Professional practices, training, and funding mechanisms: A survey of pediatric primary care psychologists

The integration of mental health services in primary care settings has expanded rapidly in recent years with psychologists being at the forefront of efforts to promote healthy behaviors, reduce disease, and care for behavioral, emotional, and developmental needs to promote overall health and well-being for children and families (Asarnow, Kolko, Miranda,&Kazak, 2017; Stancin& Perrin, 2014). While there are many psychologists working in pediatric primary care (PPC), little is known about the specific activities that these psychologists engage in, the training they receive, or funding mechanisms that support their work. This study sought to address this gap in the literature through a survey of psychologists working in PPC. An anonymous online survey was disseminated to members of professional organizations and listservs who were identified as having interest in PPC. Psychologists (N-65) currently practicing in PPC completed the survey by reporting on clinical roles and practices, professional training, practice settings, and funding supports in PPC settings. Results indicate that psychologists assume a number of roles in PPC including providing individual and family therapy, conducting screenings for child mental health concerns, and providing consultation to medical colleagues. Many psychologists also provide supervision and offer educational opportunities for those in related fields, such as medicine and social work. Engagement in research activities was identified as a secondary activity. It was reported that a number of clinical activities were not billed for on a regular basis. Additional areas of research will be discussed along with implications for clinical services in PPC.. © 2017 American Psychological Association

Modulation of endothelial organelle size as an antithrombotic strategy

BACKGROUND: It is long-established that Von Willebrand Factor (VWF) is central to haemostasis and thrombosis. Endothelial VWF is stored in cell-specific secretory granules, Weibel-Palade bodies (WPBs), organelles generated in a wide range of lengths (0.5 to 5.0 μm). WPB size responds to physiological cues and pharmacological treatment, and VWF secretion from shortened WPBs dramatically reduces platelet and plasma VWF adhesion to an endothelial surface. OBJECTIVE: We hypothesised that WPB-shortening represented a novel target for antithrombotic therapy. Our objective was to determine whether compounds exhibiting this activity do exist. METHODS: Using a microscopy approach coupled to automated image analysis, we measured the size of WPB bodies in primary human endothelial cells treated with licensed compounds for 24 h. RESULTS AND CONCLUSIONS: A novel approach to identification of antithrombotic compounds generated a significant number of candidates with the ability to shorten WPBs. In vitro assays of two selected compounds confirm that they inhibit the pro-haemostatic activity of secreted VWF. This set of compounds acting at a very early stage of the haemostatic process could well prove to be a useful adjunct to current antithrombotic therapeutics. Further, in the current SARS-CoV-2 pandemic, with a considerable fraction of critically ill COVID-19 patients affected by hypercoagulability, these WPB size-reducing drugs might also provide welcome therapeutic leads for frontline clinicians and researchers

Corrigendum: Image-based siRNA screen to identify kinases regulating Weibel-Palade body size control using electroporation.

This corrects the article DOI: 10.1038/sdata.2017.22

Phosphatidylinositol 4-kinase IIβ negatively regulates invadopodia formation and suppresses an invasive cellular phenotype

The type II PI 4-kinases enzymes synthesise the lipid phosphatidylinositol 4-phosphate (PI(4)P) which has been detected at the Golgi complex and endosomal compartments, and which recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear.We found that depletion of PI4KIIα and PI4KIIβ using siRNA led to actin remodelling. Depletion of PI4KIIβ also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP).Depletion of PI4KII isoforms also differentially affected TGN pools of PI(4)P and post-TGN traffic. PI4KIIβ depletion caused increased MT1-MMP trafficking to invasive structures at the plasma membrane and was accompanied by reduced colocalisation of MT1-MMP with membranes containing the endosomal markers Rab5 and Rab7, but increased localisation with the exocytic Rab8. Depletion of PI4KIIβ was sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIβ mRNA is associated with human cancers. This finding supports the cell data and suggests that PI4KIIβ may be a clinically significant suppressor of invasion. We propose that PI4KIIβ synthesises a pool of PI(4)P that maintains MT1-MMP traffic in the degradative pathway and suppresses the formation of invadopodia

Cell-type-specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes

Vitamin D is widely reported to inhibit innate immune signalling and dendritic cell (DC) maturation as a potential immunoregulatory mechanism. It is not known whether vitamin D has global or gene-specific effects on transcriptional responses downstream of innate immune stimulation, or whether vitamin D inhibition of innate immune signalling is common to different cells. We confirmed vitamin D inhibition of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signalling in monocyte-derived DC (MDDC) stimulated with lipopolysaccharide (LPS). This was associated with global but modest attenuation of LPS-induced transcriptional changes at genome-wide level. Surprisingly, vitamin D did not inhibit innate immune NF-κB activation in monocyte-derived macrophages. Consistent with our findings in MDDC, ex vivo vitamin D treatment of primary peripheral blood myeloid DC also led to significant inhibition of LPS-inducible NF-κB activation. Unexpectedly, in the same samples, vitamin D enhanced activation of both NF-κB and MAPK signalling in primary peripheral blood monocytes. In a cross-sectional clinical cohort, we found no relationship between peripheral blood vitamin D levels and LPS-inducible activation of NF-κB and MAPK pathways in monocytes of myeloid DC. Remarkably, however, in vivo supplementation of people with vitamin D deficiency in this clinical cohort also enhanced LPS-inducible MAPK signalling in peripheral blood monocytes. Therefore, we report that vitamin D differentially modulates the molecular response to innate immune stimulation in monocytes, macrophages and dendritic cells. These results are of importance in the design of studies on vitamin D supplementation in infectious and immunological diseases

Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter

The mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+ entry, plays important roles in physiology and pathology. However, only few pharmacological compounds directly and selectively modulate its activity. Here, we perform high-throughput screening on a US Food and Drug Administration (FDA)-approved drug library comprising 1,600 compounds to identify molecules modulating mitochondrial Ca2+ uptake. We find amorolfine and benzethonium to be positive and negative MCU modulators, respectively. In agreement with the positive effect of MCU in muscle trophism, amorolfine increases muscle size, and MCU silencing is sufficient to blunt amorolfine-induced hypertrophy. Conversely, in the triple-negative breast cancer cell line MDA-MB-231, benzethonium delays cell growth and migration in an MCU-dependent manner and protects from ceramide-induced apoptosis, in line with the role of mitochondrial Ca2+ uptake in cancer progression. Overall, we identify amorolfine and benzethonium as effective MCU-targeting drugs applicable to a wide array of experimental and disease conditions

A Two-Tier Golgi-Based Control of Organelle Size Underpins the Functional Plasticity of Endothelial Cells

Weibel-Palade bodies (WPBs), endothelial-specific secretory granules that are central to primary hemostasis and inflammation, occur in dimensions ranging between 0.5 and 5 μm. How their size is determined and whether it has a functional relevance are at present unknown. Here, we provide evidence for a dual role of the Golgi apparatus in controlling the size of these secretory carriers. At the ministack level, cisternae constrain the size of nanostructures (“quanta”) of von Willebrand factor (vWF), the main WPB cargo. The ribbon architecture of the Golgi then allows copackaging of a variable number of vWF quanta within the continuous lumen of the trans-Golgi network, thereby generating organelles of different sizes. Reducing the WPB size abates endothelial cell hemostatic function by drastically diminishing platelet recruitment, but, strikingly, the inflammatory response (the endothelial capacity to engage leukocytes) is unaltered. Size can thus confer functional plasticity to an organelle by differentially affecting its activities

Enhancements in Glovebox Design Resulting from Laboratory-Conducted FIre Tests

The primary mission of the Pit Disassembly and Conversion Facility (PDCF) Project was to disassemble nuclear weapons pits and convert the resulting special nuclear materials to a form suitable for further disposition. Because of the nature of materials involved, the fundamental system which allowed PDCF to perform its mission was a series of integrated and interconnected gloveboxes which provided confinement and containment of the radioactive materials being processed. The high throughput planned for PDCF and the relatively high neutron and gamma radiation levels of the pits required that gloveboxes be shielded to meet worker dose limits. The glovebox shielding material was required to contain high hydrogen concentrations which typically result in these materials being combustible. High combustible loadings created design challenges for the facility fire suppression and ventilation system design. Combustible loading estimates for the PDCF Plutonium (Pu) Processing Building increased significantly due to these shielding requirements. As a result, the estimates of combustible loading substantially exceeded values used to support fire and facility safety analyses. To ensure a valid basis for combustible loading contributed by the glovebox system, the PDCF Project funded a series of fire tests conducted by the Southwest Research Institute on door panels and a representative glovebox containing Water Extended Polyester (WEP) radiological shielding to observe their behavior during a fire event. Improvements to PDCF glovebox designs were implemented based on lessons learned during the fire test. In particular, methods were developed to provide high levels of neutron shielding while maintaining combustible loading in the glovebox shells at low levels. Additionally, the fire test results led to design modifications to mitigate pressure increases observed during the fire test in order to maintain the integrity of the WEP cladding. These changes resulted in significantly reducing the credited combustible loading of the facility. These advances in glovebox design should be considered for application in nuclear facilities within the Department of Energy complex in the future