DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity.

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a Rho-guanosine triphosphate hydrolases involved in actin cytoskeleton dynamics, among many cellular functions.

Treatment of two or more metatarsal fractures.

Introduction: Metatarsal fractures are the most common type of foot fracture. When surgical treatment is needed, pinning is typically used, either percutaneous or open. However, this fixation method has been criticized by some authors who lament residual malunion and prefer to use plate and/or screws.

Peptidomics of enteroendocrine cells and characterisation of potential effects of a novel preprogastrin derived-peptide on glucose tolerance in lean mice.

Objectives: To analyse the peptidomics of mouse enteroendocrine cells (EECs) and human gastrointestinal (GI) tissue and identify novel gut derived peptides.

Methods: High resolution nano-flow liquid chromatography mass spectrometry (LC-MS/MS) was performed on (i) flow-cytometry purified NeuroD1 positive cells from mouse and homogenised human intestinal biopsies, (ii) supernatants from primary murine intestinal cultures, (iii) intestinal homogenates from mice fed high fat diet. Candidate bioactive peptides were selected on the basis of species conservation, high expression/biosynthesis in EECs and evidence of regulated secretionin vitro.

Time is money: quantifying savings in outpatient appendectomy.

Background: Laparoscopic appendectomy can be performed on a fast-track, short-stay, or outpatient basis with high success rates, low morbidity, low readmission rates, and shorter length of hospital stay. Cost savings from outpatient appendectomy have not been well described. We hypothesize that outpatient laparoscopic appendectomy is associated with cost savings.

Subunit disassembly and inhibition of TNFα by a semi-synthetic bicyclic peptide.

Macrocyclic peptides are potentially a source of powerful drugs, but their de novo discovery remains challenging. Here we describe the discovery of a high-affinity (Kd = 10 nM) peptide macrocycle (M21) against human tumor necrosis factor-alpha (hTNFα), a key drug target in the treatment of inflammatory disorders, directly from diverse semi-synthetic phage peptide repertoires. The bicyclic peptide M21 (ACPPCLWQVLC) comprises two loops covalently anchored to a 2,4,6-trimethyl-mesitylene core and upon binding induces disassembly of the trimeric TNFα cytokine into dimers and monomers.

Inhibition of platelet adhesion by peptidomimetics mimicking the interactive β-hairpin of glycoprotein Ibα.

β-Hairpin peptidomimetics mimicking the interaction sites of the platelet receptor glycoprotein (GP)Ibα with von Willebrand factor (vWF) were synthesised and evaluated for their ability to increase platelet velocity under high shear conditions and to inhibit shear-induced platelet aggregation. A cyclic and bridged dodecapeptide 2e containing a heterochiral diproline motif was identified as a lead compound for the generation of a novel class of potential antiplatelet agents.

CycloPs: generating virtual libraries of cyclized and constrained peptides including nonnatural amino acids.

We introduce CycloPs, software for the generation of virtual libraries of constrained peptides including natural and nonnatural commercially available amino acids. The software is written in the cross-platform Python programming language, and features include generating virtual libraries in one-dimensional SMILES and three-dimensional SDF formats, suitable for virtual screening. The stand-alone software is capable of filtering the virtual libraries using empirical measurements, including peptide synthesizability by standard peptide synthesis techniques, stability, and the druglike properties of the peptide.

Ligand switching in cell-permeable peptides: manipulation of the alpha-integrin signature motif.

A synthetic cell-permeable peptide corresponding to the highly conserved alpha-integrin signature motif, Palmityl-K(989)VGFFKR(995) (Pal-FF), induces integrin activation and aggregation in human platelets. Systematic replacement of the F(992)-F(993) with amino acids of greater or lesser hydrophobicity to create Pal-KVGxxKR peptides demonstrate that hydrophobic amino acids (isoleucine, phenylalanine, tyrosine, tryptophan) are essential for agonist potency. In marked contrast, substitution with small and/or hydrophilic amino acids (glycine, alanine, serine) causes a switch in the biological activity resulting in inhibition of platelet aggregation, adhesion, ADP secretion, and thromboxane synthesis.

A peptide affinity column for the identification of integrin alpha IIb-binding proteins.

To understand the regulation of integrin alpha(IIb)beta(3), a critical platelet adhesion molecule, we have developed a peptide affinity chromatography method using the known integrin regulatory motif, LAMWKVGFFKR. Using standard Fmoc chemistry, this peptide was synthesized onto a Toyopearl AF-Amino-650 M resin on a 6-aminohexanoic acid (Ahx) linker. Peptide density was controlled by acetylation of 83% of the Ahx amino groups.

Development of lipopeptides for inhibiting 20S proteasomes.

Proteasomes are responsible for the cytoplasmic turnover of the vast majority of proteins including regulatory proteins. We have synthesized lipopeptides a new class of non-covalent inhibitors of the 20S proteasome and assayed their inhibitory capacities. Their ability to inhibit at micromolar concentrations chymotrypsin-like and post-acid activities depends on peptide length (3 or 6 amino acids), sequence (presence of a positively or negatively charged amino acid), and alkyl chain length (C6-C18).