(C) 2011 Elsevier Inc All rights reserved “
“Although vario

(C) 2011 Elsevier Inc. All rights reserved.”
“Although various cultured cells are used for propagating influenza A viruses, the types of cells which can support replication of and plague production by low pathogenic avian influenza (LPAI) viruses without supplementary trypsin are limited. In this study, the infectivity and growth kinetics of as well as plaque production by LPAI viruses in Caco-2 cells were investigated. The suitability of this cell line for virus isolation

was examined and compared with virus isolation in embryonated chicken eggs. Generation of Caco-2 mediated viral variants, if any, was assessed phenotypically and genotypically. It was found that Caco-2 cells can readily support continued replication of LPAI viruses without supplementary trypsin. Viruses replicate to high titer compared SB431542 ic50 to embryonated chicken eggs, and more efficiently

than in MDCK cells, without trypsin. Also, GSK621 in vitro LPAI viruses produced plagues in Caco-2 cells. However, these cells were found to be less sensitive than embryonated chicken eggs for virus isolation. Notably, no phenotypic and genotypic changes of the viruses were observed during viral passages (at least up to 10th passage) in Caco-2 cells. These findings indicate that Caco-2 cells may provide an appropriate substrate for studying and cultivating AIVs. (C) 2010 Elsevier B.V. All rights reserved.”
“The development of major depression requires both genetic and environmental factors. A brain proteomic investigation on the genetic model of Flinders sensitive and resistant line (FSL-FRL) rats was performed. Maternal separation (MS) was also applied to identify protein networks affected by stress exposure, since early-life trauma is considered an important antecedent of depression. Hippocampus

(HIP) and prefrontal/frontal cortex proteins were extracted and separated FG-4592 chemical structure by 2-Dimensional (2-D) gel electrophoresis. After image analysis, significantly modulated proteins in the different conditions analysed were identified by mass spectrometry. The expression of proteins involved in energy metabolism, cellular localization and transport, cytoskeleton organization and apoptosis differed in the two lines. Maternal separation differently affected the genetic backgrounds, by modulating cytoskeleton and neuron morphogenesis proteins in FSL; energy metabolism, cellular localization, neuron differentiation and intracellular transport in FRL. The present work shows that different mechanisms could be involved in the pathophysiology of depression and the vulnerability to stress, suggesting possible new cellular pathways and key markers for the study of affective disorders. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”
“A loop-mediated isothermal amplification (LAMP) assay was developed specifically for detection and differentiation of pseudorabies virus (PRV).

The floral transition of Cardamine flexuosa, a herbaceous biennia

The floral transition of Cardamine flexuosa, a herbaceous biennial-to-perennial plant, requires exposure to cold temperature, a treatment known as vernalization. C. buy Batimastat flexuosa younger than 5 weeks old are not fully responsive to cold treatment.

We demonstrate that the levels of two age-regulated microRNAs, miR156 and miR172, regulate the timing of sensitivity in response to vernalization. Age and vernalization pathways coordinately regulate flowering through modulating the expression of CfSOC1, a flower-promoting MADS-box gene. The related annual Arabidopsis thaliana, which has both vernalization and age pathways, does not possess an age-dependent vernalization response. Thus, the recruitment of age cue in response to environmental signals contributes to the evolution of life cycle in plants.”
“The mTOR complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act through the Rag guanosine triphosphatases (GTPases) to promote mTORC1 translocation to the lysosomal surface, its site of activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors also exist. Here, we identify GATOR as a complex that interacts with

the Rags and is composed of two subcomplexes we call GATOR1 and -2. Inhibition of GATOR1 subunits beta-catenin inhibitor (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24,

WDR59, Seh1L, and Sec13) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive LDC000067 concentration to rapamycin, an mTORC1 inhibitor. Thus, we identify a key negative regulator of the Rag GTPases and reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer.”
“alpha-Tocopherol (vitamin E) transfer protein (alpha-7P) regulates the secretion of a-tocopherol from liver cells. Missense mutations of some arginine residues at the surface of alpha-TIP cause severe vitamin E deficiency in humans, but the role of these residues is unclear. Here, we found that wild-type a-UP bound phosphatidylinositol phosphates (PIPs), whereas the arginine mutants did not. In addition, PIPs in the target membrane promoted the intermembrane transfer of alpha-tocopherot by alpha-UP. The crystal structure of the alpha-UP PIPs complex revealed that the disease-related arginine residues interacted with phosphate groups of the PIPs and that the PIPs binding caused the lid of the alpha-tocopherol binding pocket to open. Thus, PIPs have a rote in promoting the release of a ligand from a lipid-transfer protein.

