Homo floresiensis, a primitive hominin species discovered in Late Pleistocene sediments at Liang Bua (Flores, Indonesia), has generated wide interest and scientific debate. A major reason this taxon ...is controversial is because the H. floresiensis-bearing deposits, which include associated stone artefacts and remains of other extinct endemic fauna, were dated to between about 95 and 12 thousand calendar years (kyr) ago. These ages suggested that H. floresiensis survived until long after modern humans reached Australia by ~50 kyr ago. Here we report new stratigraphic and chronological evidence from Liang Bua that does not support the ages inferred previously for the H. floresiensis holotype (LB1), ~18 thousand calibrated radiocarbon years before present (kyr cal. BP), or the time of last appearance of this species (about 17 or 13-11 kyr cal. BP). Instead, the skeletal remains of H. floresiensis and the deposits containing them are dated to between about 100 and 60 kyr ago, whereas stone artefacts attributable to this species range from about 190 to 50 kyr in age. Whether H. floresiensis survived after 50 kyr ago--potentially encountering modern humans on Flores or other hominins dispersing through southeast Asia, such as Denisovans--is an open question.
The Ubiquitin-Specific Protease 22 (USP22) is a deubiquitinating subunit of the mammalian SAGA transcriptional co-activating complex. USP22 was identified as a member of the so-called ..."death-from-cancer" signature predicting therapy failure in cancer patients. However, the importance and functional role of USP22 in different types and subtypes of cancer remain largely unknown. In the present study, we leveraged human cell lines and genetic mouse models to investigate the role of USP22 in HER2-driven breast cancer (HER2
-BC) and demonstrate for the first time that USP22 is required for the tumorigenic properties in murine and human HER2
-BC models. To get insight into the underlying mechanisms, we performed transcriptome-wide gene expression analyses and identified the Unfolded Protein Response (UPR) as a pathway deregulated upon USP22 loss. The UPR is normally induced upon extrinsic or intrinsic stresses that can promote cell survival and recovery if shortly activated or programmed cell death if activated for an extended period. Strikingly, we found that USP22 actively suppresses UPR induction in HER2
-BC cells by stabilizing the major endoplasmic reticulum (ER) chaperone HSPA5. Consistently, loss of USP22 renders tumor cells more sensitive to apoptosis and significantly increases the efficiency of therapies targeting the ER folding capacity. Together, our data suggest that therapeutic strategies targeting USP22 activity may sensitize tumor cells to UPR induction and could provide a novel, effective approach to treat HER2
-BC.
Abstract
On 2016 July 03, several instruments onboard ESA's Rosetta spacecraft detected signs of an outburst event on comet 67P, at a heliocentric distance of 3.32 au from the Sun, outbound from ...perihelion. We here report on the inferred properties of the ejected dust and the surface change at the site of the outburst. The activity coincided with the local sunrise and continued over a time interval of 14–68 min. It left a 10-m-sized icy patch on the surface. The ejected material comprised refractory grains of several hundred microns in size, and sub-micron-sized water ice grains. The high dust mass production rate is incompatible with the free sublimation of crystalline water ice under solar illumination as the only acceleration process. Additional energy stored near the surface must have increased the gas density. We suggest a pressurized sub-surface gas reservoir, or the crystallization of amorphous water ice as possible causes.
Consumers are increasingly concerned with the form and quantity of fat present in the foods they consume. This is leading to a shift in the way food is produced. In particular the animal industry is ...increasing the number of organic and naturally finished meat animals rather than finishing them on grains. The objective of this study was to determine if different pasture compositions (i.e. grass only or grass legume mixtures) would impact the fatty acid (FA) meat composition of beef steers (
Bos taurus L.). The pasture treatments were tall fescue
Lollium arundinaceum (Schreb.) S.J. Darbysh only, or tall fescue combined with either red clover (
Trifolium pretense L.) or alfalfa (
Medicago sativa L. ssp.
sativa L.). Beef steers (
n
=
9–10 per treatment) rotationally grazed each pasture treatment. Forage from treatments were different for crude protein (CP),
in vitro true digestibility (IVTD) and the FA myristric (C14:0), palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1), linoleic (C18:2), and total FA. Steers grazing mixtures with either red clover (RC) or alfalfa (ALF) had greater average daily gains (ADG) than tall fescue only. Additionally, RC treatment steers had larger ribeye areas (REA) and greater finishing weights than those in the ALF treatment. However, the differences found between pasture treatments in FA concentration did not translate to any differences in the FA concentration of meat harvested from steers. Thus, it is concluded that although the pastures contained different FA concentrations, with the levels of legumes present, this does not influence the FA composition of beef.
