Analysis of conditional gene deletion using probe based Real-Time PCR

Following publication of this article [1] the authors noticed that an incorrect probe reference was cited on page 3, 4, 5 and 6 ("UP #69, Roche Applied Science"). The correct probe that was used for the 1lox/2lox allele ratio analysis in the paper is as follow

Formation of singularities for equivariant 2+1 dimensional wave maps into the two-sphere

In this paper we report on numerical studies of the Cauchy problem for equivariant wave maps from 2+1 dimensional Minkowski spacetime into the two-sphere. Our results provide strong evidence for the conjecture that large energy initial data develop singularities in finite time and that singularity formation has the universal form of adiabatic shrinking of the degree-one harmonic map from $\mathbb{R}^2$ into $S^2$.Comment: 14 pages, 5 figures, final version to be published in Nonlinearit

Host-pathogen evolutionary signatures reveal dynamics and future invasions of vampire bat rabies

Anticipating how epidemics will spread across landscapes requires understanding host dispersal events that are notoriously difficult to measure. Here, we contrast host and virus genetic signatures to resolve the spatiotemporal dynamics underlying geographic expansions of vampire bat rabies virus (VBRV) in Peru. Phylogenetic analysis revealed recent viral spread between populations that, according to extreme geographic structure in maternally inherited host mitochondrial DNA, appeared completely isolated. In contrast, greater population connectivity in biparentally inherited nuclear microsatellites explained the historical limits of invasions, suggesting that dispersing male bats spread VBRV between genetically isolated female populations. Host nuclear DNA further indicated unanticipated gene flow through the Andes mountains connecting the VBRV-free Pacific coast to the VBRV-endemic Amazon rainforest. By combining Bayesian phylogeography with landscape resistance models, we projected invasion routes through northern Peru that were validated by real-time livestock rabies mortality data. The first outbreaks of VBRV on the Pacific coast of South America could occur by June 2020, which would have serious implications for agriculture, wildlife conservation, and human health. Our results show that combining host and pathogen genetic data can identify sex biases in pathogen spatial spread, which may be a widespread but underappreciated phenomenon, and demonstrate that genetic forecasting can aid preparedness for impending viral invasions

The geodesic approximation for lump dynamics and coercivity of the Hessian for harmonic maps

The most fruitful approach to studying low energy soliton dynamics in field theories of Bogomol'nyi type is the geodesic approximation of Manton. In the case of vortices and monopoles, Stuart has obtained rigorous estimates of the errors in this approximation, and hence proved that it is valid in the low speed regime. His method employs energy estimates which rely on a key coercivity property of the Hessian of the energy functional of the theory under consideration. In this paper we prove an analogous coercivity property for the Hessian of the energy functional of a general sigma model with compact K\"ahler domain and target. We go on to prove a continuity property for our result, and show that, for the CP^1 model on S^2, the Hessian fails to be globally coercive in the degree 1 sector. We present numerical evidence which suggests that the Hessian is globally coercive in a certain equivariance class of the degree n sector for n>1. We also prove that, within the geodesic approximation, a single CP^1 lump moving on S^2 does not generically travel on a great circle.Comment: 29 pages, 1 figure; typos corrected, references added, expanded discussion of the main function spac

Disturbance and Predictability of Flowering Patterns in Bird-Pollinated Cloud Forest Plants

The distribution and flowering patterns of hummingbird—pollinated plants were compared from July 1981 to June 1983 in three patch types in cloud forest at Monteverde, Costa Rica. Study plots were: (1) four recent, large (1100—2500 m2) disturbances ("cutovers") produced by cutting vegetation, (2) six recent, smaller (200—600 m2) disturbances caused by treefalls, and (3) four plots (1600—1800 m2) of canopied forest. Based on published literature dealing with communities that characterize different regimes of disturbance, we tested one assumption and two hypotheses. Assumption: Plant species composition differs among the three patch types. Hypothesis 1: Phenotypic specialization by plants for co—evolved interactions with hummingbirds will be lowest in large gaps, highest in forest, and intermediate in treefalls. Hypothesis 2: Predictability of flowering phenologies and nectar production will be lowest in large gaps, highest in forest, intermediate in treefalls. Neither the assumption nor the hypotheses were supported by the results. The patch mosaic in this cloud forest was not associated with major differences in species composition of bird—pollinated plants. Most species studied were self—compatible. Most abundant in cutovers were species with long corollas, relatively specialized for attracting long—billed hummingbirds. Species with short corollas, which can be visited by many hummingbird species and some insects, were most abundant in treefalls and forest. Variation in phenological patterns showed no consistent trends among patch types. Predictability of flower and nectar production tended to be greatest in treefalls, which are foci of concentrated flowering activity by all species. Discrepancies between our results and previous studies can be ascribed to two facts. (1) Much of the literature dealing with ecological consequences of disturbance has dealt with large—scale anthropogenic disturbances such as old fields of the eastern USA, whereas we studied small, natural, or quasi—natural disturbances. (2) Studies of forest disturbance have focused on the tree layer, whereas we studied the understory herbs, shrubs, and epiphytes. Natural disturbance usually involves death and replacement of one or more trees, whereas individuals of other life forms may persist through the disturbance

Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: an investigation of twenty-two hemizygous male patients

BACKGROUND: Fabry disease (FD, OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. While the progressive systemic deposition of uncleaved glycosphingolipids throughout the body is known to have protean clinical manifestations, few data are available regarding the cochlear involvement. METHODS: We non-invasively investigated cochlear functions in 22 consecutive hemizygous males (age 19–64 years, mean 39) affected with classic FD. Conventional audiometry, tympanometry, ABR audiometry, otoacoustic emissions were performed in all patients, together with medical history record and physical examination as part of an exhaustive baseline evaluation prior to enzyme replacement therapy. RESULTS: A total of 12 patients (54.5%) with classic FD were found to have abnormal audition. Five patients had progressive hearing loss and seven patients (32%) experienced sudden deafness. In addition, a hearing loss on high-tone frequencies was found in 7 out of the 10 remaining patients without clinical impairment, despite their young age at time of examination. The incidence of hearing loss appeared significantly increased in FD patients with kidney failure (P < 0.01) or cerebrovascular lesions (P < 0.01), whereas there was no correlation with left ventricular hypertrophy. In addition, tinnitus aurium was also found in six patients (27%). CONCLUSION: This is the first evidence of a high incidence of both progressive hearing loss and sudden deafness in a cohort of male patients affected with classic Fabry disease. The exact pathophysiologic mechanism(s) of the cochlear involvement deserves further studies

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

BACKGROUND: Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). OBJECTIVE/METHODS: BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. RESULTS: Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m2 and plasma lyso-Gb3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was − 5.90 (1.34) mL/min/1.73 m2/year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m2/year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. CONCLUSION: Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN: NCT03018730. Date of registration: January 2017

Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase

Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency

Experimental Tests of Neutron Shielding for the ATLAS Forward Region

Experimental tests devoted to the optimization of the neutron shielding for the ATLAS forward region were performed at the CERN-PS with a 4 GeV/c proton beam. Spectra of fast neutrons, slow neutrons and gamma rays escaping a block of iron (40$\times$40$\times$80 cm$^3$) shielded with different types of neutron and gamma shields (pure polyethylene - PE, borated polyethylene - BPE, lithium filled polyethylene - LiPE, lead, iron) were measured by means of plastic scintillators, a Bonner spectrometer, a HPGe detector and a slow neutron detector. Effectiveness of different types of shielding agaisnt neutrons and $\gamma$-rays were compared. The idea of a segmented outer layer shielding (iron, BPE, iron, LiPE) for the ATLAS Forward Region was also tested