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General equilibrium impacts on the U.S. economy of a disruption to Chinese cobalt supply
Not Available
Endocrine disrupting chemical mixture exposure and risk of papillary thyroid cancer in U.S. military personnel: A nested case-control study
Not provided.
Long non-coding RNA GClnc1 knockdown suppresses progression of epithelial ovarian cancer by recruiting FOXC2 to disrupt the NOTCH1/NF-κB/Snail pathway
Highlights: • GClnc1 is highly expressed in EOC patients and is associated with poor prognosis. • shGClnc1 inhibits the growth and metastasis of EOC cells and promotes apoptosis. • GClnc1 transcriptionally activates NOTCH1 by recruiting FOXC2 in the nucleus. • NOTCH1 promotes the activation of the NF-κB/Snail signaling. • GClnc1 may be one of the possible targets for the treatment of EOC. Epithelial ovarian cancer (EOC) is a highly fatal gynecological cancer. A long noncoding RNA (lncRNA) gastric cancer-associated lncRNA1 (GClnc1) has been revealed to play critical roles in metastasis. Therefore, the present study aims to explore the correlation between GClnc1 and the metastasis and progression of EOC.
Expression of membrane protein disulphide isomerase A1 (PDIA1) disrupt a reducing microenvironment in endometrial epithelium for embryo implantation
Various proteins in the endometrial epithelium are differentially expressed in the receptive phase and play a pivotal role in embryo implantation. The Protein Disulphide Isomerase (PDI) family contains 21 members that function as chaperone proteins through their redox activities. Although total PDIA1 protein expression was high in four common receptive (Ishikawa and RL95-2) and non-receptive (HEC1-B and AN3CA) endometrial epithelial cell lines, significantly higher membrane PDIA1 expression was found in non-receptive AN3CA cells. In Ishikawa cells, oestrogen up-regulated while progesterone down-regulated membrane PDIA1 expression. Moreover, mid-luteal phase hormone treatment down-regulated membrane PDIA1 expression. Furthermore, oestrogen at 10 nM reduced spheroid attachment on Ishikawa cells. Interestingly, inhibition of PDIA1 function by bacitracin or 16F16 increased the spheroid attachment rate onto non-receptive AN3CA cells. Over-expression of PDIA1 in receptive Ishikawa cells reduced the spheroid attachment rate and significantly down-regulated integrin β3 levels, but not integrin αV and E-cadherin. Addition of reducing agent TCEP induced a sulphydryl-rich microenvironment and increased spheroid attachment onto AN3CA cells and human primary endometrial epithelial cells collected at LH+7/8 days. The luminal epithelial cells from human endometrial biopsies had higher PDIA1 protein expression in the proliferative phase than in the secretory phase. Our findings suggest oestrogen and progesterone regulate PDIA1 expression, resulting in the differential expressions of membrane PDIA1 protein to modulate endometrial receptivity. This suggests that membrane PDIA1 expression prior to embryo transfer could be used to predict endometrial receptivity and embryo implantation in women undergoing assisted reproduction treatment.
MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance
CD4{sup +}CD25{sup +} regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4{sup +} T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.
Disruption of acyl-acyl carrier protein (acyl-ACP) synthetase in cyanobacteria impairs lipid remodeling as revealed by acyl-ACP measurements
Free fatty acid (FFA) production in bacteria is a key target for metabolic engineering. The knockout of the acyl-ACP synthetase (AAS) prevents reincorporation of FFA into the fatty acid biosynthetic cycle and is widely used to enhance their secretion. However, the role of AAS in membrane lipid remodeling under environmental stress, such as altered temperature, remains poorly understood. In cyanobacteria, temperature shifts are known to affect fatty acid desaturation and membrane fluidity, yet it is unclear whether AAS contributes to these adaptive responses through re-esterification of membrane-released acyl chains. We elucidated unique aspects of fatty acid metabolism in response to temperature changes in biotechnologically relevant microbes with the development of an efficient method for quantifying acyl-ACP intermediates using anion exchange chromatography (AEX). In Escherichia coli, which performs desaturation during fatty acid biosynthesis, we detected saturated and unsaturated acyl-ACPs that confirm biosynthetic pathway operation. In the cyanobacteria, Picosynechococcus sp. PCC 7002 and the Δaas strain, changes between two temperatures were interpreted with support from proteomic and lipidomic analyses and indicated that the AAS is tied to membrane lipid remodeling. Further, polyunsaturated acyl-ACPs were detected in the Δaas strain, which was unexpected because fatty acid synthesis does not produce polyunsaturates in cyanobacteria, suggesting the presence of alternative acyl-activating enzymes or unknown acyl-ACP desaturases. This study highlights the possible link between acyl chain recycling and lipid remodeling in cyanobacteria and demonstrates the utility of AEX-based acyl-ACP profiling in dissecting fatty acid metabolism.
