Per/polyfluoroalkyl substances modulate plasmid transfer of antibiotic resistance genes: A balance between oxidative stress and energy support.

Emerging contaminants can accelerate the transmission of antibiotic resistance genes (ARGs) from environmental bacteria to human pathogens via plasmid conjugation, posing a great challenge to the public health. Although the toxic effects of per/polyfluoroalkyl substances (PFAS) as persistent organic pollutants have been understood, it is still unclear whether and how PFAS modulate the transmission of ARGs. In this study, we for the first time reported that perfluorooctanoic acid (PFOA), perfluorododecanoic acid (PFDoA) and ammonium perfluoro (2-methyl-3-oxahexanoate) (GenX) at relatively low concentrations (0.01, 0.1 mg/L) promoted the conjugative transfer of plasmid RP4 within Escherichia coli, while the plasmid conjugation was inhibited by PFOA, PFDoA and GenX at relatively high concentrations (1, 10 mg/L). The non-unidirectional conjugation result was ascribed to the co-regulation of ROS overproduction, enhanced cell membrane permeability, shortage of energy support as well as l-arginine pool depletion. Taking the well-known PFOA as an example, it significantly enhanced the conjugation frequency by 1.4 and 3.4 times at relatively low concentrations (0.01, 0.1 mg/L), respectively. Exposure to PFOA resulted in enhanced cell membrane permeability and ROS overproduction in donor cells. At high concentrations of PFOA (1, 10 mg/L), although enhanced oxidative stress and cell membrane permeability still occurred, the ATP contents in E. coli decreased, which contributed to the inhibited conjugation. Transcriptome analysis further showed that the expression levels of genes related to arginine biosynthesis (argA, argC, argF, argG, argI) and transport (artJ, artM, artQ) pathways were significantly increased. Intracellular l-arginine concentration deficiency were observed at high concentrations of PFOA. With the supplementary exogenous arginine, it was demonstrated that arginine upregulated conjugation transfer- related genes (trfAp, trbBp) and restores the cell number of transconjugants in PFOA-treated group. Therefore, the inhibited conjugation at high concentrations PFOA were attributed to the shortage of ATP and the depletion of L-arginine pool. These findings provide important insights into the effect environmental concentrations of PFAS on the conjugative transfer of ARGs, and update the regulation mechanism of plasmid conjugation, which is critical for the management of antibiotic resistance in aquatic environments.

Photoallosteric Polymersomes toward On-Demand Drug Delivery and Multimodal Cancer Immunotherapy.

Allosteric transitions can modulate the self-assembly and biological function of proteins. It remains, however, tremendously challenging to design synthetic allosteric polymeric assemblies with spatiotemporally switchable hierarchical structures and functionalities. Here, a photoallosteric polymersome is constructed that undergoes a rapid conformational transition from ß-sheet to α-helix upon exposure to near-infrared light irradiation. In addition to improving nanoparticle cell penetration and lysosome escape, photoinduced allosteric behavior reconstructs the vesicular membrane structure, which stimulates the release of hydrophilic cytolytic peptide melittin and hydrophobic kinase inhibitor sorafenib. Combining on-demand delivery of multiple therapeutics with phototherapy results in apoptosis and immunogenic death of tumor cells, remold the immune microenvironment and achieve an excellent synergistic anticancer efficacy in vivo without tumor recurrence and metastasis. Such a light-modulated allosteric transition in non-photosensitive polymers provides new insight into the development of smart nanomaterials for biosensing and drug delivery applications.

Identifying causality, genetic correlation, priority and pathways of large-scale complex exposures of breast and ovarian cancers.

