Dominant contribution of atmospheric nonlinearities to ENSO asymmetry and extreme El Niño events.

Extreme El Niño events have outsized impacts and strongly contribute to the El Niño Southern Oscillation (ENSO) warm/cold phase asymmetries. There is currently no consensus on the respective importance of oceanic and atmospheric nonlinearities for those asymmetries. Here, we use atmospheric and oceanic general circulation models that reproduce ENSO asymmetries well to quantify the atmospheric nonlinearities contribution. The linear and nonlinear components of the wind stress response to Sea Surface Temperature (SST) anomalies are isolated using ensemble atmospheric experiments, and used to force oceanic experiments. The wind stress-SST nonlinearity is dominated by the deep atmospheric convective response to SST. This wind-stress nonlinearity contributes to ~ 40% of the peak amplitude of extreme El Niño events and ~ 55% of the prolonged eastern Pacific warming they generate until the following summer. This large contribution arises because nonlinearities consistently drive equatorial westerly anomalies, while the larger linear component is made less efficient by easterly anomalies in the western Pacific during fall and winter. Overall, wind-stress nonlinearities fully account for the eastern Pacific positive ENSO skewness. Our findings underscore the pivotal role of atmospheric nonlinearities in shaping extreme El Niño events and, more generally, ENSO asymmetry.

A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib.

PURPOSE: Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated. METHODS: A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study. RESULTS: A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642-5.364 µg/L) and rats (0.782-2.565 µg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4 mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6 mg. CONCLUSION: The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.

Impact of projected sea surface temperature biases on tropical cyclones projections in the South Pacific.

Climate model projections generally indicate fewer but more intense tropical cyclones (TCs) in response to increasing anthropogenic emissions. However these simulations suffer from long-standing biases in their Sea Surface Temperature (SST). While most studies investigating future changes in TC activity using high-resolution atmospheric models correct for the present-day SST bias, they do not consider the reliability of the projected SST changes from global climate models. The present study illustrates that future South Pacific TC activity changes are strongly sensitive to correcting the projected SST changes using an emergent constraint method. This additional correction indeed leads to a strong reduction of the cyclogenesis (-55%) over the South Pacific basin, while no statistically significant change arises in the uncorrected simulations. Cyclogenesis indices suggest that this strong reduction in the corrected experiment is caused by stronger vertical wind shear in response to a South Pacific Convergence Zone equatorward shift. We thus find that uncertainty in the projected SST patterns could strongly hamper the reliability of South Pacific TC projections. The strong sensitivity found in the current study will need to be investigated with other models, observational constraint methods and in other TC basins in order to assess the reliability of regional TC projections.

Contagious agalactia monitoring in caprine herds through regular bulk tank milk sampling.

Surveillance and control of Mycoplasma spp. responsible for contagious agalactia (CA) in caprine herds are important challenges in countries with a large small-ruminant dairy industry. In the absence of any clinical signs, being able to determine the potential circulation of mycoplasmas within a herd could help to prevent biosecurity issues during animal exchanges between farms and improve health management practices. The objective of this study was to determine whether regular sampling of bulk tank milk was suitable for such surveillance. Twenty farms were sampled once a month for 2 yr and CA-responsible mycoplasmas were detected by real-time PCR on DNA extracted from milk, using 3 different DNA extraction methods. The pattern of mycoplasma excretion in bulk tank milk was assessed over time and several herd characteristics were recorded together with any event occurring within the herds. In general, the results obtained with the different detection methods were comparable and mainly agreed with the culture results. Several patterns of excretion were observed but were not related to herd characteristics (size, breed, and so on). Recurrence of the same (sub)species and same pulsed-field gel electrophoresis subtype during the 2-yr period is indicative of the considerable persistence of mycoplasmas. This persistence was associated with intermittent excretion. In conclusion, bulk tank milk sampling could be valuable for controlling CA in caprine herds provided it is repeated several times, yet to be defined, per year and analyzed using an appropriate methodology and the right cut-off for interpretation.

Serosurvey of Schmallenberg Virus Infection in the Highest Goat-Specialized Region of France.

The monitoring of both the spread and clinical impact of Schmallenberg virus (SBV) infection within its full host range is important for the control of the epidemic and potential new outbreaks. In France, a national surveillance plan based on voluntary notifications of congenital malformations in newborn ruminants revealed that goats were the less affected host species. However, seroprevalence studies only targeted sheep and cattle, preventing accurate estimations of the real impact of SBV infection in goats. Here, a serological survey was conducted in the highest goat-specialized region of France between June 2012 and January 2013. A total of 1490 goat sera from 50 herds were analysed by ELISA. The between-herd and within-herd prevalences were estimated at 62% and 13.1%, respectively. Seroprevalence was not uniformly distributed throughout the territory and markedly differed between intensive and extensive herds. The low within-herd seroprevalence demonstrates that a large fraction of the French goat population remains susceptible to SBV infection.

[Utilization of Essure® micro-insert for hydrosalpynx occlusion in infertile women]. / Utilisation du micro-implant Essure® pour exclusion d'hydrosalpinx dans un contexte d'infertilité.

OBJECTIVE: To assess the feasibility and the results on fertility of tubal hysteroscopic proximal occlusion with Essure(®) micro-insert in women with hydrosalpinges. PATIENTS AND METHODS: Thirteen infertile women with hydrosalpinges, who underwent hysteroscopic tubal exclusion by Essure(®) prior to IVF procedure. RESULTS: The placement of micro-insert was feasible and easy in every patient, with no intra-operative complication. Only one postoperative infectious complication (pyosalpinx) occurred. We report a 64 % rate of pregnancy, and a 18 % rate of normally ongoing pregnancies with no Essure(®)-related complication. CONCLUSION: Hydrosalpinges occlusion by Essure(®) device might be an easy and safe alternative to laparoscopic treatment, with successful results on fertility and without adverse effects on pregnancy outcomes.

[Influence duration of the use of estrogens beyond the menses in estradiol IVF antagonist programming cycles]. / Influence de la durée de prise d'estrogènes au-delà des règles dans les cycles FIV antagonistes programmés par les estrogènes.

OBJECTIVE: To evaluate by the birth rate the impact of the number of days of estrogens continued beyond the menses in a four days estradiol IVF antagonist programming cycles. PATIENTS AND METHODS: Retrospective study from September 2004 to January 2009 among women of age ranging between 25 and 38 years. Four milligrams of provames is prescribed 3 to 5 days before the theorical menses and continued until the beginning day of stimulation, which is distributed equitably between Thursday and Sunday. The birth rate is evaluated according to the number of days of estrogen continued beyond the menses within a limit from 1 to 8. RESULTS: No significant difference appears neither in the duration of stimulation, in the quantity of gonadotrophin, the oocytes pick up, nor in the rate of birth between the groups. CONCLUSION: The programming by estrogens of the antagonist IVF cycles implies a variable number of days of estrogens continued beyond the menses, which does not seem to affect the birth rate.

[Efficiency of antagonist IVF cycle programming by estrogens]. / Efficacité de la programmation des cycles FIV en antagonistes par les estrogènes.

OBJECTIVE: Assess the efficiency of estradiol programming in In Vitro Fertilization (IVF) with antagonists by comparing with classical long luteal agonist protocol. PATIENTS AND METHODS: It is a prospective randomized study, comparing 426 cycles in the arm estradiol antagonist with 412 cycles in the arm long agonist. Estradiol 4 mg/day begins on the 25th day of the previous cycle and continues during the menses until the first day of the stimulation which is from Thursday to Sunday whatever the beginning of the menses. The luteal protocol use Decapeptyl 0,1mg which begins on the 20th day of the previous cycle. RESULTS: Our two populations are similar. No pick-up has been done on Sunday. We have got significantly less oocytes and embryos in estradiol-antagonist (6,8+/-5,3 vs 7,6+/-5,7) and (3,7+/-3,2 vs 4,1+/-3,6) respectively. The ongoing pregnancy rate is comparable in the two groups: 28,6 % for estradiol antagonist 27,9 % for agonist for the whole population and 37 % vs 34,8 % respectively when at least one top embryo was transferred. DISCUSSION AND CONCLUSION: Programming antagonist cycles with estradiol allows the organization of the center; it is easy to implement and seems to give results as good as a long agonist protocol.

[Cytological study of 191 women with invasive cancer of the uterine cervix in Brittany, France]. / Histoire cytologique de 191 patientes atteintes d'un cancer invasif du col de l'utérus en région Bretagne.

INTRODUCTION: The cancer of the cervix annually occurs in 150 women in Brittany in the absence of organized screening. MATERIAL AND METHODS: Retrospective study concerning 191 patients treated for an invasive cancer of the uterine cervix between 2000 and 2005 analyzing their cytological past. The average age of the patients was 52 years (22-87 years). The socioeconomic level of the patients was recorded. The distribution of under histological types was: squamous, 73% (54 years average age) and adenocarcinoma, 22% (average age 47 years). All the stages were represented: stage I 46%, II 32%, III 9% and stage IV 13%. RESULTS: Cancer was symptomatic in 89% of the cases and 72% of the patients had not profited from cytological screening according to French recommendations (50% no follow-up, 22% follow-up between three and 10 years), while 28% of the patients had a smear in the three years. The socioeconomic level of the patients strongly influenced the participation in screening. The proportion of patients having an invasive adenocarcinom was 31% in the patients with a smear going back to less than three years (versus 22% in our total population) and this histological subtype was mainly represented in patients less than 35 years old (35%). Lastly, 2,6% of the patients were lost after realization of a pathological smear. CONCLUSION: The extension of screening and its organization remain a priority in our area. The average sensitivity of the smear is illustrated by the on-representation of the adenocarcinoma, in particular among young women.

Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells.

The hdm-2 oncogene is overexpressed in several types of malignancies including osteosarcomas, soft tissue sarcomas and gliomas and hdm-2 has been associated with accelerated tumor formation in both hereditary and sporadic cancers. Among the other key binding partners, hdm-2 forms a complex with the tumor suppressor p53, resulting in a rapid proteasome-mediated degradation of the p53 protein. This positions the hdm-2-p53 complex as an attractive target for the development of anticancer therapy and recently the first small molecule hdm-2 antagonist has been reported. Development of hdm-2 antagonists is currently focused on malignancies containing a wild-type p53 genotype, which is the case in approximately half of human cancer indications. However, hdm-2 has also been implicated in oncogenesis in the absence of p53. We therefore studied the effect of hdm-2 antagonists in p53-deficient human H1299 lung carcinoma cells. The hdm-2 antagonistic peptide caused G1 cell cycle arrest, inhibited colony growth and induced expression of G1 checkpoint regulatory proteins, such as p21(waf1,cip1). These data demonstrate that hdm-2 regulates the G1 cell cycle checkpoint in a p53-independent manner, suggesting that hdm-2 antagonists represent a novel class of anticancer therapeutics with broad applicability towards tumors with different p53 genetic backgrounds.

Human Mus81-associated endonuclease cleaves Holliday junctions in vitro.

Mus81, a protein with homology to the XPF subunit of the ERCC1-XPF endonuclease, is important for replicational stress tolerance in both budding and fission yeast. Human Mus81 has associated endonuclease activity against structure-specific oligonucleotide substrates, including synthetic Holliday junctions. Mus81-associated endonuclease resolves Holliday junctions into linear duplexes by cutting across the junction exclusively on strands of like polarity. In addition, Mus81 protein abundance increases in cells following exposure to agents that block DNA replication. Taken together, these findings suggest a role for Mus81 in resolving Holliday junctions that arise when DNA replication is blocked by damage or by nucleotide depletion. Mus81 is not related by sequence to previously characterized Holliday junction resolving enzymes, and it has distinct enzymatic properties that suggest it uses a novel enzymatic strategy to cleave Holliday junctions.

The budding yeast Rad9 checkpoint protein is subjected to Mec1/Tel1-dependent hyperphosphorylation and interacts with Rad53 after DNA damage.

The Saccharomyces cerevisiae RAD9 checkpoint gene is required for transient cell-cycle arrests and transcriptional induction of DNA repair genes in response to DNA damage. Polyclonal antibodies raised against the Rad9 protein recognized several polypeptides in asynchronous cultures, and in cells arrested in S or G2/M phases while a single form was observed in G1-arrested cells. Treatment with various DNA damaging agents, i.e. UV, ionizing radiation or methyl methane sulfonate, resulted in the appearance of hypermodified forms of the protein. All modifications detected during a normal cell cycle and after DNA damage were sensitive to phosphatase treatment, indicating that they resulted from phosphorylation. Damage-induced hyperphosphorylation of Rad9 correlated with checkpoint functions (cell-cycle arrest and transcriptional induction) and was cell-cycle stage- and progression-independent. In asynchronous cultures, Rad9 hyperphosphorylation was dependent on MEC1 and TEL1, homologues of the ATR and ATM genes. In G1-arrested cells, damage-dependent hyperphosphorylation required functional MEC1 in addition to RAD17, RAD24, MEC3 and DDC1, demonstrating cell-cycle stage specificity of the checkpoint genes in this response to DNA damage. Analysis of checkpoint protein interactions after DNA damage revealed that Rad9 physically associates with Rad53.

The late expression factors 8 and 9 and possibly the phosphoprotein p78/83 of Autographa californica multicapsid nucleopolyhedrovirus are components of the virus-induced RNA polymerase.

Attempts were made to identify some of the subunits of the baculovirus-induced RNA polymerase following purification of its enzymatic activity by conventional chromatography. Polymerase activity was extracted from lysates of insect cells infected with Autographa californica multicapsid nucleopolyhedrovirus by polyethylenimine precipitation and subsequently purified by phosphocellulose, anion exchange, poly(A) Sepharose affinity, and gel filtration chromatography. The presence of the polymerase was monitored by its alpha-amanitin-resistant activity in in vitro transcription assays. A number of polypeptides associated with the enzymatic activity were identified. Peptide-specific antibodies were generated against a variety of late-expression factors (LEFs) and these antibodies, along with antisera directed against several other baculovirus proteins, were used in an immunoblot analysis of the purified polymerase. The results revealed that both the viral helicase (p143) and the virogenic stroma protein, pp31, copurify with the baculovirus-induced RNA polymerase activity through several chromatographic steps and may be loosely associated with the RNA polymerase. LEF8, LEF9 and p78/83, a nucleocapsid-associated phosphoprotein, were found to associate with the viral-induced polymerase activity. LEF8 and LEF9 contain regions of sequence homology with components of other DNA-directed RNA polymerases, while a portion of p78/83 exhibits some homology to the sigma factor of bacterial RNA polymerase, the RAP30 protein found in the mammalian transcription complex TFIIF, and the RAP94 polypeptide associated with vaccinia virus RNA polymerase. The p78/83 protein has previously been shown by our laboratory to be a capsid protein, but it may also play some role with the RNA polymerase. These results represent a first attempt to identify specific components of the RNA polymerase associated with infections of insect cells by A. californica nucleopolyhedrovirus.

A novel role for the budding yeast RAD9 checkpoint gene in DNA damage-dependent transcription.

Cells respond to DNA damage by arresting cell cycle progression and activating several DNA repair mechanisms. These responses allow damaged DNA to be repaired efficiently, thus ensuring the maintenance of genetic integrity. In the budding yeast, Saccharomyces cerevisiae, DNA damage leads both to activation of checkpoints at the G1, S and G2 phases of the cell cycle and to a transcriptional response. The G1 and G2 checkpoints have been shown previously to be under the control of the RAD9 gene. We show here that RAD9 is also required for the transcriptional response to DNA damage. Northern blot analysis demonstrated that RAD9 controls the DNA damage-specific induction of a large 'regulon' of repair, replication and recombination genes. This induction is cell-cycle independent as it was observed in asynchronous cultures and cells blocked in G1 or G2/M. RAD9-dependent induction was also observed from isolated damage responsive promoter elements in a lacZ reporter-based plasmid assay. RAD9 cells deficient in the transcriptional response were more sensitive to DNA damage than wild-type cells, even after functional substitution of checkpoints, suggesting that this activation may have an important role in DNA repair. Our findings parallel observations with the Escherichia coli SOS system and suggest the existence of an analogous eukaryotic network coordinating the cellular responses to DNA damage.

[Socioeconomic approach to the practice of in vitro fertilization in the Brittany region in 1993]. / Approche socio-économique de la pratique de la fécondation in vitro en région Bretagne en 1993.

AIM OF THE STUDY: to estimate the social and economical point of view of the practice of in vitro fertilization (IVF) in Brittany in 1993. METHODS: we made a prospective study of 152 cases of IVF. We studied the medical history of sterility of the patients, treatments during IVF, hormonal and ultrasound monitoring, oocytes retrieval and embryo transfer, and the screening until beta-hCG > 1,000 UI or evidence of pregnancy with ultrasound scan. After analysing results of IVF, we studied the cost of all these steps, including hospitalization, transports and stoppage. RESULTS: we estimated the mean price of one IVF cycle at 11,084 francs. We analysed the portion of each step in the total cost and discussed with the view of literature. CONCLUSION: the cost of IVF seems reasonable in this context.

