Modulation of Cerebral Artery Smooth Muscle BK Channel Function by Neurosteroids

Voltage-gated and Ca2+ activated K+ channels of large conductance (BK) channels are essential for many key physiological processes, such as controlling the contraction of smooth muscle, including cerebrovascular smooth muscle. Importantly, BK channels are made up of a homotetramer of α subunits which associate with accessory β subunits. These β subunits alter the activity of the channel; this modulation is subunit-specific. Moreover, these accessory subunits have tissue-specific expression, such that the β1 subunit is highly expressed within cerebrovascular smooth muscle and greatly increases the open probability of BK channels. Increased BK channel open probability is linked to increased dilation of cerebral arterial smooth muscle. The tissue specificity and functional effects of the β1 subunit offer a unique opportunity for the identification of pharmacological activators to be developed with few off-target effects. While many steroids have been implicated to have vasoactive effects, including but not limited to, pregnenolone and progesterone, these effects have been mainly attributed to the actions produced by the activation of traditional steroid receptors. Importantly, both pregnenolone and progesterone are currently under investigation for clinical applications, including substance- and alcohol-use disorders, and treatments for ischemic-related brain injury, respectively. Additionally, cholesterol maintains clinical importance as the western diet maintains high levels of cholesterol which are known to increase the risk of heart disease and stroke through maladaptive vasoactive effects. Since the precursor to, and the neurosteroids all produce vasoactive effects, it is important to identify the molecular mediators modulating these effects. This body of work examines the cerebrovascular effects of and determines the mechanisms of action by which the neurosteroids pregnenolone, progesterone, and the precursor cholesterol, modulate the BK channel activity while investigating pre-clinical implications for the K+ channel activators. Through functional, biochemical, and molecular analysis we are able to determine: 1. the physiological implications of; 2. the subunit-specificity for; 3. binding site(s) of; and 4. the gating parameters affected by, the direct binding of neurosteroids to the BK channel complex

Helping the Community from the Bottom Up: Distributing Diapers to the Williamsburg Community

There is a great need for a sustainable supply of clean diapers for low-income residents of Williamsburg since this region is without a diaper bank. Being unable to afford diapers can have a myriad of negative consequences from being unable to send children to child care to increased health risks involved in leaving a baby in a soiled diaper. Our model of a diaper bank differs from most because we mail diapers directly to families, eliminating transportation needs. We hope to partner with community agencies and The College of William & Mary to expand our services and create a more sustainable model in order to serve families in the Greater Williamsburg area. We believe that providing diapers will help break many unhealthy cycles and create a brighter future for our community

Variability in Infants' Functional Brain Network Connectivity Is Associated With Differences in Affect and Behavior

Variability in functional brain network connectivity has been linked to individual differences in cognitive, affective, and behavioral traits in adults. However, little is known about the developmental origins of such brain-behavior correlations. The current study examined functional brain network connectivity and its link to behavioral temperament in typically developing newborn and 1-month-old infants (M [age] = 25 days; N = 75) using functional near-infrared spectroscopy (fNIRS). Specifically, we measured long-range connectivity between cortical regions approximating fronto-parietal, default mode, and homologous-interhemispheric networks. Our results show that connectivity in these functional brain networks varies across infants and maps onto individual differences in behavioral temperament. Specifically, connectivity in the fronto-parietal network was positively associated with regulation and orienting behaviors, whereas connectivity in the default mode network showed the opposite effect on these behaviors. Our analysis also revealed a significant positive association between the homologous-interhemispheric network and infants' negative affect. The current results suggest that variability in long-range intra-hemispheric and cross-hemispheric functional connectivity between frontal, parietal, and temporal cortex is associated with individual differences in affect and behavior. These findings shed new light on the brain origins of individual differences in early-emerging behavioral traits and thus represent a viable novel approach for investigating developmental trajectories in typical and atypical neurodevelopment

Embedding effective depression care: using theory for primary care organisational and systems change

Background: depression and related disorders represent a significant part of general practitioners (GPs) daily work. Implementing the evidence about what works for depression care into routine practice presents a challenge for researchers and service designers. The emerging consensus is that the transfer of efficacious interventions into routine practice is strongly linked to how well the interventions are based upon theory and take into account the contextual factors of the setting into which they are to be transferred. We set out to develop a conceptual framework to guide change and the implementation of best practice depression care in the primary care setting.Methods: we used a mixed method, observational approach to gather data about routine depression care in a range of primary care settings via: audit of electronic health records; observation of routine clinical care; and structured, facilitated whole of organisation meetings. Audit data were summarised using simple descriptive statistics. Observational data were collected using field notes. Organisational meetings were audio taped and transcribed. All the data sets were grouped, by organisation, and considered as a whole case. Normalisation Process Theory (NPT) was identified as an analytical theory to guide the conceptual framework development.Results: five privately owned primary care organisations (general practices) and one community health centre took part over the course of 18 months. We successfully developed a conceptual framework for implementing an effective model of depression care based on the four constructs of NPT: coherence, which proposes that depression work requires the conceptualisation of boundaries of who is depressed and who is not depressed and techniques for dealing with diffuseness; cognitive participation, which proposes that depression work requires engagement with a shared set of techniques that deal with depression as a health problem; collective action, which proposes that agreement is reached about how care is organised; and reflexive monitoring, which proposes that depression work requires agreement about how depression work will be monitored at the patient and practice level. We describe how these constructs can be used to guide the design and implementation of effective depression care in a way that can take account of contextual differences.Conclusions: ideas about what is required for an effective model and system of depression care in primary care need to be accompanied by theoretically informed frameworks that consider how these can be implemented. The conceptual framework we have presented can be used to guide organisational and system change to develop common language around each construct between policy makers, service users, professionals, and researchers. This shared understanding across groups is fundamental to the effective implementation of change in primary care for depressio

