The Nafion-212-EC-PC electrolyte is electrochemically stable up to 6 V, indicating its suitability for high-energy density batteries. It has an ionic conductivity of 1.9 × 10−4 S/cm at 25 °C and a high lithium transference number. The symmetric Li|Nafion-212-EC-PC|Li cell shows a very low overvoltage of ~0.3 V at a current density of ±0.1 mA/cm2. At 25 °C, the LiFePO4|Nafion-212-EC-PC|Li battery exhibits a capacity of 141, 136, 125, and 100 mAh/g at 0.1, 0.2, 0.5, and 1C rates, respectively. It maintains a capacity of 120 mAh/g at 0 °C and 0.1C with stable performance for 50 charge/discharge cycles. The mechanism of conductivity and capacity retention at low temperatures is discussed.The use of cation-exchange membranes as electrolytes for lithium metal batteries can prevent the formation of lithium dendrites during extended cycling and guarantee safe battery operation. In our study, the Nafion-212 membrane in lithium form solvated by a mixture of ethylene carbonate and propylene carbonate (EC-PC) was used as an electrolyte in a lithium metal battery with the LiFePO Achievieach 0.8 . For theeach 0.8 ,13,14,153− groups bonded to a perfluorinated polymer matrix are of great interest due to their outstanding transport properties as well as their excellent chemical, thermal, and electrochemical stability [2-CF(CF3)-O-CF2-CF2-SO3Li, which effectively delocalizes negative charge. Nafion membranes solvated by organic polar aprotic solvents, which are commonly used in conventional lithium-ion batteries, exhibit high ionic conductivity (10−4 S/cm), high Li+ transference numbers (>0.9), and stable battery performance when used as electrolytes [Perfluorinated sulfonic acid membranes with -SOtability ,17. Nafitrolytes ,21,22,23trolytes . The add4 cathode and lithium anode [There are several papers in the literature devoted to the use of solvated Nafion membranes in lithium metal and lithium-ion batteries. For example, the commercial Nafion-211 membrane exhibited an ionic conductivity of 0.21 mS/cm at 70 °C after being soaked in propylene carbonate. Meanwhile, the discharge capacity of the Li-S battery was found to be 1072.8 mAh/g (per sulfur) at a cycling rate of 0.05C and 895 mAh/g, with 89% capacity retention after 100 cycles at 1C . The eleum anode . The proAnother important problem with lithium metal batteries is their behavior at negative temperatures associated with insufficient ionic conductivity of solid-state electrolytes or freezing of liquid electrolytes. The use of cation-exchange membranes with nanosized pores can help solve this problem. Due to the presence of both nonpolar (hydrophobic) perfluorinated matrix and polar (hydrophilic) terminal functional groups in perfluorinated sulfonic acid membranes, self-organization processes occur in which polar functional groups aggregate and form nanoscale clusters. As a result, solvents in solvated cation-exchange membranes can freeze at lower temperatures than pure solvents  due to t4 cathode and lithium anode were tested, including performance at low temperatures.The aim of this study was to produce and characterize polymer electrolytes based on commercial perfluorinated sulfocationic membranes, namely Nafion-212, solvated by a mixture of ethylene carbonate and propylene carbonate (EC-PC). The lithium conductivity, transference numbers, and electrolyte stability against lithium metal were investigated for the first time. Temperature effects were studied for Nafion-212 membranes swelled in an EC-PC mixture in the temperature range −100–+130 °C by the DSC technique. In addition, battery cells with the Nafion-212-based electrolyte and the LiFePO2O , ethylene carbonate , propylene carbonate , N-methyl-2-pyrrolidone , liquid electrolyte containing 1 M LiPF6 in ethylene carbonate, dimethyl carbonate, and diethyl carbonate (4:3:3) + vinylene carbonate , lithium metal , polyvinylidene fluoride , Super P-Li .The following reagents were used in this work: Nafion-212 membrane ), LiOH·H+-form after conditioning was kept in 0.5 M NaCl for 24 h under constant stirring. The solution was then titrated with ~0.01 M NaOH. The exact concentration of the sodium hydroxide solution was determined by titration with a 0.1 M HCl solution prepared by dilution of the standard titrant. The equivalence point was determined by changing the color of the universal indicator ZIV-1. IEC values were calculated by Equation (1):m is the weight of a dry membrane (g), and Before use as an electrolyte, commercial Nafion-212 membranes were conditioned using a standard procedure to remove monomer impurities and solvent residues . Ion-exc+ form, they were treated with a 0.1 M LiOH solution under continuous stirring for 48 h. To remove the remaining ions, membranes were washed multiple times using deionized water and then dried under vacuum at 50 °C for 12 h to remove the remaining water.To convert the membranes to LiTo prepare the Nafion-212-EC-PC polymer electrolyte, the Nafion-212 membrane was transferred into an argon-filled glove box with a moisture and oxygen content of <5 ppm  and then immersed in a solution containing equal volumes of ethylene carbonate and propylene carbonate (EC-PC) for 24 h.The degree of membrane solvation was determined by the ratio of solvent molecules to membrane functional groups. The solvated membrane was analyzed using differential scanning calorimetry in aluminum crucibles in a helium atmosphere at temperatures ranging from −100 to +130 °C with a heating rate of 10 °C/min using a NETZSCH STA 449F1 .The ionic conductivity of the Nafion-212-EC-PC polymer electrolyte was investigated by impedance spectroscopy in the temperature range −20…+50 °C. Measurements were carried out using an AC bridge Elins Z-1500J  in the frequency range of 2.5 MHz–10 Hz in an Al|membrane|Al CR2032 coin-type cell. A Binder MKF115 climate chamber  was used to set the required temperature. The resistivity was determined by the cutoff on the active resistance axis in Nyquist plots in the higher-temperature range (from +30 to +50 °C) or by extrapolation of the semicircle on the active resistance axis using the ZView 4 program at lower temperatures (from −20 to +25 °C). The activation energy of ionic conductivity was calculated using the Arrhenius equation from the slope of the temperature dependence of conductivity.+ transference numbers (Li+T) were estimated according to the Bruce-Vincent method [I0) and after f)(I polarization was measured. The interface impedance was measured before (R0) and after (fR) polarization by impedance spectroscopy in the frequency range of 500 kHz to 10 mHz. The TLi+ values were calculated using Equation (2):Lit method  in symme+ was determined by linear voltammetry using a multichannel potentiostat-galvanostat Elins P-20X8 . The membrane sample was placed between a stainless steel electrode  and a lithium electrode (as the counter and reference electrode) and assembled in a coin-type CR2032 cell. Potential scans were performed from 0.0 to 6.0 V (vs. Li/Li+) with a sweep rate of 1.0 mV/s. Cyclic voltammetry was performed in the potential range of 2.5–4.1 V in SS|electrolyte|Li cells with a sweep rate of 1.0 mV/s for 10 cycles.The electrochemical stability window of the Nafion-212-EC-PC polymer electrolyte vs. Li/Li2 in a symmetric Li|Nafion-212-EC-PC|Li cell using Elins P-20X8 multichannel potentiostat-galvanostat. The cycle time was 1 h (0.05 mAh/cm2). Before experiments, the lithium surface was mechanically cleaned from lithium oxide and lithium carbonate.To evaluate the stability of the polymer electrolyte against lithium metal, galvanostatic cycling was carried out at a current density of 0.1 mA/cm4@C (LFP) composite prepared by the solvothermal method using sucrose as a carbon source according to the procedure described in Ref. [N-methyl-2-pyrrolidone (the ratio of LFP:carbon black:PVDF was 85:10:5). The resulting slurry was homogenized on a magnetic stirrer under vigorous stirring for 2 h, then subjected to ultrasonic treatment with an ultrasonic probe for 10 s. The obtained electrode paste was applied to aluminum foil with a thickness of 9 μm using the doctor-blade technique; the thickness of rolling was 200 μm. The resulting cathode sheets were dried at 90 °C for 1 h, then pressed under 1 ton, followed by additional holding at 120 °C in vacuum for 24 h. Round electrodes of 1.6 cm in diameter (2 cm2 area with ~5 mg/cm2 loading) were cut from the coated foil. During assembly of electrochemical cells, the cathode material was impregnated with a small amount (~30 μL) of liquid electrolyte containing 1 M LiPF6 in EC-DMC-DEC-VC.To evaluate the possibility of using the Nafion-212-EC-PC polymer electrolyte in lithium metal batteries, we tested a coin-type cell with a positive electrode based on LiFePO in Ref. . To prepI, t, and m are current (A), time (s), and weight (g) of active cathode material, respectively. The Coulombic efficiency (CE) was calculated using Equation (4):dQ and cQ are the discharge and charge capacities, respectively.Electrochemical testing was carried out in galvanostatic mode at cycling rates of 0.1C (17 mA/g), 0.2C (34 mA/g), 0.5C (85 mA/g), and 1C (170 mA/g) at 25 °C in a potential range of 2.5 to 4.1 V using an Elins P-20X8 multichannel potentiostat-galvanostat and at 0 and −5 °C at a cycling rates of 0.1C and 0.5C. The cell capacity Q (mAh/g) was calculated by Equation (3):Nafion-212 membrane has an ion-exchange capacity of 0.87 mg-eq/g, as determined by acid-base titration. Solvent sorption during solvation of the Nafion-212 membrane results in an increase in its thickness and weight. After being soaked in the EC-PC solvent mixture, Nafion-212 exhibited a degree of solvation of 7.8 solvent molecules per sulfonic acid group, resulting in a thickness increase from 50 μm to 62 μm.