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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).