Glia Accumulate Evidence that Actions Are Futile and Suppress Unsuccessful Behavior.

When a behavior repeatedly fails to achieve its goal, animals often give up and become passive, which can be strategic for preserving energy or regrouping between attempts. It is unknown how the brain identifies behavioral failures and mediates this behavioral-state switch. In larval zebrafish swimming in virtual reality, visual feedback can be withheld so that swim attempts fail to trigger expected visual flow. After tens of seconds of such motor futility, animals became passive for similar durations. Whole-brain calcium imaging revealed noradrenergic neurons that responded specifically to failed swim attempts and radial astrocytes whose calcium levels accumulated with increasing numbers of failed attempts. Using cell ablation and optogenetic or chemogenetic activation, we found that noradrenergic neurons progressively activated brainstem radial astrocytes, which then suppressed swimming. Thus, radial astrocytes perform a computation critical for behavior: they accumulate evidence that current actions are ineffective and consequently drive changes in behavioral states. VIDEO ABSTRACT.

Tracking ultrafast non-adiabatic dissociation dynamics of the deuterated water dication molecule.

We applied reaction microscopy to elucidate fast non-adiabatic dissociation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV with synchrotron radiation. For the very rare D+ + O+ + D breakup channel, the particle momenta, angular, and energy distributions of electrons and ions, measured in coincidence, reveal distinct electronic dication states and their dissociation pathways via spin-orbit coupling and charge transfer at crossings and seams on the potential energy surfaces. Notably, we could distinguish between direct and fast sequential dissociation scenarios. For the latter case, our measurements reveal the geometry and orientation of the deuterated water molecule with respect to the polarization vector that leads to this rare 3-body molecular breakup channel. Aided by multi-reference configuration-interaction calculations, the dissociation dynamics could be traced on the relevant potential energy surfaces and particularly their crossings and seams. This approach also unraveled the ultrafast time scales governing these processes.

Atomic autoionization in the photo-dissociation of super-excited deuterated water molecules fragmenting into D+ + O+ + D.

We present the relaxation dynamics of deuterated water molecules via autoionization, initiated by the absorption of a 61 eV photon, producing the very rare D+ + O+ + D breakup channel. We employ the COLd target recoil ion momentum spectroscopy method to measure the 3D momenta of the ionic fragments and emitted electrons from the dissociating molecule in coincidence. We interpret the results using the potential energy surfaces extracted from multi-reference configuration interaction calculations. The measured particle energy distributions can be related to a super-excited monocationic state located above the double ionization threshold of D2O. The autoionized electron energy shows a sharp distribution centered around 0.5 eV, which is a signature of the atomic oxygen autoionization occurring in the direct and sequential dissociation processes of D2O+* at a large internuclear distance. In this way, an O+ radical fragment and a low-energy electron are created, both of which can trigger secondary reactions in their environment.

High-energy molecular-frame photoelectron angular distributions: a molecular bond-length ruler.

We present a study on molecular-frame photoelectron angular distributions (MFPADs) of small molecules using circularly polarized synchrotron light. We find that the main forward-scattering peaks of the MFPADs are slightly tilted with respect to the molecular axis. This tilt angle is directly connected to the molecular bond length by a simple, universal formula. We apply the derived formula to several examples of MFPADs of C 1s and O 1s photoelectrons of CO, which have been measured experimentally or obtained by means of ab initio modeling. In addition, we discuss the influence of the back-scattering contribution that is superimposed over the analyzed forward-scattering peak in the case of homo-nuclear diatomic molecules such as N2.

Efficiency of charge transfer in changing the dissociation dynamics of OD+ transients formed after the photo-fragmentation of D2O.

We present an investigation of the relaxation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV. We focus on the very rare D+ + O+ + D reaction channel in which the sequential fragmentation mechanisms were found to dominate the dynamics. Aided by theory, the state-selective formation and breakup of the transient OD+(a1Δ, b1Σ+) is traced, and the most likely dissociation path-OD+: a1Δ or b1Σ+ → A 3Π â†’ X 3Σ- → B 3Σ--involving a combination of spin-orbit and non-adiabatic charge transfer transitions is determined. The multi-step transition probability of this complex transition sequence in the intermediate fragment ion is directly evaluated as a function of the energy of the transient OD+ above its lowest dissociation limit from the measured ratio of the D+ + O+ + D and competing D+ + D+ + O sequential fragmentation channels, which are measured simultaneously. Our coupled-channel time-dependent dynamics calculations reproduce the general trends of these multi-state relative transition rates toward the three-body fragmentation channels.

