BepiColombo mission confirms stagnation region of Venus and reveals its large extent.

The second Venus flyby of the BepiColombo mission offer a unique opportunity to make a complete tour of one of the few gas-dynamics dominated interaction regions between the supersonic solar wind and a Solar System object. The spacecraft pass through the full Venusian magnetosheath following the plasma streamlines, and cross the subsolar stagnation region during very stable solar wind conditions as observed upstream by the neighboring Solar Orbiter mission. These rare multipoint synergistic observations and stable conditions experimentally confirm what was previously predicted for the barely-explored stagnation region close to solar minimum. Here, we show that this region has a large extend, up to an altitude of 1900 km, and the estimated low energy transfer near the subsolar point confirm that the atmosphere of Venus, despite being non-magnetized and less conductive due to lower ultraviolet flux at solar minimum, is capable of withstanding the solar wind under low dynamic pressure.

[SAMHD1 acts at stalled replication forks to prevent interferon induction]. / SAMHD1 agit sur les fourches de réplication bloquées pour empêcher l'induction d'interféron.

DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are frequently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. This slowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutières syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not been characterized. SAMHD1 is frequently mutated in the Aicardi-Goutières syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutières syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy.

La réplication de l'ADN est un processus extrêmement complexe, impliquant des milliers de fourches de réplication progressant le long des chromosomes. Ces fourches sont fréquemment ralenties ou arrêtées par différents obstacles, tels que des structures secondaires de l'ADN, des protéines agissant sur la chromatine ou encore un manque de nucléotides. Ce ralentissement, qualifié de stress réplicatif, joue un rôle central dans le développement tumoral. Des processus complexes, qui ne sont pas encore totalement connus, sont mis en place pour répondre à ce stress. Certaines nucléases, comme MRE11 et DNA2, dégradent l'ADN néorépliqué au niveau des fourches bloquées, ce qui permet le redémarrage des réplisomes. La voie interféron est un mécanisme de défense contre les agents pathogènes qui détecte la présence d'acides nucléiques étrangers dans le cytoplasme et active la réponse immunitaire innée. Des fragments d'ADN issus du métabolisme de l'ADN génomique (réparation, rétrotransposition) peuvent diffuser dans le cytoplasme et activer cette voie. Une manifestation pathologique de ce processus est le syndrome d'Aicardi-Goutières, une maladie rare caractérisée par une inflammation chronique générant des problèmes neurodégénératifs et développementaux. Dans le cadre de cette encéphalopathie, il a été suggéré que la réplication de l'ADN pouvait générer des fragments d'ADN cytosoliques, mais les mécanismes impliqués n'avaient pas été caractérisés. SAMHD1 est fréquemment muté dans le syndrome d'Aicardi-Goutières ainsi que dans certains cancers, mais son rôle dans l'étiologie de ces maladies était jusqu'à présent largement inconnu. Nous montrons que de l'ADN cytosolique s'accumule dans les cellules déficientes pour SAMHD1, particulièrement en présence de stress réplicatif, activant la réponse interféron. Par ailleurs, SAMHD1 est important pour la réplication de l'ADN en conditions normales et pour le processing des fourches arrêtées, indépendamment de son activité dNTPase. De plus, SAMHD1 stimule l'activité exonucléase de MRE11 in vitro. Lorsque SAMHD1 est absent, la dégradation de l'ADN néosynthétisé est inhibée, ce qui empêche l'activation du checkpoint de réplication et entraine un défaut de redémarrage des fourches de réplication. De plus, la résection des fourches de réplication est réalisée par un mécanisme alternatif qui libère des fragments d'ADN dans le cytosol, activant la réponse interféron. Les résultats obtenus montrent, pour la première fois, un lien direct entre la réponse au stress réplicatif et la production d'interférons. Ces résultats ont des conséquences importantes dans notre compréhension du syndrome d'Aicardi Goutières et des cancers liés à SAMHD1. Par exemple, nous avons démontré que MRE11 et RECQ1 sont responsables de la production des fragments d'ADN qui déclenchent la réponse inflammatoire dans les cellules déficientes pour SAMHD1. Nous pouvons donc imaginer que bloquer l'activité de ces enzymes pourrait diminuer la production des fragments d'ADN et, in fine, l'activation de l'immunité innée dans ces cellules. Par ailleurs, la voie interférons joue un rôle essentiel dans l'efficacité thérapeutique de l'irradiation et de certains agents chimiothérapiques comme l'oxaliplatine. Moduler cette réponse pourrait donc avoir un intérêt beaucoup plus large en thérapie anti-tumorale.

Breakthrough behavior of 17.5 mol% water in methanol, ethanol, isopropanol, and t-butanol vapors passed over corn grits.

