Development and preliminary testing of the psychosocial adjustment to hereditary diseases scale

Background: The presence of Lynch syndrome (LS) can bring a lifetime of uncertainty to an entire family as members adjust to living with a high lifetime cancer risk. The research base on how individuals and families adjust to genetic-linked diseases following predictive genetic testing has increased our understanding of short-term impacts but gaps continue to exist in knowledge of important factors that facilitate or impede long-term adjustment. The failure of existing scales to detect psychosocial adjustment challenges in this population has led researchers to question the adequate sensitivity of these instruments. Furthermore, we have limited insight into the role of the family in promoting adjustment. Methods: The purpose of this study was to develop and initially validate the Psychosocial Adjustment to Hereditary Diseases (PAHD) scale. This scale consists of two subscales, the Burden of Knowing (BK) and Family Connectedness (FC). Items for the two subscales were generated from a qualitative data base and tested in a sample of 243 participants from families with LS. Results: The Multitrait/Multi-Item Analysis Program-Revised (MAP-R) was used to evaluate the psychometric properties of the PAHD. The findings support the convergent and discriminant validity of the subscales. Construct validity was confirmed by factor analysis and Cronbach’s alpha supported a strong internal consistency for BK (0.83) and FC (0.84). Conclusion: Preliminary testing suggests that the PAHD is a psychometrically sound scale capable of assessing psychosocial adjustment. We conclude that the PAHD may be a valuable monitoring tool to identify individuals and families who may require therapeutic interventions

Xanthine-based photoaffinity probes allow assessment of ligand engagement by TRPC5 channels

TRPC1/4/5 cation channels are emerging drug targets for the treatment of, amongst others, central nervous system (CNS) disorders, kidney disease, and cardiovascular and metabolic disease. Various small-molecule TRPC1/4/5 modulators have been reported, including highly potent xanthine derivatives that distinguish between specific TRPC1/4/5 tetramers. However, tools to profile ligand engagement by TRPC1/4/5 channels in live cells are lacking. Here, we report a set of potent xanthine-based photoaffinity probes that functionally mimic the xanthines Pico145 and AM237. Using these probes, we have developed a photoaffinity labelling protocol for TRPC5 channels, providing the first method for the quantitative assessment of binding interactions of TRPC5 with small molecules in cells. This method could be important for drug discovery efforts targeting the xanthine/lipid binding site of TRPC1/4/5 channels

Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients

Modern microwave methods in solid state inorganic materials chemistry: from fundamentals to manufacturing

No abstract available

Genetic variability of drought-avoidance root traits in the mini-core germplasm collection of chickpea (Cicer arietinum L.).

Extensive and deep root systems have been recognized as one of the most important traits for improving chickpea (Cicer arietinum L.) productivity under progressively receding soil moisture conditions. However, available information on the range of variation for root traits is still limited. Genetic variability for the root traits was investigated using a cylinder culture system during two consecutive growth seasons in the mini-core germplasm collection of ICRISAT plus several wild relatives of chickpea. The largest genetic variability was observed at 35 days after sowing for root length density (RLD) (heritability, h 2 = 0.51 and 0.54) across seasons, and followed by the ratio of plant dry weight to root length density with h 2 of 0.37 and 0.50 for first and second season, respectively. The root growth of chickpea wild relatives was relatively poor compared to C. arietinum, except in case of C. reticulatum. An outstanding genotype, ICC 8261, which had the largest RLD and one of the deepest root system, was identified in chickpea mini-core germplasm collection. The accession ICC 4958 which was previously characterized as a source for drought avoidance in chickpea was confirmed as one with the most prolific and deep root system, although many superior accessions were also identified. The chickpea landraces collected from the Mediterranean and the west Asian region showed a significantly larger RLD than those from the south Asian region. In addition, the landraces originating from central Asia (former Soviet Union), characterized by arid agro-climatic conditions, also showed relatively larger RLD. As these regions are under-represented in the chickpea collection, they might be interesting areas for further germplasm exploration to identify new landraces with large RLD. The information on the genetic variability of chickpea root traits provides valuable baseline knowledge for further progress on the selection and breeding for drought avoidance root traits in chickpea

Loss of functional pRB is not a ubiquitous feature of B-cell malignancies

Human cancers frequently sustain genetic mutations that alter the function of their G1 cell cycle control check point. These include changes to the retinoblastoma gene and to the genes that regulate its phosphorylation, such as the cyclin-dependent kinase inhibitor p16(INK4a). Altered expression of retinoblastoma protein (pRb) is associated with non-Hodgkin's lymphoma, particularly centroblastic and Burkitt's lymphomas. pRb is expressed in normal B-cells and its regulatory phosphorylation pathway is activated in response to a variety of stimuli. Since human B-lymphoma-derived cell lines are often used as in vitro model systems to analyse the downstream effects of signal transduction, we examined the functional status of pRb in a panel of human B-cell lines. We identified eleven cell lines which express the hyperphosphorylated forms of pRb. Furthermore, we suggest that the pRb protein appears to be functional in these cell lines

BRITAIN, THE TWO WORLD WARS, AND THE PROBLEM OF NARRATIVE

AbstractThe concept of coming to terms with the past originated in post-1945 West Germany but such historical therapy is evident in all the belligerent countries. In that process, the two world wars are intricately connected, each seen refractively through the prism of the other. This article focuses on Britain whose national obsession with the two world wars is particularly acute. The first and second sections suggest that British public discourse has been able to construct a satisfying narrative of 1939–45 but not of 1914–18, meaning a narrative that has both a clear beginning, middle, and end and also a stark moral meaning. Viable narratives draw on the events themselves, the words used to conceptualize them, and the interpretations of 'instant' histories and memoirs. The third section argues that the elevation of 1939–45 in national discourse as our ‘finest hour’ (Churchill) has aggravated the problematic nature of 1914–18 for the British. In the wake of Brexit, the last section argues that Britain – unlike France and Germany – has found it difficult to move on from the era of the two world wars by locating these conflicts in a more positive narrative of the twentieth century as the eventual triumph of European integration.</jats:p