The rockefeller university

Recent reports have revealed myelodysplastic syndromes (MDS) to arise from cancer stem cells phenotypically similar to physiological hematopoietic stem cells. Myelodysplastic hematopoiesis maintains a hierarchical organization, but the proportion of several hematopoietic compartments is skewed and multiple surface markers are aberrantly expressed. These aberrant antigen expression patterns hold diagnostic and therapeutic promise. However, eradication of MDS requires targeting of early myelodysplasia propagating stem cells. This warrants an exact assessment of the differentiation stage at which aberrant expression occurs in transformed hematopoiesis. Here, we report results on the prospective and extensive dissection of the hematopoietic hierarchy in 20 patients with either low-risk MDS or MDS with excess blasts and compare it to hematopoiesis in patients with non-malignancy associated cytopenia or B cell lymphoma without bone marrow infiltration. We found patients with MDS with excess blasts to exhibit characteristic expansions of specific immature progenitor compartments. We also identified the aberrant expression of several markers including ALDH, CLL-1, CD44, and CD47 to be specific features of hematopoiesis in MDS with excess blasts. We show that amongst these, aberrant CLL-1 expression manifested at the early uncommitted hematopoietic stem cell level, suggesting a potential role as a therapeutic target.

Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females-which we leverage to illustrate the behavioral and pharmacologic relevance of these findings-and of S1c6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.

Insulin receptor (IR) signaling plays a critical role in the regulation of metabolism and growth in multicellular organisms. IRs are unique among receptor tyrosine kinases in that they exist exclusively as covalent (a beta)(2) homodimers at the cell surface. Transmembrane signaling by the IR can therefore not be based on ligand-induced dimerization as such but must involve structural changes within the existing receptor dimer. In this study, using glycosylated full-length human IR reconstituted into lipid nanodiscs, we show by single-particle electron microscopy that insulin binding to the dimeric receptor converts its ectodomain from an inverted U-shaped conformation to a T-shaped conformation. This structural rearrangement of the ectodomain propagates to the transmembrane domains, which are well separated in the inactive conformation but come close together upon insulin binding, facilitating autophosphorylation of the cytoplasmic kinase domains.

Background: Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. Objective: Evaluate interleukin 22 blockade in adults with moderate-to-severe atopic dermatitis (AD). Methods: We performed a randomized, double-blind, placebo-controlled trial with intravenous fezakinumab monotherapy every 2 weeks for 10 weeks, with follow-up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. Results: At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 +/- 2.7 in the fezakinumab arm and 8.0 +/- 3.1 in the placebo arm (P=.134). In the severe AD patient subset (with a baseline SCORAD of >= 50), SCORAD decline was significantly stronger in the drug-treated patients than placebo-treated patients at 12 weeks (21.6 +/- 3.8 vs 9.6 +/- 4.2, P=.029) and 20 weeks (27.4 +/- 3.9 vs 11.5 +/- 5.1, P=.010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug-treated than placebo-treated patients (12.4% +/- 2.4 vs 6.2% +/- 2.7; P=.009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug-treated than placebo-treated patients (0.7 +/- 0.2 vs 0.3 +/- 0.1; P=.034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. Limitations: The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. Conclusion: Fezakinumab was well-tolerated, with sustained clinical improvements after last drug dosing.

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.

A search for a heavy right-handed W boson (W-R) decaying to a heavy right-handed neutrino and a charged lepton in events with two same-flavor leptons (e or mu) and two jets, is presented. The analysis is based on proton-proton collision data, collected by the CMS Collaboration at the LHC in 2016 and corresponding to an integrated luminosity of 35.9 fb(-1). No significant excess above the standard model expectation is seen in the invariant mass distribution of the dilepton plus dijet system. Assuming that couplings are identical to those of the standard model, and that only one heavy neutrino flavor N-R contributes significantly to the W-R decay width, the region in the two-dimensional (m(WR), m(NR)) mass plane excluded at 95% confidence level extends to approximately m(WR) = 4 : 4TeV and covers a large range of right-handed neutrino masses below the W-R boson mass. This analysis provides the most stringent limits on the W-R mass to date.

A search is presented for the decays of heavy exotic long-lived particles (LLPs) that are produced in proton-proton collisions at a center-of-mass energy of 13TeV at the CERN LHC and come to rest in the CMS detector. Their decays would be visible during periods of time well separated from proton-proton collisions. Two decay scenarios of stopped LLPs are explored: a hadronic decay detected in the calorimeter and a decay into muons detected in the muon system. The calorimeter (muon) search covers a period of sensitivity totaling 721 (744) hours in 38.6 (39.0) fb(-1) of data collected by the CMS detector in 2015 and 2016. The results are interpreted in several scenarios that predict LLPs. Production cross section limits are set as a function of the mean proper lifetime and the mass of the LLPs, for lifetimes between 100 ns and 10 days. These are the most stringent limits to date on the mass of hadronically decaying stopped LLPs, and this is the fi rst search at the LHC for stopped LLPs that decay to muons.

A search for a new heavy particle decaying to a pair of vector bosons (WW or WZ) is presented using data from the CMS detector corresponding to an integrated luminosity of 35.9 fb(-1) collected in proton-proton collisions at a centre-of-mass energy of 13 TeV in 2016. One of the bosons is required to be a W boson decaying to e nu or mu nu, while the other boson is required to be reconstructed as a single massive jet with substructure compatible with that of a highly-energetic quark pair from a W or Z boson decay. The search is performed in the resonance mass range between 1.0 and 4.4 TeV. The largest deviation from the background-only hypothesis is observed for a mass near 1.4 TeV and corresponds to a local significance of 2.5 standard deviations. The result is interpreted as an upper bound on the resonance production cross section. Comparing the excluded cross section values and the expectations from theoretical calculations in the bulk graviton and heavy vector triplet models, spin-2 WW resonances with mass smaller than 1.07 TeV and spin-1 WZ resonances lighter than 3.05 TeV, respectively, are excluded at 95% confidence level.

A search for long-lived particles was performed with data corresponding to an integrated luminosity of 2.6 fb(-1) collected at a center-of-mass energy of 13 TeV by the CMS experiment in 2015. The analysis exploits two customized topological trigger algorithms, and uses the multiplicity of displaced jets to search for the presence of a signal decay occurring at distances between 1 and 1000 mm. The results can be interpreted in a variety of different models. For pair-produced long-lived particles decaying to two b quarks and two leptons with equal decay rates between lepton flavors, cross sections larger than 2.5 fb are excluded for proper decay lengths between 70-100 mm for a long-lived particle mass of 1130 GeV at 95% confidence. For a specific model of pair-produced, long-lived top squarks with R-parity violating decays to a b quark and a lepton, masses below 550-1130 GeV are excluded at 95% confidence for equal branching fractions between lepton flavors, depending on the squark decay length. This mass bound is the most stringent to date for top squark proper decay lengths greater than 3 mm. (C) 2018 The Author(s). Published by Elsevier B.V.

The lateral habenula (LHb) is a key brain region involved in the pathophysiology of depression. It is activated by stimuli associated with negative experiences and is involved in encoding aversive signals. Hyperactivity of LHb is found in both rodent models of depression and human patients with depression. However, little is known about the underlying molecular mechanisms. Here we show that in LHb neurons, p11, a multifunctional protein implicated in depression, is significantly upregulated by chronic restraint stress. Knockdown of p11 expression in LHb alleviates the stress-induced depression-like behaviors. Moreover, chronic restraint stress induces bursting action potentials in LHb neurons, which are abolished by p11 knockdown. Overexpression of p11 in dopamine D2 receptor-containing LHb neurons of control mice induces depression-like behaviors. These results have identified p11 in LHb as a key molecular determinant regulating negative emotions, which may help to understand the molecular and cellular basis of depression.