The prod eff: Partially producing items moderates the production effect.

Current accounts of the production effect suggest that production leads to the encoding of additional production-associated features and/or better feature encoding. Thus, if it is the act of production that leads to the storage and/or enhanced encoding of these features, then less of this act should reduce the resulting production effect. In two experiments, we provide a direct test of this idea by manipulating how much of a given item is produced within a single mode of production (typing). Results demonstrate that such partial production can yield a significant production effect that is smaller than the effect that emerges from producing the entire item. These results suggest that how much of an item is produced can moderate the size of the production effect and are considered in the context of recent modelling efforts.

Aetiology, risk factors and microbiota composition in children with prolonged diarrhoea: A prospective case-controlled cohort study.

AIM: Prolonged diarrhoea (ProD) refers to acute-onset diarrhoea that persists for longer than 1 week. As the aetiology, risk factors and management are poorly defined, we prospectively enrolled children hospitalised in a high-income setting to assess these outcomes and investigate the potential role of gut microbiota. METHODS: All children aged 30 days to 14 years admitted for acute-onset diarrhoea lasting 7-14 days were included. Children consecutively admitted in the same period for acute diarrhoea (AD) served as controls. High-throughput sequencing of 16S rRNA gene amplicons was used to analyse stool samples from a subset of patients and healthy controls. RESULTS: Sixty-eight with ProD and 104 with AD were enrolled. Intestinal infections were the main aetiology of diarrhoea in both groups (ProD 92.9% vs. AD 97.8%). ProD children showed a higher prevalence of bacterial infections compared to AD (30.8% vs. 8.9%, p = 0.024). Neither age, host-related factors, nor microbiome alterations were specifically linked to ProD. However, ProD children had a more severe initial clinical presentation than AD. CONCLUSION: ProD is often the result of an unusually severe intestinal infection that runs a course longer than expected but generally resolves without further problems. No specific management or therapies should be undertaken in most cases.

Reduced graphene oxide-persimmon tannin/Pt@Pd nanozyme-based cascade colorimetric sensor for detection of 1,5-anhydroglucitol.

1,5-anhydroglucitol (1,5-AG) is of considerable clinical relevance as a biochemical marker of glucose metabolism in the assessment and monitoring of diabetes. Herein, a simple colorimetric biosensor was constructed for the identification and detection of 1,5-AG by using pyranose oxidase (PROD) enzyme cascaded with reduced graphene oxide/persimmon tannin/Pt@Pd (RGO-PT/Pt@Pd NPs) nanozyme. The as-prepared RGO-PT/Pt@Pd NPs had excellent peroxidase-like activity and can be applied as a nanozyme. First, PROD enzyme reacts with the target 1,5-AG, decomposing 1,5-AG into 1,5-anhydrofuctose (1,5-AF) and H2O2. At this point, the highly catalytic RGO-PT/Pt@Pd NPs nanozyme produces a cascade with PROD enzyme which catalyzes the decomposition of H2O2 to produce O2. This in turn oxidizes the substrate 3,3',5,5'-tetramethylbenzidine (TMB) and produces a color change in the solution. Finally, the detection of 1,5-AG was achieved by measuring the absorption peak at 652 nm with an ultraviolet visible (UV-vis) spectrophotometer. Under optimal conditions, the linear operating range of the 1,5-AG enzyme cascade colorimetric sensor was 1.0-100.0 µg/mL, and the limit of detection (LOD) was 0.81 µg/mL. The proposed colorimetric biosensor was successfully applied to detect 1,5-AG in spiked human serum samples with the recoveries of 97.2-103.9% and RSDs of 1.94-4.48%. It provides a promising developmental assay for clinical detection of 1,5-AG.

Psychotic-Like Experiences and Concurrent Substance Use Among People Who Use New Psychoactive Substances.

New psychoactive substances (NPS) are a group of substances that mimic established drugs, e.g., cannabinoids, stimulants, and opioids. NPS use has been associated with psychotic-like experiences, but current research is limited. This study focused on NPS use and psychotic-like experiences in persons attending substance use services in South-West Finland. The primary aim was to evaluate if NPS use associates with psychotic-like experiences, and if the association is independent of comorbid psychotic illness. As a secondary aim, this study evaluated concurrent substance use among people who use NPS.The study was based on a voluntary and anonymous survey administered on-site for people attending substance use services. The survey was conducted in 17 substance use service centers in South-West Finland in 2019, totaling 219 respondents. Information on substance use, service use due to psychotic episodes, and comorbid psychotic illness was collected. A validated PROD questionnaire was used for information on psychotic-like experiences.In all, 17% of 219 participants (n = 38) reported NPS use. After adjustments with comorbid psychotic illness, age, and gender, NPS use associated with PROD-screen positivity, i.e., reporting at least three psychotic-like symptoms. NPS use also associated with service use due to substance-induced psychotic episodes, and extensive use of several substances.In this study, NPS use associated with psychotic-like experiences independently of comorbid psychotic illness. However, as NPS use is also associated with heavy use of several substances, this study implicates concurrent substance use as a confounding factor when studying NPS use, which should be considered in future research.

Effects of body size and countermeasure exercise on estimates of life support resources during all-female crewed exploration missions.

Employing a methodology reported in a recent theoretical study on male astronauts, this study estimated the effects of body size and aerobic countermeasure (CM) exercise in a four-person, all-female crew composed of individuals drawn from a stature range (1.50- to 1.90-m) representative of current space agency requirements (which exist for stature, but not for body mass) upon total energy expenditure (TEE), oxygen (O2) consumption, carbon dioxide (CO2) and metabolic heat (Hprod) production, and water requirements for hydration, during space exploration missions. Assuming geometric similarity across the stature range, estimates were derived using available female astronaut data (mean age: 40-years; BMI: 22.7-kg·m-2; resting VO2 and VO2max: 3.3- and 40.5-mL·kg-1·min-1) on 30- and 1080-day missions, without and with, ISS-like countermeasure exercise (modelled as 2 × 30-min aerobic exercise at 75% VO2max, 6-day·week-1). Where spaceflight-specific data/equations were not available, terrestrial equivalents were used. Body size alone increased 24-h TEE (+ 30%), O2 consumption (+ 60%), CO2 (+ 60%) and Hprod (+ 60%) production, and water requirements (+ 17%). With CM exercise, the increases were + 25-31%, + 29%, + 32%, + 38% and + 17-25% across the stature range. Compared to the previous study of theoretical male astronauts, the effect of body size on TEE was markedly less in females, and, at equivalent statures, all parameter estimates were lower for females, with relative differences ranging from -5% to -29%. When compared at the 50th percentile for stature for US females and males, these differences increased to - 11% to - 41% and translated to larger reductions in TEE, O2 and water requirements, and less CO2 and Hprod during 1080-day missions using CM exercise. Differences between female and male theoretical astronauts result from lower resting and exercising O2 requirements (based on available astronaut data) of female astronauts, who are lighter than male astronauts at equivalent statures and have lower relative VO2max values. These data, combined with the current move towards smaller diameter space habitat modules, point to a number of potential advantages of all-female crews during future human space exploration missions.

Genetic parameters for production, quality, and colors from eggs in Brazilian lineages of chickens.

Genetic parameters were estimated for egg production, egg quality, and eggshell colors in eight lineages of Brazilian laying hens. Age at first egg (AFE), total egg production up to the 45th week (PROD), egg weight (EW), albumen height (AH), yolk color (YC), the Haugh units (HU), eggshell strength (ESS), eggshell thickness (EST), yolk weight (YW), eggshell weight (ESW), and eggshell color (L*, a*, and b*) were measured in 2030 eggs obtained from 645 laying hens. Variance components were estimated from a mixed animal model, which included the fixed effects of contemporary groups, cage location, and hen line, and the additive genetic, permanent environmental, and residual as random effects. In general, heritabilities were low to moderate (h2 = 0.11 to 0.48). Genetic correlations among eggshell quality traits were moderate to high (0.36 and 0.69). High genetic correlations were obtained between the eggshell color traits [rg = -0.90 (L* and a*); rg = -0.64 (L* and b*); and rg = 0.65 (a* and b*)]. Results suggest that EW is strongly correlated with ESW, but the genetic correlations between EW and ESS and between EW and EST were low. Genetic correlations between L* and eggshell quality traits were low to moderate, suggesting that L* has little or no relation with external egg quality. However, genetic correlations between a* and b* values and eggshell quality traits were high. The genetic correlations between eggshell color and eggshell quality traits were low, suggesting that the eggshell color does not influence external egg quality. Genetic correlations between PROD and egg quality traits were negative and varied between -0.42 and -0.05. This antagonistic relationship emphasizes the importance of adopting breeding schemes that allow the simultaneous genetic progress of these traits by considering their genetic correlation and economic relevance, such as the selection index.

Biologically relevant reductions in fetal testosterone and Insl3 induced by in utero exposure to high levels of di-isononyl phthalate (DINP) in male rats.

Some phthalate esters alter male rat reproductive development during sexual differentiation by interfering with fetal testis maturation resulting in reduced Leydig Cell synthesis of testosterone and insulin-like 3 (Insl3) hormones. Gene transcripts associated with steroid hormone and cholesterol transport, and cholesterol synthesis and lipid metabolism also are reduced. These alterations cause permanent malformations of hormone-dependent tissues, sperm production and fertility in male offspring; effects known as the "Phthalate Syndrome." We have shown that administration of a high dose of 750 mg diisononyl phthalate (750 mg/kg/d DINP) during sex differentiation reduced fetal testis testosterone production (T Prod), testis gene expression and induced a low incidence of reproductive malformations in male rat offspring. In the current study we administered DINP at even higher dose levels (1.0 and 1.5 g/kg/d) from gestational day (GD) 14 to postnatal (PND) 3 to determine if these effects were dose related and if the magnitude of the effects could be predicted from a statistical model of fetal testosterone production (T Prod) and Insl3 mRNA levels. These models were previously developed using dipentyl phthalate (DPeP) data from fetal T Prod and postnatal studies. We found that the severity of the demasculinizing effects on the androgen-dependent organs and gubernaculum by DINP were accurately predicted from the statistical models of fetal T prod and Insl3 mRNA, respectively. Taken together, our results indicate that reductions fetal T prod and Insl3 predict the severity of demasculinizing effects in utero exposure to the phthalates DINP and DPeP regardless of potency.

Patient-centred outcomes of imaging tests: recommendations for patients, clinicians and researchers.

BACKGROUND: Imaging tests are one of the most frequently used diagnostic modalities in healthcare, but the benefits of their direct impacts on clinical decision-making have been countered by concerns that they can be overused. Assessing the relative value of imaging tests has largely focused on measures of test accuracy, which overlooks more comprehensive benefits and risks of imaging tests, particularly their impact on patient-centred outcomes (PCOs). We present the findings of the Patient Reported Outcomes of Diagnostics (PROD) research study in response to a methodological gap in the area of diagnostic test comparative effectiveness research. METHODS: Over a 3-year period, the PROD Study engaged with multiple stakeholders to identify existing conceptual models related to PCOs for imaging testing, conducted primary research and evidence synthesis, and developed consensus recommendations to describe and categorise PCOs related to imaging testing. RESULTS: The PROD framework categorises PCOs from imaging studies within four main domains: information or knowledge yielded, physical impact, emotional outcomes and test burden. PCOs interact with each other and influence effects across domains, and can be modified by factors related to the patient, clinical situation, healthcare team and the testing environment. CONCLUSIONS: Using PCOs to inform healthcare decision-making will require ways of collating and presenting information on PCOs in ways that can inform patient-provider decision-making, and developing methods to determine the relative importance of outcomes (including test accuracy) to one another.

Enhancing crop yields through improvements in the efficiency of photosynthesis and respiration.

