ABSTRACT
This study is intended to explore the effect of hypoxia-inducible factor-1α (HIF-1α) activation on lipid accumulation in the diabetic kidney. A type 1 diabetic rat model was established by STZ intraperitoneal injection. Cobalt chloride (CoCl2) and YC-1 were used as the HIF-1α activator and antagonist, respectively. CoCl2 treatment significantly increased HIF-1α expression, accelerated lipid deposition, and accelerated tubular injury in diabetic kidneys. In vitro, CoCl2 effectively stabilized HIF-1α and increased its transportation from the cytoplasm to the nucleus, which was accompanied by significantly increased lipid accumulation in HK-2 cells. Furthermore, results obtained in vivo showed that HIF-1α protein expression in the renal tubules of diabetic rats was significantly downregulated by YC-1 treatment. Meanwhile, lipid accumulation in the tubules of the DM + YC-1 group was markedly decreased in comparison to the DM + DMSO group. Accordingly, PAS staining revealed that the pathological injury caused to the tubular epithelial cells was alleviated by YC-1 treatment. Furthermore, the blood glucose level, urine albumin creatinine ratio, and NAG creatinine ratio in the DM + YC-1 group were significantly decreased compared to the DM + DMSO group. Moreover, the protein expression levels of transforming growth factor ß1 (TGF-ß1) and connective tissue growth factor (CTGF) in diabetic kidneys were decreased by YC-1 treatment. Our findings demonstrate that the activation of HIF-1α contributed to interstitial injury in a rat model of diabetic nephropathy and that the underlying mechanism involved the induction of lipid accumulation.
Subject(s)
Cobalt , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Hypoxia-Inducible Factor 1, alpha Subunit , Animals , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Rats , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Male , Rats, Sprague-Dawley , Kidney Tubules/pathology , Kidney Tubules/metabolism , Transforming Growth Factor beta1/metabolism , Indazoles/pharmacology , Humans , Connective Tissue Growth Factor/metabolism , Lipid Metabolism/drug effects , Cell LineABSTRACT
Heterogeneous palladium catalysts with high efficiency, high Pd atom utilization, simplified separation, and recycle have attracted considerable attention in the field of synthetic chemistry. Herein, we reported a zirconium-based two-dimensional metal-organic framework (2D-MOF)-based Pd(II) photocatalyst (Zr-Ir-Pd) by merging the Ir photosensitizers and Pd(II) species into the skeletons of the 2D-MOF for the Pd(II)-catalyzed oxidation reaction. Morphological and structural characterization identified that Zr-Ir-Pd with a specific nanoflower-like structure consists of ultrathin 2D-MOF nanosheets (3.85 nm). Due to its excellent visible-light response and absorption capability, faster transfer and separation of photogenerated carriers, more accessible Pd active sites, and low mass transfer resistance, Zr-Ir-Pd exhibited boosted photocatalytic activity in catalyzing sterically hindered isocyanide insertion of diarylalkynes for the construction of fused tetracyclic heterocycles, with up to 12 times the Pd catalyst turnover number than the existing catalytic systems. In addition, Zr-Ir-Pd inhibited the competitive agglomeration of Pd(0) species and could be reused at least five times, owing to the stabilization of 2D-MOF on the single-site Pd and Ir sites. Finally, a possible mechanism of the photocatalytic synthesis of fused tetracyclic heterocycles catalyzed by Zr-Ir-Pd was proposed.
ABSTRACT
BACKGROUND: Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid peroxidation-induced ferroptosis contributes to the occurrence and course of SAE. This study aimed to investigate the relationship between neuronal injury and lipid peroxidation-induced ferroptosis in SAE. METHODS: Baseline data were collected from pediatric patients upon admission, and the expression levels of various markers related to lipid peroxidation and ferroptosis were monitored in the serum and peripheral blood mononuclear cells (PBMCs) of patients with SAE as well as SAE model mice. The hippocampal phosphatidylethanolamine-binding protein (PEBP)-1/15-lysine oxidase (LOX)/ glutathione peroxidase 4 (GPX4) pathway was assessed for its role on the inhibitory effect of ferroptosis in SAE treatment. RESULTS: The results showed elevated levels of S100 calcium-binding protein beta (S-100ß), glial fibrillary acidic protein, and malondialdehyde in the serum of SAE patients, while superoxide dismutase levels were reduced. Furthermore, analysis of PBMCs revealed increased transcription levels of PEBP1, LOX, and long-chain fatty acyl-CoA synthetase family member 4 (ACSL4) in SAE patients, while the transcription levels of GPX4 and cystine/glutamate transporter xCT (SLC7A11) were decreased. In comparison to the control group, the SAE mice exhibited increased expression of S-100ß and neuron-specific enolase (NSE) in the hippocampus, whereas the expression of S-100ß and NSE were reduced in deferoxamine (DFO) mice. Additionally, iron accumulation was observed in the hippocampus of SAE mice, while the iron ion levels were reduced in the DFO mice. Inhibition of ferroptosis alleviated the mitochondrial damage (as assessed by transmission electron microscopy, hippocampal mitochondrial ATP detection, and the JC-1 polymer-to-monomer ratio in the hippocampus) and the oxidative stress response induced by SAE as well as attenuated neuroinflammatory reactions. Further investigations revealed that the mechanism underlying the inhibitory effect of ferroptosis in SAE treatment is associated with the hippocampal PEBP-1/15-LOX/GPX4 pathway. CONCLUSION: These results offer potential therapeutic targets for the management of neuronal injury in SAE and valuable insights into the potential mechanisms of ferroptosis in neurological disorders.
Subject(s)
Ferroptosis , Hippocampus , Lipid Peroxidation , Phosphatidylethanolamine Binding Protein , Phospholipid Hydroperoxide Glutathione Peroxidase , Sepsis-Associated Encephalopathy , Ferroptosis/drug effects , Animals , Hippocampus/metabolism , Hippocampus/drug effects , Hippocampus/pathology , Humans , Sepsis-Associated Encephalopathy/drug therapy , Sepsis-Associated Encephalopathy/metabolism , Sepsis-Associated Encephalopathy/pathology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Lipid Peroxidation/drug effects , Mice , Male , Female , Phosphatidylethanolamine Binding Protein/metabolism , Phosphatidylethanolamine Binding Protein/genetics , Neurons/metabolism , Neurons/drug effects , Neurons/pathology , Coenzyme A Ligases/metabolism , Coenzyme A Ligases/genetics , Coenzyme A Ligases/antagonists & inhibitors , Inflammation/metabolism , Inflammation/pathology , Inflammation/drug therapy , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , S100 Calcium Binding Protein beta Subunit/metabolism , S100 Calcium Binding Protein beta Subunit/genetics , Disease Models, Animal , Child, Preschool , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/drug effects , Signal Transduction/drug effects , Child , Glial Fibrillary Acidic Protein/metabolism , Glial Fibrillary Acidic Protein/genetics , Malondialdehyde/metabolism , Sepsis/complications , Sepsis/metabolism , Sepsis/drug therapy , InfantABSTRACT
α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1-72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology.
Subject(s)
Parkinson Disease , alpha-Synuclein , Humans , alpha-Synuclein/metabolism , Phosphorylation , Parkinson Disease/pathology , Protein Processing, Post-Translational , Amyloid/metabolism , IronABSTRACT
Metal-organic frameworks (MOFs) have emerged as a promising class of materials for solar-driven hydrogen peroxide (H2O2) generation due to their porosity, large surface area and designable molecular building blocks; however, producing H2O2 from oxygen and water without sacrificial agents remains a major challenge. Herein, we have constructed two UiO-67-type MOFs, UiO-67-NH2 and UiO-67-(NH2)2, by a solvothermal method using 2-amino-4,4'-biphenyldicarboxylic acid and 2,2'-diamino-4,4'-biphenyldicarboxylic acid as ligands, respectively. A variety of photochemical measurements have shown that the introduction of diamino groups into UiO-67-(NH2)2 not only enhances its absorption ability for visible light, but also facilitates the separation of photogenerated electron/hole pairs. Consequently, compared to monoamino-functionalized UiO-67-NH2, UiO-67-(NH2)2 exhibits a 5.5 times higher H2O2 production rate in pure water for 1 h. A two-step one-electron oxygen reduction reaction pathway for photocatalytic H2O2 production was suggested based on a series of control experiments and active species trapping tests by electron paramagnetic resonance spectra. This work provides new insights into the regulation of functionalized MOF ligands at the molecular level and a catalytic mechanism towards MOF-based photocatalysts for H2O2 production with high activity.