BACKGROUND: Genetic correlations, causalities and pathways between large-scale complex exposures and ovarian and breast cancers need systematic exploration. METHODS: Mendelian randomisation (MR) and genetic correlation (GC) were used to identify causal biomarkers from 95 cancer-related exposures for risk of breast cancer [BC: oestrogen receptor-positive (ER + BC) and oestrogen receptor-negative (ER - BC) subtypes] and ovarian cancer [OC: high-grade serous (HGSOC), low-grade serous, invasive mucinous (IMOC), endometrioid (EOC) and clear cell (CCOC) subtypes]. RESULTS: Of 31 identified robust risk factors, 16 were new causal biomarkers for BC and OC. Body mass index (BMI), body fat mass (BFM), comparative body size at age 10 (CBS-10), waist circumference (WC) and education attainment were shared risk factors for overall BC and OC. Childhood obesity, BMI, CBS-10, WC, schizophrenia and age at menopause were significantly associated with ER + BC and ER - BC. Omega-6:omega-3 fatty acids, body fat-free mass and basal metabolic rate were positively associated with CCOC and EOC; BFM, linoleic acid, omega-6 fatty acids, CBS-10 and birth weight were significantly associated with IMOC; and body fat percentage, BFM and adiponectin were significantly associated with HGSOC. Both GC and MR identified 13 shared factors. Factors were stratified into five priority levels, and visual causal networks were constructed for future interventions. CONCLUSIONS: With analysis of large-scale exposures for breast and ovarian cancers, causalities, genetic correlations, shared or specific factors, risk factor priority and causal pathways and networks were identified.

Roles for circulating polyunsaturated fatty acids in ischemic stroke and modifiable factors: a Mendelian randomization study.

BACKGROUND: Available data about the effects of circulating polyunsaturated fatty acids (PUFAs) on ischemic stroke (IS) and its main risk factors remains limited and conflicting. Therefore, we conducted Mendelian randomization (MR) to assess whether genetically predicted PUFA affected IS, lipids and blood pressure (BP). METHODS: Genetic instruments associated with IS were derived from ISGC Consortium (n = 29,633), with lipids were derived from GLGC(n = 188,577), with BP were derived from Neale Lab(n = 337,000). The inverse-variance weighted method was the main analysis to estimate the effect of exposure on outcome. Sensitivity analyses included principal components analysis, MR-Egger, weighted median, and weighted mode. RESULTS: Per SD increases in serum α-linolenic acid (ALA) were associated with lower IS risk, with odd ratio (OR) of 0.867(0.782,0.961), arachidonic acid (AA) were associated with higher IS risk (OR: 1.053(1.014,1.094)). Likewise, Per SD increases in ALA were associated with the lower-level low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) (ß:-0.122(- 0.144, - 0.101), - 0.159(- 0.182, - 0.135), - 0.148(- 0.171, - 0.126), respectively), AA were associated with the higher-level of LDL-C, HDL-C and TC (ß:0.045(0.034,0.056), 0.059(0.050,0.067), 0.055(0.046,0.063), respectively). Linoleic acid (LA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) had little or no association with IS, lipids or BP at Bonferroni-corrected significance. Different analytic methods supported these findings. The intercept test of MR-Egger implied no pleiotropy. CONCLUSIONS: High-level plasma ALA was protective for IS but AA was the opposite. LA, EPA, DHA, and DPA had no effects on IS.

The Mechanism of Relaxation by Viewing a Japanese Garden: A Pilot Study.

AIM: To explore people's visual attention and psychological and physiological responses to viewing a Japanese garden (an asymmetrically designed garden) and an herb garden (a symmetrically designed garden). BACKGROUND: There are few studies of eye movements when observing different style gardens, and how they are connected to the interpretation of the space, and physiological and psychological responses. METHOD: Thirty subjects were recruited and their physiological and psychological responses to viewing the garden types were assessed using a heart-rate monitor and questionnaire. Eye movements while viewing projected slide images of the gardens were tracking using an eye-tracking monitor. RESULTS: A significant decrease in heart rate was observed when subjects were viewing the Japanese garden as opposed to viewing the herb garden. Mood was significantly improved in both gardens, but eye-gaze patterns differed. The Japanese garden elicited far more comments about expectations for the coming season; unlike the herb garden, it also induced memories of viewing other landscapes. CONCLUSION: The physiological and psychological responses to viewing gardens differs based on the quality of landscape design and the prior experience of viewers.

Spatiotemporal variations of magnetic susceptibility in the deep gray matter nuclei from 1 month to 6 years: A quantitative susceptibility mapping study.

BACKGROUND: Quantitative susceptibility mapping (QSM) is emerging as a technique that quantifies the paramagnetic nonheme iron in brain tissue. Brain iron quantification during early development provides insights into the underlying mechanism of brain maturation. PURPOSE: To quantify the spatiotemporal variations of brain iron-related magnetic susceptibility in deep gray matter nuclei during early development by using QSM. STUDY TYPE: Retrospective. SUBJECTS: Eighty-seven infants and children aged 1 month to 6 years. FIELD STRENGTH/SEQUENCE: Enhanced T2 *-weighted angiography using a 3D gradient-echo sequence at 3.0T. ASSESSMENT: QSM was calculated by modified sophisticated harmonic artifact reduction for phase data and sparse linear equations and sparse least squares-based algorithm. Means of susceptibility in deep gray matter nuclei (caudate nucleus, putamen, globus pallidus, thalamus) relative to that in splenium of corpus callosum were measured. STATISTICAL TESTS: Relationships of mean susceptibility with age and referenced iron concentration were tested by Pearson correlation. Differences of mean susceptibility between the selected nuclei in each age group were compared by one-way analysis of variance (ANOVA) and Fisher's Linear Significant Difference (LSD) test. RESULTS: Positive correlations of susceptibility with both referenced iron concentration and age were found (P < 0.0001); particularly, globus pallidus showed the highest correlation with age (correlation coefficient, 0.882; slope, 1.203; P < 0.001) and greatest susceptibility (P < 0.05) among the selected nuclei. DATA CONCLUSION: QSM allows the feasible quantification of iron deposition in deep gray matter nuclei in infants and young children, which exhibited gradual accumulation at different speeds. The fastest and highest iron accumulation was observed in the globus pallidus with increasing age during early development. LEVEL OF EVIDENCE: 4 Technical Efficacy:Stage 2 J. Magn. Reson. Imaging 2018.

Glycine Relieves Intestinal Injury by Maintaining mTOR Signaling and Suppressing AMPK, TLR4, and NOD Signaling in Weaned Piglets after Lipopolysaccharide Challenge.

This study was conducted to envaluate whether glycine could alleviate Escherichia coli lipopolysaccharide (LPS)-induced intestinal injury by regulating intestinal epithelial energy status, protein synthesis, and inflammatory response via AMPK, mTOR, TLR4, and NOD signaling pathways. A total of 24 weanling piglets were randomly allotted to 1 of 4 treatments: (1) non-challenged control; (2) LPS-challenged control; (3) LPS + 1% glycine; (4) LPS + 2% glycine. After 28 days feeding, piglets were injected intraperitoneally with saline or LPS. The pigs were slaughtered and intestinal samples were collected at 4 h postinjection. The mRNA expression of key genes in these signaling pathways was measured by real-time PCR. The protein abundance was measured by Western blot analysis. Supplementation with glycine increased jejunal villus height/crypt depth ratio. Glycine also increased the jejunal and ileal protein content, RNA/DNA ratio, and jejunal protein/DNA ratio. The activities of citroyl synthetase in ileum, and α-ketoglutarate dehydrogenase complex in jejunum, were increased in the piglets fed diets supplemented with glycine. In addition, glycine decreased the jejunal and ileal phosphorylation of AMPKα, and increased ileal phosphorylation of mTOR. Furthermore, glycine downregulated the mRNA expression of key genes in inflammatory signaling. Meanwhile, glycine increased the mRNA expression of negative regulators of inflammatory signaling. These results indicate that glycine supplementation could improve energy status and protein synthesis by regulating AMPK and mTOR signaling pathways, and relieve inflammation by inhibiting of TLR4 and NOD signaling pathways to alleviate intestinal injury in LPS-challenged piglets.

The effect of Mg2+ on digestion performance and microbial community structures in sludge digestion systems.

The important criteria in anaerobic digestion is the rate-limiting step which decides the fate of value-added products especially from waste-activated sludge (WAS). Hence, the present study investigated the effect of magnesium (Mg2+) addition on anaerobic digestion of WAS. The lab-scale experiments were conducted at 25 °C with Mg2+ doses ranging from 0.01 to 0.2 mol/L. Maximum total volatile fatty acids (VFAs) production (372.78 mg COD/L) occurred at a Mg2+ dose of 0.2 mol/L, which was about eight times higher than the control tests. Further, Mg2+ addition facilitated sludge dewaterability and phosphorus removal. The mechanism of improved VFAs generation was analyzed from the view of both chemical and biological effects. Chemical effect significantly enhanced the release of calcium and iron in WAS, resulting in the disintegration of WAS, which benefited hydrolysis and acidification processes. Illumina MiSeq sequencing analysis revealed that enrichment of functional bacteria and the increase of bacterial diversity were obtained in the 0.2 mol Mg2+/L experiment, while the influence was negative on the reactor with 0.025 mol/L Mg2+. Meanwhile, methanogens were accordantly inhibited in the experiments with Mg2+ addition.

The Power of Traditional Design Techniques: The Effects of Viewing a Japanese Garden on Individuals With Cognitive Impairment.

PURPOSE: This study is to examine how viewing a Japanese garden affects Japanese patients with dementia. BACKGROUND: In a previous study, authors explored the effect on individuals with Alzheimer's disease of viewing an indoor Japanese garden at a nursing home in the United States and reported that viewing the garden significantly reduced the heart rate, evoked short-term and long-term memories, and improved behavioral symptoms. However, it was unclear whether these effects were caused by the design of Japanese garden or unfamiliarity of the design to Caucasians. METHODS: We constructed a Japanese garden on the rooftop of a hospital in Japan and assessed with a total of 25 subjects on the following categories: (1) eye movement, (2) heart rate, and (3) behavior under four different conditions: (a) open view of the site before construction of the Japanese garden (the control space), (b) open view of the Japanese garden, (c) view of the Japanese garden through closed door, and (d) view of Japanese garden through closed door with the chrysanthemum scent. Findings/Results: Viewers' eyes scanned larger area while viewing the Japanese garden, and viewing the Japanese garden significantly reduced heart rate and improved behavioral symptoms than the control space. We also found that the effect of viewing the same Japanese garden differed across three conditions: the view through an open door, a closed door, and a closed door with added scent.

Effects of injection of anti-corticotropin release hormone serum in the lateral ventricles and electroacupuncture analgesia on pain threshold in rats with adjuvant arthritis.

Rat models of adjuvant arthritis were established, and anti-corticotropin release hormone serum injection in the lateral ventricles and electroacupuncture at right Jiaji (EX-B2) were performed. The pain threshold was decreased at 45 and 60 minutes after injection of the anti-corticotropin release hormone serum. Electroacupuncture at Jiaji can resist this effect. Immunohistochemical staining results showed that the expression of corticotropin release hormone in the hypothalamic paraventricular nucleus was greater in the electroacupuncture + anti-corticotropin release hormone serum group compared with the anti-corticotropin release hormone serum group. The expression of corticotropin release hormone was correlated with the pain threshold. The effect of endogenous corticotropin release hormone in pain modulation can be obstructed by anti-corticotropin release hormone serum. The analgesia of electroacupuncture can partially resist the depressed pain threshold caused by injection of anti-corticotropin release hormone serum. The analgesic effect of electroacupuncture is associated with the corticotropin release hormone content in the hypothalamus.