Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson’s disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence

Spatial Variation in Population Structure and Its Relation to Movement and the Potential for Dispersal in a Model Intertidal Invertebrate

Dispersal, the movement of an individual away from its natal or breeding ground, has been studied extensively in birds and mammals to understand the costs and benefits of movement behavior. Whether or not invertebrates disperse in response to such attributes as habitat quality or density of conspecifics remains uncertain, due in part to the difficulties in marking and recapturing invertebrates. In the upper Bay of Fundy, Canada, the intertidal amphipod Corophium volutator swims at night around the new or full moon. Furthermore, this species is regionally widespread across a large spatial scale with site-to-site variation in population structure. Such variation provides a backdrop against which biological determinants of dispersal can be investigated. We conducted a large-scale study at nine mudflats, and used swimmer density, sampled using stationary plankton nets, as a proxy for dispersing individuals. We also sampled mud residents using sediment cores over 3 sampling rounds (20–28 June, 10–17 July, 2–11 August 2010). Density of swimmers was most variable at the largest spatial scales, indicating important population-level variation. The smallest juveniles and large juveniles or small adults (particularly females) were consistently overrepresented as swimmers. Small juveniles swam at most times and locations, whereas swimming of young females decreased with increasing mud presence of young males, and swimming of large juveniles decreased with increasing mud presence of adults. Swimming in most stages increased with density of mud residents; however, proportionally less swimming occurred as total mud resident density increased. We suggest small juveniles move in search of C. volutator aggregations which possibly act as a proxy for better habitat. We also suggest large juveniles and small adults move if potential mates are limiting. Future studies can use sampling designs over large spatial scales with varying population structure to help understand the behavioral ecology of movement, and dispersal in invertebrate taxa

Effects of sildenafil on maximum walking time in patients with arterial claudication: The ARTERIOFIL study

BACKGROUND: Patients with lower extremity peripheral artery disease (PAD) frequently experience claudication, a clinical symptom indicative of reduced walking capacity. Recommended care consists of exercise rehabilitation combined with optimal medical treatment and surgery. The effects of a single oral dose of sildenafil, a phosphodiesterase type-5 inhibitor, on patients with claudication are discussed. The aim of this study was to test the efficacy of a single 100 mg dose of sildenafil compared to placebo in terms of maximal walking time (MWT) in patients with claudication. METHODS: The ARTERIOFIL study is a crossover, double-blind, prospective, randomized, single-center study conducted at Angers University Hospital in France. MWT (primary endpoint) was assessed using a treadmill test (10% incline; 3.2 km/h). Secondary endpoints (pain-free walking time (PFWT), transcutaneous oximetry during exercise and redox cycle parameters and safety) were also studied. RESULTS: Fourteen patients were included of whom two were ultimately excluded. In the 12 remaining patients, the MWT was significantly improved during the sildenafil period compared with the placebo period (300 s [95% CI 172 s-428 s] vs 402 s [95% CI 274 s-529 s] p < 0.01). Sildenafil had no significant effect on pain-free walking time or skin tissue oxygenation during exercise. According to redox cycle parameters, sildenafil significantly reduced blood glucose and pyruvate levels and the 3-hydroxybutyrate/acetoacetate ratio, while there was no significant effect on lactate, 3-hydroxybutyrate, acetoacetate and free fatty acid levels. Symptomatic transient hypotension was observed in two women. CONCLUSIONS: The ARTERIOFIL study has shown that a single 100 mg oral dose of sildenafil had a significant effect on increase in MWT but had no significant effects on PFWT and oxygenation parameters in patients with claudication. A double-blind, prospective, randomized, multicenter study (VIRTUOSE©) is ongoing to evaluate the chronic effect of six month-long sildenafil treatment on MWT in PAD patients with claudication. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at clinicaltrials.gov, registration. number: NCT02832570, (https://clinicaltrials.gov/ct2/show/NCT02832570)

Astroparticle Physics with a Customized Low-Background Broad Energy Germanium Detector

The MAJORANA Collaboration is building the MAJORANA DEMONSTRATOR, a 60 kg array of high purity germanium detectors housed in an ultra-low background shield at the Sanford Underground Laboratory in Lead, SD. The MAJORANA DEMONSTRATOR will search for neutrinoless double-beta decay of 76Ge while demonstrating the feasibility of a tonne-scale experiment. It may also carry out a dark matter search in the 1-10 GeV/c^2 mass range. We have found that customized Broad Energy Germanium (BEGe) detectors produced by Canberra have several desirable features for a neutrinoless double-beta decay experiment, including low electronic noise, excellent pulse shape analysis capabilities, and simple fabrication. We have deployed a customized BEGe, the MAJORANA Low-Background BEGe at Kimballton (MALBEK), in a low-background cryostat and shield at the Kimballton Underground Research Facility in Virginia. This paper will focus on the detector characteristics and measurements that can be performed with such a radiation detector in a low-background environment.Comment: Submitted to NIMA Proceedings, SORMA XII. 9 pages, 4 figure

