911 research outputs found
Acid catalyzed synthesis of dimethyl isosorbide via dimethyl carbonate chemistry
Dimethyl isosorbide (DMI) is a bio-based solvent that can be used as green alternative for conventional dipolar
media (dimethyl sulfoxide, dimethylformamide, and dimethylacetamide). The main synthetic procedures to DMI
reported in the literature are based on the methylation of isosorbide employing different alkylating agents
including toxic halogen compounds such as alkyl halides. A more sustainable alternative would be to employ
dimethyl carbonate (DMC), a well-known green reagent and solvent, considered one of the most promising
methylating agents for its good biodegradability and low toxicity. Indeed, in recent years, DMC-promoted
methylation of isosorbide has been extensively exploited although mostly in the presence of a base or an
amphoteric catalyst. In this work, we report for the first time a comprehensive investigation on the synthesis of
DMI via DMC chemistry promoted by heterogeneous acid catalyst (Amberlyst-36 and Purolite CT275DR). Re-
action conditions were optimized and then applied for the methylation of isosorbide and its epimers, isoidide and
isomannide. Considerations on the related reaction mechanism were reported highlighting the difference in the
preferred reaction pathways among this new synthetic approach and the previously reported base-catalyzed
procedures
Cosmology with baryons: modelling the cosmic matter distribution for Large-Scale Structure analyses.
La interacción entre las fuerzas gravitatorias e hidrodinámicas en la formación de la estructura del Universo es compleja y aún se desconoce en gran medida. Las fuerzas gravitatorias son dominantes a gran escala, donde las perturbaciones de la densidad son pequeñas y, por tanto, se pueden describir mediante una teoría lineal. Sin embargo, en las escalas pequeñas surgen no linealidades y, por lo tanto, la teoría analítica no es suficiente. El gas es perturbado tanto por las fuerzas hidrodinámicas como por la gravedad, y tienen lugar varios procesos astrofísicos. La formación de galaxias desencadena explosiones de supernovas y la inyección de energía de los agujeros negros supermasivos que se acrecientan, perturbando la distribución de la masa y remodelando el potencial gravitatorio, lo que provoca posteriormente una reacción inversa en la materia oscura.La falta de una modelización precisa de estos procesos bariónicos es una de las principales fuentes de incertidumbre en los actuales estudios de lentes gravitatorias débiles, y se espera que su impacto aumente drásticamente en las próximas campañas de observación previstas.En esta tesis, queremos desarrollar un marco para modelar de forma consistente la distribución espacial y la evolución temporal de la materia oscura, el gas y las galaxias, en la Estructura a Gran Escala del Universo. Utilizamos un enfoque basado en simulaciones, variando simultáneamente la cosmología y los procesos astrofísicos. El núcleo de nuestro marco está dado por grandes simulaciones de alta resolución, que garantizan una modelización robusta de las no linealidades a pequeñas escalas, y predicciones precisas a grandes escalas. En una fase de posprocesamiento, desplazamos las partículas en nuestras simulaciones para explorar diferentes escenarios cosmológicos y bariónicos, mediante la combinación de dos algoritmos de última generación: el modelo de escalado cosmológico y el de corrección bariónica. Implementamos versiones extendidas y optimizadas de ambos algoritmos, para alcanzar la precisión requerida por los estudios de próxima generación, y los probamos sistemáticamente por separado y en combinación. Por último, utilizamos técnicas modernas de aprendizaje automático, y en concreto redes neuronales artificiales, entrenadas para aprender las conexiones entre los parámetros cosmológicos y astrofísicos y las estadísticas relevantes del campo de materia cósmica, tal y como se miden en nuestras simulaciones. De este modo, nuestras predicciones pueden realizarse con un coste computacional insignificante, y la contribución lineal, no lineal y bariónica puede calcularse por separado. Nuestros emuladores de redes neuronales están disponibles públicamente y pueden incorporarse fácilmente a una análisis de lentes gravitatorias débiles. Utilizando nuestro marco de trabajo, la modelización de la densidad cosmica puede extenderse a escalas pequeñas sin precedentes, de forma muy precisa y con una aceleración consistente en el tiempo de cálculo. Esperamos que las técnicas desarrolladas y los resultados presentados aquí sean útiles para una amplia gama de aplicaciones en los análisis de estructuras a gran escala, y en particular en studios de lentes gravitatorias débiles y galaxias.<br /
