Genome-wide identification and characterization of tomato 14-3-3 (SlTFT) genes and functional analysis of SlTFT6 under heat stress.

The plant 14-3-3 proteins are essential for many biological processes and responses to abiotic stress. We performed genome-wide identification and analysis of the 14-3-3 family genes in tomato. To explore the properties of the thirteen Sl14-3-3 found in the tomato genome, their chromosomal location, phylogenetic, and syntenic relationships were analyzed. The Sl14-3-3 promoters were found to have a number of growth-, hormone-, and stress-responsive cis-regulatory elements. Moreover, the qRT-PCR assay revealed that Sl14-3-3 genes are responsive to heat and osmotic stress. Subcellular localization experiments evidenced that the SlTFT3/6/10 proteins occur in the nucleus and cytoplasm Additional analysis on Sl14-3-3 putative interactor proteins revealed a number of prospective clients that potentially participate in stress reactions and developmental processes. Furthermore, overexpression of an Sl14-3-3 family gene, SlTFT6, improved tomato plants thermotolerance. Taken together, the study provides basic information on tomato 14-3-3 family genes in plant growth and abiotic stress response (high temperature stress), which can be helpful to further study the underlying molecular mechanisms. This article is protected by copyright. All rights reserved.

Immunomodulatory potential of mesenchymal stem cell-derived extracellular vesicles: Targeting immune cells.

Various intractable inflammatory diseases caused by disorders of immune systems have pressed heavily on public health. Innate and adaptive immune cells as well as secreted cytokines and chemokines are commanders to mediate our immune systems. Therefore, restoring normal immunomodulatory responses of immune cells is crucial for the treatment of inflammatory diseases. Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are nano-sized double-membraned vesicles acting as paracrine effectors of MSCs. MSC-EVs, containing a variety of therapeutic agents, have shown great potential in immune modulation. Herein, we discuss the novel regulatory functions of MSC-EVs from different sources in the activities of innate and adaptive immune cells like macrophages, granulocytes, mast cells, natural killer (NK) cells, dendritic cells (DCs) and lymphocytes. Then, we summarize the latest clinical trials of MSC-EVs in inflammatory diseases. Furthermore, we prospect the research trend of MSC-EVs in the field of immune modulation. Despite the fact that the research on the role of MSC-EVs in regulating immune cells is in infancy, this cell-free therapy based on MSC-EVs still offers a promising solution for the treatment of inflammatory diseases.

Therapeutic potential of artemisinin and its derivatives in managing kidney diseases.

Artemisinin, an antimalarial traditional Chinese herb, is isolated from Artemisia annua. L, and has shown fewer side effects. Several pieces of evidence have demonstrated that artemisinin and its derivatives exhibited therapeutic effects on diseases like malaria, cancer, immune disorders, and inflammatory diseases. Additionally, the antimalarial drugs demonstrated antioxidant and anti-inflammatory activities, regulating the immune system and autophagy and modulating glycolipid metabolism properties, suggesting an alternative for managing kidney disease. This review assessed the pharmacological activities of artemisinin. It summarized the critical outcomes and probable mechanism of artemisinins in treating kidney diseases, including inflammatory, oxidative stress, autophagy, mitochondrial homeostasis, endoplasmic reticulum stress, glycolipid metabolism, insulin resistance, diabetic nephropathy, lupus nephritis, membranous nephropathy, IgA nephropathy, and acute kidney injury, suggesting the therapeutic potential of artemisinin and its derivatives in managing kidney diseases, especially the podocyte-associated kidney diseases.

Development and validation of a radiomics-based nomogram for predicting a major pathological response to neoadjuvant immunochemotherapy for patients with potentially resectable non-small cell lung cancer.

Introduction: The treatment response to neoadjuvant immunochemotherapy varies among patients with potentially resectable non-small cell lung cancers (NSCLC) and may have severe immune-related adverse effects. We are currently unable to accurately predict therapeutic response. We aimed to develop a radiomics-based nomogram to predict a major pathological response (MPR) of potentially resectable NSCLC to neoadjuvant immunochemotherapy using pretreatment computed tomography (CT) images and clinical characteristics. Methods: A total of 89 eligible participants were included and randomly divided into training (N=64) and validation (N=25) sets. Radiomic features were extracted from tumor volumes of interest in pretreatment CT images. Following data dimension reduction, feature selection, and radiomic signature building, a radiomics-clinical combined nomogram was developed using logistic regression analysis. Results: The radiomics-clinical combined model achieved excellent discriminative performance, with AUCs of 0.84 (95% CI, 0.74-0.93) and 0.81(95% CI, 0.63-0.98) and accuracies of 80% and 80% in the training and validation sets, respectively. Decision curves analysis (DCA) indicated that the radiomics-clinical combined nomogram was clinically valuable. Discussion: The constructed nomogram was able to predict MPR to neoadjuvant immunochemotherapy with a high degree of accuracy and robustness, suggesting that it is a convenient tool for assisting with the individualized management of patients with potentially resectable NSCLC.

Families under pressure: A qualitative study of stressors in families of children with congenital heart disease.

The objective of this study was to better understand the stressors in families of children with congenital heart disease (CHD) to assist with formulating targeted stress management plans for such families. A descriptive qualitative study was undertaken at a tertiary referral hospital in China. Following purposeful sampling, interviews were conducted with 21 parents of children with CHD regarding the stressors in their families. Following content analysis, 11 themes were generated from the data and categorised into six main domains: the initial stressor and associated hardships, normative transitions, prior strains, the consequences of family efforts to cope, intrafamily and social ambiguity, and sociocultural values. The 11 themes include confusion regarding the disease, hardships encountered during treatment, the heavy financial burden, the unusual growth track of the child due to the disease, normal events becoming abnormal for the family, impaired family functioning, family vulnerability, family resilience, family boundary ambiguity induced by role alteration, a lack of knowledge about community support and family stigma. Various and complex stressors exist for families of children with CHD. Medical personnel should fully evaluate the stressors and take targeted measures before implementing family stress management practices. It is also necessary to focus on the posttraumatic growth of families of children with CHD and strengthen resilience. Moreover, family boundary ambiguity and a lack of knowledge about community support should not be ignored, and further research is needed to explore these variables. Most importantly, policymakers and healthcare providers should adopt a range of strategies to address the stigma of being in a family of a child with CHD.

Application of molecular dynamics simulation for exploring the roles of plant biomolecules in promoting environmental health.

Understanding the dynamic changes of plant biomolecules is vital for exploring their mechanisms in the environment. Molecular dynamics (MD) simulation has been widely used to study structural evolution and corresponding properties of plant biomolecules at the microscopic scale. Here, this review (i) outlines structural properties of plant biomolecules, and the crucial role of MD simulation in advancing studies of the biomolecules; (ii) describes the development of MD simulation in plant biomolecules, determinants of simulation, and analysis parameters; (iii) introduces the applications of MD simulation in plant biomolecules, including the response of the biomolecules to multiple stresses, their roles in corrosive environments, and their contributions in improving environmental health; (iv) reviews techniques integrated with MD simulation, such as molecular biology, quantum mechanics, molecular docking, and machine learning modeling, which bridge gaps in MD simulation. Finally, we make suggestions on determination of force field types, investigation of plant biomolecule mechanisms, and use of MD simulation in combination with other techniques. This review provides comprehensive summaries of the mechanisms of plant biomolecules in the environment revealed by MD simulation and validates it as an applicable tool for bridging gaps between macroscopic and microscopic behavior, providing insights into the wide application of MD simulation in plant biomolecules.

A synergistic therapeutic nano-eyedrop for dry eye disease based on ascorbic acid-coupled exosomes.

