Differential brain activity during emotional versus nonemotional reversal learning

The ability to change an established stimulus–behavior association based on feedback is critical for adaptive social behaviors. This ability has been examined in reversal learning tasks, where participants first learn a stimulus–response association (e.g., select a particular object to get a reward) and then need to alter their response when reinforcement contingencies change. Although substantial evidence demonstrates that the OFC is a critical region for reversal learning, previous studies have not distinguished reversal learning for emotional associations from neutral associations. The current study examined whether OFC plays similar roles in emotional versus neutral reversal learning. The OFC showed greater activity during reversals of stimulus–outcome associations for negative outcomes than for neutral outcomes. Similar OFC activity was also observed during reversals involving positive outcomes. Furthermore, OFC activity is more inversely correlated with amygdala activity during negative reversals than during neutral reversals. Overall, our results indicate that the OFC is more activated by emotional than neutral reversal learning and that OFC's interactions with the amygdala are greater for negative than neutral reversal learning.

Impact of the enhanced permeability and retention (EPR) effect and cathepsins levels on the activity of polymer-drug conjugates

Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i) the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR) effect) and (ii) the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B). Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates). An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer), although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.

Divergent evolution of the activity and regulation of the glutamate decarboxylase systems in Listeria monocytogenes EGD-e and 10403S : roles in virulence and acid tolerance

The glutamate decarboxylase (GAD) system has been shown to be important for the survival of Listeria monocytogenes in low pH environments. The bacterium can use this faculty to maintain pH homeostasis under acidic conditions. The accepted model for the GAD system proposes that the antiport of glutamate into the bacterial cell in exchange for γ-aminobutyric acid (GABA) is coupled to an intracellular decarboxylation reaction of glutamate into GABA that consumes protons and therefore facilitates pH homeostasis. Most strains of L. monocytogenes possess three decarboxylase genes (gadD1, D2 & D3) and two antiporter genes (gadT1 & gadT2). Here, we confirm that the gadD3 encodes a glutamate decarboxylase dedicated to the intracellular GAD system (GADi), which produces GABA from cytoplasmic glutamate in the absence of antiport activity. We also compare the functionality of the GAD system between two commonly studied reference strains, EGD-e and 10403S with differences in terms of acid resistance. Through functional genomics we show that EGD-e is unable to export GABA and relies exclusively in the GADi system, which is driven primarily by GadD3 in this strain. In contrast 10403S relies upon GadD2 to maintain both an intracellular and extracellular GAD system (GADi/GADe). Through experiments with a murinised variant of EGD-e (EGDm) in mice, we found that the GAD system plays a significant role in the overall virulence of this strain. Double mutants lacking either gadD1D3 or gadD2D3 of the GAD system displayed reduced acid tolerance and were significantly affected in their ability to cause infection following oral inoculation. Since EGDm exploits GADi but not GADe the results indicate that the GADi system makes a contribution to virulence within the mouse. Furthermore, we also provide evidence that there might be a separate line of evolution in the GAD system between two commonly used reference strains.

Ground-based and satellite observations of high-latitude auroral activity in the dusk sector of the auroral oval

On 7 December 2000, during 13:30-15:30 UT the MIRACLE all-sky camera at Ny Alesund observed auroras at high-latitudes (MLAT similar to 76) simultaneously when the Cluster spacecraft were skimming the magnetopause in the same MLT sector (at similar to 16:00-18:00 MLT). The location of the auroras (near the ionospheric convection reversal boundary) and the clear correlation between their dynamics and IMF variations suggests their close relationship with R1 currents. Consequently, we can assume that the Cluster spacecraft were making observations in the magnetospheric region associated with the auroras, although exact magnetic conjugacy between the ground-based and satellite observations did not exist. The solar wind variations appeared to control both the behaviour of the auroras and the magnetopause dynamics. Auroral structures were observed at Ny Alesund especially during periods of negative IMF B-Z. In addition, the Cluster spacecraft experienced periodic (T similar to 4 - 6 min) encounters between magnetospheric and magnetosheath plasmas. These undulations of the boundary can be interpreted as a consequence of tailward propagating magnetopause surface waves. Simultaneous dusk sector ground-based observations show weak, but discernible magnetic pulsations (Pc 5) and occasionally periodic variations (T - 2 - 3 min) in the high-latitude auroras. In the dusk sector, Pc 5 activity was stronger and had characteristics that were consistent with a field line resonance type of activity. When IMF BZ stayed positive for a longer period, the auroras were dimmer and the spacecraft stayed at the outer edge of the magnetopause where they observed electromagnetic pulsations with T similar to 1 min. We find these observations interesting especially from the viewpoint of previously presented studies relating poleward-moving high-latitude auroras with pulsation activity and MHD waves propagating at the magnetospheric boundary layers.

The response of ionospheric convection in the polar cap to substorm activity

We report multi-instrument observations during an isolated substorm on 17 October 1989. The EISCAT radar operated in the SP-UK-POLI mode measuring ionospheric convection at latitudes 71°-78°. SAMNET and the EISCAT Magnetometer Cross provide information on the timing of substorm expansion phase onset and subsequent intensifications, as well as the location of the field aligned and ionospheric currents associated with the substorm current wedge. IMP-8 magnetic field data are also included. Evidence of a substorm growth phase is provided by the equatorward motion of a flow reversal boundary across the EISCAT radar field of view at 2130 MLT, following a southward turning of the interplanetary magnetic field (IMF). We infer that the polar cap expanded as a result of the addition of open magnetic flux to the tail lobes during this interval. The flow reversal boundary, which is a lower limit to the polar cap boundary, reached an invariant latitude equatorward of 71° by the time of the expansion phase onset. A westward electrojet, centred at 65.4°, occurred at the onset of the expansion phase. This electrojet subsequently moved poleward to a maximum of 68.1° at 2000 UT and also widened. During the expansion phase, there is evidence of bursts of plasma flow which are spatially localised at longitudes within the substorm current wedge and which occurred well poleward of the westward electrojet. We conclude that the substorm onset region in the ionosphere, defined by the westward electrojet, mapped to a part of the tail radially earthward of the boundary between open and closed magnetic flux, the “distant” neutral line. Thus the substorm was not initiated at the distant neutral line, although there is evidence that it remained active during the expansion phase. It is not obvious whether the electrojet mapped to a near-Earth neutral line, but at its most poleward, the expanded electrojet does not reach the estimated latitude of the polar cap boundary.

EISCAT observations of unusual flows in the morning sector associated with weak substorm activity

A discussion is given of plasma flows in the dawn and nightside high-latitude ionospheric regions during substorms occurring on a contracted auroral oval, as observed using the EISCAT CP-4-A experiment. Supporting data from the PACE radar, Greenland magnetometer chain, SAMNET magnetometers and geostationary satellites are compared to the EISCAT observations. On 4 October 1989 a weak substorm with initial expansion phase onset signatures at 0030 UT, resulted in the convection reversal boundary observed by EISCAT (at \sim0415 MLT) contracting rapidly poleward, causing a band of elevated ionospheric ion temperatures and a localised plasma density depletion. This polar cap contraction event is shown to be associated with various substorm signatures; Pi2 pulsations at mid-latitudes, magnetic bays in the midnight sector and particle injections at geosynchronous orbit. A similar event was observed on the following day around 0230 UT (\sim0515 MLT) with the unusual and significant difference that two convection reversals were observed, both contracting poleward. We show that this feature is not an ionospheric signature of two active reconnection neutral lines as predicted by the near-Earth neutral model before the plasmoid is “pinched off”, and present two alternative explanations in terms of (1) viscous and lobe circulation cells and (2) polar cap contraction during northward IMF. The voltage associated with the anti-sunward flow between the reversals reaches a maximum of 13 kV during the substorm expansion phase. This suggests it to be associated with the polar cap contraction and caused by the reconnection of open flux in the geomagnetic tail which has mimicked “viscous-like” momentum transfer across the magnetopause.

