Survey of pharmaceutical industry's best practices around in vitro transporter assessment and Implications for Drug Development: Considerations from the IQ Transporter Working Group.

The IQ Transporter Working Group had a rare opportunity to analyse a cross-pharma collation of in vitro data and assay methods for the evaluation of drug transporter substrate and inhibitor potential. Experiments were generally performed in accordance with regulatory guidelines. Discrepancies, such as not considering the impact of pre-incubation for inhibition and free or measured in vitro drug concentrations, may be due to the retrospective nature of the dataset and analysis. Lipophilicity was a frequent indicator of cross-transport inhibition (P-gp, BCRP, OATP1B and OCT1) with high molecular weight ({greater than or equal to}500 Da) also common for OATP1B and BCRP inhibitors. A high level of overlap in in vitro inhibition across transporters was identified for BCRP, OATP1B1 and MATE1 suggesting that prediction of DDIs for these transporters will be common. In contrast inhibition of OAT1 did not coincide with inhibition of any other transporter. Neutrals, bases, and compounds with intermediate-high lipophilicity tended to be P-gp and/or BCRP substrates whilst compounds with MW <500 Da tended to be OAT3 substrates. Interestingly the majority of in vitro inhibitors were not reported to be followed up with a clinical study by the submitting company, whilst those compounds identified as substrates generally were. Approaches to metabolite testing were generally found to be similar to parent testing with metabolites generally being equally or less potent than parent compounds. However, examples where metabolites inhibited transporters in vitro were identified supporting the regulatory requirement for in vitro testing of metabolites to enable integrated clinical DDI risk assessment. Significance Statement A diverse dataset showed transporter inhibition often correlated with lipophilicity and molecular weight (>500 Da). Overlapping transporter inhibition was identified, particularly that inhibition of BCRP, OATP1B1 and MATE1 was frequent if the compound inhibited other transporters. In contrast inhibition of OAT1 did not correlate with the other drug transporters tested.

Food-Borne Biotoxin Neutralization in Vivo by Nanobodies: Current Status and Prospects.

Food-borne biotoxins from microbes, plants, or animals contaminate unclean, spoiled, and rotten foods, posing significant health risks. Neutralizing such toxins is vital for human health, especially after food poisoning. Nanobodies (Nbs), a type of single-domain antibodies derived from the genetic cloning of a variable domain of heavy chain antibodies (VHHs) in camels, offer unique advantages in toxin neutralization. Their small size, high stability, and precise binding enable effective neutralization. The use of Nbs in neutralizing food-borne biotoxins offers numerous benefits, and their genetic malleability allows tailored optimization for diverse toxins. As nanotechnology continues to evolve and improve, Nbs are poised to become increasingly efficient and safer tools for toxin neutralization, playing a pivotal role in safeguarding human health and environmental safety. This review not only highlights the efficacy of these agents in neutralizing toxins but also proposes innovative solutions to address their current challenges. It lays a solid foundation for their further development in this crucial field and propels their commercial application, thereby contributing significantly to advancements in this domain.

A novel AP/PA total body irradiation technique using abutting IMRT fields at extended SSD.

PURPOSE: To develop a Total Body Irradiation (TBI) technique using IMRT at extended SSD that can be performed in any size Linac room. METHODS: Patients studied were placed on a platform close to the floor, directly under the gantry with cranial-caudal axis parallel to the gantry rotation plane and at SSD ∼200 cm. Two abutting fields with the same external isocenter at gantry angles of ±21˚, collimator angle of 90˚, and field size of 25 × 40 cm2 are employed for both supine and prone positions. An iterative optimization algorithm was developed to generate a uniform dose at the patient mid-plane with adequate shielding to critical organs such as lungs and kidneys. The technique was validated in both phantom and patient CT images for treatment planning, and dose measurement and QA were performed in phantom. RESULTS: A uniform dose distribution in the mid-plane within ±5% of the prescription dose was reached after a few iterations. This was confirmed with ion-chamber measurements in phantom. The mean dose to lungs and kidneys can be adjusted according to clinical requirements and can be as low as ∼25% of the prescription dose. For a typical prescription dose of 200 cGy/fraction, the total MU was ∼2400/1200 for the superior/inferior field. The overall treatment time for both supine/prone positions was ∼54 min to meet the maximum absorbed dose rate criteria of 15 cGy/min. IMRT QA with portal dosimetry shows excellent agreement. CONCLUSIONS: We have developed a promising TBI technique using abutting IMRT fields at extended SSD. The patient is in a comfortable recumbent position with good reproducibility and less motion during treatment. An additional benefit of this technique is that full 3D dose distribution is available from the TPS with a DVH summary for organs of interest. The technique allows precise sparing of lungs and kidneys and can be executed in any linac room.