Mapping brain activity at scale with cluster computing.

Understanding brain function requires monitoring and interpreting the activity of large networks of neurons during behavior. Advances in recording technology are greatly increasing the size and complexity of neural data. Analyzing such data will pose a fundamental bottleneck for neuroscience. We present a library of analytical tools called Thunder built on the open-source Apache Spark platform for large-scale distributed computing. The library implements a variety of univariate and multivariate analyses with a modular, extendable structure well-suited to interactive exploration and analysis development. We demonstrate how these analyses find structure in large-scale neural data, including whole-brain light-sheet imaging data from fictively behaving larval zebrafish, and two-photon imaging data from behaving mouse. The analyses relate neuronal responses to sensory input and behavior, run in minutes or less and can be used on a private cluster or in the cloud. Our open-source framework thus holds promise for turning brain activity mapping efforts into biological insights.

Awake vs. anesthetized: layer-specific sensory processing in visual cortex and functional connectivity between cortical areas.

During general anesthesia, global brain activity and behavioral state are profoundly altered. Yet it remains mostly unknown how anesthetics alter sensory processing across cortical layers and modulate functional cortico-cortical connectivity. To address this gap in knowledge of the micro- and mesoscale effects of anesthetics on sensory processing in the cortical microcircuit, we recorded multiunit activity and local field potential in awake and anesthetized ferrets (Mustela putoris furo) during sensory stimulation. To understand how anesthetics alter sensory processing in a primary sensory area and the representation of sensory input in higher-order association areas, we studied the local sensory responses and long-range functional connectivity of primary visual cortex (V1) and prefrontal cortex (PFC). Isoflurane combined with xylazine provided general anesthesia for all anesthetized recordings. We found that anesthetics altered the duration of sensory-evoked responses, disrupted the response dynamics across cortical layers, suppressed both multimodal interactions in V1 and sensory responses in PFC, and reduced functional cortico-cortical connectivity between V1 and PFC. Together, the present findings demonstrate altered sensory responses and impaired functional network connectivity during anesthesia at the level of multiunit activity and local field potential across cortical layers.

Anesthesia differentially modulates spontaneous network dynamics by cortical area and layer.

Anesthesia is widely used in medicine and research to achieve altered states of consciousness and cognition. Whereas changes to macroscopic cortical activity patterns by anesthesia measured at the spatial resolution of electroencephalography have been widely studied, modulation of mesoscopic and microscopic network dynamics by anesthesia remain poorly understood. To address this gap in knowledge, we recorded spontaneous mesoscopic (local field potential) and microscopic (multiunit activity) network dynamics in primary visual cortex (V1) and prefrontal cortex (PFC) of awake and isoflurane anesthetized ferrets (Mustela putoris furo). This approach allowed for examination of activity as a function of cortical area, cortical layer, and anesthetic depth with much higher spatial and temporal resolution than in previous studies. We hypothesized that a primary sensory area and an association cortical area would exhibit different patterns of network modulation by anesthesia due to their different functional roles. Indeed, we found effects specific to cortical area and cortical layer. V1 exhibited minimal changes in rhythmic structure with anesthesia but differential modulation of input layer IV. In contrast, anesthesia profoundly altered spectral power in PFC, with more uniform modulation across cortical layers. Our results demonstrate that anesthesia modulates spontaneous cortical activity in an area- and layer-specific manner. These finding provide the basis for 1) refining anesthesia monitoring algorithms, 2) reevaluating the large number of systems neuroscience studies performed in anesthetized animals, and 3) increasing our understanding of differential dynamics across cortical layers and areas.

"Masson's pseudoangiosarcoma" in a popliteal aneurysm: tumor or thrombus? Cause or effect?

A 44-year-old male presented to our vascular surgery unit with a partially thrombosed 22 mm popliteal aneurysm giving rise to progressive distal ischemia. Microscopy of embolus retrieved from the posterior tibial artery at bypass surgery revealed the unexpected finding of intravascular papillary endothelial hyperplasia (Masson's pseudoangiosarcoma).

Alcohol, amines, and alkaloids: a possible biochemical basis for alcohol addiction.

