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

Feasibility of Screening Programs for Domestic Violence in Pediatric and Child and Adolescent Mental Health Services: A Literature Review

Each year, 275 million children worldwide are exposed to domestic violence (DV) and suffer negative mental and physical health consequences; however, only a small proportion receive assistance. Pediatricians and child psychiatrists can play a central role in identifying threatened children. We reviewed experiences of DV screening in pediatric and child and adolescent mental health services (CAMHS) to understand its feasibility and provide clues for its implementation. We performed bibliographic research using the Sapienza Library System, PubMed, and the following databases: MEDLINE, American Psychological Association PsycArticles, American Psychological Association PsycInfo, ScienceDirect, and Scopus. We considered a 20-year interval when selecting the articles and we included studies published in English between January 2000 and March 2021. A total of 23 out of 2335 studies satisfied the inclusion criteria. We found that the prevalence of disclosed DV ranged from 4.2% to 48%, with most prevalence estimates between 10% and 20%. Disclosure increases with a detection plan, which is mostly welcomed by mothers (70-80% acceptance rates). Written tools were used in 55% of studies, oral interviews in 40%, and computer instruments in 20%. Mixed forms were used in three studies (15%). The most used and effective tool appeared to be the Conflict Tactics Scale (CTS) (30% of studies). For young children, parental reports are advisable and written instruments are the first preference; interviews can be conducted with older children. Our research pointed out that the current literature does not provide practical clinical clues on facilitating the disclosure in pediatric clinics and CAMHS. Further studies are needed on the inpatient population and in the field of children psychiatry

One-step syntheses of very large cage-type molecules from aromatic sub-units

Polycondensation of a trifunctional, ketone-activated fluoroarene with bis- or tris-phenoxides under pseudo-high dilution conditions affords a series of very large macropolycyclic aromatic ether ketones; isolation and characterisation of these materials by NMR, MALDI-TOF MS and, for one example (after reduction of the carbonyl groups to methylene linkages) by X-ray crystallography, confirms that polycondensations which would normally lead to highly branched or cross-linked polymers can also give rise to large, closed-network molecules

Sulfur and Nitrogen Mustard Carbonate Analogues

Sulfur and nitrogen half-mustard compounds lose their aggressive properties when the chlorine atom is replaced by a carbonate moiety. The anchimeric effect of the novel mustard carbonate analogues is investigated. The reaction follows first-order kinetics, does not need any base, and occurs with OH, NH and acidic CH nucleophiles. Most of these molecules are unexplored and might provide a novel strategy for the preparation of compounds previously not easily accessible

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

Synthesis of a [2]Catenane around a Ru(diimine)32+ Scaffold by Ring-Closing Metathesis of Olefins

The synthesis of a ruthenium[2]catenane is described. One ring includes two 1,10-phenanthroline moieties, the other a bipyridinic unit. The interlocking ring system was formed by using a double ring closing metathesis reaction. Under irradiation, a rapid and selective decoordination of the bipyridinic fragment was observed, leading to a new catenane in which the metal is only coordinated to the bis-phenanthroline moiety

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

Straightforward, Metal-free, and Stereoselective Synthesis of 9-Oxo- and 10-Hydroxy-2(E)-decenoic acids, Important Components of Honeybee (Apis mellifera) secretions

10-Hydroxy-2E-decenoic (10-HDA) and 9-oxo-2E-decenoic (9-ODA) acids, two components identified in honeybee secretions, have both received considerable recent interest due to their involvement in caste switch and maintenance. Herein we report for the first time a metal-free, gram scale, and stereoselective synthesis of these honeybee secretion components by TEMPO catalyzed oxidation of readily available alcohols and subsequent Doebner–Knoevenagel reactions between the resulting aldehydes and malonic acid. Mechanistic investigations undertaken highlighted the crucial role of the Doebner–Knoevenagel reaction in the high yielding and selective preparation of the α,β-unsaturated acids 10-HDA and 9-ODA. The combination of inexpensive and environmentally friendly reagents with simple synthetic procedures renders this approach a valuable green strategy for the gram scale preparation of these biologically relevant natural molecules

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