The overall yield of the purified Al-BMP was about 15% as related

The overall yield of the purified Al-BMP was about 15% as related to the initial amount of the hemeprotein. Al-BMP possesses extensive fluorescence

in the 550650 nm region with excitation in the porphyrin absorbance bands. The protein was shown to bind substrates of P450BM-3 (palmitic, arachidonic, and cis-parinaric acids) with affinities similar to those of the native enzyme (36 mu M). However, the substrate-induced changes in fluorescence SN-38 of Al-PP reveal the existence of a second, low-affinity substrate-binding site, which cannot be detected by the spin shift in the native, heme-containing BMP. Using fluorescence resonance energy transfer, we have demonstrated that Al-BMP forms a complex with the flavoprotein domain of P450BM-3 labeled with

7-ethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin maleimide, revealing the affinity similar to that of native BMP (Kd = 5 mu M at 0.06 M ionic strength). Therefore, aluminum-substituted BMP may serve as a valuable tool in studies on the mechanisms of interactions of P450s with their substrates and protein partners.”
“Novel geldanamycin derivative, 4,5-dihydro-thiazino-geldanamycin (3), was characterized from the gdmP mutant in Streptomyces hygroscopicus 17997, besides expected 4,5-dihydro-geldanamycin (2). The presence of this compound would suggest an unknown post-PKS modification in geldanamycin biosynthesis. Compound BTSA1 3 exhibited moderate anti-HSV-1-virus activity and higher water solubility than geldanamycin (1). Cysteine served as a precursor to synthesize 3, whose formation required obligatory enzymatic assistance.”
“Sleep deprivation impairs contextual but not cued learned fear, and it has been suggested that this SRT2104 chemical structure pattern reflects an insensitivity of the amygdala to sleep loss. The lack of effect of sleep deprivation on cued conditioning, however, might simply be due to the strong

attention drawn by the typically loud cue tone. We reduced tone volume from our standard 80 dB to either 70 or 60 dB, to test if reduced cue volume allowed effects of sleep deprivation to be detected. Using the platform-over-water method, male C57BL/6 mice were sleep-deprived for 24 h: control mice were moved to novel cages for 24 h. Mice then underwent fear conditioning with a standard “delay” protocol, and were tested for contextual and cued learning the next day. A control group received no footshock during conditioning. In the cue test, and for both cue volumes, SD had no effect on freezing to the tone, which was very robust in conditioned mice regardless of sleep treatment. As expected, freezing to the tone in the no-shock groups was essentially absent. Also, freezing prior to the tone was low in all mice. At the lowest volume, the tone was only similar to 10 dB above background noise. 24 h sleep deprivation, however, blocked contextual fear in the same mice.

We further used HSV-1 glycoprotein B (gB) as a representative mol

We further used HSV-1 glycoprotein B (gB) as a representative molecule to study the PILR-SA interaction. Deploying site-directed mutagenesis, this website we demonstrated that three residues (Y2, R95, and W108) presented on the surface of PILR alpha form the SA binding site equivalent to those in siglecs but are arranged in a unique linear mode. PILR beta differs from PILR alpha in one of these three residues (L108), explaining its inability to engage gB. Mutation of L108 to tryptophan

in PILR beta restored the gB-binding capacity. We further solved the structure of this PILR beta mutant complexed with SA, which reveals the atomic details mediating PILR/SA recognition. In comparison with the free PILR structures, amino acid Y2 oriented variantly in the complex structure, thereby disrupting the linear arrangement of PILR residues Y2, R95, Sapanisertib nmr and W108. In conclusion, our study provides significant implications for the PILR-SA interaction and paves the way for understanding PILR-related ligand binding.”
“Objectives The goal of this study was to investigate carotid plaque characteristics in symptomatic versus asymptomatic patients with the use of nonocclusive optical coherence tomography (OCT). Background

The identification of asymptomatic patients with carotid disease who are at risk of stroke remains a challenge. There is an increasing awareness that plaque characteristics may best risk-stratify this population. We hypothesized that OCT, a new high-resolution (similar to 10 mu m) imaging modality, might be useful for the identification of low-risk versus high-risk carotid plaque features and help us to understand the relationship between carotid diameter stenosis and plaque morphology to ischemic stroke. Methods Fifty-three patients undergoing diagnostic carotid angiography were studied with OCT. Data analysis was carried out by imaging experts who were unaware of the clinical characteristics of the study population. Results Plaque with American Heart Association type VI complicated

features was more common in symptomatic than asymptomatic patients (74.1% vs. 36.4%, p = 0.02). This was JNK assay largely driven by differences in the incidence of thin-cap fibroatheroma with rupture (40.7% vs. 13.6%, p = 0.056) and thrombus (67.7% vs. 36.4%, p = 0.034). Conversely, non-type VI plaques were more common in asymptomatic than symptomatic patients (63.6% vs. 25.9%, p = 0.02). No association between the degree of stenosis and plaque morphology was identified. Conclusions This retrospective analysis of carotid OCT data supports the hypothesis that the evaluation of carotid plaque characteristics with this high-resolution imaging technique has the potential to alter the understanding and treatment of carotid artery disease.

2%, 41 7%, and 4 1%, respectively Conclusions: The mean SBH is t

2%, 41.7%, and 4.1%, respectively. Conclusions: The mean SBH is the highest in the area of the anterior border of the sinus; it declines significantly toward the posterior maxilla, reaches its minimum in the area of the first molar, and increases again significantly in the second molar region. From a clinical point of view, the lateral window technique of sinus elevation remains the dominant augmentative procedure in the molar area, whereas in the premolar area, less invasive alternative methods may be more appropriate. INT J ORAL MAXILLOFAC IMPLANTS 2012;27:48-54″
“(Leaf functional traits in sun and shade leaves of gallery forest trees in Distrito Federal, Brazil). Gallery forest is a forest formation that covers

about 10% of the cerrado biome and represents

about 1/3 of cerrado tree diversity in Brazil. Recent studies demonstrate the importance of gallery forest in central AZD7762 datasheet regions of Brazil, but little is known about the physiology and plasticity of gallery forest species in relation to environmental variability, particularly in terms of light availability. In this study we compared in situ physiological and nutritional aspects of shade and sun leaves, in ten tree species commonly found in gallery forests. Relative to shade leaves, VX-809 sun leaves had higher values of CO(2) assimilation rates on an area basis (A(area)), of stomatal conductance (gs), of quantum yield of Photosystem II (Phi(PSII)); and a larger fraction of PSII centers in the open state (q(L)), while shade leaves showed higher specific leaf area However, shade and sun leaves did not differ in terms of leaf water potential. CO(2) assimilation on a mass basis and in leaf concentrations

of macronutrients. Phi(PSII) and gs were the main factors that influenced A(area) sun leaves, while only Phi(PSII) significantly affected A(area) shade leaves. The differences found here demonstrate that, like in other forest formations worldwide, gallery forest trees are able to acclimate to contrasting irradiance levels that typically occur in this type of environment.”
“Aim: To examine the electrophysiological effects of sophocarpine on action potentials (AP) and ionic currents of cardiac myocytes and to compare some of these effects with those of amiodarone.\n\nMethods: selleck kinase inhibitor Langendorff perfusion set-up was used in isolated guinea pig heart, and responses to sophocarpine were monitored using electrocardiograph. Conventional microelectrode, voltage clamp technique and perforated patch were employed to record fast response AP (fAP), slow response AP (sAP) and ionic currents in guinea pig papillary muscle or rabbit sinus node cells.\n\nResults: Tachyarrhythmia produced by isoprenaline (15 mu mol/L) could be reversed by sophocarpine (300 mu mol/L). Sophocarpine (10 mu mol/L) decreased the amplitude by 4.0%, maximal depolarization velocity (V(max)) of the fAP by 24.4%, and Na(+) current (I(Na)) by 18.0%, while it prolonged the effective refractory period (ERP) by 21.1%.

Results: A total of 230 children (31 with behavioral insomnia

\n\nResults: A total of 230 children (31 with behavioral insomnia, 29 with feeding disorders, 170 controls) were enrolled. Their mean age was 16.1 +/- 7.6 months. Maternal cognitions/perceptions about sleep (maternal cognition infant sleep questionnaire, MCISQ) did not differ significantly between the behavioral insomnia

group and the feeding disorders group. The MCISQ score was significantly higher in the behavioral insomnia group compared with controls (P <.02). Mothers of children with feeding disorders reported being significantly more frustrated or anxious when they selleck inhibitor fed their child (P <.0005), less confident about their child getting enough food (P <.0005), and less confident CSF-1R inhibitor in their ability to manage their child’s behavior at mealtime (P <.02) compared to the controls. Significant positive correlations were found between the MCISQ scores and the Beck Depression Inventory scores (r = 0.29, P <.0002), and between the MCISQ scores and the maternal cognitions of their child’s feeding scores

(r = 0.26, P <.0002). The latter remained significant after controlling for maternal depression (r = 0.25, P <.002).\n\nConclusions: Mothers of children with either behavioral insomnia or feeding disorders differ significantly from mothers of controls regarding their cognitions about sleep and feeding. Maternal cognitions about infant sleep behavior correlated with their cognitions about infant feeding. Maternal cognitions are a modifiable factor Selleck YAP-TEAD Inhibitor 1 that may serve as a target for intervention in both sleep and feeding disorders in children. (C) 2012 Elsevier B.V. All rights reserved.”
“Purpose. Mathematical and simulation models are increasingly used to plan for and evaluate health sector responses to disasters, yet no clear consensus exists regarding best practices for the design, conduct, and reporting

of such models. The authors examined a large selection of published health sector disaster response models to generate a set of best practice guidelines for such models. Methods. The authors reviewed a spectrum of published disaster response models addressing public health or health care delivery, focusing in particular on the type of disaster and response decisions considered, decision makers targeted, choice of outcomes evaluated, modeling methodology, and reporting format. They developed initial recommendations for best practices for creating and reporting such models and refined these guidelines after soliciting feedback from response modeling experts and from members of the Society for Medical Decision Making. Results.

Conclusion: It is therefore suggested that extracts from M arven

Conclusion: It is therefore suggested that extracts from M. arvensis could be used as a source of plant-derived natural products with resistance-modifying activity, such as in the case of aminoglycosides, constituting a new weapon against bacterial resistance to antibiotics, as with chlorpromazine.”
“Background. Albuminuria is a sensitive marker of renal derangement and has been included in a number of studies investigating chronic kidney diseases (CKDs). This study is aimed to evaluate the diagnostic performances of a strip for measuring the albumin/creatinine ratio (ACR) in the general population and to compare it with those found in

a diabetic population.\n\nMethods. Urine samples were obtained HSP990 cost from 201 consecutive subjects enrolled in an epidemiological study and from 259 type 2 diabetic patients. Urine was tested for albumin and creatinine using the strip (Clinitek Microalbumin) and laboratory methods. A hundred samples were stored under various conditions to assess analyte stability.\n\nResults. In the general population, the strip test reached a 90% sensitivity and 91% specificity, considering the laboratory method as the ‘gold standard’, sparing > 80% of subjects the laboratory tests at the expense of a 1% false negative rate and an 8% false positive rate. Regarding sensitivity and specificity, the ACR test performs very similarly in the general

population and in the diabetics. The stability study showed that storage at -20 3-MA clinical trial degrees C induced a significant decrease in

the albumin concentration with both methods, such that 5% of the samples were re-classified in the lower ACR class. Storage at -80 degrees C for up to 12 months did not affect the measurement with both methods.\n\nConclusion. Clinitek Microalbumin strips can be used for screening purposes in the general population since they correctly classify a significant percentage of subjects, particularly those with a normal albuminuria. Storage at -80 degrees C does not affect strip results. Screening with the strip and confirming positive results with a wet chemistry method are an efficient strategy for detecting albuminuria in the general population.”
“Objective: To compare the this website efficacy and tolerability of surgical excision and radiotherapy with those of cryotherapy and intralesional steroid treatment of keloids. Subjects and Methods: Twenty-six patients with a total of 76 keloids were enrolled in this study. Nineteen patients with 44 keloids underwent surgical excision combined with immediate 12-Gy irradiation (group A) while the remaining 9 patients with 32 keloids received multiple sessions of intralesional steroid treatment after cryotherapy which continued until flattening of lesion(s) occurred (group B). Two patients were included in both treatment groups. All patients were followed up at regular intervals for at least 1 year.

Results: The overall prevalence of depression was 23 9% (n = 256)

Results: The overall prevalence of depression was 23.9% (n = 256). Depression was more prevalent

in women with only 4-7 years of education, in Barasertib women who belong to socioeconomic class D or E, in those who abuse or are dependent on alcohol, or in women who showed an anxiety disorder or suicide risk (p < 0.050). Discussion: Based on these findings, we emphasize the integration of mental health care into primary care through diagnostic evaluations and treatment protocols that cover depression and its comorbidities. Molina MRAL, et al. / Rev Psiq Clin. 2012; 39(6): 194-7″
“Aberrant redeployment of the ‘transient’ events responsible for bone development and postnatal longitudinal growth has been reported in some diseases in what is otherwise inherently ‘stable’ cartilage. Lessons may be learnt from the molecular mechanisms underpinning transient Selleck 3 Methyladenine chondrocyte differentiation and function, and their application may better identify disease aetiology. Here, we review the current evidence supporting this possibility. We firstly outline endochondral ossification and the cellular and physiological mechanisms

by which it is controlled in the postnatal growth plate. We then compare the biology of these transient cartilaginous structures to the inherently stable articular cartilage. Finally, we highlight specific scenarios in which the redeployment of these embryonic processes may contribute to disease development, with the foresight that deciphering those mechanisms regulating pathological changes and loss of Selleckchem Napabucasin cartilage

stability will aid future research into effective disease-modifying therapies.”
“Increased insulin-like growth factor (IGF) signalling has been observed in breast cancer, including endocrine-responsive cancers, and has been linked to disease progression and recurrence. In particular, IGF-1 has the ability to induce and promote lymphangiogenesis through the induction of vascular endothelial growth factor C (VEGFC). In the present study, we analyzed serum and tumour samples from 60 patients with endocrine-positive breast cancer to determine the expression and the possible relationship of circulating IGF-1, IGF binding protein 3 (IGFBP3), and VEGFC with the presence of lymphatic metastasis and other immunohistochemical parameters. The analysis revealed a clear and significant correlation between high basal levels of IGF-1, IGFBP3, and VEGFC and lymph node metastasis in endocrine-responsive breast cancer. In addition, expression of those molecules was significantly higher in breast cancer patients than in healthy control subjects. Those findings may enable more accurate prediction of prognosis in patients with breast cancer.”
“Purpose of review\n\nTopics relating to the spondyloarthropathies have been reviewed recently, but the detailed roles of Chlamydia trachomatis and C.

As predicted, subjects treated daily with corticosterone healed m

As predicted, subjects treated daily with corticosterone healed more

slowly than did controls. In contrast, subjects that had been chased daily healed at the same rate as controls. Surprisingly, repeated chasing did not elevate plasma corticosterone despite causing drops in body mass and survival. Additionally, females healed more slowly than males, possibly due to energetic constraints. (C) 2015 Elsevier Inc. All rights reserved.”
“BACKGROUND. Conventional karyorype has an established role in myelodysplastic syndrome (MDS) and is included in the International Prognostic Scoring System (IPSS) for patient risk stratification and treatment selection. Although some chromosomal abnormalities have been well

characterized, the significance of several miscellaneous, infrequent, single chromosomal abnormalities remains to be defined. In addition, the emerging therapeutic agents may change the natural Course of disease in patients with MDS and the cytogenetic impact on risk stratification.\n\nMETHODS. Clinicopathologic data were retrieved on 1029 patients who had a diagnosis of primary MDS and had available cytogenetic data (karyotype) on file.\n\nRESULTS. Cytogenetic abnormalities were identified in 458 patients (45%) and occurred most frequently in patients who had refractory anemia with excess blasts (62%). Overall, the 3 cytogenetic risk groups defined by the IPSS-good, intermediate, and poor-effectively stratified CBL0137 the patients’ overall survival (OS) (64 months, 31 months, and 12 months, respectively; P < .001). With the exception of gain of chromosome 8, single cytogenetic abnormalities within

the intermediate group were extremely infrequent in the series but demonstrated variable OS ranging from 10 months for patients who had isochromosome (17q) to 69 months for patients who had deletion of 12p [del(12p)], suggesting different prognostic significance. In the poor cytogenetic risk group, patients with isolated del(7q) 3-MA supplier and derivative (1;7)(q10;p10) had a significantly better median OS than patients who had either loss of chromosome 7 or a complex karyotype (P < .05).\n\nCONCLUSIONS. The Current data generated from a large cohort of patients with primary MDS indicated that some specific cytogenetic abnormalities carry different risk than their IPSS cytogenetic risk-group assignment, especially in the new treatment era. Because of the extreme low frequency, additional combined studies are needed to better categorize some rare single cytogenetic abnormalities within the intermediate cytogenetic risk group. Cancer 2008;113:3331-40. (C) 2008 American Cancer Society.”
“Staphylococcus aureus is a frequent cause of acute endophthalmitis, and infection with this virulent bacterium is often associated with a poor visual outcome.

