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Abstract The medaka (Oryzias latipes) egg envelope (chorion) is composed of three major glycoproteins, Zona Interna (ZI)-1, -2, and -3, that originate in the spawning female liver as the precursor proteins Choriogenin (Chg.)H, Chg.Hm, and Chg.L, respectively. These ZI and Chg. proteins contain a structural ZP protein domain that is conserved among the egg envelope proteins of all animals. While ovarian expression of ZP proteins (e.g., ZPCs and ZPB) has been reported in medakas, the functions of these proteins remain unknown. Thus, the present study aimed to determine whether the ovary-expressed medaka ZP protein, mZPC5, is involved in forming the chorion matrix. The mZPC5 gene (mzpc5) was expressed in the ovaries but not the livers of mature female medakas, as shown by reverse transcription-polymerase chain reaction assays with mzpc5-specific primers. In situ hybridization analysis revealed that ovarian mzpc5 expression was restricted to the ooplasm of early (stage I–III) previtellogenic oocytes, and its expression signal weakened with oocyte growth. Following sodium-dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis with anti-mZPC5 antibodies, two immunoreactive proteins were detected in the ovary and chorion extracts. These proteins were approximately 50 and 74 kDa in size, like ZI-3 and ZI-2, respectively. Immunohistochemical assays using anti-mZPC5 and anti-Chg.H antibodies localized the mZPC5 protein in the ooplasm of early previtellogenic oocytes. With oocyte growth, mZPC5 tended to accumulate in the chorion, co-localizing with Chg.H. We previously showed that ovary-expressed ZP proteins could not compensate for Chg.L function loss in gene knock-out (chg.l -/-) medakas. As in our previous study, the chg.l-/- females produced oocytes with thin chorions, resulting in infertile soft eggs. However, in the present study, mZPC5 and Chg.H were co-localized in the chg.l-/- chorions. These results suggested that in the medaka previtellogenic oocyte, 1) mZPC5 is secreted from the ooplasm and deposited on the outer surface of its plasma membrane, creating the thin chorion layer; and 2) following the accumulation of liver-derived Chgs., the 3D structure of the chorion matrix is formed cooperatively with mZPC5 and Chgs. during oogenesis. More research is needed to confirm the functions of mZPC5 in chorion structure and physiology.

The report is a summary of the History of Science Society Annual Meeting in 2023, which focused on the theme of "Shifting Standards, Creating Change." The meeting explored social justice work in response to global humanitarian crises and the Black Lives Matter movement. It featured panels and papers on topics such as the history of science, restorative projects, and diversity in the field. The report also highlights the winners of the HSS Prizes for 2023, which recognized outstanding contributions to the history of science. The award-winning books and essays cover a range of topics, including early modern European thought on extinction, the use of fish to combat malaria in colonial India, nonbinary gender, the relationship between humans and the sky, and the history of quantification. These works provide valuable insights into the intersections of science, culture, and society throughout history. [Extracted from the article]

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Common preclinical models for testing anticancer treatment include cultured human tumor cell lines in monolayer, and xenografts derived from these cell lines in immunodeficient mice. Our goal was to determine how similar the xenografts are compared with their original cell line and to determine whether it is possible to predict the stability of a xenograft model beforehand. We studied a selection of 89 protein markers of interest in 14 human cell cultures and respective subcutaneous xenografts using the reverse-phase protein array technology. We specifically focused on proteins and posttranslational modifications involved in DNA repair, PI3K pathway, apoptosis, tyrosine kinase signaling, stress, cell cycle, MAPK/ERK signaling, SAPK/JNK signaling, NFκB signaling, and adhesion/cytoskeleton. Using hierarchical clustering, most cell culture-xenograft pairs cluster together, suggesting a global conservation of protein signature. Particularly, Akt, NFkB, EGFR, and Vimentin showed very stable protein expression and phosphorylation levels highlighting that 4 of 10 pathways were highly correlated whatever the model. Other proteins were heterogeneously conserved depending on the cell line. Finally, cell line models with low Akt pathway activation and low levels of Vimentin gave rise to more reliable xenograft models. These results may be useful for the extrapolation of cell culture experiments to in vivo models in novel targeted drug discovery.

Abstract Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS‐mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple‐Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS‐mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.

La production bovine allaitante européenne est surtout développée dans les zones herbagères plutôt défavorisées où peu d’alternatives existent. C’est le cas en France dans le Massif central, mais aussi en Espagne où elle s’est beaucoup accrue dans les montagnes sèches et au Royaume-Uni dans les collines d’Ecosse. Dans un contexte d’évolution à la hausse du coût des intrants et de stagnation des prix à la production, des stratégies bien différenciées depuis 2003/2005 ont été mises en évidence. En France et au Royaume-Uni, les éleveurs ont privilégié l’augmentation de la productivité de la main-d’œuvre. Cela s’est fait avec peu de conséquences sur les performances techniques, mais surtout en mobilisant davantage d’équipements et de mécanisation. Ces investissements, essentiellement en France, se sont souvent accompagnés d’endettement. A l’inverse en Espagne et en Irlande, les éleveurs ont moins modifié leurs dispositifs de production et ont eu une conduite économe en particulier sur le plan des investissements. Les politiques incitatives de soutien sont différentes : les primes à la vache allaitante demeurent en France et en Espagne alors que seules les primes à la surface existent au Royaume-Uni. Dans cet espace européen avec des conditions pédoclimatiques extrêmement différentes, des structures de taille et de niveaux d’investissements divers, quels que soient les stratégies choisies par les pays, les revenus nets moyens des éleveurs restent autour de 15 k€ par Unité de Travail Familial avec des différences qui se réduisent entre pays. Ces revenus restent inférieurs à ceux des autres productions agricoles.

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of “palliative” RT (10 × 3 Gy) or “radical” RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the “palliative” protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the “radical” protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial).

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L’augmentation de la demande mondiale pour les protéines végétales animales à destination de l’alimentation humaine est une véritable opportunité pour la production bovine. En France, les niveaux d’autonomie massique, protéique et énergétique varient d’un système de production laitière à l’autre mais restent plutôt un niveau élevé (88 %, 77 % et 87 % respectivement). Ces niveaux élevés d’autonomie sont fortement impacté par un lien important avec le sol de l’élevage français. Cependant, des voies d’amélioration restent possibles comme l’utilisation de toute l’herbe disponible, en utilisant les ressources de protéines locales (coproduits) et en intégrant les légumineuses dans les rotations de cultures.

Le terme « innovation » est largement utilisé, notamment dans le domaine de la recherche. L’innovation se démarque de l’invention, processus en amont, et se caractérise par différentes modalités de mise en place de quelque chose de nouveau dans un système existant. Les sources de l’innovation peuvent être exogènes à la structure qui innove, ou bien endogènes dans le cas où l’innovation est initiée par celui qui pilote la structure (ici les exploitations agricoles). En agriculture, et en élevage en particulier, les innovations organisationnelles (faire autrement avec les mêmes choses) sont aussi importantes que les innovations technologiques (utiliser un objet nouveau ou un ancien objet modifié), notamment quand les animaux (en tant qu’êtres vivants) sont directement en jeu. Le type d’innovation considéré, ainsi que le degré et la nature du changement qui lui sont associés, sont essentiels dans la compréhension des processus d’innovation. De même, les facteurs favorables ou, au contraire, défavorables à ce processus, doivent être identifiés afin d’y contribuer efficacement en tant que chercheurs. Des exemples pris dans le domaine de l’élevage, en France ou ailleurs dans le monde, illustrent les différentes notions liées à l’innovation, tout au long du texte.

Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5′-end to facilitate its cellular uptake. We report here the preclinical pharmacokinetic and toxicology studies of subcutaneous coDbait administration in rodents and monkeys. Maximum plasma concentration occurred between 2 to 4 hours in rats and at 4 hours in monkeys. Increase in mean AUC0–24h was linear with dose reaching 0.5 mg·h/ml for the highest dose injected (32 mg) for both rats and monkeys. No sex-related differences in maximum concentration (Cmax) nor AUC0–24h were observed. We extrapolated these pharmacokinetic results to humans as the subcutaneous route has been selected for evaluation in clinical trials. Tri-weekly administration of coDbait (from 8 to 32 mg per dose) for 4 weeks was overall well tolerated in rats and monkeys as no morbidity/mortality nor changes in clinical chemistry and histopathology parameters considered to be adverse effects have been observed.

Prolonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet.The effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)), ubiquinone 10 (Ub(10)) and decyl-ubiquinone (DUb) were studied in freshly isolated rat hepatocytes, cultured rat liver Clone-9 cells and cancerous rat liver MH1C1 cells. PTP regulation by ubiquinones differed significantly in permeabilized Clone-9 and MH1C1 cells from that previously reported in liver mitochondria. Ub(0) inhibited PTP opening in isolated hepatocytes and Clone-9 cells, whereas it induced PTP opening in MH1C1 cells. Ub(5) did not affect PTP opening in isolated hepatocytes and MH1C1 cells, but it induced PTP opening in Clone-9 cells. Ub(10) regulated PTP in isolated hepatocytes, whereas it did not affect PTP opening in Clone-9 and MH1C1 cells. Only DUb displayed the same effect on PTP regulation in the three hepatocyte lines tested. Despite such modifications in PTP regulation, competition between ubiquinones still occurred in Clone-9 and MH1C1 cells. As expected, Ub(5) induced a PTP-dependent cell death in Clone-9, while it did not affect MH1C1 cell viability. Ub(0) induced a PTP-dependent cell death in MH1C1 cells, but was also slightly cytotoxic in Clone-9 by an oxidative stress-dependent mechanism.We found that various ubiquinone analogs regulate PTP in different ways depending on the cell studied. We took advantage of this unique property to develop a PTP opening-targeted strategy that leads to cell death specifically in cells where the ubiquinone analog used induces PTP opening, while sparing the cells in which it does not induce PTP opening.