The Majorana project

Building a 0νβ β experiment with the ability to probe neutrino mass in the inverted hierarchy region requires the combination of a large detector mass sensitive to 0νβ β, on the order of 1-tonne, and unprecedented background levels, on the order of or less than 1 count per year in the 0νβ β signal region. The Majorana Collaboration proposes a design based on using high-purity enriched 76Ge crystals deployed in ultra- low background electroformed Cu cryostats and using modern analysis techniques that should be capable of reaching the required sensitivity while also being scalable to a 1- tonne size. To demonstrate feasibility, the collaboration plans to construct a prototype system, the Majorana Demonstrator, consisting of 30 kg of 86% enriched 76Ge detectors and 30 kg of natural or isotope-76-depleted Ge detectors. We plan to deploy and evaluate two different Ge detector technologies, one based on a p-type configuration and the other on n-type

Search for Neutrinoless Double- β Decay in Ge 76 with the Majorana Demonstrator

The Majorana Collaboration is operating an array of high purity Ge detectors to search for neutrinoless double-β decay in Ge76. The Majorana Demonstrator comprises 44.1 kg of Ge detectors (29.7 kg enriched in Ge76) split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. Here we present results from data taken during construction, commissioning, and the start of full operations. We achieve unprecedented energy resolution of 2.5 keV FWHM at Qββ and a very low background with no observed candidate events in 9.95 kg yr of enriched Ge exposure, resulting in a lower limit on the half-life of 1.9×1025 yr (90% C.L.). This result constrains the effective Majorana neutrino mass to below 240-520 meV, depending on the matrix elements used. In our experimental configuration with the lowest background, the background is 4.0-2.5+3.1 counts/(FWHM t yr)

Role of the ammonium group in the diffusion of quaternary ammonium compounds in Streptococcus mutans biofilms

Objectives: Cetylpyridinium chloride (CPC), a quaternary ammonium compound, was shown to interact irreversibly with Streptococcus mutans biofilms, leading to a slow diffusion compared with poly(ethylene glycol) (PEG) molecules of similar size. The objective of this work is to determine if the retardation of CPC diffusion and its strong binding to biofilms is caused by interactions between the ammonium group of CPC and the exopolysaccharide (EPS) matrix. Methods: First, we characterized the diffusion of two analogues of CPC in S. mutans biofilms: dodecylpyridinium chloride (DPC), carrying a shorter alkyl chain than CPC, and tetramethylene bispyridinium chloride (TMBPC), a compound carrying two positively charged ammonium groups. Second, we cultured biofilms with different densities of EPS and examined the impact of this density on the transport properties of CPC. The diffusion of these compounds was probed using infrared spectroscopy with attenuated total reflectance sampling. Results: The diffusion of CPC, DPC and TMBPC in S. mutans biofilm is slower than that of PEG10k. In addition, TMBPC and DPC, as PEG10k, could be readily washed out from the biofilms while CPC association was practically irreversible. The penetration of CPC through the EPS matrix was found to be not significantly affected by the increased EPS density, whereas the penetration of PEG with a molar mass of 10k was considerably reduced. Conclusions: These results suggest that the interactions between the quaternary ammonium groups and the EPS matrices are not the prime contribution of the strong CPC binding, and the alkyl chain length plays a role in this association, likely through hydrophobic interactions

Global climate forcing on late Miocene establishment of the Pampean aeolian system in South America

Wind-blown dust from southern South America links the terrestrial, marine, atmospheric, and biological components of Earth’s climate system. The Pampas of central Argentina (~33°–39° S) contain a Miocene to Holocene aeolian record that spans an important interval of global cooling. Upper Miocene sediment provenance based on n = 3299 detrital-zircon U-Pb ages is consistent with the provenance of Pleistocene–Holocene deposits, indicating the Pampas are the site of a long-lived fluvial-aeolian system that has been operating since the late Miocene. Here, we show the establishment of aeolian sedimentation in the Pampas coincided with late Miocene cooling. These findings, combined with those from the Chinese Loess Plateau (~33°–39° N) underscore: (1) the role of fluvial transport in the development and maintenance of temporally persistent mid-latitude loess provinces; and (2) a global-climate forcing mechanism behind the establishment of large mid-latitude loess provinces during the late Miocene. © 2023, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]