ABSTRACT
We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer-nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates. Avidity sequencing achieves high accuracy, with 96.2% and 85.4% of base calls having an average of one error per 1,000 and 10,000 base pairs, respectively. We show that the average error rate of avidity sequencing remained stable following a long homopolymer.
Subject(s)
DNA , Nucleotides , Nucleotides/genetics , Nucleotides/chemistry , DNA/genetics , DNA/chemistry , DNA Replication , Base Pairing , PolymersABSTRACT
Indoor fires pose significant threats in terms of casualties and economic losses globally. Thus, it is vital to accurately detect indoor fires at an early stage. To improve the accuracy of indoor fire detection for the resource-constrained embedded platform, an indoor fire detection method based on multi-sensor fusion and a lightweight convolutional neural network (CNN) is proposed. Firstly, the Savitzky-Golay (SG) filter is used to clean the three types of heterogeneous sensor data, then the cleaned sensor data are transformed by means of the Gramian Angular Field (GAF) method into matrices, which are finally integrated into a three-dimensional matrix. This preprocessing stage will preserve temporal dependency and enlarge the characteristics of time-series data. Therefore, we could reduce the number of blocks, channels and layers in the network, leading to a lightweight CNN for indoor fire detection. Furthermore, we use the Fire Dynamic Simulator (FDS) to simulate data for the training stage, enhancing the robustness of the network. The fire detection performance of the proposed method is verified through an experiment. It was found that the proposed method achieved an impressive accuracy of 99.1%, while the number of CNN parameters and the amount of computation is still small, which is more suitable for the resource-constrained embedded platform of an indoor fire detection system.
ABSTRACT
A visible-light-induced ß-acyl difunctionalization of alkenes with acyl oxime esters and various nucleophiles was developed to achieve molecular complexity from readily available raw materials via oxidative radical-polar crossover. A variety of nucleophiles, including NH-sulfoximines, indoles, indazole, and trimethoxybenzene, were all effectively applicable to the sustainable reaction system. The novel synthetic strategy features mild reaction conditions, a broad substrate scope (39 examples), easy scale-up, and excellent regioselectivity.
ABSTRACT
LiDAR camera systems are now becoming an important part of autonomous driving 3D object detection. Due to limitations in time and resources, only a few critical frames of the synchronized camera data and acquired LiDAR points may be annotated. However, there is still a large amount of unannotated data in practical applications. Therefore, we propose a LiDAR-camera-system-based unsupervised and weakly supervised (LCUW) network as a novel 3D object-detection method. When unannotated data are put into the network, we propose an independent learning mode, which is an unsupervised data preprocessing module. Meanwhile, for detection tasks with high accuracy requirements, we propose an Accompany Construction mode, which is a weakly supervised data preprocessing module that requires only a small amount of annotated data. Then, we generate high-quality training data from the remaining unlabeled data. We also propose a full aggregation bridge block in the feature-extraction part, which uses a stepwise fusion and deepening representation strategy to improve the accuracy. Our comparative, ablation, and runtime test experiments show that the proposed method performs well while advancing the application of LiDAR camera systems.
