Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy.

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects.FundingGalderma International S.A.S., Paris, France

Inhibitory Effects of Securinine and Related Compounds on Toxoplasma gondii and Mechanistic Insights into Transcript-Specific Translational Repression in the Bradyzoite Developmental Stage

Toxoplasma gondii is an intracellular protozoan parasite that infects warm blooded animals the world over. In the host, the parasite exists as either rapidly growing tachyzoites or immunologically protected slowly dividing bradyzoites. While tachyzoites are generally cleared by the host\u27s immune system, bradyzoites persist for life. If the immune system becomes compromised, bradyzoites reconvert to tachyzoites and cause severe illness. Bradyzoites develop in response to stressful stimuli, therefore discovering factors that modulate bradyzoite conversion as well as determining how Toxoplasma\u27s stress response pathways operate are essential to understanding parasite disease. In this work, the plant alkaloid securinine as well as ten pyrrolidine derivatives were shown to have in vitro anti-Toxoplasma activity in the micromolar range. These compounds act in different capacities, either restricting parasite\u27s invasion or by reducing the parasite\u27s rate of replication. One of the hallmarks of the bradyzoite life stage is slowed replication. When tested, only securinine induced bradyzoite formation at comparable levels to treatment with alkaline media, suggesting that it initiates a stressful stimulus. When in the bradyzoite stage, Toxoplasma induces a global translational repression allowing for the remodeling of the transcriptome. However it remains unclear how certain transcripts are maintained throughout the long term translational repression seen in bradyzoites. Analysis of one such transcript, lactate dehydrogenase 1, showed a 40 nucleotide cis-acting element with its 5\u27UTR responsible for this activity. The formation of 16 nucleotide regulatory RNA hairpin is necessary for inducing sustained translational repression in bradyzoites, suggesting that it acts as a recognizable feature. Characterization of the transcript reveals that its poly(A) tail does not shorten in bradyzoites, indicating that it is likely targeted for long term storage instead of degraded under stress. Efforts were made to capture and analyse the protein complement interacting with the cis-acting element using RNA aptamer technologies, however they were unfruitful. Using extracellular parasites, it was determined that a rapid induction of stress is insufficient to selectively repress the transcript. This suggests that the reprogramming of the proteome may be necessary for the sustained translational repression of lactate dehydrogenase 1 in Toxoplasma bradyzoites

Global Analysis and Forecasts of Carbon Monoxide on Mars

Spatial and temporal variations in the Martian carbon monoxide (CO) cycle have been investigated through combining Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) retrievals of carbon monoxide mixing ratio and Mars Climate Sounder (MCS) temperature profiles with a Martian global circulation model (GCM) to produce the first global reanalysis of the Martian CO cycle. The reanalysis reduces the root mean square error between the forecast and CRISM CO retrievals by a factor of 2–4, dependent on the time of year. Forecasts initiated from the reanalysis show an improved match to standalone CRISM CO retrievals from northern winter solstice to northern summer solstice, indicating the benefit of data assimilation in simulating the CO abundance. The northern summer solstice CO minimum between 10∘S – 50∘S in the CRISM CO retrievals is found to be caused by a suppression of CO-enriched air leaking from the Hellas and Argyre basins, and is also strongly influenced by the amount of carbon dioxide condensing at the time. The GCM is the first reported to simulate the local CO minimum however it is weaker in strength, as CO-enriched air is also released northward in the area of Argyre basin in the GCM because of a shifted boundary between the southern polar vortex and mid-latitudes. The reanalysis, as a result of the assimilation of MCS temperature profiles, indicates that the polar vortex boundary is northward of Argyre basin and hence no northerly transport of CO-enriched air should be present over this location. Differences in local CO abundance between the reanalysis and GCM are also evident in spatio-temporal regions where no nearby CRISM CO retrievals are available as a result of alterations in local circulation and the sublimation/condensation of carbon dioxide through the combined assimilation of CRISM CO retrievals alongside MCS temperature profiles, illustrating how constraints can be imposed indirectly on the CO cycle through the powerful technique of data assimilation

High School Media Too: A School Day in the Lives of Fifteen Teenagers

An observational study of media consumption and exposure throughout the school day of fifteen middle- and high-school students. The study measures exposure in ten second increments in all locations from home and car through school and others and details incidence and duration os media use. Results also details incidence of Concurrent Media Exposure (multi-tasking)

Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.

HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4. C34-conjugated coreceptors were expressed on the surface of T cell lines and primary CD4 T cells, retained the ability to mediate chemotaxis in response to cognate chemokines, and were highly resistant to HIV-1 utilization for entry. Notably, C34-conjugated CCR5 and CXCR4 each exhibited potent and broad inhibition of HIV-1 isolates from diverse clades irrespective of tropism (i.e., each could inhibit R5, X4 and dual-tropic isolates). This inhibition was highly specific and dependent on positioning of the peptide, as HIV-1 infection was poorly inhibited when C34 was conjugated to the amino terminus of CD4. C34-conjugated coreceptors could also inhibit HIV-1 isolates that were resistant to the soluble HR2 peptide inhibitor, enfuvirtide. When introduced into primary cells, CD4 T cells expressing C34-conjugated coreceptors exhibited physiologic responses to T cell activation while inhibiting diverse HIV-1 isolates, and cells containing C34-conjugated CXCR4 expanded during HIV-1 infection in vitro and in a humanized mouse model. Notably, the C34-conjugated peptide exerted greater HIV-1 inhibition when conjugated to CXCR4 than to CCR5. Thus, antiviral effects of HR2 peptides can be specifically directed to the site of viral entry where they provide potent and broad inhibition of HIV-1. This approach to engineer HIV-1 resistance in functional CD4 T cells may provide a novel cell-based therapeutic for controlling HIV infection in humans

Critical fluctuations in cortical models near instability

Australian Research Council, the National Health and Medical Research Council, the Brain Network Recovery Group Grant JSMF22002082, and Netherlands Organization for Scientific Research (NWO #451–10-030

Final Report: Predicting Effects of Climate Change on Riparian Obligate Species in the Southwestern United States

The Lower Colorado River and Rio Grande Basins are home to many riparian vertebrate species with different degrees of rarity. In our study, we focused on two species of birds and two species of gartersnakes that are associated with riparian areas: the Yellow-breasted Chat (Icteria virens), the Yellow Warbler (Setophaga petechia), the Northern Mexican Gartersnake (Thamnophis eques megalops) and the Narrow-headed Gartersnake (T. rufipunctatus). While the extent of distributions of these species is relatively large, they are often patchily distributed in populations that are small; in addition, both gartersnake species are listed as threatened under the Endangered Species Act. Aside from detrimental effects of direct habitat loss and degradation throughout the southwestern United States, future changes in water availability might threaten the long-term persistence of populations of any one of these species. To evaluate this vulnerability at a landscape scale, we built species distribution models under current and future projected climates for each species. For modeling, we relied on climatic and hydrological predictions (downscaled CMIP3 climate and hydrology projections) developed by the Bureau of Reclamation and its partners as part of the West-Wide Climate Risk Assessments within the WATERSmart initiative. We also relied on NASAs Moderate-Resolution Imaging Spectroradiometer (MODIS) to derive a spatially explicit index that quantifies riparian vegetation in space and time. Using downscaled climate projections and other landscape data, we were able to project these riparian vegetation metric forward in time. The projected changes in water availability by end of the century will directly affect the availability of permanent water and riparian vegetation creating the habitats of our study species. Our results suggest significant and negative changes in future landscape suitability for all species (up to 64% loss of suitable area), which are in addition to already identified threats facing these species. Best models included the index of riparian vegetation (linked to water availability) as an important component of the predictions, but we also note that finer scale examination of hydrology and climate effects on habitats would be much more useful for effective management.\u2

A Comparative Study of the ReCell® Device and Autologous Spit-Thickness Meshed Skin Graft in the Treatment of Acute Burn Injuries.

Early excision and autografting are standard care for deeper burns. However, donor sites are a source of significant morbidity. To address this, the ReCell® Autologous Cell Harvesting Device (ReCell) was designed for use at the point-of-care to prepare a noncultured, autologous skin cell suspension (ASCS) capable of epidermal regeneration using minimal donor skin. A prospective study was conducted to evaluate the clinical performance of ReCell vs meshed split-thickness skin grafts (STSG, Control) for the treatment of deep partial-thickness burns. Effectiveness measures were assessed to 1 year for both ASCS and Control treatment sites and donor sites, including the incidence of healing, scarring, and pain. At 4 weeks, 98% of the ASCS-treated sites were healed compared with 100% of the Controls. Pain and assessments of scarring at the treatment sites were reported to be similar between groups. Significant differences were observed between ReCell and Control donor sites. The mean ReCell donor area was approximately 40 times smaller than that of the Control (P < .0001), and after 1 week, significantly more ReCell donor sites were healed than Controls (P = .04). Over the first 16 weeks, patients reported significantly less pain at the ReCell donor sites compared with Controls (P ≤ .05 at each time point). Long-term patients reported higher satisfaction with ReCell donor site outcomes compared with the Controls. This study provides evidence that the treatment of deep partial-thickness burns with ASCS results in comparable healing, with significantly reduced donor site size and pain and improved appearance relative to STSG

Selective Association Between Tetris Game Play and Visuospatial Working Memory: A Preliminary Investigation

Recent experimental and clinical research has suggested that Tetris game play can disrupt maladaptive forms of mental imagery because Tetris competes for limited cognitive resources within visuospatial working memory (WM) that contribute to imagery. Whether or not Tetris performance is selectively associated with visuospatial WM remains to be tested. In this study, young adults (N = 46) completed six standardized measures indexing verbal and non-verbal reasoning, verbal and visuospatial short-term memory, and verbal and visuospatial WM. They also played Tetris. Consistent with the hypothesis that visuospatial WM resources support Tetris game play, there was a significant moderate positive relationship between Tetris scores and visuospatial WM performance but no association with other cognitive ability measures. Findings suggest that Tetris game play involves both storage and processing resources within visuospatial WM. These preliminary results can inform interventions involving computer games to disrupt the development of maladaptive visual imagery, for example, intrusive memories of trauma.Copyright © 2017 John Wiley & Sons, Ltd.Funded by - United Kingdom Medical Research Council intramural programme. Grant Numbers: MC-A060-5PR50, MC-APQ500 - The Cambridge Commonwealth, European and International Trus

Computer Game Play Reduces Intrusive Memories of Experimental Trauma via Reconsolidation-Update Mechanisms.

Memory of a traumatic event becomes consolidated within hours. Intrusive memories can then flash back repeatedly into the mind's eye and cause distress. We investigated whether reconsolidation-the process during which memories become malleable when recalled-can be blocked using a cognitive task and whether such an approach can reduce these unbidden intrusions. We predicted that reconsolidation of a reactivated visual memory of experimental trauma could be disrupted by engaging in a visuospatial task that would compete for visual working memory resources. We showed that intrusive memories were virtually abolished by playing the computer game Tetris following a memory-reactivation task 24 hr after initial exposure to experimental trauma. Furthermore, both memory reactivation and playing Tetris were required to reduce subsequent intrusions (Experiment 2), consistent with reconsolidation-update mechanisms. A simple, noninvasive cognitive-task procedure administered after emotional memory has already consolidated (i.e., > 24 hours after exposure to experimental trauma) may prevent the recurrence of intrusive memories of those emotional events