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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.

Unmanned aerial systems (UASs) are powerful tools for research and monitoring of wildlife. However, the effects of these systems on most marine mammals are largely unknown, preventing the establishment of guidelines that will minimize animal disturbance. In this study, we evaluated the behavioral responses of coastal bottlenose dolphins (Tursiops truncatus) and Antillean manatees (Trichechus manatus manatus) to small multi-rotor UAS flight. From 2015 to 2017, we piloted 211 flights using DJI quadcopters (Phantom II Vision +, 3 Professional and 4) to approach and follow animals over shallow-water habitats in Belize. The quadcopters were equipped with high-resolution cameras to observe dolphins during 138 of these flights, and manatees during 73 flights. Aerial video observations of animal behavior were coded and paired with flight data to determine whether animal activity and/or the UAS's flight patterns caused behavioral changes in exposed animals. Dolphins responded to UAS flight at altitudes of 11-30 m and responded primarily when they were alone or in small groups. Single dolphins and one pair responded to the UAS by orienting upward and turning toward the aircraft to observe it, before quickly returning to their pre-response activity. A higher number of manatees responded to the UAS, exhibiting strong disturbance in response to the aircraft from 6 to 104 m. Manatees changed their behavior by fleeing the area and sometimes this elicited the same response in nearby animals. If pursued post-response, manatees repeatedly responded to overhead flight by evading the aircraft's path. These findings suggest that the invasiveness of UAS varies across individuals, species, and taxa. We conclude that careful exploratory research is needed to determine the impact of multi-rotor UAS flight on diverse species, and to develop best practices aimed at reducing the disturbance to wildlife that may result from their use.

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%.

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.

Dispersed H3K27 trimethylation (H3K27me3) of the AGAMOUS (AG) genomic locus is mediated by CURLY LEAF (CLF), a component of the Polycomb Repressive Complex (PRC) 2. Previous reports have shown that the AG second intron, which confers AG tissue-specific expression, harbors sequences targeted by several positive and negative regulators. Using RACE reverse transcription polymerase chain reaction, we found that the AG intron 2 encodes several noncoding RNAs. RNAi experiment showed that incRNA4 is needed for CLF repressive activity. AG-incRNA4RNAi lines showed increased leaf AGmRNA levels associated with a decrease of H3K27me3 levels; these plants displayed AG overexpression phenotypes. Genetic and biochemical analyses demonstrated that the AG-incRNA4 can associate with CLF to repress AG expression in leaf tissues through H3K27me3-mediated repression and to autoregulate its own expression level. The mechanism of AG-incRNA4-mediated repression may be relevant to investigations on tissue-specific expression of Arabidopsis MADS-box genes.

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.

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.