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1.
Chem Commun (Camb) ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134051

RESUMO

A hexanuclear cluster [(Cp*Dy)6K4Cl16(THF)6], [Cp*Dy]6, has been constructed from six {Cp*DyIII} synthons in which the strongly coordinating Cp*- caps determine the local anisotropy axes. Structural characterization of [Cp*Dy]6 shows two almost parallel triangular (Cp*Dy)3 fragments that are linked by the K+ and Cl- ions. Magnetic measurements reveal slow thermal relaxation and fast quantum tunneling relaxation in the absence of an external dc field. After applying a weak dc field, the quantum tunneling relaxation is efficiently suppressed, giving a sizable energy barrier of 561 K, which represents the current record energy barrier for high nuclearity organometallic SMMs.

2.
Cell Death Differ ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152555

RESUMO

Sepsis is a systemic inflammatory disease causing life-threatening multi-organ dysfunction. Accumulating evidences suggest that two forms of programmed necrosis, necroptosis and pyroptosis triggered by the pathogen component lipopolysaccharide (LPS) and inflammatory cytokines, play important roles in the development of bacterial sepsis-induced shock and tissue injury. Sepsis-induced shock and tissue injury required receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) phosphorylation, caspase11 activation and gasdermin D (GSDMD) cleavage. However, the synergistic effect of necroptosis and pyroptosis in the pathological progress of sepsis remains elusive. In this study, we found that blockage of both necroptosis and pyroptosis (double deletion of Ripk3/Gsdmd or Mlkl/Gsdmd) resulted in accumulative protection against septic shock, systemic blood clotting and multi-organ injury in mice. Bone marrow transplantation confirmed that necroptosis and pyroptosis in both myeloid and nonmyeloid cells are indispensable in the progression of sepsis-induced multi-organ injury. Both RIPK3 and GSDMD signaling collaborated to amplify necroinflammation and tissue factor release in macrophages and endothelial cells, which led to tissue injury. Furthermore, cell death induced by inflammatory cytokines and high-mobility group box 1 could be prevented by double ablation of Ripk3/Gsdmd or Mlkl/Gsdmd, suggesting that a positive feedback loop interconnecting RIPK3/MLKL and GSDMD machinery and inflammation facilitated sepsis progression. Collectively, our findings demonstrated that RIPK3-mediated necroptosis and GSDMD-mediated pyroptosis collaborated to amply inflammatory signaling and enhance tissue injury in the process of sepsis, which may shed new light on two potential targets of combined therapeutic interventions for this highly lethal disorder.

3.
Sci Data ; 7(1): 104, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32218446

RESUMO

Targeted SWATH-MS data analysis is critically dependent on the spectral library. Comprehensive spectral libraries of human or several other organisms have been published, but the extensive spectral library for mouse, a widely used model organism is not available. Here, we present a large murine spectral library covering more than 11,000 proteins and 240,000 proteotypic peptides, which included proteins derived from 9 murine tissue samples and one murine L929 cell line. This resource supports the quantification of 67% of all murine proteins annotated by UniProtKB/Swiss-Prot. Furthermore, we applied the spectral library to SWATH-MS data from murine tissue samples. Data are available via SWATHAtlas (PASS01441).

4.
Nat Commun ; 11(1): 1349, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152304

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

5.
Blood ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016282

RESUMO

Bacterial infection not only stimulates innate immune responses but also activates the coagulation cascades. Over-activation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC through amplifying the release of high mobility box group box 1 (HMGB1) into the blood stream. Inhibition of the expression of type 1 IFNs, disruption of their receptor IFN-α/ßR or downstream effector (e.g., HMGB1) uniformly decreased Gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the pro-coagulant activity of tissue factor (TF) by promoting the externalization of phosphatidylserine (PS) to the outer cell surface, where PS assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.

6.
Sci Rep ; 10(1): 987, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969603

RESUMO

Stable or marginal mass loss dominating in Karakoram has been reported widely through satellite and ground investigations. This work aimed to verify the variation in glacier mass by collecting ground-based data. By tracking profiles from the first survey by China-Pakistan Batura Glacier Investigation Group in 1974-1975, we revisited Batura Glacier and conducted an updated comparable measurement of the glacier surface elevation and ice thickness of this large valley glacier of Karakoram, in August 2017. Results of ground penetrating radar (GPR) measurement were used to improve the accuracy of an ice thickness distribution model (GlabTop2). The model calculation agreed reasonably with the measurement when the optimal basal shear stress (100 kPa for clean ice to 140 kPa for heavy debris cover) and shape factor (0.9) were used. We then used a glacier bed topographies map to calculate the ice flux. By subtracting the glacier surface topographies from the remote-sensing measurements, we observed a marginal thinning in Batura during 2000-2016, with a rate of variation in glacier surface elevation of -0.12 ± 0.27 m a-1. It indicated that the mass gain in the accumulation area nearly compensated the mass loss in the ablation area. In addition, both ground and satellite remote measurement reveal a steady rate of decrease in surface of the Batura tongue, implying an absence of significant variation during the past 40 years. Moreover, the mass conservation equation was applied to the Batura tongue, in combination with surface elevation variation and ice flux evolution. The tongue-averaged mass balance diminished by more than half from the 1970s to the 2010s. In summary, we inferred a near-steady state of Batura Glacier post 2000 based on the above-mentioned evidence of "Karakoram Anomaly".

7.
BMC Genomics ; 21(1): 13, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906852

RESUMO

BACKGROUND: Myopia is one of the most common vision defects worldwide. microRNAs can regulate the target gene expression, influencing the development of diseases. RESULTS: To investigate the alterations of microRNA profiling in negative lens-induced myopia (NLIM) guinea pigs and to explore the regulatory role of microRNAs in the occurrence and the development of myopia, we first established the NLIM guinea pig model after induction for 2 weeks. Further, we isolated sclera to purify total messenger RNA (mRNA) in both NLIM and NLIM fellow sclera. Using next generation sequencing technique and bioinformatics analysis, we identified the differentially expressed microRNAs in NLIM guinea pigs, performed the bioinformatics annotation for the differentially expressed microRNAs, and validated the expression of differentially expressed microRNAs. As a result, we successfully established an NLIM model in guinea pigs, identified 27 differentially expressed microRNAs in NLIM guinea pig sclera, including 10 upregulated and 17 downregulated microRNAs. The KEGG annotation showed the main signaling pathways were closely associated with PPAR signaling, pyruvate and propanoate metabolisms, and TGF-beta signaling pathways. CONCLUSIONS: Our findings indicate that the development of myopia is mainly involved in the disorder of metabolic processes in NLIM guinea pigs. The PPAR signaling, pyruvate and propanoate metabolism pathways may play roles in the development of myopia.

8.
Am J Infect Control ; 48(2): 178-183, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31540834

RESUMO

BACKGROUND: Urinary catheterization, even of short duration, increases the risk of subsequent urinary tract infection (UTI). Whether the bacteria found on the surface of catheters placed for <3 days are associated with UTI risk is unknown. METHODS: We screened the biofilms found on the extraluminal surface of 127 catheters placed for <3 days in women undergoing elective gynecologic surgery, using targeted quantitative polymerase chain reaction and an untargeted 16S rRNA taxonomic screen. RESULTS: Using quantitative polymerase chain reaction, Enterococcus spp were found on virtually all catheters and lactic acid bacteria in most catheters regardless of duration, but neither genus was associated with UTI development during follow-up. Enterococcus, Streptococcus, and Staphylococcus were the most commonly identified genera in the taxonomic screen but were not associated with subsequent UTIs. Although the most common cause of UTI following catheter removal was Escherichia coli, detectable E coli on the catheter surface was not associated with subsequent UTIs. CONCLUSIONS: Our analysis does not suggest that the presence of bacteria on the surface of catheters placed for <3 days leads to subsequent UTIs. Other aspects of catheter care are likely more important than preventing bacterial colonization of the catheter surface for preventing UTIs following short-term catheter placement.

9.
Environ Res ; 180: 108813, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31627158

RESUMO

Hydrometric information collected by monitoring networks is fundamental for effective management of water resources. In recent years, entropy-based multi-objective criterions have been developed for the evaluation and optimization of hydrometric networks, and copula functions have been frequently used in hydrological frequency analysis to model multivariate dependence structures. This study developed a dual entropy-transinformation criterion (DETC) to identify and prioritize significant stations and generate candidate network optimization solutions. The criterion integrated an entropy index computed with mathematical floor function and a transinformation index computed with copula entropy through a tradeoff weight. The best fitted copula models were selected from three Archimedean copula families, i.e., Gumbel, Frank and Clayton. DETC was applied to a streamflow monitoring network in the Fenhe River basin and two rainfall monitoring networks in the Beijing Municipality and the Taihu Lake basin, which covers different network classification, network scale, and climate type. DETC was assessed by the commonly used dual entropy-multiobjective optimization (DEMO) criterion and was compared with a minimum transinformation (MinT) based criterion for network optimization. Results showed that DETC could effectively prioritize stations according to their significance and incorporate decision preference on information content and information redundancy. Comparison of the isohyet maps of two rainstorm events between DETC and MinT showed that DETC had advantage of restoring the spatial distribution of precipitation.

