Novel mechanistic study of HDAC6 regulation of rheumatoid arthritis via CMA: exploring potential therapeutic targets.

Objective: Rheumatoid arthritis (RA) is a systemic autoimmune disease. Its pathogenesis has not yet been clarified, so it is urgent to explore therapeutic targets. Here, we clarified the role of HDAC6 in the mechanism of action of RA through mediating chaperone-mediated autophagy (CMA) to provide a clinical treatment of RA. Methods: We used rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis mice (CIA mice) as models of RA and pharmacological inhibitors as well as genetic interference with adeno-associated viruses to reduce the expression of HDAC6. We explored the influence of CAY10603 on RA-FLS proliferation and inflammation, as well as the expression of proteins related to the CMA signaling pathway. CIA model was constructed using DBA/1J mice. Arthritis symptoms in CIA mice were evaluated, and the expression and localization of CMA-related proteins in mouse ankle joints were examined. Results: CAY10603 inhibited proliferation as well as the level of the molecular chaperone autophagy in RA-FLS. HDAC6 shRNA significantly reduced the clinical signs of arthritis in CIA mice, as did the expression of HDAC6 in the serum and ankle synovial tissues of CIA mice. Finally, it significantly inhibited the level of Hsc70 and LAMP-2A, which are involved in the CMA signaling pathway, in ankle joint tissues. Conclusion: Downregulation of HDAC6 may inhibit CMA and thereby ameliorate RA.

Fabrication of caffeoylquinic acid-loaded burdock polysaccharide nanoparticles and their antioxidant activity in hydrogen peroxide-damaged HepaRG cells.

Herein, burdock polysaccharide (BP) and modified burdock polysaccharide (MBP) were prepared, followed by the fabrication of chlorogenic acid (CA)-BP, CA-MBP, isochlorogenic acid A (ICA)-BP, and ICA-MBP nanoparticles. Afterward, the structural characteristics, physical stability, digestive characteristics, and antioxidant activity of hydrogen peroxide (H2O2)-damaged HepaRG cells were evaluated. The result indicated that the loading capacities of CA in BP-CA and MBP-CA were 0.14 and 0.53 µg/mg, respectively. Conversely, the loading capacities of ICA in BP-ICA and MBP-ICA were 0.36 and 0.60 µg/mg, respectively. Four complex nanoparticles exhibited excellent physical stability under different pH values, temperatures, and ionic concentrations, especially MBP-CA and MBP-ICA. Moreover, four complex nanoparticles could protect caffeoylquinic acid from being released in gastric fluid. All six samples exhibited high antioxidant activity in H2O2-induced HepaRG cells, especially BP and MBP-CA. These findings indicated that caffeoylquinic acid-polysaccharide complexes were successfully prepared and highlighted the potential of polysaccharides as natural carriers for hydrophobic bioactive molecules.

Mutation analysis of RHO in patients with non-syndromic retinitis pigmentosa.

PURPOSE: To identify RHO mutations in patients with non-syndromic retinitis pigmentosa (NS-RP). METHODS: A total of 143 probands (46 family history and 97 sporadic cases) with NS-RP were recruited from Southeast China. The coding exons and adjacent intronic regions of RHO were PCR-amplified and sequenced by Sanger sequencing. The candidate variant was evaluated by the guidelines of American College of Medical Genetics and further validated through co-segregation analysis within the family. RESULTS: Five heterozygous mutations in RHO were detected in 5 out of 143 probands, where the frequency of RHO mutations in our cohort was approximately 3.5% (5/143) and 10.8% (5/46) for probands and families with NS-RP, respectively. Three known disease-causing mutations including c.C1030T (p.Q344X), c.C173G (p.T58R), and c.G266A (p.G89D) were identified in three unrelated families. The other two previously unreported mutations c.557C>A (p.S186X) and c.944delA (p.N315TfsX43) were confirmed in Family RP-087 and Family RP-139, respectively. These mutations co-segregated with available affected individuals in each family were not observed in the unaffected family members or in the 112 unrelated controls. CONCLUSIONS: This report expands the mutational spectrum of RHO gene associated with NS-RP and demonstrates the frequency of RP RHO mutations in Southeast Chinese populations.

Novel Variants of HPS6 Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of HPS6 Variants.

INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations. METHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed. RESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C>T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease. CONCLUSION: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.

A novel single domain bispecific antibody targeting VEGF and TNF-α ameliorates rheumatoid arthritis.

Anti-TNF-α therapy fails in 30% of patients, where TNF-α may not be the key causative factor in these patients. We developed a bispecific single-domain antibody block TNF-α and VEGF (V5-3).The experiments showed that V5-3 effectively activated proliferation and migration of RA-FLS and HUVEC, tube-forming role of HUVEC, and expression of inflammatory factors in vitro. Besides, the experiments indicated that the anti-RA activity of V5-3 was superior to Anbainuo in vivo. Application of V5-3 reduced the expression of inflammatory factors, extent of synovial inflammation and angiogenesis and attenuated the severity of autoimmune arthritis in collagen-induced arthritis (CIA) mice. Mechanistically, V5-3 suppressed p65, AKT and VEGFR2 phosphorylation, as well as production of TNF-α and VEGF in joint tissues. These results demonstrated that V5-3 displayed a superior effect of anti-RA, may be a new therapy to overcome the limitations of anti-TNF-α monoclonal antibody.

Direct cytoplasmic delivery of RNAi therapeutics through a non-lysosomal pathway for enhanced gene therapy.

The first approved RNAi therapeutics, ONPATTRO, in 2017 moves the concept of RNA interference (RNAi) therapy from research to clinical reality, raising the hopes for the treatment of currently incurable diseases. However, RNAi therapeutics are still facing two main challenges-susceptibility to enzymatic degradation and low ability to escape from endo/lysosome into the cytoplasm. Therefore, we developed disulfide-based nanospheres (DBNPs) as universal vehicles to achieve efficient RNA delivery to address these problems. Notably, the DBNPs possess unique and desirable features, including improved resistance to nuclease degradation, direct cytoplasmic delivery through thiol-mediated cellular uptake, and cytosolic environment-responsive release, greatly enhancing the bioavailability of RNA therapeutics. Additionally, DBNPs are superior in terms of overcoming formidable physiological barriers, including vascular barriers and impermeable tumor tissues. Owning to these advantages, the DBNPs exhibit efficient gene silencing effect when delivering either small interfering RNA (siRNA) or microRNA in various cell lines and generate remarkable growth inhibition in the zebrafish and mouse model of pancreatic tumors as compared to traditional delivery vectors, such as PEI. Therefore, DBNPs have potential application prospect in RNAi therapy both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: RNA interference (RNAi) therapeutics could target and alter any disease-related mRNA translation, thus have great potential in clinical application. Delivery efficiency of RNA modalities into cell cytoplasm is the main problem that currently limit RNAi therapeutics to release their full potential. Most of the known delivery materials suffer from the endo/lysosomal entrapment and enzymatic degradation during endocytosis-dependent uptake, resulting unsatisfied efficiency of the cytoplasmic release. Here, we developed disulfide-based nanospheres could directly transfer RNA modalities into the cytoplasm and significantly enhance the delivery efficiency, thus holding great potential in RNAi therapy.

Change of Composition, Source Contribution, and Oxidative Effects of Environmental PM2.5 in the Respiratory Tract.

Fine particulate matter is a leading air pollutant, and its composition profile relates to sources and health effects. The human respiratory tract hosts a warmer and more humid microenvironment in contrast with peripheral environments. However, how the human respiratory tract impacts the transformation of the composition of environmental PM2.5 once they are inhaled and consequently changes of source contribution and health effects are unknown. Here, we show that the respiratory tract can make these properties of PM2.5 reaching the lung different from environmental PM2.5. We found via an in vitro model that the warm and humid conditions drive the desorption of nitrate (about 60%) and ammonium (about 31%) out of PM2.5 during the inhalation process and consequently make source contribution profiles for respiratory tract-deposited PM2.5 different from that for environmental PM2.5 as suggested in 11 Chinese cities and 12 US cities. We also observed that oxidative potential, one of the main health risk causes of PM2.5, increases by 41% after PM2.5 travels through the respiratory tract model. Our results reveal that PM2.5 inhaled in the lung differs from environmental PM2.5. This work provides a starting point for more health-oriented source apportionment, physiology-based health evaluation, and cost-effective control of PM2.5 pollution.

Targeted delivery of inhalable drug particles in the tracheobronchial tree model of a pediatric patient with bronchopneumonia: A numerical study.

