g. CD2 or CD28, with their ligands on APCs. During antigen-specific T-cell activation, these surface receptors, along with intracellular signaling or scaffolding proteins, organize in supramolecular

activation clusters (SMACs) and form an immunological synapse 1, 2. Functionally, this immune synapse provides a stop signal on APCs for migrating T cells 3 and is important for enhancing, directing or terminating T-cell immunity 4. Since the immune synapse has an important function in T-cell Selleckchem VX770 activation, sustained signaling, and effector functions 4, 5, it is important to elucidate whether clinically used immunosuppressive drugs interfere with immune synapse formation or stabilization. Glucocorticoids are commonly used immunosuppressants in organ transplantation or the treatment of dermatitis, arthritis, or inflammatory bowel disease. The immunosuppressive action of glucocorticoids is thought to be mainly based on the inhibition of cytokine expression and dependent on the regulation of cytoplasmic glucocorticoid receptors (GRs). Whether glucocorticoids influence costimulatory signals required for immune synapse formation and the dynamic actin rearrangement of untransformed

human T cells was so far unexplored. It has been known for a long time that the formation and stabilization of the immune synapse requires dynamic rearrangements of the actin cytoskeleton as well as costimulation 6, 7. We have recently shown that expression of the actin-bundling protein L-plastin is crucial for actin polymerization after antigen encounter, immune synapse maturation, Ceritinib and sustained T-cell signaling 5. L-plastin is post-translationally regulated by phosphorylation on Ser5 and this phosphorylation is induced in primary human T cells via costimulation, i.e. TCR/CD3 plus CD28 or CD2 8, 9. This phosphorylation facilitates the surface transport of activation-induced receptors like CD69

8. Furthermore, it was demonstrated by others that phosphorylated L-plastin has a higher affinity toward F-actin in HEK293T cells 10. Although it is known that Vorinostat in vitro expression of L-plastin is mandatory for the maturation of the immune synapse 5, the role of L-plastin phosphorylation on Ser5 in that process remained as yet unclear. Moreover, it was unknown whether commonly used immunosuppressive drugs influence the actin regulatory functions of L-plastin required for the formation of the immune synapse upon antigen encounter. Here, we demonstrate that phosphorylation of the actin-bundling protein L-plastin is crucial for the formation of a stable immune synapse and the increased F-actin content in superantigen-stimulated untransformed human T cells. Interestingly, the immunosuppressive drug dexamethasone interferes with L-plastin phosphorylation and T-cell functions that rely on L-plastin phosphorylation, such as actin polymerization and immune synapse formation.

In addition, multivariate regression analysis showed that 3 parameters (donor type, eGFR at 2004 and total or high-molecular

ADPN levels) were independently related to the initial DeGFR in renal transplanted subjects. Low-molecular weight adiponectin ratio was significantly increased at last 4 year (P < 0.001 R428 clinical trial by the paired t-test). The late 4 years DeGFR became slower than those of initial levels at −1.1(−8.2∼3.2) ml/min/1.73 m2/year in 85 subjects. The late DeGFR was related with the alteration of HDL-C or low-molecular ADPN levels (r = 0.317, p = 0.006; r = −0.260, p = 0.026, respectively). Conclusion: Lower LDL-C/HDL-C ratio and the usage of statin itself could preserve the renal function judged

by DeGFR in Japanese transplanted subjects. Initial ADPN levels were reversely correlated with eGFR and DeGFR, like previously reported as an “ADPN paradox” even in transplanted subjects. However, long-term observation revealed that higher HDL-C and lower low-molecular ADPN levels preserved the renal function of allografts, and resolved the paradox between the renal function and ADPN levels mainly caused by the increase of low-molecular ADPN in renal allograft dysfunction. SHIGA TAKAHIRO1, TANAKA HARUKA1, ISHIDA KAORI2, KAWATA TETSUNORI2, SUZUKI TSUKASA1, YAMAMOTO YUJI1, KOBAYASHI KEN-ICHI1 1Dept. Appl. Biol. Chem., Tokyo Univ. of Agri.; 2Grad. Sch. of Edu., Okayama Univ. Introduction: Vitamin B12 is a water soluble Rapamycin vitamin, serves as an essential cofactor for two enzymes, methionine synthase and metylmalonyl-CoA mutase. Vitamin A is a fat-soluble vitamin, plays a role in a various functions, such as vision, immune function, embryonic development, and gene transcription. A common reabsorption receptor of these vitamins in the kidney is megalin that is a 600 kDa type 1 transmembrane protein. However, mutual relationship between these vitamins in the megalin mediated reabsorption is not well understood. The aim of this study is to Myosin reveal the effect of vitamin B12 deficiency on renal reabsorption of

