The primate cortical LFP exhibits multiple spectral and temporal gradients and widespread task dependence during visual short-term memory.

Although cognitive functions are hypothesized to be mediated by synchronous neuronal interactions in multiple frequency bands among widely distributed cortical areas, we still lack a basic understanding of the distribution and task dependence of oscillatory activity across the cortical map. Here, we ask how the spectral and temporal properties of the local field potential (LFP) vary across the primate cerebral cortex, and how they are modulated during visual short-term memory. We measured the LFP from 55 cortical areas in two macaque monkeys while they performed a visual delayed match to sample task. Analysis of peak frequencies in the LFP power spectra reveals multiple discrete frequency bands between 3 and 80 Hz that differ between the two monkeys. The LFP power in each band, as well as the sample entropy, a measure of signal complexity, display distinct spatial gradients across the cortex, some of which correlate with reported spine counts in cortical pyramidal neurons. Cortical areas can be robustly decoded using a small number of spectral and temporal parameters, and significant task-dependent increases and decreases in spectral power occur in all cortical areas. These findings reveal pronounced, widespread, and spatially organized gradients in the spectral and temporal activity of cortical areas. Task-dependent changes in cortical activity are globally distributed, even for a simple cognitive task.NEW & NOTEWORTHY We recorded extracellular electrophysiological signals from roughly the breadth and depth of a cortical hemisphere in nonhuman primates (NHPs) performing a visual memory task. Analyses of the band-limited local field potential (LFP) power displayed widespread, frequency-dependent cortical gradients in spectral power. Using a machine learning classifier, these features allowed robust cortical area decoding. Further task dependence in LFP power were found to be widespread, indicating large-scale gradients of LFP activity, and task-related activity.

Spawning and maturity traits of coexisting Platycephalidae (Platycephalus caeruleopunctatus, Platycephalus grandispinis, Platycephalus richardsoni) from southeast Australia.

Examination of the spawning and maturity traits of coexisting Platycephalus caeruleopunctatus, Platycephalus grandispinis and Platycephalus richardsoni (Pisces: Platycephalidae) in coastal waters of southeastern Australia identified many commonalities. Each species was gonochoristic, reproductively active for a prolonged period each year, displayed asynchronous oocyte development with indeterminate fecundity and thus likely spawned multiple times throughout each spawning season. Males of all three species matured at smaller total lengths and younger ages than females, with skewed sex ratios reflecting divergent growth characteristics between sexes. Reproductive isolation among species is likely maintained through behavioural and morphological factors as well as species-specific depth-related separation of reproductively active individuals. General similarities in the reproductive strategies of each species and with other sympatric coastal teleosts suggest similar ecological adaptations to a variable coastal environment.

Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection.

Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Gα13 but not Gα12, Gαq, or Gαi. Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P3 KO mouse heart. CYM-51736, an S1P3-specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P3 receptor- and Gα13-mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P3 receptors could provide therapeutic benefits in ischemic heart disease.

CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α.

Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKIIδ isoforms and downstream mechanisms are responsible for the salutary effects of CaMKIIδ gene deletion. In this study we sought to compare the roles of the CaMKIIδB and CaMKIIδC subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKIIδKO, and mice expressing only CaMKIIδB or δC were subjected to ex vivo global ischemia for 25min followed by reperfusion. Infarct formation was assessed at 60min reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKIIδ conferred significant protection from ex vivo I/R. Re-expression of CaMKIIδC in the CaMKIIδKO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKIIδB was protective. Selective activation of CaMKIIδC in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and tumor necrosis factor alpha (TNF-α) expression by CaMKIIδB and CaMKIIδC. Selective activation of CaMKIIδC was also observed and associated with NF-κB activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-κB or TNF-α significantly ameliorated infarct formation in WT mice and those that re-express CaMKIIδC, demonstrating distinct roles for CaMKIIδ subtypes in I/R and implicating acute activation of CaMKIIδC and NF-κB in the pathogenesis of reperfusion injury.

Reductions in the Cardiac Transient Outward K+ Current Ito Caused by Chronic ß-Adrenergic Receptor Stimulation Are Partly Rescued by Inhibition of Nuclear Factor κB.