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition.

Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting bile salt export pump (BSEP) is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including those with discontinued development or use, boxed warnings, and clean labels for DILI. The study also included rifampicin and omeprazole, pregnane X receptor and aryl hydrocarbon receptor ligands, and four mitogen-activated protein kinase kinase (MEK1/2) inhibitors. BSEP inhibitors with more severe DILI, notably pazopanib and CP-724714, significantly upregulated the expression of 7 alpha-hydroxylase (CYP7A1), independent of small heterodimer partner (SHP) expression. CYP7A1 expression was marginally induced by omeprazole. In contrast, its expression was suppressed by mometasone (10-fold), vinblastine (18-fold), hexachlorophene (2-fold), bosentan (2.1-fold), and rifampin (2-fold). All four MEK1/2 inhibitors that show clinical DILI were not potent BSEP inhibitors but significantly induced CYP7A1 expression, accompanied by a significant SHP gene suppression. Sulfotransferase 2A1 and BSEP were marginally upregulated, but no other genes were altered by the drugs tested. Protein levels of CYP7A1 were increased with the treatment of CYP7A1 inducers and decreased with obeticholic acid, an farnesoid X receptor ligand. CYP7A1 inducers significantly increased bile acid (BA) production in hepatocytes, indicating the overall regulatory effects of BA metabolism. This study demonstrates that CYP7A1 induction via various mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition, and it should be evaluated early in drug discovery. SIGNIFICANCE STATEMENT: Kinase inhibitors, pazopanib and CP-724714, inhibit BSEP and induce CYP7A1 expression independent of small heterodimer partner (SHP) expression, leading to increased bile acid (BA) production and demonstrating clinically elevated drug-induced liver toxicity. MEK1/2 inhibitors that show BSEP-independent drug-induced liver injury (DILI) induced the CYP7A1 gene accompanied by SHP suppression. CYP7A1 induction via SHP-dependent or independent mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition. Monitoring BA production in hepatocytes can reliably detect the total effects of BA-related gene regulation for de-risking.

A self-supervised learning approach for registration agnostic imaging models with 3D brain CTA.

Deep learning-based neuroimaging pipelines for acute stroke typically rely on image registration, which not only increases computation but also introduces a point of failure. In this paper, we propose a general-purpose contrastive self-supervised learning method that converts a convolutional deep neural network designed for registered images to work on a different input domain, i.e., with unregistered images. This is accomplished by using a self-supervised strategy that does not rely on labels, where the original model acts as a teacher and a new network as a student. Large vessel occlusion (LVO) detection experiments using computed tomographic angiography (CTA) data from 402 CTA patients show the student model achieving competitive LVO detection performance (area under the receiver operating characteristic curve [AUC] = 0.88 vs. AUC = 0.81) compared to the teacher model, even with unregistered images. The student model trained directly on unregistered images using standard supervised learning achieves an AUC = 0.63, highlighting the proposed method's efficacy in adapting models to different pipelines and domains.

Triterpenoids from the hook-bearing stems of Uncaria rhynchophylla.

An unprescribed nortriterpenoid with an aromatic E ring, uncanortriterpenoid A (1), together with fourteen known triterpenoids (2-15), were isolated from the hook-bearing stems of Uncaria rhynchophylla Miq. Based on extensive spectroscopic analyses, the NMR data of 2, 5, and 10 in CD3OD were assigned for the first time, and the wrongly assigned δC of C-27 and C-29 of 2 were revised. Among the known compounds, 7, 13, and 15 were isolated from this species for the first time, and 15 represents the first lanostane triterpenoid bearing an extra methylidene at C-24 for the Rubiaceae family. Additionally, compounds 6 and 14 exhibited moderate ferroptosis inhibitory activity, with an EC50 value of 14.74 ± 0.20 µM for 6 and 23.11 ± 1.31 µM for 14.

Building a Predictive PBPK Model for Human OATP Substrates: a Strategic Framework for Early Evaluation of Clinical Pharmacokinetic Variations Using Pitavastatin as an Example.

To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (Vss). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CLint,active, CLint,passive, and CLint,bile, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized Ki values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates.

Response of salivary microbiome to temporal, environmental, and surface characteristics under in vitro exposure.

The microbiome of saliva stains deposited at crime scenes and in everyday settings is valuable for forensic investigations and environmental ecology. However, the dynamics and applications of microbial communities in these saliva stains have not been fully explored. In this study, we analyzed saliva samples that were exposed to indoor conditions for up to 1 year and to different carriers (cotton, sterile absorbent cotton swab, woolen, dacron) in both indoor and outdoor environments for 1 month using high-throughput sequencing. The analysis of microbial composition and Mfuzz clustering showed that the salivary flora, specifically Streptococcus (cluster7), which was associated with microbial contamination, remained stable over short periods of time. However, prolonged exposure led to significant differences due to the invasion of environmental bacteria such as Pseudomonas and Achromobacter. The growth and colonization of environmental flora were promoted by humidity. The neutral model predictions indicated that the assembly of salivary microbial communities in outdoor environments was significantly influenced by stochastic processes, with environmental characteristics having a greater impact on community change compared to surface characteristics. By incorporating data from previous studies on fecal and vaginal secretion microbiology, we developed RF and XGBoost classification models that achieved high accuracy (>98 %) and AUC (>0.8). Additionally, a RF regression model was created to determine the time since deposition (TsD) of the stains. Time inference models yielded a mean absolute error (MAE) of 7.1 days for stains exposed for 1 year and 14.2 h for stains exposed for 14 days. These findings enhance our understanding of the changes in the microbiome of saliva stains over time, in different environments, and on different surfaces. They also have potential applications in assessing potential microbial contamination, identifying body fluids, and inferring the time of deposition.

Molecular characterization of the grass carp bscl2 gene and its expression response to lipid accumulation, nutritional status, insulin and glucagon.

Bscl2 plays a role in lipid metabolism of mammals, however its role in teleost fish remains unclear. Using the grass carp (Ctenopharyngodon idella) as a model, the bscl2 gene was isolated from the brain and characterized. Thereafter, the tissue distribution of the gene was examined, before expression was analyzed as a function of fasting, refeeding, oral glucose administration and overfeeding. In addition, bscl2 mRNA levels were evaluated in grass carp primary hepatocytes treated with glucagon, insulin, oleic acid, and glucose. Results showed that the cloned bscl2 gene was 1341 bp, encoding 446 amino acids, and was highly expressed in the brain, heart, and gonad. Following oral glucose administration, bscl2 expression increased. Expression of bscl2 decreased in fasted fish but increased following refeeding. Overfeeding, which resulted in elevated lipid accumulation, also stimulated bscl2 expression. In primary hepatocytes, bscl2 levels were increased by glucose, oleic acid, and insulin treatments, and reduced by glucagon treatment. These data suggest that bscl2 may play an important role in nutrient metabolism in teleost fish.

Cloning grass carp (Ctenopharyngodon idella) ccdc3 and its expression affected by nutrition state, insulin, and glucagon.

As an adipokine, coiled-coil domain-containing 3 (CCDC3) plays multiple physiological roles in fatty liver, lipid metabolism, and abdominal obesity. Grass carp was selected as the experimental animal in this study to investigate the roles of Ccdc3 in teleosts. Results showed that the open reading frame (ORF) of cloned ccdc3 was 831 bp and encoded 276 amino acids. Three N-glycosylation sites and a predicted coiled-coil domain motif were located in the identified Ccdc3. Moreover, a nuclear localization signal (NLS) was contained in the coiled-coil domain motif of the identified Ccdc3. The results on tissue distribution revealed that ccdc3 was highly detected in grass carp fat and brain tissue. In the oral glucose tolerance test (OGTT), the expression of ccdc3 increased remarkably in the brain, hypothalamus, and visceral fat in the glucose treatment group. In the fasting and refeeding experiment, the ccdc3 expression levels were remarkably reduced in the brain, hypothalamus, and visceral fat after 14 days of fasting. In the refeeding group, the ccdc3 expression levels were considerably elevated compared with those in the fasting group. In the induced overfeeding experiment, the ccdc3 expression increased remarkably in the hepatopancreas, brain, and visceral fat tissues. The ccdc3 expression in the primary hepatocytes was remarkably increased with glucose, oleic acid, and insulin treatment. However, ccdc3 expression was markedly decreased with glucagon treatment. In conclusion, these results indicate that Ccdc3 is involved in regulating glucose and lipid metabolism of teleosts.

Toward improved predictions of pharmacokinetics of transported drugs in hepatic impairment: Insights from the extended clearance model.

Hepatic impairment (HI) moderately (<5-fold) affects the systemic exposure (i.e., area under the plasma concentration-time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine. However, the effect of HI on their AUC is much greater (>10-fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) over the sum of metabolic and biliary CLs as important in predicting the impact of HI on the AUC of dual OATP/CYP3A substrates. Because HI may reduce hepatic CYP3A-mediated CL to a greater extent than biliary efflux CL, the greater the contribution of the former versus the latter, the greater the impact of HI on drug AUC ratio (AUCRHI ). Using physiologically-based pharmacokinetic modeling and simulation, we predicted relatively well the AUCRHI of OATP substrates that are not significantly metabolized (pitavastatin, rosuvastatin, valsartan, and gadoxetic acid). However, there was a trend toward underprediction of the AUCRHI of the dual OATP/CYP3A4 substrates fimasartan and atorvastatin. These predictions improved when the sinusoidal efflux CL of these two drugs was increased in healthy volunteers (i.e., before incorporating the effect of HI), and by modifying the directionality of its modulation by HI (i.e., increase or decrease). To accurately predict the effect of HI on AUC of hepatobiliary cleared drugs it is important to accurately predict all hepatobiliary pathways, including sinusoidal efflux CL.

Lycorine promotes IDH1 acetylation to induce mitochondrial dynamics imbalance in colorectal cancer cells.

Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors, especially for colorectal cancer (CRC). However, the underlying molecular mechanism still remains unclear. In this study, IDH1 was identified as a crucial cellular target of a natural-derived anti-CRC small molecule lycorine, using the unbiased thermal proteome profiling (TPP) strategy. We found that lycorine directly targeted a unique C-terminal domain of IDH1, and disrupted IDH1 interaction with deacetylase sirtuin 1 (SIRT1), thereby significantly promoting IDH1 acetylation modification. Then, lycorine noticeably triggered oxidative stress in CRC cells to cause mitochondrial membranes injury, and subsequently facilitated mitochondrial fission. Specific knockdown of IDH1 or SIRT1 markedly aggrieved lycorine-mediated oxidative stress and mitochondrial fragmentation in CRC cells. Furthermore, the combination of lycorine and sirtuins blocker nicotinamide (NAM) exhibited a synergic therapeutic effect in CRC cells. Collectively, our results reveal that IDH1 may serve as a promising therapeutic target for CRC via pharmacologically driving oxidative stress-dependent mitochondrial dynamics imbalance.

Interpretation of Protein-Mediated Uptake of Statins by Hepatocytes Is Confounded by the Residual Statin-Protein Complex.

Inclusion of plasma (or plasma proteins) in human hepatocyte uptake studies narrows, but does not close, the gap in in vitro to in vivo extrapolation (IVIVE) of organic anion transporting polypeptide (OATP)-mediated hepatic clearance (CLh) of statins. We have previously shown that this "apparent" protein-mediated uptake effect (PMUE) of statins by OATP1B1-expressing cells, in the presence of 5% human serum albumin (HSA), is mostly an artifact caused by residual statin-HSA complex remaining in the uptake assay. We determined if the same was true with plated human hepatocytes (PHH) and if this artifact can be reduced using suspended human hepatocytes (SHH) and the oil-spin method. We quantified the uptake of a cocktail of five statins by PHH and SHH in the absence and presence of 5% HSA. After terminating the uptake assay, the amount of residual HSA was quantified by quantitative targeted proteomics. For both PHH and SHH, except for atorvastatin and cerivastatin, the increase in total, active, and passive uptake of the statins, in the presence of 5% HSA, was explained by the estimated residual stain-HSA complex. In addition, the increase in active statin uptake by SHH, where present, was marginal (<50%), much smaller than that observed with PHH. Such a marginal increase cannot bridge the gap in IVIVE of CLh of statins. These data disprove the prevailing hypotheses for the in vitro PMUE. A true PMUE should be evaluated using the uptake data corrected for the residual drug-protein complex. SIGNIFICANCE STATEMENT: We show that the apparent protein-mediated uptake (PMUE) of statins by human hepatocytes is largely confounded by residual statin when plated or suspended human hepatocytes are used. Therefore, mechanisms other than PMUE need to be explored to explain the underprediction of the in vivo human hepatic clearance of statins by human hepatocyte uptake assays.

Changes in the microbial community after vaginal fluid exposure in different simulated forensic situations.

If vaginal fluid is found on clothing or on the body of the suspect, it may indicate the occurrence of sexual assault. Therefore, it is important to collect the victim's vaginal fluid at different sites from the suspect. Previous studies have revealed that fresh vaginal fluids can be identified based on 16S rRNA gene sequencing data. However, the influence of environmental factors on the stability of microbial markers must be investigated before being used in forensic practice. We collected vaginal fluid from nine unrelated individuals and placed each individual of vaginal swab on five different substrates. A total of 54 vaginal swabs were analyzed using 16S rRNA on the V3-V4 regions. Then, we constructed a random forest model including the samples of all vaginal fluids in this study and the other four types of body fluids in our previous studies. The alpha diversity of vaginal samples increased after exposure to the substrate environment for 30 days. The dominant vaginal bacteria were Lactobacillus and Gardnerella, which remained relatively stable after exposure, with Lactobacillus being the most abundant in all substrates, while Gardnerella was more abundant in other substrates than in the polyester fiber substrate. Except for bed sheets, Bifidobacterium significantly declined when placed on other substrates. Rhodococcus and Delftia from the substrate environment migrated to the vaginal samples. Rhodococcus was abundant in polyester fibers, and Delftia was abundant in wool substrates, while those environmental bacteria were all in low abundance in bed sheets. Overall, the bed sheet substrates showed a good retention capacity for the dominant flora and could reduce the number of taxa migrated by the environment compared with the other substrates. Both fresh and exposed vaginal samples of the same individuals could mostly be clustered and clearly distinguished from different individuals, showing the potential of individual identification, and the confusion matrix value of body fluid identification for vaginal samples was 1. In summary, vaginal samples placed on the surface of different substrates retained their stability and demonstrated good application potential for individual and body fluid identification.

Development and application of a multiplex PCR system for forensic salivary identification.

