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This study compared preferred rice varieties by millers and farmers in Bangladesh, hypothesizing that public breeders would focus on public goods like disease resistance, whereas private breeders would focus on profits in the entire chain. Primary data were collected from 99 farmers and 68 millers, who are among the key stakeholders in the rice production system. A four-point rating scale was designed to assess the level of preference for different traits of the selected rice varieties. It was found that farmers who prioritize disease resistance prefer the public over privately bred Aman rice varieties. In general, they prefer rice varieties that are high yielding, have high market value and are of short duration while millers prefer rice verities considering the size and shape, color, and milling performance of the grains. Most significantly, millers prefer privately bred rice varieties if compared to farmers. It can be concluded that public rice breeders should take efforts to also consider the needs of intermediaries in the chain.

Wiskott-Aldrich syndrome protein (WASP) is a cytoskeletal regulator that is largely restricted to hematopoietic cells. While WASP expression in both lymphocytes and macrophages play a critical role in maintaining intestinal homeostasis, the function of WASP in innate lymphoid cells is unknown. Here we analyzed the role of WASP in the differentiation and function of group 3 innate lymphoid cells (ILC3s). WASP-deficient mice (Was-/-) have a marked reduction in ILC3s. Moreover, antimicrobial peptide expression in response to ILC3-derived IL-22 was also reduced in the absence of WASP. In Was-/- mice, we observed a reduction in CCR6+ ILC3s, cells known to restrict immune responses to commensal bacteria. WASP-deficient mice were more susceptible to Citrobacter rodentium, an enteric infection controlled by ILC3s. Interestingly, there was no reduction in ILC3s in Was-/- germ-free mice when compared to WT germ-free mice. ILC3s lacking WASP expression also demonstrated microbially-dependent alterations in gene expression associated with cell migration. Finally, ILC3-like (Rorgt+CD3-) cells were reduced in the GI tract of WASP-deficient patients. In conclusion, ILC3-specific expression of WASP is critical for the generation and function of ILC3s in the presence of commensal microflora. Aberrant ILC3 function in the setting of WASP-deficiency may contribute to underlying disease pathogenesis.

Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was−/−) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was−/− mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. Results Was−/− mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was−/− mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was−/− colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was−/− compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii’s relative abundance was negatively correlated with LCN2 in Was−/− mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was−/−compared to WT mice. Conclusions These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics.

This work presents a numerical method of analyzing near-field infrared nanospectroscopy experimental data and considers the probe geometry in sufficient detail. Previous methods of analysis in the literature rely on simplifying the probe geometry which limits their utility and accuracy.

Thin films of the manganite (La$_{1-y}$Pr$_y$)$_{1-x}$Ca$_x$MnO$_3$ exhibit dynamic phase coexistence with micrometer scale, fluid-like ferromagnetic metallic (FMM) regions interspersed in a charge-order insulating (COI) background. It has been previously reported that a uniform electric field realigns the fluid-like FMM regions due to a phenomenon similar to dielectrophoresis. Here we report that non-uniform electric fields have a stronger effect on the FMM regions as expected from the dielectrophoresis model. The dynamic percolation of the FMM regions is observed over a wider range of temperatures compared to the results in a uniform field. Additionally, in a non-uniform electric field, the time required for dynamic percolation along the magnetic hard axis ($t_{\mathrm{B}}$) decreased with increasing applied voltage ($V_{\mathrm{A}}$) as a power law, $V_{\mathrm{A}}^{-\delta}$ with $\delta \approx 5$ while $\delta < 2$ for a uniform electric field. Our results in a non-uniform electric field provide strong evidence in favor of the dielectrophoresis model and a unique method for manipulating micrometer-sized ferromagnetic regions using electric fields., Comment: 6 pages, 5 figures

Mutations in Wiskott–Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both WASP and DOCK8, and that IL-10 signalling modulates a WASP-DOCK8 complex., Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.

The JAK-STAT pathway critically regulates T-cell differentiation, and STAT1 is postulated to regulate several immune-mediated diseases by inducing proinflammatory subsets. Here we show that STAT1 enables CD4+ T-cell-mediated intestinal inflammation by protecting them from natural killer (NK) cell-mediated elimination. Stat1−/− T cells fail to expand and establish colitis in lymphopenic mice. This defect is not fully recapitulated by the combinatorial loss of type I and II IFN signaling. Mechanistically, Stat1−/− T cells have reduced expression of Nlrc5 and multiple MHC class I molecules that serve to protect cells from NK cell-mediated killing. Consequently, the depletion of NK cells significantly rescues the survival and spontaneous proliferation of Stat1−/− T cells, and restores their ability to induce colitis in adoptive transfer mouse models. Stat1−/− mice however have normal CD4+ T cell numbers as innate STAT1 signaling is required for their elimination. Overall, our findings reveal a critical perspective on JAK-STAT1 signaling that might apply to multiple inflammatory diseases., The JAK-STAT signaling pathway is important for cytokine responses and CD4 T-cell differentiation. Here the authors show that Stat1 also serves to protect CD4 T cells from natural killer cell-mediated killing, potentially by promoting the expression of Nlrc5 and MHC-I, to preserve the induction of experimental colitis via the adoptive transfer of CD4 T cells.

The perovskite material (La0.4Pr0.6)0.67Ca0.33MnO3 (LPCMO) has complex electronic and magnetic behavior based on phase competition between ferromagnetic metallic (FMM) and insulating phases with similar free energies. Experimental evidence has indicated that in-plane stress anisotropy influences these phases and can affect electronic and magnetic properties. Here we investigate the roles that both stress and shape anisotropies may play in controlling the coercive field of the material. LPCMO thin films of various thicknesses (20, 25, and 30 nm) were deposited on (110) NdGaO3 (NGO) substrates using pulsed laser deposition and the coercive fields were measured. Photolithography was then used to fabricate microstructured arrays of LPCMO on the NGO substrates for each of the films. The coercive fields of these arrays of LPCMO were compared to the behavior of the corresponding unpatterned LPCMO thin films across a range of temperatures. Microstructure arrays for the thicker (25 and 30 nm) films showed a substantial increase in the coercive field after forming the arrays, whereas a thinner film (20 nm) showed almost no change in the coercive field. Stress anisotropy continues to play a dominant role in the behavior of LPCMO thin films and dimensionality of the magnetic domains also influences the results. The films show 2D behavior when film thickness approaches the size of the critical radius for single-to-multidomain transitions. Making thicker films allows for 3D behavior and a role for shape anisotropy to influence the coercive fields.

Congenital neutropenia is characterized by low absolute neutrophil numbers in blood, leading to recurrent bacterial infections, and patients often require life-long granulocyte CSF (G-CSF) support. X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich syndrome protein (WASp). To understand the pathophysiology in XLN and the role of WASp in neutrophils, we here examined XLN patients and 2 XLN mouse models. XLN patients had reduced myelopoiesis and extremely low blood neutrophil number. However, their neutrophils had a hyperactive phenotype and were present in normal numbers in XLN patient saliva. Murine XLN neutrophils were hyperactivated, with increased actin dynamics and migration into tissues. We provide molecular evidence that the hyperactivity of XLN neutrophils is caused by WASp in a constitutively open conformation due to contingent phosphorylation of the critical tyrosine-293 and plasma membrane localization. This renders WASp activity less dependent on regulation by PI3K. Our data show that the amplitude of WASp activity inside a cell could be enhanced by cell-surface receptor signaling even in the context in which WASp is already in an active conformation. Moreover, these data categorize XLN as an atypical congenital neutropenia in which constitutive activation of WASp in tissue neutrophils compensates for reduced myelopoiesis. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:128 issue:9 pages:4115-4131 ispartof: location:United States status: published

Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.

