Search

Presents a correction to an article about tunable laser operation, previously published in the journal "Applied Physics B."

Radiotherapy (RT) triggers an immune response that contributes to antitumor effects. Induction of IFNβ is a key event in this immunogenicity of RT. We have previously shown that TRIM33, a chromatin reader, restrains IFNβ expression in Toll-like receptor-activated myeloid cells. In this study, we explored whether deleting Trim33 in myeloid cells might improve the radio-induced immune response and subsequent efficiency of RT. We first established that Trim33-/- bone marrow-derived macrophages showed increased expression of IFNβ in response to direct irradiation, or to treatment with irradiated cancer cells, further supporting our hypothesis. We then tested the efficiency of a single-dose RT in three subcutaneous tumor models and one orthotopic tumor model. In all models, myeloid deletion of Trim33 led to a significantly improved response after RT, leading to a complete and durable response in most of the treated mice bearing orthotopic oral tumors. This effect required the involvement of the type I IFN pathway and the presence of CD8+ T lymphocytes but not NK cells. In addition, cured mice were capable of rejecting a secondary tumor challenge, demonstrating an in situ vaccination effect. We conclude that deleting Trim33 in myeloid cells improves RT efficiency, through a mechanism involving the type I IFN pathway and the immune response. Our work suggests that myeloid Trim33 is a host factor affecting the tumor response to RT, thus representing a new potential therapeutic target for modifying RT responses., (©2024 American Association for Cancer Research.)

The lateral wall of the mouse subventricular zone harbors neural stem cells (NSC, B cells) which generate proliferating transient-amplifying progenitors (TAP, C cells) that ultimately give rise to neuroblasts (NB, A cells). Molecular profiling at the single-cell level struggles to distinguish these different cell types. Here, we combined transcriptome analyses of FACS-sorted cells and single-cell RNAseq to demonstrate the existence of an abundant, clonogenic and multipotent population of immature neuroblasts (iNB cells) at the transition between TAP and migrating NB (mNB). iNB are reversibly engaged in neuronal differentiation. Indeed, they keep molecular features of both undifferentiated progenitors, plasticity and unexpected regenerative properties. Strikingly, they undergo important progressive molecular switches, including changes in the expression of splicing regulators leading to their differentiation in mNB subdividing them into two subtypes, iNB1 and iNB2. Due to their plastic properties, iNB could represent a new target for regenerative therapy of brain damage., Competing Interests: CB, MM, MD, TK, BD, VB, SC, ND, VM, LB, CA, AC, FB No competing interests declared, (© 2023, Bernou et al.)

