Brca2 and Trp53 deficiency cooperate in the progression of mouse prostate tumourigenesis.

Epidemiological studies have shown that one of the strongest risk factors for prostate cancer is a family history of the disease, suggesting that inherited factors play a major role in prostate cancer susceptibility. Germline mutations in BRCA2 predispose to breast and ovarian cancer with its predominant tumour suppressor function thought to be the repair of DNA double-strand breaks. BRCA2 has also been implicated in prostate cancer etiology, but it is unclear the impact that mutations in this gene have on prostate tumourigenesis. Here we have undertaken a genetic analysis in the mouse to determine the role of Brca2 in the adult prostate. We show that deletion of Brca2 specifically in prostate epithelia results in focal hyperplasia and low-grade prostate intraepithelial neoplasia (PIN) in animals over 12 months of age. Simultaneous deletion of Brca2 and the tumour suppressor Trp53 in prostate epithelia gave rise to focal hyperplasia and atypical cells at 6 months, leading to high-grade PIN in animals from 12 months. Epithelial cells in these lesions show an increase in DNA damage and have higher levels of proliferation, but also elevated apoptosis. Castration of Brca2;Trp53 mutant animals led to regression of PIN lesions, but atypical cells persisted that continued to proliferate and express nuclear androgen receptor. This study provides evidence that Brca2 can act as a tumour suppressor in the prostate, and the model we describe should prove useful in the development of new therapeutic approaches

Real time dynamic strain monitoring of optical links using the backreflection of live PSK data.

A major cause of faults in optical communication links is related to unintentional third party intrusions (normally related to civil/agricultural works) causing fiber breaks or cable damage. These intrusions could be anticipated and avoided by monitoring the dynamic strain recorded along the cable. In this work, a novel technique is proposed to implement real-time distributed strain sensing in parallel with an operating optical communication channel. The technique relies on monitoring the Rayleigh backscattered light from optical communication data transmitted using standard modulation formats. The system is treated as a phase-sensitive OTDR (ΦOTDR) using random and non-periodical non-return-to-zero (NRZ) phase-shift keying (PSK) pulse coding. An I/Q detection unit allows for a full (amplitude, phase and polarization) characterization of the backscattered optical signal, thus achieving a fully linear system in terms of ΦOTDR trace coding/decoding. The technique can be used with different modulation formats, and operation using 4 Gbaud single-polarization dual PSK and 4 Gbaud dual-polarization quadrature PSK is demonstrated. As a proof of concept, distributed sensing of dynamic strain with a sampling of 125 kHz and a spatial resolution of 2.5 cm (set by the bit size) over 500 m is demonstrated for applied sinusoidal strain signals of 500 Hz. The limitations and possibilities for improvement of the technique are also discussed.This work was supported by the European Research Council through Starting Grant UFINE (Grant no. 307441), the Spanish MINECO through project TEC2013-45265-R, PCIN-2015- 219, and the regional program SINFOTON-CM: S2013/MIT-2790. HFM acknowledges EU funding through the FP7 ITN ICONE program, gr. #608099. SML acknowledges funding from the Spanish MINECO through a “Ramon y Cajal” contract. UK EPSRC funding through project EP/J008842/1

Three-dimensional culture models to study glioblastoma:current trends and future perspectives

International audienc

Rabi Spectroscopy and Excitation Inhomogeneity in a 1D Optical Lattice Clock

We investigate the influence of atomic motion on precision Rabi spectroscopy of ultracold fermionic atoms confined in a deep, one dimensional (1D) optical lattice. We analyze the spectral components of longitudinal sideband spectra and present a model to extract information about the transverse motion and sample temperature from their structure. Rabi spectroscopy of the clock transition itself is also influenced by atomic motion in the weakly confined transverse directions of the optical lattice. By deriving Rabi flopping and Rabi lineshapes of the carrier transition, we obtain a model to quantify trap state dependent excitation inhomogeneities. The inhomogeneously excited ultracold fermions become distinguishable, which allows s-wave collisions. We derive a detailed model of this process and explain observed density shift data in terms of a dynamic mean field shift of the clock transition.Comment: 11 pages, 8 figures, to appear in Phys. Rev. A. Changes to abstract, text, and figures, new referenc