ABSTRACT
Supported metal nanocatalyst is one of the efficient tools for organic transformations. However, catalyst deactivation caused by the migration, aggregation, and leaching of active metal species in the reaction process remains challenging. Herein, a metal-organic framework (MOF), MIL-101, was employed to covalently graft the PPh3 ligand on its surface and then supported palladium nanoparticles (Pd NPs), affording Pd/MIL-101-PPh3. A variety of spectral characterizations and DFT calculation reveal that there is an electron-donating effect of the MOF surface PPh3 toward Pd NPs, which markedly boosts the activation of the carbon-halogen bond in aryl halides. Consequently, Pd/MIL-101-PPh3 exhibits excellent activity for the three-component reaction of 2-iodoaniline, CO2, and isocyanide, as well as Suzuki-Miyaura and Heck coupling reactions, far exceeding amino-functionalized Pd/MIL-101-NH2, naked Pd/MIL-101, and other commercial-supported Pd catalysts. Furthermore, Pd/MIL-101-PPh3 can also frustrate the migration, aggregation, and leaching of reactive Pd species in the reaction process due to the molecular fence effect generated by MOF surface functionalization.
ABSTRACT
Background: Current mainstream treatment of major depressive disorder (MDD) has a disadvantage in delayed onset of efficacy, making detection of early signatures predicative of the long-term treatment efficacy urgent. Methods: MDD patients were scored with HAMD-24 and serum brain-derived neurotrophic factor (BDNF) levels were measured at different times in two independent trials: a single-arm observation of Yueju pill, a clinically approved traditional multiherbal medicine, and a two-arm random placebo-controlled trial for Yueju vs escitalopram. The ratio of the BDNF level to HAMD-24 score, or neuroplasticity index (NI), and its derived parameters were used for correlation analysis and receiver operating characteristic (ROC) analysis. Results: On both the early (4th) and final (28th) days, Yueju and escitalopram significantly reduced HAMD-24 scores, compared to baselines, but only Yueju increased BDNF at both times. For either Yueju or escitalopram treatment, NI, but not BDNF, at baseline was correlated to NIs at the early or final treatment day. NI at early time was significantly correlated to early NI enhancement from the baseline for both Yueju and escitalopram, and to final NI enhancement from the baseline for Yueju in both trials. ROC analysis supported the predictability of Yueju's final treatment efficacy from early NI enhancement. Limitations: The small sample size and 28 days of treatment time may lead to the impossibility of ROC analysis of escitalopram. Conclusion: Early NI enhancement is useful for prediction of long-term efficacy of Yueju and presumably some other antidepressants. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR1900021114].
ABSTRACT
Angiogenesis is considered playing an important role in bone regeneration. Studies have shown that angiogenesis is affected by biological factors, oxygen tension, and blood flow. In this paper, we propose a bone regeneration model with angiogenesis based on the theories of mechanobiology regulation, vascular network modeling, oxygen-induced secretion of vascular endothelial growth factor (VEGF), and vascular remodeling. The results showed that this model can describe the distribution and concentration of vascular endothelial growth factor induced by oxygen tension during bone regeneration, the growth and remodeling of vascular tissue under the influence of vascular endothelial growth factor and mechanical loading, and the correspondence between vascular tissue and bone regeneration.
Subject(s)
Oxygen , Vascular Endothelial Growth Factor A , Bone Regeneration , Humans , Neovascularization, Physiologic , Vascular Endothelial Growth Factors , Vascular RemodelingABSTRACT
ZBTB38 belongs to the zinc finger protein family and contains the typical BTB domains. As a transcription factor, ZBTB38 is involved in cell regulation, proliferation and apoptosis, whereas, functional deficiency of ZBTB38 induces the human neuroblastoma (NB) cell death potentially. To have some insight into the role of ZBTB38 in NB development, high throughput RNA sequencing was performed using the human NB cell line SH-SY5Y with the deletion of ZBTB38. In the present study, 2,438 differentially expressed genes (DEGs) in ZBTB38-/- SH-SY5Y cells were obtained, 83.5% of which was down-regulated. Functional annotation of the DEGs in the Kyoto Encyclopedia of Genes and Genomes database revealed that most of the identified genes were enriched in the neurotrophin TRK receptor signaling pathway, including PI3K/Akt and MAPK signaling pathway. we also observed that ZBTB38 affects expression of CDK4/6, Cyclin E, MDM2, ATM, ATR, PTEN, Gadd45, and PIGs in the p53 signaling pathway. In addition, ZBTB38 knockdown significantly suppresses the expression of autophagy-related key genes including PIK3C2A and RB1CC1. The present meeting provides evidence to molecular mechanism of ZBTB38 modulating NB development and targeted anti-tumor therapies.
