Transformations et influences dans «l'historiographie» juive de la fin du VIIe s. av. notre ère jusqu'à l'époque perse

The origins of biblical historiography may be dated to the end of the VIIth c. and linked to those of the deuteronomic school itself. In order to justify Josiah's politics, his scribes elaborated a collection of texts (Deut, Josh, Kings, a vita Mosis in Gen-Nb) which were widely inspired by Assyrian ideology. During the Babylonian exile, this literature underwent a transformation: the new created « Deuteronomistic History, (Deut-2 Kings) converted propaganda into theodicee. The Deuteronomists were still at work in the Persian period as can be seen in numerous texts in Deut-2 Kings, as well as in the edition of the prophetic corpus. From now on, dtr ideology was centered on three points: the restauration by law, the end of prophecy and the need to separate Israel from the « others » (cf. EsdNeh). But the Persian period was also the, time of compromise. The Pentateuch was made by putting together dtr and priestly ideologies, « autochtonous » and « exodic » views about the origins of Israel.

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.

Application of K-feldspar-jadeite-quartz barometry to eclogite facies metagranites and metapelites in the Sesia Lanzo Zone (Western Alps, Italy)

The eclogite facies assemblage K-feldspar-jadeite-quartz in metagranites and metapelites from the Sesia-Lanzo Zone (Western Alps, Italy) records the equilibration pressure by dilution of the reaction jadeite + quartz = albite. The metapelites show partial transformation from a pre-Alpine assemblage of garnet (Alm(63)Prp(26)Grs(10))-K-feldspar-plagioclase-biotite +/- sillimanite to the Eo-Alpine high-pressure assemblage garnet (Alm(50)Prp(14)Grs(35))-jadeite (Jd(80-97)Di(0-4)Hd(0-8)Acm(0-7))=zoisite-phengite. Plagioclase is replaced by jadeite-zoisite-kyanite-K-feldspar-quartz and biotite is replaced by garnet-phengite or omphacite-kyanite-phengite. Equilibrium was attained only in local domains in the metapelites and therefore the K-feldspar-jadeite-quartz (KJQ) barometer was applied only to the plagioclase pseudomorphs and K-feldspar domains. The albite content of K-feldspar ranges from 4 to 11 mol% in less equilibrated assemblages from Val Savenca and from 4 to 7 mol% in the partially equilibrated samples from Monte Mucrone and the equilibrated samples from Montestrutto and Tavagnasco. Thermodynamic calculations on the stability of the assemblage K-feldspar-jadeite-quartz using available mixing data for K-feldspar and pyroxene indicate pressures of 15-21 kbar (+/- 1.6-1.9 kbar) at 550 +/- 50 degrees C. This barometer yields direct pressure estimates in high-pressure rocks where pressures are seldom otherwise fixed, although it is sensitive to analytical precision and the choice of thermodynamic mixing model for K-feldspar. Moreover, the KJQ barometer is independent of the ratio P-H2O/P-T. The inferred limiting a(H2O) for the assemblage jadeite-kyanite in the metapelites from Val Savenca is low and varies from 0.2 to 0.6.

Metallogenic model of the Trepca Pb-Zn-Ag skarn deposit, Kosovo: Evidence from fluid inclusions, Rare Earth Elements, and stable isotope data

