In summary, the present study has added another example showing t

In summary, the present study has added another example showing that IgA antibodies targeting internal viral antigens could proactively participate in mucosal immune protection by intracellular neutralization and has provided evidence that M protein might be included as a target antigen in future AZD6244 purchase MV vaccine design.”
“The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT2A and 5-HT2C receptors, modulates dopamine function. In these experiments we examined the effects

of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03 mg/kg/infusion, IV) on either a FR5 or a progressive ratio schedule of reinforcement. Ro60-0175 reduced responding for nicotine on both schedules. While Ro60-0175 also reduced responding for food reinforcement,

response rates under drug treatment were several-fold higher than in animals responding for nicotine. M100907 did not alter responding for nicotine, or food, on either schedule. In tests CB-839 of reinstatement of nicotine-seeking, rats were first trained to lever press for IV infusions of nicotine; each infusion was also accompanied by a compound cue consisting of a light and tone. This response was then extinguished over multiple sessions. Injecting rats with a nicotine prime (0.15 mg/kg) reinstated responding; reinstatement was also observed when responses were accompanied by the nicotine associated cue. Ro60-0175 attenuated reinstatement of responding induced by nicotine and by the cue. The effects of Ro60-0175 on both forms of reinstatement were blocked by the 5-HT2C receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT2C and 5-HT2A receptors may be potential targets for therapies to treat some Cyclin-dependent kinase 3 aspects of nicotine dependence. (C)

2012 Elsevier Ltd. All rights reserved.”
“The feasibility of using virtual reality (VR) technology to induce a physiological response to stress was assessed in 12 volunteers during a laboratory session in which each participant completed a speech task within a VR environment and a math task outside the VR environment. Both tasks were effective in eliciting a physiological response with significant increases observed in response to each stress task in systolic and diastolic blood pressure and heart rate. Increases in plasma epinephrine and norepinephrine concentrations were observed during the speech task and in plasma epinephrine concentrations during the math task although these differences did not reach statistical significance.

Participants collected genital swabs four times daily for quantit

Participants collected genital swabs four times daily for quantitative HSV DNA PCR. Clinical data were masked from laboratory personnel. The primary endpoint was within-person comparison of shedding rate in each study group. Analysis was per protocol. The trials are registered at (NCT00362297,

NCT00723229, NCT01346475).

Results Of 113 participants randomised, 90 were eligible for analysis of the primary endpoint. Participants collected 23 605 swabs; 1272 (5.4%) were HSV-positive. The this website frequency of HSV shedding was significantly higher in the no medication group (n=384, 18.1% of swabs) than in the standard-dose aciclovir group (25, 1.2%; incidence rate ratio [IRR] 0.05, C646 solubility dmso 95% CI 0.03-0.08). High-dose aciclovir was associated with less shedding than standard-dose valaciclovir (198 [4.2%] vs 209 [4.5%]; IRR 0.79, 95% CI 0.63-1.00). Shedding was less frequent in the high-dose valaciclovir group than in the standard-dose valaciclovir group (164 [3.3%] vs 292 [5.8%]; 0.54, 0.44-0.66). The number of episodes per person-year did not differ significantly for standard-dose valaciclovir

(22.6) versus high-dose aciclovir (20.2; p=0.54), and standard-dose valaciclovir (14.9) versus high-dose valaciclovir (16.5; p=0.34), but did for no medication (28.7) and standard-dose aciclovir (10.0; p=0.001). Median episode duration was longer for no medication than for standard-dose aciclovir (13 h vs 7 h; p=0.01) and for standard-dose valaciclovir than for high-dose valaciclovir (10 h vs 7 h; p=0.03), but did not differ significantly between standard-dose valaciclovir and high-dose aciclovir (8 h vs 8 h; p=0.23). Likewise, maximum log 10 copies of HSV detected per mL was higher for no medication than for standard-dose aciclovir (3.3 vs 2.9; p=0.02), and for standard-dose valaciclovir than for high-dose valaciclovir (2.5 vs 3.0; p=0.001), but no significant difference was recorded for standard-dose valaciclovir versus high-dose aciclovir (2.7 vs 2.8; p=0.66). 80% of episodes were subclinical in all study groups. Except

for a higher frequency of headaches with high-dose valaciclovir (n=13, 30%) than with other regimens, all regimens were well tolerated.

Interpretation Short bursts 4-Aminobutyrate aminotransferase of subclinical genital HSV reactivation are frequent, even during high-dose antiherpes therapy, and probably account for continued transmission of HSV during suppressive antiviral therapy. More potent antiviral therapy is needed to eliminate HSV transmission.”
“Modern factor analysis is the outgrowth of Spearman’s original “”2-factor”" model of intelligence. according to which a mental test score is regarded as the sum of a general factor and a specific factor. As early as 1914, Godfrey Thomson realized that the data did not require this interpretation and he demonstrated this by proposing what became known as his “”bonds”" model of intelligence. Van der Maas et al.

Several orexin receptor

antagonists have been reported in

Several orexin receptor

antagonists have been reported in recent years, but currently there are no imaging tools to probe the density and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomography (PET) radiotracer development could be used to elucidate the association of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compounds based on diazepane orexin receptor antagonists previously described. One of the synthesized compounds, [C-11]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR check details imaging. PET Apoptosis inhibitor scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [C-11]CW4 exhibited

fast kinetics and high nonspecific binding, as determined after co-administration of [C-11]CW4 and unlabeled CW4. These properties indicate that [C-11]CW4 has excellent brain penetrance and could be used as a lead compound for developing new CNS-penetrant PET imaging probes of orexin receptors.(C) 2013 Elsevier Inc. All rights reserved.”
“Purpose: Senescence related regulatory pathways serve as barriers to cancer immortalization and progression but they are currently not well defined. FILIP1L is a growth inhibitory gene with multiple isoforms whose expression is increased in senescent prostate and prostate cancer cells, and decreased in many cancers. We investigated whether DNA methylation Flavopiridol (Alvocidib) regulates FILIP1L in senescence and in prostate cancer development.

Materials and Methods: FILIP1L mRNA expression

was assessed in prostate cancer and associated normal prostate tissues using quantitative polymerase chain reaction. A tissue microarray was constructed using 95 prostate cancer specimens and 45 benign prostate specimens. Vectra (TM) imaging was used to quantitate nuclear and cytoplasmic FILIP1L protein expression. Bisulfite sequencing and Pyrosequencing (R) were used to assess methylation. Prostate cancer cell lines were treated with 2′-deoxy-5-azacytidine and mRNA expression was assessed.

Results: FILIP1L isoform 2 mRNA was increased in replicatively senescent human prostate epithelial cells and decreased in prostate cancer specimens. We verified a reduction in nuclear FILIP1L protein in prostate cancer using tissue microarrays (p = 0.006). A CpG island 5′ of the isoform 2 translational start site was identified that showed hypermethylation in prostate cancer cell lines and tumors compared to normal prostate cells and tissues. Pyrosequencing confirmed FILIP1L hypermethylation in all 14 tumors compared to paired normal tissues (p < 0.0001).

Furthermore, some botanicals and herbs may be proconvulsant or ma

Furthermore, some botanicals and herbs may be proconvulsant or may alter AED metabolism. In spite of these limitations, further preclinical evaluation of botanicals and herbs and their constituent compounds using validated scientific methods is warranted based on numerous anecdotal observations of clinical

benefit in patients with epilepsy and published reports showing mechanisms of action relevant to epilepsy or anticonvulsant effects in animal models of epilepsy. This review highlights the use of herbal therapies for epilepsy, outlines the role of the U.S. Food and Drug Dibutyryl-cAMP Administration in regulating herbal products, and presents the author’s approach to the scientific assessment of herbal therapies as potential therapies for patients with epilepsy.”
“Next-generation high-throughput DNA sequencing techniques are opening fascinating opportunities in the life sciences. Novel fields

and applications in biology and medicine are becoming a reality, beyond the genomic sequencing which was original development goal and application. Serving as examples are: personal genomics with detailed analysis of individual genome stretches; precise analysis of RNA transcripts for gene expression, surpassing and replacing in several selleck compound respects analysis by various microarray platforms, for instance in reliable and precise quantification of transcripts and as a tool for identification and analysis of DNA regions interacting with regulatory proteins in functional regulation of gene expression. The next-generation sequencing technologies offer novel and rapid ways for genome-wide characterisation

and profiling of mRNAs, small RNAs, transcription factor regions, structure of chromatin and DNA methylation patterns, microbiology and metagenomics. In this article, development of commercial sequencing devices is reviewed and some European contributions to the field are mentioned. Presently commercially available very high-throughput DNA sequencing platforms, as well Urease as techniques under development, are described and their applications in bio-medical fields discussed.”
“The sustainable use of resources by Nature to synthesize the required products at the right place, when they are needed, continues to be the role model for total synthesis and production in general. The combination of molecular and engineering science and technology in the biotechnological approach needs no protecting groups at all and has therefore been established for numerous large-scale routes to both natural and synthetic products in industry. The use of biobased raw materials for chemical synthesis, and the economy of molecular transformations like atom economy and step economy are of growing importance.

We focus our review on four visual discrimination paradigms that

We focus our review on four visual discrimination paradigms that have been successfully translated into the human arena: configural concurrent discriminations, pair-wise “”morph”" discriminations, oddity discriminations, and configural oddity discriminations. The data from the animal studies are first reviewed, followed by illustrations of how the tasks have been utilized in human research. We then turn to the canonical impairment in animal models of amnesia, object recognition, and show how impairments in object recognition can be understood within the representational-hierarchical framework. This is followed by a discussion of predictions of the view related to classic issues in

amnesia research, namely whether CH5424802 in vivo amnesia is due to a deficit of encoding, storage or retrieval, and the related issue of the role of interference in amnesia. Finally, we provide evidence Ispinesib cell line from animal and human studies that even the hippocampus almost universally regarded as a module for memory may be better understood within the representational-hierarchical paradigm. (C) 2010 Elsevier Ltd. All rights reserved.”

present a new computationally efficient method for large-scale polypeptide folding using coarse-grained elastic networks and gradient-based continuous optimization techniques. The folding is governed by minimization of energy based on Miyazawa-Jernigan contact potentials. Using this method we are able to substantially reduce the computation time on ordinary desktop computers for simulation of polypeptide folding starting from a fully unfolded state. We compare our results with available native state structures from Protein Data Bank (PDB) for a few de-novo proteins and two natural proteins, Ubiquitin and Lysozyme. Based on our simulations we are able to draw the energy landscape

for a small de-novo protein. Chignolin. We also Niclosamide use two well known protein structure prediction software, MODELLER and GROMACS to compare our results. In the end, we show how a modification of normal elastic network model can lead to higher accuracy and lower time required for simulation. (C) 2009 Elsevier Ltd. All rights reserved.”
“Despite a half century of development, the orthodox monkey model of human amnesia needs improvement, in part because of two problems inherent in animal models of advanced human cognition. First, animal models are perforce comparative, but the principles of comparative and evolutionary biology have not featured prominently in developing the orthodox model. Second, no one understands the relationship between human consciousness and cognition in other animals, but the orthodox model implicitly assumes a close correspondence. If we treat these two difficulties with the deference they deserve, monkeys can tell us a lot about human amnesia and memory.

maltophilia isolates were involved in a herd outbreak of mastitis

maltophilia isolates were involved in a herd outbreak of mastitis to some extent. Bovine S.maltophilia isolates exhibited resistance to many classes of antimicrobials. Significance and impact of study: This is a rare report of a herd outbreak of bovine mastitis involving closely related S.maltophilia isolates.”
“BACKGROUND: An alternative treatment option to whole-brain irradiation after surgical resection of brain metastases is resection cavity stereotactic radiosurgery (SRS).

OBJECTIVE: To review the dynamics check details of cavity volume change after surgical resection with the goal of determining the optimal timing for cavity SRS.

METHODS: Preresection

tumor, postresection/pre-SRS cavity, and post-SRS cavity volumes were measured for 68 cavities in 63 patients treated with surgery and postresection cavity SRS. Percent differences between volumes were calculated and correlation analyses were performed to assess volume changes before and after SRS.

RESULTS: For the majority of tumors, the postresection cavity volume was smaller than the preresection tumor volume by a median percent volume change

of -29% (range, -82% to 1258%), with larger preresection tumors resulting in greater cavity shrinkage (P < .001). To determine the optimal timing for cavity SRS, we examined cavity volume dynamics by comparing the early postresection (postoperative days 0-3) and treatment planning magnetic resonance imaging scans (median time to magnetic resonance imaging, 20 days; range, 9-33 days) and found no association between the postresection day number and

volume change (P = .75). The volume decrease resulting from tumor resection was offset by the addition of a 2-mm clinical target volume margin, which is our current technique.

CONCLUSION: The greatest volume change occurs immediately after surgery (postoperative days 0-3) with no statistically ADP ribosylation factor significant volume change occurring up to 33 days after surgery for most patients. Therefore, there is no benefit of cavity shrinkage in waiting longer than the first 1 to 2 weeks to perform cavity SRS.”
“The aim of this study is to update age and sex mortality rates for suicide in Italy; to evaluate the methods of suicide; to consider the effect of under-reporting on mortality rate for suicide; to compare age-adjusted mortality rates for suicide; and to examine some possible causes for the misclassification of suicide. Temporal trends, from 1980 to 2002, were analyzed using joinpoint regression. Suicide rates decreased from 1980 to 2002 by 10.5% for men and by 44% for women. The change in suicide methods indicated an increasing use of highly lethal methods. The under-reporting of suicide seems to have no effect on temporal changes in mortality rates or on the geographical distribution. These data indicate that Italy is a country at low risk for suicide. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

These findings are consistent with previously published genetic s

These findings are consistent with previously published genetic studies implicating GABA(B), and NMDA transporter and receptor genes in OCD. It is posited that dysregulation of such mechanisms may lead to the generation and persistence of intrusive thoughts that form

the basis for this disorder. Neuropsychopharmacology (2012) 37, 1144-1151; doi:10.1038/npp.2011.300; published online 14 December 2011″
“Recent data indicate that the synchronisation of oscillatory activity is relevant for INCB018424 the development of cortical circuits as demonstrated by the involvement of neural synchrony in synaptic plasticity and changes in the frequency and synchronisation of neural oscillations during development. Analyses see more of resting-state and task-related neural synchrony indicate that gamma-oscillations emerge during early childhood and precise temporal coordination through neural synchrony continues

to mature until early adulthood. The late maturation of neural synchrony is compatible with changes in the myelination of cortico-cortical connections and with late development of GABAergic neurotransmission. These findings highlight the role of neural synchrony for normal brain development as well as its potential importance for understanding neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia.”
“Our previous study on immune-related changes in the aged liver described immune cell infiltration and elevation of inflammation with age. Levels of interferon (IFN)-gamma, a known cell cycle inhibitor, were elevated in the aging liver. Here, we determine the role played by IFN-gamma in the delayed regenerative response observed in the aged livers. We observed elevated IFN signaling in both aged hepatocytes and regenerating livers post-partial hepatectomy. HA-1077 research buy In vivo deletion of the major IFN-gamma producers-the macrophages and the

natural killer cells, leads to a reduction in the IFN-gamma levels accompanied with the restoration of the DNA synthesis kinetics in the aged livers. Eighteen-month-old IFN-gamma-/- mice livers, upon resection, exhibited an earlier entry into the cell cycle compared with age-matched controls. Thus, our study strongly suggests that an age-related elevation in inflammatory conditions in the liver often dubbed as “”inflammaging”" has a detrimental effect on the regenerative response.”
“Lung fibroblast plays a pivotal role in lung repair and remodeling, and also contributes to lung inflammation. The present study investigated differential protein profiling of normal human lung fibroblasts stimulated with tumor necrosis factor (TNF)-alpha. Total proteins from lung fibroblasts were separated by 2-DE, and differentially expressed proteins were identified by MALDI-TOF MS.

72), postoperative renal dysfunction (odds ratio, 1 9), dialysis

72), postoperative renal dysfunction (odds ratio, 1.9), dialysis (odds ratio, 1.82), stroke (odds ratio, 2.6) arrhythmia (odds ratio, 1.42), and hospital stay > 7 days (odds ratio, 1.65).

Conclusions: Occult renal dysfunction is an independent risk factor for early mortality and morbidity in patients undergoing coronary artery bypass grafting. (J Thorac Cardiovasc Surg 2011;141:771-6)”
“Older human listeners demonstrate

perceptual deficits in temporal selleck products processing even when audibility has been controlled. These age-related auditory deficits in temporal processing are thought to originate in the central auditory pathway. Precise temporal processing is necessary to detect and discriminate auditory cues such as modulation frequency, modulation depth and envelope shape which are critical for perception of speech and environmental sounds. This

study aims to further understanding of temporal processing in aging using non-invasive electrophysiological measurements. Amplitude modulation following responses (AMFRs) and frequency modulation following responses (FMFRs) were recorded from aged (92-95-weeks old) and young (9-12-weeks old) Fischer-344 (F-344) rats for sinusoidally amplitude modulated (sAM) tones, PF-02341066 research buy sinusoidally frequency modulated (sFM) tones and ramped and damped amplitude modulation (AM) Amisulpride stimuli which differ in their envelope shapes. The modulation depth for the sAM and sFM stimuli and envelope shape for the ramped and damped stimuli were systematically varied. There was a monotonic decrease in AMFR and FMFR amplitudes with decreases in modulation depth across age for sAM and sFM stimuli. There was no significant difference between the response amplitudes of the young and aged animals for the largest modulation depths. However, a reduction in modulation depth resulted in a significant decrease in the response amplitudes and higher modulation detection thresholds for sAM and sFM stimuli

with age. The aged animals showed significantly lower response amplitudes for ramped stimuli but not for damped stimuli. Cross correlating the responses with the ramped, symmetric, or damped stimulus envelopes revealed a decreased fidelity in encoding envelope shapes with age. These results indicate that age related temporal processing deficits become apparent only with reduced modulation depths or when discriminating envelope shapes. This has implications for psychophysical or diagnostic testing as well as for constraining potential cellular and network mechanisms responsible for these deficits. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Ascorbic acid (0 1-10

mg/kg, i p , 1-10 mg/kg p o or 0 1

Ascorbic acid (0.1-10

mg/kg, i.p., 1-10 mg/kg p.o. or 0.1 nmol/mice i.c.v.) produced an antidepressant-like effect in the TST, but not in the FST without altering the locomotor activity. The effect of ascorbic acid (0.1 mg/kg, i.p.) in the TST was Acadesine order prevented by i.p. pre-treatment with NAN-190 (0.5 mg/kg), ketanserin (5 mg/kg), MDL72222 (0.1 mg/kg), prazosin (62.5 mu g/kg), yohimbine (1 mg/kg), propranolol (2 mg/kg), haloperidol (0.2 mg/kg), sulpiride (50 mg/kg), but not with SCH23390 (0.05 mg/kg, s.c.). Additionally, ascorbic acid (1 mg/kg, p.o.) potentiated the effect of subeffective doses (p.o. route) of fluoxetine (1 mg/kg), imipramine (0.1 mg/kg), or bupropion (1 mg/kg) in the TST. The combined treatment of ascorbic acid with antidepressants produced no alteration in the locomotion in the open-field test. In conclusion, our results show that administration of ascorbic acid produces an antidepressant-like effect in TST, which is dependent on its interaction with the monoaminergic system. Moreover, ascorbic acid caused a synergistic antidepressant-like effect with conventional antidepressants. Therefore, the present findings warrant further studies to evaluate the therapeutical relevance of ascorbic acid for the treatment

of depression and as a co-adjuvant treatment with antidepressants. (C) 2009 Elsevier Inc. All rights reserved.”
“Cisplatin is a highly effective chemotherapeutic drug; however, its use is limited by nephrotoxicity. Studies showed that the renal injury produced Caspase Inhibitor VI mw by cisplatin

ADP ribosylation factor involves oxidative stress and cell death mediated by apoptosis and necrosis in proximal tubular cells. The use of antioxidants to decrease cisplatin-induced renal cell death was suggested as a potential therapeutic measure. In this study the possible protective effects of carvedilol, a beta blocker with antioxidant activity, was examined against cisplatin-induced apoptosis in HK-2 human kidney proximal tubular cells. The mitochondrial events involved in this protection were also investigated. Four groups were used: controls (C), cisplatin alone at 25 mu M (CIS), cisplatin 25 mu M plus carvedilol 50 mu M (CV + CIS), and carvedilol alone 50 mu M (CV). Cell viability, apoptosis, caspase-9, and caspase-3 were determined. Data demonstrated that carvedilol effectively increased cell viability and minimized caspase activation and apoptosis in HK-2 cells, indicating this may be a promising drug to reduce nephrotoxicity induced by cisplatin.”
“To behave adaptively, we must learn from the consequences of our actions. Studies using event-related potentials (ERPs) have been informative with respect to the question of how such learning occurs. These studies have revealed a frontocentral negativity termed the feedback-related negativity (FRN) that appears after negative feedback.

Adult male rats underwent

either an FPI or sham injury A

Adult male rats underwent

either an FPI or sham injury. Additional rats were only exposed to anesthesia. HPA regulation was evaluated by measuring the effects of dexamethasone (DEX) treatment on CORT and ACTH. Tail vein blood was collected following 30-min restraint stress, at post-injury days (PID) 1, 7 and 14, prior to (0 min) and at 30, 60, 90 and 120 min after stress onset. Results from these studies indicate that the stress response was significantly more pronounced after FPI in that CORT and ACTH restraint-induced increases were more pronounced and longer lasting compared to controls. DEX suppression of CORT and ACTH was observed in all groups, suggesting that stress hyper-responsiveness after mild FPI is not attributable to reduced sensitivity of CORT feedback regulation. The increased sensitivity to stressful events in the first two post-injury weeks after check details a mild FPI may have a negative impact on early rehabilitative therapies. (c) 2011 IBRO.

Published by Elsevier Ltd. All rights reserved.”
“While endocannabinoid modulation of both GABAergic and glutamatergic synaptic transmission and plasticity has been extensively investigated, our understanding of the role of endocannabinoids in protecting neurons from harmful insults remains limited. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous ligand and a full agonist Combretastatin A4 ic50 for cannabinoid receptors, exhibits anti-inflammatory and neuroprotective effects via a CBI receptor ZD1839 solubility dmso (CB1R)-mediated mechanism. However, it is still not clear whether 2-AG is also able to protect neurons from beta-amyloid (A beta)-induced neurodegeneration. Here, we demonstrate that exogenous application of 2-AG significantly protected hippocampal neurons in culture against A beta-induced neurodegeneration and apoptosis. This neuroprotective effect was blocked by SR141716 (SR-1), a selective CB1R antagonist,

but not by SR144528 (SR-2), a selective CB2R antagonist, or capsazepine (CAP), a selective transient receptor potential cation channels, subfamily V, member 1 (TRPV1) receptor antagonist. To determine whether endogenous 2-AG is capable of protecting neurons from A beta insults, hippocampal neurons in culture were treated with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), the enzyme hydrolyzing 2-AG. MAGL inhibition that elevates endogenous levels of 2-AG also significantly reduced A beta-induced neurodegeneration and apoptosis. The 2-AG-produced neuroprotective effects appear to be mediated via CB1R-dependent suppression of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-kappa B (NF-kappa B) phosphorylation and cyclooxygenase-2 (COX-2) expression. Our results suggest that elevation of endogenous 2-AG by inhibiting its hydrolysis has potential as a novel efficacious therapeutic approach for preventing, ameliorating or treating Alzheimer’s disease. (c) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.