King Center

During spermatogenesis, the unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI) and form a heterochromatic XY body. Defects in MSCI lead to meiotic arrest and male infertility. Although DNA damage response (DDR) factors are established as key initiators of MSCI, how transcriptional silencing is subsequently achieved remains elusive. Here, we identify the nucleolar components NPM1, SENP3, and rRNA as essential downstream effectors of DDR signaling in MSCI. During pachytene, these components migrate to and transiently cover the XY body during MSCI establishment, before becoming restricted to a corner of the XY body. Genetic deletion of Npm1 or Senp3, or inhibition of rRNA transcription severely impairs MSCI. Mechanistically, SENP3-mediated deSUMOylation of NPM1 promotes its interaction with rRNA, enabling liquid-liquid phase separation, via which they exclude Pol II from the XY body. Together, these data reveal a critical role of nucleolar components in the transcriptional regulation of MSCI in mammalian spermatogenesis.

The germ cell fate in zebrafish is determined by germ plasm, whereas mammalian germ cell fate is induced by bone morphogenetic protein (BMP) signaling. It remains elusive whether BMP signaling is implicated in zebrafish germ cell development. Here, we demonstrate that BMP-Smad1/9 signaling plays a critical role in zebrafish primordial germ cell (PGC) maintenance rather than fate determination. BMP inhibition or smad1/9 knockdown reduces PGC numbers. Furthermore, we generated PGC-specific smad1/9 knockouts using a transgenic approach with PGC-specifically expressed Cas9 and ubiquitously expressed guide RNAs. Smad1/9 deficiency in PGCs leads to impaired PGC proliferation and increased apoptosis, consequently reducing PGC numbers. Transcriptome analysis revealed unchanged PGC-specific gene expression, but a marked upregulation of DNA damage response-related genes, which is validated by ectopic ATR-pChk1 activation in PGCs and PGC restoring by ATR inhibition. Collectively, these findings underscore conserved but functionally distinct roles of BMP signaling in vertebrate PGC development.

Historia Polskiej Rzeczypospolitej Ludowej (PRL) stanowi jeden z najbardziej istotnych, a zarazem najbardziej kontrowersyjnych obszarów polskiej historiografii. Od lat 70. i 80. XX w., w kontekście cyklicznych kryzysów politycznych i gospodarczych, część badaczy zaczęła podważać obowiązujące paradygmaty badawcze, starając się dotrzeć do tzw. prawdy. Równolegle historycy związani z ówczesnym reżimem kładli nacisk na osiągnięcia socjalistycznej Polski, odpowiadając na krytykę płynącą ze środowiska naukowego. Choć pod koniec lat 80. PRL formalnie zakończyła swoje istnienie, zainteresowanie tym okresem nie osłabło – wręcz przeciwnie, debaty historyczne zaczęły koncentrować się wokół zagadnień niepodległości, modernizacji oraz „prawdziwej Polski”. Artykuł analizuje przemiany w pisarstwie historycznym dotyczącym PRL w okresie transformacji ustrojowej i ukazuje je jako wyraz zmian strukturalnych i ducha epoki, formę zaangażowania politycznego badaczy oraz przestrzeń ścierania się pamięci zbiorowej i emocji osobistych.

SummaryBackgroundAccess to modern family planning impacts women's health, education, and economic well-being. Persistent barriers to accessing long-acting methods, such as price and lack of information, limit adoption. This study highlights the potential of a novel payment and incentive structure for pharmacies, a key access point for contraceptives for young women in particular, to improve access to subcutaneous depot medroxyprogesterone acetate (DMPA-SC). By targeting incentives to either patients or providers through a low-cost digital tool, the intervention aims to enhance contraceptive choice cost-effectively with potential for scale.MethodsWe randomized 137 pharmacies in Kenya into three intervention arms, varying patient copay, pharmacy profit, or pharmacy cost to stock DMPA-SC, plus a status quo control group that conducted pharmacy operations as usual. All pharmacies used an app-based platform for sales and inventory tracking, and a digital tool to manage family planning sales, through which client discounts for DMPA-SC, pharmacy cost to stock DMPA-SC, or pharmacy profit for DMPA-SC were experimentally varied in the intervention arms. We used double/debiased machine learning for adjusted models, with the primary outcome being uptake of DMPA-SC, and secondary outcomes being couple-years of protection, and an analysis of price and information mechanisms.FindingsWe analyzed data from 26,883 family planning visits (C = 7605, T1 = 7774, T2 = 5009, T3 = 6495) between August 2022 and May 2023. Providing consumer discounts and provider incentives through a pharmacy-facing intervention increases adoption of DMPA-SC by 14 percentage points (control mean: 0.03), while decreasing use of short-acting methods by 13 percentage points (control mean: 0.92), compared to a control group. Interventions alleviated both price and information barriers to access through a 100% price pass through in the consumer discount arm and an increase in comprehensive counseling by 68 percentage points in the provider-side arms, all compared to the status quo control group. Targeted incentives increase couple-years of protection (CYP) for $2.56–$12.50 per CYP.InterpretationPharmacy-based interventions that reduce price and information barriers of DMPA-SC can expand women's contraceptive options, with implications for choosing longer-acting methods. Pharmacies are crucial access points for family planning in Kenya and globally. Understanding how pharmacy-specific interventions influence access to modern methods can generate evidence on this understudied and important care setting.FundingThis study was funded by the 10.13039/100010409Children's Investment Fund Foundation and The Weiss Fund for Research in Development Economics at the University of Chicago. This study was prospectively registered with the AEA registry for randomized controlled trials (AEARCTR-0009020) and is registered with the Pan-African Clinical Trials Network (PACTR202506634961987).

<title>Abstract</title> The dorsal organizer, essential for vertebrate embryonic axis formation, is induced by microtubule-mediated transport of maternal determinants. Maternal Huluwa (Hwa) has been identified as an essential organizer inducer in zebrafish and frogs, functioning at midblastula stages to activate β-catenin signaling in the preorganizer. It remains unknown if maternal Hwa functions at or before fertilization. Here, we report that maternal Hwa protein is critical for organizing the vegetal parallel microtubule array immediately after fertilization in zebrafish. Hwa protein and mRNA are enriched at the vegetal pole and facilitate microtubule network formation, enabling asymmetrical transport of dorsal determinants. Loss of maternal Hwa disrupts this microtubule architecture and abrogates mRNA transport, revealing a self-reinforcing mechanism where Hwa regulates its own asymmetrical distribution. Our findings establish a dual-phase model of dorsal specification: Hwa initially governs symmetry breaking through postfertilization microtubule organization and later on activates β-catenin signaling at blastula stages. This work provides fundamental insights into how the key maternal factor regulates the organizer and body axis formation at different developmental stages.

The mammalian brain contains diverse neuronal and immune cell types that exhibit dynamic motions in response to distinct extracellular environments. However, technical limitations make it difficult to investigate complex cellular motions in the developing brain in vivo. Here, we establish the intravital imaging of externally immobilized embryos (IMEE) method for long-term, large-field, and deep-depth imaging of mouse embryos, excelling in viewing angle flexibility, procedural simplicity, and functional applicability. Through combining IMEE with in utero retro-orbital injection and topological analysis of vector fields, we characterize distinct neuronal migration patterns and illustrate interactions among neurons, immune cells, and vasculature under physiological conditions and environmental stress during brain development. Our results suggest that neuronal migration guidance and immune surveillance depend on cellular adaptation to the local environment through distinct motion patterns of somata or processes. Our findings provide critical insight into the environmentally adaptive nature of neural cells in the developmental landscape.

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