"I'm still here, but no one hears you" : a qualitative study of young women's experiences of persistent distress post family-based treatment for adolescent anorexia nervosa

Background: Family-based treatment (FBT) is the current treatment of choice for adolescent AN based on positive outcomes that include weight restoration in around two-thirds of adolescents. Nevertheless around a quarter dropout from treatment, particularly in the earlier phases, and a notable proportion of treated adolescents are reported to experience ongoing psychological distress during and post-treatment. This study explores the under-researched experiences of these adolescents. Method: Fourteen participants from Australia, New Zealand and the United Kingdom were interviewed about their experiences of FBT. An inductive thematic analysis of interview transcript data generated key themes related to their experiences, identity negotiations and the discursive materials these used to construct these. Results: The participants identified working as a family unit as key to their recovery, highlighting the importance of family therapy interventions for adolescent AN. However, they perceived an almost exclusive focus on weight restoration in the first phase of FBT was associated with experiences that included a relative neglect of their psychological distress and a loss of voice. Key within these experiences were processes whereby the adolescent engaged in identity negotiation and (re)claiming of their voice and implicit in their family standing with them in the treatment was that their life was worth saving. What was noted as most helpful was when therapists advocated and took into consideration their unique needs and preferences and tailored treatment interventions to these. Conclusions: There is a need to develop and research treatments that address, from the outset of treatment, the adolescents’ psychological distress (including as experienced in the context of their weight restoration). This should be with priority accorded to the adolescent’s voice and identity negotiations, as they and their families take steps to address the physical crisis of AN and in doing so, support more holistic and durable recovery

Roomful of Teeth

Roomful of Teeth is a GRAMMY-winning vocal project dedicated to reimagining the expressive potential of the human voice. Through study with masters from vocal traditions the world over, the eight-voice ensemble continually expands its vocabulary of singing techniques and, through an ongoing commissioning process, forges a new repertoire without borders.https://digitalcommons.usu.edu/music_programs/1084/thumbnail.jp

Target-D: a stratified individually randomized controlled trial of the diamond clinical prediction tool to triage and target treatment for depressive symptoms in general practice: study protocol for a randomized controlled trial.

BackgroundDepression is a highly prevalent and costly disorder. Effective treatments are available but are not always delivered to the right person at the right time, with both under- and over-treatment a problem. Up to half the patients presenting to general practice report symptoms of depression, but general practitioners have no systematic way of efficiently identifying level of need and allocating treatment accordingly. Therefore, our team developed a new clinical prediction tool (CPT) to assist with this task. The CPT predicts depressive symptom severity in three months' time and based on these scores classifies individuals into three groups (minimal/mild, moderate, severe), then provides a matched treatment recommendation. This study aims to test whether using the CPT reduces depressive symptoms at three months compared with usual care.MethodsThe Target-D study is an individually randomized controlled trial. Participants will be 1320 general practice patients with depressive symptoms who will be approached in the practice waiting room by a research assistant and invited to complete eligibility screening on an iPad. Eligible patients will provide informed consent and complete the CPT on a purpose-built website. A computer-generated allocation sequence stratified by practice and depressive symptom severity group, will randomly assign participants to intervention (treatment recommendation matched to predicted depressive symptom severity group) or comparison (usual care plus Target-D attention control) arms. Follow-up assessments will be completed online at three and 12 months. The primary outcome is depressive symptom severity at three months. Secondary outcomes include anxiety, mental health self-efficacy, quality of life, and cost-effectiveness. Intention-to-treat analyses will test for differences in outcome means between study arms overall and by depressive symptom severity group.DiscussionTo our knowledge, this is the first depressive symptom stratification tool designed for primary care which takes a prognosis-based approach to provide a tailored treatment recommendation. If shown to be effective, this tool could be used to assist general practitioners to implement stepped mental-healthcare models and contribute to a more efficient and effective mental health system.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR 12616000537459 ). Retrospectively registered on 27 April 2016. See Additional file 1 for trial registration data

A High Spectral Resolution Study of the Soft X-ray Background with the X-ray Quantum Calorimeter

We present here a combined analysis of four high spectral resolution observations of the Diffuse X-ray Background (DXRB), made using the University of Wisconsin-Madison/Goddard Space Flight Center X-ray Quantum Calorimeter (XQC) sounding rocket payload. The observed spectra support the existence of a $\sim0.1~$keV Local Hot Bubble and a $\sim0.2~$keV Hot Halo, with discrepancies between repeated observations compatible with expected contributions of time-variable emission from Solar Wind Charge Exchange (SWCX). An additional component of $\sim0.9~$keV emission observed only at low galactic latitudes can be consistently explained by unresolved dM stars.Comment: 21 pages, 6 figures, accepted for publication in Ap