Estrogen modulates mesenchyme-epidermis interactions in the adult nipple

Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts

Space Science Opportunities Augmented by Exploration Telepresence

Since the end of the Apollo missions to the lunar surface in December 1972, humanity has exclusively conducted scientific studies on distant planetary surfaces using teleprogrammed robots. Operations and science return for all of these missions are constrained by two issues related to the great distances between terrestrial scientists and their exploration targets: high communication latencies and limited data bandwidth. Despite the proven successes of in-situ science being conducted using teleprogrammed robotic assets such as Spirit, Opportunity, and Curiosity rovers on the surface of Mars, future planetary field research may substantially overcome latency and bandwidth constraints by employing a variety of alternative strategies that could involve: 1) placing scientists/astronauts directly on planetary surfaces, as was done in the Apollo era; 2) developing fully autonomous robotic systems capable of conducting in-situ field science research; or 3) teleoperation of robotic assets by humans sufficiently proximal to the exploration targets to drastically reduce latencies and significantly increase bandwidth, thereby achieving effective human telepresence. This third strategy has been the focus of experts in telerobotics, telepresence, planetary science, and human spaceflight during two workshops held from October 3–7, 2016, and July 7–13, 2017, at the Keck Institute for Space Studies (KISS). Based on findings from these workshops, this document describes the conceptual and practical foundations of low-latency telepresence (LLT), opportunities for using derivative approaches for scientific exploration of planetary surfaces, and circumstances under which employing telepresence would be especially productive for planetary science. An important finding of these workshops is the conclusion that there has been limited study of the advantages of planetary science via LLT. A major recommendation from these workshops is that space agencies such as NASA should substantially increase science return with greater investments in this promising strategy for human conduct at distant exploration sites

Space Science Opportunities Augmented by Exploration Telepresence

Since the end of the Apollo missions to the lunar surface in December 1972, humanity has exclusively conducted scientific studies on distant planetary surfaces using teleprogrammed robots. Operations and science return for all of these missions are constrained by two issues related to the great distances between terrestrial scientists and their exploration targets: high communication latencies and limited data bandwidth. Despite the proven successes of in-situ science being conducted using teleprogrammed robotic assets such as Spirit, Opportunity, and Curiosity rovers on the surface of Mars, future planetary field research may substantially overcome latency and bandwidth constraints by employing a variety of alternative strategies that could involve: 1) placing scientists/astronauts directly on planetary surfaces, as was done in the Apollo era; 2) developing fully autonomous robotic systems capable of conducting in-situ field science research; or 3) teleoperation of robotic assets by humans sufficiently proximal to the exploration targets to drastically reduce latencies and significantly increase bandwidth, thereby achieving effective human telepresence. This third strategy has been the focus of experts in telerobotics, telepresence, planetary science, and human spaceflight during two workshops held from October 3–7, 2016, and July 7–13, 2017, at the Keck Institute for Space Studies (KISS). Based on findings from these workshops, this document describes the conceptual and practical foundations of low-latency telepresence (LLT), opportunities for using derivative approaches for scientific exploration of planetary surfaces, and circumstances under which employing telepresence would be especially productive for planetary science. An important finding of these workshops is the conclusion that there has been limited study of the advantages of planetary science via LLT. A major recommendation from these workshops is that space agencies such as NASA should substantially increase science return with greater investments in this promising strategy for human conduct at distant exploration sites

A Wake-Up Call: Information Contagion and Strategic Uncertainty

A successful speculative attack against one currency is a wake-up call for speculators elsewhere. Currency speculators have an incentive to acquire costly information about exposures across countries to infer whether their monetary authority's ability to defend its currency is weakened. Information acquisition per se increases the likelihood of speculative currency attacks via heightened strategic uncertainty among speculators. Contagion occurs even if speculators learn that there is no exposure. Our new contagion mechanism offers a compelling explanation for the 1997 Asian currency crisis and the 1998 Russian crisis, both of which spread across countries with seemingly unrelated fundamentals and limited interconnectedness. The proposed contagion mechanism applies generally in global coordination games and can also be applied to bank runs, sovereign debt crises, and political regime change

‘Placing’ Space: exploring the socio-spatial impacts of cosmopolitan place-marketing approaches on British migrants in Spain

This article explores the sociospatial underpinnings of cosmopolitan place-marketing narratives and their impacts on British migrants living in Sitges, an affluent tourist town in Spain. Sitges’ place-marketing suggests that moving there automatically fosters a cosmopolitan identity. For British migrants in Sitges, this was understood to be exemplified through integration into the local community. Yet the vast majority found such integration impossible, not least because this conceptualization of cosmopolitanism overlooked the subjectivity of locals themselves, by whom they were most often rejected. It is argued that this mismatch between British migrants’ experiences and Sitges’ cosmopolitan place-marketing occurs because it relies on an understanding of subjective identity as generated locationally, enacted via movement to a specific “type” of place that incorporates particular understandings of space, place, and culture in relation to that identity. This overrides the necessity of relationality, undermining the ideal of reflexive identity-making on which cosmopolitan place-marketing narratives rely

Trans-pQTL study identifies immune crosstalk between Parkinson and Alzheimer loci

Objective: Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes. Methods: We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study. Linear regression was used to identify associations between 24 PD risk variants and protein expression. The 2 cohorts were meta-analyzed in a discovery analysis, and the 4 most strongly suggestive results were validated in an independent cohort of 50 PGP participants. Results: We discovered and validated an association between the PD risk allele rs12456492G in the RIT2 locus and increased CD33 expression (pjoint = 3.50 × 10−5) and found strongly suggestive evidence that rs11060180A in the CCDC62/HIP1R locus decreased PTK2B expression (pjoint = 1.12 × 10−4). Furthermore, in older individuals, increased CD33 expression on peripheral monocytes was associated with a greater burden of parkinsonism (p = 0.047), particularly bradykinesia (p = 6.64 × 10−3). Conclusions: We find that the rs12456492 PD risk variant affects expression of AD-associated protein CD33 in peripheral monocytes, which suggests that genetic factors for these 2 diseases may converge to influence overlapping innate immune-mediated mechanisms that contribute to neurodegeneration. Furthermore, the effect of the rs12456492G PD risk allele on increased CD33 suggests that the inhibition of certain myeloid functions may contribute to PD susceptibility, as is the case for AD

Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients is Associated with Microbial Translocation and Bacteremia

Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19