AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance. In response to metabolic stress, it acts to redress energy imbalance through promotion of ATP-generating catabolic ...processes and inhibition of ATP-consuming processes, including cell growth and proliferation. While findings that AMPK was a downstream effector of the tumour suppressor LKB1 indicated that it might act to repress tumourigenesis, more recent evidence suggests that AMPK can either suppress or promote cancer, depending on the context. Prior to tumourigenesis AMPK may indeed restrain aberrant growth, but once a cancer has arisen, AMPK may instead support survival of the cancer cells by adjusting their rate of growth to match their energy supply, as well as promoting genome stability. The two isoforms of the AMPK catalytic subunit may have distinct functions in human cancers, with the AMPK-α1 gene often being amplified, while the AMPK-α2 gene is more often mutated. The prevalence of metabolic disorders, such as obesity and Type 2 diabetes, has led to the development of a wide range of AMPK-activating drugs. While these might be useful as preventative therapeutics in individuals predisposed to cancer, it seems more likely that AMPK inhibitors, whose development has lagged behind that of activators, would be efficacious for the treatment of pre-existing cancers.
The development of COVID-19 vaccines is occurring at a rapid pace, with the potential for a vaccine to be available within 6 months. So who should be prioritized for vaccination when in the first ...instance, there will be insufficient supply to meet demand? There is no doubt that health-care workers in all settings should be vaccinated first, but who comes next will be a complex decision based on local epidemiology, societal values, and the ability of the vaccines to prevent both severe disease and to reduce transmission thereby eliciting herd protection. The decision on who to vaccinate should be equitable, highly contextualized, and based on the property of each vaccine. In some settings, the elderly may be prioritized, in others, it may be the population most likely to get infected and responsible for community spread. To support decision-making on who to be prioritized for vaccination requires urgent additional research on the epidemiology of COVID-19; preexisting immunity and who is responsible for transmission in a variety of settings; the safety, immunogenicity, and efficacy of COVID-19 vaccines in children and pregnant women; and determining whether COVID-19 vaccines prevent asymptomatic infection and transmission.
From the foods we eat and the houses we construct, to our religious practices and political organization, to who we can marry and the types of games we teach our children, the diversity of cultural ...practices in the world is astounding. Yet, our ability to visualize and understand this diversity is limited by the ways it has been documented and shared: on a culture-by-culture basis, in locally-told stories or difficult-to-access repositories. In this paper we introduce D-PLACE, the Database of Places, Language, Culture, and Environment. This expandable and open-access database (accessible at https://d-place.org) brings together a dispersed corpus of information on the geography, language, culture, and environment of over 1400 human societies. We aim to enable researchers to investigate the extent to which patterns in cultural diversity are shaped by different forces, including shared history, demographics, migration/diffusion, cultural innovations, and environmental and ecological conditions. We detail how D-PLACE helps to overcome four common barriers to understanding these forces: i) location of relevant cultural data, (ii) linking data from distinct sources using diverse ethnonyms, (iii) variable time and place foci for data, and (iv) spatial and historical dependencies among cultural groups that present challenges for analysis. D-PLACE facilitates the visualisation of relationships among cultural groups and between people and their environments, with results downloadable as tables, on a map, or on a linguistic tree. We also describe how D-PLACE can be used for exploratory, predictive, and evolutionary analyses of cultural diversity by a range of users, from members of the worldwide public interested in contrasting their own cultural practices with those of other societies, to researchers using large-scale computational phylogenetic analyses to study cultural evolution. In summary, we hope that D-PLACE will enable new lines of investigation into the major drivers of cultural change and global patterns of cultural diversity.
The most crucial data to convince us that a 1 + 1 schedule is non-inferior to a 2 + 1 schedule are whether invasive pneumococcal disease cases remain stable in the highest risk period between the ...first dose at age 14 weeks and the second dose at age 12 months, and whether infants too young to be vaccinated continue to be protected via indirect effects. A clinical trial in Fiji found that one dose of 7-valent PCV had a similar effect on serotype carriage as two doses up to 12 months of age, indicating good direct protection in the first year of life.6 Two-dose (1 + 1) trials in India, Viet Nam, and South Africa found similar or non-inferior serotype carriage effects versus three doses in the second year of life, indicating the potential for two doses (1 + 1) to generate similar indirect protection as three (2 + 1).7–9 Importantly, Bertran and colleagues found that vaccine failures and breakthrough infections did not change with the implementation of a two-dose schedule—the number of meningitis cases did not increase but the proportion of invasive pneumococcal disease cases with meningitis did (possibly due to changes in circulating serotypes)—and that there were no deaths in vaccinated children.1 Nevertheless, this increase in the proportion of meningitis cases highlights the importance of ongoing surveillance. Flickr – Heather Hazzan (Self magazine) For vaccine data see www.view-hub.org FMR has received grants or contracts from the National Health and Medical Research Council, The Wellcome Trust, the Australian Department of Foreign Affairs and Trade, and WHO, has received travel support from the Meningitis Research Foundation UK and the World Society of Pediatric Infectious Disease to attend conferences, and has received travel support from WHO to attend a meeting.
We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched ...samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher's exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.
The AMP-activated protein kinase (AMPK) acts as a cellular energy sensor. Once switched on by increases in cellular AMP : ATP ratios, it acts to restore energy homeostasis by switching on catabolic ...pathways while switching off cell growth and proliferation. The canonical AMP-dependent mechanism of activation requires the upstream kinase LKB1, which was identified genetically to be a tumour suppressor. AMPK can also be switched on by increases in intracellular Ca
, by glucose starvation and by DNA damage via non-canonical, AMP-independent pathways. Genetic studies of the role of AMPK in mouse cancer suggest that, before disease arises, AMPK acts as a tumour suppressor that protects against cancer, with this protection being further enhanced by AMPK activators such as the biguanide phenformin. However, once cancer has occurred, AMPK switches to being a tumour promoter instead, enhancing cancer cell survival by protecting against metabolic, oxidative and genotoxic stresses. Studies of genetic changes in human cancer also suggest diverging roles for genes encoding subunit isoforms, with some being frequently amplified, while others are mutated.
Cordycepin (3′-deoxyadenosine) is a major bioactive agent in Cordyceps militaris, a fungus used in traditional Chinese medicine. It has been proposed to have many beneficial metabolic effects by ...activating AMP-activated protein kinase (AMPK), but the mechanism of activation remained uncertain. We report that cordycepin enters cells via adenosine transporters and is converted by cellular metabolism into mono-, di-, and triphosphates, which at high cordycepin concentrations can almost replace cellular adenine nucleotides. AMPK activation by cordycepin in intact cells correlates with the content of cordycepin monophosphate and not other cordycepin or adenine nucleotides. Genetic knockout of AMPK sensitizes cells to the cytotoxic effects of cordycepin. In cell-free assays, cordycepin monophosphate mimics all three effects of AMP on AMPK, while activation in cells is blocked by a γ-subunit mutation that prevents activation by AMP. Thus, cordycepin is a pro-drug that activates AMPK by being converted by cellular metabolism into the AMP analog cordycepin monophosphate.
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•Cordycepin (100 μM) activates AMPK in human cells; higher concentrations are toxic•Cordycepin is taken up into cells and converted into mono-, di-, and triphosphates•AMPK activation correlates with the cellular content of cordycepin monophosphate•Cordycepin monophosphate mimics all three effects of AMP on AMPK in cell-free assays
Cordycepin is a major bioactive component of Cordyceps militaris, a parasitic fungus much prized in traditional Chinese medicine. Hawley et al. report that it is taken into cells and converted by the metabolism into mono-, di-, and triphosphates. Cordycepin monophosphate activates AMPK by mimicking multiple effects of its natural activator, AMP.
The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong ...consequences for the mother and child, our knowledge of the human placenta is limited owing to a lack of functional experimental models
. After implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, proliferative villous cytotrophoblast cells differentiate into two main sub-populations: syncytiotrophoblast, the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast cells, which anchor the placenta to the maternal decidua and transform the maternal spiral arteries
. Here we describe the generation of long-term, genetically stable organoid cultures of trophoblast that can differentiate into both syncytiotrophoblast and extravillous trophoblast. We used human leukocyte antigen (HLA) typing to confirm that the organoids were derived from the fetus, and verified their identities against four trophoblast-specific criteria
. The cultures organize into villous-like structures, and we detected the secretion of placental-specific peptides and hormones, including human chorionic gonadotropin (hCG), growth differentiation factor 15 (GDF15) and pregnancy-specific glycoprotein (PSG) by mass spectrometry. The organoids also differentiate into HLA-G
extravillous trophoblast cells, which vigorously invade in three-dimensional cultures. Analysis of the methylome reveals that the organoids closely resemble normal first trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.
AMP-activated protein kinase (AMPK) is the central component of a signalling pathway that senses energy stress and triggers a metabolic switch away from anabolic processes and towards catabolic ...processes. There has been a prolonged focus in the pharmaceutical industry on the development of AMPK-activating drugs for the treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. However, recent findings suggest that AMPK inhibitors might be efficacious for treating certain cancers, especially lung adenocarcinomas, in which the
gene (encoding the α1 catalytic subunit isoform of AMPK) is often amplified. Here, we study two potent AMPK inhibitors, BAY-3827 and SBI-0206965. Despite not being closely related structurally, the treatment of cells with either drug unexpectedly caused increases in AMPK phosphorylation at the activating site, Thr172, even though the phosphorylation of several downstream targets in different subcellular compartments was completely inhibited. Surprisingly, the two inhibitors appear to promote Thr172 phosphorylation by different mechanisms: BAY-3827 primarily protects against Thr172 dephosphorylation, while SBI-0206965 also promotes phosphorylation by LKB1 at low concentrations, while increasing cellular AMP:ATP ratios at higher concentrations. Due to its greater potency and fewer off-target effects, BAY-3827 is now the inhibitor of choice for cell studies, although its low bioavailability may limit its use in vivo.
The epidermis is maintained by multiple stem cell populations whose progeny differentiate along diverse, and spatially distinct, lineages. Here we show that the transcription factor Gata6 controls ...the identity of the previously uncharacterized sebaceous duct (SD) lineage and identify the Gata6 downstream transcription factor network that specifies a lineage switch between sebocytes and SD cells. During wound healing differentiated Gata6
cells migrate from the SD into the interfollicular epidermis and dedifferentiate, acquiring the ability to undergo long-term self-renewal and differentiate into a much wider range of epidermal lineages than in undamaged tissue. Our data not only demonstrate that the structural and functional complexity of the junctional zone is regulated by Gata6, but also reveal that dedifferentiation is a previously unrecognized property of post-mitotic, terminally differentiated cells that have lost contact with the basement membrane. This resolves the long-standing debate about the contribution of terminally differentiated cells to epidermal wound repair.
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