Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Recent advances in super-resolution optical imaging based on aggregation-induced emission.

Super-resolution imaging has rapidly emerged as an optical microscopy technique, offering advantages of high optical resolution over the past two decades; achieving improved imaging resolution requires significant efforts in developing super-resolution imaging agents characterized by high brightness, high contrast and high sensitivity to fluorescence switching. Apart from technical requirements in optical systems and algorithms, super-resolution imaging relies on fluorescent dyes with special photophysical or photochemical properties. The concept of aggregation-induced emission (AIE) was proposed in 2001, coinciding with unprecedented advancements and innovations in super-resolution imaging technology. AIE probes offer many advantages, including high brightness in the aggregated state, low background signal, a larger Stokes shift, ultra-high photostability, and excellent biocompatibility, making them highly promising for applications in super-resolution imaging. In this review, we summarize the progress in implementation methods and provide insights into the mechanism of AIE-based super-resolution imaging, including fluorescence switching resulting from photochemically-converted aggregation-induced emission, electrostatically controlled aggregation-induced emission and specific binding-regulated aggregation-induced emission. Particularly, the aggregation-induced emission principle has been proposed to achieve spontaneous fluorescence switching, expanding the selection and application scenarios of super-resolution imaging probes. By combining the aggregation-induced emission principle and specific molecular design, we offer some comprehensive insights to facilitate the applications of AIEgens (AIE-active molecules) in super-resolution imaging.

Mycobacterium vaccae alleviates allergic airway inflammation and airway hyper-responsiveness in asthmatic mice by altering intestinal microbiota.

Host immunity can influence the composition of the gut microbiota and consequently affect disease progression. Previously, we reported that a Mycobacterium vaccae vaccine could ameliorate allergic inflammation in asthmatic mice by regulating inflammatory immune processes. Here, we investigated the anti-inflammatory effects of M. vaccae on allergic asthma via gut microbiota modulation. An ovalbumin (OVA)-induced asthmatic murine model was established and treated with M. vaccae. Gut microbiota profiles were determined in 18 BALB/c mice using 16S rDNA gene sequencing and metabolomic profiling was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Mycobacterium vaccae alleviated airway hyper-reactivity and inflammatory infiltration in mice with OVA-induced allergic asthma. The microbiota of asthmatic mice is disrupted and that this can be reversed with M. vaccae. Additionally, a total of 24 differential metabolites were screened, and the abundance of PI(14:1(9Z)/18:0), a glycerophospholipid, was found to be correlated with macrophage numbers (r = 0.52, p = 0.039). These metabolites may affect chemokine (such as macrophage chemoattractant protein-1) concentrations in the serum, and ultimately affect pulmonary macrophage recruitment. Our data demonstrated that M. vaccae might alleviate airway inflammation and hyper-responsiveness in asthmatic mice by reversing imbalances in gut microbiota. These novel mechanistic insights are expected to pave the way for novel asthma therapeutic strategies.

Integrated unsupervised-supervised modeling and prediction of protein-peptide affinities at structural level.

Cell signal networks are orchestrated directly or indirectly by various peptide-mediated protein-protein interactions, which are normally weak and transient and thus ideal for biological regulation and medicinal intervention. Here, we develop a general-purpose method for modeling and predicting the binding affinities of protein-peptide interactions (PpIs) at the structural level. The method is a hybrid strategy that employs an unsupervised approach to derive a layered PpI atom-residue interaction (ulPpI[a-r]) potential between different protein atom types and peptide residue types from thousands of solved PpI complex structures and then statistically correlates the potential descriptors with experimental affinities (KD values) over hundreds of known PpI samples in a supervised manner to create an integrated unsupervised-supervised PpI affinity (usPpIA) predictor. Although both the ulPpI[a-r] potential and usPpIA predictor can be used to calculate PpI affinities from their complex structures, the latter seems to perform much better than the former, suggesting that the unsupervised potential can be improved substantially with a further correction by supervised statistical learning. We examine the robustness and fault-tolerance of usPpIA predictor when applied to treat the coarse-grained PpI complex structures modeled computationally by sophisticated peptide docking and dynamics simulation. It is revealed that, despite developed solely based on solved structures, the integrated unsupervised-supervised method is also applicable for locally docked structures to reach a quantitative prediction but can only give a qualitative prediction on globally docked structures. The dynamics refinement seems not to change (or improve) the predictive results essentially, although it is computationally expensive and time-consuming relative to peptide docking. We also perform extrapolation of usPpIA predictor to the indirect affinity quantities of HLA-A*0201 binding epitope peptides and NHERF PDZ binding scaffold peptides, consequently resulting in a good and moderate correlation of the predicted KD with experimental IC50 and BLU on the two peptide sets, with Pearson's correlation coefficients Rp = 0.635 and 0.406, respectively.

Antibody-secreting cells as a source of NR1-IgGs in N-methyl-D-aspartate receptor-antibody encephalitis.

BACKGROUND: The pathogenicity of NR1-IgGs in N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is known, but the immunobiological mechanisms underlying their production remain unclear. METHODS: For the first time, we explore the origin of NR1-IgGs and evaluate the contribution of B-cells to serum NR1-IgGs levels. Peripheral blood mononuclear cells (PBMCs) were obtained from patients and healthy controls (HCs). Naïve, unswitched memory (USM), switched memory B cells (SM), antibody-secreting cells (ASCs), and PBMC depleted of ASCs were obtained by fluorescence-activated cell sorting and cultured in vitro. RESULTS: For some patients, PBMCs spontaneously produced NR1-IgGs. Compared to the patients in PBMC negative group, the positive group had higher NR1-IgG titers in cerebrospinal fluid and Modified Rankin scale scores. The proportions of NR1-IgG positive wells in PBMCs cultures were correlated with NR1-IgGs titers in serum and CSF. The purified ASCs, SM, USM B cells produced NR1-IgGs in vitro. Compared to the patients in ASCs negative group, the positive group exhibited a worse response to second-line IT at 3-month follow-up. Naïve B cells also produce NR1-IgGs, implicating that NR1-IgGs originate from naïve B cells and a pre-germinal centres defect in B cell tolerance checkpoint in some patients. For HCs, no NR1-IgG from cultures was observed. PBMC depleted of ASCs almost eliminated the production of NR1-IgGs. CONCLUSIONS: These collective findings suggested that ASCs might mainly contribute to the production of peripheral NR1-IgG in patients with NMDAR-antibody encephalitis in the acute phase. Our study reveals the pathogenesis and helps develop tailored treatments (eg, anti-CD38) for NMDAR-antibody encephalitis.

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

Bone fracture is associated with incident myocardial infarction in long-term follow-up.

BACKGROUND: The association between bone fracture and cardiovascular diseases is examined in this study. While basic research has established a connection between fractures and heart attacks through the linkage between bones and arteries, population studies have not provided clear evidence. The aim of the present study is to investigate the association between bone fracture and the occurrence of myocardial infarction in a natural population during long-term follow-up. METHODS: A total of 13,196 adult participants with bone fracture history at baseline from the China Health and Nutrition Survey (CHNS) prospective cohort were included in this study. Baseline investigation was performed in 1997-2009 and the outcome was followed up till 2015. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. RESULTS: From 1997 to 2015, a total of 329 incident myocardial infarction cases were identified. In univariate and multivariate Cox regression analysis, a history of bone fracture was associated with an increased risk of myocardial infarction incidence in the total population (for the crude model: HR = 2.56, 95% CI 1.83-3.53, P < 0.001; for the multivariate model: HR = 1.43, 95% CI 1.02-1.99, P = 0.036). In the stratified analysis, bone fracture was not associated with an increased risk of incident myocardial infarction in subjects with age < 50 years (HR = 0.71, 95% CI 0.34-1.47, P = 0.356), but significantly associated with an increased risk of incident myocardial infarction in subjects with age ≥ 50 years (HR = 1.80, 95% CI 1.23-2.63, P = 0.003). CONCLUSIONS: It is suggested by the present study that bone fracture may be associated with an increased risk of incident myocardial infarction in the elderly population during long-term follow-up.

Antitumor efficacy and reduced toxicity using an anti-CD137 Probody therapeutic.

Costimulation via CD137 (4-1BB) enhances antitumor immunity mediated by cytotoxic T lymphocytes. Anti-CD137 agonist antibodies elicit mild liver inflammation in mice, and the maximum tolerated dose of Urelumab, an anti-human CD137 agonist monoclonal antibody, in the clinic was defined by liver inflammation-related side effects. A protease-activated prodrug form of the anti-mouse CD137 agonist antibody 1D8 (1D8 Probody therapeutic, Pb-Tx) was constructed and found to be selectively activated in the tumor microenvironment. This construct, which encompasses a protease-cleavable linker holding in place a peptide that masks the antigen binding site, exerted antitumor effects comparable to the unmodified antibody but did not result in liver inflammation. Moreover, it efficaciously synergized with both PD-1 blockade and adoptive T-cell therapy. Surprisingly, minimal active Pb-Tx reached tumor-draining lymph nodes, and regional lymphadenectomy did not abrogate antitumor efficacy. By contrast, S1P receptor-dependent recirculation of T cells was absolutely required for efficacy. The preferential cleavage of the anti-CD137 Pb-Tx by tumor proteases offers multiple therapeutic opportunities, including neoadjuvant therapy, as shown by experiments in which the Pb-Tx is given prior to surgery to avoid spontaneous metastases.

Target-regulated photoactivities of CdS/Ni-MOF heterojunction with [Ru(bpy)2dppz]2+ intercalator: a bisphenol A photoelectrochemical aptasensor.

Bisphenol A (BPA), an important endocrine disrupting compound, has infiltrated human daily lives through electronic devices, food containers, and children's toys. Developing of novel BPA assay methods with high sensitivity holds tremendous importance in valuing the pollution state. Here, we constructed an ultrasensitive photoelectrochemical (PEC) aptasensor for BPA determination by regulating photoactivities of CdS/Ni-based metal-organic framework (CdS/Ni-MOF) with [Ru(bpy)2dppz]2+ sensitizer. CdS/Ni-MOF spheres exhibited excellent photocatalytic performance, serving as a potential sensing platform for the construction of target recognition process. [Ru(bpy)2dppz]2+ were embedded into DNA double-stranded structure, functioning as sensitizer for modulating the signal response of the developed PEC aptasensor. The proposed PEC sensor exhibited outstanding analytical performances, including a wide linear range (0.1 to 1000.0 nM), low detection limit (0.026 nM, at 3σ/m), excellent selectivity, and high stability. This work provides a perspective for the design of ideal photosensitive materials and signal amplification strategies and extends their application in environment analysis.

Local injection of abaloparatide promotes mandibular condyle lengthening in adolescent rats via enhancing chondrogenesis and ossification.

BACKGROUND: Mandibular condylar hypoplasia negatively affects patient's facial appearance and dentofacial function. OBJECTIVE: To investigate the effect of local injection of the drug abaloparatide (ABL), an analogue of parathyroid hormone related protein (PTHrP), on promoting lengthening of the mandibular condyle. METHODS: Thirty adolescent male Sprague-Dawley rats were randomly divided into two groups, which received the injection of ABL or normal saline (the control) every 3 days in the temporomandibular joint (TMJ) cavity. Cone-beam computed tomography and immunohistochemistry assays were performed at 2, 4 and 6 weeks since the injection. Mandibular condylar chondrocytes (MCC) and pre-osteoblasts were treated with ABL or PBS, followed by the CCK-8 detection, IC50, real-time PCR assay, Western Blot and immunofluorescence staining. RESULTS: In vivo, compared with the control, the ABL group significantly increased the mandibular condylar process length (by 1.34 ± 0.59 mm at 6 weeks), the thickness of the cartilage layer, and enhanced the matrix synthesis. The ABL group had significant up-regulation of SOX 9, COL II, PTHrP and PTH1R, down-regulation of COL X in the cartilage, up-regulation of RUNX 2, and unchanged osteoclastogenesis in the subchondral bone. In vitro, the intra-TMJ injection of ABL promoted the MCC proliferation, with up-regulated expression of chondrogenic genes, and enhanced osteogenic differentiation of the pre-osteoblasts. CONCLUSIONS: Intra-TMJ injection of abaloparatide promotes mandibular condyle lengthening in the adolescent rats via enhancing chondrogenesis in the mandibular condylar cartilage and ossification in the subchondral bone.

Identifying Potential Sources of Phthalate Contamination in the Leaves of Stevia Rebaudiana (Bertoni) and the Development of Removal Technology.

Steviosides extracted from the leaves of the plant Stevia rebaudiana are increasingly used in the food industry as natural low-calorie sweeteners. Phthalates in food are often assumed to arise from food containers or packaging materials. Here, experiments were carried out to identify the potential sources of DMP, DBP, DIBP, and DEHP in the leaves of stevioside through investigation of their content in native stevioside tissues, soils, and associated agronomic materials. The results show that phthalate contamination was present in all the samples tested, and the influence of regional factors at the provincial level on the content of plasticizers in stevia leaves was not significant. Phthalates in stevia leaves can be absorbed into the plant body through leaves and roots. Using resin removal, the phthalate content in stevioside glycosides was reduced to less than 0.05 ppm, and some indicators were far lower than the limit standard in EU food.

Unilateral injection of botulinum toxin type A into the masseter muscle induces mandibular asymmetry in adolescent rats by suppressing the angular process growth.

INTRODUCTION: Mandibular asymmetry has negative impacts on maxillofacial aesthetics and psychological well-being. This study investigated the effects of unilateral injection of botulinum toxin type A (BTX-A) into the masseter muscle on mandibular symmetry. METHODS: Forty Wistar rats (4-week-old) were divided into 4 groups (n = 10): control, group 1 (1U BTX-A), group 2 (3U BTX-A), and group 3 (1U BTX-A for 3 times). BTX-A was injected into the right masseter of treatment groups. Cone-beam computerized tomography scans were taken before the injection and then at 2 weeks, 4 weeks, and 6 weeks after injection. Histologic and immunohistochemical staining were done for the condylar cartilage. RNA sequencing and quantitative reverse transcription polymerase chain reaction were used to detect gene expression in the angular process. RESULTS: In Groups 2 and 3, the right angular process length and the ramus height were reduced 4 weeks after injection, resulting in the mandibular midline deviating to the right side; the right condylar cartilage had reduced thickness and decreased expression of RUNX2, SOX9, and COL II (P <0.05). Two hundred sixty-one genes were differentially expressed (256 downregulated) in the angular process at 3 days post-BTX-A injection, and the calcium signaling pathway was unveiled through the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, TRPC1, Wnt5a, CaMKII, Ctnnb1, and RUNX2 expression were significantly downregulated at 1 and 3 days postinjection. CONCLUSIONS: Unilateral injection of BTX-A into the masseter muscle in adolescent rats induces mandibular asymmetry by suppressing the angular process growth on the injected side.

[Effect of metabolic reprogramming on abdominal aortic aneurysm].

Abdominal aortic aneurysm (AAA) is a life-threatening disease that remains undetected until it acutely ruptures. Due to lack of effective pharmaceutic therapies, it is urgent to explore new prevention and treatment strategies. Metabolic reprogramming is a cellular process through which cells change their metabolic patterns to meet material and energy requirements, including glucose metabolism, lipid metabolism and amino acid metabolism. Recently, the regulatory role of metabolic reprogramming in cardiovascular diseases, especially AAA, has attracted significant attention. This review article focuses on the research progress regarding the effects of metabolic reprogramming of vascular smooth muscle cells (VSMCs) and macrophages on the occurrence and development of AAA, especially their roles in major pathological processes such as VSMCs apoptosis and phenotype transformation, extracellular matrix remodeling, oxidative stress, and inflammatory response. The aim is to provide new clues for the mechanism research and clinical treatment of AAA from the perspective of metabolism.

Astragaloside IV improves pulmonary arterial hypertension by increasing the expression of CCN1 and activating the ERK1/2 pathway.

The aim of the present study was to investigate the underlying mechanism of AS-IV and CCN1 in PAH and to evaluate whether the protective effect of AS-IV against PAH is associated with CCN1 and its related signalling pathway. In vivo, male SD rats were intraperitoneally injected with monocrotaline (MCT, 60 mg/kg) or exposed to hypoxia (10% oxygen) and gavaged with AS-IV (20, 40 and 80 mg/kg/day) to create a PAH model. In vitro, human pulmonary artery endothelial cells (hPAECs) were exposed to hypoxia (3% oxygen) or monocrotaline pyrrole (MCTP, 60 µg/mL) and treated with AS-IV (10, 20 and 40 µM), EGF (10 nM, ERK agonist), small interfering CCN1 (CCN1 siRNA) and recombinant CCN1 protein (rCCN1, 100 ng/mL). We identified the differences in the expression of genes in the lung tissues of PAH rats by proteomics. At the same time, we dynamically detected the expression of CCN1 by Western blot both in vivo and in vitro. The Western blot experimental results showed that the expression of CCN1 increased in the early stage of PAH and decreased in the advanced stage of PAH. The results showed that compared with the control group, MCT- and hypoxia-induced increased the hemodynamic parameters and apoptosis. AS-IV can improve PAH, as characterized by decreased hemodynamic parameters, vascular wall area ratio (WA%), vascular wall thickness ratio (WT%) and α-SMA expression and inhibition of cell apoptosis. Moreover, the improvement of PAH by AS-IV was accompanied by increased CCN1 expression, which activated the ERK1/2 signalling pathway. Meanwhile, CCN1 and p-ERK1/2 were inhibited by siCCN1 and promoted by rCCN1. EGF not only activated the ERK1/2 signalling pathway but also induced the expression of CCN1. In conclusion, AS-IV improves PAH by increasing the expression of CCN1 and activating the ERK1/2 signalling pathway. The results of our study provide a theoretical basis for additional study on the protective effect of AS-IV against PAH.

Machine annealing-guided navigation of antihypertensive food peptide selectivity between human ACE N- and C-domains in structurally interacting diversity space.

Human angiotensin-converting enzyme (ACE) is a well-established druggable target for the treatment of hypertension (HTN), which contains two structurally homologous but functionally distinct N- and C-domains. Selective inhibition of the C-domain primarily contributes to the antihypertensive efficiency and can be exploited as medicinal agents and functional additives for regulating blood pressure with high safety. In this study, we used a machine annealing (MA) strategy to guide the navigation of antihypertensive peptides (AHPs) in structurally interacting diversity space with the two ACE domains based on their crystal/modeled complex structures and an in-house protein-peptide affinity scoring function, aiming to optimize the peptide selectivity for C-domain over N-domain. The strategy generated a panel of theoretically designed AHP hits with a satisfactory C-over-N (C > N) selectivity profile, from which several hits were found to have a good C > N selectivity, which is roughly comparable with or even better than the BPPb, a natural C > N-selective ACE-inhibitory peptide. Structural analysis and comparison of domain-peptide noncovalent interaction patterns revealed that (i) longer peptides (>4 amino aids) generally exhibit stronger selectivity than shorter peptides (<4 amino aids), (ii) peptide sequence can be divided into two, section I (including peptide C-terminal region) and section II (including peptide middle and N-terminal regions); the former contributes to both peptide affinity (primarily) and selectivity (secondarily), while the latter is almost only responsible for peptide selectivity, and (iii) charged/polar amino acids confer to peptide selectivity relative to hydrophobic/nonpolar amino acids (that confer to peptide affinity).

Plasma Exosome Gene Signature Differentiates Colon Cancer from Healthy Controls.

BACKGROUND: Liquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls. METHODS: Plasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas. RESULTS: Unsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors. CONCLUSIONS: Plasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer.

Variations in amino acids caused by drought stress mediate the predisposition of Carya cathayensis to Botryosphaeria canker disease.

Abiotic stresses can affect the outcome of plant-pathogen interactions, mostly by predisposing the host plant to infection; however, the crosstalk between pathogens and plants related to such predisposition remains unclear. Here, we investigated the predisposition of Carya cathayensis to infection by the fungal pathogen Botryosphaeria dothidea (Bd) caused by drought in the host plant. High levels of drought stress resulted in a significant increase in plant susceptibility to Bd. Drought significantly induced the accumulation of H2O2 and the free amino acids Pro, Leu, and Ile, and in the phloem tissues of plants, and decreased the content of non-structural carbohydrates. In vitro assays showed that Bd was sensitive to H2O2; however, Pro played a protective role against exogenous H2O2. Leu, Ile, and Pro induced asexual reproduction of Bd. Our results provide the first analysis of how drought predisposes C. cathayensis to Botrysphaeria canker via amino acid accumulation in the host plant, and we propose a model that integrates the plant-pathogen interactions involved.

Transcriptome profiling reveals ethylene formation in rice seeds by trichloroisocyanuric acid.