A palaeoenvironmental context for terminal upper Palaeolithic and Mesolithic activity in the Colne Valley: offsite records contemporary with occupation at three ways Wharf, Uxbridge

Multi-proxy analyses from floodplain deposits in the Colne Valley, southern England, have provided a palaeoenvironmental context for the immediately adjacent Terminal Upper Palaeolithic and Early Mesolithic site of Three Ways Wharf. These deposits show the transition from an open cool environment to fully developed heterogeneous floodplain vegetation during the Early Mesolithic. Several distinct phases of burning are shown to have occurred that are chronologically contemporary with the local archaeological record. The floodplain itself is shown to have supported a number of rare Urwaldrelikt insect species implying human manipulation of the floodplain at this time must have been limited or episodic. By the Late Mesolithic a reed-sedge swamp had developed across much of the floodplain, within which repeated burning of the in situ vegetation took place. This indicates deliberate land management practices utilising fire, comparable with findings from other floodplain sequences in southern Britain. With similar sedimentary sequences known to exist across the Colne Valley, often closely associated with contemporary archaeology, the potential for placing the archaeological record within a spatially explicit palaeoenvironmental context is great.

GRID and docking analyses reveal a molecular basis for flavonoid inhibition of src-family kinase activity

Flavonoids reduce cardiovascular disease risk through anti-inflammatory, anti-coagulant and anti-platelet actions. One key flavonoid inhibitory mechanism is blocking kinase activity that drives these processes. Flavonoids attenuate activities of kinases including phosphoinositide-3-kinase (PI3K), Fyn, Lyn, Src, Syk, PKC, PIM1/2, ERK, JNK, and PKA. X-ray crystallographic analyses of kinase-flavonoid complexes show that flavonoid ring systems and their hydroxyl substitutions are important structural features for their binding to kinases. A clearer understanding of structural interactions of flavonoids with kinases is necessary to allow construction of more potent and selective counterparts. We examined flavonoid (quercetin, apigenin and catechin) interactions with Src-family kinases (Lyn, Fyn and Hck) applying the Sybyl docking algorithm and GRID. A homology model (Lyn) was used in our analyses to demonstrate that high quality predicted kinase structures are suitable for flavonoid computational studies. Our docking results revealed potential hydrogen bond contacts between flavonoid hydroxyls and kinase catalytic site residues. Identification of plausible contacts indicated that quercetin formed the most energetically stable interactions, apigenin lacked hydroxyl groups necessary for important contacts, and the non-planar structure of catechin could not support predicted hydrogen bonding patterns. GRID analysis using a hydroxyl functional group supported docking results. Based on these findings, we predicted that quercetin would inhibit activities of Src-family kinases with greater potency than apigenin and catechin. We validated this prediction using in vitro kinase assays. We conclude that our study can be used as a basis to construct virtual flavonoid interaction libraries to guide drug discovery using these compounds as molecular templates.

Future changes in the Western North Pacific tropical cyclone activity projected by a multidecadal simulation with a 16-km global atmospheric GCM

How tropical cyclone (TC) activity in the northwestern Pacific might change in a future climate is assessed using multidecadal Atmospheric Model Intercomparison Project (AMIP)-style and time-slice simulations with the ECMWF Integrated Forecast System (IFS) at 16-km and 125-km global resolution. Both models reproduce many aspects of the present-day TC climatology and variability well, although the 16-km IFS is far more skillful in simulating the full intensity distribution and genesis locations, including their changes in response to El Niño–Southern Oscillation. Both IFS models project a small change in TC frequency at the end of the twenty-first century related to distinct shifts in genesis locations. In the 16-km IFS, this shift is southward and is likely driven by the southeastward penetration of the monsoon trough/subtropical high circulation system and the southward shift in activity of the synoptic-scale tropical disturbances in response to the strengthening of deep convective activity over the central equatorial Pacific in a future climate. The 16-km IFS also projects about a 50% increase in the power dissipation index, mainly due to significant increases in the frequency of the more intense storms, which is comparable to the natural variability in the model. Based on composite analysis of large samples of supertyphoons, both the development rate and the peak intensities of these storms increase in a future climate, which is consistent with their tendency to develop more to the south, within an environment that is thermodynamically more favorable for faster development and higher intensities. Coherent changes in the vertical structure of supertyphoon composites show system-scale amplification of the primary and secondary circulations with signs of contraction, a deeper warm core, and an upward shift in the outflow layer and the frequency of the most intense updrafts. Considering the large differences in the projections of TC intensity change between the 16-km and 125-km IFS, this study further emphasizes the need for high-resolution modeling in assessing potential changes in TC activity.

