HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in , which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration.

The Value of PET-CT in Ovarian Epithelial Carcinoma: A Population-Based Study in British Columbia, Canada.

Introduction: In epithelial ovarian cancer (EOC), consensus regarding optimal use of PET/CT is lacking. Limited evidence suggests its accuracy in preoperative staging, investigating recurrence and predicting optimal secondary debulking. This study evaluated indications for PET/CT, impact of PET/CT results on EOC management, and its added value over conventional imaging.

PARP Inhibitors and the Evolving Landscape of Ovarian Cancer Management: A Review.

As a drug class, inhibitors of poly-(ADP-ribose) polymerase (PARP) have had their greatest impact on the treatment of women with epithelial ovarian cancers (EOC), in particular, those with the most common histological subtype, high-grade serous cancer, as it has high rates of homologous recombination (HR) deficiency. PARP inhibition exploits this cancer vulnerability by further disrupting DNA repair, thus leading to genomic catastrophe. Early clinical data demonstrated the effectiveness of PARP inhibition in women with recurrent EOC harbouring BRCA1/2 mutations and those with platinum-sensitive recurrences.

Mononuclear complexes of a tridentate redox-active ligand with sulfonamido groups: structure, properties, and reactivity.

The design of molecular complexes of earth-abundant first-row transition metals that can catalyze multi-electron C-H bond activation processes is of interest for achieving efficient, low-cost syntheses of target molecules. To overcome the propensity of these metals to perform single-electron processes, redox-active ligands have been utilized to provide additional electron equivalents. Herein, we report the synthesis of a novel redox active ligand, [ibaps], which binds to transition metals such as Fe and Co in a meridional fashion through the three anionic nitrogen atoms and provides additional coordination sites for other ligands.

Air-Liquid Interface Method To Study Epstein-Barr Virus Pathogenesis in Nasopharyngeal Epithelial Cells.

Unlabelled: Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that establishes a latent reservoir in peripheral B-lymphocytes with sporadic reactivation. EBV also infects epithelial cells, predominantly resulting in a lytic infection, which may contribute to EBV transmission from saliva. In the nasopharynx, EBV infection can lead to the clonal expansion of a latently infected cell and the development of nasopharyngeal carcinoma (NPC).

Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation.

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that persistently infects humans, with nearly 95% seropositivity in adults. Infection in differentiating epithelia is permissive, but EBV-associated nasopharyngeal carcinoma (NPC) tumors harbor a clonal and nonproductive latent infection. However, in explanted NPC cultures and epithelial cell lines, episomal EBV genomes are frequently lost.

Molecular designs for controlling the local environments around metal ions.

The functions of metal complexes are directly linked to the local environment in which they are housed; modifications to the local environment (or secondary coordination sphere) are known to produce changes in key properties of the metal centers that can affect reactivity. Noncovalent interactions are the most common and influential forces that regulate the properties of secondary coordination spheres, which leads to complexities in structure that are often difficult to achieve in synthetic systems. Using key architectural features from the active sites of metalloproteins as inspiration, we have developed molecular systems that enforce intramolecular hydrogen bonds (H-bonds) around a metal center via incorporation of H-bond donors and acceptors into rigid ligand scaffolds.

Lessons from Nature: A Bio-Inspired Approach to Molecular Design.

Metalloproteins contain actives sites with intricate structures that perform specific functions with high selectivity and efficiency. The complexity of these systems complicates the study of their function and the understanding of the properties that give rise to their reactivity. One approach that has contributed to the current level of understanding of their biological function is the study of synthetic constructs that mimic one or more aspects of the native metalloproteins.

Iron(II) complexes supported by sulfonamido tripodal ligands: endogenous versus exogenous substrate oxidation.

High-valent iron species are known to act as powerful oxidants in both natural and synthetic systems. While biological enzymes have evolved to prevent self-oxidation by these highly reactive species, development of organic ligand frameworks that are capable of supporting a high-valent iron center remains a challenge in synthetic chemistry. We describe here the reactivity of an Fe(II) complex that is supported by a tripodal sulfonamide ligand with both dioxygen and an oxygen-atom transfer reagent, 4-methylmorpholine-N-oxide (NMO).

Synthesis and reactivity of tripodal complexes containing pendant bases.

The synthesis of a new tripodal ligand family that contains tertiary amine groups in the second-coordination sphere is reported. The ligands are tris(amido)amine derivatives, with the pendant amines attached via a peptide coupling strategy. They were designed to function as new molecular catalysts for the oxygen reduction reaction (ORR), in which the pendant acid/base group could improve the catalyst performance.

Heterobimetallic Complexes with M-(OH)-M Cores (M = Fe, Mn, Ga; M = Ca, Sr, and Ba): Structural, Kinetic, and Redox Properties.

The effects of redox-inactive metal ions on dioxygen activation were explored using a new Fe complex containing a tripodal ligand with 3 sulfonamido groups. This iron complex exhibited a faster initial rate for the reduction of O than its Mn analog. Increases in initial rates were also observed in the presence of group 2 metal ions for both the Fe and Mn complexes, which followed the trend NMe < Ba < Ca = Sr.