VIS analyses of 42 carnitine moieties in plasma samples from fast

VIS analyses of 42 carnitine moieties in plasma samples from fasting type 2 diabetics (n = 44) and noncliabetics (n = 12) with or without the UCP3 g/a polymorphism in = 28/genotype: 22 diabetic, 6 nondiabetic/genotype) were conducted. Contrary to our hypothesis, genotype had a negligible impact on plasma metabolite patterns. However, a comparison of nondiabetics vs. type 2 diabetics revealed a striking increase in the concentrations

of fatty acylcarnitines reflective of incomplete LCFA beta-oxidation in the latter (i.e. summed C10- to C14-carnitine concentrations were similar to 300% of controls; P = 0.004). Across all volunteers (n = 56), acetylcarnitine rose and propionylcarnitine decreased with increasing hemoglobin A1c (r = 0.544, P < 0.0001; and r = -0.308, P SIS3 nmr < 0.05, respectively) and with increasing total plasma acylcarnitine

concentration. In proof-of-concept studies, we made the novel observation that C12-C14 acylcarnitines significantly stimulated nuclear factor kappa-B activity (up to 200% of controls) in RAW264.7 cells. These results are consistent with the working hypothesis that inefficient tissue LCFA beta-oxidation, due in part to a relatively low tricarboxylic acid cycle capacity, increases tissue accumulation of acetyl-CoA and generates chain-shortened AZD1390 acylcarnitine molecules that activate proinflammatory pathways implicated in insulin resistance. J. Nutr. 139: 1073-1081, 2009.”
“Ginsenoside Rb1 is the most abundant ginsenoside in Panax Epigenetic signaling pathway inhibitor (ginseng). The hydrolysis of this ginsenoside produces compound K, the biologically active ginsenoside of ginseng. We previously identified a fungus Paecilomyces Bainier sp. 229 (sp. 229), which can efficiently convert ginsenoside Rb1 to compound K. In this report,

the ginsenoside hydrolyzing beta-glucosidases were isolated from sp. 229 and the pathway of the biotransformation of ginsenoside Rb1 to compound K by sp. 229 was investigated. Based on reverse-phase HPLC and TLC analysis, we found the main metabolic pathway is as follows: ginsenoside Rb1 -> ginsenoside Rd -> ginsenoside F2 -> compound K. Moreover, the results showed that there were other metabolic pathways: ginsenoside Rb1 -> ginsenoside XVII -> ginsenoside F2 -> compound K and ginsenoside Rb1 -> ginsenoside Rg3 -> ginsenoside Rh2. These processes would allow the specific bioconversion of ginsenoside Rb1 to various ginsenosides using an appropriate combination of specific microbial enzymes. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.”
“Concurrent EEG/fMRI recordings represent multiple, simultaneously active, regionally overlapping neuronal mass responses.

This study provided clues to the establishment of a cutoff value

This study provided clues to the establishment of a cutoff value for HLA antibody screening in an evidence-based manner for the prevention of TRALI.”
“In this study, serum samples collected from 200 cattle, 200 sheep and 223 equids (114 horse, 67 donkey, 42 mule) in five province include (Samsun, Sinop, Ordu, Amasya and Tokat) in Blacksea Region. The seroprevalances were detected for bluetongue by competitive ELISA (cELISA), for akabane and bovine ephemeral E1 Activating inhibitor fever by blocking ELISA, and for equine infectious anemia by agar gel immunodiffusion test (AGID). According to obtained data, the seroprevalance of bluetongue was

