160delCp.Leu54Serfs*18) and a missense variant (c.1259 T > Cp.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C240, C250, and C260) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C240 β-oxidation activity was dramatically reduced. Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient’s fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.Excessive Cd accumulation in cereals, especially in high-consumption staple crops, such as rice, is of major concern. Therefore, elucidation of cultivar-specific variation in rice grain Cd bioaccessibility and toxicity in humans would help the development of remedial strategies for Cd accumulation and toxicity. The present study combined an in vitro gastrointestinal digestion model with a human HL-7702 cell and assessed Cd bioaccessibility and toxicity to humans from the grains of 30 rice cultivars of different types harvested from Cd-contaminated paddy soil. The mean grain Cd content of cultivars within the type exceeded acceptable national standards. Cadmium bioaccessibility was high in all grains (9.08-23.6%) except the low accumulator (LA) rice cultivar (7.93%). The mean estimated daily intake of Cd via the cultivars (except LA) exceeded the FAO/WHO permissible limit based not only on the total grain Cd concentration but also on bioaccessible Cd concentration. A dose-proportional correlation between the in vitro bioaccessible and total grain Cd concentrations was observed, suggesting that Cd bioaccessibility accurately reflects the transfer of Cd from rice grain to humans. Toxicity assay results demonstrated that Cd from rice grains could commence oxidative stress and injury in HL-7702 cells, except the LA rice, which did not exhibit significant alteration in HL-7702 cells owing to its low Cd concentration. These results provide primary evidence to suggest that the cultivation of the LA rice cultivar is an effective agronomic approach to avert Cd entry into the food chain and alleviate Cd toxicity in humans.Antibiotics are a typical group of pharmaceutical and personal care products (PPCPs) with emerging pollutant effects. The presence of residual antibiotics in the environment is a prominent issue owing to their potential hazards, toxic effects, and persistence. Several treatments have been carried out in aquatic environments in order to eliminate antibiotic residues. Among these, photodegradation is regarded as an environmentally-friendly and efficient option. Indirect photodegradation is the main pathway for the degradation of residual antibiotics in natural water, as opposed to direct photodegradation. Algae, working as photosensitizers, play an important role in the indirect photolysis of residual antibiotics in natural water bodies. They promote this reaction by secreting extracellular organic matters (EOMs) and inducing the generation of active species. In order to provide a thorough understanding of the effects of algae on residual antibiotic degradation in the environment, this paper comprehensively reviews the latest research regarding algae-induced antibiotic photodegradation. The summary of the different pathways and photosensitive mechanisms involved in this process show that EOMs are indispensable to antibiotic photodegradation. The influencing factors of algae-induced photodegradation are also discussed here these include algae species, antibiotic types, and environmental variables such as light source, ferric ion presence, temperature, and ultrasound treatment. Based on the review of existing literature, this paper also considers several pathways for the future study of algae-induced antibiotic photodegradation.The mechanisms of soot’s photochemistry are still unclear, especially, how the microstructure and composition of soot influence its photoactivity. In the current study, we started with the exploration of the microstructure of soot particles and gained new insights. The elemental-carbon fraction of soot (E-soot), considered the core component of soot and can reflect the intrinsic characteristics of soot, was extracted by organic solvents and characterized in terms of structure and chemical reactivity. The intrinsic structure of E-soot was found to be more analogous to reduced graphene oxide than to graphene, in terms of containing similar levels of defective sites such as oxygen-containing functional groups and environmentally persistent free radicals, as well as exhibiting similar optoelectronic performance. The generation of reactive oxygen species via an electron transfer pathway under visible light suggests that reduced graphene oxide-like E-soot can serve as a potential carbo-photocatalyst, which facilitates elucidating the mechanism of E-soot’s role during soot’s photochemical aging. Our study reveals the intrinsic structure of soot and its role in photo-triggered reactive oxygen species production, which is vital for atmospheric and health effects.It is known that Di (2-ethylhexyl) phthalate (DEHP) may impact mammalian reproduction and that in females one target of the drug’s action is follicle assembly. Here we revisited the phthalate’s action on the ovary and from bioinformatics analyses of the transcriptome performed on newborn mouse ovaries exposed in vitro to DEHP, up-regulation of PDE3A, as one of the most important alterations caused by DEHP on early folliculogenesis, was identified. We obtained some evidence suggesting that the decrease of cAMP level in oocytes and the parallel decrease of PKA expression, consequent on the PDE3A increase, were a major cause of the reduction of follicle assembly in the DEHP-exposed ovaries. In fact, Pde3a RNAi on cultured ovaries reducing cAMP and PKA decrease counteracted the primordial follicle assembly impairment caused by the compound. Moreover, RNAi normalized the level of Kit, Nobox, Figla mRNA and GDF9, BMP15, CX37, γH2AX proteins in oocytes, and KitL transcripts in granulosa cells as well as their proliferation rate altered by DEHP exposure. Taken together, these results identify PDE3A as a new critical target of the deleterious effects of DEHP on early oogenesis in mammals and highlight cAMP-dependent pathways as major regulators of oocyte and granulosa cell activities crucial for follicle assembly. Moreover, we suggest that the level of intracellular cAMP in the oocytes may be an important determinant for their capability to repair DNA lesions caused by DNA damaging compounds including DEHP.Although studies have reported that polybrominated diphenyl ethers (PBDEs) can transfer from mothers to fetuses, the underlying transplacental transport and barrier mechanisms are still unclear. Therefore, we conducted a series of comprehensive experiments in humans, Sprague-Dawley rats, and a BeWo cell monolayer model, as well as a molecular docking study. PBDEs in mothers can transfer to fetuses with a ratio of approximately 0.46, suggesting that the placenta could not efficiently acts as a barrier to PBDE transplacental transport. Similar results were observed in pregnant rats, although varying times were required for different congeners to reach a steady-state in fetuses. The transport ratios at pregnancy day 14 in rats were generally higher than those at pregnancy day 18, which demonstrated that the barrier capacity of immature placentas was lower than that of mature placentas. None concentration-dependent transplacental transport was observed in BeWo cells with efflux ratios of 1.73-2.32, which suggested passive diffusion mechanisms govern the influx of PBDEs through placenta. The accumulated ratios of PBDEs and the inhibitor assay indicated that the effluent channel of P-glycoprotein was partially inhibited by PBDEs. Using molecular docking studies, three pocket sites were identified for different congeners in P-glycoprotein, which demonstrated that the inhibition of P-glycoprotein efflux pump through the pocket sites.Metabolic disorders induced by endocrine disruptors (ED) may contribute to amphibian population declines but no transgenerational studies have evaluated this hypothesis. Here we show that Xenopus tropicalis, exposed from the tadpole stage, to the ED benzo[a]pyrene (BaP, 50 ng.L-1) produced F2 progeny with delayed metamorphosis and sexual maturity. At the adult stage, F2-BaP females displayed fatty liver with inflammation, tissue disorganization and metabolomic and transcriptomic signatures typical of nonalcoholic steato-hepatitis (NASH). This phenotype, similar to that observed in F0 and F1 females, was accompanied by a pancreatic insulin secretory defect. Metabolic disrupted F2-BaP females laid eggs with metabolite contents significantly different from the control and these eggs did not produce viable progeny. This study demonstrated that an ED can induce transgenerational disruption of metabolism and population collapse in amphibians under laboratory conditions. These results show that ED benzo[a]pyrene can impact metabolism over multiple generations and support epidemiological studies implicating environmental EDs in metabolic diseases in humans.Azoxystrobin (AZ) and pyraclostrobin (PY) are strobilurin fungicides that inhibit fungal mitochondrial respiration. In this study, a representative model, zebrafish (Danio rerio), was used as a test species for acute and developmental toxicity. Survival and malformation rates were observed only PY-treated embryos, with an LC50 value of 77.75 ppb accompanied by a dramatic decrease in hatching rate, while AZ did not show great mortality. Morphological changes were observed in PY-treated embryos with the occurrence of pericadial edema at 25 ppb. A delay in growth was observed after treatment with pyraclostrobin at 50 ppb. Use of genetically engineered Tg(cmlcEGFP) allowed fluorescence observation during heart development. PY interfered with normal heart development via upregulation of the nppa gene responsible for the expression of natriuretic peptides. Heart function was dramatically reduced as indicated by reduced heart rates. Increased expression of the nppa gene was also seen in AZ-treated embryos. The expression level of cyp24a1 was also up-regulated, while ugt1a1 and sult1st6 were down-regulated after treatment of zebrafish embryos with AZ or PY. Overall, strobilurin fungicides might inhibit normal heart formation and function within the range of concentrations tested.Urban areas often contain large numbers of migratory bird species during seasonal migration, many of which are nocturnal migrants. How artificial light at night (ALAN) and urban landcover are associated with the diurnal occurrence of nocturnal migrants within urban areas across seasons has not been explored. Here, we use eBird bird occurrence information to estimate the seasonal species richness of nocturnally migrating passerines (NMP) within 333 well surveyed urban areas within the contiguous USA. We model the relationship between seasonal NMP species richness and ALAN, proportion of tree canopy cover, and proportion of impervious surface. NMP species richness reached its highest levels during spring and autumn migration and lowest during the winter and summer. Greater tree canopy cover was associated with higher NMP species richness during spring and autumn migration and the summer. A 10% increase in the proportion of tree canopy cover was associated with a 2.0% increase in NMP species richness during spring migration, a 1.8% increase during autumn migration, and a 0.9% increase during the summer. More impervious surface was associated with higher NMP species richness during the winter. A 10% increase in the proportion of impervious surface was associated with a 6.1-9.8% increase in NMP species richness. Higher ALAN was associated with lower NMP species richness during the winter and summer, and higher NMP species richness during spring and autumn migration. A 50% increase in ALAN was associated with a 3.0-3.6% decrease in NMP species richness during the winter, a 1.7% increase during spring migration, a 2.1% decrease during the summer, and a 5.0% increase during autumn migration. These findings highlight the variable effects of ALAN and urban landcover on the seasonal occurrence of NMP species in urban areas, the value of tree canopy cover during migration and the breeding season, and the importance of reducing ALAN during migration.A seven-year long-term comprehensive measurement of non-refractory submicron particles (NR-PM1) in autumn and winter in Beijing from 2012 to 2018 was conducted to evaluate the effectiveness of the clean air actions implemented by the Chinese government in September 2013 on aerosols from different sources and chemical processes. Results showed that the NR-PM1 concentrations decreased by 44.1% in autumn and 73.2% in winter from 2012 to 2018. Sulfate showed a much larger reduction than nitrate and ammonium in both autumn (55%) and winter (86%) and that nitrate even slightly increased by 15.8% in autumn. As a result, aerosol pollution in winter gradually changed from sulfate-rich to nitrate-rich with a sudden change after 2016 and the dominant role of nitrate in autumn was also strengthened after 2016. Among primary organic aerosol (OA) types, biomass burning OA and coal combustion OA exhibited the largest decline in autumn and winter, with reductions of 87.5% and 77.3%, respectively, while hydrocarbon-like OA (HOA) exhibited the smallest decline in both autumn (24.4%) and winter (37.1%). These significant changes in aerosol compositions were highly consistent with the much faster reduction of SO2 (75-85%) than NOx (36-59%) and were mainly due to the clean air actions rather than the impact of meteorological conditions. What’s more, the enhanced atmospheric oxidizing capacity, which was indicated by increased O3, altered the chemical processes of oxygenated OA (OOA), especially in autumn. Both of less-oxidized OOA (LO-OOA) and more-oxidized OOA showed elevated contributions in OA by 4% in autumn. The increased oxygen-to-carbon ratios of LO-OOA in autumn (from 0.42 to 0.58) and winter (from 0.44 to 0.52) indicated the enhanced atmospheric oxidizing capacity strengthened photochemical reactions and resulted in the increased oxidation degree of LO-OOA. This study demonstrates the effectiveness of the clean air actions for air quality improvement in Beijing.Bird feathers are one of the most widely used animal tissue in mercury biomonitoring, owing to the ease of collection and storage. They are also the principal excretory pathway of mercury in birds. However, limitations in our understanding of the physiology of mercury deposition in feathers has placed doubt on the interpretation of feather mercury concentratoins. Throughout the literature, moult sequence and the depletion of the body mercury pool have been taken to explain patterns such as the decrease in feather mercury from the innermost (P1) to the outermost primary feather (P10) of the wing. However, it has been suggested that this pattern is rather a measurement artefact as a result of the increased feather mass to length ratio along the primaries, resulting in a dilution effect in heavier feathers. Here, we attempt to untangle the causes of variation in feather mercury concentrations by quantifying the mercury concentration as μg of mercury (i) per gram of feather, (ii) per millimetre of feather, and (iii) per day of feather growth in the primary feathers of Bulwer’s Petrel Bulweria bulwerii chicks, effectively controlling for some of the axes of variation that may be acting in adults, and monitoring the growth rate of primary feathers in chicks. The mercury concentration in Bulwer’s Petrel chicks’ primaries increased from the innermost to the outermost primary for all three concentration measures, following the order of feather emergence. These observations confirm that the pattern of mercury concentration across primary feathers is not an artefact of the measure of concentration, but is likely an effect of the order of feather growth, whereby the earlier grown feathers are exposed to higher blood mercury concentrations than are later moulted feathers as a result of blood mercury depletion.The overnight stagnation of tap water in plumbing systems can lead to water quality deterioration. Meanwhile, the indoor heating can improve the indoor temperature in cold areas during winter, which may affect the quality of tap water during stagnation. However, indoor heating drives bacterial ecological links with tap water stagnation during winter are not well understood. The results indicated that the water temperature increased significantly after stagnation during indoor heating periods. Moreover, the average intact cell number and total adenosine triphosphate (ATP) concentration increased 1.53-fold and 1.35-fold after stagnation, respectively (P less then 0.01). In addition, the increase in the ATP per cell number indicated that the combined effects of stagnation and indoor heating could enhance the bacterial activity. Biolog data showed that the bacterial community metabolic capacity was significantly higher in stagnant water than that of fresh water. Co-occurrence networks suggested that the bacterial metabolic profile changed after stagnation during the heating periods. DNA analysis indicated that the composition of the bacterial community changed dramatically after stagnation. The abundances of potential pathogens such as Mycobacterium sp. and Pseudomonas sp. also increased after stagnation. These results will give novel insights on comprehensive understanding the combined effects of indoor heating and overnight stagnation on the water bacterial community ecology of plumbing systems, and provide a scientific basis for tap water quality management after overnight stagnation during the indoor heating periods.In this work, two deep subsurface wastewater infiltration systems (SWISs) were constructed and fed with domestic sewage (control system, S1) and mixed wastewater consisting of old landfill leachate and domestic sewage (experimental system, S2). S1 and S2 exhibited favorable removal efficiencies, with TP (98.8%, 98.7%), COD (87.6%, 86.9%), NH4+-N (99.8%, 99.9%) and TN (99.2%, 98.9%). Even when increasing the pollutant load in S2 by adding old landfill leachate, the almost complete removal performance could be maintained in terms of low effluent concentrations and even increased in terms of load removal capabilities, which included COD (19.4, 25.9 g∙m-2·d-1), NH4+-N (8.2, 19.9 g∙m-2·d-1), TN (8.9, 20.6 g∙m-2·d-1). To investigate the transformation of dissolved organic matter along depth, Three-Dimensional Excitation Emission Matrix fluorescence spectroscopy combined with Fluorescence Regional Integration analysis was applied. The results showed that PⅠ,n and PⅡ,n (the proportions of biodegradable fractions) increased gradually from 6.59% to 21.8% at S2_20 to 10.8% and 27.7% at S2_110, but PⅢ,n and PⅤ,n (the proportions of refractory organics) declined from 23.1% to 27.8% at S2_20 to 21.1% and 16.4% at S2_110, respectively. In addition, high-throughput sequencing technology was employed to observe the bacterial community at different depths, and the predicted functional potential of the bacterial community was analyzed by PICRUSt. The results showed that the genera Flavobacterium, Pseudomonas, Vogesella, Acinetobacter and Aquabacterium might be responsible for refractory organic degradation and that their products might serve as the carbon source for denitrifiers to achieve simultaneous nitrate and refractory organic removal. PICRUSt further demonstrated that there was a mutual response between refractory organic degradation and denitrification. Overall, the combined treatment of domestic sewage and old leachate in rural areas by SWIS is a promising approach to achieve comprehensive treatment.The construction of noise maps is of great significance for the development of urban sustainability and the protection of residents’ physical and mental health. The traditional noise map construction method is difficult to be widely used because of its low update frequency and high drawing cost. Based on the crowd-sensing technology and Latent Factor Model (LFM), this paper proposes a new noise map completion method called Spatial-Temporally Related LFM (STR-LFM) for solving the problem of data sparseness. First, the geographic information features including Point of Interest (POI), road network and building outline are fully excavated, and then combine the correlation of the samples in the time dimension to construct the similarity matrixes. After that, use the k-nearest neighbor algorithm to find out the similar samples of missing positions, and finally regard their weighted fusion as the predicted values. Experimental results show that the recovery error is lower than other commonly used methods, and the proposed method has better stability when faced with data sparseness problems at different levels.The European Noise Directive proposes using strategic noise maps as tools to assess populations affected by environmental noise. It recommends using computational methods instead of in situ measurements when possible. A sound source’s emission power is an important factor in the calculation of noise indicators. For traffic noise, this parameter is usually defined based on vehicle flow considering an emission spectrum that depends on the type of vehicle and its speed. This study analysed the possibility of using the categorisation method to propose an alternative method of defining a sound source’s emission power to develop noise maps. This was accomplished using previously published values of the emission power per unit length. Another method is also proposed that estimates traffic flows. To verify their estimation capacity, the results of both methods were compared with the values obtained from in situ measurements. The results demonstrated similar uncertainties in both methods and were in the range of expected average uncertainties compared to the results obtained by calculating a noise map with the measured experimental values. In particular, for the differences between calculations and measurements, in absolute values, the mean uncertainties were approximately 2 dBA in estimating different long-term noise indicators. For the differences, the mean of the uncertainties obtained via the categorisation method did not present significant differences for the null value for all the analysed noise indicators. Street stratification is a rapid and low-cost approach for road traffic noise mapping without increasing uncertainties.Cadmium (Cd) is a major pollutant in farmland, which not only greatly restricts crop production, but also brings a serious threat to human health through entering the food chain. Our previous study showed that hemin treatment could reduce the accumulation of Cd in pak choi seedlings. However, the underlying mechanism remains unclear. In this study, we used non-invasive micro-test technology (NMT) to detect the real-time Cd2+ flux from pak choi roots and demonstrated that hemin treatment decreased Cd uptake rather than its translocation within plants. Moreover, through comparing the responses of different chemical treatments in pak choi seedlings and Arabidopsis wild-type and heme oxygenase-1 (HO-1) mutant, we provided evidence that hemin-decreased Cd uptake was HO-1 dependent. Furthermore, analyses of hemin degradation products suggested that the hemin-derived suppression of Cd uptake suppression was probably relying on its degradation by-products, ferrous iron (Fe2+) and carbon monoxide (CO), via repressing the expression of a Fe2+/Cd2+ transporter BcIRT1 in pak choi roots.