Dry eye disease (DED), a complex ocular surface disease with a high prevalence rate, is associated with corneal injury, excess oxidative stress and inflammation. Current therapeutic strategies, including artificial tears and anti-inflammatory agents, are unable to address all the deleterious factors or to achieve a clinical cure due to their temporary or side effects. Here, we prepared a multiple-functional eyedrop based on the deposition of gold nanoparticles (AuNPs) reduced by ascorbic acid (AA) onto the exosomal phospholipid membrane of mesenchymal stem cell (mExo)-derived exosomes in situ (mExo@AA). The therapeutic value of mExo@AA for DED was demonstrated in a mouse DED model. Combining the benefits of mExo and AA, mExo@AA effectively improves corneal epithelium recovery and anti-inflammation capacity, decreases corneal reactive oxygen species, and restores tear secretion without adverse effects. Thus, this study suggests that mExo@AA is effective and safe as a therapeutic agent for the treatment of DED.

Comparison of recombinant human FSH biosimilar QL1012 with Gonal-f® for ovarian stimulation: a phase-three trial.

RESEARCH QUESTION: Are QL1012 and Gonal-f® equivalent in women undergoing ovarian stimulation for assisted reproductive technology (ART)? DESIGN: This multicentre, randomized, assessor-blinded, phase-three trial was conducted at 13 centres in China. Eligible patients were infertile women; age 20-39 years; body mass index 18-30 kg/m2; regular menstrual cycles; and indication for ART. After successful pituitary downregulation, patients were randomly assigned (1:1) to receive QL1012 or Gonal-f®, stratified by age (initial dose of 75-150 IU for women younger than 30 years, 150-225 IU for women aged 30-34 years and 225-300 IU for women aged ≥35 years, subcutaneously, once daily). The primary end point was the number of oocytes retrieved. RESULTS: Between October 2018, and June 2019, 341 patients were included in the per-protocol set. The mean numbers of oocytes retrieved were 14.7 ± 7.0 in the QL1012 group (n = 169) and 13.4 ± 6.1 in the Gonal-f® group (n = 172). Adjusted by analysis of covariance model, the least-squares mean difference was 1.3 oocytes (95% CI -0.1 to 2.7; P = 0.0650), within the pre-defined equivalence margins of ±3.0. Similar results were observed in the full analysis set. Additionally, no statistical differences were found in secondary end points except oestradiol concentration (median 3948.0 pg/ml versus 3545.3 pg/ml; P = 0.0015). Ovarian hyperstimulation syndrome (12.4% versus 13.1 %) and other adverse events were similar between the two groups. CONCLUSIONS: Therapeutic equivalence and similar safety profiles were demonstrated between QL1012 and Gonal-f® in women undergoing ovarian stimulation for ART.

Evaluation of bottom-up modeling of the blood-brain barrier to improve brain penetration prediction via physiologically based pharmacokinetic modeling.

Predicting the brain penetration of drugs has been notoriously difficult; however, recently, permeability-limited brain models have been constructed. Lead optimization for central nervous system compounds often focuses on compounds that have low transporter efflux, where passive permeability could be a main driver in determining cerebrospinal fluid (CSF)/brain concentrations. The main objective of this study was to evaluate the translatability of passive permeability data generated from different in vitro systems and its impact on the prediction of human CSF/brain concentrations using physiologically-based pharmacokinetic (PBPK) modeling. In vitro data were generated using gMDCK and parallel artificial membrane permeability assay-blood-brain barrier for comparison and predictions using a quantitative structure-activity relationship model were also evaluated. PBPK modeling was then performed for seven compounds with moderate-high permeability and a range of efflux in vitro, and the CSF/brain mass concentrations and Kpuu were reasonably predicted. This work provides the first step of a promising approach using bottom-up PBPK modeling for CSF/brain penetration prediction to support lead optimization and clinical candidate selection.

Formulation and Evaluation of Lipidized Imiquimod as an Effective Adjuvant.

