This effort reports the first redox-neutral visible-light photocatalytic intramolecular dipolar cycloaddition for the diastereoselective synthesis of chromenoisoxazolidines. The authors have found ...that alkenylphenyl nitrones with a diverse substitution pattern on the aromatic ring and the alkenyl substituent undergo visible-light-promoted cycloadditions in the presence of catalytic amounts of Ru(bpy)3Cl2 in high yields and selectivities. Evidence indicates that the proposed redox-neutral pathway is the predominant photoredox mechanism for this transformation.
Substituted and stereochemically dense carbacycles can be prepared by sequential dipolar cycloaddition and reductive cleavage from enals and hydroxylamines. The reaction sequence proceeds with high ...efficiency for a wide variety of enals and hydroxylamines. The reaction is regio- and diastereoselective for the initial formation of a bridged bisisoxazolidine intermediate, which then undergoes quantitative double N–O cleavage to produce carbacycles as single diastereomers.
Objective Traditionally integrated coronary artery revascularization has been described as a 2-stage procedure. We evaluated the safety and feasibility of 1-stage, simultaneous, hybrid, robotically ...assisted coronary artery bypass grafting surgery and percutaneous coronary intervention. Methods Fifty-eight patients underwent simultaneous, integrated coronary artery revascularization in an operating theater equipped with angiographic equipment. Forty-five patients were men. The mean age was 59 years. All internal thoracic arteries were harvested with robotic assistance. All anastomoses were manually constructed through a small anterior non–rib-spreading incision without cardiopulmonary bypass on the beating heart. Immediately after and within the same operative suite, both angiographic confirmation of graft patency and percutaneous coronary intervention were performed. In 52 patients therapeutic anticoagulation was achieved with the direct thrombin inhibitor bivalirudin. Results There were no deaths or wound infections. There was 1 perioperative myocardial infarction. One patient had a stroke, and 3 patients required re-exploration for bleeding. The median lengths of intensive care and hospital stay were 1 and 4 days, respectively. All patients were alive and symptom free at follow-up (mean, 20.2 months; range, 1.1–40.8 months). Long-term angiographic follow-up in 54 patients showed 49 (91%) patent grafts (mean, 9.0 months; range, 4.3–40.8 months). There were 7 in-stent restenoses and 2 occluded stents. Conclusion For multivessel coronary artery disease, simultaneous integrated coronary artery revascularization with bivalirudin is safe and feasible. This approach enables complete multivessel revascularization with decreased surgical trauma and postoperative morbidity. Further studies are necessary to better determine patient selection and long-term outcomes.
HIV-1’s subtype C V3 loop consensus sequence exhibits increased resistance to anti-V3 antibody-mediated neutralization as compared to the subtype B consensus sequence. The dynamic 3D structure of the ...consensus C V3 loop crown, visualized by ab initio folding, suggested that the resistance derives from structural rigidity and non-β-strand secondary protein structure in the N-terminal strand of the β-hairpin of the V3 loop crown, which is where most known anti-V3 loop antibodies bind. The observation of either rigidity or non-β-strand structure in this region correlated with observed resistance to antibody-mediated neutralization in a series of chimeric pseudovirus (psV) mutants. The results suggest the presence of an epitope-independent, neutralization-relevant structural difference in the antibody-targeted region of the V3 loop crown between subtype C and subtype B, a difference that we hypothesize may contribute to the divergent pattern of global spread between these subtypes. As antibodies to a variable loop were recently identified as an inverse correlate of risk for HIV infection, the structure-function relationships discussed in this study may have relevance to HIV vaccine research.
A gene encoding a predicted mitochondrially targeted single-stranded DNA binding protein (mtSSB) was identified in the Arabidopsis thaliana genome sequence. This gene (At4g11060) codes for a protein ...of 201 amino acids, including a 28-residue putative mitochondrial targeting transit peptide. Protein sequence alignment shows high similarity between the mtSSB protein and single-stranded DNA binding proteins (SSB) from bacteria, including residues conserved for SSB function. Phylogenetic analysis indicates a close relationship between this protein and other mitochondrially targeted SSB proteins. The predicted targeting sequence was fused with the GFP coding region, and the organellar localization of the expressed fusion protein was determined. Specific targeting to mitochondria was observed in in-vitro import experiments and by transient expression of a GFP fusion construct in Arabidopsis leaves after microprojectile bombardment. The mature mtSSB coding region was overexpressed in Escherichia coli and the protein was purified for biochemical characterization. The purified protein binds single-stranded, but not double-stranded, DNA. MtSSB stimulates the homologous strand-exchange activity of E. coli RecA. These results indicate that mtSSB is a functional homologue of the E. coli SSB, and that it may play a role in mitochondrial DNA recombination.
