The rockefeller university

Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) by the TNF-alpha convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-alpha also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-alpha shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII-deficient mice (F8(-/-) mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture-induced bleeding leads to increased TNF-alpha levels in the affected joint of F8(-/-) mice. Moreover, inactivation of TNF-alpha or iRhom2 in F8(-/-) mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-alpha pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients.

We explore some consequences of a theory of internal symmetries for elementary particles based on exceptional quantum mechanical spaces based on Jordan algebra formulation that admit exceptional groups as gauge groups.

Psoriasis vulgaris is a common, heterogeneous, chronic inflammatory skin disease characterized by thickened, red, scaly plaques and systemic inflammation. Psoriasis is also associated with multiple comorbid conditions, such as joint destruction, cardiovascular disease, stroke, hypertension, metabolic syndrome, and chronic kidney disease. The discovery of IL-17-producing T cells in a mouse model of autoimmunity transformed our understanding of inflammation driven by T lymphocytes and associations with human inflammatory diseases, such as psoriasis. Under the regulation of IL-23, T cells that produce high levels of IL-17 create a self-amplifying, feed-forward inflammatory response in keratinocytes that drives the development of thickened skin lesions infiltrated with a mixture of inflammatory cell populations. Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 (secukinumab, ixekizumab, and brodalumab) and IL-23 (guselkumab and tildrakizumab) signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed.

A measurement is presented of the Z/gamma*->tau tau cross section in pp collisions at root s = 13 TeV, using data recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 2.3 fb(-1). The product of the inclusive cross section and branching fraction is measured to be sigma(pp -> Z/gamma*+X) B(Z/gamma*->tau tau) = 1848 +/- 12 (stat) +/- 67 (syst + lumi) pb, in agreement with the standard model expectation, computed at next-to-next-to-leading order accuracy in perturbative quantum chromodynamics. The measurement is used to validate new analysis techniques relevant for future measurements of tau lepton production. The measurement also provides the reconstruction efficiency and energy scale for tau decays to hadrons + nu(tau) final states, determined with respective relative uncertainties of 2.2 and 0.9%.

Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients and type I interferon (IFN) has been evaluated in a few infected transplantation patients in vivo. However, no effective and specific treatments against HEV infections are currently available. In this study, we evaluated the natural compound silvestrol, isolated from the plant Aglaia foveolata, and known for its specific inhibition of the DEAD-box RNA helicase eIF4A in state-of-the-art HEV experimental model systems. Silvestrol blocked HEV replication of different subgenomic replicons in a dose-dependent manner at low nanomolar concentrations and acted additive to ribavirin (RBV). In addition, HEV p6-based full length replication and production of infectious particles was reduced in the presence of silvestrol. A pangenotypic effect of the compound was further demonstrated with primary isolates from four different human genotypes in HEV infection experiments of hepatocyte-like cells derived from human embryonic and induced pluripotent stem cells. In vivo, HEV RNA levels rapidly declined in the feces of treated mice while no effect was observed in the vehicle treated control animals. In conclusion, silvestrol could be identified as pangenotypic HEV replication inhibitor in vitro with additive effect to RBV and further demonstrated high potency in vivo. The compound therefore may be considered in future treatment strategies of chronic hepatitis E in immunocompromised patients.

A search is presented for additional neutral Higgs bosons in the tau tau final state in proton-proton collisions at the LHC. The search is performed in the context of the minimal supersymmetric extension of the standard model (MSSM), using the data collected with the CMS detector in 2016 at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). To enhance the sensitivity to neutral MSSM Higgs bosons, the search includes production of the Higgs boson in association with b quarks. No significant deviation above the expected background is observed. Model-independent limits at 95% confidence level (CL) are set on the product of the branching fraction for the decay into tau leptons and the cross section for the production via gluon fusion or in association with b quarks. These limits range from 18 pb at 90 GeV to 3.5 fb at 3.2 TeV for gluon fusion and from 15 pb (at 90 GeV) to 2.5 fb (at 3.2TeV) for production in association with b quarks, assuming a narrow width resonance. In the m(h)(mod+) scenario these limits translate into a 95% CL exclusion of tan beta > 6 for neutral Higgs boson masses below 250 GeV, where tan beta is the ratio of the vacuum expectation values of the neutral components of the two Higgs doublets. The 95% CL exclusion contour reaches 1.6TeV for tan beta = 60.

search for pair production of heavy scalar leptoquarks (LQs), each decaying into a top quark and a tau lepton, is presented. The search considers final states with an electron or a muon, one or two tau leptons that decayed to hadrons, and additional jets. The data were collected in 2016 in proton-proton collisions at root s = 13 TeV with the CMS detector at the LHC, and correspond to an integrated luminosity of 35.9fb(-1). No evidence for pair production of LQs is found. Assuming a branching fraction of unity for the decay LQ -> t tau, upper limits on the production cross section are set as a function of LQ mass, excluding masses below 900 GeV at 95% confidence level. These results provide the most stringent limits to date on the production of scalar LQs that decay to a top quark and a tau lepton.

LEM domain (LEM-D) proteins are conserved components of the nuclear lamina (NL) that contribute to stem cell maintenance through poorly understood mechanisms. The Drosophila emerin homolog Otefin (Ote) is required for maintenance of germline stem cells (GSCs) and gametogenesis. Here, we show that ote mutants carry germ cell-specific changes in nuclear architecture that are linked to GSC loss. Strikingly, we found that both GSC death and gametogenesis are rescued by inactivation of the DNA damage response (DDR) kinases, ATR and Chk2. Whereas the germline checkpoint draws from components of the DDR pathway, genetic and cytological features of the GSC checkpoint differ from the canonical pathway. Instead, structural deformation of the NL correlates with checkpoint activation. Despite remarkably normal oogenesis, rescued oocytes do not support embryogenesis. Taken together, these data suggest that NL dysfunction caused by Otefin loss triggers a GSC-specific checkpoint that contributes to maintenance of gamete quality.

Clonal evolution of B cells in germinal centers (GCs) is central to affinity maturation of antibodies in response to pathogens. Permanent or tamoxifen-induced multi-color recombination of B cells based on the brainbow allele allows monitoring the degree of color dominance in the course of the GC reaction. Here, we use computer simulations of GC reactions in order to replicate the evolution of color dominance in silico and to define rules for the interpretation of these data in terms of clonal dominance. We find that a large diversity of clonal dominance is generated in simulated GCs in agreement with experimental results. In the extremes, a GC can be dominated by a single clone or can harbor many co-existing clones. These properties can be directly derived from the measurement of color dominance when all B cells are stained before the GC onset. Upon tamoxifen-induced staining, the correlation between clonal structure and color dominance depends on the timing and duration of the staining procedure as well as on the total number of stained B cells. B cells can be stained with 4 colors if a single brainbow allele is used, using both alleles leads to 10 different colors. The advantage of staining with 10 instead of 4 colors becomes relevant only when the 10 colors are attributed with rather similar probability. Otherwise, 4 colors exhibit a comparable predictive power. These results can serve as a guideline for future experiments based on multi-color staining of evolving systems.