ALS-associated mutant SOD1(G93A )causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease that causes motor neuron degeneration, paralysis and death. Mutations in Cu, Zn superoxide dismutase (SOD1) are one cause for the familial form of this disease. Transgenic mice expressing mutant SOD1 develop age-dependent motor neuron degeneration, skeletal muscle weakness, paralysis and death similar to humans. The mechanism whereby mutant SOD1 induces motor neuron degeneration is not understood but widespread mitochondrial vacuolation has been observed during early phases of motor neuron degeneration. How this vacuolation develops is not clear, but could involve autophagic vacuolation, mitochondrial permeability transition (MPT) or uncharacterized mechanisms. To determine which of these possibilities are true, we examined the vacuolar patterns in detail in transgenic mice expressing mutant SOD1(G93A). RESULTS: Vacuolar patterns revealed by electron microscopy (EM) suggest that vacuoles originate from the expansion of the mitochondrial intermembrane space and extension of the outer mitochondrial membrane. Immunofluorescence microscopy and immuno-gold electron microscopy reveal that vacuoles are bounded by SOD1 and mitochondrial outer membrane markers, but the inner mitochondrial membrane marker is located in focal areas inside the vacuoles. Small vacuoles contain cytochrome c while large vacuoles are porous and lack cytochrome c. Vacuoles lack lysosomal signal but contain abundant peroxisomes and SOD1 aggregates. CONCLUSION: These findings demonstrate that mutant SOD1, possibly by toxicity associated with its aggregation, causes mitochondrial degeneration by inducing extension and leakage of the outer mitochondrial membrane, and expansion of the intermembrane space. This could release the pro-cell death molecules normally residing in the intermembrane space and initiate motor neuron degeneration. This Mitochondrial Vacuolation by Intermembrane Space Expansion (MVISE) fits neither MPT nor autophagic vacuolation mechanisms, and thus, is a previously uncharacterized mechanism of mitochondrial degeneration in mammalian CNS

Defect filtering for thermal expansion induced dislocations in III-V lasers on silicon

Epitaxially integrated III-V semiconductor lasers for silicon photonics have the potential to dramatically transform information networks, but currently, dislocations limit performance and reliability even in defect tolerant InAs quantum dot (QD) based lasers. Despite being below critical thickness, QD layers in these devices contain previously unexplained misfit dislocations, which facilitate non-radiative recombination. We demonstrate here that these misfit dislocations form during post-growth cooldown due to the combined effects of (1) thermal-expansion mismatch between the III-V layers and silicon and (2) precipitate and alloy hardening in the active region. By incorporating an additional sub-critical thickness, indium-alloyed misfit dislocation trapping layer, we leverage these mechanical hardening effects to our advantage, successfully displacing 95% of misfit dislocations from the QD layer in model structures. Unlike conventional dislocation mitigation strategies, the trapping layer reduces neither the number of threading dislocations nor the number of misfit dislocations. It simply shifts the position of misfit dislocations away from the QD layer, reducing the defects' impact on luminescence. In full lasers, adding a misfit dislocation trapping layer both above and below the QD active region displaces misfit dislocations and substantially improves performance: we measure a twofold reduction in lasing threshold currents and a greater than threefold increase in output power. Our results suggest that devices employing both traditional threading dislocation reduction techniques and optimized misfit dislocation trapping layers may finally lead to fully integrated, commercially viable silicon-based photonic integrated circuits.Comment: 9 pages, 6 figure

Epitope Mapping of Antibodies Suggests the Novel Membrane Topology of B-Cell Receptor Associated Protein 31 on the Cell Surface of Embryonic Stem Cells: The Novel Membrane Topology of BAP31

When located in the endoplasmic reticulum (ER) membrane, B-cell receptor associated protein 31 (BAP31) is involved in the export of secreted proteins from the ER to the plasma membrane. In a previous study, we generated two monoclonal antibodies (mAbs), 297-D4 and 144-A8, that bound to surface molecules on human embryonic stem cells (hESCs), but not to surface molecules on mouse embryonic stem cells (mESCs). Subsequent studies revealed that the mAbs recognized BAP31 on the surface of hESCs. To investigate the membrane topology of BAP31 on the cell surface, we first examined the epitope specificity of 297-D4 and 144-A8, as well as a polyclonal anti-BAP31 antibody (alpha-BAP31). We generated a series of GST-fused BAP31 mutant proteins in which BAP31 was serially deleted at the C-terminus. GST-fused BAP31 mutant proteins were then screened to identify the epitopes targeted by the antibodies. Both 297-D4 and 144-A8 recognized C-terminal residues 208-217, while alpha-BAP31 recognized C-terminal residues 165-246, of BAP31 on hESCs, suggesting that the C-terminal domain of BAP31 is exposed on the cell surface. The polyclonal antibody alpha-BAP31 bound to mESCs, which confirmed that the C-terminal domain of BAP31 is also exposed on the surface of these cells. Our results show for the first time the novel membrane topology of cell surface-expressed BAP31 as the extracellular exposure of the BAP31 C-terminal domain was not predicted from previous studies.published_or_final_versio

