There are already substantial costs to farms and agribusiness from non-biosecure

diseases/conditions. Experts preferred an equal allocation of resources between these biosecure and non-biosecure diseases/conditions, with emphasis on adopting/adapting international models, education and awareness-raising. The results from this study provide robust insights about non-regulatory animal health priorities in Ireland, as perceived by experts and farmers, using methodologies that are both transparent and inclusive. They have already been extremely influential in shaping national policy, as a foundation BEZ235 PI3K/Akt/mTOR inhibitor for interdisciplinary (and multi-agency) cooperation, as a contribution to efforts to encourage stakeholder responsibility-taking, and to ongoing development of postgraduate and undergraduate veterinary education in Ireland. (C) 2010 Elsevier B.V. All rights reserved.”
“Greenhouse experiments were conducted to assess the effects of soil salinity on emergence, growth, water status, proline content and mineral accumulation of seedlings of Avicennia marina (Forssk.) Vierh. NaCl was added to the soil and salinity was maintained at 0.2, 2.5, 5.1, 7.7, 10.3, 12.6, 15.4, 17.9, 20.5, 23.0, 25.6 and 28.2 psu. A negative relationship between seedling emergence and salt concentration was obtained. selleck Nevertheless, this mangrove is highly salt tolerant during germination. Growth

GSK1120212 manufacturer of seedlings was significantly promoted by low salinity and optimum growth was obtained at 15.4 psu. Higher salinities inhibited plant growth. Growth and dry matter accumulation in tissues followed the same optimum curve. Water potential of tissues became significantly more negative with increasing salinity, and praline content

significantly increased. Moreover, water potential and praline content of tissues displayed an S-curve with the inflection point below similar to 10 psu. The concentration of Na in tissues increased significantly, whereas K, Ca, Mg, N and P content decreased. (C) 2010 Elsevier B.V. All rights reserved.”
“Joint bleeds in haemophilia result in iron-mediated synovitis and cartilage damage. It was evaluated whether deferasirox, an iron chelator, was able to limit the development of haemophilic synovitis and cartilage damage. Haemophilic mice were randomly assigned to oral treatment with deferasirox (30 mg/kg) or its vehicle (control) (30 mg/kg). Eight weeks after start of treatment, haemarthrosis was induced. After another five weeks of treatment, blood-induced synovitis and cartilage damage were determined. Treatment with deferasirox resulted in a statistically significant (p smaller than 0.01) decrease in plasma ferritin levels as compared to the control group (823 ng/ml +/- 56 and 1220 ng/ml +/- 114, respectively). Signs of haemophilic synovitis, as assessed by the Valentino score [range 0 (normal) - 10 (most affected)], were not different (p=0.

For reactions of histidine, tryptophan, and tyrosine with ClO2, products vary depending MAPK inhibitor largely on the molar ratios

of ClO2 with the specific amino acid. Products of ClO2 oxidation differ with the presence or absence of oxygen in the reaction mixture. Excess molar amounts of ClO2 relative to amino acids are associated with the production of low molecular weight compounds. The oxidation of the biochemically important compounds bovine serum albumin and glucose-6-phosphate dehydrogenase by ClO2 suggests a denaturing of proteins by ClO2 by an attack on tryptophan and tyrosine residues and relates to the inactivation of microbes by ClO2.”
“Changes in body temperature are significant physiological consequences of stressful stimuli in mammals and birds.

Pigeons (Columba livia) prosper in (potentially) stressful urban environments and are common subjects Selleck PF-04929113 in neurobehavioral studies; however, the thermal responses to stress stimuli by pigeons are poorly known. Here, we describe acute changes in the telemetrically recorded celomatic (core) temperature (Tc) in pigeons given a variety of potentially stressful stimuli, including transfer to a novel cage (ExC) leading to visual isolation from conspecifics, the presence of the experimenter (ExpR), gentle handling (H), sham intracelomatic injections (SI), and the induction of the tonic immobility (TI) response. Transfer to the ExC cage provoked short-lived hyperthermia (10-20 min) followed by a long-lasting Elafibranor mw and substantial decrease in Tc, which returned to baseline levels 2 h after the start of the test After a 2-hour stay in the ExC, the other potentially stressful stimuli evoked only weak, marginally significant hyperthermic (ExpR, IT) or hypothermic (SI) responses. Stimuli delivered 26 h after transfer to the ExC induced definite and intense increases in Tc (ExpR,