Background Inflammatory bowel disease (IBD) affects 1.6 million people in the United States. IBD is associated with an increased risk of thrombosis, which rises with disease activity. The pathogenesis of IBD and its increased thrombotic risk is not completely understood. Ultra large von Willebrand factor (ULVWF) multimers are secreted from activated endothelium, leading to recruitment of platelets and leukocytes. A disintegrin and metalloproteinase with thrombospondin type I repeats motif 13 (ADAMTS13) cleaves highly adhesive ULVWF into smaller, less bioactive, multimers, releasing them into circulation. Mice deficient in ADAMTS13 (ADAMTS13−/−) have heightened inflammatory and thrombotic responses. Objectives We hypothesized that upon colitis induction, ADAMTS13−/− mice would have more severe symptoms compared with wild-type (WT) mice, and rhADAMTS13 administration to mice with colitis would improve their condition. Results Dextran sodium sulfate–induced colitis was worse in ADAMTS13−/− mice than WT. ADAMTS13−/− showed increased weight loss, worse anemia, and increased clinical and histologic colitis severity, compared with WT mice. ADAMTS13−/− mice had increased VWF release, with accumulation at inflamed colonic sites. Also, the majority of mice showed one or more submucosal colonic thrombi. ADAMTS13 deficiency worsened colitis and propagated intestinal inflammation, most likely through increased platelet–leukocyte recruitment by VWF. Treatment of WT mice with rhADAMTS13 decreased colitis severity without worsening anemia. Additionally, several immune-mediated chronic murine colitis models, and inflamed colon tissue specimens from IBD patients, showed increased VWF release at inflamed sites, suggesting a generalizability of our findings. Conclusion Measuring VWF/ADAMTS13 levels could have clinical utility. When applicable, the administration of ADAMTS13, in addition to primary treatment, may improve outcomes for IBD patients.

We investigate the temperature dependence of infrared properties at nanometer length scales in La

The design, development and operational characteristics of a compact corona pre-ionized helium-free TEA CO2 laser is discussed. Remarkably high efficiency of about 19% was obtained in this laser, which is attributed to the optimum concentration of CO2 and N2 gas, reduction in energy dissipation in the pre-ionization loop and the switch, minimizing the diffraction losses and finally optimization of the output coupler reflectivity. The helium-free TEA CO2 laser has also been analysed using a comprehensive theoretical model, developed based on the Boltzmann transport equations and the discharge excitation circuit equations. The voltage and current waveforms of the pulsed discharge were simulated and used as input to the laser rate equations to estimate the laser pulse energies and the pulse shapes. The theoretical estimations of the laser pulse energy agree fairly well with the experimental results. The accuracy of our theoretical model becomes evident from the numerically evaluated laser pulse shapes, which show remarkable resemblance with the experimentally measured pulse shapes. A detailed comparison with the helium-rich case is included to highlight the key aspects of a suitably designed helium-free TEA laser.

The pseudoperovskite BiMnO3 is a multiferroic candidate, but missing details of materials properties are impeding potential technological applications. BiMnO3 has a centrosymmetric structure that precludes ferroelectricity in bulk stoichiometric samples, while some films have reported ferroelectricity along with a decreased magnetic response. This puzzle motivated a study of one such film, deposited by pulsed laser deposition onto SrTiO3. Probes utilized include microscopy, diffraction, reflectometry, and X-ray absorption. These experiments in the context of the existing literature show an anomalous unit-cell volume and a (magnetic) depth profile. Then, the resulting inhomogeneous deficiency of Bi and Mn metals may stabilize a multiphase system that explains the decreased magnetism. Film nanostructure and strain effects are also considered.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

Films of photomagnetic Prussian blue analogue KjCok[Fe(CN)6] (CoFe-PBA) were deposited on thin manganite substrates (La0.4Pr0.6)0.67Ca0.33MnO3 (LPCMO) to investigate whether the photoinduced changes of the CoFe-PBA can give rise to changes in the transport properties of the LPCMO. When the CoFe-PBA was directly deposited on the LPCMO substrate, the photomagnetic properties of the CoFe-PBA were not present because of oxidation of the CoII to CoIII by the Mn in the substrate. The CoII oxidation can be suppressed by using a buffer layer of the non-photomagnetic KjNik[Cr(CN)]6 (NiCr-PBA) between the CoFe-PBA and the LPCMO substrate. Using the buffer layer, the photomagnetic properties of the CoFe-PBA are recovered. Additionally, the transport properties of the LPCMO substrate are not affected by the light-induced changes in the CoFe-PBA.