The Emerging Scholarly Brain

It is now a commonplace observation that human society is becoming a coherent super-organism, and that the information infrastructure forms its emerging brain. Perhaps, as the underlying technologies are likely to become billions of times more powerful than those we have today, we could say that we are now building the lizard brain for the future organism.Comment: to appear in Future Professional Communication in Astronomy-II (FPCA-II) editors A. Heck and A. Accomazz

Distinctive Genetic Activity Pattern of the Human Dental Pulp between Deciduous and Permanent Teeth

published_or_final_versio

Blocking analysis of persistent resource allocations for M2M applications in wireless systems

Wide area wireless systems conventionally employ dynamic scheduling for stochastic or bursty applications and persistent resource allocations of a given period for deterministic applications such as voice. When considering persistent resource allocations for machine-to-machine (M2M) applications from different markets, a wide range of allocation periods may be required to fully support the diversity of applications. The set of periods supported by the wireless system is a compromise between efficient use of the available resources and supporting as many M2M applications as possible. We consider two schemes: a simply periodic system which offers a limited set of periods with very efficient use of resources, and a complex periodic system which offers a wider range of periods at the cost of lower efficiency. We derive formulae for the blocking probability of these two systems by considering different resource sharing policies of the Erlang Multirate Loss Model (EMLM) and the concepts of packing (when a new persistent allocation is admitted to the system) and repacking (when an existing persistent allocation leaves the system). The theoretical models are verified using a discrete event simulation with variable offered traffic loads. The concepts discussed in this paper are generic, but may find particular application in Long Term Evolution (LTE) and Worldwide Interoperability for Microwave Access (WiMAX) networks for the purposes of system configuration (particularly in terms of the set of periods supported for persistent allocations), resource dimensioning and system performance characterisation

Factors affecting British revisit intention to Crete, Greece: high vs. low spending tourists

Determinants (i.e., destination image, tourist motivation, and perceived quality), satisfaction, perceived value, complaints are related to the intention to revisit a tourist destination. These three determinants also relate to tourist satisfaction through the moderating role of tourist expenditure (TE) for future re-visitation. The sampling targets to test these assumptions were British tourists on holiday in Crete, Greece. We used a component-based approach using the partial least squares method to analyze the data. The results of this study show that destination image, tourist motivation, and perceived quality have a significant effect on satisfaction, which subsequently affects tourists' perceived value on a destination, which, in turn, influences the level of complaints and the decision to revisit a tourist destination in the context of British tourists to Crete. Therefore, the results urge tourist destination managers to anticipate tourist satisfaction, perceived value, and complaint when determining revisit for tourist destinations through destination image, tourist motivation, and perceived quality. Furthermore, this study examines the differences between low-TE and high-TE groups on relationships between three determinants and tourist satisfaction, revealing that the relationships between destination image and satisfaction, between tourist motivation and satisfaction, and between perceived quality and satisfaction are significantly different according to the low-TE and high-TE groups. Thus, tourist destination marketers should consider TE as a key factor in market segmentation

Personality Factors Predicting Smartphone Addiction Predisposition: Behavioral Inhibition and Activation Systems, Impulsivity, and Self-control

The purpose of this study was to identify personality factor-associated predictors of smartphone addiction predisposition (SAP). Participants were 2,573 men and 2,281 women (n = 4,854) aged 20-49 years (Mean +/- SD: 33.47 +/- 7.52); participants completed the following questionnaires: the Korean Smartphone Addiction Proneness Scale (K-SAPS) for adults, the Behavioral Inhibition System/Behavioral Activation System questionnaire (BIS/BAS), the Dickman Dysfunctional Impulsivity Instrument (DDII), and the Brief Self-Control Scale (BSCS). In addition, participants reported their demographic information and smartphone usage pattern (weekday or weekend average usage hours and main use). We analyzed the data in three steps: (1) identifying predictors with logistic regression, (2) deriving causal relationships between SAP and its predictors using a Bayesian belief network (BN), and (3) computing optimal cut-off points for the identified predictors using the Youden index. Identified predictors of SAP were as follows: gender (female), weekend average usage hours, and scores on BAS-Drive, BAS-Reward Responsiveness, DDII, and BSCS. Female gender and scores on BAS-Drive and BSCS directly increased SAP. BAS-Reward Responsiveness and DDII indirectly increased SAP. We found that SAP was defined with maximal sensitivity as follows: weekend average usage hours > 4.45, BAS-Drive > 10.0, BAS-Reward Responsiveness > 13.8, DDII > 4.5, and BSCS > 37.4. This study raises the possibility that personality factors contribute to SAP. And, we calculated cut-off points for key predictors. These findings may assist clinicians screening for SAP using cut-off points, and further the understanding of SA risk factors.111413Ysciescopu

Epigenetic memory in induced pluripotent stem cells.

Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment