Mutations in the Arabidopsis Peroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series

COMATOSE (CTS), the Arabidopsis homologue of human Adrenoleukodystrophy protein (ALDP), is required for import of substrates for peroxisomal β-oxidation. A new allelic series and a homology model based on the bacterial ABC transporter, Sav1866, provide novel insights into structure-function relations of ABC subfamily D proteins. In contrast to ALDP, where the majority of mutations result in protein absence from the peroxisomal membrane, all CTS mutants produced stable protein. Mutation of conserved residues in the Walker A and B motifs in CTS nucleotide-binding domain (NBD) 1 resulted in a null phenotype but had little effect in NBD2, indicating that the NBDs are functionally distinct in vivo. Two alleles containing mutations in NBD1 outside the Walker motifs (E617K and C631Y) exhibited resistance to auxin precursors 2,4-dichlorophenoxybutyric acid (2,4-DB) and indole butyric acid (IBA) but were wild type in all other tests. The homology model predicted that the transmission interfaces are domain-swapped in CTS, and the differential effects of mutations in the conserved "EAA motif" of coupling helix 2 supported this prediction, consistent with distinct roles for each NBD. Our findings demonstrate that CTS functions can be separated by mutagenesis and the structural model provides a framework for interpretation of phenotypic data

Treatment outcomes in trigeminal neuralgia–a systematic review of domains, dimensions and measures

Background Trigeminal neuralgia (TN) is a painful disorder characterized by sudden electric shock–like pain. It is a rare condition for which multiple treatments are available, including medical and surgical. The best treatment option is yet to be defined, and this is related to the lack of definition in the treatment outcomes and outcome measures. The aim of this systematic review was to summarize all the outcomes and outcomes measures that have been published to date and highlight variability in their use. Methods We have conducted a literature search using a wide range of databases (1946–2019 for medical and 2008–2019 for surgical treatment), for all intervention studies in TN. Four hundred and sixty-seven studies were selected for data extraction on TN classification, data collection method, intervention, and treatment outcomes mapped to the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT guidelines). Results Most studies collected data on pain (n = 459) and side effects (n = 386) domains; however, very few collected data on the impact of treatment on physical (n = 46) and emotional functioning (n = 17) and on patient satisfaction (n = 35). There was high variability on outcome measures used for pain relief (n = 10), pain intensity (n = 9), and frequency of pain episodes (n = 3). Conclusions A clear definition of what are the important outcomes for patients with TN is essential. The choice of standardized outcome measures allowing for consistent reporting in TN treatment will allow for comparison of studies and facilitate treatment choice for patients and clinicians thus, improving health outcomes and reducing health care cost

Muon sites in PbF2 and YF3: Decohering environments and the role of anion Frenkel defects

Muons implanted into ionic fluorides often lead to a so-called F– μ –F state, in which the time evolution of the muon spin contains information about the geometry and nature of the muon site. Nuclei more distant from the muon than the two nearest-neighbor fluorine ions result in decoherence of the F– μ –F system, and this can yield additional quantitative information about the state of the muon. We demonstrate how this idea can be applied to the determination of muon sites within the ionic fluorides α − PbF 2 and YF 3 , which contain fluoride ions in different crystallographic environments. Our results can be used to distinguish between different crystal phases and provide strong evidence for the existence of anion Frenkel defects in α − PbF 2

Targeted vs universal provision of support in high-risk communities: comparison of characteristics in two populations recruited to parenting interventions

Purpose – To compare the characteristics of parents and children recruited for two randomised-controlled trials (RCTs) of parenting support in disadvantaged communities in Wales in order to explore the effects of community-based vs individual-based targeting in early prevention. Design/methodology/approach – Parents from high-risk disadvantaged communities in Wales, where additional early intervention services were targeted as part of a Welsh Government early intervention strategy, were recruited to two RCTs of parenting interventions. In the first study parents of targeted three- and four-year-old children, who were screened, and deemed at risk of long-term problems, were recruited from Sure Start (SS) areas in Wales. In the second study parents of one- and two-year-old children living in disadvantaged Flying Start (FS) areas were recruited, with residence within the FS area being the only recruitment criterion. Findings – FS areas are more strategically targeted as communities with a greater percentage of families with high levels of socio-economic disadvantage and associated risk than SS areas. Families in the toddler parenting trial based in FS areas, recruited without any additional screening, were experiencing higher levels of socio-economic deprivation, mental health problems and parenting stress as well as other known risks to child outcomes than the general population. However, when compared with the individually targeted population recruited for the SS study, they were shown to be experiencing significantly lower levels of these and other risks factors for poor child outcomes than the sample recruited for the SS trial where recruitment was based on known child risk factors. The paper discusses these findings and explores the implications of targeting by geographical area (community level targeting) alone vs targeting individual families by known risk factors. The findings suggest that screening measures would identify children at greatest risk of poor outcomes and whose families might benefit from additional targeted services. Suggestions for possible screening measures are also made. Originality/value – This paper contributes to discussion about effective ways of allocating limited resources to best effect. </jats:sec

Initial data for a head on collision of two Kerr-like black holes with close limit