Adjuvants are essential for the induction of robust immune responses against vaccine antigens. Small-molecule TLR7 agonists hold high potential for this purpose. In this communication, imiquimod (IMQ) bearing a cholesterol lipid moiety derivative, IMQ-Chol, was designed and synthesized as a vaccine adjuvant, which could release parent IMQ molecules in aqueous conditions via amide bond hydrolysis. We performed a series of immunological evaluations by cooperating with the inactivated foot-and-mouth disease virus (FMDV). All of the results confirmed that IMQ-Chol could stimulate the body for a prolonged time to produce strong humoral and cellular immunity with a balanced Th1/Th2 immune response through a TLR7-related MAPK pathway. In addition, the results of the proof-of-concept vaccine indicated IMQ-Chol had a good effect on preventing and treating FMD in pigs.

Multi-omics analysis reveals copper-induced growth inhibition mechanisms of earthworm (Eisenia fetida).

Exposure to high concentrations of copper can cause toxic effects on the growth and development of organisms, but the relevant toxic mechanisms are far from fully understood. This study investigated the changes of metabolites, genes, and gut microorganisms in earthworms (Eisenia fetida) exposed to 0 (control), 67.58 (low), 168.96 (medium), and 337.92 (high) mg/kg of Cu in soil for 60 days. Differentially expressed genes (DEGs) and differential metabolites (DMs) at the low-, medium-, and high-level Cu exposure groups were identified and introduced into Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Integrated metabolomic and transcriptomic analysis revealed that amino acid metabolism, lipid metabolism, and carbohydrate metabolism are the major metabolic pathways disturbed by Cu exposure. Furthermore, Cu exposure significantly decreased the diversity of the intestinal bacterial community and affected the relative abundance (increased or decreased) of intestinal colonizing bacteria. This resulted in high energy expenditure, inhibited nutrient absorption and fatty acid synthesis, and weakened antioxidant and detoxification abilities, ultimately inhibiting the growth of E. fetida. These findings offer important clues and evidence for understanding the mechanism of Cu-induced growth and development toxicity in E. fetida and provide further data for risk assessment in terrestrial ecosystems.

Enhanced visible light photo-Fenton catalysis by lanthanum-doping BiFeO3 for norfloxacin degradation.

Efficient photo-Fenton removal of antibiotic effluent is a widely followed and significant attempt to deal with the growing environmental pollution. In this study, BiFeO3 and lanthanum doped BiFeO3 catalysts were synthesized via one-step hydrothermal method as hydrogen peroxide activator for mineralization of norfloxacin (NOR). Various characterization measurements were used to verify La was successfully doped into the lattice of perovskite and investigated the effect of La doping molar ratio on BiFeO3 through the characterization of the morphology and physicochemical properties. The degradation experiment and reaction rate constants showed that the La-doped BiFeO3 particle exhibited superior photo-Fenton catalytic performance to undoped BiFeO3. Especially, the degradation efficiency of 15% La-doped BiFeO3 could reach up to 84.94%. And the first order kinetic constant of optimized conditions was 0.01638 min-1, which was about 6.9 times than that of undoped BiFeO3.The influence of pH, oxidizer content and catalyst dosage in photo-Fenton reaction were investigated detailedly. Besides, the synthetic catalyst possessed favorable stability and reusability with little metal leaching after many cycles of use. Radical scavenger experiments and electron spin resonance tests were carried out to conclude that the ·OH and holes were regarded as the dominate active species in the catalytic process. The narrow band gap and excellent electron transfer efficiency were the key factors for La-doped BiFeO3 to have high catalytic efficiency in the photo-Fenton system. Current works demonstrated the great promise of La-doped BiFeO3 in the elimination of antibiotic organics.

One Stone, Two Birds: A Peptide-Au(I) Infinite Coordination Supermolecule for the Confederate Physical and Biological Radiosensitization in Cancer Radiation Therapy.

