Climate prediction: an evidence-based perspective

This paper considers climate prediction from the perspective of the experimental, physical sciences, and discusses three ways in which the two differ. First, the construction of long-term climate series requires benchmark measurements, i.e., measurements calibrated in situ against international standards. An instrument capable of accurate, benchmark measurements of thermal, spectral radiances from space is available but has yet to be used. Second, objective criteria are needed to evaluate measurements for the purpose of improving climate predictions. Techniques based on Bayesian inference are now available. Third is the question of how to use suitable data to improve a climate prediction, when they are available. A method based on the Bayesian Evidence Function is, in principle, available, but has yet to be exploited. None of these three aspects are considered in current operational climate forecasting. All three are potentially capable of improving forecasts, and all are subjects of current research programs, with the likelihood of their eventual adoption

A Functional Three-Dimensional Microphysiological Model of Myeloma Bone Disease

Multiple myeloma (MM) is a hematologic cancer caused by a mature B cell neoplasm, or plasmacytoma, that infiltrates the skeleton at several sites. The disease is characterized by uninhibited transformed plasma cell proliferation that disrupts skeletal homeostasis leading to decreased bone modeling and increased bone resorption. Osteolytic lesions (OL) or voids left in the bone, remain long after the treatment of the cancer and indicate disease progression to myeloma bone disease (MBD). Current combinatorial MM therapies inhibit malignant plasma cell proliferation, slow the progression towards MBD, and increase the mean five-year survival rate, but do little to improve osteoblastic function and restore skeletal homeostasis. Conversely, several novel MBD treatments have been developed to heal OLs, including monoclonal antibodies that target receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin. A functional in vitro three-dimensional (3D) microphysiological human MM bone model was developed to aid in the identification of improved combinatorial treatments that suppress plasma cell proliferation while healing osteolytic lesions. Bone Marrow Stromal Cell-derived (BMSC) osteoblasts and Bone Marrow macrophage-derived osteoclasts maintained as a homeostatic coculture capable of bone formation and resorption form mineralized bone fragments. The introduction of human plasmacytoma cell lines induce lesions in the Mini-bones decreasing the cumulative hydroxyapatite (HA) content while increasing resorption markers, like C-Terminal Telopeptides Type Collagen 1 (CTX-1) recapitulating physiological conditions of MBD. 3D myeloma disease-induced bone fragments treated with a combination of immunomodulatory and bone modifying agents had lower free CTX-1 and more HA present after twelve days of exposure. These alterations in bone integrity and resorption were dose-dependent and demonstrated the model’s potential to evaluate novel combinatorial therapies

Evidence for Hox-specified positional identities in adult vasculature

<p>Abstract</p> <p>Background</p> <p>The concept of specifying positional information in the adult cardiovascular system is largely unexplored. While the <it>Hox </it>transcriptional regulators have to be viewed as excellent candidates for assuming such a role, little is known about their presumptive cardiovascular control functions and <it>in vivo </it>expression patterns.</p> <p>Results</p> <p>We demonstrate that conventional reporter gene analysis in transgenic mice is a useful approach for defining highly complex <it>Hox </it>expression patterns in the adult vascular network as exemplified by our <it>lacZ </it>reporter gene models for <it>Hoxa3 </it>and <it>Hoxc11</it>. These mice revealed expression in subsets of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) located in distinct regions of the vasculature that roughly correspond to the embryonic expression domains of the two genes. These reporter gene patterns were validated as authentic indicators of endogenous gene expression by immunolabeling and PCR analysis. Furthermore, we show that persistent reporter gene expression in cultured cells derived from vessel explants facilitates <it>in vitro </it>characterization of phenotypic properties as exemplified by the differential response of <it>Hoxc11-lacZ</it>-positive <it>versus</it>-negative cells in migration assays and to serum.</p> <p>Conclusion</p> <p>The data support a conceptual model of <it>Hox-</it>specified positional identities in adult blood vessels, which is of likely relevance for understanding the mechanisms underlying regional physiological diversities in the cardiovascular system. The data also demonstrate that conventional <it>Hox </it>reporter gene mice are useful tools for visualizing complex <it>Hox </it>expression patterns in the vascular network that might be unattainable otherwise. Finally, these mice are a resource for the isolation and phenotypic characterization of specific subpopulations of vascular cells marked by distinct <it>Hox </it>expression profiles.</p

Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis

OBJECTIVE: Intrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS. METHODS: We combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders. MS patients were stratified according to cortical lesion (CL) load. RESULTS: We identified 227 proteins differently expressed between the patients with high and low CL load. These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively). Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P &lt; 0.0001), free hemoglobin (Hb) (P &lt; 0.05), haptoglobin (P &lt; 0.0001), and fibrinogen (P &lt; 0.01) were detected. By contrast, CSF levels of sCD14 were significantly (P &lt; 0.05) higher in MS patients with low CL load. Furthermore, CSF levels of sCD163 positively correlated (P &lt; 0.01) with CSF levels of neurofilament, fibrinogen, and B cell-related molecules, such as CXCL13, CXCL12, IL10, and BAFF. INTERPRETATION: Intrathecal dysregulation of iron homeostasis and coagulation pathway as well as B-cell and monocyte activity are strictly correlated with cortical damage at early disease stages

