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Abstract Objective This study aims to explore the clinical effect of Tetrandrine (Tet) on progressive massive fibrosis (PMF) of pneumoconiosis. Methods This retrospective study collected 344 pneumoconiosis patients with PMF, and 127 were eligible for the final analysis, including 57 patients in the Tet group and 70 patients in the control group. The progress of imaging and lung function were compared between the two groups. Results After 13 months (median) of treatment, the size of PMF was smaller in the Tet group than that in the control group (1526 vs. 2306, p=0.001), and the size was stable in the Tet group (1568 vs. 1526, p= 0.381), while progressed significantly in the control group (2055 vs. 2306, p=0.000). The small nodule profusion and emphysema were also milder than that in the control group (6.0 vs. 7.5, p=0.046 and 8.0 vs. 12, p=0.016 respectively). Pulmonary ventilation function parameters FVC and FEV1 improved in the Tet group (3222 vs. 3301, p=0.021; 2202 vs. 2259, p=0.025 respectively) and decreased in the control group (3272 vs. 3185, p= 0.00; 2094 vs. 1981, p=0.00 respectively). FEV1/FVC was also significantly higher in the Tet group than that in the control group (68.45vs. 60.74, p=0.001). However, similar result was failed to observed for DLco%, which showed a significant decrease in both groups. Conclusion Tet has shown great potential in the treatment of PMF by slowing the progression of pulmonary fibrosis and the decline of lung function.

Abstract An open jet wind tunnel has low-frequency pressure pulsation in common wind speed range due to its unique structural form, which seriously damages the quality of flow field in the test section. The low-frequency pressure fluctuation performance and control mechanism of Jilin University open jet and return flow wind tunnel are investigated by experiments and numerical simulation. The results show that the low-frequency pressure fluctuation is a narrow pulse phenomenon that only occurs in certain intervals, and several velocity intervals may be found in the same wind tunnel. The reliability of the numerical simulation is verified by comparing the peak frequency and amplitude of pressure fluctuation in numerical simulation and wind tunnel tests. A simplified model similar to and amplifying the phenomenon is established. The flow structure and vortex evolution are analyzed via detached eddy simulation. In the test section, large-scale shedding vortices are formed at the nozzle exit, introducing periodic pulsating instantaneous velocity and acting with the collector to form an edge-feedback. This acoustic feedback forms resonance with the pipeline circuit, resulting in poor flow field quality. In accordance with the mechanism of nozzle jet, two methods of controlling pulsation are proposed: spoiler and flow-follow device. The study shows that the effects of two methods are abrupt, and the frequency of pressure pulsation is changed. The spoiler destroys the complete structure of vortex ring in free jet and develops into a complementary double vortex ring structure, which is highly sensitive to size factors. The flow-follow device supplements the velocity loss of the free jet at the nozzle and develops into a double vortex ring with master–slave structure in the middle of the test section. Its vibration reduction effect is greatly affected by the flow velocity. It takes effect in an appropriate range where the flow velocity is higher than the nozzle velocity. If the follow velocity is extremely low, the flow-follow device cannot change the original jet structure. If the follow velocity is extremely high, the momentum of the fan will be greatly reduced, the flow field will be unstable, and another order of pulsation may be induced. This work lays a solid foundation for further understanding the aerodynamic characteristics and optimization mechanism of open jet wind tunnel.

Lead (Pb) is a widespread environmental contaminant, associated with a higher risk of functional impairment that can lead to frailty in older adults. However, few studies focused on the association of Pb exposure with frailty among the oldest old (aged ≥ 80 years). In this study, we aimed to assess the associations of Pb with frailty and its components in the oldest old. The included individuals were the oldest old aged ≥ 80 years who participated in a 2017 cross-sectional survey of the Healthy Aging and Biomarkers Cohort Study. Frailty was ascertained by the frailty index, which was created based on health deficits. We used logistic regression models to estimate the association of blood Pb with frailty and its components. The geometric mean and median of blood Pb were 38.51 μg/L and 36.27 μg/L among the oldest old, respectively. Compared with the first quartile of blood Pb, participants in the fourth quartile had higher risk of frailty and its components, the ORs are 1.71 (1.22–2.41), 1.99 (1.35–2.94), 1.91 (1.25–2.93), 1.57 (1.13–2.17) and 1.43 (1.05–1.96), for frailty, ADL disability, IADL disability, functional limitations, and hearing loss in the oldest old, respectively. There was a significant interaction between blood Pb and frailty in different age groups. In conclusion, our findings provide preliminary evidence that higher blood Pb may increase the risk of frailty among the oldest old by increasing the risk of disability in four physical functions: disability in ADL, disability in IADL, functional limitations, and hearing loss.

