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Stargardt disease (STGD1, OMIM 248200) is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene (ABCA4) were identified as contributing to the family's STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1. [ABSTRACT FROM AUTHOR]

Objective: Toll-like receptor 4 (TLR4) is crucial in induction of innate immune response through recognition of invading pathogens or endogenous alarming molecules. Ligand-triggered dimerization of TLR4 is essential for the activation of NF-κB and IRF3 through MyD88- or TRIF-dependent pathways. Saquinavir (SQV), an FDA-approved HIV protease inhibitor, has been shown to attenuate the activation of NF-κB induced by HMGB1 by blocking TLR4-MyD88 association in proteasome independent pathway. This study aims to define whether SQV is an HMGB1-specific and MyD88-dependent TLR4 signaling inhibitor and which precise signaling element of TLR4 is targeted by SQV. Materials and Methods: PMA differentiated human THP-1 macrophages or reconstituted HEK293 cells were pretreated with SQV before stimulated by different TLR agonists. TNF-a level was evaluated through ELISA assay. NF-κB activation was analyzed using NF-κB SEAP reporting system. The levels of MyD88/TRIF pathways-related factors were examined by immunoblot. TLR4 endocytosis was assessed by immunocytochemistry. TLR4 dimerization was determined using immunoprecipitation between different tagged TLR4 and an in silico molecular docking experiment was performed to explore the possible binding site of SQV on its target. Results: Our data showed that SQV suppresses both MyD88- and TRIF-dependent pathways in response to lipopolysaccharide (LPS), a critical sepsis inducer and TLR4 agonist, leading to downregulation of NF-κB and IRF3. SQV did not suppress MyD88-dependent pathway triggered by TLR1/2 agonist Pam3csk4. In the only TRIF-dependent pathway, SQV did not alleviate IRF3 phosphorylation induced by TLR3 agonist Poly(I:C). Furthermore, dimerization of TLR4 following LPS or HMGB1 stimulation was decreased by SQV. Conclusion: We concluded that TLR4 receptor complex is one of the mammalian targets of SQV, and TLR4-mediated immune responses and consequent risk for uncontrolled inflammation could be modulated by FDA-approved drug SQV. [ABSTRACT FROM AUTHOR]

Uniform crushed straw throwing and seed-sowing machines can achieve the processes of straw chopping, straw transport, sowing, fertilization, and straw mulching at the same time, which is widely used in many areas of China. Conveying device is one of the important components used to convey, elevate and throw straw. However, the problems of high power consumption and congestion affect the promotion of the machine. Therefore, the conveying device of uniform crushed straw throwing and seed-sowing machine was analyzed in order to determine its device operation mechanism. Kinematic and dynamic analyses of particles of crushed rice straw during lifting and dispersion are used to develop a flexible-body model of rod-shaped and agglomerate-shaped crushed straw and a coupling model including the mechanical structure of the device. By integrating computational fluid dynamics and the discrete element method, the gas-solid coupling theory in numerical simulations and motion analysis of crushed straw particles is used to determine how the flow field and motion characteristics affect the conveying performance. Besides, regression equations to describe the relationships between the factors and each assessment index were established by using the regression analysis and response surface analysis with the software Design-Expert. The effect of throwing blade speed X1, conveying volume of crushed straw X2, and pipeline diameter X3 on the throwing speed of crushed straw Y1 and specific power consumption Y2 were investigated. The highest throwing speed of crushed straw and lowest specific power consumption are the optimization goal. The results of optimization showed that the predict the best optimal parameters were 2000 r/min throwing blade rotational speed, 1.4 kg/s conveying volume, and 220 mm pipeline diameter, the planter achieved a throwing speed of 12.2 m/s and specific power consumption of 9179 m²/s². And then a field test verification was conducted. The planter achieved a throwing speed 12.4 m/s and specific power consumption 9070 m²/s² while selecting the best optimal parameters. Thus, the optimal parameters can provide a high-performance operation and satisfy the actual operation requirements The results provide a theoretical basis and data support for seeding technology innovation and equipment optimization to ensure uniform crushed straw throwing in dense rice stubble fields. [ABSTRACT FROM AUTHOR]

