Since the first discovery of deep-sea hydrothermal vents along the Galápagos Rift in 1977, numerous vent sites and endemic faunal assemblages have been found along mid-ocean ridges and back-arc ...basins at low to mid latitudes. These discoveries have suggested the existence of separate biogeographic provinces in the Atlantic and the North West Pacific, the existence of a province including the South West Pacific and Indian Ocean, and a separation of the North East Pacific, North East Pacific Rise, and South East Pacific Rise. The Southern Ocean is known to be a region of high deep-sea species diversity and centre of origin for the global deep-sea fauna. It has also been proposed as a gateway connecting hydrothermal vents in different oceans but is little explored because of extreme conditions. Since 2009 we have explored two segments of the East Scotia Ridge (ESR) in the Southern Ocean using a remotely operated vehicle. In each segment we located deep-sea hydrothermal vents hosting high-temperature black smokers up to 382.8°C and diffuse venting. The chemosynthetic ecosystems hosted by these vents are dominated by a new yeti crab (Kiwa n. sp.), stalked barnacles, limpets, peltospiroid gastropods, anemones, and a predatory sea star. Taxa abundant in vent ecosystems in other oceans, including polychaete worms (Siboglinidae), bathymodiolid mussels, and alvinocaridid shrimps, are absent from the ESR vents. These groups, except the Siboglinidae, possess planktotrophic larvae, rare in Antarctic marine invertebrates, suggesting that the environmental conditions of the Southern Ocean may act as a dispersal filter for vent taxa. Evidence from the distinctive fauna, the unique community structure, and multivariate analyses suggest that the Antarctic vent ecosystems represent a new vent biogeographic province. However, multivariate analyses of species present at the ESR and at other deep-sea hydrothermal vents globally indicate that vent biogeography is more complex than previously recognised.
Electric bike (e-bike) incentives are gaining popularity to increase ownership of e-bikes, with goals of increased mobility while reducing emissions. This study is among the first to experimentally ...analyze prospective purchase behavior of e-bike consumers to assess price sensitivity, behavioral response to incentives, and consumer value of e-bike attributes. We present results of a nationwide (20 cities) stated-preference survey and find e-bike incentives are powerful levers to shift behavior. Different incentive mechanisms have different behavioral utility. Point-of-purchase discounts are the most influential at shifting behavior, followed by tax credits, then mail-in rebates. Point-of-purchase discounts are 30% more effective than mail-in rebates. Across point-of-purchase scenarios, the average inframarginal cost of an added e-bike purchase is $4252 (range $3719 to $4799). Income-based schemes that are often aimed at increasing equity result in cost-effectiveness trade-offs. Policy makers should evaluate the investment in e-bike purchase incentives across benefits from added e-bike ownership that include not only greenhouse gas reductions, but also health benefits, increased mobility, travel affordability, safety, and congestion reductions.
Transportan 10 (TP10) is a 21-residue, cationic, α-helical cell-penetrating peptide that can be used as a delivery vector for various bioactive molecules. Based on recent confocal microscopy studies, ...it is believed that TP10 can translocate across neutral lipid membrane passively, possibly as a monomer, without the formation of permanent pore. Here, we performed extensive molecular dynamics (MD) simulations of TP10W (Y3W variant of TP10) to find the microscopic details of binding, folding and insertion of TP10W to transmembrane state in POPC bilayer. Binding study with CHARMM36 force field showed that TP10W initially binds to the membrane surface in unstructured configuration, but it spontaneously folds into α-helical conformation under the lipid head groups. Further insertion of TP10W, changing from a surface bound state to a vertically oriented transmembrane state, was investigated via umbrella simulations. The resulting free energy profile shows a relatively small barrier between two states, suggesting a possible translocation pathway as a monomer. In fact, unbiased simulation of transmembrane TP10W revealed how a charged Lys side chain can move from one leaflet to the other without a significant free energy cost. Finally, we compared the results of TP10W simulations with those of point mutated variants (TP10W-K12A18 and TP10W-K19L) to understand the effect of charge distribution on the peptide. It was observed that such a conservative mutation can cause noticeable changes in the conformations of both surface bound and transmembrane states. The results of present study will be discussed in relation to the experimentally observed activities of TP10W against neutral membrane.
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•Molecular dynamics studies of binding, folding and insertion of TP10W to POPC bilayer•Observed spontaneous folding of TP10W to α-helical conformation on POPC bilayer•15–21 kJ/mol free energy barrier between the surface bound and transmembrane states•Mechanism of spontaneous transfer of a charged residue between two leaflets of POPC•Study of point-mutated variants of TP10W to see the effect of charge distribution
Daily activities require the constant searching and tracking of visual targets in dynamic and complex scenes. Classic work assessing visual search performance has been dominated by the use of simple ...geometric shapes, patterns, and static backgrounds. Recently, there has been a shift toward investigating visual search in more naturalistic dynamic scenes using virtual reality (VR)-based paradigms. In this direction, we have developed a first-person perspective VR environment combined with eye tracking for the capture of a variety of objective measures. Participants were instructed to search for a preselected human target walking in a crowded hallway setting. Performance was quantified based on saccade and smooth pursuit ocular motor behavior. To assess the effect of task difficulty, we manipulated factors of the visual scene, including crowd density (i.e., number of surrounding distractors) and the presence of environmental clutter. In general, results showed a pattern of worsening performance with increasing crowd density. In contrast, the presence of visual clutter had no effect. These results demonstrate how visual search performance can be investigated using VR-based naturalistic dynamic scenes and with high behavioral relevance. This engaging platform may also have utility in assessing visual search in a variety of clinical populations of interest.
Individuals with cerebral visual impairment (CVI) often present with deficits related to visuospatial processing. However, the neurophysiological basis underlying these higher order perceptual ...dysfunctions have not been clearly identified. We assessed visual search performance using a novel virtual reality based task paired with eye tracking to simulate the exploration of a naturalistic scene (a virtual toy box). This was combined with electroencephalography (EEG) recordings and an analysis pipeline focusing on time frequency decomposition of alpha oscillatory activity. We found that individuals with CVI showed an overall impairment in visual search performance (as indexed by decreased success rate, as well as increased reaction time, visual search area, and gaze error) compared to controls with neurotypical development. Analysis of captured EEG activity following stimulus onset revealed that in the CVI group, there was a distinct lack of strong and well defined posterior alpha desynchronization; an important signal involved in the coordination of neural activity related to visual processing. Finally, an exploratory analysis revealed that in CVI, the magnitude of alpha desynchronization was associated with impaired visual search performance as well as decreased volume of specific thalamic nuclei implicated in visual processing. These results suggest that impairments in visuospatial processing related to visual search in CVI are associated with alterations in alpha band oscillations as well as early neurological injury at the level of visual thalamic nuclei.
•Cerebral visual impairment (CVI) presents with deficits related to visuospatial processing.•We assessed visual search performance with eye tracking and combined with electroencephalography (EEG) recordings.•CVI was associated with impaired visual search performance and distinct lack of posterior alpha desynchronization activity.•There are potential associations between alpha desynchronization, behavioral performance, and neuroanatomical markers.
Recent evidence suggest that extracorporeal cardiopulmonary resuscitation (ECPR) may improve survival rates for nontraumatic out-of-hospital cardiac arrest (OHCA). Eligibility criteria for ECPR are ...often based on patient age, clinical variables, and facility capabilities. Expanding access to ECPR across the U.S. requires a better understanding of how these factors interact with transport time to ECPR centers.
We constructed a Geographic Information System (GIS) model to estimate the number of ECPR candidates in the U.S. We utilized a Resuscitation Outcome Consortium (ROC) database to model time-dependent rates of ECPR eligibility and the Cardiac Arrest Registry to Enhance Survival (CARES) registry to determine the total number of OHCA patients who meet pre-specified ECPR criteria within designated transportation times. The combined model was used to estimate the total number of ECPR candidates.
There were 588,203 OHCA patients in the CARES registry from 2013 to 2020. After applying clinical eligibility criteria, 22,104 (3.76%) OHCA patients were deemed eligible for ECPR. The rate of ROSC increased with longer resuscitation time, which resulted in fewer ECPR candidates. The proportion of OHCA patients eligible for ECPR increased with older age cutoffs. Only 1.68% (9,889/588,203) of OHCA patients in the U.S. were eligible for ECPR based on a 45-minute transportation time to an ECMO-ready center model.
Less than 2% of OHCA patients are eligible for ECPR in the U.S. GIS models can identify the impact of clinical criteria, transportation time, and hospital capabilities on ECPR eligibility to inform future implementation strategies.
Cerebral visual impairment (CVI) often presents with deficits associated with higher order visual processing. We report a case of an individual with CVI who uses a verbal mediation strategy to ...perceive and interact with his visual surroundings. Visual perceptual performance was assessed using a virtual reality based visual search task combined with eye tracking. Functional magnetic resonance imaging (fMRI) was employed to identify the neural correlates associated with this strategy. We found that when using verbal mediation, the individual could readily detect and track the target within the visual scene which was associated with robust activation within a network of occipito-parieto-temporal visual cortical areas. In contrast, when not using verbal mediation, the individual was completely unable to perform the task, and this was associated with dramatically reduced visual cortical activation. This unique compensatory strategy may be related to the individual's use of verbal working memory for the purposes of understanding complex visual information.
•CVI presents with higher order visual processing deficits.•We report a case of an individual with CVI who uses verbal mediation to perceive and interact with his visual surroundings.•Verbal mediation was associated with robust activation within a network of occipito-parieto-temporal visual cortical areas.
SGC-GAK-1 (
) is a potent, selective, cell-active chemical probe for cyclin G-associated kinase (GAK). However,
was rapidly metabolized in mouse liver microsomes by cytochrome P450-mediated ...oxidation, displaying rapid clearance in liver microsomes and in mice, which limited its utility in in vivo studies. Chemical modifications of
that improved metabolic stability, generally resulted in decreased GAK potency. The best analog in terms of GAK activity in cells was 6-bromo-
-(1
-indazol-6-yl)quinolin-4-amine (
) (IC
= 1.4 μM), showing improved stability in liver microsomes while still maintaining a narrow spectrum activity across the kinome. As an alternative to scaffold modifications we also explored the use of the broad-spectrum cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) to decrease intrinsic clearance of aminoquinoline GAK inhibitors. Taken together, these approaches point towards the development of an in vivo chemical probe for the dark kinase GAK.
Cerebral visual impairment (CVI) is a brain-based disorder associated with the maldevelopment of central visual pathways. Individuals with CVI often report difficulties with daily visual search tasks ...such as finding a favorite toy or familiar person in cluttered and crowded scenes. We developed two novel virtual reality (VR)-based visual search tasks combined with eye tracking to objectively assess higher order processing abilities in CVI. The first (virtual toybox) simulates a static object search, while the second (virtual hallway) represents a dynamic human search task. Participants were instructed to search for a preselected target while task demand was manipulated with respect to the presence of surrounding distractors. We found that CVI participants (when compared to age-matched controls) showed an overall impairment with visual search on both tasks and with respect to all gaze metrics. Furthermore, CVI participants showed a trend of worsening performance with increasing task demand. Finally, search performance was also impaired in CVI participants with normal/near normal visual acuity, suggesting that reduced stimulus visibility alone does not account for these observations. This novel approach may have important clinical utility in helping to assess environmental factors related to functional visual processing difficulties observed in CVI.
4‐Anilinoquinolines were identified as potent and narrow‐spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization ...of the 4‐anilino group and the 6,7‐quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000‐fold selectivity relative to other members of the numb‐associated kinase (NAK) subfamily, and a compound (6,7‐dimethoxy‐N‐(3,4,5‐trimethoxyphenyl)quinolin‐4‐amine; 49) with a narrow‐spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases.
Targeting GAK: The availability of chemical probes with improved selectivity for cyclin G associated kinase (GAK) or a different spectrum of off‐targets would be useful in target validation studies. Herein we report the synthesis and characterization of 4‐anilinoquinolines and 4‐anilinoquinazolines as potent narrow‐spectrum GAK inhibitors. Several of these compounds have the potential for development into high‐quality chemical probes for the study of GAK biology.
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