Background IL10 receptor (IL10R) deficiency causes severe infantile-onset IBD. Intact IL10R-dependent signals have been shown to be important for innate and adaptive immune cell function in mice. We have previously reported a key role of IL10 is the generation and function of human anti-inflammatory macrophages. Independent of innate immune cell defects, the aim of the current study was to determine the role of IL10R signaling in regulating human CD4+ T cell function. Methods Peripheral blood mononuclear cells and intestinal biopsies cells were collected from IL10/IL10R-deficient patients and controls. Frequencies of CD4+ T cell subsets, naïve T cell proliferation, regulatory T cell (Treg)-mediated suppression and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling was performed by NanoString and quantitative real-time PCR. RNA in situ hybridization was used to determine the quantities of various transcripts in intestinal mucosa. Results Analysis of 16 IL10- and IL10R-deficient patients demonstrated similar frequencies of peripheral blood and intestinal Tregs, compared to control subjects. In addition, in vitro Treg suppression of CD4+ T cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naïve cells exhibited significantly higher proliferative capacity, a strong TH17 signature and an increase in polarization towards TH17 cells, compared to controls. Moreover, the frequency of TH17 cells was increased in the colon and ileum of IL10R-deficient patients. Finally, we show that stimulation of IL10R-deficient Tregs in the presence of IL1 leads to enhanced production of IL17A. Conclusions IL10R signaling regulates TH17 polarization and T cell proliferation in humans, but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the TH17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.

Upon encounter with antigen, CD4 1 T cells differentiate into effector Th subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important Th functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD4 1 T cell subset that helps B cells is the T follicular helper (TFH) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C–X–C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. TFH cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of TFH cells. Although TFH cells have been found to produce cytokines characteristic of other Th subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated TFH function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal TFH development and function as well as in progression of autoimmune responses.

Mixed-valence manganese oxides present striking properties like the colossal magnetoresistance, metal-insulator transition (MIT) that may result from coexistence of ferromagnetic, metallic and insulating phases. Percolation of such phase coexistence in the vicinity of MIT leads to first-order transition in these manganites. However the length scales over which the electronic and magnetic phases are separated across MIT which appears compelling for bulk systems has been elusive in (La1−yPry)1−xCaxMnO3 films. Here we show the in-plane length scale over which charge and magnetism are correlated in (La0.4Pr0.6)1−xCaxMnO3 films with x = 0.33 and 0.375, across the MIT temperature. We combine electrical transport (resistance) measurements, x-ray absorption spectroscopy (XAS), x-ray magnetic circular dichroism (XMCD), and specular/off-specular x-ray resonant magnetic scattering (XRMS) measurements as a function of temperature to elucidate relationships between electronic, magnetic and morphological structure of the thin films. Using off-specular XRMS we obtained the charge-charge and charge-magnetic correlation length of these LPCMO films across the MIT. We observed different charge-magnetic correlation length for two films which increases below the MIT. The different correlation length shown by two films may be responsible for different macroscopic (transport and magnetic) properties.

