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SummaryIn mammalian cells expression of repetitive genomic sequences is repressed by heterochromatin, underscoring the potential threat of repeat expression to cellular homeostasis. However, the specific consequences of ectopic repeat expression remains unclear. Here we demonstrate that EZH2 inhibitors stimulate repeat misexpression and cell death in resting splenic B cells. We show that B cells are uniquely sensitive to these agents because of high levels of H3K27me3 at repeats and correspondingly low DNA methylation. We generated a pattern recognition receptor loss-of-function mouse model called RIC with mutations inRigi,Ifih1(MDA5), andCgasto specifically block the consequences of repeat misexpression. In both WT and RIC mutant B cells, EZH2 inhibition caused focused loss of H3K27me3 at repetitive elements and upregulated their expression. However, expression of inflammatory chemokines and cell death were interrupted by the RIC mutations. Furthermore, the chemokine expression patterns induced by EZH2 inhibitors resemble the B cell response to Epstein-Barr virus infection. This study demonstrates a viral mimicry effect induced by pharmacological activation of repeat expression that induces inflammation and B cell death.

5D warped extra dimension models with multiple 3-branes can naturally realize multiple hierarchical mass scales which are ubiquitous in physics beyond the Standard Model. We discuss cosmological consequences of such multi-brane models with stabilized radions. It is confirmed that for temperatures below the scale of the IR brane at the end of the extra dimension, we recover the ordinary expansion of the Universe, with the Hubble expansion rate determined by sum of the physical energy densities on all 3-branes where they are localized. In addition, we explore the cosmology for temperatures above the scales of the intermediate and IR branes where the Universe is described by a spacetime with the 3-branes replaced by an event horizon. As the temperature of the Universe cools down, phase transitions are expected to take place, and the intermediate and IR branes come out from behind the event horizon. The Goldberger-Wise mechanism for radion stabilization has a well-known problem of having a supercooled phase transition, which typically does not get completed in time. This problem is even more severe when an intermediate brane is introduced, whose scale is well above TeV, as the corresponding Hubble rate is much larger. We circumvent the problem by employing an alternative mechanism for radion stabilization with dark Yang-Mills fields, which prevents a long supercooling epoch, but still allows the strong first order phase transitions. As a result, the phase transitions in our multi-brane Universe predict a stochastic gravitational wave background with a unique multi-peak signature, which is within the sensitivity reach of future space-based gravitational wave observers. We also show that there are $N-1$ radions for an $N$ 3-brane set-up, unlike a recent claim that there exists only one radion., Comment: 34 pages, 6 figures

Neutral particles are notoriously difficult to observe through electromagnetic interactions. As a result, they naturally elude detection in most collider detectors. In this paper, we point out that neutral particles that interact through a dipole interaction can nevertheless be detected in far-forward detectors designed to search for long-lived particles (LLPs). In contrast to previous analyses that focused on neutral particles with elastic interactions, we consider inelastic interactions. This naturally leads to LLPs, and we demonstrate that FASER (and future experiments at the Forward Physics Facility) will be able to probe substantial regions of the associated parameter space. In particular, we find that FASER is capable of probing the region of parameter space wherein thermal freeze-out gives rise to an $\mathcal{O}$(GeV) dark-matter candidate with the appropriate relic abundance, as well as regions of parameter space that are difficult to probe at fixed-target experiments. FASER and its successor experiments may therefore play a critical role in the discovery of such a dark-matter candidate., Comment: 24 pages, LaTeX, 5 figures, 1 table

We examine the possibility of building a natural non-supersymmetric model of spontaneous CP violation equipped with the Nelson-Barr (NB) mechanism to address the strong CP problem. Our approach is to utilize a doubly composite dynamics where the first confinement of the CFT occurs at the scale of spontaneous CP violation (SCPV) and the second confinement at the TeV scale. A holographic dual description of this 4D set-up via a warped extra dimension with three 3-branes provides an explicit realization of this idea.In this model, radiative corrections to the strong CP phase are well under control, and the coincidence of mass scales, which we generally encounter in NB models, is addressed. Our model also provides an explanation to the quark Yukawa hierarchies, and a solution to the gauge hierarchy problem just as in the usual Randall-Sundrum model with the Higgs being localized on the TeV brane., 9 pages, 5 figures, model updated, published version

