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Activation of Toll-like receptors (TLRs) by pathogens triggers cytokine production and T cell activation, immune defense mechanisms that are linked to immunopathology. Here we show that IFN-γ production by CD4 + T H 1 cells during mucosal responses to the

We report on our ongoing search for timing, duration, and depth variations in the exoplanet TrES-2. In Raetz et al. (2009) we already presented ten different transits obtained at the University Observatory Jena. Between November 2008 and August 2010 twelve additional transits could be observed. The timing, depth and duration of each individual event was analyzed and is presented here.

Time-frequency domain signal processing of neural recordings, from high-density microelectrode arrays implanted in the cortex, is highly desired to ease the bandwidth bottleneck associated with data transfer to extra-cranial processing units. Because of its energy compactness features, discrete wavelet transform (DWT) has been shown to provide efficient data compression for neural records without compromising the information content. This paper describes an area-power minimized hardware implementation of the lifting scheme for multilevel, multichannel DWT with quantized filter coefficients and integer computation. Performance tradeoffs and key design decisions for implantable neuroprosthetics are presented. A 32-channel 4-level version of the circuit has been custom designed in 0.18-mum CMOS and occupies only 0.22 mm2 area and consumes 76 muW of power, making it highly suitable for implantable neural interface applications requiring wireless data transfer. [ABSTRACT FROM PUBLISHER]

Introduction: While liquid chromatography coupled to mass spectrometric detection in the selected reaction monitoring detection mode offers the best quantification sensitivity for omics, the number of target analytes is limited, must be predefined and specific methods developed. Data independent acquisition (DIA), including SWATH using quadrupole time of flight or orbitrap mass spectrometers and generic acquisition methods, has emerged as a powerful alternative technique for quantitative and qualitative analyses since it can cover a wide range of analytes without predefinition., Objectives: Here we review the current state of DIA, SWATH-MS and highlight novel acquisition strategies for metabolomics and lipidomics and opportunities for data analysis tools., Method: Different databases were searched for papers that report developments and applications of DIA and in particular SWATH-MS in metabolomics and lipidomics., Results: DIA methods generate digital sample records that can be mined retrospectively as further knowledge is gained and, with standardized acquisition schemes, used in multiple studies. The different chemical spaces of metabolites and lipids require different specificities, hence different acquisition and data processing approaches must be considered for their analysis., Conclusions: Although the hardware and acquisition modes are well defined for SWATH-MS, a major challenge for routine use remains the lack of appropriate software tools capable of handling large datasets and large numbers of analytes.

A hybrid SWATH/MS and HR-SRM/MS acquisition approach using multiple unit mass windows and 100 u precursor selection windows has been developed to interface with a chromatographic lipid class separation. The method allows for the simultaneous monitoring of sum compositions in MS1 and up to 48 lipids in MS2 per lipid class. A total of 240 lipid sum compositions from five phospholipid classes could be monitored in MS2 (HR-SRM/MS) while there was no limitation in the number of analytes in MS1 (HR-SIM/MS). On average, 92 lipid sum compositions and 75 lipid species could be quantified in human plasma samples. The robustness and precision of the workflow has been assessed using technical triplicates of the subject samples. Lipid identification was improved using a combined qualitative and quantitative data processing based on prediction instead of library search. Lipid class specific extracted ion currents of precursors and the corresponding molecular species fragments were extracted based on the information obtained from lipid building blocks and a combinatorial strategy. The SWATH/MS approach with the post-acquisition processing is not limited to the analyzed phospholipid classes and can be applied to other analytes and samples of interest. Graphical abstract.

Maternal obesity and a high-fat diet (HFD) during the perinatal period have documented short- and long-term adverse outcomes for offspring. However, the mechanisms of maternal HFD effects on neonatal offspring are unclear. While the effects of maternal HFD exposure during pregnancy on the offspring are increasingly being appreciated, we do not know if maternal HFD alters the microbiota or affects neonatal susceptibility to inflammatory conditions, nor the mechanisms involved. In this study, we show that the offspring of mothers exposed to HFD develop a unique microbiota, marked by expansion of Firmicutes, and an increase in IL-17-producing type 3 innate lymphoid cells (ILC3s). The expansion of ILC3s was recapitulated through neocolonization with HFD microbiota alone. Further, the HFD offspring were susceptible to a neonatal model of inflammation that was reversible with IL-17 blockade. Collectively, these data suggest a previously unknown and unique role for ILC3s in the promotion of an early inflammatory susceptibility in the offspring of mothers exposed to HFD.

