Self-patterning of human stem cells into post-implantation lineages.

Investigating human development is a substantial scientific challenge due to the technical and ethical limitations of working with embryonic samples. In the face of these difficulties, stem cells have provided an alternative to experimentally model inaccessible stages of human development in vitro1-13. Here we show that human pluripotent stem cells can be triggered to self-organize into three-dimensional structures that recapitulate some key spatiotemporal events of early human post-implantation embryonic development. Our system reproducibly captures spontaneous differentiation and co-development of embryonic epiblast-like and extra-embryonic hypoblast-like lineages, establishes key signalling hubs with secreted modulators and undergoes symmetry breaking-like events. Single-cell transcriptomics confirms differentiation into diverse cell states of the perigastrulating human embryo14,15 without establishing placental cell types, including signatures of post-implantation epiblast, amniotic ectoderm, primitive streak, mesoderm, early extra-embryonic endoderm, as well as initial yolk sac induction. Collectively, our system captures key features of human embryonic development spanning from Carnegie stage16 4-7, offering a reproducible, tractable and scalable experimental platform to understand the basic cellular and molecular mechanisms that underlie human development, including new opportunities to dissect congenital pathologies with high throughput.

KDM6A/UTX promotes spermatogenic gene expression across generations and is not required for male fertility†.

Paternal chromatin undergoes extensive structural and epigenetic changes during mammalian spermatogenesis, producing sperm with an epigenome optimized for the transition to embryogenesis. Lysine demethylase 6a (KDM6A, also called UTX) promotes gene activation in part via demethylation of H3K27me3, a developmentally important repressive modification abundant throughout the epigenome of spermatogenic cells and sperm. We previously demonstrated increased cancer risk in genetically wild-type mice derived from a paternal germ line lacking Kdm6a (Kdm6a cKO), indicating a role for KDM6A in regulating heritable epigenetic states. However, the regulatory function of KDM6A during spermatogenesis is not known. Here, we show that Kdm6a is transiently expressed in spermatogenesis, with RNA and protein expression largely limited to late spermatogonia and early meiotic prophase. Kdm6a cKO males do not have defects in fertility or the overall progression of spermatogenesis. However, hundreds of genes are deregulated upon loss of Kdm6a in spermatogenic cells, with a strong bias toward downregulation coinciding with the time when Kdm6a is expressed. Misregulated genes encode factors involved in chromatin organization and regulation of repetitive elements, and a subset of these genes was persistently deregulated in the male germ line across two generations of offspring of Kdm6a cKO males. Genome-wide epigenetic profiling revealed broadening of H3K27me3 peaks in differentiating spermatogonia of Kdm6a cKO mice, suggesting that KDM6A demarcates H3K27me3 domains in the male germ line. Our findings highlight KDM6A as a transcriptional activator in the mammalian male germ line that is dispensable for spermatogenesis but important for safeguarding gene regulatory state intergenerationally.

A second wave of Notch signaling diversifies the intestinal secretory lineage.

The small intestine is well known for the function of its nutrient-absorbing enterocytes; yet equally critical for the maintenance of homeostasis is a diverse set of secretory cells, all of which are presumed to differentiate from the same intestinal stem cell. Despite major roles in intestinal function and health, understanding how the full spectrum of secretory cell types arises remains a longstanding challenge, largely due to their comparative rarity. Here, we investigate the fate specification of a rare and distinct population of small intestinal epithelial cells found in rats and humans but not mice: C FTR Hi gh E xpressers (CHEs). We use pseudotime trajectory analysis of single-cell RNA-seq data from rat intestinal jejunum to provide evidence that CHEs are specified along the secretory lineage and appear to employ a second wave of Notch-based signal transduction to distinguish these cells from other secretory cell types. We further validate the general order of transcription factors that direct these cells from unspecified progenitors within the crypt and experimentally demonstrate that Notch signaling is necessary to induce CHE fate both in vivo and in vitro . Our results suggest a model in which Notch is reactivated along the secretory lineage to specify the CHE population: a rare secretory cell type with putative functions in localized coordination of luminal pH and direct relevance to cystic fibrosis pathophysiology.

A rockslide-generated tsunami in a Greenland fjord rang Earth for 9 days.

Climate change is increasingly predisposing polar regions to large landslides. Tsunamigenic landslides have occurred recently in Greenland (Kalaallit Nunaat), but none have been reported from the eastern fjords. In September 2023, we detected the start of a 9-day-long, global 10.88-millihertz (92-second) monochromatic very-long-period (VLP) seismic signal, originating from East Greenland. In this study, we demonstrate how this event started with a glacial thinning-induced rock-ice avalanche of 25 × 106 cubic meters plunging into Dickson Fjord, triggering a 200-meter-high tsunami. Simulations show that the tsunami stabilized into a 7-meter-high long-duration seiche with a frequency (11.45 millihertz) and slow amplitude decay that were nearly identical to the seismic signal. An oscillating, fjord-transverse single force with a maximum amplitude of 5 × 1011 newtons reproduced the seismic amplitudes and their radiation pattern relative to the fjord, demonstrating how a seiche directly caused the 9-day-long seismic signal. Our findings highlight how climate change is causing cascading, hazardous feedbacks between the cryosphere, hydrosphere, and lithosphere.

A utilização do código de quick response no ensino da anatomia humana do aparelho locomotor / The use of quick response code in teaching musculoskeletal anatomy

O estudo da Anatomia Humana (AH) é parte integrante e de relevância inquestionável na graduação dos cursos da saúde. Com a constante redução na carga horária destinada à AH e diante dos debates sobre os novos métodos de ensino, o uso do código de quick response (código QR) se mostrou promissor. Nesse sentido, foi desenvolvido no Departamento de Anatomia da Universidade Estadual de Londrina (UEL) o processo de catalogação das estruturas anatômicas com o uso do código QR, sendo nosso objetivo relatar esta experiência. Neste processo, as estruturas dissecadas no Laboratório de Anatomia da UEL foram catalogadas com base em uma planilha contendo a correlação entre estruturas e números e, as informações de cada estrutura transcritas em um código QR através de um gerador eletrônico, sendo então impresso, plastificado e anexado à peça anatômica. As marcações foram realizadas por meio da sutura de etiquetas enumeradas. Dentro da discussão dos métodos alternativos de ensino há como exemplos a plastinação, a projeção em três dimensões e a prospecção. Em destaque neste relato, o uso do código QR mostrou-se como uma alternativa válida na agregação de conhecimento nos currículos acadêmicos. Por meio das atividades empreendidas no processo de catalogação, foi possível, além da aquisição de mais tempo dedicado ao conhecimento teórico-prático em AH, ampliar a independência no estudo e no desenvolvimento de pesquisas. Dessa forma, tem-se a oportunidade de se expandir as análises voltadas ao ensino da AH e aos novos métodos de aprendizado.

The study of human anatomy is a relevant part of the curriculum of health course graduation students. Given the constant reduction of hours destinated to the study of Anatomy and the debates regarding new teaching methods, the use of the Quick Response Code (QR code) has shown to be promising. Therefore, the Anatomy Department at the State University of Londrina (UEL) has developed a cataloging process concerning anatomical structures with the application of QR code, and this paper has the purpose of reporting on such experience. In the process, the structures dissected in UEL's Anatomy Laboratory were cataloged based on a spreadsheet which contained the correlation between these structures and numbers; the information regarding each structure was then transcribed into a QR code using a digital generator, with posterior printing, lamination and attachment to the body part. The labels were made by sewing the numbered tags onto the structures. Within the discussion regarding alternative teaching methods, examples can be given regarding lamination, three-dimension projection and prospection. The use of the QR code has proven to be a valid alternative in aggregating knowledge to academic curriculum. Through the activities performed in the process of cataloging, it was possible not only to dedicate more time to the theorical and practical learning of human anatomy, but also to increase the independence in studying and developing research. Furthermore, there is an opportunity to expand the analysis directed toward human anatomy teaching and toward new learning methods.