Probabilistic microkinetic modeling: Species balance equations for a catalyst surface containing multiple short-range order parameters to capture spatial correlations.

Adsorbed molecules on a catalyst almost always arrange themselves in a manner that is far from perfectly random, which gives rise to spatial correlations. These correlations are a result of the interactions between the adsorbed species (adspecies) as well as elementary processes such as diffusion and reaction events that shape the adspecies arrangements. Despite their importance, spatial correlations are usually ignored while writing species balance equations for the modeling of heterogeneous catalytic systems. Recently, we have introduced a probabilistic microkinetic modeling (p-MKM) framework that aims at incorporating spatial correlations in the form of a short-ranged order (SRO) parameter into species balance equations. Here, we extend the approach to catalytic systems of higher complexity, namely, longer interactions and multiple species. This is made possible by including multiple pair probabilities in the p-MKM model for the first time. The interplay between different SRO parameters is probed. An important consideration is how many pair probabilities should be included to capture the underlying complexity with sufficient accuracy.

Adipose tissue macrophage-derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity.

Management of chronic obesity-associated metabolic disorders is a key challenge for biomedical researchers. During chronic obesity, visceral adipose tissue (VAT) undergoes substantial transformation characterized by a unique lipid-rich hypoxic AT microenvironment (ATenv) which plays a crucial role in VAT dysfunction, leading to insulin resistance (IR) and type 2 diabetes(T2D). Here, we demonstrate that obese ATenv triggers the release of miR-210-3p microRNA-loaded extracellular vesicles (EVs) from adipose tissue macrophages (ATMs), which disseminate miR-210-3p to neighboring adipocytes, skeletal muscle cells, and hepatocytes through paracrine and endocrine actions, thereby influencing insulin sensitivity. Moreover, EVs collected from Dicer-silenced miR-210-3p-overexpressed bone marrow-derived macrophages (BMDMs), induce glucose intolerance and IR in lean mice. Mechanistically, miR-210-3p interacts with the 3'-UTR of GLUT4 mRNA and silences its expression, compromising cellular glucose uptake and insulin sensitivity. Therapeutic inhibition of miR-210-3p in VAT notably rescues high-fat diet (HFD)-fed mice from obesity-induced systemic glucose intolerance. Thus, targeting ATM-specific miR-210-3p during obesity could be a promising strategy for managing IR and T2D.

Navigating the signaling landscape of Ralstonia solanacearum: a study of bacterial two-component systems.

Ralstonia solanacearum, the bacterium that causes bacterial wilt, is a destructive phytopathogen that can infect over 450 different plant species. Several agriculturally significant crop plants, including eggplant, tomato, pepper, potato, and ginger, are highly susceptible to this plant disease, which has a global impact on crop quality and yield. There is currently no known preventive method that works well for bacterial wilt. Bacteria use two-component systems (TCSs) to sense their environment constantly and react appropriately. This is achieved by an extracellular sensor kinase (SK) capable of sensing a suitable signal and a cytoplasmic response regulator (RR) which gives a downstream response. Moreover, our investigation revealed that R. solanacearum GMI1000 possesses a substantial count of TCSs, specifically comprising 36 RRs and 27 SKs. While TCSs are known targets for various human pathogenic bacteria, such as Salmonella, the role of TCSs in R. solanacearum remains largely unexplored in this context. Notably, numerous inhibitors targeting TCSs have been identified, including GHL (Gyrase, Hsp, and MutL) compounds, Walk inhibitors, and anti-TCS medications like Radicicol. Consequently, the investigation into the involvement of TCSs in virulence and pathogenesis has gained traction; however, further research is imperative to ascertain whether TCSs could potentially supplant conventional anti-wilt therapies. This review delves into the prospective utilization of TCSs as an alternative anti-wilt therapy, focusing on the lethal phytopathogen R. solanacearum.

An Observational Dosimetric Study in Definitively Treated Primary Head and Neck Cancers: To Assess the Effect of Weight Loss and Change in Lateral Neck Dimensions on the Difference Between Dose Planned and Received by the Parotid(s) and Correlation with Adaptive Radiation Therapy.

