The rockefeller university

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of primary liver cancer that affects adolescents and young adults without underlying liver disease. Surgery remains the mainstay of therapy; however, most patients are either not surgical candidates or suffer from recurrence. There is no approved systemic therapy and the overall survival remains poor. Historically classified as a subtype of hepatocellular carcinoma (HCC), FLC has a unique clinical, histological, and molecular presentation. At the genomic level, FLC contains a single 400kB deletion in chromosome 19, leading to a functional DNAJB1-PRKACA fusion protein. In this review, we detail the recent advances in our understanding of the molecular underpinnings of FLC and outline the current knowledge gaps.

A search for standard model production of four top quarks (t (t) over bart (t) over bar) is reported using events containing at least three leptons (e, mu) or a same-sign lepton pair. The events are produced in proton-proton collisions at a center-of-mass energy of 13 TeVat the LHC, and the data sample, recorded in 2016, corresponds to an integrated luminosity of 35.9 fb(-1). Jet multiplicity and flavor are used to enhance signal sensitivity, and dedicated control regions are used to constrain the dominant backgrounds. The observed and expected signal significances are, respectively, 1.6 and 1.0 standard deviations, and the t (t) over bart (t) over bar cross section ismeasured to be 16.9(-11.4)(+13.8) fb, in agreement with next-to-leading-order standard model predictions. These results are also used to constrain the Yukawa coupling between the top quark and the Higgs boson to be less than 2.1 times its expected standard model value at 95% confidence level.

Nearly all eukaryotic messenger RNA precursors must undergo cleavage and polyadenylation at their 3'-end for maturation. A crucial step in this process is the recognition of the AAUAAA polyadenylation signal (PAS), and the molecular mechanism of this recognition has been a long-standing problem. Here, we report the cryo-electron microscopy structure of a quaternary complex of human CPSF-160, WDR33, CPSF-30, and an AAUAAA RNA at 3.4-angstrom resolution. Strikingly, the AAUAAA PAS assumes an unusual conformation that allows this short motif to be bound directly by both CPSF-30 and WDR33. The A1 and A2 bases are recognized specifically by zinc finger 2 (ZF2) of CPSF-30 and the A4 and A5 bases by ZF3. Interestingly, the U3 and A6 bases form an intramolecular Hoogsteen base pair and directly contact WDR33. CPSF-160 functions as an essential scaffold and preorganizes CPSF-30 and WDR33 for high-affinity binding to AAUAAA. Our findings provide an elegant molecular explanation for how PAS sequences are recognized for mRNA 3'-end formation.

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.

Results are reported from a search for new physics in 13 TeV proton-proton collisions in the final state with large missing transverse momentum and two Higgs bosons decaying via H -> b(b)over bar. The search uses a data sample accumulated by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 35.9 fb(-1). The search is motivated by models based on gauge-mediated supersymmetry breaking, which predict the electroweak production of a pair of Higgsinos, each of which can decay via a cascade process to a Higgs boson and an undetected lightest supersymmetric particle. The observed event yields in the signal regions are consistent with the standard model background expectation obtained from control regions in data. Higgsinos in the mass range 230-770 GeV are excluded at 95% confidence level in the context of a simplified model for the production and decay of approximately degenerate Higgsinos.

In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed.

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.

Polymorphisms at IFNL4 strongly influence spontaneous resolution and interferon therapeutic response in hepatitis C virus (HCV) infection. In chronic HCV, unfavorable alleles are associated with elevated interferon (IFN)-stimulated gene (ISG) expression in the liver, but extrahepatic effects are less well characterized. We used RNA sequencing (RNA-Seq) to examine whether IFNL4 genetic variation (rs368234815) modulates ISG expression in peripheral blood mononuclear cells (PBMC) during chronic HCV infection. ISG expression was elevated in unstimulated PBMC homozygous for the unfavorable Delta G IFNL4 variant; expression following IFN-alpha stimulation was comparable across genotypes. These findings suggest that lambda interferons may have broader systemic effects during HCV infection.

To ensure their sensitivity to weak periodic signals, some physical systems likely operate near a Hopf bifurcation. Many systems operating near such a bifurcation exhibit stochastic resonance, but it is unclear which mechanisms for resonance are inherent to the bifurcation. To address this question, we study the sinusoidally forced dynamics of noisy supercritical and subcritical Hopf oscillators. We find four qualitatively different mechanisms for stochastic resonance and determine the conditions for each type of resonance.