PO-292 Exercise Delays Alzheimer's Disease Through Enhancing Lysosomal Function

Objective Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by aggregation of amyloid-β (Aβ) peptides. Reduction of progressive accumulation of Aβ will delay the progression of AD. As a main digestive organelles in cells, lysosome is crucial to clear the harmful proteins from extracellular and intracellular. Recent evidences have shown that exercise improves cognitive function of AD, but the reason is not very clear. This manuscript is to study the effect of long-term running exercise training on lysosomal function in mouse brain and explore its relationship with the progress of Alzheimer’s disease. Methods  the APP/PSEN1 transgenic mice were used as the AD model to examine the relationship between AD, exercise and lysosomes.  The mice were trained on a treadmill from the 5 months old, 60 min/day and 5 days/week for 5 months. The Lashley water maze and the novel object recognition test were used to estimate the cognitive ability of the mice; the balance beam and the rotating rod experiment were used to estimate motor coordination. The Aβ accumulation was measured with brain section and immunochemistry. The effects of long-term exercise on lysosomal function of cerebral cortex, striatum and hippocampus were measured. Among them, the autophagy/lysosome associated proteins level was determined by Western blot and the autophagy vacuoles and lysosome were observed through electron microscope. TFEB nuclear translocation was determined by Western blot and Immunofluorescence. The transcription of the TFEB-regulating genes were determined by quantitative PCR (qPCR).   Results Long-term exercise improved the cognitive ability and physical coordination of AD transgenic mice. Exercise reduced Aβ accumulation through increase the clearance of Aβ and affected little on the production of Aβ. Exercise, not only increased the colocalization of lysosomes with Aβ, but also increased the mature type of lysosomal protease cathepsin D and cathepsin L. In the meanwhile, exercise promoted the nuclear translocation of TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy, and increased the transcription of genes associated with the biogenesis of lysosome. Conclusions Long-term exercise training delays the progress of Alzheimer's disease through activating function of lysosome and enhancing the biogenesis of lysosome. Exercise may be a therapeutic approach for the treatment of Alzheimer's disease

The components of tumor microenvironment as biomarker for immunotherapy in metastatic renal cell carcinoma

Substantial improvement in prognosis among metastatic renal cell carcinoma (mRCC) patients has been achieved, owing to the rapid development and utilization of immunotherapy. In particular, immune checkpoint inhibitors (ICIs) have been considered the backbone of systemic therapy for patients with mRCC alongside multi-targeted tyrosine kinase inhibitors (TKIs) in the latest clinical practice guidelines. However, controversies and challenges in optimal individualized treatment regarding immunotherapy remains still About 2/3 of the patients presented non-response or acquired resistance to ICIs. Besides, immune-related toxicities, namely immune-related adverse events, are still elusive and life-threatening. Thus, reliable biomarkers to predict immunotherapeutic outcomes for mRCC patients are needed urgently. Tumor microenvironment (TME), consisting of immune cells, vasculature, signaling molecules, and extracellular matrix and regulates tumor immune surveillance and immunological evasion through complex interplay, plays a critical role in tumor immune escape and consequently manipulates the efficacy of immunotherapy. Various studied have identified the different TME components are significantly associated with the outcome of mRCC patients receiving immunotherapy, making them potential valuable biomarkers in therapeutic guidance. The present review aims to summarize the latest evidence on the associations between the components of TME including immune cells, cytokines and extracellular matrix, and the therapeutic responses among mRCC patients with ICI-based treatment. We further discuss the feasibility and limitation of these components as biomarkers

Scaling from single-point sap velocity measurements to stand transpiration in a multispecies deciduous forest: Uncertainty sources, stand structure effect, and future scenarios

