ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes.

Phase transitions of cellular proteins and lipids play a key role in governing the organisation and coordination of intracellular biology. The frequent juxtaposition of proteinaceous biomolecular condensates to cellular membranes raises the intriguing prospect that phase transitions in proteins and lipids could be co-regulated. Here we investigate this possibility in the ribonucleoprotein (RNP) granule-ANXA11-lysosome ensemble, where ANXA11 tethers RNP granule condensates to lysosomal membranes to enable their co-trafficking.

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation.

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids.

Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.

Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors.

Vigilin interacts with signal peptide peptidase.

Background: Signal peptide peptidase (SPP), a member of the presenilin-like intra-membrane cleaving aspartyl protease family, migrates on Blue Native (BN) gels as 100 kDa, 200 kDa and 450 kDa species. SPP has recently been implicated in other non-proteolytic functions such as retro-translocation of MHC Class I molecules and binding of misfolded proteins in the endoplasmic reticulum (ER). These high molecular weight SPP complexes might contain additional proteins that regulate the proteolytic activity of SPP or support its non-catalytic functions.

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) View Article and Find Full Text PDF

Laparoscopic omental harvest for flap coverage in complex mediastinitis.

Mediastinitis is one of the most serious complications of cardiac surgery. The standard of care in mediastinitis includes thorough sequential debridement, flap coverage, and culture-directed antibiotics. The most frequently utilized muscles for flap reconstruction include the rectus abdominus and the pectoralis major.

Hemodynamic effects of the vacuum-assisted closure device on open mediastinal wounds.

Background: Application of the Vacuum-Assisted Closure device (VAC) to open sternal wounds has negative hemodynamic effects. We hypothesized that the interposition of a muscle flap attenuates these negative hemodynamic effects.

Materials And Methods: After institutional approval, monitoring lines were placed in anesthetized, ventilated pigs.

Speech benefits of posterior pharyngeal flap are preserved after surgical flap division for obstructive sleep apnea: experience with division of 12 flaps.

Attachment of a posterior pharyngeal flap is commonly performed for the surgical management of velopharyngeal insufficiency. Obstructive sleep apnea has been found to occur in as many as 38% of patients undergoing posterior pharyngeal flap attachment. Often, this is temporary in the early postoperative period.

Innovative techniques in bony reconstruction to facilitate hand salvage.

Mutilating injuries of the hand and congenital hand anomalies can present challenging reconstructive scenarios for salvage and restoration of function. During a 5-year period from 1993 to 1997, the plastic and reconstructive surgical unit of East Carolina University Medical Center was presented with a series of unique reconstructive challenges as a result of complex hand injuries that resulted in unexpected opportunities for the salvage of distal components. These traumatic injuries were unique in that, although devastating to the hand, they left the opportunity for salvage of distal vascularized and sensate components of the hand.