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Volatile methylsiloxanes (VMSs) earned serious concerns due to their detection and toxicities after their release to the environments. They were also detected in rivers around the globe, but their distribution remained to be explored in larger rivers with longer length, higher water volume and wider watershed. In the present study, 8 cyclic VMSs (cVMSs) and 7 linear ones (lVMSs) were investigated in 42 water samples (27 surface water (including 7 drinking source water) and 15 wastewater) from the Yangtze River Basin, China. Results showed that VMSs were detected in all sampling sites. In surface water, the concentrations of total cVMSs ranged from 17.3 to 4.57 × 10 3  ng/L, while those of lVMSs ranged from 1.72 to 81.6 ng/L. In wastewater, the total concentrations of cVMSs and lVMSs showed ranges of 17.6-1.66 × 10 3  ng/L and 2.59-252 ng/L, respectively. Apparently, cVMSs showed significantly higher concentrations than lVMSs. The concentrations of cVMSs followed an order of lower > upper > middle reaches, while those of lVMSs did not show clear distribution patterns. Among cVMSs, those with less Si numbers were dominant, while those with more Si numbers were dominant in lVMSs. Notably, the VMSs were also detected in 7 surface waters that served as drinking source waters, which earned them further concerns. In addition, the VMSs in surface water showed positive correlation with those in wastewater, which led to necessity in management on industrial emissions in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Artificial sweeteners (ASs) entered the environments after application and emissions. Recent studies showed that some ASs had obesogenic risks. However, it remained unclear whether such risks are common and how they provoke such effects. Presently, the effects of 8 widely used ASs on lipid accumulation were measured in Caenorhabditis elegans. Potential mechanisms were explored with feeding and locomotion behavior, lipid metabolism and neural regulation. Results showed that acesulfame (ACE), aspartame (ASP), saccharin sodium (SOD), sucralose (SUC) and cyclamate (CYC) stimulated lipid accumulation at μg/L levels, showing obesogenic potentials. Behavior investigation showed that ACE, ASP, SOD, SUC and CYC biased more feeding in the energy intake aspect against the locomotion in the energy consumption one. Neotame (NEO), saccharin (SAC) and alitame (ALT) reduced the lipid accumulation without significant obesogenic potentials in the present study. However, all 8 ASs commonly disturbed enzymes (e.g., acetyl-CoA carboxylase) in lipogenesis and those (e.g., carnitine palmitoyl transferase) in lipolysis. In addition, ASs disturbed PPARγ (via expressions of nhr-49), TGF-β/DAF-7 (daf-7) and SREBP (sbp-1) pathways. Moreover, they also interfered neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh), with influences in Gsα (e.g., via expressions of gsα-1, ser-7), glutamate (e.g., mgl-1), and cGMP-dependent signaling pathways (e.g., egl-4). In summary, environmental ASs commonly disturbed neural regulation connecting behavior and lipid metabolism, and 5 out of 8 showed clear obesogenic potentials. ENVIRONMENTAL IMPLICATION: Artificial sweeteners (ASs) are become emerging pollutants after wide application and continuous emission. Recent studies showed that some environmental ASs had obesogenic risks. The present study employed Caenorhabditis elegans to explore the influences of 8 commonly used ASs on lipid metabolisms and also the underlying mechanisms. Five out of 8 ASs stimulated lipid accumulation at μg/L levels, and they biased energy intake against energy consumption. The other three ASs reduced the lipid accumulation. ASs commonly disturbed lipogenesis and lipolysis via PPARγ, TGF-β and SREBP pathways, and also influenced neurotransmitters with Gsα, glutamate and cGMP-dependent signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

As emerging pollutants, antibiotics were widely detected in water bodies and dietary sources. Recently, their obesogenic effects raised serious concerns. So far, it remained unclear whether their obesogenic effects would be influenced by water- and diet-borne exposure routes. In present study, Caenorhabditis elegans, nematodes free-living in air-water interface and feeding on bacteria, were exposed to water- and diet-borne erythromycin antibiotic (ERY). The statuses of the bacterial food, inactivated or alive, were also considered to explore their influences on the effects. Results showed that both water- and diet-borne ERY significantly stimulated body width and triglyceride contents. Moreover, diet-borne ERY's stimulation on the triglyceride levels was greater with alive bacteria than with inactivated bacteria. Biochemical analysis showed that water-borne ERY inhibited the activities of enzymes like adipose triglyceride lipase (ATGL) in fatty acid β-oxidation. Meanwhile, diet-borne ERY inhibited the activities of acyl-CoA synthetase (ACS) and carnitine palmitoyl transferase (CPT) in lipolysis, while it stimulated the activities of fatty acid synthase (FAS) in lipogenesis. Gene expression analysis demonstrated that water-borne ERY with alive bacteria significantly upregulated the expressions of daf-2, daf-16 and nhr-49, without significant influences in other settings. Further investigation demonstrated that ERY interfered with bacterial colonization in the intestine and the permeability of the intestinal barrier. Moreover, ERY decreased total long-chained fatty acids (LCFAs) in bacteria and nematodes, while it decreased total short-chained fatty acids (SCFAs) in bacteria but increased them in nematodes. Collectively, the present study demonstrated the differences between water- and diet-borne ERY's obesogenic effects, and highlighted the involvement of insulin and nhr-49 signaling pathways, SCFAs metabolism and also the interaction between intestinal bacteria and the host., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perfluorooctanoic acid (PFOA) exposure correlated with various cancers and their mortality. Its persistence in the environment made its long-term multigenerational influences of significant concerns. However, it remained unanswered whether its multigenerational exposure could influence metastasis which contributes ~90 % to cancer mortality. In the present study, long-term effects of PFOA were measured in Drosophila melanogaster over 3 consecutive generations. In the morning-eclosed (AM) adult flies, PFOA significantly promoted tumor invasion rates and distances which increased over generations. Regarding metabolic reprogramming, PFOA disturbed the expressions of Glut1 and Pdk1, activities and contents of FASN1 (fatty acid synthase), ACC (acetyl-CoA carboxylase) and SREBP1 (sterol regulatory element binding protein). Regarding antioxidant responses, PFOA exposure generated provoked oxidative stress via H 2 O 2 and stimulated antioxidants including glutathione (GSH), catalase (CAT), melatonin, serotonin and cortisol, with downregulations on PI3K/AKT pathways and upregulations on MAPK ones. The biochemical and molecular effects altered over generations. In the afternoon-eclosed (PM) adult flies, the metastasis of PFOA was more deteriorated than in AM adults. The significant influences of dysrhythmia were also observed in the multigenerational effects of PFOA on the metabolism reprogramming and antioxidant responses. The effects on rhythm-regulating gene expressions and protein levels explained the dysrhythmia and also indicated close interactions among metabolism reprogramming, antioxidant responses and rhythm regulation. ENVIRONMENTAL IMPLICATION: Numerous emerging per- and polyfluoroalkyl substances (PFASs) are being detected. Meanwhile, the toxicities of the emerging PFASs still depend on the progress of legacy PFASs for the continuity of scientific studies. As one legacy PFAS, perfluorooctanoic acid (PFOA) exposure correlated with various cancers and their mortality. Its persistence in the environment made its long-term multigenerational influences of significant concerns. However, it remained unanswered whether its multigenerational exposure could influence metastasis which contributes ~90 % to cancer mortality. The present study performed PFOA exposure for 3 consecutive generations. Results showed that the metastasis by PFOA increased over generations, and it was further deteriorated by dysrhythmia. Further analysis demonstrated the interactive involvement of metabolism reprogramming, antioxidant responses and rhythm regulation. The findings of the present study would highlight considerate points for studying the toxicities of emerging PFASs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Di-n-octyl phthalate (DOP) is one important phthalate analog whose toxicities need comprehensive investigation to fully demonstrate phthalates health risks. In the present study, apical effects of DOP on behavior, lifespan and reproduction and the underlying mechanisms were explored in Caenorhabditis elegans for four consecutive generations (F1 to F4) and the trans-generational effects were also measured in the great-grand-children (T4 and T4') of F1 and F4. Multi-generational results showed that DOP caused both stimulation and inhibition on head swing, body bending, reverse, Omega steering, pharyngeal pump and satiety quiescence. The stimulation and inhibition altered over concentrations and across generations, and the alteration was the greatest in reverse locomotion which showed both concentration-dependent hormesis and trans-hormesis. DOP stimulated lifespan and inhibited reproduction, showing trade-off relationships. Significant trans-generational residual effects were found in T4 and T4' where the exposure was completed eliminated. Moreover, both similar and different effects were found in comparisons between F1 and F4, between F1 and T4, between F4 and T4' and also between T4 and T4'. Further analysis showed close connections between effects of DOP on neurotransmitters (including dopamine, acetylcholine, γ-aminobutyric acid and serotonin) and enzymes in lipid metabolism (including lipase, acetyl CoA carboxylase, fatty acid synthetase, carnitine palmitoyl-transferase, glycerol phosphate acyltransferase and acetyl CoA synthetase). Moreover, the close connections were also found between biochemical and apical effects. Notably, the connections were different in multi- and trans-generational effects, which urged further studies to reveal the response strategies underlying the exposure scenarios., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This study aimed to investigate the predictive value of 18 F-FDG PET/CT for pathological response after neoadjuvant immunochemotherapy (NICT) in patients with esophageal squamous cell carcinoma (ESCC)., Methods: The clinical data of 54 patients with ESCC who underwent two cycles of NICT followed by surgery were retrospectively analyzed. NICT consisted of PD-1 blockade therapy combined with chemotherapy. 18 F-FDG PET/CT scans were performed before and after NICT. The pathological results after surgery were used to assess the degree of pathological response. The scan parameters of 18 F-FDG PET/CT and their changes before and after NICT were compared with the pathological response., Results: Among the 54 patients, 10 (18.5%) achieved complete pathological response (pCR) and 21 (38.9%) achieved major pathological response (MPR). The post-NICT scan parameters and their changes were significantly associated with the pathological response. In addition, the values of the changes in the scanned parameters before and after treatment can further predict the pathological response of the patient., Conclusion: 18 F-FDG PET/CT is a useful tool to evaluate the efficacy of NICT and predict pathological response in patients with ESCC. The post-NICT scan parameters and their changes can help identify patients who are likely to achieve pCR or MPR., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn't. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses., (© 2023. The Author(s).)

Geminal and vicinal borosilanes are useful building blocks in synthetic chemistry and material science. Hydrosilylation/hydroborylation of unsaturated systems offer expedient access to these motifs. In contrast to the well-established transition-metal-catalyzed methods, radical approaches are rarely explored. Herein we report the synthesis of geminal borosilanes from α-selective hydrosilylation of alkenyl boronates via photoinduced hydrogen atom transfer (HAT) catalysis. Mechanistic studies implicate that the α-selectivity originates from a kinetically favored radical addition and an energetically favored HAT process. We further demonstrate selective synthesis of vicinal borosilanes through hydrosilylation of allyl boronates via 1,2-boron radical migration. These strategies exhibit broad scopes across primary, secondary, and tertiary silanes and various boron compounds. The synthetic utility is evidenced by access to multi-borosilanes in a diverse fashion and scaling up by continuous-flow synthesis., (© 2023. The Author(s).)

General anesthesia is an indispensable procedure in clinical practice. Anesthetic drugs induce dramatic changes in neuronal activity and cerebral metabolism. However, the age-related changes in neurophysiology and hemodynamics during general anesthesia remain unclear. Therefore, the objective of this study was to explore the neurovascular coupling between neurophysiology and hemodynamics in children and adults during general anesthesia. We analyzed frontal electroencephalogram (EEG) and functional near-infrared spectroscopy (fNIRS) signals recorded from children (6-12 years old, n = 17) and adults (18-60 years old, n = 25) during propofol-induced and sevoflurane-maintained general anesthesia. The neurovascular coupling was evaluated in wakefulness, maintenance of a surgical state of anesthesia (MOSSA), and recovery by using correlation, coherence and Granger-causality (GC) between the EEG indices [EEG power in different bands and permutation entropy (PE)], and hemodynamic responses the oxyhemoglobin (Δ[HbO]) and deoxy-hemoglobin (Δ[Hb]) from fNIRS in the frequency band in 0.01-0.1 Hz. The PE and Δ[Hb] performed well in distinguishing the anesthesia state (p > 0.001). The correlation between PE and Δ[Hb] was higher than those of other indices in the two age groups. The coherence significantly increased during MOSSA (p < 0.05) compared with wakefulness, and the coherences between theta, alpha and gamma, and hemodynamic activities of children are significantly stronger than that of adults' bands. The GC from neuronal activities to hemodynamic responses decreased during MOSSA, and can better distinguish anesthesia state in adults. Propofol-induced and sevoflurane-maintained combination exhibited age-dependent neuronal activities, hemodynamics, and neurovascular coupling, which suggests the need for separate rules for children's and adults' brain states monitoring during general anesthesia., Competing Interests: The authors declare no conflicts of interest., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Ionic liquids (ILs) are emergent pollutants and their reproductive toxicities show hormesis, earning attentions on their environmental risk. Yet, their reproductive effects over generations and the mechanisms were seldom explored. In the present study, the reproductive effects of 1-ethyl-3-methylimidazolium hexafluorophosphate ([C 2 mim]PF 6 ) on Caenorhabditis elegans were measured in 11 continuously exposed generations (F1 to F11) to explore the multi-generational effects, and also in the non-exposed generations of F1 and F11 (i.e., their great-grand-daughters, T4 and T4') to explore the trans-generational effects. In multi-generational reproductive effects, there were concentration-dependent hormetic effects with hazard-benefit alteration between low and high concentrations (e.g., in F3). There were also generation-dependent hormetic effects with hazard-benefit alterations over generations (e.g., between F4 and F5, between F8 and F9, and between F10 and F11). Meanwhile, the results also showed benefit-hazard alteration between F2 and F3, between F6 and F7, and between F9 and F10. Trans-generational effects showed common inhibitions in T4 and T4' at both low and high concentrations. In the biochemical analysis, hormones and hormone-like substances including progesterone (P), estradiol (E2), prostaglandin (PG) and testosterone (T) showed multi- and trans-generational changes with inhibition and stimulation, which contributed to the reproductive outcomes in each generation. Such contribution was also observed in the hormones' precursor cholesterol and the proteins that are essential for reproduction including vitellogenin (Vn) and major sperm protein (MSP). Moreover, the biochemicals showed significant involvement in the connection among generations. Furthermore, the multi- and trans-generational effects of [C 2 mim]PF 6 and histidine showed similar modes of actions despite some differences, implying the contribution of their shared imidazole structure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Environmental antibiotics raise serious health concerns due to their contribution to the obesity prevalence. Moreover, antibiotics promote antibiotic-resistance bacteria (ARB) which represent another emerging pollutant. However, the interaction between antibiotic and ARB in the obesogenic effects remained unexplored. In the present study, the obesogenic effects of tetracycline antibiotic (TCH) and ARB containing tetA were studied on C. elegans, and E. coli OP50 (OP50) was referred as a normal bacterial food. Results showed that TCH stimulated nematode triglyceride contents, while ARB alone had no significant influences. The combination of TCH and ARB showed less obesogenic effects than TCH alone, showing antagonism. Biochemical assays showed that the combination of TCH and ARB showed similar effects to ARB alone, and had less increases in lipid metabolism enzymes or metabolites than those of TCH or ARB alone, supporting the antagonism. In the nontargeted metabolomic analysis, TCH with ARB showed less significantly changed metabolites (SCMs) in the nematodes than TCH or ARB alone, partially explaining the antagonism. The metabolomic results also pointed out the significant involvement of amino acids, the carboxylic acids and derivatives, and also the benzene and substituted derivatives in the obesogenic effects of TCH and ARB. The findings of the present study provided a direct support for interaction between antibiotics and ARB underlying their health risks., Competing Interests: Declaration of competing interest The authors did not report any conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In recent years, atomic force microscopes have been used for cell transfection because of their high-precision micro-indentation mode; however, the insertion efficiency of the tip of AFM into cells is extremely low. In this study, NIH3T3 mouse fibroblast cells cultured on a flexible dish with micro-groove patterns were subjected to various substrate strains at 5%, 10%, 15%, and 20%. It was found that the cell stiffness depends on the prestress of the cell membrane, and that the insertion rate of AFM tips into the cell membrane is proportional to the stiffness through the AFM indentation experiment. The finite element analysis proves that prestress increases the bending stiffness of the cytoskeleton, allowing it to better support the cell membrane, which realizes the stress concentration in the contact area between the AFM tip and the cell membrane. The results indicate that the prestress contributes to the mechanical properties of the cell and suggest that the insertion efficiency could be greatly improved with an increase of the prestress of the cell membrane.

Antibiotics have been identified as obesogens contributing to the prevalence of obesity. Moreover, their environmental toxicity shows sex dependence, which might also explain the sex-dependent obesity observed. Yet, the direct evidence for such a connection and the underlying mechanisms remain to be explored. In this study, the effects of tetracycline, which is a representative antibiotic found in both environmental and food samples, on Drosophila melanogaster were studied with consideration of both sex and circadian rhythms (represented by the eclosion rhythm). Results showed that in morning-eclosed adults, tetracycline significantly stimulated the body weight of females (AM females) at 0.1, 1.0, 10.0 and 100.0 µg/L, while tetracycline only stimulated the body weight of males (AM males) at 1.0 µg/L. In the afternoon-eclosed adults, tetracycline significantly stimulated the body weight of females (PM females) at 0.1, 1.0 and 100.0 µg/L, while it showed more significant stimulation in males (PM males) at all concentrations. Notably, the stimulation levels were the greatest in PM males among all the adults. The results showed the clear sex dependence of the obesogenic effects, which was diminished by dysrhythmia. Further biochemical assays and clustering analysis suggested that the sex- and rhythm-dependent obesogenic effects resulted from the bias toward lipogenesis against lipolysis. Moreover, they were closely related to the preference for the energy storage forms of lactate and glucose and also to the presence of excessive insulin, with the involvement of glucolipid metabolism. Such relationships indicated potential bridges between the obesogenic effects of pollutants and other diseases, e.g., cancer and diabetes., (Copyright © 2021. Published by Elsevier B.V.)

Metastasis includes tumor invasion and migration and underlies over 90% of cancer mortality. The metastatic effects of environmental carcinogens raised serious health concerns. However, the underlying mechanisms remained poorly studied. In the present study, an in vivo Ras V12 /lgl -/- model of the fruitfly, Drosophila melanogaster, with an 8-day exposure was employed to explore the metastatic effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126), perfluorooctanoic acid (PFOA) and cadmium chloride (CdCl 2 ). At 1.0 mg/L, PCB126, PFOA, and CdCl 2 significantly increased tumor invasion rates by 1.32-, 1.33-, and 1.29-fold of the control, respectively. They also decreased the larval body weight and locomotion behavior. Moreover, they commonly disturbed the expression levels of target genes in MAPK and UPR pathways, and their metastatic effects were significantly abolished by the addition of p38 inhibitor (SB203580), JNK inhibitor (SP600125) and IRE1 inhibitor (KIRA6). Notably, the addition of the IRE inhibitor significantly influenced sna/E-cad pathway which is essential in both p38 and JNK regulations. The results demonstrated an essential role of sna/E-cad in connecting the effects of carcinogens on UPR and MAPK regulations and the resultant metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Plastics contamination in the environment is a major concern. Risk assessment of micro- and nanoplastics (MPL and NPL) poses significant challenges due to MPL and NPL heterogeneity regarding compositional polymers, particle sizes and morphologies in the environment. Yet, there exists considerable toxicological literature on commercial polystyrene (PS) micro- and nanospheres. Although such particles do not directly represent the environmental MPL and NPL, their toxicity data should be used to advance the hazard assessment of plastics. Here, toxicity data of PS micro- and nanospheres for microorganisms, aquatic and terrestrial invertebrates, fish, and higher plants was collected and analyzed. The evaluation of 294 papers revealed that aquatic invertebrates were the most studied organisms, nanosized PS was studied more often than microsized PS, acute exposures prevailed over chronic exposures, the toxicity of PS suspension additives was rarely addressed, and ∼40 % of data indicated no organismal effects of PS. Toxicity mechanisms were mainly studied in fish and nematode Caenorhabditis elegans, providing guidance for relevant studies in higher organisms. Future studies should focus on environmentally relevant plastics concentrations, wide range of organisms, co-exposures with other pollutants, and method development for plastics identification and quantification to fill the gap of bioaccumulation assessment of plastics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Ionic liquids (ILs) are difficult to degrade and even accumulate in the environment. Accordingly, their long-term toxicities are particularly important to demonstrate their accurate risk assessment. However, their long-term toxicities over generations and the toxicity mechanisms lacked thorough investigation. Presently, N-butylpyridinium bromide ([bpyr]Br), a representative IL, was chosen to measure its long-term effects on Caenorhabditis elegans for seven consecutive generations at 0.0225 and 22.5 mg/L. Toxicity mechanisms were explored in F1, F3, F5 and F7 by combining both antioxidant responses and lipid metabolism. Results showed that [bpyr]Br at low concentration provoked oscillatory effects on the reproduction over 7 generations, with inhibition in F1 and F7 and stimulation in F2, F4 and F5. At high concentration, [bpyr]Br showed similar multi-generational oscillation with greater inhibition in F1 and greater stimulation in F5. The effects of [bpyr]Br on the antioxidant responses to oxidative stress also showed oscillation over generations. The integrated biomarker response (IBR) values showed that [bpyr]Br at low concentration did not provoke significant influences on the overall antioxidant homeostasis in F1 and F3, but significantly stimulated it in F5 and F7. Meanwhile, [bpyr]Br at high concentration stimulated the antioxidant homeostasis in F1 and F7 with non-significant influences in F3 and F5. The IBR values regarding indicators in lipid metabolism showed that [bpyr]Br significantly and commonly stimulated the overall metabolism without concentration-dependent differences. Further analysis implied that [bpyr]Br provoked different mechanisms underlying the responses at low and high concentrations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

SARS-CoV-2 infection induces imbalanced immune response such as hyperinflammation in patients with severe COVID-19. Here, we studied the immunometabolic regulatory mechanisms for the pathogenesis of COVID-19. We depicted the metabolic landscape of immune cells, especially macrophages, from bronchoalveolar lavage fluid of patients with COVID-19 at single-cell level. We found that most metabolic processes were upregulated in macrophages from lungs of patients with mild COVID-19 compared to cells from healthy controls, whereas macrophages from severe COVID-19 showed downregulation of most of the core metabolic pathways including glutamate metabolism, fatty acid oxidation, citrate cycle, and oxidative phosphorylation, and upregulation of a few pathways such as glycolysis. Rewiring cellular metabolism by amino acid supplementation, glycolysis inhibition, or PPARγ stimulation reduces inflammation in macrophages stimulated with SARS-CoV-2. Altogether, this study demonstrates that metabolic imbalance of bronchoalveolar macrophages may contribute to hyperinflammation in patients with severe COVID-19 and provides insights into treating COVID-19 by immunometabolic modulation., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

The reproductive toxicities over generations are essential to assess the long-term impacts environmental fluoroquinolone antibiotics (FQs). In the present study, the multi-generational effects of ofloxacin (OFL) and norfloxacin (NOR) on reproduction were studied on Caenorhabditis elegans from 9 successive generations (F1-F9). Results showed that OFL showed no effects in F1, stimulation in F2 to F4, and inhibition F5 to F9. The effects of NOR also showed oscillation between stimulation and inhibition across generations. Further biochemical analysis demonstrated that the reproductive toxicities of OFL and NOR were more closely connected with total cholesterol (TCHO), progesterone (P) and testosterone (T), than major sperm protein (MSP) and vitellogenin (Vn). Moreover, OFL and NOR also showed significant trans-generational reproductive toxicities in T4 and T4', the great-grand-daughter of F1 and F9. Differences between T4 and T4' and between OFL and NOR, indicated influences of multi-generational exposure and urged more exploration on different mechanisms between FQs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a kind of central nervous system (CNS) autoimmune disease, which mainly damages nerves, the brain, and the spinal cord. Recently, several clinical cases reported the relativity between Coronavirus Disease 2019 (COVID-19) and the development of MS, but the mechanism of how COVID-19 affects the occurrence of MS was still not clear. It is bioinformatics technology that we use to explore the potential association at the gene level. The genetic information related to the two diseases was collected from the DisGNET platform for functional protein network analysis and used STRING to identify the complete gene set. The protein-protein interaction (PPI) network was analyzed by STRING. Finally, in the GEO database, we selected peripheral blood mononuclear cell (PBMC) RNA sequencing data (GSE164805, GSE21942) from COVID-19 patients and MS patients to verify the potential cross mechanism between the two diseases. The similar gene set of immune or inflammation existed between the patients with COVID-19 and ones with MS, including L2RA, IFNG, IL1B, NLRP3, and TNF. Interaction network analysis among proteins revealed that IL1B, P2RX7, IFNB1, IFNB1, TNF, and CASP1 enhanced the network connectivity between the combined gene set of COVID-19 and MS associated with NOD-like receptor (NLR) signaling. The involvement of NLR signaling in both diseases was further confirmed by comparing peripheral blood monocyte samples from COVID-19 and MS patients. Activation of NLR signaling was found in both COVID-19 and MS. The PBMC samples analyses also indicated the involvement of the NLR signaling pathway. Taken together, our data analyses revealed that the NLR signaling pathway might play a critical role in the COVID-19-related MS., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Carbonaceous materials are considered strong candidates as anode materials for sodium-ion batteries (SIBs), which are expected to play an indispensable role in the carbon-neutral era. Herein, novel braided porous carbon fibres (BPCFs) are prepared using the chemical vapour deposition (CVD) method. The BPCFs possess interwoven porous structures and abundant vacancies. The growth mechanism of the BPCFs can be attributed to the polycrystalline transformation of the nanoporous copper catalyst in the early stage of CVD process. Density functional theory calculations suggest that the Na + adsorption energies of the mono-vacancy edges of the BPCFs (-1.22 and -1.09 eV) are lower than that of an ideal graphene layer (-0.68 eV), clarifying in detail the adsorption-dominated sodium storage mechanism. Hence, the BPCFs as an anode material present an outstanding discharge capacity of 401 mAh g -1 at 0.1 A g-1 after 500 cycles. Remarkably, this BPCFs anode, under high-mass-loading of 5 mg cm-2, shows excellent long-term cycling ability with a reversible capacity of 201 mAh g -1 at 10 A g -1 over 1000 cycles. This study provided a novel strategy for the development of high-performance carbonaceous materials for SIBs., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Environmental obesogens contributed significantly to the obesity prevalence. Recently, antibiotics joined the list of environmental obesogens, while the underlying mechanisms remained to be explored. In the present study, effects of erythromycin (ERY), one widely used macrolide antibiotic, were measured on C. elegans to investigate the obesogenic mechanism. Results showed that ERY at 0.1 μg/L significantly increased the fat content by 17.4% more than the control and also stimulated triacylglycerol (TAG) levels by 25.7% more than the control. Regarding the obesogenic mechanisms, ERY provoked over-eating by stimulation on the pharyngeal pumping and reduction on the satiety quiescence percentage and duration. Such effects were resulted from stimulation on the neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh). The nervous responses involved the up-regulation of Gsα (e.g., ser-7, gsa-1, acy-1 and kin-2) signaling pathway and the down-regulation of TGFβ (daf-7) but not via cGMP-dependent regulations (e.g., egl-4). Moreover, ERY stimulated the activities of fatty acid synthase (FAS) and glycerol-3-phosphateacyl transferases (GPAT) that catalyze lipogenesis, while ERY inhibited those of acyl-CoA synthetase (ACS), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) that catalyze lipolysis. The unbalance between lipogenesis and lipolysis resulted in the fat accumulation which was consistent with up-regulation on mgl-1 and mgl-3 which are the down-steam of TGFβ regulation. Such consistence supported the close connection between nervous regulation and lipid metabolism. In addition, ERY also disturbed insulin which connects lipid with glucose in metabolism., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although the polyether ether ketone (PEEK) has excellent comprehensive properties, its non-antibacterial and low wear-resistant limit the wide application in the field of artificial joint materials. In this paper, Nano-ZnO was generated in situ on the surface of PEEK powder by one-step hydrothermal method, which improved the binding force of Nano-ZnO and PEEK matrix. Then the PEEK-based nanocomposites were prepared by melt blending with the synthesized Nano-ZnO-PEEK powders and PEEK powders. The microstructure, mechanical, biological and tribological properties of PEEK-based nanocomposites were studied. The results showed that the compressive strength of PEEK-based nanocomposites can reach up to 319.2 ± 2.4 MPa. Both PEEK and PEEK-based nanocomposites were non-toxic to cells. Meanwhile, PEEK-based nanocomposites showed good antibacterial activity against E.coli and Staphylococcus aureus, and the antibacterial activity was better with the increase of Nano-ZnO content. In addition, when the Nano-ZnO content was 5%, the wear rate of PEEK-based nanocomposites was about 68% lower than that of pure PEEK materials. Thus, PEEK-based nanocomposites has a dual function of good antibacterial property and excellent wear resistance., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Antibiotics are ubiquitous environmental pollutants and they can provoke multi-generational impacts due to their pseudo-persistence. However, their multi-generational effects and potential mechanisms remained poorly studied. Presently, effects of enrofloxacin (ENR) were studied on Caenorhabditis elegans with a continuous exposure over 9 generations (from F1 to F9) at an environmentally realistic level. Regarding reproduction, ENR showed stimulation in F1 (1.18-fold of the control) and F2 (1.08), inhibition in F3 (0.70), stimulation in F4 (1.86), F5 (3.18) and F6 (1.53), inhibition in F7 (0.73) and F8 (0.69) and stimulation again in F9 (1.89). That is to say, ENR provoked multi-generational oscillatory effects on the reproduction. Such oscillation was also observed in effects on lifespan with much less magnitudes than those on reproduction. Biochemical assays were performed in F1, F3, F4 and F9 which represented the oscillation over generations. Results showed more antioxidants (e.g., superoxide dismutase and glutathione), mild oxidative stress (e.g., reactive oxygen species) and less oxidative damage (i.e., protein carbonyl) underlying the generation-dependent stimulation. Moreover, ENR provoked multi-generational oscillation on the enzymes that regulate the lipogenesis (e.g., fatty acid synthase and acetyl-CoA carboxylase) and lipolysis (e.g., acyl-CoA synthetase), with similarities to the effects on the oxidative stress and damage. Further analysis on SKN-1 and its activating PMK-1 and GSK-3 demonstrated their involvement in regulating both antioxidant detoxification and lipid metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A metal-free sulfenylation/spirocyclization of indolyl-ynones realized by organosulfenyl chloride, generated in situ from the reaction of disulfides and PhICl 2 , is presented. This cascade one-pot process enables a chemoselective synthesis of diverse sulfenylated spiroindolenines depending on the substituent pattern at the two-position of indolyl-ynones.

Brain endothelial cells (ECs) are an important component of the blood-brain barrier (BBB) and play key roles in restricting entrance of possible toxic components and pathogens into the brain. However, identifying endothelial genes that regulate BBB homeostasis remains a time-consuming process. Although somatic genome editing has emerged as a powerful tool for discovery of essential genes regulating tissue homeostasis, its application in brain ECs is yet to be demonstrated in vivo. Here, we used an adeno-associated virus targeting brain endothelium (AAV-BR1) combined with the CRISPR/Cas9 system (AAV-BR1-CRISPR) to specifically knock out genes of interest in brain ECs of adult mice. We first generated a mouse model expressing Cas9 in ECs ( Tie2 Cas9 ). We selected endothelial β-catenin ( Ctnnb1 ) gene, which is essential for maintaining adult BBB integrity, as the target gene. After intravenous injection of AAV-BR1-sg Ctnnb1 -tdTomato in 4-week-old Tie2 Cas9 transgenic mice resulted in mutation of 36.1% of the Ctnnb1 alleles, thereby leading to a dramatic decrease in the level of CTNNB1 in brain ECs. Consequently, Ctnnb1 gene editing in brain ECs resulted in BBB breakdown. Taken together, these results demonstrate that the AAV-BR1-CRISPR system is a useful tool for rapid identification of endothelial genes that regulate BBB integrity in vivo ., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

An interrupted Pummerer reaction of PhICl 2 and sulfoxides was found to in situ generate reactive organosulfenyl chloride, which enabled the intramolecular electrophilic cyclization of 2-alkynylanilines, generating 3-sulfenylated indole with a good to excellent yield under metal-free conditions. One striking feature of the approach is that sulfoxide regeneration can be realized via the oxidation of the formed sulfides by the generated hypervalent iodine species.

[Figure: see text].

Short-chained perfluorobutane sulfonate (PFBS, four-carbon) and perfluorohexane sulfonate (PFHxS, six-carbon) are widely employed to substitute long-chained per- and poly-fluoroalkyl substances (PFASs). Recent studies showed the potential persistence of PFBS and PFHxS, and also reported their correlation with obesity. However, the long-term outcome and underlying mechanisms remained poorly understood. Presently, the effects of PFBS and PFHxS were studied on C. elegans with multi- and trans-generational experiments. The multi-generational effects were measured in continuous four generational exposure (i.e., F1 to F4). Results showed that PFBS did not stimulate the fat content in F1 but in F4 with continuous but different disturbances on the lipid metabolism and the insulin and insulin-like (IIS) pathway. PFHxS stimulated the fat content in F1 and F4 with similar disturbances on the lipid metabolism and IIS pathway. The trans-generational results showed that the effects of PFBS and PFHxS on the lipid metabolism and IIS pathway were not totally recovered in the offspring of F1 (i.e., T1-T3) and F4 (i.e., T1'-T3') which were not continuously exposed. PFHxS showed a common pattern to up-regulate daf-7 in both multi- and trans-generational effects. The long-term consequences of the short-chained PFASs substitutes should be concerned and epigenetic regulations should be considered in future mechanism studies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The nitrile group is an important functional group widely found in both pharmaceutical agents and natural products. More than 30 nitrile-containing pharmaceuticals have been approved by the FDA for the management of a broad range of clinical conditions in the last few decades. Incorporation of a nitrile group into lead compounds has gradually become a promising strategy in rational drug design as it can bring additional benefits including enhanced binding affinity to the target, improved pharmacokinetic profile of parent drugs, and reduced drug resistance. This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses., (© 2021. The Author(s).)

Ammonia is a major pollutant in the water environment, which could cause severe harm to aquatic organisms. To explore the pathological and physiological effects of ammonia in Chinese striped-necked turtles (Mauremys sinensis), the individuals (body mass: 218.26 ± 12.65 g) were divided into two groups: control group and ammonia exposed group (6.25 mM total ammonia), then the expression levels of signaling factors involved in the endoplasmic reticulum stress and apoptotic pathways were determined. The results showed that ammonia exposure up-regulated the transcriptional and protein levels of endoplasmic reticulum stress marker gene Bip. Meanwhile, the relative mRNA levels of key genes (PERK, ATF6, eIF2α, ATF4, IRE1α and XBP1) involved in unfolded protein response up-regulated, and the phosphorylation levels of PERK, eIF2α and IRE1α increased correspondingly. In addition, the protein and transcriptional levels of CHOP and JNK related to apoptotic pathway induced by unfolded protein reaction increased under ammonia exposure. Moreover, Bcl-2 mRNA expression levels and protein levels decreased, whereas BAX and caspase-3 showed an opposite trend, and the cleaved protein of caspase-3 appeared when the turtles in the elevated ammonia. Furthermore, the apoptotic cells in liver increased after ammonia exposure. These results suggested ammonia exposure induced endoplasmic reticulum stress, then activated unfolded protein response, followed by apoptosis in M. sinensis. The results will contribute to a better understanding of the toxicity mechanism of ammonia to aquatic turtles., (Copyright © 2021. Published by Elsevier B.V.)

A series of alkoxylated isobenzofuranones were conveniently synthesized from the reaction of 2-(1-arylvinyl)benzoic acids with PhI(OR)2, generated in situ from the reaction of iodosobenzene (PhIO) with alkyl alcohols. This hypervalent iodine mediated one-pot transformation is postulated to undergo a cascade reaction involving lactonization, 1,2-aryl migration and alkoxylation processes. The organocatalytic and chiral organoiodine-catalyzed asymmetric reactions of the current transformation were also probed.

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients' sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with β-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients., Competing Interests: The authors have declared that no competing interests exist.

A highly substituent-dependent rearrangement allows for the novel and SOCl 2 -induced divergent synthesis of 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones through intramolecular electrophilic cyclization of N -aryl propyamides. DMSO acts as both solvent and sulfur source, and use of DMSO- h 6 / d 6 enables the incorporation of SCH 3 or SCD 3 moieties to the 3-position of the heterocyclic framework. Different para -substituents trigger divergent reaction pathways leading to the formation of quinolin-2-ones for mild substituents and spiro[4,5]trienones for both electron-withdrawing and -donating substituents, respectively. On the basis of both computational and experimental results, a new mechanism has been put forward that accounts for the exclusive spirolization/defluorination process and the surprising substituent effects.

Objective: This study aims to understand the neural and hemodynamic responses during general anesthesia in order to develop a comprehensive multimodal anesthesia depth monitor using simultaneous functional Near Infrared Spectroscopy (fNIRS) and Electroencephalogram (EEG)., Methods: 37 adults and 17 children were monitored with simultaneous fNIRS and EEG, during the complete general anesthesia process. The coupling of fNIRS signals with neuronal signals (EEG) was calculated. Measures of complexity (sample entropy) and phase difference were also quantified from fNIRS signals to identify unique fNIRS based biomarkers of general anesthesia., Results: A significant decrease in the complexity and power of fNIRS signals characterize the anesthesia maintenance phase. Furthermore, responses to anesthesia vary between adults and children in terms of neurovascular coupling and frontal EEG alpha power., Conclusions: This study shows that fNIRS signals could reliably quantify the underlying neuronal activity under general anesthesia and clearly distinguish the different phases throughout the procedure in adults and children (with less accuracy)., Significance: A multimodal approach incorporating the specific differences between age groups, provides a reliable measure of anesthesia depth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Antibiotics are gaining attention due to their roles as emerging pollutants and environmental obesogens, yet several aspects between their environmental exposure and obesogenic influence on organisms remain poorly explored. Here, Drosophila melanogaster were exposed to erythromycin (ERY, 0.1 μg/L) for three consecutive generations (F1 to F3). Body weight, circadian rhythm (represented by eclosion timing) and lipid metabolism were measured. ERY increased the size of lipid droplets in larvae of all three generations. It modestly inhibited body weight in adults that abnormally eclosed in the morning (AM adults) in the F1 and F2 generations, and the inhibition was less in adults that eclosed in the afternoon (PM adults). In contrast, it stimulated body weight in F3 adults. Notably, ERY promoted morning eclosion of females. Combining the effects from F1 to F3, acyl-CoA oxidase (ACO) was commonly increased in AM female and male adults and also in PM female ones, while it was commonly decreased in PM male adults. Glucokinase (GCK) was commonly increased in both sexes of AM adults but decreased in PM male adults across generations. The IIS pathway showed a common up-regulation in the AM adults despite some differences between sexes, but it did not show any shared changes in the PM adults with dysrhythmia. The AMPK pathway was involved across generations without particular shared changes. Collectively, the effects of ERY on the key metabolites and enzymes in glucolipid metabolism and the genetic regulations depended on sex, rhythm and exposure generation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sulfate radical (SO 4 ·- )-based advanced oxidation processes (AOPs) attract increasing attention in the control of micropollutants. However, SO 4 ·- can react with other chemicals present in water and result in undesired oxidation by-products (OBPs) generation. The formation and degradation mechanisms of CX 3 R-type OBPs during cobalt catalyzed peroxymonosulfate (Co 2+ /PMS) oxidation were investigated. In the formation of CX 3 R-type OBPs, both Co 3+ and SO 4 ·- could convert chloride to free chlorine that then reacted with natural organic matter, leading to the formation of CX 3 R-type OBPs. The concentrations of trichloromethane, chloral hydrate, dichloroacetonitrile, dichloroacetamide and trichloroacetamide after 15 min reaction were 9.8, 3.9, 1.2, 5.9 and 22.3 nM, respectively. Compared to SO 4 ·- , Co 3+ played a more significant role in the CX 3 R-type OBP formation and calculated toxicity values of CX 3 R-type OBPs. CX 3 R-type OBPs could not only be formed but also be degraded at the same time during Co 2+ /PMS oxidation. As for the degradation of CX 3 R-type OBPs, both Co 3+ and SO 4 ·- could transform CX 3 R-type OBPs to chloride. Compared to Co 3+ , SO 4 ·- played a more important role in the degradation of CX 3 R-type OBPs and the conversion from chloride to final by-product chlorate. The adverse effects that results from Co 3+ need more attention in SO 4 ·- -based AOPs application., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs), a key component of the endosomal sorting complex required for transport (ESCRT), has been implicated in many essential biological processes. However, the physiological role of endogenous Hgs in the vascular system has not previously been explored. Here, we have generated brain endothelial cell (EC) specific Hgs knockout mice to uncover the function of Hgs in EC polarity and cerebrovascular stability., Methods and Results: Knockout of Hgs in brain ECs led to impaired endothelial apicobasal polarity and brain vessel collapse in mice. We determined that Hgs is essential for recycling of vascular endothelial (VE)-cadherin to the plasma membrane, since loss of Hgs blocked trafficking of endocytosed VE-cadherin from early endosomes to recycling endosomes, and impaired the motility of recycling endosomes. Supportively, overexpression of the motor kinesin family member 13A (KIF13A) restored endosomal recycling and rescued abrogated polarized trafficking and distribution of VE-cadherin in Hgs knockdown ECs., Conclusion: These data uncover a novel physiological function of Hgs and support an essential role for the ESCRT machinery in the maintenance of EC polarity and cerebrovascular stability., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The development of tissue-engineered blood vessels provides a new source of donors for coronary artery bypass grafting and peripheral blood vessel transplantation. Fibrin fiber has good biocompatibility and is an ideal tissue engineering vascular scaffold, but its mechanical property needs improvement., Methods: We mixed polyurethane (PU) and fibrin to prepare the PU/fibrin vascular scaffolds by using electrospinning technology in order to enhance the mechanical properties of fibrin scaffold. We investigated the morphological, mechanical strength, hydrophilicity, degradation, blood and cell compatibility of PU/fibrin (0:100), PU/fibrin (5:95), PU/fibrin (15:85) and PU/fibrin (25:75) vascular scaffolds. Based on the results in vitro, PU/fibrin (15:85) was selected for transplantation in vivo to repair vascular defects, and the extracellular matrix formation, vascular remodeling, and immune response were evaluated., Results: The results indicated that the fiber diameter of the PU/fibrin (15:85) scaffold was about 712nm. With the increase of PU content, the mechanical strength of the composite scaffolds increased, however, the degradation rate decreased gradually. The PU/fibrin scaffold showed good hydrophilicity and hemocompatibility. PU/fibrin (15:85) vascular scaffold could promote the adhesion and proliferation of mesenchymal stromal cells (MSCs). Quantitative RT-PCR experimental results showed that the expression of collagen, survivin and vimentin genes in PU/fibrin (15:85) was higher than that in PU/fibrin (25:75). The results in vivo indicated the mechanical properties and compliance of PU/fibrin grafts could meet clinical requirements and the proportion of thrombosis or occlusion was significantly lower. The graft showed strong vasomotor response, and the smooth muscle cells, endothelial cells, and ECM deposition of the neoartery were comparable to that of native artery after 3 months. At 3 months, the amount of macrophages in PU/fibrin grafts was significantly lower, and the secretion of pro-inflammatory and anti-inflammatory cytokines decreased., Conclusion: PU/fibrin (15:85) vascular scaffolds had great potential to be used as small-diameter tissue engineering blood vessels., Competing Interests: The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (© 2020 Yang et al.)