Tetrahydropapaveroline is a benzyltetrahydroisoquinoline alkaloidderivative of the biogenic amine, dopnmine. Alcohol, by way of its primary metabolite, acetaldehyde, competitively inhibits nicotinamide-adenine Sinucleotide-linked aldehyde dehydrogenase and augments the formation of tetrahydropapaveroline in vitro. The limited capacity of brain to oxidize aldehydes may be of pharmacological importance because it facilitates the production of tetrahydropapaveroline in the presence of drugs which inhibit this enzyme.

A major role for VCAM-1, but not ICAM-1, in early atherosclerosis.

VCAM-1 and ICAM-1 are endothelial adhesion molecules of the Ig gene superfamily that may participate in atherogenesis by promoting monocyte accumulation in the arterial intima. Both are expressed in regions predisposed to atherosclerosis and at the periphery of established lesions, while ICAM-1 is also expressed more broadly. To evaluate functions of VCAM-1 in chronic disease, we disrupted its fourth Ig domain, producing the murine Vcam1(D4D) allele. VCAM-1(D4D) mRNA and protein were reduced to 2-8% of wild-type allele (Vcam1(+)) levels but were sufficient to partially rescue the lethal phenotype of VCAM-1-null embryos. After crossing into the LDL receptor-null background, Vcam1(+/+) and Vcam1(D4D/D4D) paired littermates were generated from heterozygous intercrosses and fed a cholesterol-enriched diet for 8 weeks. The area of early atherosclerotic lesions in the aorta, quantified by en face oil red O staining, was reduced significantly in Vcam1(D4D/D4D) mice, although cholesterol levels, lipoprotein profiles, and numbers of circulating leukocytes were comparable to wild-type. In contrast, deficiency of ICAM-1 either alone or in combination with VCAM-1 deficiency did not alter nascent lesion formation. Therefore, although expression of both VCAM-1 and ICAM-1 is upregulated in atherosclerotic lesions, our data indicate that VCAM-1 plays a dominant role in the initiation of atherosclerosis.

The effects of centralisation of vascular surgical services in the Bath, Bristol and Weston area on the carotid endarterectomy pathway.

Introduction Patients who experience a transient ischaemic attack are at the highest risk of having a subsequent stroke immediately after their symptoms. A carotid endarterectomy should be performed on symptomatic, surgically suitable patients who present with a greater than 50% North American Symptomatic Carotid Endarterectomy Trial stenosis of the internal carotid artery within 2 weeks of their symptoms. This study aimed to determine whether the effectiveness of the carotid endarterectomy pathway has been impacted by the centralisation of vascular surgical services in the Bath, Bristol and Weston area. Materials and Methods From October 2013 to October 2015, critical steps in the patient carotid endarterectomy pathway that vascular surgeons from the Royal United Hospital Bath, Bristol Royal Infirmary and North Bristol NHS Trust input into the Royal College of Surgeons National Vascular Registry were collected. The dates of patient's symptoms, referral, first scan, surgical team review and surgery were analysed. Results Carotid endarterectomy data was collected for 261 patients. Overall, no significant difference in median time (days) from symptom to surgery from precentralisation data compared with post-centralisation data was seen (P = .175), with 65% patients meeting the national target of symptom to surgery in less than 14days. Discussion and Conclusion Centralisation has not significantly impacted the overall efficiency of the carotid endarterectomy pathway. This study highlights areas where improvement across the vascular network is required. This includes addressing the 35% patients that are not currently meeting the 14-day target and standardising the provision of care to outlying communities. Further follow-up is required to assess the longer term effects of centralisation.

Modeling the future of irrigation: A parametric description of pressure compensating drip irrigation emitter performance.

Drip irrigation is a means of distributing the exact amount of water a plant needs by dripping water directly onto the root zone. It can produce up to 90% more crops than rain-fed irrigation, and reduce water consumption by 70% compared to conventional flood irrigation. Drip irrigation may enable millions of poor farmers to rise out of poverty by growing more and higher value crops, while not contributing to overconsumption of water. Achieving this impact will require broadening the engineering knowledge required to design new, low-cost, low-power drip irrigation technology, particularly for poor, off-grid communities in developing countries. For more than 50 years, pressure compensating (PC) drip emitters-which can maintain a constant flow rate under variations in pressure, to ensure uniform water distribution on a field-have been designed and optimized empirically. This study presents a parametric model that describes the fluid and solid mechanics that govern the behavior of a common PC emitter architecture, which uses a flexible diaphragm to limit flow. The model was validated by testing nine prototypes with geometric variations, all of which matched predicted performance to within R2 = 0.85. This parametric model will enable irrigation engineers to design new drip emitters with attributes that improve performance and lower cost, which will promote the use of drip irrigation throughout the world.

A Practical Guide to Light Sheet Microscopy.

Light sheet fluorescence microscopy is an efficient method for imaging large volumes of biological tissue, including brains of larval zebrafish, at high spatial and fairly high temporal resolution with minimal phototoxicity.Here, we provide a practical guide for those who intend to build a light sheet microscope for fluorescence imaging in live larval zebrafish brains or other tissues.

Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women, particularly black women.

Controversy has arisen concerning whether gender influences the prognosis after myocardial infarction. Although some studies have shown there to be no difference between the sexes, most have indicated a worse prognosis for women, attributing this to differences in baseline characteristics. It has been further suggested that black women have a particularly poor prognosis after infarction. To determine the contribution of gender and race to the course of infarction, 816 patients with confirmed myocardial infarction who were enrolled in the Multicenter Investigation of the Limitation of Infarct Size (MILIS) were analyzed. Of those patients, 226 were women and 590 were men, 142 were black and 674 were white. The cumulative mortality rate at 48 months was 36% for women versus 21% for men (p less than 0.001, mean follow-up 32 months). The cumulative mortality rate by race was 34% for blacks versus 24% for whites (p less than 0.005). Both women and blacks exhibited more baseline characteristics predictive of mortality than did their male or white counterparts. It was possible to account for the greater mortality rate of blacks by identifiable baseline variables; however, even after adjustment, the mortality rate for women remained significantly higher (p less than 0.002). The poorer prognosis for women was influenced by a particularly high mortality rate among black women (48%); the mortality rate for white women was 32%, for black men 23% and for white men 21%. The mortality for black women was significantly greater than that of the other subgroups. Thus, findings in the MILIS population indicate that the prognosis after myocardial infarction is worse for women, particularly black women.

Use of a standardized heparin nomogram to achieve therapeutic anticoagulation after thrombolytic therapy in myocardial infarction. TIMI 4 investigators. Thrombolysis in Myocardial Infarction.

BACKGROUND: The recently completed Thrombolysis in Myocardial Infarction (TIMI) 4 Study compared three thrombolytic treatment regimens for acute myocardial infarction. The treatment arms included front-loaded recombinant tissue plasminogen activator (rtPA), anistreplase (APSAC), or both, in conjunction with an intravenous bolus of 5000 U of heparin, followed by 1000 U/h. To facilitate anticoagulation, a heparin nomogram was developed to maintain the therapeutic activated partial thromboplastin time at 1 1/2 to 2 times the control value. METHODS: A poll revealed that nine centers made use of the recommended heparin nomogram and six did not, adjusting the heparin dosage according to local practice. Anticoagulation parameters, major hemorrhagic events, and the frequency of heparin interruption were compared between centers that used and did not use the nomogram. RESULTS: Subtherapeutic activated partial thromboplastin time values were noted in 4%, 14%, 29%, 46%, 37%, and 34% of patients 8, 12, 24, 48, 72, and 96 hours, respectively, after heparin treatment was begun. Patients with subtherapeutic values at 24 hours were younger (mean +/- SD, 55.2 +/- 10.6 vs 59.6 +/- 10.6 years, P = .02) and weighed more (86.4 +/- 13.5 vs 78.9 +/- 15.7 kg, P = .007) than patients with therapeutic values. Centers that used the nomogram had significantly fewer subtherapeutic values at 48 and 96 hours. In addition, heparin therapy was interrupted less frequently at centers that used the nomogram (38.1% vs 68.7%, P < .001). Major spontaneous hemorrhage, reinfarction, and reocclusion rates were low and were about the same in the two groups. CONCLUSIONS: The use of a heparin nomogram provided improved anticoagulation in patients treated with thrombolytic therapy for myocardial infarction. Weight- and age-adjusted heparin dosing may provide further improvement in anticoagulation with heparin therapy. Our findings support the need for frequent monitoring of the activated partial thromboplastin time and for a standardized approach to adjusting the heparin dosage.