Abstract Background Infestation by tea green leafhoppers (Empoasca (Matsumurasca) onukii) can cause a series of biochemical changes in tea leaves. As a typical cell-rupture feeder, E. onukii secretes proteases while using its stylet to probe the tender shoots of tea plants (Camellia sinensis). This study identified and analyzed proteases expressed specifically in the salivary gland (SG) and gut of E. onukii through enzymatic activity assays complemented with an integrated analysis of transcriptomic and proteomic data. Results In total, 129 contigs representing seven types of putative proteases were identified. Transcript abundance of digestive proteases and enzymatic activity assays showed that cathepsin B-like protease, cathepsin L-like protease, and serine proteases (trypsin- and chymotrypsin-like protease) were highly abundant in the gut but moderately abundant in the SG. The abundance pattern of digestive proteases in the SG and gut of E. onukii differed from that of other hemipterans, including Nilaparvata lugens, Laodelphax striatellus, Acyrthosiphum pisum, Halyomorpha halys and Nephotettix cincticeps. Phylogenetic analysis showed that aminopeptidase N-like proteins and serine proteases abundant in the SG or gut of hemipterans formed two distinct clusters. Conclusions Altogether, this study provides insightful information on the digestive system of E. onukii. Compared to five other hemipteran species, we observed different patterns of proteases abundant in the SG and gut of E. onukii. These results will be beneficial in understanding the interaction between tea plants and E. onukii.

Gelsemium elegans (G. elegans) Benth., recognized as a toxic plant, has been used as traditional Chinese medicine for the treatment of neuropathic pain and cancer for many years. In the present study, we aim to obtain the anti-tumor effects of alkaloids of G. elegans and their active components in hepatocellular carcinoma (HCC) and the potential mechanism was also further investigated. We demonstrated that sempervirine induced HCC cells apoptosis and the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and down-regulation of cyclin D1, cyclin B1 and CDK2. Furthermore, sempervirine inhibited HCC tumor growth and enhances the anti-tumor effect of sorafenib in vivo. In addition, inactivation of Wnt/β-catenin pathway was found to be involved in sempervirine-induced HCC proliferation. The present study demonstrated that alkaloids of G. elegans were a valuable source of active compounds with anti-tumor activity. Our findings justified that the active compound sempervirine inhibited proliferation and induced apoptosis in HCC by regulating Wnt/β-catenin pathway.

Objective: Understanding the heterogeneity and pathophysiology of osteoarthritis (OA) is critical to support the development of tailored disease-modifying treatments. To this aim, transcriptomics tools are highly relevant to delineate dysregulated molecular pathways and identify new therapeutic targets. Methods: We review the methodology and outcomes of transcriptomics studies conducted in OA, based on a comprehensive literature search of the PubMed and Google Scholar databases using the terms “osteoarthritis”, “OA”, “knee OA”, “hip OA”, “genes”, “RNA-seq”, “microarray”, “transcriptomic” and “PCR” as key words. Beyond target-focused RT-qPCR, more comprehensive techniques include microarrays, RNA sequencing (RNA-seq) and single cell RNA-seq analyses. Results: The standardization of those methods to ensure the quality of both RNA extraction and sequencing is critical to get meaningful insights. Transcriptomics studies have been conducted in various tissues involved in the pathogenesis of OA, including articular cartilage, subchondral bone and synovium, as well as in the blood of patients. Molecular pathways dysregulated in OA relate to cartilage degradation, matrix and bone remodeling, neurogenic pain, inflammation, apoptosis and angiogenesis. This knowledge has direct application to patient stratification and further, to the identification of candidate therapeutic targets and biomarkers intended to monitor OA progression. Conclusion: In light of its high-throughput capabilities and ability to provide comprehensive information on major biological processes, transcriptomics represents a powerful method to support the development of new disease-modifying drugs in OA.