10.
Immunity ; 51(6): 983-996.e6, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31836429

RESUMO

Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1ß, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.


Assuntos
Caspases Iniciadoras/metabolismo , Coagulação Intravascular Disseminada/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Fosfatidilserinas/metabolismo , Tromboplastina/metabolismo , Animais , Coagulação Sanguínea/fisiologia , Caspases Iniciadoras/genética , Linhagem Celular Tumoral , Endotoxemia/patologia , Ativação Enzimática , Células HT29 , Células HeLa , Humanos , Interleucina-1alfa/sangue , Interleucina-1beta/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/genética , Piroptose/fisiologia , Transdução de Sinais/fisiologia
11.
ChemMedChem ; 14(23): 1963-1967, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31677239

RESUMO

Host Defense Peptides (HDPs) have gained considerable interest due to the omnipresent threat of bacterial infection as a serious public health concern. However, development of HDPs is impeded by several drawbacks, such as poor selectivity, susceptibility to proteolytic degradation, low-to-moderate activity and requiring complex syntheses. Herein we report a class of lipo-linear α/urea-γ-AApeptides with a hybrid backbone and low molecular weight. The heterogeneous backbone not only enhances chemodiversity, but also shows effective antimicrobial activity against Gram-positive bacteria and is capable of disrupting bacterial membranes and killing bacteria rapidly. Given their low molecular weight and ease of access via facile synthesis, they could be practical antibiotic agents.

12.
Nature ; 575(7784): 618-621, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31776491

RESUMO

All stellar-mass black holes have hitherto been identified by X-rays emitted from gas that is accreting onto the black hole from a companion star. These systems are all binaries with a black-hole mass that is less than 30 times that of the Sun1-4. Theory predicts, however, that X-ray-emitting systems form a minority of the total population of star-black-hole binaries5,6. When the black hole is not accreting gas, it can be found through radial-velocity measurements of the motion of the companion star. Here we report radial-velocity measurements taken over two years of the Galactic B-type star, LB-1. We find that the motion of the B star and an accompanying Hα emission line require the presence of a dark companion with a mass of [Formula: see text] solar masses, which can only be a black hole. The long orbital period of 78.9 days shows that this is a wide binary system. Gravitational-wave experiments have detected black holes of similar mass, but the formation of such massive ones in a high-metallicity environment would be extremely challenging within current stellar evolution theories.

13.
Healthcare (Basel) ; 7(4)2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31756891

RESUMO

A running exhaustion experiment was used to explore the correlations between the time-frequency domain indexes extracted from the surface electromyography (EMG) signals of targeted muscles, heart rate and exercise intensity, and subjective fatigue. The study made further inquiry into the feasibility of reflecting and evaluating the exercise intensity and fatigue effectively during running using physiological indexes,thus providing individualized guidance for running fitness. Twelve healthy men participated in a running exhaustion experiment with an incremental and constant load. The percentage of heart rate reserve (%HRR), mean power frequency (MPF) and root mean square (RMS) from surface EMG (sEMG) signals of the rectus femoris (RF), biceps femoris (BF), tibialis anterior muscle (TA), and the lateral head of gastrocnemius (GAL) were obtained in real-time. The data were processed and analyzed with the rating of perceived exertion (RPE) scale. The experimental results show that the MPF on all the muscles increased with time, but there was no significant correlation between MPF and RPE in both experiments. Additionally, there was no significant correlation between RMS and RPE of GAL and BF, but there was a negative correlation between RMS and RPE of RF. The correlation coefficient was lower in the constant load mode, with the value of only -0.301. The correlation between RMS and RPE of TA was opposite in both experiments. There was a significant linear correlation between %HRR and exercise intensity (r = 0.943). In the experiment, %HRR was significantly correlated with subjective exercise fatigue (r = 0.954). Based on the above results,the MPF and RMS indicators on the four targeted muscles could not conclusively identify fatigue of lower extremities during running. The %HRR could be used to identify exercise intensity and human fatigue during running and could be used as an indicator of recognizing fatigue and exercise intensity in runners.