Homo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago
. Twelve H. erectus calvaria (skull caps) and two tibiae ...(lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 1933
, and are of the youngest, most-advanced form of H. erectus
. Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated
. Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish-to our knowledge-the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence,
argon/
argon (
Ar/
Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series-electron-spin resonance (US-ESR) dating to non-human fossils to directly date our re-excavation of Ngandong
. We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum)
and 134 and 118 ka (US-ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions
. These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species.
Strontium isotope ratios (87Sr / 86Sr) are a key geochemical tracer used in a wide range of fields including archaeology, ecology, food and forensic sciences. These applications are based on the ...principle that the Sr isotopic ratios of natural materials reflect the sources of strontium available during their formation. A major constraint for current studies is the lack of robust reference maps to evaluate the source of strontium isotope ratios measured in the samples. Here we provide a new data set of bioavailable Sr isotope ratios for the major geologic units of France, based on plant and soil samples (Pangaea data repository doi:10.1594/PANGAEA.819142). The IRHUM (Isotopic Reconstruction of Human Migration) database is a web platform to access, explore and map our data set. The database provides the spatial context and metadata for each sample, allowing the user to evaluate the suitability of the sample for their specific study. In addition, it allows users to upload and share their own data sets and data products, which will enhance collaboration across the different research fields. This article describes the sampling and analytical methods used to generate the data set and how to use and access the data set through the IRHUM database. Any interpretation of the isotope data set is outside the scope of this publication.
Exposure to polychlorinated biphenyls (PCBs) from indoor air can lead to a significant increase in lower chlorinated congeners in human blood. Lower chlorinated congeners with short biological ...half‐lives can exhibit an indirect genotoxic potential via their highly reactive metabolites. However, little is known about their occurrence in indoor air and, therefore, about the effects of possible exposure to these congeners. We analyzed all mono‐, di‐, and trichlorinated biphenyls in the indoor air of 35 contaminated offices, as well as in the blood of the 35 individuals worked in these offices for a minimum of 2 years. The median concentration of total PCB in the indoor air was 479 ng/m3. The most prevalent PCBs in the indoor air samples were the trichlorinated congeners PCB 31, PCB 18, and PCB 28, with median levels of 39, 31, and 26 ng/m3, respectively. PCB 8 was the most prevalent dichlorinated congener (median: 9.1 ng/m3). Monochlorinated biphenyls were not detected in relevant concentrations. In the blood samples, the most abundant congener was PCB 28; nearly 90% of all mono‐, di‐, and trichlorinated congeners were attributed to this congener (median: 12 ng/g blood lipid).
More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and ...women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+) to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination.
In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks.
We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. After 5-8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0·17, 95% CI 0·11-0·25) among girls aged 13-19 years, and decreased significantly by 66% (RR 0·34, 95% CI 0·23-0·49) among women aged 20-24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0·46, 95% CI 0·33-0·66) among girls aged 13-19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0·33, 95% CI 0·24-0·46) among girls aged 15-19 years, decreased significantly by 54% (RR 0·46, 95% CI 0.36-0.60) among women aged 20-24 years, and decreased significantly by 31% (RR 0·69, 95% CI 0·53-0·89) among women aged 25-29 years. Among boys aged 15-19 years anogenital wart diagnoses decreased significantly by 48% (RR 0·52, 95% CI 0·37-0·75) and among men aged 20-24 years they decreased significantly by 32% (RR 0·68, 95% CI 0·47-0·98). After 5-9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0·49, 95% CI 0·42-0·58) among screened girls aged 15-19 years and decreased significantly by 31% (RR 0·69, 95% CI 0·57-0·84) among women aged 20-24 years.
This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects.
WHO, Canadian Institutes of Health Research, Fonds de recherche du Québec - Santé.
Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early ...detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions.
and
were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of
in pancreatic CTCs. A combinatorial approach using both
and
expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples.
is thus proposed as a novel biomarker of pancreatic cancer CTCs.
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