vitamin A. Methods: Wistar rats weaned from parent rats fed on a Vitamin B12 deficient diet during pregnancy and lactation were divided four groups, (1) Control; group administered 1 ug/rat/day of cyanocobalamin (CNB12) for 100 days, (2) B12-Def, (3) 24 hrs-CNB12; group administered 1 ug/rat/day of CNB12 for a day before sacrifice, and (4) 7days-CNB12; group administered CNB12 for 7 days before sacrifice. These rats were fed on Vitamin B12-deficient diet for 100 days. Serum Vitamin B12 and vitamin A were measured. Localization of megalin, cubilin and retinol-binding protein (RBP) was investigated by immunohistochemistry using light and laser confocal microscopy. The mRNA and protein expression of megalin and RBP were analized by real-time PCR and western blotting respectively.

The relative contribution to transmission by find more cell-associated or cell-free virus is still not defined for the different routes

of transmission. Although the main target cells for HIV-1 replication are the CD4+ T lymphocytes, which are rapidly depleted both in the periphery and in the mucosal tissues, dendritic cells, Langerhans’ cells, and macrophages are players in each of these processes. The predominant cells involved may differ according to the tract of the gut and the route of transmission. The microenvironment of the intestinal mucosa, including mucus, antibodies, or chemo-cytokines, can as well influence infection and replication of the virus: their role is still under investigation. The understanding of these processes may help in developing efficient prevention strategies. “
“The O-polysaccharide chain of the lipopolysaccharide (O-antigen) on the bacterial cell surface is one of the most structurally variable cell components and serves as a basis for serotyping of Gram-negative bacteria, including human opportunistic

pathogens of the genus Providencia. PD-332991 In this work, the O-antigen of Providencia alcalifaciens O40 was obtained by mild acid degradation of the isolated lipopolysaccharide and studied by chemical methods and high-resolution NMR spectroscopy. The following structure of the O-polysaccharide was established: 4)-β-d-Quip3NFo-(13)-α-d-Galp-(13)-β-d-GlcpA-(13)-β-d-GalpNAc-(1,

where GlcA stands for glucuronic acid and Qui3NFo for 3,6-dideoxy-3-formamidoglucose. The GABA Receptor O40-antigen was found to be structurally and serologically related to the O-antigens of P. alcalifaciens O5 and Providencia stuartii O18. The O40-antigen gene cluster between cpxA and yibK was sequenced, and the gene functions were predicted in silico. In agreement with the O-polysaccharide structure established, the genes for the synthesis of dTDP-d-Qui3NFo, UDP-d-Gal, UDP-d-GlcA, and UDP-d-GalNAc as well as those encoding three glycosyltransferases, flippase (Wzx), and O-antigen polymerase (Wzy) were recognized. In addition, homologues of wza, wzb, and wzc genes, which are required for the surface expression of capsular polysaccharides, were found within the gene cluster, suggesting that the O-polysaccharide studied is a part of the capsule-related form of the lipopolysaccharide called KLPS. Gram-negative bacteria of the genus Providencia are opportunistic pathogens that are isolated from a wide variety of environment and organisms, ranging from fruit flies and sea turtles to humans (Galac & Lazzaro, 2011). Currently, the genus consists of eight species (O’Hara et al., 2000; Somvanshi et al., 2006; Juneja & Lazzaro, 2009), among which P. stuartii, P. rettgeri, P. rustigianii, and P. alcalifaciens are the most common Providencia species that cause human infection. P.

Protein kinases have thus already been suggested as promising targets in drug design against schistosomiasis (74), 3-Methyladenine solubility dmso and their suitability as targets in cestodes has recently been demonstrated by Gelmedin et al. (75) who identified pyridinyl imidazoles, directed against the p38 subfamily of mitogen-activated protein kinases (MAPK), as a novel family of anti-Echinococcus compounds. A number of E. multilocularis protein kinases such as the Erk- and p38-like MAPKs EmMPK1 (76) and EmMPK2 (75), respectively, the MAPK kinases EmMKK1 and

EmMKK2 (77), or the Raf-like MAPK kinase kinase EmRaf (78) have already been characterized on the molecular and biochemical level, and particularly in the case of the two

