A synaptic nidogen: developmental regulation and role of nidogen-2 at the neuromuscular junction

Background: The skeletal neuromuscular junction is a useful model for elucidating mechanisms that regulate synaptogenesis. Developmentally important intercellular interactions at the neuromuscular junction are mediated by the synaptic portion of a basal lamina that completely ensheaths each muscle fiber. Basal laminas in general are composed of four main types of glycosylated proteins: laminins, collagens IV, heparan sulfate proteoglycans and nidogens (entactins). The portion of the muscle fiber basal lamina that passes between the motor nerve terminal and postsynaptic membrane has been shown to bear distinct isoforms of the first three of these. For laminins and collagens IV, the proteins are deposited by the muscle; a synaptic proteoglycan, z-agrin, is deposited by the nerve. In each case, the synaptic isoform plays key roles in organizing the neuromuscular junction. Here, we analyze the fourth family, composed of nidogen-1 and -2.Results: In adult muscle, nidogen-1 is present throughout muscle fiber basal lamina, while nidogen- 2 is concentrated at synapses. Nidogen-2 is initially present throughout muscle basal lamina, but is lost from extrasynaptic regions during the first three postnatal weeks. Neuromuscular junctions in mutant mice lacking nidogen-2 appear normal at birth, but become topologically abnormal as they mature. Synaptic laminins, collagens IV and heparan sulfate proteoglycans persist in the absence of nidogen-2, suggesting the phenotype is not secondary to a general defect in the integrity of synaptic basal lamina. Further genetic studies suggest that synaptic localization of each of the four families of synaptic basal lamina components is independent of the other three.Conclusion: All four core components of the basal lamina have synaptically enriched isoforms. Together, they form a highly specialized synaptic cleft material. Individually, they play distinct roles in the formation, maturation and maintenance of the neuromuscular junction

Visible Effects of the Hidden Sector

The renormalization of operators responsible for soft supersymmetry breaking is usually calculated by starting at some high scale and including only visible sector interactions in the evolution equations, while ignoring hidden sector interactions. Here we explain why this is correct only for the most trivial structures in the hidden sector, and discuss possible implications. This investigation was prompted by the idea of conformal sequestering. In that framework hidden sector renormalizations by nearly conformal dynamics are critical. In the original models of conformal sequestering it was necessary to impose hidden sector flavor symmetries to achieve the sequestered form. We present models which can evade this requirement and lead to no-scale or anomaly mediated boundary conditions; but the necessary structures do not seem generic. More generally, the ratios of scalar masses to gaugino masses, the $\mu$-term, the $B\mu$-term, $A$-terms, and the gravitino mass can be significantly affected.Comment: 23 pages, no figure

Quality of life among cancer inpatients 80 years and older: a systematic review

Objective The aim of this systematic review was to summarize and assess the literature on quality of life (QoL) among cancer patients 80 years and older admitted to hospitals and what QoL instruments have been used. Methods We searched systematically in Medline, Embase and Cinahl. Eligibility criteria included studies with any design measuring QoL among cancer patients 80 years and older hospitalized for treatment (surgery, chemotherapy or radiation therapy). Exclusion criteria: studies not available in English, French, German or Spanish. We screened the titles and abstracts according to a predefined set of inclusion criteria. All the included studies were assessed according to the Critical Appraisal Skills Programme checklists, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement checklist was used to ensure rigor in conducting and reporting. This systematic review was registered in PROSPERO (CRD42017058290). Results We included 17 studies with 2005 participants with various cancer diagnoses and Classification of Malignant Tumors stages (TNM). The included studies used a range of different QoL instruments and had different aims and outcomes. Both cancer-specific and generic instruments were used. Only one of the 17 studies used an age-specific instrument. All the studies included patients 80 years and older in their cohort, but none specifically analyzed QoL outcomes in this particular subgroup. Based on findings in the age-heterogeneous population (age range 20–100 years), QoL seems to be correlated with the type of diagnosed carcinoma, length of stay, depression and severe symptom burden. Conclusion We were unable to find any research directly exploring QoL and its determinants among cancer patients 80 years and older since none of the included studies presented specific analysis of data in this particular age subgroup. This finding represents a major gap in the knowledge base in this patient group. Based on this finding, we strongly recommend future studies that include this increasingly important and challenging patient group to use valid age- and diagnosis-specific QoL instruments.publishedVersio