The types of items preferred also shifted with

condition,

The types of items preferred also shifted with

condition, with subjects only being biased toward expensive items when instructed to maximize profit. Item preferences even differed depending on whether participants were acquiring versus removing items, even though the task only differed superficially in the two conditions. Acquisitiveness reflects a complex mix of affective, cognitive, and personality factors that extend well beyond the drive to acquire valuable resources, with important implications for basic decision science, sustainability, and pathologies associated with compulsive acquisition. (C) 2012 Elsevier Ltd. All rights reserved.”
“Islets produce a variety of cytokines and chemokines in response to physiologic and pathologic stimulation find more by nutrients. The cellular source of these inflammatory mediators includes alpha-, beta-, endothelial-, ductal- and recruited immune cells. Islet-derived cytokines promote alpha- and beta-cell adaptation and repair in the short term. Eventually, chronic metabolic stress can induce a deleterious autoinflammatory process in islets leading to insulin secretion

failure and type 2 diabetes. Understanding the specific role of islet derived cytokines and chemokines has opened the door to targeted clinical interventions aimed at remodeling islet inflammation from destruction to adaptation. In this article, we review the islet cellular origin of various cytokines and chemokines and describe their regulation and respective roles in physiology and diabetes.”
“We GSK621 chemical structure compared the effects of bilateral amygdala, hippocampal or orbital frontal cortex lesions on emotional and hormonal reactivity in rhesus monkeys (Macaca mulatta). Experiment 1 measured behavioral

reactivity to an unfamiliar human intruder before and after surgery. Animals with amygdala lesions demonstrated decreases in one passive defensive behavior (freezing), whereas animals with hippocampal lesions showed decreases in a more stimulus-directed defensive Megestrol Acetate behavior (tooth grinding). Orbital frontal cortex lesions also reduced these two defensive behaviors, as well as decreased cage-shaking dominance displays. Animals with amygdala, hippocampal or sham lesions also demonstrated increased tension-related behaviors after surgery, but those with orbital frontal lesions did not. Finally, all three lesions diminished the operated animals’ ability to modulate tension-related behaviors depending on the magnitude of threat posed by the human intruder. Experiment 2 measured circulating levels of cortisol and testosterone when a subset of these same animals was at rest and following physical restraint, temporary isolation, exposure to threatening objects and social interactions with an unfamiliar conspecific. None of the lesions impacted on testosterone levels in any condition.

Methods: 66 patients having CKD stage 3-5 were included in the st

Methods: 66 patients having CKD stage 3-5 were included in the study. Nine consecutive measurements were made according to the ESH-IP2 protocol. Results: The Omron M3 Intellisense device fulfills the validation Semaxanib nmr criteria of the ESH-1P2 for stage 3-5 CKD patients. Conclusion: Although arterial stiffness can affect accurate BP measurement, there are limited data

regarding the use of automated oscillometric devices in CKD. To our knowledge, this is the first study investigating validation of an oscillometric device in stage 3-5 predialysis CKD patients. This study validates the Omron M3 Intellisense upper arm device for stage 3-5 CKD patients. New validation studies investigating other oscillometric sphygmomanometers for CKD patients and involvement of nephrologists in these studies

have great potential to increase patient care in CKD. Copyright (C) 2011 CH5183284 mouse S. Karger AG, Basel”
“Hydrogen sulfide (H2S), an endogenous gasotransmitter, modulates various biological functions, including nociception. It is known that H2S causes neurogenic inflammation and elicits hyperalgesia. Here we show that H2S activates mouse transient receptor potential ankyrin 1 (TRPA1) channels and elicits acute pain, using TRPA1-gene deficient mice (TRPA1(-/-)) and heterologous expression system. In wild-type mouse sensory neurons, H2S increased the intracellular Ca2+ concentration ([Ca2+](i)), which THZ1 molecular weight was inhibited by ruthenium red (a nonselective TRP channel blocker) and HC-030031 (a TRPA1 blocker). H2S-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. [Ca2+](i) responses to H2S were observed in neurons from transient receptor potential vanilloid 1 (TRPV1(-/-)) mice but not from TRPA1(-/-) mice. Heterologously expressed mouse TRPA1, but not mouse TRPV1, was activated by H2S. H2S-induced [Ca2+](i) responses were inhibited by dithiothreitol, a reducing agent. Analyses of the TRPA1 mutant channel revealed that two cysteine residues located in the N-terminal internal

domain were responsible for the activation by H2S. Intraplantar injection of H2S into the mouse hind paw caused acute pain which was significantly less in TRPA1(-/-) mice. The [Ca2+](i); responses to H2S in sensory neurons and in heterologously expressed channels, and pain-related behavior induced by H2S were enhanced under acidic conditions. These results suggest that H2S functions as a nociceptive messenger through the activation of TRPA1 channels. TRPA1 may be a therapeutic target for H2S-related algesic action, especially under inflammatory conditions. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons.

e , difficulties to form a coherent narrative consisting of an or

e., difficulties to form a coherent narrative consisting of an ordered sequence of events). Participants with depersonalization disorder (n = 14) and healthy control participants (n = 14) viewed an emotional video clip while their skin conductance (SC) levels were measured. Peritraumatic dissociation was measured before and after the clip, and memory performance was measured

35 min after viewing. Compared to controls, depersonalized participants exhibited a distinctly different ABT-737 datasheet temporal pattern of autonomic responding, characterized by an earlier peak and subsequent flattening of SCLs. Maximum SCLs did not differ between the two groups. Moreover, unlike the control group, depersonalized participants showed no SC recovery after clip offset. In terms of memory performance, patients exhibited objective memory fragmentation, which they also reported subjectively. However, they did not differ from controls in free recall performance.

Apparently, emotional responding in DPD is characterized by a shortened latency to peak with subsequent flattening and is accompanied by memory fragmentation in the light of otherwise unremarkable memory functioning. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“The present study aimed to investigate whether side differences in olfactory bulb (OB) volume correlate to respective differences learn more in olfactory function. In a total of 164 healthy volunteers volumetric measures of the OBs were performed plus lateralized measurements of odor thresholds and odor discrimination. Side differences were defined as 10% difference between the left and right

OB. In 39 cases volumes on the right side were larger than Selleck BLZ945 on the left side, whereas in 29 cases it was the other way around. Subjects with larger right-sided OB volumes were found to be more sensitive to odorous stimulation of the right as compared to the left nostril in terms of odor thresholds and odor detection; higher sensitivity of the left nostrils (decreased odor threshold) was observed in individuals with larger OB volumes on the left side. These data appear to suggest that OB volume may be partly dependent on lateralized influences on the olfactory system, reflecting its lateralized organization. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.”
“An H5N1 avian influenza virus (AIV) designated A/Parrot/Guangdong/C99/2005 (H5N1) was first isolated from a sick parrot in Guangdong in southern China in 2005. The complete genome of this strain was analyzed. Genome sequence analysis showed that all 8 gene segments of the virus nucleotide had 99.0% homology to A/chicken/Henan/12/2004 (H5N1). Phylogenetic analysis demonstrated that all 8 gene segments of the virus were derived from the Eurasian lineage.

Age, sex and the presence of DM, hypertension, hyperlipidaemia, s

Age, sex and the presence of DM, hypertension, hyperlipidaemia, stroke, coronary artery disease and cancers were compared between DAVF and control subjects. Data for control were obtained from the Korean National Health and Nutrition Examination Survey. The relationship of DM and DAVF location, presenting symptoms (benign vs. aggressive) and classification (Borden and Geibprasert) were assessed using the Pearson’s chi-square test.

Prevalence of DM was higher in DAVF patients (19.8 %) than in controls (9.5 %; p = 0.004). Univariate analysis showed that DM (odds ratio (OR), 2.356; 95 % confidence interval

(CI), 1.634-3.399; p < 0.001) and age (OR, 1.022; 95 % CI, 1.012-1.032; p < 0.001) increased the odds of DAVF. This was supported by multivariate analysis PF-562271 concentration (DM: OR, 2.092; 95 % CI, 1.391-3.145; p = 0.0004 and Age: OR, 1.021; 95 % CI, 1.009-1.033; p = 0.001). When these analyses were repeated after stratification by sex, there was no relation between age and DAVF in men. Borden II and III (p = 0.038) and aggressive symptoms (p = 0.023) were related to DM.

There was a positive relation between DM and DAVF in a Korean population. DAVFs with aggressive symptoms and behaviour were more commonly related to DM.”
“Biomarkers have enormous potential to improve patient care by establishing tests of diagnosis, prognosis, and treatment effects. Successfully translating

a biomarker from discovery to clinical application demands high-quality discovery research and high-quality selleck kinase inhibitor clinical studies for biomarker validation; however, there are additional challenges that face biomarker research in pediatrics. There are also additional characteristics of pediatric medicine that make biomarker research especially needed. This review focuses on the fundamentals of biomarkers, the additional considerations needed for applying biomarker research to children, and recommendations for advancing pediatric biomarker research.”
“Objective:

Robotic total endoscopic coronary artery bypass grafting (TECAB) has been under development buy YM155 for 10 years. With increasing experience and technological improvement, double-vessel TECAB has become feasible. The aim of the present study was to compare the current outcomes of single-and double-vessel TECAB.

Methods: Between 2001 and 2011, 484 patients underwent TECAB by 4 surgeons at 2 institutions. The median patient age was 60 years (range, 31-90), and the median European System for Cardiac Operative Risk Evaluation was 2 (range, 0-13). Single-vessel (n = 334) and double-vessel (n 150) procedures were performed using the da Vinci, da Vinci S, and da Vinci Si robotic systems.

Results: Compared with the single-vessel procedure, double-vessel TECAB required a longer operative time (median, 375 minutes; range, 168-795; vs median, 240; range, 112-605; P < .001) and had an increased conversion rate to a larger thoracic incision (31/150 [20.7%] vs 31/334 [9.3%]; P < .001).

The model also generated a number of novel predictions, for examp

The model also generated a number of novel predictions, for example, the effect of threat on reaction time only occurs when the target stimulus is unattended, and the IAP inhibitor P3a indexes prefrontal cortex activity involved in redirecting attention toward response processes

on that trial and sensory processes on subsequent trials.”
“The present study was designed to address the role of macrophages in Mn-induced neurotoxicity and to test the hypothesis that minocycline, a tetracycline derivative, attenuates the biochemical and morphological sequelae of Mn. Mn was unilaterally microinjected into rat nigra followed by systemic minocycline or saline administration 24 h later, daily for 3 days. At 72 h after the intranigral Mn microinjection, tyrosine hydroxylase immunostaining (TH-IS) was evaluated

in the striatum, along with the number of macrophages (as indicated by CD11b immunostaining) in the substantia nigra. Mn significantly reduced striatal TH-IS, and causes an increased macrophage number at the lesion site when compared with the control group. The effects of Mn on striatal TH-IS and the number of macrophages at the lesion site were concentration dependent. Consistent with the stated hypothesis, minocycline significantly DihydrotestosteroneDHT clinical trial reduced the macrophage number in the lesion site and minimized the TH-IS striatal loss induced by Mn. These results indicate that an inflammatory response mediated by macrophages is induced by intranigral Mn microinjection, which is fully attenuated by minocycline treatment, suggesting that suppression of macrophage infiltration provides neuroprotection to dopaminergic neurons. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“The

