent mutations in other genes, with an overall study concordance of 50.4% and sensitivity and specificity of 53.8% and 47.3%, respectively. Cell-free (cfDNA) concentrations were found to be significantly associated with some clinical features, including tumor stage and subtype. Importantly, the presence of cfDNA had a higher positive predictive value than that of currently used protein tumor biomarkers. This study demonstrates the feasibility of identifying plasma ctDNA mutations in the earliest stage lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the clinical management of NSCLC., Competing Interests: Authors F.L., J.-B.Z., H.Y., W.C., M.-Y.Z., X.-X.S. and R.S. are employees of San Valley Biotechnology Inc. in Beijing, China. All other authors declare no conflict of interest.

Glaucoma, the second leading cause of blindness, is an irreversible optic neuropathy. The mechanism of optic nerve injury caused by glaucoma is undefined at present. There is no effective treatment method for the injury. Stem cells have the capacity of self-renewal and differentiation. These two features have made them become the research focus on improving the injury at present. This paper reviews the application progress on different types of stem cells therapy for optic nerve injury caused by glaucoma.

Purposes: In the present study, we investigated whether flurbiprofen axetil (FA) alleviates hypoxemia during one-lung ventilation (OLV) by reducing the pulmonary shunt/total perfusion (Q s/Q t) ratio, and examined the relationship between the Q s/Q t ratio and the thromboxane B2 (TXB2)/6-keto-prostaglandin F1α (6-K-PGF1α) ratio., Methods: Sixty patients undergoing esophageal resection for carcinoma were randomly assigned to groups F and C (n = 30 for each group). FA and placebo were administered i.v. 15 min before skin incision in groups F and C, respectively. The partial pressure of arterial oxygen (PaO2) was measured and the Q s/Q t ratio was calculated. Serum TXB2, 6-K-PGF1α, and endothelin (ET) were measured by radioimmunoassay. The relationship between TXB2/6-K-PGF1α and Q s/Q t was investigated., Results: Compared with group C, PaO2 was higher and the Q s/Q t ratio was lower during OLV in group F (P < 0.05). After treatment with FA, both serum TXB2 and 6-K-PGF1α decreased significantly (P < 0.05) but the TXB2/6-K-PGF1α ratio increased significantly (P < 0.01). Increases in the TXB2/6-K-PGF1α ratio were correlated with reductions in the Q s/Q t ratio during OLV in group F (r = -0.766, P < 0.01). There was no significant difference in serum ET between groups F and C., Conclusions: Treatment with FA reduced the Q s/Q t ratio and further increased the PaO2 level during OLV, possibly due to upregulation of the vasoactive agent TXB2/6-K-PGF1α ratio.

Background: Converting large undergraduate classes from the classroom to online has been an effective way to increase enrollments in high-demand courses in undergraduate education. However, challenges exist to maintaining students' high-quality learning interaction and engagement in large online courses. This article presents a collaborative model between faculty in health sciences and instructional designers to redesign and redevelop three high-enrollment courses to online at Boise State University., Method: Health studies course faculty and eCampus instructional designers conducted this study to reflect the collaborative online course development process at Boise State., Results: The offering of high-enrollment nursing courses met enrollment demand and maintained student retention. Challenges related to instruction were addressed by using a careful course redesign process and continuous improvement., Conclusion: Implications of this educational innovation for health science educators, instructional designers, and lessons learned are provided., (Copyright 2015, SLACK Incorporated.)

Background: In 2002, China launched the largest public health insurance scheme in the world, the New Cooperative Medical Scheme (NCMS). It is intended to enable rural populations to access health care services, and to curb medical impoverishment. Whether the scheme can reach its equity goals depends on how it is used, and by whom. Our goal is to shed light on whether and how income levels affect the ability of members to reap insurance benefits., Methods: We exploit primary panel data consisting of a complete census (over 3500 individuals) in three villages in Puding County, Guizhou province, collected in 2004, 2006, 2009 and 2011. Data was collected during in-person interviews with household member(s). The data include yearly gross and net medical expenses for all individuals, and socio-economic information. We apply probit, ordinary least squares, and tobit multivariate regression analyses to the three waves in which NCMS was active (2006, 2009 and 2011). Explained variables include obtainment, levels and rates of NCMS reimbursement. Household income is the main explanatory variable, with household- and individual-level controls. We restrict samples to rule out self-selection, and exploit the 2009 NCMS reform to highlight equity-enhancing features of insurance., Results: Prior to 2009 reforms, higher income in our sample was statistically significantly related to higher probability of obtaining reimbursement, as well as higher levels and rates of reimbursement. These relations all disappear after the reform, suggesting lower-income households were better able to reap insurance benefits after the scheme was reformed. Regression results suggest this is partly explained by reimbursement for chronic diseases., Conclusions: The post-reform NCMS distributed benefits more equitably in our study area. Making health insurance pro-poor may require a focus on outpatient costs, credit constraints and chronic diseases, rather than catastrophic illnesses.

