859 research outputs found

    Development of the Swimbladder Surfactant System and Biogenesis of Lysosome-Related Organelles Is Regulated by BLOS1 in Zebrafish

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    Hermansky-Pudlak syndrome (HPS) is a human autosomal recessive disorder that is characterized by oculocutaneous albinism and a deficiency of the platelet storage pool resulting from defective biogenesis of lysosome-related organelles (LROs). To date, 10 HPS genes have been identified, three of which belong to the octamer complex BLOC-1 (biogenesis of lysosome-related organelles complex 1). One subunit of the BLOC-1 complex, BLOS1, also participates in the BLOC-1-related complex (BORC). Due to lethality at the early embryo stage in BLOS1 knockout mice, the function of BLOS1 in the above two complexes and whether it has a novel function are unclear. Here, we generated three zebrafish mutant lines with a BLOC-1 deficiency, in which melanin and silver pigment formation was attenuated as a result of mutation of bloc1s1, bloc1s2, and dtnbp1a, suggesting that they function in the same complex. In addition, mutations of bloc1s1 and bloc1s2 caused an accumulation of clusters of lysosomal vesicles at the posterior part of the tectum, representing a BORC-specific function in zebrafish. Moreover, bloc1s1 is highly expressed in the swimbladder during postembryonic stages and is required for positively regulating the expression of the genes, which is known to govern surfactant production and lung development in mammals. Our study identified BLOS1 as a crucial regulator of the surfactant system. Thus, the zebrafish swimbladder might be an easy system to screen and study genetic modifiers that control surfactant production and homeostasis.</p

    In vitro evaluation of a novel pH neutral calcium phosphosilicate bioactive glass that does not require preconditioning prior to use

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    It is well known that bioactive glasses can cause a significant increase in pH due to the rapid release of calcium and/or sodium ions. Consequently, preconditioning of the glass is usually required prior to surgery to negate the effect of this sudden release of ions. However, preconditioning for several days is far from ideal and also preconditioning is not practical for novel organic/inorganic sol-gel hybrids currently being developed since the organic phase will start to hydrolyze and dissolve. This study describes a bioactive glass that dissolves without causing a significant change in pH from physiologically optimal values and requires no preconditioning prior to use. The bioactivity of the pH neutral glass, hydroxyapatite formation, and cellular responses, are measured and compared directly with results from archetypal 45S5 and S70C30 bioactive glasses. A hydroxyapatite layer was found to rapidly form (within 1 day) on the surface of the pH neutral glass upon reacting with simulated body fluid. In addition, improved cell compatibility was observed compared with 45S5 and S70C30 glasses. Therefore, this pH neutral glass has significant potential for bone repair applications

    The M-T hook structure increases the potency of HIV-1 fusion inhibitor sifuvirtide and overcomes drug resistance

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    Objectives Peptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp41 are potent fusion inhibitors. We have recently demonstrated that the unique M-T hook structure preceding the pocket-binding motif of CHR peptide-based inhibitors can greatly improve their antiviral activity. In this study, we applied the M-T hook structure to optimize sifuvirtide (SFT), a potent CHR-derived inhibitor currently under Phase III clinical trials in China. Methods The peptide MT-SFT was generated by incorporating two M-T hook residues (Met-Thr) into the N-terminus of sifuvirtide. Multiple structural and functional approaches were used to determine the biophysical properties and antiviral activity of MT-SFT. Results The high-resolution crystal structure of MT-SFT reveals a highly conserved M-T hook conformation. Compared with sifuvirtide, MT-SFT exhibited a significant improvement in the ability to bind to the N-terminal heptad repeat, to block the formation of the six helix bundle and to inhibit HIV-1 Env-mediated cell fusion, viral entry and infection. Importantly, MT-SFT was fully active against sifuvirtide- and enfuvirtide (T20)-resistant HIV-1 variants and displayed a high genetic barrier to developing drug resistance. Conclusions Our studies have verified that the M-T hook structure offers a general strategy for designing novel HIV-1 fusion inhibitors and provide new insights into viral entry and inhibitio

    Machine learning-based prediction of compressive strength in circular FRP-confined concrete columns

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    This research aims to evaluate the compressive strength of FRP-confined columns using machine learning models. By systematically organizing codes and models proposed by various researchers, significant indicators influencing compressive strength have been identified. A comprehensive database comprising 366 samples, including both CFRP and GFRP, has been assembled. Based on this database, a machine learning model was developed to accurately predict compressive strength. A thorough evaluation was conducted, comparing models proposed by codes and researchers. Additionally, a detailed parameter analysis was performed using the XGBoost model. The findings highlight the importance of both code-based and researcher-proposed models in enhancing our understanding of compressive strength. However, certain models show tendencies towards conservative or overestimated predictions, indicating the need for further accuracy enhancement. Among the models considered, the XGBoost model demonstrated the highest goodness of fit (0.97) and the lowest coefficient of variation (8%), making it a suitable choice for investigating compressive strength. Notable parameters significantly influencing compressive strength include FRP thickness, elastic modulus, and concrete strength