The fast transient outward potassium current (Ito,f) plays a critical role in the electrical and contractile properties of the myocardium. Ito,f channels are formed by the co-assembly of the pore-forming α-subunits, Kv4.2 and Kv4.3, together with the accessory ß-subunit KChIP2. Reductions of Ito,f are common in the diseased heart, which is also associated with enhanced stimulation of ß-adrenergic receptors (ß-ARs). We used cultured neonatal rat ventricular myocytes to examine how chronic ß-AR stimulation decreases Ito,f. To determine which downstream pathways mediate these Ito,f changes, adenoviral infections were used to inhibit CaMKIIδc, CaMKIIδb, calcineurin, or nuclear factor κB (NF-κB). We observed that chronic ß-AR stimulation with isoproterenol (ISO) for 48 h reduced Ito,f along with mRNA expression of all three of its subunits (Kv4.2, Kv4.3, and KChIP2). Inhibiting either CaMKIIδc nor CaMKIIδb did not prevent the ISO-mediated Ito,f reductions, even though CaMKIIδc and CaMKIIδb clearly regulated Ito,f and the mRNA expression of its subunits. Likewise, calcineurin inhibition did not prevent the Ito,f reductions induced by ß-AR stimulation despite strongly modulating Ito,f and subunit mRNA expression. In contrast, NF-κB inhibition partly rescued the ISO-mediated Ito,f reductions in association with restoration of KChIP2 mRNA expression. Consistent with these observations, KChIP2 promoter activity was reduced by p65 as well as ß-AR stimulation. In conclusion, NF-κB, and not CaMKIIδ or calcineurin, partly mediates the Ito,f reductions induced by chronic ß-AR stimulation. Both mRNA and KChIP2 promoter data suggest that the ISO-induced Ito,f reductions are, in part, mediated through reduced KChIP2 transcription caused by NF-κB activation.

Mitochondrial reprogramming induced by CaMKIIδ mediates hypertrophy decompensation.

RATIONALE: Sustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation. OBJECTIVE: To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq. METHODS AND RESULTS: Compared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion. CONCLUSIONS: Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.

Controlled Penetration of a Novel Dimeric Ceramide into and across the Stratum Corneum Using Microemulsions and Various Types of Semisolid Formulations.

Ceramides (CERs) are integral parts of the intercellular lipid lamellae of the stratum corneum (SC), which is responsible for the barrier function of the skin. Many skin diseases such as atopic dermatitis and psoriasis are associated with the depletion or disturbance of the level of CERs in the SC. Administration of an exogenous novel dimeric ceramide (dCER) deep into the SC may help to stabilize the SC barrier substantially and to treat some skin disease conditions. Consequently, with the help of the existing technology, it might be possible to formulate various pharmaceutical dosage forms that can facilitate penetration of dCER into the SC. Therefore, the penetration of dCER was studied using a high-performance liquid chromatography/atmospheric-pressure ionization/mass spectrometry method for the detection and quantification of exogenous dCER in the SC as well as other skin layers. Penetration studies were carried out in the Franz diffusion cell using excised human skin ex vivo. Penetration of dCER was studied with 3 model formulations: a colloidal formulation (microemulsion), a cream formulation with ethoxydiglycol as penetration enhancer and a nanoformulation. The highest concentrations of dCER in the different skin layers were found after application of the cream with penetration enhancer. Surprisingly, the lowest concentrations of dCER in the different skin layers were found after application of the microemulsion.

Frontoparietal correlation dynamics reveal interplay between integration and segregation during visual working memory.

Working memory requires large-scale cooperation among widespread cortical and subcortical brain regions. Importantly, these processes must achieve an appropriate balance between functional integration and segregation, which are thought to be mediated by task-dependent spatiotemporal patterns of correlated activity. Here, we used cross-correlation analysis to estimate the incidence, magnitude, and relative phase angle of temporally correlated activity from simultaneous local field potential recordings in a network of prefrontal and posterior parietal cortical areas in monkeys performing an oculomotor, delayed match-to-sample task. We found long-range intraparietal and frontoparietal correlations that display a bimodal distribution of relative phase values, centered near 0° and 180°, suggesting a possible basis for functional segregation among distributed networks. Both short- and long-range correlations display striking task-dependent transitions in strength and relative phase, indicating that cognitive events are accompanied by robust changes in the pattern of temporal coordination across the frontoparietal network.