The Trepca Pb-Zn-Ag skarn deposit (29 Mt of ore at 3.45% Pb, 2.30% Zn, and 80 g/t Ag) is located in the Kopaonik block of the western Vardar zone, Kosovo. The mineralization, hosted by recrystallized limestone of Upper Triassic age, was structurally and lithologically controlled. Ore deposition is spatially and temporally related with the postcollisional magmatism of Oligocene age (23-26 Ma). The deposit was formed during two distinct mineralization stages: an early prograde closed-system and a later retrograde open-system stage. The prograde mineralization consisting mainly of pyroxenes (Hd(54-100)Jo(0-45)Di(0-45)) resulted from the interaction of magmatic fluids associated with Oligocene (23-26 Ma) postcollisional magmatism. Whereas there is no direct contact between magmatic rocks and the mineralization, the deposit is classified as a distal Pb-Zn-Ag skarn. Abundant pyroxene reflects low oxygen fugacity (<10(-31) bar) and anhydrous environment. Fluid inclusion data and mineral assemblage limit the prograde stage within a temperature range between 390 degrees and 475 degrees C. Formation pressure is estimated below 900 bars. Isotopic composition of aqueous fluid, inclusions hosted by hedenbergite (delta D = -108 to -130 parts per thousand; delta O-18 = 7.5-8.0 parts per thousand), Mn-enriched mineralogy and high REE content of the host carbonates at the contact with the skarn mineralization suggest that a magmatic fluid was modified during its infiltration through the country rocks. The retrograde mineral assemblage comprises ilvaite, magnetite, arsenopyrite, pyrrhotite, marcasite, pyrite, quartz, and various carbonates. Increases in oxygen and sulfur fugacities, as well as a hydrous character of mineralization, require an open-system model. The opening of the system is related to phreatomagmatic explosion and formation of the breccia. Arsenopyrite geothermometer limits the retrograde stage within the temperature range between 350 degrees and 380 degrees C and sulfur fugacity between 10(-8.8) and 10(-7.2) bars. The principal ore minerals, galena, sphalerite, pyrite, and minor chalcopyrite, were deposited from a moderately saline Ca-Na chloride fluid at around 350 degrees C. According to the isotopic composition of fluid inclusions hosted by sphalerite (delta D = -55 to -74 parts per thousand; delta O-18 = -9.6 to -13.6 parts per thousand), the fluid responsible for ore deposition was dominantly meteoric in origin. The delta S-31 values of the sulfides spanning between -5.5 and +10 parts per thousand point to a magmatic origin of sulfur. Ore deposition appears to have been largely contemporaneous with the retrograde stage of the skarn development. Postore stage accompanied the precipitation of significant amount of carbonates including the travertine deposits at the deposit surface. Mineralogical composition of travertine varies from calcite to siderite and all carbonates contain significant amounts of Mn. Decreased formation temperature and depletion in the REE content point to an influence of pH-neutralized cold ground water and dying magmatic system.

Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab.

Metastatic melanoma has a poor prognosis with high resistance to chemotherapy and radiation. Recently, the anti-CTLA-4 antibody ipilimumab has demonstrated clinical efficacy, being the first agent to significantly prolong the overall survival of inoperable stage III/IV melanoma patients. A major aim of patient immune monitoring is the identification of biomarkers that predict clinical outcome. We studied circulating myeloid-derived suppressor cells (MDSC) in ipilimumab-treated patients to detect alterations in the myeloid cell compartment and possible correlations with clinical outcome. Lin(-) CD14(+) HLA-DR(-) monocytic MDSC were enriched in peripheral blood of melanoma patients compared to healthy donors (HD). Tumor resection did not significantly alter MDSC frequencies. During ipilimumab treatment, MDSC frequencies did not change significantly compared to baseline levels. We observed high inter-patient differences. MDSC frequencies in ipilimumab-treated patients were independent of baseline serum lactate dehydrogenase levels but tended to increase in patients with severe metastatic disease (M1c) compared to patients with metastases in skin or lymph nodes only (M1a), who had frequencies comparable to HD. Interestingly, clinical responders to ipilimumab therapy showed significantly less lin(-) CD14(+) HLA-DR(-) cells as compared to non-responders. The data suggest that the frequency of monocytic MDSC may be used as predictive marker of response, as low frequencies identify patients more likely benefitting from ipilimumab treatment. Prospective clinical trials assessing MDSC frequencies as potential biomarkers are warranted to validate these observations.

Quality of care and survival of haemodialysed patients in western Switzerland.

BACKGROUND: Many factors affect survival in haemodialysis (HD) patients. Our aim was to study whether quality of clinical care may affect survival in this population, when adjusted for demographic characteristics and co-morbidities. METHODS: We studied survival in 553 patients treated by chronic HD during March 2001 in 21 dialysis facilities in western Switzerland. Indicators of quality of care were established for anaemia control, calcium and phosphate product, serum albumin, pre-dialysis blood pressure (BP), type of vascular access and dialysis adequacy (spKt/V) and their baseline values were related to 3-year survival. The modified Charlson co-morbidity index (including age) and transplantation status were also considered as a predictor of survival. RESULTS: Three-year survival was obtained for 96% of the patients; 39% (211/541) of these patients had died. The 3-year survival was 50, 62 and 69%, respectively, in patients who had 0-2, 3 and >or=4 fulfilled indicators of quality of care (test for linear trend, P < 0.001). In a Cox multivariate analysis model, the absence of transplantation, a higher modified Charlson's score, decreased fulfilment of indicators of good clinical care and low pre-dialysis systolic BP were independent predictors of death. CONCLUSION: Good clinical care improves survival in HD patients, even after adjustment for availability of transplantation and co-morbidities.

Pentateuque, Hexateuque et historiographie deutéronomiste. Le problème du début et de la fin du livre de Josué

The book of Joshua is in the very center of the recent discussion about the existence of a coherent deuteronomistic redaction in Deut to 2 Kings during the exilic period. This article analyses the beginning (Josh 1.1-9) and the end (Josh 23 and 24) of Josh. Josh 1.1-2,5-7 and chapter 23 belong to the dtr edition. Josh 23 was followed by Judg 2.6ff. During the Persian period, Deuteronomists and priests intended to publish one Law for the whole community. There was probably a discussion whether the Torah should be a Penta- or a Hexateuch. This discussion may explain such a text as Josh 24 which clearly tries to construct an Hexateuch (cf. also Gen. 50.25: Exod 13.19; Josh 24.32). But since the Torah is about foundations, the main theological trends agreed to have its end with the death of Moses.

Risk of mental disorders in children of parents with alcohol or heroin dependence: a controlled high-risk study.

Aim: To assess the specific effect of alcohol dependence (AD) or heroin dependence (HD) in patients and their spouses on the risk of psychopathology in their 276 6.0- to 17.9- year-old children (mean 11.3 years). Methods: The sample included 101 offspring of patients with AD, 23 of patients with HD, and 152 of medical controls, as well as their 2 parents. Participants were assessed using semistructured diagnostic interviews and family history reports by psychologists blind to patient diagnoses. Results: Children of HD and AD patients had largely elevated rates of recurrent major depressive disorder. Children of HD patients were also at an increased risk for attention deficit hyperactivity disorder and substance use disorders (SUD). There were interactions between SUD in the 2 parents to increase the risk of SUD in offspring. Conclusions: These results emphasize the need for prompt identification and treatment of these children and highlight the need to pay clinical attention not only to the patient, but also to the co-parent in order to optimize prevention in offspring.

Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease.

The mechanisms underlying preferential atrophy of the striatum in Huntington's disease (HD) are unknown. One hypothesis is that a set of gene products preferentially expressed in the striatum could determine the particular vulnerability of this brain region to mutant huntingtin (mHtt). Here, we studied the striatal protein µ-crystallin (Crym). Crym is the NADPH-dependent p38 cytosolic T3-binding protein (p38CTBP), a key regulator of thyroid hormone (TH) T3 (3,5,3'-triiodo-l-thyronine) transportation. It has been also recently identified as the enzyme that reduces the sulfur-containing cyclic ketimines, which are potential neurotransmitters. Here, we confirm the preferential expression of the Crym protein in the rodent and macaque striatum. Crym expression was found to be higher in the macaque caudate than in the putamen. Expression of Crym was reduced in the BACHD and Knock-in 140CAG mouse models of HD before onset of striatal atrophy. We show that overexpression of Crym in striatal medium-size spiny neurons using a lentiviral-based strategy in mice is neuroprotective against the neurotoxicity of an N-terminal fragment of mHtt in vivo. Thus, reduction of Crym expression in HD could render striatal neurons more susceptible to mHtt suggesting that Crym may be a key determinant of the vulnerability of the striatum. In addition our work points to Crym as a potential molecular link between striatal degeneration and the THs deregulation reported in HD patients.

Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood.

Highly quantitative biomarkers of neurodegenerative disease remain an important need in the urgent quest for disease-modifying therapies. For Huntington's disease (HD), a genetic test is available (trait marker), but necessary state markers are still in development. In this report, we describe a large battery of transcriptomic tests explored as state biomarker candidates. In an attempt to exploit the known neuroinflammatory and transcriptional perturbations of disease, we measured relevant mRNAs in peripheral blood cells. The performance of these potential markers was weak overall, with only one mRNA, immediate early response 3 (IER3), showing a modest but significant increase of 32% in HD samples compared with controls. No statistically significant differences were found for any other mRNAs tested, including a panel of 12 RNA biomarkers identified in a previous report [Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, et al. (2005) Proc Natl Acad Sci USA 102:11023-11028]. The present results may nonetheless inform the future design and testing of HD biomarker strategies.

Intravitreal ranibizumab for age-related macular degeneration - optical coherence tomography guided retreatment intervals and their intra- and inter-individual variability

PURPOSE:To determine whether the need for retreatment after an initial loading phase of 3 monthly intravitreal injections of ranibizumab shows an intra-individual regular rhythm and to what degree it varies between different patients.SETTING:Prospective mono-centre cohort study.METHODS:Prospective study with 42 patients with exudative age-related macular degeneration (AMD), treatment na?ve, giving informed consent. Loading dose of 3 monthly doses of ranibizumab (0,5mg), followed by a 12 months pro re nata (PRN) regimen according to early exudative signs on spectral domain optical coherence tomography (HD-OCT Cirrus Zeiss?, cube 512x126). The follow-up visits were intensified (week 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, 24, etc after each injection) in order to detect exudative recurrences early, and injection followed within 3 days in cases of subretinal fluid, or intraretinal cysts, or central thickness increase of >50?m. Intervals were calculated between injections and the following recurrence was calculated for the 12 month follow-up with PRN treatment. Variability was expressed as standard deviation (SD). RESULTS Visual acuity (VA) improved from a mean ETDRS letter score of 61.6 (SD 10.8) at baseline to 68.0 (SD 10.2, +6.4 letters) at month 3 and increased further to 74.7 (SD 9.0, +13.1 letters from baseline) at month 12. The 15 patients who have completed the study by October 2010 showed maintenance of the VA improvement. Retinal thickness of the central foveal subfield improved from a mean value of 366?m(baseline) to 253?m(month 3), well maintained thereafter. Mean number of injections was 8.8 (SD 3.5) per 12 months of follow-up (after 3 loading doses), ranging from 0 to 12, with mean individual treatment-recurrence intervals ranging from 28 to >365 days (mean 58 days). Intraindividual variability of treatment-recurrence intervals, measured as SD of the individual intervals, was 7.1days as a mean value(range 1.7 ? 22.6 days) for the 33 patients with more than 1 injection during follow-up. SD was higher for longer intervals of an individual patient. It ranged within 20% of the mean intra-individual interval for 30 patients(91%) and within 15% for 21 patients(64%). The first interval was within 1 week of the mean intra-individual interval in 64% of patients and within 2 weeks in 89% of patients.CONCLUSIONS:The majority of AMD patients showed a relatively stable rhythm for PRN injections of intravitreal ranibizumab after initial loading phase, associated with excellent functional and anatomical results. The initial interval between last loading dose and first recurrence may have a predictive value for further need of treatment, therefore potentially facilitating follow-up and patient care.

Homeodomain binding motifs modulate the probability of odorant receptor gene choice in transgenic mice.

Odorant receptor (OR) genes constitute with 1200 members the largest gene family in the mouse genome. A mature olfactory sensory neuron (OSN) is thought to express just one OR gene, and from one allele. The cell bodies of OSNs that express a given OR gene display a mosaic pattern within a particular region of the main olfactory epithelium. The mechanisms and cis-acting DNA elements that regulate the expression of one OR gene per OSN - OR gene choice - remain poorly understood. Here, we describe a reporter assay to identify minimal promoters for OR genes in transgenic mice, which are produced by the conventional method of pronuclear injection of DNA. The promoter transgenes are devoid of an OR coding sequence, and instead drive expression of the axonal marker tau-β-galactosidase. For four mouse OR genes (M71, M72, MOR23, and P3) and one human OR gene (hM72), a mosaic, OSN-specific pattern of reporter expression can be obtained in transgenic mice with contiguous DNA segments of only ~300 bp that are centered around the transcription start site (TSS). The ~150bp region upstream of the TSS contains three conserved sequence motifs, including homeodomain (HD) binding sites. Such HD binding sites are also present in the H and P elements, DNA sequences that are known to strongly influence OR gene expression. When a 19mer encompassing a HD binding site from the P element is multimerized nine times and added upstream of a MOR23 minigene that contains the MOR23 coding region, we observe a dramatic increase in the number of transgene-expressing founders and lines and in the number of labeled OSNs. By contrast, a nine times multimerized 19mer with a mutant HD binding site does not have these effects. We hypothesize that HD binding sites in the H and P elements and in OR promoters modulate the probability of OR gene choice.

Magmatic-dominated fluid evolution in the Jurassic Nambija gold skarn deposits (southeastern Ecuador)

