[Distribution, Source, and Ecological Risk Assessment of Persistent Organic Pollutants in Surface Sediments of Boao Coastal Waters].

Persistent organic pollutants (POPs) in the environment have the characteristics of persistence, bioaccumulation, teratogenicity, carcinogenicity, and mutagenicity. Long-term exposure of low-content POPs will also have a certain impact on marine ecosystems and human beings. The contents of three typical persistent organic pollutants[polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and polycyclic biphenyls (PCBs)] of surface sediments were analyzed using gas chromatography and mass spectrometry (GC-MS) to assess the pollution characteristics of persistent organic pollutants in Boao coastal waters. The distribution and source of persistent organic pollutants were analyzed in this study, and the ecological risk was assessed using three different methods:the effect interval low/median method (ERL/ERM), mean effect interval median quotient method (M-ERM-Q), and mean potential impact concentration quotient method (M-PEC-Q). The results indicated that the contents (measured by dry weight) of ΣPAHs, ΣOCPs, and ΣPCBs in the study area were 4.5-367.50, 3.99-175.30, and ND-2.89 ng·g-1, respectively, which were at a low level, and the overall distribution showed a trend of gradually increasing toward the sea. The results of POPs source analysis showed that the PAHs in the study area were mainly from the combustion of wood and coal. Among OCPs, the HCH was mainly from lindane, the historical land-based input had been completely degraded, and the DDT was mainly the traditional DDTs pesticides, with additional continuous DDT input. The PCBs were primarily pentachlorobiphenyls, which might have come from the release of paint on the bottom of the hull in the early stage of shipping and the peeling off of paint from old ships. The ecological risk assessment results showed that there was little difference among the assessment results of the three methods, which showed that only phenanthrene monomer of PAHs in the study area had a slight negative impact, and the DDT and the γ-HCH among PAHs would cause great ecological risk, whereas PCBs and other pollutants would not cause ecological risk. On the whole, the possibility of comprehensive ecological risk caused by the three pollutants was very small.

Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.

Predicting tumor repopulation through the gene panel derived from radiation resistant colorectal cancer cells.

BACKGROUND: Tumor cells with the capability of radiation resistance can escape the fate of cell death after radiotherapy, serving as the main cause of treatment failure. Repopulation of tumors after radiotherapy is dominated by this group of residual cells, which greatly reduce the sensitivity of recurrent tumors to the therapy, resulting in poor clinical outcomes. Therefore, revealing the mechanism of radiation resistant cells participating in tumor repopulation is of vital importance for cancer patients to obtain a better prognosis. METHODS: Co-expressed genes were searched by using genetic data of radiation resistant cells (from GEO database) and TCGA colorectal cancer. Univariate and multivariate Cox regression analysis were performed to define the most significant co-expressed genes for establishing prognostic indicator. Logistic analysis, WGCNA analysis, and other types of tumors were included to verify the predictive ability of the indicator. RT-qPCR was carried out to test expression level of key genes in colorectal cancer cell lines. Colongenic assay was utilized to test the radio-sensitivity and repopulation ability of key gene knockdown cells. RESULTS: Prognostic indicator based on TCGA colorectal cancer patients containing four key radiation resistance genes (LGR5, KCNN4, TNS4, CENPH) was established. The indicator was shown to be significantly correlated with the prognosis of colorectal cancer patients undergoing radiotherapy, and also had an acceptable predictive effect in the other five types of cancer. RT-qPCR showed that expression level of key genes was basically consistent with the radiation resistance level of colorectal cancer cells. The clonogenic ability of all key gene knockdown cells decreased after radiation treatment compared with the control groups. CONCLUSIONS: Our data suggest that LGR5, KCNN4, TNS4 and CENPH are correlated with radiation sensitivity of colorectal cancer cells, and the indicator composed by them can reflect the prognosis of colorectal cancer patients undergoing radiation therapy. Our data provide an evidence of radiation resistant tumor cells involved in tumor repopulation, and give patients undergoing radiotherapy an approving prognostic indicator with regard to tumor progression.

Modeling nutrient flows from land to rivers and seas - A review and synthesis.

Water quality modeling facilitates management of nutrient flows from land to rivers and seas, in addition to environmental pollution management in watersheds. In the present paper, we review advances made in the development of seven water quality models and highlight their respective strengths and weaknesses. Afterward, we propose their future development directions, with distinct characteristics for different scenarios. We also discuss the practical problems that such models address in the same region, China, and summarize their different characteristics based on their performance. We focus on the temporal and geographical scales of the models, sources of pollution considered, and the main problems that can be addressed. Summary of such characteristics could facilitate the selection of appropriate models for resolving practical challenges on nutrient pollution in the corresponding scenarios globally by stakeholders. We also make recommendations for model enhancement to expand their capabilities.

Synergistic/antagonistic effects of nitrate/ammonium enrichment on fatty acid biosynthesis and translocation in coral under heat stress.

Superimposed on ocean warming, nitrogen enrichment caused by human activity puts corals under even greater pressure. Biosynthesis of fatty acids (FA) is crucial for coral holobiont survival. However, the responses of FA biosynthesis pathways to nitrogen enrichment under heat stress in coral hosts and Symbiodiniaceae remain unknown, as do FA translocation mechanisms in corals. Herein, we used the thermosensitive coral species Acropora hyacinthus to investigate changes in FA biosynthesis pathways and polyunsaturated FA translocation of coral hosts and Symbiodiniaceae with respect to nitrate and ammonium enrichment under heat stress. Heat stress promoted pro-inflammatory FA biosynthesis in coral hosts and inhibited FA biosynthesis in Symbiodiniaceae. Nitrate enrichment inhibited anti-inflammatory FA biosynthesis in Symbiodiniaceae, and promoted pro-inflammatory FA biosynthesis in coral hosts and translocation to Symbiodiniaceae, leading to bleaching after 14 days of culture. Intriguingly, ammonium enrichment promoted anti-inflammatory FA biosynthesis in Symbiodiniaceae and translocation to hosts, allowing corals to better endure heat stress. We constructed schematic diagrams of the shift in FA biosynthesis and translocation in and between A. hyacinthus and its Symbiodiniaceae under heat stress, heat and nitrate co-stress, and heat and ammonium co-stress. The findings provide insight into the mechanisms of coral bleaching under environmental stress from a fatty acid perspective.

Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor.

Repopulation of residual tumor cells impedes curative radiotherapy, yet the mechanism is not fully understood. It is recently appreciated that cancer cells adopt a transient persistence to survive the stress of chemo- or targeted therapy and facilitate eventual relapse. Here, it is shown that cancer cells likewise enter a "radiation-tolerant persister" (RTP) state to evade radiation pressure in vitro and in vivo. RTP cells are characterized by enlarged cell size with complex karyotype, activated type I interferon pathway and two gene patterns represented by CST3 and SNCG. RTP cells have the potential to regenerate progenies via viral budding-like division, and type I interferon-mediated antiviral signaling impaired progeny production. Depleting CST3 or SNCG does not attenuate the formation of RTP cells, but can suppress RTP cells budding with impaired tumor repopulation. Interestingly, progeny cells produced by RTP cells actively lose their aberrant chromosomal fragments and gradually recover back to a chromosomal constitution similar to their unirradiated parental cells. Collectively, this study reveals a novel mechanism of tumor repopulation, i.e., cancer cell populations employ a reversible radiation-persistence by poly- and de-polyploidization to survive radiotherapy and repopulate the tumor, providing a new therapeutic concept to improve outcome of patients receiving radiotherapy.

Ecological risk assessment of heavy metals in the sediments and their impacts on bacterial community structure: A case study of Bamen Bay in China.