Sarcopenia Does Not Worsen Survival in Patients With Cirrhosis Undergoing Transjugular Intrahepatic Portosystemic Shunt for Refractory Ascites
INTRODUCTION: The impact of sarcopenia in patients undergoing transjugular intrahepatic portosystemic shunt (TIPSS) insertion for refractory ascites is unknown. METHODS: All adult patients who underwent TIPSS insertion for refractory ascites between 2010 and 2018 were included. Skeletal muscle index at L3 was used to determine sarcopenia status. RESULTS: One hundred seven patients were followed for 14.2 months. Sarcopenia was present in 57% of patients. No patient had history of pre-TIPSS hepatic encephalopathy (HE). De novo HE occurred in 30% of patients. On multivariate analysis, only platelet count and L3-SMI predicted de novo HE. On multivariate analysis, age and model for end-stage liver disease with sodium predicted mortality, whereas L3-SMI and sarcopenia did not. In patients with repeat imaging, L3-SMI improved significantly post-TIPSS compared with baseline. DISCUSSION: Sarcopenia should not be considered as a contraindication to TIPSS insertion in refractory ascites because it is not associated with de novo HE or increased mortality
MOLECULAR CHARACTERISATION OF A NOVEL ADP-RIBOSYLATING PUTATIVE TOXIN OF NEISSERIA MENINGITIDIS
Molecular characterisation of a novel ADP-ribosylating putative toxin of Neisseria meningitidis
VEGGIi D, *BALDUCCI E, MASIGNANI V, DI MARCELLO F, SAVINO S, ARICO’ B, COMANDUCCI M, PIZZA M, RAPPUOLI R
IRIS, Chiron SpA, Via Fiorentina 1, 53100 Siena Italy; *Dipartimento Scienze morfologiche e Biochimiche Comparate, Università degli Studi di Camerino, Camerino, Italy
Session: Surface antigens
Introduction: By computer analysis on the Neisseria meningitidis (serogroup B, MC 58 strain) genome sequence, a protein with a feature similar to known bacterial ADP-ribosylating toxins (CT produced by Vibrio cholerae, LT by Escherichia coli and PT by Bordetella pertussis) has been identified. Enzymatic assay has shown that this protein (NM-ADPRT) possesses both NAD glycohydrolase and ADP-ribosyltransferase activity. In this study we describe the identification of the putative catalytic residues, their site-directed mutagenesis, and the resulting activity of the mutants.
Materials and methods: The novel NM-ADPRT and the correspondent mutants, were expressed in E. coli as C-terminus His-tag protein fusions. Site-directed mutagenesis was performed using the Multi Site-Directed Mutagenesis Kit (QuikChange). Recombinant NM-ADPRT forms were purified from E. coli in their soluble form by metal chelate affinity chromatography.
Both the wild-type and the mutants were assayed for their ADP-ribosylation and NAD-glycohydolase activites, using [adenine –U-14C] NAD and agmatine as ADP-ribose acceptor. Antisera against NM-ADPRT and the mutant derivatives were obtained by immunization of CD1 mice. 20μg of each recombinant protein were given i.p. together with CFA for the first dose and IFA for the second (day 21) and the third (day 35) booster doses. Blood sample were taken on days 34 and 49. Immune sera were used in western blot and tested in a bactericidal assay.
Results and discussion: On the basis of sequence homology of NM-ADPRT with LT, CT and PT we have identified the putative residues involved in enzymatic activity. These residues have been changed by site-directed mutagenesis and the purified mutant toxins have been tested for both ADP-ribosylating and NAD-glycohydrolase activities. Interestingly, some of the mutants show reduced or abolished enzymatic activity indicating that the identified residues play a role in catalysis. Antisera against the wild-type and mutant toxins have bactericidal activity. The titers induced by two mutants were higher than those induced by the wild-type form. These data suggest that the mutations introduced could influence not only the enzymatic activity but also the in vivo stability of the toxin.