The innate immune system serves as the first line of defense by detecting microbes and initiating inflammatory responses. Although both Toll-like receptor (TLR) and nucleotide binding domain and leucine-rich repeat (NLR) proteins are important for this process, their excessive activation is hazardous to hosts; thus, tight regulation is required. Endotoxin tolerance is refractory to repeated lipopolysaccharide (LPS) stimulation and serves as a host defense mechanism against septic shock caused by an excessive TLR4 response during gram-negative bacterial infection. Gram-positive bacteria as well as their cell wall components also induce shock. However, the mechanism underlying tolerance is not understood. Here, we show that activation of Nod2 by its ligand, muramyl dipeptide (MDP) in the bacterial cell wall, induces rapid degradation of Nod2, which confers MDP tolerance in vitro and in vivo. Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. Upon MDP stimulation, Hsp90 rapidly dissociates from Nod2, which subsequently undergoes ubiquitination and proteasomal degradation. The SOCS-3 protein induced by Nod2 activation further facilitates this degradation process. Therefore, Nod2 protein stability is a key factor in determining responsiveness to MDP stimulation. This indicates that TLRs and NLRs induce a tolerant state through distinct molecular mechanisms that protect the host from septic shock.

The human intestine harbors a large number of bacteria that are constantly interacting with the intestinal immune system, eliciting non-pathological basal level immune responses. Increasing evidence points to dysbiosis of microbiota in the intestine as an underlying factor in inflammatory bowel disease susceptibility. Loss-of-function mutations in NOD2 are among the stronger genetic factors linked to ileal Crohn's disease. Indeed, Nod2 is a key regulator of microbiota in the intestine, as microflora in the terminal ileum is dysregulated in Nod2-deficient mice. Nod2 is highly expressed in Paneth cells, which are responsible for the regulation of ileal microflora by anti-microbial compounds, and Nod2-deficient ileal intestinal epithelia are unable to kill bacteria efficiently. It is therefore likely that NOD2 mutations in Crohn's disease may increase disease susceptibility by altering interactions between ileal microbiota and mucosal immunity.

Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat (NLR) proteins are two major forms of innate immune receptors that trigger inflammatory responses by various biological mechanisms such as cytokine production, recruitment of inflammatory cells, or activation of adaptive immunity. Although the innate immune system is designed to fight against infectious pathogens, excessive activation of TLR or NLR signaling pathways may lead to unwarranted inflammation with hazardous outcomes, including septic shock or inflammatory diseases. As part of the search for effective therapeutics to regulate these responses, here we show that a novel aminosaccharide compound, named DFK1012, inhibits immune responses caused by TLR and NLR activation. Treatment with DFK1012, but not its derivatives DFK845 or DFK846, strongly inhibited pro-inflammatory cytokine production upon stimulation via either TLR or NLR proteins in macrophages. Importantly, we have not observed cytotoxicity in any range of its working concentration. Treatment with DFK1012 did not interfere with TLR- or NLR-induced activation of p38 and JNK, phosphorylation/degradation of IκB, and subsequent nuclear translocation of NF-κB subunit p65, suggesting that the inhibitory activity of DFK1012 is not due to the suppression of downstream signaling. Indeed, DFK1012 did not impair transcription of pro-inflammatory cytokine genes but rather promoted post-translational degradation of pro-inflammatory cytokines. Therefore, DFK1012 is a novel anti-inflammatory compound that drives proteolysis of proinflammatory cytokines induced by TLR and NLR stimulation. DFK1012 may represent a novel class of potential therapeutic agents aimed at the treatment of inflammatory disorders.

A healthy intestinal tract is characterized by controlled homeostasis due to the balanced interaction between commensal bacteria and the host mucosal immune system. Human and animal model studies have supported the hypothesis that breakdown of this homeostasis may underlie the pathogenesis of inflammatory bowel diseases (IBDs). However it is not well understood how intestinal microflora stimulate the intestinal mucosal immune system and how such activation is regulated. Using a spontaneous, commensal bacteria-dependent colitis model in IL-10-deficient mice, we investigated the role of Toll-like receptors (TLRs) and their negative regulation in intestinal homeostasis. In addition to IL-10−/−MyD88−/− mice, IL-10−/−TLR4−/− mice exhibited reduced colitis compared to IL-10−/− mice, indicating that TLR4 signaling plays an important role in inducing colitis. Interestingly, the expression of IRAK-M, a negative regulator of TLR signaling, is dependent on intestinal commensal flora, as IRAK-M expression was reduced in mice re-derived into a germ-free environment, and introduction of commensal bacteria into germ-free mice induced IRAK-M expression. IL-10−/−IRAK-M−/− mice exhibited exacerbated colitis with increased inflammatory cytokine gene expression. Therefore, this study indicates that intestinal microflora stimulate the colitogenic immune system through TLRs and negative regulation of TLR signaling is essential in maintaining intestinal homeostasis.