Acknowledgments We thank the participants of the FPF meetings and the Snowmass working groups for discussions that have contributed both directly and indirectly to this study. We gratefully acknowledge the invaluable support of the CERN Physics Beyond Colliders study group and the work of CERN technical teams related to civil engineering studies (SCE-DOD), safety discussions (HSE-OHS, HSE-RP, EP-DI-SO), integration (EN-ACE), and discussions on services (EN-CV, EN-EL, EN-AA) and simulations (SY-STI). The work by J Alameddine, W Rhode, T Ruhe, and A Sandrock has been supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Collaborative Research Center SFB 876 and SFB 1491. L A Anchordoqui is supported by the US National Science Foundation (NSF) Grant PHY-2112527. T Araki is supported by JP18H01210. A Ariga is supported by JSPS KAKENHI Grant JP20K23373 and the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (Grant 101002690). T Ariga acknowledges support from JSPS KAKENHI Grant JP19H01909. K Asai is supported by JSPS KAKENHI Grant JP19J13812 and JP21K20365. A Bacchetta and F G Celiberto acknowledge support from the INFN/NINPHA project. P Bakhti and M Rajaee are supported by the National Research Foundation of Korea (NRF-2020R1I1A3072747). B Barman received funding from the Patrimonio Autónomo—Fondo Nacional de Financiamiento para la Ciencia, la Tecnología y la Innovación Francisco José de Caldas (MinCiencias—Colombia) Grant 80740-465-2020 and the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant Agreement No. 860881-HIDDeN. The work of B Batell is supported by the US Department of Energy (DOE) Grant DE–SC0007914. The work of A Berlin, T J Hobbs, S Hoeche, and J G Morfín was supported by the Fermi National Accelerator Laboratory (Fermilab), a US DOE, Office of Science, HEP User Facility. Fermilab is managed by Fermi Research Alliance, LLC (FRA), acting under Contract DE-AC02-07CH11359. M Becker, E Copello and J Harz acknowledge support from the DFG Emmy Noether Grant HA 8555/1-1. E Copello acknowledges also support from the DFG Collaborative Research Centre 'Neutrinos and Dark Matter in Astro- and Particle Physics' (SFB 1258). E Bertuzzo acknowledges financial support from FAPESP Contracts 2015/25884-4 and 2019/15149-6 and is indebted to the Theoretical Particle Physics and Cosmology group at King's College London for hospitality. The work of J Bian and W Wu is supported in part by US DOE Grant DE-SC0009920 and Heising-Simons Foundation Grant 2022-3319. The work of A Boyarsky and M Ovchynnikov is supported by the ERC under the European Union's Horizon 2020 Research and Innovation Programme (GA 694896). A Carmona acknowledges funding from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement No. 754446 and UGR Research and Knowledge Transfer Found—Athenea3i. A Carmona also acknowledges partial support by the Ministry of Science and Innovation and SRA (10.13039/501100011033) Grant PID2019-106087GB-C22 and by the Junta de Andalucía Grant A-FQM-472-UGR20. F G Celiberto thanks the Università degli Studi di Pavia for the warm hospitality. The work of G Chachamis was supported by the Fundação para a Ciência e a Tecnologia (Portugal) under Project CERN/FIS-PAR/0024/2019 and Contract 'Investigador auxiliar FCT—Individual Call/03216/2017'. The work of M Citron and D Stuart is supported by US DOE Grant DE-SC0011702. The work of L Darme is supported by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant Agreement 101028626. P B Denton acknowledges support from the US DOE Grant Contract DE-SC0012704. The work of P S Bhupal Dev was supported in part by the US DOE Grant DE-SC0017987. The research activities of K R Dienes were supported in part by the US DOE Grant DE-FG02-13ER41976/DE-SC0009913 and also by the US NSF through its employee IR/D program. M V Diwan acknowledges support from the US DOE Grant Contract DE-SC0012704. Y Du and J H Yu are supported in part by National Key Research and Development Program of China Grant 2020YFC2201501, and the National Science Foundation of China (NSFC) under Grants 12022514, 11875003 and 12047503, and CAS Project for Young Scientists in Basic Research YSBR-006, and the Key Research Program of the CAS Grant XDPB15. The work of B Dutta and S Ghosh are supported in part by the US DOE Grant DE-SC0010813. The work of S Ghosh is also supported in part by National Research Foundation of Korea (NRF)'s Grants, Grant 6N021413. Y Farzan has received financial support from Saramadan Contract ISEF/M/400279 as well as from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement 860881-HIDDeN. The work of J L Feng is supported in part by US NSF Grants PHY-1915005 and PHY-2111427, Simons Investigator Award #376204, Simons Foundation Grant 623683, and Heising-Simons Foundation Grants 2019-1179 and 2020-1840. M Fieg is supported in part by US NSF Grant PHY-1915005 and by NSF Graduate Research Fellowship Award DGE-1839285. A L Foguel is supported by FAPESP Contract 2020/00174-2. The work of P Foldenauer is supported by the UKRI Future Leaders Fellowship DARKMAP. The work of S Foroughi-Abari and A Ritz is supported in part by NSERC, Canada. The work of J-F Fortin is supported in part by NSERC, Canada. A Friedland is supported by the US DOE Grant DE-AC02-76SF00515. E Fuchs acknowledges support by the DFG Germany's Excellence Strategy—EXC-2123 'QuantumFrontiers'—390837967. M Fucilla, M M A Mohammed, and A Papa acknowledge support from the INFN/QFT@COLLIDERS project. A Garcia acknowledges support from the European Union's H2020-MSCA Grant Agreement 101025085. C A García Canal and S J Sciutto acknowledge support from CONICET and ANPCyT M V Garzelli acknowledges support the from German BMBF Contract 05H21GUCCA. V P Goncalves was partially financed by the Brazilian funding agencies CNPq, CAPES, FAPERGS and INCT-FNA (Process Number 464898/2014-5). S Goswami acknowledges the J C Bose Fellowship (JCB/2020/000011) of Science and Engineering Research Board of Department of Science and Technology, Government of India. The work of M Guzzi is supported by US NSF Grant PHY-2112025. L Harland-Lang thanks the Science and Technology Facilities Council (STFC) for support via Grant Award ST/L000377/1. The work of S P Harris is supported by the US DOE Grant DE-FG02-00ER41132 as well as the US NSF Grant PHY-1430152 (JINA Center for the Evolution of the Elements). J C Helo acknowledge support from Grant ANID FONDECYT-Chile 1201673 and ANID—Millennium Science Initiative Program ICN2019-044. The work of M Hirsch is supported by the Spanish Grants PID2020-113775GB-I00 (AEI/10.13039/501100011033) and PROMETEO/2018/165 (Generalitat Valenciana). The work of A Hryczuk and M Laletin is supported by the National Science Centre, Poland, research Grant 2018/31/D/ST2/00813. The research activities of F Huang are supported by the International Postdoctoral Exchange Fellowship Program and in part by US NSF Grant PHY-1915005. A Ismail is supported by NSERC (Reference Number 557763) and by US NSF Grant PHY-2014071. Y S Jeong acknowledges support from the National Research Foundation of Korea (NRF) grant funded by the Korea government through Ministry of Science and ICT Grant 2021R1A2C1009296. K Jodlowski and L Roszkowski are supported by the National Science Centre, Poland, research Grant 2015/18/A/ST2/00748. S R Klein is supported in part by the US NSF Grant PHY-1307472 and the US DOE Contract DE-AC-76SF00098. F Kling and P Quílez are supported by the DFG under Germany's Excellence Strategy—EXC 2121 Quantum Universe—390833306. P Ko is supported in part by KIAS Individual Grant PG021403 and by National Research Foundation of Korea (NRF) Grant NRF-2019R1A2C3005009. S Kulkarni is supported by the Austrian Science Fund Elise-Richter Grant V592-N27. The work of J Kumar is supported in part by US DOE Grant DE-SC0010504. J-L Kuo is supported by US NSF Theoretical Physics Program, Grant PHY-1915005. The work of C Le Roux and K Zapp is part of a project that has received funding from the ERC under the European Union's Horizon 2020 Research and Innovation Programme (Grant Agreement 803183, collectiveQCD). The work of H-S Lee was supported in part by the National Research Foundation of Korea (NRF-2021R1A2C2009718). S J Lee was supported by the Samsung Science and Technology Foundation. Ji Li is supported by the National Natural Science Foundation of China Grant 11905149. K-F Lyu and Z Liu are supported in part by the US DOE Grant DE-SC0022345. The work of R Maciula and A Szczurek was partially supported by the Polish National Science Centre under Grant 2018/31/B/ST2/03537. R Mammen Abraham and A Ismail acknowledge support from the US DOE Grant DE-SC0016013. M R Masouminia is supported by the UK Science and Technology Facilities Council (Grant ST/P001246/1). The work of J McFayden was supported by the Royal Society Fellowship Grant URF R1 201519. The work of O Mikulenko is supported by the NWO Physics Vrij Programme 'The Hidden Universe of Weakly Inter-acting Particles' with Project Number 680.92.18.03 (NWO Vrije Programma), which is (partly) financed by the Dutch Research Council (NWO). P Nadolsky and F Olness acknowledge support through US DOE Grant DE-SC0010129. E R Nocera thanks the STFC for support by the Grant Awards ST/P000630/1and ST/T000600/1. The work of N Okada is supported by the US DOE Grant DE-SC0012447. V