    Arginine Relieves the Inflammatory Response and Enhances the Casein Expression in Bovine Mammary Epithelial Cells Induced by Lipopolysaccharide

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    As one of functional active amino acids, L-arginine holds a key position in immunity. However, the mechanism that arginine modulates cow mammary inflammatory response in ruminant is unclear. Therefore, this study was conducted to investigate the effects of L-arginine on inflammatory response and casein expression after challenging the bovine mammary epithelial cells (BMECs) with lipopolysaccharide (LPS). The cells were divided into four groups, stimulated with or without LPS (10 g/mL) and treated with or without arginine (100 g/mL) for 12 h. The concentration of proinflammatory cytokines, inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and Toll-like receptor 4 (TLR4) signaling pathways as well as the casein was determined. The results showed that arginine reduced the LPS-induced production like IL-1 , IL-6, TNF-, and iNOS. Though the expression of NF-B was attenuated and the mTOR signaling pathway was upregulated, arginine had no effect on TLR4 expression. In addition, our results show that the content of -casein and the total casein were enhanced after arginine was supplemented in LPS-induced BMECs. In conclusion, arginine could relieve the inflammatory reaction induced by LPS and enhance the concentration of -casein and the total casein in bovine mammary epithelial cells

    Metabolomic Analysis of Alfalfa (Medicago sativa L.) Root-Symbiotic Rhizobia Responses under Alkali Stress

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    Alkaline salts (e.g., NaHCO3 and Na2CO3) causes more severe morphological and physiological damage to plants than neutral salts (e.g., NaCl and Na2SO4) due to differences in pH. The mechanism by which plants respond to alkali stress is not fully understood, especially in plants having symbotic relationships such as alfalfa (Medicago sativa L.). Therefore, a study was designed to evaluate the metabolic response of the root-nodule symbiosis in alfalfa under alkali stress using comparative metabolomics. Rhizobium-nodulized (RI group) and non-nodulized (NI group) alfalfa roots were treated with 200 mmol/L NaHCO3 and, roots samples were analyzed for malondialdehydyde (MDA), proline, glutathione (GSH), superoxide dismutase (SOD), and peroxidase (POD) content. Additionally, metabolite profiling was conducted using gas chromatography combined with time-of-flight mass spectrometry (GC/TOF-MS). Phenotypically, the RI alfalfa exhibited a greater resistance to alkali stress than the NI plants examined. Physiological analysis and metabolic profiling revealed that RI plants accumulated more antioxidants (SOD, POD, GSH), osmolytes (sugar, glycols, proline), organic acids (succinic acid, fumaric acid, and alpha-ketoglutaric acid), and metabolites that are involved in nitrogen fixation. Our pairwise metabolomics comparisons revealed that RI alfalfa plants exhibited a distinct metabolic profile associated with alkali putative tolerance relative to NI alfalfa plants. Data provide new information about the relationship between non-nodulized, rhizobium-nodulized alfalfa and alkali resistance

    Achieving blood pressure control targets in hypertensive patients of rural China - A pilot randomized trial

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    Background: This study aimed to test the feasibility and titration methods used to achieve specific blood pressure (BP) control targets in hypertensive patients of rural China. Methods: A randomized, controlled, open-label trial was conducted in Rongcheng, China. We enrolled 105 hypertensive participants aged over 60 years, and who had no history of stroke or cardiovascular disease. The patients were randomly assigned to one of three systolic-BP target groups: standard: 140 to \u3c 150 mmHg; moderately intensive: 130 to \u3c 140 mmHg; and intensive: \u3c 130 mmHg. The patients were followed for 6 months. Discussion: The optimal target for systolic blood pressure (SBP) lowering is still uncertain worldwide and such information is critically needed, especially in China. However, in China the rates of awareness, treatment and control are only 46.9%, 40.7%, and 15.3%, respectively. It is challenging to achieve BP control in the real world and it is very important to develop population-specific BP-control protocols that fully consider the population\u27s characteristics, such as age, sex, socio-economic status, compliance with medication, education level, and lifestyle. This randomized trial showed the feasibility and safety of the titration protocol to achieve desirable SBP targets (\u3c 150, \u3c 140, and \u3c 130 mmHg) in a sample of rural, Chinese hypertensive patients. The three BP target groups had similar baseline characteristics. After 6 months of treatment, the mean SBP measured at an office visit was 137.2 mmHg, 131.1 mmHg, and 124.2 mmHg, respectively, in the three groups. Home BP and central aortic BP measurements were also obtained. At 6 months, home BP measurements (2 h after drug administration) showed a mean SBP of 130.9 mmHg in the standard group, 124.9 mmHg in the moderately intensive group, and 119.7 mmHg in the intensive group. No serious adverse events were recorded over the 6-month study period. Rates of adverse events, including dry cough, palpitations, and arthralgia, were low and showed no significant differences between the three groups. This trial provided real-world experience and laid the foundation for a future, large-scale, BP target study. Trial registration: Feasibility Study of the Intensive Systolic Blood Pressure Control; ClinicalTrials.gov, ID: NCT02817503. Registered retrospectively on 29 June 2016

