Engineering membrane asymmetry to increase medium-chain fatty acid tolerance in Saccharomyces cerevisiae.

Saccharomyces cerevisiae is an attractive chassis for the production of medium-chain fatty acids, but the toxic effect of these compounds often prevents further improvements in titer, yield, and productivity. To address this issue, Lem3 and Sfk1 were identified from adaptive laboratory evolution mutant strains as membrane asymmetry regulators. Co-overexpression of Lem3 and Sfk1 [Lem3(M)-Sfk1(H) strain] through promoter engineering remodeled the membrane phospholipid distribution, leading to an increased accumulation of phosphatidylethanolamine in the inner leaflet of the plasma membrane. As a result, membrane potential and integrity were increased by 131.5% and 29.2%, respectively; meanwhile, the final OD600 in the presence of hexanoic acid, octanoic acid, and decanoic acid was improved by 79.6%, 73.4%, and 57.7%, respectively. In summary, this study shows that membrane asymmetry engineering offers an efficient strategy to enhance medium-chain fatty acids tolerance in S. cerevisiae, thus generating a robust industrial strain for producing high-value biofuels.

Discussion on machine learning technology to predict tacrolimus blood concentration in patients with nephrotic syndrome and membranous nephropathy in real-world settings.

BACKGROUND: Given its narrow treatment window, high toxicity, adverse effects, and individual differences in its use, we collected and sorted data on tacrolimus use by real patients with kidney diseases. We then used machine learning technology to predict tacrolimus blood concentration in order to provide a basis for tacrolimus dose adjustment and ensure patient safety. METHODS: This study involved 913 hospitalized patients with nephrotic syndrome and membranous nephropathy treated with tacrolimus. We evaluated data related to patient demographics, laboratory tests, and combined medication. After data cleaning and feature engineering, six machine learning models were constructed, and the predictive performance of each model was evaluated via external verification. RESULTS: The XGBoost model outperformed other investigated models, with a prediction accuracy of 73.33%, F-beta of 91.24%, and AUC of 0.5531. CONCLUSIONS: Through this exploratory study, we could determine the ability of machine learning to predict TAC blood concentration. Although the results prove the predictive potential of machine learning to some extent, in-depth research is still needed to resolve the XGBoost model's bias towards positive class and thereby facilitate its use in real-world settings.

Systemic lupus erythematosus monocytes are less responsive to interleukin-10 in the presence of immune complexes.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic inflammatory disease characterized by autoantibody production and immune complex deposition. The level of interleukin-10 (IL-10), predominantly an antiinflammatory cytokine, is paradoxically elevated in patients with SLE. The aim of this study was to examine the hypothesis that the antiinflammatory function of IL-10 is impaired in monocytes from patients with SLE with long-term exposure to immune complexes. METHODS: CD14+ monocytes were isolated from healthy donors and patients with SLE. Cultured CD14+ cells were treated with heat-aggregated human IgG (325 µg/ml) in the presence or absence of IL-10 (20 ng/ml). To study gene expression, RNA was extracted 3 hours after treatment. To study cytokine production, supernatants were harvested after 8 hours. To study IL-10 signaling, cell lysates were obtained from CD14+ cells treated with human IgG (325 µg/ml) for 1 hour followed by IL-10 (20 ng/ml) treatment for 10 minutes. Western blot analysis was used to assess STAT-3 phosphorylation. All experiments were performed in pairs. RESULTS: When stimulated with human IgG, SLE monocytes produced more tumor necrosis factor α (TNFα) and IL-6 than did control cells. The suppressive effect of IL-10 on human IgG-induced TNFα and IL-6 production was lower in SLE monocytes compared with control monocytes, although IL-10 receptor expression was similar in SLE and control monocytes. Human IgG suppressed IL-10 receptor expression and altered IL-10 signaling in control monocytes. Like SLE monocytes, interferon-α (IFNα)-primed control monocytes stimulated with human IgG were also less responsive to IL-10. CONCLUSION: Human IgG and IFNα modulate IL-10 function. In SLE monocytes, which are considered to be IFNα primed and persistently exposed to immune complexes, responses to IL-10 are abnormal, limiting the antiinflammatory effect of this cytokine.

Imaging of Strong Nanoscale Vortex Pinning in GdBaCuO High-Temperature Superconducting Tapes.

The high critical current density of second-generation high-temperature superconducting (2G-HTS) tapes is the result of the systematic optimisation of the pinning landscape for superconducting vortices through careful engineering of the size and density of defects and non-superconducting second phases. Here, we use scanning Hall probe microscopy to conduct a vortex-resolved study of commercial GdBaCuO tapes in low fields for the first time and complement this work with "local" magnetisation and transport measurements. Magnetic imaging reveals highly disordered vortex patterns reflecting the presence of strong pinning from a dense distribution of nanoscale Gd2O3 second-phase inclusions in the superconducting film. However, we find that the measured vortex profiles are unexpectedly broad, with full-width-half-maxima typically of 6 µm, and exhibit almost no temperature dependence in the range 10-85 K. Since the lateral displacements of pinned vortex cores are not expected to exceed the superconducting layer thickness, this suggests that the observed broadening is caused by the disruption of the circulating supercurrents due to the high density of nanoscale pinning sites. Deviations of our local magnetisation data from an accepted 2D Bean critical state model also indicate that critical state profiles relax quite rapidly by flux creep. Our measurements provide important information about the role second-phase defects play in enhancing the critical current in these tapes and demonstrate the power of magnetic imaging as a complementary tool in the optimisation of vortex pinning phenomena in 2G-HTS tapes.

Analysis and Optimization of a Microchannel Heat Sink with V-Ribs Using Nanofluids for Micro Solar Cells.

It is crucial to control the temperature of solar cells for enhancing efficiency with the increasing power intensity of multiple photovoltaic systems. In order to improve the heat transfer efficiency, a microchannel heat sink (MCHS) with V-ribs using a water-based nanofluid as a coolant for micro solar cells was designed. Numerical simulations were carried out to investigate the flows and heat transfers in the MCHS when the Reynolds number ranges from 200 to 1000. The numerical results showed that the periodically arranged V-ribs can interrupt the thermal boundary, induce chaotic convection, increase heat transfer area, and subsequently improve the heat transfer performance of a MCHS. In addition, the preferential values of the geometric parameters of V-ribs and the physical parameters of the nanofluid were obtained on the basis of the Nusselt numbers at identical pump power. For MCHS with V-ribs on both the top and bottom wall, preferential values of V-rib are rib width d / W = 1 , flare angle α = 75 ° , rib height h r / H = 0.3 , and ratio of two slant sides b / a = 0.75 , respectively. This can provide sound foundations for the design of a MCHS in micro solar cells.

Parametric Investigation on a Micro-Array Heat Sink with Staggered Trapezoidal Bumps.

More efficient heat sinks are required due to the rapid increase of power density in microelectronic devices. In this study, a micro-array heat sink with stagger trapezoidal bumps was designed. Numerical simulations for the flow and heat transfer under various conditions were carried out to help us to fully understand the mechanisms of the heat transfer enhancement in such a heat sink. The effects of the structure of the heat sink, parameters of the bumps, and volume fraction of the nanofluid on the performance of heat sink were studied. The results show us that the bumps in the heat sink can result in chaotic convection, interrupting the thermal boundary layer and increasing the cooling area, subsequently improving the heat transfer performance. Furthermore, parametric investigations for trapezoidal bumps were conducted to obtain preferential values for parameters, such as the bump width, fore rake angle of the bump, bump height, and bump pitch.

Vortex shaking study of REBCO tape with consideration of anisotropic characteristics.

The second generation high temperature superconductor, specifically REBCO, has become a new research focus in the development of a new generation of high-field (>25 T) magnets. One of the main challenges in the application of the magnets is the current screening problem. Previous research shows that for magnetized superconducting stacks and bulks the application of an AC field in plane with the circulating current will lead to demagnetization due to vortex shaking, which provides a possible solution to remove the shielding current. This paper provides an in-depth study, both experimentally and numerically, to unveil the vortex shaking mechanism of REBCO stacks. A new experiment was carried out to measure the demagnetization rate of REBCO stacks exposed to an in-plane AC magnetic field. Meanwhile, 2D finite element models, based on the E-J power law, are developed for simulating the vortex shaking effect of the AC magnetic field. Qualitative agreement was obtained between the experimental and the simulation results. Our results show that the applied in-plane magnetic field leads to a sudden decay of trapped magnetic field in the first half shaking cycle, which is caused by the magnetic field dependence of critical current. Furthermore, the decline of demagnetization rate with the increase of tape number is mainly due to the cross-magnetic field being screened by the top and bottom stacks during the shaking process, which leads to lower demagnetization rate of inner layers. We also demonstrate that the frequency of the applied AC magnetic field has little impact on the demagnetization process. Our modeling tool and findings perfect the vortex shaking theory and provide helpful guidance for eliminating screening current in the new generation REBCO magnets.

Insoluble immune complexes are most effective at triggering IL-10 production in human monocytes and synergize with TLR ligands and C5a.

PURPOSE: In systemic lupus erythematosus (SLE), a disease of immune complex (IC) deposition, interleukin-10 (IL-10) is thought to promote B-lymphocyte hyperactivity and autoantibody production. Both ICs and Toll-like receptor (TLR) ligands have been shown to stimulate the production of IL-10 by human monocytes. Using an in vitro model, we studied how IC solubility, complement activation products, and TLR ligands could affect IL-10 production by human monocytes stimulated with ICs. METHODS: Human monocytes were stimulated with soluble or insoluble heat-aggregated human IgG with or without TLR ligands or C5a. Cytokine levels in cell culture supernatants were measured by ELISA. To study cytokine signaling, cell lysates were analyzed by Western blot for total or tyrosine-phosphorylated STAT3. RESULTS: Insoluble ICs were most effective at stimulating production of IL-10, and costimulation LPS enhanced synthesis of IL-10. In addition, stimulation with insoluble ICs together with C5a enhanced the production of IL-10 by 2-4 fold in either the presence or absence of TLR ligands. Increased STAT3 phosphorylation correlated temporally with enhanced IL-10 production and was reduced by an IL-10 receptor blocking antibody, suggesting that IL-10 was responsible for observed STAT3 phosphorylation. CONCLUSIONS: Because the immune deposits of SLE are, by definition, insoluble; and because IL-10 is thought to be important for B-cell hyperactivity and autoantibody production, these observations provide a critical link, bridging current views of B-cell hyperactivity with the early concept that SLE may arise from defective clearance of immune complexes.