HIV-1 Transgenic Rat: Selective Alterations In Motivation And Histological Examination Of Medium Spiny Neurons Of The Nucleus Accumbens

Motivational alterations in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry and the nucleus accumbens. In the present study, the HIV-1 transgenic (Tg) rat was used to assess long-term HIV-1 viral protein exposure on motivated behavior using activity chambers (40x40cm) and voluntary wheel running. Adult ovariectomized female HIV-1 Tg animals (n=21) to F344 controls (n=26) were pair-housed under a 12:12 light/dark cycle. Voluntary running was measured with 34 cm-diameter running wheels for ~60 minutes/day for 3 ½ months. There were no significant differences between HIV-1 Tg and F344 control rats in voluntary wheel running during the light phase. Animals were subsequently run in the nocturnal phase of their light/dark cycle. The F344 controls continued to escalate their overall running distances and surpassed the stabilized HIV-1 Tg group after ~4 weeks of nocturnal running, until reaching their asymptotic plateau at week 11. Neither maximal running speed, nor the latency to initiate running or running bout length were significantly different between groups. However, the groups were different in the number of running bouts per session, as a function of the HIV-1 transgene. Collectively, the selective alterations in the motivation for voluntary wheel running and activity chamber locomotor activity, suggests a disruption of the motivational circuitry within the HIV-1 Tg rat brain. Examination of Medium Spiny Neurons of the nucleus accumbens showed significant alterations in dendritic spine length and spine head diameter. Further study of these alterations in spine parameters may help elucidate the mechanisms of motivational alterations in HIV-1+individuals

Exercise as a therapeutic for HIV-1-associated neurocognitive deficits

Human Immunodeficiency Virus (HIV-1) afflicts nearly 38 million individuals worldwide (Joseph et al., 2013; “WHO | HIV/AIDS,” 2016). Despite the reduction in disease mortality due to increased use of antiretroviral medication, HIV-1 associated neurocognitive disorder (HAND) affects approximately 50% of HIV infected individuals (Antinori et al., 2007; Castellon, Hinkin, Wood, & Yarema, 1998; Castelo, Sherman, Courtney, Melrose, & Stern, 2006; Cysique & Brew, 2009; Heaton et al., 2011, 2015). The brain itself is particularly sensitive to HIV-1 related viral proteins and viral infection (Masliah, DeTeresa, Mallory, & Hansen, 2000), thus, it is vital to empirically examine potentially effective therapeutics which may be capable of improving cognition in HIV-1 patients. In the contemporary literature, cognitive deficiencies encompassed by HAND include deficits in: attention/information processing, language, abstraction-executive function, complex perceptual motor skills, memory (short-term and working memory), learning and recall, simple motor skills and sensory perceptual abilities, as defined by the most recent HIV-1 nosology (Antinori et al., 2007). Therapeutics capable of improving neurocognitive dysfunction in the HIV-1 brain has yet to be established; therefore, the current study examined a potential therapeutic theoretically capable of improving HAND related cognitive dysfunction: physical activity. Physical activity has been shown to be the strongest environmental factor capable of promoting the genesis of new neurons in the subgranular zone of the hippocampal dentate gyrus (Fuss et al., 2014; Ji et al., 2014; Klein et al., 2016; M.-H. Lee et al., 2013; Naylor et al., 2008; van Praag, Christie, Sejnowski, & Gage, 1999; van Praag, Kempermann, & Gage, 1999; van Praag et al., 2002; van Praag, Shubert, Zhao, & Gage, 2005; Vivar & van Praag, 2013). Furthermore, when examining the relationship between physical activity and HIV-1 associated cognitive decline, there appears to be an association between acute physical activity and cognitive function in human HIV-1+ patients (Dufour et al., 2013, 2018), evidence which suggests physical activity may be capable of preserving/promoting cognitive function in the HIV-1 brain. The current study determined whether promoting neurogenesis through physical activity can act as a neuroprotective/neurorestorative therapeutic agent capable of attenuating the progression of HIV-1 cognitive pathology. Upon completion of the current study, the role of chronic HIV-1 viral protein expression on dentate gyrus neurogenesis in the HIV-1 transgenic (Tg) rat brain was empirically established. The current results provide evidence that HIV-1 viral proteins do inhibit neurogenesis (as determined by doublecortin immunolableling), and that wheel running did not significantly increase neurogenesis. However, wheel running significantly increased dendritic spine length, volume and head diameter, as well as dendritic length. These results suggest that physical activity may be an effective therapeutic for improving HIV-1-dependent neurological synaptodendritic damage due to the expression of HIV-1 viral proteins

