Translated clinically, this suggests that patients suffering from autoimmune diseases may develop steroid resistance due to persistent CORT exposure; in the absence of careful control over steroid resistance measures,

click here patients may thereby enter a vicious cycle where they become dependent on increasing doses of steroids. Eight-week-old C57BL/6 mice were purchased from Harlan (Jerusalem, Israel) and were allowed to acclimatize to our animal facility for 7 days prior to the experimental period. All mice were housed under standard environmental conditions (12:12 light:dark cycle with light onset at 7:00 a.m.) and were allowed free access to food and water throughout the experimental period. Surgical and experimental procedures were approved by the Institutional Animal Care Ivacaftor and Use Committee (IACUC) of Ben-Gurion University of the Negev, Israel. To detect intracellular FoxP3 we used C57BL/6 transgenic mice expressing enhanced green florescent protein under the control of the mouse FoxP3 promoter. The mice were kindly provided by Dr. Eli Lewis. Mice were randomly assigned into two groups: (i) a group of isolated mice exposed to CVS for 24 days as described below, (ii) and a group of nonstressed mice, kept in groups of 4–8 mice per cage and manipulated only once a week for urine collection and body weight measurement. Following the 24-day experimental period,

mice in the stressed and nonstressed groups were further divided into three groups: (i) mice subjected to behavioral tests, after which they were killed for immunological analysis; (ii) mice injected with MOG35-55 emulsified Meloxicam in CFA to induce EAE as described below; and (iii) mice injected with the CORT antagonist mifepristone (Sigma, Israel) daily, 2 hours before exposure to the stressful conditions, throughout the stress period. Mifepristone was dissolved in 100% ethanol and diluted to 5% ethanol in corn oil to a final concentration of 3 mg/mL. A daily dose of 30 mg/kg was injected subcutaneously. Chronic unpredictable stress paradigms typically

follow a schedule of repeated exposure to several randomly assigned stressors a day. The CVS procedure was developed based on several paradigms previously validated as stress inducers in rodents. These included isolation [55]; exposure to cat urine [56]; restraint (placing the mouse in a well-ventilated 50 mL polypropylene tube, 2.8 cm in diameter and 11.5 cm in length) [57]; swimming in cold (4°C) water [58]; illumination during the dark phase, and tilting the home cage at a 45o inclination for 24 hours [30]. Stressor types and stress durations throughout the experiment are provided in Table 1. Stressed and nonstressed mice were tested to evaluate anxiety-like behaviors 24 hours after termination of the experimental protocol (i.e. on day 25) using the following behavioral tests.

In particular, DCs can transpresent IL-15 in complex https://www.selleckchem.com/products/XL184.html with the IL-15Rα-chain to central memory T cells and IL-15 transpresented by macrophages can support both effector and memory CD8+ T cells [17]. In our study, about 40% of the transferred memory T cells are in close proximity to either an F4/80+ or a CD11c+ cell. Recent studies show that human BM memory T cells are in close contact with cells expressing IL-15 message [43]. With our system, we did not observe enrichment of IL-15-expressing cells in proximity to

the CD8+ memory T cells, as we found less than 2% of memory T cells in contact with IL-15+ cells. This might be due to the limited sensitivity of the IL-15 antibody stain, resulting in us only detecting cells with the highest IL-15 expression. It has been reported that adoptively transferred leukemic cells as well as DCs and B cells populate perivascular regions in cranial bones of mice [44, 45]. In contrast to those studies, we did not observe enrichment of the transferred memory T cells to sub-regions within the BM, rather they were found randomly scattered throughout the BM. A reason for this difference in results might be the different T-cell types analyzed and/or differences in cellular organization in long bones as compared to the cranium. We also detected other cell types located in close proximity to the transferred CD8+ memory T cells. The most abundant of these were the Gr1+ cells, whose

proximity to ZD1839 purchase the CD8+ memory T cells was not statistically different than that of the VCAM-1+ stromal cells. Based on flow cytometry, the Gr1hi granulocytes do not express 4–1BBL,

whereas, 4–1BBL was detected on Gr1o MHC II+, CD11b+ F480+ cells in the BM of unimmunized mice (Supporting Information Fig. 6). We do not know if our microscopy is only detecting the abundant Gr1hi granulocyte population or also includes this 4–1BBL+ Gr1lo population. About 35% of the memory T cells were found near B220+ cells. However, B220+ cells from the BM do not express 4–1BBL (Supporting Information Fig. 6A) and moreover, B cells are not essential for CD8+ T-cell memory [46] making it unlikely that the B cells make nonredundant contributions to the support of CD8+ memory T cells. It is also possible that these tangencies (with VCAM-1+, Gr1+, or B220+ cells) are merely coincidental, as we observed memory from T cells touching up to eight cells in one section. Additionally, the cells could also be competing for similar stromal cell factors as the CD8+ T cells. In conclusion, this study begins to define the cells that contribute to the maintenance of CD8+ memory T cells by 4–1BB and 4–1BBL. We demonstrate that 4–1BB on an αβ T-cell allows increased recall responses of CD8+ T cells. We further show that 4–1BBL on a radioresistant cell with lesser effects of 4–1BBL on a radiosensitive cell allows increased recovery of memory CD8+ T cells after parking in mice without antigen.

According to a report studied by WHO, 2 billion people are infected with Mycobacterium tuberculosis and 8–12 million new cases occur each year, accounting for 2–3 million deaths annually [1]. Epidemiological studies

indicate that 5–10% of people infected with M. Tuberculosis will develop active tuberculosis [2]. Nowadays, the prevalence of tuberculosis is worse in China owing to the increasing number of mobile population, the aggravating environment and the transformed biology of bacilli. To date, several candidate genes have been associated with the onset of TB [3, 4]. Therefore, the candidate genes such as vitamin D receptor genes and others have provided PD0325901 in vivo us the understanding of pulmonary tuberculosis (PTB) infection. Killer cell immunoglobulin-like receptor (KIR), a large group of polymorphic receptor expressed on NK cells and T cells, recognizing human leucocyte antigen (HLA) class I molecules and playing a pivotal

role in immune responses. KIR click here haplotypes can be simplified into two distinct groups, A and B [5]. Group A haplotype has a fixed number of genes that encode inhibitory receptors with the exception of 2DS4, whereas group B has variable gene content including additional activating receptor genes (KIR2DS1, 2, 3, 5 and KIR3DS1) as well as two inhibitory receptors (KIR2DL2 and KIR2DL5). When this distinction is used, all individuals can be assigned to have 1 of 2 genotypes: A/A, which Decitabine clinical trial is homozygous for group A haplotype, or B/x, which includes A/B heterozygotes or B/B homozygotes. HLA class I is the most polymorphic region of the human genome. HLA class I genes are found at the A, B and C loci of chromosome 6 and have been shown to play an important role in controlling of infection [6]. In addition, HLA-C molecules are classified as either C1 group with Ser77Asn80 in the HLA H chain (HLA-Cw*01, HLA-Cw*03, HLA-Cw*07, HLA-Cw*08, HLA-Cw*12, HLA-Cw*14 and HLA-Cw*16) or C2 group with Asn77Lys80 in the H chain (HLA-Cw*02,

HLA-Cw*04, HLA-Cw*05, HLA-Cw*06, HLA-Cw*15, HLA-Cw*16, HLA-Cw*17 and HLA-Cw*18). KIR polymorphisms and allelic variation affect the KIR-HLA binding specificity and are linked to the outcome of diseases [7, 8]. The peptide-binding motif for HLA-Cw*0304 has been formally determined [9]. Recent genome-wide association research has indicated the significant role of HLA-Cw genes [10]. However, HLA-Cw alleles have been less well studied than their HLA-A and HLA-B counterparts. Although some effective measures have been taken to control this disease [11], the incidence of TB has recently re-emerged as a public health problem in many countries. To investigate the influence of KIR and HLA-Cw genes on the risk of PTB development, a case–control study was conducted in patients with PTB and controls by using sequence-specific primer polymerase chain reaction (SSP-PCR) method. Our findings provided a better understanding on the genetic diversity of KIR-HLA across patients with PTB. Patients group.

Measurements were carried out using the O2C monitoring system under temporary digital occlusion of the pedicle. After 4 weeks, 17 free flaps were found to be autonomized indicated by the O2C measurements comparing both values before and after digital compression of this website the vascular pedicle. After 12 weeks, 41 patients had completion of free flap autonomization, as

indicated by the HbO2 and CF before and after pedicle compression. The location of free flap in the lower jaw (P < 0.0001 after 4 weeks, P = 0.013 after 12 weeks), fasciocutaneous radial forearm flaps after 4 weeks (P < 0.0001), and not irradiated recipient site after 4 weeks (P = 0.014) were found to be positive factors significantly influencing autonomization. In conclusion, free flap autonomization depends on several variables which should be considered before further surgery after free flap reconstruction as the transferred

tissue can be still dependent on its pedicle. © 2012 Wiley Periodicals, Inc. Microsurgery, 2012. “
“Skull base reconstruction is challenging due to its proximity to important anatomical structures. This report evaluates the use of perforator flaps for Neratinib in vitro reconstruction of skull base defects after advanced recurrent tumor resection. Fourteen free perforator flaps were transferred to reconstruct skull base defects in 14 consecutive patients, from October 2004 to May 2011. All patients had advanced recurrent neoplasms that were previously treated with either radiation therapy or surgery. The surgical defects were reconstructed using various perforator flaps mainly the deep inferior epigastric artery perforator flaps, anterolateral thigh (ALT) flaps, or thoracodorsal artery perforator flaps. The outcomes following reconstruction

and associated complications were evaluated. The overall free flap success rate was 93% (13/14). One ALT flap was lost. Three patients (20%) had a cerebrospinal fluid fistula, and two of them developed meningitis. No complications were observed at the donor site. The use of old perforator flaps may be a viable option for reconstruction of skull base defects after the resection of advanced recurrent tumor. © 2014 Wiley Periodicals, Inc. Microsurgery 34:623–628, 2014. “
“Purpose: Assessment of donor site morbidity and recipient site complications following free radial forearm osteocutaneous flap (FRFOCF) harvest and evaluation of patient perceived upper limb disability for free radial forearm osteocutaneous versus fasciocutaneous flaps (FRFF). Methods: First a case series was undertaken of 218 patients who underwent an FRFOCF at two tertiary referral centers between February 1998 and November 2010. Outcomes included forearm donor site morbidity and recipient site complications.

The causative association of allergen-specific Immunglobulin E (IgE), the high-affinity IgE receptor (FcεRI), and mast cells for immediate type allergy and anaphylaxis has been studied for decades [3-5]. However, since the discovery of anaphylaxis in IgE-deficient mice [6] and more recently studies on basophil biology, a number of publications

have focused on the contribution of alternative pathways to anaphylaxis [7-9]. It has become evident that the isotype, quantity, and quality of the sensitizing antibodies are important parameters for anaphylaxis [9]. In summary, at least two mutually nonexclusive pathways exist that employ allergen-mediated cross-linking of either receptor bound IgE and/or receptor bound IgG and Alpelisib price lead to activation of mast cells and/or basophils leading to release of inflammatory substances, e.g. histamine or platelet activating factor [7, 10]. Nevertheless, experiments to examine the role of the active polyclonal antibody response in anaphylaxis are hampered by the low expression of IgE and a low frequency of IgE expressing B cells in WT mice [11, 12]. In order to circumvent this problem, we generated an IgE knock-in mouse strain to

study the role of IgE regulation in vivo. We created a high-IgE expressing mouse model AG-014699 price for allergy research based on work by Rajewsky et al. [13], who showed that the replacement of the murine IgG1 heavy chain locus by human IgG1 leads to humanized antibody production in vivo. We adapted this approach and replaced the exons encoding the soluble part of the constant region of murine IgG1 with the murine IgE counterpart. The advantage of this approach over conventional Protirelin IgE transgenic mice is twofold. First, it is possible to study the regulatory influences of the genetic region in a defined way, excluding positional effects of the classic transgenic approach. Second, it allows the natural usage of the endogenous variable, diversity, and joining segment of the antibody gene region and, therefore, the generation of polyclonal

IgE antibody responses against any given antigen and not only the monoclonal IgE production against a single model antigen [13, 14]. Indeed, both IgE and IgG1 are dependent on Th-2 type T-cell and cytokine signals, e.g. CD40–CD40L interaction and IL-4. However, a number of studies suggest that the developmental switch to IgE has unique features as it can occur outside secondary lymphoid structures [15] or initiate in germinal centers (GCs) and rapidly progresses to IgE+ plasma cells located outside the GC [16]. Recently, membrane IgE GFP-reporter mouse strains suggested a scenario where IgE+ B cells develop with similar kinetics compared with those of IgG1+ B cells, but without an IgG1+ intermediate stage.

The cells were analysed by flow cytometry on a FACSCanto II (BD Biosciences) using FACS Diva software. Specificity of signal was determined by inhibition of staining using purified AID (AICDA, Dundee Cell Products) or A3G (Immunodiagnostics Inc.). Where cells were double-labelled for AID and A3G a monoclonal antibody (mAb) to A3G (Immunodiagnostics Inc.) was used and the secondary antibodies were FITC anti-goat immunoglobulin (Sigma-Aldrich) and a phycoerythrin-conjugated anti-mouse immunoglobulin antibody

(Southern Biotechnology Associates, Birmingham, AL). To detect A3G 10 × 106 cells were lysed in 1 ml RIPA buffer for 30 min on ice, cleared by centrifugation and equal volume of 2 × SDS sample buffer was added under reducing conditions before SDS–PAGE. After Sotrastaurin mouse transfer of proteins to a PVDF membrane, Western blotting was carried out with mouse mAb to A3G (#7105; ImmunoDiagnostics) and β-actin (clone AC-15; Sigma), using horseradish peroxidase-conjugated anti-mouse IgG antibody and Immobilon Western HRP Substrate (Millipore, Watford, UK). About 5 × 106 B cells were harvested and washed with PBS, before extraction of RNA with the Promega SV Total RNA Isolation System. RNA was reverse transcribed according to the manufacturer’s instructions with oligo(dT) primers

and AMV reverse transcriptase (Promega, Southampton, UK). Real-time PCR with cDNA as template selleck was performed with Sigma’s SYBR Green JumpStart Taq Ready Mix (Sigma-Aldrich) Niclosamide and gene-specific primers for A3G (5′-TTGTTGCCCGCCTCTACTAC-3′, 5′-TTGGCTGTACACGAA CTTGC-3′), AID (5′-AGAGGCGTGACAGTGCTACA-3′, 5′-TGTAGCGGAGGAAG AGC AAT-3′) and glyceraldehyde 3-phosphate dehydrogense

(GAPDH: 5′-CTTTTGCGTCGCCAGCCGAG-3′, 5′-ACCAGGCGCCC AATACGACC-3′) as housekeeping control. A Corbett Rotor-Gene 6000 PCR cycler was used to run the reactions and manufacturer’s software to analyse data with the ‘Two Standard Curve’ method. The resulting data were normalized to the housekeeping gene GAPDH and expressed relative to unstimulated cells which were accorded an arbitrary value of 100. To determine the concentrations of CD40L + IL-4 that will induce optimum AID and A3G mRNA relative to unstimulated cells, these were titrated from 50 to 200 ng/ml CD40L and 20–100 units/ml IL-4. The results suggested that 100 U/ml IL-4 with 100 ng/ml CD40L were most consistent in eliciting AID and A3G. The effect of AID expression was examined in isolated CD19+ B cells by flow cytometry analysis for cell surface IgM, IgG and IgA isotypes using the following fluorochrome-conjugated mAbs: anti-IgG-FITC and anti-IgM-phycoerythrin (BD Pharmingen, Oxford, UK), anti-IgE-FITC and anti-IgA-FITC (Miltenyi Biotec; Bisley, Surrey, UK).

TRIF mediates TLR3 signaling and TLR4-induced MyD88-independent pathway, such as delayed NF-κB activation 11–13. The interaction between TRIF and TLR4 is mediated by TRAM 14–16. As a newly discovered member of the TLR-adaptor family, the function of SARM is relatively unknown, yet it is the most conserved TIR domain-containing protein, having homologues in Drosophila17, zebrafish

18, Caenorhabditis BVD-523 elegans19 and horseshoe crab 20. These homologues share a common domain architecture constituted of N-terminal Armadillo motifs (ARM), two sterile α motif (SAM) domains and a C-terminal TIR domain 21. The unique combination of three protein–protein interaction domains in SARM suggests that amongst the family of TLR adaptors, SARM probably functions differently from the other adaptor molecules 21, 22. In fact, SARM seems to exhibit multiple RXDX-106 roles, and its functions differ in different species and under different circumstances. SARM negatively regulates NF-κB and IRF3-mediated TLR3 and TLR4 signaling, both in the human 23 and in the horseshoe crab 20. These earlier studies showed that such inhibition is restricted to the TRIF pathway. It was reported that the overexpression of SARM blocks the induction of TRIF-dependent, but not MyD88-dependent genes,