9 páginas.-- 5 figuras.-- 2 tablas.-- 58 referencias[EN] A major challenge in studies estimating stand water use in mixed-species forests is how to effectively scale data from individual trees to the stand. This is the case for forest ecosystems in the northeastern USA where differences in water use among species and across different size classes have not been extensively studied, despite their relevance for a wide range of ecosystem services. Our objectives were to assess the importance of different sources of variability on transpiration upscaling and explore the potential impacts of future shifts in species composition on the forest water budget. We measured sap velocity in five tree species (Fagus grandifolia Ehrh., Acer rubrum L., Acer saccharum Marsh., Betula alleghaniensis Britton, and Betula papyrifera Marsh.) in a mature stand and a young stand in New Hampshire, USA. Our results showed that the greatest potential source of error was radial variability and that tree size was more important than species in determining sap velocity. Total sapwood area was demonstrated to exert a strong controlling influence on transpiration, varying depending on tree size and species. We conclude that the effect of potential species shifts on transpiration will depend on the sap velocity, determined not only by radial variation and tree size, but also by the sapwood area distribution in the stand.[FR] Les études dont le but est d'estimer l'utilisation de l'eau a` l'échelle du peuplement dans les forêts mélangées font face a` un défi majeur : comment passer efficacement de l'échelle des arbres individuels a` l'échelle du peuplement. C'est le cas pour les écosystèmes forestiers dans le nord-est des États-Unis où les différences dans l'utilisation de l'eau entre les espèces et parmi les différentes catégories de taille n'ont pas fait l'objet d'études approfondies malgré leur pertinence pour une vaste gamme de services de l'écosystème. Nos objectifs consistaient a` évaluer l'importance des différentes sources de variation sur l'extrapolation de la transpiration et a` explorer les impacts potentiels des changements futurs dans la composition en espèces sur le bilan hydrique de la forêt. Nous avons mesuré la vitesse de la sève chez cinq espèces d'arbre (Fagus grandifolia Ehrh., Acer rubrum L., Acer saccharum Marsh., Betula alleghaniensis Britton et Betula papyrifera Marsh.) dans un peuplement mature et dans un jeune peuplement au New Hampshire (É.-U.). Nos résultats ont montré que la plus grande source potentielle d'erreur était la variation radiale et que la vitesse de la sève était davantage déterminée par la taille des arbres que par l'espèce. La surface totale de bois d'aubier avait un effet très déterminant sur la transpiration qui variait selon la taille et l'espèce d'arbre. Nous concluons que l'effet des changements potentiels dans la composition en espèces sur la transpiration dépendra de la vitesse de la sève qui est principalement déterminée par la variation radiale et la taille des arbres mais aussi de la distribution de la surface de bois d'aubier dans le peuplement.This work was funded by the University of New Hampshire and the New Hampshire Agricultural Experiment Station. The Bartlett Experimental Forest is operated by the USDA Forest Service Northern Research Station. S. Mcgraw, P. Pellissier, C. Breton, S. Alvarado-Barrientos, R. Snyder, and Z. Aldag assisted in the field and in the lab. The 2011 stand inventory was led by S. Goswami. Tree heights were measured and compiled by C. Blodgett, T. Fahey, and L. Liu. A. Richardson shared meteorology and solar radiation data from the Bartlett Amerflux tower. The stands used in this experiment are maintained and monitored by the MELNHE project under the direction of R. Yanai and M. Fisk, with funding from NSF grants DEB 0235650 and DEB 0949324Peer reviewe

Triglyceride-inflammation score established on account of random survival forest for predicting survival in patients with nasopharyngeal carcinoma: a retrospective study

ObjectiveThis study aimed to establish an effective prognostic model based on triglyceride and inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), to predict overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). Additionally, we aimed to explore the interaction and mediation between these biomarkers in their association with OS.MethodsA retrospective review was conducted on 259 NPC patients who had blood lipid markers, including triglyceride and total cholesterol, as well as parameters of peripheral blood cells measured before treatment. These patients were followed up for over 5 years, and randomly divided into a training set (n=155) and a validation set (n=104). The triglyceride-inflammation (TI) score was developed using the random survival forest (RSF) algorithm. Subsequently, a nomogram was created. The performance of the prognostic model was measured by the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). The interaction and mediation between the biomarkers were further analyzed. Bioinformatics analysis based on the GEO dataset was used to investigate the association between triglyceride metabolism and immune cell infiltration.ResultsThe C-index of the TI score was 0.806 in the training set, 0.759 in the validation set, and 0.808 in the entire set. The area under the curve of time-dependent ROC of TI score in predicting survival at 1, 3, and 5 years were 0.741, 0.847, and 0.871 respectively in the training set, and 0.811, 0.837, and 0.758 in the validation set, then 0.771, 0.848, and 0.862 in the entire set, suggesting that TI score had excellent performance in predicting OS in NPC patients. Patients with stage T1-T2 or M0 had significantly lower TI scores, NLR, and PLR, and higher LMR compared to those with stage T3-T3 or M1, respectively. The nomogram, which integrated age, sex, clinical stage, and TI score, demonstrated good clinical usefulness and predictive ability, as evaluated by the DCA. Significant interactions were found between triglyceride and NLR and platelet, but triglyceride did not exhibit any medicating effects in the inflammatory markers. Additionally, NPC tissues with active triglyceride synthesis exhibited high immune cell infiltration.ConclusionThe TI score based on RSF represents a potential prognostic factor for NPC patients, offering convenience and economic advantages. The interaction between triglyceride and NLR may be attributed to the effect of triglyceride metabolism on immune response

Estimated glomerular filtration rate is a biomarker of cognitive impairment in Parkinson’s disease

BackgroundsThe relationship between kidney function and cognitive impairment in Parkinson’s disease (PD) is poorly understood and underexplored. This study aims to explore whether renal indices can serve as indicators to monitor the cognitive impairment of PD.MethodsA total of 508 PD patients and 168 healthy controls from the Parkinson’s Progression Markers Initiative (PPMI) were recruited, and 486 (95.7%) PD patients underwent longitudinal measurements. The renal indicators including serum creatinine (Scr), uric acid (UA), and urea nitrogen, as well as UA/Scr ratio and estimated glomerular filtration rate (eGFR), were measured. Cross-sectional and longitudinal associations between kidney function and cognitive impairment were evaluated using multivariable-adjusted models.ResultseGFR was associated with lower levels of cerebrospinal fluid (CSF) Aβ1–42 (p = 0.0156) and α-synuclein (p = 0.0151) and higher serum NfL (p = 0.0215) in PD patients at baseline. Longitudinal results showed that decreased eGFR predicted a higher risk of cognitive impairment (HR = 0.7382, 95% CI = 0.6329–0.8610). Additionally, eGFR decline was significantly associated with higher rates of increase in CSF T-tau (p = 0.0096), P-tau (p = 0.0250), and serum NfL (p = 0.0189), as well as global cognition and various cognitive domains (p < 0.0500). The reduced UA/Scr ratio was also linked to higher NfL levels (p = 0.0282) and greater accumulation of T-tau (p = 0.0282) and P-tau (p = 0.0317). However, no significant associations were found between other renal indices and cognition.ConclusioneGFR is altered in PD subjects with cognitive impairment, and predict larger progression of cognitive decline. It may assist identifying patients with PD at risk of rapid cognitive decline and have the potential to monitoring responses to therapy in future clinical practice

An essential role for the Id1/PI3K/Akt/NFkB/survivin signalling pathway in promoting the proliferation of endothelial progenitor cells in vitro

The enhancement of re-endothelialisation is a critical therapeutic option for repairing injured blood vessels. Endothelial progenitor cells (EPCs) are the major source of cells that participate in endothelium repair and contribute to re-endothelialisation by reducing neointima formation after vascular injury. The over-expression of the inhibitor of differentiation or DNA binding 1 (Id1) significantly improved EPC proliferation. This study aimed to investigate the effects of Id1 on the phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor kappa B (NFκB)/survivin signalling pathway and its significance in promoting EPC proliferation in vitro. Spleen-derived EPCs were cultured as previously described. Id1 was presented at low levels in EPCs, and was rapidly up-regulated by stimulation with vascular endothelial growth factor. We demonstrated that transient transfection of Id1 into EPCs activated the PI3K/Akt/NFκB/survivin signalling pathway and promoted EPC proliferation. The proliferation of EPCs was extensively inhibited by silencing of endogenous Id1, and knockdown of Id1 expression led to suppression of PI3K/Akt/NFκB/survivin signalling pathway in EPCs. In addition, blockade by the PI3K-specific inhibitor LY294002, Akt inhibitor, the NFκB inhibitor BAY 11-7082, the survivin inhibitor Curcumin, or the survivin inhibitor YM155 reduced the effects of Id1 transfection. These results suggest that the Id1/PI3K/Akt/NFκB/survivin signalling pathway plays a critical role in EPC proliferation. The Id1/PI3K/Akt/NFκB/survivin signalling pathway may represent a novel therapeutic target in the prevention of restenosis after vascular injury

Direct Measurements of the Branching Fractions for D0→K−e+νeD^0 \to K^-e^+\nu_e and D0→π−e+νeD^0 \to \pi^-e^+\nu_e and Determinations of the Form Factors f+K(0)f_{+}^{K}(0) and f+π(0)f^{\pi}_{+}(0)

The absolute branching fractions for the decays $D^0 \to K^-e ^+\nu_e$ and $D^0 \to \pi^-e^+\nu_e$ are determined using $7584\pm 198 \pm 341$ singly tagged $\bar D^0$ sample from the data collected around 3.773 GeV with the BES-II detector at the BEPC. In the system recoiling against the singly tagged $\bar D^0$ meson, $104.0\pm 10.9$ events for $D^0 \to K^-e ^+\nu_e$ and $9.0 \pm 3.6$ events for $D^0 \to \pi^-e^+\nu_e$ decays are observed. Those yield the absolute branching fractions to be $BF(D^0 \to K^-e^+\nu_e)=(3.82 \pm 0.40\pm 0.27)$ and $BF(D^0 \to \pi^-e^+\nu_e)=(0.33 \pm 0.13\pm 0.03)$. The vector form factors are determined to be $|f^K_+(0)| = 0.78 \pm 0.04 \pm 0.03$ and $|f^{\pi}_+(0)| = 0.73 \pm 0.14 \pm 0.06$. The ratio of the two form factors is measured to be $|f^{\pi}_+(0)/f^K_+(0)|= 0.93 \pm 0.19 \pm 0.07$.Comment: 6 pages, 5 figure

Measurements of J/psi Decays into 2(pi+pi-)eta and 3(pi+pi-)eta

Based on a sample of 5.8X 10^7 J/psi events taken with the BESII detector, the branching fractions of J/psi--> 2(pi+pi-)eta and J/psi-->3(pi+pi-)eta are measured for the first time to be (2.26+-0.08+-0.27)X10^{-3} and (7.24+-0.96+-1.11)X10^{-4}, respectively.Comment: 11 pages, 6 figure

BESII Detector Simulation

A Monte Carlo program based on Geant3 has been developed for BESII detector simulation. The organization of the program is outlined, and the digitization procedure for simulating the response of various sub-detectors is described. Comparisons with data show that the performance of the program is generally satisfactory.Comment: 17 pages, 14 figures, uses elsart.cls, to be submitted to NIM