Pneumonia is a common cause of hospitalization and death in children worldwide. Inhalation therapy is one of the methods treating pneumonia However, there are limited studies that distinguish between the physiology of children and adults, especially with respect to targeted drug delivery. A tracheobronchial (TB) tree model of an 11-year-old child with bronchopneumonia is selected as a testbed for in silico trials of targeted drug delivery. The airflow and particle transport are solved by the computational fluid dynamics method at an airflow rate of 15 LPM. The results indicate that the distribution of deposited particles shows aggregation on the particle release map. Point-source aerosol release (PSAR) method can significantly reduce the deposition efficiency (DE) of particles in the TB tree model. Specifically, the PSAR method can reduce the DE of large particles (i.e., 7.5 µm and 10 µm) by 7.57% and 9.61%, respectively. This enables rapid design of patient-specific treatment for different population age groups and different airway diseases.

Prediction of transport, deposition, and resultant immune response of nasal spray vaccine droplets using a CFPD-HCD model in a 6-year-old upper airway geometry to potentially prevent COVID-19.

This study focuses on the transport, deposition, and triggered immune response of intranasal vaccine droplets to the angiotensin-converting-enzyme-2-rich region, i.e., the olfactory region (OR), in the nasal cavity of a 6-year-old female to possibly prevent corona virus disease 19 (COVID-19). To investigate how administration strategy can influence nasal vaccine efficiency, a validated multi-scale model, i.e., computational fluid-particle dynamics (CFPD) and host-cell dynamics (HCD) model, was employed. Droplet deposition fraction, size change, residence time, and the area percentage of OR covered by the vaccine droplets, and triggered immune system response were predicted with different spray cone angles, initial droplet velocities, and compositions. Numerical results indicate that droplet initial velocity and composition have negligible influences on the vaccine delivery efficiency to OR. In contrast, the spray cone angle can significantly impact the vaccine delivery efficiency. The triggered immunity was not significantly influenced by the administration investigated in this study due to the low percentage of OR area covered by the droplets. To enhance the effectiveness of the intranasal vaccine to prevent COVID-19 infection, it is necessary to optimize the vaccine formulation and administration strategy so that the vaccine droplets can cover more epithelial cells in OR to minimize the number of available receptors for SARS-CoV-2.

An Integrated Autonomous Dynamic Navigation Approach toward a Composite Air-Ground Risk Construction Scenario.

Unmanned transportation in construction scenarios presents a significant challenge due to the presence of complex dynamic on-ground obstacles and potential airborne falling objects. Consequently, the typical methodology for composite air-ground risk avoidance in construction scenarios holds enormous importance. In this paper, an integrated potential-field-based risk assessment approach is proposed to evaluate the threat severity of the environmental obstacles. Meanwhile, the self-adaptive dynamic window approach is suggested to manage the real-time motion planning solution for air-ground risks. By designing the multi-objective velocity sample window, we constrain the vehicle's speed planning instructions within reasonable limits. Combined with a hierarchical decision-making mechanism, this approach achieves effective obstacle avoidance with multiple drive modes. Simulation results demonstrate that, in comparison with the traditional dynamic window approach, the proposed method offers enhanced stability and efficiency in risk avoidance, underlining its notable safety and effectiveness.

Study of the Repellent Activity of 60 Essential Oils and Their Main Constituents against Aedes albopictus, and Nano-Formulation Development.

Mosquitoes are one of the most important disease vectors from a medical viewpoint in that they transmit several diseases such as malaria, filariasis, yellow and Dengue fever. Mosquito vector control and personal protection from mosquito bites are currently the most efficient ways to prevent these diseases. Several synthetic repellents such as DEET, ethyl butylacetylaminopropionate (IR3535) and 1-(1-methylpropoxycarbonyl)-2-(2-hydroxyethyl)piperidine) (Picaridin), have been widely used to prevent humans from receiving mosquito bites. However, the use of synthetic repellents has raised several environment and health concerns. Therefore, essential oils (EOs) as natural alternatives receive our attention. In order to discover highly effective mosquito repellents from natural sources, the repellent activity of 60 commercial EOs against Ae. albopictus was screened in this study. Eight EOs including cinnamon, marjoram, lemongrass, bay, chamomile, jasmine, peppermint2, and thyme, showed a suitable repellent rate (>40%) at the tested dose of 10 µg/cm2. Then, their main constituents were analyzed by GC-MS, and the active constituents were identified. The most active compounds including cinnamaldehyde, citral and terpinen-4-ol, exhibited an 82%, 65% and 60% repellent rate, respectively. Moreover, the nanoemulsions of the three active compounds were prepared and characterized. In the arm-in-cage assay, the protection times of the nanoemulsions of cinnamaldehyde and citral were significantly extended compared with their normal solutions. This study provides several lead compounds to develop new mosquito repellents, and it suggests that nanoemulsification is an effective method for improving the duration of the activity of natural repellents.

Prediction of Transport, Deposition, and Resultant Immune Response of Nasal Spray Vaccine Droplets using a CFPD-HCD Model in a 6-Year-Old Upper Airway Geometry to Potentially Prevent COVID-19.

This study focuses on the transport, deposition, and triggered immune response of intranasal vaccine droplets to the Angiotensin-converting enzyme 2-rich region (i.e., the olfactory region (OR)) in the nasal cavity of a 6-year-old female to possibly prevent COVID-19. To investigate how administration strategy can influence nasal vaccine efficiency, a validated multiscale model (i.e., computational fluid-particle dynamics (CFPD) and host-cell dynamics (HCD) model) was employed. Droplet deposition fraction, size change, residence time, and the area percentage of OR covered by the vaccine droplets and triggered immune system response were predicted with different spray cone angles, initial droplet velocities, and compositions. Numerical results indicate that droplet initial velocity and composition have negligible influences on the vaccine delivery efficiency to OR. In contrast, the spray cone angle can significantly impact the vaccine delivery efficiency. The triggered immunity was not significantly influenced by the administration investigated in this study, due to the low percentage of OR area covered by the droplets. To enhance the effectiveness of the intranasal vaccine to prevent COVID-19 infection, it is necessary to optimize the vaccine formulation and administration strategy so that the vaccine droplets can cover more epithelial cells in OR to minimize the available receptors for SARS-CoV-2.

FOC winding defect detection based on improved texture features and low-rank representation model.

The defect detection of fiber-optic coils (FOCs) plays an important role in the quality control of the FOC production. In order to overcome the problems of poor performance and low reliability of existing methods, this paper provides a solution for winding defect detection of FOCs based on low-rank representation (LRR) technology. First, we design a feature matrix, which represents the image. Then the LRR model is employed to formulate the defect detection task as a problem of low rank and sparse matrix decomposition. Meanwhile, Laplacian regularization is introduced as a smoothness constraint to expand the distance between defect regions and low-rank background. Experiments are performed on a real dataset to verify the algorithm. The results show that the proposed winding defect detection method of FOCs achieves the highest detection accuracy and lowest false alarm rate compared to other methods, verifying the effectiveness of the proposed method.

Septoplasty Effect on the Enhancement of Airflow Distribution and Particle Deposition in Nasal Cavity: A Numerical Study.

The surgery outcomes after fixing nasal airway obstruction (NAO) are sometimes not satisfactory in improving ventilations of airflow. A case study is presented in this paper with computational fluid dynamics applied to determine the key factors for successful septoplasty plans for a patient with a deviated nasal septum. Specifically, airflow, as well as particle transport and deposition were predicted in a pre-surgery nasal cavity model reconstructed from patient-specific Computer Tomography (CT) images and two post-surgery nasal cavity models (i.e., VS1 and VS2) with different virtual surgery plans A and B. Plan A corrected the deviated septal cartilage, the perpendicular plate of the ethmoid bone, vomer, and nasal crest of the maxilla. Plan B further corrected the obstruction in the nasal vestibule and caudal nasal septal deviation based on Plan A. Simulations were performed in the three nose-to-throat airway models to compare the airflow velocity distributions and local particle depositions. Numerical results indicate that the VS2 model has a better improvement in airflow allocation between the two sides than the VS1 model. In addition, the deposition fractions in the VS2 model are lower than that in both the original and VS1 models, up to 25.32%. The better surgical plan (i.e., Plan B) reduces the particle deposition on the convex side, but slightly increases the deposition on the concave side. However, the overall deposition in the nasal cavity is reduced.

Structural Characterization and Hypoglycemic Activity of a Novel Pumpkin Peel Polysaccharide-Chromium(III) Complex.

