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British architectural theory 1540-1750 : an anthology of texts
Although it is often assumed that British writing on architectural theory really started in the 18th century, there is in fact a large corpus of writing on architecture pre-dating the introduction of Palladianism by Lord Burlington. Some of it, such as the English editions of Serlio and Palladio, belongs to the Vitruvian tradition. But many texts elude such easy classification, such as the prolonged (but hardly studied) discussions on church architecture, which are both in form and content very different from the way that theme was handled in Italian Renaissance treatises. This collection of English writing on architecture from 1540 to 1750 offers a large selection of fragments, some of them never published before. They discuss the nature of architecture, the practicalities of building, the sense of the past, religious architecture and classicism.
Book
SUMO wrestling with Drp1 at mitochondria
The term mitochondrion is derived from the Greek mitos (thread) and khondrion (small grain), emphasizing the fundamental nature of its varied tubular and vesicular appearances within cells. Even this description belies the highly dynamic nature of mitochondria, which undergo continuous cycles of ssion and fusion. Maintaining the proper balance between these competing processes is crucial for cellular homeostasis, and a variety of regulatory mechanisms ne tune this balance in different cellular contexts. The key players in mitochondrial fusion in metazoans are large, membrane-bound GTPases in the dynamin superfamily mitofusin-1 and -2 and optic atrophy-1 (OPA1). Although a number of proteins including Mff, MiD49/51, Fis1, and actin cytoskeletal proteins have been implicated in the regulation of ssion, they appear to do so predominantly through their effects on the dynamin-related GTPase Drp1, a protein present mostly in the cytoplasm that is specically recruited to the mitochondrial outer membrane.
Journal Article
Franz's phantasmagorical machine
\"From an early age, Franz Gsellmann is drawn to machines like the family cuckoo clock. He hears a tiny whisper calling him to imagine, discover, create... but growing up on a farm in rural Austria means there's no time for playing and imagining. Despite having to quit school to do farm work, Franz never loses his urge to invent. He collects hundreds of parts and interesting materials, often working late into the night to build them into something fantastic: a phantasmagorical contraption he calls his World Machine. Powered by curiosity and the joy of creating, he ignores the ridicule of townspeople, working in secret, until finally, he finds an audience who understands the true value of his machine.\"-- Provided by publisher.
CHILDBOOK
Integration of the Salmonella Typhimurium Methylome and Transcriptome Reveals That DNA Methylation and Transcriptional Regulation Are Largely Decoupled under Virulence-Related Conditions
While recent breakthroughs have enabled intense study of bacterial DNA modifications, limitations in current work have potentiated a surprisingly untested narrative that DNA methylation is a common mechanism of the bacterial response to environmental conditions. Essentially, whether epigenetic regulation of bacterial transcription is a common, generalizable phenomenon is a critical unanswered question that we address here. Despite being in a golden age of bacterial epigenomics, little work has systematically examined the plasticity and functional impacts of the bacterial DNA methylome. Here, we leveraged single-molecule, real-time sequencing (SMRT-seq) to examine the m 6 A DNA methylome of two Salmonella enterica serovar Typhimurium strains: 14028s and a Δ metJ mutant with derepressed methionine metabolism, grown in Luria broth or medium that simulates the intracellular environment. We found that the methylome is remarkably static: >95% of adenosine bases retain their methylation status across conditions. Integration of methylation with transcriptomic data revealed limited correlation between changes in methylation and gene expression. Further, examination of the transcriptome in Δ yhdJ bacteria lacking the m 6 A methylase with the most dynamic methylation pattern in our data set revealed little evidence of YhdJ-mediated gene regulation. Curiously, despite G(m 6 A)TC motifs being particularly resistant to change across conditions, incorporating dam mutants into our analyses revealed two examples where changes in methylation and transcription may be linked across conditions. This includes the novel finding that the Δ metJ motility defect may be partially driven by hypermethylation of the chemotaxis gene tsr . Together, these data redefine the S. Typhimurium epigenome as a highly stable system that has rare but important roles in transcriptional regulation. Incorporating these lessons into future studies will be critical as we progress through the epigenomic era. IMPORTANCE While recent breakthroughs have enabled intense study of bacterial DNA modifications, limitations in current work have potentiated a surprisingly untested narrative that DNA methylation is a common mechanism of the bacterial response to environmental conditions. Essentially, whether epigenetic regulation of bacterial transcription is a common, generalizable phenomenon is a critical unanswered question that we address here. We found that most DNA methylation is static in Salmonella enterica serovar Typhimurium, even when the bacteria are grown under dramatically different conditions that cause broad changes in the transcriptome. Further, even when the methylation of individual bases change, these changes generally do not correlate with changes in gene expression. Finally, we demonstrate methods by which data can be stratified in order to identify coupled changes in methylation and gene expression.
Journal Article
Nutritional Characterisation of Childhood Chronic Kidney Disease: Trace Element Malnutrition in Paediatric Renal Disease (TeMPeReD) Study
Background/Objectives: In chronic kidney disease (CKD), poor nutrition is associated with poorer clinical outcomes. There are limited data on milder stages of childhood CKD. Methods: This study characterised the nutritional state of a cohort of children with CKD. Results: Within the cohort (mean age 10.5 years, mean eGFR = 57 mL/min/1.73 m2), obesity defined by body mass index rates was comparable to that in the general population, but central obesity (waist-to-height ratio > 0.5) was evident in 44% of children. Although average nutrient intakes for the cohort were acceptable, there was marked variability in the risk of poor nutrient intake (
Journal Article
Assessment and management of vitamin status in children with CKD stages 2–5, on dialysis and post-transplantation: clinical practice points from the Pediatric Renal Nutrition Taskforce
Children with chronic kidney disease (CKD) are at risk for vitamin deficiency or excess. Vitamin status can be affected by diet, supplements, kidney function, medications, and dialysis. Little is known about vitamin requirements in CKD, leading to practice variation.