The 1,629-nucleotide open reading frame located downstream of the Autographa californica nuclear polyhedrosis virus polyhedrin gene encodes a nucleocapsid-associated phosphoprotein.

A 78-kDa protein was produced in bacteria from a clone of the 1,629-nucleotide open reading frame located immediately downstream from the polyhedrin gene of Autographa californica nuclear polyhedrosis virus. The identity of this protein was confirmed by its reactivity with peptide antiserum and amino terminal peptide sequencing after purification from transformed bacteria. The polypeptide was used to produce polyclonal antisera in rabbits. Immunoblot analysis of insect cells infected with the baculovirus indicated that two related proteins with molecular masses of 78 and 83 kDa were synthesized late in infection. Biochemical fractionation studies indicated that both of these proteins were present in purified nucleocapsids from budded and occluded virus preparations. Immunoprecipitation of 32P-labeled proteins and treatment of purified nucleocapsids with alkaline phosphatase demonstrated that the 83-kDa protein was a phosphorylated derivative of the 78-kDa protein. Furthermore, immunoelectron microscopy revealed that the proteins were localized to regions of nucleocapsid assembly within the infected cell and appeared to be associated with the end structures of mature nucleocapsids.

Bacterial luciferase produced with rapid-screening baculovirus vectors is a sensitive reporter for infection of insect cells and larvae.

Bacterial luciferase, derived from a fusion of the luxA and luxB genes of Vibrio harveyi, has been expressed at very high levels in caterpillars and insect cells. The coding sequence for luciferase was inserted into vectors developed in our laboratory which were designed to expedite screening of recombinant virus. These vectors contained the beta-galactosidase indicator gene under control of immediate early (IE1), early (ETL), or very late (P10) promoters and a cloning site for inserting the fused luciferase gene next to the polyhedrin promoter. Recombinant baculoviruses containing the luciferase gene as well as the beta-galactosidase gene could be easily selected when Bluo-gal (beta-galactosidase indicator) was included in the plaque assays. Using cells derived from the fall armyworm (Spodoptera frugiperda), luciferase was strongly expressed very late in infection (48-72 h). The bacterial luciferase assay was sufficiently sensitive that light production could be detected from an extract of a single cell. In addition, live insects, including the cabbage looper (Trichoplusia ni) and saltmarsh caterpillar (Estigmene acrea) were infected by mixing recombinant baculovirus into their diet. Cabbage loopers (with an average wet weight of 223 mg) produced at least 195 micrograms of active luciferase and levels of synthesis peaked between 96-120 h. The results indicate that bacterial luciferase may be used as a reporter of gene expression in insects.

[Experimental paratuberculosis in sheep after intravenous or oral inoculation: pathogenicity and biologic diagnosis]. / Paratuberculose expérimentale chez le mouton après inoculation par voie veineuse ou par voie orale: pouvoir pathogène et diagnostic biologique.

An experimental paratuberculosis study was performed in sheep. One group of 6 lambs was inoculated intravenously with the equivalent of 50 mg (wet weight) of live bacilli, another group of 6 lambs was inoculated orally by placing 500 mg (wet weight) of live organisms in milk feed and a group of 3 lambs was used as controls. The degree of cellular immunity was followed by examining delayed hypersensitivity using 3 allergens (bovine tuberculin PPD, avian tuberculin PPD and johnine PPD) and that of humoral immunity using complement fixation test, agar gel immunodiffusion test and ELISA. The elimination of bacilli in the faeces was examined simultaneously. After 2 years no macroscopic or microscopic lesion was observed in intravenously inoculated lambs and in those exposed orally to M paratuberculosis; cultures were negative. It appears that domestic sheep were able to control the infection. Nevertheless, most of them developed cellular and humoral immunity against paratuberculosis antigen. The best results were obtained in intravenously inoculated lambs.

[Intratubal transfer of an embryo or a zygote. (TET or GIFT) Past, present and future? Comparative study of tubal embryo transfer (TET) versus in vitro fertilization]. / Le transfert intratubaire d'embryon ou de zygote (TET ou ZIFT). Passé, présent et avenir? Etude comparative tubal embryotransfer (TET) versus FIVETE.

The pregnancy rate per transfer does not appear to be increased if the embryos are placed in the Fallopian tube rather than using in-vitro fertilization or inserting the gametes into the tubule ampulla. Consequently, the indications are specific to particular cases.