Stringent Phenomenological Investigation into Heterotic String Optical Unification

For the weakly coupled heterotic string (WCHS) there is a well-known factor of twenty conflict between the minimum string coupling unification scale, Lambda_H ~5x10^(17) GeV, and the projected MSSM unification scale, Lambda_U ~ 2.5x10^(16) GeV, assuming an intermediate scale desert (ISD). Renormalization effects of intermediate scale MSSM-charged exotics (ISME) (endemic to quasi-realistic string models) can resolve this issue, pushing the MSSM scale up to the string scale. However, for a generic string model, this implies that the projected Lambda_U unification under ISD is accidental. If the true unification scale is 5.0x10^(17) GeV, is it possible that illusionary unification at 2.5x10^(17) GeV in the ISD scenario is not accidental? If it is not, then under what conditions would the assumption of ISME in a WCHS model imply apparent unification at Lambda_U when ISD is falsely assumed? Geidt's "optical unification" suggests that Lambda_U is not accidental, by offering a mechanism whereby a generic MSSM scale Lambda_U < Lambda_H is guaranteed. A WCHS model was constructed that offers the possibility of optical unification, depending on the availability of anomaly-cancelling flat directions meeting certain requirements. This paper reports on the systematic investigation of the optical unification properties of the set of stringent flat directions of this model. Stringent flat directions can be guaranteed to be F-flat to all finite order (or to at least a given finite order consistent with electroweak scale supersymmetry breaking) and can be viewed as the likely roots of more general flat directions. Analysis of the phenomenology of stringent flat directions gives an indication of the remaining optical unification phenomenology that must be garnered by flat directions developed from them.Comment: standard latex, 18 pages of tex

What are the experiences of adults returning to work following recovery from Guillain-Barré syndrome? An interpretative phenomenological analysis

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2009 Informa UK Ltd.Purpose. Guillain-Barré syndrome (GBS) is a transient inflammatory disorder affecting peripheral nerves, characterised by weakness and numbness in limbs, upper body and face. Residual problems affect a large minority, and complicate return to work. This qualitative study explored the experiences of people who returned to work following their diagnosis of GBS and recovery, to gain insight into factors that facilitated or inhibited this process. Method. Five people participated in in-depth interviews. Individual and common experiences were explored through interpretative phenomenological analysis. Findings. Three recurring themes are presented: the perceived value of work; losing and recovering a familiar identity at work; and dilemmas around using support and adaptations at work. Certain individual issues also emerged but are beyond the scope of this article. Participants tended to measure their recovery in terms of returning to work yet continued to experience certain physical and psychosocial difficulties at work related to GBS, which required active coping strategies. Limited public awareness of GBS was perceived as a hindrance when returning to work. Conclusion. This study provides a rich account of the experiences that people encounter returning to work following GBS. Rehabilitation specialists may offer more effective preparation for this process, drawing upon the issues identified

A dynamic network approach for the study of human phenotypes

The use of networks to integrate different genetic, proteomic, and metabolic datasets has been proposed as a viable path toward elucidating the origins of specific diseases. Here we introduce a new phenotypic database summarizing correlations obtained from the disease history of more than 30 million patients in a Phenotypic Disease Network (PDN). We present evidence that the structure of the PDN is relevant to the understanding of illness progression by showing that (1) patients develop diseases close in the network to those they already have; (2) the progression of disease along the links of the network is different for patients of different genders and ethnicities; (3) patients diagnosed with diseases which are more highly connected in the PDN tend to die sooner than those affected by less connected diseases; and (4) diseases that tend to be preceded by others in the PDN tend to be more connected than diseases that precede other illnesses, and are associated with higher degrees of mortality. Our findings show that disease progression can be represented and studied using network methods, offering the potential to enhance our understanding of the origin and evolution of human diseases. The dataset introduced here, released concurrently with this publication, represents the largest relational phenotypic resource publicly available to the research community.Comment: 28 pages (double space), 6 figure

