Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review).

The prognosis for patients with non­small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5­year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5­30 mm, or whole­brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial­to­mesenchymal transition, overexpression of programmed cell death­ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes­associated protein­1, on cerebral metastases originating from lung cancer.

Magnitude and Durability of the Antibody Response to mRNA-Based Vaccination Among SARS-CoV-2 Seronegative and Seropositive Health Care Personnel.

Few studies have described changes in SARS-CoV-2 antibody levels in response to infection and vaccination at frequent intervals and over extended follow-up periods. The purpose of this study was to assess changes in SARS-CoV-2-specific antibody responses among a prospective cohort of health care personnel over 18 months with up to 22 samples per person. Antibody levels and live virus neutralization were measured before and after mRNA-based vaccination with results stratified by (1) SARS-CoV-2 infection status prior to initial vaccination and (2) SARS-CoV-2 infection at any point during follow-up. We found that the antibody response to the first dose was almost 2-fold higher in individuals who were seropositive prior to vaccination, although neutralization titers were more variable. The antibody response induced by vaccination appeared to wane over time but generally persisted for 8 to 9 months, and those who were infected at any point during the study had slightly higher antibody levels over time vs those who remained uninfected. These findings underscore the need to account for SARS-CoV-2 natural infection as a modifier of vaccine responses, and they highlight the importance of frequent testing of longitudinal antibody titers over time. Together, our results provide a clearer understanding of the trajectories of antibody response among vaccinated individuals with and without prior SARS-CoV-2 infection.

Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer.

The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n = 45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48 h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumor of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumor specimens.

Pediatric Neural Changes to Physical and Emotional Pain After Intensive Interdisciplinary Pain Treatment: A Pilot Study.

Brain areas activated during pain can contribute to enhancing or reducing the pain experience, showing a potential connection between chronic pain and the neural response to pain in adolescents and youth. This study examined changes in brain activation associated with experiencing physical pain, and the observation of physical and emotional pain in others, by using functional magnetic resonance imaging (fMRI) before and after intensive interdisciplinary pain treatment (IIPT). Eighteen youth (age 14 to 18) with widespread chronic pain completed fMRI testing before and after IIPT to assess changes in brain activation in response to physical and emotional pain. Broadly, brain activation changes were observed in frontal, somatosensory, and limbic regions. These changes suggest improvements in descending pain modulation via thalamus and caudate, and the different pattern of brain activation after treatment suggests better discrimination between physical and emotional pain. Brain activation changes were also correlated with improvements in clinical outcomes of catastrophizing (reduced activation in right caudate, right mid-cingulate, and postcentral gyrus) and pain-related disability (increased activation in precentral gyrus, left hippocampus, right middle occipital cortex, and left superior frontal gyrus). These changes support interpretation that reduced brain protective responses to pain were associated with treatment-related improvements. This pilot study highlights the need for larger trials designed to better understand the brain mechanisms involved in pediatric widespread pain treatment.

Associations between the Trauma Memory Quality Questionnaire and posttraumatic stress symptoms in youth: A systematic review and meta-analysis .

Cognitive models of posttraumatic stress disorder (PTSD) propose that trauma memory characteristics are implicated in the etiology of the disorder. Empirical support for cognitive models in youth is necessary to ensure psychological interventions are based on appropriate theory. This meta-analysis was conducted to quantitatively investigate the strength of the associations between self-reported trauma memory characteristics (e.g., sensory and temporal features), measured using the Trauma Memory Quality Questionnaire (TMQQ), and posttraumatic stress symptoms (PTSS) in children and adolescents. PsycINFO, MEDLINE, CINAHL, PTSDPubs, and ProQuest Dissertations and Theses Global were searched for relevant literature. In total, 11 studies (N = 1,270 participants) met the inclusion criteria for the random-effects meta-analysis. A large effect size was observed for the association between trauma memory characteristics and PTSS, r = .51, 95% CI [.44, .58], and was maintained in subgroup analyses of the prospective association between trauma memory characteristics and later PTSS (k = 5, n = 6 28), r = .51, 95% CI [.42, .59]. A slightly larger effect size was observed in subgroup analyses of the cross-sectional association between trauma memory characteristics and concurrent PTSS (k = 11, N = 1,270), r = .62, 95% CI [.53, .70]. Sensitivity analyses on study quality, TMQQ alteration, chronic trauma exposure, geographical location, and PTSS measure supported the robustness of these results. These findings provide empirical support for the role of trauma memory characteristics in PTSS, congruent with cognitive models, suggesting this theoretical framework is appropriate for youth populations. Limitations and recommendations for future research are discussed.

SARS-CoV-2 Infection in Health Care Personnel and Their Household Contacts at a Tertiary Academic Medical Center: Protocol for a Longitudinal Cohort Study.

BACKGROUND: Health care personnel (HCP) are at high risk for exposure to the SARS-CoV-2 virus. While personal protective equipment (PPE) may mitigate this risk, prospective data collection on its use and other risk factors for seroconversion in this population is needed. OBJECTIVE: The primary objectives of this study are to (1) determine the incidence of, and risk factors for, SARS-CoV-2 infection among HCP at a tertiary care medical center and (2) actively monitor PPE use, interactions between study participants via electronic sensors, secondary cases in households, and participant mental health and well-being. METHODS: To achieve these objectives, we designed a prospective, observational study of SARS-CoV-2 infection among HCP and their household contacts at an academic tertiary care medical center in North Carolina, USA. Enrolled HCP completed frequent surveys on symptoms and work activities and provided serum and nasal samples for SARS-CoV-2 testing every 2 weeks. Additionally, interactions between participants and their movement within the clinical environment were captured with a smartphone app and Bluetooth sensors. Finally, a subset of participants' households was randomly selected every 2 weeks for further investigation, and enrolled households provided serum and nasal samples via at-home collection kits. RESULTS: As of December 31, 2020, 211 HCP and 53 household participants have been enrolled. Recruitment and follow-up are ongoing and expected to continue through September 2021. CONCLUSIONS: Much remains to be learned regarding the risk of SARS-CoV-2 infection among HCP and their household contacts. Through the use of a multifaceted prospective study design and a well-characterized cohort, we will collect critical information regarding SARS-CoV-2 transmission risks in the health care setting and its linkage to the community. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25410.

Mild sleep restriction increases 24-hour ambulatory blood pressure in premenopausal women with no indication of mediation by psychological effects.

BACKGROUND: Studies assessing the impact of sleep restriction (SR) on blood pressure (BP) are limited by short study length, extreme SR (<4 hours a night), and lack of attention to psychological distress as a possible mediator. METHODS: A community-based cohort was assembled with 237 women (age 34.1 ±â€¯13.5 years; body mass index 25.4 ±â€¯5.4 kg/m2), and a randomized, crossover, intervention study was conducted in 41 women (24 completed: age 30.2 ±â€¯6.5 years; body mass index 24.3 ±â€¯2.8 kg/m2) to determine the causal effect of SR on BP. Sleep was maintained as usual (HS) or reduced by 1.5 hours a night (SR) for 6 weeks. In the cohort, associations between sleep and psychosocial factors were evaluated using multivariable models adjusted for demographic and clinical confounders. In the intervention study, in-office BP was measured weekly; ambulatory BP was measured at end point. Psychological factors were assessed at baseline and end point. Mixed-model analyses with total sleep time (TST, main predictor), week and fraction of time spent in physical activity (covariates), and subject (random effect) were performed. RESULTS: Among the community cohort, higher perceived stress, stressful events and distress, and lower resilience were associated with shorter sleep, worse sleep quality, and greater insomnia symptoms (P < .05). In the intervention, systolic BP increased as TST decreased (TST × week interaction, [coefficient ±â€¯standard error] -0.0097 ±â€¯0.0046, P = .036). Wake ambulatory diastolic blood pressure (-0.059 ±â€¯0.022, P = .021) and mean arterial pressure (-0.067 ±â€¯0.023, P = .018) were higher after SR versus HS. Psychological distress variables were not affected by TST and did not mediate the effects of SR on BP. CONCLUSIONS: These results suggest that SR influences CVD risk in women via mechanisms independent of psychological stressors.

A qualitative analysis of emotion and emotion regulation in hoarding disorder.

OBJECTIVE: The role of emotion regulation (ER) has been receiving increased attention in relation to various forms of psychopathology including hoarding disorder (HD). However, questionnaire designs are limited to finding associations of ER with symptoms or symptom groups, without finding out how such constructs might be involved in the disorder. METHODS: This study was a qualitative investigation of ER in a clinical HD sample (N = 11). RESULTS: Prominent themes provided support for ER difficulties in hoarding. In particular, difficulties with identifying and describing feelings, unhelpful attitudes toward the emotional experience, the use of avoidance-based strategies, and a perceived lack of effective ER strategies were prominent themes. Furthermore, emotional factors were identified as being associated with the onset and/or exacerbation of hoarding behavior, and possessions and acquiring behavior appeared to serve an ER function. CONCLUSION: The current paper provides a nuanced account of the role of ER in hoarding difficulties.

Fetal alcohol spectrum disorder and youth justice: a prevalence study among young people sentenced to detention in Western Australia.

OBJECTIVES: To estimate the prevalence of fetal alcohol spectrum disorder (FASD) among young people in youth detention in Australia. Neurodevelopmental impairments due to FASD can predispose young people to engagement with the law. Canadian studies identified FASD in 11%-23% of young people in corrective services, but there are no data for Australia. DESIGN: Multidisciplinary assessment of all young people aged 10-17 years 11 months and sentenced to detention in the only youth detention centre in Western Australia, from May 2015 to December 2016. FASD was diagnosed according to the Australian Guide to the Diagnosis of FASD. PARTICIPANTS: 99 young people completed a full assessment (88% of those consented; 60% of the 166 approached to participate); 93% were male and 74% were Aboriginal. FINDINGS: 88 young people (89%) had at least one domain of severe neurodevelopmental impairment, and 36 were diagnosed with FASD, a prevalence of 36% (95% CI 27% to 46%). CONCLUSIONS: This study, in a representative sample of young people in detention in Western Australia, has documented a high prevalence of FASD and severe neurodevelopmental impairment, the majority of which had not been previously identified. These findings highlight the vulnerability of young people, particularly Aboriginal youth, within the justice system and their significant need for improved diagnosis to identify their strengths and difficulties, and to guide and improve their rehabilitation.

The error-related negativity (ERN) is an electrophysiological marker of motor impulsiveness on the Barratt Impulsiveness Scale (BIS-11) during adolescence.

OBJECTIVES: Previous studies have postulated that the error-related negativity (ERN) may reflect individual differences in impulsivity; however, none have used a longitudinal framework or evaluated impulsivity as a multidimensional construct. The current study evaluated whether ERN amplitude, measured in childhood and adolescence, is predictive of impulsiveness during adolescence. METHODS: Seventy-five children participated in this study, initially at ages 7-9 years and again at 12-18 years. The interval between testing sessions ranged from 5 to 9 years. The ERN was extracted in response to behavioural errors produced during a modified visual flanker task at both time points (i.e. childhood and adolescence). Participants also completed the Barratt Impulsiveness Scale - a measure that considers impulsiveness to comprise three core sub-traits - during adolescence. RESULTS: At adolescence, the ERN amplitude was significantly larger than during childhood. Additionally, ERN amplitude during adolescence significantly predicted motor impulsiveness at that time point, after controlling for age, gender, and the number of trials included in the ERN. In contrast, ERN amplitude during childhood did not uniquely predict impulsiveness during adolescence. CONCLUSIONS: These findings provide preliminary evidence that ERN amplitude is an electrophysiological marker of self-reported motor impulsiveness (i.e. acting without thinking) during adolescence.

Allelic variation in dopamine D2 receptor gene is associated with attentional impulsiveness on the Barratt Impulsiveness Scale (BIS-11).

OBJECTIVES: Previous studies have postulated that noradrenergic and/or dopaminergic gene variations are likely to underlie individual differences in impulsiveness, however, few have shown this. The current study examined the relationship between catecholamine gene variants and self-reported impulsivity, as measured by the Barratt Impulsiveness Scale (Version 11; BIS-11) Methods: Six hundred and seventy-seven non-clinical adults completed the Barratt Impulsiveness Scale (BIS-11). DNA was analysed for a set of 142 single-nucleotide polymorphisms (SNPs) across 20 autosomal catecholamine genes. Association was tested using an additive regression model with permutation testing used to control for the influence of multiple comparison. RESULTS: Analysis revealed an influence of rs4245146 of the dopamine D2 receptor (DRD2) gene on the BIS-11 attention first-order factor, such that self-reported attentional impulsiveness increased in an additive fashion with each copy of the T allele. CONCLUSIONS: These findings provide preliminary evidence that allelic variation in DRD2 may influence impulsiveness by increasing the propensity for attentional lapses.

Gender Differences in Associations Between Stress and Cardiovascular Risk Factors and Outcomes.

Psychological stress, a subjective perception of an adverse environmental change, is a hallmark of modern society. Although psychological stress has previously been established as a risk factor for cardiovascular disease (CVD), it is unclear whether stress influences cardiovascular risk differently in men versus women. Gender disparities exist in the prevalence of stress as well as in the prevalence and prognosis of CVD; therefore, associations between stress and CVD risk and mortality may vary by sex. The purpose of this review was to summarize the evidence from recent and landmark studies on gender differences in the associations of stress with CVD risk factors and end points and to highlight clinical and public health implications as well as future research directions in this field. Taken together, research to date indicates that while stress is associated with poorer cardiovascular health metrics in both men and women, the influence of stress on measures of glucose regulation and dyslipidemia and on overall CVD risk may be stronger among women. However, men may be more susceptible to the influence of stress on body adiposity, blood pressure, and CVD mortality. In terms of behavioral risk factors for CVD, associations between stress and diet quantity and quality appear to be stronger among women, but the influence of stress on sedentary behaviors and sleep may be stronger among men. Given that gender disparities exist in the prevalence of overall and different types of stress (eg, financial stress, caregiving stress, and occupational stress), future studies should decipher the potential differential associations between types of stress and cardiovascular risk among men and women to identify vulnerable populations and develop targeted interventions.

Responsibility and hand washing behaviour.

BACKGROUND AND OBJECTIVES: Recent research suggests that compulsions persist due to a self-perpetuating mechanism of poor memory confidence and repetition. However, most of this work has examined checking compulsions and findings may not generalize well to washing compulsions. This study examined the role of responsibility in the persistence of washing behaviour. METHODS: Hand washing was examined in undergraduates (n = 80) high and low in contamination fears (CF) under conditions of high or low responsibility (RL). Wash duration and number of visits to objects/locations key to the wash (e.g., soap) were examined. RESULTS: Overvalued responsibility predicted washing duration across groups. Neither wash duration nor number of visits was associated with memory for the wash. Wash duration predicted post-wash certainty that the wash had prevented harm, but only in the high CF group, and that effect varied according to RL: longer wash duration predicted greater certainty under conditions of low RL but predicted less certainty under conditions of high RL. Greater repetition predicted poorer sensory confidence, but only in the high CF group under high RL conditions. LIMITATIONS: The data were collected in an analogue sample of modest size. Replication in a clinical sample is required. CONCLUSIONS: Self-perpetuating mechanisms identified in perseverative checking seem to also be present in perseverative washing, but only under conditions of high responsibility. Sensory confidence may be more important to perseverative washing than memory confidence. More research is required to understand self-perpetuating mechanisms at play when washing to under conditions of high responsibility.

A Model for Recruiting Clinical Research Participants With Anxiety Disorders in the Absence of Service Provision: Visions, Challenges, and Norms Within a Canadian Context.

High-quality research in clinical psychology often depends on recruiting adequate samples of clinical participants with formally diagnosed difficulties. This challenge is readily met within the context of a large treatment center, but many clinical researchers work in academic settings that do not feature a medical school, hospital connections, or an in-house clinic. This article describes the model we developed at the University of Waterloo Centre for Mental Health Research for identifying and recruiting large samples of people from local communities with diagnosable mental health problems who are willing to participate in research but for whom treatment services are not offered. We compare the diagnostic composition, symptom profile, and demographic characteristics of our participants with treatment-seeking samples recruited from large Canadian and American treatment centers. We conclude that the Anxiety Studies Division model represents a viable and valuable method for recruiting clinical participants from the community for psychopathology research.

Emotional regulation, attachment to possessions and hoarding symptoms.

This study aimed to test which particular facets of emotion regulation (ER) are most linked to symptoms of hoarding disorder, and whether beliefs about emotional attachment to possessions (EA) mediate this relationship. A non-clinical sample of 150 participants (108 females) completed questionnaires of emotional tolerance (distress tolerance, anxiety sensitivity, negative urgency - impulsivity when experiencing negative emotions), depressed mood, hoarding, and beliefs about emotional attachment to possessions. While all emotional tolerance measures related to hoarding, when considered together and controlling for depression and age, anxiety sensitivity and urgency were the significant predictors. Anxiety sensitivity was fully mediated, and urgency partially mediated, via beliefs regarding emotional attachment to possessions. These findings provide further support for (1) the importance of anxiety sensitivity and negative urgency for hoarding symptoms, and (2) the view that individuals with HD symptoms may rely on items for emotion regulation, leading to stronger beliefs that items are integral to emotional wellbeing.

Interactions of dietary flavonoids with proteins: insights from fluorescence spectroscopy and other related biophysical studies.

In 1936, Rusznyak and Szent-Györgyi first drew attention to the therapeutically beneficial role of dietary flavonoids, which are the most common group of polyphenols ubiquitously present in plant based food and beverages. Recent years have witnessed a renascence of interest on these nutraceuticals, which, because of their high potency and low systemic toxicity, are gradually emerging as promising alternatives to conventional therapeutic drugs. There is a mounting evidence that various proteins frequently serve as targets for therapeutically important flavonoids. In this article we present perspectives exemplifying the growing potential of fluorescence spectroscopy as an exquisitely sensitive tool for noninvasive sensing of protein-flavonoid interactions at physiologically relevant concentrations, via measurements of steady state emission parameters as well as decay kinetics studies of the intrinsic fluorescence of the target (protein) and/or ligand (flavonoid). Especially, we highlight novel applications of the remarkably environment sensitive 'two color' fluorescence exhibited by many important flavonoids, which permits multiparametric and ratiometric measurements. To consolidate findings obtained via fluorescence spectroscopy, use of other relevant experimental biophysical techniques and molecular modeling have proved to be valuable and are also discussed here. Such complementary studies provide additional insights regarding the thermodynamics and conformational aspects of the protein-flavonoid interactions, together with details, at atomistic level, of the dominant noncovalent interactions involved in the docking of different flavonoids to their target proteins.

Characterization of diadzein-hemoglobin binding using optical spectroscopy and molecular dynamics simulations.

The present study establishes the effectiveness of natural drug delivery mechanisms and investigates the interactions between drug and its natural carrier. The binding between the isoflavone diadzein (DZN) and the natural carrier hemoglobin (HbA) was studied using optical spectroscopy and molecular dynamics simulations. The inherent fluorescence emission characteristics of DZN along with that of tryptophan (Trp) residues of the protein HbA were exploited to elucidate the binding location and other relevant parameters of the drug inside its delivery vehicle HbA. Stern-Volmer studies at different temperatures indicate that static along with collisional quenching mechanisms are responsible for the quenching of protein fluorescence by the drug. Molecular dynamics and docking studies supported the hydrophobic interactions between ligand and protein, as was observed from spectroscopy. DZN binds between the subunits of HbA, ∼15 Å away from the closest heme group of chain α1, emphasizing the fact that the drug does not interfere with oxygen binding site of HbA.

A CRITICAL STUDY ON THE INTERACTIONS OF HESPERITIN WITH HUMAN HEMOGLOBIN: FLUORESCENCE SPECTROSCOPIC AND MOLECULAR MODELING APPROACH.

Hesperitin, a ubiquitous bioactive flavonoid abundant in citrus fruits is known to possess antioxidant, anti-carcinogenic, hypolipidemic, vasoprotective and other important therapeutic properties. Here we have explored the interactions of hesperitin with normal human hemoglobin (HbA), using steady state and time resolved fluorescence spectroscopy, far UV circular dicroism (CD) spectroscopy, combined with molecular modeling computations. Specific interaction of the flavonoid with HbA is confirmed from flavonoid-induced static quenching which is evident from steady state fluorescence as well as lifetime data. Both temperature dependent fluorescence measurements and molecular docking studies reveal that apart from hydrogen bonding and van der Waals interactions, electrostatic interactions also play crucial role in hesperitin-HbA interactions. Furthermore, electrostatic surface potential calculations indicate that the hesperitin binding site in HbA is intensely positive due to the presence of several lysine and histidine residues.

Thromboxane prostanoid receptor stimulation induces shedding of the transmembrane chemokine CX3CL1 yet enhances CX3CL1-dependent leukocyte adhesion.

In atherosclerosis, chemokines recruit circulating mononuclear leukocytes to the vascular wall. A key factor is CX(3)CL1, a chemokine with soluble and transmembrane species that acts as both a chemoattractant and an adhesion molecule. Thromboxane A(2) and its receptor, TP, are also critical to atherogenesis by promoting vascular inflammation and consequent leukocyte recruitment. We examined the effects of TP stimulation on processing and function of CX(3)CL1, using CX(3)CL1-expressing human ECV-304 cells and primary human vascular endothelial cells. TP agonists promoted rapid shedding of cell surface CX(3)CL1, which was inhibited by pharmacological inhibitors or specific small interfering RNA targeting tumor necrosis factor-alpha-converting enzyme (TACE). Because it reduced cell surface CX(3)CL1, we predicted that TP stimulation would inhibit adhesion of leukocytes expressing the CX(3)CL1 cognate receptor but, paradoxically, saw enhanced adhesion. We questioned whether the enhanced ability of the remaining membrane-associated CX(3)CL1 to bind targets was caused by changes in its lateral mobility. Using fluorescence recovery after photobleaching, we found that plasmalemmal CX(3)CL1 was initially tethered but ultimately mobilized by TP agonists. TP stimulation provoked clustering of transmembrane CX(3)CL1 at sites of contact with adherent leukocytes. These data demonstrate that TP stimulation induces two distinct effects: a rapid cleavage of surface CX(3)CL1, thereby releasing the soluble chemoattractant, plus mobilization of the remaining transmembrane CX(3)CL1 to enhance the avidity of interactions with adherent leukocytes. The dual effect of TP allows CX(3)CL1 to recruit leukocytes to sites of vascular inflammation while enhancing their adhesion once recruited.