Multigeneration Reproductive Study of Hydroxyprogesterone Caproate (HPC) in the Rat: Laboratory Results and Clinical Significance

To demonstrate reproductive safety of a new commercial product for reducing the risk of preterm birth, HPC (17α‐hydroxyprogesterone caproate, Makena; manufactured by Baxter Pharmaceutical Solutions, Bloomington IN for Ther‐Rx Corporation, St. Louis, MO) was administered intramuscularly in Charles River LaboratoryCD strain rats. HPC was given at intervals equal to the half‐life measured in rats during three phases of embryo‐fetal development: during the period of ovarian development (RP1, days 8, 14, and 20), following implantation of the embryo (TP, days 6, 12, and 18), and, corresponding to the start of the drug in week 16 or later in humans, after gonadal formation including differentiation of the testes (RP2, day 17). Dose levels up to 30× the human therapeutic doses were utilized including 0 (vehicle), 5, 25, and 150 mg/kg (volume 0.6 ml/kg). Four groups of 25 time‐mated rats each were used for each phase. In addition, equal numbers of naïve (untreated) rats of opposite gender were used for F₁ breeding studies. HPC did not produce any consistent test‐article–related findings in the treated F₀ dams, their developing F₁ fetuses and did not affect the ability of the latter to produce a viable F₂ generation. The F₁ offspring did not evidence any adverse effects during their behavioral, sensory, and developmental assessments, including teratogenicity. Based on the cumulative data obtained from rats treated over two generations and during development in this study, the No‐observable‐effect‐level (NOEL) was established as 150 mg/kg. This study supports the absence of reproductive toxicity with HPC in published studies in animal models and in human clinical trials.     

Developing best practices for the restoration of massive corals and the mitigation of predation impacts: influences of physical protection,colony size,and genotype on outplant mortality

Coral Reefs - Coral reefs have undergone drastic declines due to anthropogenic and natural disturbances. In response, restoration efforts were developed to recover lost ecosystem services....     

Higher Vulnerability and Stress Sensitivity of Neuronal Precursor Cells Carrying an Alpha-Synuclein Gene Triplication

Parkinson disease (PD) is a multi-factorial neurodegenerative disorder with loss of dopaminergic neurons in the substantia nigra and characteristic intracellular inclusions, called Lewy bodies. Genetic predisposition, such as point mutations and copy number variants of the SNCA gene locus can cause very similar PD-like neurodegeneration. The impact of altered α-synuclein protein expression on integrity and developmental potential of neuronal stem cells is largely unexplored, but may have wide ranging implications for PD manifestation and disease progression. Here, we investigated if induced pluripotent stem cell-derived neuronal precursor cells (NPCs) from a patient with Parkinson’s disease carrying a genomic triplication of the SNCA gene (SNCA-Tri). Our goal was to determine if these cells these neuronal precursor cells already display pathological changes and impaired cellular function that would likely predispose them when differentiated to neurodegeneration. To achieve this aim, we assessed viability and cellular physiology in human SNCA-Tri NPCs both under normal and environmentally stressed conditions to model in vitro gene-environment interactions which may play a role in the initiation and progression of PD. Human SNCA-Tri NPCs displayed overall normal cellular and mitochondrial morphology, but showed substantial changes in growth, viability, cellular energy metabolism and stress resistance especially when challenged by starvation or toxicant challenge. Knockdown of α-synuclein in the SNCA-Tri NPCs by stably expressed short hairpin RNA (shRNA) resulted in reversal of the observed phenotypic changes. These data show for the first time that genetic alterations such as the SNCA gene triplication set the stage for decreased developmental fitness, accelerated aging, and increased neuronal cell loss. The observation of this “stem cell pathology” could have a great impact on both quality and quantity of neuronal networks and could provide a powerful new tool for development of neuroprotective strategies for PD.     

Outplanting optimized: developing a more efficient coral attachment technique using Portland cement

Coral reefs are among the most valuable and vulnerable ecosystems on Earth. Their decline has spurred global interest in efforts to augment native coral populations through coral gardening. As these efforts expand, practitioners are constantly looking for new techniques to reduce costs and increase their restoration footprint. However, commonly employed coral attachment methods limit the numbers of corals that can be outplanted per day, representing a substantial bottleneck in the coral restoration process. Cement has potential as a more cost‐ and time‐efficient coral attachment technique, but research is needed to understand its effects on coral survivorship and develop best practices for its use. Here, we use lab and field tests in a three‐stage elimination format to determine the most effective cement mixture for outplanting Acropora cervicornis. We then compare this new method to two commonly used coral attachment techniques: the nail and cable tie method and two‐part epoxy putty. Our tests identified the optimal cement mix to be a combination of 10 parts type I/II Portland cement to one part silica fume. This mix yielded equivalent survivorship to the other two methods, is quick and easy to use making it ideal for citizen scientists, and has roughly one‐tenth of the material cost of other methods. These results support the wider use of cement for coral outplanting in order to minimize costs, maximize efficiency, and increase the effectiveness of coral restoration efforts around the world.