Peripheral blood mononuclear cells (PBMC) of breast cancer patients show altered prolactin (PRL)-induced proinflammatory response and express short form of prolactin receptor (PRL-R), besides secreting elevated level of interleukin (IL)-10 than that of the normal counterparts. IL-10 depleted the functional long form of PRL-R mRNA and protein, expressed PRL-R (SF) mRNA and blocked the PRL response found in normal individuals, which could be a mechanism to suppress the proinflammatory immune responses during malignancy.

Immunomodulatory activity of Nelumbo nucifera rhizome was evaluated for its standardized extract (NNRE) with respect to betulinic acid. Various key parameters including erythrocyte membrane stabilization, inhibition of histamine release, reduction in nitric oxide production and depletion of expression of costimulatory molecules of macrophages were estimated. The result displayed that NNRE stabilized erythrocyte membrane significantly at 10 (42.05%) and 100 microg/mL (44.31%). Although considering the protection of mast cells from degranulation, NNRE showed 38.66% (100 microg/mL) and 69.66% (10 microg/mL) degranulation against compound 48/80 (C 48/80). NNRE at 1 and 5 microg/mL inhibited lipopolysaccharide (LPS)-induced activation of macrophages by decreasing the expression of costimulatory molecules. Expression of CD40, CD80, and CD86 by NNRE was seen significantly at 5 microg/mL compared to LPS-treated group. The extracts also inhibited the nitrite concentration at 1 and 5 microg/mL compared to LPS-treated group.

Porin of Shigella dysenteriae was incorporated in liposome (PIL) and presented to mouse splenic dendritic cells (DC). PIL up-regulated Toll-like receptor (TLR) 2 and TLR6 on DC, showing that co-expression of the two TLRs is involved in recognition of porin. Detection of myeloid differentiating factor 88 (MyD88)-TLR2 complex confirmed interaction between the two for triggering the downstream signaling, which ultimately led to TLR2-dependent nuclear translocation of nuclear factor-kappa B. PIL-induced expression of MHC class II (I-Ab), CD40 and CD80 showed maturation of DC, whereas up-regulation of intercellular adhesion molecule-1 and CCR7 implicated the capacity of splenic DC to migrate. Induction of messenger ribonucleic acid for the chemokines, macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta and regulated upon activation, normal T cell expressed and secreted indicated a strong bias of PIL for type 1 polarization that was supported by the intracellular expression and release of tumor necrosis factor (TNF)-alpha and IL-12. Along with CD40 and CD80 expression, release of the cytokines of CD11c+ JAWS II cells was inhibited by TLR2 or simultaneous TLR2 and 6 knockdown showing that recognition of PIL by the two TLRs is essential for DC activation and type 1 polarization. The signaling pathway initiated upon recognition of PIL by the TLRs was MyD88 dependent as confirmed by inhibition of IL-6, TNF-alpha and IL-12 release of MyD88-knockdown JAWS II cells. The maturation and polarization of DC induced T(h)1 phenotype, as evident from proliferation, activation and IFN-gamma release of allogeneic CD4+ T cells in response to PIL-stimulated DC, thereby suggesting that the adjuvant activity of PIL can successfully bridge the innate and adaptive immunity.

