Case report of whole genome sequencing in the XY female: identification of a novel SRY mutation and revision of a misdiagnosis of androgen insensitivity syndrome

Background: The 46,XY female is characterised by a male karyotype and female phenotype arising due to any interruption in the sexual development pathways in utero. The cause is usually genetic and various genes are implicated. Case presentation: Herein we describe a 46,XY woman who was first diagnosed with androgen insensitivity syndrome (testicular feminisation) at 18 years; however, this was later questioned due to the presence of intact Müllerian structures. The clinical phenotype suggested several susceptibility genes including SRY, DHH, NR5A1, NR0B1, AR, AMH, and AMHR2. To study candidate genes simultaneously, we performed whole genome sequencing. This revealed a novel and likely pathogenic missense variant (p.Arg130Pro, c.389G>C) in SRY, one of the major genes implicated in complete gonadal dysgenesis, hence securing this condition over androgen insensitivity syndrome as the cause of the patient’s disorder of sexual development. Conclusion: This case highlights the emerging clinical utility of whole genome sequencing as a tool in differentiating disorders of sexual development.Sunita M. C. De Sousa, Karin S. Kassahn, Liam C. McIntyre, Chan-Eng Chong, Hamish S. Scott and David J. Torp

Characterization of the Positivity of the Density Matrix in Terms of the Coherence Vector Representation

A parameterization of the density operator, a coherence vector representation, which uses a basis of orthogonal, traceless, Hermitian matrices is discussed. Using this parameterization we find the region of permissible vectors which represent a density operator. The inequalities which specify the region are shown to involve the Casimir invariants of the group. In particular cases, this allows the determination of degeneracies in the spectrum of the operator. The identification of the Casimir invariants also provides a method of constructing quantities which are invariant under {\it local} unitary operations. Several examples are given which illustrate the constraints provided by the positivity requirements and the utility of the coherence vector parameterization.Comment: significantly rewritten and submitted for publicatio

Antiproton constraints on dark matter annihilations from internal electroweak bremsstrahlung

If the dark matter particle is a Majorana fermion, annihilations into two fermions and one gauge boson could have, for some choices of the parameters of the model, a non-negligible cross-section. Using a toy model of leptophilic dark matter, we calculate the constraints on the annihilation cross-section into two electrons and one weak gauge boson from the PAMELA measurements of the cosmic antiproton-to-proton flux ratio. Furthermore, we calculate the maximal astrophysical boost factor allowed in the Milky Way under the assumption that the leptophilic dark matter particle is the dominant component of dark matter in our Universe. These constraints constitute very conservative estimates on the boost factor for more realistic models where the dark matter particle also couples to quarks and weak gauge bosons, such as the lightest neutralino which we also analyze for some concrete benchmark points. The limits on the astrophysical boost factors presented here could be used to evaluate the prospects to detect a gamma-ray signal from dark matter annihilations at currently operating IACTs as well as in the projected CTA.Comment: 32 pages; 13 figure

Tight Beltrami fields with symmetry

Let $M$ be a compact orientable Seifered fibered 3-manifold without a boundary, and $\alpha$ an $S^1$-invariant contact form on $M$. In a suitable adapted Riemannian metric to $\alpha$, we provide a bound for the volume $\text{Vol}(M)$ and the curvature, which implies the universal tightness of the contact structure $\xi=\ker\alpha$.Comment: 26 page

Benzylmorpholine analogs as selective inhibitors of lung cytochrome P450 2A13 for the chemoprevention of lung cancer in tobacco users

Purpose: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. Methods: Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is a major challenge in compound design. Results: A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. Conclusions: Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure

Experiences with Modelling Issues in Building Probabilistic Networks

Abstract. Building a probabilistic network for a real-life application is a difficult and time-consuming task. Methodologies for building such a network, however, are still lacking. Also, literature on network-specific modelling issues is quite scarce. As we have developed a large proba-bilistic network for a complex medical domain, we have encountered and resolved numerous non-trivial modelling issues. Since many of these is-sues pertain not only to our application but are likely to emerge for other applications as well, we feel that sharing them will contribute to engineering probabilistic networks in general.

Active Galaxies in the UV

In this article we present different aspects of AGN studies demonstrating the importance of the UV spectral range. Most important diagnostic lines for studying the general physical conditions as well as the metalicities in the central broad line region in AGN are emitted in the UV. The UV/FUV continuum in AGN excites not only the emission lines in the immediate surrounding but it is responsible for the ionization of the intergalactic medium in the early stages of the universe. Variability studies of the emission line profiles of AGN in the UV give us information on the structure and kinematics of the immediate surrounding of the central supermassive black hole as well as on its mass itself.Comment: 29 pages, 13 figures, Ap&SS in pres

On non-local variational problems with lack of compactness related to non-linear optics

We give a simple proof of existence of solutions of the dispersion manage- ment and diffraction management equations for zero average dispersion, respectively diffraction. These solutions are found as maximizers of non-linear and non-local vari- ational problems which are invariant under a large non-compact group. Our proof of existence of maximizer is rather direct and avoids the use of Lions' concentration compactness argument or Ekeland's variational principle.Comment: 30 page

A place-based approach to payments for ecosystem services

Payment for Ecosystem Services (PES) schemes are proliferating but are challenged by insufficient attention to spatial and temporal inter-dependencies, interactions between different ecosystems and their services, and the need for multi-level governance. To address these challenges, this paper develops a place-based approach to the development and implementation of PES schemes that incorporates multi-level governance, bundling or layering of services across multiple scales, and shared values for ecosystem services. The approach is evaluated and illustrated using case study research to develop an explicitly place-based PES scheme, the Peatland Code, owned and managed by the International Union for the Conservation of Nature’s UK Peatland Programme and designed to pay for restoration of peatland habitats. Buyers preferred bundled schemes with premium pricing of a primary service, contrasting with sellers’ preferences for quantifying and marketing services separately in a layered scheme. There was limited awareness among key business sectors of dependencies on ecosystem services, or the risks and opportunities arising from their management. Companies with financial links to peatlands or a strong environmental sustainability focus were interested in the scheme, particularly in relation to climate regulation, water quality, biodiversity and flood risk mitigation benefits. Visitors were most interested in donating to projects that benefited wildlife and were willing to donate around £2 on-site during a visit. Sellers agreed a deliberated fair price per tonne of CO2 equivalent from £11.18 to £15.65 across four sites in Scotland, with this range primarily driven by spatial variation in habitat degradation. In the Peak District, perceived declines in sheep and grouse productivity arising from ditch blocking led to substantially higher prices, but in other regions ditch blocking was viewed more positively. The Peatland Code was developed in close collaboration with stakeholders at catchment, landscape and national scales, enabling multi-level governance of the management and delivery of ecosystem services across these scales. Place-based PES schemes can mitigate negative trade-offs between ecosystem services, more effectively include cultural ecosystem services and engage with and empower diverse stakeholders in scheme design and governance

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

BACKGROUND: PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. METHODS: Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. RESULTS: We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. CONCLUSION: Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype