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Spermatogonial stem cells regenerate and maintain spermatogenesis throughout life, making testis a good model for studying stem cell biology. The effects of chemotherapy on fertility have been well‐documented previously. This study investigates how busulfan, an alkylating agent that is often used for chemotherapeutic purposes, affects male fertility. Specifically, the role of the TGR5 pathway is investigated on spermatogonia homeostasis using in vivo, in vitro, and pharmacological methods. In vivo studies are performed using wild‐type and Tgr5‐deficient mouse models. The results clearly show that Tgr5 deficiency can facilitate restoration of the spermatogonia homeostasis and allow faster resurgence of germ cell lineage after exposure to busulfan. TGR5 modulates the expression of key genes of undifferentiated spermatogonia such as Gfra1 and Fgfr2. At the molecular level, the present data highlight molecular mechanisms underlying the interactions among the TGR5, GLIS2, and TP53 pathways in spermatogonia associated with germ cell apoptosis following busulfan exposure. This study makes a significant contribution to the literature because it shows that TGR5 plays key role on undifferentiated germ cell homeostasis and that modulating the TGR5 signaling pathway could be used as a potential therapeutic tool for fertility disorders. The present data show that TGR5 signaling interferes with GLIS2 and TP53 signaling pathways, which control stem cell renewal and survival, explaining its impacts on germ cells following injuries as illustrated using chemodrug exposures. The study makes a significant contribution to the literature because it shows that modulating the TGR5 signaling pathway could be used as a potential therapeutic tool for fertility disorders.

Membrane contact sites are functional nodes at which organelles reorganize metabolic pathways and adapt to changing cues. In Saccharomyces cerevisiae , the nuclear envelope subdomain surrounding the nucleolus, very plastic and prone to expansion, can establish contacts with the vacuole and be remodeled in response to various metabolic stresses. While using genotoxins with unrelated purposes, we serendipitously discovered a fully new remodeling event at this nuclear subdomain: the nuclear envelope partitions into its regular contact with the vacuole and a dramatic internalization within the nucleus. This leads to the nuclear engulfment of a globular, cytoplasmic portion. In spite of how we discovered it, the phenomenon is likely DNA damage-independent. We define lipids supporting negative curvature, such as phosphatidic acid and sterols, as bona fide drivers of this event. Mechanistically, we suggest that the engulfment of the cytoplasm triggers a suction phenomenon that enhances the docking of proton pump-containing vesicles with the vacuolar membrane, which we show matches a boost in autophagy. Thus, our findings unveil an unprecedented remodeling of the nucleolus-surrounding membranes with impact on metabolic adaptation.

Spermatogenesis is a process within the testis that leads to the production of spermatozoa. It is based on a population of spermatogonial stem cells, which have the capacity to self-renew and to differentiate throughout life to ensure the functions of reproduction are maintained. Male fertility disorders are responsible for half of the cases of infertility in couples worldwide. It is well known that cancer treatments are associated with reversible or irreversible fertility disorders. Busulfan (Bu) is an alkylating agent that significantly inhibits spermatogenesis. The present study relied on a combination of in vivo and in vitro approaches as well as RNAseq analysis to characterize the effects of Bu, in which mouse testes were used as a model. An in silico analysis revealed that many of the Bu-modulated genes are potentially regulated by the SIN3 Transcription Regulator Family Member A (SIN3A) and E2F Transcription Factor (E2F) families of transcription factors. The results demonstrate that the deregulated genes function in processes related to the cell cycle, DNA repair, and cell death mechanisms, including the Tumor Protein 53 (TP53) pathway. This reinforces the role of the TP53 signaling pathway as a major player in Bu effects. In addition, Bu altered the patterns of mRNA accumulation for various genes in undifferentiated spermatogonia. This work provides significant insight into the kinetics and impacts of busulfan, which could pave the way for developing strategies to minimize the impact of chemodrugs and, thus, could lead to germ cell lineage regeneration following anticancer treatments.