Ionising γ radiation produces reactive oxygen species by water radiolysis, providing an interesting model approach for studying oxidative stress in plants. Three-week old plants of Arabidopsis thaliana were exposed to a low dose rate (25 mGy h -1 ) of γ radiation for up to 21 days. This treatment had no effect on plant growth and morphology, but it induced chronic oxidation of lipids which was associated with an accumulation of reactive carbonyl species (RCS). However, contrary to lipid peroxidation, lipid RCS accumulation was transient only, being maximal after 1 day of irradiation and decreasing back to the initial level during the subsequent days of continuous irradiation. This indicates the induction of a carbonyl-metabolising process during chronic ionising radiation. Accordingly, the γ-radiation treatment induced the expression of xenobiotic detoxification-related genes (AER, SDR1, SDR3, ALDH4, and ANAC102). The transcriptomic response of some of those genes (AER, SDR1, and ANAC102) was deregulated in the tga256 mutant affected in three TGAII transcription factors, leading to enhanced and/or prolonged accumulation of RCS and to a marked inhibition of plant growth during irradiation compared to the wild type. These results show that Arabidopsis is able to acclimate to chronic oxidative stress and that this phenomenon requires activation of a carbonyl detoxification mechanism controlled by TGAII. This acclimation did not occur when plants were exposed to an acute γ radiation stress (100 Gy) which led to persistent accumulation of RCS and marked inhibition of plant growth. This study shows the role of secondary products of lipid peroxidation in the detrimental effects of reactive oxygen species., (© 2024 The Author(s). Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Because of reproducibility and repeatability problems with reference measurements made with an ionisation chamber in a self-protected GSRD1 irradiator, a comparison was made with alanine dosimetry for a whole-body mouse irradiation setup in a sterile box. The twisting of the cables in the cable duct and in the irradiator cell and the irradiation of the ionisation chamber connector are likely to have caused the problems encountered. These problems are not observed on other types of irradiators with more suitable cable passages. A difference up to 8.4% was observed between the alanine dosimetry and ionisation chamber. The influence of the number of animals in the sterile box on the whole-body dose of the animals was also evaluated with alanine and found to be <2%., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Research Question: What is the impact of radiation exposure on oocyte quality and female fertility?, Design: Prepubertal mice underwent whole-body irradiation with a single dose (0.02, 0.1, 0.5, 2, 8 Gy) of gamma- or X-rays. Oocytes were quantified in irradiated (n = 36) and sham-treated (n = 8) mice. After a single exposure to 2 Gy, formation of DNA double-strand breaks (n = 10), activation of checkpoint kinase (Chk2) (n = 10) and dynamics of follicular growth (n = 18) were analysed. Fertility assessment was performed in adult irradiated mice and controls from the number of pups per mouse (n = 28) and the fetal abortion rate (n = 24). Ploidy of mature oocytes (n = 20) was analysed after CREST immunostaining, and uterine sections were examined., Results: Radiation exposure induced a massive loss of primordial follicles with LD 50 below 50 mGy for both gamma and X-rays. Growing follicles survived doses up to 8 Gy. This difference in radiosensitivity was not due to a different amount of radio-induced DNA damage, and Chk2 was activated in all oocytes. Exposure to a 2 Gy dose abolished the long-term fertility of females due to depletion of the ovarian reserve. Detailed analysis indicates that surviving oocytes were able to complete folliculogenesis and could be fertilized. This transient fertility allowed irradiated females to produce a single litter albeit with a high rate of fetal abortion (23%, P = 0.0096), related to altered ploidy in the surviving oocytes (25.5%, P = 0.0035)., Conclusions: The effects of radiation on surviving oocyte quality question natural conception as a first-line approach in cancer survivors. Together, the data emphasize the need for fertility preservation before radiation exposure and call for reassessment of the use of cryopreserved oocytes., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

High-Z metallic nanoparticles (NPs) are new players in the therapeutic arsenal against cancer, especially radioresistant cells. Indeed, the presence of these NPs inside malignant cells is believed to enhance the effect of ionizing radiation by locally increasing the dose deposition. In this context, the potential of platinum nanoparticles (PtNPs) as radiosensitizers was investigated in two breast cancer cell lines, T47D and MDA-MB-231, showing a different radiation sensitivity. PtNPs were internalized in the two cell lines and localized in lysosomes and multivesicular bodies. Analyses of cell responses in terms of clonogenicity, survival, mortality, cell-cycle distribution, oxidative stress, and DNA double-strand breaks did not reveal any significant enhancement effect when cells were pre-exposed to PtNPs before being irradiated, as compared to radiation alone. This result is different from that reported in a previous study performed, under the same conditions, on cervical cancer HeLa cells. This shows that the efficacy of radio-enhancement is strongly cell-type-dependent. Simulation of the early stage ionization processes, taking into account the irradiation characteristics and realistic physical parameters in the biological sample, indicated that PtNPs could weakly increase the dose deposition (by 3%) in the immediate vicinity of the nanoparticles. Some features that are potentially responsible for the biological effect could not be taken into account in the simulation. Thus, chemical and biological effects could explain this discrepancy. For instance, we showed that, in these breast cancer cell lines, PtNPs exhibited ambivalent redox properties, with an antioxidant potential which could counteract the radio-enhancement effect. This work shows that the efficacy of PtNPs for enhancing radiation effects is strongly cell-dependent and that no effect is observed in the case of the breast cancer cell lines T47D and MDA-MB-231. Thus, more extensive experiments using other relevant biological models are needed in order to evaluate such combined strategies, since several clinical trials have already demonstrated the success of combining nanoagents with radiotherapy in the treatment of a range of tumor types.

