Completing the triad: Synthesis and full characterization of homoleptic and heteroleptic carbonyl and nitrosyl complexes of the group VI metals

Oxidation of M(CO)$_{6}$ (M = Cr, Mo, W) with the synergistic oxidative system Ag[WCA]/0.5 I$_{2}$ yields the fully characterized metalloradical salts [M(CO)$_{6}$]+˙[WCA]− (weakly coordinating anion WCA = [F-{Al(OR$^{F}$)$_{3}$}$_{2}$]$^{-}$, R$^{F}$ = C(CF$_{3}$)$_{3}$). The new metalloradical cations with M = Mo and W showcase a similar structural fluxionality as the previously reported [Cr(CO)$_{6}$]$^{+}$˙. Their reactivity increases from M = Cr < Mo < W and their syntheses allow for in-depth insights into the properties of the group 6 carbonyl triad. Furthermore, the reaction of NO$^{+}$[WCA]$^{-}$ with neutral carbonyl complexes M(CO)$_{6}$ gives access to the heteroleptic carbonyl/nitrosyl cations [M(CO)$_{5}$(NO)]$^{+}$ as salts of the WCA [Al(ORF)$_{4}$]$^{-}$, the first complete transition metal triad of their kind

Proteomic mapping of atrial and ventricular heart tissue in patients with aortic valve stenosis

Aortic valve stenosis (AVS) is one of the most common valve diseases in the world. However, detailed biological understanding of the myocardial changes in AVS hearts on the proteome level is still lacking. Proteomic studies using high-resolution mass spectrometry of formalin-fixed and paraffin-embedded (FFPE) human myocardial tissue of AVS-patients are very rare due to methodical issues. To overcome these issues this study used high resolution mass spectrometry in combination with a stem cell- derived cardiac specific protein quantification-standard to profile the proteomes of 17 atrial and 29 left ventricular myocardial FFPE human myocardial tissue samples from AVS-patients. In our proteomic analysis we quantified a median of 1980 (range 1495–2281) proteins in every single sample and identified significant upregulation of 239 proteins in atrial and 54 proteins in ventricular myocardium. We compared the proteins with published data. Well studied proteins reflect disease-related changes in AVS, such as cardiac hypertrophy, development of fibrosis, impairment of mitochondria and downregulated blood supply. In summary, we provide both a workflow for quantitative proteomics of human FFPE heart tissue and a comprehensive proteomic resource for AVS induced changes in the human myocardium

the State of Utah v. Walter Preston Boggess, Jr. : Brief of Respondent

An Appeal from a Judgment of the District Court of the Fourth Judicial District, The Honorable J, Robert Bullock, District Court Judg

Quantitative proteomics identifies biomarkers to distinguish pulmonary from head and neck squamous cell carcinomas by immunohistochemistry

The differentiation between a pulmonary metastasis and a newly developed squamous cell carcinoma of the lung in patients with prior head and neck squamous cell carcinoma (HNSCC) is difficult due to a lack of biomarkers but is crucially important for the prognosis and therapy of the affected patient. By using high-resolution mass spectrometry in combination with stable isotope labelling by amino acids in cell culture, we identified 379 proteins that are differentially expressed in squamous cell carcinomas of the lung and the head and neck. Of those, CAV1, CAV2, LGALS1, LGALS7, CK19, and UGDH were tested by mmunohistochemistry on 194 tissue samples (98 lung and 96 HNSCCs). The combination of CAV1 and LGALS7 was able to distinguish the origin of the squamous cell carcinoma with high accuracy (area under the curve 0.876). This biomarker panel was tested on a cohort of 12 clinically classified lung tumours of unknown origin after HNSCC. Nine of those tumours were immunohistochemically classifiable

Elucidation of tonic and activated B-cell receptor signaling in Burkitt's lymphoma provides insights into regulation of cell survival.

Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments

高温環境下における筋労作時並びに安静時の発汗反応に及ぼす運動鍛錬の影響

博士（医学）神戸大

Molecular Classification of Neuroendocrine Tumors of the Thymus

INTRODUCTION: The WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems. METHODS: One hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Society, and a grading-related PNET classification. Low coverage whole-genome sequencing and immunohistochemical studies were performed in 63 cases. A copy number instability (CNI) score was applied to compare tumors. Eleven LCNEC were further analyzed using targeted next-generation sequencing. Morphologic classifications were tested against molecular features. RESULTS: Whole-genome sequencing data fell into three clusters: CNIlow, CNIint, and CNIhigh. CNIlow and CNIint comprised not only TC and AC, but also six LCNECs. CNIhigh contained all SCC and nine LCNEC, but also three AC. No morphologic classification was able to predict the CNI cluster. Cases where primary tumors and metastases were available showed progression from low-grade to higher-grade histologies. Analysis of LCNEC revealed a subgroup of intermediate NET G3 tumors that differed from LCNEC by carcinoid morphology, expression of chromogranin, and negativity for enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). CONCLUSIONS: TNETs fall into three molecular subgroups that are not reflected by the current WHO classification. Given the large overlap between TC and AC on the one hand, and AC and LCNEC on the other, we propose a morphomolecular grading system, Thy-NET G1-G3, instead of histologic classification for patient stratification and prognostication. peerReviewe

Hybrid Agents Based Architecture on Automated Dynamic Environments

This paper presents a hybrid agents based architecture that uses case-based reasoning and case-based planning systems as reasoning mechanism in deliberative BDI agents to manage daily tasks and hardware devices on dynamic environments. This architecture is also founded on Ambient Intelligence, joining a set of technologies, such as radio frequency identification, wireless networks and wireless control devices, which can be implemented on a wide diversity of environments

Towards Our Common Digital Future. Flagship Report.

In the report “Towards Our Common Digital Future”, the WBGU makes it clear that sustainability strategies and concepts need to be fundamentally further developed in the age of digitalization. Only if digital change and the Transformation towards Sustainability are synchronized can we succeed in advancing climate and Earth-system protection and in making social progress in human development. Without formative political action, digital change will further accelerate resource and energy consumption, and exacerbate damage to the environment and the climate. It is therefore an urgent political task to create the conditions needed to place digitalization at the service of sustainable development

Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia

The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia..O. and T. Berg (BE 4198/1-1 and BE 4198/2-1) are supported by the Deutsche Forschungsgemeinschaft (DFG). K.S. is supported by a Leukemia and Lymphoma Society Scholar Award and by the National Cancer Institute (R01 CA140292). F.C. is supported by an EMBO long-term fellowship (1305-2015 and Marie Curie ActionsLTFCOFUND2013/GA-2013-609409). F.K. was supported by grants from Deutsche Krebshilfe (grant 109420; Max-Eder program), fellowship 2010/04 by the European Hematology Association, and by the DFG (SFB 1074, project A5). A.R. was supported by the DFG (SFB 1074, project A5) and the gender equality program by the DFG (SFB 1074, project Z2), a fellowship from the Canadian Institutes of Health Research, and the Baustein Startförderung Program of the Medical Faculty, Ulm University. Work in the Department of Haematology in Cambridge is supported by Bloodwise (grant ref. 13003), the Wellcome Trust (grant ref. 104710/Z/14/Z), the Medical Research Council (MC_PC_12009), the Kay Kendall Leukemia Fund (KKL952), the Cambridge NIHR Biomedical Research Center (NF-BR-0412-10321), the Cambridge Experimental Cancer Medicine Centre itself receives funding from NIHR (NF-EC-0412-10442), the Leukemia and Lymphoma Society of America (grant ref. 07037), and core support grants from the Wellcome Trust (100140/Z/12/Z and 097922/Z/11/Z) and MRC (MC_PC_12009)