The aim of our study was to synthesize a pumpkin peel polysaccharide (PPP)-Cr(III) complex and investigate its hypoglycemic activity. Firstly, a novel PPP-Cr(III) complex with a Cr content of 23.77 mg/g was synthesized and characterized. Physicochemical characterization indicated that PPP-Cr(III) had some changes in chemical composition, monosaccharide composition, and morphological structure compared with PPP. The molecular weights of PPP-Cr(III) and PPP were 1.398 × 106 g/mol and 3.386 × 106 g/mol, respectively, showing a lower molecular weight after the introduction of Cr(III). Fourier transform infrared spectroscopy showed that a new characteristic absorption peak of Cr-O appeared at 534 cm-1 in PPP-Cr(III), indicating that Cr(III) was successfully complexed with PPP. Secondly, the hypoglycemic activity of PPP-Cr(III) based on α-glucosidase inhibitory and insulin resistance (IR)-HepG2 cells was evaluated. Compared with PPP, PPP-Cr(III) exhibited a more significantly α-glucosidase inhibitory activity. The IR-HepG2 cells confirmed an obvious increase in glucose consumption. Western blot analysis demonstrated that the treated IR-HepG2 cells were able to increase the protein levels of p-AMPK and p-GSK-3ß, indicating that IR-HepG2 cells exerted hypoglycemic activity via the AMPK/GSK-3ß signaling pathway. These results suggested that PPP-Cr(III) had good hypoglycemic activity, which could provide theoretical support for the development of novel hypoglycemic products.

Targeted delivery of inhalable drug particles in a patient-specific tracheobronchial tree with moderate COVID-19: A numerical study.

The coronavirus disease 2019 (COVID-19) pandemic has led to severe social and economic disruption worldwide. Although currently no consent has been reached on a specific therapy that can treat COVID-19 effectively, several inhalation therapy strategies have been proposed to inhibit SARS-CoV-2 infection. These strategies include inhalations of antiviral drugs, anti-inflammatory drugs, and vaccines. To investigate how to enhance the therapeutic effect by increasing the delivery efficiency (DE) of the inhaled aerosolized drug particles, a patient-specific tracheobronchial (TB) tree from the trachea up to generation 6 (G6) with moderate COVID-19 symptoms was selected as a testbed for the in silico trials of targeted drug delivery to the lung regions with pneumonia alba, i.e., the severely affected lung segments (SALS). The 3D TB tree geometry was reconstructed from spiral computed tomography (CT) scanned images. The airflow field and particle trajectories were solved using a computational fluid dynamics (CFD) based Euler-Lagrange model at an inhalation flow rate of 15 L/min. Particle release maps, which record the deposition locations of the released particles, were obtained at the inlet according to the particle trajectories. Simulation results show that particles with different diameters have similar release maps for targeted delivery to SALS. Point-source aerosol release (PSAR) method can significantly enhance the DE into the SALS. A C++ program has been developed to optimize the location of the PSAR tube. The optimized simulations indicate that the PSAR approach can at least increase the DE of the SALS by a factor of 3.2× higher than conventional random-release drug-aerosol inhalation. The presence of the PSAR tube only leads to a 7.12% change in DE of the SALS. This enables the fast design of a patient-specific treatment for reginal lung diseases.

Long Non-Coding RNA NR-133666 Promotes the Proliferation and Migration of Fibroblast-Like Synoviocytes Through Regulating the miR-133c/MAPK1 Axis.

Long non-coding RNA (lncRNA) is involved in the regulation of rheumatoid arthritis (RA) and many other diseases. In this study, a new lncRNA, NR-133666, was identified to be highly expressed in the adjuvant-induced arthritis rat model using the Agilent lncRNA microarray assay. qRT-PCR verified that NR-133666 was upregulated in fibroblast-like synoviocyte of a collagen-induced arthritis (CIA) rat model. Fluorescence in situ hybridization analysis showed that NR-133666 is mainly expressed in the cytoplasm of collagen-induced arthritis FLS. MTT assay and EdU staining results showed that the proliferation of CIA FLS was inhibited after NR-133666 was knocked down, and the wound healing assay showed that the migration of CIA FLS was also suppressed. Dual luciferase detection was used to confirm the relationship among NR-133666, miR-133c and MAPK1. MAPK1 is the target gene of miR-133c, where NR-133666 acts as a sponge of miR-133c to reduce the inhibitory effect of miR-133c on MAPK1. Overexpression of NR-133666 and MAPK1 can promote the proliferation and migration of CIA FLS, and overexpression of miR-133c can reverse this phenomenon. Western blot indicated that it may be related to the ERK/MAPK signaling pathway. Collectively, we identified that lncRNA NR-133666 acted as a miR-133c sponge that can promote the proliferation and migration of CIA FLS through regulating the miR-133c/MAPK1 axis.

