Gravi-Sensitivity of Mosses and Their Gravity-Dependent Ontogenetic Adaptations.

Gravi-morphoses affect the variability of plants and are the morphogenetic adaptation to different environmental conditions. Gravity-dependent phenotypic plasticity of gametophytes as well as gravi-sensitivity of moss protonemata in microgravity and simulated microgravity conditions are discussed. The moss protonema, a filamentous multicellular system, representing a juvenile stage of moss development, develops as a result of the elongation and division of the apical cell. This apical cell of the protonema is a unique object for research on moss gravi-sensitivity, as graviperception and gravitropic growth occur within the same single cell. Attention is focused on the influence of gravity on bryophyte ontogenesis, including the gravitropic reactivity of moss protonemata, gravi-sensitivity at the stage of leafy shoot development and sporogonium formation, gravity-influenced morphogenesis of apical cell budding, and gravity-dependent spiral growth patterns. The role of gravireceptors in the growth processes of mosses at the cellular level under microgravity conditions are being discussed, as well as the involvement of auxin transport, Ca2+-induced gravitropism and the cytoskeleton in gravitropic reactions.

Hippocampal Neuroimaging-Informed Clinical Trial Enrichment Tool for Amnestic Mild Cognitive Impairment Using Open Data.

Our goal was to assess the enrichment utility of hippocampal volume (HV) as an enrichment biomarker in amnestic mild cognitive impairment (aMCI) clinical trials, and, hence, develop an HV neuroimaging-informed clinical trial enrichment tool. Modeling of integrated longitudinal patient-level data came from open-access natural history studies in patients diagnosed with aMCI-the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2-and indicated that a decrease of 1 cm3 with respect to the analysis dataset median baseline intracranial volume-adjusted HV (ICV-HV; ~ 5 cm3 ) is associated with > 50% increase in disease progression rate as measured by the Clinical Dementia Rating Scale-Sum of Boxes. Clinical trial simulations showed that the inclusion of aMCI subjects with baseline ICV-HV below the 84th or 50th percentile allowed an approximate reduction in trial size of at least 26% and 55%, respectively. This clinical trial enrichment tool can help design more efficient and informative clinical trials.

Regulatory-accepted drug development tools are needed to accelerate innovative CNS disease treatments.

Central Nervous System (CNS) diseases represent one of the most challenging therapeutic areas for successful drug approvals. Developing quantitative biomarkers as Drug Development Tools (DDTs) can catalyze the path to innovative treatments, and improve the chances of drug approvals. Drug development and healthcare management requires sensitive, reliable, validated, and regulatory accepted biomarkers and endpoints. This review highlights the regulatory paths and considerations for developing DDTs required to advance biomarker and endpoint use in clinical development (e.g., consensus CDISC [Clinical Data Interchange Standards Consortium] data standards, precompetitive sharing of anonymized patient-level data, and continual alignment with regulators). Summarized is the current landscape of biomarkers in a range of CNS diseases including Alzheimer disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorders, Depression, Huntington's disease, Multiple Sclerosis and Traumatic Brain Injury. Advancing DDTs for these devastating diseases that are both validated and qualified will require an integrated, cross-consortium approach to accelerate the delivery of innovative CNS therapeutics.

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size.

Gravitropic moss cells default to spiral growth on the clinostat and in microgravity during spaceflight.

In addition to shoots and roots, the gravity (g)-vector orients the growth of specialized cells such as the apical cell of dark-grown moss protonemata. Each apical cell of the moss Ceratodon purpureus senses the g-vector and adjusts polar growth accordingly producing entire cultures of upright protonemata (negative gravitropism). The effect of withdrawing a constant gravity stimulus on moss growth was studied on two NASA Space Shuttle (STS) missions as well as during clinostat rotation on earth. Cultures grown in microgravity (spaceflight) on the STS-87 mission exhibited two successive phases of non-random growth and patterning, a radial outgrowth followed by the formation of net clockwise spiral growth. Also, cultures pre-aligned by unilateral light developed clockwise hooks during the subsequent dark period. The second spaceflight experiment flew on STS-107 which disintegrated during its descent on 1 February 2003. However, most of the moss experimental hardware was recovered on the ground, and most cultures, which had been chemically fixed during spaceflight, were retrieved. Almost all intact STS-107 cultures displayed strong spiral growth. Non-random culture growth including clockwise spiral growth was also observed after clinostat rotation. Together these data demonstrate the existence of default non-random growth patterns that develop at a population level in microgravity, a response that must normally be overridden and masked by a constant g-vector on earth.