TIMASSS: The IRAS16293-2422 Millimeter And Submillimeter Spectral Survey. I. Observations, calibration and analysis of the line kinematics

While unbiased surveys observable from ground-based telescopes have previously been obtained towards several high mass protostars, very little exists on low mass protostars. To fill up this gap, we carried out a complete spectral survey of the bands at 3, 2, 1 and 0.8 mm towards the solar type protostar IRAS16293-2422. The observations covered about 200\,GHz and were obtained with the IRAM-30m and JCMT-15m telescopes. Particular attention was devoted to the inter-calibration of the obtained spectra with previous observations. All the lines detected with more than 3 sigma and free from obvious blending effects were fitted with Gaussians to estimate their basic kinematic properties. More than 4000 lines were detected (with sigma \geq 3) and identified, yielding a line density of approximatively 20 lines per GHz, comparable to previous surveys in massive hot cores. The vast majority (~2/3) of the lines are weak and due to complex organic molecules. The analysis of the profiles of more than 1000 lines belonging 70 species firmly establishes the presence of two distinct velocity components, associated with the two objects, A and B, forming the IRAS16293-2422 binary system. In the source A, the line widths of several species increase with the upper level energy of the transition, a behavior compatible with gas infalling towards a ~1 Mo object. The source B, which does not show this effect, might have a much lower central mass of ~0.1 Mo. The difference in the rest velocities of both objects is consistent with the hypothesis that the source B rotates around the source A. This spectral survey, although obtained with single-dish telescope with a low spatial resolution, allows to separate the emission from 2 different components, thanks to the large number of lines detected. The data of the survey are public and can be retrieved on the web site http://www-laog.obs.ujf-grenoble.fr/heberges/timasss.Comment: 41 pages (26 pages of online Tables), 7 Tables and 6 Figure

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

Multiscale modeling of progressive damage in elasto-plastic composite materials

Modeling failure and progressive damage of composite materials presents a challenging task. Phenomenological macroscale models are state of the art for failure investigations in many practicable applications. These models assume homogeneous material behavior and are usually based on macroscopic failure criteria. Furthermore, multiscale modeling and simulation techniques were developed to capture nonlinear material effects directly on a finer length scale. One of these techniques is the FE2 approach [1] which considers by means of a fully coupled micro-macro simulation process different length scales of the material structure. Due to the increased computational costs coming along with the application of the multiscale framework an effective solution of the micro boundary value problem (BVP) is necessary. In this contribution we propose an alternative multiscale framework similar to FE2 which uses the Fast-Fourier Transformation (FFT) to solve an equivalent elastic micro BVP formulation, the so called Lippmann-Schwinger equation (see [2]). Advantages of this method are its efficiency in terms of memory consumption and computational time. The calculation is carried out on a regular voxel grid which can be obtained from 3D images like tomographies without using any complicated mesh generation. The fine scale problem is integrated in a standard Finite Element framework which is used to solve the macroscopic BVP. For both structural phases simple isotropic constitutive laws are formulated. Based on the work of Spahn et al. [3] a multiscale method for elastoplastic fiber reinforced composite materials including progressive damage is presented. Finally, the simulated results are compared with experimental data obtained from injection molded specimens

Elevated nitric oxide production mediates beta-amyloid-induced mitochondria failure

Mitochondrial dysfunction has been identified in a large proportion of neurodegenerative disorders including Alzheimer's disease (AD). In addition, the involvement of nitric oxide (NO) has been implicated in the pathogenesis of AD. Thus, we investigated the effects of the Swedish double mutation (K670M/N671L) in the beta-amyloid precursor protein (APPsw) on NO levels and mitochondrial function in PC12 cells. Interestingly, APPsw PC12 cells showed increased NO levels, decreased cytochrome C oxidase activity and reduced ATP levels compared to wild-type APP bearing cells and empty vector transfected cells. On the basis of our data, we propose a hypothetical sequence of events linking amyloid beta-peptide and NO production with mitochondria failure

Interactive computer-training as a therapeutic tool in Alzheimer's disease

The current study sought to evaluate a novel kind of interactive computer-based cognitive training (ICT) in Alzheimer's disease (AD). AD patients (N = 9), age- and gender-matched patients with a major depressive episode (N = 9), and healthy control subjects (N = 10) were trained to use an ICT program that relates to activities of daily living (ADL). Digital photographs of a shopping route were implemented in a close-to-reality simulation on a computer touch-screen. The task was to find a predefined shopping route, to buy three items, and to answer correctly 10 multiple-choice questions addressing knowledge related to the virtual tasks. Training performance was rated using the number of mistakes (wrong way), time needed for the tasks, number of correct multiple-choice answers, and of repeat of instruction. Compared to normal controls and depressed patients, AD patients performed significantly worse with regard to all variables. Within a 4-week training period including 12 sessions, however, substantial training gains were observed, including a significant reduction of mistakes. Training effects were sustained until follow-up 3 weeks later. The performance of the depressed patients and the normal controls improved as well, with no difference between the two groups. Self-reported effects revealed that the training was well perceived. Thus, the task performance of AD patients improved substantially and subjects appeared to have liked this approach to ICT. New interactive media, therefore, may yield interesting opportunities for rehabilitation and (psycho)therapeutic interventions

Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multicenter trial with 1-year follow-up

BACKGROUND: Neuraxial blockade is used as primary anesthetic technique in one third of surgical procedures. The authors tested whether bisoprolol would protect patients at risk for cardiovascular complications undergoing surgery with spinal block. METHODS: The authors performed a double-blinded, placebo-controlled, multicenter trial to compare the effect of bisoprolol with that of placebo on 1-yr composite outcome including cardiovascular mortality, nonfatal myocardial infarction, unstable angina, congestive heart failure, and cerebrovascular insult. Bisoprolol was given orally before and after surgery for a maximum of 10 days. Adrenergic receptor polymorphisms and safety outcome measures of bisoprolol therapy were also determined. RESULTS: A total of 224 patients were enrolled. Spinal block could not be established in 5 patients. One hundred ten patients were assigned to the bisoprolol group, and 109 patients were assigned to the placebo group. The mean duration of treatment was 4.9 days in the bisoprolol group and 5.1 days in the placebo group. Bisoprolol therapy reduced mean heart rate by 10 beats/min. The primary outcome was identical between treatment groups and occurred in 25 patients (22.7%) in the bisoprolol group and 24 patients (22.0%) in the placebo group during the 1-yr follow-up (hazard ratio, 0.97; 95% confidence interval, 0.55-1.69; P = 0.90). However, carriers of at least one Gly allele of the beta1-adrenergic receptor polymorphism Arg389Gly showed a higher number of adverse events than Arg homozygous (32.4% vs. 18.7%; hazard ratio, 1.87; 95% confidence interval, 1.04-3.35; P = 0.04). CONCLUSIONS: Perioperative bisoprolol therapy did not affect cardiovascular outcome in these elderly at-risk patients undergoing surgery with spinal block

Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice

BACKGROUND: Mitochondrial dysfunction has been identified in neurodegenerative disorders including Alzheimer's disease, where accumulation of beta-amyloid (Abeta) and oxidative stress seem to play central roles in the pathogenesis, by probably directly leading to mitochondrial dysfunction. OBJECTIVE: In order to study the in vivo effect of Abeta load during aging, we evaluated the mitochondrial function of brain cells from transgenic mice bearing either mutant amyloid precursor protein (tgAPP) or mutant amyloid precursor protein and mutant PS1 (tgAPP/PS1) as well as from nontransgenic wild-type littermates. tgAPP mice exhibit onset of Abeta plaques at an age of 6 months, but the intracellular soluble Abeta load is already increased at 3 months of age. In contrast, onset of Abeta plaques starts at an age of 3 months in tgAPP/PS1 mice. In addition, we investigated the effects of different Abeta preparations on mitochondrial function of brain cells from tau transgenic mice. RESULTS: Of note, mitochondrial damage such as reduced mitochondrial membrane potential and ATP levels can already be detected in the brains from these mice before the onset of plaques. In agreement with our findings in tgAPP mice, soluble Abeta induced mitochondrial dysfunction in brain cells from tau transgenic mice. CONCLUSION: Our results indicate that mitochondrial dysfunction is exacerbated by the presence of soluble Abeta species as a very early event during pathogenesis