and that this interaction is enhanced by LPS 23, suggesting that SARM is specifically responsible for downregulating TRIF-mediated TLR signaling during Gram-negative bacterial infection. Some recent findings add further complexity to the function of SARM, indicating upregulation 24 or downregulation 25 of its expression upon immune activation. Yet another

study showed a viral infection-mediated immune activation of SARM in the mouse brain 26. Besides immune function, SARM has also been implicated in the neuronal system 27, 28. Overall, the conundrum of the function of SARM remains unsolved. Besides NF-κB and IRF3, AP-1 is another transcription factor activated by TLR signaling. Although SARM specifically inhibits TRIF-dependent activation of NF-κB and IRF3, Thalidomide it is unknown whether SARM also inhibits AP-1, and whether it is also restricted to the TRIF pathway. Since the TLR-mediated pathway for AP-1 activation is distinctive from those which activate NF-κB and IRF3 29, it is possible that SARM uses different mechanisms to regulate AP-1 signaling. In neuronal stress, SARM recruits activated JNK3 into the mitochondria 27, suggesting its potential involvement in MAPK signaling to promote neuronal apoptosis. In C. elegans, the SARM homolog, TIR-1, functions through a p38 MAPK signal transduction cascade 30, 31. However, the role of human SARM in MAPK pathway is unmapped. Here, we demonstrate that human SARM is capable of blocking the LPS-induced MyD88- and TRIF-mediated AP-1 activation. The effect of SARM against the LPS-mediated AP-1 activation was verified by suppression of endogenous SARM with siRNA, which resulted in increased basal AP-1 level.

Differing and temporally specific roles of different MMPs after CNS injury, along with the implication of MMPs in neuropathic pain states following spinal cord injury means the premise of broad spectrum MMP alteration warrants natural caution. Although it may be noted that the synthetic tetracycline derivative minocycline has weak broad-spectrum MMP inhibitory activity and, alongside safety, reports a nonsignificant trend towards improved neurological

and functional recovery following a phase II clinical trial as a therapeutic for spinal find more cord injury (http://www.clinicaltrials.gov/SHOW/NCT00559494), [229]. In addition, MMP substrates are extremely wide-ranging and many are highly

nonspecific. https://www.selleckchem.com/products/AZD1152-HQPA.html As an example, while MMP-3 degrades candidate CSPGs upregulated after CNS injury, it also degrades collagen types II, III, IV, IX and X, fibronectin, laminin and elastin and activates other MMPs including MMP-1, MMP-7 and the pro-inflammatory MMP-9. In addition there is redundancy; aggrecan, as an example, is cleaved by MMP-1, -2, -3, -7, -8, -9, -11, -13, -14, -15, -19, -20 [230]. Due to broad specificity and wide-ranging orchestrated and inter-regulatory roles of MMPs, attention is also drawn to other, more specific, endogenous matrix remodelling enzymes. MMPs belong to the metzincin superfamily of metalloproteinases, also including astacins, ADAMs (a protein with a disintegrin and metalloprotease domain) and ADAM-TS (an ADAM with a thrombospondin-like motif) proteases. Of

particular interest, ADAMTS-4 reverses the proteoglycan-mediated inhibition of neurite outgrowth in vitro [231] and in vivo, ADAMTS-4 has been shown to promote functional recovery after moderate thoracic contusion in the rat when delivered intrathecally via osmotic mini-pump [232]; interestingly, functional improvement was Rolziracetam of the same magnitude to that seen with the more commonly used enzyme chondroitinase (the use of chondroitinase as a tool to promote repair following CNS injury will be discussed below). With increasing specificity in terms of proteolytic target, a recent study reports use of the mammalian enzyme arylsulphatase B (ARSB) (N-acetylgalactosamine 4-sulphatase) which removes the C-4-S moieties from CSPGs, previously reported to be inhibitory to neuronal growth [185]. Following moderate and severe thoracic spinal compression injuries in the mouse, a single intraspinal injection of human ARSB removed immunoreactivity for C-4-S which was associated with increased serotonergic and tyrosine hydroylase positive axon sprouting and functional locomotor recovery [233]. The authors suggest that ARSB has interesting advantages in that its enzymatic activity is optimal at acidic pH and the CNS injury environment has been reported to display mild acidosis [234].

Microsurgery, 2011. “
“Introduction: Microsurgical lower extremity flap reconstruction provides a valuable option for soft tissue reconstruction in comorbid patients. Limb salvage with flap reconstruction can result in limb length preservation. Despite this, few PF-6463922 studies have examined the impact of salvage on patient-centered metrics in this cohort of patients. Therefore, we investigated quality of life and patient satisfaction following microsurgical

lower extremity reconstruction in this high-risk patient population. Factors that resulted in improved patient-centered outcomes were also identified. Methods: A retrospective review was conducted of all patients who had lower Selleckchem MAPK Inhibitor Library extremity free flap reconstruction (FFR) following lower extremity wounds. High-risk patients were identified as having multiple comorbidities and chronic wounds. Patients with traumatic wounds were excluded from analysis. Quality of life was evaluated with the Short Form-12 (SF-12) validated survey. Phone interviews were conducted for survey evaluations. Results: From 2005 to 2010, 57 patients had lower extremity flap reconstruction that met the inclusion criteria. Average follow-up was 236.6 weeks (range, 111–461). Comorbidities included diabetes (36%),

PVD (24.6%), and ESRD (7%). Limb length preservation and ambulation occurred in 82.5% (47/57). Revisional surgery occurred in 33.3% (19/57). Survey response rate was 63%. Average SF-12 PCS and MCS scores were 44.9 and 59.8 for patients able to achieve ambulation and 27.6 and 61.2 for nonambulatory patients. Conclusions: Microsurgical flap reconstruction is a valuable reconstructive

option in high-risk patients. Quality of life is comparable with Methamphetamine a normalized population if limb salvage is successful. Quality of life is decreased significantly when failure to ambulate occurs in this patient cohort. © 2013 Wiley Periodicals, Inc. Microsurgery 34:1–4, 2014. Lower extremity reconstruction with the aim toward limb salvage in the co-morbid patient population is a difficult undertaking for the reconstructive surgeon. Co-morbidities such as diabetes mellitus, peripheral vascular disease, and renal failure add complexity to microsurgical reconstruction. Systemic vascular changes such as recipient vessel disease, recipient site scarring, and donor vessel disease may pose a technical challenge. However, successful outcomes in lower extremity reconstruction are well demonstrated in this patient population and provide patients with the option of limb salvage.[1, 2] Early successful outcomes are predicated by overcoming compromised vascular inflow and by controlling infection. Following the early postoperative period, achieving successful long-term outcomes becomes more challenging. Traditionally flap survival was the marker for defining a successful outcome.

As argued by Aslin and Newport (2012), the degree of generalization is a function of the patterning of the input to which the learner is exposed. Even canonical Selleck MK-8669 statistical-learning studies that only test exemplars drawn from the specific stimulus materials to which the learner is exposed can be viewed as an inference problem (Goldwater, Griffiths, & Johnson, 2009).

For example, the words and part-words used as test items in Saffran et al. (1996) were drawn from the continuous stream of syllables presented during the familiarization phase. Thus, neither of these test items were exact replicas of what had been presented for “learning”. Yet, infants readily showed reliable differences in “recognition” of these test items. Thus, the proper way to conceptualize any learning task is to ask what are the most plausible inferences that the learner could make based on the patterning of the input. Reeder, Newport, and Aslin (2013) provided extensive evidence that adults will either generalize freely or restrict generalization depending on the patterning of the context in which nonsense words are presented across a family of utterances. Their task consisted of listening to several hundred utterances of variable word lengths and then being tested on (1) a subset of these familiar utterances, (2)

a set of novel utterances that conformed to the underlying grammar, and (3) a set of novel utterances that violated the underlying grammar. AZD9291 clinical trial Crucially, the number of grammatical categories and which nonsense words were assigned to these categories were unknown to the subjects. In each of eight separate experiments, the patterning of the nonsense words that surrounded a critical target category differed—in some experiments all possible surrounding contexts were presented in GNA12 the familiarization utterances, in others some of the surrounding contexts were consistently absent, and in yet others

only a single context was present. Thus, as in Gerken (2006), the surrounding contexts varied from providing consistent evidence for generalization to inconsistent evidence for generalization, and finally little or no evidence for generalization (i.e., strong evidence for restricting generalization). Moreover, in two follow-up experiments that more closely mimicked the variability in word frequency (K. D. Schuler, P. A. Reeder, E. L. Newport, & R. N. Aslin, unpublished data) and the presence of subcategories (Reeder, Newport, & Aslin, 2010) that add a further level of context, adults readily generalized or restricted generalization depending on these same principles of patterning in the surrounding contexts. Thus, distributional cues are sufficient to induce learning and modulate generalization.