1B) This demonstrated that the enhanced fitness of F5 T cells tr

1B). This demonstrated that the enhanced fitness of F5 T cells transferred to Rag1−/− hosts was indeed IL-7 dependent. We wished to examine the molecular mechanisms that were responsible for the range of cellular fitness observed in F5 T cells receiving different strengths of IL-7 signalling in vivo. First, we asked whether IL-7R– F5 T cells PD-0332991 mouse had an increased susceptibility to apoptosis. We examined caspase activity in IL-7R– F5 T cells at the earliest stages of in vitro culture by assessing fluorescently-labelled caspase inhibitor peptide (FLICA) binding to active caspases. While little caspase activity was apparent

in control F5 T cells, caspase activation was readily detectable in a significant population of IL-7R− F5 T cells during the 1 h in vitro duration of the assay (Fig. 2A). We also assessed onset of apoptosis by measuring annexin V binding to phosphatidylserine, whose translocation from inner see more to outer membrane leaf is an early event during cell death. While few viable IL-7R+ or IL-7R– F5 T cells were annexin V+ ex vivo, 1 h culture of IL-7R– F5 T cells was sufficient to induce a substantial population of high forward scatter (FSChi) Annexin V+ cells not evident in control

IL-7R+ F5 T cells (Fig. 2B). Finally, we also assessed specific activation of caspase 3, one of the executioner caspases, in IL-7R– F5 T cells directly ex vivo and following culture in vitro. Ex vivo, neither IL-7R+ F5 control nor IL-7R– F5 T cells had elevated levels of activated caspase 3, suggesting that there were not high levels of detectable apoptosis in vivo. However, following culture

for 24 h, activated caspase 3 was readily detectable in both cell types but was particularly elevated in IL-7R– F5 T cells in which viability was also more reduced (Fig. 2C). Taken together, these data indicate that the reduced fitness of IL-7R– F5 T cells Interleukin-2 receptor is associated with a very substantial elevation in their susceptibility to induction of apoptosis. It has long been recognized that T cells cultured in vitro with IL-7 up-regulate Bcl2 and this is thought to be a key mechanism through which cell survival is promoted. We therefore investigated whether modulation of Bcl2 expression in vivo by IL-7 signalling could account for the differential survival of IL-7R– F5 T cells and IL-7R+ F5 T cells from lymphopenic hosts. Examination of F5 T cells transferred to Rag1−/− hosts revealed a robust increase in Bcl2 expression levels (Fig. 3A and C), consistent with the continued survival of these cells in vitro in the absence of exogenous growth factors (Fig. 1B). The increase in Bcl2 levels observed was similar to that previously reported in F5 T cells cultured in vitro with exogenous IL-7 2. Surprisingly, in IL-7R− F5 T cells that were incapable of receiving IL-7 signalling 2, Bcl2 levels were identical to those in control IL-7R+ F5 T cells (Fig. 3B and C).

Despite conventional and empirical treatments, the patient develo

Despite conventional and empirical treatments, the patient developed progressive neurological deterioration leading to death. Autopsy showed Primary angiitis of the CNS (PACNS) with predominant cranial neuropathy, spinal cord involvement

and extensive myelomalacia. “
“Meningiomas are the most common primary intracranial tumors. They are usually benign and slowly growing; however, they may show histologically malignant features categorizing them into grade II or III of World Health Organization (WHO) classification. Rhabdoid meningioma (RM) is an uncommon meningioma variant categorized as WHO grade III. The clinical course of RM is determined by local recurrences, invasion of adjacent brain and/or dura, widespread leptomeningeal

dissemination, remote EPZ-6438 solubility dmso metastases and fatal clinical outcome. Herein we report a case with recurrent aggressive left occipital parasagittal region RM in which the patient initially declined radiation treatment. The tumor was resected four times in 5 years. Histopathological examination revealed a rhabdoid meningioma with metaplastic, papillary and chordoid differentiation. Six months after her fourth operation the patient died of progressive disease. RM is a rare subtype of malignant meningioma and the role of different adjuvant therapeutic options are still unknown. Clinical presentation, radiological features and pathologic findings of this uncommon tumor are discussed. “
“K. Morgan (2011) Neuropathology and Applied Neurobiology37, 353–357 The three new pathways leading to Alzheimer’s disease Genome-wide association studies (GWAS) promise a significant impact on the understanding of late-onset Alzheimer’s Ponatinib disease (LOAD) as the genetic components have been estimated to account for 60–80% of the disease. The recent publication of results from large GWAS suggests that LOAD is now one of the best-understood complex disorders. Four recent large

LOAD GWAS have resulted in the identification of nine novel loci. These genes are CLU– clusterin, PICALM– phosphatidylinositol-binding clathrin assembly protein, CR1– complement receptor 1, BIN1– bridging integrator 1, ABCA7– ATP-binding cassette transporter, MS4A cluster – membrane-spanning 4-domains subfamily A, CD2AP– CD2-associated crotamiton protein, CD33– sialic acid-binding immunoglobulin-like lectin and EPHA1– ephrin receptor A1. Collectively, these genes now explain around 50% of LOAD genetics and map on to three new pathways linked to immune system function, cholesterol metabolism and synaptic cell membrane processes. These three new pathways are not strongly linked to the amyloid hypothesis that has driven so much recent thinking and open up avenues for intensive research with regard to the potential for therapeutic intervention. “
“Materials from our first autopsied case of diffuse Lewy body disease (DLBD), that was originally reported in 1976, were re-examined using recent immunohistochemical methods.

In addition, stimulating the cells with 50 μM S1P resulted in oxy

In addition, stimulating the cells with 50 μM S1P resulted in oxygen radical formation comparable to ROS production in the presence of find more 4 μM CXCL4, while 5 or 0.5 μM S1P were not effective

(Fig. 6B). Furthermore, exogenously added S1P (50 μM) significantly reduces caspase-9 activation as compared with the unstimulated control (Fig. 6C). While this effect appears to be incomplete after 24 h of treatment, inhibition of caspase-9 was comparable to that observed following CXCL4 stimulation after 48 h of incubation with S1P. Moreover, stimulation with 50 μM S1P resulted in Erk phosphorylation after 24 h of stimulation, while CXCL4 mediates a more prolonged activation of Erk (Fig. 6D). In summary, treatment with high dosages of exogenous S1P resulted in Erk phosphorylation, reduced caspase

activation, and induction of ROS production in monocytes. To address the question whether overexpression of SphK1 alone is sufficient to mimick CXCL4 stimulation, we transfected monocytes with either SphK1-plasmid or empty vector. As a control we used CXCL4-stimulated cells in the presence of the transfection reagent, and SphK1 expression as well as cell viability was tested after 72 h. As shown in Fig. 6E (right panels) CXCL4 stimulation results in a fivefold increase in SphK1 expression compared with the unstimulated control. Transfection of the empty vector already leads to a sixfold increased SphK1 expression, which is further increased to 16-fold in HDAC phosphorylation SphK1-plasmid transfected cells. As expected, stimulation with CXCL4 results in significant reduction in both apoptotic and necrotic cell death (Fig. 6E, left panels). Furthermore, transfection with the vector or SphK1-plasmid both resulted in a significant decrease of apoptotic cells and a significant increase in necrotic cells.

More importantly, no difference could be detected between vector transfected and SphK1 overexpressing cells. These data indicate that overexpression of SphK1 is not sufficient to rescue monocytes from cell death, and at least one additional signal provided by CXCL4 ADP ribosylation factor is required for monocyte survival. S1P is a unique signaling molecule in that it can act both as an extracellular ligand for S1P receptors (G protein-coupled receptors) and as an intracellular second messenger. It has been described that monocytes mainly express two S1P receptors, S1P1 and S1P2, and that these receptors interact amongst others with Gi proteins 12. In a next set of experiments, we tested whether CXCL4 and S1P stimulated monocyte functions are dependent on Gi protein-coupled S1P receptors. In these experiments cells were preincubated in the presence or absence of pertussis toxin (PTX) (500 ng/mL; 90 min). Subsequently, cells were stimulated with CXCL4 (4 μM), S1P (50 μM), or fMLP (1 μM; as a control) and production of ROS was recorded for 60 min. Preincubation of the cells with PTX resulted in a significant reduction of fMLP- and S1P-mediated respiratory burst by 85 and 61%, respectively (Fig.

Thereafter the posterior thighs

Thereafter the posterior thighs Hedgehog antagonist were dissected from medial to lateral, distinguishing the perforators at the level of the superficial fascia. The perforators were localized and origin, source, length and diameter of the perforators were documented. Analysis occurred using ANOVA and the two proportion Z test. The distribution of musculocutaneous and septocutaneous perforators was respectively 69.1% and 30.9% (P = 0.002). The PTR was divided in thirds. Most perforators (53.2%) were found in de middle third of the PTR. The deep femoral artery (DFA) was the main origin of perforators (61.7%), followed by the superficial femoral artery (SFA) (27.7%) and the popliteal

artery (PA) (10.6%). The DFA buy BGB324 perforators were the longest with a mean length of 13.7 ± 4,69 cm, the SFA perforators were 9.79 ± 3.76 cm and the PA perforators were 8.6 ± 3.37 cm. The PTR offers a sufficient number of suitable perforators to serve as an adequate donorsite for pedicled and free flaps. © 2013 Wiley Periodicals, Inc. Microsurgery 33:376–382, 2013. “
“Defects of the Achilles tendon and the overlying soft tissue are challenging to reconstruct. The lateral-arm flap has our preference in this region as it provides thin pliable skin, in addition, the fascia and tendon can be included in the flap

as well. The aim of this report is to share the experience the authors gained with this type of reconstruction. The authors report the largest series in the published reports today. Patients and methods: A retrospective review was performed of all patients treated between January 2000 and January 2009 with a lateral-arm flap for a soft-tissue defect overlying the Achilles tendon. Results: In the reviewed period, 16 soft-tissue defects overlying the Achilles tendon were reconstructed, with a mean follow-up of 63 months. In three cases, tendon was included into the flap and in two, a sensory nerve was coapted. Fifteen cases (94%) were successful, one failed. In seven cases, a secondary procedure PI-1840 was necessary for thinning of the flap. Conclusion: The lateral-arm flap

is a good and safe option for the reconstruction of defects overlying the Achilles tendon. © 2012 Wiley Periodicals, Inc. Microsurgery, 2012. “
“Severe injuries at foot and ankle level with loss of soft tissues and bone are often treated by means of amputation. The transfer of composite free flaps from various donor sites may provide anatomical reconstruction of the foot and ankle and function. Ten patients who sustained severe combined tissue injuries of the foot requiring reconstruction with composite free flaps were studied with a mean follow-up of 3.4 years. A thorough clinical examination was performed, and gait analysis was carried out with kinetic and kinematic parameters. Bone integration and healing was observed with satisfactory foot morphology.

As a consequence the intestinal environment changes dramatically,

As a consequence the intestinal environment changes dramatically, Selisistat order and yet there is no immediate acute loss of worms as in other intestinal nematode infections in rodents. These intestinal changes are consistent with Th2-driven immune mechanisms operating in the mucosa and are similar to responses described for other intestinal nematodes (21,22), although

the erosion of villi may also be attributable partly in this case to the feeding behaviour of adult worms, which browse on the villi (4,23). Of particular significance is the duration of these changes, which are sustained in infected hamsters for many weeks, and not just a few days around the time of acute

worm loss, as in other intestinal nematode-rodent models (18,20). One response, which contrasts with that to other species of nematodes, is the response of Paneth cells, a cell type selleck screening library that is known to have a key role in defence against bacterial infections in the intestinal mucosa (24). In most mammalian hosts, Paneth cell numbers increase after helminth infection in the intestine (25–27), but in hamsters infected with A. ceylancium, they consistently drop within 12–14 days of primary exposure to infective larvae (18). In contrast to events during primary exposure to A. ceylanicum, relatively little is known about the precise kinetics of mucosal cellular responses to challenge. Diflunisal A single primary infection, when removed with anthelmintic leaves hamsters strongly resistant to challenge infection as long as the worms are removed after the larvae have completed development to adults, and this acquired response is primarily directed at the L3 and L4 stages of development, which occur early during infection, so the bulk of the secondary

infection is actually rejected within a week of challenge (19,28). Any worms that survive this immediate response, and successfully develop into adults, then live for some time despite the hostile environment in the inflamed intestinal tract (19). Preliminary published data indicate that there is a mucosal mast cell and goblet cell response, (28) but these are only marginally higher than values persisting in the mucosa from the primary immunizing infections (19). There is an evidence for enhanced specific anti-parasite antibody levels in both the serum and the intestinal tract of immune-challenged hamsters (15,19). In this paper, we report an experiment in which we quantified cellular and morphological changes in the intestinal environment of hamsters that had experienced a low-level immunizing infection, which had been abbreviated by treatment with an anthelmintic 5 weeks after primary exposure.