14.
Oral Oncol ; 98: 141-146, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31586896

RESUMO

OBJECTIVES: This study aimed to validate the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system for nasopharyngeal carcinoma (NPC) in non-endemic region. MATERIALS AND METHODS: We recruited 607 patients with histology-proven, previously untreated, non-metastatic NPC treated by intensity-modulated radiotherapy (IMRT) at our center. Harrell's concordance index (c-index) and Akaike information criterion (AIC) were applied to compare the prognostic discrimination between the 7th and 8th edition staging system. RESULTS: For T category, the local recurrence-free survival (LRFS) Kaplan-Meier curves of T1, T2 and T3 were well separated in the 8th edition; however, LRFS did not significantly differ between T3 and T4 (P = 0.166). Moreover, the 7th edition achieved higher c-index (0.702 [95% CI, 0.618-0.787] vs. 0.685 [95% CI, 0.604-0.767]) and lower AIC (766.1 vs. 770.8) than 8th edition for LRFS. With regard to N category, the 8th edition achieved higher c-index (0.796 [95% CI, 0.749-0.843] vs. 0.751 [95% CI, 0.696-0.805]) and lower AIC (1439.4 vs. 1471.9) for distant metastasis-free survival. In terms of overall stage, the 8th edition also had higher c-index (0.798 [95% CI, 0.753-0.844] vs. 0.721 [95% CI, 0.672-0.770]) and lower AIC (1963.9 vs. 2007.2) compared with the 7th edition for overall survival. Furthermore, interval validation by bootstrapping the sample randomly for ~100-1000 times also validated above findings. CONCLUSION: The 8th edition of AJCC/UICC TNM staging system achieved significantly better prognostic discrimination than the 7th edition with regard to N category and overall stage but not T category.

15.
Nat Commun ; 10(1): 4044, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492850

RESUMO

Acute graft-versus-host disease (GVHD) remains a major obstacle for the wider usage of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an effective therapy for hematopoietic malignancy. Here we show that caspase-11, the cytosolic receptor for bacterial endotoxin (lipopolysaccharide: LPS), enhances GVHD severity. Allo-HSCT markedly increases the LPS-caspase-11 interaction, leading to the cleavage of gasdermin D (GSDMD). Caspase-11 and GSDMD mediate the release of interleukin-1α (IL-1α) in allo-HSCT. Deletion of Caspase-11 or Gsdmd, inhibition of LPS-caspase-11 interaction, or neutralizing IL-1α uniformly reduces intestinal inflammation, tissue damage, donor T cell expansion and mortality in allo-HSCT. Importantly, Caspase-11 deficiency does not decrease the graft-versus-leukemia (GVL) activity, which is essential to prevent cancer relapse. These findings have major implications for allo-HSCT, as pharmacological interference with the caspase-11 signaling might reduce GVHD while preserving GVL activity.


Assuntos
Caspases/genética , Doença Enxerto-Hospedeiro/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transdução de Sinais/genética , Animais , Caspases/metabolismo , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/metabolismo , Análise de Sobrevida , Transplante Homólogo
17.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(7): 847-851, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31441408

RESUMO

OBJECTIVE: To investigate the relationship between plasma oxidative stress factors levels and organ damage parameters as well as prognosis in patients with sepsis. METHODS: A case-control study was conducted. Twenty-five patients admitted to surgical intensive care unit (ICU) of the First Affiliated Hospital of Sun Yat-sen University from March to December in 2016 and diagnosed as sepsis were enrolled as study subjects. Another 15 patients without sepsis admitted to surgical ICU in the same period were enrolled as controls. General demographic data, main diagnoses, acute physiology and chronic health evaluation II (APACHE II) score within 24 hours, clinical laboratory indicators [alanine aminotransferase (ALT), aspartate transaminase (AST), serum creatinine (SCr), blood urea nitrogen (BUN), C-reactive protein (CRP), procalcitonin (PCT), white blood count (WBC)] and oxidative stress indicators [superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO)] as well as length of ICU stay, total hospital stay and 28-day mortality were recorded. Spearman or Pearson correlation method was used to analyze the correlation between oxidative stress indicators and organ damage indicators as well as prognosis in patients with sepsis. Receiver operator characteristic (ROC) curve was plotted to evaluate the predictive value of oxidative stress indicators for 28-day mortality in patients with sepsis. RESULTS: The length of ICU stay in sepsis group was significantly longer than that in non-sepsis group [days: 7.0 (5.5, 11.0) vs. 4.0 (1.0, 11.0), P < 0.05], and AST, BUN, CRP, PCT, plasma MDA and NO levels were significantly higher than those in non-sepsis group [AST (U/L): 50.76±19.53 vs. 28.53±14.02, BUN (mmol/L): 9.99±5.26 vs. 6.97±4.32, CRP (mg/L): 109.28±42.79 vs. 60.33±46.68, PCT (µg/L): 5.4 (0.3, 24.0) vs. 0.6 (0.1, 1.5), MDA (ng/L): 488.31±76.68 vs. 399.30±50.23, NO (ng/L): 5.08±0.89 vs. 4.42±0.88, all P < 0.05]. There was no significant difference in gender, age, APACHE II score, total hospital stay, 28-day mortality, ALT, SCr, WBC or plasma SOD activity between the two groups. The correlation analysis between oxidative stress parameters and organ damage parameters as well as prognosis in patients with sepsis showed that MDA and NO were positively correlated with SCr (r value was 0.426 and 0.431, respectively, both P < 0.05), and there was a positive correlation between MDA and NO (r = 0.990, P < 0.01); plasma SOD activity was negatively correlated with 28-day mortality (r = -0.468, P < 0.05), while MDA and NO levels were positively correlated with 28-day mortality (r value was 0.598 and 0.611, respectively, both P < 0.01). ROC curve analysis showed that plasma SOD, MDA and NO levels had a good independent predictive effect on 28-day mortality, the area under ROC curve (AUC) was 0.816±0.087, 0.904±0.078 and 0.912±0.071, and the best cut-off value was 40.76% (sensitivity 68.4%, specificity 100%), 487.93 ng/L (sensitivity 83.3%, specificity 89.5%) and 5.31 ng/L (sensitivity 83.3%, specificity 89.5%), respectively. CONCLUSIONS: The plasma levels of oxidative stress factors in patients with sepsis are significantly increased, which is closely related to organ damage and poor prognosis. The plasma SOD, MDA and NO levels can be used as independent bio-marker to predict the 28-day mortality of patients with sepsis.


Assuntos
Estresse Oxidativo/fisiologia , Sepse/diagnóstico , Estudos de Casos e Controles , Humanos , Prognóstico , Sepse/metabolismo
18.
Beilstein J Org Chem ; 15: 1203-1209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293667

RESUMO

The synthesis of conjugates of perylene diimide (PDI) and naphthalene diimide (NDI) modified with two benzo-21-crown-7 ethers (B21C7) are herein described. Their self-assembly behavior in various solvents was investigated particularly in aqueous medium, due to the recently discovered hydrophilic properties of B21C7 crown macrocycle. An unexpected fluorescence quenching phenomenon was observed in the PDI-B21C7 macrocycle conjugate in chloroform. The detailed UV-vis absorption and fluorescence spectra of these PDI/NDI derivatives in different solvents as well as their morphologies were investigated.

19.
Cell Metab ; 30(3): 508-524.e12, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31204282

RESUMO

Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD+ levels in aged muscles, rejuvenating the animals' running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose.

20.
Inorg Chem ; 58(18): 11903-11911, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31192594

RESUMO

Four hexanuclear circular helicates, {[Dy6L6(DMF)12]·6CF3SO3·12DMF}2 (1Dy), {[Gd6L6(DMF)12]·6CF3SO3·12DMF}2 (1Gd), [Dy6L6(DMF)10(H2O)2]·6ClO4·4H2O·10DMF (2Dy), and [Gd6L6(DMF)12]·6ClO4·2H2O·10DMF (2Gd), where DMF = N,N-dimethylformamide, were synthesized by employing a glutaratedihydrazide-bridged bis(3-methoxysalicylaldehyde) ligand (H2L) and characterized structurally and magnetically. Direct-current magnetic susceptibility studies indicated predominant weak antiferromagnetic exchange interactions among gadolinium analogues, which were quantified using the PHI software, giving J = -0.003 cm-1 with g = 2.00 for 1Gd and J = -0.001 cm-1 with g = 2.02 for 2Gd. Alternating-current magnetic susceptibility measurements indicated that complexes 1Dy and 2Dy show slow relaxation of magnetization behavior, further supported by theoretical calculations that also highlighted the toroidal arrangement of the magnetic moments.

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