Frequency-band signatures of visual responses to naturalistic input in ferret primary visual cortex during free viewing.

Neuronal firing responses in visual cortex reflect the statistics of visual input and emerge from the interaction with endogenous network dynamics. Artificial visual stimuli presented to animals in which the network dynamics were constrained by anesthetic agents or trained behavioral tasks have provided fundamental understanding of how individual neurons in primary visual cortex respond to input. In contrast, very little is known about the mesoscale network dynamics and their relationship to microscopic spiking activity in the awake animal during free viewing of naturalistic visual input. To address this gap in knowledge, we recorded local field potential (LFP) and multiunit activity (MUA) simultaneously in all layers of primary visual cortex (V1) of awake, freely viewing ferrets presented with naturalistic visual input (nature movie clips). We found that naturalistic visual stimuli modulated the entire oscillation spectrum; low frequency oscillations were mostly suppressed whereas higher frequency oscillations were enhanced. In average across all cortical layers, stimulus-induced change in delta and alpha power negatively correlated with the MUA responses, whereas sensory-evoked increases in gamma power positively correlated with MUA responses. The time-course of the band-limited power in these frequency bands provided evidence for a model in which naturalistic visual input switched V1 between two distinct, endogenously present activity states defined by the power of low (delta, alpha) and high (gamma) frequency oscillatory activity. Therefore, the two mesoscale activity states delineated in this study may define the degree of engagement of the circuit with the processing of sensory input.

Assessment of Age-Related Differences in Functional Capacity Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT).

Clinical trials for primary prevention and early intervention in preclinical AD require measures of functional capacity with improved sensitivity to deficits in healthier, non-demented individuals. To this end, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) was developed as a direct performance-based assessment of functional capacity that is sensitive to changes in function across multiple populations. Using a realistic virtual reality environment, the VRFCAT assesses a subject's ability to complete instrumental activities associated with a shopping trip. The present investigation represents an initial evaluation of the VRFCAT as a potential co-primary measure of functional capacity in healthy aging and preclinical MCI/AD by examining test-retest reliability and associations with cognitive performance in healthy young and older adults. The VRFCAT was compared and contrasted with the UPSA-2-VIM, a traditional performance-based assessment utilizing physical props. Results demonstrated strong age-related differences in performance on each VRFCAT outcome measure, including total completion time, total errors, and total forced progressions. VRFCAT performance showed strong correlations with cognitive performance across both age groups. VRFCAT Total Time demonstrated good test-retest reliability (ICC=.80 in young adults; ICC=.64 in older adults) and insignificant practice effects, indicating the measure is suitable for repeated testing in healthy populations. Taken together, these results provide preliminary support for the VRFCAT as a potential measure of functionally relevant change in primary prevention and preclinical AD/MCI trials.

Correlation between low levels of estrogen receptors and estrogen responsiveness in two rat osteoblast-like cell lines.

With the knowledge that estrogen replacement therapy can circumvent postmenopausal osteoporosis and with the discovery of estrogen receptors (ER) in cultures of normal osteoblast-like cells, extensive investigations have been directed toward understanding the role of the ER in normal bone homeostasis. ROS 17/2.8 and UMR-106-01, two established osteoblast-like cell lines derived from rat osteosarcomas, have been shown to have estrogen-regulated biologic responses. Only the ROS 17/2.8 cell line has been reported to contain ER. In this study, high-affinity, saturable binding sites characteristic of the ER were detected in UMR-106-01 cells by binding assays with the high-affinity ligand, [125I]17 beta-estradiol. An initial immunoconcentration step before western blot analysis also allowed detection of the full-length ER protein. In addition, northern blot analysis indicated that the entire ER transcript was expressed and that the half-life of the ER message was increased following cycloheximide treatment. Message levels were also regulated by removal of serum and treatment with estradiol. An estrogen-regulated reporter vector, ERET81CAT, was transfected into the UMR-106-01 cells to determine whether the detected level of ER was transcriptionally functional. Using this assay, estrogen responsiveness was evident; however, the response was inconsistent. Multiple factors, such as serum, estradiol, and cell density, influence the ER levels in these cells and probably cause fluctuations in the abundance of receptors available to induce the CAT response. When the cells are responsive, the ICI 164,384 antagonist could block the estrogen-induced activation of CAT.(ABSTRACT TRUNCATED AT 250 WORDS)