The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric kidney dietitians and pediatric nephrologists, was established to develop evidence-based clinical practice points (CPPs) to address challenges and to serve as a resource for nutritional care. Questions were formulated using PICO (Patient, Intervention, Comparator, Outcomes), and literature searches undertaken to explore clinical practice from assessment to management of vitamin status in children with CKD stages 2–5, on dialysis and post-transplantation (CKD2-5D&T). The CPPs were developed and finalized using a Delphi consensus approach. We present six CPPs for vitamin management for children with CKD2-5D&T. We address assessment, intervention, and monitoring. We recommend avoiding supplementation of vitamin A and suggest water-soluble vitamin supplementation for those on dialysis. In the absence of evidence, a consistent structured approach to vitamin management that considers assessment and monitoring from dietary, physical, and biochemical viewpoints is needed. Careful consideration of the impact of accumulation, losses, comorbidities, and medications needs to be explored for the individual child and vitamin before supplementation can be considered. When supplementing, care needs to be taken not to over-prescribe. Research recommendations are suggested.
Journal Article
Planktonic foraminifera organic carbon isotopes as archives of upper ocean carbon cycling
The carbon cycle is a key regulator of Earth’s climate. On geological time-scales, our understanding of particulate organic matter (POM), an important upper ocean carbon pool that fuels ecosystems and an integrated part of the carbon cycle, is limited. Here we investigate the relationship of planktonic foraminifera-bound organic carbon isotopes (δ
13
C
org-pforam
) with δ
13
C
org
of POM (δ
13
C
org-POM
). We compare δ
13
C
org-pforam
of several planktonic foraminifera species from plankton nets and recent sediment cores with δ
13
C
org-POM
on a N-S Atlantic Ocean transect. Our results indicate that δ
13
C
org-pforam
of planktonic foraminifera are remarkably similar to δ
13
C
org-POM
. Application of our method on a glacial sample furthermore provided a δ
13
C
org-pforam
value similar to glacial δ
13
C
org-POM
predictions. We thus show that δ
13
C
org-pforam
is a promising proxy to reconstruct environmental conditions in the upper ocean, providing a route to isolate past variations in δ
13
C
org-POM
and better understanding of the evolution of the carbon cycle over geological time-scales.
Our understanding of ancient organic carbon cycling in marine environments is limited. Here the authors developed a method to reconstruct upper ocean organic carbon chemistry in the geological past, which when applied, can help to create a better understanding of the evolution of the carbon cycle.
Journal Article
Local Delivery of Therapeutics to the Inner Ear: The State of the Science
Advances in the understanding of the genetic and molecular etiologies of inner ear disorders have enabled the identification of therapeutic targets and innovative delivery approaches to the inner ear. As this field grows, the need for knowledge about effective delivery of therapeutics to the inner ear has become a priority. This review maps all clinical and pre-clinical research published in English in the field to date, to guide both researchers and clinicians about local drug delivery methods in the context of novel therapeutics.
A systematic search was conducted using customized strategies in Cochrane, pubmed and EMBASE databases from inception to 30/09/2018. Two researchers undertook study selection and data extraction independently.
Our search returned 12,200 articles, of which 837 articles met the inclusion criteria. 679 were original research and 158 were reviews. There has been a steady increase in the numbers of publications related to inner ear therapeutics delivery over the last three decades, with a sharp rise over the last 2 years. The intra-tympanic route accounts for over 70% of published articles. Less than one third of published research directly assesses delivery efficacy, with most papers using clinical efficacy as a surrogate marker.
Research into local therapeutic delivery to the inner ear has undergone a recent surge, improving our understanding of how novel therapeutics can be delivered. Direct assessment of delivery efficacy is challenging, especially in humans, and progress in this area is key to understanding how to make decisions about delivery of novel hearing therapeutics.
Journal Article
RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition
The outlook for patients with advanced renal cell cancer (RCC) has been improved by targeted agents including inhibitors of the PI3 kinase (PI3K)-AKT-mTOR axis, although treatment resistance is a major problem. Here, we aimed to understand how RCC cells acquire resistance to PI3K-mTOR inhibition. We used the RCC4 cell line to generate a model of in vitro resistance by continuous culture in PI3K-mTOR kinase inhibitor NVP-BEZ235 (BEZ235, Dactolisib). Resistant cells were cross-resistant to mTOR inhibitor AZD2014. Sensitivity was regained after 4 months drug withdrawal, and resistance was partially suppressed by HDAC inhibition, supporting an epigenetic mechanism. BEZ235-resistant cells up-regulated and/or activated numerous proteins including MET, ABL, Notch, IGF-1R, INSR and MEK/ERK. However, resistance was not reversed by inhibiting or depleting these pathways, suggesting that many induced changes were passengers not drivers of resistance. BEZ235 blocked phosphorylation of mTOR targets S6 and 4E-BP1 in parental cells, but 4E-BP1 remained phosphorylated in resistant cells, suggesting BEZ235-refractory mTORC1 activity. Consistent with this, resistant cells over-expressed mTORC1 component RAPTOR at the mRNA and protein level. Furthermore, BEZ235 resistance was suppressed by RAPTOR depletion, or allosteric mTORC1 inhibitor rapamycin. These data reveal that RAPTOR up-regulation contributes to PI3K-mTOR inhibitor resistance, and suggest that RAPTOR expression should be included in the pharmacodynamic assessment of mTOR kinase inhibitor trials.
Journal Article