It is important to investigate the influence of surfactants on structures and physical/chemical properties of oil/water interfaces. This work reports a second harmonic generation study of the adsorption of malachite green (MG) on the surfaces of oil droplets in a hexadecane/water emulsion in the presence of surfactants including sodium dodecyl sulfate, polyoxyethylene-sorbitan monooleate (Tween80), and cetyltrimethyl ammonium bromide. It is revealed that surfactants with micromolar concentrations notably influence the adsorption of MG at the oil/water interface. Both competition adsorption and charge-charge interactions played very important roles in affecting the adsorption free energy and the surface density of MG at the oil/water interface. The sensitive detection of the changing oil/water interface with the adsorption of surfactants at such low concentrations provides more information for understanding the behavior of these surfactants at the oil/water interface. [ABSTRACT FROM AUTHOR]

Pseudolarix amabilis (Nelson) Rehd, is a monotypic genus plant belonging to the family Pinaceae. The root bark, known as "Tu-Jin-Pi" has been used for the treatment of skin diseases. During our activity screening, the water-soluble part of the 70% EtOH extract of P. amabilis bark showed excellent inhibitory bioactivities on PTP1B enzyme, leading to the phytochemical isolation of the root bark of P. amabilis. Three oleanane-type compounds (1-3) and seven phenolic compounds (4-10) were isolated, in which oleanolic acid 3-O-ß-D-glucuronyl-6'-ethyl ester (1) was identified as a new saponin. The chemical structures of these compounds were elucidated by 1D/2D nuclear magnetic resonance and high resolution mass spectra. In addition, their pharmacological inhibitory bioactivities on PTP1B enzyme were evaluated, and the three oleanane-type compounds 1-3 exhibited inhibitory bioactivities with IC50 values of 1.90 ± 0.37, 19.15 ± 0.10 and 10.44 ± 0.59 µM, respectively. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common female cancer found worldwide. It is responsible for 25% of all cancer patients in females. Hereditary BC accounts for about 5–10% of all BC cases. The breast cancer 1 gene (BRCA1) and the breast cancer 2 gene (BRCA2) are the two most-studied BC susceptibility genes. Genetic testing for disease-causing mutations in BRCA1, BRCA2, and other BC susceptibility genes is strongly recommended for members of families having a BC family history. The present study found a heterozygous c.5722_5723del mutation in the BRCA2 exon 11 of a large Han-Chinese BC family using whole exome sequencing and Sanger sequencing. It may cause DNA double-strand breaks repair dysfunction by disturbing homologous recombination, further resulting in BC. The study findings may help supplement and further improve genetic testing strategies and BC risk estimation methodologies in China. [ABSTRACT FROM AUTHOR]

Extracellular high-mobility group box 1 (HMGB1) (disulfide form), via activation of toll-like receptor 4 (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1-induced TLR4 activation, as assayed by the production of TNF-α by human monocyte-derived macro - phages (THP-1). We further report on the identification of mammalian cathepsin V, a protease, as a novel target of these inhibitors. Cellular as well as recombinant protein studies show that the mechanism of action involves a direct interaction between cathepsin V with TLR4 and its adaptor protein MyD88. Treatment with SQV, 334 or the known cathepsin inhibitor SID26681509 (SID) significantly improved survival in murine models of sepsis and reduced liver damage following warm liver ischemia/reperfusion (I/R) models, both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4- driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside. Disulfide HMGB1 drives pathologic inflammation in many models by activating signaling through TLR4. Cell-based screening identified the mammalian protease cathepsin V as a novel therapeutic target to inhibit TLR4-mediated inflammation induced by extracellular HMGB1 (disulfide form). We identified two protease inhibitors (PIs) that block cathepsin V and thereby inhibit disulfide HMGB1-induced TLR4 activation: saquinavir (SQV), a firstgeneration PI targeting viral HIV protease and STO33438 (334), targeting mammalian proteases. We discovered that cathepsin V binds TLR4 under basal and HMGB1-stimulated conditions, but dissociates in the presence of SQV over time. Thus cathepsin V is a novel target for first-generation HIV PIs and represents a potential therapeutic target of pathologic inflammation. [ABSTRACT FROM AUTHOR]