The rate with which crop yields per hectare increase each year is plateauing at the same time that human population growth and other factors increase food demand. Increasing yield potential ( Y p ) of crops is vital to address these challenges. In this review, we explore a component of Y p that has yet to be optimised - that being improvements in the efficiency with which light energy is converted into biomass ( ε c ) via modifications to CO2 fixed per unit quantum of light (α), efficiency of respiratory ATP production ( ε prod ) and efficiency of ATP use ( ε use ). For α, targets include changes in photoprotective machinery, ribulose bisphosphate carboxylase/oxygenase kinetics and photorespiratory pathways. There is also potential for ε prod to be increased via targeted changes to the expression of the alternative oxidase and mitochondrial uncoupling pathways. Similarly, there are possibilities to improve ε use via changes to the ATP costs of phloem loading, nutrient uptake, futile cycles and/or protein/membrane turnover. Recently developed high-throughput measurements of respiration can serve as a proxy for the cumulative energy cost of these processes. There are thus exciting opportunities to use our growing knowledge of factors influencing the efficiency of photosynthesis and respiration to create a step-change in yield potential of globally important crops.

Development of a strategy to identify and evaluate direct and indirect activators of constitutive androstane receptor in rats.

Constitutive androstane receptor (CAR) is a nuclear receptor that plays a key role in drug metabolism and disposition and in the development of liver tumors in rodents. CAR is activated by ligands and indirect activators, which do not bind to the receptor but activate it through cellular signaling. In this study, we sought to identify direct and indirect activators of rat CAR (rCAR). Assessment of the influence of mutations on the transcriptional activity of rCAR identified a mutant termed rCAR-3A-G354Q that displays low constitutive activity and high ligand responsiveness. Reporter assays using the mutant were performed with compounds that increased the mRNA levels of Cyp2b1, a CAR target gene, in rat primary hepatocytes. Several compounds activated rCAR-3A-G354Q and were implicated as rCAR ligands. Since indirect CAR activators are considered to display little species differences, we then determined CYP2B6 mRNA levels in human hepatocyte-like HepaRG cells after treatment with compounds that increased Cyp2b1 mRNA levels in rat hepatocytes but did not activate rCAR-3A-G354Q. The results demonstrated six compounds as possible rCAR indirect activators. Taken together, the combined measurement of Cyp2b1 mRNA levels in rat primary hepatocytes and rCAR-3A-G354Q activation in reporter assays can be useful for evaluating rCAR activation by chemicals.

Improving Node Classification through Convolutional Networks Built on Enhanced Message-Passing Graph.

Enhancing message propagation is critical for solving the problem of node classification in sparse graph with few labels. The recently popularized Graph Convolutional Network (GCN) lacks the ability to propagate messages effectively to distant nodes because of over-smoothing. Besides, the GCN with numerous trainable parameters suffers from overfitting when the labeled nodes are scarce. This article addresses the problem via building GCN on Enhanced Message-Passing Graph (EMPG). The key idea is that node classification can benefit from various variants of the input graph that can propagate messages more efficiently, based on the assumption that the structure of each variant is reasonable when more unlabeled nodes are labeled properly. Specifically, the proposed method first maps the nodes to a latent space through graph embedding that captures the structural information of the input graph. Considering the node attributes together, the proposed method constructs the EMPG by adding connections between the nodes in close proximity in the latent space. With the help of the added connections, the EMPG allows a node to propagate its message to the right nodes at long distances, so that the GCN built on the EMPG need not stack multiple layers. As a result, over-smoothing is avoided. However, dense connections may cause message propagation saturation and lead to overfitting. Seeing the EMPG as an accumulation of some potential variants of the original graph, the proposed method utilizes dropout to extract a group of variants from the EMPG and then builds multichannel GCNs on them. The multichannel features learned from different dropout EMPGs are aggregated to compute the final prediction jointly. The proposed method is flexible, as a brod range of GCNs can be incorporated easily. Additionally, it is efficient and robust. Experimental results demonstrate that the proposed method yields improvements in node classification.

A 28-day whole-body inhalation study to evaluate octamethylcyclotetrasiloxane (D4) absorption/distribution in two rat strains.

To investigate the potential toxicity of Octamethylcyclotetrasiloxane (D4), studies in laboratory rats have used primarily one of two strains, Sprague-Dawley (SD) and Fischer-344 (F-344). Reproductive studies used SD rats whereas F-344 rats were used in D4 pharmacokinetics, metabolism, acute/subacute/chronic toxicity and oncogenicity studies. Here, we assessed specific endpoints related to D4 pharmacokinetics and biochemistry in SD and F-344 rats within a single study, which allows for direct comparisons between strain and sex. This assessment included determination of microsomal total P450, NADPH-cytochrome c reductase, epoxide hydrolase, CYP2B1/2, CYP1A1/2, CYP3A1/2, CYP2C11, and CYP2A1. Aside from slight brown pigment in the liver, the treated animals experienced no toxicologically significant weight loss, decrease in food consumption, or clinical signs. Concentrations of D4 in plasma and fat were generally greater in females relative to males in both strains. SD females appeared to have statistically significantly greater plasma and fat concentrations following 28 days of repeated exposure to D4 relative to F-344 rats, suggesting the existence of potential sex and strain differences in D4 pharmacokinetics. The effect of D4 exposure on liver enzyme expression was similar among and between sexes and strain and was consistent with that for phenobarbital-like inducers. Notable differences included a finding of elevated CYP2B1/2 protein levels without a similar magnitude of increase in CYP2B/1 activity and a greater degree of CYP3A1/2 induction (protein and activity) for female SD rats. The importance of these findings is unclear, however reduced CYP2B1/2 activity may give rise to lower rates of D4 metabolism and clearance, consistent with the higher tissue levels of D4 in SD relative to F-344 female rats.

Enantioselective metabolism of chiral polychlorinated biphenyl 2,2',3,4,4',5',6-Heptachlorobiphenyl (CB183) by human and rat CYP2B subfamilies.

Chiral polychlorinated biphenyls (PCBs) have atropisomers that have different axial chiralities and exist as racemic mixtures. However, biochemical processes often result in the unequal accumulation of these atropisomers in organisms. This phenomenon leads to enantiospecific toxicity enhancement or reduction because either of the atropisomers mainly affects toxicity expression. Enantioselective accumulation is caused by cytochrome P450 (CYP, P450) monooxygenases, especially the CYP2B subfamilies. Therefore, this study investigates the metabolism of a chiral PCB in vitro. Both atropisomers isolated from racemic 2,2',3,4,4',5',6-heptachlorobiphenyl (CB183) were metabolized by human CYP2B6, but not rat CYP2B1. This may be due to the difference in the size of the substrate-binding cavities of CYP2B6 and CYP2B1. The stable accommodation of (-)-CB183 in the cavity without any steric hindrance explained the preferential metabolism of (-)-CB183 compared to (+)-CB183. Two hydroxylated metabolites, 3'-OH-CB183 and 5-OH-CB183, were identified. The docking study showed that the 3'-position of the trichlorophenyl ring closely approaches the heme of CYP2B6. To our knowledge, this is the first study to elucidate the structural basis of chiral PCB metabolism by P450 isozymes. These results will help promote the precise toxicity evaluation of chiral PCBs and provide an explanation of the structural basis of chiral PCB metabolism.

Association of Blood Pressure Lowering Intensity With White Matter Network Integrity in Patients With Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Diffusion tensor imaging (DTI) networks integrate damage from a variety of pathologic processes in cerebral small vessel disease (SVD) and may be a sensitive marker to detect treatment effects. We determined whether brain network analysis could detect treatment effects in the PRESERVE trial data set, in which intensive vs standard blood pressure (BP) lowering was compared. The primary end point of DTI had not shown treatment differences. METHODS: Participants with lacunar stroke were randomized to standard (systolic 130-140 mm Hg) or intensive (systolic ≤ 125 mm Hg) BP lowering and followed for 2 years with MRI at baseline and at 2 years. Graph theory-based metrics were derived from DTI data to produce a measure of network integrity weighted global efficiency and compared with individual MRI markers of DTI, brain volume, and white matter hyperintensities. RESULTS: Data were available in 82 subjects: standard n = 40 (mean age 66.3 ± 1.5 years) and intensive n = 42 (mean age 69.6 ± 1.0 years). The mean (SD) systolic BP was reduced by 13(14) and 23(23) mm Hg in the standard and intensive groups, respectively (p < 0.001 between groups). Significant differences in diffusion network metrics were found, with improved network integrity (weighted global efficiency, p = 0.002) seen with intensive BP lowering. In contrast, there were no significant differences in individual MRI markers including DTI histogram metrics, brain volume, or white matter hyperintensities. DISCUSSION: Brain network analysis may be a sensitive surrogate marker in trials in SVD. This work suggests that measures of brain network efficiency may be more sensitive to the effects of BP control treatment than conventional DTI metrics. TRIAL REGISTRATION INFORMATION: The trial is registered with the ISRCTN Registry (ISRCTN37694103; doi.org/10.1186/ISRCTN37694103) and the NIHR Clinical Research Network (CRN 10962; public-odp.nihr.ac.uk/QvAJAXZfc/opendoc.htm?document=crncc_users%5Cfind%20a%20clinical%20research%20study.qvw&lang=en-US&host=QVS%40crn-prod-odp-pu&anonymous=true). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intensive BP lowering in patients with SVD results in improved brain network function when assessed by DTI-based brain network metrics.

Novel cudraisoflavone J derivatives as potent neuroprotective agents for the treatment of Parkinson's disease via the activation of Nrf2/HO-1 signaling.

Parkinson's disease (PD) is a neurodegenerative disorder that causes uncontrollable movements. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, and only trials to relieve symptoms have been evaluated. Recently, we reported the total synthesis of cudraisoflavone J and its chiral isomers [Lu et al., J. Nat. Prod. 2021, 84, 1359]. In this study, we designed and synthesized a series of novel cudraisoflavone J derivatives and evaluated their neuroprotective activities in neurotoxin-treated PC12 cells. Among these compounds, difluoro-substituted derivative (13m) and prenylated derivative (24) provided significant protection to PC12 cells against toxicity induced by 6-hydroxydopamine (6-OHDA) or rotenone. Both derivatives inhibited 6-OHDA- or rotenone-induced production of reactive oxygen species and partially attenuated lipid peroxidation in rat brain homogenates, indicating their antioxidant properties. They also increased the expression of the antioxidant enzyme, heme oxygenase (HO)-1, and enhanced the nuclear translocation of Nrf2, the transcription factor that regulates the expression of antioxidant proteins. The neuroprotective effects of 13m and 24 were eliminated by Zn(II)-protoporphyrin IX, an HO-1 inhibitor, demonstrating the critical role of HO-1 in their actions. Moreover, upregulation of HO-1 was abolished by nuclear factor erythroid 2-related factor (Nrf2) knockdown, verifying that Nrf2 is an upstream regulator of HO-1. Compounds 13m and 24 triggered phosphorylation of ERK1/2, JNK, and Akt. Most importantly, 13m- and 24-induced enhancement of Nrf2 translocation and HO-1 expression was reversed by U0126 (an ERK inhibitor), SP600125 (a JNK inhibitor), and LY294002 (an Akt inhibitor). Collectively, our results show that compounds 13m and 24 exert neuroprotective and antioxidant effects through the Nrf2/HO-1 pathway mediated by phosphorylation of ERK1/2, JNK, or Akt in PC12 cells. Based on our findings, both derivatives could serve as potential therapeutic candidates for the neuroprotective treatment of PD.

Nanozyme-mediated cascade reaction system for electrochemical detection of 1,5-anhydroglucitol.

Diabetes is one of metabolic diseases affecting major human health. The early diagnosis and treatment of diabetes have significant benefits. 1,5-anhydroglucitol (1,5-AG) accurately reflects a patient's average blood glucose level for the past 3-7 days and becomes a promising marker for real-time detection of diabetes. In this study, a novel biosensor for determination 1,5-AG is constructed using reduce graphene oxide-carboxymethylated chitosan-hemin@platinum nanocomposites (rGO-CMC-H@Pt NCs) nanozyme and pyranose oxidase (PROD) enzyme as the electrochemical biosensing platform. The rGO-CMC-H@Pt NCs nanozyme has good electro-conductibility, high specific surface area, and admirable peroxide-like catalysis effect to enhance the electrochemical response. 1,5-AG is catalyzed by PROD and produces hydrogen peroxide (H2O2), which in turn can be decomposed by rGO-CMC-H@Pt NCs and produce a current signal recorded by differential pulse voltammetry (DPV) technique. Under optimal conditions, the response currents have a linear relationship in the 1,5-AG concentration of 0.1-2.0 mg/mL with R2 of 0.9869. The sensitivity is 2.1895 µA/µg·mL-1 and the limit of detection (LOD) is 38.2 µg/mL (S/N = 3). In addition, the specificity, reproducibility, stability and recovery (94.5-107.6%) of 1,5-AG biosensors all exhibit good performance. Therefore, the designed 1,5-AG biosensor has a good effect and can be used for the diagnosis of diabetes.

Differences in Enantioselective Hydroxylation of 2,2',3,6-Tetrachlorobiphenyl (CB45) and 2,2',3,4',6-Pentachlorobiphenyl (CB91) by Human and Rat CYP2B Subfamilies.

Although polychlorinated biphenyls (PCBs) were commercially banned half a century ago, contamination of the environment and organisms by PCBs is still observed. PCBs show high persistence and bioaccumulation, resulting in toxicity. Among PCBs, chiral PCBs with more than three chlorine atoms at the ortho-position exhibit developmental and neurodevelopmental toxicity. Because toxicity is dependent on the atropisomer, atropisomer-specific metabolism is vital in determining toxicity. However, structural information on enantioselective metabolism remains elusive. Cytochrome P450 (CYP, P450) monooxygenases, particularly human CYP2B6 and rat CYP2B1, metabolize separated atropisomers of 2,2',3,6-tetrachlorobiphenyl (CB45) and 2,2',3,4',6-pentachlorobiphenyl (CB91) to dechlorinated and hydroxylated metabolites. Docking studies using human CYP2B6 predict 4'-hydroxy (OH)-CB45 from (aR)-CB45 as a major metabolite of CB45. Di-OH- and dechlorinated OH-metabolites from human CYP2B6 and rat CYP2B1 are also detected. Several hydroxylated metabolites are derived from CB91 by both P450s; 5-OH-CB91 is predicted as a major metabolite. CB91 dechlorination is also detected by identifying 3-OH-CB51. A stable conformation of PCBs in the substrate-binding cavity and close distance to P450 heme are responsible for high metabolizing activities. As hydroxylation and dechlorination change PCB toxicity, this approach helps understand the possible toxicity of chiral PCBs in mammals.

Effects of Heat Acclimation Following Heat Acclimatization on Whole Body Heat Exchange in Trained Endurance Athletes.

The purpose of this study was to examine the changes in metabolic heat production (Hprod), evaporative heat loss (Hevap), and dry heat loss (Hdry), following heat acclimatization (HAz) and heat acclimation (HA). Twenty-two male endurance athletes (mean ± standard deviation; age, 37 ± 12 y; body mass, 73.4 ± 8.7 kg; height, 178.7 ± 6.8 cm; and VO2max, 57.1 ± 7.2 mL·kg−1·min−1) completed three trials (baseline; post-HAz; and post-HA), which consisted of 60 min steady state exercise at 59 ± 2% velocityVO2max in the heat (ambient temperature [Tamb], 35.2 ± 0.6 °C; relative humidity [%rh] 47.5 ± 0.4%). During the trial, VO2 and RER were collected to calculate Hprod, Hevap, and Hdry. Following the baseline trial, participants completed self-directed outdoor summer training followed by a post-HAz trial. Then, five days of HA were completed over eight days in the heat (Tamb, 38.7 ± 1.1 °C; %rh, 51.2 ± 2.3%). During the HA sessions, participants exercised to maintain hyperthermia (38.50 °C and 39.75 °C) for 60 min. Then, a post-HA trial was performed. There were no differences in Hprod between the baseline (459 ± 59 W·m−2), post-HAz (460 ± 61 W·m−2), and post-HA (464 ± 55 W·m−2, p = 0.866). However, Hevap was significantly increased post-HA (385 ± 84 W·m−2) compared to post-HAz (342 ± 86 W·m−2, p = 0.043) and the baseline (332 ± 77 W·m−2, p = 0.037). Additionally, Hdry was significantly lower at post-HAz (125 ± 8 W·m−2, p = 0.013) and post-HA (121 ± 10 W·m−2, p < 0.001) compared to the baseline (128 ± 7 W·m−2). Hdry at post-HA was also lower than post-HAz (p = 0.049). Hprod did not change following HAz and HA. While Hdry was decreased following HA, the decrease in Hdry was smaller than the increases in Hevap. Adaptations in body heat exchange can occur by HA following HAz.

