Phosphoproteomics Screen Reveals Akt Isoform-Specific Signals Linking RNA Processing to Lung Cancer

The three Akt isoforms are functionally distinct. Here we show that their phosphoproteomes also differ, suggesting that their functional differences are due to differences in target specificity. One of the top cellular functions differentially regulated by Akt isoforms is RNA processing. IWS1, an RNA processing regulator, is phosphorylated by Akt3 and Akt1 at Ser720/Thr721. The latter is required for the recruitment of SETD2 to the RNA Pol II complex. SETD2 trimethylates histone H3 at K36 during transcription, creating a docking site for MRG15 and PTB. H3K36me3-bound MRG15 and PTB regulate FGFR-2 splicing, which controls tumor growth and invasiveness downstream of IWS1 phosphorylation. Twenty-one of the twenty-four non-small-cell-lung carcinomas we analyzed express IWS1. More importantly, the stoichiometry of IWS1 phosphorylation in these tumors correlates with the FGFR-2 splicing pattern and with Akt phosphorylation and Akt3 expression. These data identify an Akt isoform-dependent regulatory mechanism for RNA processing and demonstrate its role in lung cancer

Extreme Food-Plant Specialisation in Megabombus Bumblebees as a Product of Long Tongues Combined with Short Nesting Seasons

© 2015 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. http://creativecommons.org/licenses/by/4.0/ The attached file is the published version of the article

Photocytotoxicity of mTHPC (Temoporfin) Loaded Polymeric Micelles Mediated by Lipase Catalyzed Degradation

Purpose. To study the in vitro photocytotoxicity and cellular uptake of biodegradable polymeric micelles loaded with the photosensitizer mTHPC, including the effect of lipase-catalyzed micelle degradation. Methods. Micelles of mPEG750-b-oligo(ɛ-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group were formed and loaded with mTHPC by the film hydration method. The cellular uptake of the loaded micelles, and their photocytotoxicity on human neck squamous carcinoma cells in the absence and presence of lipase were compared with free and liposomal mTHPC (Fospeg ®). Results. Micelles composed of mPEG750-b-OCL5 with benzoyl and naphtoyl end groups had the highest loading capacity up to 30 % (w/w), likely due to π–π interactions between the aromatic end group and the photosensitizer. MTHPC-loaded benzoylated micelles (0.5 mg/mL polymer) did not display photocytotoxicity or any mTHPC-uptake by the cells, in contrast to free and liposomal mTHPC. After dilution of the micelles below the critical aggregation concentration (CAC), or after micelle degradation by lipase, photocytotoxicity and cellular uptake of mTHPC were restored. Conclusion. The high loading capacity of the micelles, the high stability of mTHPC-loaded micelles above the CAC, and the lipase-induced release of the photosensitizer makes these micelles very promising carriers for photodynamic therapy in vivo. KEY WORDS: drug release; enzymatic degradation; meta-tetra(hydroxyphenyl)chlorin (mTHPC); photodynamic therapy (PDT); polymeric micelles

Deathscapes of Settler Colonialism : The necro-settlement of Stoney Creek, Ontario, Canada

This is the Accepted Manuscript of an article published by Taylor & Francis Group in annals of Association of American Geographers on 23 January 2018, available online https://doi.org/10.1080/24694452.2017.1406327. The Accepted Manuscript is under embargo until 23 January 2019.This article considers the influence of burials and memorials to colonial soldiers from an earlier era on contemporary social and cultural landscapes in Canada. Through the example of a landscape centered on Smith’s Knoll, a burial ground for war dead from the British-American War of 1812, it explores the process of necro-settlement: the strengthening of settler colonial claims to land based on the development of complex, meaningladen landscapes of dead and memory. This article consists of three parts: The first situates geographical studies of deathscapes alongside theories about settler colonialism through intersecting discourses of land use. The second includes a settler colonial microhistorical geography of Smith’s Knoll and the local deathscape that surrounds it. The third section draws on this case study to reveal new perspectives on the role of burial and memorial in settler colonial place-making and the erasure of Indigenous histories and peoples.Peer reviewedFinal Accepted Versio

A "critical" climatic evaluation of last interglacial (MIS 5e) records from the Norwegian Sea

Sediment cores from the Norwegian Sea were studied to evaluate interglacial climate conditions of the marine isotope stage 5e (MIS 5e). Using planktic forminiferal assemblages as the core method, a detailed picture of the evolution of surface water conditions was derived. According to our age model, a step-like deglaciation of the Saalian ice sheets is noted between ca. 135 and 124.5 Kya, but the deglaciation shows little response with regard to surface ocean warming. From then on, the rapidly increasing abundance of subpolar forminifers, concomitant with decreasing iceberg indicators, provides evidence for the development of interglacial conditions sensu stricto (5e-ss), a period that lasted for about 9 Ky. As interpreted from the foraminiferal records, and supported by the other proxies, this interval of 5e-ss was in two parts: showing an early warm phase, but with a fresher, i.e., lower salinity, water mass, and a subsequent cooling phase that lasted until ca. 118.5 Kya. After this time, the climatic optimum with the most intense advection of Atlantic surface water masses occurred until ca. 116 Kya. A rapid transition with two notable climatic perturbations is observed subsequently during the glacial inception. Overall, the peak warmth of the last interglacial period occurred relatively late after deglaciation, and at no time did it reach the high warmth level of the early Holocene. This finding must be considered when using the last interglacial situation as an analogue model for enhanced meridional transfer of ocean heat to the Arctic, with the prospect of a future warmer climate

SPSB1-mediated inhibition of TGF-β receptor-II impairs myogenesis in inflammation

BACKGROUND: Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation. METHODS: We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as vastus lateralis of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses. RESULTS: SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6 increased the Spsb1 expression in C2C12 myotubes. TNF- and IL-1β-induced Spsb1 expression was mediated by NF-κB, whereas IL-6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice. CONCLUSIONS: Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1-mediated inhibition of TβRII-Akt-Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation

The Genetics Journey: A Case Report of a Genetic Diagnosis Made 30 Years Later

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re‐evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family’s clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that “the patient” can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient’s daughter’s pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient’s husband’s internet search of his wife’s clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re‐evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147210/1/jgc40894.pd

The anthropology of extraction: critical perspectives on the resource curse

Attempts to address the resource curse remain focussed on revenue management, seeking technical solutions to political problems over examinations of relations of power. In this paper, we provide a review of the contribution anthropological research has made over the past decade to understanding the dynamic interplay of social relations, economic interests and struggles over power at stake in the political economy of extraction. In doing so, we show how the constellation of subaltern and elite agency at work within processes of resource extraction is vital in order to confront the complexities, incompatibilities, and inequities in the exploitation of mineral resources

Carbon fluxes resulting from land-use changes in the Tamaulipan thornscrub of northeastern Mexico

Information on carbon stock and flux resulting from land-use changes in subtropical, semi-arid ecosystems are important to understand global carbon flux, yet little data is available. In the Tamaulipan thornscrub forests of northeastern Mexico, biomass components of standing vegetation were estimated from 56 quadrats (200 m2 each). Regional land-use changes and present forest cover, as well as estimates of soil organic carbon from chronosequences, were used to predict carbon stocks and fluxes in this ecosystem