Objective:
Open surgical pyeloplasty has been the gold standard for the correction of ureteropelvic junction obstruction (UPJO). Endourological management of UPJO has gained increased acceptance, ...with reported success rates of 57–87%. It has been suggested that Acucise
® endopyelotomy (AE) should be the procedure of choice for patients with UPJO. The aim of this study was to assess the effectiveness of AE in the treatment of UPJO and the factors contributing to surgical outcome.
Materials and Methods:
Forty-two patients (34 primary, 8 secondary UPJO) underwent AE between June 1995 and December 1999. Presenting symptoms were; pain 34 (80.9%), UTI 10 (23.8%) and haematuria 5 (11.9%). Pre-operative evaluation included ultrasound and/or intravenous urogram with diuretic renography. Hydronephrosis was graded in 36 patients. Of these 4, 14, 9 and 9 had grade I, II, III and IV hydronephrosis, respectively. Twenty-four patients were stented prior to endopyelotomy and one required nephrostomy. Overall (true) success was defined as clinically pain free and radiologically no evidence of obstruction on diuretic scan.
Results:
The average operating time was 45
min and mean hospital stay was 2.7 days. Mean follow-up was 27 months (range 6–55). The objective success rate was 52% and the subjective success rate was 64%. A total of 19 patients (45.2%) had long lasting clinical and radiographic treatment success. Three (7%) patients required nephrectomy and five (12%) underwent open pyeloplasty. Success rate for grade I/II hydronephrosis was 55.5% and only 27.7% with grade III/IV hydronephrosis. Normal renograms were found in 12 (48%) of those with perioperative extravasation compared to three (25%) without. Only one of the eight patients with secondary UPJO had a normal post-operative renogram. Size or type of stent used had no effect on surgical outcome. The substandard results were noted in patients with grade III/IV hydronephrosis, poor pre-operative renal function, secondary UPJO and without perioperative extravasation.
Conclusions:
Acucise
® endopyelotomy is a safe and minimally invasive procedure for the management of UPJO. Although the results of AE are suboptimal, its lower degree of invasiveness makes it reasonable choice for first-line treatment. Careful selection of patients will improve the results of AE, although multicentre randomized trials are needed to make a valued comparison with other techniques.
The antigenic diversity of HIV-1 has long been an obstacle to vaccine design, and this variability is especially pronounced in the V3 loop of the virus' surface envelope glycoprotein. We previously ...proposed that the crown of the V3 loop, although dynamic and sequence variable, is constrained throughout the population of HIV-1 viruses to an immunologically relevant β-hairpin tertiary structure. Importantly, there are thousands of different V3 loop crown sequences in circulating HIV-1 viruses, making 3D structural characterization of trends across the diversity of viruses difficult or impossible by crystallography or NMR. Our previous successful studies with folding of the V3 crown used the ab initio algorithm accessible in the ICM-Pro molecular modeling software package (Molsoft LLC, La Jolla, CA) and suggested that the crown of the V3 loop, specifically from positions 10 to 22, benefits sufficiently from the flexibility and length of its flanking stems to behave to a large degree as if it were an unconstrained peptide freely folding in solution. As such, rapid ab initio folding of just this portion of the V3 loop of any individual strain of the 60,000+ circulating HIV-1 strains can be informative. Here, we folded the V3 loop of the R2 strain to gain insight into the structural basis of its unique properties. R2 bears a rare V3 loop sequence thought to be responsible for the exquisite sensitivity of this strain to neutralization by patient sera and monoclonal antibodies. The strain mediates CD4-independent infection and appears to elicit broadly neutralizing antibodies. We demonstrate how evaluation of the results of the folding can be informative for associating observed structures in the folding with the immunological activities observed for R2.
In his early years in practice, Malcolm attended some 50 home confinements a year. He always had a special interest in heart disease, and, unusually for those times, had his own electrocardiograph.
Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated ...risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.
Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.
Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.
MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
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