KEY MESSAGE: Ethylene formation via methionine reacting with trichloroisocyanuric acid under FeSO4 condition in a non-enzymatical manner provides one economically and efficiently novel ethylene-forming approach in planta. Rice seed germination can be stimulated by trichloroisocyanuric acid (TCICA). However, the molecular basis of TCICA in stimulating rice seed germination remains unclear. In this study, the molecular mechanism on how TCICA stimulated rice seed germination was examined via comparative transcriptome. Results showed that clustering of transcripts of TCICA-treated seeds, water-treated seeds, and dry seeds was clearly separated. Twenty-two and three hundred differentially expressed genes were identified as TCICA treatment responsive genes and TCICA treatment potentially responsive genes, respectively. Two and one TCICA treatment responsive genes were involved in ethylene signal transduction and iron homeostasis, respectively. Seventeen of the three hundred TCICA treatment potentially responsive genes were significantly annotated to iron ion binding. Meanwhile, level of methionine (ethylene precursor) showed a 73.9% decrease in response to TCICA treatment. Ethylene was then proved to produce via methionine reacting with TCICA under FeSO4 condition in vitro. Revealing ethylene formation by TCICA not only may bring novel insights into crosstalk between ethylene and other phytohormones during rice seed germination, but also may provide one economically and efficiently novel approach to producing ethylene in planta independently of the ethylene biosynthesis in plants and thereby may broaden its applications in investigational and applied purposes.

Five New Diarylbutyrolactones and Sesquilignans from Saussurea medusa and Their Inhibitory Effects on LPS-induced NO Production.

Five new diarylbutyrolactones and sesquilignans (1A/1B:  - 4: ), including one pair of enantiomers (1A/1B: ), together with 10 known analogues (5:  - 14: ), were isolated from the whole plants of Saussurea medusa. Compound 1: was found to possess an unusual 7,8'-diarylbutyrolactone lignan structure. Separation by chiral HPLC analysis led to the isolation of one pair of enantiomers, (+)-1A: and (-)-1B: . The structures of the new compounds were elucidated by extensive spectroscopic data. All compounds, except compounds 5, 7: and 9: , were isolated from S. medusa for the first time. Moreover, compounds 1:  -  4, 8: and 10:  - 14: had never been obtained from the genus Saussurea previously. Compounds (+)- 1A, 2, 5, 7: , and 9:  - 11: were found to inhibit the lipopolysaccharide (LPS)-induced release of NO by RAW264.7 cells with IC50 values ranging from 10.1 ± 1.8 to 41.7 ± 2.1 µM. Molecular docking and iNOS expression experiments were performed to examine the interactions between the active compounds and the iNOS enzyme.

Global, regional, and national burden of kidney dysfunction from 1990 to 2019: a systematic analysis from the global burden of disease study 2019.

OBJECTIVE: We aim to explore the prevalence and temporal trends of the burden of kidney dysfunction (KD) in global, regional and national level, since a lack of related studies. DESIGN: Cross-sectional study. MATERIALS: The data of this research was obtained from Global Burden of Diseases Study 2019. The estimation of the prevalence, which was measured by the summary exposure value (SEV), and attributable burden of KD was performed by DisMod-MR 2.1, a Bayesian meta-regression tool. The Spearman rank order correlation method was adopted to perform correlation analysis. The temporal trends were represented by the estimated annual percentage change (EAPC). RESULTS: In 2019, there were total 3.16 million deaths and 76.5 million disability-adjusted life years (DALYs) attributable to KD, increased by 101.1% and 81.7% compared with that in 1990, respectively. From 1990 to 2019, the prevalence of KD has increased in worldwide, but decreased in High-income Asia Pacific. Nearly 48.5% of countries globally, such as South Africa, Egypt and Mexico had increased mortality rates of KD from 1990 to 2019 while 44.6% for disability rate. Countries with lower socio-demographic index (SDI) are facing a higher prevalence as well as mortality and disability rate compared with those with higher SDI. Compared with females, the prevalence of KD was lower in males, however the attributable mortality and disability rate were higher in all years from 1990 to 2019. CONCLUSION: With the progress of senescent, we will face more severe challenges of reducing the prevalence and attributable burden of KD, especially in regions with lower SDI. Effective measures are urgently required to alleviate the prevalence and burden of KD.