Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.G1002279/MRC_/Medical Research Council/United Kingdom R25 NS065729/NS/NINDS NIH HHS/United States Z01 AG000949/ImNIH/Intramural NIH HHS/United States R01 NS062869/NS/NINDS NIH HHS/United States F31 NS105404/NS/NINDS NIH HHS/United Statespre-print, post-print, publisher's version/PD

From attosecond to zeptosecond coherent control of free-electron wave functions using semi-infinite light fields

Light-electron interaction in empty space is the seminal ingredient for free-electron lasers and also for controlling electron beams to dynamically investigate materials and molecules. Pushing the coherent control of free electrons by light to unexplored timescales, below the attosecond, would enable unprecedented applications in light-assisted electron quantum circuits and diagnostics at extremely small timescales, such as those governing intramolecular electronic motion and nuclear phenomena. We experimentally demonstrate attosecond coherent manipulation of the electron wave function in a transmission electron microscope, and show that it can be pushed down to the zeptosecond regime with existing technology. We make a relativistic pulsed electron beam interact in free space with an appropriately synthesized semi-infinite light field generated by two femtosecond laser pulses reflected at the surface of a mirror and delayed by fractions of the optical cycle. The amplitude and phase of the resulting coherent oscillations of the electron states in energymomentum space are mapped via momentum-resolved ultrafast electron energy-loss spectroscopy. The experimental results are in full agreement with our theoretical framework for light-electron interaction, which predicts access to the zeptosecond timescale by combining semi-infinite X-ray fields with free electrons.Comment: 22 pages, 6 figure

Clinical translation of positive metastases identified on prostate-specific membrane antigen positron emission tomography/computed tomography imaging in the management of de novo synchronous oligometastatic prostate cancer

Recent randomised evidence supports the diagnostic superiority of prostate-specific membrane antigen (PSMA) PET/CT, over conventional imaging, in the detection of distant occult metastasis in men with newly diagnosed high-risk prostate cancer. This may result in a rise in the detection of de novo synchronous hormone-sensitive “oligometastatic” prostate cancer. We outline the evidence supporting PSMA PET/CT imaging in primary staging. We also discuss the translation of positive areas, with a high probability of distant metastasis, into clinical therapeutic targets for metastasis-directed interventions. Finally, we highlight the role of PSMA PET/CT as an imaging biomarker. This may have future utility in disease monitoring and prediction of response to systemic, local cytoreductive and metastasis-directed interventions. Patient Summary: A new whole-body scan can accurately detect cancer deposits, in men in whom distant prostate cancer spread is suspected. This may be useful to monitor and predict response to drug therapy, treatments to the prostate and cancer deposits

Design of an electron microscope phase plate using a focused continuous-wave laser

We propose a Zernike phase contrast electron microscope that uses an intense laser focus to convert a phase image into a visible image. We present the relativistic quantum theory of the phase shift caused by the laser-electron-interaction, study resonant cavities for enhancing the laser intensity, and discuss applications in biology, soft materials science, and atomic and molecular physics.Comment: 5 pages, 3 figure

Energy Spectra, Altitude Profiles and Charge Ratios of Atmospheric Muons

We present a new measurement of air shower muons made during atmospheric ascent of the High Energy Antimatter Telescope balloon experiment. The muon charge ratio mu+ / mu- is presented as a function of atmospheric depth in the momentum interval 0.3-0.9 GeV/c. The differential mu- momentum spectra are presented between 0.3 and about 50 GeV/c at atmospheric depths between 13 and 960 g/cm^2. We compare our measurements with other recent data and with Monte Carlo calculations of the same type as those used in predicting atmospheric neutrino fluxes. We find that our measured mu- fluxes are smaller than the predictions by as much as 70% at shallow atmospheric depths, by about 20% at the depth of shower maximum, and are in good agreement with the predictions at greater depths. We explore the consequences of this on the question of atmospheric neutrino production.Comment: 11 pages, 8 figures, to appear in Phys. Rev. D (2000

Midwives\u27 use of best available evidence in practice: An integrative review

Aims and objectives: To synthesise international research that relates to midwives\u27 use of best available evidence in practice settings and identify key issues relating to the translation of latest evidence into everyday maternity care. Background: Midwifery is a research‐informed profession. However, a gap persists in the translation of best available evidence into practice settings, compromising gold standard maternity care and delaying the translation of new knowledge into everyday practice. Design: A five‐step integrative review approach, based on a series of articles published by the Joanna Briggs Institute (JBI) for conducting systematic reviews, was used to facilitate development of a search strategy, selection criteria and quality appraisal process, and the extraction and synthesis of data to inform an integrative review. Methods: The databases CINAHL, MEDLINE, Web of Science, Implementation Science Journal and Scopus were searched for relevant articles. The screening and quality appraisal process complied with the PRISMA 2009 checklist. Narrative analysis was used to develop sub‐categories and dimensions from the data, which were then synthesised to form two major categories that together answer the review question. Results: The six articles reviewed report on midwives\u27 use of best available evidence in Australia, the UK and Asia. Two major categories emerged that confirm that although midwifery values evidence‐based practice (EBP), evidence‐informed maternity care is not always employed in clinical settings. Additionally, closure of the evidence‐to‐practice gap in maternity care requires a multidimensional approach. Conclusion: Collaborative partnerships between midwives and researchers are necessary to initiate strategies that support midwives\u27 efforts to facilitate the timely movement of best available evidence into practice. Relevance to clinical practice: Understanding midwives\u27 use of best available evidence in practice will direct future efforts towards the development of mechanisms that facilitate the timely uptake of latest evidence by all maternity care providers working in clinical settings

Observations of the Askaryan Effect in Ice

We report on the first observations of the Askaryan effect in ice: coherent impulsive radio Cherenkov radiation from the charge asymmetry in an electromagnetic (EM) shower. Such radiation has been observed in silica sand and rock salt, but this is the first direct observation from an EM shower in ice. These measurements are important since the majority of experiments to date that rely on the effect for ultra-high energy neutrino detection are being performed using ice as the target medium. As part of the complete validation process for the Antarctic Impulsive Transient Antenna (ANITA) experiment, we performed an experiment at the Stanford Linear Accelerator Center (SLAC) in June 2006 using a 7.5 metric ton ice target, yielding results fully consistent with theoretical expectations.Comment: 4 pages, 5 figures, minor correction

The Energy Spectra and Relative Abundances of Electrons and Positrons in the Galactic Cosmic Radiation

Observations of cosmic-ray electrons and positrons have been made with a new balloon-borne detector, HEAT (the "High-Energy Antimatter Telescope"), first flown in 1994 May from Fort Sumner, NM. We describe the instrumental approach and the data analysis procedures, and we present results from this flight. The measurement has provided a new determination of the individual energy spectra of electrons and positrons from 5 GeV to about 50 GeV, and of the combined "all-electron" intensity (e+ + e-) up to about 100 GeV. The single power-law spectral indices for electrons and positrons are alpha = 3.09 +/- 0.08 and 3.3 +/- 0.2, respectively. We find that a contribution from primary sources to the positron intensity in this energy region, if it exists, must be quite small.Comment: latex2e file, 30 pages, 15 figures, aas2pp4.sty and epsf.tex needed. To appear in May 10, 1998 issue of Ap.

Aromatic L-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies

Aromatic L-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. In order to better characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic (mDA) neuronal model of AADC deficiency from induced pluripotent stem cells (iPSCs). The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by L-3,4-dihydroxyphenylalanine (L-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where L-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalised therapeutic approaches