−4 S/cm, meeting the necessary criteria for electrolytes for lithium metal batteries [The Nyquist plots and the temperature dependence of the ionic conductivity are shown in atteries . The ionThe DSC curve of the Nafion-212-EC-PC membrane shows a significant endothermic peak with an onset temperature of −5.7 °C c. It can+. In fact, the observed cathodic peaks at 4.1 and 5.1 V were characterized by relatively small intensities (<10 μA/cm2). Compared with liquid electrolytes stable in the range of ~1–4.5 V [Based on the linear sweep voltammetry data a, no ano~1–4.5 V ,35, the ~1–4.5 V ,37,38.Based on cyclic voltammetry in the potential range of 2.5−4.1 V, consistent with the operating range of the LFP cathodes, a gradual decrease in the potential difference between charge-discharge plateaus compared with the first cycle is observed b. This d2, the Nafion-212-EC-PC electrolyte exhibits an overvoltage of ~320 mV after 100 cycles  potential difference until the system reaches a steady state with a constant concentration gradient [The Ligradient . This megradient . There agradient , electrogradient , the Hitgradient , and thegradient . The dis3− groups, which leads to their orientation towards the electrodes under the applied potential difference. Moreover, the concentration of cations at one electrode and cation vacancies at the opposite electrode, which occur because of the polarization , also contribute to this difference. The results show that the Nafion-212-EC-PC polymer electrolyte is more selective for cation transfer than liquid electrolytes, which have a transference number of ~0.3 [ of ~0.3 .4, indicating the Fe2+↔Fe3+ transition. Meanwhile, the difference between the average potential of charge and discharge plateaus in the cell using the Nafion-212-EC-PC membrane electrolyte is similar to that in cells with liquid electrolytes at the same rates of charge and discharge [To evaluate the electrochemical performance of a lithium metal battery with an electrolyte based on Nafion-212 solvated by EC-PC, the LFP|Li cell was tested at different charge–discharge rates . Charge–ischarge ,51, indiischarge .The discharge capacity of the Li|Nafion-212-EC-PC|LFP cell was 141 mAh/g at 0.1C, which is less than the capacity of a similar cell with liquid electrolyte by only 11% . This ca4/FePO4 transformation [Notable is the fact that the cell capacity with the polymer electrolyte remains stable at low temperatures, showing a Coulombic efficiency of ~100%. However, the cell capacity decreased to 100 and 120 mAh/g when cycling at 0.1C at −5 and 0 °C, respectively . This coormation ,54.The performance of the Li|Nafion-212-EC-PC|LFP cell at room temperature is comparable with data for other single-ion conducting polymer electrolytes or even surpasses them ,19,55. T−4 S/cm at 25 °C. The LiFePO4|Nafion-212-EC-PC|Li cell exhibited capacities ranging from 100 to 141 mAh/g at different C-rates (0.1C–1C) at room temperature and a capacity of 120 mAh/g at 0 °C and 0.1C. The battery showed stable performance over 50 charge and discharge cycles with a Coulombic efficiency of ~100%. Moreover, the electrolyte is electrochemically stable up to 6 V, indicating its suitability for high-energy-density batteries.The polymer electrolyte for lithium metal batteries was prepared using a Nafion-212 membrane solvated by a mixture of ethylene carbonate and propylene carbonate. The Nafion-212-EC-PC electrolyte has a high lithium transference number and ionic conductivity of 1.9 × 10


Raptor and Rictor, the two essential components for mTORC1 and mTORC2, will be summarized and discussed.The mechanistic target of rapamycin (mTOR) kinase is a central regulator of cell growth and metabolism. It is the catalytic subunit of two distinct large protein complexes, mTOR complex 1 (mTORC1) and mTORC2. mTOR activity is subjected to tight regulation in response to external nutrition and growth factor stimulation. As an important mechanism of signaling transduction, the ‘second messenger’ cyclic nucleotides including cAMP and cGMP and their associated cyclic nucleotide-dependent kinases, including protein kinase A (PKA) and protein kinase G (PKG), play essential roles in mediating the intracellular action of a variety of hormones and neurotransmitters. They have also emerged as important regulators of mTOR signaling in various physiological and disease conditions. However, the mechanism by which cAMP and cGMP regulate mTOR activity is not completely understood. In this review, we will summarize the earlier work establishing the ability of cAMP to dampen mTORC1 activation in response to insulin and growth factors and then discuss our recent findings demonstrating the regulation of mTOR signaling by the PKA- and PKG-dependent signaling pathways. This signaling framework represents a new non-canonical regulation of mTOR activity that is independent of AKT and could be a novel mechanism underpinning the action of a variety of G protein-coupled receptors that are linked to the mTOR signaling network. We will further review the implications of these signaling events in the context of cardiometabolic disease, such as obesity, non-alcoholic fatty liver disease, and cardiac remodeling. The metabolic and cardiac phenotypes of mouse models with targeted deletion of  The mechanistic target of rapamycin (mTOR) kinase is a central regulator of cell growth and metabolism. It acts as a signaling node that integrates the external inputs and coordinates the major anabolic and catabolic pathways to maintain metabolic homeostasis . The mTOThe regulatory-associated protein of mTOR (RAPTOR) and the rapamycin-insensitive companion of mTOR (RICTOR) are the defining components for mTORC1 and mTORC2, respectively . RapamycmTOR activity is tightly regulated to sense the nutrients and growth factors to orchestrate cell growth and metabolic program. The integrated upstream signals that control mTORC1 activity mainly include two sets of small G proteins, RHEB (Ras homolog mTORC1 binding) and RAGs (Ras-related GTPases) . RHEB isAs briefly reviewed in Part 1, the mTOR signaling cascades are tightly regulated in response to external nutrition and growth factors to coordinate cell growth and metabolism. As an important mechanism of signaling transduction, the ‘second messenger’ cyclic nucleotides including cAMP and cGMP and their associated cyclic nucleotide-dependent kinases, including protein kinase A (PKA) and protein kinase G (PKG), have been shown to exert both positive and negative regulation of mTOR signaling in various physiological contexts and disease conditions. In the following part, we will summarize the earlier work establishing the ability of cAMP to dampen mTORC1 activation in response to insulin and growth factors and then discuss our recent findings demonstrating the regulation of mTOR signaling by the PKA- and PKG-dependent signaling pathways that represent a new non-canonical pathway independent of AKT, and we will review the implications of these signaling events in cardiometabolic disease, such as obesity, non-alcoholic fatty liver disease, and cardiac remodeling.The seven transmembrane-spanning G protein-coupled receptors (GPCRs) are cell surface proteins that, upon agonist stimulation, can interact with heterotrimeric G proteins that in turn regulate various effector enzymes or ion channels -dependent activation of S6K1 in IL-2-responsive lymphoid cells . Scott aStudies have also been conducted in primary cell culture or physiologically relevant tissues. Mothe-Satney and colleagues showed that, in primary cultures of hepatocytes, glucagon increases the mTOR phosphorylation at Ser2448 as insulin or amino acids do, but glucagon inhibits the insulin- and amino acid-induced activation of S6K1 and phosphorylation of 4E-BP1 . AnotherSeveral other studies have also linked cAMP with mTORC1 activation. For example, Kwon and colleagues reported that the GLP-1 (glucagon-like peptide-1) receptor agonist, Exenatide, dose-dependently enhanced phosphorylation of S6K1 in isolated rat islets through a glucose-dependent and cAMP-mediated mechanism . They alIn 2016, our group reported the novel observation that mTORC1 activation is required for the β-adrenergic stimulation of adipose tissue browning . PharmacNewer studies are demonstrating that, like PKA, the cGMP/PKG pathway can also control mTORC1 activity . The carPKG has also been reported to regulate mTOR signaling by phosphorylating other components of the mTOR network. Ranek and colleagues reported that PKG1 activates TSC2 by direct phosphorylation at Ser1365 and Ser1366 in cardiomyocytes, thereby inhibiting mTORC1 and promoting autophagy activity to counter adverse remodeling during cardiac stress . In addiAs the major effector kinases of second messenger signaling, several reports have suggested that PKA and PKG can regulate mTOR activity through indirect mechanisms via several downstream signaling regulators, such as p38 mitogen-activated protein kinases (MAPKs) and glycogen synthase kinase 3 (GSK3) .2O2 and anisomycin, were able to activate TORC1 in mammalian and Drosophila tissue culture [p38 is a class of MAPKs that is responsive to stress stimuli and plays a central role in a diverse range of stress-induced signaling pathways ,48. Li a culture . This st culture . The dec culture . In addi culture . Given t culture ,54 and P culture ,55,56 siGSK3β is an established negative regulator of mTORC1 signaling. After the primed phosphorylation of TSC2 by AMPK at S1345, GSK3β phosphorylates TSC2 at several amino acid residues  and results in mTORC1 inhibition . GSK3 acPKA might regulate mTORC2 activity through both direct and indirect mechanisms. As mentioned earlier, a study from our group identified three PKA phosphorylation sites in mTOR, and phosphorylation-resistant mutations of these sites  resulted in impaired mTORC1 activation as indicated by S6K1 phosphorylation . Thus, iObesity develops as increased adiposity in fat mass due to a chronic surplus of calorie intake over energy expenditure. According to the guidelines, a body mass index (BMI) over 25 is considered overweight and over 30 is obese . Body weInsulin acts through the PI3K cascade to activate two downstream pathways to mTORC2 as well as via TSC to mTORC1. The dysregulation of mTOR signaling results in insulin resistance, a hallmark of metabolic syndrome . In the Raptor knockout mice have demonstrated that mTORC1 is essential for adipose tissue function and homeostasis  expression and expansion of beige/brite adipocytes in white adipose tissue (WAT) [Adipoq-Cre) causes progressive lipodystrophy and fatty liver disease [Raptor knockout (Adipoq-Cre) mice are resistant to high-fat diet (HFD)-induced obesity, but this is due to failed adipose tissue expansion and not increased energy expenditure, which in turn results in severe hepatomegaly associated with hyperphagia and defective dietary lipid absorption [Raptor deletion (Adipoq-Cre) failed to completely suppress lipolysis in the fed state and displayed prominent hypertriglyceridemia and hypercholesterolemia [Raptor (Adipoq-Cre) increased prostaglandin (PG) production by cyclooxygenase-2 (COX-2) and promoted differentiation of progenitor cells to beige adipocytes [Studies with adipose tissue-specific eostasis . Polak asistance . Howeverhe brain ,76,77, aue (WAT) . Mechaniue (WAT) . This st disease . Adiposesorption . Thus, merolemia . This stipocytes . This stRictor deletion by Fabp4/aP2-Cre have increased body size due to an increase in the size of non-adipose organs [Fabp4/aP2-Cre driver, which can also alter mTORC2 activity in non-adipose tissues due to this leaky expression [Rictor in mature adipocytes (Adipoq-Cre) decreases ChREBPβ expression, which reduces DNL in WAT, and impairs hepatic insulin sensitivity [Rictor loss in the Myf5+ precursor lineage (Myf5-Cre) shifts BAT metabolism to a more oxidative and less lipogenic state and protects mice against obesity and metabolic disease [Rictor in murine brown adipocytes (Ucp1-Cre) inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obesity and hepatic steatosis [Rictor in brown adipocytes appears to drive lipid catabolism independently of AKT by promoting FoxO1 deacetylation, and this occurs in a pathway distinct from its positive role in anabolic lipid synthesis [mTORC2 signaling also plays an important role in adipose tissue function and homeostasis . Early we organs . These me organs . These fpression ,76,77. Tsitivity . Mechanisitivity . Thus, m disease . Jung anteatosis . Deletinynthesis . These fAs a crucial arm of the energy balance in obesity, feeding behavior is subjected to short-term and long-term controls for the initiation and termination of meals and the status of energy storage ,65. The Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver disease ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic hepatic steatosis (NASH), the latter of which could advance to cirrhosis and hepatocellular carcinoma (HCC) (reviewed in ). NAFL iAfter feeding, glucose taken up by the liver is converted into acetyl-CoA through a stepwise process of glycolysis, tricarboxylic acid (TCA) cycle and citrate lyase . HepaticmTOR signaling plays an essential role in hepatic lipid metabolism (reviewed in ). As themTORC1 controls the activation of SREBPs through both S6K1-dependent and S6K1-independent mechanisms (reviewed in ). The S6Autophagy plays a critical role in shuttling lipid droplets in the hepatocyte to the lysosome for hydrolysis, a process termed lipophagy . mTORC1 Raptor in the liver suppresses DNL through the inhibition of the SREBP-1c-regulated lipogenic gene program and protects mice from hepatic steatosis [Raptor in the liver have increased steatosis [Given its critical role in lipid metabolism, the role of mTORC1 in NAFLD is well appreciated but turns out to be complicated . Deletioteatosis . Howeverteatosis ,112. Andteatosis  and liveteatosis . Thus, tteatosis . In a reteatosis . This diteatosis . TFE3 inteatosis . In anotteatosis . Utiliziteatosis . Mice witeatosis . Forced Rictor deletion displayed a loss in AKT Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis and impaired glycolysis and lipogenesis [Rictor in the liver (LrictorKO) failed to inhibit hepatic glucose output in response to insulin [Studies also demonstrated that mTORC2 plays important roles in liver lipid homeostasis . Hagiwarogenesis . These l insulin . LrictorTsc1 and Pten specifically in the liver (termed L-dKO mice) exhibited concomitant activation of mTORC1 and mTORC2 signaling and displayed hepatosteatosis progressing to hepatocellular carcinoma (HCC) [Dysregulation of mTOR signaling in the liver also results in cancer progression. Guri and colleagues reported that mice lacking ma (HCC) . LongituThe mTOR pathway regulates both physiological and pathological processes in the heart . ItmTORC1 is a critical regulator of cardiac hypertrophy and remodeling . CardiacThe activity of mTORC1 can be modified by other pathways during cardiac stress conditions. Studies showed that p38 MAPK contributes to the maladaptive hypertrophy during stress conditions by enhancing mTORC1 activity. As described earlier, reactive oxygen species (ROS) can activate p38, which in turn reduces the level of REDD1 . The decMyocardial ischemia or energy stress leads to mTORC1 inhibition and protective adaption such as autophagy, which in turn limits myocardial infarction . RHEB isRictor in cardiomyocytes induces cardiac dysfunction and dilation in response to pressure overload [Rictor deletion in adults also leads to cardiac dysfunction in mice undergoing TAC [Rictor decreases lifespan in male mice, suggesting a protective role of mTORC2 against aging [Unlike the adverse effect of mTORC1, studies have shown that mTORC2 activation promotes compensatory cardiac growth and limits maladaptive hypertrophy . Constitoverload . Rictor oing TAC . In addist aging . Furtherst aging . Of notest aging . Thus, ist aging .In this review, we summarize the recent findings demonstrating the regulation of the mTOR signaling network by cAMP and cGMP, as well as by their associated cyclic nucleotide-dependent protein kinases PKA and PKG. Although these signaling crosstalks could be mediated by various mechanisms as reported in previous studies, further effort is needed to elucidate the role of these signaling events in physiological and disease conditions.


Fibroblast growth factors (FGFs) encode a large family of growth factor proteins that activate several intracellular signaling pathways to control diverse physiological functions. The human genome encodes 22 FGFs that share a high sequence and structural homology with those of other vertebrates. FGFs orchestrate diverse biological functions by regulating cellular differentiation, proliferation, and migration. Dysregulated FGF signaling may contribute to several pathological conditions, including cancer. Notably, FGFs exhibit wide functional diversity among different vertebrates spatiotemporally. A comparative study of FGF receptor ligands and their diverse roles in vertebrates ranging from embryonic development to pathological conditions may expand our understanding of FGF. Moreover, targeting diverse FGF signals requires knowledge regarding their structural and functional heterogeneity among vertebrates. This study summarizes the current understanding of human FGF signals and correlates them with those in mouse and Xenopus models, thereby facilitating the identification of therapeutic targets for various human disorders. Fibroblast growth factors (FGFs) were first identified in 1973 in bovine pituitary extract . FGFs haFGFs—present in invertebrates and vertebrates—are highly conserved in gene structure and amino acid sequence. Additionally, FGFs are the most diverse group of growth factors in vertebrates; approximately 22 members of FGFs have been identified in vertebrates, with a molecular mass of 17–34 kDa and 13–17% amino acid identity . Based oMoreover, diversified FGF signaling requires the precise regulation of FGF activity and receptor specificity. The FGF family is extensively complex , and strFgf genes are dispersed throughout the vertebrate genome. The human and mouse Fgf families comprise 22 members, and the Xenopus Fgf family codes for approximately 19–20 FGFs . F. F166]. FGF23 advances prostate cancer as an autocrine, paracrine, or endocrine growth factor. In vitro studies showed that FGF23 promotes prostate cancer cell line proliferation, invasion, and anchorage-independent growth; however, FGF23 knockdown slows tumor growth in vivo . These iCurrent understanding of the roles of FGF signaling in various biological and developmental processes has substantially improved in the last few decades. The FGF/FGFR system influences the pathophysiology of numerous human ailments, including hereditary disorders, metabolic diseases, and cancers. Moreover, the molecular structures of FGFs and their specific receptors regulate the transduction specificity and activation of FGF signaling. Therefore, knowledge regarding the structural and functional diversity of FGFs among different species is pertinent to understanding their influence on health and disease progression. In this review, we outlined the structures and functions of several vertebrate FGFs and correlated them with various human disorders.The precise roles of specific FGFs/FGFRs in the onset and progression of diseases, their spatiotemporal expression patterns, and underlying mechanisms remain largely unclear. During various developmental and pathological processes, an extensive crosstalk occurs between the FGF pathway and other signaling pathways, including the BMP/TGF-β, PTH, hedgehog, and retinoid pathways. Therefore, an understanding of the interaction mechanism of FGF signaling with multiple signaling pathways in different species will provide a molecular foundation for designing combination therapies . AdditioFurthermore, precision medicine considerably relies on biomarkers and genetic variants. Therefore, identifying specific mutations and biomarkers associated with FGF-related diseases will facilitate the development of more targeted treatments. However, the commonly employed technique for determining the contribution of certain FGFs to disease etiology has drawbacks.We need new methodologies to gain insights into FGF-targeted therapy, including more spatiotemporally programmable genetic methods, single-cell analysis, in vivo imaging, additional species of model organisms, and omics technologies. From the patient care perspective, big data and artificial intelligence (AI) can be used to analyze patient data to find trends that predict the evolution of FGF-related diseases and how well they will respond to therapy.On the bright side, scientists are approaching these targeted therapies in diverse ways. For example, clinical trials have evaluated several FGF aptamers targeting bone-forming sites in skeletal tissues and small molecule disrupters targeting several cancers. Disrupter drugs such as PD173074 and bemarituzumab are the potent and selective blockers of FGFR1 and FGFR3, and FGFR2b, respectively ,175, andConclusively, detailed studies on the structure- and function-based drug designing of agonists and antagonists are warranted to improve therapeutic development.


Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid blasts in the bone marrow (BM). Despite advances in therapy, the prognosis for AML patients remains poor, and there is a need to identify novel molecular pathways regulating tumor cell survival and proliferation. F-box ubiquitin E3 ligase, FBXO21, has low expression in AML, but expression correlates with survival in AML patients and patients with higher expression have poorer outcomes. Silencing FBXO21 in human-derived AML cell lines and primary patient samples leads to differentiation, inhibition of tumor progression, and sensitization to chemotherapy agents. Additionally, knockdown of FBXO21 leads to up-regulation of cytokine signaling pathways. Through a mass spectrometry-based proteomic analysis of FBXO21 in AML, we identified that FBXO21 ubiquitylates p85α, a regulatory subunit of the phosphoinositide 3-kinase (PI3K) pathway, for degradation resulting in decreased PI3K signaling, dimerization of free p85α and ERK activation. These findings reveal the ubiquitin E3 ligase, FBXO21, plays a critical role in regulating AML pathogenesis, specifically through alterations in PI3K via regulation of p85α protein stability. FBXO21, is differentially expressed in leukemia compared to normal bone marrow (BM). Interestingly, low expression of FBXO21 correlates with better overall survival in AML patients .–41.39–41These findings identify a novel role for FBXO21 in PI3K signaling by ubiquitination of p85α. Although p85α is a regulatory sub-unit of PI3K signaling and lacks kinase activity, excess free p85α following silencing leads to dimerization and decreased interaction with its catalytic sub-unit p110. Taken together, the data suggest targeting FBXO21 could inhibit canonical PI3K signaling and impedes growth of AML, but may also impede growth of other cancer sub-types dependent on canonical PI3K signaling.+ Expansion Supplement (StemCell Technologies). The shRNA plasmids were purchased from Sigma-Aldrich. FBXO21 and ∆FBXO21 were subcloned from pCDNA  into pMIGR1 with tandem Strep and Flag tags, and retrovirus was produced as previously described [HEK293T, PHOENIX-Amphos, HL-60, KASUMI-1, THP-1, and MOLM-13 cells were purchased from ATCC and DSMZ. Human AML cells  were cultured in StemSpan SFEM II media with CD34escribed , 42. Len5 MOLM-13 cells were transplanted into sub-lethally (250 cGy) irradiated 6–10 week old NSG mice . All experiments performed were approved by the Institutional Animal Care and Use Committee of the University of Nebraska Medical Center in accordance with NIH guidelines.For transplants, 5 × 10For apoptosis, staining was performed following BioLegend apoptosis staining protocol. Antibodies listed in supplemental materials and methods.Total RNA was harvested from cells using the Monarch Total RNA Miniprep Kit . RNA sequencing and analysis was performed by Novogene.Cytokine arrays were performed in accordance with the manufacturer’s protocol . CXCL10 ELISA assays were performed per manufacturer’s protocol .Samples were prepared and TMT-labeled per manufacturer’s protocol (ThermoFisher TMT16plex Mass Tag Labeling Kits). Following TMT labeling, acetonitrile was removed by speedvac, and samples were resuspended in 0.1% trifluoroacetic acid. Sample concentrations were re-quantified (Pierce Quantitative Colorimetric Peptide Assay kit) and combined in equal concentration. Following combination, samples were fractionated by ThermoFisher high pH reverse phase fractionation kit following manufacturer’s protocol. Fractions were dried and resuspended in 0.1% Formic Acid for MS analysis as previously described , 44. K-εFBXO21, HA-ΔFBXO21, or GFP-p85α. 48 h post transfection, HA-FBXO21, HA-ΔFBXO21, or GFP-p85α were immunopurified from the whole cell extracts using Anti-HA (Sigma) or Anti-GFP  beads overnight at 4 °C. The immunopurified HA-FBXO21 or HA-ΔFBXO21 (0.5 µg) proteins were incubated with immunopurified GFP-p85α (0.5 µg), E1 (500 ng), E2-UbcH5a (500 ng), FLAG-ubiquitin (0.5 µg) (BostonBiochem), and ATP (10 mM). Ubiquitylation reactions were performed in 100 mM NaCl, 1 mM DTT, 5 mM MgCl2, 25 mM Tris-Cl (pH 7.5), incubated at 30 °C for 2 h, and stopped with 2× laemmli buffer (10 min at 95 °C).HEK293T cells were transfected with plasmids encoding HA-t test assuming samples of equal variance. Error bars depict the standard deviation ± mean. For survival curve, the p value was calculated using a Log-rank (Mantel-cox) test.All experiments were performed in triplicate unless noted and statistical analyses were performed using unpaired two-tailed Student’s Suuplemental materialSupplemental Tables


Uric acid lithiasis accounts for about 10% of all types of renal lithiasis. The most common causes of uric acid lithiasis are low urinary pH, followed by high concentration of urinary uric acid, and low diuresis. Treatment of patients consists of alkalinization of urine, reducing the consumption of purine-rich foods, and administration of xanthine oxidase inhibitors, because there are no established therapeutic inhibitors of uric acid crystallization. We recently found that theobromine inhibited uric acid crystallization in vitro, and that the increased urinary level of theobromine following its oral consumption was associated with the prevention of uric acid crystallization. In this study, we evaluated the inhibitory effects of theobromine metabolites and other methylxanthine-related compounds on uric acid crystallization. We also measured the urinary concentrations of theobromine and its metabolites in samples from healthy individuals and patients with uric acid stones and compared the extent of uric acid supersaturation and uric acid crystal formation in these different samples. Theobromine and other methylxanthines that lacked a substituent at position 1 inhibited uric acid crystallization, but other methylxanthines did not have this effect. Individuals with clinical parameters that favored uric acid crystallization did not develop uric acid crystals when theobromine and its metabolites were in the urine at high levels. Thus, theobromine and its metabolites reduced the risk of uric acid lithiasis. Renal lithiasis has a worldwide prevalence of about 10% ,3, and tThere are different types of renal stones, and these different stones have different etiologies. Stone formation can be affected by metabolic factors, genetic factors, and lifestyle factors, including diet and drug use. Urinary alterations and physiochemical factors also affect the risk of crystallization. An important etiological factor is urinary supersaturation of compounds that readily crystallize.The main etiologic factors associated with the development of UA stones are urinary pH below 5.5, hyperuricosuria , and low diuresis ,11,12. TAlthough the major etiological factors associated with UA lithiasis are low urinary pH, followed by high urinary levels of UA, and low diuresis, many individuals who have elevated urinary UA levels or low urinary pH do not develop UA stones . This inThe traditional treatments for UA lithiasis are alkalinization of urine, restricting the consumption of purine-rich foods, and pharmacological treatment with a xanthine oxidase inhibitor . In contAfter intake of theobromine, the human body metabolizes it and excretes different products into the urine, mainly 7-methylxanthine (36%), unmetabolized theobromine 21%), 3-methylxanthine (21%), and 3,7-dimethyluric acid (1.3%)  (IB3414). All participants provided written informed consent before participation. Three spot urine samples were collected from each participant at intervals of at least 7 days. Samples were collected under standard conditions in a sterile container, with no additives or preservatives, as they were processed immediately after collection. All participants were instructed to follow their usual diets. Patients with UA stones received oral theobromine 120 mg/day) for 14 days before collection of the third sample, and the results are included in a previously published study [ mg/day fThe main urinary parameters related to UA lithogenesis were determined. Thus, urinary pH was measured using a Crison pH meter, and UA concentration was determined using the uricase method. Theobromine and its metabolites were measured using ultra-high-performance liquid chromatography and high-resolution mass spectrometry (UHPLC/HRMS), as previously described .UA) of a sample. As previously described [UA were calculated using the following formulas at the pH of the sample:UA are at the pH of the sample, Ksp is the solubility product of UA (2.25 × 10−9 mol2L−2 at 37 °C), Ka1 is the first dissociation constant of UA (4.2 × 10−6 mol/L at 37 °C) [γHU− is the monovalent ion activity coefficient of HU− at the characteristic ionic strength of urine (~0.75) [The urinary pH and UA concentrations were used to determine the UA supersaturation  , γHU− is (~0.75) , and cH2e sample . UA crystallization was determined by measuring the formation of UA crystals in polystyrene non-treated culture dishes , in which 5 mL of urine was maintained for 24 h at room temperature and then carefully removed via aspiration with a pipette. This test is a simplified version of the Risk for UA Crystallization (RUAC) test . A resulp-value less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 23.0 .Intergroup comparisons (Δ induction time between compounds) and intragroup comparisons (Δ induction time between different concentrations of the same compound) were performed using a one-way ANOVA test. A two-tailed Theobromine and other methylxanthines that lacked a substituent at position 1 inhibited UA crystallization, but other methylxanthines did not have this effect. Individuals with clinical parameters that favored UA crystallization did not develop UA crystals when theobromine and its metabolites were in the urine at high levels. Thus, theobromine and its metabolites reduced the risk of UA lithiasis.


Farming in India faces a sustainability challenge due to its overreliance on chemical inputs. For every US$ 1,000 investment in sustainable farming, a US$ 100,000 subsidy is allocated for chemical fertilizers. Indian farming system is far off the optimal nitrogen efficiency, calling for substantial reforms in policy towards the transition to sustainable inputs. We examine the propensity of Indian farmers to adopt biofertilizers and other sustainable inputs. While small farmers are inclined towards chemical inputs, sustainable inputs are costly. Here we show that less than 5 per cent of the farming population contributes to the 95 per cent usage of the bio-fertilizer in India. However, small and marginal farmers contribute substantially to food security. Shifting from chemical to sustainable inputs calls for autonomous investment by the state to augment the capacity and improve affordability. We illustrate the transition to sustainability through a framework that includes scale, affordability, and sustainable inputs. Although the share of agriculture in the Gross Domestic Product (GDP) has been declining over the decades, it still generates close to two-fifth of employment while its share in the national income is nearly one-fifth4. Most Indian farms (85%) are marginal and small, relying on the monsoon5. Fertilizer is a crucial input in farming6. Broadly, fertilizers are of two types: chemical and bio. However, the relationship between fertilizer and soil health is not unidirectional but non-linear9. Although the scientific literature posits improvements in yield due to chemical fertilizers, there is no dearth of inferences pointing to emerging disadvantages11. The question of optimal fertilizer use is rather difficult for an individual farmer to answer unless they have access to knowledge inputs14. Although the advocacy for the chemical regime emerges from an angle of food security, it is now increasingly regarded as a threat to sustainability. Sustainability in agriculture refers to increasing yield per unit without negatively affecting soil and water, and non-agricultural sectors15. Society encounters two types of challenges: (1) adopting sustainable agricultural practices to feed people now and in the foreseeable future and (2) doubling food production to meet the required demand across the world by 205016. A pertinent question is the pace of transition. The path is not linear. Instead, it requires resources and public goods. A discrete transition from chemical to bio inputs may debilitate the region’s ability to coordinate the public distribution system. Hence, the challenge is to have a balanced transition which is inclusive. Therefore, in this paper, we examine the propensity of Indian farmers to adopt bio-fertilizers and other sustainable inputs.India’s progress in crossing the threshold towards a sustainable linkage between farming and food security is slow. It failed to move from the Sustainable Nitrogen Management Index (SNMI) precarious zone to a safer zone18. Fundamentally, the problem involves two dimensions: capacity and usage. In India, capacity is yet to come up for a balanced transition that absorbs marginal to medium land holdings21. Compared to the large subsidy for chemical inputs, the public investment in bio inputs is much lower than the threshold. The chemical fertilizer subsidy in India is worth Rs. 1,400 billion (US$ 18 billion), whereas the total allocation for organic inputs is only Rs. 13.2 billion (US$ 0.17 billion)22. In other words, for every US$ 1,000 investment in sustainable farming, a US$ 100,000 subsidy is allocated for chemical fertilizers. However, recent policy initiatives like the Paramparagat Krishi Vikas Yojana (PKVY) aim to promote farming units to use bio inputs and provide financial support and provisioning of inputs. Such policy interventions may be helpful in terms of cost reduction, even though they may induce a slight revenue decline. Studies have shown that compared to conventional techniques, farms which adopt organic inputs yield better efficiency24. However, significant challenges emanate from inordinate delays in provisioning financial resources, inadequate training, and lack of scientific facilities25.Although bio inputs are associated with efficiency and return, there are capacity constraints in production, distribution, storage and quality26. Therefore, exploring the relationship between scale heterogeneity and the propensity to use bio inputs is crucial. For this purpose, we structure farming units into bins, bagging small, medium and large units in distinctive groups, to gauge the variation in chemical inputs and the adoption of bio inputs using nationally representative farmer-level microdata27. Our empirical analysis examines four farming systems focusing on sustainability and scale. Further, we discuss the transition in input usage across the systems. An example is transitioning from low-scale and low-sustainable input to low-scale and high-sustainable input usage.Although the capacity side generated considerable scholarly interest, studies on the usage of bio inputs in India's context are nascentThe performance of the farms in the Indian agriculture sector is sensitive to the scale of value and quality of inputs and gross value of outputs (GVO). GVO is a measure of sales or revenue from products and by-products. To examine GVO across production classes, we split the farming households into four quartiles based on GVO per unit of land cultivated. Box-whisker plots in Fig. 28. The second quartile is not discernibly different from the previous one  across deciles  used in agriculture. The expenditure on agricultural inputs in India consists of improved seeds, fertilizers, crop protection , machinery, irrigation, land rent, payments for extension, crop insurance premiums, and other miscellaneous expenditures. We reinvestigate the input cost in terms of chemical fertilizer, pesticide, biofertilizer, manure, biopesticide, labour, irrigation and crop insurance by inscribing it in the deciles of the GVO Fig. a. Intereles Fig. .Figure 230. The Government of India's recently launched soil health card scheme aimed to cover all sections of the farming category. While the awareness for the scheme is high, indicating the benefits for high fertilizer-consuming crops such as paddy or cotton, careful planning is needed to obtain widespread benefits to agriculture and the environment in the country31. These include specially designed pilot projects, use of technology, reduction in the subsidy of nitrogenous fertilizers, doorstep delivery of micro-nutrients, and prioritized funding for the development of supply chain infrastructure31.Among the inputs, the cost of fertilizer and labour are the principal ones, varying across deciles. The area of the decile depicts the share of fertilizer to the total value of inputs. We divide each decile in Fig.  by the f33. It is crucial to assess the outcomes if we divide these inputs by land  to the total value of inputs as the sustainability component (SC). We compute the deciles of either the value of the output or its unit value Fig. b, c. AcrRegarding affordability, it is crucial to know if the SC varies across the economic strata, measured by the deciles of per capita monthly consumption expenditure (MPCE). For every decile, we compute the average of SC at a 95% confidence interval Fig. a. There 34. Gini and Lorenz get widely adopted in literature to examine the income and wealth distribution in society. The Gini index takes values between 0 and 1. The closer the index is to 0, the more equal the distribution is and vice-versa34. The Lorenz curve shows the graphical distribution of income by the proportion of the society. We use Gini and Lorenz curve for the distribution of expenditure used on fertilizer  survey on the theme of “land and livestock holding of households and situation assessment of agricultural households”. National Statistical Office conducts the survey, Government of India. The data was collected during 2018–2019, which captured the information for two cropping seasons. There were separate visits for both seasons. While the first round captured the data for July to December 2018 (monsoon season), the second round was from January to June 2019 (post-monsoon season). Since Indian agriculture is predominantly rainfed, we examine only the data from the monsoon season. The farming household is the unit of analysis. Either the head of the household or a key informant (a representative of the household familiar with farming details) is the respondent. Samples were drawn from 5940 first-stage units (hamlet groups). Our sample comprises 58,035 households across India (except for the union territory Andaman and Nicobar Islands).Rhizobium, Bacillus sp., and Mycorrhiza. Manure is a natural substance that emerges from the waste of plants and animals, for example, cow dung. Pesticide refers to chemical plant protection material like Copper Sulphate or Lime-Sulphur. Biopesticides are non-chemical plant protection materials like Azadirachta indica (Neem oil), Brassica napus (Rapeseed oil) and Mentha piperita (Mint oil).Fundamentally the analysis examines the monetary value of output and input used in agriculture. Further, these measures are also divided by the area of land operated for farming (in ha). The value of output refers to the monetary value of the output produced. The value of the input is the sum of the monetary value of diverse components. These components include chemical fertilizers, manure, biofertilizers, chemical pesticides, biopesticides, labour, irrigation, crop insurance, and other inputs. Chemical fertilizers are either inorganic materials or synthetic ones. It supplies nutrients to the growth of plants. For example, ammonium sulphate, nitrate, phosphate, and urea are chemical fertilizers. Biofertilizers have living microorganisms that contribute to the growth of the crop, for example, Labour costs are the value of payments to the hired labour irrespective of the nature of the contract . Irrigation, crop insurance, and other inputs are valued per actual expenses incurred. Apart from the value of inputs and output, we analyse the monthly consumption expenditure of the household. It is divided by the size of the households to arrive at monthly per-capita consumption expenditure. This variable captures regular spending on durables and non-durables incurred by the household. And it is a proxy for the economic well-being of the household.D , while the highest quartile is the topmost strata (highest 25%). To visualize the quartile, the box plot is used. If an observation lies outside the box, it is called an outlier, situating in either extreme. Within the box, the median is the crucial indicator of central tendency used for comparison across quartiles. It is crucial to analyze the deciles for incisive data slicing. Decile implies that data is split into ten equal-sized bins with nine cut points. Its utility lies in a more microscopic assessment of tails. We compute the median for every decile and divide ith decile mentclass2pt{minimquations  describeSupplementary Information.


