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

Postscripts

Bojan Bujić When is a musette not a musette? A response to Robert S. Hatten Robert S. Hatten A response to Bojan Buji

Myosin II Motors and F-Actin Dynamics Drive the Coordinated Movement of the Centrosome and Soma during CNS Glial-Guided Neuronal Migration

SummaryLamination of cortical regions of the vertebrate brain depends on glial-guided neuronal migration. The conserved polarity protein Par6α localizes to the centrosome and coordinates forward movement of the centrosome and soma in migrating neurons. The cytoskeletal components that produce this unique form of cell polarity and their relationship to polarity signaling cascades are unknown. We show that F-actin and Myosin II motors are enriched in the neuronal leading process and that Myosin II activity is necessary for leading process actin dynamics. Inhibition of Myosin II decreased the speed of centrosome and somal movement, whereas Myosin II activation increased coordinated movement. Ectopic expression or silencing of Par6α inhibited Myosin II motors by decreasing Myosin light-chain phosphorylation. These findings suggest leading-process Myosin II may function to “pull” the centrosome and soma forward during glial-guided migration by a mechanism involving the conserved polarity protein Par6α

WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation

During normal cerebellar development, the remarkable expansion of granule cell progenitors (GCPs) generates a population of granule neurons that outnumbers the total neuronal population of the cerebral cortex, and provides a model for identifying signaling pathways that may be defective in medulloblastoma. While many studies focus on identifying pathways that promote growth of GCPs, a critical unanswered question concerns the identification of signaling pathways that block mitogenic stimulation and induce early steps in differentiation. Here we identify WNT3 as a novel suppressor of GCP proliferation during cerebellar development and an inhibitor of medulloblastoma growth in mice. WNT3, produced in early postnatal cerebellum, inhibits GCP proliferation by down-regulating proproliferative target genes of the mitogen Sonic Hedgehog (SHH) and the bHLH transcription factor Atoh1. WNT3 suppresses GCP growth through a non-canonical Wnt signaling pathway, activating prototypic mitogen-activated protein kinases (MAPKs), the Ras-dependent extracellular-signal-regulated kinases 1/2 (ERK1/2) and ERK5, instead of the classical β-catenin pathway. Inhibition of MAPK activity using a MAPK kinase (MEK) inhibitor reversed the inhibitory effect of WNT3 on GCP proliferation. Importantly, WNT3 inhibits proliferation of medulloblastoma tumor growth in mouse models by a similar mechanism. Thus, the present study suggests a novel role for WNT3 as a regulator of neurogenesis and repressor of neural tumors. © 2013 Anne et al

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

TGF-beta(2)- and H2O2-Induced Biological Changes in Optic Nerve Head Astrocytes Are Reduced by the Antioxidant Alpha-Lipoic Acid

Background/Aims: The goal of the present study was to determine whether transforming growth factor-beta(2) (TGF-beta(2))- and oxidative stress-induced cellular changes in cultured human optic nerve head (ONH) astrocytes could be reduced by pretreatment with the antioxidant alpha-lipoic acid (LA). Methods: Cultured ONH astrocytes were treated with 1.0 ng/ml TGF-beta(2) for 24 h or 200 mu M hydrogen peroxide (H2O2) for 1 h. Lipid peroxidation was measured by a decrease in cis-pari-naric acid fluorescence. Additionally, cells were pretreated with different concentrations of LA before TGF-beta 2 or H2O2 exposure. Expressions of the heat shock protein (Hsp) alpha B-crystallin and Hsp27, the extracellular matrix (ECM) component fibronectin and the ECM-modulating protein connective tissue growth factor (CTGF) were examined with immunohistochemistry and real-time PCR analysis. Results: Both TGF-beta(2) and H2O2 increased lipid peroxidation. Treatment of astrocytes with TGF-beta(2) and H2O2 upregulated the expression of alpha B-crystallin, Hsp27, fibronectin and CTGF. Pretreatment with different concentrations of LA reduced the TGF-beta(2)- and H2O2-stimulated gene expressions. Conclusion: We showed that TGF-beta(2)- and H2O2-stimulated gene expressions could be prevented by pretreatment with the antioxidant LA in cultured human ONH astrocytes. Therefore, it is tempting to speculate that the use of antioxidants could have protective effects in glaucomatous optic neuropathy. Copyright (C) 2012 S. Karger AG, Base

Striking a Chord: Dementia and Song

We have co-written this piece to relay what can be achieved with song and music in familial and non-familial settings when caring for a person with dementia. This article started as a conversation we had in the Wellcome Collection cafe in London to catch up with each other while Prabhjot was en route from Canada to India, to meet her father. We shared how dementia was becoming a part of our parents’ lives. This article is dedicated to the chords Prabhjot Parmar has struck with her father, Major Harbhajan Singh (25 Dec 1925 – 16 April 2018) and Nirmal Puwar has had the pleasure of sharing with her mother, Kartar Kaur. Both of us have been drawn to understanding how our own performance of song with our respective parent enabled them and us to maintain a register of connection. Song became a means of trying to keep striking a parental and musical chord. We aimed to connect by engendering ‘therapeutic atmospheres’ (Sonntag 2016) through song. We use song and music interchangeably, operating with performance as an umbrella term that includes gesture, utterance, dance, singing and playing musical instruments, for example. Two autoethnographic relational contributions provide a substantive basis to our article, each written by a researcher-carer-daughter, seeking to sustain contact with what remains in her parent living with dementia

Structure-guided microbial targeting of antistaphylococcal prodrugs

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs i