The synergistic effect with nystatin was determined similarly. The effect of licorice compounds on biofilm formation was evaluated using a microplate assay and crystal violet staining. The effect of licorice compounds Selleck Lumacaftor on yeast-hyphal transition was determined by microscopic observation. The toxicity of licorice compounds towards oral epithelial cells was evaluated with an MTT assay. Glabridin and licochalcone A showed antifungal activity on C. albicans while glycyrrhizic acid had no effect. Complete growth inhibition occurred with sub-inhibitory concentrations

of nystatin with either glabridin or licochalcone A. Biofilm formation was inhibited by 35–60% in the presence of licochalcone A (0.2 μg ml−1). A strong inhibitory effect (>80%) on hyphal formation was observed with licochalcone A or glabridin (100 μg ml−1). Glabridin and licochalcone A at high concentrations showed toxicity towards oral epithelial cells. In summary, glabridin HSP phosphorylation and licochalcone

A are potent antifungal agents and may act in synergy with nystatin to inhibit growth of C. albicans. Licochalcone A has a significant effect on biofilm formation, while both licochalcone A and glabridin prevented yeast-hyphal transition in C. albicans. These results suggest a therapeutic potential of licochalcone A and glabridin for C. albicans oral infections. “
“Caspofungin is a member of the echinocandin class of antifungal compounds that inhibit 1,3-β-d-Glucan synthase. As patient exposure to caspofungin (CAS) broadens, the number of infecting strains with reduced susceptibility to this drug is expected to rise. In the present study, the in vitro effects of varying concentrations of CAS

against Candida albicans isolates presenting reduced susceptibility to CAS were studied in comparison with a reference strain. Two C. albicans isolates presenting high minimal inhibitory concentrations (MIC = 8 μg ml−1) were selected: one isolate obtained in the laboratory under continuous antifungal selection pressure (CaIn-R) and one clinical isolate (CaClin-R) from a patient with a therapeutic failure. Results showed that after 24 h of CAS exposure, CaIn-R and CaClin-R presented a partial growth inhibition in comparison with the reference strain. Moreover, scanning electron Sorafenib clinical trial microscopy and transmission electron microscopy studies showed that the cell walls of CaIn-R and CaClin-R were less altered than that of the reference strain. These observations suggested that although CaIn-R and CaClin-R cells were misshapen after CAS exposure, cell lysis was limited after 24 h of treatment indicating higher survival ability for CaIn-R and CaClin-R in the presence of CAS. “
“This study describes the isolation of Cryptococcus neoformans and Cryptococcus gattii from patients with chronic meningitis who were admitted to 16 Malaysian hospitals, from 2003 to 2004. Of the 96 cryptococcal cases reported over the 2-year period, 74 (77.1%) patients were male and 45 (46.

Interestingly, Alectinib nmr these authors suggested that H2O2 generation occurs at the vascular smooth muscle cell plasma membrane rather than in the endothelium [12]. In coronary arterioles from heart failure patients [44,58], flow-induced vasodilation is inhibited by catalase and by inhibitors of potassium channels, providing evidence that H2O2 functions as an EDHF in this vascular bed. Similar observations have been made in other human microvascular beds [32,53,69]. For example, Matoba et al. [53] found that H2O2 is a

primary EDHF in human mesenteric resistance arteries and Phillips et al. [69] observed that H2O2 could replace NO• as the primary vasodilatory agent in microvessels from human visceral fat. Interestingly, Hatoum et al. [32] observed that H2O2 is released by the vascular endothelium of human submucosal intestinal microvessels, but that it does not act as EDHF in these vessels; on the contrary, it produces vasoconstriction LY294002 in denuded vessels. Overall these results indicate that H2O2 functions as an EDHF

in human arterioles; however, the net vasoactive effect of H2O2 may depend on the vascular bed and the health status of the patients being studied [32]. In a recent study of the human cutaneous microcirculation, Medow et al. [57], showed that H2O2 scavenging with Ebselen (Sigma, St. Louis, MO, USA) reduced cutaneous vasodilation to heat in healthy young subjects. These results provide evidence that H2O2 contributes to control of local blood flow in vivo and emphasize the need for further studies to establish the mechanisms of H2O2 generation and action in the

human microcirculation in vivo. Moreover, it would be interesting to use this in vivo model to study the role of H2O2 in regulation of cutaneous blood flow in elderly subjects. Although numerous studies have now implicated a role for H2O2 in regulation of vascular resistance in humans, virtually nothing Clomifene is known regarding the effects of age on H2O2 signaling in the microcirculation of humans. The work of Miura et al. suggests that H2O2 functions as a significant endothelium-dependent vasodilator in coronary arterioles from heart failure patients [57], a disease that is more prevalent in elderly populations. It is possible that H2O2 compensates for a loss of NO•-mediated vasodilation in elderly humans. Alternatively, if dysregulation of H2O2 production/degradation occurs with age, damage to either the endothelium or the vascular smooth muscle could ensue and contribute to age-induced vascular dysfunction. Further studies in human subjects are needed to assess the effects of age on (1) regulation of vascular H2O2 production/scavenging, and (2) H2O2 signaling in both the endothelium and vascular smooth muscle. Although increased oxidative stress in the endothelial cell can result in increased production of ONOO•− (Figure 1), an increase in ONOO•− does not necessarily decrease NO• bioavailability.

Values are given as 2−delta

CT. RORγt primer (Metabion, Planegg-Martinsried, Germany) and probes were obtained from Eurogentec (Cologne, Germany) using the previously described sequences [70]. t-bet and PNOC panel were purchased from Applied Biosystems (Foster City, CA, USA) with the numbers Mm00450960_m1 and Mm00803087_m1. To analyse cytokine release during aTreg restimulation, this website supernatants were collected and stored at –80°C. Cytokine content was quantified using the CBA kit (FlowCytomix) from Bender MedSystems® (Vienna, Austria). The supernatants were prepared according to the manufacture’s protocol. Samples were analysed on a FACSCalibur (Becton Dickinson, San Jose, USA). To determine the frequency of Treg cells, cells were stained for CD3ε-PerCP (clone

145–2C11, Biolegend Fell, Germany), CD25-PE (clone 3C7, Miltenyi® Biotec) and Foxp3-FITC Stem Cell Compound Library molecular weight (clone FJK-16, eBioscience). The cells were first stained for the surface expression of CD3ε and CD25 for 15 min at 4°C. Cells were then washed, fixed and permeabilised (30 min; 4°C) using the buffer from the Foxp3 staining kit (eBioscience) followed by an intracellular staining for Foxp3 and/or Helios-AlexaFluor 647 (clone 22F6, Biolegend Fell, Germany) for 30 min at 4°C. The percentage of CD4+CD25+Foxp3+ Treg cells was determined on a FACSCalibur (BD). The maturation of B cells was measured using CD19-FITC (clone 6D5, Miltenyi® Biotec), IAb–PE (clone M5/ 114.15.2, eBioscience) and CD86-Biotin (clone GL-1)/Streptavidin-PerCP (both Biolegend, Fell, Germany). Data were analysed with CellQuest software. For intracellular cytokine staining, cells were harvested after 7 days of primary culture washed once and restimulated with 1 μg/mL ionomycin and 10 ng/mL phorbol myristate acetate (both Biotrend Chemikalien GmbH, Cologne, Germany) for 4 h at 37°C. After 2 h, 2 μg/mL Brefeldin A (Sigma-Aldrich Chemie

GmbH, Steinheim, Germany) was added to imbed the cytokines inside the cells. Subsequently, cells were labelled with the live/dead stain (Fixable Viability Dye eFluor 506, eBioscience), their surface expression of CD3ε and CD25 (15 min; 4°C), and additionally fixed and BCKDHA permeabilised with the Foxp3 staining kit. Intracellular staining for IFN-γ allophycocyanin (clone XMG1.2, Biolegend), IL-17-FITC (clone ebio17B7, eBioscience) and Foxp3– Alexa Fluor 488 (FJK-16s, eBioscience) was done for 30 min. Samples were measured by LSR II (BD) and analysed with FlowJo software (Treestare, Ashland, OR, USA). Neuropilin-1 was stained on the surface of the cells using Neuropiln-1-PerCP (R&D Systems) CD40L staining was done as described by Kirchhoff et al. [71]. aTreg cells were isolated from primary culture and restimulated with allogeneic B cells. To prevent exportation and degradation of CD40L, we added 5 μg/mL Brefeldin A after 2 h of stimulation. The next day CD40L (PE, R&D Systems) was stained intracellularly using the Foxp3 staining kit.

The paper point was then transferred to 200 μL of PBS. The extracted chromosomal DNA served as the PCR template. As shown in Table 2, the prevalence of live E. faecalis cells ranged from 0 to 8.6 × 102 cells (0–73.3%), while that of dead cells ranged from 8.0 × 101 to 1.9 × 104 cells (26.7–100%). In this study, no live cells were observed in the samples from patients 5 and 6. However, previous testing

with real-time PCR without PMA had identified these samples as positive VX-809 mw for E. faecalis. Thus, real-time PCR and PMA can be used to distinguish live from dead E. faecalis. This method makes it possible to obtain detailed information about apical periodontitis. In this study, we observed no obvious relationship between the clinical symptoms of apical inflammation (pus discharge and percussion pain) and live/dead cell numbers. However, a larger sample number should clarify in more detail the relationship between clinical features and live/dead cell numbers. Our data will help clarify the role of E. faecalis in the etiology of apical periodontitis. This study was supported in part by Grants-in-Aid (C) 22592341 (A.Y.) Tamoxifen mouse and (B) 22390403 (T.A.) from the Ministry of Education, Culture, Sports, Science,

and Technology of Japan. None of the authors has any financial arrangements with any company whose product figures prominently in the manuscript. “
“IL-27 and TCRγδ+ T lymphocytes play critical roles in both innate and adaptive immune responses in health and disease, including infection and tumors. Although the activity of IL-27 is well characterized in different human immune cells, no information is available on the role of IL-27 in human TCRγδ+ T lymphocytes. Here, we provide the first evidence that TCRγδ+ T lymphocytes express both gp130 and WSX-1 chains of IL-27R, and that IL-27 may function in TCRγδ+ T cells by (i) inducing STAT1 and STAT3 phosphorylation, Anidulafungin (LY303366) (ii) stimulating cytotoxicity against

tumor cells through upregulation of cytotoxic granules production, (iii) reducing the release of Th2-related cytokines, such as IL-5 and IL-13, and inducing IFN-γ production, and (iv) upregulating the expression of CD62L. These results highlighted a novel immunoregulatory property of human IL-27 that may be relevant in the immune response against tumors. Our results may offer new perspectives for the development of future clinical trials using IL-27 and TCRγδ+ cells for cancer immunotherapy. IL-27 is an heterodimeric cytokine of the IL-12 family [[1, 2]] that binds to a heterodimeric receptor composed of the gp130 and WSX-1 chains [[3]]. It is predominantly produced by APCs and plays critical roles in the regulation of human T- and B-cell functions through the activation of STAT molecules [[1, 2, 4, 5]].

mansoni actin 1.1 gene (23) was constructed and transfected into schistosomes

by electroporation of larval stages together with mRNAs encoding the piggyBac transposase. The activity of piggyBac was determined by plasmid excision assays, and the recovery of excised plasmids from tissues of transformed schistosomules in these assays indicated that piggyBac was Selleckchem BVD-523 active in the worm. Southern blot hybridization analysis of genomic DNAs from populations of schistosomules transformed with donor constructs plus helper transposase mRNA detected numerous variable length luciferase-positive signals. These findings further indicated piggyBac transposon insertions into the schistosome chromosomes. piggyBac integration sites were detected by a PCR technique. Numerous piggyBac integrations were detected and, after cloning, the fragments sequenced

ranged in size from approximately 1·5 to 4 kb. Sequence analysis indicated that integration of piggyBac took place at numerous loci in the schistosome genome at target TTAA sites. The discovery of sequence-specific Selleckchem RXDX-106 gene silencing in response to double-stranded RNAs (dsRNA) has had an enormous impact on molecular biology by uncovering an unsuspected layer of gene regulation. The process, also known as RNA interference (RNAi) or RNA silencing, involves complementary pairing of dsRNAs with their homologous messenger RNA targets, thereby preventing their expression, and leading ultimately to their degradation, or interfering with protein translation (33). Since its discovery, RNAi technology has been used widely as a reverse genetics tool in C. elegans, Drosophila and many other organisms, including zebrafish, plants, human, mouse and mammalian cell culture. The ability to inhibit gene activity on a post-transcriptional

level allows generation Thalidomide of loss-of-function mutants to study gene function, or identification and validation of novel therapeutic targets [reviewed in ref. (34)]. In C. elegans, silencing was found to have high potency and specificity, and was activated throughout the treated animal (35,36), even in cells that did not encounter the double-stranded RNA. It has now been revealed that a complex protein machinery is involved in the transport of the silencing signal. This raises the possibility that animals can communicate gene-specific silencing information between cells (37). In schistosomes, the presence of transcripts encoding dicer and RISC-associated proteins (piwi/argonaute orthologs) was relatively recently described (6,38,39). SmDicer was later shown to contain all domains that are characteristic of metazoan dicers including an amino terminal helicase domain, DUF283, a PAZ domain, two RNAse III domains and an RNA binding domain. An examination of the available S.

To understand why cruising may also effect change in infants’ reaching patterns, we must consider the central role of the

upper extremities for manual control of balance and haptic exploration. Cruisers keep balance manually and prioritize manual information to such an extent that they often fail to pay attention to perceptual information from any Epigenetic Reader Domain inhibitor source other than their arms. As long as cruising infants have a continuous handrail to hold on to they will blithely cruise along into a 3-foot drop off in the floor—even when a researcher points it out to them (Adolph, Berger & Leo, 2011). Cruising infants use their hands to obtain haptic information about their surface of support (S. E. Berger, G. L. Y. Chan, & K. E. Adolph, unpublished data). They rub, tap, squeeze, etc., the support surface in the same way that infants explore toys and other novel objects (Klatzky, Lederman, & Mankinen, 2005; Lederman, Summers, & Klatzky, 1996; Lobo & Galloway, 2008). Although the arms and legs move independently in cruising (Vereijken & Adolph,

1999), the arms’ new role in exploration, balance control, and locomotion is complementary suggesting that the onset of cruising prompts an increase in bimanual reaching. It is not until the arms are rigidly coupled in the high guard position at the onset of walking that infants’ reaching preferences are overwhelmingly bimanual. At the systemic level, https://www.selleckchem.com/products/NVP-AUY922.html the interconnectedness of the neuromotor system means that changes in one area may prompt changes in another. For example, the onset of the transition from crawling to walking HA-1077 concentration is associated

with increased instability for lateralization preferences (Berger et al., 2011; Goldfield, 1993). Even more broadly, changes in motor skill have effects beyond the motor domain (Berger & Scher, 2011). For example, the onset of sitting precipitates a decrement in infants’ ability to process faces and the onset of walking elicits an increase in perseverative behaviors (Berger, 2010; Cashon, Ha, Allen, & Barna, 2013). Situated in this broader context, infants’ preference for unimanual reaching may decrease at the onset of cruising because infants may need to reallocate attentional resources as they focus on acquiring the new skills of cruising and walking (Berger, 2010). Infants return to less adaptive, but less demanding behaviors to compensate for the overload of processing complex, novel information (e.g., Cashon et al., 2013; Cohen & Cashon, 2006; Cohen, Chaput, & Cashon, 2002).

Dialysis treatment results in prolongation of life for most patients. However, patients

on dialysis face limited survival combined with considerable loss of Health Related Quality Of Life (HRQOL). In addition, dialysis treatment itself generates considerable burden on daily life in terms of chores to be completed, time taken to obtain dialysis, expense of treatment and hospitalization for surgical procedures or complications. QOL is greatly influenced by HRQOL, and is probably just as, if not a more important determinant of successful treatment as is survival. This guideline subtopic aims to explore the evidence base and assist discussions about QOL with patients as they consider dialysis as an option for treatment. selleck chemical Due to the lack of systematic evidence, the recommendations are presented as ‘Suggestions For Clinical Care’. Databases searched: MeSH terms and text words for haemodialysis, peritoneal dialysis and pre-dialysis were combined with MeSH terms and text words for QOL, psychological stress or adaptation, depression, anxiety and combined with MeSH terms and text words for randomized controlled trial and systematic review. Transplantation topics were removed from the search and it was limited to 1997–2008 year of publication. The search

was carried out in Medline (1950–January, Week 1, 2008). The Cochrane Central Register of Controlled Cyclopamine Trials (CENTRAL) was also searched for clinical trials not indexed in Medline. Date of search: 10 January 2008. While there is a considerable amount of published literature on QOL, there is a paucity of longitudinal studies across the continuum from the earlier stages of chronic kidney disease (CKD) through to dialysis and survival on dialysis. Individual studies have, however, looked at various factors like stage of kidney disease, QOL at the start of and with continued dialysis, age,