The revised Baux score (age total body surface area (TBSA) burned and inhalation injury)) is predictive of mortality in burn patients. Our study objective was to assess whether the addition of body mass index (BMI) to the revised Baux score would be of value. We posited that increasing BMI follows a pattern similar to age and TBSA in the revised Baux score after severe burn injury.

Patient data from the burn registry was queried for patients admitted between 1/1/2013 to 8/31/2019. Patients 12 years or older with a TBSA of 20% or greater burn were included. Inpatient outcomes were analyzed based on BMI.

56 of 1365 patients met inclusion criteria. Mean age of the study population was 48.25 years and 64.3% of patients were male. Median BMI was 25.8 and median TBSA was 26.5. Inhalation injury was present in 44.6% (25/56) of patients. Median hospital length of stay (LOS) and ICU LOS were 21.5 and 17 days respectively. On bivariate analysis, non-survivors had higher TBSA (41.5% vs 25.5%, p = 0.034), more inhalation injury (83.3%, 10/12 vs 34.8%, 15/43 p = 0.003) and higher complication rates (91.6%, 11/12 vs 59.1 %, 25/43, p = 0.043). Survivors also had higher BMI (28.2 vs 23, p = 0.003) and increased hospital LOS (24 vs 5.5, p = 0.003). Automatic model fit in binary logistic regression showed a negative relationship between BMI and mortality.

We found a negative relationship between BMI and mortality. Pre-obesity appears to have a protective role, but BMI was not found to be a useful addition to the revised Baux score. Larger sample sizes may be of benefit a for a for a more definitive understanding of the role of BMI with regards to burn survival.

We found a negative relationship between BMI and mortality. Pre-obesity appears to have a protective role, but BMI was not found to be a useful addition to the revised Baux score. Larger sample sizes may be of benefit a for a for a more definitive understanding of the role of BMI with regards to burn survival.

Naringenin is naturally isolated from citrus fruits possessing many pharmacological activities. However, little is known about the effect of naringenin on nonalcoholic steatohepatitis (NASH) in the model of metabolic syndrome.

The present study is aimed to investigate the effect of naringenin on NASH in 12-mo-old male ApoE

mice and its possible underlying mechanism.