Fire as a fundamental ecological process: Research advances and frontiers

© 2020 The Authors. Journal of Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society Fire is a powerful ecological and evolutionary force that regulates organismal traits, population sizes, species interactions, community composition, carbon and nutrient cycling and ecosystem function. It also presents a rapidly growing societal challenge, due to both increasingly destructive wildfires and fire exclusion in fire-dependent ecosystems. As an ecological process, fire integrates complex feedbacks among biological, social and geophysical processes, requiring coordination across several fields and scales of study. Here, we describe the diversity of ways in which fire operates as a fundamental ecological and evolutionary process on Earth. We explore research priorities in six categories of fire ecology: (a) characteristics of fire regimes, (b) changing fire regimes, (c) fire effects on above-ground ecology, (d) fire effects on below-ground ecology, (e) fire behaviour and (f) fire ecology modelling. We identify three emergent themes: the need to study fire across temporal scales, to assess the mechanisms underlying a variety of ecological feedbacks involving fire and to improve representation of fire in a range of modelling contexts. Synthesis: As fire regimes and our relationships with fire continue to change, prioritizing these research areas will facilitate understanding of the ecological causes and consequences of future fires and rethinking fire management alternatives

of Education or Offices within it. NCEO Core Staff

assessment: Results of a comparative study (Technical Report 64). Minneapolis, MN: University of Minnesota, National Center on Educationa

Evolutionary Changes in the Complexity of the Tectum of Nontetrapods: A Cladistic Approach

Background: The tectum is a structure localized in the roof of the midbrain in vertebrates, and is taken to be highly conserved in evolution. The present article assessed three hypotheses concerning the evolution of lamination and citoarchitecture of the tectum of nontetrapod animals: 1) There is a significant degree of phylogenetic inertia in both traits studied (number of cellular layers and number of cell classes in tectum); 2) Both traits are positively correlated accross evolution after correction for phylogeny; and 3) Different developmental pathways should generate different patterns of lamination and cytoarchitecture. Methodology/Principal Findings: The hypotheses were tested using analytical-computational tools for phylogenetic hypothesis testing. Both traits presented a considerably large phylogenetic signal and were positively associated. However, no difference was found between two clades classified as per the general developmental pathways of their brains. Conclusions/Significance: The evidence amassed points to more variation in the tectum than would be expected by phylogeny in three species from the taxa analysed; this variation is not better explained by differences in the main course of development, as would be predicted by the developmental clade hypothesis. Those findings shed new light on th

Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture

Alzheimer's disease (AD) is pathologically characterised by the age-dependent deposition of β-amyloid (Aβ) in senile plaques, intraneuronal accumulation of tau as neurofibrillary tangles, synaptic dysfunction and neuronal death. Neuroinflammation, typified by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of AD. We have used primary rat neuronal, astrocytic and mixed cortical cultures to investigate the contribution of astrocyte-mediated inflammatory responses during Aβ-induced neuronal loss. We report that the presence of small numbers of astrocytes exacerbate Aβ-induced neuronal death, caspase-3 activation and the production of caspase-3-cleaved tau. Furthermore, we show that astrocytes are essential for the Aβ-induced tau phosphorylation observed in primary neurons. The release of soluble inflammatory factor(s) from astrocytes accompanies these events, and inhibition of astrocyte activation with the anti-inflammatory agent, minocycline, reduces astrocytic inflammatory responses and the associated neuronal loss. Aβ-induced increases in caspase-3 activation and the production of caspase-3-truncated tau species in neurons were reduced when the astrocytic response was attenuated with minocycline. Taken together, these results show that astrocytes are important mediators of the neurotoxic events downstream of elevated Aβ in models of AD, and suggest that mechanisms underlying pro-inflammatory cytokine release might be an important target for therapy