H) or hypothermic responses (SI). These Tc changes appear to be unrelated to modifications in general activity (as measured via telemetrically recorded actimetric data). Repeated testing failed to affect the hypothermic responses to the transference to the ExC, even after nine trials and at 1- or 8-day intervals, suggesting that the social (visual) isolation from conspecifics may be a strong and poorly controllable stimulus in this species. The present data indicated that stress-induced changes in Tc may be a consistent and reliable physiological parameter of stress but that they may also show stressor type-, direction- and species-specific attributes. (C) 2014 Elsevier Inc. All rights reserved.”
“Type 2 diabetes is often developed in genetically predisposed subjects combined with sedentary life style or environmental factors. In women with polycystic ovary syndrome, hyperandrogenism is often accompanied with hyperinsulinemia and insulin resistance. Further, some studies have found associations of hyperandrogenemia with beta-cell dysfunction and type 2 diabetes.

\n\nOur in vitro experiments suggest an involvement of the 5-HT7 receptor subtype in contractility of equine intestine. While the 5-HT7 receptor has been established

to be constitutively active and inhibits smooth muscle contractility, our experiments demonstrate an increase in contractility by the 5-HT7 receptor ligand P5091 price SB-269970, suggesting it exerting inverse agonist properties. (C) 2009 Elsevier Ltd. All rights reserved.”
“Patient safety has been the subject of surgical investigation for the past century. A specific focus on safety and medical errors has incited public attention, government oversight, and research funding. Traditional efforts have been focused on the individual responsible for the “mistake,” while current procedure focuses on a systems approach. A critical analysis of medical errors, their frequency and cause, and outcomes associated with their occurrence has allowed the identification of system-based issues and the implementation of corrective changes to improve these systems. Constant vigilance examining errors and how they occur will allow identification of strategies to reduce errors.”
“Evidence is accumulating that commonly used pesticides are linked

to decline of pollinator populations; adverse effects of three neonicotinoids on bees have led to bans on their use across the European Union. Developing insecticides that pose negligible risks to JQ1 datasheet beneficial organisms such as honeybees is desirable and timely. One strategy is to use recombinant fusion proteins containing neuroactive peptides/proteins linked to a ‘carrier’ protein that confers oral toxicity. Hv1a/GNA (Galanthus nivalis agglutinin), containing an insect-specific spider venom calcium channel blocker (omega-hexatoxin-Hv1a) linked to snowdrop lectin (GNA) as a ‘carrier’, is an effective oral biopesticide towards various insect pests. Effects of Hv1a/GNA towards a non-target species, Apis mellifera,

were assessed through a thorough early-tier risk assessment. Following feeding, honeybees internalized Hv1a/GNA, which reached the brain within 1 h after exposure. However, survival was only slightly affected by ingestion (LD50 bigger than 100 mu g bee(-1)) or injection of fusion protein. https://www.selleckchem.com/products/ON-01910.html Bees fed acute (100 mu g bee(-1)) or chronic (0.35 mg ml(-1)) doses of Hv1a/GNA and trained in an olfactory learning task had similar rates of learning and memory to no-pesticide controls. Larvae were unaffected, being able to degrade Hv1a/GNA. These tests suggest that Hv1a/GNA is unlikely to cause detrimental effects on honeybees, indicating that atracotoxins targeting calcium channels are potential alternatives to conventional pesticides.”
“The importance of cellular pH has been shown clearly in the study of cell activity, pathological feature, and drug metabolism.