Helicobacter pylori (H. pylori) infection as its important risk factor has been a hot and challenging research area. Among the numerous pathogenic factors of H. pylori, the virulence protein CagA has been widely studied as the only bacterial-derived oncoprotein. It was found that CagA entering into gastric epithelial cells (GECs) can induce the dysregulation of multiple cellular pathways such as MAPK signaling pathway, PI3K/Akt signaling pathway, NF-κB signaling pathway, Wnt/β-catenin signaling pathway, JAK-STAT signaling pathway, Hippo signaling pathway through phosphorylation and non-phosphorylation. These disordered pathways cause pathological changes in morphology, adhesion, polarity, proliferation, movement, and other processes of GECs, which eventually promotes the occurrence of GC. With the deepening of H. pylori-related research, the research on CagA-induced abnormal signaling pathway has been updated and deepened to some extent, so the key signaling pathways activated by CagA are used as the main stem to sort out the pathogenesis of CagA in this paper, aiming to provide new strategies for the H. pylori infection and treatment of GC in the future.Gastric cancer (GC), a common and high-mortality disease, still occupies an important position in current cancer research, and  Several. pylori , so in t2CagA is a 128-145 kDa protein  that incThe C-terminal variable region of CagA protein has a repetitive region of the EPIYA Motif, which plays a crucial role in membrane localization in non-polarized host cells and can be classified into four different types according to the amino acid sequence around each EPIYA motif: EPIYA-A, EPIYA-B, EPIYA-C, and EPIYA-D, which constitute the classical EPIYA-repeat region by different combinations and have evident regional variability Figure 1E sequence and CMW sequence respectively based on this difference. Most East Asian CagA proteins have only one CM sequence downstream of the EPIYA-D fragment. In contrast, in Western CagA, the CM sequence is located in the N-terminal part of the EPIYA-C fragment and downstream of the final EPIYA-C fragment, so the number of CM motifs in Western CagA increases along with the multiplication of the EPIYA-C fragment  upon non-phosphorylation ; that isfragment Figure 1fragment .3H. pylori to GECs, CagA enters the host cell through the synergistic action of various molecules such as the type IV secretion system encoded by the Cag pathogenicity island (Cag PAI), externalized phosphatidylserine (PS), multiple adhesion factors  and the host cell integrin ɑ5β1  motif with PS plays a major role in the membrane binding of CagA, whereas in non-polarized cells, it is the EPIYA motif that is critical for CagA membrane binding (H. pylori can shed Outer Membrane Vesicles (OMVs) from its outer membrane surface and enter human gastric adenocarcinoma (AGS) cells by macropinocytosis/phagocytosis, like other Gram-negative bacilli   , so OMVsnd UreA) . Studiesogenesis , althougogenesis .CagA immobilized at the plasma membrane undergoes selective tyrosine phosphorylation at the EPIYA site mediated by src family kinase (SFK) and c-Abl tyrosine kinase, where EPIYA-C or EPIYA-D is phosphorylated by SFK at the onset of infection (0.5-2h), followed by rapid inactivation of SFK by phosphorylated CagA and C-terminal Src kinase (Csk) , and pos44.1MAPK signaling pathway is a cellular pathway that regulates cell growth, differentiation, stress, inflammation, immunity, and other important physiopathological responses through sequential activation of MAP kinase (MAPK), MAPK kinase  and MEK kinase  . Among t4.1.1H. pylori -related junction protein (via the tyrosine phosphorylation motif (B-TPM) of EPIYA-B repeat region, thereby inducing the PI3K/Akt signaling pathway  When CagA is not phosphorylated, the CM motif interacts with the hepatocyte growth factor receptor-C-met , represe protein , causing protein . (2) Cag pathway . The B-T binding . Howeveraffinity . So CagAaffinity . (3) Sch gerbils , which i gerbils . The PI3 gerbils . So, the4.34.3.1Downstream of the PI3K/Akt signal pathway, NF-κB is an important inflammatory target, which acts as an essential nuclear transcription factor regulating the inflammatory response/immune response of bodies and apoptotic, stress response of cells . NF-κB ivia tumor necrosis factor receptor-associated molecule 6 (TRAF6)  . The act (TRAF6) , release (TRAF6) , and ind (TRAF6) . Investi (TRAF6) . The act (TRAF6) . This pa (TRAF6) . CagA-ac (TRAF6) . NF-κB a (TRAF6) . Therefo (TRAF6) .4.3.2The JAK-STAT signaling pathway consists of three components: tyrosine kinase-associated receptors that receive the signal, tyrosine kinase JAK that transmits the signal, and transcription factor STAT that produces the effect . As a stH. pylori, the upregulation of IL-6 and IL-11 expression in GECs depends on non-phosphorylated CagA, and induces STAT3 tyrosine phosphorylation through the gp130 subunit of the IL-6 receptor to manipulate host immunity and promote immune evasion  family transcription factors, which induces the expression of cancer-related genes such as Cyclin D1 and c-myc to affect cell differentiation, proliferation, migration, and adhesion, leading to tumorigenesis  and its accessory receptor low-density lipoprotein receptor-related protein (LRP) . Activatigenesis . H. pyloGC cells , so the 4.5The Hippo signaling pathway, as a conserved pathway originally defined through Drosophila protein kinase (Hippo), mostly controls organ size by regulating cell proliferation and apoptosis, and acts as a key role in embryonic development, organ growth, tissue regeneration, stem cell pluripotency, and tumorigenesis . There iH. pylori infection induces abnormal Hippo signaling in GECs and promotes the activation and nucleation of the critical effector molecule YAP, during which CagA upregulates LATS2 and significantly increases the expression of YAP and TAZ, which induces the expression of downstream target genes, thereby inducing EMT and intestinal epithelial to increase the risk of early GC  Promoting morphological changes ; (2) Facilitating immune dysregulation and exacerbating inflammatory responses; (3) Inducing gene mutations and inhibiting apoptosis, releasing sustained proliferative signals to increase cancer risk; (4) Regulate gene transcription, downregulate multiple tumor suppressors such as RUNX3, p53, and Siva1, and reduce oncogenic activity. These findings systematically demonstrate the mechanism of CagA in H. pylori-induced transformation of chronic gastritis to GC, so blocking the expression of key factors in MAPK signaling pathway, PI3K/Akt signaling pathway, NF-κB signaling pathway, JAK-STAT signaling pathway, Wnt/β-catenin signaling pathway, and Hippo signaling pathway, will be a new strategy to eradicate H. pylori and treat GC.GC is one type of cancer that develops gradually through a multi-step histopathological cascade reaction over a long period of time . BreakinHW, MZ, and LZ concepted and designed the review. MZ, FS and SZ wrote the manuscript. HW, LX, and LZ revised the manuscript. HW and MZ should be considered joint first author. All authors contributed to the article and approved the submitted version.


The cerebellum is classically associated with fine motor control, motor learning, and timing of actions. However, while its anatomy is well described and many synaptic plasticity have been identified, the computation performed by the cerebellar cortex is still debated. We, here, review recent advances on how the description of the functional synaptic connectivity between granule cells and Purkinje cells support the hypothesis that the cerebellum stores internal models of the body coordinates. We propose that internal models are specific of the task and of the locomotor context of each individual.  One of the major role of the cerebellum in sensorimotor adaptation is to learn to predict the future in order to adjust or correct the course of our actions –3. To doThe cerebellar cortex receives two major excitatory inputs, the climbing (CF) and the mossy fibers (MF), which are both topographically organized –11. A giAs opposed to the strict sagittal orientation of the CF inputs, MF inputs, which contact GCs, project to many different GC layer areas in a given lobule sending the same information into multiple microzones , 25. IndThe organization of MF inputs into the GC layer expands encoding possibilities and is in agreement with the long-standing Marr–Albus–Ito hypothesis, suggesting that expansion recoding in the GC layer enables pattern separation of similar MF inputs –42. MoreGlutamate uncaging combined with patch-clamp recordings can be used on acute brain slices –49. ThisMany in vitro and in vivo experiments demonstrated that while direct stimulation of PF beams can activate PCs along the beam, GC or MF activation actually modulate specific groups of PCs –58. In vBy repeating photostimulation and establishing excitatory GC-PC and GC-MLI connectivity maps in an identified set of microzones across many mice, several other operational rules were described , 24: (1)Altogether, these operational rules underlying microzonal communication in the cerebellar cortex are likely at the core of cerebellar computation . The desThis assumption might appear in contradiction with the dense activation of GCs observed using two-photon imaging of genetically encoded calcium indicators in behaving mice or zebrafishes , 65, 66.To conclude, patchy connectivity maps at the GC-MLI-PC connections may underlie the communication between specific microzones in the cerebellar cortex. Graph network properties of GC-PC connectivity maps suggest that context-dependent and task-specific internal models are encoded at the GC-PC synapses. Next step will be to describe how the feedforward inhibition influences connectivity maps and intermodular communication. Unraveling the rules governing the coordination between microzones will shed light on how the cerebellar cortex controls the output stage of the cerebellum. As an appealing perspective, it will be important to describe how the MF-GC-MLI pathway correlates microzones using genetically encoded voltage sensitive indicators combined with two-photon imaging. Knowing the combination of microzones and their sequence of activation in a specific behavior will help designing and refining cerebellar stimulation protocols to compensate for cerebellar dysfunction in pathological models .


The aim of this study was to analyze the relationship between serum amyloid A (SAA) concentrations in patients with obstructive sleep apnea–hypopnea syndrome (OSAHS) and their magnetic resonance imaging (MRI) of resting brain function.Male patients with OSAHS were enrolled from January to June 2019 in Suzhou Ninth People’s Hospital Affiliated to Soochow University, and nineteen healthy male volunteers were selected as the normal control group. The patients with OSAHS were divided into mild, moderate, and severe groups according to their apnea-hypopnea index (AHI). Early in the morning after the polysomnography (PSG), blood samples were collected and serum levels of serum amyloid A (SAA) were measured by enzyme-linked immunosorbent assay. All subjects were scored by the Auditory Verbal Learning Test (AVLT) scale. Resting brain function images of healthy male volunteers and patients in the severe group were collected by 3.0 T magnetic resonance scanner. SPSS25.0 software was used for statistical analysis.n = 43) were higher than those of control group (n = 19). The scores of AVLT-immediate and AVLT-delay in the severe OSAHS group were lower than those in the control group (P < 0.05), and it was negatively correlated with SAA. In the severe OSAHS group, the rest state Function Connection (rsFC) in temporal lobe, marginal lobe, and frontal lobe was lower than that in the control group (P < 0.05) and was significantly negatively correlated with SAA. The rsFC in bilateral parietal lobes was higher than that in the control group (P < 0.05), was significantly positively correlated with SAA, and was negatively correlated with AVLT-delay.The SAA of the OSAHS group (The significant increase in SAA concentration in patients with OSAHS correlated with brain rsFC intensity, providing a reference role for the diagnosis, treatment, and prognosis of cognitive dysfunction in patients with OSAHS. Obstructive sleep apnea–hypopnea syndrome (OSAHS) is a chronic respiratory disease of sleep characterized by recurrent hypopneas and apneas caused by partial or complete obstruction of the upper airway. OSAHS causes intermittent hypoxemia, repeated micro-arousals, and sleep structure disorders, and is associated with multi-system complications . AccordiCognitive dysfunction is the main complication of the nervous system in patients with OSAHS , 4. OSAHResting-state functional magnetic resonance imaging (rs-fMRI), based on blood oxygenation level dependence (BOLD), is an important technology in studying cognitive impairment with an ability to detect brain structure and function noninvasively. Studies have shown that patients with OSAHS have an abnormal resting-state default network, including changes between internal functional connections –10. HoweIn this study, we aimed to analyze the relationship between SAA, resting-state brain functional connectivity, and cognitive function. From January to June 2019, male patients with OSAHS were selected from outpatients or inpatients in Suzhou Ninth People’s Hospital affiliated with Soochow University, and were further divided into a mild group, moderate group, and severe group according to AHI. Healthy male volunteers were selected as the normal control group. All selected patients and controls met their respective trial inclusion criteria.The inclusion criteria of patients with OSAHS were as follows: (1) patients with OSAHS diagnosed by PSG had no other sleep disorders; (2) no history of airway and throat surgery, such as tonsillectomy and adenoidectomy; (3) age ≥ 20 years old and ≤ 60 years old; (4) right-handedness; (5) no alcohol addiction or illegal drug use; (6) no use of psychotropic drugs or medication which may affect on oxygen saturation, such as selective serotonin reuptake inhibitors; (7) no organic brain diseases and no serious cognitive impairment, such as meningioma, pituitary tumor, Parkinson’s disease, and Alzheimer’s disease, and scores on Minimum Mental State Examination (MMSE) > 24/30; (8) no lung disease or other chronic inflammatory diseases by CT examination and pulmonary function test, such as chronic bronchitis; (9) no MRI scan contraindications .The inclusion criteria of the normal control group were as follows: (1) no OSAHS or other sleep disorders confirmed by PSG; (2) age, education background, and handedness were matched with the selected patients with OSAHS; (3) healthy, without any history of neurological diseases, psychiatric medication, or lung disease; (4) no contraindications to MRl examination. This study was reviewed by the Ethics Committee of Suzhou Ninth Hospital Affiliated to Soochow University (No.2019005), and all subjects signed informed consent.Night PSG was carried out in the sleep monitoring Center of Suzhou Ninth People’s Hospital. Subjects were instructed to avoid behaviors including smoking, drinking alcohol, drinking coffee, taking sedative psychotropic drugs that may affect the monitoring process or outcomes within 24 h before the PSG examination. All PSG monitoring was performed with the Alice 6 polysomnography monitoring system of Philips Wellcome, USA. All subjects slept at least 7 h during the PSG; monitoring content included electrocardiogram, electroencephalography, electroophthalmography, electromyography, oral and nasal breathing airflow, chest and abdominal excursions, snoring and blood oxygen saturation. All data were stored, then automatically processed by computer software, and manually corrected by a professional sleep technician. According to the AASM manual definition, OSAHS was diagnosed when more than five respiratory obstruction events per hour were scored. Sleep stages were classified according to the AASM manual with respiratory events scored using standard criteria . SpecifiFor all subjects, 2 ml fasting venous blood was collected on the morning after PSG monitoring. Blood samples stood at room temperature for 2 h and centrifuged at low speed for 5 min, collected and SAA concentration was determined by ELISA. According to instructions of the ELISA kit, the concentration of SAA in peripheral blood was quantitatively detected by double-antibody sandwich method. The operational steps were carried out in strict accordance with the instructions, and the absorbance value was measured by multifunctional microplate meter (O.D.) to calculate the concentration of SAA in the sample according to the O.D.ESS ≥ 9 was considered sleepiness. (2) The Mini-Mental State Examination (MMSE) excluded subjects with significant cognitive impairment and senile dementia; (3) Auditory Verbal Learning Test (AVLT) included immediate recall and delayed recall used to evaluate the memory function of subjects. The total score of immediate memory is 75, delayed memory is 15, the bound score is 15, immediate memory and delayed memory a 4, and the lower the score, the worse the memory.(1) ESS  this questionnaire was used to assess daytime sleepiness of the subjects conducted before PSG examination. A total score of http://resting-fMRI.sourceforge.net) was used to extract BOLD sequence in the resting region of interest, and voxelwise was applied to do correlation analysis with other regions of DMN, so as to obtain brain regions with significant connections to region of interest. Two groups of data were obtained after the single sample T test, and the two groups of brain regions were selected as the MASK during the double-sample T test. When making multiple comparisons, the AlphaSim program provided by REST was used to correct the resulting positive result image (P < 0.05) presented by the REST software. During the correlation analysis, the REST software was used to extract the Z value of the brain region changed by rsFC, and the correlation analysis was conducted with AHI, ODI, ESS, MMSE, SAA, AVLT-immediate, and AVLT-delay.Data were collected using a 3.0 T magnetic resonance scanner (GE Discovery MR750 3.0 T) with a standard head 24 channel phase control coil. The data were preprocessed by the APABI software on a MATLAB platform. Functional connection analysis: at the resting state, the posterior cingulate cortex (PCC) of the human brain is one of the most intense areas of brain activity at the resting state . Therefot test. In patients with severe OSAHS, correlation analysis was performed between the rsFC abnormal brain areas and SAA, ESS score, AHI, ODI, MMSE score, AVLT-immediate, and AVLT-delay score. P < 0.05 was considered statistically significant.SPSS 25.0 statistical software was used for statistical analysis. Data are expressed as means ± standard deviation. Homogeneity of variance testing was performed before comparisons were conducted. Age, years of education, BMI, ESS score, AHI, ODI, MMSE score, AVLT-immediate score, AVLT-delay score, serum SAA concentration level, and rsFC between the two groups were examined by independent sample P > 0.05). Compared with the normal control group, BMI, AHI, ODI, and ESS of the OSAHS group were significantly greater (P < 0.05). Specific results are shown in Table In this study, all patients were male, and there was no statistical difference in age, education, and MMSE between the 43 patients with OSAHS and the 19 normal controls (P < 0.05). Compared with normal control group, there were significant differences between AVLT-immediate and AVLT-delay in the severe OSAHS group (P < 0.05). Compared with the mild group, there were significant differences between AVLT-immediate and AVLT-delay in severe OSAHS group (P < 0.05). There was no statistical significance between the other two groups (P > 0.05). See Table Overall comparison of AVLT-immediate and AVLT-delay in each group showed significant differences (P < 0.05). Further comparison of LSD between the two groups showed that SAA concentration was significantly increased in the mild OSAHS group (P < 0.05) and significantly increased in the moderate and severe OSAHS groups (P < 0.01) compared with the normal control group. There were also significant differences between mild and moderate groups, mild and severe groups, and moderate and severe groups . The concentration of SAA increased with the degree of severity of OSAHS. See Table Overall comparison of SAA concentrations in each group revealed significant differences (P < 0.05), and SAA was negatively correlated with AVLT-immediate and AVLT-delay (P < 0.05). See Table Correlation analysis results showed that SAA concentration in serum of patients with OSAHS was significantly positively correlated with AHI, ODI, and ESS score (P < 0.05); the frontal lobe showed a significant decrease in rsFC (P < 0.05), while rsFC in the left parietal lobe and right parietal lobe showed a significant increase (P < 0.05). See Fig. Compared with the normal control group, the severe OSAHS group showed significant reduction of rsFC in the temporal lobe, marginal lobe, and parahippocampal gyrus (P < 0.05), while the right parietal lobe was significantly positively correlated with ESS, AHI, ODI, and SAA (P < 0.05). The temporal lobe, marginal lobe, and parahippocampal gyrus were significantly negatively correlated with ESS, AHI, ODI, and SAA (P < 0.05). The frontal lobe was negatively correlated with ESS, AHI, ODI, and SAA (P < 0.05). Temporal lobe, limbic lobe, parahippocampal gyrus, and frontal lobe had no significant correlation with MMSE score, AVLT-immediate, and AVLT-delay. There was no significant correlation between the bilateral parietal lobe in MMSE and AVLT-immediate. The left parietal lobe and the right parietal lobe were negatively correlated with AVLT-delay (P < 0.05), respectively. See Table Bivariate correlation analysis showed that the left parietal lobe was significantly positively correlated with ESS, AHI, ODI, and SAA P < 0.0, while tF = 235.633, P < 0.001) (Table P < 0.05)  Table .The resu5) Table .Table 6AIn this study, seed point correlation analysis found that abnormal changes in resting-state brain functional connectivity occurred in patients with severe OSAHS, with different types of rsFC changes in the temporal, limbic, parahippocampal gyrus, frontal, and parietal lobe. The limbic system areas are related to memory and learning, mainly the cingulate gyrus and hippocampus, and the inferior parietal leaflets in the parietal lobe are related to digital memory and logic. The hippocampus, a core subregion of DMN, is closely related to memory, is very sensitive to hypoxia, and was found to have functional connectivity altered  related Although in this study, rsFC in severe OSAHS was significantly reduced, ODI was significantly increased, and AVLT immediate memory and delayed memory were significantly different. No correlation was found between parahippocampus and AVLT immediate memory and delayed memory, so hypoxia appears to lead to hippocampal damage, but this damage has not been transformed into the external performance of cognitive impairment. The subparietal leaflet in the parietal lobe is related to affective memory . This stIn this study, the correlation analysis found that SAA was related to cognitive impairment in patients with OSAHS, and associated with abnormalities of functional connectivity in the corresponding brain. Studies have shown that through CPAP treatment, patients with OSAHS improve daytime sleepiness, memory loss, and inattentive concentration, and serum SAA concentration decreased  comparedPrior studies , 19 haveThe findings of this study suggest that intermittent hypoxia of OSAHS may lead to increased levels of SAA and may be associated with impairment of neurocognitive function. Patients with severe OSAHS showed rsFC changes in the temporal, limbic, parahippocampal gyrus, frontal, and bilateral parietal lobes, which may be a neural mechanism related to cognitive impairment in patients with OSAHS. It is possible that the concentration of SAA of patients with OSAHS may indirectly reflect the changes of patients’ cognitive function and brain function. Thus, SAA may have a reference role for the diagnosis and prognosis of cognitive dysfunction in patients with clinically severe OSAHS.