MAPKs, functional biochemical Talazoparib assays have been established that can be used for compound screening (75,76). Of further interest are already characterized receptor kinases of the insulin- (EmIR; 79), the epidermal growth factor- (EmER; 80) and the transforming growth factor-β- (EmTR1; 81) receptor families that are expressed by the E. multilocularis metacestode stage and that are involved in host–parasite cross-communication by interacting with the evolutionary conserved cytokine- and hormone-ligands that are abundantly present in the intermediate host’s liver (1,72). In total, we could thus far identify ∼250 protein kinase-encoding genes on the genome assembly versions of E. multilocularis

(Table 3) and E. granulosus, the majority of which displays considerable homologies to orthologous genes in schistosomes, which could be particularly important for the design of compounds that have a broad spectrum of activity not only against cestodes but also against other parasitic flatworms. An important issue in rational drug design is not only the identification Phosphoprotein phosphatase of targets that display structural and functional differences between the respective parasite and host components, thus ensuring that compounds with sufficient parasite specificity can be found, but also the general ‘druggability’ of the target, i.e., whether it contains structural features that favour interactions with small molecule compounds (82). Apart from protein kinases, several other protein families such as G-protein-coupled receptors (GPCR) or ligand-gated ion channels proved to be particularly druggable in previous compound screens and chemogenomic approaches (83). For a selection of protein families that are particularly suitable as drug targets, Table 3 lists the number of coding genes that we have identified using the current E. multilocularis genome assembly. In addition to a large number of protein kinases, several of which are already under study in the E.

Probiotics are live bacteria that confer

a health benefit to the host when administrated in adequate amounts (WAO/WHO, 2002), and lactic acid bacteria (LAB) including lactobacilli and bifidobacteria are commonly used as probiotics. LAB exhibit a variety of immunomodulating effects, including preventive effects against various infections (Nomoto, 2005; Namba et al., 2010; Fukuda et al., 2011) and carcinogenesis (Reddy & Rivenson, 1993; Takagi et al., 2001) as well as antiallergic effects (Fujiwara et al., 2004; Xiao et al., 2006a ,b). Leyer et al. (2009) have reported that intake of the combination of probiotic strains reduced cold and influenza-like symptom incidence and duration in healthy children during the winter season. Several studies have demonstrated find more that some strains of LAB protect against influenza virus (IFV) infection in a murine model and that the protective effects might be mediated

by the augmentation of secreted immunoglobulin A production and the enhancement of innate immunity in the host (Yasui et al., 1999, 2004; Hori et al., 2002; Maeda et al., 2009; Kawase et al., 2010; Kobayashi et al., 2010). Influenza is an acute viral respiratory disease caused by IFV, which attacks the host respiratory tract mucosa. IFV infection sometimes causes lethal pneumonia in the elderly and encephalopathy in children, which results in high morbidity and significant mortality. After IFV infection in the lung, viruses are initially detected and destroyed nonspecifically by innate

immune responses, in which macrophages C59 wnt chemical structure and natural killer (NK) cells are involved, and if the viruses escape the early defense mechanisms, they are detected and eliminated specifically by adaptive immune responses (Tamura & Kurata, 2004). Following viral infection in the lung, alveolar macro-phages secrete various cytokines Non-specific serine/threonine protein kinase such as interleukin-12 (IL-12) that induce early NK cell-mediated interferon-γ (IFN-γ) production (Monteiro et al., 1998). The activated NK cells lyse virus-infected cells and contribute to the inhibition of early viral replication (Stein-Streilein & Guffee, 1986). In the adaptive immune response, secretory IgA and cytotoxic T lymphocytes specific for the viral antigen are induced and contribute to the recovery from viral infection (Wiley et al., 2001; Asahi et al., 2002). However, adaptive immunity requires several days for clonal expansion and the differentiation of naive lymphocytes into effector cells. Thus, as a method for preventing IFV infection, it would be crucial to enhance innate immunity that acts at the early stage of viral infection. Several studies have demonstrated that the strains of LAB that induce IL-12 elicit NK cell activities and IFN-γ production in an IL-12-dependent manner and enhance innate immunity (Ogawa et al., 2006; Shida et al., 2006a; Koizumi et al.

In this

issue of the European Journal of Immunology, a study reports the identification of an intrathymic DC precursor that is likely to be unrelated to the earliest physiological T-cell progenitors. Thus this intrathymic DC precursor may constitute a “missing link” between extrathymic DC precursor-types, which are able to generate DCs in secondary lymphoid organs and intrathymic DCs, and supports the notion that intrathymic DCs and thymocytes arise from different precursors. DCs epitomize antigen-presenting cells, thus initiating adaptive immune responses in secondary lymphoid organs (SLOs). In addition, DCs contribute to the deletion of autoreactive thymocytes during negative selection in the thymus. Within the lymphoid organs, non-migratory DCs can be subdivided learn more into plasmacytoid Talazoparib (p)DCs and two populations of classical (c)DCs, which play different roles in antigen presentation. Phenotypically, these two cDC subsets can be distinguished as CD8α+ and CD8α− DCs 1. The expression of the bona fide lymphoid marker CD8α on one of these subsets of cDCs suggested that this subset is of lymphoid

origin, whereas the CD8α− cDCs are of myeloid origin. However, it has become increasingly clear that both types of cDCs residing in SLOs are mostly of myeloid origin, although lymphoid progenitors may, to a minor extent, feed into the cDC lineage 2, 3. The recent identification of a series of progressively lineage-restricted DC progenitor populations has established a firm link between DCs and myeloid progenitors 4. In contrast, the origin of CD8α+ thymic (t)DCs remains elusive and controversial. On the one hand, a considerable body of evidence points to a lymphoid past for these cells and on the other hand, intrathymic committed DC precursors had remained undetected. Thus, whereas CD8α+ tDCs harbor Phosphoprotein phosphatase DHJH rearrangements, such rearrangements are virtually absent in splenic CD8α+ DCs 5. In addition, both human and mouse tDCs have been reported to express the pre-TCRα chain 3, 6. Furthermore, the earliest intrathymic T-cell precursors and even later

developmental stages along the T lineage have been shown to be able to generate DCs, and CD8α+ tDCs develop intrathymically with kinetics paralleling those of T cells 7–9. In this issue of the European Journal of Immunology, Luche et al. report the identification of an intrathymic DC precursor, which is distinct from the earliest canonical T-cell precursors and bears phenotypic similarities to extrathymic pre-DCs 10. Thus, Luche et al. provide a “missing link” between the recently established differentiation pathway of DCs residing in SLOs and tDCs, suggesting that the developmental origin of CD8α+ tDCs might, in fact, not be dissimilar to that of other CD8α+ DCs. Phenotypically, this novel DC precursor is located within the so-called double negative (DN1c) population of thymocytes, based on the nomenclature introduced by Petrie and colleagues 11.

On the other hand, the binding of integrin extracelluar domains to ligands or other agonists (stimulatory antibody, PMA, Mg2+ or Mn2+), and physiological force exerted on the bond, could initiate conformational change of the integrin, which then sends biochemical and mechanical signalling into the cell to regulate multiple cellular functions; this is termed ‘outside-in’ signalling.12,13 In T cells, integrin bidirectional signals lead to the formation of the immunological synapse, stabilization of T-cell–APC contact to facilitate T-cell activation, proliferation and cytokine secretion (e.g. interleukin-2, interferon-γ).19–21 In macrophages, integrin activation induces cytoskeletal rearrangement during the

process of phagocytosis, cytokine mRNA stabilization (e.g. interleukin-1β) and cell differentiation.22 Integrin signalling also enhances neutrophil

degranulation and activation of NADPH oxidase, leading to production of reactive oxygen species,23 or induces Atezolizumab research buy polarization of cytolytic granules in natural killer cells or cytolytic T lymphocytes.24 In the following discussion, we will describe those key effectors involved in integrin bidirectional signalling pathways, with particular attention to the signalling molecules in T lymphocytes. After the TCR/CD3 complex is engaged with the MHC–peptide complex, Src kinase (lymphocyte-specific protein tyrosine kinase; LCK) is phosphorylated and activated, leading to phosphorylation check details of immunoreceptor tyrosine-based activation motifs on the TCRξ/CD3 chains. Kinase ζ-associated protein of molecular weight 70 000 (ZAP-70) is recruited to the TCR/CD3 complex www.selleck.co.jp/products/Fludarabine(Fludara).html and is phosphorylated by LCK. Activated ZAP-70 then phosphorylates a number of downstream adaptors, including linker for activation of T cells (LAT) and Src homology

2 (SH2) domain-containing leucocyte protein of molecular weight 76 000 (SLP-76) (Fig. 1). Elevated levels of LCK in cloned cytolytic T cells markedly increase cytolytic activity and enhance LFA-1 expression levels with increased cell binding to the ligand intercellular adhesion molecule 1 (ICAM-1).25 In LCK-deficient Jurkat cells (i.e. JCaM1.6 cells) or in Src kinase inhibitor PP2-treated Jurkat cells, CD3 ligation-induced adhesion to ICAM-1 is dramatically reduced.26 These studies suggest that LCK is a positive regulator for integrin activation. Similarly, ZAP-70-deficient Jurkat cells fail in TCR-induced integrin β1-mediated adhesion and the kinase activity of ZAP-70 required for LAT phosphorylation is crucial for integrin activation.27 This fits with the defective integrin activation and adhesion in LAT-deficient Jurkat cells. Further, LAT is associated directly or indirectly with a number of key signalling proteins, including phosphatidylinositol 3-kinase, the inducible T-cell kinase (ITK), SLP-76, and phospholipase C-γ1 (Fig. 1). These kinases, adaptors or enzymes have been implicated to play critical roles in TCR-induced ‘inside-out’ signalling for integrin activation.

We investigated whether the disulfide bonds in recombinant wild-type MoPrP and PrPSc are cleaved in the presence of reducing agents. Recombinant PrP and PrPSc were labeled with mBBr following reduction with DTT or 2ME. The fluorescence intensities

of mBBr-labeled MoPrP increased in proportion to the reagent concentration; that of MoPrP treated with 100 mM DTT appeared to reach a plateau (Fig. 1a). When the fluorescence signal of 100 mM DTT-treated MoPrP was compared with that of a 100 mM DTT-treated single-Cys substitution mutant (C213S), the signal intensity of the treated MoPrP was about 1.8 times that of treated C213S. We estimated that more than 70% of C213S formed dimers through an intermolecular Venetoclax disulfide bond under nonreducing conditions, but almost all C213S molecules were present as monomers in the presence of 100 mM DTT, suggesting that all C213S molecules had been reduced. As MoPrP contains two Cys residues, its mBBr signal intensity was expected to be twice that of C213S. Therefore, MoPrP was likely reduced almost completely in the presence of 100 mM DTT. Next, we investigated whether Chandler PrPSc was also reduced in the presence of 100 mM DTT (Fig. 1b). Chandler PrPSc was indeed reduced, but only

by about 30% (data not shown). To investigate the effect of reducing conditions on the binding of MoPrP with PrPSc and conversion of MoPrP into PrPres, binding and cell-free conversion PD-1/PD-L1 signaling pathway assays were first performed using Chandler PrPSc as seed. Addition of both DTT and 2ME resulted in a decrease in the binding and conversion efficiencies in a concentration-dependent manner, but the differences between the reduced and nonreduced samples were not significant (Fig. 2). Addition of another reducing agent, tris(2-carboxyethyl)phosphine, gave similar results (data not shown). These data suggest Unoprostone that reducing conditions did not significantly affect the binding

of MoPrP to Chandler PrPSc or conversion of MoPrP into PrPres. We then investigated the effects of DTT on binding and conversion in several mouse-adapted prion strains. The binding efficiencies of MoPrP with 79A, ME7, Obihiro, and mBSE PrPSc under nonreducing conditions were 104%, 56%, 45%, and 87%, respectively, of that of Chandler (100%) (Fig. 3a, open columns). The efficiencies of ME7 and Obihiro were about half that of Chandler, although there was no significant difference between the two strains and Chandler. On the other hand, the efficiencies of conversion of MoPrP in the 79A, ME7, Obihiro, and mBSE-seeded strains under nonreducing conditions were 94%, 23%, 13%, and 21%, respectively, of that of Chandler. Except for 79A, the differences between Chandler and the other prion strains were significant (P < 0.001) (Fig. 3b, open columns).

The presence of a significantly increased number of TCR Vβ8+ lymphocytes in Peyer’s patches upon chronic DSS-induced colitis

is associated with aggravated mucosal inflammation, as determined by significantly increased weight loss and MEICS score of Bim–/– compared to wild-type mice. Data from spleen weight, colon length and histological score confirmed this suggestion. Interestingly, TCR Vβ8+ lymphocytes can bind SEB. Wild-type mice treated with a single intrarectal instillation of SEB displayed a time- and dose-dependent colonic inflammation which was further increased significantly in ovalbumin transgenic mice with 95% TCR Vβ8+ lymphocytes [24]. Enhanced expression of the pro-survival proteins BCL-2 and BCL-xL was determined in PD98059 supplier lamina propria T cells of patients with CD when compared with controls. Lamina propria T cells in CD patients show activation of the STAT-3 signalling pathway mediated by IL-6. Activation of STAT-3 is followed by the induction of anti-apoptotic genes such as BCL-2 and BCL-xL [14]. Resistance of CD T cells to multiple apoptotic signals is associated with increased BCL-2 expression. An abnormal BCL-2 expression in lamina propria mononuclear cells from patients with CD was demonstrated [15]. A significantly higher BCL-2/Bax ratio in CD mucosa compared to controls was reported [16]. These data are consistent

with a recent report showing significant resistance to Fas-induced apoptosis of peripheral T cells from CD patients

[17]. The same immunological consequence resulting from the extended lifespan of antigen-primed T cells is PI3K Inhibitor Library supported by a reduced survival or function of Treg cells. Apoptosis is elevated strongly in mucosal and peripheral CD4+CD25highforkhead box protein 3 (FoxP3)+ Treg cells of patients with IBD [25]. Failure of the apoptotic mechanism of lymphocyte control can lead to the development of autoimmunity or lymphoma. Bim deficiency perturbed thymic T cell development. As expected for the loss of a pro-apoptotic molecule, PTK6 the numbers of both the CD4−8− pro-T cells and the mature T cells (CD4+8− and CD4−8+) were two- to threefold higher than in wild-type animals. Surprisingly, however, the CD4+8+ pre-T cells, the predominant thymic subpopulation, were only half the normal level [8]. Interestingly, we observed rectum prolapses in Bim–/– animals. The trigger for the appearance of prolapses was not investigated in this work. As described for mice homozygous for Il10tm1Cgn, targeted mutations leading to altered lymphocyte populations are most likely to be involved in prolapse formation. As described for IL-10–/– mice, animal housing conditions and the microbiome influence prolapse development. However, our mice were housed in IVC in a SPF facility where a less developed microbiome could be expected. We found significantly increased inflammation in Bim–/– animals compared to wild-type mice upon chronic DSS-induced colitis.

However, this may not be simply an issue of general capacity limits, but the unique way in which word–object mappings must be used in the switch task may also create task-specific difficulty (e.g., Swingley & Aslin, 2002). However, there

are two interpretations of infants’ difficulties with this task: it could indicate that phoneme perception is robust at this age, but that a difficult task masks children’s ability to deploy these skills (e.g., Werker & Fennell, 2006). Alternatively, our work suggests that this difficult task reveals specific difficulties in speech perception. In an easy task, such as a checkerboard dishabituation or a looking-preference task, the nature of the task only requires infants to discriminate pairs of speech sounds—it is not necessary to ignore selleck any dimension, as a detectable difference in any of them should be sufficient to drive discrimination. In Maye et al.’s (2002, 2008) work, the

relevant statistics within a cue were sufficient to alter discrimination. However, the switch task is closer to a categorization task, in which many sources of information (irrelevant or relevant) selleckchem may be associated with the response. Thus, it may reveal a second component of perceptual development, dimensional weighting. Dimensional weighting is a key feature of PRIMIR (Werker & Curtin, 2005), but it was not explicitly tied to switch-task failure due to lack of empirical evidence. The results of our experiments suggest that this explicit relationship. For 14-month-olds

in the switch task, the statistics of contrastive cues are less helpful (as they are relevant to a problem that is already solved) than the statistics of noncontrastive cues (which are relevant to the problem Ribociclib of weighting). Thus, as numerous researchers have pointed out, the nature of the task is of fundamental importance to understanding results like these (Swingley & Aslin, 2002; Werker & Fennell, 2006; Yoshida et al., 2009). However, the overall difficulty of task perhaps does not fully describe why. Rather, what is important is the way that the task shapes how particular (and perhaps nonobvious) sources of information contribute to learning, the particular mappings that must be employed at test, and the kind of information used in those mappings (for a similar discussion, see Yoshida et al., 2009). Our interpretation of these results is that it is not that a difficult switch task masks intact phoneme perception, but rather that this difficult task highlights an aspect of speech perception is not yet well developed at this age. We may be left with the original conclusion of Stager and Werker (1997) that speech perception may not be developed sufficiently in 14-month-olds to fully support word learning. Importantly, the ability of variation to shape dimensional learning is likely to break down differently depending on the acoustic/phonetic properties in question.