KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA polymerase II activity

KAP1 (KRAB-associated protein 1) is best known as a co-repressor responsible for inducing heterochromatin formation, notably at transposable elements. However, it has also been observed to bind the transcription start site of actively expressed genes. To address this paradox, we characterized the protein interactome of KAP1 in the human K562 erythro-leukaemia cell line. We found that the regulator can associate with a wide range of nucleic acid binding proteins, nucleosome remodellers, chromatin modifiers and other transcription modulators. We further determined that KAP1 is recruited at actively transcribed polymerase II promoters, where its depletion resulted in pleomorphic effects, whether expression of these genes was normally constitutive or inducible, consistent with the breadth of possible KAP1 interactors. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'

MontanAqua : Wasserbewirtschaftung in Zeiten von Knappheit und globalem Wandel. Wasserbewirtschaftungsoptionen für die Region Crans-Montana-Sierre im Wallis

Das nationale Forschungsprogramm NFP 61 «Nachhaltige Wassernutzung » des Schweizerischen Nationalfonds hat sich zum Ziel gesetzt, wissenschaftliche Grundlagen zur nachhaltigen Wasserbewirtschaftung in der Schweiz zu liefern. Als Teil dieses Forschungsvorhabens wurde im Rahmen des Projektes MontanAqua die Wasserbewirtschaftung der Region Crans-Montana-Sierre (Wallis) untersucht. Es ging dabei darum, in enger Zusammenarbeit mit den in der Region betroffenen Akteuren nachhaltige Wassernutzungsstrategien für die Zukunft zu entwickeln. MontanAqua hat sich vertieft mit den bestehenden Systemen der Wasserbewirtschaftung auf der regionalen Skala (11 Gemeinden) auseinandergesetzt. Dazu wurden die zukünftigen Auswirkungen der klimatischen und sozioökonomischen Veränderungen einbezogen. Das Forschungsteam analysierte die aktuelle Situation anhand von quantitativen, qualitativen sowie kartografischen Methoden und kombinierte diese mit Modellberechnungen. Für die Modellierung der Zukunft wurden regionale Klimaszenarien und vier mit lokalen Akteuren entwickelte sozioökonomische Szenarien verwendet. Dieser Überblick fasst die Resultate des Projektes MontanAqua zusammen. Fünf wesentliche Fragen werden beantwortet und fünf Kernbotschaften erläutert. Zudem sind Empfehlungen für die Verantwortlichen der regionalen und kantonalen Wasserbewirtschaftung formuliert

Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8⁺ T cells and reprogramming macrophages.

Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1 <sup>+</sup> T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8 <sup>+</sup> T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1 <sup>+</sup> stem-like T cells

A snow and glacier hydrological model for large catchments – case study for the Naryn River, central Asia

In this paper we implement a degree day snowmelt and glacier melt model in the Dynamic fluxEs and ConnectIvity for Predictions of HydRology (DECIPHeR) model. The purpose is to develop a hydrological model that can be applied to large glaciated and snow-fed catchments yet is computationally efficient enough to include model uncertainty in streamflow predictions. The model is evaluated by simulating monthly discharge at six gauging stations in the Naryn River catchment (57 833 km2) in central Asia over the period 1951 to a variable end date between 1980 and 1995 depending on the availability of discharge observations. The spatial distribution of simulated snow cover is validated against MODIS weekly snow extent for the years 2001–2007. Discharge is calibrated by selecting parameter sets using Latin hypercube sampling and assessing the model performance using six evaluation metrics. The model shows good performance in simulating monthly discharge for the calibration period (NSE is 0.74&lt;NSE&lt;0.87) and validation period (0.7&lt;NSE&lt;0.9), where the range of NSE values represents the 5th–95th percentile prediction limits across the gauging stations. The exception is the Uch-Kurgan station, which exhibits a reduction in model performance during the validation period attributed to commissioning of the Toktogul reservoir in 1975 which impacted the observations. The model reproduces the spatial extent in seasonal snow cover well when evaluated against MODIS snow extent; 86 % of the snow extent is captured (mean 2001–2007) for the median ensemble member of the best 0.5 % calibration simulations. We establish the present-day contributions of glacier melt, snowmelt and rainfall to the total annual runoff and the timing of when these components dominate river flow. The model predicts well the observed increase in discharge during the spring (April–May) associated with the onset of snow melting and peak discharge during the summer (June, July and August) associated with glacier melting. Snow melting is the largest component of the annual runoff (89 %), followed by the rainfall (9 %) and the glacier melt component (2 %), where the values refer to the 50th percentile estimates at the catchment outlet gauging station Uch-Kurgan. In August, glacier melting can contribute up to 66 % of the total runoff at the highly glacierized Naryn headwater sub-catchment. The glaciated area predicted by the best 0.5 % calibration simulations overlaps the Landsat observations for the late 1990s and mid-2000s. Despite good predictions for discharge, the model produces a large range of estimates for the glaciated area (680–1196 km2) (5th–95th percentile limits) at the end of the simulation period. To constrain these estimates further, additional observations such as glacier mass balance, snow depth or snow extent should be used directly to constrain model simulations.</p

Muzej Hrvatskih Arheoloških Spomenika

interior, view to sea, view along architectural straight lines to large rectangular window with view of ocean, 198

Muzej Hrvatskih Arheoloških Spomenika

interior, first floor view showing ceiling, windows, and people in relation to the building, 198

Muzej Hrvatskih Arheoloških Spomenika

interior, view through main hall to windows, their reflection on floor, balcony, ceiling, 198

Muzej Hrvatskih Arheoloških Spomenika

interior, dark view first floor near museum entrance, blocky structures, row of high windows and curved partition of glass, 198