Highly selective photoenhanced wet etching of GaN for defect investigation and device fabrication

ABSTRACTPhotoenhanced electro-chemical (PEC) wet etching has been shown to be suitable for dislocation-density estimation in n-GaN films as well as for GaN-based device fabrication. We report on PEC etching of n-GaN samples grown by MBE and HVPE methods in unstirred aqueous KOH solution under He-Cd laser illumination. Characterization of the etched samples was carried out using atomic force microscopy (AFM) in both cross-sectional and plan-view configurations and scanning electron microscopy (SEM). At moderate illumination densities, the SEM and AFM analyses reveal sub-100 nm scale threading vertical wires on the etched surfaces. The calculated density (∼1×10 9cm−2) is in agreement with dislocation density found by transmission electron microscopy. Using cross-sectional AFM, we find that these vertical wires are ∼1[.proportional]m high and are perpendicular to the sapphire surface. Applying a higher illumination density or an external voltage, we obtain a higher etch rate with a smooth free-feature etched surface. Some highly resistive samples that cannot be etched under normal conditions because the band bending is too small to confine the holes to the surface for them to participate in the PEC process, can be etched with the application of a voltage to the sample. In this case, the etch rate depends on both the polarity and the magnitude of the voltage applied. In an MBE-grown sample with an AlN/GaN superstructure inside, we report on high selectivity between AlN and GaN (AlN is an etch stop); the selectivity is due to the etching mechanism of the PEC process

Observation of T-2 Toxin and HT-2 Toxin Glucosides from Fusarium sporotrichioides by Liquid Chromatography Coupled to Tandem Mass Spectrometry (LC-MS/MS)

The trichothecenes produced by solid and liquid cultures of Fusarium sporotrichioides were evaluated with high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Along with the expected T-2 toxin HT-2 toxin and neosolaniol, two additional compounds were detected, which had ions 162 m/z higher than those in the mass spectra of T-2 toxin or HT-2 toxin. Fragmentation behavior of these two compounds was similar to that of T-2 toxin and HT-2 toxin. Based on LC-MS/MS behavior, it is proposed that the two compounds are T-2 toxin 3-O-glucoside and HT-2 toxin 3-O-glucoside. Production of the two glucosides was measured in kernels from wheat and oat inoculated with F. sporotrichiodes, as well as in cultures grown in liquid media and on cracked corn or rice. Production of glucosides in wheat and oats suggest that they may also be present in naturally contaminated cereals

Application of isotope dilution mass spectrometry: determination of ochratoxin A in the Canadian Total Diet Study

Analytical methods are generally developed and optimized for specific commodities. Total Diet Studies, representing typical food products ‘as consumed’, pose an analytical challenge since every food product is different. In order to address this technical challenge, a selective and sensitive analytical method was developed suitable for the quantitation of ochratoxin A (OTA) in Canadian Total Diet Study composites. The method uses an acidified solvent extraction, an immunoaffinity column (IAC) for clean-up, liquid chromatography-tandem mass spectrometry (LC-MS/MS) for identification and quantification, and a uniformly stable isotope-labelled OTA (U-[13C20]-OTA) as an internal recovery standard. Results are corrected for this standard. The method is accurate (101% average recovery) and precise (5.5% relative standard deviation (RSD)) based on 17 duplicate analysis of various food products over 2 years. A total of 140 diet composites were analysed for OTA as part of the Canadian Total Diet Study. Samples were collected at retail level from two Canadian cities, Quebec City and Calgary, in 2008 and 2009, respectively. The results indicate that 73% (102/140) of the samples had detectable levels of OTA, with some of the highest levels of OTA contamination found in the Canadian bread supply

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases.

Funder: FP7 Ideas: European Research Council; Grant(s): 278535, 305280, 324400, 315997The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD

Accessible Data Curation and Analytics for International-Scale Citizen Science Datasets

The Covid Symptom Study, a smartphone-based surveillance study on COVID-19 symptoms in the population, is an exemplar of big data citizen science. Over 4.7 million participants and 189 million unique assessments have been logged since its introduction in March 2020. The success of the Covid Symptom Study creates technical challenges around effective data curation for two reasons. Firstly, the scale of the dataset means that it can no longer be easily processed using standard software on commodity hardware. Secondly, the size of the research group means that replicability and consistency of key analytics used across multiple publications becomes an issue. We present ExeTera, an open source data curation software designed to address scalability challenges and to enable reproducible research across an international research group for datasets such as the Covid Symptom Study dataset