Safe and just Earth system boundaries.

The stability and resilience of the Earth system and human well-being are inseparably linked1-3, yet their interdependencies are generally under-recognized; consequently, they are often treated independently4,5. Here, we use modelling and literature assessment to quantify safe and just Earth system boundaries (ESBs) for climate, the biosphere, water and nutrient cycles, and aerosols at global and subglobal scales. We propose ESBs for maintaining the resilience and stability of the Earth system (safe ESBs) and minimizing exposure to significant harm to humans from Earth system change (a necessary but not sufficient condition for justice)4. The stricter of the safe or just boundaries sets the integrated safe and just ESB. Our findings show that justice considerations constrain the integrated ESBs more than safety considerations for climate and atmospheric aerosol loading. Seven of eight globally quantified safe and just ESBs and at least two regional safe and just ESBs in over half of global land area are already exceeded. We propose that our assessment provides a quantitative foundation for safeguarding the global commons for all people now and into the future.

Stratifying TAD boundaries pinpoints focal genomic regions of regulation, damage, and repair.

Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site-clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries.

Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.

dbEmbryo multi-omics database for analyses of synergistic regulation in early mammalian embryo development.

During early mammalian embryo development, different epigenetic marks undergo reprogramming and play crucial roles in the mediation of gene expression. Currently, several databases provide multi-omics information on early embryos. However, how interconnected epigenetic markers function together to coordinate the expression of the genetic code in a spatiotemporal manner remains difficult to analyze, markedly limiting scientific and clinical research. Here, we present dbEmbryo, an integrated and interactive multi-omics database for human and mouse early embryos. dbEmbryo integrates data on gene expression, DNA methylation, histone modifications, chromatin accessibility, and higher-order chromatin structure profiles for human and mouse early embryos. It incorporates customized analysis tools, such as "multi-omics visualization," "Gene&Peak annotation," "ZGA gene cluster," "cis-regulation," "synergistic regulation," "promoter signal enrichment," and "3D genome." Users can retrieve gene expression and epigenetic profile patterns to analyze synergistic changes across different early embryo developmental stages. We showed the uniqueness of dbEmbryo among extant databases containing data on early embryo development and provided an overview. Using dbEmbryo, we obtained a phase-separated model of transcriptional control during early embryo development. dbEmbryo offers web-based analytical tools and a comprehensive resource for biologists and clinicians to decipher molecular regulatory mechanisms of human and mouse early embryo development.

Global spread characteristics of CTX-M-type extended-spectrum ß-lactamases: A genomic epidemiology analysis.

BACKGROUND: Extended-spectrum ß-lactamases (ESBLs) producing bacteria have spread worldwide and become a global public health concern. Plasmid-mediated transfer of ESBLs is an important route for resistance acquisition. METHODS: We collected 1345 complete sequences of plasmids containing CTX-Ms from public database. The global transmission pattern of plasmids and evolutionary dynamics of CTX-Ms have been inferred. We applied the pan-genome clustering based on plasmid genomes and evolution analysis to demonstrate the transmission events. FINDINGS: Totally, 48 CTX-Ms genotypes and 186 incompatible types of plasmids were identified. The geographical distribution of CTX-Ms showed significant differences across countries and continents. CTX-M-14 and CTX-M-55 were found to be the dominant genotypes in Asia, while CTX-M-1 played a leading role in Europe. The plasmids can be divided into 12 lineages, some of which forming distinct geographical clusters in Asia and Europe, while others forming hybrid populations. The Inc types of plasmids are lineage-specific, with the CTX-M-1_IncI1-I (Alpha) and CTX-M-65_IncFII (pHN7A8)/R being the dominant patterns of cross-host and cross-regional transmission. The IncI-I (Alpha) plasmids with the highest number, were presumed to form communication groups in Europe-Asia and Asia-America-Oceania, showing the transmission model as global dissemination and regional microevolution. Meanwhile, the main kinetic elements of blaCTX-Ms showed genotypic preferences. ISEcpl and IS26 were most frequently involved in the transfer of CTX-M-14 and CTX-M-65, respectively. IS15 has become a crucial participant in mediating the dissemination of blaCTX-Ms. Interestingly, blaTEM and blaCTX-Ms often coexisted in the same transposable unit. Furthermore, antibiotic resistance genes associated with aminoglycosides, sulfonamides and cephalosporins showed a relatively high frequency of synergistic effects with CTX-Ms. CONCLUSIONS: We recognized the dominant blaCTX-Ms and mainstream plasmids of different continents. The results of this study provide support for a more effective response to the risks associated with the evolution of blaCTX-Ms-bearing plasmids, and lay the foundation for genotype-specific epidemiological surveillance of resistance, which are of important public health implications.

Deciphering the pivotal role of people with high-frequency occupational animal exposure in antibiotic resistance transmission between humans and animals.

BACKGROUND: The spread of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) among humans and food-producing animals has been widely reported. However, the transmission routes and associated risk factors remain incompletely understood. METHODS: Here, we used commensal Escherichia coli bacteria strains from faeces of pigs and local citizens [HEG: high exposure group (pig breeders, butchers or restaurant chefs) and LEG: low exposure group (other occupations)] to explore the dynamics of ARB and ARG transmission between animals and humans. RESULTS: Most ARGs (96%) present in pigs were shared with humans. Carriage rates of the shared ARGs suggest two transmission patterns among pigs, the HEG and LEG: one pattern was highest in pigs, gradually decreasing in the HEG and LEG (e.g. floR and cmlA1); the other pattern was increasing from pigs to the HEG but then decreasing in the LEG (e.g. mcr-1.1). Carriage rates of the HEG were higher than in the LEG in both patterns, implicating the HEG as a crucial medium in transmitting ARB and ARGs between food-producing animals and humans. Moreover, frequent inter/intragroup transmission via strains, plasmids and/or mobile elements was evident. Carriage of mcr-1.1 on human-gut-prevalent plasmids possibly promoted its enrichment in the HEG. CONCLUSIONS: The HEG is a crucial factor in transmitting ARB and ARGs between food-producing animals and humans. Rational measures to contain the risks of occupational exposure are urgently needed to keep dissemination of antibiotic resistance in check and safeguard public health.

Soybean-mediated suppression of BjaI/BjaR1 quorum sensing in Bradyrhizobium diazoefficiens impacts symbiotic nitrogen fixation.

The acyl-homoserine lactones (AHLs)-mediated LuxI/LuxR quorum sensing (QS) system orchestrates diverse bacterial behaviors in response to changes in population density. The role of the BjaI/BjaR1 QS system in Bradyrhizobium diazoefficiens USDA 110, which shares homology with LuxI/LuxR, remains elusive during symbiotic interaction with soybean. Here this genetic system in wild-type (WT) bacteria residing inside nodules exhibited significantly reduced activity compared to free-living cells, potentially attributed to soybean-mediated suppression. The deletion mutant strain ΔbjaR1 showed significantly enhanced nodulation induction and nitrogen fixation ability. Nevertheless, its ultimate symbiotic outcome (plant dry weight) in soybeans was compromised. Furthermore, comparative analysis of the transcriptome, proteome, and promoter activity revealed that the inactivation of BjaR1 systematically activated and inhibited genomic modules associated with nodulation and nitrogen metabolism. The former appeared to be linked to a significant decrease in the expression of NodD2, a key cell-density-dependent repressor of nodulation genes, while the latter conferred bacterial growth and nitrogen fixation insensitivity to environmental nitrogen. In addition, BjaR1 exerted a positive influence on the transcription of multiple genes involved in a so-called central intermediate metabolism within the nodule. In conclusion, our findings highlight the crucial role of the BjaI/BjaR1 QS circuit in positively regulating bacterial nitrogen metabolism and emphasize the significance of the soybean-mediated suppression of this genetic system for promoting efficient symbiotic nitrogen fixation by B. diazoefficiens.IMPORTANCEThe present study demonstrates, for the first time, that the BjaI/BjaR1 QS system of Bradyrhizobium diazoefficiens has a significant impact on its nodulation and nitrogen fixation capability in soybean by positively regulating NodD2 expression and bacterial nitrogen metabolism. Moreover, it provides novel insights into the importance of suppressing the activity of this QS circuit by the soybean host plant in establishing an efficient mutual relationship between the two symbiotic partners. This research expands our understanding of legumes' role in modulating symbiotic nitrogen fixation through rhizobial QS-mediated metabolic functioning, thereby deepening our comprehension of symbiotic coevolution theory. In addition, these findings may hold great promise for developing quorum quenching technology in agriculture.

Serum long non-coding Ribonucleic Acid H19 serves as a biomarker for systemic lupus erythematosus and participates in the disease progression.

AIM: This study aimed to investigate the expression of H19 and its possible molecular mechanism in systemic lupus erythematosus (SLE). METHODS: The expression of H19 and miR-19b in serum and peripheral blood mononuclear cells (PBMCs) were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Receiver operator characteristic (ROC) curve was constructed to evaluate the diagnostic value of serum H19 in SLE. Pearson correlation coefficient was used to analyze the correlation between serum levels of H19 and miR-19b. Flow cytometry and Cell counting kit-8 (CCK-8) assay were performed to detect cell apoptosis and viability. The levels of pro-inflammatory and anti-inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA). Luciferase reporter gene assay was conducted to verify the interaction between H19 and miR-19b. RESULTS: The expression of H19 and miR-19b in SLE group were up-regulated and down-regulated, respectively. Serum H19 has certain clinical diagnostic value in SLE. In in vitro studies, overexpression of H19 can significantly inhibit the viability of PBMCs and promote apoptosis and inflammatory response of PBMCs by interacting with miR-19b. CONCLUSIONS: The expression of H19 is upregulated in patients with SLE and plays a role in cell function and inflammation by targeting miR-19b in PBMCs, which may be one of the pathological mechanisms of SLE.

The definition and global epidemiology of nonmobile colistin resistance (NMCR-3) determinants in Aeromonas from 1968 to 2022.

Polymyxins are the last line of defense in infections caused by multidrug-resistant Gram-negative bacteria. The chromosomal EptA in Aeromonas genus was defined as a nonmobile colistin resistance determinant 3 (NMCR-3). A total of 14 NMCR-3 genotypes were identified. The global prevalence of Aeromonas-borne NMCRs and MCRs indicates an increasing trend from 1968 to 2022. And an index of resistance risk, i.e, the ratio of η = MCR/NMCR, was proposed to evaluate the propagation potential of NMCR-3. The colistin resistance in North America and Europe faced a high risk of increasing incidence of MCR since large proportions of NMCR-3 variants disseminated from Aeromonas sources. We concluded that NMCR-3 variants act natural progenitors for MCR-3/5/7, and the future MCR variant(s) will most likely be MCR-5 or MCR-7, which is also an early warning of next MCR(s) emerging in Aeromonas.

Analysis of the effect of optical thickness on polarization in a sea fog stratified environment.

Since there are usually multiple layers present in a real-world sea fog environment, and because previous studies have tended to analyze sea fog as a single layer rather than as refined layered sea fog, this paper splits sea fog into two categories: water fog and salt fog double-layer environments. By adjusting the optical thickness of the two layers of media, we may investigate the issue of the law governing the transmission of polarized light. In this paper, the analysis is mainly carried out through a simulation and experimental tests. The simulation portion is based mostly on the improved layered Monte Carlo approach, which builds a simulation model more appropriate for multilayer non-spherical media by using the accumulation principle to determine the scattering and transmission properties between layers. The tests are conducted by altering the double-layer medium's optical thickness, incoming wavelength, and polarization state, and then getting the polarization information of visible light after transmission through the complicated environment. The findings demonstrate that the optical thickness of the sea fog double-layer media affects polarized light transmission in a non-negligible way. Longer wavelength polarized light may keep polarization information better as the optical thickness increases, and circularly polarized light has polarization-preserving properties that are superior to linearly polarized light. By contrasting the simulation findings with the experimental data, the consistency of the two conclusions is confirmed, and the study offers a helpful resource for the transmission of polarized light in the sea fog environment.