An OBSL1-Cul7Fbxw8 Ubiquitin Ligase Signaling Mechanism Regulates Golgi Morphology and Dendrite Patterning

The elaboration of dendrites in neurons requires secretory trafficking through the Golgi apparatus, but the mechanisms that govern Golgi function in neuronal morphogenesis in the brain have remained largely unexplored. Here, we report that the E3 ubiquitin ligase Cul7Fbxw8 localizes to the Golgi complex in mammalian brain neurons. Inhibition of Cul7Fbxw8 by independent approaches including Fbxw8 knockdown reveals that Cul7Fbxw8 is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo. Inhibition of Cul7Fbxw8 also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons. Using an immunoprecipitation/mass spectrometry screening approach, we also uncover the cytoskeletal adaptor protein OBSL1 as a critical regulator of Cul7Fbxw8 in Golgi morphogenesis and dendrite elaboration. OBSL1 forms a physical complex with the scaffold protein Cul7 and thereby localizes Cul7 at the Golgi apparatus. Accordingly, OBSL1 is required for the morphogenesis of the Golgi apparatus and the elaboration of dendrites. Finally, we identify the Golgi protein Grasp65 as a novel and physiologically relevant substrate of Cul7Fbxw8 in the control of Golgi and dendrite morphogenesis in neurons. Collectively, these findings define a novel OBSL1-regulated Cul7Fbxw8 ubiquitin signaling mechanism that orchestrates the morphogenesis of the Golgi apparatus and patterning of dendrites, with fundamental implications for our understanding of brain development

Rad17 Plays a Central Role in Establishment of the Interaction between TopBP1 and the Rad9-Hus1-Rad1 Complex at Stalled Replication Forks

Rad17 is critical for the ATR-dependent activation of Chk1 during checkpoint responses. It is known that Rad17 loads the Rad9-Hus1-Rad1 (9-1-1) complex onto DNA. We show that Rad17 also mediates the interaction of 9-1-1 with the ATR-activating protein TopBP1 in Xenopus egg extracts. Studies with Rad17 mutants indicate that binding of ATP to Rad17 is essential for the association of 9-1-1 and TopBP1. Furthermore, hydrolysis of ATP by Rad17 is necessary for the loading of 9-1-1 onto DNA and the elevated, checkpoint-dependent accumulation of TopBP1 on chromatin. Significantly, a mutant 9-1-1 complex that cannot bind TopBP1 has a normal capacity to promote elevated accumulation of TopBP1 on chromatin. Taken together, we propose the following mechanism. First, Rad17 loads 9-1-1 onto DNA. Second, TopBP1 accumulates on chromatin in a manner that depends on both Rad17 and 9-1-1. Finally, 9-1-1 and TopBP1 dock in a Rad17-dependent manner before activation of Chk1

The Role of Thioredoxin Reductases in Brain Development

The thioredoxin-dependent system is an essential regulator of cellular redox balance. Since oxidative stress has been linked with neurodegenerative disease, we studied the roles of thioredoxin reductases in brain using mice with nervous system (NS)-specific deletion of cytosolic (Txnrd1) and mitochondrial (Txnrd2) thioredoxin reductase. While NS-specific Txnrd2 null mice develop normally, mice lacking Txnrd1 in the NS were significantly smaller and displayed ataxia and tremor. A striking patterned cerebellar hypoplasia was observed. Proliferation of the external granular layer (EGL) was strongly reduced and fissure formation and laminar organisation of the cerebellar cortex was impaired in the rostral portion of the cerebellum. Purkinje cells were ectopically located and their dendrites stunted. The Bergmann glial network was disorganized and showed a pronounced reduction in fiber strength. Cerebellar hypoplasia did not result from increased apoptosis, but from decreased proliferation of granule cell precursors within the EGL. Of note, neuron-specific inactivation of Txnrd1 did not result in cerebellar hypoplasia, suggesting a vital role for Txnrd1 in Bergmann glia or neuronal precursor cells