One single oral administration was not enough to suppress specific serum Ig and IgG1 levels in the Aa-fed group, although

it was efficient to induce suppression in the control group. The present results indicate that the stimulation by dietary proteins alters both inflammatory reactivity and regulatory immune reactivity in mice probably due to their effect in the maturation of the immune system.”
“Background: Cortical inhibition (CI) deficits have been demonstrated in schizophrenia using transcranial magnetic stimulation (TMS). These CI deficits may be related to decreased GABA activity which may be involved in schizophrenia pathophysiology. Previous cross-sectional studies have also demonstrated greater CI Rigosertib inhibitor in patients treated Selleckchem JQ1 with clozapine than other typical/atypical antipsychotics. However, it is not clear if these differences in CI are a result of treatment-resistant illness which necessitates clozapine or

are related to clozapine treatment. Methods: TMS measures of CI (i.e., cortical silent period (CSP) and short-interval cortical inhibition (SICI)) were measured over the motor cortex in 16 patients with schizophrenia before starting clozapine, then 6 weeks and 6 months after starting clozapine. Results: CSP was significantly longer after 6 weeks of treatment with clozapine (p = 0.014). From 6 weeks to 6 months, there was no significant difference in CSP (p bigger than 0.05). Short-interval cortical inhibition (SICI) was not significantly different at any time after treatment with clozapine (p bigger than 0.05). Conclusions: This prospective-longitudinal study demonstrates that treatment with clozapine is associated with an increase in GABA(B) mediated inhibitory neurotransmission. Potentiation of GABA(B) may be a novel neurotransmitter mechanism that is involved in the pathophysiology and treatment of schizophrenia. (C) 2015 Elsevier B.V. All rights reserved.”
“Background/aims The study involved eyes affected by pigment dispersion syndrome (PDS) or pigmentary Selleckchem Rigosertib glaucoma (PG) investigated

by ultrasound biomicroscopy (UBM). Different irido-corneal parameters were assessed and compared with those from healthy controls. The aim was to investigate the capacity of the UBM in differentiating the cases and, potentially, in confirming the pathogenic mechanisms.\n\nMethods Patients with a first diagnosis of PDS or PG were included. A cohort of healthy volunteers matched for sex, age and refractive errors was recruited. All underwent UBM examination: the following parameters were assessed in relaxed and stimulated accommodative state in one eye: iris-lens contact (ILC), irido-corneal angle (ICA) and iris concavity (IC). A receiver operating characteristic (ROC) analysis assessed the ability of UBM to discriminate between subjects with and without PDS/PG.\n\nResults There were 24 eyes in the case group: four diagnosed as PG and the remaining 20 as PDS. There were 25 eyes in the control group.

Perfusate biomarker concentrations

had no relevant correlation with cold ischemic time or renal vascular resistance on the pump.\n\nConclusions. Increased GST, NAG, or H-FABP concentrations during MP are an indication to adjust posttransplant recipient management. However, this study shows for the first time that perfusate biomarker measurements should not lead to kidney discard.”
“Free-breathing image acquisition is desirable in first-pass gadolinium-enhanced magnetic resonance imaging (MRI), KPT-8602 concentration but the breathing movements hinder the direct automatic analysis of the myocardial perfusion and qualitative readout by visual tracking. Nonrigid registration can be used to compensate for these movements but needs to deal with local contrast and intensity changes with time. We propose an automatic registration scheme that exploits the quasiperiodicity

of free breathing to decouple movement from intensity change. First, we identify and register a subset of the images corresponding to the same phase of the breathing cycle. This registration step deals with small differences caused by movement but maintains the full range of intensity change. The remaining images are then registered to synthetic references that are created as a linear combination of images Cell Cycle inhibitor belonging to the already registered subset. Because of the quasiperiodic respiratory movement, the subset images are distributed evenly over time and, therefore, the synthetic references exhibit intensities similar to their corresponding unregistered images. Thus, this second registration step needs to account only for the movement. Validation experiments were performed on data obtained from AZD1208 mw six patients, three slices per patient, and the automatically obtained perfusion profiles were compared with profiles obtained by manually segmenting the myocardium. The results show that our automatic approach is well suited to compensate for the free-breathing movement and that it achieves a significant improvement in the average Pearson correlation coefficient between manually and automatically

obtained perfusion profiles before (0.87 +/- 0.18) and after (0.96 +/- 0.09) registration.”
“Rationale, aims and objectives There are a variety of resources to obtain health information, but few studies have examined if main and allied health professionals prefer different methods. The current study was to investigate their information-searching behaviours. Methods A constructed questionnaire survey was conducted from January through April 2011 in nationwide regional hospitals of Taiwan. Questionnaires were mailed to main professionals (physicians and nurses) and allied professionals (pharmacists, physical therapists, technicians and others), with 6160 valid returns collected. Results Among all professional groups, the most commonly used resource for seeking health information was a Web portal, followed by colleague consultations and continuing education.