recognition that computational ideas from reinforcement learning are relevant to the study of neural circuits AZD5582 nmr has taken the cognitive neuroscience community by storm. A central tenet of these models is that discrepancies between actual and expected outcomes can be used for learning. Neural correlates of such prediction-error signals have been observed now in midbrain dopaminergic neurons, striatum, amygdala and even prefrontal cortex, and models incorporating prediction errors have been invoked to explain complex phenomena such as the transition from goal-directed to habitual behavior. Yet, like any revolution, the fast-paced progress has left an uneven understanding in its wake. Here, we provide answers to ten simple questions about prediction errors, with the aim of exposing both the strengths and the limitations of this active area of neuroscience research.”
“The N2pc component has recently become a popular tool in attention research. To investigate whether this component exclusively reflects attentional target selection or also prior stages in attentional processing (covert orienting, target-unspecific spatial attention), a spatial cuing procedure was combined with a visual search task.

55, p < 0 01) The tension-free vaginal tape obturator procedu

55, p < 0.01). The tension-free vaginal tape obturator procedure tape migrated distally with time but remained in the same position relative to the urethra (60th percentile). Concomitant pelvic surgery did not affect the position and motion of the bladder neck or tension-free

vaginal tape obturator procedure tape except for mesh reinforcement anterior colporrhaphy in which the tape was displaced proximally. Postoperatively 5 types of urethral descent in relation to the tape during stress were seen. One type of vertical and 1 type of rotational urethral descent during straining were observed in women in whom surgery failed, while 2 other types of vertical and 1 of rotational descent were not associated with failure.

Conclusions: The dynamic interaction between the tension-free vaginal Wnt inhibitor tape obturator procedure tape and urethra depends on the proximity of the tape and the type of urethral descent.”
“Unlike

patients with neglect, neurological patients with extinction can detect a single event presented at any location. However, when shown two brief near-simultaneous stimuli they only report the ipsilesional item. The question of what inter-stimulus delay leads to maximal extinction has clear clinical and theoretical implications. di Pellegrino et al. [di Pellegrino, G., Basso, G., & Frassinetti, F. (1997). Spatial extinction on double asynchronous stimulation. Neuropsychologia, 35,1215-1223] report that extinction Pritelivir order is maximal when the two stimuli are presented simultaneously, with less extinction when either item has a slight temporal lead.

This finding supports traditional clinical diagnosis (which only presents simultaneous events), and is in accord with theories of extinction that entail individuation of objects (e.g. “”token”" accounts). In contrast, Cate and Behrmann [Cate, A., & Behrmann, M. (2002). Spatial and temporal influences of extinction. Neuropsychologia, 40, 2206-2225] report that extinction Acalabrutinib is maximal when the ipsilesional item is presented slightly prior to the contralesional item. This finding appears to support disengage models of attention. Our aim was to reveal whether the difference between these studies reflects different patients, or different methods. Specifically, we note that the stimuli used by Cate and Behrmann were biased both temporally (more ipsilesional first trials) and spatially (more items presented in ipsilesional field). We examined the performance of nine individuals with extinction, and found that maximal extinction was not influenced by temporal biases, but extinction was modulated by the spatial location of stimuli. This finding reconciles previous studies and offers new insight into this syndrome. (C) 2008 Elsevier Ltd. All rights reserved.”
“Purpose: We assessed preoperative and postoperative urinary symptoms, and determined risk factors for de novo stress urinary incontinence after transvaginal urethral diverticulectomy.

The percent change in the glomerular

The percent change in the glomerular

Z-IETD-FMK mw filtration rate was similar between patients with an orthotopic substitute and an ileal conduit. Post-void residual urine was a significant risk factor for febrile urinary tract infection and subsequent hydronephrosis in the absence of obstruction as well as an independent predictor of a significant glomerular filtration rate decrease (p = 0.009).

