Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation

The p85α protein regulates flux through the PI3K/PTEN signaling pathway, and also controls receptor trafficking via regulation of Rab-family GTPases. In this report, we determined the impact of several cancer patient-derived p85α mutations located within the N-terminal domains of p85α previously shown to bind PTEN and Rab5, and regulate their respective functions. One p85α mutation, L30F, significantly reduced the steady state binding to PTEN, yet enhanced the stimulation of PTEN lipid phosphatase activity. Three other p85α mutations (E137K, K288Q, E297K) also altered the regulation of PTEN catalytic activity. In contrast, many p85α mutations reduced the binding to Rab5 (L30F, I69L, I82F, I177N, E217K), and several impacted the GAP activity of p85α towards Rab5 (E137K, I177N, E217K, E297K). We determined the crystal structure of several of these p85α BH domain mutants (E137K, E217K, R262T E297K) for bovine p85α BH and found that the mutations did not alter the overall domain structure. Thus, several p85α mutations found in human cancers may deregulate PTEN and/or Rab5 regulated pathways to contribute to oncogenesis. We also engineered several experimental mutations within the p85α BH domain and identified L191 and V263 as important for both binding and regulation of Rab5 activit

Inherited biotic protection in a Neotropical pioneer plant

Chelonanthus alatus is a bat-pollinated, pioneer Gentianaceae that clusters in patches where still-standing, dried-out stems are interspersed among live individuals. Flowers bear circum-floral nectaries (CFNs) that are attractive to ants, and seed dispersal is both barochorous and anemochorous. Although, in this study, live individuals never sheltered ant colonies, dried-out hollow stems - that can remain standing for 2 years - did. Workers from species nesting in dried-out stems as well as from ground-nesting species exploited the CFNs of live C. alatus individuals in the same patches during the daytime, but were absent at night (when bat pollination occurs) on 60.5% of the plants. By visiting the CFNs, the ants indirectly protect the flowers - but not the plant foliage - from herbivorous insects. We show that this protection is provided mostly by species nesting in dried-out stems, predominantly Pseudomyrmex gracilis. That dried-out stems remain standing for years and are regularly replaced results in an opportunistic, but stable association where colonies are sheltered by one generation of dead C. alatus while the live individuals nearby, belonging to the next generation, provide them with nectar; in turn, the ants protect their flowers from herbivores. We suggest that the investment in wood by C. alatus individuals permitting stillstanding, dried-out stems to shelter ant colonies constitutes an extended phenotype because foraging workers protect the flowers of live individuals in the same patch. Also, through this process these dried-out stems indirectly favor the reproduction (and so the fitness) of the next generation including both their own offspring and that of their siblings, alladding up to a potential case of inclusive fitness in plants

Socio-demographic and clinical characteristics of re-presentation to an Australian inner-city emergency department: implications for service delivery

BACKGROUND: People who have complex health care needs frequently access emergency departments for treatment of acute illness and injury. In particular, evidence suggests that those who are homeless, or suffer mental illness, or have a history of substance misuse, are often repeat users of emergency departments. The aim of this study was to describe the socio-demographic and clinical characteristics of emergency department re-presentations. Re-presentation was defined as a return visit to the same emergency department within 28 days of discharge from hospital. METHODS: A retrospective cohort study was conducted of emergency department presentations occurring over a 24-month period to an Australian inner-city hospital. Characteristics were examined for their influence on the binary outcome of re-presentation within 28 days of discharge using logistic regression with the variable patient fitted as a random effect. RESULTS: From 64,147 presentations to the emergency department the re-presentation rate was 18.0% (n = 11,559) of visits and 14.4% (5,894/40,942) of all patients. Median time to re-presentation was 6 days, with more than half occurring within one week of discharge (60.8%; n = 6,873), and more than three-quarters within two weeks (80.9%; n = 9,151). The odds of re-presentation increased three-fold for people who were homeless compared to those living in stable accommodation (adjusted OR 3.09; 95% CI, 2.83 to 3.36). Similarly, the odds of re-presentation were significantly higher for patients receiving a government pension compared to those who did not (adjusted OR 1.73; 95% CI, 1.63 to 1.84), patients who left part-way through treatment compared to those who completed treatment and were discharged home (adjusted OR 1.64; 95% CI, 1.36 to 1.99), and those discharged to a residential-care facility compared to those who were discharged home (adjusted OR 1.46: 95% CI, 1.03 to 2.06). CONCLUSION: Emergency department re-presentation rates cluster around one week after discharge and rapidly decrease thereafter. Housing status and being a recipient of a government pension are the most significant risk factors. Early identification and appropriate referrals for those patients who are at risk of emergency department re-presentation will assist in the development of targeted strategies to improve health service delivery to this vulnerable group

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by deficiency of frataxin protein, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron–sulfur cluster (ISC) biogenesis and low-frataxin expression is due to a GAA repeat expansion in intron 1 of the FXN gene. FRDA cells are genomically unstable, with increased levels of reactive oxygen species and sensitivity to oxidative stress. Here we report the identification of elevated levels of DNA double strand breaks (DSBs) in FRDA patient and YG8sR FRDA mouse model fibroblasts compared to normal fibroblasts. Using lentivirus FXN gene delivery to FRDA patient and YG8sR cells, we obtained long-term overexpression of FXN mRNA and frataxin protein levels with reduced DSB levels towards normal. Furthermore, γ-irradiation of FRDA patient and YG8sR cells revealed impaired DSB repair that was recovered on FXN gene transfer. This suggests that frataxin may be involved in DSB repair, either directly by an unknown mechanism, or indirectly via ISC biogenesis for DNA repair enzymes, which may be essential for the prevention of neurodegeneration.Ataxia UK, FARA Australasia and FARA US

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Disentangling the Relative Importance of Changes in Climate and Land-Use Intensity in Driving Recent Bird Population Trends

Threats to biodiversity resulting from habitat destruction and deterioration have been documented for many species, whilst climate change is regarded as increasingly impacting upon species' distribution and abundance. However, few studies have disentangled the relative importance of these two drivers in causing recent population declines. We quantify the relative importance of both processes by modelling annual variation in population growth of 18 farmland bird species in the UK as a function of measures of land-use intensity and weather. Modelled together, both had similar explanatory power in accounting for annual fluctuations in population growth. When these models were used to retrodict population trends for each species as a function of annual variation in land-use intensity and weather combined, and separately, retrodictions incorporating land-use intensity were more closely linked to observed population trends than retrodictions based only on weather, and closely matched the UK farmland bird index from 1970 onwards. Despite more stable land-use intensity in recent years, climate change (inferred from weather trends) has not overtaken land-use intensity as the dominant driver of bird populations

Ranging characteristics of the domestic cat (Felis catus) in an urban environment

In many countries, high densities of domestic cats (Felis catus) are found in urban habitats where they have the potential to exert considerable predation pressure on their prey. However, little is known of the ranging behaviour of cats in the UK. Twenty cats in suburban Reading, UK, were fitted with GPS trackers to quantify movement patterns. Cats were monitored during the summer and winter for an average of 6.8 24 h periods per season. Mean daily area ranged (95 % MCP) was 1.94 ha. Including all fixes, mean maximum area ranged was 6.88 ha. These are broadly comparable to those observed in urban areas in other countries. Daily area ranged was not affected by the cat’s sex or the season, but was significantly larger at night than during the day. There was no relationship between area ranged and habitat availability. Taking available habitat into account, cat ranging area contained significantly more garden and other green space than urban habitats. If cats were shown to be negatively affecting prey populations, one mitigation option for consideration in housing developments proposed near important wildlife sites would be to incorporate a ‘buffer zone’ in which cat ownership was not permitted. Absolute maximum daily area ranged by a cat in this study was 33.78 ha. This would correspond to an exclusory limit of approximately 300–400 m to minimise the negative effects of cat predation, but this may need to be larger if cat ranging behaviour is negatively affected by population densit

Testing the leadership and organizational change for implementation (LOCI) intervention in substance abuse treatment: A cluster randomized trial study protocol

© 2017 The Author(s). Background: Evidence-based practice (EBP) implementation represents a strategic change in organizations that requires effective leadership and alignment of leadership and organizational support across organizational levels. As such, there is a need for combining leadership development with organizational strategies to support organizational climate conducive to EBP implementation. The leadership and organizational change for implementation (LOCI) intervention includes leadership training for workgroup leaders, ongoing implementation leadership coaching, 360° assessment, and strategic planning with top and middle management regarding how they can support workgroup leaders in developing a positive EBP implementation climate. Methods: This test of the LOCI intervention will take place in conjunction with the implementation of motivational interviewing (MI) in 60 substance use disorder treatment programs in California, USA. Participants will include agency executives, 60 program leaders, and approximately 360 treatment staff. LOCI will be tested using a multiple cohort, cluster randomized trial that randomizes workgroups (i.e., programs) within agency to either LOCI or a webinar leadership training control condition in three consecutive cohorts. The LOCI intervention is 12months, and the webinar control intervention takes place in months 1, 5, and 8, for each cohort. Web-based surveys of staff and supervisors will be used to collect data on leadership, implementation climate, provider attitudes, and citizenship. Audio recordings of counseling sessions will be coded for MI fidelity. The unit of analysis will be the workgroup, randomized by site within agency and with care taken that co-located workgroups are assigned to the same condition to avoid contamination. Hierarchical linear modeling (HLM) will be used to analyze the data to account for the nested data structure. Discussion: LOCI has been developed to be a feasible and effective approach for organizations to create a positive climate and fertile context for EBP implementation. The approach seeks to cultivate and sustain both effective general and implementation leadership as well as organizational strategies and support that will remain after the study has ended. Development of a positive implementation climate for MI should result in more positive service provider attitudes and behaviors related to the use of MI and, ultimately, higher fidelity in the use of MI. Trial registration: This study is registered with Clinicaltrials.gov ( NCT03042832 ), 2 February 2017, retrospectively registered

Qualitative study on the implementation of professional pharmacy services in Australian community pharmacies using framework analysis

Abbreviations: BCT, Behavioural change techniques taxonomy; BCW, Behavioural change wheel; CFIR, Consolidated framework for implementation research; EPOC, Cochrane effective practice and organisation of care; FISpH, Framework for the implementation of services in pharmacy; GIF, Generic implementation framework; KPI, Key performance indicator; TDF, Theoretical domains frameworkBackground: Multiple studies have explored the implementation process and influences, however it appears there is no study investigating these influences across the stages of implementation. Community pharmacy is attempting to implement professional services (pharmaceutical care and other health services). The use of implementation theory may assist the achievement of widespread provision, support and integration. The objective was to investigate professional service implementation in community pharmacy to contextualise and advance the concepts of a generic implementation framework previously published. Methods: Purposeful sampling was used to investigate implementation across a range of levels of implementation in community pharmacies in Australia. Twenty-five semi-structured interviews were conducted and analysed using a framework methodology. Data was charted using implementation stages as overarching themes and each stage was thematically analysed, to investigate the implementation process, the influences and their relationships. Secondary analyses were performed of the factors (barriers and facilitators) using an adapted version of the Consolidated Framework for Implementation Research (CFIR), and implementation strategies and interventions, using the Expert Recommendations for Implementing Change (ERIC) discrete implementation strategy compilation. Results: Six stages emerged, labelled as development or discovery, exploration, preparation, testing, operation and sustainability. Within the stages, a range of implementation activities/steps and five overarching influences (pharmacys' direction and impetus, internal communication, staffing, community fit and support) were identified. The stages and activities were not applied strictly in a linear fashion. There was a trend towards the greater the number of activities considered, the greater the apparent integration into the pharmacy organization. Implementation factors varied over the implementation stages, and additional factors were added to the CFIR list and definitions modified/contextualised for pharmacy. Implementation strategies employed by pharmacies varied widely. Evaluations were lacking. Conclusions: The process of implementation and five overarching influences of professional services implementation in community pharmacy have been outlined. Framework analysis revealed, outside of the five overarching influences, factors influencing implementation varied across the implementation stages. It is proposed at each stage, for each domain, the factors, strategies and evaluations should be considered. The Framework for the Implementation of Services in Pharmacy incorporates the contextualisation of implementation science for pharmacy.The study was funded as part of a University of Technology Sydney (UTS) Research Excellence Scholarship (RES), comprising of an Australian Postgraduate Award (APA) Scholarship funded by the Australian Government, plus a Top-up funded by the University of Technology Sydney, received from the primary author (JCM)

Tissue functions mediated by β3-adrenoceptors—findings and challenges

As β3-adrenoceptor agonists metamorphose from experimental tools into therapeutic drugs, it is vital to obtain a comprehensive picture of the cell and tissue functions mediated by this receptor subtype in humans. Human tissues with proven functions and/or a high expression of β3-adrenoceptors include the urinary bladder, the gall bladder, and other parts of the gastrointestinal tract. While several other β3-adrenoceptor functions have been proposed based on results obtained in animals, their relevance to humans remains uncertain. For instance, β3-adrenoceptors perform an important role in thermogenesis and lipolysis in rodent brown and white adipose tissue, respectively, but their role in humans appears less significant. Moreover, the use of tools such as the agonist BRL 37344 and the antagonist SR59230A to demonstrate functional involvement of β3-adrenoceptors may lead in many cases to misleading conclusions as they can also interact with other β-adrenoceptor subtypes or even non-adrenoceptor targets. In conclusion, we propose that many responses attributed to β3-adrenoceptor stimulation may need re-evaluation in the light of the development of more selective tools. Moreover, findings in experimental animals need to be extended to humans in order to better understand the potential additional indications and side effects of the β3-adrenoceptor agonists that are beginning to enter clinical medicine