Neutrophils are an emerging cellular source of IFN-γ, a key cytokine that mediates host defense to intracellular pathogens. Production of IFN-γ by neutrophils, in contrast to lymphoid cells, is TLR- and IL-12-independent and the events associated with IFN-γ production by neutrophils are not understood. In this study, we show that mouse neutrophils express IFN-γ during their lineage development in the bone marrow niche at the promyelocyte stage independently of microbes. IFN-γ accumulates in primary neutrophilic granules and is released upon induction of degranulation. The developmental mechanism of IFN-γ production in neutrophils arms the innate immune cells prior to infection and assures the potential for rapid release of IFN-γ upon neutrophil activation, the first step during responses to many microbial infections., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Background & Aims: Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings., Methods: We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis., Results: In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis., Conclusions: Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The intestinal microbiota changes dynamically from birth to adulthood. In this study we identified γ-Proteobacteria as a dominant phylum present in newborn mice that is suppressed in normal adult microbiota. The transition from a neonatal to a mature microbiota was in part regulated by induction of a γ-Proteobacteria-specific IgA response. Neocolonization experiments in germ-free mice further revealed a dominant Proteobacteria-specific IgA response triggered by the immature microbiota. Finally, a role for B cells in the regulation of microbiota maturation was confirmed in IgA-deficient mice. Mice lacking IgA had persistent intestinal colonization with γ-Proteobacteria that resulted in sustained intestinal inflammation and increased susceptibility to neonatal and adult models of intestinal injury. Collectively, these results identify an IgA-dependent mechanism responsible for the maturation of the intestinal microbiota.

TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. gondii profilin and are capable of forming a heterodimer complex. We also establish that the transcription factor IFN regulatory factor 8, not NF-κB, plays a central role in the regulation of the TLR11- and TLR12-dependent IL-12 response of DCs. These results suggest a central role for IFN regulatory factor 8-expressing CD8(+) DCs in governing the TLR11- and TLR12-mediated host defense against T. gondii.

IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii. Genetically altered mice lacking all lymphoid cells due to deficiencies in Recombination Activating Gene 2 and IL-2Rγc genes also produced IFN-γ in response to the protozoan parasite. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ(+) cells identified neutrophils as the cell type capable of producing IFN-γ. Selective elimination of neutrophils in TLR11(-/-) mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-γ-deficient mice. Similarly, Salmonella typhimurium infection of TLR-deficient mice induces the appearance of IFN-γ(+) neutrophils. Thus, neutrophils are a crucial source for IFN-γ that is required for TLR-independent host protection against intracellular pathogens.

Activation of Toll-like receptors (TLRs) by pathogens triggers cytokine production and T cell activation, immune defense mechanisms that are linked to immunopathology. Here we show that IFN-γ production by CD4(+) T(H)1 cells during mucosal responses to the protozoan parasite Toxoplasma gondii resulted in dysbiosis and the elimination of Paneth cells. Paneth cell death led to loss of antimicrobial peptides and occurred in conjunction with uncontrolled expansion of the Enterobacteriaceae family of Gram-negative bacteria. The expanded intestinal bacteria were required for the parasite-induced intestinal pathology. The investigation of cell type-specific factors regulating T(H)1 polarization during T. gondii infection identified the T cell-intrinsic TLR pathway as a major regulator of IFN-γ production in CD4(+) T cells responsible for Paneth cell death, dysbiosis and intestinal immunopathology.

The lead leaching potential of new brass plumbing devices has come under scrutiny as a significant source of lead in drinking water (>300 μg/L) of new buildings around the world. Experiments were conducted using ball valves that were sold as certified and known to have caused problems in practice, in order to better understand how installed products could create such problems, even if they passed "leaching tests" such as National Sanitation Foundation (NSF) Standard 61 Section 8. Diffusion of lead from within the device into water when installed can increase lead leaching by orders of magnitude relative to results of NSF testing, which once only required exposure of very small volumes of water within the device. "Normalization" of the lead-in-water result tended to produce estimates of lead concentration that were much lower than actual lead measured at the tap. Finally, the presence of flux could also dramatically increase lead leaching, whereas high water velocity had relatively little effect., (Copyright © 2012. Published by Elsevier Ltd.)

Bone loss in type 1 diabetes is accompanied by increased marrow fat, which could directly reduce osteoblast activity or result from altered bone marrow mesenchymal cell lineage selection (adipocyte vs. osteoblast). CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of both adipocyte and osteoblast differentiation. C/EBPβ-null mice have delayed bone formation and defective lipid accumulation in brown adipose tissue. To examine the balance of C/EBPβ functions in the diabetic context, we induced type 1 diabetes in C/EBPβ-null (knockout, KO) mice. We found that C/EBPβ deficiency actually enhanced the diabetic bone phenotype. While KO mice had reduced peripheral fat mass compared with wild-type mice, they had 5-fold more marrow adipocytes than diabetic wild-type mice. The enhanced marrow adiposity may be attributed to compensation by C/EBPδ, peroxisome proliferator-activated receptor-γ2, and C/EBPα. Concurrently, we observed reduced bone density. Relative to genotype controls, trabecular bone volume fraction loss was escalated in diabetic KO mice (-48%) compared with changes in diabetic wild-type mice (-22%). Despite greater bone loss, osteoblast markers were not further suppressed in diabetic KO mice. Instead, osteoclast markers were increased in the KO diabetic mice. Thus, C/EBPβ deficiency increases diabetes-induced bone marrow (not peripheral) adipose depot mass, and promotes additional bone loss through stimulating bone resorption. C/EBPβ-deficiency also reduced bone stiffness and diabetes exacerbated this (two-way ANOVA P < 0.02). We conclude that C/EBPβ alone is not responsible for the bone vs. fat phenotype switch observed in T1 diabetes and that suppression of CEBPβ levels may further bone loss and decrease bone stiffness by increasing bone resorption.