Les pratiques de conduite du troupeau (femelles et produits) et de commercialisation des animaux ont été étudiées dans 21 élevages Charolais spécialisés en production de viande bovine. Il s’agissait de tester l’hypothèse selon laquelle certains éleveurs orientent leur système de production dans l’objectif de maximiser le nombre d’animaux vendus dans les filières qualité, par rapport à d’autres pour lesquels les priorités sont différentes (simplification de la conduite). Deux échantillons d’éleveurs ont été constitués selon ces deux catégories à partir d’enquêtes auprès de 4 groupements de producteurs. Trois types de résultats ressortent de l’étude: 1) les groupements ont discriminé les deux échantillons d’abord en fonction des effectifs et de la proportion d’a nimaux transitant effectivement par eux, et non en fonction du nombre d’animaux vendus dans les filières qualité , 2) le nombre d’animaux vendus dans les filières qualité ne suffit pas à rendre compte de la capacité des éleveurs à produire des animaux conformes aux cahiers des charges de ces filières, une grande partie de ceux-ci pouvant être valorisés autrement (notamment via des bouchers), 3) les éleveurs les plus impliqués dans les filières qualité n’ont pas forcément adopté des pratiques spécifiques, notamment une gestion plus minutieuse, plus ’à l’individu’ que les autres. Par contre, ils délèguent beaucoup plus la fonction de commercialisation à la structure d’aval, quitte à une moindre valorisation de chaque animal pris individuellement. Une autre classification des éleveurs combinant à la fois les pratiques et l’implication dans les filières qualité est alors proposée et discutée, plus complexe que celle correspondant à l’hypothèse de départ (5 groupes distincts).

Medieval Monstrosity and the Female Body. By SARAH ALISON MILLER. New York: Routledge, 2010. Pp. 213. $133.00 (cloth). Sarah Alison Miller's study of medieval women and monsters--those violators of natural [...]

Copyright of Gériatrie et Psychologie Neuropsychiatrie du Vieillissement is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma.Methods: Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg.Results: The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%).Conclusions: Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01. [ABSTRACT FROM AUTHOR]

Anti-cancer drugs often increase reactive oxygen species ( ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2 AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD-/Nrf2-antioxidant response, reduces H2 AX protein levels. This effect is mediated by an enhanced interaction of H2 AX with the E3 ubiquitin ligase RNF168, which is associated with H2 AX poly-ubiquitination and promotes its degradation by the proteasome. ROS-mediated H2 AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2 AX protein levels in Triple-Negative breast cancer ( TNBC) patients. H2 AX decrease by such treatment is associated with an impaired NRF2-antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS-mediated regulation of H2 AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients. [ABSTRACT FROM AUTHOR]

Beef cow-calf farming systems are assumed to be resilient to biological disturbances that induce variations in herd demography; however, this hypothesis has not been fully investigated to date. Modeling is an interesting approach to study fanning system resilience and to evaluate the impact of biologi-cal disturbances, taking into account interactions between system components, including biological variability and management practices. Our objective was to evaluate the resilience of beef cow-calf fanning systems to varia-tions in fertility and mortality using a modeling approach. We studied the direct effect of variations in demographic parameters on production objectives without explicitly representing the causes of the variations. We developed a stochastic model to represent the population dynamics of a beef cow-calf herd with breeding by natural service and biological processes occurring at the animal level. The model was validated by comparing observed and simulat-ed distributions of the calving-to-calving interval, which were found to be consistent. Resistance was evaluated by the proportion of simulations where the objective in terms of number of weaned calves is reached even when there is a disturbance that persists for 10 yr. Reversibility was evaluated by the time needed to return to the predistur-bance production level. Beef cow-calf farming systems did not appear to be resistant to variations in mortality and infertility rates except when increases in the infertil-ity rates were low (0.02 for cows and 0.03 for heifers). Critical situations, consequently, may emerge with regard to farm production if management practices are not adapted. Reversibility was observed for disturbances that persist for up to 5 yr. However, the system needed 2 to 3 yr to recover its predisturbance production level and up to 4 yr after an increase in cow infertility of 0.12. [ABSTRACT FROM AUTHOR]

Abstract: First carpometacarpal osteoarthitis is frequent and surgery may be necessary if medical treatment is not efficient. Trapeziometacarpal arthroplasty, trapeziometacarpal arthrodesis and trapezectomy may be proposed. These surgical solutions may modify the carpometacarpal kinematics of the thumb. However, no clinical tools are currently available to assess these modifications. The goal of our study is to assess the TM kinematics, with an optoelectronic system, in patients after trapezectomy. Ten women, average age 53 (range 45 to 67) underwent trapezectomy with ligamentoplasty for trapeziometacarpal osteoarthritis. An optoelectronic device (Polaris®) was used to analyse postoperative range–of–motion of the thumb. Splints were used in order to isolate the trapeziometacarpal joint and retroreflective markers were placed both on the splints and on the thumb. Mean flexion–extension, abduction–adduction, axial rotation and circumduction were calculated. Results: The mean range–of–motion of trapeziometacarpal joint was 50 degrees for flexion–extension, 47 degrees for abduction–adduction and 11 degrees for axial rotation. The mean angle between rotation axes was 90 degrees and the mean distance d between the axes was 3 millimeters. Comparisons between patients and healthy subjects showed no significant differences in flexion–extension, abduction–adduction and axial rotation. Circumduction in patients was reduced compared to healthy subjects. No significant differences were noted between the operated side and the contralateral side. Discussion and conclusion: Our study showed that this protocol can be used in the postoperative follow-up of patients after trapezectomy. We did not find any significant differences compared to the contralateral side. However, circumduction after trapezectomy was reduced compared to healthy subjects. [Copyright &y& Elsevier]

Background: Prolonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet. Methodology/Principal Findings: The effects of ubiquinone 0 (Ub0), ubiquinone 5 (Ub5), ubiquinone 10 (Ub10) and decylubiquinone (DUb) were studied in freshly isolated rat hepatocytes, cultured rat liver Clone-9 cells and cancerous rat liver MH1C1 cells. PTP regulation by ubiquinones differed significantly in permeabilized Clone-9 and MH1C1 cells from that previously reported in liver mitochondria. Ub0 inhibited PTP opening in isolated hepatocytes and Clone-9 cells, whereas it induced PTP opening in MH1C1 cells. Ub5 did not affect PTP opening in isolated hepatocytes and MH1C1 cells, but it induced PTP opening in Clone-9 cells. Ub10 regulated PTP in isolated hepatocytes, whereas it did not affect PTP opening in Clone-9 and MH1C1 cells. Only DUb displayed the same effect on PTP regulation in the three hepatocyte lines tested. Despite such modifications in PTP regulation, competition between ubiquinones still occurred in Clone-9 and MH1C1 cells. As expected, Ub5 induced a PTP-dependent cell death in Clone-9, while it did not affect MH1C1 cell viability. Ub0 induced a PTP-dependent cell death in MH1C1 cells, but was also slightly cytotoxic in Clone-9 by an oxidative stress-dependent mechanism. Conclusions/Significance: We found that various ubiquinone analogs regulate PTP in different ways depending on the cell studied. We took advantage of this unique property to develop a PTP opening-targeted strategy that leads to cell death specifically in cells where the ubiquinone analog used induces PTP opening, while sparing the cells in which it does not induce PTP opening. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The range-of-motion of the trapeziometacarpal joint is difficult to assess clinically. The purpose of our study was to constitute a range-of-motion database from normal active trapeziometacarpal joints. Material and methods: Two hundred hands from 101 healthy subjects (50 female and 51 male) with a mean age of 23.1 years (range: 22 to 35 years) have been evaluated. An optoelectronic device (Polaris®) was used to analyse the thumbs range-of-motion. Splints were fitted so as to isolate the trapeziometacarpal joint and retroreflective markers were placed both on the splints and on the thumb. After active flexion–extension, abduction–adduction, axial rotation and circumduction, the different range-of-motion parameters were calculated. Results: The mean range-of-motion of the trapeziometacarpal joint was 41° for flexion–extension, 51° for abduction–adduction and 21° for axial rotation. Comparisons between female and male subjects showed significant differences concerning flexion–extension, abduction–adduction axial rotation and circumduction. No significant differences were noted between right and left hands except for the abduction–adduction movement. Discussion and conclusion: One hundred and one healthy subjects were analysed for the development of a database of normal active range-of-motion parameters of the trapeziometacarpal joint, with an in vivo protocol. This database should allow comparing the range-of-motion of patients with osteoarthritic trapeziometacarpal joint and assessing surgical outcome. [Copyright &y& Elsevier]