Is an Acute Perioperative Increase in Creatinine Production Rate a Potential Mechanism for an Early Creatinine-Based Signal of Renal Injury After Cardiac Surgery?

OBJECTIVES: Previous studies report a creatinine-based signal of injury within hours after cardiac surgery, which is sooner than expected based on creatinine kinetic modelling. A plausible mechanism for such an early signal has not been established, but might be explained by an acute perioperative increase in creatinine production rate (Crprod-rate). The authors sought to test the hypothesis that perioperative Crprod-rate increases from baseline in patients undergoing cardiac surgery. DESIGN: Prospective cohort study. SETTING: Academic medical center. PARTICIPANTS: Fifty adult male patients undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Based on the principle of conservation of mass, precisely timed serial measurements of patient weight, plasma and urine creatinine concentration, and urine volume were used to calculate Crprod-rate over 3 consecutive periods: a baseline period immediately before surgery (period 0), the 24-hour period starting from induction of anesthesia (period 1), and again from 24 to 48 hours after induction of anesthesia (period 2). The primary outcome was change in Crprod-rate from period 0 to period 1 (∆Crprod-rate0-1). Median Crprod-rate0 was 5.4 (interquartile range [IQR], 4.7-5.7) µmol/kg/h at baseline and increased to 6.1 (IQR, 5.6-6.5) µmol/kg/h during period 1, a median increase of 14% (95% CI, 8%-27%; p = 0.002). ∆Crprod-rate0-1 ranged from -58% to +129%, with an increase above baseline in 25 patients (76%) and an increase by ≥30% above baseline in 10 patients (30%). CONCLUSIONS: Perioperative Crprod-rate increased from baseline in patients undergoing cardiac surgery. This may represent a mechanism for an earlier creatinine-based signal of renal injury than previously thought possible.

Effects of Echinococcus multilocularis metacestodes infection and drug treatment on the activities of biotransformation enzymes in mouse liver.

The changes of biotransformation enzymes will substantially affect the host's ability to metabolize drugs and other xenobiotic compounds. In order to further elucidate this process and promote the development in treatment of echinococcosis, we investigated the effects of Echinococcus multilocularis infection and drug treatment on biotransformation enzymes in mouse liver. In microsomal and cytosolic fractions, from the six activities assayed, significant decrease of glutathione S-transferases (GST) activity and significant increase of 7-pentoxyresorufin (PROD) and NADPH-cytochrome P450 reductase (CPR) activity were observed in the mice infected with E. multilocularis metacestodes. In addition, after six weeks treatment of albendazole in E. multilocularis infected mice, significant decreased GST activity and significant increase of 7- ethoxyresorufin (EROD), PROD, and particularly 3-fold higher 7-methoxyresorufin (MROD) activity were observed. The 3-bromopyruvate treated mice only exhibited significantly lower GST activity. Our results demonstrate that E. multilocularis metacestodes infection can affect the activities of main hepatic biotransformation enzymes and such alterations of activity may further affect the hepatic biotransformation of xenobiotics. Moreover, albendazole and 3-bromopyruvate, the promising potential drug against Echinococcus, affected different hepatic biotransformation enzymes and may affect their metabolism. The findings will help to develop rational treatments with less side effects and promote the development of more efficient treatments against E. multilocularis.