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The widespread CsrA/RsmA protein regulators repress translation by binding GGA motifs in bacterial mRNAs. CsrA activity is primarily controlled through sequestration by multiple small regulatory RNAs. Here we investigate CsrA activity control in the absence of antagonizing small RNAs by examining the CsrA regulon in the human pathogen Campylobacter jejuni. We use genome-wide co-immunoprecipitation combined with RNA sequencing to show that CsrA primarily binds flagellar mRNAs and identify the major flagellin mRNA (flaA) as the main CsrA target. The flaA mRNA is translationally repressed by CsrA, but it can also titrate CsrA activity. Together with the main C. jejuni CsrA antagonist, the FliW protein, flaA mRNA controls CsrA-mediated post-transcriptional regulation of other flagellar genes. RNA-FISH reveals that flaA mRNA is expressed and localized at the poles of elongating cells. Polar flaA mRNA localization is translation dependent and is post-transcriptionally regulated by the CsrA-FliW network. Overall, our results suggest a role for CsrA-FliW in spatiotemporal control of flagella assembly and localization of a dual-function mRNA.
NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells
(2016)
Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.
NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.
According to the Selective Accessibility Model of anchoring, the comparison question in the standard anchoring paradigm activates information that is congruent with an anchor. As a consequence, this information will be more likely to become the basis for the absolute judgment which will therefore be assimilated toward the anchor. However, if the activated information overlaps with information that is elicited by the absolute judgment itself, the preceding comparative judgment should not exert an incremental effect and should fail to result in an anchoring effect. The present studies find this result when the comparative judgment refers to a general category and the absolute judgment refers to a subset of the general category that was activated by the anchor value. For example, participants comparing the average annual temperature in New York City to a high 102 °F judged the average winter, but not summer temperature to be higher than participants making no comparison. On the other hand, participants comparing the annual temperature to a low –4 °F judged the average summer, but not winter temperature to be lower than control participants. This pattern of results was shown also in another content domain. It is consistent with the Selective Accessibility Model but difficult to reconcile with other main explanations of the anchoring effect.
We employ transient absorption from the deep-UV to the visible region and fluorescence upconversion to investigate the photoinduced excited-state intramolecular proton-transfer dynamics in a biologically relevant drug molecule, 2-acetylindan-1,3-dione. The molecule is a ß-diketone which in the electronic ground state exists as exocyclic enol with an intramolecular H-bond. Upon electronic excitation at 300 nm, the first excited state of the exocyclic enol is initially populated, followed by ultrafast proton transfer (≈160 fs) to form the vibrationally hot endocyclic enol. Subsequently, solvent-induced vibrational relaxation takes place (≈10 ps) followed by decay (≈390 ps) to the corresponding ground state.
Adipose-derived stem cells (ASCs) have been extensively studied in the field of stem cell research and possess numerous clinical applications. Cell labeling is an essential component of various experimental protocols and Hoechst 33342 (H33342) represents a cost-effective and easy methodology for live staining. The purpose of this study was to evaluate the labeling of rat ASCs with two different concentrations of H33342 (0.5 μg/mL and 5 μg/mL), with particular regard to usability, interference with cell properties, and potential DNA damage. Hoechst 33342 used at a low concentration of 0.5 μg/mL did not significantly affect cell proliferation, viability, or differentiation potential of the ASCs, nor did it cause any significant DNA damage as measured by the olive tail moment. High concentrations of 5 μg/mL H33342, however, impaired the proliferation and viability of the ASCs, and considerable DNA damage was observed. Undesirable colabeling of unlabeled cocultivated cells was seen in particular with higher concentrations of H33342, independent of varying washing procedures. Hence, H33342 labeling with lower concentrations represents a usable method, which does not affect the tested cell properties. However, the colabeling of adjacent cells is a drawback of the technique.
The pathogen Staphylococcus aureus causes a broad range of severe diseases and is feared for its ability to rapidly develop resistance to antibiotic substances. The increasing number of highly resistant S. aureus infections has accelerated the search for alternative treatment options to close the widening gap in anti-S. aureus therapy. This study analyses the humoral immune response to vaccination of Balb/c mice with sublethal doses of live S. aureus. The elicited antibody pattern in the sera of intravenously and intramuscularly vaccinated mice was determined using of a recently developed protein array. We observed a specific antibody response against a broad set of S. aureus antigens which was stronger following i.v. than i.m. vaccination. Intravenous but not intramuscular vaccination protected mice against an intramuscular challenge infection with a high bacterial dose. Vaccine protection was correlated with the strength of the anti-S. aureus antibody response. This study identified novel vaccine candidates by using protein microarrays as an effective tool and showed that successful vaccination against S. aureus relies on the optimal route of administration.
Invasive fungal infections are associated with high mortality rates and are mostly caused by the opportunistic fungi Aspergillus fumigatus and Candida albicans. Immune responses against these fungi are still not fully understood. Dendritic cells (DCs) are crucial players in initiating innate and adaptive immune responses against fungal infections. The immunomodulatory effects of fungi were compared to the bacterial stimulus LPS to determine key players in the immune response to fungal infections. A genome wide study of the gene regulation of human monocyte-derived dendritic cells (DCs) confronted with A. fumigatus, C. albicans or LPS was performed and Krüppel-like factor 4 (KLF4) was identified as the only transcription factor that was down-regulated in DCs by both fungi but induced by stimulation with LPS. Downstream analysis demonstrated the influence of KLF4 on the interleukine-6 expression in human DCs. Furthermore, KLF4 regulation was shown to be dependent on pattern recognition receptor ligation. Therefore KLF4 was identified as a controlling element in the IL-6 immune response with a unique expression pattern comparing fungal and LPS stimulation.
The white-opaque switch is a bistable, epigenetic transition affecting multiple traits in Candida albicans including mating, immunogenicity, and niche specificity. To compare how the two cell states respond to external cues, we examined the fitness, phenotypic switching, and filamentation properties of white cells and opaque cells under 1,440 different conditions at 25°C and 37°C. We demonstrate that white and opaque cells display striking differences in their integration of metabolic and thermal cues, so that the two states exhibit optimal fitness under distinct conditions. White cells were fitter than opaque cells under a wide range of environmental conditions, including growth at various pHs and in the presence of chemical stresses or antifungal drugs. This difference was exacerbated at 37°C, consistent with white cells being the default state of C. albicans in the mammalian host. In contrast, opaque cells showed greater fitness than white cells under select nutritional conditions, including growth on diverse peptides at 25°C. We further demonstrate that filamentation is significantly rewired between the two states, with white and opaque cells undergoing filamentous growth in response to distinct external cues. Genetic analysis was used to identify signaling pathways impacting the white-opaque transition both in vitro and in a murine model of commensal colonization, and three sugar sensing pathways are revealed as regulators of the switch. Together, these findings establish that white and opaque cells are programmed for differential integration of metabolic and thermal cues and that opaque cells represent a more metabolically specialized cell state than the default white state.
Titanium Dioxide Nanoparticles: Synthesis, X-Ray Line Analysis and Chemical Composition Study
(2016)
TiO2 nanoparticleshave been synthesized by the sol-gel method using titanium alkoxide and isopropanolas a precursor. The structural properties and chemical composition of the TiO2 nanoparticles were studied usingX-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy.The X-ray powder diffraction pattern confirms that the particles are mainly composed of the anatase phase with the preferential orientation along [101] direction. The physical parameters such as strain, stress and energy density were investigated from the Williamson- Hall (W-H) plot assuming a uniform deformation model (UDM), and uniform deformation energy density model (UDEDM). The W-H analysis shows an anisotropic nature of the strain in nanopowders. The scanning electron microscopy image shows clear TiO2 nanoparticles with particle sizes varying from 60 to 80nm. The results of mean particle size of TiO2 nanoparticles show an inter correlation with the W-H analysis and SEM results. Our X-ray photoelectron spectroscopy spectra show that nearly a complete amount of titanium has reacted to TiO2
Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp\(^{D34N}\) mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation.
Trypanosomes are masters of adaptation to different host environments during their complex life cycle. Large-scale proteomic approaches provide information on changes at the cellular level, and in a systematic way. However, detailed work on single components is necessary to understand the adaptation mechanisms on a molecular level. Here, we have performed a detailed characterization of a bloodstream form (BSF) stage-specific putative flagellar host adaptation factor Tb927.11.2400, identified previously in a SILAC-based comparative proteome study. Tb927.11.2400 shares 38% amino acid identity with TbFlabarin (Tb927.11.2410), a procyclic form (PCF) stage-specific flagellar BAR domain protein. We named Tb927.11.2400 TbFlabarin-like (TbFlabarinL), and demonstrate that it originates from a gene duplication event, which occurred in the African trypanosomes. TbFlabarinL is not essential for the growth of the parasites under cell culture conditions and it is dispensable for developmental differentiation from BSF to the PCF in vitro. We generated TbFlabarinL-specific antibodies, and showed that it localizes in the flagellum. Co-immunoprecipitation experiments together with a biochemical cell fractionation suggest a dual association of TbFlabarinL with the flagellar membrane and the components of the paraflagellar rod.
Monitoring the spatio-temporal development of vegetation is a challenging task in heterogeneous and cloud-prone landscapes. No single satellite sensor has thus far been able to provide consistent time series of high temporal and spatial resolution for such areas. In order to overcome this problem, data fusion algorithms such as the Enhanced Spatial and Temporal Adaptive Reflectance Fusion Model (ESTARFM) have been established and frequently used in recent years to generate high-resolution time series. In order to make it applicable to larger scales and to increase the input data availability especially in cloud-prone areas, an ESTARFM framework was developed in this study introducing several enhancements. An automatic filling of cloud gaps was included in the framework to make best use of available, even partly cloud-covered Landsat images. Furthermore, the ESTARFM algorithm was enhanced to automatically account for regional differences in the heterogeneity of the study area. The generation of time series was automated and the processing speed was accelerated significantly by parallelization. To test the performance of the developed ESTARFM framework, MODIS and Landsat-8 data were fused for generating an 8-day NDVI time series for a study area of approximately 98,000 km\(^{2}\) in West Africa. The results show that the ESTARFM framework can accurately produce high temporal resolution time series (average MAE (mean absolute error) of 0.02 for the dry season and 0.05 for the vegetative season) while keeping the spatial detail in such a heterogeneous, cloud-prone region. The developments introduced within the ESTARFM framework establish the basis for large-scale research on various geoscientific questions related to land degradation, changes in land surface phenology or agriculture
The aim of this review is to use the multimedia aspects
of a purely digital online publication to explain and
illustrate the highly capable technique of m-sequences in
multifocal ophthalmic electrophysiology. M-sequences
have been successfully applied in clinical routines during
the past 20 years. However, the underlying mathematical
rationale is often daunting. These mathematical
properties of m-sequences allow one not only to
separate the responses from different fields but also to
analyze adaptational effects and impacts of former
events. By explaining the history, the formation, and the
different aspects of application, a better comprehension
of the technique is intended. With this review we aim to
clarify the opportunities of m-sequences in order to
motivate scientists to use m-sequences in their future
research.
Background: Dendritic cells (DCs) rendered suppressive by treatment with mitomycin C and loaded with the autoantigen myelin basic protein demonstrated earlier their ability to prevent experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). This provides an approach for prophylactic vaccination against autoimmune diseases. For clinical application such DCs are difficult to generate and autoantigens hold the risk of exacerbating the disease.
Methods: We replaced DCs by peripheral mononuclear cells and myelin autoantigens by glatiramer acetate (Copaxone ®), a drug approved for the treatment of MS. Spleen cells were loaded with Copaxone®, incubated with mitomycin C (MICCop) and injected into mice after the first bout of relapsing-remitting EAE. Immunosuppression mediated by MICCop was investigated in vivo by daily assessment of clinical signs of paralysis and in in vitro restimulation assays of peripheral immune cells. Cytokine profiling was performed by enzyme-linked immunosorbent assay (ELISA). Migration of MICCop cells after injection was examined by biodistribution analysis of 111Indium-labelled MICCop. The number and inhibitory activity of CD4+CD25+FoxP3+ regulatory T cells were analysed by histology, flow cytometry and in vitro mixed lymphocyte cultures. In order to assess the specificity of MICCop-induced suppression, treated EAE mice were challenged with the control protein ovalbumin. Humoral and cellular immune responses were then determined by ELISA and in vitro antigen restimulation assay.
Results: MICCop cells were able to inhibit the harmful autoreactive T-cell response and prevented mice from further relapses without affecting general immune responses. Administered MICCop migrated to various organs leading to an increased infiltration of the spleen and the central nervous system with CD4+CD25+FoxP3+ cells displaying a suppressive cytokine profile and inhibiting T-cell responses.
Conclusion: We describe a clinically applicable cell therapeutic approach for controlling relapses in autoimmune encephalomyelitis by specifically silencing the deleterious autoimmune response.
Background: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders.
Methods: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration.
Results: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up.
Conclusions: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach.
Cofacial positioning of two perylene bisimide (PBI) chromophores at a distance of 6.5 angstrom in a cyclophane structure prohibits the otherwise common excimer formation and directs photoexcited singlet state relaxation towards intramolecular symmetry-breaking charge separation (τ\(_{CS}\) = 161 +/- 4 ps) in polar CH\(_2\)Cl\(_2\), which is thermodynamically favored with a Gibbs free energy of ΔG\(_{CS}\) = -0.32 eV. The charges then recombine slowly in τ\(_{CR}\) = 8.90 +/- 0.06 ns to form the PBI triplet excited state, which can be used subsequently to generate singlet oxygen in 27% quantum yield. This sequence of events is eliminated by dissolving the PBI cyclophane in non-polar toluene, where only excited singlet state decay occurs. In contrast, complexation of electron-rich aromatic hydrocarbons by the host PBI cyclophane followed by photoexcitation of PBI results in ultrafast electron transfer (<10 ps) from the guest to the PBI in CH\(_2\)Cl\(_2\). The rate constants for charge separation and recombination increase as the guest molecules become easier to oxidize, demonstrating that charge separation occurs close to the peak of the Marcus curve and the recombination lies far into the Marcus inverted region.
Here, we report a continuous flow synthesis of nano LDH, comprising a continuous precipitation process using static mixers and followed by an immediate cleaning process via a semi-continuous centrifuge to obtain the final product in one-go. Via this synthesis setup, it is possible to independently vary the concentrations of the reactants during precipitation and at the same time ensure constant reaction conditions and an immediate "quenching" of the precipitate due to "on the flow"-washing. We found that this paves the way to adjust the synthesis parameters in a way that the final morphology of the nano-LDH particles can be controlled to be either round or platelet-like.
Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation
(2016)
Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P <= 0.01). In contrast, pretreatment with PI3K-α, -δ, and -γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P <= 0.05), -δ (P <= 0.05), and -γ (P <= 0.01), early (0-2 hour) edema -α (P <= 0.05), -δ (P <= 0.001), and -γ (P <= 0.05), and neutrophil infiltration (all P <= 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P <= 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.