The Second Sex can be read as a compelling philosophical exploration of masculinity. Beauvoir proposes to understand masculinity as a situation. It is an impasse as men are stuck in a position where they seek recognition from women, but they construct women in such a way that the recognition women can give them is incomplete and unsatisfying. This understanding of masculinity is crucial for Beauvoir’s emancipatory agenda and suggests that men have nonaltruistic reasons to take part in feminist movements. Le Deuxième Sexe peut être lu comme une enquête philosophique convaincante sur la masculinité. Si Beauvoir propose de comprendre la masculinité comme une situation, cette dernière implique toutefois une impasse: les hommes recherchent la reconnaissance des femmes et, en même temps, construisent les femmes de manière telle que cette reconnaissance ne peut demeurer qu’incomplète, insatisfaisante. Cette compréhension de la masculinité est fondamentale dans le projet émancipateur de Beauvoir, et suggère que les hommes ont des raisons non altruistes de prendre part aux mouvements féministes.

Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.

The advent of BTK inhibitors has been transformative in the management of patients with chronic lymphocytic leukemia or other B-cell lymphoproliferative disorders. However, emergence of BTK or PLCG2 mutations lead to resistance to these compounds and are now a growing concern in clinical practice. Assessing BTK mutations is now becoming a priority to guide the therapeutic decision at further relapse. To this end, targeted next-generation sequencing (NGS) is a valid tool, but lack of sensitivity and the required time for delivering results remain major challenges. Digital PCR could be more sensitive but is also limited by the number of mutations that can be screened. We here overcame these challenges by multiplexing digital PCR (mdPCR) in three assays that can cover 96% of ibrutinib-resistant cases. We investigated a cohort of 28 patients progressing on ibrutinib and for whom NGS revealed BTK mutations (C481S, C481F and C481R) and/or PLCG2 R665W mutation. Overall, 49 mutations were detected by NGS and 68 by mdPCR. We found mdPCR to bemore sensitive than NGS, particularly at low allelic frequencies, making it more suitable for the detection and quantification of small mutated clones. Thus, mdPCR offers high sensitivity, is expected to be more rapid and cost-effective than NGS in detecting resistance mutations to improve the therapeutic choice at relapse after exposure to BTK inhibitors.

Peu de travaux traitent de la portée philosophique de l'œuvre autobiographique de Beauvoir. Il s'agira d'examiner le lien, propre à l'existentialisme, que Beauvoir établit entre la vie et la philosophie sous trois aspects : comme source documentaire pour comprendre ses essais et la position philosophique originale qu'elle y défend, mise en évidence du rapport réciproque entre la philosophie et la vie, sur les plans épistémique et pratique, enfin moyen de compenser les défauts inhérents à la philosophie lorsque celle-ci s'exprime en troisième personne – seul le témoignage littéraire permet de faire surgir un universel singulier capable de révéler par l'exemple la tension entre situation et liberté. Not many works deal with the philosophical import of Beauvoir's autobiographical work. We shall examine the link, specific to existentialism, which Beauvoir establishes between life and philosophy under three headings : as a documentary source to understand her essays and the original philosophical stand she takes therein, as a manifestation of the reciprocal relationship between philosophy and life, on the practical and epistemic planes, at last as a means to compensate for the flaws inherent in philosophy when it expresses itself in the third person – only a literary evidence is able to promote a singular universal end owed with the capacity to reveal, for instance, the tension between situation and freedom.

Peu de travaux traitent de la portée philosophique de l’œuvre autobiographique de Beauvoir. Il s’agira d’examiner le lien, propre à l’existentialisme, que Beauvoir établit entre la vie et la philosophie sous trois aspects : comme source documentaire pour comprendre ses essais et la position philosophique originale qu’elle y défend, mise en évidence du rapport réciproque entre la philosophie et la vie, sur les plans épistémique et pratique, enfin moyen de compenser les défauts inhérents à la philosophie lorsque celle-ci s’exprime en troisième personne – seul le témoignage littéraire permet de faire surgir un universel singulier capable de révéler par l’exemple la tension entre situation et liberté. Not many works deal with the philosophical import of Beauvoir’s autobiographical work. We shall examine the link, specific to existentialism, which Beauvoir establishes between life and philosophy under three headings : as a documentary source to understand her essays and the original philosophical stand she takes therein, as a manifestation of the reciprocal relationship between philosophy and life, on the practical and epistemic planes, at last as a means to compensate for the flaws inherent in philosophy when it expresses itself in the third person – only a literary evidence is able to promote a singular universal end owed with the capacity to reveal, for instance, the tension between situation and freedom.