In forensics, accurate identification of the origin of body fluids is essential for reconstructing a crime scene or presenting strong evidence in court. Microorganisms have demonstrated great potential in body fluid identification. We developed a multiplex PCR system for forensic salivary identification, which contains five types of bacteria:Streptococcus salivarius, Neisseria subflava, Streptococcus. mutans, Bacteroides thetaiotaomicron, and Bacteroides. uniformis. And the validated studies were carried out following the validation guidelines for DNA analysis methods developed by the Scientific Working Group on DNA Analysis Methods (SWGDAM), which included tests for sensitivity, species specificity, repeatability, stability, and mixed samples, trace samples, case samples, and a population study. Our result depicted that the lowest detection limit of the system was 0.01 ng template DNA. Moreover, the corresponding bacteria can still be detected when the amount of saliva input is low to 0.1 µL for DNA extraction. In addition, the target bacteria were not detected in the DNA of human, seven common animals, and seven bacteria DNA and in nine other body fluid samples (skin, semen, blood, menstrual blood, nasal mucus, sweat, tears, urine, and vaginal secretions). Six common inhibitors such as indigo, EDTA, hemoglobin, calcium ions, alcohol and humic acid were well tolerated by the system. What is more, the salivary identification system recognized the saliva component in all mixed samples and simulated case samples. Among 400 unrelated individuals from the Chinese Han population analyzed by this novel system, the detection rates of N. subflava, S. salivarius, and S. mutans were 97.75%, 70.75%, and 19.75%, respectively, with 100% identification of saliva. In conclusion, the salivary identification system has good sensitivity, specificity, stability, and accuracy, which can be a new effective tool for saliva identification.

Association of urinary metal levels with metabolic syndrome in coal workers.

Studies have indicated that metal exposure is associated with an increased risk of metabolic syndrome (MetS). However, it is unclear whether overexposure to heavy metals occurs in miners and is associated with MetS risk remains unclear. In a cross-sectional study, analysis for metal exposure levels of 3428 participants from three types of workplaces was conducted. Relationships between metals in urine and MetS were characterized using a multivariate binary logistic regression model and restricted cubic spline analysis. The association between urinary metals and workplaces with respect to MetS was studied via mediation analysis and multiplicative interaction analysis. And a sensitivity analysis was performed to assess the robustness of the association between MetS and urinary metals in participants without obesity (n = 2811). Zn, Cu, Fe, Co, and Ni were found to be associated with MetS in the single-metal models, whereas only Zn and Cu showed considerable associations in the multimetal model. The odds ratios (95% CI) for MetS in the highest quartiles were 2.089 (1.611, 2.707) for urinary Zn and 1.394 (1.084, 1.794) for urinary Cu (both false discovery rate for both was < 0.05). Urinary Zn and Cu were positively associated with hypertriglyceridemia. In addition, higher Zn exposure was confirmed in underground workers than ground workers and office workers, and there was a significant association between urinary metal exposure and workplace, which together influenced the occurrence of MetS. These results provided scientific evidence for the relationship between Zn, Cu, workplaces, and MetS in coal workers and indicated that it is critical to reduce occupational metal exposure, especially in underground workers.

Synergistic Mechanism of Ultrasonic-Chemical Effects on the CH4 Adsorption-Desorption and Physicochemical Properties of Jincheng Anthracite.

Ultrasonic is a new method to enhance coalbed methane recovery. A deeper comprehension of the synergistic mechanisms of combined ultrasonic-chemical modification on the CH4 adsorption-desorption capability and physicochemical properties of coal is necessary for potential field implementation, as the modification of coal reservoirs frequently necessitates the addition of chemical reagents. This paper evaluated the CH4 adsorption-desorption properties of anthracite modified by sodium dodecyl sulfate (SDS) solution, ultrasonic modification, and combined ultrasonic-SDS modification. Fourier transform infrared spectroscopy, low-temperature nitrogen adsorption, and micro-CT were applied to elucidate the synergistic mechanism of the combined modification. The research results show that the SDS solution reduces the saturated adsorption capacity of anthracite and increases its final desorption rate by dissolving clay minerals and the physical adsorption masking effect of SDS micelles on the coal surface. Some surface groups with low bond energy are broken or evaporated under mechanical vibration and thermal effects generated by ultrasonic. The original fractures are expanded and connected, which changes the adsorption-desorption properties of anthracite. The synergistic effect of the combined modification of ultrasonic-SDS can promote the penetration range and chemical reaction efficiency of the SDS solution, which expands the effective range of ultrasonic. After combined modification, the amount of aromatics, oxygen-containing functional groups, and aliphatic hydrocarbons on the surface of coal is reduced. The connected porosity of coal samples accounts for 91.5% of the total porosity. As a result, the saturated adsorption capacity of anthracite reduces by 26.7%, and the final desorption rate increases by 28.0%. The effect of the combined ultrasonic-chemical modification is better than that of a single modification.