Naturalness and Higgs Decays in the MSSM with a Singlet

The simplest extension of the supersymmetric standard model - the addition of one singlet superfield - can have a profound impact on the Higgs and its decays. We perform a general operator analysis of this scenario, focusing on the phenomenologically distinct scenarios that can arise, and not restricting the scope to the narrow framework of the NMSSM. We reexamine decays to four b quarks and four tau's, finding that they are still generally viable, but at the edge of LEP limits. We find a broad set of Higgs decay modes, some new, including those with four gluon final states, as well as more general six and eight parton final states. We find the phenomenology of these scenarios is dramatically impacted by operators typically ignored, specifically those arising from D-terms in the hidden sector, and those arising from weak-scale colored fields. In addition to sensitivity of m_Z, there are potential tunings of other aspects of the spectrum. In spite of this, these models can be very natural, with light stops and a Higgs as light as 82 GeV. These scenarios motivate further analyses of LEP data as well as studies of the detection capabilities of future colliders to the new decay channels presented.Comment: 3 figures, 1 appendix; version to appear in JHEP; typos fixed and additional references and acknowledgements adde

Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity

YesThe duocarmycins are potent antitumour agents with potential in the development of antibody drug conjugates (ADCs) as well as being clinical candidates in their own right. In this paper, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilisation in solid phase synthesis. The synthesis was performed on a large scale and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers. Application to solid phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to previous reports for both the monomeric and extended compounds. The substitution at the C-terminus of the duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine but this had no beneficial effects on biological activity.MJS was funded by Novartis and UEA. We thank the EPSRC Mass Spectrometry Service, Swansea. We thank Richard Robinson and Julia Hatto at Novartis for help in the large scale synthesis

The robot vibrissal system: Understanding mammalian sensorimotor co-ordination through biomimetics

Chapter 10 The Robot Vibrissal System: Understanding Mammalian Sensorimotor Co-ordination Through Biomimetics Tony J. Prescott, Ben Mitchinson, Nathan F. Lepora, Stuart P. Wilson, Sean R. Anderson, John Porrill, Paul Dean, Charles ..

Uplifted supersymmetric Higgs region

We show that the parameter space of the Minimal Supersymmetric Standard Model includes a region where the down-type fermion masses are generated by the loop-induced couplings to the up-type Higgs doublet. In this region the down-type Higgs doublet does not acquire a vacuum expectation value at tree level, and has sizable couplings in the superpotential to the tau leptons and bottom quarks. Besides a light standard-like Higgs boson, the Higgs spectrum includes the nearly degenerate states of a heavy spin-0 doublet which can be produced through their couplings to the $b$ quark and decay predominantly into \tau^+\tau^- or \tau\nu.Comment: 14 pages; Signs in Eqns. (3.1) and (4.2) corrected, appendix include

Donor Centers and Absorption Spectra in Quantum Dots

We have studied the electronic properties and optical absorption spectra of three different cases of donor centers, D^{0}, D^{-} and D^{2-}, which are subjected to a perpendicular magnetic field, using the exact diagonalization method. The energies of the lowest lying states are obtained as function of the applied magnetic field strength B and the distance zeta between the positive ion and the confinement xy-plane. Our calculations indicate that the positive ion induces transitions in the ground-state, which can be observed clearly in the absorption spectra, but as zeta goes to 0 the strength of the applied magnetic field needed for a transition to occur tends to infinity.Comment: 5 pages, 4 figures, REVTeX 4, gzipped tar fil

Correlations between EMG jaw muscle activity and facial morphology in complete denture wearers

In a sample of fifteen partially edentulous subjects assigned for immediate complete denture treatment, a correlation analysis was performed between pre-extraction facial morphology determined from lateral cephalograms, and EMG activity of the anterior temporal and masseter muscles in maximal clench and tapping of teeth. Marked correlations observed between vertical and sagittal jaw relations and mean voltages of the jaw-closing muscles indicated strong biting activity in subjects with a square facial type. No significant associations were observed between biting strength and the age of the subjects. Correlations between facial morphological changes and changes in EMG biting activity after denture insertion and during 1 year of denture wear indicated that the anterior temporal muscles were extremely sensitive to sagittal changes in anterior occlusion. The masseter muscles were less sensitive, but responded in some instances to changes in vertical jaw relationship.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73816/1/j.1365-2842.1983.tb00105.x.pd

TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis

Rationale: Enhancing non–CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis (CF) and other mucoobstructive diseases. Objectives: To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Measurements and Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca21-activated Cl2 channel activity and anion secretion in human bronchial epithelial (HBE) cells from patients with CF without impacting calcium signaling. ETX001 rapidly increased fluid secretion and airway surface liquid height in CF-HBE cells under both static conditions and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with CF and non-CF mucoobstructive diseases