Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2015
Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication.
Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared with other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3) enables the cells normally unsusceptible to RV-C infection to support both virus binding and replication. ⋯ We developed a transduced HeLa cell line (HeLa-E8) stably expressing CDHR3-Y529 that supports RV-C propagation in vitro. Modeling of CDHR3 structure identified potential binding sites that could impact the virus surface in regions that are highly conserved among all RV-C types. Our findings identify that the asthma susceptibility gene product CDHR3 mediates RV-C entry into host cells, and suggest that rs6967330 mutation could be a risk factor for RV-C wheezing illnesses.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2015
National hiring experiments reveal 2:1 faculty preference for women on STEM tenure track.
National randomized experiments and validation studies were conducted on 873 tenure-track faculty (439 male, 434 female) from biology, engineering, economics, and psychology at 371 universities/colleges from 50 US states and the District of Columbia. In the main experiment, 363 faculty members evaluated narrative summaries describing hypothetical female and male applicants for tenure-track assistant professorships who shared the same lifestyle (e.g., single without children, married with children). Applicants' profiles were systematically varied to disguise identically rated scholarship; profiles were counterbalanced by gender across faculty to enable between-faculty comparisons of hiring preferences for identically qualified women versus men. ⋯ In two validation studies, 35 engineering faculty provided rankings using full curricula vitae instead of narratives, and 127 faculty rated one applicant rather than choosing from a mixed-gender group; the same preference for women was shown by faculty of both genders. These results suggest it is a propitious time for women launching careers in academic science. Messages to the contrary may discourage women from applying for STEM (science, technology, engineering, mathematics) tenure-track assistant professorships.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2015
MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome.
Epigenetic mechanisms, such as DNA methylation, regulate transcriptional programs to afford the genome flexibility in responding to developmental and environmental cues in health and disease. A prime example involving epigenetic dysfunction is the postnatal neurodevelopmental disorder Rett syndrome (RTT), which is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 regulates transcription or why RTT features appear 6-18 months after birth. ⋯ This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level of Bdnf, a gene implicated in the pathophysiology of RTT. This study thus provides insight into the molecular mechanism governing MeCP2 targeting and sheds light on the delayed onset of RTT symptoms.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2015
Asphyxia-activated corticocardiac signaling accelerates onset of cardiac arrest.
The mechanism by which the healthy heart and brain die rapidly in the absence of oxygen is not well understood. We performed continuous electrocardiography and electroencephalography in rats undergoing experimental asphyxia and analyzed cortical release of core neurotransmitters, changes in brain and heart electrical activity, and brain-heart connectivity. ⋯ Blocking the brain's autonomic outflow significantly delayed terminal ventricular fibrillation and lengthened the duration of detectable cortical activities despite the continued absence of oxygen. These results demonstrate that asphyxia activates a brainstorm, which accelerates premature death of the heart and the brain.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2015
Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis.
Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32γ gene is expressed using the surfactant protein C promoter (SPC-IL-32γTg). Wild-type and SPC-IL-32γTg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). ⋯ Furthermore, mouse macrophages made to express IL-32γ but not the splice variant IL-32β were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32γ enhances host immunity to MTB.