In vivo, 12-mo-old male ApoE

mice were administrated with naringenin by intragastric gavage for 12 weeks. At the end of experiment, the blood samples and liver tissues were collected. Metabolic parameters in serum, levels of triglyceride, cholesterol and hydroxyproline, activities of antioxidant enzymes, and content of inflammatory cytokines (TNF-α and IL-6) in liver were examined by corresponding assay kits. Pathological changes in liver were observed by hematoxylin-eosin, oil red O, masson’s trichrome, picro-sirius red and senescence β-galactosidase staining. Dihydroethidium was used for detection of reactiveoxygen species (ROS). In vid NF-κB. In vitro study, the benefits of naringenin on lipid accumulation, oxidative stress and inflammation were diminished by SIRT1 siRNA transfection.

These results indicate that naringenin administration may be a potential curative therapy for NASH treatment and the activation of hepatic SIRT1-mediated signaling cascades is involved in its beneficial effects.

These results indicate that naringenin administration may be a potential curative therapy for NASH treatment and the activation of hepatic SIRT1-mediated signaling cascades is involved in its beneficial effects.

Therapeutic regimens of breast cancer treatment are increasingly inclined to adopt combination strategy based on the broad spectrum antitumor effect of doxorubicin (Dox). Currently, combination therapy comprises of conventional anti-cancer drugs and angiogenesis inhibitors have been corroborated as an effective approach in cancer treatment.

We explored the ability of a natural anti-angiogenic compound glycyrrhetinic acid (GA), derived from an edible-medicinal herb licorice, to enhance the breast cancer suppression effect of Dox.

The drug ratio of GA and Dox with synergistic anticancer effect against MCF-7 cells was optimized by combination index (CI) value in vitro, followed by evaluation of the improved anticancer effects and reduced side-effects of this combination in vitro and in vivo.

Cell viability was measured by MTT assay. Analyses of mitochondrial membrane potential and cell apoptosis on MCF-7 cells were performed by JC-1 dye and Annexin V-FITC/PI assays. The cellular accumulation of Dox when x and GA could exhibit ideal synergistic anti-angiogenesis effect. Expectedly, the enhanced anti-tumor efficacy of Dox and reduced Dox-induced cardiotoxicity when used in combination with GA were evident in a mouse breast tumor model.

These findings support that the combination of Dox with GA is a novel and promising therapeutic strategy for the treatment of breast cancer.

These findings support that the combination of Dox with GA is a novel and promising therapeutic strategy for the treatment of breast cancer.Proteolysis-targeting chimaera (PROTAC) technology is an emerging approach for achieving targeted degradation of a protein of interest (POI) intracellularly. However, the cell permeability of PROTACs is limited by their high molecular weight and total polar surface area. Moreover, the activation of the proteasome-mediated degradation by PROTAC requires the formation of a ternary (three-component) complex, composed of the PROTAC, the POIs, and E3-ligases related proteins (E3Ps). Simplifying the three-component system to two-component system could theoretically increase the efficiency of the formation of ternary complex and enhance the protein degradation efficiency. Herein, we demonstrate that pre-fusion of PROTACs with E3Ps (called „pre-fused PROTACs”) before administration could transform the original PROTAC system to two-component system. After delivery by lipid nanoparticles, the degradation of POI by pre-fused PROTACs was dramatically increased and accelerated compared with standard PROTACs. Moreover, we demonstrated that this approach could be generalized to another hydrophobic tag (HyT) degrader by demonstrating the improved targeted protein degradation after pre-fusion the HyT degrader with heat shock protein 70 (HSP70).

Multiple social influences affect cannabis use in adolescents, including parental and peer cannabis use norms. However, the mechanisms of influence underlying these social influences remain unclear. Recent studies have suggested that cognitions about cannabis use and the effects of cannabis may mediate social influences. The current study explored the relationship between automatic self-generated cognitions and their relationship with parental influences on cannabis use in a sample of n=675 11 to 16-year-old adolescents over three years (Mean Age 13.96, SD=0.88, 56.4% female).

Participants reported perceptions of parental cannabis use and completed a cannabis word association task (CWAT), an open-ended cannabis outcome expectancy liking (COEL) task, and measures of cannabis use in the past year.

Perceived parental use did not directly predict cannabis use two years later. However, a latent construct loading on both CWAT and COEL scores strongly predicted cannabis use over the following year. Structural modelling demonstrated that the association between previous cannabis use and parental cannabis use and adolescents’ cannabis use over the next two years was fully mediated by cognitions.

The results of the study are discussed and interpreted through the lens of dual-process theories.

The results of the study are discussed and interpreted through the lens of dual-process theories.

Efforts to understand how adolescents acquire marijuana will help to contextualize its use among youth. Little is known about ways of getting marijuana and how they differ between subgroups of adolescents. The present study sought to determine how adolescents get marijuana and if modes of access vary by sociodemographic characteristics.

Data were from the nationally representative Monitoring the Future study of 12th graders in the United States from 2012 to 2018 (N=4262 students). Participants used marijuana in the past 12months and were asked how they got marijuana. Multivariable logistic regression models were used to predict modes of getting marijuana based on sex, race/ethnicity, urbanicity, parental education, and survey year. Cross-tabulation analyses compared how recent frequent and non-frequent use related to ways of getting marijuana.

The most endorsed methods of getting marijuana were given for free by friends, bought from friends, and bought from a drug dealer/stranger. Differences by sociodemographic subgroup and recent frequent use emerged, including for riskier modes of obtainment such as buying from a drug dealer/stranger (for male students, urban students, and recent frequent users). Recent frequent users were more likely to endorse getting marijuana by nearly each method, except non-frequent users were more likely to be given marijuana for free by friends.