IMP dehydrogenase mental status and other psychosocial factors. Rocco et al.1 showed in the Modification of Diet in Renal Disease study that QOL was impaired in those with CKD and correlated with glomeruler filtration rate (GFR). In a cross-sectional study comparing QOL (scored by using the SF-36 Health Survey) between end-stage kidney disease (ESKD) patients aged 70 years or older, and age-matched controls with other chronic medical conditions, Loos et al.2 showed that physical function and vitality were significantly lower in ESKD patients at first dialysis. There are no studies addressing the question of whether the QOL of patients with CKD improves with the start of dialysis per se. There are also no data supporting the use of QOL measures to recommend acceptance or denial of dialysis treatment. Other studies also show that HRQOL is significantly reduced in dialysis patients when compared with the general population.

There is also good evidence of probiotic modulation of DCs towards a proregulatory function [15,28]. Of course, not all commensals are down-regulatory, and some (like Helicobacter hepaticus) may be pathogenic in some settings, yet induce Tregs in others [29]. Furthermore, there can be significant interactions between pathogens, as in the example of intestinal bacteria aggravating the immunopathology caused by Toxoplasma infection [30]. In the latter setting, there is reduced floral complexity, either because of relative loss of more ‘regulatory’ strains or simply as a broad reflection of an altered selleck inhibitor homeostasis accompanying

pathogenesis. One consequence of the immune system’s reliance on microflora for optimal immunoregulation is that antibiotic therapies may result in unintended activation of immune effector mechanisms. In model systems, antibiotic treatment renders mice more susceptible to induction of food allergy [7] as well as allergic airway inflammation [31]. For the human population, antibiotics are seen as major modifiers of beneficial human–microbe interactions [32] learn more superimposed upon alterations caused by other exogenous factors including urbanization, global travel and dietary changes [33]. The acute effects of antibiotic treatment on the native gut

microbiota range from self-limiting diarrhoea to life-threatening pseudomembranous colitis induced by bacteria filling the niche provided by the reduction in bacterial diversity [34]. The long-term consequences of such perturbations for the human–microbial symbiosis are more difficult to discern, but chronic conditions such as asthma and atopic disease have been associated with childhood antibiotic use Tolmetin and an altered intestinal microbiota [35–37]. Because many chemical

transformations in the gut are mediated by specific microbial populations, with implications for, among others, cancer and obesity, changes in the composition of the gut microbiota could have important but undiscovered health effects. In this regard, ciprofloxacin treatment of healthy volunteers influenced the abundance of about a third of the bacterial taxa in the gut, decreasing the taxonomic richness, diversity and evenness of the community. However, the magnitude of this effect varied among individuals, and some taxa showed interindividual variation in the response to ciprofloxacin. In each individual, the taxonomic composition of the community closely resembled its pretreatment state by 4 weeks after the end of treatment, but several taxa failed to recover within 6 months [38]. The production of active anti-inflammatory mediators by particular commensal species (reviewed in [39]) provides a mechanistic framework for microbial regulation of pathology in the GI tract.

actinomycetemcomitans killing neutrophils [50–52] in test for opsonizing potential. Thus, studies of the antibody characteristics as they relate to subclass distribution and targeted functions, comparing the response to pathogens and commensals must be conducted to understand more fully the in vivo ramifications of the host discrimination of these bacteria coupled with the ability of the antibodies to modulate the oral microbial burden in health and disease.

None of the authors have any financial conflicts to disclose. “
“Tuberculosis (TB) is associated with excessive production and bioactivation of transforming growth factor bets (TGF-β) in situ. Here, modification of expression of components of plasminogen/plasmin pathway in human monocytes (MN) by inhibitors of TGF-β signalling was examined. Smad3 siRNA effectively inhibited TGF-β-induced urokinase plasminogen activator R788 supplier receptor (uPAR). Agents known to interfere with TGF-β signalling, including the Smad inhibitors SIS3 and erythromycin derivatives, and ALK5 receptor inhibitor (SB 431542) in inhibition of uPAR expression in response to Mycobacterium tuberculosis (MTB) were examined.