CaMKIIδ mediates ß-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic ß-adrenergic stimulation.

Chronic activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the deleterious effects of ß-adrenergic receptor (ß-AR) signaling on the heart, in part, by enhancing RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) leak. We used CaMKIIδ knockout (CaMKIIδ-KO) mice and knock-in mice with an inactivated CaMKII site S2814 on the ryanodine receptor type 2 (S2814A) to investigate the involvement of these processes in ß-AR signaling and cardiac remodeling. Langendorff-perfused hearts from CaMKIIδ-KO mice showed inotropic and chronotropic responses to isoproterenol (ISO) that were similar to those of wild type (WT) mice; however, in CaMKIIδ-KO mice, CaMKII phosphorylation of phospholamban and RyR2 was decreased and isolated myocytes from CaMKIIδ-KO mice had reduced SR Ca(2+) leak in response to isoproterenol (ISO). Chronic catecholamine stress with ISO induced comparable increases in relative heart weight and other measures of hypertrophy from day 9 through week 4 in WT and CaMKIIδ-KO mice, but the development of cardiac fibrosis was prevented in CaMKIIδ-KO animals. A 4-week challenge with ISO resulted in reduced cardiac function and pulmonary congestion in WT, but not in CaMKIIδ-KO or S2814A mice, implicating CaMKIIδ-dependent phosphorylation of RyR2-S2814 in the cardiomyopathy, independent of hypertrophy, induced by prolonged ß-AR stimulation.

Ca2+/Calmodulin-dependent protein kinase II δ mediates myocardial ischemia/reperfusion injury through nuclear factor-κB.

RATIONALE: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been implicated as a maladaptive mediator of cardiac ischemic injury. We hypothesized that the inflammatory response associated with in vivo ischemia/reperfusion (I/R) is initiated through CaMKII signaling. OBJECTIVE: To assess the contribution of CaMKIIδ to the development of inflammation, infarct, and ventricular dysfunction after in vivo I/R and define early cardiomyocyte-autonomous events regulated by CaMKIIδ using cardiac-specific knockout mice. METHODS AND RESULTS: Wild-type and CaMKIIδ knockout mice were subjected to in vivo I/R by occlusion of the left anterior descending artery for 1 hour followed by reperfusion for various times. CaMKIIδ deletion protected the heart against I/R damage as evidenced by decreased infarct size, attenuated apoptosis, and improved functional recovery. CaMKIIδ deletion also attenuated I/R-induced inflammation and upregulation of nuclear factor-κB (NF-κB) target genes. Further studies demonstrated that I/R rapidly increases CaMKII activity, leading to NF-κB activation within minutes of reperfusion. Experiments using cyclosporine A and cardiac-specific CaMKIIδ knockout mice indicate that NF-κB activation is initiated independent of necrosis and within cardiomyocytes. Expression of activated CaMKII in cardiomyocytes leads to IκB kinase phosphorylation and concomitant increases in nuclear p65. Experiments using an IκB kinase inhibitor support the conclusion that this is a proximal site of CaMKII-mediated NF-κB activation. CONCLUSIONS: This is the first study demonstrating that CaMKIIδ mediates NF-κB activation in cardiomyocytes after in vivo I/R and suggests that CaMKIIδ serves to trigger, as well as to sustain subsequent changes in inflammatory gene expression that contribute to myocardial I/R damage.

Modeling higher-order correlations within cortical microcolumns.

We statistically characterize the population spiking activity obtained from simultaneous recordings of neurons across all layers of a cortical microcolumn. Three types of models are compared: an Ising model which captures pairwise correlations between units, a Restricted Boltzmann Machine (RBM) which allows for modeling of higher-order correlations, and a semi-Restricted Boltzmann Machine which is a combination of Ising and RBM models. Model parameters were estimated in a fast and efficient manner using minimum probability flow, and log likelihoods were compared using annealed importance sampling. The higher-order models reveal localized activity patterns which reflect the laminar organization of neurons within a cortical column. The higher-order models also outperformed the Ising model in log-likelihood: On populations of 20 cells, the RBM had 10% higher log-likelihood (relative to an independent model) than a pairwise model, increasing to 45% gain in a larger network with 100 spatiotemporal elements, consisting of 10 neurons over 10 time steps. We further removed the need to model stimulus-induced correlations by incorporating a peri-stimulus time histogram term, in which case the higher order models continued to perform best. These results demonstrate the importance of higher-order interactions to describe the structure of correlated activity in cortical networks. Boltzmann Machines with hidden units provide a succinct and effective way to capture these dependencies without increasing the difficulty of model estimation and evaluation.

Environmental change drives long-term recruitment and growth variation in an estuarine fish.

How individuals respond to environmental change determines the strength and direction of biological processes like recruitment and growth that underpin population productivity. Ascertaining the relative importance of environmental factors can, however, be difficult given the numerous mechanisms through which they affect individuals. This is especially true in dynamic and complex estuarine environments. Here, we develop long-term otolith-based indices of recruitment and growth for estuary perch Percalates colonorum (Bemm River, Australia), to explore the importance of intrinsic (individual, demographic) and extrinsic (hydrologic, climatic, density-dependent) factors in driving estuarine fish productivity. Analyses involved a novel zero-inflated specification of catch curve regression and mixed effects modelling. The 39 years of recruitment and 46 years of growth data, spanning a period of environmental change including severe drought, displayed considerable inter-annual variation. Recruitment success was strongly related to high freshwater inflows during the spawning season, suggesting that these conditions act as spawning cues for adults and potentially provide favourable conditions for larvae. Individuals displayed age-dependent growth, with highest rates observed at younger ages in years characterized by warm temperatures, and to a lesser degree, greater magnitude base inflow conditions. We detected systematic among-year-class growth differences, but these were not attributable to year class strength, suggesting that environmental conditions experienced by individuals as juveniles can have long-lasting effects of greater importance to population productivity than density-dependent growth responses. The primacy of temperature in driving growth variation highlights that under-appreciated climatic variation can affect estuarine fish productivity through direct physiological and indirect food web mechanisms. We predict that climatic warming will promote individual growth in southerly populations of P. colonorum but concurrently limit recruitment due to forecast reductions in spawning season river discharge. Disparate trait responses are likely in other fishes as they respond to multiple and changing environmental drivers, making predictions of future population productivity challenging.

Thermal limitation of performance and biogeography in a free-ranging ectotherm: insights from accelerometry.

Theoretical and laboratory studies generally show that ectotherm performance increases with temperature to an optimum, and subsequently declines. Several physiological mechanisms probably shape thermal performance curves, but responses of free-ranging animals to temperature variation will represent a compromise between these mechanisms and ecological constraints. Thermal performance data from wild animals balancing physiology and ecology are rare, and this represents a hindrance for predicting population impacts of future temperature change. We used internally implanted accelerometers near the middle of a species' geographical distribution and gill-net catch data near the species' latitudinal extremes to quantify temperature-related activity levels of a wild predatory fish (Platycephalus fuscus). We examined our data in the context of established models of thermal performance, and the relationship between thermal performance thresholds and biogeography. Acceleration data approximated a thermal performance curve, with activity peaking at 23°C but declining rapidly at higher temperatures. Gill-net catch data displayed a similar trend, with a temperature-associated increase and decrease in catch rates in temperate and tropical regions, respectively. Extrapolated estimates of zero activity (CTmin and CTmax) from the accelerometers were similar to the minimum and maximum mean monthly water temperatures experienced at the southern and northern (respectively) limits of the species distribution, consistent with performance-limited biogeography in this species. These data highlight the fundamental influence of temperature on ectotherm performance, and how thermal performance limits may shape biogeography. Biologging approaches are rarely used to examine thermal performance curves in free-ranging animals, but these may be central to understanding the trade-offs between physiology and ecology that constrain species' biogeographies and determine the susceptibility of ectotherms to future increases in temperature.

Supression of testicular function in a male Asian elephant (Elephas maximus) treated with gonadotropin-releasing hormone vaccines.

The ability to control testosterone concentrations and sperm production is of great interest in both Asian (Elephas maximus) and African (Loxodonta africana) elephants. GnRH vaccination may pose an alternative to surgical castration. This is a case report of a male Asian elephant treated with two commercial GnRH vaccines (Equity and Improvac). Beginning at the age of 7 yr, the male was vaccinated monthly for 6 consecutive months, then every 6 mo and, finally, every 12 to 24 mo over a period of 6 yr. In order to evaluate the GnRH vaccine as a potential method of immunologic castration, behavioral observations, testosterone level analysis, body weights, ultrasound examinations, and semen collection were part of the routine monitoring of this bull (no. 1) and a half-brother (bull 2) who remained untreated and served as control. The results showed a decrease in serum testosterone concentrations after the second booster. Levels stayed continuously below 5.0 ng/ml within the study period. The combined testicle diameter of 9.03 +/- 0.3 cm prior to treatment had decreased to a size of 6.93 +/- 0.19 cm (P < 0.001) when measured 2 yr later. Accessory sex gland fluid content disappeared and penile atrophy was observed. Semen collections yielded no spermatozoa 1 yr after the initial treatment. Bull 1 showed slowed weight gain as compared to bull 2 and, due to its friendly temperament and the absence of musth, remained in free contact. This report documents the GnRH vaccine as a possible noninvasive and inexpensive method for immune-castration.

The Primate Cortical LFP Exhibits Multiple Spectral and Temporal Gradients and Widespread Task-Dependence During Visual Short-Term Memory.

Although cognitive functions are hypothesized to be mediated by synchronous neuronal interactions in multiple frequency bands among widely distributed cortical areas, we still lack a basic understanding of the distribution and task dependence of oscillatory activity across the cortical map. Here, we ask how the spectral and temporal properties of the local field potential (LFP) vary across the primate cerebral cortex, and how they are modulated during visual short-term memory. We measured the LFP from 55 cortical areas in two macaque monkeys while they performed a visual delayed match to sample task. Analysis of peak frequencies in the LFP power spectra reveals multiple discrete frequency bands between 3-80 Hz that differ between the two monkeys. The LFP power in each band, as well as the Sample Entropy, a measure of signal complexity, display distinct spatial gradients across the cortex, some of which correlate with reported spine counts in layer 3 pyramidal neurons. Cortical areas can be robustly decoded using a small number of spectral and temporal parameters, and significant task dependent increases and decreases in spectral power occur in all cortical areas. These findings reveal pronounced, widespread and spatially organized gradients in the spectral and temporal activity of cortical areas. Task-dependent changes in cortical activity are globally distributed, even for a simple cognitive task.

Protected Time for Self-Care for Veterans Health Administration (VA) Employees.

OBJECTIVES: Employee Whole Health (EWH) empowers VA employees to take charge of their well-being by integrating self-care into their workday, but employees lack time to participate. METHODS: Employees at three VA medical centers participated in a 12-month feasibility cohort study to protect 60 minutes of time per week for self-care. Questionnaire data was collected at three time points; qualitative data at two time points. Pilot offerings included education and complementary and integrative health modalities for well-being. RESULTS: Employees enrolled spring 2021 (n = 312). Complete-case regression analyses indicated significant improvements in wellness culture, resiliency, self-efficacy, perceived stress, and flourishing at twelve months. Multiple imputation analyses confirmed improvements except for self-efficacy. Qualitative findings supported quantitative findings. CONCLUSIONS: Providing protected time for self-care was feasible and supported improvements in well-being. However, high workload was identified as an ongoing barrier to participation.

Volumetric mesoscopic electrophysiology: a new imaging modality for the non-human primate.

The primate brain is a densely interconnected organ whose function is best understood by recording from the entire structure in parallel, rather than parts of it in sequence. However, available methods either have limited temporal resolution (functional magnetic resonance imaging), limited spatial resolution (macroscopic electroencephalography), or a limited field of view (microscopic electrophysiology). To address this need, we developed a volumetric, mesoscopic recording approach ( MePhys ) by tessellating the volume of a monkey hemisphere with 992 electrode contacts that were distributed across 62 chronically implanted multi-electrode shafts. We showcase the scientific promise of MePhys by describing the functional interactions of local field potentials between the more than 300,000 simultaneously recorded pairs of electrodes. We find that a subanesthetic dose of ketamine -believed to mimic certain aspects of psychosis- can create a pronounced state of functional disconnection and prevent the formation of stable large-scale intrinsic states. We conclude that MePhys provides a new and fundamentally distinct window into brain function whose unique profile of strengths and weaknesses complements existing approaches in synergistic ways.

Rain reverses diel activity rhythms in an estuarine teleost.