Understanding the prevalence of different modes of getting marijuana among adolescents and which subgroups are most susceptible to riskier means of getting marijuana will allow drug use prevention efforts to be tailored appropriately so as to maximize effectiveness.

Understanding the prevalence of different modes of getting marijuana among adolescents and which subgroups are most susceptible to riskier means of getting marijuana will allow drug use prevention efforts to be tailored appropriately so as to maximize effectiveness.

Conventional vital signs alone have limitations in determining the physiological status. Age-adjusted shock-index (SIPA), a comprehensive physiological variable, defined as the ratio of heart rate (HR) and systolic blood pressure (SBP) may be better at predicting hemodynamic stability and outcome than vital signs.

To compare discriminatory power of SIPA against vital signs in assessing higher level of care (vasopressor use and mechanical ventilation) and early mortality in severe sepsis/septic shock.

Prospective cohort study of 116children <14years with severe sepsis/septic shock admitted at emergency department of a tertiary care hospital. Association between abnormal signs (raised heart-rate; HR, lower systolic blood-pressure; SBP, high SIPA) and higher level of care and early mortality at 0 and completed 6hours (t0, t6) were assessed using univariate/multivariate analysis. Area-under-receiver-operating-characteristic curves (AUROC) of SIPA and conventional vital signs for outcome variables and their correlation with arterial lactate using Pearson’s-coefficient were noted.

High SIPA was independently associated with higher level of care i.e. vasopressor use, mechanical ventilation (AUROC t0 0.698, 0.730; AUROC t6; 0.733, 0.735) as well as early mortality (AUROC t0 0.638; AUROC t60.721) at t0 and t6. At t0, only high SIPA (r

=0.313) fairly correlated with arterial lactate (4.5mmol/L). At t6, HR and SBP showed weak and SIPA (r

=0.434) demonstrated moderate correlation with arterial lactate.

SIPA performs better than conventional vital-signs in recognising higher-level-of-care and early mortality.

SIPA performs better than conventional vital-signs in recognising higher-level-of-care and early mortality.

Emerging evidence suggests that the COVID-19 pandemic and associated lockdown restrictions may have influenced alcohol consumption. This study examines changes in high-risk alcohol consumption from before to during the COVID-19 crisis in an established cohort of middle-aged British adults.

Participants consisted of 3,358 middle-aged adults from the 1970 British Cohort Study who completed the Alcohol Use Disorders Identification Test for detecting hazardous drinkers in primary care settings in 2016-2018 (when aged 46-48 years) and May 2020 (aged 50 years). Multivariable logistic regression analysis was used to examine changes in high-risk drinking (scores of ≥5), and multinomial regression was used to compare responses with individual test items in 2016-2018 and May 2020.

Among middle-aged British adults, high-risk drinking increased by 5.2 percentage points from 19.4% to 24.6% (p<0.001) between 2016-2018 and May 2020. The increase in high-risk drinking was not moderated by sex, marital status, educational attainment, the presence of a chronic illness, or the year the baseline survey was completed. The prevalence of drinking ≥4 times a week doubled from 12.5% to 26% from before to during the pandemic (p<0.001), and there was also evidence of an increase in the frequency of being unable to stop drinking.

This study provides evidence linking the COVID-19 crisis and associated lockdown restrictions to an increase in high-risk drinking patterns and particularly frequent drinking in British adults. Potential long-term changes in drinking habits should be monitored following the emergence of the COVID-19 pandemic.

This study provides evidence linking the COVID-19 crisis and associated lockdown restrictions to an increase in high-risk drinking patterns and particularly frequent drinking in British adults. Potential long-term changes in drinking habits should be monitored following the emergence of the COVID-19 pandemic.

Atrial fibrillation (AF) is related to a higher risk of thromboembolic events and mortality. Some studies have demonstrated that the inflammatory biomarker interleukin-6 (IL-6) is associated with a higher risk of higher thrombosis in AF patients, but the real effect of IL-6 remains a controversy.

We conducted a systematic review and meta-analysis to investigate the association between IL-6 and thromboembolic events, as well as bleeding events, acute coronary syndrome (ACS) events and all-cause mortality in AF.

A total of five studies involving 22 928 patients met our inclusion criteria for the systematic review. The higher level of IL-6 in AF patients is related to long-term thromboembolic events including stroke (RR 1.44, CI 95% 1.09-1.90, p=0.01). IL-6 meant a higher risk of long-term bleeding risk (RR 1.36, CI 95% 1.06-1.74, p=0.02), ACS risk (RR 1.81, CI 95% 1.43-2.30, p<0.001) and all-cause mortality (RR 2.35, CI 95% 2.09-2.65, p<0.001).

A higher level of IL-6 may predict a greater number of long-term thromboembolic events and bleeding events, ACS events and mortality in AF patients. Further studies such as the cut-off point of IL-6 need to be conducted in the future.

A higher level of IL-6 may predict a greater number of long-term thromboembolic events and bleeding events, ACS events and mortality in AF patients. Further studies such as the cut-off point of IL-6 need to be conducted in the future.

This study aims to assess the thickness of epicardial fat tissue (EFT), a sign of cardiovascular risk, using echocardiography in patients with severe periodontitis.

Thirty-three patients with stage III or IV periodontitis and 33 healthy participants were enrolled into the study. Epicardial fat tissue thickness was measured perpendicularly via echocardiography of the free wall of the right ventricular at end-diastole in three cardiac cycles. Body mass index (BMI) was calculated by dividing weight in kilograms by the height in meters squared. EFT to BMI ratio (EFT/BMI) was measured by dividing EFT by the BMI.

