Chronic basal forebrain activation improves spatial memory, boosts neurotrophin receptor expression, and lowers BACE1 and Aß42 levels in the cerebral cortex in mice.

The etiology of Alzheimer's dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms of reflecting beta-amyloid neuropathology. To study these different biological elements, we activated the basal forebrain in 5xFAD Alzheimer's model mice and littermates. Mice received 5 months of 1 h per day intermittent stimulation of the basal forebrain, which includes cholinergic projections to the cortical mantle. Then, mice were behaviorally tested followed by tissue analysis. The 5xFAD mice performed worse in water-maze testing than littermates. Stimulated groups learned the water maze better than unstimulated groups. Stimulated groups had 2-3-fold increases in frontal cortex immunoblot measures of the neurotrophin receptors for nerve growth factor and brain-derived neurotrophic factor, and a more than 50% decrease in the expression of amyloid cleavage enzyme BACE1. Stimulation also led to lower Aß42 in 5xFAD mice. These data support a causal relationship between basal forebrain activation and both neurotrophin activation and reduced Aß42 generation and accumulation. The observation that basal forebrain activation suppresses Aß42 accumulation, combined with the known high-affinity antagonism of nicotinic receptors by Aß42, documents bidirectional antagonism between acetylcholine and Aß42.

Improved synthesis of deoxyalpinoid B and quantification of antileishmanial activity of deoxyalpinoid B and sulforaphane.

The total synthesis and antileishmanial activity of deoxyalpinoid B is reported via a cationic gold-catalyzed Meyer-Schuster rearrangement. The activity of deoxyalpinoid B and a known inducer of oxidative stress, sulforaphane, against Leishmania donovani and Leishmania infantatum are both reported for the first time. Both compounds exhibit potent antileishmanial activity against both species. We hypothesize that the activation of intracellular oxidative stress is a key molecular response for the inhibition of Leishmania.

Evaluation of a co-designed Parkinson's awareness audio podcast for undergraduate nursing students in Northern Ireland.

BACKGROUND: Parkinson's Disease (PD) is a common neurological condition that often causes stiffness, tremor and slow movement. People living with PD are likely to encounter nursing students throughout their journey from pre-diagnosis to death. Despite this, there is a paucity of evidence about current practice in PD education amongst nursing students. The present study provides an evaluation of a co-designed Parkinson's Awareness audio podcast amongst nursing students in Northern Ireland. METHODS: Following co-design of an audio podcast about PD, a mixed methods evaluation was carried out. 332 student nurses completed pre-/post-test questionnaires about their knowledge and perceptions of PD before and after listening to the audio podcast. Further to this, 35 student nurses participated in focus-group interviews six months following listening to explore how the podcast influenced practice. RESULTS: Student nurses posted a mean score of 52% before listening to the audio podcast. This mean increased to 80% post-test. These findings were statistically significant (p < 0.001), demonstrating significant increases in PD awareness after listening. Findings from the focus groups suggested that the audio podcast improved empathy and practice towards people with PD. The findings also suggested that students perceived audio podcasts to be a good way to learn about PD. CONCLUSION: Provision of a co-designed audio podcast about PD has the potential to improve student nurse knowledge and practice related to PD as evidenced in this study.

Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity.

Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.

A skeptical reflection: Contextualizing police shooting decisions with skin-tone.

This commentary expands the discussion of Cesario's Missing Forces Flaw by identifying and discussing variables that influence police shooting decisions but are often absent from bias-based research. Additionally, the closing identifies novel recommendations for future contextually related research.

Low Hesperian PCO2 constrained from in situ mineralogical analysis at Gale Crater, Mars.

Carbon dioxide is an essential atmospheric component in martian climate models that attempt to reconcile a faint young sun with planetwide evidence of liquid water in the Noachian and Early Hesperian. In this study, we use mineral and contextual sedimentary environmental data measured by the Mars Science Laboratory (MSL) Rover Curiosity to estimate the atmospheric partial pressure of CO2 (PCO2) coinciding with a long-lived lake system in Gale Crater at ∼3.5 Ga. A reaction-transport model that simulates mineralogy observed within the Sheepbed member at Yellowknife Bay (YKB), by coupling mineral equilibria with carbonate precipitation kinetics and rates of sedimentation, indicates atmospheric PCO2 levels in the 10s mbar range. At such low PCO2 levels, existing climate models are unable to warm Hesperian Mars anywhere near the freezing point of water, and other gases are required to raise atmospheric pressure to prevent lake waters from being lost to the atmosphere. Thus, either lacustrine features of Gale formed in a cold environment by a mechanism yet to be determined, or the climate models still lack an essential component that would serve to elevate surface temperatures, at least locally, on Hesperian Mars. Our results also impose restrictions on the potential role of atmospheric CO2 in inferred warmer conditions and valley network formation of the late Noachian.

Silicic volcanism on Mars evidenced by tridymite in high-SiO2 sedimentary rock at Gale crater.

Tridymite, a low-pressure, high-temperature (>870 °C) SiO2 polymorph, was detected in a drill sample of laminated mudstone (Buckskin) at Marias Pass in Gale crater, Mars, by the Chemistry and Mineralogy X-ray diffraction instrument onboard the Mars Science Laboratory rover Curiosity The tridymitic mudstone has ∼40 wt.% crystalline and ∼60 wt.% X-ray amorphous material and a bulk composition with ∼74 wt.% SiO2 (Alpha Particle X-Ray Spectrometer analysis). Plagioclase (∼17 wt.% of bulk sample), tridymite (∼14 wt.%), sanidine (∼3 wt.%), cation-deficient magnetite (∼3 wt.%), cristobalite (∼2 wt.%), and anhydrite (∼1 wt.%) are the mudstone crystalline minerals. Amorphous material is silica-rich (∼39 wt.% opal-A and/or high-SiO2 glass and opal-CT), volatile-bearing (16 wt.% mixed cation sulfates, phosphates, and chlorides-perchlorates-chlorates), and has minor TiO2 and Fe2O3T oxides (∼5 wt.%). Rietveld refinement yielded a monoclinic structural model for a well-crystalline tridymite, consistent with high formation temperatures. Terrestrial tridymite is commonly associated with silicic volcanism, and detritus from such volcanism in a "Lake Gale" catchment environment can account for Buckskin's tridymite, cristobalite, feldspar, and any residual high-SiO2 glass. These cogenetic detrital phases are possibly sourced from the Gale crater wall/rim/central peak. Opaline silica could form during diagenesis from high-SiO2 glass, as amorphous precipitated silica, or as a residue of acidic leaching in the sediment source region or at Marias Pass. The amorphous mixed-cation salts and oxides and possibly the crystalline magnetite (otherwise detrital) are primary precipitates and/or their diagenesis products derived from multiple infiltrations of aqueous solutions having variable compositions, temperatures, and acidities. Anhydrite is post lithification fracture/vein fill.

Ablation of the CD9 receptor in human lung cancer cells using CRISPR/Cas alters migration to chemoattractants including IL-16.

CD9, a member of the tetraspanin superfamily, has been implicated in regulating various physiological processes, including cell motility, adhesion, apoptosis and metastasis. Recently, interleukin-16 (IL-16), a pro-inflammatory cytokine released by normal airway and alveolar epithelial cells, has been implicated as a possible ligand for CD9 as an alternative receptor. In this study, using A549 cells as a model of human alveolar epithelium, CD9 expression was ablated using CRISPR/Cas technology. Decreased expression of CD9 mRNA and protein levels was confirmed through RT-qPCR and flow cytometry, respectively. Individual clones were generated that expressed high levels of CD9 (wild-type, WT) or significantly less CD9 (knockdown, KD). Both wild-type and knockdown A549 cell migration was quantified using a FluoroBloc transwell chemotaxis assay. Our results indicate that wild-type A549 cells migrated towards chemoattractants. Moreover, CD9 expression was required in this process since the CD9 knockdown cells had a significantly reduced migration towards growth serum and IL-16. These results support the migratory properties for CD9 in human lung cells and support the hypothesis that CD9 serves as an alternative receptor for IL-16.

Tone identification behavior in Rattus norvegicus: muscarinic receptor blockage lowers responsiveness in nontarget selective neurons, while nicotinic receptor blockage selectively lowers target responses.

Learning to associate a stimulus with reinforcement causes plasticity in primary sensory cortex. Neural activity caused by the associated stimulus is paired with reinforcement, but population analyses have not found a selective increase in response to that stimulus. Responses to other stimuli increase as much as, or more than, responses to the associated stimulus. Here, we applied population analysis at a new time point and additionally evaluated whether cholinergic receptor blockers interacted with the plastic changes in cortex. Three days of tone identification behavior caused responsiveness to increase broadly across primary auditory cortex, and target responses strengthened less than overall responsiveness. In pharmacology studies, behaviorally impairing doses of selective acetylcholine receptor blockers were administered during behavior. Neural responses were evaluated on the following day, while the blockers were absent. The muscarinic group, blocked by scopolamine, showed lower responsiveness and an increased response to the tone identification target that exceeded both the 3-day control group and task-naïve controls. Also, a selective increase in the late phase of the response to the tone identification stimulus emerged. Nicotinic receptor antagonism, with mecamylamine, more modestly lowered responses the following day and lowered target responses more than overall responses. Control acute studies demonstrated the muscarinic block did not acutely alter response rates, but the nicotinic block did. These results lead to the hypothesis that the decrease in the proportion of the population spiking response that is selective for the target may be explained by the balance between effects modulated by muscarinic and nicotinic receptors.

The origin and implications of clay minerals from Yellowknife Bay, Gale crater, Mars.

The Mars Science Laboratory (MSL) rover Curiosity has documented a section of fluvio-lacustrine strata at Yellowknife Bay (YKB), an embayment on the floor of Gale crater, approximately 500 m east of the Bradbury landing site. X-ray diffraction (XRD) data and evolved gas analysis (EGA) data from the CheMin and SAM instruments show that two powdered mudstone samples (named John Klein and Cumberland) drilled from the Sheepbed member of this succession contain up to ~20 wt% clay minerals. A trioctahedral smectite, likely a ferrian saponite, is the only clay mineral phase detected in these samples. Smectites of the two samples exhibit different 001 spacing under the low partial pressures of H2O inside the CheMin instrument (relative humidity <1%). Smectite interlayers in John Klein collapsed sometime between clay mineral formation and the time of analysis to a basal spacing of 10 Å, but largely remain open in the Cumberland sample with a basal spacing of ~13.2 Å. Partial intercalation of Cumberland smectites by metal-hydroxyl groups, a common process in certain pedogenic and lacustrine settings on Earth, is our favored explanation for these differences. The relatively low abundances of olivine and enriched levels of magnetite in the Sheepbed mudstone, when compared with regional basalt compositions derived from orbital data, suggest that clay minerals formed with magnetite in situ via aqueous alteration of olivine. Mass-balance calculations are permissive of such a reaction. Moreover, the Sheepbed mudstone mineral assemblage is consistent with minimal inputs of detrital clay minerals from the crater walls and rim. Early diagenetic fabrics suggest clay mineral formation prior to lithification. Thermodynamic modeling indicates that the production of authigenic magnetite and saponite at surficial temperatures requires a moderate supply of oxidants, allowing circum-neutral pH. The kinetics of olivine alteration suggest the presence of fluids for thousands to hundreds of thousands of years. Mineralogical evidence of the persistence of benign aqueous conditions at YKB for extended periods indicates a potentially habitable environment where life could establish itself. Mediated oxidation of Fe2+ in olivine to Fe3+ in magnetite, and perhaps in smectites provided a potential energy source for organisms.

α7 nicotinic acetylcholine receptors are necessary for basal forebrain activation to increase expression of the nerve growth factor receptor TrkA.

Activation of the basal forebrain leads to increases in the expression of the nerve growth factor receptor, Tropomyosin receptor kinase A (TrkA) and decreases in expression of the beta amyloid cleavage enzyme 1 (BACE1) in the cerebral cortex of both sexes of 5xFAD mice. The studies described in this report were designed to determine if these changes were dependent on acetylcholine receptors. Mice were stimulated unilaterally in the basal forebrain for two weeks. Animals were administered a cholinergic antagonist, or saline, 30 minutes prior to stimulation. Animals administered saline exhibited significant increases in TrkA expression and decreases in BACE1 in the stimulated hemisphere relative to the unstimulated. While both nonselective nicotinic and muscarinic acetylcholine receptor blockade attenuated the BACE1 decline, only the nicotinic receptor antagonism blocked the TrkA increase. Next, we applied selective nicotinic antagonists, and the α7 antagonist blocked the TrkA increases, but the α4ß2 antagonist did not. BACE1 declines were not blocked by either intervention. Mice with a loxP conditional knockout of the gene for the α7 nicotinic receptor were also employed in these studies. Animals were either stimulated bilaterally for two weeks, or left unstimulated. With or without stimulation, the expression of TrkA receptors was lower in the cortical region with the α7 nicotinic receptor knockdown. We thus conclude that α7 nicotinic receptor activation is necessary for normal expression of TrkA and increases caused by basal forebrain activation, while BACE1 declines caused by stimulation have dependency on a broader array of receptor subtypes.

Task-dependent modulation of SI physiological responses to targets and distractors.

Selective attention experimental designs have shown that neural responses to stimuli in primary somatosensory cortex are stronger when the sensory stimuli are task relevant. Other studies have used animals under no task demands for data collection. The relationship between neural responses in the brain during behavior, and while an animal has no task demands, remains underexplored. We trained two animals to perform somatosensory detection for several weeks, followed by somatosensory discrimination for several weeks. Data in response to physically identical stimuli were collected from cortical implants while the animal was under no task demands before each behavioral session and also during that behavioral session. The Fourier spectra of the field potentials during detection or discrimination compared with the no task condition demonstrated suppression of the somatosensory µ-rhythm that is associated with readiness and anticipation of cognitive use of somatosensory and motor inputs. Responses to the task target were stronger during detection and discrimination than in the no task condition. The amplitude normalized time course of the target evoked response was similar in both cases. Evoked responses to the task distractor were not significantly stronger during behavior than in recordings under no task demands. The normalized time course of the distractor responses showed a suppression that peaks 30-35 ms after the onset of the response. The selectivity of this within trial suppression is the same as the selectivity of enduring suppression evident in studies of sensory cortical plasticity, which suggests the same neural process may be responsible for both.

Submicroliter electrochemistry and spectroelectrochemistry using standard electrodes and a polymer electrolyte salt bridge.

The development of spectroscopic and electrochemical devices that can accommodate very small samples is of considerable importance to many areas of science and technology. We report here on the design and characteristics of a simple apparatus for the electrochemical and spectroelectrochemical analysis of submicroliter aqueous samples. The device is easily assembled from common laboratory materials and equipment, utilizing a bifurcated fiber-optic probe, standard disk electrodes of millimeter dimensions, and a polymer electrolyte film salt bridge to enable the analysis of nanoliter-scale sample volumes in a thin-layer configuration. Excellent performance has been demonstrated via measurements on aqueous ferricyanide solutions using sample volumes as low as 20 nL.

Tone-detection training enhances spectral integration mediated by intracortical pathways in primary auditory cortex.