Conclusions: Vesicoureteral reflux that develops in refluxing type urinary diversions does not significantly alter renal function regardless of its severity unless it is coupled with post-void residual urine. Post-void residual urine carries a significant risk of febrile urinary tract infection and it is an independent predictor of renal function deterioration.”
“Recent studies indicate that single-action

single-target agents are unlikely to cure CNS disorders sharing a pathogenic triad consisting of vascular damage, neuronal injury/neurodegeneration and neuroinflammation. Here we focus on a recent example of a multiple-action-multiple-target approach for CNS disorders based on newly discovered biological properties of activated protein C (APC), an endogenous plasma protease with antithrombotic, cytoprotective and anti-inflammatory activities in the CNS. We propose that APC-mediated BI 2536 manufacturer signaling through the protease activated receptor-1 (PAR1) can favorably regulate multiple pathways within the neurovascular unit in non-neuronal

cells and neurons during acute or chronic CNS insults, leading to stabilization of the blood brain barrier (BBB), neuroprotection and control of neuroinflammation. Although much remains to be understood regarding the biology of APC, preclinical studies suggest that APC has promising applications as disease-modifying therapy for ischemic stroke and other neuropathologies whose underlying pathology involves deficits in the vasculo-neuronal-inflammatory triad.”
“A recombinant glutaryl-7-aminocephalosporanic acid acylase (GLA) PCI-32765 cost from Pseudomonas N176 has been over-expressed in BL21(DE3)pLysS Escherichia coli cells. By alternating screenings of medium components and simplified factorial experimental designs, an improved microbial process was set up at shake-flask level (and then scaled up to 2L-fermentors) giving a similar to 80- and 120-fold increase in specific and volumetric enzyme productivity, respectively. Under the best expression conditions, similar to 1380U/g cell and 16,100U/L of GLA were produced versus the similar to 18U/g cell and the similar to 140U/L obtained in the initial standard conditions.

In a simplified discrete game with zero variation of fighting str

In a simplified discrete game with zero variation of fighting strength, helping neighbors is part of an evolutionarily stable strategy (ESS) only if fighting costs are low relative to those of renegotiation. However, if relative fighting costs are high then Selleckchem VE-822 an interventional

ESS remains possible with finite variation of strength. Under these conditions, neighbors may help residents fight off intruders. but only when the resident does not stand a reliable chance of winning alone. We show that neighbor intervention is more likely with low home advantage to occupying a territory, strengths combining synergistically or low probability that an ally will be usurped, amongst other factors. Our Parameterized model readily explains occasional intervention in the Australian fiddler crab, including why the ally tended to be larger than both the assisted neighbor and the intruder. Reciprocity is not necessary for this type of cooperation to persist, but also it is by no means inevitable in territorial species. (C) 2008 Elsevier Ltd. All rights reserved.”
“Methylphenidate (MPH) is commonly prescribed in childhood and DihydrotestosteroneDHT adolescence for the treatment of attention-deficit/hyperactivity

disorders. In rodents, MPH exposure during preadolescence (postnatal days (PD) 20-35) causes decreased sensitivity to drug and natural rewards, while enhancing a negative emotional state characterized

by increased sensitivity to aversive situations later in adulthood. It has been proposed that this behavioral profile may be mediated, at least in part, by changes in the expression of dynorphin, the endogenous ligand for kappa-opioid receptors (KORs). Because increases in dynorphin activity and activation of KOR induce aversive states, we examined the possibility that these behavioral deficits may be mediated by changes in KOR function, and that MPH-exposed rats would demonstrate increased sensitivity to the kappa-agonist U-50488. Sprague-Dawley male rats were treated with MPH (2 mg/kg) or its saline vehicle (VEH) during PD20-35. When adults (PD90 +), these rats were divided into groups receiving saline, U-50488 (5 mg/kg), or norbinaltorphimine (20 mg/kg), STI571 clinical trial a kappa-antagonist, and their behavioral reactivity to various emotion-eliciting stimuli was assessed. Results show that MPH exposure decreases cocaine place conditioning and sucrose preference, while increasing vulnerability to anxiety (elevated plus maze)- and stress (forced swimming)-eliciting situations, and that these behavioral deficits can be intensified by U-50488, while being normalized by nor-binaltorphimine treatment. These results are consistent with the notion that dysregulated dynorphin/kappa-opioid systems may mediate deficits in behavioral responding after developmental MPH exposure.