ABSTRACT
Apoptosis is an important contributing factor in spinal cord injury (SCI). ZBTB38 is involved in the transcriptional regulation of multiple signaling pathways, is differentially expressed at different SCI stages, and may provide a therapeutic strategy for the treatment of patients with SCI. In this study, we found that autophagy is blocked in ZBTB38 knockdown SH-SY5Y cells and that the expression levels of LC3B II/I decreased and P62 increased. We used transcriptome high-throughput sequencing to identify the target in ZBTB38 knockdown cells. From the transcriptome profile, RB1CC1 (i.e., FIP200), a key component of the initiation machinery of autophagy (FIP200-ATG13-ULK1-ATG101), was found to decrease 4.2-fold following ZBTB38 knockdown. When RB1CC1-overexpressed plasmids were transfected into ZBTB38 knockdown cells, they rescued the phenotype of ZBTB38 knockdown cells. Cell proliferation and viability were significantly enhanced by RB1CC1 overexpression, and LC3B and P62 expression returned to their original levels. We also injected ZBTB38-overexpressed lentivirus into the injured center of the spinal cord and detected significant upregulation of RB1CC1 in the spinal cord. ZBTB38 overexpression can promote autophagy and partly rescue the secondary damage of SCI. Therefore, our findings provide a new strategy for the treatment of SCI.
Subject(s)
Protein-Tyrosine Kinases/genetics , Repressor Proteins/genetics , Spinal Cord Injuries/genetics , Animals , Autophagy , Autophagy-Related Proteins , Cell Line , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Male , MiceABSTRACT
Spinal cord injury (SCI) is generally divided into primary and secondary injuries, and apoptosis is an important event of the secondary injury. As an endogenous bile acid and recognized endoplasmic reticulum (ER) stress inhibitor, tauroursodeoxycholic acid (TUDCA) administration has been reported to have a potentially therapeutic effect on neurodegenerative diseases, but its real mechanism is still unclear. In this study, we evaluated whether TUDCA could alleviate traumatic damage of the spinal cord and improve locomotion function in a mouse model of SCI. Traumatic SCI mice were intraperitoneally injected with TUDCA, and the effects were evaluated based on motor function assessment, histopathology, apoptosis detection, qRT-PCR, and western blot at different time periods. TUDCA administration can improve motor function and reduce secondary injury and lesion area after SCI. Furthermore, the apoptotic ratios were significantly reduced; Grp78, Erdj4, and CHOP were attenuated by the treatment. Unexpectedly, the levels of CIBZ, a novel therapeutic target for SCI, were specifically up-regulated. Taken together, it is suggested that TUDCA effectively suppressed ER stress through targeted up-regulation of CIBZ. This study also provides a new strategy for relieving secondary damage by inhibiting apoptosis in the early treatment of spinal cord injury.
Subject(s)
Repressor Proteins/genetics , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/genetics , Taurochenodeoxycholic Acid/therapeutic use , Up-Regulation/genetics , Animals , Apoptosis/drug effects , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress/drug effects , Male , Mice , Models, Biological , Motor Activity/drug effects , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Recovery of Function/drug effects , Repressor Proteins/metabolism , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathology , Taurochenodeoxycholic Acid/pharmacologyABSTRACT
BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2), a biomarker of oxidation and inflammation, has been associated with increased coronary artery disease risk. To date, very few studies have examined the Chinese herbal drug Danshen or its extract on Lp-PLA2 in patients with stable angina pectoris. In this study, we aim to investigate the effect of Danshen extract on Lp-PLA2 level in patients with stable angina. METHODS/DESIGN: This is a randomized, single-blind, placebo-controlled, adaptive clinical trial. A total of 156 patients meeting the eligibility criteria will be randomly assigned to either the Danshen extract (DanshenDuofensuanyan injection and Danshen drop spill) group or the placebo group in a 1:1 ratio. Participants will then undergo treatment with DanshenDuofensuanyan injection or placebo (glucose) during hospitalization, followed by open-label Danshen drop spill (30 pills/day) in Danshen extract group for 60 days after discharge. Because this is an adaptive trial, two interim analyses are prospectively planned. These will be performed after one-third and two-thirds of the patients, respectively, have completed the trial. On the basis of the results of these interim analyses, a data monitoring committee will determine how to modify aspects of the study without undermining the validity and integrity of the trial. The primary outcome measure is the serum level of Lp-PLA2 in the Danshen extract group and the placebo group. The secondary outcomes include the proportion of patients who show a clinically significant change, which is defined as at least a 20-point improvement in angina frequency score on the Seattle Angina Questionnaire and the carotid intima-media thickness, which will be measured using ultrasound. Other secondary efficacy and safety outcomes will also be assessed. DISCUSSION: This study will provide evidence that Danshen extract is beneficial for stable angina and may establish a possible mechanism of Danshen treatment effects on cardiovascular disease. This study may also validate an objective blood test (LP-PLA2 level) for assessing the effectiveness of Danshen therapy in patients with stable angina pectoris. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02870764 . Registered on 13 August 2016.
Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , Angina, Stable/drug therapy , Cardiovascular Agents/therapeutic use , Drugs, Chinese Herbal/therapeutic use , Adolescent , Adult , Aged , Angina, Stable/diagnosis , Angina, Stable/enzymology , Biomarkers/blood , Cardiovascular Agents/adverse effects , Carotid Intima-Media Thickness , China , Clinical Protocols , Drugs, Chinese Herbal/adverse effects , Female , Humans , Male , Middle Aged , Prospective Studies , Research Design , Salvia miltiorrhiza , Single-Blind Method , Surveys and Questionnaires , Time Factors , Treatment Outcome , Young AdultABSTRACT
Gramnegative (GN) bacterial infection is a main cause of bovine mastitis. The cluster of differentiation (CD) 14 gene serves an essential role in GN bacteriuminduced innate immune response. CD14 works as a bacterial lipopolysaccharide (LPS) receptor, combines with LPSliposaccharide binding protein complex, and causes cellular activation. However, the effects of CD14 single nucleotide polymorphisms (SNPs) on morbidity of clinical mastitis remain unclear. In the present study, To investigate the polymorphisms of CD14 gene and its effects on cows' susceptibility to mastitis, polymerase chain reactionsinglestrand conformation polymorphism (PCRSSCP) assay was used to detect SNPs of CD14 gene in 134 Chinese Holsteins. SNPs were identified in PCR products amplified with 3 sets of primers in CD14 exon 2. A total of three SNPs were located in that exon: g.528 AâC (147SerâArg) in allele B; g.612 AâG (175AsnâAsp) in allele D; and g.1022 AâG in allele F (synonymous mutation). The SNPs in alleles B and D affected the secondary structure of CD14. A 3dimensional (3D) structural analysis predicted three potential protein forms with a similar structure and indicated that the changes of the abovementioned alleles were on the concave surface of the protein. In more detail, 147 SerâArg induced a protein kinase C phosphorylation site to move forward, as assessed by the motif analysis. The morbidity rate of AB (mixed type g.528 A/C) and CD (mixed type g.612 A/G) was the highest among all genotypes presented in the current study, and via of tumor necrosis factorα and interleukin6 mRNA levels were upregulated in animals of this genotype compared with others. Taken together, the CD14 SNPs identified in the present study, may be closely associated with the morbidity of mastitis.