    Search for the decay J/ψ→γ+invisibleJ/\psi\to\gamma + \rm {invisible}

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    We search for J/ψJ/\psi radiative decays into a weakly interacting neutral particle, namely an invisible particle, using the J/ψJ/\psi produced through the process ψ(3686)→π+π−J/ψ\psi(3686)\to\pi^+\pi^-J/\psi in a data sample of (448.1±2.9)×106(448.1\pm2.9)\times 10^6 ψ(3686)\psi(3686) decays collected by the BESIII detector at BEPCII. No significant signal is observed. Using a modified frequentist method, upper limits on the branching fractions are set under different assumptions of invisible particle masses up to 1.2  GeV/c2\mathrm{\ Ge\kern -0.1em V}/c^2. The upper limit corresponding to an invisible particle with zero mass is 7.0×10−7\times 10^{-7} at the 90\% confidence level

    First observations of hc→h_c \to hadrons

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    Based on (4.48±0.03)×108(4.48 \pm 0.03) \times 10^{8} ψ(3686)\psi(3686) events collected with the BESIII detector, five hch_c hadronic decays are searched for via process ψ(3686)→π0hc\psi(3686) \to \pi^0 h_c. Three of them, hc→ppˉπ+π−h_c \to p \bar{p} \pi^+ \pi^-, π+π−π0\pi^+ \pi^- \pi^0, and 2(π+π−)π02(\pi^+ \pi^-) \pi^0 are observed for the first time, with statistical significances of 7.4σ\sigma, 4.9σ4.9\sigma, and 9.1σ\sigma, and branching fractions of (2.89±0.32±0.55)×10−3(2.89\pm0.32\pm0.55)\times10^{-3}, (1.60±0.40±0.32)×10−3(1.60\pm0.40\pm0.32)\times10^{-3}, and (7.44±0.94±1.56)×10−3(7.44\pm0.94\pm1.56)\times10^{-3}, respectively, where the first uncertainties are statistical and the second systematic. No significant signal is observed for the other two decay modes, and the corresponding upper limits of the branching fractions are determined to be B(hc→3(π+π−)π0)<8.7×10−3B(h_c \to 3(\pi^+ \pi^-) \pi^0)<8.7\times10^{-3} and B(hc→K+K−π+π−)<5.8×10−4B(h_c \to K^+ K^- \pi^+ \pi^-)<5.8\times10^{-4} at 90% confidence level.Comment: 17 pages, 16 figure

    Measurements of Weak Decay Asymmetries of Λc+→pKS0\Lambda_c^+\to pK_S^0, Λπ+\Lambda\pi^+, Σ+π0\Sigma^+\pi^0, and Σ0π+\Sigma^0\pi^+

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    Using e+e−→Λc+Λˉc−e^+e^-\to\Lambda_c^+\bar\Lambda_c^- production from a 567 pb−1^{-1} data sample collected by BESIII at 4.6 GeV, a full angular analysis is carried out simultaneously on the four decay modes of Λc+→pKS0\Lambda_c^+\to pK_S^0, Λπ+\Lambda \pi^+, Σ+π0\Sigma^+\pi^0, and Σ0π+\Sigma^0\pi^+. For the first time, the Λc+\Lambda_c^+ transverse polarization is studied in unpolarized e+e−e^+e^- collisions, where a non-zero effect is observed with a statistical significance of 2.1σ\sigma. The decay asymmetry parameters of the Λc+\Lambda_c^+ weak hadronic decays into pKS0pK_S^0, Λπ+\Lambda\pi^+, Σ+π0\Sigma^+\pi^0 and Σ0π+\Sigma^0\pi^+ are measured to be 0.18±0.43(stat)±0.14(syst)0.18\pm0.43(\rm{stat})\pm0.14(\rm{syst}), −0.80±0.11(stat)±0.02(syst)-0.80\pm0.11(\rm{stat})\pm0.02(\rm{syst}), −0.57±0.10(stat)±0.07(syst)-0.57\pm0.10(\rm{stat})\pm0.07(\rm{syst}), and −0.73±0.17(stat)±0.07(syst)-0.73\pm0.17(\rm{stat})\pm0.07(\rm{syst}), respectively. In comparison with previous results, the measurements for the Λπ+\Lambda\pi^+ and Σ+π0\Sigma^+\pi^0 modes are consistent but with improved precision, while the parameters for the pKS0pK_S^0 and Σ0π+\Sigma^0\pi^+ modes are measured for the first time
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