Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy

Background: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. Case presentation: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. Conclusions: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies

Urban informality and confinement: toward a relational framework

In the 21st century, a growing number of people live ‘informal’ lives within fissures between legality and informality. Concomitantly, power relations are increasingly expressed through devices of confinement. While urban informality and confinement are on the rise often occurring simultaneously, scholars have so far studied them separately. By contrast, this article proposes a new framework for analysing urban informality and confinement relationally. It generates new insights into the role of informality in the (re)production of confinement and, vice versa, the role of confinement in shaping informal practices. While these insights are valuable for urban studies in general, the article charts new lines of research on urban marginality. It also discusses how the six articles included in this special issue signal the heuristic potential of this relational framework by empirically examining distinct urban configurations of ‘confined informalities’ and ‘informal confinements’ across the Global North and the Global South

Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques.

Herpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study host-HSV-2 interactions, an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333, and/or G) at a total dose of 1 × 107 PFU of HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA were consistently shed in vaginal swabs for the first 7 to 14 days after each inoculation. Proteins associated with wound healing, innate immunity, and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. There was histologic evidence of acute herpesvirus pathology, including acantholysis in the squamous epithelium and ballooning degeneration of and intranuclear inclusion bodies in epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. Further, an intense inflammatory infiltrate was found in the cervix and vulva. Evidence of latent infection and reactivation was demonstrated by the detection of spontaneous HSV-2 shedding post-acute inoculation (102 to 103 DNA copies/swab) in 80% of RM. Further, HSV-2 DNA was detected in ganglia in most necropsied animals. HSV-2-specifc T-cell responses were detected in all animals, although antibodies to HSV-2 were detected in only 30% of the animals. Thus, HSV-2 infection of RM recapitulates many of the key features of subclinical HSV-2 infection in women but seems to be more limited, as virus shedding was undetectable more than 40 days after the last virus inoculation.IMPORTANCE Herpes simplex virus 2 (HSV-2) infects nearly 500 million persons globally, with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus type 1 (HIV-1) acquisition, and this risk does not decline with the use of antiherpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study of the initial molecular interactions of the two agents requires an animal model. We found that HSV-2 can infect RM after vaginal inoculation, establish latency in the nervous system, and spontaneously reactivate; these features mimic some of the key features of HSV-2 infection in women. RM may provide an animal model to develop strategies to prevent HSV-2 acquisition and reactivation

Why are scientists not managers!?:the importance of interdisciplinary skills in business and science

Research is the translation from money to knowledge. Innovation is the metamorphosis of knowledge to money. Thus, business management and science are interdependent. That is no big news. But, in an ever faster changing economy, companies need a new type of scientist. Someone who knows not only science, but also business administration and management. Can the educational system satisfy those needs? In our opinion more work needs to be done – especially in the minds of scientists and managers alike

Precision measurement of the neutron β-decay asymmetry

A new measurement of the neutron β-decay asymmetry A_0 has been carried out by the UCNA Collaboration using polarized ultracold neutrons (UCNs) from the solid deuterium UCN source at the Los Alamos Neutron Science Center. Improvements in the experiment have led to reductions in both statistical and systematic uncertainties leading to A_0=−0.11954(55)_(stat)(98)_(syst), corresponding to the ratio of axial-vector to vector coupling λ ≡ g_A/g_V = −1.2756(30)

MeV-mass dark matter and primordial nucleosynthesis

The annihilation of new dark matter candidates with masses $m_X$ in the MeV range may account for the galactic positrons that are required to explain the 511 keV $\gamma$-ray flux from the galactic bulge. We study the impact of MeV-mass thermal relic particles on the primordial synthesis of $^2$H, $^4$He, and $^7$Li. If the new particles are in thermal equilibrium with neutrinos during the nucleosynthesis epoch they increase the helium mass fraction for m_X\alt 10 MeV and are thus disfavored. If they couple primarily to the electromagnetic plasma they can have the opposite effect of lowering both helium and deuterium. For $m_X=4$--10 MeV they can even improve the overall agreement between the predicted and observed $^2$H and $^4$He abundances.Comment: 11 pages, 10 figures, references and two appendices added, conclusions unchanged; accepted for publication in Phys.Rev.

First direct constraints on Fierz interference in free-neutron β decay

Precision measurements of free-neutron β decay have been used to precisely constrain our understanding of the weak interaction. However, the neutron Fierz interference term b_n, which is particularly sensitive to beyond-standard-model tensor currents at the TeV scale, has thus far eluded measurement. Here we report the first direct constraints on this term, finding b_n=0.067±0.005_(stat)^(+0.090)_(−0.061)_(sys), consistent with the standard model. The uncertainty is dominated by absolute energy reconstruction and the linearity of the β spectrometer energy response