Isolation and X-ray Structures of Labile Benzoic- and Acetic-Acidium Carbocations

New carbocationic salts (via O-protonation of substituted benzoic acids) are prepared for the first time by controlled hydration of the corresponding benzoylium salts and isolated in pure crystalline form. Precise X-ray structural analyses reveal the rather unexpected (electronic) structure of the carboxylic-acidium functionality

Isolation, X-ray Structures, and Electronic Spectra of Reactive Intermediates in Friedel−Crafts Acylations

Reactive intermediates in the Friedel−Crafts acylation of aromatic donors are scrutinized upon their successful isolation and X-ray crystallography at very low temperatures. Detailed analyses of the X-ray parameters for the [1:1] complexes of different aliphatic and aromatic-acid chlorides with the Lewis acids antimony pentafluoride and pentachloride, gallium trichloride, titanium and zirconium tetrachlorides provide unexpected insight into the activation mechanism for the formation of the critical acylium carbocations. Likewise, the X-ray-structure examinations of aliphatic and aromatic acylium electrophiles also isolated as crystalline salts point to the origins of their electrophilic reactivity. Although the Wheland intermediates (as acylium adducts to arene donors) could not be isolated in crystalline form owing to their exceedingly short lifetimes, transient (UV−vis) spectra of benzenium adducts of acylium carbocations with hexamethylbenzene can be measured and directly related to Wheland intermediates with other cationic electrophiles that have been structurally established via X-ray studies

Charge Delocalization in Self-Assembled Mixed-Valence Aromatic Cation Radicals

The spontaneous assembly of aromatic cation radicals (D+•) with their neutral counterpart (D) affords dimer cation radicals (D2+•). The intermolecular dimeric cation radicals are readily characterized by the appearance of an intervalence charge-resonance transition in the NIR region of their electronic spectra and by ESR spectroscopy. The X-ray crystal structure analysis and DFT calculations of a representative dimer cation radical (i.e., the octamethylbiphenylene dimer cation radical) have established that a hole (or single positive charge) is completely delocalized over both aromatic moieties. The energetics and the geometrical considerations for the formation of dimer cation radicals is deliberated with the aid of a series of cyclophane-like bichromophoric donors with drastically varied interplanar angles between the cofacially arranged aryl moieties. X-ray crystallography of a number of mixed-valence cation radicals derived from monochromophoric benzenoid donors established that they generally assemble in 1D stacks in the solid state. However, the use of polychromophoric intervalence cation radicals, where a single charge is effectively delocalized among all of the chromophores, can lead to higher-order assemblies with potential applications in long-range charge transport. As a proof of concept, we show that a single charge in the cation radical of a triptycene derivative is evenly distributed on all three benzenoid rings and this triptycene cation radical forms a 2D electronically coupled assembly, as established by X-ray crystallography

Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases

Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A. The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes. Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T > C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 x 10(-16)). The association was confirmed in the family dataset (p a parts per thousand currency signaEuro parts per thousand 9.20 x 10(-4)). rs9258750A > G was the most associated variant in the HLA region (p = 2.06 x 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific. ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease

Photochemistry Of Monochloro Complexes Of Copper(ii) In Methanol Probed By Ultrafast Transient Absorption Spectroscopy

Ultrafast transient absorption spectra in the deep to near UV range (212-384 nm) were measured for the [Cu-II(MeOH)(5)Cl](+) complexes in methanol following 255-nm excitation of the complex into the ligand-to-metal charge-transfer excited state. The electronically excited complex undergoes sub-200 fs radiationless decay, predominantly via back electron transfer, to the hot electronic ground state followed by fast vibrational relaxation on a 0.4-4 Ps time scale. A minor photochemical channel is Cu-Cl bond dissociation, leading to the reduction of copper(H) to copper(I) and the formation of MeOH center dot Cl charge-transfer complexes. The depletion of ground-state [Cu-II(MeOH)(5)Cl](+) perturbs the equilibrium between several forms of copper(II) complexes present in solution. Complete re-equilibration between [Cu-II(MeOH)(5)Cl](+) and [Cu-II(MeOH)(4)Cl-2] is established on a 10-500 ps time scale, slower than methanol diffusion, suggesting that the involved ligand exchange mechanism is dissociative

A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset

Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?

