Tuberous sclerosis complex (TSC) is a multisystem developmental disorder caused by mutations in the TSC1 or TSC2 genes, whose protein products are negative regulators of mechanistic target of ...rapamycin complex 1 signaling. Hallmark pathologies of TSC are cortical tubers-regions of dysmorphic, disorganized neurons and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC by CRISPR-Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs). Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids. Our findings provide support for the second-hit model of cortical tuber formation and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.
•Pharmaceuticals and personal care products (PPCPs) were monitored in Lake Michigan.•Fifty-four PPCPs were assessed in surface water and sediment on six dates.•Many PPCPs, such as metformin, were ...detected 3.2km away from the shore.•Hydrophobic compounds were detected in sediment at concentrations up to 510ngg−1.•Using a risk quotient, the ecosystem risk was found to be high for many PPCPs.
The monitoring of pharmaceuticals and personal care products (PPCPs) has focused on the distribution in rivers and small lakes, but data regarding their occurrence and effects in large lake systems, such as the Great Lakes, are sparse. Wastewater treatment processes have not been optimized to remove influent PPCPs and are a major source of PPCPs in the environment. Furthermore, PPCPs are not currently regulated in wastewater effluent. In this experiment we evaluated the concentration, and corresponding risk, of PPCPs from a wastewater effluent source at varying distances in Lake Michigan. Fifty-four PPCPs and hormones were assessed on six different dates over a two-year period from surface water and sediment samples up to 3.2km from a wastewater treatment plant and at two sites within a harbor. Thirty-two PPCPs were detected in Lake Michigan and 30 were detected in the sediment, with numerous PPCPs being detected up to 3.2km away from the shoreline. The most frequently detected PPCPs in Lake Michigan were metformin, caffeine, sulfamethoxazole, and triclosan. To determine the ecological risk, the maximum measured environmental concentrations were compared to the predicted no-effect concentration and 14 PPCPs were found to be of medium or high ecological risk. The environmental risk of PPCPs in large lake systems, such as the Great Lakes, has been questioned due to high dilution; however, the concentrations found in this study, and their corresponding risk quotient, indicate a significant threat by PPCPs to the health of the Great Lakes, particularly near shore organisms.
A
bstract
We consider a non-relativistic limit of the bosonic sector of eleven-dimensional supergravity, leading to a theory based on a covariant ‘membrane Newton-Cartan’ (MNC) geometry. The local ...tangent space is split into three ‘longitudinal’ and eight ‘transverse’ directions, related only by Galilean rather than Lorentzian symmetries. This generalises the ten-dimensional stringy Newton-Cartan (SNC) theory. In order to obtain a finite limit, the field strength of the eleven-dimensional four-form is required to obey a transverse self-duality constraint, ultimately due to the presence of the Chern-Simons term in eleven dimensions. The finite action then gives a set of equations that is invariant under longitudinal and transverse rotations, Galilean boosts and local dilatations. We supplement these equations with an extra Poisson equation, coming from the subleading action. Reduction along a longitudinal direction gives the known SNC theory with the addition of RR gauge fields, while reducing along a transverse direction yields a new non-relativistic theory associated to D2 branes. We further show that the MNC theory can be embedded in the U-duality symmetric formulation of exceptional field theory, demonstrating that it shares the same exceptional Lie algebraic symmetries as the relativistic supergravity, and providing an alternative derivation of the extra Poisson equation.
The desire to develop artificial cells to imitate living cells in synthetic vesicle platforms has continuously increased over the past few decades. In particular, heterogeneous synthetic vesicles ...made from two or more building blocks have attracted attention for artificial cell applications based on their multifunctional modules with asymmetric structures. In addition to the traditional liposomes or polymersomes, polypeptides and proteins have recently been highlighted as potential building blocks to construct artificial cells owing to their specific biological functionalities. Incorporating one or more functionally folded, globular protein into synthetic vesicles enables more cell-like functions mediated by proteins. This Review highlights the recent research about synthetic vesicles toward artificial cell models, from traditional synthetic vesicles to protein-assembled vesicles with asymmetric structures. We aim to provide fundamental and practical insights into applying knowledge on molecular self-assembly to the bottom-up construction of artificial cell platforms with heterogeneous building blocks.