Polarized light transmission characteristics in a smoky ellipsoidal particle medium.

True natural environments are more complex, and light travels through non-spherical particle media, which can affect the transmission of light. The medium environment of non-spherical particles is more common than that of spherical particles, and some studies have shown that there are differences between spherical and non-spherical particles in polarized light transmission. Therefore, the use of spherical particles instead of non-spherical particles will result in great error. In view of this feature, this paper samples the scattering angle based on the Monte Carlo method, and then constructs a simulation model of a random sampling fitting phase function suitable for ellipsoidal particles. In this study, yeast spheroids and Ganoderma lucidum spores were prepared. The effects of different polarization states and optical thicknesses on the transmission of polarized light at three wavelengths were investigated using ellipsoidal particles with a ratio of 1.5 transverse to vertical axes. The results show that when the concentration of the medium environment increases, the polarized lights of different states all show obvious depolarization, but circularly polarized light has better polarization-preserving characteristics than linearly polarized light, and polarized light with larger wavelengths also shows more stable optical properties. When yeast and Ganoderma lucidum spores were used as the transport medium, the degree of polarization of polarized light had the same trend. However, the equal volume radius of yeast particles is smaller than that of Ganoderma lucidum spores, so when the laser is in the yeast particle medium, the polarization-maintaining property of polarized light is superior. This study provides an effective reference for the variation of polarized light transmission in an atmospheric transmission environment with heavy smoke.

More factors, better understanding: model verification and construct validity study on the community of inquiry in MOOC.

This study aimed to verify the applicability of the community of inquiry (CoI) survey instrument in MOOC involving 1,186 college students from 11 different disciplines in China. Exploratory factor analysis was used to explore potential factor structure models, and confirmatory factor analysis was utilized to verify the four-factor structure obtained from exploratory factor analysis. The original three- and new six-factor structure models were also included in the study. Confirmatory factor analysis results indicating that all three models fit very well with the data. Then Chi-square difference test was used to select the optimal model. Results indicate that the six-factor structure model with teaching presence, social presence, cognitive presence, design and organization, affective expression, and resolution is the optimal one, with good convergent and discriminant validity. Especially, the chi-square difference results indicate that design and organization can be significantly distinguished from teaching presence, whereas affective expression can be significantly distinguished from social presence, and resolution can be significantly distinguished from cognitive presence. Based on these findings, the present study argues that the six-factor structure model can provide a better understanding for the fine design and implementation of MOOC.

Ubiquitination-activating enzymes UBE1 and UBA6 regulate ubiquitination and expression of cardiac sodium channel Nav1.5.

Cardiac sodium channel Nav1.5 is associated with cardiac arrhythmias and heart failure. Protein ubiquitination is catalyzed by an E1-E2-E3 cascade of enzymes. However, the E1 enzyme catalyzing Nav1.5 ubiquitination is unknown. Here, we show that UBE1 and UBA6 are two E1 enzymes regulating Nav1.5 ubiquitination and expression. Western blot analysis and patch-clamping recordings showed that overexpression of UBE1 or UBA6 increased the ubiquitination of Nav1.5 and significantly reduced Nav1.5 expression and sodium current density, and knockdown of UBE1 or UBA6 expression significantly increased Nav1.5 expression and sodium current density in HEK293/Nav1.5 cells. Similar results were obtained in neonatal cardiomyocytes. Bioinformatic analysis predicted two ubiquitination sites at K590 and K591. Mutations of K590 and K591 to K590A and K591A abolished the effects of overexpression or knockdown of UBE1 or UBA6 on Nav1.5 expression and sodium current density. Western blot analysis showed that the effects of UBE1 or UBA6 overexpression on the ubiquitination and expression of Nav1.5 were abolished by knockdown of UBC9, a putative E2 enzyme reported for Nav1.5 ubiquitination by us. Interestingly, real-time RT-PCR analysis showed that the expression level of UBE1, but not UBA6, was significantly up-regulated in ventricular tissues from heart failure patients. These data establish UBE1 and UBA6 as the E1 enzymes involved in Nav1.5 ubiquitination, and suggest that UBE1 and UBA6 regulate ubiquitination of Nav1.5 through UBC9. Our study is the first to reveal the regulatory role of the UBE1 or UBA6 E1 enzyme in the ubiquitination of an ion channel and links UBE1 up-regulation to heart failure.

