A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells

Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations

Charged Lepton Flavour Violation from Massive Neutrinos in Z Decays

Present evidences for neutrino masses and lepton flavour mixings allow to predict, in the Standard Model with light neutrinos, branching rates for the decays Z --> e mu, mu tau, e tau of less than 10^{-54}, while present experimental exclusion limits from LEP 1 are of order 10^{-5}. The GigaZ option of the TESLA Linear Collider project will extend the sensitivity down to about 10^{-8}. We study in a systematic way some minimal extensions of the Standard Model and show that GigaZ might well be sensitive to the rates predicted from these scenarios.Comment: 24 pages, 4 figures, LaTeX, uses axodraw.st

Different effects of alpine woody plant expansion on domestic and wild ungulates

Changes in land-use and climate affect the distribution and diversity of plant and animal species at different spatiotemporal scales. The extent to which species-specific phenotypic plasticity and biotic interactions mediate organismal adaptation to changing environments, however, remains poorly understood. Woody plant expansion is threatening the extent of alpine grasslands worldwide, and evaluating and predicting its effects on herbivores is of crucial importance. Here, we explore the impact of shrubification on the feeding efficiency of Pyrenean chamois (Rupicapra p. pyrenaica), as well as on the three most abundant coexisting domestic ungulate species: cattle, sheep and horses. We use observational diet composition from May to October and model different scenarios of vegetation availability where shrubland and woodland proliferate at the expense of grassland. We then predicted if the four ungulate species could efficiently utilize their food landscapes with their current dietary specificities measuring their niche breath in each scenario. We observed that the wild counterpart, due to a higher trophic plasticity, is less disturbed by shrubification compared to livestock, which rely primarily on herbaceous plants and will be affected 3.6 times more. Our results suggest that mixed feeders, such as chamois, could benefit from fallow landscapes, and that mountain farmers are at a growing economic risk worldwide due to changing land-use practices and climate conditions

Quenched Lattice QCD with Domain Wall Fermions and the Chiral Limit

Quenched QCD simulations on three volumes, $8^3 \times$, $12^3 \times$ and $16^3 \times 32$ and three couplings, $\beta=5.7$, 5.85 and 6.0 using domain wall fermions provide a consistent picture of quenched QCD. We demonstrate that the small induced effects of chiral symmetry breaking inherent in this formulation can be described by a residual mass (\mres) whose size decreases as the separation between the domain walls ($L_s$) is increased. However, at stronger couplings much larger values of $L_s$ are required to achieve a given physical value of \mres. For $\beta=6.0$ and $L_s=16$, we find \mres/m_s=0.033(3), while for $\beta=5.7$, and $L_s=48$, \mres/m_s=0.074(5), where $m_s$ is the strange quark mass. These values are significantly smaller than those obtained from a more naive determination in our earlier studies. Important effects of topological near zero modes which should afflict an accurate quenched calculation are easily visible in both the chiral condensate and the pion propagator. These effects can be controlled by working at an appropriately large volume. A non-linear behavior of $m_\pi^2$ in the limit of small quark mass suggests the presence of additional infrared subtlety in the quenched approximation. Good scaling is seen both in masses and in $f_\pi$ over our entire range, with inverse lattice spacing varying between 1 and 2 GeV.Comment: 91 pages, 34 figure

Optimization of R(e+e-) and "Freezing" of the QCD Couplant at Low Energies

The new result for the third-order QCD corrections to R_{e^+e^-}, unlike the old, incorrect result, is nicely compatible with the principle-of-minimal-sensitivity optimization method. Moreover, it leads to infrared fixed-point behaviour: the optimized couplant, alpha_s/pi, for R(e+e-) does not diverge at low energies, but "freezes" to a value 0.26 below about 300 MeV. This provides some direct theoretical evidence, purely from perturbation theory, for the "freezing" of the couplant -- an idea that has long been a popular and successful phenomenological hypothesis. We use the "smearing" method of Poggio, Quinn, and Weinberg to compare the resulting theoretical prediction for R(e+e-) with experimental data down to the lowest energies, and find excellent agreement.Comment: 27 pages, LaTeX, 8 uuencoded figures, DE-FG05-92ER40717-

Presymptomatic genetic testing for hereditary cancer in young adults: a survey of young adults and parents

Presymptomatic testing for hereditary cancer syndromes should involve a considered choice. This may be particularly challenging when testing is undertaken in early adulthood. With the aim of exploring the psychosocial implications of presymptomatic testing for hereditary cancer in young adults and their parents, a cross-sectional survey was designed. Two questionnaires were developed (one for young adults who had considered presymptomatic testing, one for parents). Questionnaires were completed by 152 (65.2%) young adults and 42 (73.7%) parents. Data were analysed using descriptive statistics, inferential testing, and exploratory factor analysis and linear regression analysis. Young adults were told about their potential genetic risk at a mean age of 20 years; in most cases, information was given by a parent, often in an unplanned conversation. Although testing requests were usually made by young adults, the majority of parents felt they had control over the young adult’s decision and all felt their children should be tested. Results suggest that some young adults did not understand the implications of the genetic test but complied with parental pressure. Counselling approaches for presymptomatic testing may require modification both for young adults and their parents. Those offering testing need to be aware of the complex pressures that young adults can experience, which can influence their autonomous choices. It is therefore important to emphasise to both parents and young adults that, although testing can bring benefits in terms of surveillance and prevention, young adults have a choice

Variational Quark Mass Expansion and the Order Parameters of Chiral Symmetry Breaking