The Fossil Calibration Database—A New Resource for Divergence Dating

Fossils provide the principal basis for temporal calibrations, which are critical to the accuracy of divergence dating analyses. Translating fossil data into minimum and maximum bounds for calibrations is the most important—often least appreciated—step of divergence dating. Properly justified calibrations require the synthesis of phylogenetic, paleontological, and geological evidence and can be difficult for nonspecialists to formulate. The dynamic nature of the fossil record (e.g., new discoveries, taxonomic revisions, updates of global or local stratigraphy) requires that calibration data be updated continually lest they become obsolete. Here, we announce the Fossil Calibration Database (http://fossilcalibrations.org), a new open-access resource providing vetted fossil calibrations to the scientific community. Calibrations accessioned into this database are based on individual fossil specimens and follow best practices for phylogenetic justification and geochronological constraint. The associated Fossil Calibration Series, a calibration-themed publication series at Palaeontologia Electronica, will serve as a key pipeline for peer-reviewed calibrations to enter the databas

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue

The Fossil Calibration Database, A New Resource for Divergence Dating

Fossils provide the principal basis for temporal calibrations, which are critical to the accuracy of divergence dating analyses. Translating fossil data into minimum and maximum bounds for calibrations is the most important, and often least appreciated, step of divergence dating. Properly justified calibrations require the synthesis of phylogenetic, paleontological, and geological evidence and can be difficult for non- specialists to formulate. The dynamic nature of the fossil record (e.g., new discoveries, taxonomic revisions, updates of global or local stratigraphy) requires that calibration data be updated continually lest they become obsolete. Here, we announce the Fossil Calibration Database (http://fossilcalibrations.org), a new open- access resource providing vetted fossil calibrations to the scientific community. Calibrations accessioned into this database are based on individual fossil specimens and follow best practices for phylogenetic justification and geochronological constraint. The associated Fossil Calibration Series, a calibration-themed publication series at Palaeontologia Electronica, will serve as one key pipeline for peer-reviewed calibrations to enter the database

Species Tree Estimation for the Late Blight Pathogen, Phytophthora infestans, and Close Relatives

To better understand the evolutionary history of a group of organisms, an accurate estimate of the species phylogeny must be known. Traditionally, gene trees have served as a proxy for the species tree, although it was acknowledged early on that these trees represented different evolutionary processes. Discordances among gene trees and between the gene trees and the species tree are also expected in closely related species that have rapidly diverged, due to processes such as the incomplete sorting of ancestral polymorphisms. Recently, methods have been developed for the explicit estimation of species trees, using information from multilocus gene trees while accommodating heterogeneity among them. Here we have used three distinct approaches to estimate the species tree for five Phytophthora pathogens, including P. infestans, the causal agent of late blight disease in potato and tomato. Our concatenation-based “supergene” approach was unable to resolve relationships even with data from both the nuclear and mitochondrial genomes, and from multiple isolates per species. Our multispecies coalescent approach using both Bayesian and maximum likelihood methods was able to estimate a moderately supported species tree showing a close relationship among P. infestans, P. andina, and P. ipomoeae. The topology of the species tree was also identical to the dominant phylogenetic history estimated in our third approach, Bayesian concordance analysis. Our results support previous suggestions that P. andina is a hybrid species, with P. infestans representing one parental lineage. The other parental lineage is not known, but represents an independent evolutionary lineage more closely related to P. ipomoeae. While all five species likely originated in the New World, further study is needed to determine when and under what conditions this hybridization event may have occurred

Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD:a cohort study

Background: Hypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD Methods: We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation ≤88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia. Results: Forty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95%CI 3.05–22.6), lower baseline oxygen saturation (OR 0.70, 95%CI 0.58–0.85), self-reported heart failure (OR 6.92, 95%CI 1.56–30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95%CI 1.17–6.74), and prior severe COPD exacerbation (OR 3.31, 95%CI 1.38–7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up. Conclusions: Development of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia. Trial registration COPDGene is registered at ClinicalTrials.gov: NCT00608764 (Registration Date: January 28, 2008) Electronic supplementary material The online version of this article (doi:10.1186/s12890-016-0331-0) contains supplementary material, which is available to authorized users

Will current rotational grazing management recommendations suit future intensive pastoral systems

This review aimed to determine whether current grazing management practices will suit future intensive rotationally grazed pastoral systems. A review of literature on grazing management recommendations found that there was good agreement on the ‘principles’ required for optimal grazing management. While these management practices have stood the test of time, it is concluded that shifts in external pressures (e.g., climate, plant selection and breeding, system intensification) compared to the period when farm-level grazing recommendations were first developed, may necessitate a rethink of current grazing recommendations. Examples include greater pasture masses (e.g., around 4000 kg dry matter (DM)/ha vs. the recommended range of 2600 to 3200 kg DM/ha) where short-rotation (annual, biennial) and tetraploid ryegrasses are sown, provided a consistent post-grazing residual can be maintained (possibly between 40- and 70- mm height). Milder winters and the use of ryegrass cultivars with higher growth rates in late winter/early spring may necessitate either lower target pasture covers at calving or shorter rotation lengths during winter. Longer grazing rotations (well beyond the 3-leaf stage, i.e., equivalent to deferred grazing) can be recommended for select paddocks from mid-spring into summer, to increase seasonal resilience across the farm. Longer residuals (even up to 70 mm - i.e., almost double the recommended height) might improve plant survival during periods of high stress (e.g., heatwaves, droughts). Lastly, diverse species pastures may require specific management to suit dominant species other than perennial ryegrass

Galactic cosmic radiation exposure causes multifaceted neurocognitive impairments.

Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to 40-50 cGy acute or chronic radiations relevant to deep space travel. Results of the object in updated location task suggested that exposure to acute or chronic GCR Sim induced persistent impairments in hippocampus-dependent memory formation and reconsolidation in female mice that did not manifest robustly in irradiated male mice. Interestingly, irradiated male mice, but not females, were impaired in novel object recognition and chronically irradiated males exhibited increased aggressive behavior on the tube dominance test. Electrophysiology studies used to evaluate synaptic plasticity in the hippocampal CA1 region revealed significant reductions in long-term potentiation after each irradiation paradigm in both sexes. Interestingly, network-level disruptions did not translate to altered intrinsic electrophysiological properties of CA1 pyramidal cells, whereas acute exposures caused modest drops in excitatory synaptic signaling in males. Ultrastructural analyses of CA1 synapses found smaller postsynaptic densities in larger spines of chronically exposed mice compared to controls and acutely exposed mice. Myelination was also affected by GCR Sim with acutely exposed mice exhibiting an increase in the percent of myelinated axons; however, the myelin sheathes on small calibur (< 0.3 mm) and larger (> 0.5 mm) axons were thinner when compared to controls. Present findings might have been predicted based on previous studies using single and mixed beam exposures and provide further evidence that space-relevant radiation exposures disrupt critical cognitive processes and underlying neuronal network-level plasticity, albeit not to the extent that might have been previously predicted