Heavy metal pollution associated with human activity is of big concern in tropical bays. Microorganisms may be highly sensitive to heavy metals. Nonetheless, little is known about effects of heavy metals on microbial structure in tropical bay sediments. In this study, 16S rRNA gene sequencing and potential ecological risk index analysis were used to analyze the relationships between nine metals (arsenic, lead, cadmium, cobalt, chromium, copper, zinc, manganese, and nickel) and bacterial communities in the sediments of Bamen Bay, China. Our results showed that Bamen Bay was under a considerable ecological risk and cadmium had the highest monomial potential ecological risk. In addition, individual metal contamination correlated with bacterial community composition but not with bacterial α-diversity. Arsenic was the metal influencing bacterial community structure the most. Our findings provide a novel insight into the monitoring and remediation of heavy metal pollution in tropical bays.

Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose.

Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interrogated the effects of opioid overdose on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicted case-control status with high accuracy. We focused on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or "plexus": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid use disorder and captures genetic and environmental factors perpetuating the opioid epidemic.

Genetic analysis of dietary intake identifies new loci and functional links with metabolic traits.

Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases.

Stress-Induced Polyploid Giant Cancer Cells: Unique Way of Formation and Non-Negligible Characteristics.

Polyploidy is a conserved mechanism in cell development and stress responses. Multiple stresses of treatment, including radiation and chemotherapy drugs, can induce the polyploidization of tumor cells. Through endoreplication or cell fusion, diploid tumor cells convert into giant tumor cells with single large nuclei or multiple small nucleuses. Some of the stress-induced colossal cells, which were previously thought to be senescent and have no ability to proliferate, can escape the fate of death by a special way. They can remain alive at least before producing progeny cells through asymmetric cell division, a depolyploidization way named neosis. Those large and danger cells are recognized as polyploid giant cancer cells (PGCCs). Such cells are under suspicion of being highly related to tumor recurrence and metastasis after treatment and can bring new targets for cancer therapy. However, differences in formation mechanisms between PGCCs and well-accepted polyploid cancer cells are largely unknown. In this review, the methods used in different studies to induce polyploid cells are summarized, and several mechanisms of polyploidization are demonstrated. Besides, we discuss some characteristics related to the poor prognosis caused by PGCCs in order to provide readers with a more comprehensive understanding of these huge cells.

Gene Panel of Persister Cells as a Prognostic Indicator for Tumor Repopulation After Radiation.

Tumor repopulation during cycles of radiotherapy limits the radio-response in ensuing cycles and causes failure of treatment. It is thus of vital importance to unveil the mechanisms underlying tumor repopulating cells. Increasing evidence suggests that a subpopulation of drug-tolerant persister cancer cells (DTPs) could survive the cytotoxic treatment and resume to propagate. Whether these persister cells contribute to development of radio-resistance remains elusive. Based on the genetic profiling of DTPs by integrating datasets from Gene Expression Omnibus database, this study aimed to provide novel insights into tumor-repopulation mediated radio-resistance and identify predictive biomarkers for radio-response in clinic. A prognostic risk index, grounded on four persister genes (LYNX1, SYNPO, GADD45B, and PDLIM1), was constructed in non-small-cell lung cancer patients from The Cancer Genome Atlas Program (TCGA) using stepwise Cox regression analysis. Weighted gene co-expression network analysis further confirmed the interaction among persister-gene based risk score, radio-response and overall survival time. In addition, the predictive role of risk index was validated in vitro and in other types of TCGA patients. Gene set enrichment analysis was performed to decipher the possible biological signaling, which indicated that two forces behind persister cells, stress response and survival adaptation, might fuel the tumor repopulation after radiation. Targeting these persister cells may represent a new prognostic and therapeutic approach to enhance radio-response and prevent radio-resistance induced by tumor repopulation.

Caspase-3 knockout attenuates radiation-induced tumor repopulation via impairing the ATM/p53/Cox-2/PGE2 pathway in non-small cell lung cancer.

Radiotherapy is an effective treatment for non-small cell lung cancer (NSCLC). However, irradiated, dying tumor cells generate potent growth stimulatory signals during radiotherapy that promote the repopulation of adjacent surviving tumor cells to cause tumor recurrence. We investigated the function of caspase-3 in NSCLC repopulation after radiotherapy. We found that radiotherapy induced a DNA damage response (DDR), activated caspase-3, and promoted tumor repopulation in NSCLC cells. Unexpectedly, caspase-3 knockout attenuated the ataxia-telangiectasia mutated (ATM)/p53-initiated DDR by decreasing nuclear migration of endonuclease G (EndoG), thereby reducing the growth-promoting effect of irradiated, dying tumor cells. We also identified p53 as a regulator of the Cox-2/PGE2 axis and its involvement in caspase-3-induced tumor repopulation after radiotherapy. In addition, injection of caspase-3 knockout NSCLC cells impaired tumor growth in a nude mouse model. Our findings reveal that caspase-3 promotes tumor repopulation in NSCLC cells by activating DDR and the downstream Cox-2/PGE2 axis. Thus, caspase-3-induced ATM/p53/Cox-2/PGE2 signaling pathway could provide potential therapeutic targets to reduce NSCLC recurrence after radiotherapy.

Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS.

Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.

Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.

Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.

Genome-wide association study of breakfast skipping links clock regulation with food timing.

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.

Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration (p < 5 × 10-8; 43 loci at p < 6 × 10-9). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10-4), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis (n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.

Biomimetic Self-Cleaning Anisotropic Solid Slippery Surface with Excellent Stability and Restoration.

Anisotropic slippery surfaces are widely used in anti-fouling, smart control of liquid movement and directional liquid transportation. However, anisotropic slippery liquid-infused porous surfaces (SLIPS) cannot meet the need of practical applications owing to loss and contamination of liquid lubricants. Inspired by solid epicuticular wax on the surface of land plant leaves, we herein report a type of biomimetic anisotropic solid slippery surface (ASSS) based on paraffin wax-incorporated paper with directional micro-grooves. This ASSS material shows anisotropic sliding behavior for liquid droplets with different surface tensions. It is demonstrated to be of excellent stability compared with SLIPS as the solid lubricant cannot be lost and stain the contacting surfaces. It also exhibits outstanding acid and alkali corrosion resistance and restoration capability upon physical damage. Both hydrophilic and hydrophobic contaminants on our ASSS can be self-cleaned by using only water droplets. Our ASSS extends the fabrication of new slippery materials and overcomes some drawbacks of SLIPS.

Biological and clinical insights from genetics of insomnia symptoms.

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.

Gamma-modification of poly[(N,N-diethyldithiocarbamato)silver(I)].

In the title compound, catena-poly[[trisilver(I)-tri-mu3-N,N-diethyldithiocarbamato-3'kappaS:1kappaS':2kappaS;1kappaS:2kappaS':3kappaS;2kappaS:3kappa2S,S':1'kappaS'], [Ag3(C5H10NS2)3]n, the trigonally and tetrahedrally coordinated Ag atoms are mu3-bridged by kappa3- and kappa4-S2CNEt2 ligands to form a ribbon structure along the c axis. There is a twofold axis parallel to the b axis and passing through the tetrahedrally coordinated Ag atom. The S2CNEt2 ligands coordinate the Ag atoms in eta1,eta2- and eta2,eta2-fashions, depending on the bridging S atoms. The distances between the trigonal Ag and S atoms are 2.4915 (11)-2.6205 (11) A, while those between the tetrahedral Ag and S atoms are 2.5457 (11) and 2.7145 (10) A. The shortest Ag...Ag distance between trigonal Ag atoms is 2.8336 (7) A, which indicates a weak Ag...Ag interaction, whereas the shortest distance between trigonal and tetrahedral Ag atoms is 3.463 (6) A, which is considered as non-bonding.