Corrigendum to "Neuroprotective Effects of the Sonic Hedgehog Signaling Pathway in Ischemic Injury through Promotion of Synaptic and Neuronal Health".

[This corrects the article DOI: 10.1155/2020/8815195.].

Interference Cancellation Based Spectrum Sharing for Massive MIMO Communication Systems.

Cellular network operators are predicting an increase in space of more than 200 percent to carry the move and tremendous increase of total users in data traffic. The growing of investments in infrastructure such as a large number of small cells, particularly the technologies such as LTE-Advanced and 6G Technology, can assist in mitigating this challenge moderately. In this paper, we suggest a projection study in spectrum sharing of radar multi-input and multi-output, and mobile LTE multi-input multi-output communication systems near m base stations (BS). The radar multi-input multi-output and mobile LTE communication systems split different interference channels. The new approach based on radar projection signal detection has been proposed for free interference disturbance channel with radar multi-input multi-output and mobile LTE multi-input multi-output by using a new proposed interference cancellation algorithm. We chose the channel of interference with the best free channel, and the detected signal of radar was projected to null space. The goal is to remove all interferences from the radar multi-input multi-output and to cancel any disturbance sources from a chosen mobile Communication Base Station. The experimental results showed that the new approach performs very well and can optimize Spectrum Access.

Involvement of a Novel TetR-Like Regulator (BdtR) of Bradyrhizobium diazoefficiens in the Efflux of Isoflavonoid Genistein.

A wide variety of leguminous plant-released (iso)flavonoids, such as genistein, are potential inducers of the nodulation (nod) genes of endosymbiotic rhizobia for the production of Nod factors, which are vital signaling molecules for triggering the symbiotic process. However, these (iso)flavonoids are generally thought to be toxic to the bacterial partner to varying degrees. Here, a novel TetR-like regulator gene of the soybean symbiont Bradyrhizobium diazoefficiens USDA110, bdtR (systematic designation blr7023), was characterized. It was found to be rapidly and preferentially induced by genistein, and its mutation resulted in significantly increased expression of the neighboring bll7019-bll7021 genes, encoding a multidrug resistance efflux pump system, in the absence of this isoflavonoid. Then, the transcriptional start site of BdtR was determined, and it was revealed that BdtR acted as a transcriptional repressor of the above efflux system through the binding of an AT-rich operator, which could be completely prevented by genistein. In addition, the ΔbdtR deletion mutant strain showed higher accumulation of extracellular genistein and became less susceptible to the isoflavonoid. In contrast, the inactivation of BdtR led to the significantly decreased induction of a nodulation gene (nodY) independent of the expression of nodD1 and nodW and to much weaker nodulation competitiveness. Taken together, the results show that BdtR plays an early sensing role in maintaining the intracellular homeostasis of genistein, helping to alleviate its toxic effect on this bacterium by negatively regulating neighboring genes encoding an efflux pump system while being essentially required for nodule occupancy competitiveness.[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Transboundary Environmental Footprints of the Urban Food Supply Chain and Mitigation Strategies.

Food supply has been the central issue of human development for millennia and has become increasingly critical in an urbanizing world. However, the environmental footprints and associated mitigation strategies of food consumption have rarely been comprehensively characterized at urban or regional scales. Here, we analyze the water, carbon, reactive nitrogen, and phosphorus footprints of food consumption in Chinese urban regions and demonstrate how such information can help to formulate tailored mitigation strategies. The results show that in three of the largest urban regions of China, 44-93% of the four footprints are embodied in transboundary food supply. The size of the footprints and the effectiveness of mitigation measures in food supply chain vary across the environmental footprints and urban regions. However, targeting agriculture and food processing sectors in Hebei, Shandong, and Henan provinces can reduce these footprints by up to 47%. Our findings show that the analysis of the environmental footprints along the transboundary food supply chains could inform individualized and effective mitigation targets and strategies.