Hair-bearing human skin generated entirely from pluripotent stem cells

The skin is a multilayered organ, equipped with appendages (that is, follicles and glands), that is critical for regulating body temperature and the retention of bodily fluids, guarding against external stresses and mediating the sensation of touch and pain1,2. Reconstructing appendage-bearing skin in cultures and in bioengineered grafts is a biomedical challenge that has yet to be met3-9. Here we report an organoid culture system that generates complex skin from human pluripotent stem cells. We use stepwise modulation of the transforming growth factor β (TGFβ) and fibroblast growth factor (FGF) signalling pathways to co-induce cranial epithelial cells and neural crest cells within a spherical cell aggregate. During an incubation period of 4-5 months, we observe the emergence of a cyst-like skin organoid composed of stratified epidermis, fat-rich dermis and pigmented hair follicles that are equipped with sebaceous glands. A network of sensory neurons and Schwann cells form nerve-like bundles that target Merkel cells in organoid hair follicles, mimicking the neural circuitry associated with human touch. Single-cell RNA sequencing and direct comparison to fetal specimens suggest that the skin organoids are equivalent to the facial skin of human fetuses in the second trimester of development. Moreover, we show that skin organoids form planar hair-bearing skin when grafted onto nude mice. Together, our results demonstrate that nearly complete skin can self-assemble in vitro and be used to reconstitute skin in vivo. We anticipate that our skin organoids will provide a foundation for future studies of human skin development, disease modelling and reconstructive surgery

Age-Related Memory Impairment Is Associated with Disrupted Multivariate Epigenetic Coordination in the Hippocampus

Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape

Barriers to Predicting the Mechanisms and Risk Factors of Non-Contact Anterior Cruciate Ligament Injury

High incidences of non-contact anterior cruciate ligament (ACL) injury, frequent requirements for ACL reconstruction, and limited understanding of ACL mechanics have engendered considerable interest in quantifying the ACL loading mechanisms. Although some progress has been made to better understand non-contact ACL injuries, information on how and why non-contact ACL injuries occur is still largely unavailable. In other words, research is yet to yield consensus on injury mechanisms and risk factors. Biomechanics, video analysis, and related study approaches have elucidated to some extent how ACL injuries occur. However, these approaches are limited because they provide estimates, rather than precise measurements of knee - and more specifically ACL - kinematics at the time of injury. These study approaches are also limited in their inability to simultaneously capture many of the contributing factors to injury

Critical comments on the US Environmental Protection Agency Standards 40 CFR 191

This paper is about the US Environmental Protection Agency (EPA) ``Environmental Standards for the Disposal of Spent Nuclear Fuel, High-Level and Transuranic Wastes,`` 40 CFR 191. These standards regulate the disposal of radioactive wastes in geologic repositories. Currently, two repository sites are under investigation: The Waste Isolation Pilot Plant (WIPP) site, located near Carlsbad, New Mexico, may become the repository for defense-generated transuranic waste (TRU); and the Yucca Mountain site, located near Las Vegas, Nevada, may become the repository for spent reactor fuel and a small amount of reprocessing waste (hereinafter called high-level radioactive waste or HLW). The paper was written for readers who have an interest in 40 CFR 191 but do not have the time or inclination to ponder the technical details

Valproate regulates inositol synthesis by reducing expression of myo-inositol-3-phosphate synthase

Abstract Inositol depletion is a hypothesized mechanism of action of mood stabilization drugs used in the treatment of bipolar disorder. It was previously reported that the mood stabilizer valproate (VPA) increased phosphorylation of myo-inositol-3-phosphate synthases (MIPS), the rate limiting enzyme of inositol synthesis. Phosphosites were identified and examination of site-directed mutants suggested that phosphorylation leads to decreased enzymatic activity. In this study, we examined the extent of MIPS phosphorylation in response to VPA and used two interaction screens to identify protein kinases that interact with MIPS. Using an epitope tagged MIPS construct, we determined the fraction of phosphorylated MIPS to be very low (less than 2% of total), and we could not detect phosphorylation of untagged MIPS in response to VPA. In vitro analyses of phosphorylation revealed that putative protein kinases, PKC and CKII, have low specificity toward MIPS. These findings suggest that VPA likely depletes inositol via a mechanism other than MIPS phosphorylation. Consistent with this, mRNA levels of the MIPS-encoding gene INO1 and MIPS protein levels were significantly reduced during the mid-log growth phase in response to VPA treatment. These findings suggest that the mechanism whereby VPA causes inositol depletion is by reducing expression of the rate-limiting enzyme MIPS

Quantitative palaeobathymetric reconstructions based on foraminiferal proxies: a case study from the Neogene of south‐west Spain

International audienceQuantitative palaeobathymetric reconstructions based on foraminiferal proxies have been used in a wide variety of geological studies on tectonic, climatic and environmental changes in sedimentary basins. However, palaeo-water-depth estimates are frequently biased due to taphonomic processes (dissolution, transport) as well as local conditions (primary productivity, oxygen content, and organic matter fluxes). This study evaluated the level of reliability of three commonly used transfer equations based on planktic and benthic foraminiferal proxies that produce different palaeobathymetric results, using Neogene sediments from the Guadalquivir Basin, south-west Spain. The most trustworthy method involves removing abundant infaunal benthic foraminifera before applying the palaeo-water-depth equation based on benthic foraminiferal water-depth ranges and presence/absence of species. This new approach provides sound palaeobathymetric results that improve estimations of long and short-term relative sea-level changes with negligible influence of taphonomic as well as ecological factors. When using one equation based on planktic/benthic ratios (P/B ratios), removing all infaunal benthic foraminiferal species improves the accuracy of P/B ratios, which yields more accurate palaeodepth reconstructions despite the low level of trustworthiness of this equation for both long and short-term relative sea-level variations