3-Phenyl-6-(2-pyrid­yl)-1,2,4,5-tetra­zine

The title compound, C13H9N5, is the first asymmetric diaryl-1,2,4,5-tetra­zine to be crystallographically characterized. We have been inter­ested in this motif for incorporation into supra­molecular assemblies based on coordination chemistry. The solid state structure shows a centrosymmetric mol­ecule, forcing a positional disorder of the terminal phenyl and pyridyl rings. The mol­ecule is completely planar, unusual for aromatic rings with N atoms in adjacent ortho positions. The stacking observed is very common in diaryl­tetra­zines and is dominated by π stacking [centroid-to-centroid distance between the tetrazine ring and the aromatic ring of an adjacent molecule is 3.6 Å, perpendicular (centroid-to-plane) distance of about 3.3 Å]

Performance Analysis of Constrained Loosely Coupled GPS/INS Integration Solutions

The paper investigates approaches for loosely coupled GPS/INS integration. Error performance is calculated using a reference trajectory. A performance improvement can be obtained by exploiting additional map information (for example, a road boundary). A constrained solution has been developed and its performance compared with an unconstrained one. The case of GPS outages is also investigated showing how a Kalman filter that operates on the last received GPS position and velocity measurements provides a performance benefit. Results are obtained by means of simulation studies and real dat

Novel strategies to enhance vaccine immunity against coccidioidomycosis

Coccidioidomycosis is a potentially life-threatening respiratory mycosis endemic to the Americas and caused by inhalation of spores produced by the molds Coccidioides immitis and C. posadasii

Reductions in serum IGF-1 during aging impair health span

In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF- 1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/ IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1- deficient (iLID) mouse that allows temporal control of serum IGF- 1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology

Exercise therapy for chronic symptomatic peripheral artery disease:A clinical consensus document of the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases in collaboration with the European Society of Vascular Medicine and the European Society for Vascular Surgery

All guidelines worldwide strongly recommend exercise as a pillar in the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended to promote and assist the set up of comprehensive exercise programmes and best advice for patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are described based on the current best evidence. The document ends by highlighting supervised exercise programme access disparities across Europe and the evidence gaps requiring further research.</p

Agricultural pesticide exposure and the molecular connection to lymphomagenesis

The t(14;18) translocation constitutes the initiating event of a causative cascade leading to follicular lymphoma (FL). t(14;18) translocations are present in blood from healthy individuals, but there is a trend of increased prevalence in farmers exposed to pesticides, a group recently associated with higher risk of t(14;18)+ non-Hodgkin's lymphoma development. A direct connection between agricultural pesticide use, t(14;18) in blood, and malignant progression, however, has not yet been demonstrated. We followed t(14;18) clonal evolution over 9 yr in a cohort of farmers exposed to pesticides. We show that exposed individuals bear particularly high t(14;18) frequencies in blood because of a dramatic clonal expansion of activated t(14;18)+ B cells. We further demonstrate that such t(14;18)+ clones recapitulate the hallmark features of developmentally blocked FL cells, with some displaying aberrant activation-induced cytidine deaminase activity linked to malignant progression. Collectively, our data establish that expanded t(14;18)+ clones constitute bona fide precursors at various stages of FL development, and provide a molecular connection between agricultural pesticide exposure, t(14;18) frequency in blood, and clonal progression

Carbon budget for 1.5 and 2oC targets lowered by natural wetland and permafrost feedbacks

Methane emissions from natural wetlands and carbon release from permafrost thaw have a positive feedback on climate, yet are not represented in most state-of-the-art climate models. Furthermore, a fraction of the thawed permafrost carbon is released as methane, enhancing the combined feedback strength. We present simulations with an intermediate complexity climate model which follow prescribed global warming pathways to stabilisation at 1.5°C or 2.0°C above pre-industrial levels by the year 2100, and that incorporates a state-of-the-art global land surface model with updated descriptions of wetland and permafrost carbon release. We demonstrate that the climate feedbacks from those two processes are substantial. Specifically, permissible anthropogenic fossil fuel CO2 emission budgets are reduced by 17-23% (47-56 GtC) for stabilisation at 1.5°C, and 9-13% (52-57 GtC) for 2.0°C stabilisation. In our simulations these feedback processes respond faster at temperatures below 1.5°C, and the differences between the 1.5°C and 2°C targets are disproportionately small. This key finding is due to our interest in transient emission pathways to the year 2100 and does not consider the longer term implications of these feedback processes. We conclude that natural feedback processes from wetlands and permafrost must be considered in assessments of transient emission pathways to limit global warming

Global wheat production with 1.5 and 2.0°C above pre‐industrial warming

Efforts to limit global warming to below 2°C in relation to the pre‐industrial level are under way, in accordance with the 2015 Paris Agreement. However, most impact research on agriculture to date has focused on impacts of warming >2°C on mean crop yields, and many previous studies did not focus sufficiently on extreme events and yield interannual variability. Here, with the latest climate scenarios from the Half a degree Additional warming, Prognosis and Projected Impacts (HAPPI) project, we evaluated the impacts of the 2015 Paris Agreement range of global warming (1.5 and 2.0°C warming above the pre‐industrial period) on global wheat production and local yield variability. A multi‐crop and multi‐climate model ensemble over a global network of sites developed by the Agricultural Model Intercomparison and Improvement Project (AgMIP) for Wheat was used to represent major rainfed and irrigated wheat cropping systems. Results show that projected global wheat production will change by −2.3% to 7.0% under the 1.5°C scenario and −2.4% to 10.5% under the 2.0°C scenario, compared to a baseline of 1980–2010, when considering changes in local temperature, rainfall, and global atmospheric CO2 concentration, but no changes in management or wheat cultivars. The projected impact on wheat production varies spatially; a larger increase is projected for temperate high rainfall regions than for moderate hot low rainfall and irrigated regions. Grain yields in warmer regions are more likely to be reduced than in cooler regions. Despite mostly positive impacts on global average grain yields, the frequency of extremely low yields (bottom 5 percentile of baseline distribution) and yield inter‐annual variability will increase under both warming scenarios for some of the hot growing locations, including locations from the second largest global wheat producer—India, which supplies more than 14% of global wheat. The projected global impact of warming <2°C on wheat production is therefore not evenly distributed and will affect regional food security across the globe as well as food prices and trade

Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: The CADDementia challenge

Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n = 30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org

Tetrodotoxin (TTX) as a Therapeutic Agent for Pain

Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed