Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs.

The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analog scale for life stress in psychiatric patients, a high-risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohort design, we were successful in identifying gene expression biomarkers that were predictive of high-stress states and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis. One of the top biomarkers that survived discovery, prioritization, validation, and testing was FKBP5, a well-known gene involved in stress response, which serves as a de facto reassuring positive control. We also compared our biomarker findings with telomere length (TL), another well-established biological marker of psychological stress and show that newly identified predictive biomarkers such as NUB1, APOL3, MAD1L1, or NKTR are comparable or better state or trait predictors of stress than TL or FKBP5. Over half of the top predictive biomarkers for stress also had prior evidence of involvement in suicide, and the majority of them had evidence in other psychiatric disorders, providing a molecular underpinning for the effects of stress in those disorders. Some of the biomarkers are targets of existing drugs, of potential utility in patient stratification, and pharmacogenomics approaches. Based on our studies and analyses, the biomarkers with the best overall convergent functional evidence (CFE) for involvement in stress were FKBP5, DDX6, B2M, LAIR1, RTN4, and NUB1. Moreover, the biomarker gene expression signatures yielded leads for possible new drug candidates and natural compounds upon bioinformatics drug repurposing analyses, such as calcium folinate and betulin. Our work may lead to improved diagnosis and treatment for stress disorders such as PTSD, that result in decreased quality of life and adverse outcomes, including addictions, violence, and suicide.

Electrophysiological evaluation of extracellular spermine and alkaline pH on synaptic human GABAA receptors.

Polyamines have fundamental roles in brain homeostasis as key modulators of cellular excitability. Several studies have suggested alterations in polyamine metabolism in stress related disorders, suicide, depression, and neurodegeneration, making the pharmacological modulation of polyamines a highly appealing therapeutic strategy. Polyamines are small aliphatic molecules that can modulate cationic channels involved in neuronal excitability. Previous indirect evidence has suggested that polyamines can modulate anionic GABAA receptors (GABAARs), which mediate inhibitory signaling and provide a direct route to reduce hyperexcitability. Here, we attempted to characterize the effect that spermine, the polyamine with the strongest reported effect on GABAARs, has on human postmortem native GABAARs. We microtransplanted human synaptic membranes from the dorsolateral prefrontal cortex of four cases with no history of mental or neurological disorders, and directly recorded spermine effects on ionic GABAARs responses on microtransplanted oocytes. We show that in human synapses, inhibition of GABAARs by spermine was better explained by alkalization of the extracellular solution. Additionally, spermine had no effect on the potentiation of GABA-currents by diazepam, indicating that even if diazepam binding is enhanced by spermine, it does not translate to changes in functional activity. Our results clearly demonstrate that while extracellular spermine does not have direct effects on human native synaptic GABAARs, spermine-mediated shifts of pH inhibit GABAARs. Potential spermine-mediated increase of pH in synapses in vivo may therefore participate in increased neuronal activity observed during physiological and pathological states, and during metabolic alterations that increase the release of spermine to the extracellular milieu.

The importance of sample size in marine megafauna tagging studies.

Telemetry is a key, widely used tool to understand marine megafauna distribution, habitat use, behavior, and physiology; however, a critical question remains: "How many animals should be tracked to acquire meaningful data sets?" This question has wide-ranging implications including considerations of statistical power, animal ethics, logistics, and cost. While power analyses can inform sample sizes needed for statistical significance, they require some initial data inputs that are often unavailable. To inform the planning of telemetry and biologging studies of marine megafauna where few or no data are available or where resources are limited, we reviewed the types of information that have been obtained in previously published studies using different sample sizes. We considered sample sizes from one to >100 individuals and synthesized empirical findings, detailing the information that can be gathered with increasing sample sizes. We complement this review with simulations, using real data, to show the impact of sample size when trying to address various research questions in movement ecology of marine megafauna. We also highlight the value of collaborative, synthetic studies to enhance sample sizes and broaden the range, scale, and scope of questions that can be answered.

Increase in bacterial biosurfactant production by co-cultivation with biofilm-forming bacteria.

Considering that bacterial biosurfactants (BSFs) are released as secondary metabolites involved in biotic relations within mixed bacterial assemblages, the hypothesis that the co-cultivation of BSF producing bacteria with biofilm-forming strains would enhance BSF synthesis was tested. Environmental BSF producing strains of Bacillus licheniformis and Pseudomonas sp. were cultivated with reference biofilm-forming strains (Pseudomonas aeruginosa and Listeria innocua). BSF production and quorum-quenching effects were tested in solid media. Tensioactive and anionic BSFs were also quantified in cell-free extracts (CFEs). BSF production increased in co-cultures with inducer strains although this was not demonstrated by all screening methods. Increased concentrations of anionic BSF were detected in CFEs of co-cultures in which Pseudomonas aeruginosa was included as inducer, which is in accordance with the observation of larger halos in cetyl trimethylammonium bromide-methylene blue agar. The results demonstrate that co-cultivation positively affects the efficiency of BSF production and that higher production yields may be attained by selecting convenient inducer partners in designed consortia. SIGNIFICANCE AND IMPACT OF THE STUDY: The high production cost of biosurfactants (BSFs) still represents a major limitation to the industrial use of these otherwise advantageous alternatives to chemical surfactants. This work demonstrates that the co-cultivation of consortia of biosurfactant-producer and biofilm-forming bacteria enhances BSF production and may contribute to the cost-effectiveness of biosurfactant-based products.

Convergence of marine megafauna movement patterns in coastal and open oceans.

The extent of increasing anthropogenic impacts on large marine vertebrates partly depends on the animals' movement patterns. Effective conservation requires identification of the key drivers of movement including intrinsic properties and extrinsic constraints associated with the dynamic nature of the environments the animals inhabit. However, the relative importance of intrinsic versus extrinsic factors remains elusive. We analyze a global dataset of ∼2.8 million locations from >2,600 tracked individuals across 50 marine vertebrates evolutionarily separated by millions of years and using different locomotion modes (fly, swim, walk/paddle). Strikingly, movement patterns show a remarkable convergence, being strongly conserved across species and independent of body length and mass, despite these traits ranging over 10 orders of magnitude among the species studied. This represents a fundamental difference between marine and terrestrial vertebrates not previously identified, likely linked to the reduced costs of locomotion in water. Movement patterns were primarily explained by the interaction between species-specific traits and the habitat(s) they move through, resulting in complex movement patterns when moving close to coasts compared with more predictable patterns when moving in open oceans. This distinct difference may be associated with greater complexity within coastal microhabitats, highlighting a critical role of preferred habitat in shaping marine vertebrate global movements. Efforts to develop understanding of the characteristics of vertebrate movement should consider the habitat(s) through which they move to identify how movement patterns will alter with forecasted severe ocean changes, such as reduced Arctic sea ice cover, sea level rise, and declining oxygen content.

High-sulfate water consumption determines intake and metabolic responses to protein supplementation in lambs consuming low-quality forage.

Twenty Hampshire lambs (31 ± 4 kg BW) in individual metabolism cages were used in a 10-treatment by 2-period ( = 4) trial to evaluate the interaction between protein supplementation and sulfate water on intake and metabolic responses when lambs were fed low-quality grass hay (; 6.4% CP, 79.5% NDF). The treatment structure was a 2 × 5 factorial: 2 water qualities (WQ; low-sulfate [LS] and high-sulfate [HS]; 442 and 8,358 mg/kg total dissolved solids, respectively) and 5 soybean meal levels (SBM; 0%, 0.25%, 0.50%, 0.75%, and 1.00% BW/d). After 15 d of adaptation, periods consisted of 5 d for determination of forage and water intake, nitrogen balance, and digestion measurements (d 16 to 20) and 1 d for blood sampling and determination of ruminal hydrogen sulfide (HS) concentration (d 21). Supplemental SBM × WQ interactions were significant for forage OM intake ( = 0.04) and total OM intake ( = 0.04), whereas a tendency was observed for total tract digestible OM intake ( = 0.07). Intake values of LS lambs were higher than those of HS lambs ( < 0.05) in only the first and second levels of SBM. Water intake increased linearly ( < 0.01) with SBM level but was not affected by WQ ( = 0.39). Water quality and SBM supplementation affected total tract OM digestibility (TTOMD; < 0.01); LS lambs had lower TTOMD than HS lambs ( < 0.01). Plasma urea N increased linearly in response to SBM ( < 0.01) but was not affected by WQ ( = 0.11). Nitrogen balance was not affected by SBM × WQ interaction ( > 0.12), except for N utilization (N retained/N intake ratio; < 0.01). Regardless of WQ, N intake ( > 0.01), N urine ( > 0.01), and N balance increased linearly ( > 0.01) with SBM level. Water quality adversely affected N intake and N balance, although at the highest level of SBM no differences in N balance were observed between LS and HS lambs ( = 0.85). No changes due to WQ were observed for either urea reabsorbed by kidneys ( = 0.63) or glomerular filtration rate ( = 0.30), but renal function was affected by SBM level ( < 0.01). There was a supplemental SBM × WQ interaction for ruminal HS concentration ( < 0.01) due mainly to a greater concentration from 0.25% BW SBM in HS than in LS lambs. In conclusion, these results confirmed the existence of an interaction between sulfate water and supplemental protein, which alters intake and metabolic responses when lambs are fed low-quality grass hay.

A velocity tracking approach for the data assimilation problem in blood flow simulations.

Several advances have been made in data assimilation techniques applied to blood flow modeling. Typically, idealized boundary conditions, only verified in straight parts of the vessel, are assumed. We present a general approach, on the basis of a Dirichlet boundary control problem, that may potentially be used in different parts of the arterial system. The relevance of this method appears when computational reconstructions of the 3D domains, prone to be considered sufficiently extended, are either not possible, or desirable, because of computational costs. On the basis of taking a fully unknown velocity profile as the control, the approach uses a discretize then optimize methodology to solve the control problem numerically. The methodology is applied to a realistic 3D geometry representing a brain aneurysm. The results show that this data assimilation approach may be preferable to a pressure control strategy and that it can significantly improve the accuracy associated to typical solutions obtained using idealized velocity profiles.

Humans and seasonal climate variability threaten large-bodied coral reef fish with small ranges.

Coral reefs are among the most species-rich and threatened ecosystems on Earth, yet the extent to which human stressors determine species occurrences, compared with biogeography or environmental conditions, remains largely unknown. With ever-increasing human-mediated disturbances on these ecosystems, an important question is not only how many species can inhabit local communities, but also which biological traits determine species that can persist (or not) above particular disturbance thresholds. Here we show that human pressure and seasonal climate variability are disproportionately and negatively associated with the occurrence of large-bodied and geographically small-ranging fishes within local coral reef communities. These species are 67% less likely to occur where human impact and temperature seasonality exceed critical thresholds, such as in the marine biodiversity hotspot: the Coral Triangle. Our results identify the most sensitive species and critical thresholds of human and climatic stressors, providing opportunity for targeted conservation intervention to prevent local extinctions.

Numerical validation of a synthetic cell-based model of blood coagulation.

In Fasano et al. (2012) a new reduced mathematical model for blood coagulation was proposed, incorporating biochemical and mechanical actions of blood flow and including platelets activity. The model was characterized by a considerable simplification of the differential system associated to the biochemical network and it incorporated the role of blood slip at the vessel wall as an extra source of activated platelets. The purpose of this work is to check the validity of the reduced mathematical model, using as a benchmark the model presented in Anand et al. (2008), and to investigate the importance of the blood slip velocity in the blood coagulation process.

Growth performance, carcass and meat quality of lambs supplemented with increasing levels of a tanniferous bush (Cistus ladanifer L.) and vegetable oils.

The effects of dietary inclusion of Cistus ladanifer L. (CL) and a vegetable oil blend were evaluated on growth performance,carcass and meat quality of fifty four lambs that were assigned to 9 diets, corresponding to 3 levels of CL(50, 100 and 200 g/kg DM) and 3 levels of oil inclusion (0, 40 and 80 g/kg DM). Treatments had no effects on growth rate. Oil depressed dry matter intake (P = 0.017), carcass muscle (P = 0.041) and increased (P = 0.016) kidney knob channel fat. Chemical and physical meat quality traits were not affected by treatments. Off-flavour perception was higher for 8% of oil (P b 0.001). The level of 100 g/kg DM of CL inclusion improved meat stability after 7 days of storage. Supplementation with linseed and soybean oils (2:1) was a good approach to improve meat nutritional value from feedlot lambs, increasing total n-3 PUFA.

Effect of protein supplementation on tropical grass hay utilization by beef steers drinking saline water.

An experiment was conducted to assess the impact of increasing levels of supplemental soybean meal (SBM; 45.7% CP) in cattle consuming tropical grass hay (Panicum maximum cultivar Gatton; 7.0% CP and 81.8% NDF) and drinking low salt water (LS) or high salt water (HS). Six ruminally fistulated beef steers (BW = 375 ± 43 kg) were used in a 6-treatment, 4-period crossover experiment. Treatments were arranged as a 2 × 3 factorial, with 2 levels salt in the water (LS and HS: 786 and 6,473 mg/kg of total dissolved solids [TDS], respectively) and 3 levels of SBM (0, 0.2, and 0.4% BW/d). After 15 d of adaptation to treatments, periods consisted of 5 d for intake and digestibility determination, 1 d for monitoring ruminal fermentation, 1 d for ruminal evacuation, and 1 d for blood sampling. Supplemental SBM × water quality interactions were significant (P < 0.05) for most measures of intake, except for total tract digestible OM intake (P = 0.38) and total tract digestible NDF intake (TTDNDFI; P = 0.32). At greater levels of SBM, forage OM intake, NDF intake, and water intake seemed to reach a plateau in LS while this was not observed in HS. Total tract digestible OM intake increased linearly (P = 0.01) and TTDNDFI tended to increase (P = 0.09) in response to increased SBM. Digestibility of OM and NDF were not affected by treatment (P > 0.21). Passage rate of acid detergent insoluble ash linearly increased (P < 0.01) in response to SBM, although it was not affected by water quality (P = 0.98). Total VFA concentrations and ruminal pH were not affected (P > 0.60 and P > 0.31, respectively) by treatment. Ruminal ammonia N levels were linearly increased by SBM supplementation (P < 0.01) but were not affected by water quality (P = 0.25). However, ruminal ammonia tended (P = 0.09) to be greater in HS at 0.2% of SBM supplementation. No interaction was observed for plasma urea N (PUN; P = 0.20). Plasma urea N was affected by SBM supplementation (P = 0.05) and water quality (P < 0.01). However, PUN did not differ for 0.4% SBM supplementation (P = 0.30) either at LS or HS treatments. In conclusion, a high level of SBM supplementation (0.4% BW) counteracted the detrimental effect of high TDS in drinking water on low-quality forage consumption by cattle.

Comparison of aluminum modified natural materials in the removal of fluoride ions.

The removal behaviors of fluoride ions from aqueous solutions and drinking water by aluminum modified hematite, zeolitic tuff and calcite were determined. Drinking water containing naturally 8.29 mg of fluoride ions per liter was characterized. The hematite, zeolitic tuff and calcite were aluminum modified by an electrochemical method. The effects of contact time and the dose of adsorbent were determined. The PZC (point of zero charge) values for aluminum modified hematite, zeolitic tuff and calcite were 6.2, 5.8 and 8.4, respectively. Adsorption kinetic data were best fitted to pseudo-second-order and Elovich models and equilibrium data to Langmuir-Freundlich isotherm model. The highest fluoride sorption capacities (10.25 and 1.16 mg/g for aqueous solutions and drinking water respectively) were obtained for aluminum modified zeolite with an adsorbent dosage of 10 g/L and an initial F(-) concentration of 9 and 8.29 mg/L for aqueous solutions and drinking water respectively (the final concentrations were 0.08 and 0.7 mg/L respectively). The main mechanism involved in the adsorption of fluoride ions is chemisorption on heterogeneous materials according to the results obtained by fitting the data to kinetic and isotherm models respectively. Aluminum modified zeolitic tuff showed the best characteristics for the removal of fluoride ions from water.

Inferred global connectivity of whale shark Rhincodon typus populations.

Ten years have passed since the last synopsis of whale shark Rhincodon typus biogeography. While a recent review of the species' biology and ecology summarized the vast data collected since then, it is clear that information on population geographic connectivity, migration and demography of R. typus is still limited and scattered. Understanding R. typus migratory behaviour is central to its conservation management considering the genetic evidence suggesting local aggregations are connected at the generational scale over entire ocean basins. By collating available data on sightings, tracked movements and distribution information, this review provides evidence for the hypothesis of broad-scale connectivity among populations, and generates a model describing how the world's R. typus are part of a single, global meta-population. Rhincodon typus occurrence timings and distribution patterns make possible a connection between several aggregation sites in the Indian Ocean. The present conceptual model and validating data lend support to the hypothesis that R. typus are able to move among the three largest ocean basins with a minimum total travelling time of around 2-4 years. The model provides a worldwide perspective of possible R. typus migration routes, and suggests a modified focus for additional research to test its predictions. The framework can be used to trim the hypotheses for R. typus movements and aggregation timings, thereby isolating possible mating and breeding areas that are currently unknown. This will assist endeavours to predict the longer-term response of the species to ocean warming and changing patterns of human-induced mortality.

Sensitivity to outflow boundary conditions and level of geometry description for a cerebral aneurysm.

Mathematical models, namely the flow boundary conditions, as well as the detail of the bounding geometry, can highly influence the computed flow field. In this work, an anatomically realistic portion of cerebral vasculature with a saccular aneurysm, and its geometric idealisation, are considered. The importance of the geometric description, namely including the side branches or modelling them as holes in the main vessel, is studied. Several approaches to prescribe the outflow boundary conditions at the side branches are analysed, including the traction-free condition, zero velocity (hence neglecting the side-branch), and the coupling with simple zero-dimensional and one-dimensional models. Results of the effects of outflow boundary modelling choice on computed haemodynamic parameters are used to identify appropriateness of the models based on the physical interpretation. Estimated range of error-bars associated to outflow boundary model choice and the level of geometric details are presented for patient-specific computational haemodynamics, and can serve as invitation for future studies. The zero-dimensional and one-dimensional models are shown to provide good representations of the side branches in the case of the clipped geometry.

Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism.

The brain-derived neurotrophic factor (BDNF), a neurotrophin fundamental for brain development and function, has previously been implicated in autism. In this study, the levels of BDNF in platelet-rich plasma were compared between autistic and control children, and the role of two genetic factors that might regulate this neurotrophin and contribute to autism etiology, BDNF and NTRK2, was examined. We found that BDNF levels in autistic children (n = 146) were significantly higher (t = 6.82; P < 0.0001) than in control children (n = 50) and were positively correlated with platelet serotonin distribution (r = 0.22; P = 0.004). Heritability of BDNF was estimated at 30% and therefore candidate genes BDNF and NTRK2 were tested for association with BDNF level distribution in this sample, and with autism in 469 trio families. Genetic association analysis provided no evidence for BDNF or NTRK2 as major determinants of the abnormally increased BDNF levels in autistic children. A significant association with autism was uncovered for six single nucleotide polymorphisms (SNPs) [0.004 (Z((1df)) = 2.85) < P < 0.039 (Z((1df)) = 2.06)] and multiple haplotypes [5 × 10(-4) (χ((3df)) = 17.77) < P < 0.042 (χ((9df)) = 17.450)] in the NTRK2 gene. These results do not withstand correction for multiple comparisons, however, reflect a trend toward association that supports a role of NTRK2 as a susceptibility factor for the disorder. Genetic variation in the BDNF gene had no impact on autism risk. By substantiating the previously observed increase in BDNF levels in autistic children in a larger patient set, and suggesting a genetic association between NTRK2 and autism, this study integrates evidence from multiple levels supporting the hypothesis that alterations in BDNF/tyrosine kinase B (TrkB) signaling contribute to an increased vulnerability to autism.

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions.

Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G>A, DRD3 Ser9Gly, HTR2C c.995G>A and ABCB1 1236C>T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G>A, HTR2C c.68G>C (p.C33S), HTR6 c.7154-2542C>T and BDNF c.196G>A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G>C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression.

The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides=16, nondepressed suicides=8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.

Nuclear and mitochondrial sequences confirm complex colonization patterns and clear species boundaries for flightless weevils in the Galápagos archipelago.

Nuclear sequence data were collected from endemic Galápagos species and an introduced close relative, and contrasted with mitochondrial DNA sequences, continuing investigation into the colonization history and modes of diversification in the weevil genus Galapaganus. The current combined phylogeny together with previously published penalized likelihood age estimates builds a complex picture of the archipelago's colonization history. The present reconstruction relies on submerged platforms to explain the early divergence of the young southern Isabela endemics or the Española or San Cristobal populations. Diversity is later built through inter-island divergence starting on older islands and continuing on two simultaneous tracks towards younger islands. The amount of diversity generated through intra-island processes is skewed towards older islands, suggesting that island age significantly influences diversity. Phylogenetic concordance between nuclear and mitochondrial datasets and well-supported monophyletic species in mitochondrial derived topologies appear to reject the possibility of inter-species hybridization. These clear species boundaries might be related to the tight host associations of adult weevils in discrete ecological zones. If shared hosts facilitate hybridization, then host- or habitat-promoted divergences could prevent it, even in the case of species that share islands, since the altitudinal partitioning of habitats minimizes range overlap.

Localized hydrodynamics of clustering leukocytes.

The recruitment of leukocytes to the endothelial walls is intensively investigated both experimentally and through three dimensional computer simulations. The shear dependent viscosity has been obtained from measured values in post-capillary venules of Wistar rats' cremaster muscle. Localized velocity fields and shear stresses on the surface of leukocytes and near vessel wall attachment points have been computed and discussed for a cluster of recruited leukocytes under generalized Newtonian blood flow with shear thinning viscosity. We have observed one region of maximum shear stress and two regions of minimum shear stress on the surface of the leukocytes close to the endothelial wall. This suggests that the accumulation of selectins attains a minimum value in two regions, rather than in one region, on the surface of the leukocytes. We have also verified that the collective hemodynamic behavior of the cluster of recruited leukocytes establishes a strong motive for additional leukocyte recruitment. From this study we claim that the influence of the leukocytes rolling on the endothelial wall increases the shear stress on both the leukocyte and the endothelial wall which results in activating more signaling mediators during inflammation.