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Transforming growth factor-beta 1 (TGF-beta 1) has been used as a biomarker in disorders associated with pathologic fibrosis. However, plasma TGF-beta 1 assessment is confounded by the significant variation in reported normal values, likely reflecting variable release of the large pool of platelet TGF-beta 1 after blood drawing. Moreover, current assays measure only total TGF-beta 1, which is dominated by the latent form of TGF-beta 1 rather than the biologically active form. To address these challenges, we developed methodologies to prevent ex vivo release of TGF-beta 1 and to quantify active TGF-beta 1. We then used these techniques to measure TGF-beta 1 in healthy controls and patients with heart failure (HF) before and after insertion of left ventricular assist devices (LVAD). Total plasma TGF-beta 1 was 1.0 +/- 0.60 ng/mL in controls and 3.76 +/- 1.55ng/mL in subjects with HF (P < 0.001), rising to 5.2 +/- 2.3 ng/mL following LVAD placement (P = 0.006). These results were paralleled by the active TGF-beta 1 values; controls had 3-16 pg/mL active TGF-beta 1, whereas levels were 2.7-fold higher in patients with HF before, and 4.2-fold higher after, LVAD implantation. Total TGF-beta 1 correlated with levels of the platelet-derived protein thrombospondin-1 (r = 0.87; P < 0.001), suggesting that plasma TGF-beta 1 may serve as a surrogate indicator of in vivo platelet activation. von Willebrand factor high molecular weight multimers correlated inversely with TGF-beta 1 levels (r = -0.63; P = 0.023), suggesting a role for shear forces in loss of these multimers and platelet activation. In conclusion, accurate assessment of circulating TGF-beta 1 may provide a valuable biomarker for in vivo platelet activation and thrombotic disorders.

When viewing social scenes, humans and nonhuman primates focus on particular features, such as the models' eyes, mouth, and action targets. Previous studies reported that such viewing patterns vary significantly across individuals in humans, and also across closely-related primate species. However, the nature of these individual and species differences remains unclear, particularly among nonhuman primates. In large samples of human and nonhuman primates, we examined species differences and the effects of experience on patterns of gaze toward social movies. Experiment 1 examined the species differences across rhesus macaques, nonhuman apes (bonobos, chimpanzees, and orangutans), and humans while they viewed movies of various animals' species-typical behaviors. We found that each species had distinct viewing patterns of the models' faces, eyes, mouths, and action targets. Experiment 2 tested the effect of individuals' experience on chimpanzee and human viewing patterns. We presented movies depicting natural behaviors of chimpanzees to three groups of chimpanzees (individuals from a zoo, a sanctuary, and a research institute) differing in their early social and physical experiences. We also presented the same movies to human adults and children differing in their expertise with chimpanzees (experts vs. novices) or movie-viewing generally (adults vs. preschoolers). Individuals varied within each species in their patterns of gaze toward models' faces, eyes, mouths, and action targets depending on their unique individual experiences. We thus found that the viewing patterns for social stimuli are both individual-and species-specific in these closely-related primates. Such individual/species-specificities are likely related to both individual experience and species-typical temperament, suggesting that primate individuals acquire their unique attentional biases through both ontogeny and evolution. Such unique attentional biases may help them learn efficiently about their particular social environments.

A search for new physics is presented in final states with two oppositely charged leptons (electrons or muons), jets identified as originating from b quarks, and missing transverse momentum (p(T)(miss)). The search uses proton-proton collision data at root s = 13 TeV amounting to 35.9 fb(-1) of integrated luminosity collected using the CMS detector in 2016. Hypothetical signal events are efficiently separated from the dominant t (t) over bar background with requirements on p(T)(miss) and transverse-mass variables. No significant deviation is observed from the expected background. Exclusion limits are set in the context of simplified supersymmetric models with pair-produced top squarks. For top squarks, decaying exclusively to a top quark and a neutralino, exclusion limits are placed at 95% confidence level on the mass of the lightest top squark up to 800 GeVand on the lightest neutralino up to 360 GeV. These results, combined with searches in the single-lepton and all-jet final states, raise the exclusion limits up to 1050 GeV for the lightest top squark and up to 500 GeV for the lightest neutralino. For top squarks undergoing a cascade decay through charginos and sleptons, the mass limits reach up to 1300 GeV for top squarks and up to 800 GeV for the lightest neutralino. The results are also interpreted in a simplified model with a dark matter (DM) particle coupled to the top quark through a scalar or pseudoscalar mediator. For light DM, mediator masses up to 100 (50) GeV are excluded for scalar (pseudoscalar) mediators. The result for the scalar mediator achieves some of the most stringent limits to date in this model.

MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. This promotes ERK1/2 phosphorylation, resulting in augmented cell growth and reduced apoptosis. Our findings thus empirically define the integral role of translational repression in miRNA-induced gene silencing and reveal a critical function for this process in the control of the ERK signaling cascade in mammalian cells.

Uveal melanoma (UM) is characterized by mutually exclusive activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4, four genes in a linear pathway to activation of PLC beta in almost all tumors and loss of BAP1 in the aggressive subset. We generated mice with melanocyte-specific expression of GNA11(Q209L) with and without homozygous Bap1 loss. The GNA11(Q209L) mice recapitulated human Gq-associated melanomas, and they developed pigmented neoplastic lesions from melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as at atypical sites, including the lymph nodes and lungs. The addition of Bap1 loss increased tumor proliferation and cutaneous melanoma size. Integrative transcriptome analysis of human and murine melanomas identified RasGRP3 to be specifically expressed in GNAQ/GNA11-driven melanomas. In human UM cell lines and murine models, RasGRP3 is specifically required for GNAQ/GNA11-driven Ras activation and tumorigenesis. This implicates RasGRP3 as a critical node and a potential target in UM.

The cyclin-dependent kinase CDK1 is essential for mitosis in fungi and animals. Plant genomes contain the CDK1 ortholog CDKA and a plant kingdom-specific relative, CDKB. The green alga Chlamydomonas reinhardtii has a long G1 growth period followed by rapid cycles of DNA replication and cell division. We show that null alleles of CDKA extend the growth period prior to the first division cycle and modestly extend the subsequent division cycles, but do not prevent cell division, indicating at most a minor role for the CDK1 ortholog in mitosis in Chlamydomonas. A null allele of cyclin A has a similar though less extreme phenotype. In contrast, both CDKB and cyclin B are essential for mitosis. CDK kinase activity measurements imply that the predominant in vivo complexes are probably cyclin A-CDKA and cyclin B-CDKB. We propose a negative feedback loop: CDKA activates cyclin B-CDKB. Cyclin B-CDKB in turn promotes mitotic entry and inactivates cyclin A-CDKA. Cyclin A-CDKA and cyclin B-CDKB may redundantly promote DNA replication. We show that the anaphase-promoting complex is required for inactivation of both CDKA and CDKB and is essential for anaphase. These results are consistent with findings in Arabidopsis thaliana and may delineate the core of plant kingdom cell cycle control that, compared with the well-studied yeast and animal systems, exhibits deep conservation in some respects and striking divergence in others.

Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutieres syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and beta-amyloid (A beta), a hallmark pathological protein in AD, induces plasmin-resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since A beta oligomers have a much stronger affinity for fibrinogen than A beta monomers, we tested whether amyloid aggregation inhibitors could block the A beta-fibrinogen interaction and found that some A beta aggregation inhibitors showed moderate inhibitory efficacy against this interaction. We then modified a hit compound so that it not only showed a strong inhibitory efficacy toward the A beta-fibrinogen interaction but also retained its potency toward the A beta 42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated A beta 42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the A beta-fibrinogen interaction and A beta-aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as A beta aggregation-driven pathology in AD.