The rockefeller university

Early co-transcriptional events during eukaryotic ribosome assembly result in the formation of precursors of the small (40S) and large (60S) ribosomal subunits1. A multitude of transient assembly factors regulate and chaperone the systematic folding of pre-ribosomal RNA subdomains. However, owing to a lack of structural information, the role of these factors during early nucleolar 60S assembly is not fully understood. Here we report cryo-electron microscopy (cryo-EM) reconstructions of the nucleolar pre-60S ribosomal subunit in different conformational states at resolutions of up to 3.4 angstrom. These reconstructions reveal how steric hindrance and molecular mimicry are used to prevent both premature folding states and binding of later factors. This is accomplished by the concerted activity of 21 ribosome assembly factors that stabilize and remodel pre-ribosomal RNA and ribosomal proteins. Among these factors, three Brix-domain proteins and their binding partners form a ring-like structure at ribosomal RNA (rRNA) domain boundaries to support the architecture of the maturing particle. The existence of mutually exclusive conformations of these pre-60S particles suggests that the formation of the polypeptide exit tunnel is achieved through different folding pathways during subsequent stages of ribosome assembly. These structures rationalize previous genetic and biochemical data and highlight the mechanisms that drive eukaryotic ribosome assembly in a unidirectional manner.

A search is reported for heavy resonances decaying into e mu final states in proton-proton collisions recorded by the CMS experiment at the CERN LHC at root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). The search focuses on resonance masses above 200 GeV. With no evidence found for physics beyond the standard model in the e mu mass spectrum, upper limits are set at 95% confidence level on the product of the cross section and branching fraction for this lepton-flavor violating signal. Based on these results, resonant tau sneutrino production in R-parity violating supersymmetric models is excluded for masses below 1.7 TeV, for couplings lambda(132) = lambda(231) = lambda(311) = 0.01. Heavy Z' gauge bosons with lepton-flavor violating transitions are excluded for masses up to 4.4 TeV. The eit mass spectrum is also interpreted in terms of non-resonant contributions from quantum black-hole production in models with one to six extra spatial dimensions, and lower mass limits are found between 3.6 and 5.6 TeV. In all interpretations used in this analysis, the results of this search improve previous limits by about 1 TeV. These limits correspond to the most sensitive values obtained at colliders.

Impacts of steroid stress hormones on the brain have provided multiple opportunities for linking specific molecular phenomena to behavioral state. The negative impacts of stress on female reproductive biological processes have been documented thoroughly at the endocrine and behavioral levels. More recently, a '3-hit' theory of autism has identified early stress as one of the hits. The multiple biochemical effects of endotoxin (lipopolysaccharide, LPS) indicated that it would serve as a powerful maternal immune activator. The prenatal exposure to LPS coupled with the other two 'hits% an autism-related mutation and the Y chromosome - - heightened certain autism -like signs in mouse behavior.

Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling. We show that short-term suppression of PRC2 precludes TCR-driven T cell activation in vitro. We also demonstrate that pharmacological inhibition of PRC2 in vivo greatly attenuates the severe T cell-driven autoimmunity caused by regulatory T cell depletion. Our data reveal cytoplasmic PRC2 is one of the most potent regulators of T cell activation and point toward the therapeutic potential of PRC2 inhibitors for the treatment of T cell-driven autoimmune diseases.

Median arcuate ligament (MAL) syndrome is a rare and poorly known cause of abdominal pain. MAL narrows the celiac artery (CA), resulting in true distal aneurysms, including pancreaticoduodenal artery (PDA) aneurysms. These aneurysms often have an aggressive course, as rupture can result in hemorrhagic shock. CT scan appears to be the most effective investigation for the diagnosis of PDA aneurysms and may reveal possible celiac artery compression. In this series, we describe four cases of PDA aneurysm: two ruptured aneurysms treated by an endovascular procedure and two non-ruptured aneurysms treated by surgery. It was also decided to treat CA stenosis in three of the four patients based on the clinical presentation (ruptured or non-ruptured) and the presence of peripancreatic collateral vessels on imaging. This strategy contrasts with the approach commonly reported in the literature, in which MAL section is mandatory due to the high risk of ischemia rather than the potential risk of recurrent aneurysm. Medical teams should be aware of this disease to improve diagnosis and patient management.

A search is presented for the production of vector-like quark pairs, T (T) over bar or Y (Y) over bar, with electric charge of 2/3(T) or -4/3(Y), in proton-proton collisions at root s= 13 TeV. The data were collected by the CMS experiment at the LHC in 2016 and correspond to an integrated luminosity of 35.8 fb(-1). The T and Y quarks are assumed to decay exclusively to a W boson and a b quark. The search is based on events with a single isolated electron or muon, large missing transverse momentum, and at least four jets with large transverse momenta. In the search, a kinematic reconstruction of the final state observables is performed, which would permit a signal to be detected as a narrow mass peak (approximate to 7% resolution). The observed number of events is consistent with the standard model prediction. Assuming strong pair production of the vector-like quarks and a 100% branching fraction to bW, a lower limit of 1295 GeV at 95% confidence level is set on the T and Y quark masses. (c) 2018 The Author(s). Published by Elsevier B.V.

Patients with high-grade serous ovarian carcinoma ( HGSC) exhibit poor 5-year survival rates, which may be significantly improved by early-stage detection. The U.S. Food and Drug Administration-approved biomarkers for HGSC-CA-125 (cancer antigen 125) and HE4 (human epididymis protein 4)-do not generally appear at detectable levels in the serum until advanced stages of the disease. An implantable device placed proximal to disease sites, such as in or near the fallopian tube, ovary, uterine cavity, or peritoneal cavity, may constitute a feasible strategy to improve detection of HGSC. We engineered a prototype optical sensor composed of an antibody-functionalized carbon nanotube complex, which responds quantitatively to HE4 via modulation of the nanotube optical bandgap. The complexes measured HE4 with nanomolar sensitivity to differentiate disease from benign patient biofluids. The sensors were implanted into four models of ovarian cancer, within a semipermeable membrane, enabling the optical detection of HE4 within the live animals. We present the first in vivo optical nanosensor capable of noninvasive cancer biomarker detection in orthotopic models of disease.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1-master regulators of carbohydrate metabolic subtypesmodulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.

Increasing our understanding of Earth's biodiversity and responsibly stewarding its resources are among the most crucial scientific and social challenges of the new millennium. These challenges require fundamental new knowledge of the organization, evolution, functions, and interactions among millions of the planet's organisms. Herein, we present a perspective on the Earth BioGenome Project (EBP), a moonshot for biology that aims to sequence, catalog, and characterize the genomes of all of Earth's eukaryotic biodiversity over a period of 10 years. The outcomes of the EBP will inform a broad range of major issues facing humanity, such as the impact of climate change on biodiversity, the conservation of endangered species and ecosystems, and the preservation and enhancement of ecosystem services. We describe hurdles that the project faces, including data-sharing policies that ensure a permanent, freely available resource for future scientific discovery while respecting access and benefit sharing guidelines of the Nagoya Protocol. We also describe scientific and organizational challenges in executing such an ambitious project, and the structure proposed to achieve the project's goals. The far-reaching potential benefits of creating an open digital repository of genomic information for life on Earth can be realized only by a coordinated international effort.

The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. During its assembly in the nucleolus, many ribosome biogenesis factors, an RNA chaperone, and ribosomal proteins associate with the nascent pre-rRNA. Biochemical studies have elucidated the rRNA-subdomain dependent recruitment of these factors during SSU processome assembly and have been complemented by structural studies of the assembled particle. Ribosome biogenesis factors encapsulate and guide subdomains of preribosomal RNA in distinct compartments. This prevents uncoordinated maturation and enables processing of regions not accessible in the mature subunit. By sequentially reducing conformational freedom, flexible proteins facilitate the incorporation of dynamic subcomplexes into a globular particle. Large rearrangements within the SSU processome are required for compaction into the mature small ribosomal subunit.