The Hedgehog (Hh) pathway is essential for embryonic development and tissue homeostasis. Aberrant Hh signaling may occur in a wide range of human cancers, such as medulloblastoma, the most common ...brain malignancy in childhood. Here, we identify endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptive antitumor immune responses, as a previously unknown player in the Hh signaling pathway. We demonstrate that ERAP1 binds the deubiquitylase enzyme USP47, displaces the USP47-associated βTrCP, the substrate-receptor subunit of the SCF
ubiquitin ligase, and promotes βTrCP degradation. These events result in the modulation of Gli transcription factors, the final effectors of the Hh pathway, and the enhancement of Hh activity. Remarkably, genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo. Our findings unveil an unexpected role for ERAP1 in cancer and indicate ERAP1 as a promising therapeutic target for Hh-driven tumors.
Abstract
Natural peatlands contribute significantly to global carbon sequestration and storage of biomass, most of which derives from
Sphagnum
peat mosses. Atmospheric CO
2
levels have increased ...dramatically during the twentieth century, from 280 to > 400 ppm, which has affected plant carbon dynamics. Net carbon assimilation is strongly reduced by photorespiration, a process that depends on the CO
2
to O
2
ratio. Here we investigate the response of the photorespiration to photosynthesis ratio in
Sphagnum
mosses to recent CO
2
increases by comparing deuterium isotopomers of historical and contemporary
Sphagnum
tissues collected from 36 peat cores from five continents. Rising CO
2
levels generally suppressed photorespiration relative to photosynthesis but the magnitude of suppression depended on the current water table depth. By estimating the changes in water table depth, temperature, and precipitation during the twentieth century, we excluded potential effects of these climate parameters on the observed isotopomer responses. Further, we showed that the photorespiration to photosynthesis ratio varied between
Sphagnum
subgenera, indicating differences in their photosynthetic capacity. The global suppression of photorespiration in
Sphagnum
suggests an increased net primary production potential in response to the ongoing rise in atmospheric CO
2
, in particular for mire structures with intermediate water table depths.
Northern peatlands are important carbon (C) sinks and while the patterns of C accumulation have been frequently investigated, nitrogen (N) and phosphorus (P) accumulation are often neglected. Here we ...link the C:N:P stoichiometry from foliar plant tissues, through senescent litters to peat, and determine C, N and P accumulation rates at Mer Bleue Bog, eastern Canada. Average C:N:P ratios changed from 794:17:1 in the foliar tissues to 911:10:1 in litter and 1285:32:1 in acrotelm peat. The increase in C:N and C:P ratios from mature to senescent tissues is related to nutrient resorption. The increase in C:P and N:P ratios in peat, which was contrary to that observed in Canadian forest soils, may be related to plant/mycorrhizae uptake of P. The long-term apparent rates of C, N and P accumulation were 29.5 ± 2.1 (SE) g C, 0.87 ± 0.01 g N and 0.017 ± 0.002 g P m−2 yr−1, respectively. The significant correlation between the accumulation rates of N and P and that of C suggests more attention be placed on C:N:P stoichiometry in peatland biogeochemistry, in particular in understanding why C:P ratios are so large in the lower parts of the profile.
Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as ...osteosarcoma and Ewing's sarcoma or secondary bone tumors such as bone metastases from prostate carcinoma. Gap junctions are specialized plasma membrane structures consisting of transmembrane channels that directly link the cytoplasm of adjacent cells, thereby enabling the direct exchange of small signaling molecules between cells. Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function. Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is thus a main mechanism for tumor cells to communicate with other tumor cells and their surrounding microenvironment to survive and proliferate. If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells. If so, connexin expression would facilitate secondary tumor dissemination. This paper discusses evidence that suggests that connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.
Excess reactive nitrogen (N) is linked to a myriad of environmental problems that carry large social costs. Nitrogen footprint tools can help institutions understand how their direct and indirect ...activities are associated with N release to the environment through energy use, food, and transportation. However, little is known about how geographic context shapes the environmental footprints of institutions. Defining the system boundaries over which institutions are responsible and able to control individual drivers of N footprints is also a challenge. Here, we compare and contrast the circa 2017 N footprints for two research intensive universities located in Montréal, Canada, with a combined full-time equivalent campus population of ∼83 000. Our estimate of McGill University's N footprint (121.2 t N yr−1) is 48% greater than Université de Montréal's (74.1 t N yr−1), which is also reflected on a per capita basis (3.3 and 1.6 kg N capita−1 yr−1, respectively). Key institutional factors that explain the differences include McGill's larger residential and international student populations, research farm, and characteristics of its on-campus fuel use. We use a series of counterfactual scenarios to test how shared urban geographic context factors lead to an effective reduction of the N footprints at both universities: the relatively small direct role of both institutions in food intake on campus (29%-68% reduction compared to a counterfactual scenario), energy from hydroelectricity (17%-21% reduction), and minimal car commuting by students (2%-3% reduction). In contrast, the near-zero N removal from the municipal wastewater system effectively increases the N footprints (11%-13% increase compared to a modest N removal and offset scenario). Our findings suggest that a shared geographic context of a dense city with plentiful off-campus housing, food options, and access to hydroelectricity shapes the absolute N footprints of Montréal's two main universities more than the divergent institutional characteristics that influence their relative N footprints.