No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20–40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16–2.77; P=0.008), haemoglobin ⩽11.5 g l−1 (HR, 1.48; 95% CI, 1.06–2.05; P=0.019), CEA level >50 ng ml−1 (HR, 1.86; 95% CI, 1.21–2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16–2.53; P=0.006), and time-to-progression under first-line chemotherapy ⩽6 months (HR, 1.97; 95% CI, 1.39–2.80; P<0.0001). A prognostic index was constructed dividing patients into low- (no risk factor), intermediate- (one to two risk factors), or high- (three to five risk factors) risk groups, and median survival times for each group were 12.7 months, 7.1 months, and 3.3 months, respectively (P<0.001). In the absence of data deriving from randomised trials, this analysis suggests that some easily available clinical factors may help to select patients with advanced gastric cancer who could derive more benefit from second-line chemotherapy

Tuberculosis chemotherapy: current drug delivery approaches

Tuberculosis is a leading killer of young adults worldwide and the global scourge of multi-drug resistant tuberculosis is reaching epidemic proportions. It is endemic in most developing countries and resurgent in developed and developing countries with high rates of human immunodeficiency virus infection. This article reviews the current situation in terms of drug delivery approaches for tuberculosis chemotherapy. A number of novel implant-, microparticulate-, and various other carrier-based drug delivery systems incorporating the principal anti-tuberculosis agents have been fabricated that either target the site of tuberculosis infection or reduce the dosing frequency with the aim of improving patient outcomes. These developments in drug delivery represent attractive options with significant merit, however, there is a requisite to manufacture an oral system, which directly addresses issues of unacceptable rifampicin bioavailability in fixed-dose combinations. This is fostered by the need to deliver medications to patients more efficiently and with fewer side effects, especially in developing countries. The fabrication of a polymeric once-daily oral multiparticulate fixed-dose combination of the principal anti-tuberculosis drugs, which attains segregated delivery of rifampicin and isoniazid for improved rifampicin bioavailability, could be a step in the right direction in addressing issues of treatment failure due to patient non-compliance

Impact of DOTS expansion on tuberculosis related outcomes and costs in Haiti

BACKGROUND: Implementation of the World Health Organization's DOTS strategy (Directly Observed Treatment Short-course therapy) can result in significant reduction in tuberculosis incidence. We estimated potential costs and benefits of DOTS expansion in Haiti from the government, and societal perspectives. METHODS: Using decision analysis incorporating multiple Markov processes (Markov modelling), we compared expected tuberculosis morbidity, mortality and costs in Haiti with DOTS expansion to reach all of the country, and achieve WHO benchmarks, or if the current situation did not change. Probabilities of tuberculosis related outcomes were derived from the published literature. Government health expenditures, patient and family costs were measured in direct surveys in Haiti and expressed in 2003 US$. RESULTS: Starting in 2003, DOTS expansion in Haiti is anticipated to cost$4.2 million and result in 63,080 fewer tuberculosis cases, 53,120 fewer tuberculosis deaths, and net societal savings of $131 million, over 20 years. Current government spending for tuberculosis is high, relative to the per capita income, and would be only slightly lower with DOTS. Societal savings would begin within 4 years, and would be substantial in all scenarios considered, including higher HIV seroprevalence or drug resistance, unchanged incidence following DOTS expansion, or doubling of initial and ongoing costs for DOTS expansion. CONCLUSION: A modest investment for DOTS expansion in Haiti would provide considerable humanitarian benefit by reducing tuberculosis-related morbidity, mortality and costs for patients and their families. These benefits, together with projected minimal Haitian government savings, argue strongly for donor support for DOTS expansion