Hematopoietic stem cells are responsible for life-long blood cell production and are highly sensitive to exogenous stresses. The effects of low doses of ionizing radiations on radiosensitive tissues such as the hematopoietic tissue are still unknown despite their increasing use in medical imaging. Here, we study the consequences of low doses of ionizing radiations on differentiation and self-renewal capacities of human primary hematopoietic stem/progenitor cells (HSPC). We found that a single 20 mGy dose impairs the hematopoietic reconstitution potential of human HSPC but not their differentiation properties. In contrast to high irradiation doses, low doses of irradiation do not induce DNA double strand breaks in HSPC but, similar to high doses, induce a rapid and transient increase of reactive oxygen species (ROS) that promotes activation of the p38MAPK pathway. HSPC treatment with ROS scavengers or p38MAPK inhibitor prior exposure to 20 mGy irradiation abolishes the 20 mGy-induced defects indicating that ROS and p38MAPK pathways are transducers of low doses of radiation effects. Taken together, these results show that a 20 mGy dose of ionizing radiation reduces the reconstitution potential of HSPC suggesting an effect on the self-renewal potential of human hematopoietic stem cells and pinpointing ROS or the p38MAPK as therapeutic targets. Inhibition of ROS or the p38MAPK pathway protects human primary HSPC from low-dose irradiation toxicity., (Copyright© 2020 Ferrata Storti Foundation.)

Objective: The primary aim of this study was to characterize the rate of adverse pregnancy outcomes in a multicultural group of low-income women., Methods: Data were extracted from the Montreal Diet Dispensary's database between June 2013 and December 2015. Risk was evaluated using logistic regression adjusted for covariates., Results: Of the 1,387 pregnancies, the prevalence of gestational diabetes mellitus (GDM) was 17.2% (95% confidence interval [CI], 15.1% to 19.3%), maternal anemia 44.9% (95% CI, 41.9% to 47.9%) and hypertension 3.8% (95% CI, 2.8% to 4.8%). The prevalence of small-for-gestational-age infants was 5.5% (95% CI, 4.3% to 6.7%), preterm births 4.7% (95% CI, 3.6% to 5.9%), low birthweight 4.2% (95% CI, 3.1% to 5.2%) and large-for-gestational-age infants was 10.6% (95% CI, 9.0% to 12.2%). Asian women had an increased odds of gestational diabetes mellitus (adjusted odds ratio [aOR], 1.86; 95% CI, 1.17 to 2.98) and SGA infants (aOR, 2.35; 95% CI 1.21 to 4.57) compared with white women. Anemia was more likely for black women compared with white women (aOR, 1.74; 95% CI, 1.29 to 2.35). Black women were more at risk of preterm birth (aOR, 1.79; 95% CI, 1.01 to 3.19). Immigrants showed an increased risk of maternal anemia compared with Canadian-born women (aOR, 1.85; 95% CI, 1.06 to 3.21)., Conclusions: As disparities in maternal and infant outcomes were present, nutritional intervention(s) need to be targeted toward prevention of adverse pregnancy outcomes, prioritization of higher-risk groups and adaptation of the program to a multiethnic low-income population., (Copyright © 2019 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

The enzyme UGT2B7 is one of the most active UDP-glucuronosyltransferases (UGTs) involved in drug metabolism and in maintaining homeostasis of endogenous compounds. We recently reported the existence of 22 UGT2B7 mRNAs, two with a classic 5' region but alternative 3' ends namely UGT2B7&#95;v5 (containing a novel terminal exon 6b) and &#95;v7 (exon 5 excluded) that encode enzymatically inactive isoforms 2 and 4 (i2 and i4), respectively. The v1 mRNA encoding the UGT2B7 enzyme (renamed isoform 1 or i1) is coexpressed with the splice variants v5 and v7 in human liver, kidney, and small intestine and the hepatic cell lines HepG2 and C3A. The presence of alternate v5 and v7 transcripts in isolated polysomes from these hepatic cells further supports endogenous protein translation. Cellular fractionation of clonal HEK293 cell lines overexpressing UGT2B7 isoforms demonstrates that i1, i2, and i4 proteins colocalize in the microsomal/Golgi fraction, whereas i2 and i4 can also be found in the cytosol; a finding sustained by immunofluorescence experiments using tagged proteins. By modifying splice variant abundance in overexpression in HEK293 and HepG2 cells as well as RNA interference experiments in HepG2 and C3A cells, we observe drug glucuronidation phenotypes compatible with variant-mediated repression of UGT2B7 activity without consequent alteration of the apparent enzyme affinity (K(m)). Finally, coimmunoprecipitation experiments support a direct protein-protein interaction of i2 and i4 proteins with the functional UGT2B7 enzyme as a potential causative mechanism. These findings point toward a novel autoregulatory mechanism of the UGT2B7 glucuronidation pathway by naturally occurring alternative i2 and i4 proteins.

Objective: UDP-glucuronosyltransferase 2B7 (UGT2B7) plays a major detoxification role in commonly prescribed drugs and endogenous lipophilic molecules. Additional exons and multiple alternative splicing events (ASEs) at the UGT2B7 locus were recently discovered., Materials and Methods: Novel and classical ASEs were quantified in 27 human tissues, as well as in fetal and tumoral tissues. The activity of the alternative UGT2B7 promoters was studied in cell lines., Results: UGT2B7 expression is driven by an alternate promoter 1a associated with transcripts containing exon 1b, which is located ∼44 kb upstream of the known promoter 1 associated with transcripts containing exon 1 required for enzyme activity. The exon 1 was expressed most abundantly in the liver and gastrointestinal tract, whereas exon 1b was expressed predominantly in other extrahepatic tissues. Experimental evidence indicated endogenous translation that yields alternative UGT2B7s derived from the use of exon 1b are enzymatically inactive. Alternate 5' ASE predominates in fetal tissues (kidney, lung) and kidney tumor samples compared with normal adult kidney. These changes further correlate with reduced glucuronidation in neoplastic kidneys. This differential expression pattern was further confirmed using four liver and kidney cell lines and was consistent with the differential usage of alternate promoters in hepatic (promoter 1) and kidney cells (1a)., Conclusion: UGT2B7 is characterized by two mutually exclusive exons 1, both flanked by a unique 5' promoter region. Data also indicated a switch toward functional enzyme upon maturation in the kidney and reversal of this process in neoplastic cells, considerably modifying the glucuronidation potential across human tissues and cells.

Continuous wave laser operation at 1.87 μm of liquid-phase epitaxially (LPE) grown Tm(3+)-doped YLiF(4) (Tm:YLF) layers is demonstrated. The waveguide laser delivers 560 mW by pumping with a Ti:Sapphire laser at 780 nm leading to an efficiency of 76% with respect to the absorbed pump power. This constitutes the first Tm(3+)-doped crystalline fluoride waveguide laser ever demonstrated as well as a record in efficiency and output power for an LPE grown waveguide laser operating in the 2 μm spectral range.

QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch-clamp technique was used to assess the I(Kr) -, I(Ks) -, and I(Na) -blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea-pig hearts was used to evaluate the MAPD(90) -, MAP amplitude-, phase 0 dV/dt-, and ECG-modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an I(Kr) blocker. IC(50) was estimated at 34 μm. In contrast, bupropion had hardly any effect on I(Ks) and I(Na) . Bupropion had no significant MAPD(90) -modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 dV/dt. A modest but significant QRS-widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its I(Kr) -blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS-widening, MAP amplitude- and phase 0 dV/dt -reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti-arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling., (© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.)

Objective: UGT2B7 is a key member of the UDP-glucuronosyltransferase (UGT) family that participates in glucuronidation of endogenous compounds and pharmaceuticals. Much evidence suggests a large interindividual variability of UGT2B7-mediated glucuronidation, which is still unexplained by polymorphisms. We hypothesized that alternative splicing may be responsible for the variability in the UGT2B7 function., Methods: We carried out a comprehensive scan for additional exons at this locus and discovered multiple alternative splicing events. We then determined transcript expression profiles across a large variety of human tissues and assessed some of these variants for their glucuronidation activity in human cells., Results: In-depth analysis of the UGT2B7 gene structure led to the discovery of six novel exons. Kidney and liver samples presented the greatest enrichment of tissue-specific splicing, with 21 new UGT2B7 transcripts isolated. Furthermore, transcription from the proximal promoter (exon 1), associated with the active UGT2B7 mRNA isoform 1 (UGT2B7&#95;v1), is most commonly observed in the gastrointestinal tract, whereas a distal promoter (exon 1a) induces the exclusion of the canonical exon 1 and is active in hormone-related tissues. We also showed that novel transcripts with alternative 3' ends could be translated into proteins lacking glucuronosyltransferase activity in human cells but acting as negative regulators on transferase activity when coexpressed with the active UGT2B7 protein., Conclusion: Our findings point toward a significant variability in structure, abundance, and tissue-specific UGT2B7 transcriptome, in addition to novel functions for UGT2B7-derived proteins, all of which may ensure the production of tissue-specific proteomes and functions.

Background: Endometrial cancer is the most common gynecological malignancy. Estrogen exposure is strongly associated with endometrial cancer. Whereas this cancer occurs predominantly in postmenopausal women lacking estrogen production by ovaries, the conversion of adrenal androgen-estrogen precursors to estradiol (E(2)), estrone (E(1)), and its sulfate (E(1)-S) has been well documented in peripheral tissues., Experimental Design: We initially explored whether circulating levels of estrogens, measured by validated mass spectrometry assays, differ in women with endometrial cancer (n = 126) compared with healthy women (n = 110). We then evaluated by quantitative real-time PCR from purified RNA whether the expression profile of 19 estrogen-related synthesis and metabolic genes is modified in peritumoral normal endometrium (n = 36) compared with tumoral (n = 49) tissues., Results: In endometrial cancer cases, circulating levels of E(1), E(2), and E(1)-S were significantly higher compared with unaffected controls. In agreement with plasma levels, findings support an enhanced biosynthesis of E(2) in tumors. The expression of E(2) biosynthesis pathways [E(1)-S (sulfatase) --> E(1) (17beta-hydroxysteroid dehydrogenase) --> E(2)] was shown to predominate in peritumoral normal endometrium and was significantly increased in tumors. In addition, the inactivation pathways mediated by several uridine diphosphate-glucuronosyltransferases were also enhanced in endometrial tumors compared with peritumoral normal endometrium., Conclusion: We concluded that the higher levels of circulating estrogens in women with endometrial cancer are likely associated with an imbalance of multiple biotransformation pathways in endometrial tumor tissues.

Background and Aims: UGT2B4 is a member of the UDP-glucuronosyltransferase (UGT) superfamily, a major detoxifying system in humans. UGT2B4 is involved in bile acids metabolism and highly expressed in liver and extrahepatic tissues. The aim of this study was to uncover new molecular mechanisms underlying interindividual variability in the UGT2B4 pathway., Methods: We carried out a comprehensive scan for additional exons at this locus and discovered multiple alternative splicing events. We then assessed the expression profile of alternatively spliced transcripts in human tissues and the activity of the corresponding overexpressed proteins toward bile acids., Results: We discovered three previously unidentified UGT2B4 exons, increasing the total known gene length to 46 kb. Molecular analyses revealed at least eight distinct mRNAs produced by (i) alternative promoter usage, (ii) complete and partial exon skipping, and (iii) use of alternative 3' splice sites. These splice variants were predominantly expressed in liver, gastrointestinal tract, and other extrahepatic tissues. Quantitative analyses of splicing events further sustain their prevalence in the liver. UGT2B4 proteins produced from these mRNA variants had undetectable transferase activity in human cells. However, when stably co-expressed with the active UGT2B4 isoform 1, three newly identified UGT2B4 isoforms (i2, i3, and i5) were found to negatively regulate glucuronidation., Conclusion: In addition to heritable genetic mutations and control of gene expression, the newly discovered diversity of UGT2B4 mRNAs may introduce variability in this glucuronidation pathway.