The Jurassic (approximately 145 Ma) Nambija oxidized gold skarns are hosted by the Triassic volcanosedimentary Piuntza unit in the sub-Andean zone of southeastern Ecuador. The skarns consist dominantly of granditic garnet (Ad(20-98)) with subordinate pyroxene (Di(46-92)Hd(17-42)Jo(0-19)) and epidote and are spatially associated with porphyritic quartz-diorite to granodiorite intrusions. Endoskarn is developed at the intrusion margins and grades inwards into a potassic alteration zone. Exoskarn has an outer K- and Na-enriched zone in the volcanosedimentary unit. Gold mineralization is associated with the weakly developed retrograde alteration of the exoskarn and occurs mainly in sulfide-poor vugs and milky quartz veins and veinlets in association with hematite. Fluid inclusion data for the main part of the prograde stage indicate the coexistence of high-temperature (500A degrees C to > 600A degrees C), high-salinity (up to 65 wt.% eq. NaCl), and moderate- to low-salinity aqueous-carbonic fluids interpreted to have been trapped at pressures around 100-120 MPa, corresponding to about 4-km depth. Lower-temperature (510-300A degrees C) and moderate- to low-salinity (23-2 wt.% eq. NaCl) aqueous fluids are recorded in garnet and epidote of the end of the prograde stage. The microthermometric data (Th from 513A degrees C to 318A degrees C and salinity from 1.0 to 23 wt.% eq. NaCl) and delta(18)O values between 6.2aEuro degrees and 11.5aEuro degrees for gold-bearing milky quartz from the retrograde stage suggest that the ore-forming fluid was dominantly magmatic. Pressures during the early retrograde stage were in the range of 50-100 MPa, in line with the evidence for CO(2) effervescence and probable local boiling. The dominance of magmatic low-saline to moderately saline oxidizing fluids during the retrograde stage is consistent with the depth of the skarn system, which could have delayed the ingression of external fluids until relatively low temperatures were reached. The resulting low water-to-rock ratios explain the weak retrograde alteration and the compositional variability of chlorite, essentially controlled by host rock compositions. Gold was precipitated at this stage as a result of cooling and pH increase related to CO(2) effervescence, which both result in destabilization of gold-bearing chloride complexes. Significant ingression of external fluids took place after gold deposition only, as recorded by delta(18)O values of 0.4aEuro degrees to 6.2aEuro degrees for fluids depositing quartz (below 350A degrees C) in sulfide-rich barren veins. Low-temperature (< 300A degrees C) meteoric fluids (delta(18)O(water) between -10.0aEuro degrees and -2.0aEuro degrees) are responsible for the precipitation of late comb quartz and calcite in cavities and veins and indicate mixing with cooler fluids of higher salinities (about 100A degrees C and 25 wt.% eq. NaCl). The latter are similar to low-temperature fluids (202-74.5A degrees C) with delta(18)O values of -0.5aEuro degrees to 3.1aEuro degrees and salinities in the range of 21.1 to 17.3 wt.% eq. CaCl(2), trapped in calcite of late veins and interpreted as basinal brines. Nambija represents a deep equivalent of the oxidized gold skarn class, the presence of CO(2) in the fluids being partly a consequence of the relatively deep setting at about 4-km depth. As in other Au-bearing skarn deposits, not only the prograde stage but also the gold-precipitating retrograde stage is dominated by fluids of magmatic origin.

Modulation of the c-Jun N-terminal kinase activity in the embryonic heart in response to anoxia-reoxygenation: involvement of the Ca2+ and mitoKATP channels.

Whether the response of the fetal heart to ischemia-reperfusion is associated with activation of the c-Jun N-terminal kinase (JNK) pathway is not known. In contrast, involvement of the sarcolemmal L-type Ca2+ channel (LCC) and the mitochondrial KATP (mitoKATP) channel has been established. This work aimed at investigating the profile of JNK activity during anoxia-reoxygenation and its modulation by LCC and mitoK(ATP) channel. Hearts isolated from 4-day-old chick embryos were submitted to anoxia (30 min) and reoxygenation (60 min). Using the kinase assay method, the profile of JNK activity in the ventricle was determined every 10 min throughout anoxia-reoxygenation. Effects on JNK activity of the LCC blocker verapamil (10 nM), the mitoK(ATP) channel opener diazoxide (50 microM) and the blocker 5-hydroxydecanoate (5-HD, 500 microM), the mitochondrial Ca2+ uniporter (MCU) inhibitor Ru360 (10 microM), and the antioxidant N-(2-mercaptopropionyl) glycine (MPG, 1 mM) were determined. In untreated hearts, JNK activity was increased by 40% during anoxia and peaked fivefold relative to basal level after 30-40 min reoxygenation. This peak value was reduced by half by diazoxide and was tripled by 5-HD. Furthermore, the 5-HD-mediated stimulation of JNK activity during reoxygenation was abolished by diazoxide, verapamil or Ru360. MPG had no effect on JNK activity, whatever the conditions. None of the tested pharmacological agents altered JNK activity under basal normoxic conditions. Thus, in the embryonic heart, JNK activity exhibits a characteristic pattern during anoxia and reoxygenation and the respective open-state of LCC, MCU and mitoKATP channel can be a major determinant of JNK activity in a ROS-independent manner.