Explore the vast range of titles available.

\"Jessica Fletcher investigates a mysterious manuscript with deadly consequences in the latest entry in this USA Today bestselling series Jessica Fletcher has had plenty to worry about over her storied career, both as a bestselling novelist and amateur sleuth. But she never had any reason to worry about her longtime publisher, Lane Barfield, who also happens to be a trusted friend. When mounting evidence of financial malfeasance leads to an FBI investigation of Lane, Jessica can't believe what she's reading. So when Barfield turns up dead, Jessica takes on the task of proving Barfield's innocence she can't fathom someone she's known and trusted for so long cheating her. Sure enough, Jessica's lone wolf investigation turns up several oddities and inconsistencies in Barfield's murder. Jessica knows something is being covered up, but what exactly? The trail she takes to answer that question reveals something far more nefarious afoot, involving shadowy characters from the heights of power in Washington. At the heart of Jessica's investigation lies a manuscript Barfield had intended to bring out after all other publishers had turned it down. The problem is that manuscript has disappeared, all traces of its submission and very existence having been wiped off the books. With her own life now in jeopardy, Jessica refuses to back off and sets her sights on learning the contents of that manuscript and what about it may have led to several murders. Every step she takes brings her closer to the truth of what lies in the pages, as well as the person who penned them\"-- Provided by publisher.

N-glycosylation has a great impact on glycoprotein structure, conformation, stability, solubility, immunogenicity and enzyme activity. Structural characterization of N-glycoproteome has been challenging but can provide insights into the extent of protein folding and surface topology. We describe a highly sensitive proteomics method for large-scale identification and quantification of glycoproteins in Arabidopsis through 15N-metabolic labeling, selective enrichment of glycopeptides, data-dependent MS/MS analysis and automated database searching. In-house databases of Arabidopsis glycoproteins and glycopeptides containing Asn-X-Ser/Thr/Cys motifs were constructed by reducing 20% and 90% of the public database size, respectively, to enable a rapid analysis of large datasets for comprehensive identification and quantification of glycoproteins and heterogeneous N-glycans in a complex mixture. Proteome-wide analysis identified c. 100 stress-related N-glycoproteins, of which the endoplasmic reticulum (ER) resident proteins were examined to be up-regulated. Quantitative measurements provided a molecular signature specific to glycoproteins for determining the degree of plant stress at low temperature. Structural N-glycoproteomics following time-course cold treatments revealed the stressresponsive degradation of high-mannose type N-glycans in ER in response to chilling stress, which may aid in elucidating the cellular mechanisms of protein relocation, transport, trafficking, misfolding and degradation under stress conditions.

Background Brachypodium distachyon is emerging as a widely recognized model plant that has very close relations with several economically important Poaceae species. MAPK cascade is known to be an evolutionarily conserved signaling module involved in multiple stresses. Although the gene sequences of MAPK and MAPKK family have been fully identified in B. distachyon , the information related to the upstream MAPKKK gene family especially the regulatory network among MAPKs, MAPKKs and MAPKKKs upon multiple stresses remains to be understood. Results In this study, we have identified MAPKKKs which belong to the biggest gene family of MAPK cascade kinases. We have systematically investigated the evolution of whole MAPK cascade kinase gene family in terms of gene structures, protein structural organization, chromosomal localization, orthologs construction and gene duplication analysis. Our results showed that most BdMAPK cascade kinases were located at the low-CpG-density region, and the clustered members in each group shared similar structures of the genes and proteins. Synteny analysis showed that 62 or 21 pairs of duplicated orthologs were present between B. distachyon and Oryza sativa, or between B. distachyon and Arabidopsis thaliana respectively. Gene expression data revealed that BdMAPK cascade kinases were rapidly regulated by stresses and phytohormones. Importantly, we have constructed a regulation network based on co-expression patterns of the expression profiles upon multiple stresses performed in this study. Conclusions BdMAPK cascade kinases were involved in the signaling pathways of multiple stresses in B. distachyon . The network of co-expression regulation showed the most of duplicated BdMAPK cascade kinase gene orthologs demonstrated their convergent function, whereas few of them developed divergent function in the evolutionary process. The molecular evolution analysis of identified MAPK family genes and the constructed MAPK cascade regulation network under multiple stresses provide valuable information for further investigation of the functions of BdMAPK cascade kinase genes.

\"A working mother strives to balance her demanding career with the stress of raising two young children and maintaining a healthy marriage in this comedy adapted from the best-selling novel by Allison Pearson. By day, Kate Reddy (Sarah Jessica Parker) works for a Boston-based financial management firm; by night, she's a devoted mother to two adoring children and the happily married wife of out-of-work architect Richard (Greg Kinnear). Though balancing those two worlds has its fair share of challenges, Kate generally manages to come out on top thanks to the support of her best friend, Allison (Christina Hendricks), who's had plenty of experience balancing kids and a career. Meanwhile, on the other end of the spectrum, Kate's sharp-as-a-tack junior associate assistant, Momo (Olivia Munn), possesses a fear of children and a strong work ethic. Just when Kate lands a lucrative new account that will see her traveling across the country on a regular basis, however, her new business associate Jack (Pierce Brosnan) reveals his flirtatious side and Richard receives a job offer he can't turn down. Though it looks as if Kate and Richard couldn't possibly take on any more responsibility, the demands of modern living ensure they'll never have a dull moment, even if they try\"--Allmovie.com, September 28, 2018.

Dietary restriction (DR) is a dietary regimen that extends lifespan in many organisms. One mechanism contributing to the conserved effect of DR on longevity is the cellular recycling process autophagy, which is induced in response to nutrient scarcity and increases sequestration of cytosolic material into double-membrane autophagosomes for degradation in the lysosome. Although autophagy plays a direct role in DR-mediated lifespan extension in the nematode Caenorhabditis elegans, the contribution of autophagy in individual tissues remains unclear. In this study, we show a critical role for autophagy in the intestine, a major metabolic tissue, to ensure lifespan extension of dietary-restricted eat-2 mutants. The intestine of eat-2 mutants has an enlarged lysosomal compartment and flux assays indicate increased turnover of autophagosomes, consistent with an induction of autophagy in this tissue. This increase in intestinal autophagy may underlie the improved intestinal integrity we observe in eat-2 mutants, since whole-body and intestinal-specific inhibition of autophagy in eat-2 mutants greatly impairs the intestinal barrier function. Interestingly, intestinal-specific inhibition of autophagy in eat-2 mutants leads to a decrease in motility with age, alluding to a potential cell non-autonomous role for autophagy in the intestine. Collectively, these results highlight important functions for autophagy in the intestine of dietary-restricted C. elegans.

Co-design as a participatory method aims to improve health service design and implementation. It is being used more frequently by researchers and practitioners in various health and social care settings. Co-design has the potential for achieving positive outcomes for the end users involved in the process; however, involvement of diverse ethnic minority population in the process remains limited. While the need to engage with diverse voices is identified, there is less information available on how to achieve meaningful engagement with these groups. Ethnic minorities are super-diverse population and the diversity between and within these groups need consideration for optimising their participation in co-design. Based on our experience of working with diverse ethnic minority groups towards the co-design of consumer engagement strategies to improve patient safety in cancer services as part of the two nationally-funded research projects in Australia, we outline reflections and practical techniques to optimise co-design with people from diverse ethnic backgrounds. We identify three key aspects of the co-design process pertinent to the involvement of this population; 1) starting at the pre-commencement stage to ensure diverse, seldom heard consumers are invited to and included in co-design work, 2) considering logistics and adequate resources to provide appropriate support to address needs before, during and beyond the co-design process, and 3) supporting and enabling a diversity of contributions via the co-design process.

[This corrects the article DOI: 10.1371/journal.pgen.1006135.].

