Fully Collapsed Imploded Cryptophanes in Solution and in the Solid State

Cryptophanes with flexible linkers derived from (±)‐tris‐(4‐formyl‐phenyl)‐cyclotriguaiacylene with either bisoxydi(ethylamine) or bis(aminopropyl)ether were isolated as single crystals, the crystal structures of which showed the proposed, but previously uncharacterised, out‐in conformation, in which both cyclotriguaiacylene fragments adopt a crown conformation with one crown sitting inside the other. The usual cage‐like out‐out conformation of the cryptophanes was observed when crystals were dissolved upon heating, and the molecules collapsed back to the out‐in isomers over time. In contrast, a cryptophane also derived from (±)‐tris‐(4‐formyl‐phenyl)‐cyclotriguaiacylene but with rigid dibenzalhydrazine linkers was isolated as the more usual out‐out isomer

Annual direct and indirect costs attributable to nocturia in Germany, Sweden, and the UK

OBJECTIVE: Our aim was to estimate the prevalence-based cost of illness imposed by nocturia (≥2 nocturnal voids per night) in Germany, Sweden, and the UK in an average year. METHODS: Information obtained from a systematic review of published literature and clinicians was used to construct an algorithm depicting the management of nocturia in these three countries. This enabled an estimation of (1) annual levels of healthcare resource use, (2) annual cost of healthcare resource use, and (3) annual societal cost arising from presenteeism and absenteeism attributable to nocturia in each country. RESULTS: In an average year, there are an estimated 12.5, 1.2, and 8.6 million patients ≥20 years of age with nocturia in Germany, Sweden, and the UK, respectively. In an average year in each country, respectively, these patients were estimated to have 13.8, 1.4, and 10.0 million visits to a family practitioner or specialist, ~91,000, 9000, and 63,000 hospital admissions attributable to nocturia and 216,000, 19,000, and 130,000 subjects were estimated to incur a fracture resulting from nocturia. The annual direct cost of healthcare resource use attributable to managing nocturia was estimated to be approximately €2.32 billion in Germany, 5.11 billion kr (€0.54 billion) in Sweden, and £1.35 billion (€1.77 billion) in the UK. The annual indirect societal cost arising from both presenteeism and absenteeism was estimated to be approximately €20.76 billion in Germany and 19.65 billion kr (€2.10 billion) in Sweden. In addition, in the UK, the annual indirect cost due to absenteeism was an estimated £4.32 billion (€5.64 billion). CONCLUSIONS: Nocturia appears to impose a substantial socioeconomic burden in all three countries. Clinical and economic benefits could accrue from an increased awareness of the impact that nocturia imposes on patients, health services, and society as a whole

Hypertension genomics and cardiovascular prevention.

Hypertension continues to be a major risk factor for global mortality, and recent genome-wide association studies (GWAS) have expanded in size, leading to the identification of further genetic loci influencing blood pressure. In light of the new knowledge from the largest cardiovascular GWAS to date, we review the potential impact of genomics on discovering potential drug targets, risk stratification with genetic risk scores, drug selection with pharmacogenetics, and exploring insights provided by gene-environment interactions

Intercultural New Media Studies: The Next Frontier in intercultural Communication

New media (ICT\u27s) are transforming communication across cultures. Despite this revolution in cross cultural contact, communication researchers have largely ignored the impact of new media on intercultural communication. This groundbreaking article defines the parameters of a new field of inquiry called Intercultural New Media Studies (INMS), which explores the intersection between ICT\u27s and intercultural communication. Composed of two research areas—(1) new media and intercultural communication theory and (2) culture and new media—INMS investigates new digital theories of intercultural contact as well as refines and expands twentieth-century intercultural communication theories, examining their salience in a digital world. INMS promises to increase our understanding of intercultural communication in a new media age and is the next frontier in intercultural communication

On passion and moral behavior in achievement settings: The mediating role of pride

The Dualistic Model of Passion (Vallerand et al., 2003) distinguishes two types of passion: harmonious passion (HP) and obsessive passion (OP) that predict adaptive and less adaptive outcomes, respectively. In the present research, we were interested in understanding the role of passion in the adoption of moral behavior in achievement settings. It was predicted that the two facets of pride (authentic and hubristic; Tracy & Robins, 2007) would mediate the passion-moral behavior relationship. Specifically, because people who are passionate about a given activity are highly involved in it, it was postulated that they should typically do well and thus experience high levels of pride when engaged in the activity. However, it was also hypothesized that while both types of passion should be conducive to authentic pride, only OP should lead to hubristic pride. Finally, in line with past research on pride (Carver, Sinclair, & Johnson, 2010; Tracy et al., 2009), only hubristic pride was expected to negatively predict moral behavior, while authentic pride was expected to positively predict moral behavior. Results of two studies conducted with paintball players (N=163, Study 1) and athletes (N=296, Study 2) supported the proposed model. Future research directions are discussed in light of the Dualistic Model of Passion

Patients' perceptions of the potential of breathing training for asthma: a qualitative study.

Poor symptom control is common in asthma. Breathing training exercises may be an effective adjunct to medication; it is therefore important to understand facilitators and barriers to uptake of breathing training exercises

Increased NBCn1 expression, Na+/HCO3- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension.

Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3- co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure

Convergence and divergence in the evolution of cat skulls: temporal and spatial patterns of morphological diversity

Background: Studies of biological shape evolution are greatly enhanced when framed in a phylogenetic perspective. Inclusion of fossils amplifies the scope of macroevolutionary research, offers a deep-time perspective on tempo and mode of radiations, and elucidates life-trait changes. We explore the evolution of skull shape in felids (cats) through morphometric analyses of linear variables, phylogenetic comparative methods, and a new cladistic study of saber-toothed cats. Methodology/Principal Findings: A new phylogenetic analysis supports the monophyly of saber-toothed cats (Machairodontinae) exclusive of Felinae and some basal felids, but does not support the monophyly of various sabertoothed tribes and genera. We quantified skull shape variation in 34 extant and 18 extinct species using size-adjusted linear variables. These distinguish taxonomic group membership with high accuracy. Patterns of morphospace occupation are consistent with previous analyses, for example, in showing a size gradient along the primary axis of shape variation and a separation between large and small-medium cats. By combining the new phylogeny with a molecular tree of extant Felinae, we built a chronophylomorphospace (a phylogeny superimposed onto a two-dimensional morphospace through time). The evolutionary history of cats was characterized by two major episodes of morphological divergence, one marking the separation between saber-toothed and modern cats, the other marking the split between large and small-medium cats. Conclusions/Significance: Ancestors of large cats in the ‘Panthera’ lineage tend to occupy, at a much later stage, morphospace regions previously occupied by saber-toothed cats. The latter radiated out into new morphospace regions peripheral to those of extant large cats. The separation between large and small-medium cats was marked by considerable morphologically divergent trajectories early in feline evolution. A chronophylomorphospace has wider applications in reconstructing temporal transitions across two-dimensional trait spaces, can be used in ecophenotypical and functional diversity studies, and may reveal novel patterns of morphospace occupation

Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells.

We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)2D3). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (P<0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1alpha,25(OH)2D3 can be restored by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 nM) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1alpha,25(OH)2D3 plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1alpha,25(OH)2D3 plus TSA cooperatively upregulated eight (out of 1176) genes, including MAPK-APK2 and GADD45alpha. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45alpha induction by 1alpha,25(OH)2D3 alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45alpha was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1alpha,25(OH)2D3-insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors

Pro-inflammatory polarization and colorectal cancer modulate alternative and intronic polyadenylation in primary human macrophages

Macrophages are essential cells of the immune system that alter their inflammatory profile depending on their microenvironment. Alternative polyadenylation in the 3'UTR (3'UTR-APA) and intronic polyadenylation (IPA) are mechanisms that modulate gene expression, in particular in cancer and activated immune cells. Yet, how polarization and colorectal cancer (CRC) cells microenvironment affect 3'UTR-APA and IPA in primary human macrophages remains unknown. Here, primary human monocytes were isolated from healthy donors, differentiated and polarized into a pro-inflammatory state and ChrRNA-Seq and 3'RNA-Seq were performed to quantify gene expression and characterize new 3’UTR-APA and IPA mRNA isoforms. Our results show that polarization of human macrophages from naïve to a pro-inflammatory state causes a marked increase both in proximal polyA site selection in the 3'UTR and in IPA events, in genes relevant for macrophage functions. Additionally, we found a negative correlation between differential gene expression and IPA during pro-inflammatory polarization of primary human macrophages. As macrophages are abundant immune cells in the CRC microenvironment that either promote or abrogate cancer progression, we investigated how indirect exposure to CRC cells affects macrophage gene expression and 3'UTR-APA and IPA mRNA events. Co-culture with CRC cells alters the inflammatory phenotype of macrophages, increases the expression of pro tumoral genes and induce 3’UTR-APA alterations. Notably, some of these gene expression differences were also found in tumour-associated macrophages of CRC patients, indicating that they are physiological relevant. Upon macrophage pro inflammatory polarization SRSF12 is the pre-mRNA processing gene that is most upregulated. After SRSF12 knockdown in M1 macrophages there is a global downregulation of gene expression, in particular in genes involved in gene expression regulation and in immune responses. Our results reveal new 48 3’UTR-APA and IPA mRNA isoforms produced during pro-inflammatory polarization of primary human macrophages and CRC co-culture that may be used in the future as diagnostic or therapeutic tools