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To investigate the effects of notched root stress gradient and geometric size parameters on the fatigue performance of engineering components, a new multiaxial fatigue life prediction model is established. First, based on the energy‐critical plane method, the location of the dangerous plane is determined with the help of finite element (FE) analysis. Second, the sixth‐order multinomial stress function is used to study the stress/strain distribution state on the critical plane, and the relative stress gradient (RSG) function is used to find the stationary point to determine the RSG value and the magnitude of the fatigue damage zone boundary value. Specifically, for specimens with different notch types, the indexes to determine the high‐stress influence zone and the size influence factor are proposed. Finally, a multiaxial fatigue life prediction model considering RSG and size effect is established, and the compared results show that the new model has a high fatigue life prediction capability. Highlights: Relative stress gradient values and size of fatigue damage zone boundaries are determined by a sixth‐order multinomial stress function.A high‐stress influence zone index is proposed.The relationship between size effect and fatigue life is characterized.A fatigue life equation considering the relative stress gradient and the size effect is established. [ABSTRACT FROM AUTHOR]

The sedimentary records of organic matter in lakes can reflect the response of lakes to global warming. Multiple organic proxies in the sediment core samples collected from Luoma Lake and Hongze Lake in Jiangsu were used to expound the effects of global warming and anthropogenic activities on lacustrine productivity and deposition of polycyclic aromatic hydrocarbons (PAHs). Total organic carbon, algal organic matter proxies (S2 and hydrogen index), and nutrients such as total phosphorus and total nitrogen were measured. The source apportionment modeling and the principal component analysis demonstrated that algal organic matter and bacteria organic matter showed an upcore increasing trend and an obvious enrichment effect on PAHs, which was also related to the increasing temperature and algal productivity in the lakes. Global warming enhanced the lacustrine productivity and the accumulation of PAHs in sediments. Therefore, the organic geochemical indicators in lake sediments can effectively reflect the impact of climate warming on the lacustrine productivity and the accumulation of PAHs, and provide data support for the management of lakes. Plain Language Summary: The impact of global warming on the environment is increasing, and previous research was mainly on the polar region, and there are relatively few studies on the impact on inland lake environments. In this paper, a typical organic pollutant, polycyclic aromatic hydrocarbons (PAHs), is taken as the starting point, and two lakes in eastern China, Luoma Lake, and Hongze Lake, are taken as the research objects. The sedimentary records of diatoms and bacteria were also analyzed to explore the interaction between diatoms and bacteria in the lake and PAHs. The results showed that diatoms had bioaccumulation effects on PAHs, especially HMW‐PAHs, and bacteria were the main contributors to the secondary productivity of the lake. In addition, changes in atmospheric temperature of Xuzhou and Bengbu recorded by weather stations near the lake show that the average annual atmospheric temperature has risen by nearly 2°C over the past 70 years, indicating a warming phenomenon in the region. Next, we analyzed the three factors related to algal growth in lakes, temperature, total nitrogen, and total phosphorus, and correlated them with PAH content and algal and bacterial biomarker content. There were significant positive correlations, especially for HMW‐PAHs, indicating that the increase in plankton productivity caused by climate warming promotes the accumulation of HMW‐PAHs in lake sediments. Key Points: The source apportionment model demonstrated the increasing aquatic productivityGlobal warming enhanced the accumulation of aquatic organic matterThe increasing aquatic productivity was critical to the bioaccumulation of polycyclic aromatic hydrocarbon [ABSTRACT FROM AUTHOR]

This paper investigates the effect of stress gradient on the fatigue life of U‐notched specimens under multiaxial proportional loading by studying the shear stress gradient and normal stress gradient on the crack initiation plane separately. First, based on the energy method and critical plane method, an energy‐critical plane method for determining the direction of crack initiation is proposed. Second, with the help of the concept of stress field intensity, the shear stress gradient and normal stress gradient on the critical plane are studied. Finally, a multiaxial fatigue life prediction model is established by combining the equivalent stress field intensity, composed of the shear stress field intensity and normal stress field intensity, with the Manson–Coffin equation. Theoretical analysis is verified by the experiments of Q345 steel notched specimens, and the results show that the predicted accuracy of the proposed method is not conservative and is superior to the local stress–strain method. [ABSTRACT FROM AUTHOR]

