Designed endocytosis-inducing proteins degrade targets and amplify signals.

Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by endogenous ligands. Therapeutic approaches such as lysosome-targeting chimaeras (LYTACs) and cytokine receptor-targeting chimeras (KineTACs) have used this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. Although powerful, these approaches can be limited by competition with native ligands and requirements for chemical modification that limit genetic encodability and can complicate manufacturing, and, more generally, there may be no native ligands that stimulate endocytosis through a given receptor.

Choice of fusion proteins, expression host, and analytics solves difficult-to-produce protein challenges in discovery research.

High quality biological reagents are a prerequisite for pharmacological research. Herein a protein production screening approach, including quality assessment methods, for protein-based discovery research is presented. Trends from 2895 expression constructs representing 253 proteins screened in mammalian and bacterial hosts-91% of which are successfully expressed and purified-are discussed.

Designed Endocytosis-Triggering Proteins mediate Targeted Degradation.

Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by interaction with endogenous ligands. Therapeutic approaches such as LYTAC and KineTAC, have taken advantage of this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. While powerful, these approaches can be limited by possible competition with the endogenous ligand(s), the requirement in some cases for chemical modification that limits genetic encodability and can complicate manufacturing, and more generally, there may not be natural ligands which stimulate endocytosis through a given receptor.

HectD1 E3 ligase modifies adenomatous polyposis coli (APC) with polyubiquitin to promote the APC-axin interaction.

The adenomatous polyposis coli (APC) protein functions as a negative regulator of the Wnt signaling pathway. In this capacity, APC forms a "destruction complex" with Axin, CK1α, and GSK3β to foster phosphorylation of the Wnt effector β-catenin earmarking it for Lys-48-linked polyubiquitylation and proteasomal degradation. APC is conjugated with Lys-63-linked ubiquitin chains when it is bound to Axin, but it is unclear whether this modification promotes the APC-Axin interaction or confers upon APC an alternative function in the destruction complex.

Critical role of activation induced cytidine deaminase in experimental autoimmune encephalomyelitis.

Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder caused by chronic inflammation and demyelination within the central nervous system (CNS). Clinical studies in MS patients have demonstrated efficacy with B cell targeted therapies such as anti-CD20. However, the exact role that B cells play in the disease process is unclear.

Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance.

Aquaporin (AQP) 4 is the predominant water channel in the mammalian brain, abundantly expressed in the blood-brain and brain-cerebrospinal fluid interfaces of glial cells. Its function in cerebral water balance has implications in neuropathological disorders, including brain edema, stroke, and head injuries. The 1.

Endoscopic antireflux therapy: the Stretta procedure.

The Stretta procedure is safe and effective for the treatment of GERD. There are well-documented clinical trial data supporting its use, including a randomized sham-controlled study, single- and multi-center prospective trials, and community practice reports. The complication rate is within the acceptable range for therapeutic endoscopic procedures and less than the published complication rate for laparoscopic fundoplication.

Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract.

The purpose of this literature review is to examine recent advances in technique and technology of endoscopic mucosal resection of superficial early cancers of the upper gastrointestinal tract. Endoscopic mucosal resection (EMR) of superficial early cancers of the upper gastrointestinal tract is standard technique in Japan and is increasingly used in Western countries. Newer techniques of EMR allow removal of larger lesions en-bloc.

Endoscopic therapy for Barrett's esophagus.

With the increase in the rate of esophageal adenocarcinoma in the United States and the Western world matched with the high morbidity and mortality of esophagectomy, there is an increasing need for new and effective techniques to treat and prevent esophageal adenocarcinoma. A wide variety of endoscopic mucosal ablative techniques have been developed for early esophageal neoplasia. However, long-term control of neoplasic risk has not been demonstrated.

Baclofen toxicity in an 8-year-old with an intrathecal baclofen pump.

Baclofen delivered by intrathecal pumps (ITB) is increasingly being utilized in the pediatric population, however, resources and education to support problems with these devices are limited. Typical management strategies for systemic baclofen overdose include removal of baclofen from the device reservoir or removal of cerebrospinal fluid from the adjacent device catheter. Appropriate care of these patients requires awareness of the clinical patterns of toxicity and mechanics of the ITB pump delivery system.