2-Methylsulfanylbenzo[f]isoquinoline

S-Methylation of a 4-(naphth-2-yl)-β-thiolactam gives an intermediate 4-(naphth-2-yl) substituted 1-azetine which undergoes a [2+2] ring-opening followed by electrocyclic ring closure of the resulting 2-azadiene to give a benzo[f]isoquinolin

Neighborhood analysis for metropolitan areas

Call number: LD2668 .R4 1968 H

Generalized Ostrowski inequalities and computational integration

We state and prove three generalized results related to Ostrowski inequality by using differentiable functions which are bounded, bounded below only and bounded above only, respectively. From our proposed results we get number of established results as our special cases. Some applications in numerical integration are also given which gives us some standard and nonstandard quadrature rules

Open, Honest, Passionate and with Some Humor: Understanding Trust Building Between British Muslims and the Wider Community

open access articleThe “Trust Building” initiative, launched in the United Kingdom in April 2016, aimed to dispel myths about Islam and build trust between Muslims and the wider community. This community-led initiative involved trained Trust Building “Ambassadors” delivering workshops at places of work and other community settings to talk about Islam and facilitate open dialogue. Previously, the project reported trust among participants had significantly improved, but the reasons for this were not explored. In this paper, we unpack how and why trust was being built. Providing a forum that permits open dialogue between Muslims and the wider community allowed opportunities for stories and experiences to be shared, enabling negative stereotypes to be uncovered and addressed, and for mutual values to be recognised. With negative media portrayal and rise in hate crime towards minorities, this research is a promising model that has important implications to address the trust deficit seen within our society

Ionomic profiling of pericardial fluid in ischemic heart disease

Metals are essential cofactors that play a crucial role in heart function at the cell and tissue level. Information regarding the role of metals in the pericardial fluid and its ionome in ischemic heart disease (IHD) is limited. We aimed to determine the association of elements in pericardial fluid and serum samples of IHD patients and their correlation with systolic and diastolic function. IHD patients have been studied with systolic and diastolic dysfunction categorized on the basis of echocardiographic parameters. We measured concentrations of sixteen elements in the pericardial fluid and serum of 46 patients obtained during open heart surgery with IHD by ICP-MS. The levels of chromium and nickel in pericardial fluid were significantly higher as compared with serum samples of IHD patients (p \u3c 0.05). The chromium, nickel and manganese levels in pericardial fluid were lower in patients with ejection fraction (EF) \u3c 45% as compared to EF \u3e 45% (p \u3c 0.05). There was no significant difference in pericardial concentrations of elements in diastolic dysfunction grade 0–1 with 2 in IHD patients. We also found that decreased concentration of these elements in pericardial fluid is associated with decreased systolic function. These results suggest that pericardial fluid concentrations of these metals may reflect the extent of ischemic heart disease. These findings are hypothesis generating with regards to a role in the pathogenesis of the disorder

Pericardial fluid proteomic label-free quantification of differentially expressed proteins in ischemic heart disease patients with systolic dysfunction by nano-LC-ESI-MS/MS analysis

Left ventricular systolic dysfunction (LVSD) is common in patients with pre-existing ischemic heart disease (IHD) and myocardial infarction. An untargeted proteomic approach is used to improve the understanding of the molecular mechanisms associated with LVSD and to find out potential proteomic signatures in pericardial fluid. The pericardial fluid of IHD (n = 45) patients was grouped into two categories according to the left ventricular ejection fraction, LVEF ≥45 (n = 33) and LVEF \u3c45 (n = 12), and analyzed by using nano-liquid chromatography–mass spectrometry (nano-LC-MS/MS) technique. The nano-LC-MS/MS analysis resulted in the identification of 709 pericardial fluid (PF) proteins in both normal and impaired systolic functional groups (LVEF ≥45 vs. LVEF \u3c45). Sixteen proteins were found to be differentially expressed (p \u3c 0.05, fold change \u3e2) including 12 down-regulated and 4 up-regulated in the impaired systolic functional group (LVEF \u3c45) compared to the normal group (LVEF ≥45). Among the differentially expressed proteins the inflammatory marker albumin, atherosclerosis marker apolipoprotein A-IV and hedgehog-interacting protein marker of angiogenesis were predominantly associated with the impaired LVEF \u3c45 group. KEGG pathway analysis revealed that the hedgehog (Hh) signalling pathway is up-regulated in LVSD reflecting the underlying molecular and pathophysiological processes

A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities

We describe a large consanguineous pedigree from a remote area of Northern Pakistan, with a complex developmental disorder associated with wide-ranging symptoms, including mental retardation, speech and language impairment and other neurological, psychiatric, skeletal and cardiac abnormalities. We initially carried out a genetic study using the HumanCytoSNP-12 v2.1 Illumina gene chip on nine family members and identified a single region of homozygosity shared amongst four affected individuals on chromosome 7p22 (positions 3059377–5478971). We performed whole-exome sequencing on two affected individuals from two separate branches of the extended pedigree and identified a novel nonsynonymous homozygous mutation in exon 9 of the WIPI2 (WD-repeat protein interacting with phosphoinositide 2) gene at position 5265458 (c.G745A;pV249M). WIPI2 plays a critical role in autophagy, an evolutionary conserved cellular pathway implicated in a growing number of medical conditions. The mutation is situated in a highly conserved and critically important region of WIPI2, responsible for binding PI(3)P and PI(3,5)P2, an essential requirement for autophagy to proceed. The mutation is absent in all public databases, is predicted to be damaging and segregates with the disease phenotype. We performed functional studies in vitro to determine the potential effects of the mutation on downstream pathways leading to autophagosome assembly. Binding of the V231M mutant of WIPI2b to ATG16L1 (as well as ATG5–12) is significantly reduced in GFP pull-down experiments, and fibroblasts derived from the patients show reduced WIPI2 puncta, reduced LC3 lipidation and reduced autophagic flux