Water‐soluble carbon dots (CDs) were synthesized using a one‐step hydrothermal treatment of chloroplast dispersions extracted from fresh leaves as a green carbon source. The CD solution showed an emission peak centred at 445 nm when excited at 300 nm. The synthesized CDs were uniform and monodispersed with an average size of 5.6 nm. When adding ferric(III) ions (Fe3+) to the solution of the original CDs, the fluorescence intensity decreased significantly. Based on the linear relationship between fluorescence intensity and concentration of Fe3+ ions, an effective method for rapid, sensitive and selective Fe3+ sensing in aqueous solution could be established. Under optimum conditions, the extent of the fluorescence quenching of prepared CDs strongly depended on the Fe3+ ions over a wide concentration range 1.0–100.0 μM with a detection limit (3σ/k) of 0.3 μM. Furthermore, the quantitative determination of Fe3+ ions in environmental water samples was realized. [ABSTRACT FROM AUTHOR]

Toll‐like receptors (TLRs) are important pattern recognition receptors (PRRs) that are critical for the defense against invading pathogens. IL‐1β is an important pro‐inflammatory cytokine that also plays pivotal roles in shaping the adaptive immune response. TLRs and interleukin‐1 receptor (IL‐1R) share similar cytosolic domains and signaling processes. In this study, we identify the E3 ubiquitin ligase RNF152 as a positive regulator of TLR/IL‐1R‐mediated signaling. Overexpression of RNF152 potentiates IL‐1β‐ and LPS‐induced NF‐κB activation in an ubiquitination‐independent manner, whereas knockdown of RNF152 has the opposite effects. RNF152‐deficient mice produce less inflammatory cytokines in response to LPS and are more resistant to LPS‐induced lethal endotoxemia. Mechanistically, RNF152 interacts with the adaptor protein MyD88 and enhances oligomerization of MyD88, which is essential for the recruitment of downstream signaling components and activation of TLR/IL‐1R‐mediated signal transduction. Our findings suggest that RNF152‐mediated oligomerization of MyD88 is important for TLR/IL‐1R‐mediated inflammatory response. Synopsis: The adapter protein MyD88 functions downstream of both toll‐like receptors (TLRs) and interleukin‐1 receptor (IL‐1R) to activate inflammatory responses. RNF152 positively regulates TLR/IL‐1R‐mediated signaling by enhancing oligomerization of MyD88. Positive regulation of TLR/IL‐1R‐mediated signaling by RNF152 is independent of its E3 ubiquitin ligase activity.RNF152‐deficient mice show impaired inflammatory responses to LPS challenge compared with wild‐type mice.RNF152 interacts with MyD88 and enhances the oligomerization of MyD88. [ABSTRACT FROM AUTHOR]

γ-Secretase inhibitors ( GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase ( SPP/ SPPL) family members. Extending these findings to mammosphere inhibition assays in triple-negative breast cancer lines, we establish that these GSIs have different functional effects. We also demonstrate that the processive γ-secretase cleavage pattern established for amyloid precursor protein ( APP) occurs in multiple substrates and that potentiation of γ-secretase cleavage is attributable to a direct action of low concentrations of GSIs on γ-secretase. Such data definitively demonstrate that the clinical GSIs are not biological equivalents, and provide an important framework to evaluate results from ongoing and completed human trials with these compounds. [ABSTRACT FROM AUTHOR]

Background: Based on the premise that protein aggregation and accumulation in AD and many other neurodegenerative disorders is a key, causal, pathologic event, therapeutic strategies need to focus on i) prevention of aggregate formation ii) enhancement of clearance of the aggregate or iii) neutralization of "toxic" signaling by the aggregate. Enhancing clearance of the target protein via phagocytic mechanisms is the most direct way to test the hypothesis that enhancing clearance will be beneficial. We cloned two novel chimeric phagocytic receptors (CPRs), fused to a previously characterized anti‐Abeta scFv. The present work aims to explore whether astrocyte expressed CPRs targeting Aβ enhance phagocyte clearance and alter the target pathology, when delivered into the brain of the Alzheimer's disease mouse model, CRND8, as a prevention paradigm, before the pathology develops, or after amyloid aggregation already occurred. Method: Anti‐Abeta recombinant scFvs fused to two most promising CPRs were packaged in AAV under astrocytic GFAP promoter and delivered into the brains of newborn CRND8 mice (prevention paradigm) as well as older mice with preexisting pathology (treatment paradigm). Amyloid burden and Aβ levels in the soluble, SDS soluble and SDS‐insoluble, Formic Acid soluble fractions, as well as the state of astrocytosis and astrogliosis were compared between various cohorts. Backbone of the CPR without the scFv as well as pAAV‐EGFP served as controls. Result: Initially we evaluated expression, amyloid burden and GFAP and IBA staining in mice that were injected with 2 CPRs, pAAV‐MRC1‐GFAP‐scFv9, pAAV‐FCRG‐GFAP‐scFv9, as well as pAAV‐MRC1‐BB (backbone control) and pAAV‐EGFP control. Amyloid staining revealed a significant clearance of amyloid staining in the area around the injection site, which overlapped with the expression of CPR. Additionally, expression of CPRs resulted in increased astrocytes and microglia burden. Conclusion: These results suggest a significant amyloid alteration by chosen CPRs. Future studies will optimize brain delivery as well as determine therapeutic potential of CPRs following transplantation of the CPR expressing microglia/monocytes into the brain mice with preexisting pathology. [ABSTRACT FROM AUTHOR]

