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The long non-coding RNA EPR is expressed in epithelial tissues, binds to chromatin and controls distinct biological activities in mouse mammary gland cells. Because of its high expression in the intestine, in this study we have generated a colon-specific conditional targeted deletion (EPR cKO) to evaluate EPR in vivo functions in mice. EPR cKO mice display epithelium hyperproliferation, impaired mucus production and secretion, as well as inflammatory infiltration in the proximal portion of the large intestine. RNA sequencing analysis reveals a rearrangement of the colon crypt transcriptome with strong reduction of goblet cell-specific factors including those involved in the synthesis, assembly, transport and control of mucus proteins. Further, colon mucosa integrity and permeability are impaired in EPR cKO mice, and this results in higher susceptibility to dextran sodium sulfate (DSS)-induced colitis and tumor formation. Human EPR is down-regulated in human cancer cell lines as well as in human cancers, and overexpression of EPR in a colon cancer cell line results in enhanced expression of pro-apoptotic genes. Mechanistically, we show that EPR directly interacts with select genes involved in mucus metabolism whose expression is reduced in EPR cKO mice and that EPR deletion causes tridimensional chromatin organization changes.

In the treatment of obesity, nutritional and behavioral modifications are difficult to implement and maintain. Since vegetable consumption is a fundamental part of many dietary interventions and daily nutrient requirements, we developed a novel cellulose-based superabsorbent hydrogel (CB-SAH) platform, inspired by the composition and mechanical properties of raw vegetables, as a mechanobiological therapy. The CB-SAHs properties were studied in a simulated gastrointestinal environment, while their impact on gut tissue was investigated by an ex vivo organ culture (EVOC) model. Functional fibers and raw vegetables were used as reference. CB-SAHs demonstrated orders of magnitude higher elasticity in comparison to the tested functional fibers, however performed similar to the tested raw vegetables. Notably, the biomimetic CB-SAHs with elasticity levels similar to raw vegetables showed benefits in preserving and regulating the gut tissue in the EVOC model. Non-systemic oral mechanotherapeutics based on this technology were advanced through clinical studies, with a first product cleared as an aid for weight management in the US and Europe.

There has been a significant interest in modifications of the standard $\Lambda$ Cold Dark Matter ($\Lambda$CDM) cosmological model prompted by tensions between certain datasets, most notably the Hubble tension. The late-time modifications of the $\Lambda$CDM model can be parametrized by three time-dependent functions describing the expansion history of the Universe and gravitational effects on light and matter in the Large Scale Structure. We perform the first joint Bayesian reconstruction of these three functions from a combination of recent cosmological observations, utilizing a theory-informed prior built on the general Horndeski class of scalar-tensor theories. This reconstruction is interpreted in light of the well-known $H_0$, the $S_8$ and the $A_L$ tensions. We identify the phenomenological features that alternative theories would need to have in order to ease some of the tensions, and deduce important constraints on broad classes of modified gravity models. Among other things, our findings suggest that late-time dynamical dark energy and modifications of gravity are not likely to offer a solution to the Hubble tension, or simultaneously solve the $A_L$ and $S_8$ tensions., Comment: 17 pages, 11 figures

The success of preclinical drug discovery strongly relies on the ability of experimental models to resemble human pathophysiology. The number of compounds receiving approval for clinical use is limited, and this has led to the development of more physiologically relevant cellular models aimed at making preclinical results more prone to be successfully translated into clinical use. In this review, we summarize the technologies available in the field of high-throughput screening (HTS) using complex cellular models, and describe collaborative initiatives, such as EU-OPENSCREEN, which can efficiently support researchers to easily access state-of-the-art chemical biology platforms for improving the drug discovery process.

Gelesis' Oral superabsorbent hydrogels (OSH) are crosslinked cellulose-based materials that expand upon hydration in the gastrointestinal tract and are engineered to mimic the mechanical properties of masticated vegetables. One OSH prototype, denoted Gel-B, was tested in both preventative and treatment settings in murine models of diet-induced obesity. Gel-B administration blunted weight gain, reversed gut atrophy, improved metabolic parameters (glucose and insulin tolerance tests; GTT and ITT) and restored barrier function. Here, we investigated the functional role of the gut microbiome to partially explain these protective metabolic effects. Metabolic disease was induced in both Donor (n=24) and Recipient (n=24) C57BL6/J mice via consumption of a high fat and high cholesterol/carbohydrate (HFHCC) diet for weeks (wks) . Donor mice continued on HFHCC or were treated with HFHCC+Gel-B (2 or 4%) for an additional 6 wks. After 2 wks treatment, Donor fecal samples were processed every other day for intestinal microbiota transplantation (IMT) . Recipient mice continued HFHCC and received IMT derived from either HFHCC or Gel-B (2 or 4%) treated Donors via gavage every other day for 4 wks. At 4 wks, the HFHCC-corrected % body weight difference in Recipients was -10.8% and -9.6% for the 2% Gel-B-derived IMT (p=0.02) , and 4% Gel-B-derived IMT (p= 0.02) respectively. Glucose excursions, AUC 0-2h from GTT, were significantly reduced in both Recipient groups (p=0.for both 2% and 4% Gel-B-derived IMT) . The AUC 0-2h from ITT were significantly increased in the 4% Gel-B-derived IMT Recipients (p=0.04) and trended for the 2% Gel-B-derived IMT group (p=0.13) . The present study demonstrates for the first time that IMT from Gel-B treated Donors confers beneficial metabolic effects in HFHCC treated mice. Future experiments will define Gel-B associated microbiota and examine engraftment and durability of IMT. Disclosure A.Silvestri: None. A.Gil-gomez: None. E.Chiquette: Employee; Gelesis. C.Demitri: Stock/Shareholder; Gelesis. B.W.Jones: Employee; Gelesis. A.Sannino: None. M.Rescigno: Research Support; Gelesis.

E. Abdalla, G. F. Abellán, A. Aboubrahim et al., The standard Λ Cold Dark Matter (ΛCDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions that make the standard model look like an approximation to a more realistic scenario yet to be found. In this paper, we list a few important goals that need to be addressed in the next decade, taking into account the current discordances between the different cosmological probes, such as the disagreement in the value of the Hubble constant H0, the σ8–S8 tension, and other less statistically significant anomalies. While these discordances can still be in part the result of systematic errors, their persistence after several years of accurate analysis strongly hints at cracks in the standard cosmological scenario and the necessity for new physics or generalisations beyond the standard model. In this paper, we focus on the 5.0σ tension between the Planck CMB estimate of the Hubble constant H0 and the SH0ES collaboration measurements. After showing the H0 evaluations made from different teams using different methods and geometric calibrations, we list a few interesting new physics models that could alleviate this tension and discuss how the next decade's experiments will be crucial. Moreover, we focus on the tension of the Planck CMB data with weak lensing measurements and redshift surveys, about the value of the matter energy density Ωm, and the amplitude or rate of the growth of structure (σ8, fσ8). We list a few interesting models proposed for alleviating this tension, and we discuss the importance of trying to fit a full array of data with a single model and not just one parameter at a time. Additionally, we present a wide range of other less discussed anomalies at a statistical significance level lower than the H0–S8 tensions which may also constitute hints towards new physics, and we discuss possible generic theoretical approaches that can collectively explain the non-standard nature of these signals. Finally, we give an overview of upgraded experiments and next-generation space missions and facilities on Earth that will be of crucial importance to address all these open questions., Amin Aboubrahim is supported by the BMBF under contract 05P21PMCAA and by the DFG through the Research Training Network 2149 “Strong and Weak Interactions - from Hadrons to Dark Matter”. Adriano Agnello is supported by a Villum Experiment Grant, project number 36225. Özgür Akarsu acknowledges the support by the Turkish Academy of Sciences in the scheme of the Outstanding Young Scientist Award (TÜBA-GEBİP). Yashar Akrami is supported by Richard S. Morrison Fellowship and LabEx ENS-ICFP: ANR-10-LABX-0010/ANR-10-IDEX-0001-02 PSL*. George Alestas is supported by the project “Dioni: Computing Infrastructure for Big-Data Processing and Analysis” (MIS No. 5047222) co-funded by European Union (ERDF) and Greece through Operational Program “Competitiveness, Entrepreneurship and Innovation”, NSRF 2014-2020. Luca Amendola acknowledges support from DFG project 456622116 and from the CAPES-DAAD bilateral project “Data Analysis and Model Testing in the Era of Precision Cosmology”. Luis A. Anchordoqui and Jorge F. Soriano are supported by the U.S. National Science Foundation (NSF Grant PHY-2112527). Mario Ballardini acknowledges financial support from the contract ASI/INAF for the Euclid mission n.2018-23-HH.0. Micol Benetti acknowledges the Istituto Nazionale di Fisica Nucleare (INFN), sezione di Napoli, iniziativa specifica QGSKY. David Benisty acknowledges the support the supports of the Blavatnik and the Rothschild fellowships. John Blakeslee is supported by NOIRLab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the US National Science Foundation. Thomas Buchert has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement ERC advanced grant 740021–ARTHUS, PI: Thomas Buchert). Erminia Calabrese acknowledges support from the STFC Ernest Rutherford Fellowship ST/M004856/2, STFC Consolidated Grant ST/S00033X/1 and from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 849169). Salvatore Capozziello acknowledges the Istituto Nazionale di Fisica Nucleare (INFN), sezione di Napoli, iniziative specifiche QGSKY and MOONLIGHT2. Javier de Cruz Pérez is supported by a FPI fellowship associated to the project FPA2016-76005-C2-1-P. Peter Denton acknowledges support from the US Department of Energy under Grant Contract DE-SC0012704. Eleonora Di Valentino is supported by a Royal Society Dorothy Hodgkin Research Fellowship. Keith R. Dienes was supported in part by the U.S. Department of Energy under Grant DE-FG02-13ER41976 / DE-SC0009913, and also by the U.S. National Science Foundation through its employee IR/D program. Celia Escamilla-Rivera is supported by DGAPA-PAPIIT UNAM Project TA100122 and acknowledges the Royal Astronomical Society as FRAS 10147 and the Cosmostatistics National Group (CosmoNag) project. Noemi Frusciante is supported by Fundação para a Ciência e a Tecnologia (FCT) through the research grants UIDB/04434/2020, UIDP/04434/2020, PTDC/FIS-OUT/29048/2017, CERN/FIS-PAR/0037/2019 and the personal FCT grant “CosmoTests – Cosmological tests of gravity theories beyond General Relativity” with ref. number CEECIND/00017/2018 and the FCT project “BEYLA–BEYond LAmbda” with ref. number PTDC/FIS-AST/0054/2021. Adrià Gómez-Valent is funded by the Instituto Nazionale di Fisica Nucleare (INFN) through the project “Dark Energy and Modified Gravity Models in the light of Low-Redshift Observations” (n. 22425/2020). Asta Heinesen has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement ERC advanced grant 740021–ARTHUS, PI: Thomas Buchert). J. Colin Hill acknowledges support from NSF grant AST-2108536. The Flatiron Institute is supported by the Simons Foundation. Mustapha Ishak acknowledges that this material is based upon work supported in part by the Department of Energy, Office of Science, under Award Number DE-SC0022184. Michael Klasen is supported by the BMBF under contract 05P21PMCAA and by the DFG through the Research Training Network 2149 “Strong and Weak Interactions - from Hadrons to Dark Matter”. Suresh Kumar gratefully acknowledges support from the Science and Engineering Research Board (SERB), Govt. of India (File No. CRG/2021/004658). Ruth Lazkoz is supported by the Spanish Ministry of Science and Innovation through research projects FIS2017-85076-P (comprising FEDER funds), and also by the Basque Government and Generalitat Valenciana through research projects GIC17/116-IT956-16 and PROMETEO/2020/079 respectively. Benjamin L'Huillier would like to acknowledge the support of the National Research Foundation of Korea (NRF-2019R1I1A1A01063740) and the support of the Korea Institute for Advanced Study (KIAS) grant funded by the government of Korea. Jackson Levi Said would like to acknowledge support from Cosmology@MALTA which is supported by the University of Malta. Roy Maartens is supported by the South African Radio Astronomy Observatory and the National Research Foundation (Grant No. 75415). Valerio Marra thanks CNPq (Brazil) and FAPES (Brazil) for partial financial support. The work of Yuto Minami was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI, Grants No. JP20K14497. The work of Carlos Martins was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation (POCI), and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia in the framework of the project POCI-01-0145-FEDER-028987 and PTDC/FIS-AST/28987/2017. Olga Mena is supported by the Spanish grants PID2020-113644GB-I00, PROMETEO/2019/083 and by the European ITN project HIDDeN (H2020-MSCA-ITN-2019//860881-HIDDeN). Cristian Moreno-Pulido is funded by PID2019-105614GB-C21 and FPA2016-76005-C2-1-P (MINECO, Spain), 2017-SGR-929 (Generalitat de Catalunya) and CEX2019-000918-M (ICCUB) and partially supported by the fellowship 2019 FI_B 00351. Michele Moresco acknowledges support from MIUR, PRIN 2017 (grant 20179ZF5KS) and grants ASI n.I/023/12/0 and ASI n.2018-23-HH.0. Suvodip Mukherjee is supported by the Simons Foundation. Research at Perimeter Institute is supported in part by the Government of Canada through the Department of Innovation, Science and Economic Development and by the Province of Ontario through the Ministry of Colleges and Universities. Pran Nath is supported in part by the NSF Grant PHY-1913328. Savvas Nesseris acknowledges support from the Research Project No. PGC2018-094773-B-C32 and the Centro de Excelencia Severo Ochoa Program No. CEX2020-001007-S. Rafael Nunes acknowledges support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation) under the project No. 2018/18036-5. Eoin Ó Colgáin was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIT) (NRF-2020R1A2C1102899). Supriya Pan acknowledges the financial supports from the Science and Engineering Research Board, Govt. of India, under Mathematical Research Impact-Centric Support Scheme (File No. MTR/2018/000940) and The Department of Science and Technology (DST), Govt. of India, under the Scheme “Fund for Improvement of S&T Infrastructure (FIST)” [File No. SR/FST/MS-I/2019/41]. Santiago E. Perez Bergliaffa acknowledges partial support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)- Código de Financiamento 001, and Universidade do Estado do Rio de Janeiro (Brazil). Leandros Perivolaropoulos acknowledges support by the Hellenic Foundation for Research and Innovation (H.F.R.I.), under the “First call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment Grant” (Project Number: 789). Fabrizio Renzi is supported by the NWO and the Dutch Ministry of Education, Culture and Science (OCW), and from the D-ITP consortium, a program of the NWO that is funded by the OCW. Nils Schöneberg acknowledges the support of the following Maria de Maetzu fellowship grant: Esta publicación es parte de la ayuda CEX2019-000918-M, financiado por MCIN/AEI/10.13039/501100011033. Anjan A Sen acknowledges the funding from SERB, Govt of India under the research grants no: CRG/2020/004347 and MTR/20l9/000599. Arman Shafieloo would like to acknowledge the support by National Research Foundation of Korea NRF-2021M3F7A1082053, and the support of the Korea Institute for Advanced Study (KIAS) grant funded by the government of Korea. M.M. Sheikh-Jabbari acknowledges the support by SarAmadan grant No. ISEF/M/400122. Joan Solà Peracaula is funded by PID2019-105614GB-C21 and FPA2016-76005-C2-1-P (MINECO, Spain), 2017-SGR-929 (Generalitat de Catalunya), CEX2019-000918-M (ICCUB) and also partially supported by the COST Association Action CA18108 “Quantum Gravity Phenomenology in the Multimessenger Approach (QG-MM)”. Denitsa Staicova is supported by Bulgarian NSF grant KP-06-N 38/11. Glenn Starkman is partly supported by a Department of Energy grant DESC0009946 to the particle astrophysics theory group at CWRU. Brooks Thomas is supported in part by the National Science Foundation under Grant PHY-2014104. Luca Visinelli has received support from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement “TALeNT” No. 754496 (H2020-MSCA-COFUND-2016 FELLINI). Shao-Jiang Wang is supported by the National Key Research and Development Program of China Grant No. 2021YFC2203004, No. 2021YFA0718304, the National Natural Science Foundation of China Grant No. 12105344, and the China Manned Space Project with NO.CMS-CSST-2021-B01. Weiqiang Yang has been supported by the National Natural Science Foundation of China under Grants No. 12175096 and No. 11705079, and Liaoning Revitalization Talents Program under Grant no. XLYC1907098. Gong-Bo Zhao is supported by the National Key Basic Research and Development Program of China (No. 2018YFA0404503), NSFC Grants 11925303, 11720101004, and a grant of CAS Interdisciplinary Innovation Team.

In a General Relativistic framework, Gravitational Waves (GW) and Electromagnetic (EM) waves are expected to respond in the same way to the effects of matter perturbations between the emitter and the observer. A different behaviour might be a signature of alternative theories of gravity. In this work we study the cross-correlation of resolved GW events (from compact objects mergers detected by the Einstein Telescope, either assuming or excluding the detection of an EM counterpart) and EM signals (coming both from the Intensity Mapping of the neutral hydrogen distribution and resolved galaxies from the SKA Observatory), considering weak lensing, angular clustering and their cross term ($\mathrm{L \times C}$) as observable probes. Cross-correlations of these effects are expected to provide promising information on the behaviour of these two observables, hopefully shedding light on beyond GR signatures. We perform a Fisher matrix analysis with the aim of constraining the $\{\mu_0,\eta_0,\Sigma_0\}$ parameters, either opening or keeping fixed the background parameters $\{w_0,w_a\}$. We find that, although lensing-only forecasts provide significantly unconstrained results, the combination with angular clustering and the cross-correlation of all three considered tracers (GW, IM, resolved galaxies) leads to interesting and competitive constraints. This offers a novel and alternative path to both multi-tracing opportunities for Cosmology and the Modified Gravity sector., Comment: 36 pages, 13 figures, 4 tables. Matches the published version

BackgroundNatural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms.MethodsNK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models.ResultsWe found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts.ConclusionOur work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies.

The standard Lambda Cold Dark Matter cosmological model provides an amazing description of a wide range of astrophysical and astronomical data. However, there are a few big open questions, that make the standard model look like a first-order approximation to a more realistic scenario that still needs to be fully understood. In this Letter of Interest we will list a few important goals that need to be addressed in the next decade, also taking into account the current discordances present between the different cosmological probes, as the Hubble constant H-0 value, the sigma S-8(8) tension, and the anomalies present in the Planck results. Finally, we will give an overview of upgraded experiments and next-generation space-missions and facilities on Earth that will be of crucial importance to address all these questions. (C) 2021 Elsevier B.V. All rights reserved.

Recently, in [1], we presented the first combined non-parametric reconstruction of the three time-dependent functions that capture departures from the standard cosmological model, $\Lambda$CDM, in the expansion history and gravitational effects on matter and light from the currently available combination of the background and large scale structure data. The reconstruction was performed with and without a theory-informed prior, built on the general Horndeski class of scalar-tensor theories, that correlates the three functions. In this work, we perform a decomposition of the prior and posterior covariances of the three functions to determine the structure of the modes that are constrained by the data relative to the Horndeski prior. We find that the combination of all data can constrain 15 combined eigenmodes of the three functions with respect to the prior. We examine and interpret their features in view of the well-known tensions between datasets within the $\Lambda$CDM model. We also assess the bias introduced by the simplistic parameterizations commonly used in the literature for constraining deviations from GR on cosmological scales., Comment: 19 pages, 6 figures

A precise measurement of the curvature of the Universe is of prime importance for cosmology since it could not only confirm the paradigm of primordial inflation but also help in discriminating between different early-Universe scenarios. Recent observations, while broadly consistent with a spatially flat standard Λ Cold Dark Matter ( Λ CDM) model, show tensions that still allow (and, in some cases, even suggest) a few percent deviations from a flat universe. In particular, the Planck Cosmic Microwave Background power spectra, assuming the nominal likelihood, prefer a closed universe at more than 99% confidence level. While new physics could be at play, this anomaly may be the result of an unresolved systematic error or just a statistical fluctuation. However, since positive curvature allows a larger age of the Universe, an accurate determination of the age of the oldest objects provides a smoking gun in confirming or falsifying the current flat Λ CDM model.

Item does not contain fulltext Information exists when it is being copied—a rather important notion—think of bits, DNA and lottery. This concept is highlighted by Shannon’s classical paper on Information theory which describes a mathematical theory of communication, communication being equal to the copying of information. The second leading notion is that the copying process only works when agreements have been made. Actually, everything we do with computers is based on agreements among people— often in the form of standards.

Gravitational waves can provide an accurate measurement of the luminosity distance to the source, but cannot provide the source redshift unless the degeneracy between mass and redshift can be broken. This makes it essential to infer the redshift of the source independently to measure the expansion history of the Universe. We show that by exploiting the clustering scale of the gravitational wave sources with galaxies of known redshift, we can infer the expansion history from redshift unknown gravitational wave sources. By using gravitational wave sources of unknown redshift that are detectable from the network of gravitational wave detectors with Advanced LIGO design sensitivity, we will be able to obtain accurate and precise measurements of the local Hubble constant, the expansion history of the universe, and the gravitational wave bias parameter, which captures the distribution of gravitational wave sources with respect to the redshift tracer distribution. While we showcase its application to low redshift gravitational waves, this technique will be applicable also to the high redshift gravitational wave sources detectable from Laser Interferometer Space Antenna (LISA), Cosmic Explorer (CE), and Einstein Telescope (ET). Moreover, this method will also be applicable to samples of supernovae and fast radio bursts with unknown or photometric redshifts., 16 pages, 4 figures. Minor changes in the text. Accepted for publication in Phys. Rev. D

Luminosity distance estimates from electromagnetic and gravitational wave sources are generally different in models of dynamical dark energy and gravity beyond the standard cosmological scenario. We show that this leaves a unique imprint on the angular power-spectrum of fluctuations of the luminosity distance of gravitational-wave observations which tracks inhomogeneities in the dark energy field. Exploiting the synergy in supernovae and gravitational wave distance measurements, we build a joint estimator that directly probes dark energy fluctuations, providing a conclusive evidence for their existence in case of detection. Moreover, such measurement would also allow to probe the running of the Planck mass. We discuss experimental requirements to detect these signals., Comment: 9 pages, 2 figures. Matching published version

Lignin-derived degradation products from non-treated (NT) and heat-treated (T) Corsican pine (Pinus nigra subsp. laricio) obtained by pyrolysis–gas chromatography–mass spectrometry (Py–GC–MS) were ...

The standard Λ Cold Dark Matter cosmological model provides a wonderful fit to current cosmological data, but a few statistically significant tensions and anomalies were found in the latest data analyses. While these anomalies could be due to the presence of systematic errors in the experiments, they could also indicate the need for new physics beyond the standard model. In this Letter of Interest we focus on the tension between Planck data and weak lensing measurements and redshift surveys, in the value of the matter energy density Ω m and the amplitude σ 8 (or the growth rate f σ 8 ) of cosmic structure. We list a few promising models for solving this tension, and discuss the importance of trying to fit multiple cosmological datasets with complete physical models, rather than fitting individual datasets with a few handpicked theoretical parameters.

We reconstruct the Equation of State of Dark Energy (EoS) from current data using a non-parametric approach where, rather than assuming a specific time evolution of this function, we bin it in time. We treat the transition between the bins with two different methods, i.e. a smoothed step function and a Gaussian Process reconstruction, investigating whether or not the two approaches lead to compatible results. Additionally, we include in the reconstruction procedure a correlation between the values of the EoS at different times in the form of a theoretical prior that takes into account a set of viability and stability requirements that one can impose on models alternative to $\Lambda$CDM. In such case, we necessarily specialize to broad, but specific classes of alternative models, i.e. Quintessence and Horndeski gravity. We use data coming from CMB, Supernovae and BAO surveys. We find an overall agreement between the different reconstruction methods used; with both approaches, we find a time dependence of the mean of the reconstruction, with different trends depending on the class of model studied. The constant EoS predicted by the $\Lambda$CDM model falls anyway within the $1\sigma$ bounds of our analysis., Comment: 17 pages, 5 figures. Prepared for submission to JCAP

We present a major upgrade of MGCAMB, a patch for the Einstein-Boltzmann solver CAMB used for phenomenological tests of general relativity against cosmological datasets. This new version is compatible with the latest CosmoMC code and includes a consistent implementation of massive neutrinos and dynamical dark energy. The code has been restructured to make it easier to modify to fit the custom needs of specific users. To illustrate the capabilities of the code, we present joint constraints on the modified growth, massive neutrinos and the dark energy equation of state from the latest cosmological observations, including the recent galaxy counts and weak lensing measurements from the Dark Energy Survey, and find a good consistency with the {\Lambda}CDM model., Comment: 11 pages, 3 figures, codes available at https://github.com/sfu-cosmo/MGCAMB and https://github.com/sfu-cosmo/MGCosmoMC

BACKGROUND: Intestinal barrier dysfunction exists when the epithelial tight-junctions are disrupted and permit translocation of bacterial lipopolysaccharides into the blood. The resulting endotoxemia cause systemic low-grade inflammation that contributes to the development of comorbidities associated with obesity like type 2 diabetes and NASH. Superabsorbent hydrogels based on the Gelesis platform technology are orally administered and synthesized from crosslinked modified cellulose. Gelesis100, the first in this class, demonstrated significant weight loss in patients with obesity and improvement in insulin sensitivity. We hypothesized that Gel-B with specific mechanical properties, designed to improve intestinal barrier function, would prevent translocation of small molecule into the blood after intestinal barrier injury. METHODS: Groups of 8 to 15 C57BI/6 male mice were administered 3% dextran sodium sulfate (DSS) in drinking water for a total of 6 days, and randomized to either Vehicle, Gel-B (0.5 to 4%) in their food from days 5 to 19. An active control group received anti-p40 IP q3 days on days 6-18. On day 19, all animals were fasted for 4 hours prior to FITC-Dextran dosing. Three hours post dosing, the mice were sacrificed, colon specimen fixed, and blood collected. The incidence of epithelial barrier breaks was assessed with E-cadherin immunohistochemistry. To verify the involvement of epithelial tight junctions, the expression of ZO-1 was assessed in C57BL/6J mice (5 per group) fed chow, for 4 weeks, with or without Gel-B. RESULTS: The level of FITC-Dextran in the serum of mice receiving DSS and vehicle (mean ± SEM, 7.1 ± 4.1) was 3.4 times higher than the naïve mice (2.1 ± 1.1) demonstrating a significant defect in the gut barrier function. In turn, the mice assigned to Gel-B 1% to 4% had meaningful reduction in FITC-Dextran serum levels compared to vehicle treated mice. The highest dose (4%) of Gel-B prevented spilling of dextran into the circulation with serum levels numerically lower than the naïve group with an intact gut barrier (1.4 ± 0.4 compared to 2.1 ± 1.1, respectively). Accordingly, a reduction in epithelial barrier breaks in distal colon samples was observed in the highest dose of Gel-B (0.58 ± 0.15) compared to vehicle treated animals (0.86 ± 0.1). Healthy mice treated with Gel-B (8%) showed increased expression of ZO-1, essential to tight junction assembly between epithelial cells. CONCLUSION: The present study demonstrated that treatment with Gel-B prevented the translocation of small molecule into the circulation indicating an improved intestinal barrier function. This effect may be explained by a decrease in gaps between the epithelial cells, and increased expression of tight junctions. These findings and future studies could provide new therapeutic approaches for diseases affected by a compromised intestinal barrier function such as obesity, diabetes and NASH. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

The splashback radius $r_\mathrm{sp}$ has been identified in cosmological $N$-body simulations as an important scale associated with gravitational collapse and the phase-space distribution of recently accreted material. We employ a semi-analytical approach to study the spherical collapse of dark matter haloes in symmetron gravity and provide insights into how the phenomenology of splashback is affected. The symmetron is a scalar-tensor theory of gravity which exhibits a screening mechanism whereby higher-density regions are screened from the effects of a fifth force. In this model, we find that, as over-densities grow over cosmic time, the inner region becomes heavily screened. In particular, we identify a sector of the parameter space for which material currently sitting at $r_\mathrm{sp}$ has followed, during the collapse, the formation of this screened region. As a result, we find that for this part of the parameter space the splashback radius is maximally affected by the symmetron force and we predict changes in $r_\mathrm{sp}$ up to around $10\%$ compared to its General Relativity value. Because this margin is within the precision of present splashback experiments, we expect this feature to soon provide constraints for symmetron gravity on previously unexplored scales., 9 pages, 3 figures. Comments are welcome

Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel "sibling" 3D cultures established from a single KRAS-mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients.

The tachyonic instability is associated with the unboundedness of the Hamiltonian from below and results in an unstable low-$k$ regime. In the cosmological exploration of modified gravity, it is seldom taken into account, with more focus given to the popular no-ghost and no-gradient conditions. The latter though are intrinsically high-$k$ statements. Here we combine all three conditions into a full set of requirements that we show to guarantee stability on the whole range of cosmological scales. We then explore the impact of the different conditions on the parameter space of scalar-tensor gravity, with particular emphasis on the no-tachyon one. We focus on Horndeski gravity and also consider separately the two subclasses of $f(R)$ and Generalized Brans Dicke theories. We identify several interesting features, for instance in the parameter space of designer $f(R)$ on a $w$CDM background, shedding light on previous findings. When looking at the phenomenological functions $\Sigma$ and $\mu$, associated to the weak lensing and clustering potential respectively, we find that in the case of Generalized Brans Dicke the no-tachyon condition clearly cuts models with $\mu\,,\,\Sigma>1$. This effect is less prevalent in the Horndeski case due to the larger amount of free functions in the theory., Comment: 9 pages, 4 figures - accepted version by JCAP

Ongoing and upcoming cosmological surveys will significantly improve our ability to probe the equation of state of dark energy, ${w}_{\mathrm{DE}}$, and the phenomenology of large scale structure. They will allow us to constrain deviations from the $\mathrm{\ensuremath{\Lambda}}$ cold dark matter predictions for the relations between the matter density contrast and the weak lensing and the Newtonian potential, described by the functions $\mathrm{\ensuremath{\Sigma}}$ and $\ensuremath{\mu}$, respectively. In this work, we derive the theoretical prior for the joint covariance of ${w}_{\mathrm{DE}}$, $\mathrm{\ensuremath{\Sigma}}$ and $\ensuremath{\mu}$, expected in general scalar-tensor theories with second order equations of motion (Horndeski gravity), focusing on their time-dependence at certain representative scales. We employ Monte Carlo methods to generate large ensembles of statistically independent Horndeski models, focusing on those that are physically viable and in broad agreement with local tests of gravity, the observed cosmic expansion history and the measurement of the speed of gravitational waves from a binary neutron star merger. We identify several interesting features and trends in the distribution functions of ${w}_{\mathrm{DE}}$, $\mathrm{\ensuremath{\Sigma}}$ and $\ensuremath{\mu}$, as well as in their covariances; we confirm the high degree of correlation between $\mathrm{\ensuremath{\Sigma}}$ and $\ensuremath{\mu}$ in scalar-tensor theories. The derived prior covariance matrices will allow us to reconstruct jointly ${w}_{\mathrm{DE}}$, $\mathrm{\ensuremath{\Sigma}}$ and $\ensuremath{\mu}$ in a nonparametric way.

The expansion history of the Universe reconstructed from a combination of recent data indicates a preference for a changing Dark Energy (DE) density. Moreover, the DE density appears to be increasing with cosmic time, with its equation of state being below -1 on average, and possibly crossing the so-called phantom divide. Scalar-tensor theories, in which the scalar field mediates a force between matter particles, offer a natural framework in which the effective DE equation of state can be less than -1 and cross the phantom barrier. We consider the generalized Brans-Dicke (GBD) class of scalar-tensor theories and reconstruct their Lagrangian given the effective DE density extracted from recent data. Then, given the reconstructed Lagrangian, we solve for the linear perturbations and investigate the characteristic signatures of these reconstructed GBD in the cosmological observables, such as the cosmic microwave background (CMB) anisotropy, the galaxy number counts, and their cross-correlations. In particular, we demonstrate that the Integrated Sachs-Wolfe (ISW) effect probed by the cross-correlation of CMB with the matter distribution can rule out scalar-tensor theories as the explanation of the observed DE dynamics independently from the laboratory and solar system fifth force constraints., Comment: 16 pages, 12 figures; a typo in the Section II title corrected in Version 2

Graphical abstract, Highlights • During diet-induced dysbiosis the gut vascular barrier is disrupted. • Gut vascular barrier disruption is responsible for the translocation of bacteria or bacterial products systemically. • Inhibiting gut vascular barrier disruption prevents the development of non-alcoholic steatohepatitis. • Obeticholic acid can control gut vascular barrier disruption both in a preventive and therapeutic way., Background & Aims Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. Methods C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. Results We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. Conclusions We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. Lay summary The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH.

We consider Horava gravity within the framework of the effective field theory (EFT) of dark energy and modified gravity. We work out a complete mapping of the theory into the EFT language for an action including all the operators which are relevant for linear perturbations with up to sixth order spatial derivatives. We then employ an updated version of the EFTCAMB/EFTCosmoMC package to study the cosmology of the low-energy limit of Horava gravity and place constraints on its parameters using several cosmological data sets. In particular we use cosmic microwave background (CMB) temperature-temperature and lensing power spectra by Planck 2013, WMAP low-l polarization spectra, WiggleZ galaxy power spectrum, local Hubble measurements, Supernovae data from SNLS, SDSS and HST and the baryon acoustic oscillations measurements from BOSS, SDSS and 6dFGS. We get improved upper bounds, with respect to those from Big Bang Nucleosynthesis, on the deviation of the cosmological gravitational constant from the local Newtonian one. At the level of the background phenomenology, we find a relevant rescaling of the Hubble rate at all epoch, which has a strong impact on the cosmological observables; at the level of perturbations, we discuss in details all the relevant effects on the observables and find that in general the quasi-static approximation is not safe to describe the evolution of perturbations. Overall we find that the effects of the modifications induced by the low-energy Horava gravity action are quite dramatic and current data place tight bounds on the theory parameters., v1: 27 pages, 7 figures. v2: 28 pages, 7 figures. Changes in Figs. 2,3,4,6,7 and Tabs. 1,2. Matches published version in Phys. Dark Univ

Metformin is the most frequently prescribed drug for type 2 diabetes. In addition to its hypoglycemic effects, metformin also lowers cancer incidence. This anti-cancer activity is incompletely understood. Here, we profiled the metformin-dependent changes in the proteome and phosphoproteome of breast cancer cells using high-resolution mass spectrometry. In total, we quantified changes of 7,875 proteins and 15,813 phosphosites after metformin changes. To interpret these datasets, we developed a generally applicable strategy that overlays metformin-dependent changes in the proteome and phosphoproteome onto a literature-derived network. This approach suggested that metformin treatment makes cancer cells more sensitive to apoptotic stimuli and less sensitive to pro-growth stimuli. These hypotheses were tested in vivo; as a proof-of-principle, we demonstrated that metformin inhibits the p70S6K-rpS6 axis in a PP2A-phosphatase dependent manner. In conclusion, analysis of deep proteomics reveals both detailed and global mechanisms that contribute to the anti-cancer activity of metformin.

Measurements of time delays between multiple quasar images produced by strong lensing are reaching a sensitivity that makes them a promising cosmological probe. Future surveys will provide significantly more measurements, reaching unprecedented depth in redshift, making strong lensing time delay (SLTD) observations competitive with other background probes. We forecast constraints on the nature of dark energy from upcoming SLTD surveys, simulating future catalogues with different numbers of lenses distributed up to redshift $z\sim 1$ and focusing on cosmological parameters such as the Hubble constant $H_0$ and parametrisations of the dark energy equation of state. We also explore the impact of our ability to precisely model the lens mass profile and its environment, on the forecasted constraints. We find that in the most optimistic cases, SLTD will constrain $H_0$ at the level of $\sim 0.1\%$, while the CPL equation of state parameters, $w_0$ and $w_a$, can be determined with errors $\sigma_{w_0}\sim 0.05$ and $\sigma_{w_a}\sim 0.3$, respectively. Furthermore, we investigate the bias introduced when a wrong cosmological model is assumed for the analysis. We find that the value of $H_0$ could be biased up to $10 \sigma$, assuming a perfect knowledge of the lens profile, when a $\Lambda$CDM model is used to analyse data that really belong to a $w$CDM cosmology with $w=-0.9$. Based on these findings, we identify a consistency check of the assumed cosmological model in future SLTD surveys, by splitting the dataset in several redshift bins. Depending on the characteristics of the survey, this could provide a smoking gun for dark energy., Comment: 24 pages, 8 figures

We revisit the cosmology of Covariant Galileon gravity in view of the most recent cosmological data sets, including weak lensing. As a higher derivative theory, Covariant Galileon models do not have a $\Lambda$CDM limit and predict a very different structure formation pattern compared with the standard $\Lambda$CDM scenario. Previous cosmological analyses suggest that this model is marginally disfavoured, yet can not be completely ruled out. In this work we use a more recent and extended combination of data, and we allow for more freedom in the cosmology, by including a massive neutrino sector with three different mass hierarchies. We use the Planck measurements of Cosmic Microwave Background temperature and polarization; Baryonic Acoustic Oscillations measurements by BOSS DR12; local measurements of $H_0$; the joint light-curve analysis supernovae sample; and, for the first time, weak gravitational lensing from the KiDS collaboration. We find, that in order to provide a reasonable fit, a non-zero neutrino mass is indeed necessary, but we do not report any sizable difference among the three neutrino hierarchies. Finally, the comparison of the Bayesian Evidence to the $\Lambda$CDM one shows that in all the cases considered, Covariant Galileon models are statistically ruled out by cosmological data., Comment: 8 pages, 5 figures, 2 tables. The Covariant Galileon patch of EFTCAMB is released in the EFTCAMB developers version - accepted version by PRD

We compare Einstein-Boltzmann solvers that include modifications to General Relativity and find that, for a wide range of models and parameters, they agree to a high level of precision. We look at three general purpose codes that primarily model general scalar-tensor theories, three codes that model Jordan-Brans-Dicke (JBD) gravity, a code that models f(R) gravity, a code that models covariant Galileons, a code that models Ho\v{r}ava-Lifschitz gravity and two codes that model non-local models of gravity. Comparing predictions of the angular power spectrum of the cosmic microwave background and the power spectrum of dark matter for a suite of different models, we find agreement at the sub-percent level. This means that this suite of Einstein-Boltzmann solvers is now sufficiently accurate for precision constraints on cosmological and gravitational parameters., Comment: 23 pages; 11 figures. Matches version accepted in PRD

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Dysregulation of protein synthesis plays a major role in carcinogenesis, a process regulated at multiple levels, including translation of mRNA into proteins. Ribosome assembly requires correct association of ribosome subunits, which is ensured by eukaryotic translation initiation factors (eIFs). eIFs have become targets in cancer therapy studies, and promising data on eIF6 in various cancer entities have been reported. Therefore, we hypothesised that eIF6 represents a crossroad for pulmonary carcinogenesis. High levels of eIF6 are associated with shorter patient overall survival in adenocarcinoma (ADC), but not in squamous cell carcinoma (SQC) of the lung. We demonstrate significantly higher protein expression of eIF6 in ADC and SQC than in healthy lung tissue based on immunohistochemical data from tissue microarrays (TMAs) and on fresh frozen lung tissue. Depletion of eIF6 in ADC and SQC lung cancer cell lines inhibited cell proliferation and induced apoptosis. Knockdown of eIF6 led to pre-rRNA processing and ribosomal 60S maturation defects. Our data indicate that eIF6 is upregulated in NSCLC, suggesting an important contribution of eIF6 to the development and progression of NSCLC and a potential for new treatment strategies against NSCLC.