There was no significant difference between study patients and the control group as regards to the frequency of diabetes, hypertension, smoking, and hyperlipidemia. The EFT and EFT/ BMI ratio were significantly different in the control and periodontitis groups (0.51±0.17 vs. 0.77±0.16, respectively; p ≤0.001) (0.021±0.008 vs. 0.030±0.006, respectively; p≤0.001). Pearson’s correlation coefficient demonstrated a significant relationship between EFT and the clinical parameters of periodontitis (p<0.001) CONCLUSIONS EFT thickness measured by echocardiography appears to be associated with severe periodontitis and may thus be an indirect sign of cardiovascular disease in periodontitis patients.

There was no significant difference between study patients and the control group as regards to the frequency of diabetes, hypertension, smoking, and hyperlipidemia. The EFT and EFT/ BMI ratio were significantly different in the control and periodontitis groups (0.51±0.17 vs. 0.77±0.16, respectively; p ≤0.001) (0.021±0.008 vs. 0.030±0.006, respectively; p≤0.001). Pearson’s correlation coefficient demonstrated a significant relationship between EFT and the clinical parameters of periodontitis (p less then 0.001) CONCLUSIONS EFT thickness measured by echocardiography appears to be associated with severe periodontitis and may thus be an indirect sign of cardiovascular disease in periodontitis patients.

Dual antiplatelet therapy (DAPT) is a mainstay for myocardial infarction (MI) therapy. However, in patients with myocardial infarction with non-obstructive coronary artery disease (MINOCA), clear recommendations are lacking in the literature. This study aims to identify the cases in which DAPT is currently prescribed at discharge for MINOCA.

The authors analyzed a cohort of patients from a multicenter national registry enrolling patients who suffered their first MI between 2010 and 2017, and underwent coronary angiography revealing absence of stenosis ≥50%. Individual antithrombotic therapy was identified. A logistic regression analysis was applied to search for predictors of DAPT.

From a total of 16 237 patients analyzed, 709 (4.4%) were categorized as MINOCA. Mean age was 64±13 years, 46.3% (n=409) were females. 390 (55.0%) of MINOCA patients were discharged on DAPT. Males (OR 1.67, CI 95 [1.05-2.38], p=0.027), active smokers (OR=1.82, CI 95 [1.05-3.16], p=0.033), previous percutaneous intervention (OR 3.18, CI 95 [1.48-6.81], p=0.003), ST elevation MI (OR 2.70, CI 95 [1.59-4.76], p<0.001) and sinus rhythm at admission (OR=3.94, CI 95 [2.07-7.48], p<0.001) were independent predictors of DAPT use.

In this nationwide registry, DAPT was prescribed at discharge in 55% of MINOCA patients. Beyond sinus rhythm, the variables presented as independent predictors for DAPT use identify subgroups of patients who are classified as more prone to thrombotic events. The issue of how to handle antithrombotic agents in MINOCA patients is a topic open for discussion.

In this nationwide registry, DAPT was prescribed at discharge in 55% of MINOCA patients. Beyond sinus rhythm, the variables presented as independent predictors for DAPT use identify subgroups of patients who are classified as more prone to thrombotic events. The issue of how to handle antithrombotic agents in MINOCA patients is a topic open for discussion.The prevalence of mitotically heritable clonal random monoallelic expression of autosomal genes (aRME) remains controversial. Specifically, presence of clonal aRME is well supported in vitro but remains elusive in vivo. Here, we provide critical insights into this matter and discuss whether prevalent clonal aRME is natural or artifactual.The mechanistic target of rapamycin complex 1 (mTORC1) is a central modulator of inflammation and tumorigenesis in the gastrointestinal tract. Growth factors upregulate mTORC1 via the PI3K/AKT and/or Ras/MAPK signal pathways. Curcumin (CUR), a polyphenol found in turmeric roots (Curcuma longa) can repress mTORC1 kinase activity in colon cancer cell lines; however, key aspects of CUR mechanism of action remain to be elucidated including its primary cellular target. We investigated the molecular effects of physiologically attainable concentration of CUR (20 μM) in the intestinal lumen on mTORC1 signaling in Caco-2 cells. CUR markedly inhibited mTORC1 kinase activity as determined by the decreased phosphorylation of p70S6K (Thr389, -99%, P less then 0.0001) and S6 (Ser235/236, -92%, P less then 0.0001). Mechanistically, CUR decreased IRS-1 protein abundance (-80%, P less then 0.0001) thereby downregulating AKT phosphorylation (Ser473, -94%, P less then 0.0001) and in turn PRAS40 phosphorylation (Thr246, -99%, P less then 0.0001) while total PRAS40 abundance was unchanged. The use of proteasome inhibitor MG132 showed that CUR-mediated loss of IRS-1 involved proteasomal degradation. CUR lowered Raptor protein abundance, which combined with PRAS40 hypophosphorylation, suggests CUR repressed mTORC1 activity by inducing compositional changes that hinder the complex assembly. In addition, CUR activated AMPK (Thr172 phosphorylation, P less then 0.0001), a recognized repressor of mTORC1, and AMPK upstream regulator LKB1. Although cargo adapter protein p62 was decreased by CUR (-49%, P less then 0.004), CUR did not significantly induce autophagy. Inhibition of AKT/mTORC1 signaling by CUR may have lifted the cross-inhibition onto MAPK signaling, which became induced; p-ERK1/2 (+670%, P less then 0.0001), p-p38 (+1433%, P less then 0.0001). By concomitantly targeting IRS-1 and AMPK, CUR’s mechanism of mTORC1 inhibition is distinct from that of rapamycin.