Ground corn is now used in industry as an adsorbent to remove water from ethanol vapors. It is stable and inexpensive at 10 cents/lb (22 cents/kg). For regeneration it requires less than 2000 Btu/gal of 190 proof ethanol processed. If necessary, it could be readily saccharified and fermented into ethanol after use. This renewable resource has further exciting potential as an inexpensive adsorbent for water removal from other alcohols, including methanol, isopropanol, and t-butanol. Water sorption capacity in a fixed bed, nonisothermal adsorption column appears to be a function of the heat capacity of the non-adsorbed alcohol vapor, relative to the heat capacity of the corn adsorbent. Methanol, ethanol, isopropanol, and t-butanol containing 17.5 mol% water gave 105,151, 284, and 358 g anhydrous product/kg adsorbent, respectively, per adsorption cycle. This adsorbent, having operational temperature ranges between 80 and 100 degrees C, is indicated to be of potential utility in solvent recycle processes using these industrially important alcohols. Observed adsorption characteristics are discussed in terms of the alcohol properties of molecular size, heat capacity, and diffusivity. The adsorption mechanism is hypothesized to include transport of water molecules into the structure of adjacent starch molecules present in small spherical bodies (diameter of several microns) immobilized on the surface of the corn grit particles.

Analysis of telomerase expression and proliferative activity in the different layers of cyclic endometrium.

To gain better insights into cell kinetics under physiological conditions, telomerase activity in the functional and basal layers of cyclic endometrium (n = 33) was compared with the immunostaining of glandular and stromal cells within these layers (n = 25). Two immunohistochemical proliferation markers were used to demarcate cells in the G1 phase of the cell cycle. In contrast to previous expectations, telomerase activity and both glandular and stromal proliferative activities were all significantly higher in the functional than in the basal endometrium (P < 0.002). The course of telomerase activity in the endometrial layers during the ovarian cycle was significantly associated with the proliferative scores for the functional and basal endometrial glands and the functional stroma but not the stromal compartment of the basal layer. Our findings indicate that the telomerase activity in cyclic endometrium is associated with the total number of proliferating glandular and stromal cells in the functional layer. Proliferating daughter cells of telomerase-competent stem cells may account for the lower levels of telomerase detected in normal basal endometrium.

The dose-range effects of sufentanil added to 0.125% bupivacaine on the quality of patient-controlled epidural analgesia during labor.

UNLABELLED: To determine the minimal sufentanil concentration required to improve the quality of patient-controlled epidural analgesia during labor, we compared the efficacy of a combination of 0.125% bupivacaine with 1:800,000 epinephrine and different concentrations of sufentanil in a double-blinded randomized study. Concentrations were no sufentanil (n = 66), 0.078 microg/mL sufentanil (n = 65), 0.156 microg/mL sufentanil (n = 65), 0.312 microg/mL sufentanil (n = 65), and 0.468 microg/mL sufentanil (n = 67). The patient-controlled epidural analgesia setting was a 12-mL bolus dose and a 25-min lockout interval. Pain was scored at 5-6 cm, 7-8 cm, and full cervical dilation by using a 10-cm visual analog scale. At full cervical dilation, the pain scores were lower in the groups receiving a solution of at least 0.156 microg/mL sufentanil. Few differences were observed when using the larger concentrations, except for increased pruritus intensity. The duration of labor and the mode of delivery were similar in each group. Rescue analgesia, which consisted of 6 mL of 0.25% bupivacaine, was infrequent and comparable between groups. The use of the pump did not differ between groups. Adding a small concentration of sufentanil to 0.125% bupivacaine for patient-controlled epidural analgesia during labor improved the quality of analgesia but did not modify the bupivacaine requirement. Reducing the sufentanil concentrations to 0.156 microg/mL decreased the pruritus intensity without reducing analgesia. IMPLICATIONS: Adding a small concentration of sufentanil to 0.125% bupivacaine for patient-controlled epidural analgesia during labor improved the quality of analgesia but did not modify the bupivacaine requirement. Reducing the sufentanil concentrations to 0.156 microg/mL decreased the pruritus intensity without reducing analgesia.

Patient-controlled epidural analgesia during labor: the effects of the increase in bolus and lockout interval.

UNLABELLED: Most studies use a bolus size of <6 mL of 0.125% bu- pivacaine for patient-controlled epidural analgesia (PCEA) during labor. In this double-blinded, randomized study, we compared the efficacy of a larger bolus injected via a PCEA pump to a conventional PCEA setting. By using a combination of 0.125% bupivacaine with 1:800,000 epinephrine and 0.625 microg/mL sufentanil, the first PCEA setting was typical (4 mL/8 min), whereas the other combined a 12-mL bolus dose and a 25-min lockout interval, i.e., similar maximal hourly dose. Rescue analgesia was provided with 6 mL of 0.25% bupivacaine. Patient satisfaction and pain were scored on verbal and visual analog scales. Data were analyzed from 103 parturients in the 12-mL/25-min group and 100 in the 4-mL/8-min group. In the 12-mL/25-min group, the median pain score on a 0- to 10-cm visual analog scale was lower at 6-cm cervical dilation (1 [range = 0-8] vs 3 [0-8]) and at delivery (1 [0-10] vs 2 [0-10]). Satisfaction was also better (70% vs 38% "excellent" opinions, at 6-cm cervical dilation). Use of the pump (ratio of successful and total demands) was high and similar in both groups. Rescue analgesia was comparable. Doses of analgesics were greater in the 12-mL/25-min group (hourly bupivacaine dose = 13.9 +/- 5.3 [mean+/- SD] vs 9.4 +/- 4.1 mg). No differences were noted between groups for the severity of hypotension, ephedrine requirement, outcome of the delivery, and Apgar scores. IMPLICATIONS: A patient-controlled epidural analgesia setting that allows a parturient to receive an increased analgesic dose improves satisfaction with patient-controlled epidural analgesia during labor.