Vibrio cholerae hemolysin (HlyA) can exist as a monomer with hemolytic activity and an oligomer that agglutinates erythrocytes. Biochemical differences accompanying the change in state of aggregation led us to weigh possible differences between the two forms from mucosal immunoregulation perspective. HlyA oligomer-treated murine B-1a cells up-regulated TLR2 and involved the signaling molecules MyD88, TRAF6 and NF-kappaB. The cells subsequently expressed IgM and IgA. HlyA monomer treatment although resulted in TLR2 up-regulation, could not induce these effects. Apoptosis was detected in majority of the monomer-treated cells that involved caspase-9 and caspase-3. This study shows for the first time that two forms of the same protein could drive the host immune cell to two different outcomes, one of death and the other towards activation.

Atomically flat and epitaxial thin films of the electronically phase-separated compound $$(\hbox {La}_{0.5}\hbox {Pr}_{0.5})_{0.67}\hbox {Ca}_{0.33}\hbox {MnO}_{3}$$ were grown on as-received and treated (110) $$\hbox {NdGaO}_{3}$$ substrates by fine tuning of oxygen pressure during deposition. The optimal conditions were determined using surface morphology, transport, magnetization, and X-ray diffraction measurements. Optimal thin films show step flow growth mode and bulk-like physical properties compared to thin films grown in off-optimal oxygen pressures, viz. the highest maximum temperature coefficient of resistance, the highest peak resistivity temperature, and reduced coercive fields.

Macrophages treated with porin of Shigella dysenteriae were potent stimulators of naive T(h) cells since the porin-pulsed macrophages strongly proliferated the T cells and up-regulated the activation molecules CD69 and CD25 on CD4(+) T cells in allogeneic mixed leukocyte reaction. Immunization of C57BL/6 mice with porin selectively induced the intracellular expression and release of IFN-gamma and had no effect on IL-4 expression. In parallel to the predominant release of the T(h)1 cytokine IFN-gamma, up-regulation of CCR5 on the immune CD4(+) T cells and messenger ribonucleic acid (mRNA) expression of the T cell chemokines macrophage inflammatory protein-1 alpha and regulated on activation normal T cell expressed and secreted showed T(h)1 bias. The porin-primed CD4(+) T cells expressed the mRNA for T-box expressed in T cells, a T(h)1-specific transcription factor confirming the adjuvant-induced transition of T cells to polarized effector T(h)1 cells. The immune CD4(+) T cells proliferated and released IL-2 and IFN-gamma profoundly in response to re-challenge with porin-pulsed macrophages but not to BSA-pulsed macrophages in vitro, which demonstrated the presence of porin-specific CD4(+) T cells of T(h)1 phenotype. The study highlights that porin has the capacity of an adjuvant to unfold and maintain the T cell function and thereby to activate adaptive immunity.

Thin films of strongly-correlated electron materials (SCEM) are often grown epitaxially on planar substrates and typically have anisotropic properties that are usually not captured by edge-mounted four-terminal electrical measurements, which are primarily sensitive to in-plane conduction paths. Accordingly, the correlated interactions in the out-of-plane (perpendicular) direction cannot be measured but only inferred. We address this shortcoming and show here an experimental technique in which the SCEM under study, in our case a 600 Angstrom-thick (La1-yPry)0.67Ca0.33MnO3 (LPCMO) film, serves as the base electrode in a metal-insulator-metal (MIM) trilayer capacitor structure. This unconventional arrangement allows for simultaneous determination of colossal magnetoresistance (CMR) associated with dc transport parallel to the film substrate and colossal magnetocapacitance (CMC) associated with ac transport in the perpendicular direction. We distinguish two distinct strain-related direction-dependent insulator-metal (IM) transitions and use Cole-Cole plots to establish a heretofore unobserved collapse of the dielectric response onto a universal scale-invariant power-law dependence over a large range of frequency, temperature and magnetic field., Comment: 32 pages, 4 figures, Supplementary section included, Submitted to Nature Physics

Transport across a CrC2/Ag/YBCO interface was studied using a flip-chip configuration. The results were interpreted in the Andreev reflection scenario. It is shown that the surface spin-polarization of CrO2 film, even after exposing to air, remained close to 100% to the T c of YBa2Cu3O7− x , a temperature limited by this method.