Vitreous humor (VH) is a specimen of great value in forensic investigations and is being used for evaluating possible post-mortem formation of ethanol. Ethyl glucuronide (EtG) is an ethanol metabolite that has found interest for the same purpose. Both compounds can be measured in VH and because of differences in rate of distribution and elimination they may offer complementary information.

VH, femoral blood (FB) and urine were collected from 117 autopsy cases for forensic investigation. Ethanol was measured with headspace gas chromatography, while EtG was measured with liquid chromatography – tandem mass spectrometry.

Ethanol was detected in all matrices in 39 cases, while EtG was present in 62 cases. The VH-FB and the VH-urine ethanol concentrations in the 39 cases were statistically correlated (p < 0.00001). In one case with an ethanol concentration of 0.11 g/L in FB, no ethanol was detected in VH and urine, and no EtG in any specimen, indicating a possible post-mortem formation. EtG was present in The correlation between the EtG concentrations in VH and FB was statistically significant (p less then 0.0003) as was the case also for VH and urine (p less then 0.001). The combined information on ethanol and EtG concentrations in the three matrices can be used to interpret alcohol drinking habit before death. This study confirms the value of using VH as a specimen in forensic investigations regarding recent exposure to ethanol. EtG can be used not only for investigating post-mortem ethanol formation but also for estimating recent alcohol drinking.Since the discovery of Deoxyribonucleic acid (DNA) capability in forensic investigation, it has been an important part of the criminal justice system. In most criminal cases DNA profile originating from evidence sample collected from the crime scene is compared with the DNA profile from the reference sample. However, when a reference sample is not available for comparison, familial DNA analysis can provide important investigation leads in a criminal investigation process by identifying an individual. Moreover, this analysis is also proving effective in the identification of ethnicity and ancestry of an individual. A number of different methodologies and software are being used for familial DNA analysis. This review describes the importance of familial DNA analysis, methodologies used for familial DNA searching and identification, and its advantages in forensic. Moreover, ethical, legal and social issues associated with familial DNA analysis have also been discussed along with future directions for the proper implementation of this technology.Glioblastoma the most aggressive form of brain cancer, comprises a complex mixture of tumor cells and nonmalignant stromal cells, including neurons, astrocytes, microglia, infiltrating monocytes/macrophages, lymphocytes, and other cell types. All nonmalignant cells within and surrounding the tumor are affected by the presence of glioblastoma. Astrocytes use multiple modes of communication to interact with neighboring cells. Extracellular vesicle-directed intercellular communication has been found to be an important component of signaling between astrocytes and glioblastoma in tumor progression. In this review, we focus on recent findings on extracellular vesicle-mediated bilateral crosstalk, between glioblastoma cells and astrocytes, highlighting the protumor and antitumor roles of astrocytes in glioblastoma development.The vast majority of fast inhibitory transmission in the brain is mediated by GABA acting on GABAA receptors (GABAARs), which provides inhibitory balance to excitatory drive and controls neuronal output. GABAARs are also effectively targeted by clinically important drugs for treatment in a number of neurological disorders. It has long been hypothesized that function and pharmacology of GABAARs are determined by the channel pore-forming subunits. However, recent studies have provided new dimensions in studying GABAARs due to several transmembrane proteins that interact with GABAARs and modulate their trafficking and function. In this review, we summarize recent findings on these novel GABAAR transmembrane regulators and highlight a potential avenue to develop new GABAAR psychopharmacology by targeting these receptor-associated membrane proteins.Nitroimidazoles based compounds remain a hot topic of research in medicinal chemistry due to their numerous biological activities. Moreover, many clinical candidates based on this chemical core have been reported to be valuable in the treatment of human diseases. Metronidazole (MTZ) derived conjugates demonstrated a potential application in medicinal chemistry research over the last decade. In this review, we summarize the synthesis, key structure-activity-relationship (SAR) and associated biological activities such as antimicrobial, anticancer, antidiabetic, anti-inflammatory, anti-HIV and anti-parasitic (Anti-trichomonas, antileishmanial, antiamoebic and anti-giardial) of explored MTZ-conjugates. The molecular docking analysis is also presented simultaneously, which will assist in developing an understanding towards designing of new MTZ-conjugates for target-based drug discovery against multiple disease areas.

We assessed the association of Mediterranean diet with NAFLD and their interaction in predicting ten-year diabetes onset and first fatal/non-fatal cardiovascular disease (CVD) incidence.

The ATTICA prospective observational study in Athens, Greece included 1,514 men and 1,528 women (>18 years old) free-of-CVD at baseline. Liver steatosis and fibrosis indices were calculated. Mediterranean diet adherence was assessed through MedDietScore. At the ten-year follow-up visit, CVD evaluation was performed in an a priori specified subgroup of n=2,020 participants and diabetes onset in n=1,485 free-of-diabetes participants.

MedDietScore was inversely associated with steatosis and fibrosis; e.g. in the case of the TyG index the Odds Ratio (OR) of the 3rd vs. 1st MedDietScore tertile was=0·53, [95% Confidence Interval (95% CI) (0·29, 0·95)] and the associations persisted in multi-adjusted models. NAFLD predicted incident diabetes prospectively over a ten year period [HR=1·87, 95% CI (0·75, 4·61)] and the association remained significant only in subjects with low MedDietScore (below median) whereas diabetes onset among subjects with higher MedDietScore was not influenced by NAFLD.