Cesium Substitution Disrupts Concerted Cation Dynamics in Formamidinium Hybrid Perovskites
Abstract not provided
Hydrogen Bond Network Disruption by Hydration Layers in Water Solutions with Salt and Hydrogen-Bonding Polymers (PEO)
A mean field theory model describing the interaction of ion hydration layers with the network of hydrogen bonds of both water and the nonionic polymer poly(ethylene oxide) (PEO) is presented. The predictions of the model for types and statistics of hydrogen bonds, the number of water molecules bound to PEO, or their dependence on temperature are successfully verified from all-atom simulations at different NaCl and PEO concentrations. Furthermore, our simulations show that the binding of cations to PEO increases monotonically with salt concentration, in agreement with recent experimental results, through a mechanism in which the sum of the number of bound water and cations is independent of salt concentration. Here, the model introduced is general and can describe any salt or hydrogen-bond-forming polymer.
Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions
Not provided.
Trimer-to-Monomer Disruption Mechanism for a Potent, Protease-Resistant Antagonist of Tumor Necrosis
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A Growing Freshwater Lens in the Arctic Ocean With Sustained Climate Warming Disrupts Marine Ecosystem Function
One of the most robust changes in the hydrological cycle predicted by Earth System Models (ESMs) during the remainder of 21st century is an increase in the difference between precipitation and evapotranspiration (P-E) in arctic and boreal regions. We explore the long-term consequences of this change for marine ecosystems in the Arctic Ocean using the Community Earth System Model forced with a business as usual scenario of future greenhouse gas concentrations. We find that by the year 2300 increases in freshwater delivery considerably reduce Arctic Ocean surface salinity, creating a freshwater lens that has far-reaching impacts on marine biogeochemistry. The expanding freshwater lens limits vertical nutrient supply into the euphotic zone by enhancing vertical stratification and accelerating surface lateral mixing with surface waters in the North Atlantic, which become increasingly nutrient depleted from weakening of the Atlantic Meridional Overturning Circulation (AMOC). The resulting increase in nutrient stress reduces marine export production in the Arctic Ocean by 53% in 2300 relative to the 1990s and triggers a shift in community composition with small phytoplankton replacing diatoms. At the same time, the seasonal timing of export production undergoes a 2-month forward shift, with the peak advancing from July to May. This suggests that the threat to food webs and higher trophic levels may intensify after the year 2100 as gains in productivity from sea ice loss saturate and freshwater impacts on nutrient stress continue to strengthen. Our analysis highlights the critical importance of changing terrestrial hydrology and land-ocean coupling as drivers of long-term biogeochemical change in the Arctic Ocean and the necessity of multi-century climate change projections.
Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization
First proposed as antimicrobial agents, histones were later recognized for their role in condensing chromosomes. Histone antimicrobial activity has been reported in innate immune responses. However, how histones kill bacteria has remained elusive. The co-localization of histones with antimicrobial peptides (AMPs) in immune cells suggests that histones may be part of a larger antimicrobial mechanism in vivo. Here we report that histone H2A enters E. coli and S. aureus through membrane pores formed by the AMPs LL-37 and magainin-2. H2A enhances AMP-induced pores, depolarizes the bacterial membrane potential, and impairs membrane recovery. Inside the cytoplasm, H2A reorganizes bacterial chromosomal DNA and inhibits global transcription. Whereas bacteria recover from the pore-forming effects of LL-37, the concomitant effects of H2A and LL-37 are irrecoverable. Their combination constitutes a positive feedback loop that exponentially amplifies their antimicrobial activities, causing antimicrobial synergy. More generally, treatment with H2A and the pore-forming antibiotic polymyxin B completely eradicates bacterial growth.
A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
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Non-coding structural variants disrupt FOXG1 transcriptional regulation in early neurodevelopment
The FOXG1 transcription factor is a crucial regulator of embryonic brain development. Pathogenic FOXG1 variants cause FOXG1 syndrome. Although structural variants in the non-coding region downstream of FOXG1 have been reported in 38 individuals with similar characteristics, the regulatory pathomechanisms remain unknown. Here, we identify two non-coding structural variants in individuals with FOXG1 syndrome-like features, allowing us to delineate a ~ 124 kb commonly affected regulatory region. Using epigenomic profiling and in vivo enhancer assays, we characterize and validate regulatory elements within the commonly affected regulatory region and wider FOXG1 TAD. We see strong activation of previously validated forebrain enhancers, and identify an enhancer cluster and progenitor-specific enhancer region that are strongly activated during forebrain-directed neural progenitor cell differentiation, a process in which FOXG1 is an important regulator. Perturbation of these elements results in varying degrees of reduced FOXG1 transcription in forebrain neural progenitor cells and in population shifts within these cells, while removal of the TAD boundary leads to aberrant expression of the neighbouring PRKD1 gene. Our findings characterize enhancer and architectural elements essential for proper FOXG1 transcription during neurodevelopment, therefore improving variant interpretation in this region.
Disrupting the Hofmeister bias in salt liquid–liquid extraction with an arylethynyl bisurea anion receptor
Host-mediated liquid–liquid extraction is a convenient method for the separation of inorganic salts.
Resilience-Based Adaptive Traffic Signal Strategy against Disruption at Single Intersection
Not provided.