Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2014
Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li-Fraumeni cancer predisposition syndrome.
The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. ⋯ No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2014
Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases.
Brain stimulation, a therapy increasingly used for neurological and psychiatric disease, traditionally is divided into invasive approaches, such as deep brain stimulation (DBS), and noninvasive approaches, such as transcranial magnetic stimulation. The relationship between these approaches is unknown, therapeutic mechanisms remain unclear, and the ideal stimulation site for a given technique is often ambiguous, limiting optimization of the stimulation and its application in further disorders. In this article, we identify diseases treated with both types of stimulation, list the stimulation sites thought to be most effective in each disease, and test the hypothesis that these sites are different nodes within the same brain network as defined by resting-state functional-connectivity MRI. ⋯ A lack of functional connectivity identified sites where stimulation was ineffective, and the sign of the correlation related to whether excitatory or inhibitory noninvasive stimulation was found clinically effective. These results suggest that resting-state functional connectivity may be useful for translating therapy between stimulation modalities, optimizing treatment, and identifying new stimulation targets. More broadly, this work supports a network perspective toward understanding and treating neuropsychiatric disease, highlighting the therapeutic potential of targeted brain network modulation.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2014
Noble gases identify the mechanisms of fugitive gas contamination in drinking-water wells overlying the Marcellus and Barnett Shales.
Horizontal drilling and hydraulic fracturing have enhanced energy production but raised concerns about drinking-water contamination and other environmental impacts. Identifying the sources and mechanisms of contamination can help improve the environmental and economic sustainability of shale-gas extraction. We analyzed 113 and 20 samples from drinking-water wells overlying the Marcellus and Barnett Shales, respectively, examining hydrocarbon abundance and isotopic compositions (e.g., C2H6/CH4, δ(13)C-CH4) and providing, to our knowledge, the first comprehensive analyses of noble gases and their isotopes (e.g., (4)He, (20)Ne, (36)Ar) in groundwater near shale-gas wells. ⋯ Where fugitive gas contamination occurred, the relative proportions of thermogenic hydrocarbon gas (e.g., CH4, (4)He) were significantly higher (P < 0.01) and the proportions of atmospheric gases (air-saturated water; e.g., N2, (36)Ar) were significantly lower (P < 0.01) relative to background groundwater. Noble gas isotope and hydrocarbon data link four contamination clusters to gas leakage from intermediate-depth strata through failures of annulus cement, three to target production gases that seem to implicate faulty production casings, and one to an underground gas well failure. Noble gas data appear to rule out gas contamination by upward migration from depth through overlying geological strata triggered by horizontal drilling or hydraulic fracturing.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2014
Hemolysis-induced lethality involves inflammasome activation by heme.
The increase of extracellular heme is a hallmark of hemolysis or extensive cell damage. Heme has prooxidant, cytotoxic, and inflammatory effects, playing a central role in the pathogenesis of malaria, sepsis, and sickle cell disease. However, the mechanisms by which heme is sensed by innate immune cells contributing to these diseases are not fully characterized. ⋯ The activation of NLRP3 by heme required spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and K(+) efflux, whereas it was independent of heme internalization, lysosomal damage, ATP release, the purinergic receptor P2X7, and cell death. Importantly, our results indicated the participation of macrophages, NLRP3 inflammasome components, and IL-1R in the lethality caused by sterile hemolysis. Thus, understanding the molecular pathways affected by heme in innate immune cells might prove useful to identify new therapeutic targets for diseases that have heme release.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2014
Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade.
Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. ⋯ Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.