We report a low-temperature specific heat study of Pr 0.5 (Sr 1-y Ca y ) 0.5 MnO 3 (0

We have studied the physical properties of epitaxial La0.67−xPrxCa0.33MnO3(LPCMO) (x=0.13, 0.20, 0.27) thin films under different type and degree of substrate induced biaxial strain. Films with thickness of 300, 600, and 1000 A grown on crystalline NdGaO3 (negligible strain), LaAlO3 (compressive strain), and SrTiO3 (tensile strain) by pulsed laser deposition are examined. Our data suggest occurrence of metastable phase mixtures in these films, with the volume fractions controlled by strain. In particular, melting of the charge ordered phase is seen to occur in thin films on SrTiO3 at fields as low as 1 T, in the low temperature regime. The deviation of ρ(T) from the effective medium theory further indicates that LPCMO thin films cannot be described as simple metal–insulator mixtures.

We report a giant linear magnetoelectric coupling in strained BiMnO3 thin films in which the disorder associated with an islanded morphology gives rise to extrinsic relaxor ferroelectricity that is not present in bulk centrosymmetric ferromagnetic crystalline BiMnO3. Strain associated with the disorder is treated as a local variable which couples to the two ferroic order parameters, magnetization M and polarization P. A straightforward "gas under a piston" thermodynamic treatment explains the observed correlated temperature dependencies of the product of susceptibilities and the magnetoelectric coefficient together with the enhancement of the coupling by the proximity of the ferroic transition temperatures close to the relaxor freezing temperature. Our interpretation is based on a trilinear coupling term in the free energy of the form L(PXM) where L is a hidden antiferromagnetic order parameter, previously postulated by theory for BiMnO3. This phenomenological invariant not only preserves inversion and time reversal symmetry of the strain-induced interactions but also explains the pronounced linear magnetoelectric coupling without using the more conventional higher order biquadratic interaction proportional to (PM)^2., Comment: 10 pages, 6 figures

Selective multi-photon dissociation (MPD) of Freon-22 (CF2HC1) molecules has been carried out using a TEA CO2 laser at various CO2 laser lines (9P(20)-9P(26)) in order to maximize the yield of C-13 isotope in the product (C2F4) at an enrichment factor of 100. The effects of laser pulse tail due to the presence of N2 in the laser mixture on the enrichment factor and yield of C-13 are investigated. It is found that the addition of a small amount of N2 is possible in the laser mixture without a significant drop in the yield at desired enrichment factor. Addition of a small amount of N2 improves the laser efficiency considerably. At a given pulse energy, a slight change in the near field intensity distribution of a laser severely affects the selectivity of C-13 isotope. The computed far-field intensity distributions of the measured near-field intensities show marked spatial variation in the focal spots that leads to a drop in selectivity. For macroscopic production of C-13 isotope a simple and novel multi-pass cavity has been designed and tested to focus the energy repeatedly keeping the optimum fluence constant at each focal spot.

We investigate the temperature dependence of infrared properties at nanometer length scales in La0.67Sr0.33MnO3 (LSMO) thin film with a thickness of 47 unit cells grown on SrTiO3 substrate. The infrared nano-imaging experiments were performed using a near-field optical microscope in conjunction with a variable temperature heating stage. The near-field infrared data is consistent with the bulk of the LSMO film undergoing the thermally-driven non-percolative second-order transition from a metallic, ferromagnetic phase to an insulating, paramagnetic phase. We find persistent infrared contrast on the nanoscale that is independent of temperature and which we attribute to two novel phases with different conductivities coexisting in the vicinity of the film-substrate interface. These two coexisting phases at the film-substrate interface do not undergo the metal-insulator transition (MIT) and hence are different from the metallic, ferromagnetic and insulating, paramagnetic phases in the bulk of the film. At temperatures approaching the nominal MIT temperature, repeated scans of the same microscopic area at constant temperature reveal bimodal fluctuation of the near-field infrared amplitude. We interpret this phenomenon as slow, critical fluctuations of the conductivity in the bulk of the LSMO film.