Inhibition by SIS3 only inhibited uPAR mRNA significantly. SIS3 may prove to be an effective adjunct to TB therapy. A prominent role for TGF-β in macrophage deactivation and suppression of T cell responses to Mycobacterium tuberculosis (MTB) is well established (Reviewed in [1]). Excessive PD0325901 molecular weight TGF-β activity is a feature of active pulmonary TB [2], and human mononuclear phagocytes that are infected or exposed to MTB or its components in vitro. Importantly, lung lavage from patients with active TB contain Atazanavir bioactive TGF-β [3], implicating that conditions for TGF-β signalling are present in situ. In a murine model of M. bovis pulmonary infection, administration of latency-associated peptide of TGF-β, modified TGF-β bioactivity

in situ and both decreased BCG growth in the lung and enhanced antigen-specific T cell responses [4]. In vitro, MTB stimulation of human mononuclear phagocytes also leads to production of bioactive TGF-β [5]. Collectively, these data implicate that both production of TGF-β itself and the molecular context necessary for its bioactivation are present at sites of MTB infection. Recently, several inhibitors of TGF-β bioactivity have been developed. Whether TGF-β signalling can be aborted by any of these agents during MTB infection is currently unknown. Inhibitors of TGF-β signalling, however, may have a role as adjuncts to antituberculosis therapy. Binding of bioactive TGF-β to homodimeric type II TGF-β receptor leads to recruitment and activation of homodimeric type 1 receptor (also known as activin-like receptor kinases [ALK]. This then leads to phosphorylation of Smads2 and 3, which in turn form heterodimers with Smad4, and then the complex translocates into the nucleus, ultimately leading to TGF-β bioactivity [6].

This demonstrates a STAT4-dependent, IL-12/IL-23-independent pathway of parasite control. Type I IFNs

are important in viral and other infections and can activate STAT4. We found that IFN-α/βR-deficient mice have a nonpersistent, early IFN-γ defect, and a persistent, early IL-10 defect, without changes in serum IL-12 or LN-derived nitric oxide. We found less IL-10 per cell in CD25+CD4+ T cells and possibly fewer IL-10-producing cells in the draining LN of IFN-α/βR-deficient vs. wild-type mice. IFN-α/βR-deficient mice have chronic, nonprogressive disease, like wild-type mice, suggesting that IL-10 and IFN-γ defects may balance each other. Our data indicate that although type I IFNs help promote early Th1 responses, they are not the missing activators of STAT4 responsible for partial control R788 clinical trial of L. mexicana. Also, the lack of lesion resolution in IFN-α/βR-deficient mice despite lower IL-10 levels indicates that other pathways independent of T cell IL-10 help prevent an IL-12-driven clearance of parasites. Leishmania (L.) mexicana, a New World intracellular protozoan parasite, causes chronic cutaneous infection in mice and humans. The immunology and outcome of infection

of L. mexicana are quite different from those of the better-studied Old World relative, L. major. In C57BL/6 (B6) Metformin chemical structure mice, L. major induces a strong Th1 response with interleukin (IL)-12-driven interferon (IFN)-γ from CD4+ T cells. This IFN-γ leads to an upregulation of inducible nitric oxide synthase (iNOS) in infected macrophages, which in turn generates nitric oxide, leading to killing of the intracellular L. major. The outcome is that rapidly growing lesions develop but then heal,

with very low persistent parasite burdens (typically <100 per lesion). In L. mexicana infection of B6 mice, a very weak IFN-γ response occurs and parasites induce chronic, but nonprogressive, lesions that plateau in size at around 10–12 weeks post-infection, with higher parasite burdens (generally 107–108 per lesion). Understanding the similarities and differences between these two related parasite infections is instructive in dissecting the immunological mechanisms. We have found that despite these Florfenicol differing outcomes, many of the pathways involved in control of L. mexicana parallel those seen in L. major infection. B6 mice lacking IFN-γ or iNOS have progressive disease with lesions that do not plateau in size and parasite burdens much higher than in wild-type (WT) mice (1). Interestingly, the Th2 response, as determined by IL-4 production, is not increased in the IFN-γ- and iNOS-deficient mice, showing that susceptibility is because of a lack of an adequate Th1 response rather than an increased Th2 response. We also found that mice lacking STAT4, an important signalling molecule, had progressive disease (1) similar to the increased susceptibility of STAT4 knockout (KO) mice to L. major (2).