UGT2B17 and UGT2B28 are among the most commonly deleted genes in humans and encode members of the uridine diphosphate (UDP)-glucuronosyltransferase 2B (UGT2B) subfamily. They are involved, along with UGT2B15, in the catabolism of sex-steroid hormones. Despite the recent biomedical interest in UGT2B17 and UGT2B28 copy-number variations (CNVs) within human populations, the impact of their gene dosage has been hampered by the lack of precise molecular identification of the common deletion breakpoints within high homology sequence regions on chromosome 4. We have characterized these common deletions and report their coexistence in Caucasians, along with the p.D85Y (rs1902023:G>T) functional polymorphism of UGT2B15. Segmental duplications of 4.9 kb for UGT2B17 and 6.8 kb for UGT2B28 comprise purine-rich recombination sites located 117 kb and 108 kb apart on both ends of the deletions. CNVs of UGT2B17 and UGT2B28 occur in Caucasians at 27% and 13.5%, respectively. While only 43% have two copies of both genes, 57% harbor at least one deletion. Their co-occurrence on 5% of chromosomes creates a 225-kb genomic gap. CNVs of both UGT2B17 and UGT2B28, with the co-occurrence of UGT2B15:p.D85Y, generate seven distinct haplotypes. Restricting the analyses to CNV of the UGT2B17 gene without evaluating UGT2B28 CNV, along with the genotype of UGT2B15, may over- or underestimate the impact of each gene under physiological conditions or disease states.

Femtosecond mode-locked operation is demonstrated for the first time, to our knowledge, with a Yb:SrF(2) crystal. The shortest pulse duration is 143 fs for an average power of 450 mW. The highest average power is 620 mW for a pulse duration of 173 fs. Since Yb:SrF(2) corresponds to the longest-lifetime Yb-doped crystal with which the mode-locking operation has been achieved, a detailed analysis is carried out to characterize the quality of the solitonlike regime.

The UDP-glucuronosyltransferase UGT1 locus is composed of nine exon 1s, each flanked by a unique promoter region, and common exons (2, 3, 4, and the alternatively spliced exons 5a and 5b). Here, we characterized the genetic architecture of the UGT1 gene in a Caucasian sample. Overall, 98 variations in regulatory domains, exons and exon-intron boundaries were genotyped in 254 unrelated subjects, including 12 unreported UGT1 polymorphisms. We determined allele frequencies, computed pairwise linkage disequilibrium (LD), and inferred haplotypes; this thorough analysis yielding a limited number of common UGT1 haplotypes. Moreover, only 17 haplotype tagging single nucleotide polymorphisms (htSNPs) are required to capture most of the allelic diversity of the locus. Four haplotype blocks were inferred: Block 9/6 (UGT1A9, UGT1A7 and UGT1A6), Block 4 (UGT1A4), Block 3/1 (UGT1A3 and UGT1A1), and Block C (3'UTR). A high level of linkage exists between Blocks 9/6 and 3/1, while the 3'UTR SNPs are genetically isolated. The most common haplotype (16.5%) presents multiple deleterious alleles, mainly 1A1*28, 1A3*2, 1A6*2, and 1A7*4. More interestingly, we reveal the co-occurrences of multiple deleterious variations, some of which could be associated with interindividual differences in glucuronidation. Comparison with the HapMap data set demonstrated differences in haplotypic diversity between ethnic samples, but similarity between Caucasian cohorts, as observed previously. This report provides relevant data for further pharmacogenomic studies., ((c) 2009 Wiley-Liss, Inc.)

We report an in situ thermal study of Yb-doped fluorite crystals Yb:CaF(2) and Yb:SrF(2) under high power pumping, with or without laser operation. The experiment combines simultaneously thermography and measurement of the thermal aberrations. This setup allows us to measure temperature gradients, thermal lens, and absorption coefficients. From these measurements, we evaluate the thermal conductivity, fractional thermal load, and thermo-optic coefficient. Great differences are observed between the lasing and non lasing regimes. Our measured thermal lenses are greater than what are expected from the thermo-optic parameters found in previous work. Based on this thermal study, we design a laser cavity operating with large output power and TEM(00), leading to better performances for Yb:CaF(2) than Yb:SrF(2).

