NAD(H) phosphates mediate tetramer assembly of human C-terminal binding protein (CtBP)

C-terminal binding proteins (CtBPs) are co-transcriptional factors that play key roles in cell fate. We have previously shown that NAD(H) promotes the assembly of similar tetramers from either human CtBP1 and CtBP2 and that CtBP2 tetramer destabilizing mutants are defective for oncogenic activity. To assist structure-based design efforts for compounds that disrupt CtBP tetramerization, it is essential to understand how NAD(H) triggers tetramer assembly. Here, we investigate the moieties within NAD(H) that are responsible for triggering tetramer formation. Using multi-angle light scattering (MALS) we show that ADP is able to promote tetramer formation of both CtBP1 and CtBP2, whereas AMP promotes tetramer assembly of CtBP1, but not CtBP2. Other NAD(H) moieties that lack the adenosine phosphate, including adenosine and those incorporating nicotinamide, all fail to promote tetramer assembly. Our crystal structures of CtBP1 with AMP reveal participation of the adenosine phosphate in the tetrameric interface, pinpointing its central role in NAD(H) linked assembly. CtBP1 and CtBP2 have overlapping but unique roles, suggesting that a detailed understanding of their unique structural properties might have utility in the design of paralog specific inhibitors. We investigated the different responses to AMP through a series of site-directed mutants at 13 positions. These mutations reveal a central role for a hinge segment, which we term the 120s hinge, that connects the substrate with coenzyme binding domains and influences nucleotide binding and tetramer assembly. Our results provide insight into suitable pockets to explore in structure-based drug design to interfere with co-transcriptional activity of CtBP in cancer

Structured decision making as a conceptual framework to identify thresholds for conservation and management

Threshold and their relevance to conservation have become a major topic of discussion in the ecological literature. Unfortunately, in many cases the lack of a clear conceptual framework for thinking about thresholds in terms of a structured decision making process. The purpose of this framework is to promote a logical and transparent process for making informed decisions for conservation. Specification of such a framework leads naturally to consideration of definitions and roles of different kinds of thresholds in the process. We distinguish among three categories of thresholds. Ecological thresholds are values of system state variables at which small changes bring about substantial changes in system dynamics. Utility thresholds are components of management objectives (determined by human values) and are values of state or performance variables at which small changes yield substantial changes in the value of the management outcome. Decision thresholds are values of system state variables at which small changes prompt changes in management actions in order to reach specified management objectives. The approach that we present focuses directly on the objectives of management, with an aim to providing decisions that are optimal with respect to those objectives. This approach clearly distinguishes the components of the decision process that are inherently subjective (management objectives, potential management actions) from those that are more objectives (system models, estimates of system state). Optimization based on these components then leads to decision matrices specifying optimal actions to be taken at various values of system state variables. Values of state variables separating different actions in such matrices are viewed as decision thresholds. Utility thresholds are included i the objectives component, and ecological thresholds may be embedded in models projecting consequences of management actions. Decision threshold are determined by the above-listed components of a structured decision thresholds inherited from them. These dynamic decision thresholds can then be determined using adaptive management. We provide numerical examples (that are based on patch occupancy models) of structured decision processes that include all three kinds of thresholds

Structured decision making as a conceptual framework to identify thresholds for conservation and management

Thresholds and their relevance to conservation have become a major topic of discussion in the ecological literature. Unfortunately, in many cases the lack of a clear conceptual framework for thinking about thresholds may have led to confusion in attempts to apply the concept of thresholds to conservation decisions. Here, we advocate a framework for thinking about thresholds in terms of a structured decision making process. The purpose of this framework is to promote a logical and transparent process for making informed decisions for conservation. Specification of such a framework leads naturally to consideration of definitions and roles of different kinds of thresholds in the process. We distinguish among three categories of thresholds. Ecological thresholds are values of system state variables at which small changes bring about substantial changes in system dynamics. Utility thresholds are components of management objectives (determined by human values) and are values of state or performance variables at which small changes yield substantial changes in the value of the management outcome. Decision thresholds are values of system state variables at which small changes prompt changing in management actions in order to reach specified management objectives. The approach that we present focuses directly on the objectives of management, with an aim to providing decisions that are optimal with respect to those objectives. This approach clearly distinguishes the components of he decision process that are inherently subjective (management objectives, potential management actions) from those that are more objective (systems models, estimates of system state). Optimization based on these components then leads to decision matrices specifying optimal actions to be taken at various values of system state variables. Values of state variables separating different actions in such matrices are viewed as decision thresholds. Utility thresholds are included in the objectives component, and ecological thresholds may be embedded in models projecting consequences of management actions. Decision thresholds are determined by the above-listed components of a structured decision process. These components may themselves vary over time, inducing variation in the decision threshold inherited from them. These dynamic decision thresholds can then be determined using adaptive management. We provide numerical examples (that are based on patch occupancy models) of structures decision process that include all three kinds of thresholds

