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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.

GTP-binding protein 1 (GTPBP1) and GTPBP2 comprise a divergent group of translational GTPases with obscure functions, which are most closely related to eEF1A, eRF3, and Hbs1. Although recent reports implicated GTPBPs in mRNA surveillance and ribosome-associated quality control, how they perform these functions remains unknown. Here, we demonstrate that GTPBP1 possesses eEF1A-like elongation activity, delivering cognate aminoacyl-transfer RNA (aa-tRNA) to the ribosomal A site in a GTP-dependent manner. It also stimulates exosomal degradation of mRNAs in elongation complexes. The kinetics of GTPBP1-mediated elongation argues against its functioning in elongation per se but supports involvement in mRNA surveillance. Thus, GTP hydrolysis by GTPBP1 is not followed by rapid peptide bond formation, suggesting that after hydrolysis, GTPBP1 retains aa-tRNA, delaying its accommodation in the A site. In physiological settings, this would cause ribosome stalling, enabling GTPBP1 to elicit quality control programs; e.g., by recruiting the exosome. GTPBP1 can also deliver deacylated tRNA to the A site, indicating that it might function via interaction with deacylated tRNA, which accumulates during stresses. Although GTPBP2's binding to GTP was stimulated by Phe-tRNAPhe, suggesting that its function might also involve interaction with aa-tRNA, GTPBP2 lacked elongation activity and did not stimulate exosomal degradation, indicating that GTPBP1 and GTPBP2 have different functions.

In developed countries, pulmonary nontuberculous mycobacteria (NTM) infections are more prevalent than Mycobacterium tuberculosis infections. Given the differences in the pathogenesis of NTM and M. tuberculosis infections, separate studies are needed to investigate the pathological effects of NTM pathogens. Our previous study showed that anti-IFN-gamma autoantibodies are detected in NTM-infected patients. However, the role of NK cells and especially NK cell-derived IFN-gamma in this context has not been studied in detail. In the current study, we show that NK1.1 cell depletion increases bacterial load and mortality in a mouse model of pulmonary NTM infection. NK1.1 cell depletion exacerbates NTM-induced pathogenesis by reducing macrophage phagocytosis, dendritic cell development, cytokine production, and lung granuloma formation. Similar pathological phenomena are observed in IFN-gamma-deficient (IFN-gamma(-/-)) mice following NTM infection, and adoptive transfer of wild-type NK cells into IFN-gamma(-/-) mice considerably reduces NTM pathogenesis. Injection of rIFN-gamma also prevents NTM-induced pathogenesis in IFN-gamma(-/-) mice. We observed that NK cells represent the main producers of IFN-gamma in the lungs and production starts as soon as 1 d postinfection. Accordingly, injection of rIFN-gamma into IFN-gamma(-/-) mice 1 d (but not 2 wk) postinfection significantly improves immunity against NTM infection. NK cells also stimulate mycobacterial killing and IL-12 production by macrophages. Our results therefore indicate that IFN-gamma production by NK cells plays an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary NTM infection.

All immune systems use precise target recognition to interrogate foreign invaders. During CRISPR-Cas immunity, prokaryotes capture short spacer sequences from infecting viruses and insert them into the CRISPR array. Transcription and processing of the CRISPR locus generate small RNAs containing the spacer and repeat sequences that guide Cas nucleases to cleave a complementary protospacer in the invading nucleic acids. In most CRISPR systems, sequences flanking the protospacer drastically affect cleavage. Here, we investigated the target requirements of the recently discovered RNA-targeting type VI-A CRISPR-Cas system in its natural host, Listeria seeligeri. We discovered that target RNAs with extended complementarity between the protospacer flanking sequence and the repeat sequence of the guide RNA are not cleaved by the type VI-A nuclease Cas13, neither in vivo nor in vitro. These findings establish fundamental rules for the design of Cas13-based technologies and provide a mechanism for preventing self-targeting in type VI-A systems.