A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation

Unique case of esophageal rupture after a fall from height

<p>Abstract</p> <p>Background</p> <p>Traumatic ruptures of the esophagus are relatively rare. This condition is associated with high morbidity and mortality. Most traumatic ruptures occur after motor vehicle accidents.</p> <p>Case Presentation</p> <p>We describe a unique case of a 23 year old woman that presented at our trauma resuscitation room after a fall from 8 meters. During physical examination there were no clinical signs of life-threatening injuries. She did however have a massive amount of subcutaneous emphysema of the chest and neck and pneumomediastinum. Flexible laryngoscopy revealed a lesion in the upper esophagus just below the level of the upper esophageal sphincter. Despite preventive administration of intravenous antibiotics and nutrition via a nasogastric tube, the patient developed a cervical abscess, which drained spontaneously. Normal diet was gradually resumed after 2.5 weeks and the patient was discharged in a reasonable condition 3 weeks after the accident.</p> <p>Conclusions</p> <p>This case report presents a high cervical esophageal rupture without associated local injuries after a fall from height.</p

Computational design of self-assembling cyclic protein homo-oligomers

Self-assembling cyclic protein homo-oligomers play important roles in biology, and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue-pair-transform method to assess the designability of a protein-protein interface. This method is sufficiently rapid to enable the systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were characterized experimentally, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (four homodimers, six homotrimers, six homotetramers and one homopentamer) had solution small-angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each is very close to their corresponding computational model