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\"Few authors benefit from being set in their contemporary context more than Samuel Johnson. Samuel Johnson in Context is a guide to his world, offering readers a comprehensive account of eighteenth-century life and culture as it relates to his work. Short, lively and eminently readable chapters illuminate not only Johnson's own life, writings and career, but the literary, critical, journalistic, social, political, scientific, artistic, medical and financial contexts in which his works came into being. Written by leading experts in Johnson and in eighteenth-century studies, these chapters offer both depth and range of information and suggestions for further study and research. Richly illustrated, with a chronology of Johnson's life and works and an extensive bibliography, this book is a major new work of reference on eighteenth-century culture and the age of Johnson\"-- Provided by publisher.

Cancer cells upregulate glycolysis, increasing glucose uptake to meet energy needs. A small fraction of a cell's glucose enters the hexosamine biosynthetic pathway (HBP), which regulates levels of O-linked β- N -acetylglucosamine (O-GlcNAc), a carbohydrate posttranslational modification of diverse nuclear and cytosolic proteins. We discovered that breast cancer cells upregulate the HBP, including increased O-GlcNAcation and elevated expression of O-GlcNAc transferase (OGT), which is the enzyme catalyzing the addition of O-GlcNAc to proteins. Reduction of O-GlcNAcation through RNA interference of OGT in breast cancer cells leads to inhibition of tumor growth both in vitro and in vivo and is associated with decreased cell-cycle progression and increased expression of the cell-cycle inhibitor p27 Kip1 . Elevation of p27 Kip1 was associated with decreased expression and activity of the oncogenic transcription factor FoxM1, a known regulator of p27 Kip1 stability through transcriptional control of Skp2. Reducing O-GlcNAc levels in breast cancer cells decreased levels of FoxM1 protein and caused a decrease in multiple FoxM1-specific targets, including Skp2. Moreover, reducing O-GlcNAcation decreased cancer cell invasion and was associated with the downregulation of matrix metalloproteinase-2, a known FoxM1 target. Finally, pharmacological inhibition of OGT in breast cancer cells had similar anti-growth and anti-invasion effects. These findings identify O-GlcNAc as a novel mechanism through which alterations in glucose metabolism regulate cancer growth and invasion and suggest that OGT may represent novel therapeutic targets for breast cancer.

Osteoarthritis is a major contributor to pain and disability worldwide, yet there are currently no validated soluble biomarkers or disease-modifying treatments. Given that microRNAs are promising mechanistic biomarkers that can be therapeutically targeted, in this study, we aimed to identify and prioritize reproducible circulating microRNAs associated with radiographic knee osteoarthritis. Across four independent cohorts, we find circulating miR-126-3p is elevated in knee osteoarthritis versus controls. Across six primary human knee osteoarthritis tissues, miR-126-3p is highest in subchondral bone, fat pad and synovium, and lowest in cartilage. Following both intravenous and intra-articular miR-126-3p mimic treatment in a surgical mouse model of knee osteoarthritis, we show reduced disease severity in males. In human knee osteoarthritis biospecimens, miR-126-3p mimic treatment reduces genes and markers associated with angiogenesis, as well as genes linked to osteogenesis, adipogenesis, and synovitis—processes secondary to angiogenesis. Our findings indicate that miR-126-3p is elevated in knee osteoarthritis and mitigates disease severity, supporting its potential as a biomarker and therapeutic target. Though it is the most common joint disease, osteoarthritis has no molecular biomarkers or disease-modifying therapies. Here, the authors show miR-126-3p is a mechanistic biomarker that regulates angiogenesis and mitigates knee osteoarthritis severity.

The present study examined the effects of a proprietary Ashwagandha (Withania somnifera) root and leaf extract (NooGandha® Specnova LLC, USA) supplement for improving cognitive abilities, cortisol levels, and self-reported mood, stress, food cravings, and anxiety with adults who have perceived stress. Healthy adults (n = 43 women and n = 17 men; mean age = 34.41 years) who reported experiencing perceived stress were randomized to the following groups: Ashwagandha (400 mg/d), Ashwagandha (225 mg/d), and placebo for 30 days. The following outcomes were assessed at Day 0, Day 15, and Day 30: saliva cortisol levels, cognitive performance (i.e., CNS vital signs), and the self-reported measures of Trait Anxiety Inventory, Depression Anxiety Stress Scale, Perceived Stress Scale, and Food Cravings Questionnaire-15. For the self-report assessments, significant main effects for time were evidenced for anxiety, depression, perceived stress, and food cravings, p's < 0.01. The main effect for group and the interactions were non-significant. For the CNS vital signs, significant differences were observed in cognitive flexibility, visual memory, reaction time, psychomotor speed, and executive functioning, p's < 0.05, with the Ashwagandha groups often out-performing the placebo group. Both Ashwagandha groups had reductions in cortisol levels over time, with significant reductions evidenced for the Ashwagandha 225 mg/d group from Day 0 to Day 15 to Day 30. The placebo group had a non-significant increase in cortisol levels from Day 0 to Day 15–30. No adverse events were reported. In conclusion, Ashwagandha supplementation may improve the physiological, cognitive, and psychological effects of stress.

Substantial progress has been made in colorectal cancer in the past decade. Screening, used to identify individuals at an early stage, has improved outcome. There is greater understanding of the genetic basis of inherited colorectal cancer and identification of patients at risk. Optimisation of surgery for patients with localised disease has had a major effect on survival at 5 years and 10 years. For rectal cancer, identification of patients at greatest risk of local failure is important in the selection of patients for preoperative chemoradiation, a strategy proven to improve outcomes in these patients. Stringent postoperative follow-up helps the early identification of potentially radically treatable oligometastatic disease and improves long-term survival. Treatment with adjuvant fluoropyrimidine for colon and rectal cancers further improves survival, more so in stage III than in stage II disease, and oxaliplatin-based combination chemotherapy is now routinely used for stage III disease, although efficacy must be carefully balanced against toxicity. In stage II disease, molecular markers such as microsatellite instability might help select patients for treatment. The integration of targeted treatments with conventional cytotoxic drugs has expanded the treatment of metastatic disease resulting in incremental survival gains. However, biomarker development is essential to aid selection of patients likely to respond to therapy, thereby rationalising treatments and improving outcomes.

Genome-wide association studies have revealed common genetic variants with small effect sizes associated with diverse lymphoid cancers. Family studies have uncovered rare variants with high effect sizes. However, these variants explain only a portion of the heritability of these cancers. Some of the missing heritability may be attributable to rare variants with small effect sizes. We aim to identify rare germline variants associated with familial lymphoid cancers using exome sequencing. One case per family was selected from 39 lymphoid cancer families based on early onset of disease or rarity of subtype. Control data was from Non-Finnish Europeans in gnomAD exomes (N = 56,885) or ExAC (N = 33,370). Gene and pathway-based burden tests for rare variants were performed using TRAPD. Five putatively pathogenic germline variants were found in four genes: INTU , PEX7 , EHHADH , and ASXL1 . Pathway-based association tests identified the innate and adaptive immune systems, peroxisomal pathway and olfactory receptor pathway as associated with lymphoid cancers in familial cases. Our results suggest that rare inherited defects in the genes involved in immune system and peroxisomal pathway may predispose individuals to lymphoid cancers.

Background: Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation. Methods: We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases. Results: Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03–5.31, P =0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36–7.03, P =0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family. Conclusion: The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.

Bronchopneumonia is a common respiratory disease in livestock. Mannheimia haemolytica is considered the main causative pathogen leading to lung damage in sheep, with Mycoplasma ovipneumoniae and ParaInfluenza virus type 3, combined with adverse physical and physiological stress, being predisposing factors. A balance of humoral and cellular immunity is thought to be important for protection against developing respiratory disease. In the current study, we compared the ability of the trehalose glycolipid adjuvant C18Brar (C18-alkylated brartemicin analogue) and three commercially available adjuvant systems i . e ., Quil-A, Emulsigen-D, and a combination of Quil-A and aluminium hydroxide gel, to stimulate antibody and cellular immune responses to antigens from inactivated whole cells of M . haemolytica and M . ovipneumoniae in sheep. C18Brar and Emulsigen-D induced the strongest antigen-specific antibody responses to both M . haemolytica and M . ovipneumoniae , while C18Brar and Quil-A promoted the strongest antigen-specific IL-17A responses. The expression of genes with known immune functions was determined in antigen-stimulated blood cultures using Nanostring nCounter technology. The expression levels of CD40 , IL22 , TGFB1 , and IL2RA were upregulated in antigen-stimulated blood cultures from animals vaccinated with C18Brar, which is consistent with T-cell activation. Collectively, the results demonstrate that C18Brar can promote both antibody and cellular responses, notably Th17 immune responses in a ruminant species.

Background: Autozygosity, the proportion of the genome that is homozygous by descent, has been associated with variation in multiple health-related traits impacting evolutionary fitness. Autozygosity (FROH) is typically measured from runs of homozygosity (ROHs) that arise when identical-by-descent (IBD) haplotypes are inherited from each parent. Population isolates with a small set of common founders have elevated autozygosity relative to outbred populations. Methods: In this study, we examined whether degree of autozygosity was associated with variation in 96 cardiometabolic traits among 7221 Old Order Amish individuals residing in Lancaster County, PA. We estimated the average length of an ROH segment to be 6350 KB, with each individual having on average 17.2 segments 1.5 KB or larger. Measurements of genome-wide and regional FROH were used as the primary predictors of trait variation in association analysis. Results: In genome-wide FROH analysis, we did not identify any associations that withstood Bonferroni-correction (p = 0.0005). However, on regional FROH analysis, we identified associations exceeding genome-wide thresholds for two traits: serum bilirubin levels, which were significantly associated with a region on chromosome 2 localized to a region surrounding UGT1A10 (p = 1 × 10− 43), and HbA1c levels, which were significantly associated with a region on chromosome 8 localized near CHRNB3 (p = 8 × 10− 10). Conclusions: These analyses highlight the potential value of autozygosity mapping in founder populations.

Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism‐of‐action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti‐cancer drugs with genome‐wide CRISPR loss‐of‐function screens in 484 cell lines to systematically investigate cellular drug mechanism‐of‐action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein–protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin–protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on‐target and off‐target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss‐of‐fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss‐of‐function screens can elucidate mechanism‐of‐action to advance drug development. Synopsis This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response. CRISPR screens reveal important aspects of drug mechanism‐of‐action, specifically in the context of cellular activity, isoform specificity, off‐target and polypharmacological effects. By leveraging protein interaction networks that underlie drug‐responses, novel drug‐target interactions involving anti‐apoptotic MCL1 inhibitors are identified. Improved pharmacogenomic biomarker discovery using two independent and orthogonal cell viability screens. Graphical Abstract This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response.