HER2 inhibitors|HER2 pathway

However, we have identified a number of lifestyle or

environmentally related inducers that may cause metaflammation, even in the absence of obesity. In this paper, the third of a series linking obesity with broad environmental and evolutionary factors, we identify nutritional stimuli with evidence of an involvement in metaflammation. From this we propose that components of certain foods and beverages with which humans have not evolved, are more often the inducers of an inflammatory effect in the body than those with which humans have become more familiar, and to which a neutral, or anti-inflammatory response may be expected to have developed. The implications of such a finding are considered in Z-DEVD-FMK relation to broader aspects of the environment, economic growth, policy change and current global financial issues.”
“Objective:

We investigated the sexual practices of medical students as they are positioned to serve as peer educators in the fight against HIV/AIDS.\n\nMethods: This was a cross sectional study, where self-administered questionnaires were distributed to consenting 4(th) to 6(th) year medical students in Jos, Nigeria with a view of elucidating information regarding sexual practices and condom utilization. Safe sex practice was defined Ricolinostat as the use of condoms and being in a monogamous relationship.\n\nResults: Of a total of 400 questionnaires distributed, 365 respondents (249 males and 116 females) had adequate data for analysis. A large proportion (62%) of our students have never had sex before and less than 30% of them are sexually active. Only 6.1% had multiple sexual partners and homosexuality was uncommon (1.9%). Condom utilization amongst the sexually active was high (65%) and similar among male and female students (71.3% vs. 51.9% respectively, find more p = 0.08).\n\nConclusion: There exists safe sexual practice among medical students in our setting. This group could be recruited as peer educators in the war

against HIV/AIDS.”
“Objective. To evaluate whether clinical disease activity findings during 1-year followup of patients with juvenile idiopathic arthritis (JIA) is associated with changes of magnetic resonance imaging (MRI)-based disease activity scores. Methods. Patients with JIA who had active knee involvement were studied using an open-bore MRI. After followup of a median of 1.3 years, patients were re-evaluated and classified as improved or unimproved according to the American College of Rheumatology Pediatric-50 (ACR-Ped50) criteria. Baseline and followup MRI features were scored by 2 readers using the Juvenile Arthritis MRI Scoring (JAMRIS) system, comprising validated scores for synovial hypertrophy, bone marrow changes, cartilage lesions, and bone erosions. Results. Data of 40 patients were analyzed (62.5% female, mean age 12.2 yrs). After followup, 27 patients (67.5%) were classified as clinically improved, whereas 13 patients (32.5%) showed no clinical improvement.

Specific inhibitors of calcium/calmodulin kinase II (CaMKII), KN-93, protein kinase A (PICA), H-89, or phosphatidylinositol 3-kinase (PI3K), LY294002, significantly decreased the effects of antidepressant drugs on dendritic outgrowth, whereas this effect was observed only BEZ235 price with tianeptine for the PI3K inhibitor. Taken together, these results suggest that certain

antidepressant drugs can enhance synaptic protein levels and encourage dendritic outgrowth in hippocampal neurons. Furthermore, effects on dendritic outgrowth likely require CaMKII, PICA, or PI3K signaling pathways. The observed effects may be may be due to chronic treatment with antidepressant drugs. (C) 2013 Elsevier Ltd. All rights reserved.”
“Gambling is a heterogeneous and complex disorder. Multiple factors may lead to problem gambling, yet one of the most important appears to be the increased presence of cognitive biases or distortions. These biases are thought to precipitate gambling as they can lead to dysfunctional decision making under www.selleckchem.com/products/ferrostatin-1-fer-1.html risk or ambiguity. Modelling these cognitive perturbations in animals

can improve our understanding of their neurobiological bases, and potentially stimulate novel treatment options. The first aim of this review is to give a broad overview of some of the cognitive biases that are most commonly associated with gambling. Secondly, we will discuss several animal models that we have developed in which rodent decision-making appears hallmarked by the same cognitive inconsistencies as human choice. In particular, we will discuss two tasks that capture elements of risk

and loss averse decision making, and another in which rats appear susceptible to the ‘near-miss’ effect. To date, findings from both human and non-human studies suggest that these different biases are neuropharmacologically and neurostructurally Ro-3306 dissociable, and that dopamine plays a key role in their expression. Lastly, we will briefly discuss areas in both human and animal research where limitations within the field may be hampering a more complete understanding of pathological gambling as a disorder. (C) 2014 Elsevier B.V. All rights reserved.”
“LHON is one of the most common and primary causes of acute blindness in young male adults. Over 95% of LHON cases are caused by one of the three primary mutations (m.11778G>A, m.14484T>C, and m.3460G>A). In contrast to these genetically diagnosed LHON patients, there are many patients with clinical features of LHON but without the three primary mutations, and these patients have been insufficiently analyzed. We reported 10 suspected Chinese LHON families without the three primary mutations. The overall penetrance (53.4%) in these families is significantly higher than in those families with m.11778G>A (33.3%) or m.3460G>A (25.6%). Complete mtDNA genome sequencing of the 10 families showed that they belonged to different haplogroups and all identified variants (excluding m.

0001). Forty-nine patients with lymph node retrieved less than 12 were excluded from further analyses. Among various clinicopathological parameters, univariate analysis identified age (P = 0.0059), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0003), and number of positive nodes (P

< 0.0001) see more and LNR (P < 0.0001) as prognostic factors. The Cox proportional hazards model revealed that age (P = 0.014), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0002), and LNR (group 3, P = 0.0012; group 4, P < 0.0001) were independent prognostic factors. When the American Joint Committee on Cancer (AJCC) seventh staging system was added as a covariate, both AJCC stage (P < 0.0001) and LNR (P < 0.0001) were independent prognostic factors.\n\nAdding the LNR concept to the AJCC cancer staging system will improve accuracy in evaluating the nodal status of distal rectal cancer.”
“Antimicrobial peptides are produced by prokaryotes and eukaryotes with fundamental role of protection against pathogenic microbes. Staphylococcus aureus, a major virulent pathogen in humans, shows multiple drug resistance and is affected by the bacteriocin activity of Mutacin GSK126 IV. Currently, peptide therapeutics has been reported as a potential alternative for treating microbial infections specially exhibiting multiple drug resistance. However, the mechanism of action and interaction

of peptides with target proteins is not known. The current work is an attempt to address the above issue by performing molecular docking and randomization experiments. In this study, antimicrobial peptides of bacterial origin (168 peptides) were collected from APD2 database and their net charge and hydrophobicity values were retrieved. Mutacin IV (APD Id-AP01174), a 44 amino acids long peptide derived from Streptococcus mutans UA140, was selected on the basis PKC412 manufacturer of high hydrophobicity to net charge ratio (0.52) and used for in silico docking studies with

therapeutically important surface proteins viz. IsdA, IsdB, ClfB, and SasG of S. aureus using ZDOCK server. The docking result of IsdB surface protein and Mutacin IV was found better (ZDOCK score 1168.582) as compared to others. Afterwards, the native Mutacin IV sequence was randomized to generate 50 new combinations using EMBOSS (Shuffleseq) tool. The new sequence of Mutacin IV was screened on the basis of high in vivo to in vitro aggregation ratio (i.e. high in vivo aggregation and low in vitro aggregation values) and good binding energies against IsdB surface protein of S. aureus from the randomized sequences. The new peptide sequence showed an in vivo to in vitro aggregation ratio of 2.206 and 0.888, respectively which is higher than native sequence of Mutacin IV ratio (0.205). Moreover, the ZDOCK scores were found to be 1370.529 and 1687.048 which were better than the native sequence of Mutacin IV (ZDOCK score 1168.582).

Methods: The current study was a follow-up of children who were enrolled in a randomized cluster trial at 7-12 mo of age. Children in 12 intervention clusters (communities) were administered a daily 22-element MNP sachet with their food for 5 mo,

and both intervention and control groups (also 12 clusters) received nutrition, health, and hygiene education. The current study involved the assessment of children at 16-22 mo of age (22-element MNP group: n = 96; control group: n = 82) on 3 subtests of the Bayley Scales of Infant and Toddler Development III test to measure cognitive, receptive language, and expressive language development. Results: There was a significant effect of the 22-element MNP on children’s expressive language scores (d = 0.39), and stunting moderated the effect on receptive language scores; there was no effect Givinostat nmr HKI-272 in vivo on cognitive development (d = 0.08). Conclusion: An MNP may thus offer one feasible solution to improve language development of LBW-T children in low-resource community settings. This trial was registered at clinicaltrials.gov as NCT01455636.”
“The purpose

of this study was to investigate characteristics of transungual drug delivery and the feasibility of developing a drug-in-adhesive formulation of terbinafine. The permeation of terbinafine from a PSA matrix across porcine hoof membrane was determined using a plate containing poloxamer gel. The permeation rate of terbinafine across hairless mouse skin was evaluated using a flow-through diffusion cell system. The permeation of terbinafine across the hoof membranes was the highest from the silicone adhesive matrix, followed by PIB, and most of the acrylic adhesives, SIS, and

SBS. The rank order of permeation rate across mice skin was different from the rank order across porcine hooves. The amount of terbinafine permeated across the porcine hoof membranes poorly correlated with the amount of terbinafine remaining inside the hooves after 20 days, however, the ratio between rate of terbinafine partitioning into the hoof membrane and its rate of diffusion across the membrane was relatively constant BI 2536 nmr within the same type of PSA. For influence of various vehicles in enhancing permeation of terbinafine across the hoof membrane, all vehicles except Labrasol(A (R)) showed tendency to improve permeation rate. However, the enhancement ratio of a given vehicle differed from one adhesive to another with a moderate correlation between them. The infrared spectrum of the hoof treated with NMP, PPG 400 or PEG 200 indicated that the conformation of keratin changed from a non-helical to a helical structure.”
“Introduction: Obesity is an epidemic associated with significant morbidity.

(C) 2014 Journal of Shoulder and Elbow Surgery Board of Trustees.”
“Purpose: To report a case of central retinal vein occlusion (CRVO) following cannabis smoke inhalation in a young patient. Methods: An otherwise healthy 18-year-old man without risk factors for www.selleckchem.com/products/dorsomorphin-2hcl.html retinal vein occlusion presented with reduced visual acuity (20/200) secondary to CRVO following cannabis smoke

inhalation. Central retinal vein occlusion was diagnosed on the basis of slit-lamp fundus biomicroscopy and fluorescein angiography. Results: Tests for systemic causes were negative. Following one intravitreal dexamethasone implant (Ozurdex) and one ranibizumab injection (Lucentis), functional (20/20 visual acuity) and anatomic improvement was recorded. Fluorescein angiography showed a decrease in the vascular caliber and tortuosity, with no signs of retinal ischemia or edema. Conclusions: We report CRVO in a young adult following cannabis smoke inhalation. Its occurrence immediately after cannabis smoking further supports a link between the use of cannabis and vascular alterations.”
“This study has assessed the effectiveness of alternative products to agrochemicals for the control of anthracnose AZD5363 cost in the post-harvest

of ‘Uba’ mango. Physiologically mature fruit were sprayed until complete wetting with spore suspension of Colletotrichum gloeosporioides in 2.5 x 10(5) conidia/mL concentration. After air drying, the following were sprayed with distilled water (control), tween 20 (8 mL/L of solution), Prochloraz (1.10 mL Sportak 450 EC/L of solution), garlic oil (10 mL/L + 8 mL/L of

tween this website 20), Acrocomia aculeata almond oil + instant milk powder (IMP) (25 mL/L + 10 g IMP/L), A. aculeata almond oil + tween (25 mL/L + 8 mL/L of tween 20), agro-mos (R) biofertilizer (100 mu L/L), neem oil (10 mL/L + 8 mL/L of tween 20), chitosan (10 mL/L + 8 mL/L of tween 20) and citric biomass (10 mL/L + 8 mL/L of tween 20). The solvent used was distilled water. Incubation period, latent period, fresh weight loss and production of CO2 were assessed along with daily severity and incidence of the disease. Shorter incubation periods of the disease were noted in fruit treated with neem oil, water + tween and citric biomass, with approximately five days. A. aculeata almond oil + IMP and agro-mos (R) were the ones that most delayed the onset of symptoms, resulting in an incubation period of nine days after pathogen inoculation. Regarding severity, A. aculeata almond oil + IMP and Prochloraz were the most efficient in hindering the growth of the pathogen at 8 days after inoculation, but soon fruit treated with A. aculeata almond oil + IMP equaled those treated with the other products. Fruit treated with A. aculeata almond oil + IMP and A.

Although die tossing is in principle predictable, the approach to chaotic dynamics in some limit implies that our ignorance of initial conditions is translated into a probabilistic description: each face comes up with probability 1/6. (3) As is well-known, quantum

mechanics is incompatible with determinism. However, quantum probabilities differ in an essential way from the probabilities introduced previously: it has been shown from the work of John Bell that quantum probabilities are intrinsic and cannot be given an ignorance interpretation based on a hypothetical deeper level of description. (c) 2012 Elsevier Ltd. All rights reserved.”
“Purpose: Castleman’s disease (CD) is an uncommon entity characterized by a massive growth of lymphoid tissue. There are

two types: the hyaline-vascular (HV) type and GNS-1480 the plasma cell (PC) type. The purpose of this study was to evaluate the clinical value of multiple detector computed tomography (MDCT) in the diagnosis and planning of treatment for hyaline-vascular CD.\n\nMaterials and methods: Fifty-two cases of confirmed hyaline-vascular CD were retrospectively reviewed. Unenhanced and contrast-enhanced MDCT scans had been performed in all patients, followed by surgery and pathological analysis of the lesion. Original MDCT transverse and reconstructed images were used for image interpretation. Features of the lesion and its adjacent structures were identified.\n\nResults: The lesion was present in the thorax of 24 patients and the abdomen in 28. Obvious features of hyaline-vascular CD (especially feeding vessels and draining veins) and its adjacent structures NCT-501 Metabolism inhibitor were demonstrated on 52 patients.\n\nConclusion: On MDCT imaging, original MDCT transverse and reconstructed images provide an excellent tool for Barasertib clinical trial diagnosis of hyaline-vascular CD and have high value in the determination of a treatment plan. (c) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Peritoneal dialysis (PD) has achieved its current position as the most commonly used home-based dialysis therapy-and with patient survival equal

to that seen with hemodialysis-despite the use of glucose-based dialysis solutions with high concentrations of glucose, glucose degradation products and lactate, high osmolality, and low pH, features that are harmful both for the peritoneum and the patient. Newer PD solutions with alternative buffers, a higher pH and fewer glucose degradation products, or ones that contain icodextrin or amino acids as osmotic agents, have been introduced in many countries and have been shown to improve peritoneal membrane health and viability. Icodextrin solution enhances fluid and sodium removal, and the once-daily use of icodextrin and/or amino acid solutions can lessen the harmful effects caused by the exposure of the peritoneal membrane to glucose. However, whether the newer PD solutions improve patient survival over the older solutions is not clear.

Among 65 titi monkeys housed in a building, 23 (34%) developed upper respiratory symptoms that progressed to fulminant pneumonia

and hepatitis, and 19 of 23 monkeys, or 83% of those infected, died or were humanely euthanized. Whole-genome sequencing of TMAdV revealed that this adenovirus is a new species and highly divergent, sharing <57% pairwise nucleotide identity Ferroptosis assay with other adenoviruses. Cultivation of TMAdV was successful in a human A549 lung adenocarcinoma cell line, but not in primary or established monkey kidney cells. At the onset of the outbreak, the researcher in closest contact with the monkeys developed an acute respiratory illness, with symptoms persisting for 4 weeks, and had a convalescent serum sample seropositive for TMAdV. A clinically ill family member, despite having no contact with the CNPRC, also tested positive, and screening of a set of 81 random adult blood donors from the Western United States detected TMAdV-specific neutralizing antibodies in 2 individuals (2/81, or 2.5%). These findings

Endocrinology & Hormones inhibitor raise the possibility of zoonotic infection by TMAdV and human-to-human transmission of the virus in the population. Given the unusually high case fatality rate from the outbreak (83%), it is unlikely that titi monkeys are the native host species for TMAdV, and the natural reservoir of the virus is still unknown. The discovery of TMAdV, a novel adenovirus with the capacity to infect both monkeys and humans, suggests that adenoviruses should be monitored closely as potential causes of cross-species outbreaks.”
“Very little empirical work has been done to assess the potential impacts of climate change upon terrestrial biodiversity HIF inhibitor within small islands, many of which contribute to global species diversity due to high levels of endemicity. This study illustrates projections of not only individual but also the ‘collective’ response of a group of high conservation value tree species to climate change within the Caribbean small island of Trinidad. The species distribution modelling algorithm MaxEnt was used to construct models

of the realised present environmental space occupied by these species based on present day climate and other environmental factors. These models were then used to estimate present and future (2050; SRES A2) distributions of these species across Trinidad. Both present and future model output were incorporated to create change maps which illustrate projected expansions, contractions and areas of stable environmental space for each species. Individual change maps were combined to create a ‘collective’ change map portraying projected changes in the environmental space of this species group as a whole. Most individual species and the collective group response were projected to lose more than 50% of present environmental space, with the latter being limited to the southern edge of the island.

They expressed RORC and the IL-23 receptor and included subsets that secreted IL-22 and interferon-gamma. Th17 and Tc17 cells expressed high levels of C’XCR3 and CCR6, Tc17 cells also expressed CXCR6. Binding to human sinusoidal endothelium from flow was dependent on beta 1 arid beta 2 integrins, CXCR3, and, in the case of Th17 cells, VAP-1. Th17 recruitment via sinusoids in mice with liver inflammation was reduced by treatment with antibodies against CXCR3 ligands,

confirming the role of CXCR3 in Th17 recruitment in vivo. In human liver, IL-17(+) cells were detected in portal infiltrates close to inflamed bile ducts expressing the CCR6 ligand CCL20. Cytokine-treated human cholangiocytes secreted learn more CCL20 and induced CCR6-dependent migration of Th17 cells suggesting that local cholangiocyte chemokine secretion localises Th17 cells to bile ducts.\n\nConclusions: CXCR3 promotes recruitment of Th17 cells from the blood into the liver in both human and murine liver injury. Their subsequent positioning near bile ducts is dependent on cholangiocyte-secreted CCL20. (C) 2012 Published by Elsevier B.V. on behalf BI 6727 datasheet of the European Association for the Study of the Liver.”
“We present a method for recording eye-head movements

with the magnetic search coil technique in a small external magnetic field Since magnetic fields are typically non-linear, except in a relative small region in the center small field frames have not been used for head-unrestrained experiments in oculomotor studies\n\nHere we present a method for recording 3D eye movements by accounting for the magnetic non-linearities using the Biot-Savart law We show that the https://www.selleckchem.com/products/ag-881.html recording errors can be significantly reduced by monitoring current head position and thereby taking the location of the eye in the external magnetic field

into account. (C) 2010 Elsevier Ltd All rights reserved.”
“Fatty acids (FAs) are the main energy sources of living organisms and are the major components of cellular and organelle membranes. Their compositions also affect the flexibility/rigidity of cells and cell vitality. The Taenia solium metacestode (TsM) causes neurocysticercosis (NC), which is one of the most common helminthic infections of the central nerve system. We investigated the FA composition of the cyst fluid (CF) and parenchyma of the TsM, together with those of the granuloma and swine tissue surrounding the granuloma. The FA fractions of the TsM CF and swine tissue showed a composition and proportional contents comparable to each other, in which C18:0 (stearic acid), C18:1n9c (oleic acid), C20:4 (arachidonic acid) and C16:0 (palmitic acid) constituted the major fractions. However, the relative amount of individual FAs of the TsM parenchyma and granuloma differed from those of TsM CF and swine tissue, which contained enriched C16:0 and a lower amount of C20:4.

The method was developed by testing 86 metabolites, including amino acids, organic acids, sugars, purines, pyrimidines, vitamins, and nucleosides, that can be resolved by combining chromatographic and m/z dimensions. Subsequently, a targeted quantitative method was developed for 80 metabolites. The presented method combines a UPLC approach using hydrophilic interaction liquid chromatography (HILIC) and MS detection achieved by a hybrid quadrupole-time of learn more flight (Q-ToF) mass

spectrometer. The optimal setup was achieved by evaluating reproducibility and repeatability of the analytical platforms using pooled quality control samples to minimize the drift in instrumental performance over time. Then, the method was validated by analyzing extracellular metabolites from acute lymphoblastic leukemia cell lines (MOLT-4 and CCRF-CEM) treated with direct (A-769662) and indirect (AICAR) AMP activated kinase (AMPK) activators, monitoring uptake and secretion of the targeted compound over time. This analysis pointed towards a perturbed purine RG-7112 research buy and pyrimidine catabolism upon AICAR treatment. Our data suggest that the method presented can be used for qualitative and quantitative analysis of extracellular