Association and interaction analyses of eight genes under asthma linkage peaks

Background: Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits. Methods: Ninety-five single nucleotide polymorphisms (SNP) located in eight genes (CD28, CTLA4, ICOS, ADAM23, ADAMTSL1, MS4A2, CDH26 and HRH3) were genotyped in >5000 individuals from Australian (n = 1162), Dutch (n = 99) and Danish (n = 303) families. Traits tested included doctor-diagnosed asthma, atopy, airway obstruction, total serum immunoglobulin (Ig) E levels and eosinophilia. Association was tested using both multivariate and univariate methods, with gene-wide thresholds for significance determined through simulation. Gene-by-gene and gene-by-environment analyses were also performed. Results: There was no overall evidence for association with seven of the eight genes tested when considering all genetic variation assayed in each gene. The exception was MS4A2 on chromosome 11q13, which showed weak evidence for association with IgE (gene-wide P < 0.05, rs502581). There were no significant gene-by-gene or gene-by-environment interaction effects after accounting for the number of tests performed. Conclusions: The individual variants genotyped in the 2q33, 9p21 and 20q13 regions do not explain a large fraction of the variation in the quantitative traits tested or have a major impact on asthma or atopy risk. Our results are consistent with a weak effect of MS4A2 polymorphisms on the variation of total IgE levels. © 2009 John Wiley & Sons A/S

ER stress induces caspase-2-tBID-GSDME-dependent cell death in neurons lytically infected with herpes simplex virus type 2

Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV-induced neuronal cell death remain enigmatic. Here, we report that lytic HSV-2 infection of human neuron-like SH-SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV-2-induced GSDME-mediated cell death occurs downstream of replication-induced endoplasmic reticulum stress driven by inositol-requiring kinase 1α (IRE1α), leading to activation of caspase-2, cleavage of the pro-apoptotic protein BH3-interacting domain death agonist (BID), and mitochondria-dependent activation of caspase-3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC-derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress-driven pathway to execute GSDME-mediated cell death and promote inflammation.</p

Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation

233294Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.We thank Drs. N. Djouder, M. Petruzzelli, R. Ricci, F.X Real, K.D. Bissig, and members of the Wagner laboratory for critical reading of the manuscript and valuable sugges- tions; Dr. H. Schönthaler for help with the bioinformatics analysis; V. Bermeo for technical help; and G. Luque, S. Leceta, and G. Medrano for assisting with mouse experiments. The E.F. Wagner laboratory is supported by grants from the Spanish Ministry of Economy, Industry, and Competitiveness (BFU2012-40230 and SAF2015-70857, co- funded by the European Regional Development Fund), a European Research Council– advanced grant (ERC-FCK/2008/37), and Worldwide Cancer Research (13-0216). R. Hamacher was supported by the Deutsche Forschungsgemeinschaft (HA 6068/1-1), M.K. Thomsen by AUFF Nova, and S.C. Hasenfuss by a Boehringer Ingelheim Fonds PhD fellowship. The authors declare no competing financial interests. Author contributions: L. Bakiri and R. Hamacher designed and performed exper- iments, analyzed data, prepared figures, and wrote the manuscript. O. Graña analyzed RNA-seq and public microarray data, A. Guío-Carrión provided expert technical assis- tance, R. Campos-Olivas acquired and analyzed NMR data, L. Martinez analyzed flow cytometry data, M.K. Thomsen performed experiments with human cell lines, S.C. Hasenfuss performed experiments with primary hepatocytes and data mining, and H.P. Dienes performed pathological analysis on tissue sections. E.F. Wagner directed the study, approved the data, and wrote and edited the paper. All authors read and commented on the manuscript.S

The effect of immunosuppressants on the prognosis of SARS-CoV-2 infection

BACKGROUND: Immunosuppression may worsen SARS-CoV-2 infection. We conducted a nationwide cohort study of the effect of exposure to immunosuppressants on the prognosis of SARS-CoV-2 infection in Denmark. METHODS: We identified all SARS-CoV-2 test-positive patients from February to October 2020 and linked health care data from nationwide registers, including prescriptions for the exposure, immunosuppressant drugs. We estimated relative risks of hospital admission, intensive care unit (ICU) admission, and death (each studied independently up to 30 days from testing) with a log linear binomial regression adjusted for confounders using a propensity score-based matching weights model. RESULTS: A composite immunosuppressant exposure was associated with a significantly increased risk of death (adjusted relative risk 1·56 [95% confidence interval 1.10–2.22]). The increased risk of death was mainly driven by exposure to systemic glucocorticoids (aRR 2.38 [95% CI 1.72–3.30]), which were also associated with an increased risk of hospital admission (aRR 1.34 [95% CI 1.10–1.62]), but not ICU admission (aRR 1.76 [95% CI [0.93–3.35]); these risks were greater for high cumulative doses of glucocorticoids than for moderate doses. Exposure to selective immunosuppressants, tumour necrosis factor inhibitors, or interleukin inhibitors, was not associated with an increased risk of hospitalisation, ICU admission, or death, nor was exposure to calcineurin inhibitors, other immunosuppressants, hydroxychloroquine, or chloroquine. CONCLUSIONS: Exposure to glucocorticoids was associated with increased risks of hospital admission and death. Further investigation is needed to determine the optimal management of COVID-19 in patients with pre-morbid glucocorticoid usage, specifically whether these patients require altered doses of glucocorticoids

Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types