Conclusion: A novel ADP-ribosyltransferase has been identified in meningococcus B. Catalytic residues have been predicted by sequence homology and their role in catalysis has been confirmed by site-directed mutagenesis. These molecules are also able to induce a bactericidal response
Template-Directed Synthesis of Mechanically Interlocked Molecular Bundles Using Dynamic Covalent Chemistry
Mixing the dipyrido[24]crown-8 derivatives carrying one or two formyl group(s) on the 4 position(s) of their pyridine ring(s) with a 3-fold symmetrical trisammonium ion template in a 3:1 ratio in CD3NO2 results in the formation of thermodynamically stable [4]pseudorotaxanes which, upon addition of a 1,3,5 trisaminobenzene cap, form mechanically interlocked molecular bundles with one and two caps, respectively, by virtue of dynamic imine bond formation
DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma
Epigenetic deregulation is a hallmark of cancer characterized by frequent acquisition of new DNA methylation in CpG islands. To gain insight into the methylation changes of canine DLBCL, we investigated the DNA methylome in primary DLBCLs in comparison with control lymph nodes by genome-wide CpG microarray. We identified 1,194 target loci showing different methylation levels in tumors compared with controls. The hypermethylated CpG loci included promoter, 5'-UTRs, upstream and exonic regions. Interestingly, targets of polycomb repressive complex in stem cells were mostly affected suggesting that DLBCL shares a stem cell-like epigenetic pattern. Functional analysis highlighted biological processes strongly related to embryonic development, tissue morphogenesis and cellular differentiation, including HOX, BMP and WNT. In addition, the analysis of epigenetic patterns and genome-wide methylation variability identified cDLBCL subgroups. Some of these epigenetic subtypes showed a concordance with the clinical outcome supporting the hypothesis that the accumulation of aberrant epigenetic changes results in a more aggressive behavior of the tumor. Collectively, our results suggest an important role of DNA methylation in DLBCL where aberrancies in transcription factors were frequently observed, suggesting an involvement during tumorigenesis. These findings warrant further investigation to improve cDLBCL prognostic classification and provide new insights on tumor aggressiveness
Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients
X-linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)-associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV-infected cells, with dramatic clinical sequelae. Here, we investigated the NK cell education in XLP1, upon characterization of killer Ig-like receptor (KIR)/KIR-L genotype and phenotypic repertoire of self-HLA class I specific inhibitory NK receptors (self-iNKRs). We also analyzed NK-cell cytotoxicity against CD48+ or CD48− KIR-ligand matched or autologous hematopoietic cells in XLP1 patients and healthy controls. XLP1 NK cells may show a defective phenotypic repertoire with substantial proportion of cells lacking self-iNKR. These NK cells are cytotoxic and the inhibitory 2B4/CD48 pathway plays a major role to prevent killing of CD48+ EBV-transformed B cells and M1 macrophages. Importantly, self-iNKR defective NK cells kill CD48− targets, such as mature DCs. Self-iNKR− NK cells in XLP1 patients are functional even in resting conditions, suggesting a role of the inhibitory 2B4/CD48 pathway in the education process during NK-cell maturation. Killing of autologous mature DC by self-iNKR defective XLP1 NK cells may impair adaptive responses, further exacerbating the patients’ immune defect
Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry
Background Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having "sporadic" HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. Conclusion We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL
Atomic-scale combination of germanium-zinc nanofibers for structural and electrochemical evolution
Alloys are recently receiving considerable attention in the community of rechargeable batteries as possible alternatives to carbonaceous negative electrodes; however, challenges remain for the practical utilization of these materials. Herein, we report the synthesis of germanium-zinc alloy nanofibers through electrospinning and a subsequent calcination step. Evidenced by in situ transmission electron microscopy and electrochemical impedance spectroscopy characterizations, this one-dimensional design possesses unique structures. Both germanium and zinc atoms are homogenously distributed allowing for outstanding electronic conductivity and high available capacity for lithium storage. The as-prepared materials present high rate capability (capacity of similar to 50% at 20 C compared to that at 0.2 C-rate) and cycle retention (73% at 3.0 C-rate) with a retaining capacity of 546 mAh g(-1) even after 1000 cycles. When assembled in a full cell, high energy density can be maintained during 400 cycles, which indicates that the current material has the potential to be used in a large-scale energy storage system
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