Peptide Carbocycles: From −SS– to −CC– via a Late-Stage “Snip-and-Stitch”

One way to improve the therapeutic potential of peptides is through cyclization. This is commonly done using a disulfide bond between two cysteine residues in the peptide. However, disulfide bonds are susceptible to reductive cleavage, and this can deactivate the peptide and endanger endogenous proteins through covalent modification. Substituting disulfide bonds with more chemically robust carbon-based linkers has proven to be an effective strategy to better develop cyclic peptides as drugs, but finding the optimal carbon replacement is synthetically laborious. We report a new late-stage platform wherein a single disulfide bond in a cyclic peptide can serve as the progenitor for any number of new carbon-rich groups, derived from organodiiodides, using a Zn:Cu couple and a hydrosilane. We show that this platform can furnish entirely new carbocyclic scaffolds with enhanced permeability and structural integrity and that the stereochemistry of the new cycles can be biased by a judicious choice in silane

Connectivity, genus, and the number of components in vertex-deleted subgraphs

AbstractLet c(G) denote the number of components in a graph G. It is shown that if G has genus γ and isk-connected with k ⩾ 3, then c(G − X) ⩽ (2/(k − 2))(| X | − 2 + 2γ), for all X⊆ V(G) with | X | ⩾ k. Some implications of this result for planar graphs (y = 0) and toroidal graphs (y = 1) are considered

Ensnaring the Elusive Eodermdrome

We wish to introduce the recreational aspects of the eodermdrome, which is a recently formulated concept dealing with the structure of language units such as letters and words. Although this concept may eventually lead to a numerical way to compare the structural differences between languages and to trace structural development in a single language, the majority of individuals who learn about eodermdromes evince less interest in their potential scholarly ramifications than in the delightful task of creating them

Queen Labelings

We introduce and investigate the concept of Queen labeling a digraph and its connection to the well-known n-queens problem. In the general case we obtain an upper bound on the size of a queen graph and show that it is tight. We also examine the existence of possible forbid-den subgraphs for this problem and show that only two such subgraphs exist. Then we focus on specific graph families: First we show that every star is a queen graph by giving an algorithm for which we prove cor-rectness. Then we show that the problem of queen labeling a matching is equivalent to a variation of the n-queens problem, which we call the rooks-and-queens problem and we use that fact to give a short proof that every matching is a queen graph. Finally, for unions of 3-cycles we give a general solution of the problem for graphs of n(n - 1) vertices

Definitive Management of Failure After Pyeloplasty

Introduction: Failure after pyeloplasty is difficult to manage. We report our experience managing pyeloplasty failures. Methods: We retrospectively reviewed the case log of a single surgeon, from August 1996 to August 2014, to identify all patients undergoing a surgical procedure after failed pyeloplasty. We excluded patients without follow-up exceeding 1 year from initial postpyeloplasty procedure. Failure was defined as a need for additional definitive intervention. Results: Of 247 laparoscopic pyeloplasties, 68 endopyelotomies and 305 simple laparoscopic nephrectomies reviewed, 41 were performed after previous pyeloplasty and had sufficient follow-up. Laparoscopic nephrectomy was performed in nine patients. All three secondary laparoscopic pyeloplasties were successful. Of 29 secondary endopyelotomies, 10 (34%) were successful. Of the 19 failures after secondary endopyelotomy, 12 patients had tertiary pyeloplasty (5 laparoscopic and 7 open surgical), 5 (26%) underwent tertiary endopyelotomy, and 2 (11%) required nephrectomy. Our overall endopyelotomy success rate was 38% (13/34) vs 100% (11/11) for secondary or tertiary pyeloplasty (4 patients lost to follow-up). Median time to failure was 5 months for endopyelotomy. Median follow-up for patients free from intervention was 40.2 months. Conclusions: Secondary pyeloplasty (including both laparoscopic and open surgical approach) is more than twice as successful as endopyelotomy after failed pyeloplasty. Secondary pyeloplasty is an excellent alternative to endopyelotomy in select patients with failure after initial pyeloplasty.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140085/1/end.2015.0837.pd

Does addressing gender inequalities and empowering women and girls improve health and development programme outcomes?

This article presents evidence supporting the hypothesis that promoting gender equality and women's and girls' empowerment (GEWE) leads to better health and development outcomes. We reviewed the literature across six sectors-family planning (FP); maternal, newborn and child health (MNCH); nutrition; agriculture; water, sanitation and hygiene; and financial services for the poor-and found 76 studies from low and middle-income countries that met our inclusion criteria. Across these studies, we identified common GEWE variables that emerged repeatedly as significant predictors of sector outcomes. We grouped these variables into 10 thematic categories, which we termed 'gender-related levers'. These levers were then classified by the strength of evidence into Wedges, Foundations and Facilitators. Wedges are gender-related levers that had strong associations with improved outcomes across multiple sectors. They include: 'control over income/assets/resources', 'decision-making power' and 'education'. Elements of these levers overlap, but combined, they encapsulate agency. Increasing female agency promotes equality and broadly improves health and development for women, their families and their communities. The second classification, Foundations, displayed strong, positive associations across FP, MNCH and nutrition. Foundations have a more proximal relationship with sector outcomes and include: 'equitable interpersonal relationships', 'mobility' and 'personal safety'. Finally, the third group of levers, Facilitators, was associated with improved outcomes in two to three sectors and include: 'access to information', 'community groups', 'paid labour' and 'rights'. These levers make it easier for women and girls to achieve their goals and are more traditional elements of development programmes. Overall, gender-related levers were associated with improvements in a variety of health and development outcomes. Furthermore, these associations were cross-sectoral, suggesting that to fully realize the benefits of promoting GEWE, the development community must collaborate in co-ordinated and integrated ways across multiple sectors. More research is needed to identify the mechanisms by which gendered interventions work and under what circumstances

Neuromedin U receptors in GtoPdb v.2023.1

Neuromedin U receptors (provisional nomenclature as recommended by NC-IUPHAR [30]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25, NmU-25), a peptide originally isolated from pig spinal cord [92]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33) has also been identified as an endogenous agonist [97]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25

Neuromedin U receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Neuromedin U receptors (provisional nomenclature as recommended by NC-IUPHAR [29]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25, NmU-25), a peptide originally isolated from pig spinal cord [90]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33) has also been identified as an endogenous agonist [95]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25