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In patients with atrial high-rate episodes, edoxaban did not significantly reduce the incidence of stroke and cardiovascular outcomes as compared with placebo, but it led to a higher incidence of bleeding.

Stem cells make their mark Adult stem cells are an attractive alternative to embryonic stem cells for therapeutic use. As yet there is no standard method for obtaining such cells from adults and priming them to form different tissues, but a new system that generates large numbers of stem cells from the adult testicle shows promise. It makes use of a novel marker, an orphan receptor known as GPR125, found on the surface of spermatogonial stem cells. The use of specialized feeder cells to support stem cell growth allows stem cells once destined for spermatogenesis to become multipotent. This work also provides clues as to the minimal requirements for multipotency in adult cells. Adult stem cells are an ethically attractive alternative to embryonic stem cells for obtaining tissues for therapeutic purposes. However, no standardized methods exist to obtain such cells reliably from adults, and then convert them into different tissues. However, a system has been developed to generate large numbers of stem cells from the adult testicle, based on the presence of a novel marker (GPR125), specifically on the stem cell surface. Adult mammalian testis is a source of pluripotent stem cells 1 . However, the lack of specific surface markers has hampered identification and tracking of the unrecognized subset of germ cells that gives rise to multipotent cells 2 . Although embryonic-like cells can be derived from adult testis cultures after only several weeks in vitro 1 , it is not known whether adult self-renewing spermatogonia in long-term culture can generate such stem cells as well. Here, we show that highly proliferative adult spermatogonial progenitor cells (SPCs) can be efficiently obtained by cultivation on mitotically inactivated testicular feeders containing CD34 + stromal cells. SPCs exhibit testicular repopulating activity in vivo and maintain the ability in long-term culture to give rise to multipotent adult spermatogonial-derived stem cells (MASCs). Furthermore, both SPCs and MASCs express GPR125, an orphan adhesion-type G-protein-coupled receptor. In knock-in mice bearing a GPR125–β-galactosidase (LacZ) fusion protein under control of the native Gpr125 promoter (GPR125–LacZ), expression in the testis was detected exclusively in spermatogonia and not in differentiated germ cells. Primary GPR125–LacZ SPC lines retained GPR125 expression, underwent clonal expansion, maintained the phenotype of germline stem cells, and reconstituted spermatogenesis in busulphan-treated mice. Long-term cultures of GPR125 + SPCs (GSPCs) also converted into GPR125 + MASC colonies. GPR125 + MASCs generated derivatives of the three germ layers and contributed to chimaeric embryos, with concomitant downregulation of GPR125 during differentiation into GPR125 - cells. MASCs also differentiated into contractile cardiac tissue in vitro and formed functional blood vessels in vivo . Molecular bookmarking by GPR125 in the adult mouse and, ultimately, in the human testis could enrich for a population of SPCs for derivation of GPR125 + MASCs, which may be employed for genetic manipulation, tissue regeneration and revascularization of ischaemic organs.

Adult mammalian testis is a source of pluripotent stem cells. However, the lack of specific surface markers has hampered identification and tracking of the unrecognized subset of germ cells that gives rise to multipotent cells. Although embryonic-like cells can be derived from adult testis cultures after only several weeks in vitro, it is not known whether adult self-renewing spermatogonia in long-term culture can generate such stem cells as well. Here, we show that highly proliferative adult spermatogonial progenitor cells (SPCs) can be efficiently obtained by cultivation on mitotically inactivated testicular feeders containing CD34 super(+) stromal cells. SPCs exhibit testicular repopulating activity in vivo and maintain the ability in long-term culture to give rise to multipotent adult spermatogonial-derived stem cells (MASCs). Furthermore, both SPCs and MASCs express GPR125, an orphan adhesion-type G-protein-coupled receptor. In knock- in mice bearing a GPR125- beta-galactosidase (LacZ) fusion protein under control of the native Gpr125 promoter (GPR125-LacZ), expression in the testis was detected exclusively in spermatogonia and not in differentiated germ cells. Primary GPR125-LacZ SPC lines retained GPR125 expression, underwent clonal expansion, maintained the phenotype of germline stem cells, and reconstituted spermatogenesis in busulphan-treated mice. Long-term cultures of GPR125 super(+) SPCs (GSPCs) also converted into GPR125 super(+) MASC colonies. GPR125 super(+) MASCs generated derivatives of the three germ layers and contributed to chimaeric embryos, with concomitant downregulation of GPR125 during differentiation into GPR125 super(-) cells. MASCs also differentiated into contractile cardiac tissue in vitro and formed functional blood vessels in vivo. Molecular bookmarking by GPR125 in the adult mouse and, ultimately, in the human testis could enrich for a population of SPCs for derivation of GPR125 super(+) MASCs, which may be employed for genetic manipulation, tissue regeneration and revascularization of ischaemic organs.

Modern computation based on the von Neumann architecture is today a mature cutting-edge science. In the Von Neumann architecture, processing and memory units are implemented as separate blocks interchanging data intensively and continuously. This data transfer is responsible for a large part of the power consumption. The next generation computer technology is expected to solve problems at the exascale with 1018 calculations each second. Even though these future computers will be incredibly powerful, if they are based on von Neumann type architectures, they will consume between 20 and 30 megawatts of power and will not have intrinsic physically built-in capabilities to learn or deal with complex data as our brain does. These needs can be addressed by neuromorphic computing systems which are inspired by the biological concepts of the human brain. This new generation of computers has the potential to be used for the storage and processing of large amounts of digital information with much lower power consumption than conventional processors. Among their potential future applications, an important niche is moving the control from data centers to edge devices. The aim of this Roadmap is to present a snapshot of the present state of neuromorphic technology and provide an opinion on the challenges and opportunities that the future holds in the major areas of neuromorphic technology, namely materials, devices, neuromorphic circuits, neuromorphic algorithms, applications, and ethics. The Roadmap is a collection of perspectives where leading researchers in the neuromorphic community provide their own view about the current state and the future challenges. We hope that this Roadmap will be a useful resource to readers outside this field, for those who are just entering the field, and for those who are well established in the neuromorphic community. https://doi.org/10.1088/2634-4386/ac4a83

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery.