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.     

Failed Neuroprotection of Combined Inhibition of L-Type and ASIC1a Calcium Channels with Nimodipine and Amiloride

Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs—nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)—might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.     

Effects of breed and age at slaughter on degradation of muscle lipids during processing of dry‐cured hams

Hams from Landrace, Duroc and Hampshire pigs slaughtered at ages 6, 7.5 and 9 months were processed to generate Norwegian Parma‐style hams. Lipid contents and the compositions of fatty acid classes (ΣSFA, ΣMUFA, ΣPUFA) within neutral lipids, phospholipids and free fatty acids were determined. Small differences in lipid degradation and composition of the classes were revealed. However, significant sensory differences related to lipids were observed. Breed was more important than age. Dry‐cured Hampshire hams gave a more intense mature odour that may be associated with higher overall lipid degradation. Unexpectedly, these hams also demonstrated high juiciness and tenderness, which could be related to the melting characteristics of the fat. Dry‐cured Duroc hams showed a higher susceptibility towards rancidity, presumably associated with preferential oxidation of n‐6 fatty acids relative to C18:1 n‐9. Dry‐cured Landrace hams showed the lowest juiciness and tenderness, likely due to their lower fat content (marbling).     

A New Measure of Misfit for Covariance Structure Models

Various fit indices exist in structural equation models. Most of these indices are related to the noncentrality parameter (NCP) of the chi-square distribution that the involved test statistic is implicitly assumed to follow. Existing literature suggests that few statistics can be well approximated by chi-square distributions. The meaning of the NCP is not clear when the behavior of the statistic cannot be described by a chi-square distribution. In this paper we define a new measure of model misfit (MMM) as the difference between the expected values of a statistic under the alternative and null hypotheses. This definition does not need to assume that the population covariance matrix is in the vicinity of the proposed model, nor does it need for the test statistic to follow any distribution of a known form. The MMM does not necessarily equal the discrepancy between the model and the population covariance matrix as has been assumed in existing literature. Bootstrap approaches to estimating the MMM and a related quantity are developed. An algorithm for obtaining bootstrap confidence intervals of the MMM is constructed. Examples with practical data sets contrast several measures of model misfit. The quantile-quantile plot is used to illustrate the unrealistic nature of chi-square distribution assumptions under either the null or an alternative hypothesis in practice.

     

Knowledge management in production alliances

This paper develops a managerial model of production network organizations (PNOs), inter-firm alliances for product development and delivery, in which inter-firm network structure and knowledge management practices play a major role in venture performance. The paper addresses the issue of alignment between the adopted network structure, the scope of the joint production task, and consequent inter-firm information flow requirements, hypothesizing that venture performance is a joint function of network structure and task integration scope. In situations with a difficult alignment between the chosen network structure, joint task scope, and information flow requirements, knowledge management investments across the PNO are proposed as a moderating factor leading to improved venture performance. The paper demonstrates the proposed model with three case studies, providing preliminary verification of the key proposition that knowledge management interventions can mediate the impact of loose integrating structures for joint production ventures that are undertaking complex joint tasks.     

Self-monitoring and intake interviewers' therapeutic orientations.

A therapist's theoretical orientation is likely to influence every facet of the therapeutic process. We explore the relationship of therapeutic orientation and self-monitoring style. To test the hypothesis that high self-monitors would be more eclectic than low self-monitors, we surveyed 30 intake therapists at a child guidance center. Results supported the hypothesis; those frequently using more than one orientation had higher self-monitoring scores. Furthermore, self-monitoring correlated negatively with psychoanalytic endorsement, but in a positive direction with behavioral, systems and eclectic endorsements. Results are discussed in terms of training needs of those differing in self-monitoring style. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Structure and stability of an immunoglobulin superfamily domain from twitchin, a muscle protein of the nematode Caenorhabditis elegans

The NMR solution structure of an immunoglobulin superfamily module of twitchin (Ig 18') has been determined and the kinetic and equilibrium folding behaviour characterised. Thirty molecular coordinates were calculated using a hybrid distance geometry-simulated annealing protocol based on 1207 distance and 48 dihedral restraints. The atomic rms distributions about the mean coordinate for the ensemble of structures is 0.55( +/- 0.09) A for backbone atoms and 1.10( +/- 0.08) A for all heavy atoms. The protein has a topology very similar to that of telokin and the titin Ig domains and thus it falls into the I set of the immunoglobulin superfamily. The close agreement between the predicted and observed structures of Ig 18' demonstrates clearly that the I set profile can be applied in the structure prediction of immunoglobulin-like domains of diverse modular proteins. Folding studies reveal that the protein has relatively low thermodynamic stability, deltaG(H2O)U-F = 4.0 kcal mol(-1) at physiological pH. Unfolding studies suggest that the protein has considerable kinetic stability, the half life of the unfolding is greater than 40 minutes in the absence of denaturant.