Background Heart failure (HF) clustering typically relies on clinical characteristics which may not reflect underlying pathophysiology relevant for personalized medicine. We aimed to identify plasma protein profiles of HF patients with reduced ejection fraction (HFrEF). Methods Using latent class analysis, we derived clusters based on 1) clinical characteristics, and 2) proteomics (SomaScan) from 379 HFrEF patients (median age 64 years [Q1 56; Q3 72], 73% male). Survival analysis assessed associations with major cardiovascular (CV) events (HF hospitalization, CV death, or advanced therapy), HF hospitalization, CV death, and all-cause mortality. Associations were validated in 511 external patients (median age 72 years [Q1 63; Q3 79], 70% male). We identified differentially expressed proteins and explored whether proteins are targets of developmental or approved drugs. Results We show that clinical clustering identifies three patient clusters without distinct disease progression. Contrary to this, clustering based on plasma proteomics identifies three patient clusters with clear differences in disease, which are validated in the external cohort. The slowly progressing cluster 1 includes younger patients with fewer comorbidities, while the rapidly progressing cluster 3 consists of older patients with more atrial fibrillation and renal failure, and the hospitalization cluster 2 is intermediate in many characteristics. Medication use is similar across clusters. Relative to cluster 1, patients in cluster 2 have an increased risk of major CV events (HR 2.31, 95%CI 1.23; 4.36) and HF hospitalization (HR 2.30, 95%CI 1.10; 4.78). Patients in cluster 3 experienced increased  event rates of major CV events (HR 5.84), HF hospitalization (6.50), CV death (8.58), and all-cause mortality (5.07). Twelve proteins are differentially expressed across the identified clusters, including druggable CD2, GDF-15, ABO, IGFBP-1, IGFBP-2, and RNase1. Conclusions Proteomics-based clustering identifies three HFrEF clusters associated with distinct outcomes that remain undetected using only clinical characteristics. Plain language summary Heart failure affects millions of people worldwide, but symptoms and disease course varies greatly. People are often grouped based on basic clinical characteristics, which may miss important biological differences. In this study, we analyse blood proteins from people with heart failure and compare grouping based on these to a grouping based on clinical characteristics. We identify three biological groups of people with heart failure, and each group has a different future risk of hospitalization and death. The results are confirmed in an independent patient group. Our findings suggest that protein profiling can reveal hidden disease subtypes, which could help tailor treatments and improve outcomes for heart failure patients. We also identify proteins that could provide promising drug targets for specific patient groups. van Vugt, She, Kardys et al. derive and validate a publicly available clustering algorithm based on data to identify HFrEF patient clusters. Proteomics-based clustering reveals three distinct groups with markedly different risks of hospitalization, cardiovascular events, and mortality, undetected by clinical data alone.

Olanzapine and other atypical antipsychotics cause metabolic side effects leading to obesity and diabetes; although these continue to be an important public health concern, their underlying mechanisms remain elusive. Therefore, an animal model of these side effects was developed in male Sprague–Dawley rats. Chronic administration of olanzapine elevated fasting glucose, impaired glucose and insulin tolerance, increased fat mass but, in contrast to female rats, did not increase body weight or food intake. Acute studies were conducted to delineate the mechanisms responsible for these effects. Olanzapine markedly decreased physical activity without a compensatory decline in food intake. It also acutely elevated fasting glucose and worsened oral glucose and insulin tolerance, suggesting that these effects are adiposity independent. Hyperinsulinemic-euglycemic clamp studies measuring 14 C-2-deoxyglucose uptake revealed tissue-specific insulin resistance. Insulin sensitivity was impaired in skeletal muscle, but either unchanged or increased in adipose tissue depots. Consistent with the olanzapine-induced hyperglycemia, there was a tendency for increased 14 C-2-deoxyglucose uptake into fat depots of fed rats and, surprisingly, free fatty acid (FFA) uptake into fat depots was elevated approximately twofold. The increased glucose and FFA uptake into adipose tissue was coupled with increased adipose tissue lipogenesis. Finally, olanzapine lowered fasting plasma FFA, and as it had no effect on isoproterenol-stimulated rises in plasma glucose, it blunted isoproterenol-stimulated in vivo lipolysis in fed rats. Collectively, these results suggest that olanzapine exerts several metabolic effects that together favor increased accumulation of fuel into adipose tissue, thereby increasing adiposity.