recorded as 3% (6/200) in sheep, 11% (22/200) in cattle, the seroprevalance

of akabane was recorded as 0.5% (1/200) in sheep, 22% (44/200) in cattle, the seroprevalence of bovine ephemeral fever infection was found as 13.5% (27/200) in cattle. No antibody against EIAV was detected in equids.”
“Knowledge of the anatomy of the coronary sinus (CS) and cardiac venous drainage is important because of its relevance in electrophysiologic procedures and cardiac surgeries. Selleck Buparlisib Several procedures make use of the CS, such as left ventricular pacing, mapping and ablation of arrhythmias, retrograde cardioplegia, targeted drug delivery, and stem cell therapy. As a result, it is more important for physicians interpreting the results of computed tomographic (CT) examinations dedicated to the heart or including the heart to be able to identify normal variants and congenital anomalies and to understand their clinical importance. Abnormalities of the CS range from anatomic morphologic variations to hemodynamically significant anomalies such as an unroofed CS, anomalous pulmonary venous connection to the CS, and coronary artery-CS fistula. It can be important to identify some anatomic

variations, even though they are clinically occult, to ensure appropriate preprocedural planning. Both CT and magnetic resonance imaging provide excellent noninvasive depiction of the anatomy and anomalies of the CS. Supplemental material available at buy Bucladesine (C)RSNA, 2012 .”
“Background: Injection opioid use plays a significant role in the transmission of HIV infection in many communities and several regions of the world. Access to evidence-based treatments for opioid use disorders is extremely limited. Methods: HIV Prevention Trials Network 058 (HPTN 058) was a randomized controlled trial designed to compare the impact of 2 medication-assisted treatment (MAT) strategies on HIV incidence or death among opioid-dependent people who inject drugs (PWID). HIV-negative opioid-dependent PWID were recruited from 4 communities in Thailand and China with historically high prevalence of HIV among PWID.

Methods: In this prospective study, 36 melanoma patients (23 fema

Methods: In this prospective study, 36 melanoma patients (23 females and 13 males, mean age 62.7 +/- 11.1 Ispinesib purchase years) undergoing LN excision at the Department of Dermatology and Allergy, University of Bonn, were included between July 2011 and July 2012. Real-time tissue elastography was

planned prior to surgery and histopathological examination. Elasticity images had been qualitatively scored for the proportion of stiff areas from pattern 1-5 (soft to stiff) on the basis of a newly defined system for LNs. Results: A total of 42 LNs have been removed in 36 patients. Of these 42 LNs, 21 carried melanoma cells and 21 were benign LNs. Significant differences in elastographic patterns were found between metastatic and nonmetastatic LNs. In real-time tissue elastography, 19 (90.5%) of 21 metastatic LNs showed a pattern of 3, 4 or 5. Of all benign LNs, 76.2% had a pattern of 1 or 2 in their elastogram. Sensitivity and specificity of B-mode sonography combined with PDS were 80.9 and 76.2%, Wnt signaling respectively, 90.5 and 76.2% for elastography and 95.2 and 76.2% for the combined evaluation. Conclusion: An elastography pattern >= 3 was

identified as an independent significant factor, predicting a metastatic LN involvement. The combination of elastography with conventional B-mode sonography has the potential to further improve the differentiation between benign and metastatic peripheral LNs in melanoma patients. Copyright (C) 2013 S. Karger AG, Basel”
“Background: Despite the continuous efforts to improve the quality of life of Orang Asli (Aborigines) communities, these

communities are still plagued with a wide range of health problems including ML323 Ubiquitin inhibitor parasitic infections. The first part of this study aimed at determining the prevalence of soil-transmitted helminth (STH) infections and identifying their associated factors among rural Orang Asli children.\n\nMethods: A cross-sectional study was carried out among 484 Orang Asli children aged <= 15 years (235 females and 249 males) belonging to 215 households from 13 villages in Lipis district, Pahang, Malaysia. Faecal samples were collected and examined by using formalin-ether sedimentation, Kato Katz and Harada Mori techniques. Demographic, socioeconomic, environmental and behavioural information were collected by using a pre-tested questionnaire.\n\nResults: Overall, 78.1% of the children were found to be infected with one or more STH species. The prevalence of trichuriasis, ascariasis and hookworm infections were 71.7%, 37.4% and 17.6%, respectively. Almost all, three quarters and one fifth of trichuriasis, ascariasis and hookworm infections, respectively, were of moderate-to-heavy intensities.