Linking structural and functional characteristics of restored oyster reefs : A Restoration Project in the Virginia Coast Reserve

Eighteen native oyster reefs (16-m2 each) were restored using six oyster densities (0, 10, 25, 50, 100 and 250 adult oysters m-2) with three replicates of each density at an intertidal site in The Nature Conservancy’s Virginia Coast Reserve. Reef construction was successful and continues to provide a range of oyster biomass densities useful for exploring relationships between oyster reef structural and functional parameters. Between April 2012 and July 2013, a science-based monitoring program explored quantitative relationships between structural and functional characteristics of these restored reefs. Structural parameters examined included oyster abundance, oyster size/biomass, surface shell volume, reef topographic complexity and sediment characteristics. Functional parameters included denitrification rates and macrofaunal abundance and biomass. Relationships between reef structural parameters and functional parameters were complex and variable. As of July 2014, these reefs continue to serves as a platform for continued studies of the relationships between reef structural and functional characteristics

LOWER LEG MORPHOLOGY AND STRETCH-SHORTENING CYCLE PERFORMANCE IN YOUNG AND ELDERLY MALES

The purpose of this investigation was to examine bone and muscle characteristics of the lower leg and stretch-shortening cycle capabilities of the ankle in young (22.3 ± 1.3 yrs) and elderly (67.5 ± 3.3 yrs) males. Peripheral quantitiative computed tomography (pQCT) was utilized to assess bone stress-strain index, bone ultimate fracture load, muscle density, muscle cross-sectional area (CSA), fat CSA and muscle+bone CSA. Maximal voluntary isometric plantarflexion (MVIP) force and force-velocity measurments during a countermovement hop (CMH) and drop hops from 20, 30 and 40 cm (DH20, DH30, DH40) were also measured. Bone stress-strain index was significantly higher in young males as well as muscle density, muscle CSA and muscle+bone CSA in comparison to elderly males. MVIP peak force and rate of force development was significantly higher in young males in comparsion to elderly males as well. An analysis of the force-velocity curves indicated that young males had significanlty higher levels of force and velocity in both the eccentric and concentric phase during the CMH, DH20, DH30 and DH40 in comparsion to elderly males. The data from this investigation indicate that aging potentially negatively influences lower leg bone and muscle strength and this may be reflected in lower stretch-shortening cycle capabilities of the ankle

Scaling Ecosystem Services to Reef Development : Effects of oyster density on nitrogen removal and reef community structure

Eighteen native oyster experimental reefs (16-m2 each) were restored using six oyster densities (0, 10, 25, 50, 100 and 250 adult oysters m-2) with three replicates of each density at each of two sites: one subtidal site in Onancock Creek, Virginia and one intertidal site in Hillcrest Oyster Sanctuary within The Nature Conservancy’s Virginia Coast Reserve. A science-based monitoring program explored quantitative relationships between structural and functional characteristics of these restored reefs. Structural parameters examined included oyster abundance, oyster size/biomass, surface shell volume, reef topographic complexity and sediment characteristics. Functional parameters included denitrification rates and macrofaunal abundance and biomass. Data were collected from the intertidal site during six sampling periods between April 2012 and July 2013 and from the subtidal site in April and June 2012. Relationships between reef structural parameters and functional parameters were complex and variable. As of July 2014, the intertidal reefs continue to serve as a platform for continued studies of the relationships between reef structural and functional characteristics

IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System

PURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471

Wildfire Risk as a Socioecological Pathology

Wildfire risk in temperate forests has become a nearly intractable problem that can be characterized as a socioecological “pathology”: that is, a set of complex and problematic interactions among social and ecological systems across multiple spatial and temporal scales. Assessments of wildfire risk could benefit from recognizing and accounting for these interactions in terms of socioecological systems, also known as coupled natural and human systems (CNHS). We characterize the primary social and ecological dimensions of the wildfire risk pathology, paying particular attention to the governance system around wildfire risk, and suggest strategies to mitigate the pathology through innovative planning approaches, analytical tools, and policies. We caution that even with a clear understanding of the problem and possible solutions, the system by which human actors govern fire-prone forests may evolve incrementally in imperfect ways and can be expected to resist change even as we learn better ways to manage CNHS

Development of trofinetide for the treatment of Rett syndrome: from bench to bedside

Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the MECP2 gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2 years and older. Here, we present the development of trofinetide from bench research to clinical studies and emphasize how the collaboration between academia, the pharmaceutical industry, and patient advocacy led to the recent approval. The bench-to-bedside development of trofinetide underscores the value of collaboration between these groups in the development and approval of treatments for rare diseases

PRimary Care Opioid Use Disorders treatment (PROUD) trial protocol: a pragmatic, cluster-randomized implementation trial in primary care for opioid use disorder treatment

BACKGROUND: Most people with opioid use disorder (OUD) never receive treatment. Medication treatment of OUD in primary care is recommended as an approach to increase access to care. The PRimary Care Opioid Use Disorders treatment (PROUD) trial tests whether implementation of a collaborative care model (Massachusetts Model) using a nurse care manager (NCM) to support medication treatment of OUD in primary care increases OUD treatment and improves outcomes. Specifically, it tests whether implementation of collaborative care, compared to usual primary care, increases the number of days of medication for OUD (implementation objective) and reduces acute health care utilization (effectiveness objective). The protocol for the PROUD trial is presented here. METHODS: PROUD is a hybrid type III cluster-randomized implementation trial in six health care systems. The intervention consists of three implementation strategies: salary for a full-time NCM, training and technical assistance for the NCM, and requiring that three primary care providers have DEA waivers to prescribe buprenorphine. Within each health system, two primary care clinics are randomized: one to the intervention and one to Usual Primary Care. The sample includes all patients age 16-90 who visited the randomized primary care clinics from 3 years before to 2 years after randomization (anticipated to be \u3e 170,000). Quantitative data are derived from existing health system administrative data, electronic medical records, and/or health insurance claims ( electronic health records, [EHRs]). Anonymous staff surveys, stakeholder debriefs, and observations from site visits, trainings and technical assistance provide qualitative data to assess barriers and facilitators to implementation. The outcome for the implementation objective (primary outcome) is a clinic-level measure of the number of patient days of medication treatment of OUD over the 2 years post-randomization. The patient-level outcome for the effectiveness objective (secondary outcome) is days of acute care utilization [e.g. urgent care, emergency department (ED) and/or hospitalizations] over 2 years post-randomization among patients with documented OUD prior to randomization. DISCUSSION: The PROUD trial provides information for clinical leaders and policy makers regarding potential benefits for patients and health systems of a collaborative care model for management of OUD in primary care, tested in real-world diverse primary care settings

Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice

Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, though the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of SAPAP3 exhibit increased anxiety and compulsive grooming behavior leading to facial hair loss and skin lesions; both behaviors are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural, and biochemical studies of SAPAP3 mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of SAPAP3 in the striatum rescues the synaptic and behavioral defects of SAPAP3 mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviors