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The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER-­associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases.

Proteasome inhibition is used therapeutically to induce proteotoxic stress and trigger apoptosis in cancer cells that are highly dependent on the proteasome. As a mechanism of resistance, inhibition of the cellular proteasome induces the synthesis of new, uninhibited proteasomes to restore proteasome activity and relieve proteotoxic stress in the cell, thus evading apoptosis. This evolutionarily conserved compensatory mechanism is referred to as the proteasome-bounce back response and is orchestrated in mammalian cells by nuclear factor erythroid derived 2-related factor 1 (NRF1), a transcription factor and master regulator of proteasome subunit genes. Upon synthesis, NRF1 is cotranslationally inserted into the endoplasmic reticulum (ER), then is rapidly retrotranslocated into the cytosol and degraded by the proteasome. In contrast, during conditions of proteasome inhibition or insufficiency, NRF1 escapes degradation, is proteolytically cleaved by the aspartyl protease DNA damage inducible 1 homolog 2 (DDI2) to its active form, and enters the nucleus as an active transcription factor. Despite these insights, the cellular compartment where the proteolytic processing step occurs remains unclear. Here we further probed this pathway and found that NRF1 can be completely retrotranslocated into the cytosol where it is then cleaved and activated by DDI2. Furthermore, using a triple-negative breast cancer cell line MDA-MB-231, we investigated the therapeutic utility of attenuating DDI2 function. We found that DDI2 depletion attenuated NRF1 activation and potentiated the cytotoxic effects of the proteasome inhibitor carfilzomib. More importantly, expression of a point-mutant of DDI2 that is protease-dead recapitulated these effects. Taken together, our results provide a strong rationale for a combinational therapy that utilizes inhibition of the proteasome and the protease function of DDI2. This approach could expand the repertoire of cancer types that can be successfully treated with proteasome inhibitors in the clinic.

Whilst recent years have witnessed the development and exploitation of operational Earth Observation (EO) satellite constellation data, the valorisation of historical archives has been a challenge. The European Space Agency (ESA) Landsat Multi Spectral Scanner (MSS) products cover Greenland, Iceland, Continental Europe and North Africa represent an archive of over 600,000 processed Level 1 (L1) scenes that will accompany around 1 million ESA Landsat Thematic Mapper (TM) and Enhanced Thematic Mapper Plus (ETM+) products already available. ESA began acquiring MSS data in 1975 and it is well known that this dataset can be degraded due to missing data and a loss in accuracy. For these reasons, the content of the product format has been reviewed and the ESA Landsat processing baseline significantly updated to ensure products are fit for user purposes. This paper presents the new MSS product format including the updated metadata parameters for error traceability, and the specification of the Quality Assurance Band (BQA) engineered to allow the best pixel selection and also the application of image restoration techniques. This paper also discusses major improvements applied to the radiometric and geometric processing. For the benefits of the community, ESA is now able to maximize the number of L1 MSS products that can potentially be generated from the raw Level 0 (L0) data and ensure the highest possible data quality is reached. Also, by improving product format, processing and adding a pixel based quality band, the MSS archive becomes interoperable with recently reprocessed Landsat data and that from live missions by way of assuring product quality on a pixel basis.

Whilst recent years have witnessed the development and exploitation of operational Earth Observation (EO) satellite constellation data, the valorisation of historical archives has been a challenge. The ESA Multi Spectral Scanner (MSS) products cover Greenland, Iceland, Continental Europe and North Africa representing an archive of over 600,000 Level 1 (L1) scenes that join the 1 million ESA Thematic Mapper (TM) and Enhanced Thematic Mapper Plus (ETM+) products already available. This paper presents the L1 MSS product functionality, and how the dataset will be fit for multi temporal purposes. For example, a quality assurance traceability concept is implemented through an innovative pixel based Quality Assurance Band (BQA) that includes land, cloud and anomaly flagging. Land cover application areas are showcased, including vegetation monitoring and snow cover monitoring on glaciers.