Auditory-cued behavioral training can alter neural circuits in primary auditory cortex (A1), but the mechanisms and consequences of experience-dependent cortical plasticity are not fully understood. To address this issue, we trained adult rats to detect a 5 kHz target in order to receive a food reward. After 14 days training we identified three locations within A1: (i) the region representing the characteristic frequency (CF) 5 kHz, (ii) a nearby region with CF ∼10 kHz, and (iii) a more distant region with CF ∼20 kHz. In order to compare functional connectivity in A1 near to, vs. far from, the representation of the target frequency, we placed a 16-channel multiprobe in middle- (∼10 kHz) and high- (∼20 kHz) CF regions and obtained current-source density (CSD) profiles evoked by a range of tone stimuli (CF±1-3 octaves in quarter-octave steps). Our aim was to construct "CSD receptive fields" (CSD RFs) in order to determine the laminar and spectral profile of tone-evoked current sinks, and infer changes to thalamocortical and intracortical inputs. Behavioral training altered CSD RFs at the 10 kHz, but not 20 kHz, site relative to CSD RFs in untrained control animals. At the 10 kHz site, current sinks evoked by the target frequency were enhanced in layer 2/3, but the initial current sink in layer 4 was not altered. The results imply training-induced plasticity along intracortical pathways connecting the target representation with nearby cortical regions. Finally, we related behavioral performance (sensitivity index, d') to CSD responses in individual animals, and found a significant correlation between the development of d' over training and the amplitude of the target-evoked current sink in layer 2/3. The results suggest that plasticity along intracortical pathways is important for auditory learning.

Antiviral activity of (+)-sattabacin against varicella zoster.

The first report of the antiviral activity of (+)-sattabacin against varicella-zoster virus (VZV) is described. Our results show that (+)-sattabacin potently inhibits the growth of VZV at concentrations in the range of other drugs commonly prescribed for VZV infection. Experiments detailing the synthesis of (+)-sattabacin, quantification of cytotoxicity and gene expression data in human fibroblast cells are also presented. Gene expression data was obtained through microarray analysis from human fibroblast cells exposed to sattabacin in order to identify a possible mechanism by which (+)-sattabacin inhibits VZV replication.

Langerhans cell histiocytosis associated with lichen sclerosus of the vulva: case report and review of the literature.

Langerhans cell histiocytosis (LCH) is characterized by a clonal proliferation of bone marrow-derived Langerhans cells. While cutaneous involvement is relatively common, LCH restricted to the vulvar area is a rare phenomenon and can occur in different clinical settings. Occasionally, vulvar LCH heralds subsequent multi-organ involvement with an aggressive clinical course. Even cases of LCH isolated to the vulvar area can present with local recurrences despite excision and radiation. We present a case of a 68-year-old female with a 1-month history of pruritic lesions on her vulva. Physical examination showed whitish plaques with scattered nodular areas on the labia majora. A vulvar biopsy showed a background of lichen sclerosus (LS) with foci of oval to polygonal cells with moderately abundant eosinophilic cytoplasm and folded nuclei showing frequent nuclear grooves. Immunohistochemical staining showed that the cells were positive for CD1a and S-100, confirming the diagnosis of LCH. On further workup, there was no evidence of disseminated disease involving other organs. While vulvar LCH is uncommonly seen, and with only one previous case report in the literature associated in the setting of lichen sclerosus, this case illustrates the importance of recognizing this condition and ensuring proper clinical follow-up to rule out a systemic involvement.

Arc expression and neuroplasticity in primary auditory cortex during initial learning are inversely related to neural activity.

Models of learning-dependent sensory cortex plasticity require local activity and reinforcement. An alternative proposes that neural activity involved in anticipation of a sensory stimulus, or the preparatory set, can direct plasticity so that changes could occur in regions of sensory cortex lacking activity. To test the necessity of target-induced activity for initial sensory learning, we trained rats to detect a low-frequency sound. After learning, Arc expression and physiologically measured neuroplasticity were strong in a high-frequency auditory cortex region with very weak target-induced activity in control animals. After 14 sessions, Arc and neuroplasticity were aligned with target-induced activity. The temporal and topographic correspondence between Arc and neuroplasticity suggests Arc may be intrinsic to the neuroplasticity underlying perceptual learning. Furthermore, not all neuroplasticity could be explained by activity-dependent models but can be explained if the neural activity involved in the preparatory set directs plasticity.