Integrating Behavioral Health & Primary Care in New Hampshire: A Path Forward to Sustainable Practice & Payment Transformation

New Hampshire residents face challenges with behavioral and physical health conditions and the interplay between them. National studies show the costs and the burden of illness from behavioral health conditions and co-occurring chronic health conditions that are not adequately treated in either primary care or behavioral health settings. Bringing primary health and behavioral health care together in integrated care settings can improve outcomes for both behavioral and physical health conditions. Primary care integrated behavioral health works in conjunction with specialty behavioral health providers, expanding capacity, improving access, and jointly managing the care of patients with higher levels of acuity In its work to improve the health of NH residents and create effective and cost-effective systems of care, the NH Citizens Health Initiative (Initiative) created the NH Behavioral Health Integration Learning Collaborative (BHI Learning Collaborative) in November of 2015, as a project of its Accountable Care Learning Network (NHACLN). Bringing together more than 60 organizations, including providers of all types and sizes, all of the state’s community mental health centers, all of the major private and public insurers, and government and other stakeholders, the BHI Learning Collaborative built on earlier work of a NHACLN Workgroup focused on improving care for depression and co-occurring chronic illness. The BHI Learning Collaborative design is based on the core NHACLN philosophy of “shared data and shared learning” and the importance of transparency and open conversation across all stakeholder groups. The first year of the BHI Learning Collaborative programming included shared learning on evidence-based practice for integrated behavioral health in primary care, shared data from the NH Comprehensive Healthcare Information System (NHCHIS), and work to develop sustainable payment models to replace inadequate Fee-for-Service (FFS) revenues. Provider members joined either a Project Implementation Track working on quality improvement projects to improve their levels of integration or a Listen and Learn Track for those just learning about Behavioral Health Integration (BHI). Providers in the Project Implementation Track completed a self-assessment of levels of BHI in their practice settings and committed to submit EHR-based clinical process and outcomes data to track performance on specified measures. All providers received access to unblinded NHACLN Primary Care and Behavioral Health attributed claims data from the NHCHIS for provider organizations in the NH BHI Learning Collaborative. Following up on prior work focused on developing a sustainable model for integrating care for depression and co-occurring chronic illness in primary care settings, the BHI Learning Collaborative engaged consulting experts and participants in understanding challenges in Health Information Technology and Exchange (HIT/HIE), privacy and confidentiality, and workforce adequacy. The BHI Learning Collaborative identified a sustainable payment model for integrated care of depression in primary care. In the process of vetting the payment model, the BHI Learning Collaborative also identified and explored challenges in payment for Substance Use Disorder Screening, Brief Intervention and Referral to Treatment (SBIRT). New Hampshire’s residents will benefit from a health care system where primary care and behavioral health are integrated to support the care of the whole person. New Hampshire’s current opiate epidemic accentuates the need for better screening for behavioral health issues, prevention, and treatment referral integrated into primary care. New Hampshire providers and payers are poised to move towards greater integration of behavioral health and primary care and the Initiative looks forward to continuing to support progress in supporting a path to sustainable integrated behavioral and primary care

Ligand Migration and Cavities within Scapharca Dimeric HbI: Studies by Time-Resolved Crystallo- graphy, Xe Binding, and Computational Analysis

SummaryAs in many other hemoglobins, no direct route for migration of ligands between solvent and active site is evident from crystal structures of Scapharca inaequivalvis dimeric HbI. Xenon (Xe) and organic halide binding experiments, along with computational analysis presented here, reveal protein cavities as potential ligand migration routes. Time-resolved crystallographic experiments show that photodissociated carbon monoxide (CO) docks within 5 ns at the distal pocket B site and at more remote Xe4 and Xe2 cavities. CO rebinding is not affected by the presence of dichloroethane within the major Xe4 protein cavity, demonstrating that this cavity is not on the major exit pathway. The crystal lattice has a substantial influence on ligand migration, suggesting that significant conformational rearrangements may be required for ligand exit. Taken together, these results are consistent with a distal histidine gate as one important ligand entry and exit route, despite its participation in the dimeric interface

Meningococcal Disease in Patients With Human Immunodeficiency Virus Infection: A Review of Cases Reported Through Active Surveillance in the United States, 2000-2008.

BackgroundAlthough human immunodeficiency virus (HIV) infection is an established risk factor for several bacterial infections, the association between HIV infection and meningococcal disease remains unclear.MethodsExpanded chart reviews were completed on persons with meningococcal disease and HIV infection reported from 2000 through 2008 from 9 US sites participating in an active population-based surveillance system for meningococcal disease. The incidence of meningococcal disease among patients meeting Centers for Disease Control and Prevention acquired immune deficiency syndrome (AIDS) surveillance criteria was estimated using data from the National HIV Surveillance System for the participating sites.ResultsThirty-three cases of meningococcal disease in individuals with HIV infection were reported from participating sites, representing 2.0% of all reported meningococcal disease cases. Most (75.8%) persons with HIV infection were adult males aged 25 to 64 years old. Among all meningococcal disease cases aged 25 to 64 years old, case fatality ratios were similar among HIV-infected and HIV-uninfected persons (13.3% vs 10.6%; P = .6). The cumulative, mean incidence of meningococcal disease among patients aged 25 to 64 years old with HIV infection ever classified as AIDS was 3.5 cases per 100000 person years (95% confidence interval [CI], 2.1-5.6), compared with 0.3 cases per 100000 person years (95% CI, 0.3-0.3) for persons of the same age group not reported to have AIDS (relative risk = 12.9; 95% CI, 7.9-20.9).ConclusionsIndividuals with HIV infection meeting the AIDS surveillance case definition have a higher incidence of meningococcal disease compared with the general adult population

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Telehealth and Mobile Health Applied To IntegratedBehavioral Care: OpportunitiesFor Progress In New Hampshire

This paper is an accompanying document to a webinar delivered on May 16, 2017, for the New Hampshire Citizens Health Initiative (Initiative). As integrated behavioral health efforts in New Hampshire gain traction, clinicians, administrators, payers, and policy makers are looking for additional efficiencies in delivering high quality healthcare. Telehealth and mobile health (mHealth) have the opportunity to help achieve this while delivering a robust, empowered patient experience. The promise of video-based technology was first made in 1964 as Bell Telephone shared its Picturephone® with the world. This was the first device with audio and video delivered in an integrated technology platform. Fast-forward to today with Skype, FaceTime, and webinar tools being ubiquitous in our personal and business lives, but often slow to be adopted in the delivery of medicine. Combining technology-savvy consumers with New Hampshire’s high rate of electronic health record (EHR) technology adoption, a fairly robust telecommunications infrastructure, and a predominately rural setting, there is strong foundation for telehealth and mHealth expansion in New Hampshire’s integrated health continuum

A Relational Model for Honors Education: From Contagion to Permeability

This article considers the value of honors education beyond its marked contributions to enrollment management goals. Suggesting that quantitative assessments toward understanding the value of honors fail to capture its breadth, interdisciplinary focus, and engagement, authors posit a new way of measuring impacts from “contagion model” (spillover to campus and beyond) to “permeability model” (interface across campus). Pointing to the benefits of permeability for both honors and the broader campus communities, authors encourage practitioners to foster exchange in curricular offerings, spatial inputs, scholarly outputs, extramural funding, and institutional support. The meaning and history of organizational permeability is explored, and examples are provided