Subject(s)
Lipopolysaccharide Receptors/genetics , Mastitis, Bovine/epidemiology , Mastitis, Bovine/genetics , Polymorphism, Single Nucleotide/genetics , Alleles , Amino Acid Sequence , Animals , Base Sequence , Cattle , China/epidemiology , Exons/genetics , Female , Gene Amplification , Genetic Association Studies , Genetic Predisposition to Disease , Hydrophobic and Hydrophilic Interactions , Interleukin-6/genetics , Interleukin-6/metabolism , Isoelectric Point , Linkage Disequilibrium/genetics , Lipopolysaccharide Receptors/chemistry , Morbidity , Mutation/genetics , Polymorphism, Single-Stranded Conformational/genetics , Protein Structure, Secondary , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVE: Several studies have confirmed high diagnostic performance of positron emission tomography (PET) myocardial perfusion imaging (MPI) in patients with known or suspected coronary artery disease. However, whether the superior diagnostic accuracy could translate into improved mortality outcomes remains unknown. The aim of this study was to define the prognostic value of normal PET MPI. METHODS: PubMed and EMBASE were searched to identify related studies up to June 2016. All studies using PET MPI to evaluate subjects with known or suspected coronary artery disease and providing absolute number of patients with a negative test and primary data on clinical outcomes with a follow-up time ≥3 months were included for analysis. RESULTS: The search yielded 11 studies comprising 20,471 patients for final analysis. The negative-predictive value (NPV) for cardiac death, all-cause death and major adverse cardiovascular events (MACE) were 98.80% [95% confidence interval (CI), 97.64%-99.39%], 94.89% (95% CI: 92.99-96.30%) and 90.26% (95% CI: 78.01-96.03%), over 36.9 months of follow-up for cardiac death, over 26.8 months for all-cause death and 35.7 months for MACE. The corresponding annualized event rates were 0.39%, 2.29% and 3.27%, respectively. In subgroup analyses of different imaging analysis methods for PET MPI, studies using perfusion abnormity had a similar NPV as compared with those using coronary flow reserve (98.46% vs 98.86%, p-value = NS), with a corresponding annualized event rate after negative tests (equal to 1 - NPV) as 0.45% and 0.42%, respectively. CONCLUSION: Normal PET has a high NPV for cardiac death, MACE and all-cause mortality. Different indexes used for PET imaging analysis have a comparable prognostic value. Advances in knowledge: A normal PET MPI conferred a very low risk of cardiac death of 0.39% per year, which is close to that of a normal aged-matched population.
Subject(s)
Coronary Artery Disease/diagnostic imaging , Myocardial Perfusion Imaging/methods , Humans , Prognosis , RadiopharmaceuticalsABSTRACT
Intramedullary interlocking nailing is an effective technique used to treat long bone fractures. Recently, biodegradable metals have drawn increased attention as an intramedullary interlocking nailing material. In this study, numerical simulations were implemented to determine whether the degradation rate of magnesium alloy makes it a suitable material for manufacturing biodegradable intramedullary interlocking nails. Mechano-regulatory and bone-remodeling models were used to simulate the fracture healing process, and a surface corrosion model was used to simulate intramedullary rod degradation. The results showed that magnesium alloy intramedullary rods exhibited a satisfactory degradation rate; the fracture healed and callus enhancement was observed before complete dissolution of the intramedullary rod. Delayed magnesium degradation (using surface coating techniques) did not confer a significant advantage over the non-delayed degradation process; immediate degradation also achieved satisfactory healing outcomes. However, delayed degradation had no negative effect on callus enhancement, as it did not cause signs of stress shielding. To avoid risks of individual differences such as delayed union, delayed degradation is recommended. Although the magnesium intramedullary rod did not demonstrate rapid degradation, its ability to provide high fixation stiffness to achieve earlier load bearing was inferior to that of the conventional titanium alloy and stainless steel rods. Therefore, light physiological loads should be ensured during the early stages of healing to achieve bony healing; otherwise, with increased loading and degraded intramedullary rods, the fracture may ultimately fail to heal.