We investigate in some detail a "variational mass" expansion approach, generalized from a similar construction developed in the Gross-Neveu model, to evaluate the basic order parameters of the dynamical breaking of the $SU(2)_L \times SU(2)_R$ and $SU(3)_L \times SU(3)_R$ chiral symmetries in QCD. The method starts with a reorganization of the ordinary perturbation theory with the addition of an arbitrary quark mass $m$. The new perturbative series can be summed to all orders thanks to renormalization group properties, with specific boundary conditions, and advocated analytic continuation in $m$ properties. In the approximation where the explicit breakdown of the chiral symmetries due to small current quark masses is neglected, we derive ansatzes for the dynamical contribution to the "constituent" masses $M_q$ of the $u,d,s$ quarks; the pion decay constant $F_\pi$; and the quark condensate $$ in terms of the basic QCD scale $\Lambda_{\bar{MS}}$. Those ansatzes are then optimized, in a sense to be specified, and also explicit symmetry breaking mass terms can be consistently introduced in the framework. The obtained values of $F_\pi$ and $M_q$ are roughly in agreement with what is expected from other non-perturbative methods. In contrast we obtain quite a small value of $|< \bar q q >|$ within our approach. The possible interpretation of the latter results is briefly discussed.Comment: 40 pages, LaTex, 2 PS figures. Additions in section 2.2 to better explain the relation between the current mass and the dynamical mass ansatz. Minor misprints corrected. Version to appear in Phys. Rev.

Water dispersible microbicidal cellulose acetate phthalate film

BACKGROUND: Cellulose acetate phthalate (CAP) has been used for several decades in the pharmaceutical industry for enteric film coating of oral tablets and capsules. Micronized CAP, available commercially as "Aquateric" and containing additional ingredients required for micronization, used for tablet coating from water dispersions, was shown to adsorb and inactivate the human immunodeficiency virus (HIV-1), herpesviruses (HSV) and other sexually transmitted disease (STD) pathogens. Earlier studies indicate that a gel formulation of micronized CAP has a potential as a topical microbicide for prevention of STDs including the acquired immunodeficiency syndrome (AIDS). The objective of endeavors described here was to develop a water dispersible CAP film amenable to inexpensive industrial mass production. METHODS: CAP and hydroxypropyl cellulose (HPC) were dissolved in different organic solvent mixtures, poured into dishes, and the solvents evaporated. Graded quantities of a resulting selected film were mixed for 5 min at 37°C with HIV-1, HSV and other STD pathogens, respectively. Residual infectivity of the treated viruses and bacteria was determined. RESULTS: The prerequisites for producing CAP films which are soft, flexible and dispersible in water, resulting in smooth gels, are combining CAP with HPC (other cellulose derivatives are unsuitable), and casting from organic solvent mixtures containing ≈50 to ≈65% ethanol (EtOH). The films are ≈100 µ thick and have a textured surface with alternating protrusions and depressions revealed by scanning electron microscopy. The films, before complete conversion into a gel, rapidly inactivated HIV-1 and HSV and reduced the infectivity of non-viral STD pathogens >1,000-fold. CONCLUSIONS: Soft pliable CAP-HPC composite films can be generated by casting from organic solvent mixtures containing EtOH. The films rapidly reduce the infectivity of several STD pathogens, including HIV-1. They are converted into gels and thus do not have to be removed following application and use. In addition to their potential as topical microbicides, the films have promise for mucosal delivery of pharmaceuticals other than CAP

Genome-Wide Tissue-Specific Occupancy of the Hox Protein Ultrabithorax and Hox Cofactor Homothorax in Drosophila

The Hox genes are responsible for generating morphological diversity along the anterior-posterior axis during animal development. The Drosophila Hox gene Ultrabithorax (Ubx), for example, is required for specifying the identity of the third thoracic (T3) segment of the adult, which includes the dorsal haltere, an appendage required for flight, and the ventral T3 leg. Ubx mutants show homeotic transformations of the T3 leg towards the identity of the T2 leg and the haltere towards the wing. All Hox genes, including Ubx, encode homeodomain containing transcription factors, raising the question of what target genes Ubx regulates to generate these adult structures. To address this question, we carried out whole genome ChIP-chip studies to identify all of the Ubx bound regions in the haltere and T3 leg imaginal discs, which are the precursors to these adult structures. In addition, we used ChIP-chip to identify the sites bound by the Hox cofactor, Homothorax (Hth). In contrast to previous ChIP-chip studies carried out in Drosophila embryos, these binding studies reveal that there is a remarkable amount of tissue- and transcription factor-specific binding. Analyses of the putative target genes bound and regulated by these factors suggest that Ubx regulates many downstream transcription factors and developmental pathways in the haltere and T3 leg. Finally, we discovered additional DNA sequence motifs that in some cases are specific for individual data sets, arguing that Ubx and/or Hth work together with many regionally expressed transcription factors to execute their functions. Together, these data provide the first whole-genome analysis of the binding sites and target genes regulated by Ubx to specify the morphologies of the adult T3 segment of the fly

Flavor changing Z-decays from scalar interactions at a Giga-Z Linear Collider

The flavor changing decay Z -> d_I \bar{d}_J is investigated with special emphasis on the b \bar{s} final state. Various models for flavor violation are considered: two Higgs doublet models (2HDM's), supersymmetry (SUSY) with flavor violation in the up and down-type squark mass matrices and SUSY with flavor violation mediated by R-parity-violating interaction. We find that, within the SUSY scenarios for flavor violation, the branching ratio for the decay Z -> b \bar{s} can reach 10^{-6} for large \tan\beta values, while the typical size for this branching ratio in the 2HDM's considered is about two orders of magnitudes smaller at best. Thus, flavor changing SUSY signatures in radiative Z decays such as Z -> b \bar{s} may be accessible to future ``Z factories'' such as a Giga-Z version of the TESLA design.Comment: 27 pages, 15 figures, REVTeX4. A new section added and a few minor corrections were made in the tex