The Therapeutic Effect of an Anti-TNF-α/HSA/IL-6R Triple-Specific Fusion Protein Under Experimental Septic Conditions.

Sepsis caused by a dysregulated host response to infection is a life-threatening disease that can lead to organ dysfunction. Due to its unclear and complex mechanism, effective medicine for the treatment of sepsis is urgently required. The extensive release of cytokines and other mediators like TNF-α and interleukin-6 (IL-6) play critical roles in the development of sepsis. The present study aims to evaluate the potential protective effects of an anti-TNF-α/HSA/IL-6R triple-specific fusion protein (TAL-6) under septic experimental conditions. The anti-TNF-α/HSA/IL-6R triple-specific fusion protein (TAL-6), which links three published single domain antibodies, was designed and constructed in our lab. High purity fusion proteins were obtained with high binding affinity for TNF-α (94.75 pM), human serum albumin (1.83 nM) and IL-6R (2.29 nM). TAL-6 protected mouse fibroblast fibrosarcoma cells (L929) from apoptosis induced by TNF-α, establishing that the expressed fusion proteins can selectively interact with TNF-α in vitro. In vivo, the survival rate of cecal ligation and puncture (CLP) was notably increased in the group with TAL-6 treatment and significantly higher compared with the single-targeted IL-6R and TNF-α fusion protein at the same dose. After treatment with TAL-6, the serum levels of TNF-α, IL-1ß, and IL-6 were significantly decreased, and sepsis-induced pathological injuries in the kidney were remarkably attenuated. TAL-6 is therefore a potential candidate for the development of new drugs against sepsis in human.

Automated defect detection and classification for fiber-optic coil based on wavelet transform and self-adaptive GA-SVM.

The quality monitoring of fiber-optic coil (FOC) in winding systems is usually done manually. Aiming at the problem of inefficient and low accuracy of manual detection, this article is dedicated to researching a defect detection framework based on machine vision, which provides a reliable method for automatic defect detection of FOC. For this purpose, a defect detection scheme that integrates wavelet transform and nonlocal means filtering is proposed to accurately locate the defect region. Then, based on the features constructed by wavelet coefficients, a support vector machine (SVM) is used as the classifier. Additionally, a self-adaptive genetic algorithm is proposed to optimize the parameters of the SVM to form the final classifier. Through experiments on the data set obtained by our designed imaging system, the results show that our method has good defect detection performance and high classification accuracy, which provides an optimal solution for the automatic detection of FOC.

Synergistic Activity of the HSP90 Inhibitor Ganetespib With Lapatinib Reverses Acquired Lapatinib Resistance in HER2-Positive Breast Cancer Cells.

Lapatinib is an FDA-approved EGFR and HER2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer patients. However, its therapeutic efficacy is limited by primary or acquired resistance. In the present study, we established breast cancers cells with acquired lapatinib resistance and investigated the antitumor activity of the second-generation HSP90 inhibitor ganetespib in association with lapatinib in lapatinib-sensitive and -resistant cells. The combination treatment showed synergistic inhibition of HER and the downstream PI3K/Akt and Ras/MEK/ERK pathways, in addition to enhancing induction of early apoptotic cell death and G1 arrest in both parent and lapatinib-resistant cells in vitro. The joint administration of ganetespib and lapatinib depleted the aberrant nuclear transcription factor STAT3, a mediator of the cell cycle and apoptosis-related pathways that is probably involved in the lapatinib resistance of HER2-positive breast cancer cells. In conjunctive with the augmented inhibition of tumor growth observed in both SKBR3 and SKBR3-L xenografts compared to monotherapy, our data provide a sound preclinical basis for combination treatment with lapatinib and ganetespib for refractory HER2-positive breast cancer.