metabolites and it is suitable for routine applications such as in vitro drug screening.”
“Background: Hydatidiform moles carry a significant risk for developing persistent gestational trophoblastic disease. Lectins are useful tools to identify cellular glycosylation pattern and changes in glycosylation that occur during growth, development, differentiation and also, during

disease states.\n\nObjectives: Considering the changes in glycosylation that occur during cell proliferation, differentiation and transformation, the aim of the present study was 4EGI-1 ic50 to evaluate the sugar chain expression in hydatidiform mole by using HRP-conjugated lectins.\n\nMaterials and Methods: Lectin histochemistry with a panel of HRP-conjugated lectins comprising SBA, PNA, VVA, UEA-1, LTA, GS-I.(B4) and WGA were performed in 20 molar (partial & complete moles) formalin-fixed, paraffin-embedded tissue samples.\n\nResults: The partial and complete moles generally showed similar reactivity with all used lectins. None of lectins reacted with villous cytotrophoblasts, whereas 4 of 7 lectins comprising WGA, LTA, UEA-.and PNA (after pretreatment with neuraminidase) showed a moderate to strong reactivity with villous syncytiotrophoblasts in both partial and complete hydatidiform moles. The villous stroma reacted with all used lectins except VVA.\n\nConclusions: Our histochemical findings showed a relatively heavy glycosylation of syncytiotrophoblasts of both partial and complete molar tissues, which was prominent in apical portion. This may play a role in their capacity to increase trophoblastic proliferation.

We genotyped ten polymorphisms in three cytokine genes (IFNG, TNF, and TGFB1) and FAS gene. We assessed the association between polymorphisms and AA risk, and the association between polymorphisms and response to IST in three genetic models (dominant, recessive, and additive). The IFNG -2,353 T allele dominant model, OR=0.43, p=.012) and TCA haplotype (dominant model, OR=0.50, p=.038) were significantly associated with the development of AA. In addition, this relevant IFNG -2,353 T allele and TCA haplotype were related to the response of IST (dominant model, OR=0.076, p=.034). Concerning TGFB1, although its polymorphisms are not related

to AA susceptibility, P10L T allele (recessive model, OR=0.18, p=.038) and CT haplotype (dominant model, OR=5.68, p=.038) were MK2206 associated with response to IST. This exploratory study concurred with prior studies indicating that polymorphisms in IFNG are related to AA susceptibility. In addition, it was found that polymorphisms in IFNG and TGFB1 are associated with response to IST.”
“The adrenocorticotropic hormone

(ACTH) receptor has highly specific membrane expression that is limited to adrenal cells; in other cell types the polypeptide fails to be transported to the cell surface Unlike other evolutionarily related members of the melanocortin receptor family (MC1R-MC5R) that recognize different melanocortin peptides, ACTHR (MC2R) binds only ACTH. We used a mutagenesis approach involving systematic construction of chimeric ACTHR/MC4R receptors to identify the domains determining the selectivity

DMXAA supplier of ACTHR membrane transport and ACTH binding In total 15 chimeric receptors were created by replacement of selected domains of human ACTHR with the corresponding regions of human MC4R. We developed an analytical method to accurately quantify cell-membrane localization of recombinant receptors fused with enhanced green fluorescent protein by this website confocal fluorescence microscopy The chimeric receptors were also tested for their ability to bind ACTH (1-24) and the melanocyte-stimulating hormone (MSH) analog, NIe4. DPhe7-alpha-MSH, and to induce a cAMP response Our results indicate that substitution of the MC4R N-terminal segment with the homologous segment of ACTHR significantly decreased membrane transport. We also identified another signal localized in the third and fourth transmembrane regions as the main determinant of ACTHR intracellular retention In addition, we found that the fourth and fifth transmembrane domains of the ACTHR are involved in ACTH binding selectivity We discuss the mechanisms involved in bypassing these arrest signals via an interaction with melanocortin 2 receptor accessory protein (MRAP) and the possible mechanisms that determine the high ligand-binding specificity of ACTHR. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Introduction and objectives.