Peatlands are efficient carbon sinks due to waterlogged soils causing oxygen depletion and slowing organic matter decomposition, leading to peat accumulation. However, peatlands are also a natural ...source of methane (CH4), a powerful greenhouse gas, to the atmosphere. Methane production (by methanogens) and oxidation (by methanotrophs) are controlled by water table depth, soil temperature and hydrochemistry. Measuring CH4 emissions is resource demanding. Several measurements method are used, which introduces potential bias for comparisons among studies. Thus, a simple and reliable indicator tool would be desirable for both researchers and managers. Currently, such a tool does not exist. Testate amoebae (TA), an abundant and diverse group of shelled protists occurring in peatlands, are well-established proxies of present water table depth (WTD). As their shells are well preserved in peat, they are commonly used to infer past hydrological changes using predictive mathematical models called transfer functions. As CH4 emissions are also tightly linked to WTD, and although TA are not directly involved in CH4 production or consumption, we hypothesised that CH4 emissions would be significantly correlated to TA community composition and could therefore be inferred from TA communities living in peatland mosses. We tested this hypothesis using compilations of CH4 plot emissions measurements from European and North American bogs and fens, and TA data from moss samples collected from the same plots. Testate amoeba communities were significantly correlated to CH4 fluxes. As our models were based on several independent studies for both flux measurements and TA communities, methodological differences among studies (e.g., CH4 emission measurements, TA taxonomy) may potentially cause bias in the model. Nevertheless, the results are promising, and this proof-of-concept study suggests that past and present peatland CH4 emissions could be inferred from TA shells preserved in peat over centuries and in mosses growing at the surfaces of peatlands.
In 30 years of experience in responding to the HIV epidemic, critical decisions and program characteristics for successful scale-up have been studied. Now leaders face a new challenge: sustaining ...large-scale HIV prevention programs. Implementers, funders, and the communities served need to assess what strategies and practices of scaling up are also relevant for sustaining delivery at scale.
We reviewed white and gray literature to identify domains central to scaling-up programs and reviewed HIV case studies to identify how these domains might relate to sustaining delivery at scale.
We found 10 domains identified as important for successfully scaling up programs that have potential relevance for sustaining delivery at scale: fiscal support; political support; community involvement, integration, buy-in, and depth; partnerships; balancing flexibility/adaptability and standardization; supportive policy, regulatory, and legal environment; building and sustaining strong organizational capacity; transferring ownership; decentralization; and ongoing focus on sustainability. We identified one additional potential domain important for programs sustaining delivery at scale: emphasizing equity.
Today, the public and private sector are examining their ability to generate value for populations. All stakeholders are aiming to stem the tide of the HIV epidemic. Implementers need a framework to guide the evolution of their strategies and management practices. Greater research is needed to refine the domains for policy and program implementers working to sustain HIV program delivery at scale.
Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a ...strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis.
Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production.
Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages.
These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours.
This study was funded by institutional grants and charities.
Abstract Background The link between economic development and health is well established, but not necessarily straightforward. We explored the economic effect of investing in health-care ...infrastructure in Neno, Malawi. We documented findings in a teaching case that is one of the open-access Cases in Global Health Delivery on Harvard Business Publishing. The cases show value-based health-care delivery and improve students' understanding of strategy and management in health care. Methods We did background research on Malawi's history, health system, and economy. We interviewed 40 informants in Neno, including leaders of Abwenzi Pa Za Umoyo (APZU) and its founding organisation (Partners In Health), Ministry of Health administrators, hospital staff, villagers, and business owners. We reviewed quantitative data to assess indicators of development and documented changes in Neno's economy. We investigated the management decisions APZU made, while supporting the government in building a hospital and scaling up clinical and social programmes across Neno. We piloted the case in the Global Health Delivery intensive programme at Harvard. Findings The case discussion tested students' ability to assess synergies between APZU's work and the local economy, including population and employment growth, improved public infrastructure, improved patient outcomes, and increased government investment in the district. Students also assessed challenges related to the shifting political landscape in Malawi, APZU budget cuts, reduced staff morale, and the Malawian currency devaluation. Interpretation Students gained a greater understanding of how investment in health-care infrastructure leads to economic development. Funding Harvard Medical School, Harvard Global Health Institute.
In this review paper, we identify and address key uncertainties related to four local and global controls of Holocene northern peatland carbon stocks and fluxes. First, we provide up-to-date ...estimates of the current northern peatland area (3.2Mkm2) and propose a novel approach to reconstruct changes in the northern peatland area over time (Section 2). Second, we review the key methods and models that have been used to quantify total carbon stocks and methane emissions over time at the hemispheric scale, and offer new research directions to improve these calculations (Section 3). Our main proposed improvement relates to allocating different carbon stock and emission values for each of the two dominant vegetation assemblages (sedge and brown moss-dominated vs. Sphagnum-dominated peat). Third, we discuss and quantify the importance of basin heterogeneity in estimating peat volume at the local scale (Section 4.1). We also highlight the importance of age model selection when reconstructing carbon accumulation rates from a peat core (Section 4.2). Lastly, we introduce the role of biogeomorphological agents such as beaver activity in controlling carbon dynamics (Section 5.1) and review the newest research related to permafrost thaw (Section 5.2) and peat fire (Section 5.3) under climate change. Overall, this review summarizes new information from a broad range of peat-carbon studies, provides novel analysis of hemispheric-scale paleo datasets, and proposes new insights on how to translate peat-core data into carbon fluxes. It also identifies critical data gaps and research priorities, and many ways to consider and address them.
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