To assess the correlation between serum uric acid (UA) level and diabetic kidney disease among adult-onset Type 1 diabetes mellitus (T1DM) patients in China.A total of 184 patients with adult-onset T1DM between January 2014 and December 2016 were recruited, with demographics and medical data collected. Comparisons were performed between according to different serum UA gender-specific quartiles. Relationship between serum UA level with urinary ACR and eGFR was also assessed.2, respectively. The median UA was 257.4 (208.2–334.8) μmol/L. Participants with higher serum UA levels had higher urinary ACR and lower eGFR than those with lower UA (P < 0.05). Higher serum UA level was significantly associated with higher urinary ACR in Spearman's correlational analysis (P = 0.006) and multiple stepwise regression analysis (P = 0.013). The association between serum UA and urinary ACR was not linear, but showed a curve correlation, which also showed in the sensitivity analysis. Serum UA in the upper gender-specific quartile, was associated with lower eGFR (P < 0.001) and showed an independent negative correlation with eGFR in multiple stepwise regression analysis (P < 0.001).Median urinary ACR and eGFR were 21.55  mg/g and 113.86  ml/min/1.73 mThe serum UA level was negatively correlated with eGFR and had a curve correlation with urinary ACR in adult-onset T1DM patients of China.The online version contains supplementary material available at 10.1007/s00592-023-02119-7. Diabetic kidney disease (DKD) is one of the most common chronic kidney diseases (CKD), closely related to end-stage renal disease (ESRD) and increased risk of cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM) . Most neHyperuricemia is one of the modifiable factors, contributing to cardiovascular disease, CKD, and hypertension –10. The This study was a cross-sectional study conducted in a single medical center in Anhui, China. A total of 184 hospitalized patients were recruited who were considered to have adult-onset T1DM presenting at the Department of Endocrinology in Anhui Provincial Hospital between January 2014 and December 2016. The patients were excluded if they had the following reasons: adolescent-onset T1DM, no data of the serum UA level, documented ketosis or ketoacidosis in the 3 months before enrollment, documented glomerulonephritis, systemic diseases, heart failure, urinary tract infections, or active gout. The patients, especially with DKD in our study, had not received high-protein diet and health education about a high-protein diet at enrollment. The research ethics committee of Anhui Provincial Hospital approved the study design (NO.2022-RE-331).Details of methodology of research and data collection were described in our previous study . DemograHyperuricaemia was typically reported when serum UA was higher or equal to 420umol/L (7 mg/dl) . The cliChi-square test or Fisher exact test. The relationship between serum UA level and urinary ACR was performed by Spearman’s correlational analysis, Pearson's correlational analysis, and multiple stepwise regression analysis. A P value < 0.05 was considered statistically significant.All statistical analyses were performed using IBM SPSS Statistics 20.0 version . A normal distribution of continuous variables was summarized as means ± standard deviation (SD), while a skewed distribution of continuous variables was expressed as medians with interquartile ranges. For continuous data with a skewed distribution among patients in gender-specific quartiles of serum UA, nonparametric tests were used for statistical analyses. The number (n) and percentage (%) in each category were calculated for categorical variables. The categorical variables were evaluated with a 2, respectively. The number of patients with G1, G2, G3a, G3b, G4, and G5 stages was 135, 29, 9, 6, 2, and 3, respectively, while with the A1, A2, and A3 stages was 118, 44, and 22, respectively. The patients with low DKD progression risk, moderately increased DKD progression, high DKD progression risk, and very high DKD progression risk were 116, 42, 8, and 18, respectively. The median UA was 257.4 (208.2–334.8) μmol/L, and the median dosage of insulin performed by patients was 0.59  U/kg/d. The baseline characteristics of the 184 adult-onset T1DM patients divided according to the gender-specific quartiles of serum UA are shown in Table P < 0.05 for all). However, there was no significant difference among all quartiles of serum UA in onset age, BMI, HbA1c, SBP, DBP, Hb, TG, HDL-c, LDL-c, ALB, the proportion of beta-blockers, loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, lowering serum uric acid drug treatment, or the dosage of insulin performed by patients. Figure P < 0.05).Of 184 adult-onset T1DM patients, 98 (53.3%) were male with median onset age of 29  years and median diabetic duration of 5.0  years. The median urinary ACR and eGFR were 21.55  mg/g and 113.86  ml/min/1.73 m P < 0.05). No significant correlation was observed between serum UA level and HbA1c as well as insulin dosage performed by patients. After adjustment for those significant factors, stepwise multiple linear regression analysis showed an independent positive association between serum UA levels and urinary ACR and a negative correlation between serum UA levels and eGFR (P < 0.05). Higher UA was significantly associated with higher urinary ACR in unadjusted    and multiple stepwise regression analysis (P = 0.013). Although the P value was significant in Fig. R-value was low. The association between serum uric acid and urinary ACR was nonlinear but showed a curve correlation , in both female and male T1DM patients .To analyze the correlations between serum UA levels and albuminuria, Spearman's correlation analysis was conducted to examine the factors associated with serum UA. Table P < 0.05 in all), and multiple stepwise regression analysis also showed that an independent negative correlation between serum UA levels and eGFR (Table P < 0.001). Figure Supplement 4 also shows that UA in the upper quartile was associated with lower eGFR in both female and male T1DM patients (P < 0.05 in both).UA in the upper gender-specific quartile was associated with lower eGFR Table B and 4 . Serum UA and urinary ACR had a curve correlation, which showed a positive linear correlation at macroalbuminuria and no linear correlation at less than macroalbuminuria (Table Supplement 1). Serum UA level was negatively correlated with eGFR no matter whether eGFR was normal or decreased, and the correlation between UA and eGFR gradually increased with the DKD progression risk. Serum UA was also observed to have a negative correlation with eGFR in patients who had a value of HbA1c less than 7.0%. Furthermore, serum UA had no correlation with urinary ACR in patients with HbA1c less than 7.0%, which was associated with a lower likelihood of macroalbuminuria in patients with good glycemic control (Table Supplement 2).DKD is one of the most common chronic kidney diseases (CKD) and remains the leading cause of morbidity and mortality in T1DM patients. Evidence has proved that the urinary albumin levels in T1DM patients may progressively increase five years after diagnosis . MicroalPrevious studies revealed that high serum UA might contribute to initiating arterial hypertension while it has little effect on already-established hypertension . SeveralAlthough hyperuricemia was not correlated with hypertension, it was positively correlated with high TG levels in this research Table . This ar2) [However, the Preventing Early Renal Loss in Diabetes (PERL) trial showed no significant benefits of serum UA reduction with allopurinol on kidney outcomes among patients with T1DM and early-to-moderate DKD, in which the included patients had a long course of disease  and the renal complications (most eGFR < 90 ml/min/1.73m2) .These findings cannot explain the association between serum UA levels and DKD. In addition, the FEATHER trial found that stage 3 CKD patients with hyperuricemia, who had no proteinuria and a higher baseline renal function, got significant benefits in renal outcomes from lowering Serum UA . For tim. suggested that plasma UA-mediated afferent arteriolar resistances of patients with T1DM may be caused by the thickening of the afferent renal arteriole, potentiating renal injury by causing renal microcirculation ischemia [. also found that UA lowering in patients with T1DM lowered systolic BP and modulated the renal efferent resistance responses to hyperglycemia but without impacting the RAAS or NO levels, suggesting that plasma UA may augment other hemodynamic or inflammatory mechanisms that control the renal response to hyperglycemia at the efferent arteriole [Some research has revealed the possible mechanism of serum UA levels on DKD. First, UA may directly cause renal inflammation promoting intrarenal inflammation, interstitial fibrosis, albuminuria, and chronic kidney disease development by depositing intraluminal micro-crystals in collecting ducts –36. Addiischemia . Lytvyn rteriole . Furtherrteriole . Finallyrteriole .However, this research had several limitations. First, our study was a single-center, cross-sectional observational research. We could not get a causal relationship between the serum UA and DKD. No follow-up data was also a limitation as we cannot further analyze the relationship between serum UA and DKD progression. Second, our study did not analyze the relationship between the trend of serum UA level with DKD and the mechanism that serum UA on DKD. Third, whether our research findings suit other groups remains uncertain. The effect and mechanism of TG and hyperuricemia on DKD in adult-onset T1DM patients are worthy of further investigation.The serum UA level was negatively correlated with eGFR and had a curve correlation with urinary ACR in adult-onset T1DM patients in China.Supplementary file1 (DOC 130 kb)Below is the link to the electronic supplementary material.