Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset

Lewy Body Dementia Association\u27s Research Centers of Excellence Program: Inaugural Meeting Proceedings.

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator\u27s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson\u27s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics

Orbital Refinement and Stellar Properties for the HD 9446, HD 43691, and HD 179079 Planetary Systems

The Transit Ephemeris Refinement and Monitoring Survey is a project that aims to detect transits of intermediate-long period planets by refining orbital parameters of the known radial velocity planets using additional data from ground-based telescopes, calculating a revised transit ephemeris for the planet, then monitoring the planet host star during the predicted transit window. Here we present the results from three systems that had high probabilities of transiting planets: HD 9446 b and c, HD 43691 b, and HD 179079 b. We provide new radial velocity (RV) measurements that are then used to improve the orbital solution for the known planets. We search the RV data for indications of additional planets in orbit and find that HD 9446 shows a strong linear trend of 4.8σ. Using the newly refined planet orbital solutions, which include a new best-fit solution for the orbital period of HD 9446 c, and an improved transit ephemerides, we found no evidence of transiting planets in the photometry for each system. Transits of HD 9446 b can be ruled out completely and transits HD 9446 c and HD 43691 b can be ruled out for impact parameters up to b = 0.5778 and b = 0.898, respectively, due to gaps in the photometry. A transit of HD 179079 b cannot be ruled out, however, due to the relatively small size of this planet compared to the large star and thus low signal to noise. We determine properties of the three host stars through spectroscopic analysis and find through photometric analysis that HD 9446 exhibits periodic variability

Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin

<p>Abstract</p> <p>Background</p> <p>Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA). This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing.</p> <p>Results</p> <p>The conjugate SP-CTA stimulates adenylate cyclase in cultured cells that are transfected with either the NK1 or NK2 receptor, but not the NK3 receptor. We further demonstrate that intrathecal injection of SP-CTA in rats induces the phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) and also enhances the expression of the immediate early gene c-Fos. Behaviorally, low doses of SP-CTA (1 μg) injected intrathecally produce thermal hyperalgesia. At higher doses (10 μg) peripheral sensitivity is suppressed suggesting that descending inhibitory pathways may be activated by the SP-CTA induced sensitization of spinal cord neurons.</p> <p>Conclusion</p> <p>The finding that stimulation of adenylate cyclase in neurokinin receptor expressing neurons in the spinal cord produces thermal hyperalgesia is consistent with the known actions of these neurons. These data demonstrate that cholera toxin can be targeted to specific cell types by coupling the catalytic subunit to a peptide agonist for a g-protein coupled receptor. Furthermore, these results demonstrate that SP-CTA can be used as a tool to study sensitization of central neurons in vivo in the absence of an injury.</p

An Artemisinin-Derived Dimer Has Highly Potent Anti-Cytomegalovirus (CMV) and Anti-Cancer Activities

We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4) are significantly more potent in inhibiting human cytomegalovirus (CMV) replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574), lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound

The TESS-Keck Survey: Science Goals and Target Selection

Space-based transit missions such as Kepler and TESS have demonstrated that planets are ubiquitous. However, the success of these missions heavily depends on ground-based radial velocity (RV) surveys, which combined with transit photometry can yield bulk densities and orbital properties. While most Kepler host stars are too faint for detailed follow-up observations, TESS is detecting planets orbiting nearby bright stars that are more amenable to RV characterization. Here we introduce the TESS-Keck Survey (TKS), an RV program using ~100 nights on Keck/HIRES to study exoplanets identified by TESS. The primary survey aims are investigating the link between stellar properties and the compositions of small planets; studying how the diversity of system architectures depends on dynamical configurations or planet multiplicity; identifying prime candidates for atmospheric studies with JWST; and understanding the role of stellar evolution in shaping planetary systems. We present a fully-automated target selection algorithm, which yielded 103 planets in 86 systems for the final TKS sample. Most TKS hosts are inactive, solar-like, main-sequence stars (4500 K < Teff < 6000 K) at a wide range of metallicities. The selected TKS sample contains 71 small planets (Rp < 4 Re), 11 systems with multiple transiting candidates, 6 sub-day period planets and 3 planets that are in or near the habitable zone of their host star. The target selection described here will facilitate the comparison of measured planet masses, densities, and eccentricities to predictions from planet population models. Our target selection software is publicly available (at https://github.com/ashleychontos/sort-a-survey) and can be adapted for any survey which requires a balance of multiple science interests within a given telescope allocation.Comment: 23 pages, 10 figures, 5 table

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin