Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.     

BiP maintains the permeability barrier of the ER membrane by sealing the lumenal end of the translocon pore before and early in translocation

Secretory proteins are cotranslationally translocated across the mammalian ER membrane through an aqueous pore in the translocon while the permeability barrier is maintained by a tight ribosome-membrane junction. The lumenal end of the pore is also blocked early in translocation. Extraction of soluble lumenal proteins from microsomes and reconstitution with purified proteins demonstrate, by fluorescence collisional quenching, that BiP seals the lumenal end of this pore. BiP also seals translocons that are assembled but are not engaged in translocation. These ribosome-free translocons have smaller pores (9-15 A diameter versus 40-60 A in functioning translocons) and are generated when ribosomes dissociate from functioning translocons with large pores. BiP therefore maintains the permeability barrier by sealing both nontranslocating and newly targeted translocons.     

Productivity through computer management of a fully automated transportation system

The Morgantown Personal Rapid Transit System is a fully automated, collection and distribution, origin to destination, non-stop transportation system. The system consists of a feet of 73 electrically powered, rubber tired, passenger carrying vehicles, operating on a dedicated guideway network at 15 second headways. The system provides a safe, comfortable non-polluting, reliable means of public transportation between the Central Business District of Morgantown, West Virginia, and the three separated campuses of West Virginia University.

This paper will address the unique application of computers in operating a public transit system which is considered the first of its kind anywhere in the world.     

Disturbance and recovery of trunk mechanical and neuromuscular behaviours following prolonged trunk flexion: influences of duration and external load on creep-induced effects

Trunk flexion results in adverse mechanical effects on the spine and is associated with a higher incidence of low back pain. To examine the effects of creep deformation on trunk behaviours, participants were exposed to full trunk flexion in several combinations of exposure duration and external load. Trunk mechanical and neuromuscular behaviours were obtained pre- and post-exposure and during recovery using sudden perturbations. Intrinsic trunk stiffness decreased with increasing flexion duration and in the presence of the external load. Recovery of intrinsic stiffness required more time than the exposure duration and was influenced by exposure duration. Reflexive trunk responses increased immediately following exposure but recovered quickly (～2.5 min). Alterations in reflexive trunk behaviour following creep deformation exposures may not provide adequate compensation to allow for complete recovery of concurrent reductions in intrinsic stiffness, which may increase the risk of injury due to spinal instability. STATEMENT OF RELEVANCE: An increased risk of low back injury may result from flexion-induced disturbances to trunk behaviours. Such effects, however, appear to depend on the type of flexion exposure, and have implications for the design of work involving trunk flexion.