Over half of cancer patients are subjected to radiotherapy, but owing to the deficient amount of reactive oxygen radicals (ROS) and DNA double-strand breaks (DSBs), a fair number of them suffer from radiotherapy resistance and the subsequent short-term survival opportunity. To overcome it, many successes have been achieved in radiosensitizer discovery using physical strategy and/or biological strategy, but significant challenges remain regarding developing clinically translational radiosensitizers. Herein, a peptide-Au(I) infinite coordination supermolecule termed PAICS is developed that combined both physical and biological radiosensitization and possessed pharmaceutical characteristics including adequate circulatory stability, controllable drug release, tumor-prioritized accumulation, and the favorable body eliminability. As expected, monovalent gold ion endowed this supermolecule with high X-ray absorption and the subsequent radiosensitization. Furthermore, a peptide targeting CRM1, is assembled into the supermolecule, which successfully activates p53 and apoptosis pathway, thereby further sensitizing radiotherapy. As a result, PAICS showed superior ability for radiotherapy sensitization in vivo and maintained a favorable safety profile. Thus, the PAICS reported here will offer a feasible solution to simultaneously overcome both the pharmaceutical obstacles of physical and biological radiosensitizers and will enable the development of a class of nanomedicines for tumor radiotherapy sensitization.

A bHLH transcription factor, SlbHLH96, promotes drought tolerance in tomato.

Drought stress caused by water deficit reduces plant productivity in many regions of the world. In plants, basic helix-loop-helix (bHLH) transcription factors regulate a wide range of cellular activities related to growth, development and stress response; however, the role of tomato SlbHLHs in drought stress responses remains elusive. Here, we used reverse genetics approaches to reveal the function of SlbHLH96, which is induced by drought and abscisic acid (ABA) treatment. We found that SlbHLH96 functions as a positive regulator of drought tolerance in tomato. Overexpression of SlbHLH96 in tomato improves drought tolerance by stimulating the expression of genes encoding antioxidants, ABA signaling molecules and stress-related proteins. In contrast, silencing of SlbHLH96 in tomato reduces drought tolerance. SlbHLH96 physically interacts with an ethylene-responsive factor, SlERF4, and silencing of SlERF4 in tomato also decreases drought tolerance. Furthermore, SlbHLH96 can repress the expression of the ABA catabolic gene, SlCYP707A2, through direct binding to its promoter. Our results uncover a novel mechanism of SlbHLH96-mediated drought tolerance in tomato plants, which can be exploited for breeding drought-resilient crops.

Application of the robot-assisted implantation in deep brain stimulation.

Introduction: This work aims to assess the accuracy of robotic assistance guided by a videometric tracker in deep brain stimulation (DBS). Methods: We retrospectively reviewed a total of 30 DBS electrode implantations, assisted by the Remebot robotic system, with a novel frameless videometric registration workflow. Then we selected 30 PD patients who used stereotactic frame surgery to implant electrodes during the same period. For each electrode, accuracy was assessed using radial and axial error. Results: The average radial error of the robot-assisted electrode implantation was 1.28 ± 0.36 mm, and the average axial error was 1.20 ± 0.40 mm. No deaths or associated hemorrhages, infections or poor incision healing occurred. Conclusion: Robot-assisted implantation guided by a videometric tracker is accurate and safe.

LncRNA FPASL suppresses fibroblast proliferation through its DNA methylation via DNMT3b in hypertrophic scar.

Long noncoding RNAs (lncRNAs) are increasingly being implicated as key regulators of cell proliferation, apoptosis, and differentiation. However, the molecular mechanisms of specific lncRNAs in the context of hypertrophic scar remain largely unclear. Here, we find that the lncRNA FPASL (fibroblast proliferation-associated LncRNA) is downregulated in HS, and FPASL reduces fibroblast proliferation and colony formation and blocks cell cycle progression. Using GO annotation enrichment analysis along with AZC (a specific inhibitor of DNA methylation), we identify that DNA methylation is responsible for downregulating FPASL in hypertrophic scar. Subsequent studies demonstrate that high expression of DNMT3b inhibits FPASL expression in HS. Mechanistic study reveals a significant increase in fibroblast proliferation after transfection with LNA-FPASL, which is further inhibited by knockdown of DNMT3b. Thus, our study reveals that DNMT3b mediates hypermethylation of the lncRNA FPASL promoter and the downregulation of lncRNA FPASL promotes fibroblast proliferation in hypertrophic scar.

The Protective Role of Apelin in the Early Stages of Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most common and serious microvascular complications of diabetes. Although current treatments can control the progression of DR to a certain extent, there is no effective treatment for early DR. Apart from vascular endothelial growth factor, it has been noted that the apelin/APJ system contributes to the pathogenesis of DR. We used a high-fat diet/streptozotocin-induced type 2 diabetic mouse model. The mice were divided into a lentivirus control group (LV-EGFP), an apelin-overexpression group (LV-Apelin+), and an apelin-knockdown group (LV-Apelin-), all of which were administrated intravitreal injections. LV-Apelin+ ameliorated the loss of pericytes in DR mice, whereas LV-Apelin- aggravated the loss of pericytes. Similarly, LV-Apelin+ reduced the leakage of retinal vessels, whereas LV-Apelin- exacerbated it. The genes and signaling pathway related to cell adhesion molecules were downregulated, whereas the cell-cell tight junctions and anti-apoptotic genes were upregulated in response to apelin overexpression. However, the alterations of these same genes and signaling pathways were reversed in the case of apelin knockdown. Additionally, LV-Apelin+ increased ZO-1 and occludin levels, whereas LV-Apelin- decreased them. Our results suggest that apelin can reduce vascular leakage by protecting pericytes, which offers a promising new direction for the early treatment of DR.

Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block.

Immune-related cardiotoxicities are uncommon but potentially fatal. The study aims to evaluate the value of pacemakers and methylprednisolone pulse therapy (MPPT) to patients with immune-related myocarditis concomitant with complete heart block (CHB). We first reviewed medical records of three patients with immune-related myocarditis concomitant with CHB. For the pooled analysis, we searched related cases with immune-related myocarditis in the PubMed database and screened the patients. Clinical characteristics, management, and outcomes were summarized. Our three patients developed immune-related myocarditis concomitant with CHB about 2 weeks after receiving pembrolizumab, and were successfully treated with pacemaker implantation and high-dose steroids (two received MPPT). In the pooled analysis, 21 cases were eligible with an overall fatality rate of 52%. Patients with pacemakers had a fatality rate of 38%, significantly lower than patients without them (38% vs 100%; p = 0.035), particularly the MPPT subgroup (25% vs 100%; p = 0.019). All five patients without pacemakers expired. Among patients with pacemakers, MPPT patients tended to have an inferior rate compared with non-MPPT patients. Timely pacemaker implantation played a crucial role in improving the outcomes of patients with immune-related myocarditis concomitant with CHB. Patients receiving MPPT appeared to have a better prognosis. Additionally, multidisciplinary consultation should be recommended for better management.

Effect of Astaxanthin on the Antioxidant Capacity and Intestinal Microbiota of Tsinling Lenok Trout (Brachymystax lenok tsinlingensis).

Astaxanthin (Ast) has been shown to be beneficial for the antioxidant capacity, immune system, and stress tolerance of fish. This study was conducted to investigate the effects of dietary supplementation of Ast on the antioxidant capacity and intestinal microbiota of tsinling lenok trout. We formulated four diets with 0 (CT), 50 (A50), 100 (A100), and 150 (A150) mg/kg Ast. The results showed that Ast increased total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), lysozyme (LZM), and catalase (CAT) activities. Malondialdehyde (MDA) content was lower in A150 and A100 than in CT (P < 0.05). Furthermore, the activities of acid phosphatase (ACP) were higher in A100 and A150 than in CT (P < 0.05). We harvested the midgut and applied next-generation sequencing of 16S rDNA. Compared to the control group, the Ast group had a greater abundance of Halomonas. Functional analysis showed that polycyclic aromatic hydrocarbon degradation was significantly higher with Ast, while novobiocin biosynthesis and C5-branched dibasic acid metabolism were significantly lower with Ast. In conclusion, Ast could enhance the antioxidant capacity, non-specific immunity, and intestinal health of tsinling lenok trout.