Pandey acknowledges the support from US DOE Grant DE-SC0009824. The work of D Raut is supported by the US DOE Grant DE-SC0013880. P Reimitz acknowledges financial support from FAPESP Contract 2020/10004-7. M H Reno is supported in part by US DOE Grant DE-SC-0010113. The work of J Rojo is partly supported by the Dutch Research Council (NWO). L Roszkowski and S Trojanowski are supported by the grant 'AstroCeNT: Particle Astrophysics Science and Technology Centre' carried out within the International Research Agendas programme of the Foundation for Polish Science financed by the European Union under the European Regional Development Fund. S Trojanowski is also supported in part by the Polish Ministry of Science and Higher Education through its scholarship for young and outstanding scientists (Decision No. 1190/E-78/STYP/14/2019). S Trojanowski is also supported in part from the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 952480 (DarkWave 24 project). I Sarcevic is supported by US DOE Grant DOE DE-SC-0009913. The work of L Shchutska is supported by the ERC under the European Union's Horizon 2020 Research and Innovation Programme (GA 758316). The work of T Shimomura is supported by JSPS KAKENHI Grants JP18H01210, JP18K03651, and MEXT KAKENHI Grant JP18H05543. The work of K Sinha is supported in part by US DOE Grant DE-SC0009956. The work of T Sjöstrand is supported by the Swedish Research Council, Contract 2016-05996. J T Sobczyk acknowledges support from NCN Grant UMO-2021/41/B/ST2/02778. D Soldin acknowledges support from the US NSF Grant PHY-1913607. H Song is supported by the International Postdoctoral Exchange Fellowship Program. Y Soreq is supported by grants from the NSF-BSF, BSF, the ISF and by the Azrieli foundation. A Stasto acknowledges support from US DOE Grant DE-SC-0002145. S Su is supported by the US DOE Grant DE-FG02-13ER41976/DE-SC0009913. W Su is supported by a KIAS Individual Grant (PG084201) at Korea Institute for Advanced Study. Y Takubo is supported by JP20K04004. M Taoso acknowledges support from the INFN Grant 'LINDARK', the research grant 'The Dark Universe: A Synergic Multimessenger Approach 2017X7X85' funded by MIUR, and the project 'Theoretical Astroparticle Physics (TAsP)' funded by the INFN. The research activities of B Thomas are supported in part by US NSF Grant PHY-2014104. The work of Y-D Tsai is supported in part by US NSF Grant PHY-1915005. The work of A Sabio Vera has been supported by the Spanish Research Agency (Agencia Estatal de Investigación) through the Grant IFT Centro de Excelencia Severo Ochoa SEV-2016-0597, by the Spanish Government Grant FPA2016-78022-P and from the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement 824093. The work of Yongchao Zhang is supported by the National Natural Science Foundation of China Grant 12175039, the 2021 Jiangsu Shuangchuang (Mass Innovation and Entrepreneurship) Talent Program JSSCBS20210144, and the 'Fundamental Research Funds for the Central Universities'. Yue Zhang is supported by the Arthur B McDonald Canadian Astroparticle Physics Research Institute. R Zukanovich Funchal is partially supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Ciência e Tecnologia (CNPq). The opinions and conclusions expressed herein are those of the authors and do not represent any funding agencies., High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe standard model (SM) processes and search for physics beyond the standard model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential., German Research Foundation (DFG) SFB 876 SFB 1491, National Science Foundation (NSF) PHY2112527, Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) JP18H01210 JSPS KAKENHI JP20K23373 JP19H01909 JSPS KAKENHI JP19J13812 JP21K20365 JSPS KAKENHI JP18K03651, European Research Council (ERC) 101002690, National Research Foundation of Korea NRF-2020R1I1A3072747, Patrimonio Autónomo-Fondo Nacional de Financiamiento para la Ciencia Tecnología y la Innovación Francisco José de Caldas (MinCiencias-Colombia) 80740-465-2020, European Commission Joint Research Centre 860881-HIDDeN European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant 754446, United States Department of Energy (DOE) DE-SC0007914, Fermi National Accelerator Laboratory (Fermilab), a US DOE, Office of Science, HEP User Facility, Fermi Research Alliance, LLC (FRA) DE-AC02-07CH11359, German Research Foundation (DFG) HA 8555/1-1, DFG Collaborative Research Centre 'Neutrinos and Dark Matter in Astro-and Particle Physics' SFB 1258, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2015/25884-4 2019/15149-6, United States Department of Energy (DOE) DE-SC0009920, Heising-Simons Foundation 2022-3319 2019-1179 2020-1840, ERC under the European Union's Horizon 2020 Research and Innovation Programme 694896 803183, UGR Research and Knowledge Transfer Found-Athenea3i, Ministry of Science and Innovation, Spain (MICINN) Spanish Government, SRA Grant PID2019-106087GB-C22, Junta de Andalucía A-FQM-472-UGR20, Fundacao para a Ciencia e a Tecnologia (FCT) CERN/FIS-PAR/0024/2019 03216/2017, United States Department of Energy (DOE) DE-SC0011702 DE-SC0017987 DE-FG02-13ER41976/DE-SC0009913 DE-SC0012704 DE-SC0010813 DE-AC02-76SF00515 DE-FG02-00ER41132 DE-AC-76SF00098 DE-SC0010504 DE-SC0022345 DE-SC0010129, US NSF through its employee IR/D program, National Key Research and Development Program of China 2020YFC2201501, National Natural Science Foundation of China (NSFC) 12022514 11875003 12047503, CAS Project for Young Scientists in Basic Research YSBR-006, Key Research Program of the CAS XDPB15, National Research Foundation of Korea (NRF)'s Grants 6N021413, Saramadan Contract ISEF/M/400279, National Science Foundation (NSF) PHY-1915005 PHY-2111427 PHY1430152 PHY-2014071 PHY-1307472 PHY-2014104, Simons Investigator Award 376204, Simons Foundation 623683, National Science Foundation (NSF) DGE-1839285, FAPESP Contract 2020/00174-2, UKRI Future Leaders Fellowship DARKMAP, Natural Sciences and Engineering Research Council of Canada (NSERC), German Research Foundation (DFG) EXC-2123 390837967, INFN/QFT@COLLIDERS project, European Union's H2020-MSCA Grant Agreement 101025085, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), ANPCyT, Federal Ministry of Education & Research (BMBF) 05H21GUCCA, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Fundacao de Amparo a Ciencia e Tecnologia do Estado do Rio Grande do Sul (FAPERGS), INCT-FNA 464898/2014-5, J C Bose Fellowship of Science and Engineering Research Board of Department of Science and Technology, Government of India JCB/2020/000011, National Science Foundation (NSF) PHY-2112025, UK Research & Innovation (UKRI) Science & Technology Facilities Council (STFC) Science and Technology Development Fund (STDF) ST/L000377/1, Grant ANID FONDECYT-Chile 1201673, ANID-Millennium Science Initiative Program ICN2019-044, Spanish Grant (AEI) PID2020-113775GBI00, Center for Forestry Research & Experimentation (CIEF) PROMETEO/2018/165, National Science Centre, Poland 2018/31/D/ST2/00813, International Postdoctoral Exchange Fellowship Program, KIAS Individual Grant PG021403, National Research Foundation of Korea NRF-2019R1A2C3005009, Austrian Science Fund Elise-Richter Grant V592-N27, US NSF Theoretical Physics Program PHY-1915005, Samsung, National Natural Science Foundation of China (NSFC) 11905149, Polish National Science Centre 2018/31/B/ST2/03537, UK Research & Innovation (UKRI) Science & Technology Facilities Council (STFC) ST/P001246/1, Royal Society of London URF R1 201519, Netherlands Organization for Scientific Research (NWO) 680.92.18.03 Physics Vrij Programme .The Hidden Universe of Weakly Inter-acting Particles' - Dutch Research Council (NWO), UK Research & Innovation (UKRI) Science & Technology Facilities Council (STFC) ST/T000600/1 ST/P000630/1, Netherlands Organization for Scientific Research (NWO), European Union under the European Regional Development Fund, Polish Ministry of Science and Higher Education through its scholarship for young and outstanding scientists 1190/E-78/STYP/14/2019, European Commission 952480, ERC under the European Union 758316, Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENHI) JP18H05543 MEXT KAKENHI, Swedish Research Council 2016-05996, NCN UMO-2021/41/B/ST2/02778, NSF-BSF, US-Israel Binational Science Foundation, Israel Science Foundation, Azrieli foundation, KIAS Individual Grant at Korea Institute for Advanced Study PG084201, Istituto Nazionale di Fisica Nucleare (INFN), Ministry of Education, Universities and Research (MIUR) 2017X7X85', Spanish Government SEV-2016-0597 Spanish Research Agency (Agencia Estatal de Investigacion) through the Grant IFT Centro de Excelencia Severo Ochoa FPA2016-78022-P, European Union's Horizon 2020 Research and Innovation Programme 824093, National Natural Science Foundation of China (NSFC) 12175039, 2021 Jiangsu Shuangchuang (Mass Innovation and Entrepreneurship) Talent Program JSSCBS20210144, Fundamental Research Funds for the Central Universities, Arthur B McDonald Canadian Astroparticle Physics Research Institute, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), United States Department of Energy (DOE) DE-SC0012447 DE-SC0009824 DE-SC0013880 :The US DOE DE-SC-0010113 DOE DE-SC-0009913 US DOE DE-SC0009956 DE-FG02-13ER41976/DESC0009913 US DOE JP20K04004

We initiate the study of dark matter models based on a gapped continuum. Dark matter consists of a mixture of states with a continuous mass distribution, which evolves as the universe expands. We present an effective field theory describing the gapped continuum, outline the structure of the Hilbert space and show how to deal with the thermodynamics of such a system. This formalism enables us to study the cosmological evolution and phenomenology of gapped continuum DM in detail. As a concrete example, we consider a weakly-interacting continuum (WIC) model, a gapped continuum counterpart of the familiar WIMP. The DM interacts with the SM via a Z-portal. The model successfully reproduces the observed relic density, while direct detection constraints are avoided due to the effect of continuum kinematics. The model has striking observational consequences, including continuous decays of DM states throughout cosmological history, as well as cascade decays of DM states produced at colliders. We also describe how the WIC theory can arise from a local, unitary scalar QFT propagating on a five-dimensional warped background with a soft wall., 45 pages, 7 figures; Version published in PRD

We examine the possibility that dark matter (DM) consists of a gapped continuum, rather than ordinary particles. A Weakly-Interacting Continuum (WIC) model, coupled to the Standard Model via a Z-portal, provides an explicit realization of this idea. The thermal DM relic density in this model is naturally consistent with observations, providing a continuum counterpart of the "WIMP miracle". Direct detection cross sections are strongly suppressed compared to ordinary Z-portal WIMP, thanks to a unique effect of the continuum kinematics. Continuum DM states decay throughout the history of the universe, and observations of cosmic microwave background place constraints on potential late decays. Production of WICs at colliders can provide a striking cascade-decay signature. We show that a simple Z-portal WIC model provides a fully viable DM candidate consistent with all current experimental constraints., Comment: 9 pages, 5 figures; Version published in PRL

We generalize the recently proposed continuum dark matter model to the case where the dark matter consists of a spin-$1/2$ or spin-$1$ gapped continuum. We construct simple continuum analogs of weakly interacting massive particles annihilating through the $Z$ portal. We discuss all existing experimental constraints, with the strongest bounds arising from indirect detection and limits on continuum decays from the cosmic microwave background. Our models are phenomenologically viable for gap scales of $60$-$200$ GeV (spin-$1/2$) and $35$-$90$ GeV (spin-$1$), owing to the strong kinematic suppression of direct detection bounds which is unique to continuum states. We comment on future prospects for detection and suggest directions for further continuum model building., Comment: 16 + 8 pages, 3 figures; v2: added references to similar work in Introduction; v3: added comments on other experimental bounds in section 3.2.2, version accepted for publication in JHEP

Hydrogels hold much promise for 3D printing of functional living materials; however, challenges remain in tailoring mechanical robustness as well as biological performance. In addressing this challenge, the modular synthesis of functional hydrogels from 3-arm diblock copolypeptide stars composed of an inner poly(l-glutamate) domain and outer poly(l-tyrosine) or poly(l-valine) blocks is described. Physical crosslinking due to ß-sheet assembly of these star block copolymers gives mechanical stability during extrusion printing and the selective incorporation of methacrylate units allows for subsequent photocrosslinking to occur under biocompatible conditions. This permits direct ink writing (DIW) printing of bacteria-based mixtures leading to 3D objects with high fidelity and excellent bacterial viability. The tunable stiffness of different copolypeptide networks enables control over proliferation and colony formation for embedded Escherichia coli bacteria as demonstrated via isopropyl ß-d-1-thiogalactopyranoside (IPTG) induction of green fluorescent protein (GFP) expression. This translation of molecular structure to network properties highlights the versatility of these polypeptide hydrogel systems with the combination of writable structures and biological activity illustrating the future potential of these 3D-printed biocomposites.

Although the Higgs potential in the Standard Model (SM) contains only a simple electroweak symmetry breaking vacuum in the small field region, additional metastable or global vacua could exist in models beyond the SM. In this paper, we study one intriguing scenario with an additional electroweak symmetric vacuum that could be the global one. For the thermal universe ending at the current metastable vacuum, the electroweak symmetry should stay non-restored at high temperatures. We realize the scenario in a model with Higgs-portal couplings to SM singlet scalars with approximately global O(N) symmetries with a large N. For a large portion of model parameter space, both the quantum and thermal tunneling rates are suppressed such that our current metastable vacuum is long-lived enough. Our scenario predicts order-one changes for the Higgs self-couplings and a large contribution to the signal of the off-shell Higgs invisible decay. It can be partly probed at the LHC Run 3 and well tested at the high luminosity LHC. We also discuss the subcritical (anti-de Sitter) bubbles from the thermal tunneling that could have a large population and interesting cosmological implications., 38 pages, 9 figures; v2: references added, final version in JHEP

The retinoblastoma tumour suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate, and render RB inactive in late G1/S, promoting entry into S phase. Recently, mono-phosphorylated RB species were described to have distinct cell-cycle independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output. We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK, and RB S838/T841 phosphorylation. This signaling pathway disrupts RB and condensin II interaction with chromatin. Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin.

Vestibular schwannomas (VS) are benign tumors stemming from the eighth cranial nerve. Treatment options for VS include conservative management, microsurgery, stereotactic radiosurgery, and fractionated radiotherapy. Though microsurgery has been the standard of care for larger lesions, hypo-fractionated stereotactic radiotherapy (hypo-FSRT) is an emerging modality. However, its clinical efficacy and safety have yet to be established. We conducted a systematic review and meta-analysis of manuscripts indexed in PubMed, Scopus, Web of Science, Embase, and Cochrane databases reporting outcomes of VS cases treated with hypo-FSRT. Five studies representing a total of 228 patients were identified. Across studies, the pooled rates of tumor control, hearing, facial nerve, and trigeminal nerve preservation were 95%, 37%, 97%, and 98%. No instances of malignant induction were observed at median follow-up of 34.8 months. Complications included trigeminal neuropathy (n = 3), maxillary paresthesia (n = 1), neuralgia (n = 1), vestibular dysfunction (n = 1), radionecrosis (n = 1), and hydrocephalus (n = 1). Hypo-FSRT may be another useful approach to manage VS, but studies with extended follow-up times are required to establish long-term safety.

