Gamma-ray bursts (GRBs) are divided into two populations
; long GRBs that derive from the core collapse of massive stars (for example, ref.
) and short GRBs that form in the merger of two compact ...objects
. Although it is common to divide the two populations at a gamma-ray duration of 2 s, classification based on duration does not always map to the progenitor. Notably, GRBs with short (≲2 s) spikes of prompt gamma-ray emission followed by prolonged, spectrally softer extended emission (EE-SGRBs) have been suggested to arise from compact object mergers
. Compact object mergers are of great astrophysical importance as the only confirmed site of rapid neutron capture (r-process) nucleosynthesis, observed in the form of so-called kilonovae
. Here we report the discovery of a possible kilonova associated with the nearby (350 Mpc), minute-duration GRB 211211A. The kilonova implies that the progenitor is a compact object merger, suggesting that GRBs with long, complex light curves can be spawned from merger events. The kilonova of GRB 211211A has a similar luminosity, duration and colour to that which accompanied the gravitational wave (GW)-detected binary neutron star (BNS) merger GW170817 (ref.
). Further searches for GW signals coincident with long GRBs are a promising route for future multi-messenger astronomy.
Major depressive disorder (MDD) associated with chronic neglected tropical diseases (NTDs) has been identified as a significant and overlooked contributor to overall disease burden. Cutaneous ...leishmaniasis (CL) is one of the most prevalent and stigmatising NTDs, with an incidence of around 1 million new cases of active CL infection annually. However, the characteristic residual scarring (inactive CL) following almost all cases of active CL has only recently been recognised as part of the CL disease spectrum due to its lasting psychosocial impact.
We performed a multi-language systematic review of the psychosocial impact of active and inactive CL. We estimated inactive CL (iCL) prevalence for the first time using reported WHO active CL (aCL) incidence data that were adjusted for life expectancy and underreporting. We then quantified the disability (YLD) burden of co-morbid MDD in CL using MDD disability weights at three severity levels. Overall, we identified 29 studies of CL psychological impact from 5 WHO regions, representing 11 of the 50 highest burden countries for CL. We conservatively calculated the disability burden of co-morbid MDD in CL to be 1.9 million YLDs, which equalled the overall (DALY) disease burden (assuming no excess mortality in depressed CL patients). Thus, upon inclusion of co-morbid MDD alone in both active and inactive CL, the DALY burden was seven times higher than the latest 2016 Global Burden of Disease study estimates, which notably omitted both psychological impact and inactive CL.
Failure to include co-morbid MDD and the lasting sequelae of chronic NTDs, as exemplified by CL, leads to large underestimates of overall disease burden.
About the Authors: Freddie Bailey Affiliations NTDs, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom, University of Edinburgh Medical School, Edinburgh, United ...Kingdom Karina Mondragon-Shem Affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom Peter Hotez Affiliation: National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America José Antonio Ruiz-Postigo Affiliation: World Health Organization, Geneva, Switzerland Waleed Al-Salem Affiliation: National Centre for Tropical Diseases, Saudi Ministry of Health, Riyadh, Kingdom of Saudi Arabia Álvaro Acosta-Serrano Affiliations Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom, Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom ORCID http://orcid.org/0000-0002-2576-7959 David H. Molyneux * E-mail: david.molyneux@lstmed.ac.uk Affiliations NTDs, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom, Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United KingdomCitation: Bailey F, Mondragon-Shem K, Hotez P, Ruiz-Postigo JA, Al-Salem W, Acosta-Serrano Á, et al. ...there is known to be a continuation of psychological morbidity with the scarring that ensues post CL infection (both treated and self-healing). ...while both active and inactive forms of CL can be unsightly, the residual scar of inactive CL is hard to remove cosmetically, and thus in the vast majority of cases, scarring is permanent and lifelong. ...there is a much greater number of “inactive” CL patients in the world than “active” cases.
In most carcinomas, invasion of malignant cells into surrounding tissues involves their molecular reprogramming as part of an epithelial-to-mesenchymal transition (EMT). Mutation of the APC gene in ...most colorectal carcinomas (CRCs) contributes to the nuclear translocation of the oncoprotein β-catenin that upon binding to T-cell and lymphoid enhancer (TCF-LEF) factors triggers an EMT and a proinvasive gene expression profile. A key inducer of EMT is the ZEB1 transcription factor whose expression promotes tumorigenesis and metastasis in carcinomas. As inhibitor of the epithelial phenotype, ZEB1 is never present in the epithelium of normal colon or the tumor center of CRCs where β-catenin remains membranous. We show here that ZEB1 is expressed by epithelial cells in intestinal tumors from human patients (familial adenomatous polyposis) and mouse models (APCMin/+) with germline mutations of APC that result in nuclear accumulation of β-catenin. However, ZEB1 is not expressed in the epithelium of hereditary forms of CRCs that carry wild-type APC and where β-catenin is excluded from the nucleus (Lynch syndrome). We found that β-catenin/TCF4 binds directly to the ZEB1 promoter and activates its transcription. Knockdown of β-catenin and TCF4 in APC-mutated CRC cells inhibited endogenous ZEB1, whereas forced translocation of β-catenin to the nucleus in APC-wild-type CRC cells induced de novo expression of ZEB1. Upregulation of MT1-MMP and LAMC2 by β-catenin/TCF4 has been linked to invasiveness in CRCs, and we show here that both proteins are activated by ZEB1 coexpressing with it in primary colorectal tumors with mutated APC. These results set ZEB1 as an effector of β-catenin/TCF4 signaling in EMT and tumor progression.
ABSTRACT We present the first polarimetric observations of a Type I superluminous supernova (SLSN). LSQ14mo was observed with VLT/FORS2 at five different epochs in the V band, with the observations ...starting before maximum light and spanning 26 days in the rest frame (z = 0.256). During this period, we do not detect any statistically significant evolution ( ) in the Stokes parameters. The average values we obtain, corrected for interstellar polarization in the Galaxy, are Q = −0.01% ( 0.15%) and U = −0.50% ( 0.14%). This low polarization can be entirely due to interstellar polarization in the SN host galaxy. We conclude that, at least during the period of observations and at the optical depths probed, the photosphere of LSQ14mo does not present significant asymmetries, unlike most lower-luminosity hydrogen-poor SNe Ib/c. Alternatively, it is possible that we may have observed LSQ14mo from a special viewing angle. Supporting spectroscopy and photometry confirm that LSQ14mo is a typical SLSN I. Further studies of the polarization of Type I SLSNe are required to determine whether the low levels of polarization are a characteristic of the entire class and to also study the implications for the proposed explosion models.
Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During ...cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial-to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression.
We present post-jet-break Hubble Space Telescope, Very Large Array, and Chandra observations of the afterglow of the long γ-ray bursts GRB 160625B (between 69 and 209 days) and GRB 160509A (between ...35 and 80 days). We calculate the post-jet-break decline rates of the light curves and find the afterglow of GRB 160625B is inconsistent with a simple t−3/4 steepening over the break, expected from the geometric effect of the jet edge entering our line of sight. However, the favored optical post-break decline ( ) is also inconsistent with the f ∝ t−p decline (where p 2.3 from the pre-break light curve), which is expected from exponential lateral expansion of the jet; perhaps suggesting lateral expansion that only affects a fraction of the jet. The post-break decline of GRB 160509A is consistent with both the t−3/4 steepening and with f ∝ t−p. We also use boxfit to fit afterglow models to both light curves and find both to be energetically consistent with a millisecond magnetar central engine, but the magnetar parameters need to be extreme (i.e., E ∼ 3 × 1052 erg). Finally, the late-time radio light curves of both afterglows are not reproduced well by boxfit and are inconsistent with predictions from the standard jet model; instead, both are well represented by a single power-law decline (roughly f ∝ t−1) with no breaks. This requires a highly chromatic jet break ( ) and possibly a two-component jet for both bursts.
Human African trypanosomiasis (HAT), also known as sleeping sickness, persists as a public health problem in several sub-Saharan countries. Evidence-based, spatially explicit estimates of population ...at risk are needed to inform planning and implementation of field interventions, monitor disease trends, raise awareness and support advocacy. Comprehensive, geo-referenced epidemiological records from HAT-affected countries were combined with human population layers to map five categories of risk, ranging from "very high" to "very low," and to estimate the corresponding at-risk population.
Approximately 70 million people distributed over a surface of 1.55 million km(2) are estimated to be at different levels of risk of contracting HAT. Trypanosoma brucei gambiense accounts for 82.2% of the population at risk, the remaining 17.8% being at risk of infection from T. b. rhodesiense. Twenty-one million people live in areas classified as moderate to very high risk, where more than 1 HAT case per 10,000 inhabitants per annum is reported.
Updated estimates of the population at risk of sleeping sickness were made, based on quantitative information on the reported cases and the geographic distribution of human population. Due to substantial methodological differences, it is not possible to make direct comparisons with previous figures for at-risk population. By contrast, it will be possible to explore trends in the future. The presented maps of different HAT risk levels will help to develop site-specific strategies for control and surveillance, and to monitor progress achieved by ongoing efforts aimed at the elimination of sleeping sickness.
Sterile inflammation can be initiated by innate immune recognition of markers of tissue injury termed damage-associated molecular patterns (DAMPs). DAMP recognition by dendritic cells (DCs) has also ...been postulated to lead to T cell responses to foreign antigens in tumors or allografts. Many DAMPs represent intracellular contents that are released upon cell damage, notably after necrosis. In this regard, we have previously described DNGR-1 (CLEC9A) as a DC-restricted receptor specific for an unidentified DAMP that is exposed by necrotic cells and is necessary for efficient priming of cytotoxic T cells against dead cell-associated antigens. Here, we have shown that the DNGR-1 ligand is preserved from yeast to man and corresponds to the F-actin component of the cellular cytoskeleton. The identification of F-actin as a DNGR-1 ligand suggests that cytoskeletal exposure is a universal sign of cell damage that can be targeted by the innate immune system to initiate immunity.
► DNGR-1 recognizes a cell-associated ligand conserved from yeast to man ► F-actin is the ligand for DNGR-1 ► F-actin exposure permits DNGR-1 recognition of necrotic cells
Human embryonic stem cells (hESCs) can differentiate into any cell lineage. Here, we report that ZEB1 and ZEB2 promote and inhibit mesodermal-to-myogenic specification of hESCs, respectively. ...Knockdown and/or overexpression experiments of ZEB1, ZEB2, or PAX7 in hESCs indicate that ZEB1 is required for hESC Nodal/Activin-mediated mesodermal specification and PAX7+ human myogenic progenitor (hMuP) generation, while ZEB2 inhibits these processes. ZEB1 downregulation induces neural markers, while ZEB2 downregulation induces mesodermal/myogenic markers. Mechanistically, ZEB1 binds to and transcriptionally activates the PAX7 promoter, while ZEB2 binds to and activates the promoter of the neural OTX2 marker. Transplanting ZEB1 or ZEB2 knocked down hMuPs into the muscles of a muscular dystrophy mouse model, showing that hMuP engraftment and generation of dystrophin-positive myofibers depend on ZEB1 and are inhibited by ZEB2. The mouse model results suggest that ZEB1 expression and/or downregulating ZEB2 in hESCs may also enhance hESC regenerative capacity for human muscular dystrophy therapy.
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•ZEB1 is required for the generation of mesodermal and myogenic (PAX7+) progenitors•Downregulation of ZEB1 and ZEB2 induces neural and myogenic markers, respectively•ZEB1 and ZEB2 activate the promoters of myogenic PAX7 and neural OTX2, respectively•Engraftment of myogenic precursors in mdx mice depends on ZEB1 and is inhibited by ZEB2
Ninfali et al. report that ZEB1 is required for the mesodermal-to-myogenic specification of human embryonic stem cells (hESCs) and their engraftment into mouse dystrophic muscles, while ZEB2 inhibits both processes. The study suggests that modulating ZEB1 and ZEB2 in hESCs could be an approach to enhance hESC regenerative capacity in muscular dystrophies.
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