BACKGROUND We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia — phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.)

Summary Induced pluripotent stem (iPS) cells can be obtained from fibroblasts upon expression of Oct4, Sox2, Klf4 and c-Myc. To understand how these factors induce pluripotency, we carried out genome-wide analyses of their promoter binding and expression in iPS and partially reprogrammed cells. We find that target genes of the four factors strongly overlap in iPS and embryonic stem (ES) cells. In partially reprogrammed cells, many genes co-occupied by c-Myc and any of the other three factors already show an ES-like binding and expression pattern. In contrast, genes that are specifically co-bound by Oct4, Sox2 and Klf4 in ES cells and encode pluripotency regulators severely lack binding and transcriptional activation. Among the four factors, c-Myc promotes the most ES cell-like transcription pattern when expressed individually in fibroblasts. These data uncover temporal and separable contributions of the four factors during the reprogramming process and indicate that ectopic c-Myc predominantly acts before pluripotency regulators are activated.

(2017), Smaller desert dust cooling effect estimated from analysis of desert dust size and abundance, Nature Geoscience,10,[274][275][276][277][278] Desert dust aerosols affect Earth's global energy balance through direct interactions with radiation, and through indirect interactions with clouds and ecosystems. But the magnitudes of these effects are so uncertain that it remains unclear whether atmospheric dust has a net warming or cooling effect on global climate. Consequently, it is still uncertain whether large changes in atmospheric dust loading over the past century have slowed or accelerated anthropogenic climate change, or what the effects of potential future changes in dust loading will be. Here we present an analysis of the size and abundance of dust aerosols to constrain the direct radiative effect of dust. Using observational data on dust abundance, in situ measurements of dust optical properties and size distribution, and climate and atmospheric chemical transport model simulations of dust lifetime, we find that the dust found in the atmosphere is substantially coarser than represented in current global climate models. Since coarse dust warms climate, the global dust direct radiative effect is likely to be less cooling than the ~-0.4 W/m 2 estimated by models in a current global aerosol model ensemble. Instead, we constrain the dust direct radiative effect to a range between -0.48 and +0.20 W/m 2 , which includes the possibility that dust causes a net warming of the planet.The direct radiative effect (DRE) of desert dust aerosols on global climate depends sensitively on both the size distribution and atmospheric abundance of dust 1-3 . However, current global model estimates of the atmospheric loading of dust with geometric diameter D ≤ 10 µm (PM10) vary widely from ~6 to 30 Tg [4][5][6][7] . Similarly, the size distribution of atmospheric dust varies substantially across models, with the fraction of dust in the clay size range (D ≤ 2 µm) varying by over a factor of three 8 . This uncertainty in dust size and abundance is partially driven by a critical limitation of global models: the need to prescribe poorly known attributes of dust particles. In particular, the assumed dust optical properties and size distribution at emission greatly affect the resultant size-resolved dust loading 1,6 . Each model parameterizes these properties differently, and in a manner not always consistent with experimental results [8][9][10] . This divergence in assumed dust properties contributes to a wide range of estimates of the sizeresolved global dust loading 6,8 . Because fine dust cools global climate whereas coarse dust (D ≥ 5 μm) likely warms it 3 , this uncertainty in size-resolved dust loading contributes to a wide spread in model estimates of the dust DRE 1,3,9,[11][12][13][14] . Since the use of global models alone is thus unlikely to substantially narrow the uncertainty on dust climate effects 15 , we develop an alternative approach to determine the size-resolved global dust loading, which we subsequently use ...

Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity1. Herein we describe a new syndrome caused by high penetrance heterozygous germline mutations in the NFκB regulatory protein TNFAIP3 (A20) in six unrelated families with early onset systemic inflammation. The syndrome resembles Behçet’s disease (BD), which is typically considered a polygenic disorder with onset in early adulthood2. A20 is a potent inhibitor of the NFκB signaling pathway3. TNFAIP3 mutant truncated proteins are likely to act by haploinsufficiency since they do not exert a dominant-negative effect in overexpression experiments. Patients’ cells show increased degradation of IκBα and nuclear translocation of NFκB p65, and increased expression of NFκB-mediated proinflammatory cytokines. A20 restricts NFκB signals via deubiquitinating (DUB) activity. In cells expressing the mutant A20 protein, there is defective removal of K63-linked ubiquitin from TRAF6, NEMO, and RIP1 after TNF stimulation. NFκB-dependent pro-inflammatory cytokines are potential therapeutic targets for these patients.

Next-generation sequencing has greatly increased the scope and the resolution of transcriptional regulation study. RNA sequencing (RNA-Seq) and ChIP-Seq experiments are now generating comprehensive data on transcript abundance and on regulator-DNA interactions. We propose an approach for an integrated analysis of these data based on feature extraction of ChIP-Seq signals, principal component analysis, and regression-based component selection. Compared with traditional methods, our approach not only offers higher power in predicting gene expression from ChIP-Seq data but also provides a way to capture cooperation among regulators. In mouse embryonic stem cells (ESCs), we find that a remarkably high proportion of variation in gene expression (65%) can be explained by the binding signals of 12 transcription factors (TFs). Two groups of TFs are identified. Whereas the first group (E2f1, Myc, Mycn, and Zfx) act as activators in general, the second group (Oct4, Nanog, Sox2, Smad1, Stat3, Tcfcp2l1, and Esrrb) may serve as either activator or repressor depending on the target. The two groups of TFs cooperate tightly to activate genes that are differentially up-regulated in ESCs. In the absence of binding by the first group, the binding of the second group is associated with genes that are repressed in ESCs and derepressed upon early differentiation.ChIP binding ͉ pluripotency ͉ RNA-Seq ͉ transcription regulation