Glomus tumors are rare mesenchymal neoplasms with a phenotype akin to the modified smooth muscle cells of the glomus body. Most are benign, but rare examples show malignant histologic characteristics and aggressive behavior. We recently encountered a malignant glomus tumor with BRAF V600E mutation. We sought to study a large cohort for this mutation, with particular attention to associated malignant histologic characteristics. Tumors were classified based on WHO criteria as benign, uncertain malignant potential (glomus tumors of uncertain malignant potential-GT-UMP), or malignant. Tumors were screened for BRAF V600E by immunohistochemistry, and positive staining was evaluated further by Sanger sequencing. A total of 102 glomus tumors were included and classified as benign (57, 56%), GT-UMP (15, 15%) and malignant (30, 29%). Tumors occurred in patients aged 8 to 89.9 years (median: 50.2), without sex predilection (55% men). Most occurred in the superficial soft tissue (84%) and upper extremities (55%). Six of 95 tested cases had BRAF V600E mutation (6%), including 0 of 57 benign tumors, 3 of 14 GT-UMP (21%), and 3 of 24 malignant tumors (12%). Follow-up was obtained for 59 cases (median: 75.7 mo, range: 7.8 to 268.5). Three of 11 malignant tumors (27%) had progressive disease: 1 with metastasis to brain and heart, 1 with enlarging residual disease, and 1 with recurrence. Two of 4 GT-UMP (50%) had progressive disease: 1 with metastasis to lung, and 1 with local recurrence (50%). Three of 44 benign tumors (7%) had local recurrence. Two of 5 patients with BRAF V600E had progression, including 1 GT-UMP with local recurrence and 1 malignant tumor with enlarging residual disease. In summary, BRAF V600E mutation was detected in 6% of glomus tumors, all of which were malignant or GT-UMP. This mutation may be associated with a malignant phenotype, although study of additional cases is needed. In patients with progressive disease, BRAF could be a promising therapeutic target.

ADIPOQ/adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of ADIPOQ/adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that ADIPOQ/adiponectin induces a robust accumulation of autophagosomes, increases MAP1LC3B-II/LC3B-II and decreases SQSTM1/p62 in breast cancer cells. ADIPOQ/adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins. LysoTracker Red-staining and tandem-mCherry-GFP-LC3B assay show that fusion of autophagosomes and lysosomes is augmented upon ADIPOQ/adiponectin treatment. ADIPOQ/adiponectin significantly inhibits breast cancer growth and induces apoptosis both in vitro and in vivo, and these events are preceded by macroautophagy/autophagy, which is integral for ADIPOQ/adiponectin-mediated cell death. Accordingly, blunting autophagosome formation, blocking autophagosome-lysosome fusion or genetic-knockout of BECN1/Beclin1 and ATG7 effectively impedes ADIPOQ/adiponectin induced growth-inhibition and apoptosis-induction. Mechanistic studies show that ADIPOQ/adiponectin reduces intracellular ATP levels and increases PRKAA1 phosphorylation leading to ULK1 activation. AMPK-inhibition abrogates ADIPOQ/adiponectin-induced ULK1-activation, LC3B-turnover and SQSTM1/p62-degradation while AMPK-activation potentiates ADIPOQ/adiponectin's effects. Further, ADIPOQ/adiponectin-mediated AMPK-activation and autophagy-induction are regulated by upstream master-kinase STK11/LKB1, which is a key node in antitumor function of ADIPOQ/adiponectin as STK11/LKB1-knockout abrogates ADIPOQ/adiponectin-mediated inhibition of breast tumorigenesis and molecular analyses of tumors corroborate in vitro mechanistic findings. ADIPOQ/adiponectin increases the efficacy of chemotherapeutic agents. Notably, high expression of ADIPOQ receptor ADIPOR2, ADIPOQ/adiponectin and BECN1 significantly correlates with increased overall survival in chemotherapy-treated breast cancer patients. Collectively, these data uncover that ADIPOQ/adiponectin induces autophagic cell death in breast cancer and provide in vitro and in vivo evidence for the integral role of STK11/LKB1-AMPK-ULK1 axis in ADIPOQ/adiponectin-mediated cytotoxic autophagy.

To assess the utility of frequent sodium checks (every 6h) in patients receiving hypertonic saline (HS) after elective brain tumor surgeries.A single-institution retrospective review of patients having undergone elective craniotomies for brain tumors and treated with postoperative continuous intravenous infusions of 3% HS was performed. Changes in serum sodium values were analyzed at different time points. The rates of12.5, 25, and 50cc/h infusions were also examined. Healthcare cost analysis was performed by extrapolating our cohort to the total number of craniotomies performed in the United States.No significant differences among sodium values checked between 0 to 4, 4-6, 6-8, 8-10, and10h were observed (P=.64). In addition, no differences in serum sodium values among the rates of12.5, 25, and 50cc/h were found (P=.30). No patients developed symptoms of acute hypernatremia.Serum sodium values did not significantly change more than 10h after infusion of HS. Further studies are needed to determine the optimal frequency of routine sodium checks to increase the quality of care and decrease healthcare costs.

Pineal germ cell tumors (GCTs) are primarily seen in pediatric and Asian populations. These tumors are divided into germinomatous and non-germinomatous GCTs (NGGCTs). GCTs are thought to arise by misplacement of totipotent stem cells en route to gonads during embryogenesis. Intracranial GCTs display an affinity to develop along the pineal-suprasellar axis and have variable manifestations dependent upon the location of the tumor. Management and outcomes are driven by histopathologies. In this study, we highlight two cases of pineal GCTs and present a review of the literature with an emphasis on histopathologies and biomarkers.

Objective To review the literature on isolated transverse process fractures (ITPFs) and provide evidence for the current practice of conservative management. Methods The PubMed database was searched for published literature related to ITPFs. Baseline patient (age, sex, presentation, and mechanism of injury) and fracture (number of fractures, level, and single or multisegmental) characteristics were extracted. Management and outcomes were also recorded. Statistical comparisons were ascertained through n–1 Pearson χ 2 tests. Results A total of 4 studies comprised of 398 patients with 819 ITPFs were evaluated. Mean age was 33.5 years (69% men and 31% women). No patients presented with neurologic deficits. The most common mechanism of injury was motor vehicle accident (MVA), followed by fall. MVAs were more commonly the cause of ITPFs in pediatric versus adult patients (88% vs. 65%, respectively; P = 0.0001). Falls were more commonly the cause of ITPFs in adults than in children (18% vs. 9%, respectively; P = 0.05). Management strategies involved unrestricted movement, bracing, and orthotics. Radiologic evidence of spinal instability or deformity was not reported in any of the cases. Mean follow-up was 20.5 months. Conclusions Our data suggests that nonsurgical management of ITPFs leads to complete resolution of the fracture without evidence of permanent neurologic deficit or spinal instability. However, interpretation of our results is limited by the paucity of meaningful literature reporting on long-term outcomes. Nevertheless, the results provide support for conservative management and highlight the existing need to identify markers or scenarios where the diagnosis of ITPF is actually likely to be erroneous.