Translocator protein 18 kDa (TSPO) is an evolutionarily conserved 5-transmembrane domain protein, and has been considered as an important therapeutic target for the treatment of pain. We have recently reported the in vitro and in vivo pharmacological characterization of koumine as a TSPO positive allosteric modulator (PAM), more precisely ago-PAM. However, the probe dependence in the allostery of koumine is an important question to resolve, and the possible analgesic mechanism of koumine remains to be clarified. Here, we report the in vivo evaluation of the allostery of koumine when orthosteric ligand PK11195 was used and preliminarily explore the possible analgesic mechanism of koumine associated with neurosteroids. We find that koumine is an ago-PAM of the PK11195-mediated analgesic effect at TSPO, and the analgesic mechanism of this TSPO ago-PAM may be associated with neurosteroids as the analgesic effects of koumine in the formalin-induced inflammatory pain model and chronic constriction injury-induced neuropathic pain model can be antagonized by neurosteroid synthesis inhibitor aminoglutethimide. Although our results cannot fully clarify the allosteric modulatory effect of koumine, it further prove the allostery in TSPO and provide a solid foundation for koumine to be used as a new clinical candidate drug to treat pain.

Abstract State-of-the-art methods assessing pathogenic non-coding variants have mostly been characterized on common disease-associated polymorphisms, yet with modest accuracy and strong positional biases. In this study, we curated 737 high-confidence pathogenic non-coding variants associated with monogenic Mendelian diseases. In addition to interspecies conservation, a comprehensive set of recent and ongoing purifying selection signals in humans is explored, accounting for lineage-specific regulatory elements. Supervised learning using gradient tree boosting on such features achieves a high predictive performance and overcomes positional bias. NCBoost performs consistently across diverse learning and independent testing data sets and outperforms other existing reference methods.

Koumine is an alkaloid that displays notable activity against inflammatory and neuropathic pain, but its therapeutic target and molecular mechanism still need further study. Translocator protein 18 kDa (TSPO) is a vital therapeutic target for pain treatment, and recent research implies that there may be allostery in TSPO. Our previous competitive binding assay hint that koumine may function as a TSPO positive allosteric modulator (PAM). Here, for the first time, we report the pharmacological characterization of koumine as a TSPO PAM. The results imply that koumine might be a high-affinity ligand of TSPO and that it likely acts as a PAM since it could delay the dissociation of 3H-PK11195 from TSPO. Importantly, the allostery was retained in vivo, as koumine augmented Ro5-4864-mediated analgesic and anti-inflammatory effects in several acute and chronic inflammatory and neuropathic pain models. Moreover, the positive allosteric modulatory effect of koumine on TSPO was further demonstrated in cell proliferation assays in T98G human glioblastoma cells. In summary, we have identified and characterized koumine as a TSPO PAM for the treatment of inflammatory and neuropathic pain. Our data lay a solid foundation for the use of the clinical candidate koumine to treat inflammatory and neuropathic pain, further demonstrate the allostery in TSPO, and provide the first proof of principle that TSPO PAM may be a novel avenue for the discovery of analgesics.

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known FUT2 variant that confers resistance to intestinal viruses, and an APOL3 variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival. [ABSTRACT FROM AUTHOR]

Atomic force microscopy (AFM)-based single molecule force microscopy is used for studying the interaction between poly(L-glutamic acid) (PLE) and calcite crystals. The PLE-calcite interaction is examined as a function of pH as well as the calcium concentration of the aqueous solution.

Preparation of size-monodisperse hybrid nanoparticles of carboxyl-terminated generation 4.5 PAMAM dendrimers (ethylenediamine core) [G4.5-COO (super -)] that encapsulate platinum nanocrystals inside them, and the formation of monolayer films from the obtained nanoparticles as globular building blocks that make the array of dendrimers readily observable by transmission electron microscopy (TEM). The particle was identified as core/shell nanocomposites of platinum nanoparticles and PAMAM molecules.

Additive-free high-energy faces of CaCO 3in the calcite modification were synthesized and found to reconstruct fast into the stable (104) faces in solution within 2 h, which is not observed in the bad solvent ethanol. (104) faces can be detected by single molecule force spectroscopy. A novel embedding process of calcite crystals with defined exposed surfaces generated on a self-assembled surfactant monolayer into a silica monolith is described as well as the time-resolved analysis of the reconstruction of unstabilized high-energy surfaces, which is faster than assumed from the equilibrium Wulff rule. [ABSTRACT FROM AUTHOR]