Activity rhythms are ubiquitous in nature, and generally synchronized with the day-night cycle. Several taxa have been shown to switch between nocturnal and diurnal activity in response to environmental variability, and these relatively uncommon switches provide a basis for greater understanding of the mechanisms and adaptive significance of circadian (approx. 24 h) rhythms. Plasticity of activity rhythms has been identified in association with a variety of factors, from changes in predation pressure to an altered nutritional or social status. Here, we report a switch in activity rhythm that is associated with rainfall. Outside periods of rain, the estuarine-associated teleost Acanthopagrus australis was most active and in shallower depths during the day, but this activity and depth pattern was reversed in the days following rain, with diurnality restored as estuarine conductivity and turbidity levels returned to pre-rain levels. Although representing the first example of a rain-induced reversal of activity rhythm in an aquatic animal of which we are aware, our results are consistent with established models on the trade-offs between predation risk and foraging efficiency.

Location matters: clarifying the concept of nuclear and cytosolic CaMKII subtypes.

RATIONALE: Differential effects of δ(B) and δ(C) subtypes of Ca²âº/calmodulin-dependent protein kinase (CaMKII) on cardiomyocyte Ca²âº handling and survival have been suggested to result from their respective nuclear versus cytosolic localizations. CaMKIIδ subtype localization and its relationship to enzyme activation and target phosphorylation have not, however, been systematically evaluated. OBJECTIVE: To determine whether CaMKIIδ subtypes are restricted to a particular subcellular location and assess the relationship of localization to enzyme activation and function. METHODS AND RESULTS: CaMKIIδ is highly expressed in mouse heart and cardiomyocytes and concentrated in sarcoplasmic reticulum (SR)/membrane and nuclear fractions. CaMKIIδ(B) and δ(C) subtypes differ by a nuclear localization sequence, but both are present in nuclear and SR/membrane fractions. Nonselective subtype distribution is also seen in mice overexpressing CaMKIIδ(B) or δ(C), even in a CaMKIIδ null background. Fluorescently tagged CaMKIIδ(B) expressed in cardiomyocytes concentrates in nuclei whereas δ(C) concentrates in cytosol, but neither localization is exclusive. Mouse hearts exposed to phenylephrine show selective CaMKIIδ activation in the nuclear (versus SR) compartment, whereas caffeine selectively activates CaMKIIδ in SR (versus nuclei), independent of subtype. Compartmentalized activation extends to functional differences in target phosphorylation at CaMKII sites: phenylephrine increases histone deacetylase 5 phosphorylation (Ser498) but not phospholamban (Thr17), whereas the converse holds for caffeine. CONCLUSIONS: These studies demonstrate that CaMKIIδ(B) and δ(C) are not exclusively restricted to the nucleus and cytosol and that spatial and functional specificity in CaMKIIδ activation is elicited by mobilization of different Ca²âº stores rather than by compartmentalized subtype localization.

Predicting reliability through structured expert elicitation with the repliCATS (Collaborative Assessments for Trustworthy Science) process.

As replications of individual studies are resource intensive, techniques for predicting the replicability are required. We introduce the repliCATS (Collaborative Assessments for Trustworthy Science) process, a new method for eliciting expert predictions about the replicability of research. This process is a structured expert elicitation approach based on a modified Delphi technique applied to the evaluation of research claims in social and behavioural sciences. The utility of processes to predict replicability is their capacity to test scientific claims without the costs of full replication. Experimental data supports the validity of this process, with a validation study producing a classification accuracy of 84% and an Area Under the Curve of 0.94, meeting or exceeding the accuracy of other techniques used to predict replicability. The repliCATS process provides other benefits. It is highly scalable, able to be deployed for both rapid assessment of small numbers of claims, and assessment of high volumes of claims over an extended period through an online elicitation platform, having been used to assess 3000 research claims over an 18 month period. It is available to be implemented in a range of ways and we describe one such implementation. An important advantage of the repliCATS process is that it collects qualitative data that has the potential to provide insight in understanding the limits of generalizability of scientific claims. The primary limitation of the repliCATS process is its reliance on human-derived predictions with consequent costs in terms of participant fatigue although careful design can minimise these costs. The repliCATS process has potential applications in alternative peer review and in the allocation of effort for replication studies.