Freezing skeletal muscle tissue does not affect its decomposition in soil: Evidence from temporal changes in tissue mass, microbial activity and soil chemistry based on excised samples

The study of decaying organisms and death assemblages is referred to as forensic taphonomy, or more simply the study of graves. This field is dominated by the fields of entomology, anthropology and archaeology. Forensic taphonomy also includes the study of the ecology and chemistry of the burial environment. Studies in forensic taphonomy often require the use of analogues for human cadavers or their component parts. These might include animal cadavers or skeletal muscle tissue. However, sufficient supplies of cadavers or analogues may require periodic freezing of test material prior to experimental inhumation in the soil. This study was carried out to ascertain the effect of freezing on skeletal muscle tissue prior to inhumation and decomposition in a soil environment under controlled laboratory conditions. Changes in soil chemistry were also measured. In order to test the impact of freezing, skeletal muscle tissue (Sus scrofa) was frozen (−20 °C) or refrigerated (4 °C). Portions of skeletal muscle tissue (∼1.5 g) were interred in microcosms (72 mm diameter × 120 mm height) containing sieved (2 mm) soil (sand) adjusted to 50% water holding capacity. The experiment had three treatments: control with no skeletal muscle tissue, microcosms containing frozen skeletal muscle tissue and those containing refrigerated tissue. The microcosms were destructively harvested at sequential periods of 2, 4, 6, 8, 12, 16, 23, 30 and 37 days after interment of skeletal muscle tissue. These harvests were replicated 6 times for each treatment. Microbial activity (carbon dioxide respiration) was monitored throughout the experiment. At harvest the skeletal muscle tissue was removed and the detritosphere soil was sampled for chemical analysis. Freezing was found to have no significant impact on decomposition or soil chemistry compared to unfrozen samples in the current study using skeletal muscle tissue. However, the interment of skeletal muscle tissue had a significant impact on the microbial activity (carbon dioxide respiration) and chemistry of the surrounding soil including: pH, electroconductivity, ammonium, nitrate, phosphate and potassium. This is the first laboratory controlled study to measure changes in inorganic chemistry in soil associated with the decomposition of skeletal muscle tissue in combination with microbial activity.

Defining key structural determinants for the pro-osteogenic activity of flavonoids

Epidemiological studies suggest that fruits and vegetables may play a role in promoting bone growth and preventing age-related bone loss, attributable, at least in part, to phytochemicals such as flavonoids stimulating osteoblastogenesis. Through systematically screening the effect of flavonoids on the osteogenic differentiation of human mesenchymal stem cells in vitro, and correlating activity with chemical structure using comparative molecular field analysis, we have successfully identified important structural features which relate to their activity, as well as reliably predicting the activity of compounds with unknown activity. Contour maps emphasised the importance of electronegativity, steric bulk, and a 2-C-3-C double bond at the flavonoid C-ring, as well as overall electropositivity and reduced steric bulk at the flavonoid B-ring. These results support a role for certain flavonoids in promoting osteogenic differentiation, thus their potential for preventing skeletal deterioration, as well as providing a foundation for the lead optimisation of novel bone anabolics.

Induction of cold active acid phosphomonoesterase activity at low temperature in psychrotrophic ectomycorrhizal Hebeloma spp.

