Dissection of a complex transcriptional response using genome-wide transcriptional modelling

Modern genomics technologies generate huge data sets creating a demand for systems level, experimentally verified, analysis techniques. We examined the transcriptional response to DNA damage in a human T cell line (MOLT4) using microarrays. By measuring both mRNA accumulation and degradation over a short time course, we were able to construct a mechanistic model of the transcriptional response. The model predicted three dominant transcriptional activity profiles—an early response controlled by NFκB and c-Jun, a delayed response controlled by p53, and a late response related to cell cycle re-entry. The method also identified, with defined confidence limits, the transcriptional targets associated with each activity. Experimental inhibition of NFκB, c-Jun and p53 confirmed that target predictions were accurate. Model predictions directly explained 70% of the 200 most significantly upregulated genes in the DNA-damage response. Genome-wide transcriptional modelling (GWTM) requires no prior knowledge of either transcription factors or their targets. GWTM is an economical and effective method for identifying the main transcriptional activators in a complex response and confidently predicting their targets

Comparison of Cannabinoid CB1 Receptor Binding in Adolescent and Adult Rats: A Positron Emission Tomography Study Using [18F]MK-9470

Despite the important role of cannabinoid CB1 receptors (CB1R) in brain development, little is known about their status during adolescence, a critical period for both the development of psychosis and for initiation to substance abuse. In the present study, we assessed the ontogeny of CB1R in adolescent and adult rats in vivo using positron emission tomography with [18F]MK-9470. Analysis of covariance (ANCOVA) to control for body weight that would potentially influence [18F]MK-9470 values between the two groups revealed a main effect of age (F(1,109)=5.0, P = 0.02) on [18F]MK-9470 absolute binding (calculated as percentage of injected dose) with adult estimated marginal means being higher compared to adolescents amongst 11 brain regions. This finding was confirmed using in vitro autoradiography with [3H]CP55,940 (F(10,99)=140.1, P < 0.0001). This ontogenetic pattern, suggesting increase of CB1R during the transition from adolescence to adulthood, is the opposite of most other neuroreceptor systems undergoing pruning during this period

Ökonomische, ökologische und Tierwohlaspekte der Weidehaltung von Hochleistungskühen

Dieses Projekt zielte darauf ab, die Grünlandnutzung durch Weidehaltung für Milchkühe mit zu untersuchen. Vor dem Hintergrund, dass der Energiebedarf durch alleinige Weidehaltung in den Sommermonaten nicht gedeckt werden kann und Weidehaltung mit einem höheren Arbeits-aufwand verbunden sein kann, jedoch gleichwohl positive Effekte auf die Tiergesundheit dokumentiert wurden, war es das Ziel zu untersuchen, ob ein ökonomisch messbarer Weideeffekt besteht und welche Rolle das Tierwohl sowie die ökologischen Landschaftsfunktionen des Grünlandes spielen. Die Ergebnisse der on-farm Analyse zeigten, dass bei kombinierter Stall- und Weidehaltung ähnlich hohe Milchleistungen wie bei ganzjähriger Stallhaltung möglich sind. Auffälligkeiten am Integument der Tiere resultieren hauptsächlich aus Mängeln in der Haltungsumwelt und können das Tierwohl erheblich beeinträchtigen. Die Haltung auf der Weide bringt unter diesem Aspekt deutliche Vorteile, allerdings werden die Regenerationseffekte im folgenden Winter größtenteils wieder neutralisiert. Die Berücksichtigung dieser Aspekte in der Effizienzmessung zeigte, dass das mitunter größte Einsparpotential im Sinne einer Verbesserung der technischen Effizienz bei den Lahmheiten liegt. Es lässt sich kein Arbeitsmehraufwand bei den Weidebe-trieben im Saisonwechsel feststellen, da durch Einsparungen bei anderen Arbeitsvorgängen der Mehraufwand der Weidearbeiten ausgeglichen wurde. Das größte Potenzial bietet die Futterversorgung über die Weide. Hierfür ist ein eng aufeinander abgestimmtes Weide- und Herdemanagement essentiell, da unangepasstes Weidemanagement zu unterschiedlich ausgeprägten Trittschäden und in der Konsequenz zu Ertragsausfällen und Veränderungen der Futterqualität infolge von Verschieben der Artenzusammensetzung führt. Die Ergebnisse zeigten weiterhin, dass Grünlandnutzung als Weide zu einer erhöhten Humusspeicherung und somit zu einer echten klimawirksamen Kohlenstoffsequestrierung führt

Preliminary assessment of the imaging capability of the YAP-(S)PET small animal scanner in neuroscience

The new and fully engineered version of the YAP–(S)PET small animal scanner has been tested at the University of Mainz for preliminary assessment of its imaging capability for studies related to neuropharmacology and psychiatry. The main feature of the scanner is the capability to combine PET and SPECT techniques. It allows the development of new and interesting protocols for the investigation of many biological phenomena, more effectively than with PET or SPECT modalities alone. The scanner is made up of four detector heads, each one composed of a 4 � 4c m 2 of YAlO3:Ce (or YAP:Ce) matrix, and has a field of view (FOV) of 4 cm axially � 4c m + transaxially. In PET mode, the volume resolution is less than 8 mm 3 and is nearly constant over the whole FOV, while the sensitivity is about 2%. The SPECT performance is not so good, due to the presence of the multi-hole lead collimator in front of each head. Nevertheless, the YAP–PET scanner offers excellent resolution and sensitivity for performing on the availability of D2-like dopamine receptors on mice and rats in both PET and SPECT modalities

Occupational choice of return migrants in Moldova

This paper analyzes the occupational choice of return migrants. Using the survey data on different aspects of migration in Moldova, we find that those who stayed illegally in the host country tend to go into wage employment on return to the home country. We also show that relatively better educated migrants tend not to be in formal employment (i.e., appear not to participate in the labor market), whereas those with relatively lower skills or who obtained a worse-than-expected outcome in the host country are more likely to be wage employed in the home country on return. We offer an economic analysis of these paradoxical results

RELICS: Strong Lens Models for Five Galaxy Clusters From the Reionization Lensing Cluster Survey

Strong gravitational lensing by galaxy clusters magnifies background galaxies, enhancing our ability to discover statistically significant samples of galaxies at z>6, in order to constrain the high-redshift galaxy luminosity functions. Here, we present the first five lens models out of the Reionization Lensing Cluster Survey (RELICS) Hubble Treasury Program, based on new HST WFC3/IR and ACS imaging of the clusters RXC J0142.9+4438, Abell 2537, Abell 2163, RXC J2211.7-0349, and ACT-CLJ0102-49151. The derived lensing magnification is essential for estimating the intrinsic properties of high-redshift galaxy candidates, and properly accounting for the survey volume. We report on new spectroscopic redshifts of multiply imaged lensed galaxies behind these clusters, which are used as constraints, and detail our strategy to reduce systematic uncertainties due to lack of spectroscopic information. In addition, we quantify the uncertainty on the lensing magnification due to statistical and systematic errors related to the lens modeling process, and find that in all but one cluster, the magnification is constrained to better than 20% in at least 80% of the field of view, including statistical and systematic uncertainties. The five clusters presented in this paper span the range of masses and redshifts of the clusters in the RELICS program. We find that they exhibit similar strong lensing efficiencies to the clusters targeted by the Hubble Frontier Fields within the WFC3/IR field of view. Outputs of the lens models are made available to the community through the Mikulski Archive for Space TelescopesComment: Accepted to Ap

RELICS: High-Resolution Constraints on the Inner Mass Distribution of the z=0.83 Merging Cluster RXJ0152.7-1357 from strong lensing

Strong gravitational lensing (SL) is a powerful means to map the distribution of dark matter. In this work, we perform a SL analysis of the prominent X-ray cluster RXJ0152.7-1357 (z=0.83, also known as CL 0152.7-1357) in \textit{Hubble Space Telescope} images, taken in the framework of the Reionization Lensing Cluster Survey (RELICS). On top of a previously known $z=3.93$ galaxy multiply imaged by RXJ0152.7-1357, for which we identify an additional multiple image, guided by a light-traces-mass approach we identify seven new sets of multiply imaged background sources lensed by this cluster, spanning the redshift range [1.79-3.93]. A total of 25 multiple images are seen over a small area of ~0.4 $arcmin^2$, allowing us to put relatively high-resolution constraints on the inner matter distribution. Although modestly massive, the high degree of substructure together with its very elongated shape make RXJ0152.7-1357 a very efficient lens for its size. This cluster also comprises the third-largest sample of z~6-7 candidates in the RELICS survey. Finally, we present a comparison of our resulting mass distribution and magnification estimates with those from a Lenstool model. These models are made publicly available through the MAST archive.Comment: 15 Pages, 7 Figures, 4 Tables Accepted for publication in Ap

The interferon-inducible gene, Ifi204, acquires malignant transformation capability upon mutation at the Rb-binding sites

Abstractp204 overexpression in retinoblastoma (Rb)−/− mouse embryo fibroblasts or transfection of p204 mutated at both Rb-binding sites confer growth advantages, resulting in a significantly higher number of foci in a cell focus assay. To investigate the possibility that mutated p204 acquires malignant transformation capability, NIH3T3 cells were stably transfected with the expression vector pRcRSV204 double-mutant (p204dm) harboring both the C-terminal deletion up to amino acid 568 and the point mutation from glutamic acid to lysine at position 427, and analyzed for markers typical of cell immortalization and transformation. We detected a greater abundance of cell colonies in soft agar with p204dm-expressing cells than vector control cells. The p204dm-transfected cells also displayed two other characteristics associated with malignant transformation, i.e. growth under low-serum conditions and formation of tumors in athymic nude mice. Moreover, their telomerase activity was significantly higher than in the vector control cells. It would thus seem that p204, devoid of functional Rb-binding motifs, can become oncogenic

Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are based on a range of novel platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently, a novel complication of SARS-CoV-2–targeted adenovirus vaccines has emerged: immune thrombocytopenia, either isolated, or accompanied by thrombosis (then termed VITT). This complication is characterized by low platelet counts, and in the case of VITT, also by platelet-activating platelet factor 4 antibodies reminiscent of heparin-induced thrombocytopenia, leading to a prothrombotic state with clot formation at unusual anatomic sites. Here, we detected antiplatelet antibodies targeting platelet glycoprotein receptors in 30% of patients with proven VITT (n = 27) and 42% of patients with isolated thrombocytopenia after ChAdOx1 nCov-19 vaccination (n = 26), indicating broad antiplatelet autoimmunity in these clinical entities. We use in vitro and in vivo models to characterize possible mechanisms of these platelet-targeted autoimmune responses leading to thrombocytopenia. We show that IV but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation in mice. After IV injection, these aggregates are phagocytosed by macrophages in the spleen, and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of platelet-associated complications after ChAdOx1 nCov-19 administration and highlights accidental IV injection as a potential mechanism of platelet-targeted autoimmunity. Hence, preventing IV injection when administering adenovirus-based vaccines could be a potential measure against platelet-associated pathologies after vaccination