The mechanism of neuropathy in peripheral myelin protein 22 mice

Mutations in the gene for peripheral myelin protein 22 (PMP22) are associated with peripheral neuropathy in mice and humans. PMP22 is produced mainly in Schwann cells in the peripheral nervous system where it is localised to compact myelin. The function of PMP22 is unclear but its low abundance makes it unlikely to be a structural myelin protein. I have studied the peripheral nerves of two different mouse models with alterations in the pmp22 gene. (1) The Trembler-J (Tr^J) mouse which has a point mutation [L16P] in the first transmembrane domain of PMP22. (2) PMPP22 overexpressing transgenic mice which have 7 (C22), 4 (C61) and 2 (C2) copies of the human PMP22 gene in addition to the mouse pmp22 gene. In the nerves of adult Tr^J mice there was considerable evidence of abnormal Schwann cell-axon interactions. Abnormal features were reproduced in the early stages of regeneration following crush injury. This demonstrates that the abnormalities are a result of an intrinsic abnormality of Tr^J Schwann cells and not secondary changes related to demyelination. In the initial stages of postnatal development the number of axons that were singly ensheathed was the same in all the mutants examined, indicating that PMP22 does not function in the initial enclosure of groups of axons and subsequent separation of single axons. All strains examined had an increased proportion of fibres that were incompletely surrounded by Schwann cell cytoplasm indicating that this step is disrupted in PMP22 mutants. Increasing the number of copies of PMP22 resulted in an increasing severity of phenotype. In C22 (7 copy) animals myelin formation was delayed or non-existent in many fibres whereas in C61 animals myelination initially appeared normal with abnormality appearing later in a small population of fibres. The C2 strain appeared relatively unaffected. It is concluded that PMP22 functions in the initiation of myelination and most probably involves the ensheathment of the axon by the Schwann cell, and the extension of this cell along the axon. Abnormalities are most likely to result from defective interactions between the axon and the Schwann cell

QCD Strings as Constrained Grassmannian Sigma Model:

We present calculations for the effective action of string world sheet in R3 and R4 utilizing its correspondence with the constrained Grassmannian sigma model. Minimal surfaces describe the dynamics of open strings while harmonic surfaces describe that of closed strings. The one-loop effective action for these are calculated with instanton and anti-instanton background, reprsenting N-string interactions at the tree level. The effective action is found to be the partition function of a classical modified Coulomb gas in the confining phase, with a dynamically generated mass gap.Comment: 22 pages, Preprint: SFU HEP-116-9

A novel superfamily containing the β-grasp fold involved in binding diverse soluble ligands

BACKGROUND: Domains containing the β-grasp fold are utilized in a great diversity of physiological functions but their role, if any, in soluble or small molecule ligand recognition is poorly studied. RESULTS: Using sensitive sequence and structure similarity searches we identify a novel superfamily containing the β-grasp fold. They are found in a diverse set of proteins that include the animal vitamin B12 uptake proteins transcobalamin and intrinsic factor, the bacterial polysaccharide export proteins, the competence DNA receptor ComEA, the cob(I)alamin generating enzyme PduS and the Nqo1 subunit of the respiratory electron transport chain. We present evidence that members of this superfamily are likely to bind a range of soluble ligands, including B12. There are two major clades within this superfamily, namely the transcobalamin-like clade and the Nqo1-like clade. The former clade is typified by an insert of a β-hairpin after the helix of the β-grasp fold, whereas the latter clade is characterized by an insert between strands 4 and 5 of the core fold. CONCLUSION: Members of both clades within this superfamily are predicted to interact with ligands in a similar spatial location, with their specific inserts playing a role in the process. Both clades are widely represented in bacteria suggesting that this superfamily was derived early in bacterial evolution. The animal lineage appears to have acquired the transcobalamin-like proteins from low GC Gram-positive bacteria, and this might be correlated with the emergence of the ability to utilize B12 produced by gut bacteria. REVIEWERS: This article was reviewed by Andrei Osterman, Igor Zhulin, and Arcady Mushegian

Neoplastic transformation of mouse C3H 10T1/2 and Syrian hamster embryo cells by heavy ions

C3H 10T1/2 mouse-embryo fibroblasts were used for transformation experiments to study the effectiveness of various heavy ions with energies up to 20 MeV/u and LET values from 170 to 16.000 keV/μm. The transformation frequency per unit absorbed dose decreased with increasing ionization density; at the highest values of LET we found a decrease even of the transformation efficiency per unit fluence. Uranium ions at energies of 5, 9, and 16.3 MeV/u did not induced any transformation. In additional studies piimary Syrian hamster embryo cells (SHE) were exposed to heavy ions in order to characterize cytological and molecular changes which may be correlated with neoplastic transformation. Growth behaviour, chromosomal status, tumorigenicity in nude mice, and expression of oncogenes of transformed cell lines were examined

Efficacy of increased resistant starch consumption in human type 2 diabetes

Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1

Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease

We examined how HLA types A1-B8-DR3 and B27 were related to progression of clinical disease and rate of loss of CD4 lymphocytes in the Edinburgh City Hospital cohort of HIV-positive patients, mainly injection drug users. Patients (n = 692) were prospectively followed from 1985 through March 1994. Accurately estimated seroconversion times were determined retrospectively for a subgroup of 313 (45%). Of 262 patients (39%) who were fully or partially HLA typed, 155 (50%) had known seroconversions. Of 34 patients typed positive for A1-B8-DR3, 29 progressed to CDC stage IV, 22 to AIDS and 20 died. Twelve patients were typed positive for B27; six of these progressed to CDC stage IV, one to AIDS and none died. In a proportional hazards analysis of the 313 patients with known seroconversions, A1-B8-DR3 was significantly associated with covariate-adjusted relative risks of 3.7 (95% CI 1.9-7.2), 3.1 (1.6-6.0) and 1.9 (1.1-3.2) for progression from seroconversion to death, AIDS and CDC stage IV, respectively. Events for B27 were too rare to include B27 in analyses to death and AIDS, but B27 was significantly associated with slower progression to CDC stage IV (0.3, CI 0.1-0.9). Random effects growth curve models were used to estimate individual rates of loss of square root CD4 count and loss of CD4 percentage, for 603 and 617 patients, respectively. A1-B8-DR3 was associated with rapid loss of both markers (p=0.02 and p = 0.01, respectively); B27 was associated with slow loss of both markers (p=0.04 and p<0.005