We prove the existence of a family of initial data for the Einstein vacuum equation which can be interpreted as the data for two Kerr-like black holes in arbitrary location and with spin in arbitrary direction. This family of initial data has the following properties: (i) When the mass parameter of one of them is zero or when the distance between them goes to infinity, it reduces exactly to the Kerr initial data. (ii) When the distance between them is zero, we obtain exactly a Kerr initial data with mass and angular momentum equal to the sum of the mass and angular momentum parameters of each of them. The initial data depends smoothly on the distance, the mass and the angular momentum parameters.Comment: 15 pages, no figures, Latex2

Hard Instances of the Constrained Discrete Logarithm Problem

The discrete logarithm problem (DLP) generalizes to the constrained DLP, where the secret exponent $x$ belongs to a set known to the attacker. The complexity of generic algorithms for solving the constrained DLP depends on the choice of the set. Motivated by cryptographic applications, we study sets with succinct representation for which the constrained DLP is hard. We draw on earlier results due to Erd\"os et al. and Schnorr, develop geometric tools such as generalized Menelaus' theorem for proving lower bounds on the complexity of the constrained DLP, and construct sets with succinct representation with provable non-trivial lower bounds

Comparing initial-data sets for binary black holes

We compare the results of constructing binary black hole initial data with three different decompositions of the constraint equations of general relativity. For each decomposition we compute the initial data using a superposition of two Kerr-Schild black holes to fix the freely specifiable data. We find that these initial-data sets differ significantly, with the ADM energy varying by as much as 5% of the total mass. We find that all initial-data sets currently used for evolutions might contain unphysical gravitational radiation of the order of several percent of the total mass. This is comparable to the amount of gravitational-wave energy observed during the evolved collision. More astrophysically realistic initial data will require more careful choices of the freely specifiable data and boundary conditions for both the metric and extrinsic curvature. However, we find that the choice of extrinsic curvature affects the resulting data sets more strongly than the choice of conformal metric.Comment: 18 pages, 12 figures, accepted for publication in Phys. Rev.

The Role of Booster Vaccination and Ongoing Viral Evolution In Seasonal Circulation of SARS-CoV-2

Periodic resurgences of COVID-19 in the coming years can be expected, while public health interventions may be able to reduce their intensity. We used a transmission model to assess how the use of booster doses and non-pharmaceutical interventions (NPIs) amid ongoing pathogen evolution might influence future transmission waves. We find that incidence is likely to increase as NPIs relax, with a second seasonally driven surge expected in autumn 2022. However, booster doses can greatly reduce the intensity of both waves and reduce cumulative deaths by 20% between 7 January 2022 and 7 January 2023. Reintroducing NPIs during the autumn as incidence begins to increase again could also be impactful. Combining boosters and NPIs results in a 30% decrease in cumulative deaths, with potential for greater impacts if variant-adapted boosters are used. Reintroducing these NPIs in autumn 2022 as transmission rates increase provides similar benefits to sustaining NPIs indefinitely (307 000 deaths with indefinite NPIs and boosters compared with 304 000 deaths with transient NPIs and boosters). If novel variants with increased transmissibility or immune escape emerge, deaths will be higher, but vaccination and NPIs are expected to remain effective tools to decrease both cumulative and peak health system burden, providing proportionally similar relative impacts

The placental transport of [³H]vitamin K₁ in rats

In this paper we describe the placental transport of [3H]vitamin K1 in pregnant rats during the first 24 h after the oral administration of the vitamin. Vitamin K1 in the fetal livers ranged from 0.13% (3 h) to 2% (24 h) of the values found in the corresponding maternal livers. In spite of the low placental transfer of vitamin K, we found no accumulation of coagulation factor precursors in the fetal rat liver microsomes as could be expected in vitamin K deficiency. Moreover, we could not demonstrate any difference between adult and fetal rat liver microsomes with regard to the sensitivity for warfarin. From these results we conclude that a substantial placental barrier exists for the transport of pharmacological amounts of vitamin K1 but that under physiological conditions sufficient vitamin K1 appears to be present in the fetal liver to ensure a full carboxylation reaction. The vitamin K-dependent carboxylase activity rate of adult and fetal rat liver microsomes was comparable, indicating that the newborn rat has an adequate carboxylating system

Reconstruction of Black Hole Metric Perturbations from Weyl Curvature

Perturbation theory of rotating black holes is usually described in terms of Weyl scalars $\psi_4$ and $\psi_0$, which each satisfy Teukolsky's complex master wave equation and respectively represent outgoing and ingoing radiation. On the other hand metric perturbations of a Kerr hole can be described in terms of (Hertz-like) potentials $\Psi$ in outgoing or ingoing {\it radiation gauges}. In this paper we relate these potentials to what one actually computes in perturbation theory, i.e $\psi_4$ and $\psi_0$. We explicitly construct these relations in the nonrotating limit, preparatory to devising a corresponding approach for building up the perturbed spacetime of a rotating black hole. We discuss the application of our procedure to second order perturbation theory and to the study of radiation reaction effects for a particle orbiting a massive black hole.Comment: 6 Pages, Revtex