Conclusion Overall, 83% treatment success rate was achieved. However, our study findings highlight the need to improve TB services for certain vulnerable groups and in specific areas of the country. They also emphasize the need to develop unified monitoring and evaluation tools for drug-susceptible and drug-resistant TB, and call for better TB surveillance and coordination between provinces and neighbouring countries.”
“Tissue engineering offers a new approach

for the construction of vascular substitutes in vitro with proper mechanical properties. Although success has been made in the engineering of small blood vessels (< 6 mm in diameter), it remains a challenge to engineer large vessels (> 6 mm in diameter) due to their insufficient biomechanical property. In the current study, an elastic large vessel wall (6 rum in diameter) was engineered by loading a polyglycolic acid (PGA) unwoven fiber scaffold seeded with smooth muscle cells (SMCs) on a vessel PLX3397 purchase reactor designed with dynamic culture conditions. SMCs were isolated from canine carotid artery and expanded before seeding on a PGA fiber mesh. The cell-seeded PGA this website mesh was then loaded on a

vessel reactor and subjected to pulsatile stimuli. Grossly, an elastic vessel wall was formed after 8 weeks of dynamic engineering. Histological examination showed well-orientated smooth muscle cells and collagenous fibers in the group with dynamic culture. In addition, the phenotype of SMCs was confirmed by positive staining of smooth muscle alpha-actin and calponin. On the contrary, disorganized smooth muscle cells and collagenous fibers were observed in the group under static culture without stimuli. Furthermore, the engineered vessels under dynamic culture exhibited significant improvements on biomechanical property over the one from static culture. Our results selleck kinase inhibitor indicate that the approach developed in the current work is efficient for large vessel engineering. This approach may also be suitable for the engineering of other tissues with muscular tubular structure. (c) 2007 Elsevier Ltd. All rights reserved.”
“In female sheep, estradiol (E-2) stimulates

the preovulatory GnRH/LH surge and receptive behavior, whereas progesterone blocks these effects. Prenatal exposure to testosterone disrupts both the positive feedback action of E-2 and sexual behavior although the mechanisms remain unknown. The current study tested the hypothesis that both prenatal and postnatal steroids are required to organize the surge and sex differences in reproductive behavior. Our approach was to characterize the LH surge and mating behavior in prenatally untreated (Control) and testosterone-treated (T) female sheep subsequently exposed to one of three postnatal steroid manipulations: endogenous E-2, excess E-2 from a chronic implant, or no E-2 due to neonatal ovariectomy (OVX). All females were then perfused at the time of the expected surge and brains processed for estrogen receptor and Fos immunoreactivity.

The IWT subjects trained at a target of 60 min of AR-13324 fast walking at bigger than 70% peak aerobic capacity for walking ((V) over dotO(2peak)) per wk for 12 wk, while those in the CNT maintained their previous sedentary life during the same period. We measured the energy expenditure of the daily physical activity, except during sleeping and bathing, every minute and every day during the intervention. We also measured the isometric knee extension (F-EXT) and flexion (F-FLX) forces, (V) over dotO(2peak), and anaerobic threshold during the graded cycling exercise ((V) over dotO(2AT)) before

and after the intervention. All subjects, except for one in IWT, completed the protocol. FFLX increased by 23% on the operated side (P = 0.003) and 14% on the non-operated