Objective: To estimate the probability of N2 lymph node metastasis and to assist physicians in making diagnosis and treatment decisions., Methods: We reviewed the medical records of 739 patients with computed tomography-defined stage I non-small cell lung cancer (NSCLC) that had an exact tumor-node-metastasis stage after surgery. A random subset of three fourths of the patients (n=554) were selected to develop the prediction model. Logistic regression analysis of the clinical characteristics was used to estimate the independent predictors of N2 lymph node metastasis. A prediction model was then built and externally validated by the remaining one fourth (n=185) patients which made up the validation data set. The model was also compared with 2 previously described models., Results: We identified 4 independent predictors of N2 disease: a younger age, larger tumor size, central tumor location, and adenocarcinoma or adenosquamous carcinoma pathology. The model showed good calibration (Hosmer-Lemeshow test: P=0.923) with an area under the receiver operating characteristic curve (AUC) of 0.748 (95% confidence interval, 0.710-0.784). When validated with all the patients of group B, the AUC of our model was 0.781 (95% CI: 0.715-0.839) and the VA model was 0.677 (95% CI: 0.604-0.744) (P =0.04). When validated with T1 patients of group B, the AUC of our model was 0.837 (95% CI: 0.760-0.897) and Fudan model was 0.766 (95% CI: 0.681-0.837) (P < 0.01)., Conclusion: Our prediction model estimated the pretest probability of N2 disease in computed tomography-defined stage I NSCLC and was more accurate than the existing models. Use of our model can be of assistance when making clinical decisions about invasive or expensive mediastinal staging procedures.

There is a rapid transformation afoot in the rice value chain in Asia. The upstream is changing quickly-farmers are undertaking capital-led intensification and participating in burgeoning markets for land rental, fertilizer and pesticides, irrigation water, and seed, and shifting from subsistence to small commercialized farms; in some areas landholdings are concentrating. Midstream, in wholesale and milling, there is a quiet revolution underway, with thousands of entrepreneurs investing in equipment, increasing scale, diversifying into higher quality, and the segments are undergoing consolidation and vertical coordination and integration. Mills, especially in China, are packaging and branding, and building agent networks in wholesale markets, and large mills are building direct relationships with supermarkets. The downstream retail segment is undergoing a "supermarket revolution," again with the lead in change in China. In most cases the government is not playing a direct role in the market, but enabling this transformation through infrastructural investment. The transformation appears to be improving food security for cities by reducing margins, offering lower consumer rice prices, and increasing quality and diversity of rice. This paper discusses findings derived from unique stacked surveys of all value chain segments in seven zones, more and less developed, around Bangladesh, China, India, and Vietnam., (© 2014 New York Academy of Sciences.)

Objective: To study the clinical effect of the Gartland III humerus supracondylar fractures in children by manipulative reduction and Kirschner wire percataneous internal fixation., Methods: From July 2010 and July 2013, 60 patients with Gartland III humerus supracondylar fracture were selected and divided into treatment group and control group. In the treatment group 32 patients were treated with traditional bone setting tetradeca-manipulative reduction and percataneous Kirschner wire internal fixation,included 18 males and 14 females with an average age of (7.8 +/- 2.7) years old ranging from 5 to 11; in the control group 28 patients were treated with open reduction and Kirschner wire internal fixation,included 16 males and 12 females with an average age of (7.2 +/- 3.0) years old ranging from 4 to 12. The motion range of the elbow joint,the time of fracture clinical healing, and the effect after 6 months of Flynm clinical functional assessment standards were observed and compared., Results: The average fracture healing time of the control group (5.01 +/- 0.43) weeks was longer than that of the treatment group (4.29 +/- 0.29) weeks (t = 7.49, P = 0.00). At 6 months after treatment,the elbow motion range of the treatment group (146.02 +/- 2.28) was more than that of the control group (140.76 +/- 4.42) (t = -5.67, P = 0.00). At 6 months after treatment, according to Flynn evaluation, in the control group,there were 7 cases as excellent, 16 as good, 4 fair, 1 poor; in the treatment group, excellent in 21, good in 9, fair in 2 (U = 3.09, P = 0.002)., Conclusion: Manipulative reduction and Kirschner wire percataneous internal fixation for treatment of children's Gartland III humerus condyle fractures can shorten fracture clinical healing time and the clinical curative effect is better.