Phenomenological functions $\Sigma$ and $\mu$, also known as $G_{\rm light}/G$ and $G_{\rm matter}/G$, are commonly used to parameterize modifications of the growth of large-scale structure in alternative theories of gravity. We study the values these functions can take in Horndeski theories, i.e. the class of scalar-tensor theories with second order equations of motion. We restrict our attention to models that are in a broad agreement with tests of gravity and the observed cosmic expansion history. In particular, we require the speed of gravity to be equal to the speed of light today, as required by the recent detection of gravitational waves and electromagnetic emission from a binary neutron star merger. We examine the correlations between the values of $\Sigma$ and $\mu$ analytically within the quasi-static approximation, and numerically, by sampling the space of allowed solutions. We confirm that the conjecture made in [Pogosian:2016pwr], that $(\Sigma-1)(\mu -1) \ge 0$ in viable Horndeski theories, holds very well. Along with that, we check the validity of the quasi-static approximation within different corners of Horndeski theory. Our results show that, even with the tight bound on the present day speed of gravitational waves, there is room within Horndeski theories for non-trivial signatures of modified gravity at the level of linear perturbations., Comment: 12 pages, 5 figures - accepted version by PRD

Over the past decade, the development of new targeted therapeutics directed against specific molecular pathways involved in tumor cell proliferation and survival has allowed an essential improvement in carcinoma treatment. Unfortunately, the scenario is different for sarcomas, a group of malignant neoplasms originating from mesenchymal cells, for which the main therapeutic approach still consists in the combination of surgery, chemotherapy, and radiation therapy. The lack of innovative approaches in sarcoma treatment stems from the high degree of heterogeneity of this tumor type, with more that 70 different histopathological subtypes, and the limited knowledge of the molecular drivers of tumor development and progression. Currently, molecular therapies are available mainly for the treatment of gastrointestinal stromal tumor, a soft-tissue malignancy characterized by an activating mutation of the tyrosine kinase KIT. Since the first application of this approach, a strong effort has been made to understand sarcoma molecular alterations that can be potential targets for therapy. The low incidence combined with the high level of histopathological heterogeneity makes the development of clinical trials for sarcomas very challenging. For this reason, preclinical studies are needed to better understand tumor biology with the aim to develop new targeted therapeutics. Currently, these studies are mainly based on in vitro testing, since cell lines, and in particular patient-derived models, represent a reliable and easy to handle tool for investigation. In the present review, we summarize the most important models currently available in the field, focusing in particular on the three-dimensional spheroid/organoid model. This innovative approach for studying tumor biology better represents tissue architecture and cell–cell as well as cell–microenvironment crosstalk, which are fundamental steps for tumor cell proliferation and survival.

We propose a simple, nonlocal modification to general relativity (GR) on large scales, which provides a model of late-time cosmic acceleration in the absence of the cosmological constant and with the same number of free parameters as in standard cosmology. The model is motivated by adding to the gravity sector an extra spin-2 field interacting nonlocally with the physical metric coupled to matter. The form of the nonlocal interaction is inspired by the simplest form of the Deser-Woodard (DW) model, $\alpha R\frac{1}{\Box}R$, with one of the Ricci scalars being replaced by a constant $m^{2}$, and gravity is therefore modified in the infrared by adding a simple term of the form $m^2\frac{1}{\Box}R$ to the Einstein-Hilbert term. We study cosmic expansion histories, and demonstrate that the new model can provide background expansions consistent with observations if $m$ is of the order of the Hubble expansion rate today, in contrast to the simple DW model with no viable cosmology. The model is best fit by $w_0\sim-1.075$ and $w_a\sim0.045$. We also compare the cosmology of the model to that of Maggiore and Mancarella (MM), $m^2R\frac{1}{\Box^2}R$, and demonstrate that the viable cosmic histories follow the standard-model evolution more closely compared to the MM model. We further demonstrate that the proposed model possesses the same number of physical degrees of freedom as in GR. Finally, we discuss the appearance of ghosts in the local formulation of the model, and argue that they are unphysical and harmless to the theory, keeping the physical degrees of freedom healthy., Comment: 47 pages in JCAP style, 7 figures. Some discussions extended in response to referee's comments. Version accepted for publication in JCAP

We investigate the impact of general conditions of theoretical stability and cosmological viability on dynamical dark energy models. As a powerful example, we study whether minimally coupled, single field Quintessence models that are safe from ghost instabilities, can source the CPL expansion history recently shown to be mildly favored by a combination of CMB (Planck) and Weak Lensing (KiDS) data. We find that in their most conservative form, the theoretical conditions impact the analysis in such a way that smooth single field Quintessence becomes significantly disfavored with respect to the standard LCDM cosmological model. This is due to the fact that these conditions cut a significant portion of the (w0;wa) parameter space for CPL, in particular eliminating the region that would be favored by weak lensing data. Within the scenario of a smooth dynamical dark energy parametrized with CPL, weak lensing data favors a region that would require multiple fields to ensure gravitational stability., 7 pages, 4 figures

For decades of molecular cancer research, immortal cancer cell lines have served as an easily accessible source for basic cancer biology research and preclinical testing of anticancer drugs. However, numerous studies have suggested that these cell lines poorly recapitulate the diversity, heterogeneity, and resulting drug resistance or relapse in patients. The derivation and (short-term) culture of primary cells from solid tumors have thus gained significant importance in personalized cancer therapy. This chapter focuses on our current understanding and the pros and cons of different preclinical and prospective clinical models of three-dimensional primary tumor cultures. We will discuss cell culture approaches, such as biomimetic scaffolds and growth factor supplemented, chemically defined media for various forms of solid tumors. Complex culture models of primary tumor cells could finally provide a key missing link between compound screening and clinical trials and ultimately will help redefining therapeutic intervention with high translational relevance at the level of the individual patient.