side of IWT (P = 0.006), while it only increased on the operated side of CNT (P = 0.03). The (V) over dotO(2peak) 4SC-202 nmr and (V) over dotO(2AT) in IWT increased by 8% (P = 0.08) and 13% (P = 0.002), respectively, and these changes were significantly higher in the IWT than in CNT group (both, P smaller than 0.05). In conclusion, IWT might be an effective home-based training regimen for preventing the muscle atrophy from reduced daily physical activity in THA patients.”
“Alcohol is the most commonly abused drug worldwide, and chronic alcohol consumption is a major etiological factor in the development of multiple pathological sequelae, including alcoholic cardiomyopathy and hepatic cirrhosis. Here, we identify regulator of G protein signaling 6 (RGS6) as a critical regulator of both alcohol-seeking behaviors and the associated cardiac and hepatic morbidities through two mechanistically divergent signaling actions. RGS6(-/-) mice consume less www.selleckchem.com/products/mk-5108-vx-689.html alcohol when given free access and are less susceptible to alcohol-induced reward and withdrawal. Antagonism of GABA(B) receptors or dopamine D2 receptors partially reversed the reduction in alcohol

consumption in RGS6(-/-) animals. Strikingly, dopamine transporter inhibition completely restored alcohol seeking in mice lacking RGS6. RGS6 deficiency was associated with alterations in the expression of genes controlling dopamine (DA) homeostasis and a reduction in DA levels in the striatum. Taken together, these data implicate RGS6 as an essential regulator of DA bioavailability. RGS6 deficiency also provided dramatic protection against cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endo-toxemia when mice were forced to consume alcohol. Although RGS proteins canonically function as G-protein regulators, RGS6-dependent, alcohol-mediated toxicity in the heart, liver, and gastrointestinal tract involves the ability of RGS6 to promote reactive oxygen species-dependent apoptosis, an action independent of its G-protein regulatory capacity.

All rights reserved.”
“P>The purpose of the present investigation was to characterize and compare traditional sleep architecture and non-rapid eye movement (NREM) sleep microstructure in a well-defined cohort of children with regressive and non-regressive autism, and in typically developing children

(TD). We hypothesized that children with regressive autism would demonstrate a greater degree of sleep disruption either at a macrostructural or microstructural level and a more problematic sleep as reported by parents. Twenty-two VX-770 Transmembrane Transporters inhibitor children with non-regressive autism, 18 with regressive autism without comorbid pathologies and 12 with TD, aged 5-10 years, underwent standard overnight multi-channel polysomnographic evaluation. Parents completed a structured questionnaire (Childrens’ Sleep Habits Questionnaire-CSHQ). The initial hypothesis, that regressed children have more disrupted sleep, was supported by our findings that they scored significantly higher on CSHQ, particularly on bedtime resistance, sleep onset delay, sleep duration and night wakings CSHQ subdomains than non-regressed peers, and both scored more than typically developing controls. Regressive subjects had significantly less efficient sleep, less total sleep time, prolonged sleep latency, prolonged REM latency and more time awake after sleep onset

than non-regressive selleck products children and the TD group. Regressive children showed lower cyclic alternating pattern (CAP) rates and A1 index in light sleep than non-regressive and TD children. Our findings suggest AZD7762 chemical structure that, even though no particular differences in sleep architecture were found between the two groups of children with autism, those who experienced regression showed more sleep disorders and a disruption of sleep either from a macro- or from a microstructural viewpoint.”
“Introduction. An endophthalmitis following penetrating keratoplasty by

Pseudomonas aeruginosa is a devasting case with very poor visual outcomes.\n\nObjective. To determine the origin of an infection after a penetrating keratoplasty.\n\nMaterials and methods. After an endophthalmitis an epidemiological study was undertaken with the approval of the ethics committee and support of a medical team comprised of an epidemiologist, infectologist, bacteriologist and ophthalmologists specializing in cornea. Factors that may have contributed to the risk of infection were assessed, for example, the processing and preservation of the cornea in the moment of the extraction, the characteristics of the donor, recipient and infecting bacterium, as well as the details pertaining to the surgical operation.\n\nResults. No risks factors were found in the institution, in the eye bank facilities, in the donor or in the receptor.

“
“This

study was designed to compare the effectiveness of Aluminium (Al) and Iron (Fe) as electrodes to reduce the polluting nature of Palm Oil Mill Effluent (POME) and simultaneous hydrogen production using electrocoagulation (EC). Electrocoagulation of raw POME and anaerobically pretreated POME was performed using Direct Current (DC) electricity of 2.0, 3.0, and 4.0 volts in a reactor volume of 20 liters. Nutlin-3 The results of raw POME treatment reveal that the chemical oxygen demand (COD) and turbidity was decreased around 57.66% and 62.5%, respectively, using Al electrode. However, the use of iron electrodes could reduce the COD and turbidity of raw POME about 35.3% and 43.10%, respectively. The reduction in polluting factors of the

raw POME was accompanied with the production of 42% and 22.8% of hydrogen gas concentration using Al and Fe electrodes, respectively. On the other hand, the results of Electrocoagulation of POME which was pretreated in anaerobic pond show that the COD was decreased around 62.35% and 59.41% using Al and Fe respectively, and turbidity was reduced up to 90.55% and 76.96% using Al and Fe respectively. The concentration of hydrogen gas yielded as a result of EC of anaerobically pretreated POME was around 31.37% and 25.6% using Al and Fe respectively as electrodes. Removal of pollutants from POME using Electrocoagulation is faster than some other CDK inhibitor existing

processes and requires a relatively small area as compared to the conventional anaerobic treatment in pond system which is potential source of green house gases.”
“Following Ulixertinib the previous work of media layer and adventitia layer construction for vascular scaffold, we developed a suitable intima layer scaffold for endothelialization using novel human-like collagen/hyaluronic acid composite at different mass ratios of 40/1, 20/1 and 10/1 (HLC to HA) by freeze-drying process. The structure, mechanical strength, degradation and biocompatibility of the vascular HLC/HA scaffold were evaluated. The results showed that the 10/1 HLC/HA composited an optimal scaffold with (1) an interconnected porous network with a pore diameter of 12 2 pm and porosity of 89.3%, (2) better mechanical properties with higher stress of 321.7 +/- 15 kPa and strain of 45.5 +/- 0.2% than 40/1,20/1 and pure HLC scaffolds, (3) only 9% degradation upon immersion in PBS for 45 days at 37 degrees C in vitro, and (4) excellent biocompatibility. This study suggests that the 10/1 HLC/HA composite has a broad prospect of application as luminal vascular scaffold in the tissue engineering. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved.”
“The vascular system of vertebrates consists of an organized, branched network of arteries, veins, and capillaries that penetrates all the tissues of the body.

01). The effects of these polymorphisms were not modified by personal smoking or secondhand-smoke exposure.\n\nConclusions: Functional promoter variants in CAT and HMOX-1 showed ethnicity-specific associations with new-onset asthma. Oxidant gene protection was restricted to children living in low-ozone communities.”
“Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting

in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance SB203580 may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting GNS-1480 clinical trial model for the familial aggregation of prostate cancer was the mixed recessive model.

The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% Cl 46-192), and a polygenic standard deviation of 2.01 (95% Cl 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes.

Genet. Epidemiol. 34:42-50, 2010. (c) 2009 Wiley-Liss, Inc.”
“The AQP9 gene contains a negative insulin response element, suggesting that it www.selleckchem.com/products/a-1210477.html may be modulated by insulin. Previously, we reported AQP9 overexpression in preeclamptic placentas but a lack of functionality of AQP9 in water and mannitol transport. We also observed high serum levels of insulin and TNF-alpha in preeclamptic women.\n\nObjective: To evaluate whether AQP9 expression is regulated by insulin in the human placenta, and whether the dysregulation of AQP9 observed in preeclamptic placentas may be related to the inability to respond to insulin stimuli.\n\nMethods: Explants from normal and preeclamptic placentas were cultured at different concentrations of insulin. Treatment with TNF-alpha was used to induce phosphorylation of insulin receptor substrate (IRS), which may desensitize insulin action. AQP9 molecular expression and water uptake was determined.\n\nResults: Insulin decreased the molecular expression of AQP9 exclusively in explants from normal placentas in a concentration-dependent manner.