Off-shell Higgs bosons at the high mass tail may shed light on the underlying mechanism of the electroweak symmetry breaking. In the Standard Model, there is an exact cancellation of the logarithmic divergence between the box and Higgs-mediated triangle diagrams due to unitarity, such that the gg→ZZ(WW) process is left with a negligible VLVL longitudinal mode contribution in the tail region of the off-shell Higgs boson. We propose to test the unitarity of the Standard Model by probing this behavior, as new physics violating this cancellation at certain tail region can be probed by a precision study of the VLVL mode. To this end, we propose to utilize the information in angular observables to maximize the sensitivity of the VLVL final states in the high mass tail region.

Objective To identify perioperative factors that may predict postoperative cerebrospinal fluid (CSF) leak and meningitis following expanded endoscopic transsphenoidal surgery (EETS). Study Design This is a retrospective study. This study was set at the Cedars-Sinai Medical Center, Los Angeles. A total of 78 patients who underwent EETS between January 2007 and November 2018 were participated. The main outcome measures were CSF leak and meningitis. Results A total of 78 patients underwent a total of 100 EETS procedures; 17.9 and 10.3% of patients developed postoperative CSF leaks and meningitis, respectively. Out of eight, three patients with meningitis did not develop an observable CSF leak. The risk of developing meningitis in patients with a CSF leak was significantly higher than those without a leak, with an odds ratio (OR) of 11.48 (95% confidence interval, 2.33–56.47; p = 0.004). Pituicytomas were significantly associated with meningitis compared with other pathologies. No other patient-specific factors were identified as risks for leak or meningitis, including method of skull base repair, sex, tumor volume, or body mass index, although there was a strong trend toward reduced CSF leak rates in patient with nasoseptal flaps used for skull base repair, compared with those without (9.5 vs. 25%). CSF protein was consistently elevated on the first CSF values obtained when meningitis was suspected. Conclusion CSF leak and meningitis are common complications of expanded endonasal surgery No statistically significant risk factors for developing a postoperative leak other than the pathology of pituicytoma were identified, including method of skull base repair, although the use of a vascularized nasoseptal flap did trend toward a reduced CSF leak rate. CSF protein is the most sensitive marker for the presumptive diagnosis and timely treatment of meningitis.

Peripheral nerve stimulators serve as an alternative modality to treat chronic pain conditions; however, long-term complications, specifically lead migration, may occur., Introduction: Peripheral nerve stimulators have emerged as a new generation of advanced modalities to treat chronic pain and avoid opioids. They transmit electrical stimulation through implanted leads and wireless, wearable, external generators. Common complications include infection, nerve damage, and migration of stimulating leads. This article describes 2 cases of complications from lead migration. Methods: Case 1 describes a 61-year-old man with chronic groin pain who underwent an uncomplicated ultrasound-guided ilioinguinal peripheral nerve lead implantation. Case 2 describes a 54-year-old woman with left shoulder pain who underwent an uncomplicated ultrasound-guided percutaneous lead placement near the axillary nerve through a deltoid approach. Both peripheral nerve stimulators were confirmed with fluoroscopy, and each patient was followed up every 2 months for the following 2 years. Results: Both patients experienced lead migration to the skin resulting in erythema and need for lead removal. Initial unsuccessful removal by traction resulted in retained fragments and need for open surgical removal. Discussion: Neurologic complications of peripheral nerve stimulator implantation are rare, but device-associated complications, specifically lead migration, remain a source of long-term problems that can result in decreased coverage of the intended neural target. Conclusion: Thorough patient education, early postimplantation assessment, and extended routine follow-up are necessary to decrease lead-associated complications. If migration does occur, the potential impact of scar tissue on removal should be considered.

Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a novel minimally invasive modality that uses heat from laser probes to destroy tissue. Advances in probe design, cooling mechanisms, and real-time MR thermography have increased laser utilization in neurosurgery. The authors perform a systematic analysis of two commercially available MRgLITT systems used in neurosurgery: the Visualase® thermal therapy and NeuroBlate® Systems. Data extraction was performed in a blinded fashion. Twenty-two articles were included in the quantitative synthesis. A total of 223 patients were identified with the majority having undergone treatment with Visualase (n=154, 69%). Epilepsy was the most common indication for Visualase therapy (n=8 studies, 47%). Brain mass was the most common indication for NeuroBlate therapy (n=3 studies, 60%). There were no significant differences, except in age, wherein the NeuroBlate group was nearly twice as old as the Visualase group (p

Neurosurgery has undergone a technological revolution over the past several decades, from trephination to image-guided navigation. Advancements in virtual reality (VR) and augmented reality (AR) represent some of the newest modalities being integrated into neurosurgical practice and resident education. In this review, we present a historical perspective of the development of VR and AR technologies, analyze its current uses, and discuss its emerging applications in the field of neurosurgery.

HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1. VIDEO ABSTRACT.

This article examines the characteristics of transient voltage in long-distance cables in the subsea environment. The effects of changes in temperature and pressure (caused by changes in the ocean depth) on the transient voltage in cables were quantitatively analyzed. To interpret the characteristics of transient voltage, the transmission line was equalized as a π-type circuit, and the effects of inductance, resistance, and capacitance (L, R, and C) according to the changes in temperature and pressure were mathematically modeled. Thus, we confirmed that the effect of temperature on transient voltage generated in cables is approximately 10-fold greater than the effect of pressure. Furthermore, using a fast Fourier transform analysis, we verified that the rate of change in the conducted noise caused by transient voltage generation is 0.001 dB/°C. Thus, through this study, we were able to quantitatively identify the effects of the subsea environment on conducted noise generation in cables.

Pathological evidence for selective four repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10-skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.

Background: Patients undergoing arthroplasty require appropriate postsurgical pain relief. Analgesia is typically achieved through bolus doses of short-acting local anesthetics and with oral analgesics such as opiates, which are associated with systemic side effects. By formulating an injectable thermosensitive gelling system containing lidocaine, sustained and local delivery can be achieved following a single administration. Results: Poloxamer-based thermosensitive gelling formulations were prepared. Altering the weight ratios of poloxamers affected the sol-to-gel transition temperature, mechanical and rheological properties and in vitro drug release. Desirable formulations gelled between 28 and 33°C providing sustained release of lidocaine over 48 h. Conclusion: Thermosensitive gelling systems are promising for sustained drug release following patient administration and may be beneficial in addressing postoperative pain.

Introduction: Peritoneal immune system plays an important role during the peritoneal dissemination of colon cancers. Therefore, tumor-induced T cell anergy in peritoneal cavity could lead to immune evasion and the progression of peritoneal carcinomatosis. Here, we aimed to reverse the immune evasion in peritoneal cavity and effectively suppress the peritoneal carcinomatosis of colon cancer by STING-based immunotherapy. Methods: We established an animal model of peritoneal carcinomatosis by intraperitoneal injection of MC38 colon cancer cells to C57BL/6 mice. Temporal changes in peritoneal immune microenvironment during peritoneal tumor dissemination were first characterized by analyzing tumor nodules, malignant ascites, and peritoneum lavage by flow cytometry. Then, tumor-bearing mice were treated with either STING agonist (ADU-S100), and/or anti-PD-1 antibody. Tumor burden and the volume of ascites were assessed after the treatment. The tumors were analyzed with flow cytometric, histologic, and RNA sequencing analyses. Results: The intraperitoneal inoculation of MC38 colon cancer cells led to dramatic immune cell changes in peritoneal cavity. While the number of myeloid-derived suppressor cells (MDSCs) were markedly increased, the number of CD8+ T cells and dendritic cells gradually decreased after initial influx in the peritoneal cavity. Treatment with STING agonist remarkably suppressed the growth of peritoneal seeding nodules (75%). Moreover, normalization and reduction of peritoneal tumor blood vessels resulted in an overt decrease in malignant ascites (85%) in the peritoneal cavity after STING agonist treatment. In addition, the number of dendritic cells and CD8+ T cells had markedly increased, but that of MDSCs was decreased in the peritoneal cavity. Moreover, the number of IFN-gamma-secreting cytotoxic T cells were increased in tumor nodules and peritoneal cavity after STING agonist treatment. Finally, the combination immunotherapy of STING agonist and anti-PD1 antibody induced stronger adaptive immunity against peritoneal carcinomatosis than monotherapy and showed potent anti-cancer activity with reduced ascites formation. Conclusion: STING immunotherapy can normalize peritoneal tumor vasculature and immune system, and synergize with immune checkpoint blockade to control peritoneal carcinomatosis of colon cancer. Citation Format: Hannah Yang, Seung Jun Lee, Yu Seong Lee, Won Suk Lee, So Jung Kong, Beodeul Kang, Hong Jae Chon, Chan Kim. Peritoneal immune evasion can be overcome with STING agonist treatment in peritoneal carcinomatosis of colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2838.

Off-shell Higgs at the high mass tail may shed light on the underlying mechanism of the electroweak symmetry breaking. Due to the large cancellation in the standard model (SM) between the box and Higgs-mediated triangle diagrams, the $gg\to WW(ZZ)$ process in the SM is dominated by the $V_T V_T$ transverse-mode at the high mass tail. The cancellation does not necessarily hold, when there is a sufficiently large new physics contribution resulting in $V_LV_L$ longitudinal mode, which is commonly the case when the Higgs sector is modified. Thus the $V_LV_L$ final states in the high mass tail can be utilized as a sensitive probe for such models. In the paper we focus on a study of the $gg \to ZZ$ process in the fully leptonic decay modes, proposing to utilize the polarization modes of the off-shell Higgs to probe new physics, whose contribution mainly shows in the longitudinal mode. As examples, we analyze three different Higgs sector new physics cases (Higgs portal with a light scalar, a broad-width scalar that mixes with the Higgs, and quantum critical Higgs models), and demonstrate that the angular information relating to the polarization serves as very sensitive probe for such new physics., Comment: 6 pages, 2 figures, 1 table

Background Previous studies support beneficial effects of both resistance exercise training (RT) and caloric restriction (CR) on skeletal muscle strength and physical performance. The goal of this study was to determine the effects of adding CR to RT on single-muscle fiber contractility responses to RT in older overweight and obese adults. Methods We analyzed contractile properties in 1,253 single myofiber from muscle biopsies of the vastus lateralis, as well as physical performance and thigh muscle volume, in 31 older (65-80 years), overweight or obese (body mass index = 27-35 kg/m2) men (n = 19) and women (n = 12) who were randomly assigned to a standardized, progressive RT intervention with CR (RT+CR; n = 15) or without CR (RT; n = 16) for 5 months. Results Both interventions evoked an increase in force normalized to cross-sectional area (CSA), in type-I and type-II fibers and knee extensor quality. However, these improvements were not different between intervention groups. In the RT group, changes in total thigh fat volume inversely correlated with changes in type-II fiber force (r = -.691; p = .019). Within the RT+CR group, changes in gait speed correlated positively with changes in type-I fiber CSA (r = .561; p = .030). In addition, increases in type-I normalized fiber force were related to decreases in thigh intermuscular fat volume (r = -0.539; p = .038). Conclusion Single muscle fiber force and knee extensor quality improve with RT and RT+CR; however, CR does not enhance improvements in single muscle fiber contractility or whole muscle in response to RT in older overweight and obese men and women.

PD-L1 plays a central role in immune recognition of cancer cells. In this issue of Molecular Cell, Jin et al. (2019) report that a phosphorylated retinoblastoma protein contacts the DNA-binding domain of p65 NF-kB, thereby blocking transcription of PD-L1.

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development.

Antisense oligonucleotides (ASOs) are synthetic oligonucleotides that alter expression of disease-associated transcripts via Watson–Crick hybridization. ASOs that function through RNase H or the RNA-induced silencing complex (RISC) result in enzymatic degradation of target RNA. ASOs designed to sterically block access of proteins to the RNA modulate mRNA metabolism but do not typically cause degradation. Here, we rationally design steric blocking ASOs to promote mRNA reduction and characterize the terminating mechanism. Transfection of ASOs complementary to constitutive exons in STAT3 and Sod1 results in greater than 70% reduction of mRNA and protein. The ASOs promote aberrant exon skipping and generation of premature termination codon (PTC)-containing mRNAs. We inhibit the nonsense-mediated mRNA decay (NMD) pathway and show that the PTC-containing mRNAs are recognized by the UPF1 ATPase, cleaved by the SMG6 endonuclease and degraded by the XRN1 cytoplasmic exonuclease. NMD surveillance, however, does not entirely explain the mechanism of decreased STAT3 expression. In addition to exon skipping, ASO treatment causes intron retention and reduction of chromatin-associated STAT3 mRNA. The application of steric blocking ASOs to promote RNA degradation allows one to explore more nucleotide modifications than tolerated by RNase H or RISC-dependent ASOs, with the goal of improving ASO drug properties.

AITR (activation-inducible TNFR family receptor, human GITR), an inducible costimulatory receptor of human T cells, is expressed constitutively on Treg and inducible on Teff upon antigen engagement. AITR co-stimulates T cell activation and recruits certain members of TRAF family upon interaction with its ligand. We examined whether the stimulation of distinct regions of extracellular domain of AITR can generate signals that promote different subsets of CD4+ T cells. We found that crosslinking AITR by agonistic anti-AITR Abs (A27, A41, and A35), that recognize three distinct regions of the extracellular domain, polarize CD4+ T cells into Th1, Th2 and Th17, respectively. The subset polarization evoked by these antibodies was the result of recruitment of specific TRAFs, phosphorylation of distinct STATs and expression of Th subset fate-determining master regulatory genes. Stimulation with A27 recruited TRAF-1 and -2, activated STAT-1, -4 and JNK1/2, and induced transcription factor T-bet. On the other hand, activation with A35 recruited TRAF-6, activated STAT-3 and p38 MAPK, and induced RORγt. In contrast, A41 recruited TRAF-3 and -5, activated STAT-5, -6 and ERK1/2, and produced GATA-3. Remarkably, A27 induced the conversion of CD25+Foxp3+ Treg cells to IFN-γ-producing Th1 cells with a concomitant suppression of Foxp3 and TGF-β expression both in healthy individuals as well as cancer patients. A35 also, but not A41, suppressed the expression of Foxp3 and induced IL-17 in Treg cells. A27 alone, but not others produced a strong anti-tumor effect in a human tumor xenograft model of humanized mice in an IFN-γ- and Treg conversion-dependent mechanism. Taken together, the data that AITR regulates Th subset polarization and eradicates solid tumors can be a target for broad-spectrum immune check point therapeutics against cancers and autoimmune diseases. Citation Format: Byoung S. Kwon, Seung J. Lee, Young H. Kim, Joong W. Lee, Sun H. Hwang, Dass S. Vinay. Activation-inducible TNFR family receptor (AITR) signaling mediates the polarization of CD4+ T cells into Th1, Th2, and Th17, converts Treg to Teff and eradicates solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3235.

Repetitive genomic regions include tandem sequence repeats and interspersed repeats, such as endogenous retroviruses and LINE-1 elements. Repressive heterochromatin domains silence expression of these sequences through mechanisms that remain poorly understood. Here, we present evidence that the retinoblastoma protein (pRB) utilizes a cell-cycle-independent interaction with E2F1 to recruit enhancer of zeste homolog 2 (EZH2) to diverse repeat sequences. These include simple repeats, satellites, LINEs, and endogenous retroviruses as well as transposon fragments. We generated a mutant mouse strain carrying an F832A mutation in Rb1 that is defective for recruitment to repetitive sequences. Loss of pRB-EZH2 complexes from repeats disperses H3K27me3 from these genomic locations and permits repeat expression. Consistent with maintenance of H3K27me3 at the Hox clusters, these mice are developmentally normal. However, susceptibility to lymphoma suggests that pRB-EZH2 recruitment to repetitive elements may be cancer relevant.

Central neurocytoma (CN) is a rare, benign brain tumor often located in the lateral ventricles. CN may cause obstructive hydrocephalus and manifest as signs of increased intracranial pressure. The goal of treatment for CN is a gross total resection (GTR), which often yields excellent prognosis with a very high rate of tumor control and survival. Adjuvant radiosurgery and radiotherapy may be considered to improve tumor control when GTR cannot be achieved. Chemotherapy is also not considered a primary treatment, but has been used as a salvage therapy. The radiological features of CN are indistinguishable from those of other brain tumors; therefore, many histological markers, such as synaptophysin, can be very useful for diagnosing CNs. Furthermore, the MIB-1 Labeling Index seems to be correlated with the prognosis of CN. We also discuss oncogenes associated with these elusive tumors. Further studies may improve our ability to accurately diagnose CNs and to design the optimal treatment regimens for patients with CNs.

Objective: To assess the frequency of physician business card utilization among neurosurgery residents and its impact on patient satisfaction, reflected in scores on the CI-CARE patient survey. The authors hypothesize that neurosurgeons hand out business cards less frequently and that this may have potential implications for patient satisfaction. Methods: A retrospective review of patient survey results was performed. Residents were divided into two groups: 1) business card use and 2) no business card use. Scores on survey questions, which pertained to overall communication, medical expertise, and quality of care delivered were compared between groups using a Mann-Whitney U test. Results: A total of 4222 surveys of 367 residents across 9 departments were collected. PGY-1 and -2 residents were most frequently evaluated (n = 1647, 39% and n = 1416, 33.5%, respectively) and handed out the most business cards (n = 398, 25.4% and n = 302, 22%, respectively). PGY-1 and -2 residents who handed out business cards were perceived by patients to be better overall communicators and have greater medical expertise (P

Cerebellopontine angle (CPA) lipomas are rare, benign, slow-growing masses. Resections are considered in symptomatic patients who are refractory to targeted medical therapies, but at those stages the lipomas have often reached considerable sizes and encompass critical neurovascular structures. The objective of this study is to develop and to evaluate the utility of a scoring system for CPA lipomas. The hypothesis is that CPA lipomas with lower scores are probably best managed with early surgery. The PubMed database was searched using relevant terms. Data on patient and lipoma characteristics were extracted and used to design a scoring system. CPA lipomas were stratified by scores with corresponding managements and outcomes analyzed. One hundred and seventeen patients with CPA lipomas were identified and 40 CPA lipomas were scored. The remaining CPA lipomas were deficient in data and not scored. No lipomas were scored as 1. Score 2 lipomas (n = 12; 30%) most often underwent serial surveillances (n = 5; 41.6%), with the majority of symptoms remaining unimproved (n = 2; 40%). Patients with score 2 CPA lipomas treated with medical therapies (n = 3; 25%) often experienced symptom resolution (n = 2; 66.6%) (p = 0.0499). Patients with score 2 CPA lipomas undergoing surgical resections (n = 3; 25%) all experienced symptom resolution (n = 3; 100%) (p = 0.0499). Score 3 was most common (n = 16; 40%) and these lipomas were often surgically resected (n = 10; 62.5%). The majority of patients with score 3 CPA lipomas having undergone surgical resections (n = 10; 62.5%) experienced symptom improvement (n = 1; 10%) or resolution (n = 4; 40%). Score 2 CPA lipomas are smaller and would be deemed non-surgical in general practice. However, our data suggest that these lipomas may benefit from either medical therapies or early surgical resections. The advantages of early surgery are maximal resection, decreased surgical morbidity, and improved symptom relief.

This case report illustrates the potential fallacy of attributing a patient's symptoms to an incidental finding. Serial imaging of small, asymptomatic cerebellopontine angle (CPA) lipomas is favored. It is imperative to accurately diagnose CPA lipoma on imaging and differentiate it from more common CPA lesions. We herein present a patient with symptoms consistent with Bell's palsy and an incidental finding of a CPA lipoma. Additionally, we performed a review of the literature for case reports of patients presenting with facial symptoms and diagnosed with a CPA lipoma.

Atypical meningioma (AM) is an aggressive subtype of meningioma associated with a high recurrence rates (RR) following surgical resection. Recent studies have compared outcomes of various treatment strategies, but advantages of adjuvant radiosurgery (ARS) over serial surveillance (SS) following subtotal resection (STR) remain unclear. To further elucidate this issue, we systematically analyzed the current literature on AM and compared outcomes of ARS versus SS after STR.Embase, PubMed, and Cochrane databases were queried using relevant search terms. Retrospective case series that described patients with AM treated with ARS and SS after STR were included. Tests of proportions were performed to detect significant variations in RR, 5-year progression-free survival (PFS), and 5-year overall survival (OS) between the treatment strategies (ARS vs. SS) and among individual studies.A total of 619 patients (263 in the ARS group and 356 in the SS group) were identified. Mean RR, 5-year PFS, and 5-year OS were 53.5%, 50.3%, and 74.9%, respectively, for ARS versus 89.8%, 19.1%, and 89.8% for SS. RR differed between treatment strategies and ARS studies (P0.001), and 5-year PFS differed among treatment strategies, ARS, and SS studies (P0.001, P = 0.007, and P0.001, respectively).The data presented here show significant differences in RR and 5-year PFS between ARS and SS, suggesting a potential benefit of ARS. As our understanding of the clinical outcomes of various treatment strategies for AM increases, we also move closer to integrating modalities, such as radiosurgery, into management guidelines.

The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3′ untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism., Abnormal functions of RNA-binding proteins TAF15, FUS and TDP43 are associated with amyotrophic lateral sclerosis. Here, Kapeli et al. characterize the RNA targets of TAF15 and identify points of convergence and divergence between the targets of TAF15, FUS and TDP43 in several neuronal systems.

Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy. publisher: Elsevier articletitle: Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs journaltitle: Neuron articlelink: http://dx.doi.org/10.1016/j.neuron.2016.04.006 content_type: article copyright: © 2016 Elsevier Inc. ispartof: Neuron vol:90 issue:3 pages:535-550 ispartof: location:United States status: published