Ruthenium(II) Polypyridyl Complexes as FRET Donors: Structure- and Sequence-Selective DNA-Binding and Anticancer Properties

Ruthenium(II) polypyridyl complexes (RPCs) that emit from metal-to-ligand charge transfer (MLCT) states have been developed as DNA probes and are being examined as potential anticancer agents. Here, we report that MLCT-emissive RPCs that bind DNA undergo Förster resonance energy transfer (FRET) with Cy5.5-labeled DNA, forming mega-Stokes shift FRET pairs. Based on this discovery, we developed a simple and rapid FRET binding assay to examine DNA-binding interactions of RPCs with diverse photophysical properties, including non-“light switch” complexes [Ru(dppz)2(5,5′dmb)]2+ and [Ru(PIP)2(5,5′dmb)]2+ (dppz = dipyridophenazine, 5,5′dmb = 5,5′-dimethyl-2,2′-bipyridine, PIP = 2-phenyl-imidazo[4,5-f][1,10]phenanthroline). Binding affinities toward duplex, G-quadruplex, three-way junction, and mismatch DNA were determined, and derived FRET donor–acceptor proximities provide information on potential binding sites. Molecules characterized by this method demonstrate encouraging anticancer properties, including synergy with the PARP inhibitor Olaparib, and mechanistic studies indicate that [Ru(PIP)2(5,5′dmb)]2+ acts to block DNA replication fork progression

Baseline Comorbidities in a Population-Based Cohort of Rheumatoid Arthritis Patients Receiving Biological Therapy: Data from the Australian Rheumatology Association Database

Aims. To describe the baseline characteristics of an Australian population-based cohort of rheumatoid arthritis (RA) patients commencing biological therapy. Methods. Descriptive analysis from the Australian Rheumatology Association Database (ARAD). Results. Up to October 2006, there were 681 RA patients taking biologics enrolled in ARAD. Baseline data were available for 624 (72% female, mean (SD) age 57.0 (12.5) years). Of these, 59.5% reported at least one comorbid condition, most commonly hypertension (35.7%) and osteoporosis (30.4%); 61 (9.8%) had a history of malignancy (35 nonmelanoma skin, 5 breast, 4 bowel, 5 cervix, 3 melanoma, 3 prostate and 1 each of lip, lung, myeloma, testis, uterus, vagina). Self-reported infections within the previous 6 months were common (71.5%). Conclusions. History of comorbidities, including recent infections, is common among Australian RA patients commencing biologics, and 10% have a history of malignancy. This may impact future evaluations of health outcomes among this population, including attribution of adverse events of biologic therapy

Adaptive Mobile Health Intervention for Adolescents with Asthma: Iterative User-Centered Development

Background: Adolescents diagnosed with persistent asthma commonly take less than 50% of their prescribed inhaled corticosteroids (ICS), placing them at risk for asthma-related morbidity. Adolescents’ difficulties with adherence occur in the context of normative developmental changes (eg, increased responsibility for disease management) and rely upon still developing self-regulation and problem-solving skills that are integral for asthma self-management. We developed an adaptive mobile health system, Responsive Asthma Care for Teens (ReACT), that facilitates self-regulation and problem-solving skills during times when adolescents’ objectively measured ICS adherence data indicate suboptimal rates of medication use. Objective: The current paper describes our user-centered and evidence-based design process in developing ReACT. We explain how we leveraged a combination of individual interviews, national crowdsourced feedback, and an advisory board comprised of target users to develop the intervention content. Methods: We developed ReACT over a 15-month period using one-on-one interviews with target ReACT users (n=20), national crowdsourcing (n=257), and an advisory board (n=4) to refine content. Participants included 13-17–year-olds with asthma and their caregivers. A total of 280 adolescents and their caregivers participated in at least one stage of ReACT development. Results: Consistent with self-regulation theory, adolescents identified a variety of salient intrapersonal (eg, forgetfulness, mood) and external (eg, changes in routine) barriers to ICS use during individual interviews. Adolescents viewed the majority of ReACT intervention content (514/555 messages, 93%) favorably during the crowdsourcing phase, and the advisory board helped to refine the content that did not receive favorable feedback during crowdsourcing. Additionally, the advisory board provided suggestions for improving additional components of ReACT (eg, videos, message flow). Conclusions: ReACT involved stakeholders via qualitative approaches and crowdsourcing throughout the creation and refinement of intervention content. The feedback we received from participants largely supported ReACT’s emphasis on providing adaptive and personalized intervention content to facilitate self-regulation and problem-solving skills, and the research team successfully completed the recommended refinements to the intervention content during the iterative development process

Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array

BACKGROUND: Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST) that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression. RESULTS: We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported) transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic predictions of alternative splicing in cancer. CONCLUSION: Differential expression of high confidence transcripts correlated extremely well with known cancer genes and pathways, suggesting that the more speculative transcripts, largely based solely on computational prediction and mostly with no previous annotation, might be novel targets in colon cancer. Five of the identified splicing events affect mediators of cytoskeletal organization (ACTN1, VCL, CALD1, CTTN, TPM1), two affect extracellular matrix proteins (FN1, COL6A3) and another participates in integrin signaling (SLC3A2). Altogether they form a pattern of colon-cancer specific alterations that may particularly impact cell motility

Responsive Asthma Care for Teens (ReACT): Development protocol for an adaptive mobile health intervention for adolescents with asthma

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Introduction Asthma is a leading cause of youth morbidity in the USA, affecting >8% of youth. Adherence to inhaled corticosteroids (ICS) can prevent asthma-related morbidity; however, the typical adolescent with asthma takes fewer than 50% of their prescribed doses. Adolescents are uniquely vulnerable to suboptimal asthma self-management due to still-developing executive functioning capabilities that may impede consistent self-regulation and weaken attempts to use problem solving to overcome barriers to ICS adherence. Methods and analysis The aims of this project are to improve adherence to ICS as an important step towards better self-management among adolescents aged 13–17 years diagnosed with asthma by merging the efficacious behaviour change strategies found in behavioural health interventions with scalable, adaptive mobile health (mHealth) technologies to create the Responsive Asthma Care for Teens programme (ReACT). ReACT intervention content will be developed through an iterative user-centred design process that includes conducting (1) one-on-one interviews with 20 teens with asthma; (2) crowdsourced feedback from a nationally representative panel of 100 adolescents with asthma and (3) an advisory board of youth with asthma, a paediatric pulmonologist and a behavioural health expert. In tandem, we will work with an existing technology vendor to programme ReACT algorithms to allow for tailored intervention delivery. We will conduct usability testing of an alpha version of ReACT with a sample of 20 target users to assess acceptability and usability of our mHealth intervention. Participants will complete a 4-week run-in period to monitor their adherence with all ReACT features turned off. Subsequently, participants will complete a 4-week intervention period with all ReACT features activated. The study started in October 2018 and is scheduled to conclude in late 2019. Ethics and dissemination Institutional review board approval was obtained at the University of Kansas and the University of Florida. We will submit study findings for presentation at national research conferences that are well attended by a mix of psychologists, allied health professionals and physicians. We will publish study findings in peer-reviewed journals read by members of the psychology, nursing and pulmonary communities

Pneumonic Plague Cluster, Uganda, 2004

In a case cluster, pneumonic plague transmission was compatible with respiratory droplet rather than aerosol transmission

Leading Disability Research and Workforce Development: A Western Sydney Collaboration

In this White Paper we draw attention to the potential of excellence in research and workforce development as a means, in part, to foster greater inclusion and participation for people with disability. We present a critique of the current limitations in research and workforce development and highlight the urgency to address such shortcomings to realise inclusion within our communities. We demonstrate that Western Sydney University is well positioned as a leading institution to address many of these concerns. This White paper showcases the innovative work of our team, and calls for seven key actions, to advance inclusion and participation for people and communities in Greater Western Sydney, Australia, and beyond

Preventing Establishment: An Inventory of Introduced Plants in Puerto Villamil, Isabela Island, Galapagos

As part of an island-wide project to identify and eradicate potentially invasive plant species before they become established, a program of inventories is being carried out in the urban and agricultural zones of the four inhabited islands in Galapagos. This study reports the results of the inventory from Puerto Villamil, a coastal village representing the urban zone of Isabela Island. We visited all 1193 village properties to record the presence of the introduced plants. In addition, information was collected from half of the properties to determine evidence for potential invasiveness of the plant species. We recorded 261 vascular taxa, 13 of which were new records for Galapagos. Most of the species were intentionally grown (cultivated) (73.3%) and used principally as ornamentals. The most frequent taxa we encountered were Cocos nucifera (coconut tree) (22.1%) as a cultivated plant and Paspalum vaginatum (salt water couch) (13.2%) as a non cultivated plant. In addition 39 taxa were naturalized. On the basis of the invasiveness study, we recommend five species for eradication (Abutilon dianthum, Datura inoxia, Datura metel, Senna alata and Solanum capsicoides), one species for hybridization studies (Opuntia ficus-indica) and three species for control (Furcraea hexapetala, Leucaena leucocephala and Paspalum vaginatum)