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Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

With an electron-deficient rigid planar structure and excellent π–π stacking ability, hexaazatriphenylene (HAT) and its derivatives are widely used as basic building blocks for constructing covalent organic frameworks (COFs), components of organic light-emitting diodes and solar cells, and electrode materials for lithium-ion batteries (LIBs). Here, a HAT derivative, hexaazatriphenylenehexacarbonitrile, is explored as an anode material for LIBs. The HAT anode exhibited high initial reversible capacities of 672 mA h g−1 at 100 mA g−1 and 550 mA h g−1 at 400 mA g−1 and stable cycling with a capacity of 503 mA h g−1 after 1000 cycles at 400 mA g−1 corresponding to a capacity retention of 91.5%. Furthermore, the lithium storage mechanism and the cause of the first irreversible capacity loss of the HAT anode were investigated by X-ray photoelectron spectroscopy (XPS) analysis and density functional theory (DFT) calculations. We have carried out a series of analyses on the mechanism of initial capacity loss. This study provides new insight on initial capacity loss and provides valuable insights into the molecular design and the electrochemical properties of HAT-based anode materials. [ABSTRACT FROM AUTHOR]

Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B. [ABSTRACT FROM AUTHOR]

The characteristics of phase scintillation (represented by the phase scintillation indices, σφ) from GPS and Beidou are statistically analyzed using a ground‐based receiver at Zhongshan Station, Antarctica, from 2020 to 2022 for the first time. The phase scintillation of the GPS and Beidou signals present a similar pattern of occurrence. The statistical results on the occurrence morphology of phase scintillation show that the phase scintillation predominately occurs in the magnetic pre‐noon and pre‐midnight sectors. Moreover, phase scintillation performs a dependence on solar and geomagnetic activities. Furthermore, the phase scintillation also gives a seasonal variation with the maximum occurrence happened at the autumn and the minimum occurrence during the summer. Consequently, these results improve understanding of the morphological characteristics of the phase fluctuations in the less studied Antarctic region. The study also demonstrates the use of the combined data set to improve the coverage in the Antarctic region. Key Points: Morphological characteristics of phase scintillation of GPS and Beidou signals at Zhongshan station, Antarctica, for the first timeThe occurrences of phase scintillation mainly concentrated in the prenoon and pre‐midnight sectors for both signalsThe similar behaviors of phase scintillation convey the usefulness of the combined data for irregularity studies in the polar region [ABSTRACT FROM AUTHOR]

Background: Diabetic kidney disease is an established risk factor for heart failure. However, the impact of incident heart failure on the subsequent risk of renal failure has not been systematically assessed in diabetic population. We sought to study the risk of progression to end stage kidney disease (ESKD) after incident heart failure in Asian patients with type 2 diabetes. Methods: In this prospective cohort study, 1985 outpatients with type 2 diabetes from a regional hospital and a primary care facility in Singapore were followed for a median of 8.6 (interquartile range 6.2–9.6) years. ESKD was defined as a composite of progression to sustained eGFR below 15 ml/min/1.73m2, maintenance dialysis or renal death, whichever occurred first. Results: 180 incident heart failure events and 181 incident ESKD events were identified during follow-up. Of 181 ESKD events, 38 (21%) occurred after incident heart failure. Compared to those did not progress to ESKD after incident heart failure (n = 142), participants who progressed to ESKD after heart failure occurrence were younger, had higher HbA1c and higher urine albumin-to-creatinine ratio at baseline. The excess risk of ESKD manifested immediately after heart failure occurrence, persisted for two years and was moderated thereafter. Cox regression suggested that, compared to counterparts with no heart failure event, participants with heart failure occurrence had 9.6 (95% CI 5.0- 18.3) fold increased risk for incident ESKD after adjustment for baseline cardio-renal risk factors including eGFR and albuminuria. It appeared that heart failure with preserved ejection fraction had a higher risk for ESKD as compared to those with reduced ejection fraction (adjusted HR 13.7 [6.3–29.5] versus 6.5 [2.3–18.6]). Conclusion: Incident heart failure impinges a high risk for progression to ESKD in individuals with type 2 diabetes. Our data highlight the need for intensive surveillance of kidney function after incident heart failure, especially within the first two years after heart failure diagnosis. [ABSTRACT FROM AUTHOR]

This paper investigates the formation and segmentation of the tongue of ionization into two consecutive polar cap patches using multi‐instrument observations from 27 February 2014. We provide insights into how the interplanetary magnetic field (IMF) variations influence the formation and segmentation of these patches. Our findings reveal that the entry of dayside dense plasma into the polar cap is predominantly driven by the modified convection near the cusp region, which is controlled by the transition of IMF By or the sudden drop of IMF Bz. Furthermore, we observe a rapid north‐westward plasma flow within the patch segmentation region, accompanied by equatorward‐expanded and enhanced convection near the cusp region. This fast‐moving flow, approximately 1.5 km/s, is characterized by low density and high electron temperature and shows a signature of a Subauroral Polarization Stream. This suggests that the fast‐westward flow, in conjunction with the expansion and contraction of ionospheric convection, plays a crucial role in the segmentation of polar cap patches from the dayside plasma reservoir. This study provides a comprehensive observation of the evolution of polar cap patches, thereby advancing our understanding of the dynamic mechanisms governing patch formation and segmentation. Plain Language Summary: Polar cap patches are highly dense structures in the polar cap region, typically forming in the cusp region and moving toward the nightside due to ionospheric convections. To better understand the factors that govern the formation and segmentation of these patches, a combination of satellite and ground‐based observations is used to investigate two consecutive polar cap patches on 27 February 2014. We found that the configuration of IMF By and Bz significantly influences cusp region convection, causing dayside sunlit dense plasma to enter the polar cap when cusp convection expands equatorward and the flow shifts northward, a process that leads to patch formation. Additionally, we observe strong north‐westward flows of low‐density, high‐electron‐temperature plasma in the subauroral region during periods of geomagnetic disturbance, displaying characteristics of Subauroral Polarization Streams (SAPS). This flow is observed in the patch segmentation region along with the equatorward‐expanding, enhanced cusp convection. These observations indicate that SAPS, along with the expansion and contraction of ionospheric convection, play a key role in the segmentation of polar cap patches from their equatorward plasma reservoir. This study significantly advances our understanding of the dynamic mechanisms governing the formation and segmentation of polar cap patches. Key Points: The transient change of IMF By and Bz leads to the formation of the tongue of ionization and segmentation of polar cap patchesA tongue of ionization is segmented into two polar cap patches by low electron density, high electron temperature, fast westward flowsThe expansion/contraction of the ionospheric convection also plays a crucial role in the segmentation of dayside dense plasma [ABSTRACT FROM AUTHOR]

Inorganic‐organic hybrid materials are a kind of multiduty materials with high crystallinity and definite structures, built from functional inorganic and organic components with highly tunable photochemical properties. Perylenediimides (PDIs) are a kind of strong visible light‐absorbing organic dyes with π‐electron‐deficient planes and photochemical properties depending on their micro‐environment, which provides a platform for designing tunable and efficient hybrid photocatalytic materials. Herein, four radical‐doped PDI‐based crystalline hybrid materials, Cl4‐PDI⋅SiW12O40 (1), Cl4‐PDI⋅SiMo12O40 (2), Cl4‐PDI⋅PW12O40 (3), and Cl4‐PDI⋅PMo12O40 (4), were attained by slow diffusion of polyoxometalates (POMs) into acidified Cl4‐PDI solutions. The obtained PDI‐based crystalline hybrid materials not only exhibited prominent photochromism, but also possessed reactive organic radicals under ambient conditions. Furthermore, all hybrid materials could be easily photoreduced to their radical anions (Cl4‐PDI⋅−), and then underwent a second photoexcitation to form energetic excited state radical anions (Cl4‐PDI⋅−*). However, experiments and theoretical calculations demonstrated that the formed energetic Cl4‐PDI⋅−* showed unusual POM‐dependent photocatalytic efficiencies toward the oxidative coupling of amines and the iodoperfluoroalkylation of alkenes; higher photocatalytic efficiencies were found for hybrid materials 1 (anion: SiW12O404−) and 2 (anion: SiMo12O404−) compared to 3 (anion: PW12O403−) and 4 (anion: PMo12O403−). The photocatalytic efficiencies of these hybrid materials are mainly controlled by the energy differences between the SOMO‐2 level of Cl4‐PDI⋅−* and the LUMO level of the POMs. The structure‐photocatalytic activity relationships established in present work provide new research directions to both the photocatalysis and hybrid material fields, and will promote the integration of these areas to explore new materials with interesting properties. [ABSTRACT FROM AUTHOR]

The role of turbine blade cooling and coolants are significant factors in modern gas turbine aerodynamic design. This paper presents an effective and rapid airfoil design method based on CFD computation of the S1 surface and the existing loss correlations. The method can assess the coolant mixing loss by identifying each cooling hole separately and obtain the overall mainflow aerodynamic loss for cooled airfoil. The CFD computation code of the S1 surface is powered by a two-dimensional Euler equation, which is inviscid. Typical Kacker–Okapuu empirical correlations are then used to assess the airfoil friction loss, trailing edge loss, and shock loss. A novel form of the Hartsel model for coolant mixing loss is developed and employed in the CFD codes. In the reformed model, the mixing loss coefficient is directly associated with the blowing ratio and the total pressure/temperature ratio of mainstream-to-coolant, making it more convenient than the original model in the airfoil design process. Based on a transonic turbine vane airfoil, the influences of the film outflow location and outflow Mach number on the coolant mixing loss are investigated using the above prediction method and the cascade blowing test. [ABSTRACT FROM AUTHOR]

Dayside magnetosphere interactions are essential for energy and momentum transport between the solar wind and the magnetosphere. In this study, we investigate a new phenomenon within this regime. Sudden enhancements of ion fluxes followed by repeating dropouts and recoveries were observed by Magnetospheric Multiscale on 5 November 2016, which is the very end of the recovery phase from a moderate geomagnetic storm. These repetitive flux variations display energy‐dispersive characteristics with periods relevant to ion bounce motion, suggesting they are corresponding echoes. Alongside the flux variations, bipolar electric field impulses originating from external sources were detected. We traced the source region of the initial injection and found it is located near the spacecraft's position. To elucidate the underlying physics, a test‐particle simulation is conducted. The results reveal that radial transport resulting from impulse‐induced acceleration can give rise to these echoes. Observations demonstrate dayside magnetosphere interactions are more common than we previously considered, which warrants further research. Plain Language Summary: In spacecraft observations, the quasi‐periodical motion of particles in the geomagnetic field can generate repeating signals known as "echoes". Examining the relationship between the periods of echoes and the particle's energy is necessary for determining their types. The present study reports a novel mechanism responsible for generating echoes that arise from the ion bounce motion along magnetic field lines. Observations from both ground‐based stations and spacecraft, as well as numerical simulations, suggest these echoes can result from the acceleration and radial diffusion of ions responding to external field variations. These findings extend the current understanding of interactions in the dayside outer magnetosphere. Key Points: Ion acceleration and corresponding bounce echoes were observed by MMS in the dayside outer magnetosphereObservations and simulations suggest these echoes are driven by the accompanied electric field impulsesImpulse‐induced ion radial transport with positive phase space density radial gradient leads to the observed pattern [ABSTRACT FROM AUTHOR]

With an electron-deficient rigid planar structure and excellent π-π stacking ability, hexaazatriphenylene (HAT) and its derivatives are widely used as basic building blocks for constructing covalent organic frameworks (COFs), components of organic light-emitting diodes and solar cells, and electrode materials for lithium-ion batteries (LIBs). Here, a HAT derivative, hexaazatriphenylenehexacarbonitrile, is explored as an anode material for LIBs. The HAT anode exhibited high initial reversible capacities of 672 mA h g -1 at 100 mA g -1 and 550 mA h g -1 at 400 mA g -1 and stable cycling with a capacity of 503 mA h g -1 after 1000 cycles at 400 mA g -1 corresponding to a capacity retention of 91.5%. Furthermore, the lithium storage mechanism and the cause of the first irreversible capacity loss of the HAT anode were investigated by X-ray photoelectron spectroscopy (XPS) analysis and density functional theory (DFT) calculations. We have carried out a series of analyses on the mechanism of initial capacity loss. This study provides new insight on initial capacity loss and provides valuable insights into the molecular design and the electrochemical properties of HAT-based anode materials.

Mechanisms underlying the cardiovascular-kidney-metabolic (CKM) syndrome are unknown, although key small molecule metabolites may be involved. Bulk and spatial metabolomics identified adenine to be upregulated and specifically enriched in coronary blood vessels in hearts from patients with diabetes and left ventricular hypertrophy. Single nucleus gene expression studies revealed that endothelial methylthioadenosine phosphorylase (MTAP) was increased in human hearts with hypertrophic cardiomyopathy. The urine adenine/creatinine ratio in patients was predictive of incident heart failure with preserved ejection fraction. Heart adenine and MTAP gene expression was increased in a 2-hit mouse model of hypertrophic heart disease and in a model of diastolic dysfunction with diabetes. Inhibition of MTAP blocked adenine accumulation in the heart, restored heart dysfunction in mice with type 2 diabetes and prevented ischemic heart damage in a rat model of myocardial infarction. Mechanistically, adenine-induced impaired mitophagy was reversed by reduction of mTOR. These studies indicate that endogenous adenine is in a causal pathway for heart failure and ischemic heart disease in the context of CKM syndrome., Competing Interests: Competing interests: Dr. Margulies holds research grants from Amgen and serves as a scientific consultant/advisory board member for Bristol Myers Squibb and Amgen. Dr. Sharma serves on the data safety board for Cara Therapeutics and holds equity in SygnaMap. All other authors declare that they have no competing interests. Dr. Tuttle has received investigator-initiated grant support (to Providence Inland Northwest Health) from Travere and Bayer outside of the submitted work; consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk and Travere; speaker fees from AstraZeneca, Eli Lilly, and Novo Nordisk. Dr. Julia Saez-Rodriguez reports funding from GSK, Pfizer and Sanofi & fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer and Grunenthal.

This study aimed to investigate the role of macrophage polarization in the treatment of liver fibrosis by Fuzheng Huayu Tablets(FZHY) through single-cell, transcriptome sequencing and in vitro and in vivo experiments. Liver fibrosis-related datasets, transcriptomic datasets, and single-cell sequencing datasets were obtained from the Gene Expression Omnibus(GEO) database to screen differential genes. Liver fibrosis-related genes were obtained from GeneCards, DisGeNET, NCBI, PharmgKB, TTD and OMIM databases. Macrophage polarization-related genes were obtained from the GeneCards database. The above three gene sets were intersected to construct a protein-protein interaction(PPI) network. Cytoscape software was used to screen core proteins, and the expression pattern of core proteins was visualized by single-cell sequencing. A mouse model of liver fibrosis was constructed using carbon tetrachloride(CCl_4). Hematoxylin-eosin(HE) staining and Masson staining were used to observe the pathological morphology of liver tissues. The expressions of α-smooth muscle actin(α-SMA) and transforming growth factor-β1(TGF-β1) were detected by immunohistochemistry. The levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were detected by colorimetry. The le-vels of inflammatory factors in serum were detected by the enzyme-linked immunosorbent assay(ELISA). Furthermore, the expressions of α-SMA, TGF-β1, cluster of differentiation 86(CD86) and thrombospondin 1(THBS1) in liver tissues were detected by Western blot(WB). Lipopolysaccharide(LPS) was used to stimulate RAW264.7 cells to construct the M1 macrophage polarization model. The cell counting kit-8(CCK-8) method was used to detect cell viability. WB was used to detect the protein expressions of CD86 and THBS1 in cells, and the messenger ribonucleic acid(mRNA) expression levels of tumor necrosis factor-α(TNF-α) and interleukin(IL)-1β by real-time fluorescent quantitative reverse transcription polymerase chain reaction(RT-qPCR). The results showed that a total of 26 potential genes related to the polarization of liver fibrosis macrophages were obtained, and 10 core proteins related to the polarization of liver fibrosis macrophages such as THBS1, lumican(LUM) and fibulin-5(FBLN5) were screened. Single-cell data analysis indicated that THBS1, ranking highest, may be expressed by M1 macrophages. Animal experiments demonstrated that FZHY reduced inflammatory cell infiltration and collagen deposition in CCl_4-induced mouse liver, relieved liver injury and inflammation levels, and inhibited the expressions of α-SMA, TGF-β1, CD86, and THBS1 proteins. Cell experiments revealed that FZHY significantly reduced intracellular expression of CD86 and THBS1 proteins and mRNA levels of TNF-α and IL-1β. In conclusion, FZHY may ameliorate liver fibrosis by inhibiting THBS1 protein expression, suppressing M1 macrophage polarization, and reducing inflammation.

Inorganic-organic hybrid materials are a kind of multiduty materials with high crystallinity and definite structures, built from functional inorganic and organic components with highly tunable photochemical properties. Perylenediimides (PDIs) are a kind of strong visible light-absorbing organic dyes with π-electron-deficient planes and photochemical properties depending on their micro-environment, which provides a platform for designing tunable and efficient hybrid photocatalytic materials. Herein, four radical-doped PDI-based crystalline hybrid materials, Cl 4 -PDI⋅SiW 12 O 40 (1), Cl 4 -PDI⋅SiMo 12 O 40 (2), Cl 4 -PDI⋅PW 12 O 40 (3), and Cl 4 -PDI⋅PMo 12 O 40 (4), were attained by slow diffusion of polyoxometalates (POMs) into acidified Cl 4 -PDI solutions. The obtained PDI-based crystalline hybrid materials not only exhibited prominent photochromism, but also possessed reactive organic radicals under ambient conditions. Furthermore, all hybrid materials could be easily photoreduced to their radical anions (Cl 4 -PDI⋅ - ), and then underwent a second photoexcitation to form energetic excited state radical anions (Cl 4 -PDI⋅ -* ). However, experiments and theoretical calculations demonstrated that the formed energetic Cl 4 -PDI⋅ -* showed unusual POM-dependent photocatalytic efficiencies toward the oxidative coupling of amines and the iodoperfluoroalkylation of alkenes; higher photocatalytic efficiencies were found for hybrid materials 1 (anion: SiW 12 O 40 4- ) and 2 (anion: SiMo 12 O 40 4- ) compared to 3 (anion: PW 12 O 40 3- ) and 4 (anion: PMo 12 O 40 3- ). The photocatalytic efficiencies of these hybrid materials are mainly controlled by the energy differences between the SOMO-2 level of Cl 4 -PDI⋅ -* and the LUMO level of the POMs. The structure-photocatalytic activity relationships established in present work provide new research directions to both the photocatalysis and hybrid material fields, and will promote the integration of these areas to explore new materials with interesting properties., (© 2024 Wiley‐VCH GmbH.)

Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum cycloprolactam(LIGc) are derivatives of Z-ligustilide(LIG), a pharmacodynamic marker of Angelica sinensis, which has various biological functions such as anti-inflammation and inhibition of cell apoptosis. However, its protective effect on chondrocytes in the case of OA and the underlying mechanism remain unclear. This study conducted in vitro experiments to explore the molecular mechanism of LIGc in protecting chondrocytes from OA. The inflammation model of rat OA chondrocyte model was established by using interleukin-1β(IL-1β) to induce. LIGc alone and combined with glycyrrhizic acid(GA), a blocker of the high mobility group box-1 protein(HMGB1)/Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway, were used to intervene in the model, and the therapeutic effects were systematically evaluated. The viability of chondrocytes treated with different concentrations of LIGc was measured by the cell counting kit-8(CCK-8), and the optimal LIGc concentration was screened out. Annexin V-FITC/PI apoptosis detection kit was employed to examine the apoptosis of chondrocytes in each group. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the expression of cyclooxygenase-2(COX-2), prostaglandin-2(PGE2), and tumor necrosis factor-alpha(TNF-α) in the supernatant of chondrocytes in each group. Western blot was employed to determine the protein levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, HMGB1, TLR4, and NF-κB p65. The mRNA levels of HMGB1, TLR4, NF-κB p65, and myeloid differentiation factor 88(MyD88) in chondrocytes were determined by real-time fluorescent quantitative PCR(RT-qPCR). The safe concentration range of LIGc on chondrocytes was determined by CCK-8, and then the optimal concentration of LIGc for exerting the effect was clarified. Under the intervention of IL-1β, the rat chondrocyte model of OA was successfully established. The modeled chondrocytes showed increased apoptosis rate, promoted expression of COX-2, PGE2, and TNF-α, up-regulated protein levels of Bax, caspase-3, HMGB1, TLR4, and NF-κB p65 and mRNA levels of HMGB1, TLR4, NF-κB p65, and MyD88, and down-regulated protein level of Bcl-2. However, LIGc reversed the IL-1β-induced changes of the above factors. Moreover, LIGc combined with GA showed more significant reversal effect than LIGc alone. These fin-dings indicate that LIGc extracted and derived from the traditional Chinese medicine A. sinensis can inhibit the inflammatory response of chondrocytes and reduce the apoptosis of chondrocytes, and this effect may be related to the HMGB1/TLR4/NF-κB signaling pathway. The pharmacological effect of LIGc on protecting chondrocytes has potential value in delaying the progression of OA and improving the clinical symptoms of patients, and deserves further study.