Background: To compare the safety and efficacy of dexmedetomidine/propofol (DP)-total i.v. anaesthesia (TIVA) vs remifentanil/propofol (RP)-TIVA, both with spontaneous breathing, during airway foreign body (FB) removal in children., Methods: Seventy-seven children undergoing rigid bronchoscopy for FB removal were randomly allocated to receive either RP-TIVA and spontaneous ventilation (Group RP, n=38) or DP-TIVA and spontaneous ventilation (Group DP, n=39). Heart rate, arterial pressure, pulse oxygen saturation (Sp(O2)), respiratory rate, end-tidal CO2 (E'(CO2)), and induction time were recorded. Adverse events, the intervention for these events, and postoperative care duration were also assessed., Results: The mean induction times were comparable between the two groups (Group RP 12.2 min vs Group DP 13.1 min, P>0.05). At the end of the procedure, the mean (E'(CO2)) was higher in Group RP (Group RP 6.8 kPa vs Group DP 5.8 kPa, P<0.001), and respiratory rate was lower in Group RP (Group RP 20.4 vs Group DP 35.8, P<0.001). Additionally, the perioperative haemodynamic profile was more stable in Group DP than that in Group RP. The incidence rate of breath-holding and intervention were comparable between the two groups. In the post-anaesthesia care unit (PACU), no hypoxaemia was observed, and emergence time increased in Group DP (Group DP 65.1 min vs Group RP 23.8 min, P<0.0001). The incidence of cough in PACU was higher in Group RP (Group RP 55.3% vs Group DP 10.3%, P<0.0001)., Conclusions: Compared with RP-TIVA, DP-TIVA provided more stable respiratory and haemodynamic profiles, but required a longer recovery time. Clinical trial registration China Clinical Research Information Service, ChiCTR-TRC-13003018.

Background: The pathological diagnosis is of critical importance to the subsequent treatment for the pathients with superior vena cava syndrome (SVCS). The aim of this study is to report our experience in the diagnosis of SVCS by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA)., Methods: The data of 520 patients who underwent EBUS-TBNA from September 2009 to May 2012 at our institution were reviewed. Of these, there were 14 males and 6 females (mean age of 59.1 years) with SVCS who received EBUS-TBNA that were included in the analysis., Results: The mean short axis diameter of the paratracheal lesions was (3.32 ± 1.79) cm (range, 1.69 to 9.50 cm) and 6 cases also had subcarinal lymph node enlargement with a mean short axis diameter of (2.14 ± 0.49) cm (range, 1.73 to 3.01 cm). An average of 4.3 punctures was performed per lesion. Malignancy was confirmed in 16 cases (10 small cell carcinomas, 4 adenocarcinomas, 1 squamous cell carcinoma and 1 Hodgkin lymphoma). In two patients, pathological examination of tissue revealed no evidence of malignancy and for 13 to 24 months of follow-up. One patient from whom adequate tissue was not obtained refused further surgical biopsy since he had undergone endovascular stenting of the SVC. One patient in whom a diagnosis was not obtained by EBUS-TBNA underwent thoracoscopic biopsy and the final diagnosis was B cell non-Hodgkin's lymphoma. The diagnosis accuracy of EBUS-TBNA in SVCS was 18/20 patients., Conclusion: EBUS-TBNA is a highly effective and safe procedure for the diagnosis of SVCS.

Using agricultural household survey data and claim records from insurers in China, this paper analyzes hog producers' choice of the ways to prevent possible losses and identifies the relationships among biosecurity practices, vaccination, and hog insurance. By combining one probit and two structural equations, we adopt three-stage estimations by a mixed-process model to obtain results. The findings indicate that biosecurity practices provide the basic infrastructure for operating pig farms and complement both the usage of quality vaccines and the uptake of hog insurance. In addition, there is a strong substitution relationship between the quality of vaccine and the demand for hog insurance. Hog farmers that implement better biosecurity practices are more likely to seek high-quality vaccines or buy into hog insurance schemes, but not both. For those households with hog insurance, better biosecurity status, better management practices, and higher-quality vaccines significantly help to reduce loss ratios. However, we also find a moral hazard effect in that higher premium expenditures by the insured households might induce larger loss ratios., (Copyright © 2013 Elsevier Ltd. All rights reserved.)