Malnutrition—in the form of insufficient energy intakes—affects millions of people worldwide and the negative impact of this kind of hunger is well acknowledged, not least by agronomists trying to ...increase yields to ensure a sufficient supply of food. This review focuses on another, more particular and “hidden” form of malnutrition, namely mineral malnutrition. It illustrates the burden of disease that is caused by mineral deficiencies and the social and economic consequences they bring about. Mineral malnutrition has a considerable negative impact on individual well-being, social welfare and economic productivity. Agricultural scientists should keep the nutritional qualities of food in mind and—next to optimizing the agricultural properties of crops that are paramount for their adoption by farmers—in particular try to increase the micronutrient content in major staple crops as one way to address vitamin and mineral malnutrition in humans; especially plant breeding approaches promise to be very cost-effective.
In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair ...or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.
Treatment of esophageal carcinoma has changed dramatically following several landmark trials, which have proven the benefit of immunotherapy. The selective PD-1 (programmed cell death ...ligand-1)-inhibitor nivolumab has been shown to improve DFS in the adjuvant therapy setting (CheckMate-577). In the first-line treatment, PD-L1 positive (CPS ≥ 10) squamous cell carcinoma patients (pts) have been shown to have an increased OS following treatment with the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). Nivolumab also improved overall survival in the first line setting either combined with ipilimumab or with chemotherapy (CheckMate 648) compared to chemotherapy alone. In Asian first-line patients, phase III trials investigating camrelizumab (ESCORT 1), toripalimab (JUPITER 06), or sintilimab (ORIENT 15) in addition to chemotherapy also showed significant survival benefits. In the second-line setting, monotherapy with nivolumab (ATTRACTION-03), pembrolizumab (KEYNOTE-181), camrelizumab (ESCORT), and tislelizumab (RATIONALE 302) demonstrated a benefit in OS in comparison to chemotherapy. Here we will review these trials and integrate them into the current treatment algorithm.
•Big pharma companies increased their R&D spending by 6% annually (2001–2020).•Big pharma launched 251 new drugs – 46% of all FDA approvals (2001–2020).•Big pharma’s 20-year R&D efficiency is $6.16 ...billion R&D investment/new drug (2001–2020).•Nearly half of big pharma companies fail to have a positive R&D productivity.
R&D productivity continues to be the industry’s grand challenge. We analyzed the R&D input, output, and outcome of 16 leading research-based pharmaceutical companies over 20 years (2001–2020). Our analysis shows that pharma companies increased their R&D spending at a compound annual growth rate of 6% (2001–2020) to an average R&D expenditure per company of $6.7 billion (2020). The companies in our investigation launched 251 new drugs representing 46% of all CDER–related FDA approvals in the past 20 years. The average R&D efficiency of big pharma was $6.16 billion total R&D expenditures per new drug. Almost half of the leading companies needed to compensate for their negative R&D productivity through mergers and acquisitions.
The inner nuclear membrane (INM) is continuous with the endoplasmic reticulum (ER) but harbors a distinctive proteome essential for nuclear functions. In yeast, the Asi1/Asi2/Asi3 ubiquitin ligase ...complex safeguards the INM proteome through the clearance of mislocalized ER membrane proteins. How the Asi complex selectively targets mislocalized proteins and coordinates its activity with other ER functions, such as protein biogenesis, is unclear. Here, we uncover a link between INM proteome identity and membrane protein complex assembly in the remaining ER. We show that lone proteins and complex subunits failing to assemble in the ER access the INM for Asi-mediated degradation. Substrates are recognized by direct binding of Asi2 to their transmembrane domains for subsequent ubiquitination by Asi1/Asi3 and membrane extraction. Our data suggest a model in which spatial segregation of membrane protein complex assembly and quality control improves assembly efficiency and reduces the levels of orphan subunits.
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•Quality control of unassembled subunits of membrane complexes is restricted to the INM•The Asi complex promotes degradation of folded but unassembled membrane proteins•Binding of Asi2 to membrane domain of unassembled subunits mediates their recognition•INM quality control maintains complex subunits within near-stoichiometric levels
How subunits of membrane protein complexes are maintained at near-stoichiometric levels is unclear. Natarajan et al. show that assembly and quality control of membrane protein complexes are spatially uncoupled in yeast, with the degradation of unassembled subunits being restricted to the inner nuclear membrane and depending on the Asi ERAD complex.
The eighteenth and nineteenth centuries saw both the consolidation of American print culture and the establishment of an African American literary tradition, yet the two are too rarely considered in ...tandem. In this landmark volume, a stellar group of established and emerging scholars ranges over periods, locations, and media to explore African Americans' diverse contributions to early American print culture, both on the page and off. The book's seventeen chapters consider domestic novels and gallows narratives, Francophone poetry and engravings of Liberia, transatlantic lyrics and San Francisco newspapers. Together, they consider how close attention to the archive can expand the study of African American literature well beyond matters of authorship to include issues of editing, illustration, circulation, and reading-and how this expansion can enrich and transform the study of print culture more generally. Published in cooperation with the Library Company of Philadelphia.
Abstract
Summary
RNA isoforms contribute to the diverse functionality of the proteins they encode within the cell. Visualizing how isoform expression differs across cell types and brain regions can ...inform our understanding of disease and gain or loss of functionality caused by alternative splicing with potential negative impacts. However, the extent to which this occurs in specific cell types and brain regions is largely unknown. This is the kind of information that ScisorWiz plots can provide in an informative and easily communicable manner. ScisorWiz affords its user the opportunity to visualize specific genes across any number of cell types, and provides various sorting options for the user to gain different ways to understand their data. ScisorWiz provides a clear picture of differential isoform expression through various clustering methods and highlights features such as alternative exons and single-nucleotide variants. Tools like ScisorWiz are key for interpreting single-cell isoform sequencing data. This tool applies to any single-cell long-read RNA sequencing data in any cell type, tissue or species.
Availability and implementation
Source code is available at http://github.com/ans4013/ScisorWiz. No new data were generated for this publication. Data used to generate figures was sourced from GEO accession token GSE158450 and available on GitHub as example data.
Dietary mineral supplies in Africa Joy, Edward J. M; Ander, E. Louise; Young, Scott D ...
Physiologia plantarum,
July 2014, Letnik:
151, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Dietary micronutrient deficiencies (MNDs) are widespread, yet their prevalence can be difficult to assess. Here, we estimate MND risks due to inadequate intakes for seven minerals in Africa using ...food supply and composition data, and consider the potential of food‐based and agricultural interventions. Food Balance Sheets (FBSs) for 46 countries were integrated with food composition data to estimate per capita supply of calcium (Ca), copper (Cu), iron (Fe), iodine (I), magnesium (Mg), selenium (Se) and zinc (Zn), and also phytate. Deficiency risks were quantified using an estimated average requirement (EAR) ‘cut‐point’ approach. Deficiency risks are highest for Ca (54% of the population), followed by Zn (40%), Se (28%) and I (19%, after accounting for iodized salt consumption). The risk of Cu (1%) and Mg (<1%) deficiency are low. Deficiency risks are generally lower in the north and west of Africa. Multiple MND risks are high in many countries. The population‐weighted mean phytate supply is 2770 mg capita⁻¹ day⁻¹. Deficiency risks for Fe are lower than expected (5%). However, ‘cut‐point’ approaches for Fe are sensitive to assumptions regarding requirements; e.g. estimates of Fe deficiency risks are 43% under very low bioavailability scenarios consistent with high‐phytate, low‐animal protein diets. Fertilization and breeding strategies could greatly reduce certain MNDs. For example, meeting HarvestPlus breeding targets for Zn would reduce dietary Zn deficiency risk by 90% based on supply data. Dietary diversification or direct fortification is likely to be needed to address Ca deficiency risks.
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