Hebeloma strains of arctic and temperature origin, grown at 22° or 6°, were assayed for wall-bound and extracellular acid phosphomonoesterase (pNPPase) across a temperature range 2-37°. Only when grown at 6° was a cold active extracellular pNPPase induced in all the arctic strains and most of the temperature strains tested. Such enzymes are suggested to be a adaptation to low soil temperatures, and are discussed in the context of ectomycorrhizal access to soil PO4− monoesters at low temperature.

Changes in physical activity following a genetic-based internet-delivered personalized intervention: randomized controlled trial (Food4Me)

Background: There is evidence that physical activity (PA) can attenuate the influence of the fat mass- and obesity-associated (FTO) genotype on the risk to develop obesity. However, whether providing personalized information on FTO genotype leads to changes in PA is unknown. Objective: The purpose of this study was to determine if disclosing FTO risk had an impact on change in PA following a 6-month intervention. Methods: The single nucleotide polymorphism (SNP) rs9939609 in the FTO gene was genotyped in 1279 participants of the Food4Me study, a four-arm, Web-based randomized controlled trial (RCT) in 7 European countries on the effects of personalized advice on nutrition and PA. PA was measured objectively using a TracmorD accelerometer and was self-reported using the Baecke questionnaire at baseline and 6 months. Differences in baseline PA variables between risk (AA and AT genotypes) and nonrisk (TT genotype) carriers were tested using multiple linear regression. Impact of FTO risk disclosure on PA change at 6 months was assessed among participants with inadequate PA, by including an interaction term in the model: disclosure (yes/no) × FTO risk (yes/no). Results: At baseline, data on PA were available for 874 and 405 participants with the risk and nonrisk FTO genotypes, respectively. There were no significant differences in objectively measured or self-reported baseline PA between risk and nonrisk carriers. A total of 807 (72.05%) of the participants out of 1120 in the personalized groups were encouraged to increase PA at baseline. Knowledge of FTO risk had no impact on PA in either risk or nonrisk carriers after the 6-month intervention. Attrition was higher in nonrisk participants for whom genotype was disclosed (P=.01) compared with their at-risk counterparts. Conclusions: No association between baseline PA and FTO risk genotype was observed. There was no added benefit of disclosing FTO risk on changes in PA in this personalized intervention. Further RCT studies are warranted to confirm whether disclosure of nonrisk genetic test results has adverse effects on engagement in behavior change.

Seasonal forecasts of tropical cyclone activity in a high-atmospheric-resolution coupled prediction system

Seasonal forecast skill of the basinwide and regional tropical cyclone (TC) activity in an experimental coupled prediction system based on the ECMWF System 4 is assessed. As part of a collaboration between the Center for Ocean–Land–Atmosphere Studies (COLA) and the ECMWF called Project Minerva, the system is integrated at the atmospheric horizontal spectral resolutions of T319, T639, and T1279. Seven-month hindcasts starting from 1 May for the years 1980–2011 are produced at all three resolutions with at least 15 ensemble members. The Minerva system demonstrates statistically significant skill for retrospective forecasts of TC frequency and accumulated cyclone energy (ACE) in the North Atlantic (NA), eastern North Pacific (EP), and western North Pacific. While the highest scores overall are achieved in the North Pacific, the skill in the NA appears to be limited by an overly strong influence of the tropical Pacific variability. Higher model resolution improves skill scores for the ACE and, to a lesser extent, the TC frequency, even though the influence of large-scale climate variations on these TC activity measures is largely independent of resolution changes. The biggest gain occurs in transition from T319 to T639. Significant skill in regional TC forecasts is achieved over broad areas of the Northern Hemisphere. The highest-resolution hindcasts exhibit additional locations with skill in the NA and EP, including land-adjacent areas. The feasibility of regional intensity forecasts is assessed. In the presence of the coupled model biases, the benefits of high resolution for seasonal TC forecasting may be underestimated.