UGT1A3 is one of the most efficient at conjugating estrone, a precursor for biosynthesis of estradiol in peripheral tissues. We established the genetic mechanisms that might contribute to individual variation in UGT1A3 expression and activity. UGT1A3 first exon and 5'-flanking regions were sequenced in 249 Caucasians. We identified 17 polymorphisms, among them seven regulatory and 10 exonic polymorphisms with six leading to amino-acid changes. Luciferase reporter assays, site-directed mutagenesis and electrophoretic mobility shift assays using hepatoma HepG2 cells were carried out to show functionality of variant promoters. Reduced transcriptional activity was associated with all six variant promoters (two-fold; P<0.001). One of the potential mechanisms would involve the -148 T>C and -581 C>T variations that modulate gene function by affecting hepatocyte nuclear factor-1alpha and hepatocyte nuclear factor-4alpha binding, respectively. Then, estrone-conjugating activity was assessed with 11 heterologously expressed allozymes. Three phenotypes were observed; UGT1A3*1, *2 (WR, VA) and *3 (WR) with high intrinsic clearance values; UGT1A3*5 (QR, WR), *7 (FI), *9 (WR, ML), *10 (VA) and *11 (WR, VA and MI) had intermediate CLint (2X-10X lower vs. *1), whereas UGT1A3*4 (RW), *6 (WR, VA, MV) and *8 (AV) had low CLint (>10X lower vs. *1). Diplotype analyses indicate that 20.1% of individuals carry two alleles affecting UGT1A3 expression and/or activity. This study did not investigate genotype-phenotype association, but raise the possibility that genetically determined variation might contribute to variability in the inactivation of estrone by UGT1A3 and subsequent changes in lifetime exposure to estrogens potentially modifying risk of cancer.

Adipose tissue is an accessible and abundant source of mesenchymal stem cells for soft-tissue reconstruction. In an attempt to create a novel, entirely autologous tissue-engineered adipose substitute, we extracted human stromal cells from either lipoaspirated or resected fat, and assessed their capacity to produce a three-dimensional adipose tissue using an adapted "self-assembly" culture methodology. This strategy involved a concomitant induction of adipogenic differentiation whilst ascorbic acid supplementation stimulated the stromal cells to produce and organize their own "biomaterial" in the form of extracellular matrix, forming manipulatable sheets that are then assembled into thicker reconstructed adipose tissues. When compared to resected fat, lipoaspiration-derived cells featured an increased adipogenic potential and the enhanced ability to recreate an adipose substitute in vitro. When viewed by scanning electron microscopy, the appearance of these reconstructed adipose tissues was strikingly similar to subcutaneous fat. Furthermore, these substitutes secreted adipokines and mediated beta-adrenergic receptor-stimulated lipolysis, hence reproducing known major biological functions of white adipose tissue. Therefore, our cell-based tissue engineering strategy led to the production of a functional and entirely natural reconstructed adipose tissue, which offers the potential to be used for specific in vitro applications as well as for autologous soft-tissue reconstruction.

Phosphorylated polystyrene derivatives with different compositions in phosphate groups were shown to be either recognized as phospholipidic or as DNA-like surfaces by antibodies from Systemic Lupus Erythematosus patients. In order to check whether these polymers were able to interact with Vitamin K-dependent coagulation factors, phosphorylated resins of various compositions in phosphate groups were assessed with regard to their interactions with Factor II, one of the Vitamin K-dependent factors. These studies were performed either in the presence or the absence of calcium ions, and with or without albumin precoating of the polymers. The results show that the affinity of the protein for the polymer is increased in the presence of calcium ions and depends on the composition of the polymer. The protein-polymer interactions involve the formation of binary or ternary complexes and the domains of predominance of these complexes were determined as a function of the calcium ion concentration in the assay. This allowed us to propose optimal conditions for Factor II purification by highly specific liquid chromatography using phosphorylated polystyrene resins of given compositions as stationary phases.