Ongoing astrometric microlensing events from VVV and Gaia

6 pages, 2 figures, accepted MNRAS LettersWe extend predictive microlensing event searches using the Vista Variables in the Via Lactea survey and the second Gaia data release. We identify two events with maxima in 2019 that require urgent follow-up. First, we predict that the nearby M2 dwarf L 338-152 will align with a background source with a closest approach of $35^{+35}_{-23}$ mas on 2019 November $16^{+28}_{-27}$ d. This will cause a peak astrometric shift and photometric amplification of the background source of $2.7^{+3.5}_{-1.5}$ mas and $5.6^{+143.2}_{-5.2}$ mmag respectively. This event should be astrometrically detectable by both the Hubble Space Telescope (HST) and the Spectro-Polarimetric High-contrast Exoplanet Research instrument on the Very Large Telescope. Secondly, we predict the likely K dwarf NLTT 45128 will lens a background source with a closest approach of $105.3^{+12.2}_{-11.7}$ mas on 2019 September $26^{+15}_{-15}$ d. This will produce a peak astrometric shift of $0.329^{+0.065}_{-0.059}$ mas. NLTT 45128 is only 3.6 magnitudes brighter than the background source which makes it an excellent candidate for follow-up with HST. Characterisation of these signals will allow direct gravitational masses to be inferred for both L 338-152 and NLTT 45128 with an estimated precision of $\sim9$ and $\sim13$ per cent respectively.Peer reviewedFinal Published versio

A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.

Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Valpha, cardiac voltage-gated sodium channels (SCN5A), the "Back to Sleep" campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration

An expectation-maximization framework for comprehensive prediction of isoform-specific functions.

MOTIVATION: Advances in RNA sequencing technologies have achieved an unprecedented accuracy in the quantification of mRNA isoforms, but our knowledge of isoform-specific functions has lagged behind. There is a need to understand the functional consequences of differential splicing, which could be supported by the generation of accurate and comprehensive isoform-specific gene ontology annotations. RESULTS: We present isoform interpretation, a method that uses expectation-maximization to infer isoform-specific functions based on the relationship between sequence and functional isoform similarity. We predicted isoform-specific functional annotations for 85 617 isoforms of 17 900 protein-coding human genes spanning a range of 17 430 distinct gene ontology terms. Comparison with a gold-standard corpus of manually annotated human isoform functions showed that isoform interpretation significantly outperforms state-of-the-art competing methods. We provide experimental evidence that functionally related isoforms predicted by isoform interpretation show a higher degree of domain sharing and expression correlation than functionally related genes. We also show that isoform sequence similarity correlates better with inferred isoform function than with gene-level function. AVAILABILITY AND IMPLEMENTATION: Source code, documentation, and resource files are freely available under a GNU3 license at https://github.com/TheJacksonLaboratory/isopretEM and https://zenodo.org/record/7594321

Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes.

BACKGROUND: Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage). RESULTS: We addressed the hypothesis that disease-associated variants in either the Synthesis stage or Transamidase+Remodeling-stage GPI pathway genes have distinct phenotypic spectra. We reviewed clinical data from 58 publications describing 152 individual patients and encoded the phenotypic information using the Human Phenotype Ontology (HPO). We showed statistically significant differences between the Synthesis and Transamidase+Remodeling Groups in the frequencies of phenotypes in the musculoskeletal system, cleft palate, nose phenotypes, and cognitive disability. Finally, we hypothesized that phenotypic defects in the IGDs are likely to be at least partially related to defective GPI anchoring of their target proteins. Twenty-two of one hundred forty-two proteins that receive a GPI anchor are associated with one or more Mendelian diseases and 12 show some phenotypic overlap with the IGDs, represented by 34 HPO terms. Interestingly, GPC3 and GPC6, members of the glypican family of heparan sulfate proteoglycans bound to the plasma membrane through a covalent GPI linkage, are associated with 25 of these phenotypic abnormalities. CONCLUSIONS: IGDs associated with Synthesis and Transamidase+Remodeling stages of the GPI biosynthesis pathway have significantly different phenotypic spectra. GPC2 and GPC6 genes may represent a GPI target of general disruption to the GPI biosynthesis pathway that contributes to the phenotypes of some IGDs

CROSS-DISCIPLINARY TEACHING OF MATHEMATICS

In this paper we describe findings from the literature on cross-disciplinary teaching of mathematics to undergraduates, as part of a review of cross-faculty teaching of science subjects at the University of Technology, Sydney. Disciplinary differences in teaching styles can inform difficulties faced by engineering and business students. The necessity for varied teaching approaches was illuminated by differences in learning styles among students. For mathematics, a common theme is optimising presentation to engineering students, with general agreement on the need for relevance; a concept which is also raised regarding teaching statistics to business students. Innovations include the development of courses based on interdisciplinary teaching approaches, with discussions focusing on course revisions

Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

BACKGROUND The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. METHODS AND FINDINGS Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. CONCLUSIONS The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. TRIAL REGISTRATION ClinicalTrials.gov NCT00211224

Introducing open book examinations in clinical education: A case study

During the recent COVID-19 pandemic, in common with educators across the Higher Education sector, the School of Dentistry at the University of Liverpool reimagined the learning and assessment strategy by moving from proctored closed-book assessment to largely unmonitored open-book examinations (OBE). This article discusses understandings from an educator perspective following our implementation of OBE. The educator perspective discussed here indicates that OBE have the potential to be an authentic and acceptable form of assessment, but that some reframing of attitudes towards assessment from all stakeholders and their approaches to assessment is necessary when developing these innovative types of assessment

More on Chiral-Nonchiral Dual Pairs

Expanding upon earlier work of Pouliot and Strassler, we construct chiral magnetic duals to nonchiral supersymmetric electric theories based upon SO(7), SO(8) and SO(9) gauge groups with various numbers of vector and spinor matter superfields. Anomalies are matched and gauge invariant operators are mapped within each dual pair. Renormalization group flows along flat directions are also examined. We find that confining phase quantum constraints in the electric theories are recovered from semiclassical equations of motion in their magnetic counterparts when the dual gauge groups are completely Higgsed.Comment: 25 pages, harvmac and tables macros, 1 figur

Dual Descriptions of SO(10) SUSY Gauge Theories with Arbitrary Numbers of Spinors and Vectors

We examine the low energy structure of N=1 supersymmetric SO(10) gauge theory with matter chiral superfields in N_Q spinor and N_f vector representations. We construct a dual to this model based upon an SU(N_f+2N_Q-7) x Sp(2N_Q-2) gauge group without utilizing deconfinement methods. This product theory generalizes all previously known Pouliot-type duals to SO(N_c) models with spinor and vector matter. It also yields large numbers of new dual pairs along various flat directions. The dual description of the SO(10) theory satisfies multiple consistency checks including an intricate renormalization group flow analysis which links it with Seiberg's duality transformations. We discuss its implications for building grand unified theories that contain all Standard Model fields as composite degrees of freedom.Comment: 36 pages, harvmac and tables macros, 1 figur