Developmental remodeling of the sensory epithelium of the cochlea is required for the formation of an elongated, tonotopically organized auditory organ, but the cellular processes that mediate these events are largely unknown. Therefore, we used both morphological assessments of cellular rearrangements and time-lapse imaging to visualize cochlear remodeling. Analysis of cell redistribution showed that the cochlea extends through a combination of radial intercalation and cell growth. Live imaging demonstrated that concomitant cellular intercalation results in a brief period of epithelial convergence, although subsequent changes in cell size lead to medial-lateral spreading. Supporting cells, which retain contact with the basement membrane, exhibit biased protrusive activity and directed movement along the axis of extension. In contrast, hair cells lose contact with the basement membrane, but contribute to continued outgrowth through increased cell size. Regulation of cellular protrusions, movement, and intercalation within the cochlea all require Myosin II. The results establish, for the first time, many of the cellular processes that drive the distribution of sensory cells along the tonotopic axis of the cochlea.

Landsat is a joint USGS and NASA space program for Earth Observation ( EO ), which represents the world’s longest running system of satellites for moderate-resolution. The European Space Agency ( ESA ) has acquired Landsat data over Europe, Northern Africa and the Middle East during the last 40 years. A new ESA Landsat Multi-Spectral Scanner ( MSS ), Thematic Mapper ( TM ) and Enhanced Thematic Mapper Plus ( ETM+ ) processor has been developed. This enhanced processor aligns historical Landsat products to the highest quality standards that can be achieved with the current knowledge of the instruments. The updated processor is mainly based on the USGS algorithm; however it has some different features that are detailed in this paper. Current achievements include the processing and availability of approximately 860,000 new TM/ETM+ high-quality products between 1983 and 2011 from the Kiruna (S), Maspalomas (E) and Matera (I) archives; Matera includes data from the Fucino (I), Neustrelitz (D), O’Higgins (Antarctica), Malindi (Kenya), Libreville (Gabon) and Bishkek (Kyrgyzstan) ground stations. The products are freely available for immediate download to the users through a very fast and simple dissemination service (at: https://landsat-ds.eo.esa.int/app/) and through ESA’s browsing system, EOLI. The remaining MSS data, dating back more than 40 years, will gradually become available during 2015 and 2016. The ESA Landsat processor algorithm enhancement, together with the results of the ESA archive bulk-processing data regarding production, quality control and data validation are herein presented.

The Landsat program is a joint United States Geological Survey (USGS) and National Aeronautics and Space Administration (NASA) enterprise for Earth Observation (EO), that represents the world’s longest running system of satellites for moderate-resolution optical remote sensing. The European Space Agency (ESA) has acquired Landsat data over Europe through the ESA ground stations over the last 40 years, in co-operation with USGS and NASA. A new ESA Landsat Multi-Spectral Scanner (MSS), Thematic Mapper (TM) and Enhanced Thematic Mapper Plus (ETM+) processor has been developed. This enhanced processor aligns the historical Landsat products to the highest quality standards that can be achieved with the current knowledge of the instruments. The updated processor is mainly based on the USGS algorithm; however the ESA processor has some different features that are detailed in this paper. Using this upgraded processor, ESA is currently performing for the first time a bulk-processing of its entire Landsat series MSS/TM/ETM+ historical archive to make all products available to users. Current achievements include the processing and online distribution of approximately 290 000 new Landsat 5 TM high-quality products acquired at the Kiruna ground station between 1983 and 2011. The Landsat 5 TM bulk-processed products are made available for direct download after registration at: https://earth.esa.int/web/guest/pi-community/apply for-data/fast-registration. The remainder of the ESA’s Landsat data, dating back more than 40 years, will gradually become available for all users during the course of 2014. The ESA Landsat processor algorithm enhancement, together with the results of the ESA archive bulk-processing, and an overview on the data quality on a subset of the Landsat 5 TM data are herein presented.