Multiphase partitioning of endocrine-disrupting chemicals (EDCs) in the Pearl River (China) were investigated. The colloidal concentrations for 4-tert-octylphenol, 4-nonylphenol, bisphenol A (BPA), and estrone (E1) were in the ranges of 0.2 ng/L to 0.8 ng/L, 23.2 ng/L to 108 ng/L, 2.3 ng/L to 97.6 ng/L, and not detectable (nd) to 0.32 ng/L, respectively; for truly dissolved concentrations, the ranges were 0.5 ng/L to 5.4 ng/L, 39 ng/L to 319 ng/L, 13.7 ng/L to 91.2 ng/L, and nd to 1.2 ng/L, respectively. Positive correlations of EDCs with colloidal organic carbon (COC) were observed. The in situ COC normalized partitioning coefficients (log KCOC) for 4-tert-octylphenol (5.35 ± 0.42), 4-nonylphenol (5.69 ± 0.50), and BPA (5.51 ± 0.77) were within the ranges reported by other studies, whereas they were 1 to 2 orders of magnitude higher than their particulate/truly dissolved phase partition coefficients (log [ABSTRACT FROM AUTHOR]

The biological underpinnings linking stress to Alzheimer's disease ( AD) risk are poorly understood. We investigated how corticotrophin releasing factor ( CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 ( CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by β-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ-secretase. [ABSTRACT FROM AUTHOR]

The distribution of endocrine-disrupting chemicals (EDCs) and its relationship with dissolved and particulate organic carbon (DOC and POC) was investigated in selected rivers of the Pearl River Delta, South China. The aqueous concentrations (average; ng/L) and particulate concentrations (average; ng/g, dry wt) for 4- tert-octylphenol (OP), 4-nonylphenol (NP), bisphenol A (BPA), and estrone (E1) were in the ranges of not detectable to 153 (31.8), 276 to 2,457 (1,178), 8.4 to 628 (161), and less than 1.5 to 11.5 (3.2), respectively, and 4.4 to 402 (98.1), 342 to 12,053 (4,922), 12.3 to 758 (128), and not detectable to 14.4, respectively. The highly significant correlation of EDCs with DOC and POC, and the similar regression slopes, implied the critical importance of DOC and POC on the distribution, transport, and fate of EDCs in the aquatic environment. The in situ particle-water partition coefficients (log KOC) for OP (4.89 ± 0.41), NP (5.05 ± 0.33), and BPA (4.34 ± 0.50) were close to those reported by other field studies, but one to two orders of magnitude higher than those predicted with n-octanol-water partition coefficient ( KOW). The higher KOC values were attributed to the combined effects of low EDC concentrations, nonlinear sorption, and heterogeneity of POC and DOC. Moreover, a regression between in-situ KOC and KOW for phenolic xenoestrogens was observed (log KOC = 0.625 × log KOW + 2.28, r2 = 0.99), suggesting that hydrophobicity contributed predominantly to the overall sorption of OP, NP, and BPA. Environ. Toxicol. Chem. 2012; 31: 2456-2464. © 2012 SETAC [ABSTRACT FROM AUTHOR]

Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD‐associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High‐affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre‐incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD‐associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high‐affinity interaction between TREM2 and Aβ oligomers that can block interaction with another TREM2 ligand and ii) that AD‐associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization. Synopsis: Rare coding variants of TREM2 (R47H, R62H) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. Using BioLayer Interferometry and other biochemical methods, TREM2 and AD‐associated variants binding to Aβ and APOE is examined. High‐affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation which is almost "irreversible".Pre‐incubation of TREM2 with Aβ oligomers is shown to block its interaction with APOE.AD‐associated TREM2 variants bound Aβ with equivalent affinity.AD‐associated TREM2 variants reduced Aβ42 internalization and NFAT signaling activity.AD‐associated TREM2 variants showed a partial loss of function. Rare coding variants of TREM2 (R47H, R62H) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. Using BioLayer Interferometry and other biochemical methods, TREM2 and AD‐associated variants binding to Aβ and APOE is examined. [ABSTRACT FROM AUTHOR]