Male frequent attenders of general practice and their help seeking preferences

Background: Low rates of health service usage by men are commonly linked to masculine values and traditional male gender roles. However, not all men conform to these stereotypical notions of masculinity, with some men choosing to attend health services on a frequent basis, for a variety of different reasons. This study draws upon the accounts of male frequent attenders of the General Practitioner's (GP) surgery, examining their help-seeking preferences and their reasons for choosing services within general practice over other sources of support. Methods: The study extends thematic analysis of interview data from the Self Care in Primary Care study (SCinPC), a large scale multi-method evaluation study of a self care programme delivered to frequent attenders of general practice. Data were collected from 34 semi-structured interviews conducted with men prior to their exposure to the intervention. Results: The ages of interviewed men ranged from 16 to 72 years, and 91% of the sample (n= 31) stated that they had a current health condition. The thematic analysis exposed diverse perspectives within male help-seeking preferences and the decision-making behind men's choice of services. The study also draws attention to the large variation in men's knowledge of available health services, particularly alternatives to general practice. Furthermore, the data revealed some men's lack of confidence in existing alternatives to general practice. Conclusions: The study highlights the complex nature of male help-seeking preferences, and provides evidence that there should be no 'one size fits all' approach to male service provision. It also provides impetus for conducting further studies into this under researched area of interest. © 2011 WPMH GmbH

Decentralized Federated Learning Over Slotted ALOHA Wireless Mesh Networking

Federated Learning (FL) presents a mechanism to allow decentralized training for machine learning (ML) models inherently enabling privacy preservation. The classical FL is implemented as a client-server system, which is known as Centralised Federated Learning (CFL). There are challenges inherent in CFL since all participants need to interact with a central server resulting in a potential communication bottleneck and a single point of failure. In addition, it is difficult to have a central server in some scenarios due to the implementation cost and complexity. This study aims to use Decentralized Federated learning (DFL) without a central server through one-hop neighbours. Such collaboration depends on the dynamics of communication networks, e.g., the topology of the network, the MAC protocol, and both large-scale and small-scale fading on links. In this paper, we employ stochastic geometry to model these dynamics explicitly, allowing us to quantify the performance of the DFL. The core objective is to achieve better classification without sacrificing privacy while accommodating for networking dynamics. In this paper, we are interested in how such topologies impact the performance of ML when deployed in practice. The proposed system is trained on a well-known MINST dataset for benchmarking, which contains labelled data samples of 60K images each with a size $28\times 28$ pixels, and 1000 random samples of this MNIST dataset are assigned for each participant’ device. The participants’ devices implement a CNN model as a classifier model. To evaluate the performance of the model, a number of participants are randomly selected from the network. Due to randomness in the communication process, these participants interact with the random number of nodes in the neighbourhood to exchange model parameters which are subsequently used to update the participants’ individual models. These participants connected successfully with a varying number of neighbours to exchange parameters and update their global models. The results show that the classification prediction system was able to achieve higher than 95% accuracy using the three different model optimizers in the training settings (i.e., SGD, ADAM, and RMSprop optimizers). Consequently, the DFL over mesh networking shows more flexibility in IoT systems, which reduces the communication cost and increases the convergence speed which can outperform CFL

Genotype distribution of Chinese Mycoplasma bovis isolates and their evolutionary relationship to strains from other countries

This study was undertaken to determine the genotypic distribution of Chinese M. bovis strains and their similarity to isolates from other countries. Two multilocus sequence typing (MLST) schemes (MLST-1 and MLST-2) and pulsed field gel electrophoresis (PFGE) were used to compare 44 Chinese strains and the M. bovis type strain PG45. The results showed a high genetic homogeneity of Chinese isolates; 43 of 44 (97.7%) Chinese isolates were identified as ST-10 and as ST-34 by MLST-1, while for MLST-2 42 of 44 (95.5%) were identified as ST-10 with the two remaining isolates of ST-32 and ST43. PFGE clustered 42 of 44 (95.5%) of the Chinese isolates into PT-I. The overall agreement rate between the three typing methods was 97.8% (95% CI:86.8–99.9%). The type strain PG45 was identified as a unique type by all three methods. When the MLST-2 scheme was further used to analyze 16 isolates of Australian and Israeli origin ST-10 was more dominant among Australian isolates (7/8), compared with those from Israel (3/8). The evolutionary relationship of the 60 isolates typed in this study assessed together with 206 additional isolates retrieved from pubmlst/mbovis database analyzed by geoBURST Minimum spanning tree (MST) confirmed that the Chinese, Israeli and Australian M. bovis isolates typed in this study that were predominantly ST-10, were clustered in CC3 with isolates originating from the USA. Our results suggest that ST-10 is an emerging clone of M. bovis population. We hypothesized that the widespread distribution of this type is a result of global livestock movements. These findings will help further the understanding of the global evolution of M. bovis and development of novel vaccines against M. bovis