A large and complex suite of 295 legacy and new halogenated persistent organic pollutants (POPs) were investigated in fat or liver tissue samples of polar bears collected in 2013–2014 from Southern ...(SHB) and Western (WHB) subpopulations of the Canadian Arctic contaminants hotspot of Hudson Bay. A total of 210 POPs were detected and/or quantifiable with some frequency in all fat or liver samples. POP profile and concentration differences were investigated both within (e.g. age and sex) and between the two subpopulations. Two time-point comparisons were made relative to POPs reported for Hudson Bay polar bears harvested in 2007–2008. ΣPolychlorinated biphenyl (PCB) concentrations at both time points were the most concentrated of the POP groups, and were spatially uniform with no detectable influence of sex or age, as were concentrations of the dominant congener CB153. ΣChlordanes (ΣCHLs, 74–79% oxychlordane) and the Σperfluoroalkyl substances (ΣPFASs, ≈60% perfluorooctane sulfonate (PFOS)) had the second greatest POP group concentrations in SHB and WHB respectively, with ΣPFASs and ΣCHLs being significantly influenced by age and/or sex. ΣCHLs were spatially uniform but ΣPFASs were greater in the SHB bears, as were e.g. some flame retardants, due to e.g. local contamination and/or changes in bear behavior and diet. Endosulfans and hexabromocyclododecane were detectable in samples from 2007–2008 but not from 2013–2014, which is consistent with their global POP regulations. ΣPolychlorinated naphthalenes (ΣPCNs) were consistently detected at relatively high concentrations compared to other arctic wildlife, however these concentrations were low relative to legacy POPs. ΣShort-chain chlorinated paraffins (ΣSCCPs) were major contributors to the overall POPs burden with concentrations comparable to other legacy POPs, though there was no significant difference between or within subpopulations for PCNs or SCCPs. Except for octachlorostyrene, POPs concentrations were generally lower in female and male bears from SHB in 2013–2014 relative to 2007–2008, however those of WHB males were greater over the same timeframe for almost all POPs.
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•210 out of 295 legacy and new POPs were present in Hudson Bay (HB) polar bears.•ΣPCBs, ΣCHLs and PFOS were the dominant POPs in fat or liver samples.•Some POPs (e.g. ΣPFASs and ΣCHLs) were influenced by age, sex and/or subpopulation.•Some new POP concentrations were comparable (ΣSCCPs) and some lower (ΣPCNs) to legacy POPs.
Purpose
To propose guidelines based on an expert-panel-derived unified approach to the technical performance, interpretation, and reporting of MRI for baseline and post-treatment staging of rectal ...carcinoma.
Methods
A consensus-based questionnaire adopted with permission and modified from the European Society of Gastrointestinal and Abdominal Radiologists was sent to a 17-member expert panel from the Rectal Cancer Disease-Focused Panel of the Society of Abdominal Radiology containing 268 question parts. Consensus on an answer was defined as ≥ 70% agreement. Answers not reaching consensus (< 70%) were noted.
Results
Consensus was reached for 87% of items from which recommendations regarding patient preparation, technical performance, pulse sequence acquisition, and criteria for MRI assessment at initial staging and restaging exams and for MRI reporting were constructed.
Conclusion
These expert consensus recommendations can be used as guidelines for primary and post-treatment staging of rectal cancer using MRI.
We use high-quality, medium-resolution Hubble Space Telescope/Cosmic Origins Spectrograph (HST/COS) observations of 82 UV-bright active galactic nuclei (AGNs) at redshifts zAGN < 0.85 to construct ...the largest survey of the low-redshift intergalactic medium (IGM) to date: 5138 individual extragalactic absorption lines in H i and 25 different metal-ion species grouped into 2611 distinct redshift systems at zabs < 0.75 covering total redshift pathlengths ?zH i = 21.7 and zO vi = 14.5. Our semi-automated line-finding and measurement technique renders the catalog as objectively defined as possible. We find substantial clustering of H i absorbers on scales of v = 50-300 km s-1 with no significant clustering at v gsim 1000 km s-1. Splitting the sample into strong and weak absorbers, we see that most of the clustering occurs in strong, NH i gsim 1013.5 cm-2, metal-bearing IGM systems.
Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a reliable, rapid, and reproducible technique for measuring and evaluating changes in gene expression. To facilitate gene ...expression studies and obtain more accurate RT-qPCR data, normalization relative to stable reference genes is required. In this study, expression profiles of seven candidate reference genes, including β-actin (Actin), elongation factor 1 α (EF1A), glyceralde hyde-3-phosphate dehydro-genase (GAPDH), cyclophilins A (CypA), vacuolar-type H+-ATPase (ATPase), 28S ribosomal RNA (28S), and 18S ribosomal RNA (18S) from Hippodamia convergens were investigated. H. convergens is an abundant predatory species in the New World, and has been widely used as a biological control agent against sap-sucking insect pests, primarily aphids. A total of four analytical methods, geNorm, Normfinder, BestKeeper, and the ΔCt method, were employed to evaluate the performance of these seven genes as endogenous controls under diverse experimental conditions. Additionally, RefFinder, a comprehensive evaluation platform integrating the four above mentioned algorithms, ranked the overall stability of these candidate genes. A suite of reference genes were specifically recommended for each experimental condition. Among them, 28S, EF1A, and CypA were the best reference genes across different development stages; GAPDH, 28S, and CypA were most stable in different tissues. GAPDH and CypA were most stable in female and male adults and photoperiod conditions, 28S and EF1A were most stable under a range of temperatures, Actin and CypA were most stable under dietary RNAi condition. This work establishes a standardized RT-qPCR analysis in H. convergens. Additionally, this study lays a foundation for functional genomics research in H. convergens and sheds light on the ecological risk assessment of RNAi-based biopesticides on this non-target biological control agent.
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