307 research outputs found
Reactor mixing angle from hybrid neutrino masses
In terms of its eigenvector decomposition, the neutrino mass matrix (in the
basis where the charged lepton mass matrix is diagonal) can be understood as
originating from a tribimaximal dominant structure with small deviations, as
demanded by data. If neutrino masses originate from at least two different
mechanisms, referred to as "hybrid neutrino masses", the experimentally
observed structure naturally emerges provided one mechanism accounts for the
dominant tribimaximal structure while the other is responsible for the
deviations. We demonstrate the feasibility of this picture in a fairly
model-independent way by using lepton-number-violating effective operators,
whose structure we assume becomes dictated by an underlying flavor
symmetry. We show that if a second mechanism is at work, the requirement of
generating a reactor angle within its experimental range always fixes the solar
and atmospheric angles in agreement with data, in contrast to the case where
the deviations are induced by next-to-leading order effective operators. We
prove this idea is viable by constructing an -based ultraviolet
completion, where the dominant tribimaximal structure arises from the type-I
seesaw while the subleading contribution is determined by either type-II or
type-III seesaw driven by a non-trivial singlet (minimal hybrid model).
After finding general criteria, we identify all the symmetries
capable of producing such -based minimal hybrid models.Comment: 18 pages, 5 figures. v3: section including sum rules added, accepted
by JHE
Delivery of sTRAIL variants by MSCs in combination with cytotoxic drug treatment leads to p53-independent enhanced antitumor effects
Mesenchymal stem cells (MSCs) are able to infiltrate tumor tissues and thereby effectively deliver gene therapeutic payloads. Here, we engineered murine MSCs (mMSCs) to express a secreted form of the TNF-related apoptosis-inducing ligand (TRAIL), which is a potent inducer of apoptosis in tumor cells, and tested these MSCs, termed MSC.sTRAIL, in combination with conventional chemotherapeutic drug treatment in colon cancer models. When we pretreated human colorectal cancer HCT116 cells with low doses of 5-fluorouracil (5-FU) and added MSC.sTRAIL, we found significantly increased apoptosis as compared with single-agent treatment. Moreover, HCT116 xenografts, which were cotreated with 5-FU and systemically delivered MSC.sTRAIL, went into remission. Noteworthy, this effect was protein 53 (p53) independent and was mediated by TRAIL-receptor 2 (TRAIL-R2) upregulation, demonstrating the applicability of this approach in p53-defective tumors. Consequently, when we generated MSCs that secreted TRAIL-R2-specific variants of soluble TRAIL (sTRAIL), we found that such engineered MSCs, labeled MSC.sTRAIL DR5, had enhanced antitumor activity in combination with 5-FU when compared with MSC.sTRAIL. In contrast, TRAIL-resistant pancreatic carcinoma PancTu1 cells responded better to MSC.sTRAIL DR4 when the antiapoptotic protein XIAP (X-linked inhibitor of apoptosis protein) was silenced concomitantly. Taken together, our results demonstrate that TRAIL-receptor selective variants can potentially enhance the therapeutic efficacy of MSC-delivered TRAIL as part of individualized and tumor-specific combination treatments. Β© 2013 Macmillan Publishers Limited All rights reserved
Oscillatory surface rheotaxis of swimming E. coli bacteria
Bacterial contamination of biological conducts, catheters or water resources
is a major threat to public health and can be amplified by the ability of
bacteria to swim upstream. The mechanisms of this rheotaxis, the reorientation
with respect to flow gradients, often in complex and confined environments, are
still poorly understood. Here, we follow individual E. coli bacteria swimming
at surfaces under shear flow with two complementary experimental assays, based
on 3D Lagrangian tracking and fluorescent flagellar labelling and we develop a
theoretical model for their rheotactic motion. Three transitions are identified
with increasing shear rate: Above a first critical shear rate, bacteria shift
to swimming upstream. After a second threshold, we report the discovery of an
oscillatory rheotaxis. Beyond a third transition, we further observe
coexistence of rheotaxis along the positive and negative vorticity directions.
A full theoretical analysis explains these regimes and predicts the
corresponding critical shear rates. The predicted transitions as well as the
oscillation dynamics are in good agreement with experimental observations. Our
results shed new light on bacterial transport and reveal new strategies for
contamination prevention.Comment: 12 pages, 5 figure
Molecular markers of resistance to sulphadoxine-pyrimethamine one year after implementation of intermittent preventive treatment of malaria in infants in Mali
Expansion and Harvesting of hMSC-TERT
The expansion of human mesenchymal stem cells as suspension culture by means of spinner flasks and microcarriers, compared to the cultivation in tissue culture flasks, offers the advantage of reducing the requirements of large incubator capacities as well as reducing the handling effort during cultivation and harvesting. Nonporous microcarriers are preferable when the cells need to be kept in viable condition for further applications like tissue engineering or cell therapy. In this study, the qualification of Biosilon, Cytodex 1, Cytodex 3, RapidCell and P102-L for expansion of hMSC-TERT with an associated harvesting process using either trypsin, accutase, collagenase or a trypsin-accutase mixture was investigated. A subsequent adipogenic differentiation of harvested hMSC-TERT was performed in order to observe possible negative effects on their (adipogenic) differentiation potential as a result of the cultivation and harvesting method. The cultivated cells showed an average growth rate of 0.52 d-1. The cells cultivated on Biosilon, RapidCell and P102-L were harvested succesfully achieving high cell yield and vitalities near 100%. This was not the case for cells on Cytodex 1 and Cytodex 3. The trypsin-accutase mix was most effective. After spinner expansion and harvesting the cells were successfully differentiated to adipocytes
Evaluation of high-dose daptomycin for therapy of experimental Staphylococcus aureus foreign body infection
BACKGROUND: Daptomycin is a novel cyclic lipopeptide whose bactericidal activity is not affected by current antibiotic resistance mechanisms displayed by S. aureus clinical isolates. This study reports the therapeutic activity of high-dose daptomycin compared to standard regimens of oxacillin and vancomycin in a difficult-to-treat, rat tissue cage model of experimental therapy of chronic S. aureus foreign body infection. METHODS: The methicillin-susceptible S. aureus (MSSA) strain I20 is a clinical isolate from catheter-related sepsis. MICs, MBCs, and time-kill curves of each antibiotic were evaluated as recommended by NCCLS, including supplementation with physiological levels (50 mg/L) of Ca(2+ )for daptomycin. Two weeks after local infection of subcutaneously implanted tissue cages with MSSA I20, each animal received (i.p.) twice-daily doses of daptomycin, oxacillin, or vancomycin for 7 days, or was left untreated. The reductions of CFU counts in each treatment group were analysed by ANOVA and Newman-Keuls multiple comparisons procedures. RESULTS: The MICs and MBCs of daptomycin, oxacillin, or vancomycin for MSSA strain I20 were 0.5 and 1, 0.5 and 1, or 1 and 2 mg/L, respectively. In vitro elimination of strain I20 was more rapid with 8 mg/L of daptomycin compared to oxacillin or vancomycin. Twice-daily administered daptomycin (30 mg/kg), oxacillin (200 mg/kg), or vancomycin (50 mg/kg vancomycin) yielded bactericidal antibiotic levels in infected cage fluids throughout therapy. Before therapy, mean (Β± SEM) viable counts of strain I20 were 6.68 Β± 0.10 log(10 )CFU/mL of cage fluid (n = 74). After 7 days of therapy, the mean (Β± SEM) reduction in viable counts of MSSA I20 was 2.62 (Β± 0.30) log(10 )CFU/mL in cages (n = 18) of daptomycin-treated rats, exceeding by >2-fold (P < 0.01) the viable count reductions of 0.92 (Β± 0.23; n = 19) and 0.96 (Β± 0.24; n = 18) log(10 )CFU/mL in cages of oxacillin-treated and vancomycin-treated rats, respectively. Viable counts in cage fluids of untreated animals increased by 0.48 (Β± 0.24; n = 19) log(10 )CFU/mL. CONCLUSION: The improved efficacy of the twice-daily regimen of daptomycin (30 mg/kg) compared to oxacillin (200 mg/kg) or vancomycin (50 mg/kg) may result from optimisation of its pharmacokinetic and bactericidal properties in infected cage fluids
Cationic Amino Acid Transporter 2 Enhances Innate Immunity during Helicobacter pylori Infection
Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of outcomes following infection. Cationic amino acid transporter 2 (CAT2) is essential for transport of l-arginine (L-Arg) into monocytic immune cells during H. pylori infection. Once within the cell, this amino acid is utilized by opposing pathways that lead to elaboration of either bactericidal nitric oxide (NO) produced from inducible NO synthase (iNOS), or hydrogen peroxide, which causes macrophage apoptosis, via arginase and the polyamine pathway. Because of its central role in controlling L-Arg availability in macrophages, we investigated the importance of CAT2 in vivo during H. pylori infection. CAT2β/β mice infected for 4 months exhibited decreased gastritis and increased levels of colonization compared to wild type mice. We observed suppression of gastric macrophage levels, macrophage expression of iNOS, dendritic cell activation, and expression of granulocyte-colony stimulating factor in CAT2β/β mice suggesting that CAT2 is involved in enhancing the innate immune response. In addition, cytokine expression in CAT2β/β mice was altered from an antimicrobial Th1 response to a Th2 response, indicating that the transporter has downstream effects on adaptive immunity as well. These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection
Genome Sequence Analysis of Dengue Virus 1 Isolated in Key West, Florida
Dengue virus (DENV) is transmitted to humans through the bite of mosquitoes. In November 2010, a dengue outbreak was reported in Monroe County in southern Florida (FL), including greater than 20 confirmed human cases. The virus collected from the human cases was verified as DENV serotype 1 (DENV-1) and one isolate was provided for sequence analysis. RNA was extracted from the DENV-1 isolate and was used in reverse transcription polymerase chain reaction (RT-PCR) to amplify PCR fragments to sequence. Nucleic acid primers were designed to generate overlapping PCR fragments that covered the entire genome. The DENV-1 isolate found in Key West (KW), FL was sequenced for whole genome characterization. Sequence assembly, Genbank searches, and recombination analyses were performed to verify the identity of the genome sequences and to determine percent similarity to known DENV-1 sequences. We show that the KW DENV-1 strain is 99% identical to Nicaraguan and Mexican DENV-1 strains. Phylogenetic and recombination analyses suggest that the DENV-1 isolated in KW originated from Nicaragua (NI) and the KW strain may circulate in KW. Also, recombination analysis results detected recombination events in the KW strain compared to DENV-1 strains from Puerto Rico. We evaluate the relative growth of KW strain of DENV-1 compared to other dengue viruses to determine whether the underlying genetics of the strain is associated with a replicative advantage, an important consideration since local transmission of DENV may result because domestic tourism can spread DENVs
Genome-Wide Profiling of MicroRNAs in Adipose Mesenchymal Stem Cell Differentiation and Mouse Models of Obesity
In recent years, there has been accumulating evidence that microRNAs are key regulator molecules of gene expression. The cellular processes that are regulated by microRNAs include e.g. cell proliferation, programmed cell death and cell differentiation. Adipocyte differentiation is a highly regulated cellular process for which several important regulating factors have been discovered, but still not all are known to fully understand the underlying mechanisms. In the present study, we analyzed the expression of 597 microRNAs during the differentiation of mouse mesenchymal stem cells into terminally differentiated adipocytes by real-time RT-PCR. In total, 66 miRNAs were differentially expressed in mesenchymal stem cell-derived adipocytes compared to the undifferentiated progenitor cells. To further study the regulation of these 66 miRNAs in white adipose tissue in vivo and their dependence on PPARΞ³ activity, mouse models of genetically or diet induced obesity as well as a mouse line expressing a dominant negative PPARΞ³ mutant were employed
Mesodermal Progenitor Cells (MPCs) Differentiate into Mesenchymal Stromal Cells (MSCs) by Activation of Wnt5/Calmodulin Signalling Pathway
Mesenchymal Stromal Cells (MSCs) remain poorly characterized because of the absence of manifest physical, phenotypic, and functional properties in cultured cell populations. Despite considerable research on MSCs and their clinical application, the biology of these cells is not fully clarified and data on signalling activation during mesenchymal differentiation and proliferation are controversial. The role of Wnt pathways is still debated, partly due to culture heterogeneity and methodological inconsistencies. Recently, we described a new bone marrow cell population isolated from MSC cultures that we named Mesodermal Progenitor Cells (MPCs) for their mesenchymal and endothelial differentiation potential. An optimized culture method allowed the isolation from human adult bone marrow of a highly pure population of MPCs (more than 97%), that showed the distinctive SSEA-4+CD105+CD90(neg) phenotype and not expressing MSCA-1 antigen. Under these selective culture conditions the percentage of MSCs (SSEA-4(neg)CD105+CD90(bright) and MSCA-1+), in the primary cultures, resulted lower than 2%.We demonstrate that MPCs differentiate to MSCs through an SSEA-4+CD105+CD90(bright) early intermediate precursor. Differentiation paralleled the activation of Wnt5/Calmodulin signalling by autocrine/paracrine intense secretion of Wnt5a and Wnt5b (p<0.05 vs uncondictioned media), which was later silenced in late MSCs (SSEA-4(neg)). We found the inhibition of this pathway by calmidazolium chloride specifically blocked mesenchymal induction (IDβ
ββ=β 0.5 Β΅M, p<0.01), while endothelial differentiation was unaffected.The present study describes two different putative progenitors (early and late MSCs) that, together with already described MPCs, could be co-isolated and expanded in different percentages depending on the culture conditions. These results suggest that some modifications to the widely accepted MSC nomenclature are required
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