Antibiotics have recently gained attention because they are emerging environmental pollutants with obesogenic properties. In this study, Drosophila melanogaster were exposed to sulfamethoxazole (SMX), a sulfonamide antibiotic, and the effects were measured on circadian rhythm (represented by the eclosion rhythm), lipid metabolism, and microbiota. Circadian rhythm disorder was considered due to its connection with lipid metabolism and microbiota in association with obesity. SMX decreased the proportion of adult flies that eclosed in the morning (AM adults) and increased the proportion of PM adults. Moreover, SMX increased the body weight of PM adults, indicating that SMX exposure caused dysrhythmia in eclosion together with obesity. In measurements of key metabolites and metabolic enzymes, SMX exposure stimulated 3 indices in AM adults and 10 indices in PM adults. In AMP-activated protein kinase and insulin/IGF-1 signaling pathways, SMX upregulated six genes in AM adults and nine genes in PM adults. Finally, microbiota analysis demonstrated that SMX increased the Firmicutes/Bacteroides ratios (F/B) by 79.6- and 5.8-fold compared to concurrent controls in AM and PM adults. Collectively, these results suggest that SMX showed obesogenic effects accompanied with dysrhythmia and disturbances in lipid metabolism and microbiota. Further studies on the intrinsic connection are needed.

Per-and polyfluoroalkyl substances (PFASs), especially perfluorooctanoic acid (PFOA), have been showed to induce obesogenic effects which may last over generations. However, the underlying mechanisms are not yet clear. In the present study, wild-type N2 Caenorhabditis elegans and the daf-2 mutant were exposed to PFOA for 4 consecutive generations (F0 to F3) at 1.0 ng/L. Effects on fat content and fat metabolism in the directly exposed F0 to F3 generations, the offspring of F0 (T1 to T3) and also those of F3 (T1' to T3'). Results showed that PFOA significantly stimulated the fat contents in F0 (with the percentage of the control as 184.1%), T1 (189.5%), F1 (167.3%), F2 (238.0%), T2' (193.9%) and T3' (159.4%) while inhibited them in T3 (70%). The changes of fat contents over generations were accompanied with significant changes in enzymes facilitating fatty acid synthesis (e.g., acetyl-CoA carboxylase, fatty acid synthase and desaturase, and glycerol phosphate acyltransferase) and those in fatty acid consumption (e.g., acetyl CoA synthetase, fatty acid transport protein, acyl-CoA oxidase and carnitine palmitoyl transferase). Furthermore, RNA-Seq analysis was performed on F0, F3 and T3 generations. Based on the KEGG analysis of differential genes, PFOA exposure affected lipid metabolism signaling pathways including MAPK, fatty acid degradation, TGF-β signaling pathways. Notably, PFOA exposure provoked significantly different effects in daf-2 nematodes on fat contents, lipid metabolizing enzymes and even different signaling pathways. The overall results demonstrated that the obesogenic effects of PFOA were resulted from a complex combination of various enzymes and pathways with essential involvement of insulin signaling pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Increasing concerns are earned on the multigenerational hazards of antibiotics due to the connection between their mother-children transfer via cord blood and breast milk and obesity in the children. Currently, Caenorhabditis elegans was exposed to sulfamethoxazole (SMX) over 11 generations (F0-F10). Indicators of obesogenic effects and gene expressions were measured in each generation and also in T11 to T13 that were the offspring of F10. Biochemical analysis results showed that SMX stimulated fatty acids in most generations including T13. The stimulation was resulted from the balance between enzymes for fatty acid synthesis (e.g., fatty acid synthetase) and those for its consumption (e.g., fatty acid transport protein). Gene expression analysis demonstrated that the obesogenic effects of SMX involved peroxisome proliferator activated receptors (PPARs, e.g., nhr-49) and insulin/insulin-like signaling (IIS) pathways (e.g., ins-1, daf-2 and daf-16). Further epigenetic analysis demonstrated that SMX caused 3-fold more H3K4me3 binding genes than the control in F10 and T13. In F10, the most significantly activated genes were in metabolic and biosynthetic processes of various lipids, nervous system and development. The different gene expressions in T13 from those in F10 involved development, growth, reproduction and responses to chemicals in addition to metabolic processes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Increased understanding of the functions of lactate has suggested a close relationship between lactate homeostasis and normal brain activity because of its importance as an energy source and signaling molecule. Here we show that lactate levels affect adult hippocampal neurogenesis. Cerebrovascular-specific deletion of PTEN causes learning and memory deficits and disrupts adult neurogenesis with accompanying lactate accumulation. Consistently, administering lactate to wild-type animals impairs adult hippocampal neurogenesis. The endothelial PTEN/Akt pathway increases monocarboxylic acid transporter 1 (MCT1) expression to enhance lactate transport across the brain endothelium. Moreover, cerebrovascular overexpression of MCT1 or deletion of Akt1 restores MCT1 expression, decreases lactate levels, and normalizes hippocampal neurogenesis and cognitive function in PTEN mutant mice. Together, these findings delineate how the brain endothelium maintains lactate homeostasis and contributes to adult hippocampal neurogenesis and cognitive functions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dengue virus (DENV) infection causes several diseases ranging from dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome characterized by endothelial dysfunction, vascular leakage, and shock. Here, we identify a potential mechanism by which DENV induces tissue injury and vascular leakage by promoting the activation of interleukin (IL)-1β. DENV facilitates IL-1β secretion in infected patients, mice, human peripheral blood mononuclear cells (PBMCs), mouse bone marrow-derived macrophages (BMDMs), and monocyte-differentiated macrophages (THP-1) via activating the NLRP3 inflammasome. The accumulated data suggest that IL-1β probably induces vascular leakage and tissue injury in interferon-alpha/beta receptor 1 deficient C57BL/6 mice ( IFNAR -/- C57BL/6), whereas IL-1 receptor antagonist (IL-1RA) alleviates these effects of IL-1β. Finally, administration of recombinant IL-1β protein results in vascular leakage and tissue injury in C57BL/6 mice. Together, the accumulated results demonstrate that IL-1β contributes to DENV-associated pathology and suggest that IL-1RA acts as a potential agent for the treatment of DENV-associated diseases., (Copyright © 2019 Pan, Zhang, Liu, Wang, Yu, Lao, Zhang, Shen, Wan, Xiao, Shereen, Zhang, Tan, Liu, Liu, Wu, Liu, Li and Wu.)

Surface nuclear magnetic resonance (SNMR) could provide direct insights for hydrological investigations but is often limited because of its low signal-to-noise ratio. Many types of residual noise remain after denoising procedures, including despiking, power harmonic noise cancellation, and random noise attenuation. This residual noise prevents the detection of valid signals, especially in strong noise environments, such as cities and industrial areas. In this work, a lock-in amplifier modeling recovery (LIAMR) method is proposed for extracting SNMR signals from high-level residual noise after denoising. The desired SNMR signals can be extracted directly by establishing a model of the SNMR signal passing through the lock-in amplifier and then transforming mathematically the output of the amplifier. The performance of the proposed method is tested on synthetic SNMR signals under varied average relaxation times, simulation noise at different levels, and field noise. Experiment results show that LIAMR can obtain good estimations of SNMR signal parameters with residual noise. Moreover, the proposed method can provide more precise parameters compared with traditional signal extraction methods. LIAMR provides theoretical support for the application of SNMR technology in strong noise environments.

Information about toxicities of chemicals are essential in their application and waste management. For chemicals at low concentrations, the long-term effects are very important in judging their consequences in the environment and on human health. In demonstrating long-term influences, effects of chemicals over generations in recent studies provide new insight. Here, we describe protocols for studying effects of chemicals over multiple generations using free-living nematode Caenorhabditis elegans. Two aspects are presented: (1) trans-generational (TG) and (2) multi-generational effect studies, the latter of which is separated to multi-generational exposure (MGE) and multi-generational residual (MGR) effect studies. The TG effect study is robust with a simple purpose to determine whether chemical exposure to parents can result in any residual consequences on offspring. After the effects are measured on parents, sodium hypochlorite solutions are used to kill the parents and keep the offspring so as to facilitate effect measurement on the offspring. The TG effect study is used to determine whether the offspring are affected when their parent is exposed to the pollutants. The MGE and MGR effect study is systematical used to determine whether continuous generational exposure can result in adaptive responses in offspring over generations. Careful pick-up and transfer are used to distinguish generations to facilitate effect measurement on each generation. We also combined protocols to measure locomotion behavior, reproduction, lifespan, biochemical and gene expression changes. Some example experiments are also presented to illustrate the trans- and multi-generational effect studies.

Anthropogenic pressures, such as contaminant exposure, may affect stable isotope ratios in biota. These changes are driven by alterations in the nutrient allocation and metabolic pathways induced by specific stressors. In a controlled microcosm study with the amphipod Gammarus spp., we studied effects of the β-blocker propranolol on stable isotope signatures (δ15N and δ13C), elemental composition (%C and %N), and growth (protein content and body size) as well as biomarkers of oxidative status (antioxidant capacity, ORAC; lipid peroxidation, TBARS) and neurological activity (acetylcholinesterase, AChE). Based on the known effects of propranolol exposure on cellular functions, i.e., its mode of action (MOA), we expected to observe a lower scope for growth, accompanied by a decrease in protein deposition, oxidative processes and AChE inhibition, with a resulting increase in the isotopic signatures. The observed responses in growth, biochemical and elemental variables supported most of these predictions. In particular, an increase in %N was observed in the propranolol exposures, whereas both protein allocation and body size declined. Moreover, both ORAC and TBARS levels decreased with increasing propranolol concentration, with the decrease being more pronounced for TBARS, which indicates the prevalence of the antioxidative processes. These changes resulted in a significant increase of the δ15N and δ13C values in the propranolol-exposed animals compared to the control. These findings suggest that MOA of β-blockers may be used to predict sublethal effects in non-target species, including inhibited AChE activity, improved oxidative balance, and elevated stable isotope ratios. The latter also indicates that metabolism-driven responses to environmental contaminants can alter stable isotope signatures, which should be taken into account when interpreting trophic interactions in the food webs., Competing Interests: The authors have declared that no competing interests exist.

In the present work, we analyzed the concentration patterns of 20 Polycyclic Aromatic Hydrocarbons (PAHs) in 25 surface sediments and 11 sediment cores from the northern part of Taihu Lake, China. Three of the cores were dated based on 137 Cs activity for the deposition age of the sediment. The spatial distributions of the PAH concentrations show that the inflow rivers into Zhushan Bay and Meiliang Bay were the main pathway for PAHs and sediment input to the northern part of the lake. This results in substantially higher PAH concentrations (up to 5000 ng/g) and sedimentation rates (higher than the average of 3-4 mm/a) in the area close to the river outlets. In addition, results also show that PAH concentrations in the sediments considerably increased from the early 1960s, but the decreasing concentrations in the upper layers of the sediment could be attributed to the introduction of measures on environmental improvement from ca. 2000. There were both anthropogenic and biogenic origins of perylene in the lake sediments, which were distinguished based on spatial distribution patterns and also the concentration proportions of perylene to the sum of the 20 PAHs. In the cores collected close to river outlets, the concentration proportions of perylene typically range from 0.02 to 0.18 and there are significant positive linear correlations between the concentration of perylene and three anthropogenic PAHs (Benzo[a]pyrene, Benzo[e]pyrene, Pyrene), suggesting that perylene was dominated by anthropogenic input. However, the cores collected further away from the river outlets show the concentration proportions between 0.13 and 0.96, and present significant negative correlations or no correlations between perylene and the three PAHs, suggesting that perylene was mainly formed by biogenic activities. Furthermore, the different perylene sources accompanied with the location distributions imply that anthropogenic activities could inhibit its biogenic formation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Negative effects of environmental antibiotics on non-target organisms were observed in studies at various levels of the biological organization. Yet, studies combining the effects at multiple levels were required to interpret their ecological frequencies in a broader context. Currently, effects of sulfamethoxazole (SMX) was studied on the amphipod Hyalella azteca which is important in ecological stability. At the biochemical level, effects on the antioxidant capacities showed stimulation with an inverse U-shaped change over the concentrations. The stimulation was greater in male than in females. Effects on the oxidative stress showed a U-shaped change which included stimulation and inhibition in males, and solely stimulation in females. The stimulation was less in males than in females. Effects on acetylcholinesterase (AChE) activities in both sexes were well correlated with those on oxidative stress (p < 0.05). At the individual level, effects on the body weight showed an inverse U-shaped change over concentrations, and the stimulation was greater in males than in females. The stimulations were significantly correlated with the male oxidative stress (p < 0.01), and male (p < 0.1) and female AChE activities (p < 0.05). Effects of SMX on the pre-copulation behavior also showed an inverse U-shaped change which correlated with male and female antioxidant capacities (p < 0.05) and the male body weight (p < 0.05). At the population level, effects on the reproduction showed an inverse U-shaped change over concentrations, and they significantly correlated with the male body weight (p < 0.05) and the pre-copulation behavior (p < 0.05). Summing up, SMX provoked simultaneous disturbances on the amphipod at multiple levels with sex-dependent responses., (Copyright © 2018 Elsevier Ltd. All rights reserved.)