The role of reactive astrocytes in neurotoxicity induced by ultrafine particulate matter.

Epidemiological studies have shown that ambient fine particulate matter (PM) can cause various neurodegenerative diseases, including Alzheimer's disease. Reactive astrocytes are strongly induced by ambient fine PM, although their role is poorly understood. Herein, we show that A1 reactive astrocytes (A1s) were induced by neuroinflammatory microglia activated by PM with an aerodynamic diameter ≤ 0.2 µm (PM0.2). The activated-microglia induced A1s by secreting interleukin-1α, tumor necrosis factor-α, and complement 1q, and these cytokines acting together were necessary and sufficient to induce A1s. PM0.2-induced A1s could promote synaptic damage in neurons by secreting complement 3 (C3). SB 290157, a highly selective C3aR nonpeptide antagonist, partially ameliorated glial conditioned medium-induced synaptic injury. In vitro synaptic damage was partially prevented when A1 formation was blocked by minocycline. Finally, this study showed that N-acetyl-L-cysteine ameliorated PM0.2-induced neural damage independent of A1 differentiation. Collectively, these findings explain why central nervous system neurons suffer synaptic damage and neuroinflammation after PM0.2 exposure and suggest that this exposure induces A1s to contribute to synaptic damage of neurons. This study indicates a potential approach for developing improved treatment of these diseases induced by particulate exposure. SYNOPSIS: PM0.2-activated neuroinflammatory microglia induced A1 reactive astrocytes (A1s) by secreting IL-1α, TNF-α, and C1q. PM0.2-induced A1s could promote synaptic damage of neuron by secreting complement 3.

Predicting changes in the pharmacokinetics of CYP3A-metabolized drugs in hepatic impairment and insights into factors driving these changes.

Physiologically based pharmacokinetic models, populated with drug-metabolizing enzyme and transporter (DMET) abundance, can be used to predict the impact of hepatic impairment (HI) on the pharmacokinetics (PK) of drugs. To increase confidence in the predictive power of such models, they must be validated by comparing the predicted and observed PK of drugs in HI obtained by phenotyping (or probe drug) studies. Therefore, we first predicted the effect of all stages of HI (mild to severe) on the PK of drugs primarily metabolized by cytochrome P450 (CYP) 3A enzymes using the default HI module of Simcyp Version 21, populated with hepatic and intestinal CYP3A abundance data. Then, we validated the predictions using CYP3A probe drug phenotyping studies conducted in HI. Seven CYP3A substrates, metabolized primarily via CYP3A (fraction metabolized, 0.7-0.95), with low to high hepatic availability, were studied. For all stages of HI, the predicted PK parameters of drugs were within twofold of the observed data. This successful validation increases confidence in using the DMET abundance data in HI to predict the changes in the PK of drugs cleared by DMET for which phenotyping studies in HI are not available or cannot be conducted. In addition, using CYP3A drugs as an example, through simulations, we identified the salient PK factors that drive the major changes in exposure (area under the plasma concentration-time profile curve) to drugs in HI. This theoretical framework can be applied to any drug and DMET to quickly determine the likely magnitude of change in drug PK due to HI.

Facile post-gelation soaking strategy toward low-alkaline konjac glucomannan gels.

A facile post-gelation soaking strategy for producing low-alkaline konjac glucomannan (KGM) gels was investigated in this work. The dealkalization kinetics of soaking alkali-induced gels in citric acid (CA) solutions was determined. A comparison of sensory, textural, and water holding properties was made between untreated and post-soaking gels. Post-gelation exposure to acid took less time for lowering the gel pH at higher CA concentrations, eliminated the unattractive flavor of KGM gels and endowed them a higher hardness and breaking force. Comparatively, the whiteness of post-soaking gels was increased by 3.8%-13.1% with volume being decreased by 4.9%-8.6%, while the discrepancies were less apparent after a long-term storage. Low-alkaline gels treated by 4 g/L CA shared similar textural features with conventional KGM gels. Despite the difference in water distribution and water holding capacity of KGM gels, the syneresis of resultant low-alkaline KGM gels was not significantly affected.