[7], where S is the average OD value of the duplicate test sample

[7], where S is the average OD value of the duplicate test samples and B corresponds to the average

OD value of the duplicate negative controls plus three times the standard division (SD). The study protocol was approved by the Ethical Clearance Committee of the ALIPB, Addis Ababa University and the Regional Committee for Medical Research Ethics of Southern Norway. Upon recruitment, the aim of the study was explained to the study participants and written informed consent was obtained from each of the study participants. Blood sample PXD101 chemical structure collection was carried out under aseptic conditions by well-experienced technicians. Individuals tested positive for latent TB by QFTGIT were advised to consult the nearest health facility lest they develop signs/symptoms suggestive of active TB. The results of culture were reported to the health facility. Data were computerized using EpiData software v.3.1 (EpiData Association, Odense M, Denmark) and analysed using Stata version 11. (Statacorp LP, College Station, TX, USA) Frequencies and percentages were used to summarize baseline characteristics of the participants. Means of OD value were compared between categories of the characteristics of participants using the Student’s t-test for 2 independent samples. Correlation between the OD values of IgG or IgA and the level of IFN-γ was assessed using Spearman’s rank correlation coefficient. Linear regression

analysis was performed to assess the association between the OD values Talazoparib of IgG or IgA and background characteristics of the participants, including age, sex and history of BCG or close contact with TB patients. A P-value of <0.05 was considered statistically significant. A total of 166 individuals (38 patients with culture-confirmed PTB, 73 healthy individuals who were positive for Mtb infection by QFTGIT and

55 non-infected) were included in the study. There were no significant differences in the mean age of patients with culture-confirmed PTB (mean age = 37.4; SD = 14.3) and healthy Mtb-infected subjects (mean age = 35.0; SD = 14.1) (P > 0.05). Among the study participants, 27(16.3%) and 29 (17.5%) had BCG scars and selleck chemicals history of contact with TB patients, respectively. The mean OD values of IgA against ESAT-6/CFP-10 (Fig. 1) and Rv2031 (Fig. 2) antigens were significantly higher in sera of patients with culture-confirmed PTB compared with healthy Mtb-infected and non-infected cases (P < 0.001 in all cases). Similarly, the mean OD values of IgG against ESAT-6/CFP-10 (Fig. 3) and Rv2031 (Fig. 4) were significantly higher in sera of patients with culture-confirmed PTB compared with healthy Mtb-infected cases and non-infected cases (P < 0.05). The mean OD values of serum IgG to both antigens were significantly higher than that of IgA against both antigens in sera of the various study groups (data was not shown).

Ritonavir also may induce the activities of CYP1A2, CYP2C9, CYP2C

Ritonavir also may induce the activities of CYP1A2, CYP2C9, CYP2C19 and glucuronosyl transferase.126 Two small studies demonstrated that the co-administration of fluconazole produced little or no effect on the pharmacokinetics of ritonavir.123,124

phosphatase inhibitor library Similarly, voriconazole (400 mg day−1) had no apparent effect on steady-state high-dose (800 mg day−1) ritonavir exposure.126 These findings are not surprising given that fluconazole or voriconazole are not potent CYP3A4 inhibitors and the studies employed a high dose of ritonavir (800–1200 mg day−1) that now is rarely used. In addition, the studies involving fluconazole employed a relatively low fluconazole dose (200 mg day−1).123,124 In a small study, fluconazole increased the AUC (50%) and Cmax (57%)

of saquinavir administered as a hard gel-cap. However, these changes were not deemed clinically significant.124 The non-nucleoside reverse transcriptase inhibitor efavirenz is primarily metabolised by CYP3A4 and CYP2B6 and undergoes subsequent glucuronidation. Efavirenz inhibits CYP2C9, CYP2C19 and CYP3A4 at concentrations that are achieved with standard dosing.127 In addition, efavirenz induces CYP3A4 activity in a concentration-dependent manner.128 Not surprisingly, a randomised placebo-controlled interaction study Roxadustat price in healthy male volunteers demonstrated that co-administration of voriconazole (400 mg daily in divided) and efavirenz (400 mg daily) produced moderate increases in efavirenz exposure (43%) and maximum serum concentrations (37%).129 Methisazone A study in healthy volunteers using a higher voriconazole dose (800 mg daily in divided doses) and a lower efavirenz (300 mg daily) produced little or no change in efavirenz pharmacokinetic parameters.130 This mild to moderate interaction is likely caused by voriconazole inhibition of CYP3A4. However, as discussed below, efavirenz produced more significant changes in voriconazole

disposition.129,130 Interactions involving azoles and warfarin.  Warfarin is a racemic compound. The S enantiomer of warfarin (S-warfarin) is metabolised by CYP2C9 and accounts for the pharmacological activity of warfarin. Itraconazole inhibits only CYP3A4, but a case report indicates that it may interact with warfarin.131 However, this finding has not been evaluated in a larger, more rigorous analysis. Fluconazole interacts with warfarin in a highly predictable manner. This azole inhibits S-warfarin metabolism approximately 70%, which results in a 38% increase in the international normalised ratio (INR) in patients who were previously stabilised on warfarin.132 The interaction between fluconazole and warfarin will occur even if the fluconazole dose is reduced by 50%. Therefore, in practice, this combination increases the risk of significant bleeding and should be avoided if possible.133 If the two drugs are required to be used concomitantly, the INR must be closely monitored and the warfarin dose will need to be adjusted accordingly.

Emerging clinical and experimental data suggest that the injury t

Emerging clinical and experimental data suggest that the injury to the conduction system may happen through a two-stage process, which is detailed in a review by Wahren-Herlenius and Sonesson [21]. In the first step, maternal anti-Ro autoantibodies bind to foetal cardiomyocytes,

which leads to calcium dysregulation, calcium overload and subsequent apoptosis. Anti-La antibodies then subsequently bind to apoptotic cardiomyocytes, which escalate the inflammatory cascade, activating infiltrating macrophages that secrete proinflammatory and profibrotic cytokines. The subsequent evolution of more severe tissue damage, including fibrosis and calcification of conduction tissue and surrounding myocardium, the second step of the process, probably requires a genetic predisposition or susceptibility in the foetus particularly given the discordant influence of the maternal autoantibodies in twins and siblings of affected foetuses and lack of consistent findings Erismodegib chemical structure in the offspring of sera-positive women. Approximately 1–3% of foetuses and infants whose mothers are autoantibody positive develop AVB, and the risk of recurrence in subsequent offspring

is 17–18% [22–24]. Although 20–30% of the mothers have well-defined autoimmune disease, most are clinically asymptomatic and are only recognized to have the autoantibodies after the diagnosis find more of AVB is made in the foetus [14, 22]. In a prospective study of 15,000 pregnant women in the metropolitan Toronto area, we found 2.8% to have anti-Ro and/or anti-La autoantibodies (unpublished data, Maternal Autoantibodies in Pregnancy prospective study in Metropolitan Toronto). Although the subgroup

of sera-positive women at greatest risk of having an affected foetus is still not fully known, clinical observations have identified risk factors. In addition to those with a previously affected foetus [22–24], women with anti-52 kD-Ro antibodies appear to be at increased risk of having an affected foetus, and the nearly universal presence of anti-52 kD-Ro in affected mothers has suggested an important role in second the pathogenesis of AVB [23, 25]. Although absolute antibody titres have not been previously consistently linked to risk, a recent single centre investigation by Jaeggi et al. in 186 autoantibody-positive women, including 59 asymptomatic mothers, suggested that cardiac manifestations of NLE in general are associated with moderate (≥50 U/ml, 15% incidence) or high (≥100 U/ml, 85% incidence) maternal anti-Ro antibody titres [26]. This study further found foetal and neonatal cardiac manifestations to be independent of anti-La titres. This finding is in contrast with an earlier multicentre retrospective study of Gordon et al. which examined antibody titres in 125 mostly clinically symptomatic mothers of children with NLE [25]. In their cohort, they found the child of an anti-Ro (52 kD)-positive mother to have a risk of 2% of having AVB, which increased to 3.1% if the mother was anti-La positive as well [25].

Moreover, increased Prdx6 expression at both transcriptional (Fig

Moreover, increased Prdx6 expression at both transcriptional (Figure 3d) and protein level (Figure 3b, c) was evaluated by quantitative PCR and Western blot respectively. This is a first study to demonstrate that Prdx6 is upregulated in an animal model of opisthorchiasis. Prdx6 functions as part of thioredoxin reductase (27). Recently, thioredoxin/peroxidase and Prdx were characterized in O. viverrini (29). Host may directly respond

to parasite antigen by the induction of specific protein expression such as that of Prdx6. In addition, Prdx expression is mediated by NO (30) and reduces formation of peroxynitrite (ONOO˙−) (12). During inflammation, NO reacts with O2˙− to form highly reactive ONOO˙− leading to oxidative and nitrative DNA damage. NO production reaches a peak in O. viverrini-infected hamsters on day 30 post-infection Dabrafenib cell line (31). Oxidative and nitrative DNA lesions are formed in bile duct epithelial cells in the liver of O. viverrini-infected hamsters and play a key role in infection- and inflammation-related carcinogenesis (10,11). Therefore, we hypothesize that the expression of Prdxs may be involved in host defence against O. viverrini-induced diseases, including CCA development, mediated by nitrative stress. This notion is supported by observation that Prdx6 was mainly expressed

in the cytoplasm of inflammatory and PI3K Inhibitor Library supplier flat cells (fibroblast-like cell) at inflamed areas (Figure 4). We also have observed Prdx6 expression in CCA tissues obtained from human subjects (unpublished data). In addition, increased Prdx6 expression may suppress liver injury induced by free radical-mediated damage via inflammation. Likewise, an increased liver injury in Prdx6-knockout mice occurred via increased mitochondrial generation of H2O2 (32). Elevated Prdx6 expression has been observed in the spinal cord of mice expressing mutant superoxide dismutase 1 (33), in lungs with malignant mesothelioma (34),

and in squamous cell carcinoma (35). Moreover, autoantibody against Prdx6 is a novel serum marker in esophageal squamous cell carcinoma (36). Taken together, our and these findings suggest that Prdx6 is centrally involved in protection against inflammatory diseases mediated by oxidative and nitrative stress, including O. viverrini-induced acetylcholine disease and cholangiocarcinogenesis. In summary, we have demonstrated proteome analysis to examine the expression of a number of proteins in the liver of an animal model of O. viverrini infection. In addition to proteins related to liver function, proteins related to host defence were upregulated by O. viverrini infection. Among them, we identified Prdx6 as a key molecule responsible for host defence mediated by its antioxidative property, and as a promising biomarker and a chemopreventive agent for O. viverrini-induced diseases and carcinogenesis.


According NU7441 concentration to functional classification of the Gene Ontology (GO) project [30], we selected several highly expressed genes within five different categories, including membrane receptors, TFs, growth factors and cytokines, chemokines, and signal-transduction molecules, in either dNK, cNK, or pNK cells. By integrating the data generated from the genomic profiling with information from published reports and bioinformatic databases

(e.g., STRING, Gene Network Central, Transcriptional Regulatory Element Database), we were able to determine that the genes highly expressed in NK cells formed a complex network, which was analyzed and visualized using the network analysis tool GeneMANIA [31] and the visualization software Cytoscape [32] (Fig. 1). Additionally, by combining these data with information available from published reports, bioinformatic databases and network analysis tools (such as STRING [33]), we were able to predict putative target genes of the selected TFs and finally describe the transcriptional regulatory networks of NK cells (Fig. 2). TFs including Ikaros, PU.1, Ets-1, Nfil3, Id2, T-bet,

and Eomes are key regulators that have a major effect on NK-cell fate, differentiation, and function. The target genes for all TFs examined in [60] were identified or predicted by searching click here published reports and online bioinformatic databases, including STRING [33], GeneMANIA [31], and TRED [34] (Fig. 3). The interaction network was visualized by Cytoscape software [32] (Fig. 3). In addition to Cytoscape, other visualization software including 3Dscape [35], Circos [36], and Gephi [37] are also available to integrate, analyze, and visualize the network data,

complex systems, dynamics, and hierarchical graphs. Overall, we think that integrating different analysis methods takes full advantage of what can be learned from the enormous amount of data generated from gene expression profiles. Many databases, software, and online tools are available Low-density-lipoprotein receptor kinase and useful for searching and predicting the function of gene sets and particular genes of interest. Moreover, we provide here a list of the databases, software, and online tools useful for this endeavor and include information on how the network biology tools and integrative informatics can be applied to large microarray datasets (Fig. 3 and Table 3). Finally, we illustrate how this strategy can be successfully applied to a large genomic expression profile dataset in our own studies in order to make further investigations into NK-cell biology. NK-cell subpopulations have a remarkable degree of repertoire and functional diversity. In humans, these diverse subpopulations include tolerant, cytotoxic, and regulatory NK cells [38].