Understanding of metals dysregulation in patients with systolic and diastolic dysfunction in ischemic heart disease

Ischemic heart disease (IHD) is the leading cause of death and chronic disability in the world. IHD affects both the systolic and diastolic function of the heart which progressively leads to heart failure; a structural and functional impairment of filling or ejection of blood from the heart. In this study, the progression of systolic and diastolic dysfunction characterized according to their echocardiographic parameters including left ventricular ejection fraction (EF), grades of diastolic dysfunction and ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e\u27), were correlated with differential regulation of various metals in patients sera samples (n = 62) using inductive coupled plasma-mass spectrometry (ICP-MS). Chromium, nickel and selenium were found significant (p \u3c 0.05) in patients having EF \u3c 45% compared with EF \u3e 45%. In patients with systolic dysfunction (EF \u3c 45%), the level of selenium was decreased while the level of chromium and nickel was increased compared to patients with EF \u3e 45%. Selenium level was also decreased significantly (p \u3c 0.05) in grade 1A and 2 patients that are considered as higher grades of diastole dysfunction in comparison to grade 0-1. Overall, selenium deficiency was identified in both systolic and diastolic dysfunctions of IHD patients corresponding to the progression of disease that could be related to many metabolic and translational pathways specifically which involve selenoproteins

Azide based routes to tetrazolo and oxadiazolo derivatives of pyrrolobenzodiazepines and pyrrolobenzothiadiazepines

Tetrazolo- and 1,2,4-oxadiazolo-fused derivatives of the antitumour, antibiotic, DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines and their pyrrolobenzothiadiazepine derivatives have been produced as analogues of a 1,2,3-triazolo-fused pyrrolobenzothiadiazepine which was shown to be a Glut-1 transporter inhibitor with potential as an antitumour agent. The tetrazolo-fused systems were produced by intramolecular 1,3-dipolar cycloaddition between an azide and a nitrile. The 1,2,4-oxadiazolo systems were produced by nitrile oxide cycloadditions to pyrrolobenzothiadiazepines which were in turn produced from a 2-(azidobenzenesulfonyl)-1,2-thiazine 1-oxide. The latter species underwent a phosphite mediated one-pot sulfur extrusion, ring contraction and azide to amine conversion to form 1-(aminobenzenesulfonyl)pyrroles. Bischler-Napieralski ring closure gave the pyrrolobenzothiadiazepines

Whole exome sequencing identified five novel variants in CNTN2, CARS2, ARSA, and CLCN4 leading to epilepsy in consanguineous families

Introduction: Epilepsy is a group of neurological disorders characterized by recurring seizures and fits. The Epilepsy genes can be classified into four distinct groups, based on involvement of these genes in different pathways leading to Epilepsy as a phenotype. Genetically the disease has been associated with various pathways, leading to pure epilepsy-related disorders caused by CNTN2 variations, or involving physical or systemic issues along with epilepsy caused by CARS2 and ARSA, or developed by genes that are putatively involved in epilepsy lead by CLCN4 variations.Methods: In this study, five families of Pakistani origin (EP-01, EP-02, EP-04, EP-09, and EP-11) were included for molecular diagnosis.Results: Clinical presentations of these patients included neurological symptoms such as delayed development, seizures, regression, myoclonic epilepsy, progressive spastic tetraparesis, vision and hearing impairment, speech problems, muscle fibrillation, tremors, and cognitive decline. Whole exome sequencing in index patients and Sanger sequencing in all available individuals in each family identified four novel homozygous variants in genes CARS2: c.655G>A p.Ala219Thr (EP-01), ARSA: c.338T>C: p.Leu113Pro (EP-02), c.938G>T p.Arg313Leu (EP-11), CNTN2: c.1699G>T p.Glu567Ter (EP-04), and one novel hemizygous variant in gene CLCN4: c.2167C>T p.Arg723Trp (EP-09).Conclusion: To the best of our knowledge these variants were novel and had not been reported in familial epilepsy. These variants were absent in 200 ethnically matched healthy control chromosomes. Three dimensional protein analyses revealed drastic changes in the normal functions of the variant proteins. Furthermore, these variants were designated as “pathogenic” as per guidelines of American College of Medical Genetics 2015. Due to overlapping phenotypes, among the patients, clinical subtyping was not possible. However, whole exome sequencing successfully pinpointed the molecular diagnosis which could be helpful for better management of these patients. Therefore, we recommend that exome sequencing be performed as a first-line molecular diagnostic test in familial cases