Purpose: The head and neck cancer (HNC) literature is rife with reports of differences in planned versus actual radiation doses to the parotid gland (PG) due to changes in anatomy during the course of radiation therapy. We prospectively studied and quantified changes in planned and delivered doses due to weight loss and changes in lateral neck dimensions. Methods and Materials: Sixty patients were enrolled in this prospective non-randomized observational study. The inclusion criterion was having a newly diagnosed, histologically proven squamous cell carcinoma of HNC. Weight loss (WL) and change in lateral neck dimensions (LND) were assessed weekly, and new hybrid plans were generated using interval replanning CT scans. Dose variations were monitored and extrapolated for replanning CT scans and correlated with WL and change in LND. Results: The Pearson correlation coefficients for WL and difference in Dmean of ipsilateral and contralateral PG was 0.3292 (P = .0124) and 0.4232 (P = .0010), respectively. There was significantly higher change in the Dmean of bilateral PG (Ipsilateral(I) > contralateral(C)) in patients who experienced WL of >5%. Change in LND correlated with difference in Dmean of ipsilateral PG at 0.4829 (P = .0001) and difference in D50 at 0.4146 (P < .0013). Contralateral PG correlated with difference in Dmean at 0.5952 (P < .0001). The difference in Dmean for ipsilateral PG was 1.8535 Gy for those showing reduction in LND of >1 cm compared with 0.8596 Gy (P = .0091) for those who had ≤1 cm reduction in LND. Conclusions: Either WL of >5% or reduction in LND of >1 cm can be used as an external parameter to help select patients who might benefit most from replanning and adaptive radiation therapy.

Harnessing Van der Waals CrPS4 and Surface Oxides for Nonmonotonic Preset Field Induced Exchange Bias in Fe3GeTe2.

Two-dimensional van der Waals (vdW) heterostructures are an attractive platform for studying exchange bias due to their defect-free and atomically flat interfaces. Chromium thiophosphate (CrPS4), an antiferromagnetic material, possesses uncompensated magnetic spins in a single layer, rendering it a promising candidate for exploring exchange bias phenomena. Recent findings have highlighted that naturally oxidized vdW ferromagnetic Fe3GeTe2 exhibits exchange bias, attributed to the antiferromagnetic coupling of its ultrathin surface oxide layer (O-FGT) with the underlying unoxidized Fe3GeTe2. Anomalous Hall measurements are employed to scrutinize the exchange bias within the CrPS4/(O-FGT)/Fe3GeTe2 heterostructure. This analysis takes into account the contributions from both the perfectly uncompensated interfacial CrPS4 layer and the interfacial oxide layer. Intriguingly, a distinct and nonmonotonic exchange bias trend is observed as a function of temperature below 140 K. The occurrence of exchange bias induced by a "preset field" implies that the prevailing phase in the polycrystalline surface oxide is ferrimagnetic Fe3O4. Moreover, the exchange bias induced by the ferrimagnetic Fe3O4 is significantly modulated by the presence of the van der Waals antiferromagnetic CrPS4 layer, forming a heterostructure, along with additional iron oxide phases within the oxide layer. These findings underscore the intricate and complex nature of exchange bias in van der Waals heterostructures, highlighting their potential for tailored manipulation and control.

CDBProm: the Comprehensive Directory of Bacterial Promoters.

The decreasing cost of whole genome sequencing has produced high volumes of genomic information that require annotation. The experimental identification of promoter sequences, pivotal for regulating gene expression, is a laborious and cost-prohibitive task. To expedite this, we introduce the Comprehensive Directory of Bacterial Promoters (CDBProm), a directory of in-silico predicted bacterial promoter sequences. We first identified that an Extreme Gradient Boosting (XGBoost) algorithm would distinguish promoters from random downstream regions with an accuracy of 87%. To capture distinctive promoter signals, we generated a second XGBoost classifier trained on the instances misclassified in our first classifier. The predictor of CDBProm is then fed with over 55 million upstream regions from more than 6000 bacterial genomes. Upon finding potential promoter sequences in upstream regions, each promoter is mapped to the genomic data of the organism, linking the predicted promoter with its coding DNA sequence, and identifying the function of the gene regulated by the promoter. The collection of bacterial promoters available in CDBProm enables the quantitative analysis of a plethora of bacterial promoters. Our collection with over 24 million promoters is publicly available at https://aw.iimas.unam.mx/cdbprom/.

Unravelling the genomic secrets of bacterial fish pathogens: a roadmap to aquaculture sustainability.

In the field of aquaculture, bacterial pathogens pose significant challenges to fish health and production. Advancements in genomic technologies have revolutionized our understanding of bacterial fish pathogens and their interactions with their host species. This review explores the application of genomic approaches in the identification, classification, and characterization of bacterial fish pathogens. Through an extensive analysis of the literature, we have compiled valuable data on 79 bacterial fish pathogens spanning 13 different phyla, encompassing their whole genome sequences. By leveraging high-throughput sequencing techniques, researchers have gained valuable insights into the genomic makeup of these pathogens, enabling a deeper understanding of their virulence factors and mechanisms of host interaction. Furthermore, genomic approaches have facilitated the discovery of potential vaccine and drug targets, opening up new avenues for the development of effective interventions against fish pathogens. Additionally, the utilization of genomics in fish disease resistance and control in aquaculture has shown promising results, enabling the identification of genetic markers associated with disease resistance traits. This review highlights the significant contributions of genomics to the field of fish pathogen research and underscores its potential for improving disease management strategies and enhancing the sustainability of aquaculture practices.

MLDSPP: Bacterial Promoter Prediction Tool Using DNA Structural Properties with Machine Learning and Explainable AI.

Bacterial promoters play a crucial role in gene expression by serving as docking sites for the transcription initiation machinery. However, accurately identifying promoter regions in bacterial genomes remains a challenge due to their diverse architecture and variations. In this study, we propose MLDSPP (Machine Learning and Duplex Stability based Promoter prediction in Prokaryotes), a machine learning-based promoter prediction tool, to comprehensively screen bacterial promoter regions in 12 diverse genomes. We leveraged biologically relevant and informative DNA structural properties, such as DNA duplex stability and base stacking, and state-of-the-art machine learning (ML) strategies to gain insights into promoter characteristics. We evaluated several machine learning models, including Support Vector Machines, Random Forests, and XGBoost, and assessed their performance using accuracy, precision, recall, specificity, F1 score, and MCC metrics. Our findings reveal that XGBoost outperformed other models and current state-of-the-art promoter prediction tools, namely Sigma70pred and iPromoter2L, achieving F1-scores >95% in most systems. Significantly, the use of one-hot encoding for representing nucleotide sequences complements these structural features, enhancing our XGBoost model's predictive capabilities. To address the challenge of model interpretability, we incorporated explainable AI techniques using Shapley values. This enhancement allows for a better understanding and interpretation of the predictions of our model. In conclusion, our study presents MLDSPP as a novel, generic tool for predicting promoter regions in bacteria, utilizing original downstream sequences as nonpromoter controls. This tool has the potential to significantly advance the field of bacterial genomics and contribute to our understanding of gene regulation in diverse bacterial systems.

In-situ assessment of the performance of oil-water separation by superhydrophobic coated cotton under extreme conditions.

The present study aims to address the issue of oil in water pollution by application of a superhydrophobic cotton fabric. The superhydrophobic cotton fabric with a water contact angle of 158 ± 2°, is developed by a solution immersion technique using zirconium dioxide (ZrO2) nanoparticles and hexadecyltrimethoxysilane. The synthesis parameters such as concentration, curing temperature, and immersion time were optimized using Box-Behnken design method. With mechanical durability, chemical resilience and thermal stability, the coated fabric can separate different oil-water mixtures with an efficiency of 99.9 %. The coated fabric can also be reused for 50 separation cycles in acidic and neutral medium. Besides, droplet dynamic behavior of oil-water mixture has also been studied to ascertain the effect of mixture impact velocities on separation performance. Additionally, coated fabric possesses self-cleaning feature, which makes it viable for muddy oil-water separation. Prepared coated fabric holds tremendous potential for industrial use and oil-water separation in extreme conditions.

Mechanisms of Electrical Switching of Ultrathin CoO/Pt Bilayers.

We study current-induced switching of the Néel vector in CoO/Pt bilayers to understand the underlying antiferromagnetic switching mechanism. Surprisingly, we find that for ultrathin CoO/Pt bilayers electrical pulses along the same path can lead to an increase or decrease of the spin Hall magnetoresistance signal, depending on the current density of the pulse. By comparing these results to XMLD-PEEM imaging of the antiferromagnetic domain structure before and after the application of current pulses, we reveal the details of the reorientation of the Néel vector in ultrathin CoO(4 nm). This allows us to understand how opposite resistance changes can result from a thermomagnetoelastic switching mechanism. Importantly, our spatially resolved imaging shows that regions where the current pulses are applied and regions further away exhibit different switched spin structures, which can be explained by a spin-orbit torque-based switching mechanism that can dominate in very thin films.

Reverse vaccinology and immunoinformatics approach to design a chimeric epitope vaccine against Orientia tsutsugamushi.

Scrub typhus is a vector-borne infectious disease caused by Orientia tsutsugamushi and it is reportedly associated with up to 20 % of hospitalized cases of febrile illnesses. The major challenge of vaccine development is the lack of identified antigens that can induce both heterotypic and homotypic immunity including the production of antibodies, cytotoxic T lymphocyte, and helper T lymphocytes. We employed a comprehensive immunoinformatic prediction algorithm to identify immunogenic epitopes of the 56-kDa type-specific cell membrane surface antigen and surface cell antigen A of O. tsutsugamushi to select potential candidates for developing vaccines and diagnostic assays. We identified 35 linear and 29 continuous immunogenic B-cell epitopes and 51 and 27 strong-binding T-cell epitopes of major histocompatibility complex class I and class II molecules, respectively, in the conserved and variable regions of the 56-kDa type-specific surface antigen. The predicted B- and T-cell epitopes were used to develop immunogenic multi-epitope candidate vaccines and showed to elicit a broad-range of immune protection. A stable interactions between the multi-epitope vaccines and the host fibronectin protein were observed using docking and simulation methods. Molecular dynamics simulation studies demonstrated that the multi-epitope vaccine constructs and fibronectin docked models were stable during simulation time. Furthermore, the multi-epitope vaccine exhibited properties such as antigenicity, non-allergenicity and ability to induce interferon gamma production and had strong associations with their respective human leukocyte antigen alleles of world-wide population coverage. A correlation of immune simulations and the in-silico predicted immunogenic potential of multi-epitope vaccines implicate for further investigations to accelerate designing of epitope-based vaccine candidates and chimeric antigens for development of serological diagnostic assays for scrub typhus.

Long-term outcomes of laparoscopic Heller's myotomy with angle of His accentuation in patients of achalasia cardia.

BACKGROUND: Laparoscopic Heller's myotomy (LHM) is an established treatment for achalasia cardia. Anti-reflux procedures (ARP) are recommended with LHM to reduce the post-operative reflux though the optimal anti-reflux procedure is still debatable. This study reports on the long-term outcomes of LHM with Angle-of-His accentuation (AOH) in patients of achalasia cardia. METHODS: One hundred thirty-six patients of achalasia cardia undergoing LHM with AOH between January 2010 to October 2021 with a minimum follow-up of one year were evaluated for symptomatic outcomes using Eckardt score (ES), DeMeester heartburn (DMH) score and achalasia disease specific quality of life (A-DsQoL) questionnaire. Upper gastrointestinal endoscopy, high resolution manometry (HRM) and timed barium esophagogram (TBE) were performed when feasible and rates of esophagitis and improvement in HRM and TBE parameters evaluated. Time dependent rates of success were calculated with respect to improvement in ES and dysphagia-, regurgitation- and heartburn-free survival using Kaplan-Meier analysis. RESULTS: At a median follow-up of 65.5 months, the overall success (ES ≤ 3) was 94.1%. There was statistically significant improvement in ES, heartburn score and A-DsQoL score (p < 0.00001, p = 0.002 and p < 0.00001). Significant heartburn (score ≥ 2) was seen in 12.5% subjects with 9.5% patients reporting frequent PPI use (> 3 days per week). LA-B and above esophagitis was seen in 12.7%. HRM and TBE parameters also showed a significant improvement as compared to pre-operative values (IRP: p < 0.0001, column height: p < 0.0001, column width: p = 0.0002). Kaplan-Meier analysis showed dysphagia, regurgitation, and heartburn free survival of 75%, 96.2% and 72.3% respectively at 10 years. CONCLUSIONS: LHM with AOH gives a lasting relief of symptoms in patients of achalasia cardia with heartburn rates similar to that reported in studies using Dor's or Toupet's fundoplication with LHM. Hence, LHM with AOH may be a preferred choice in patients of achalasia cardia given the simplicity of the procedure.

Prognosis of consciousness disorders in the intensive care unit.

Assessments of consciousness are a critical part of prognostic algorithms for critically ill patients suffering from severe brain injuries. There have been significant advances in the field of coma science over the past two decades, providing clinicians with more advanced and precise tools for diagnosing and prognosticating disorders of consciousness (DoC). Advanced neuroimaging and electrophysiological techniques have vastly expanded our understanding of the biological mechanisms underlying consciousness, and have helped identify new states of consciousness. One of these, termed cognitive motor dissociation, can predict functional recovery at 1 year post brain injury, and is present in up to 15-20% of patients with DoC. In this chapter, we review several tools that are used to predict DoC, describing their strengths and limitations, from the neurological examination to advanced imaging and electrophysiologic techniques. We also describe multimodal assessment paradigms that can be used to identify covert consciousness and thus help recognize patients with the potential for future recovery and improve our prognostication practices.

Combined In Silico and In Vitro Study to Reveal the Structural Insights and Nucleotide-Binding Ability of the Transcriptional Regulator PehR from the Phytopathogen Ralstonia solanacearum.

The transcriptional regulator PehR regulates the synthesis of the extracellular plant cell wall-degrading enzyme polygalacturonase, which is essential in the bacterial wilt of plants caused by one of the most devastating plant phytopathogens, Ralstonia solanacearum. The bacterium has a wide global distribution infecting many different plant species, resulting in massive agricultural and economic losses. Because the PehR molecular structure has not yet been determined and the structural consequences of PehR on ligand binding have not been thoroughly investigated, we have used an in silico approach combined with in vitro experiments for the first time to characterize the PehR regulator from a local isolate (Tezpur, Assam, India) of the phytopathogenic bacterium R. solanacearum F1C1. In this study, an in silico approach was employed to model the 3D structure of the PehR regulator, followed by the binding analysis of different ligands against this regulatory protein. Molecular docking studies suggest that ATP has the highest binding affinity for the PehR regulator. By using molecular dynamics (MD) simulation analysis, involving root-mean-square deviation, root-mean-square fluctuations, hydrogen bonding, radius of gyration, solvent-accessible surface area, and principal component analysis, it was possible to confirm the sudden conformational changes of the PehR regulator caused by the presence of ATP. We used an in vitro approach to further validate the formation of the PehR-ATP complex. In this approach, recombinant DNA technology was used to clone, express, and purify the gene encoding the PehR regulator from R. solanacearum F1C1. Purified PehR was used in ATP-binding experiments using fluorescence spectroscopy and Fourier transform infrared spectroscopy, the outcomes of which showed a potent binding to ATP. The putative PehR-ATP-binding analysis revealed the importance of the amino acids Lys190, Glu191, Arg192, Arg375, and Asp378 for the ATP-binding process, but further study is required to confirm this. It will be simpler to comprehend the catalytic mechanisms of a crucial PehR regulator process in R. solanacearum with the aid of the ATP-binding process hints provided by these structural biology applications.

Sustainable approach to oil recovery from oil spills through superhydrophobic jute fabric.

Ecosystems suffer from increased oil exploitation and frequent oil spills, which calls for effective, environment-friendly, and economically viable solutions. To address this, abandoned gunny sacks as the concerned jute fabric were superhydrophobically (water contact angle ∼159°) modified, incorporating titanium dioxide (TiO2) nanoparticles and hexadecyltrimethoxysilane (HDTMS), rendering a facile drop casting procedure. The modified superhydrophobic-superoleophilic jute fabric has been identified as a high-performance filter with superior reusability that can separate oil-water mixtures in challenging environmental conditions (including potent acidic, alkaline, highly saline, aqueous, frigid, and blistering water environments) while maintaining high separation efficiency. In continuation, static conditions indulging a batch and continuous oil separation performance and dynamic conditions stimulating turbulence in the oil-water mixture were proficiently carried out, mimicking real-world circumstances. As a result, the modified jute fabric has the advantages of high separation efficiency, stable recyclable properties, and outstanding durability, highlighting its enormous potential for use in practical applications.

Laparoscopic limited hemicolectomy for descending colo-colic intussusception in an adult.

Intussusception in adults represents 1% of bowel obstructions and up to 0.02% of all hospital admissions. Amongst these, colo-colic intussusception of the descending colon forms the rarest of causes due to the fixed nature of the descending colon. Most of adult intussusceptions follow a lead point and are commonly due to colonic malignancy which may get missed on pre-operative evaluation. Surgery is usually warranted as these patients are usually symptomatic and at risk of vascular compromise, leading to perforations and obscure malignancies. We present a case of laparoscopic limited hemicolectomy and primary anastomosis in a middle-aged male who presented with colo-colic intussusception, which appeared to be following a malignant mass on imaging and lipoma on colonoscopic biopsy done twice. Keeping in mind the possibility of a malignant lead point, no attempt was made to reduce the intussusception and a vessel first approach with 5 cm margin on either side was performed.

Malondialdehyde enhances PsbP protein release during heat stress in Arabidopsis.

Under environmental conditions, plants are exposed to various abiotic and biotic stress factors, which commonly cause the oxidation of lipids and proteins. Lipid peroxidation constantly produces malondialdehyde (MDA), a secondary product of lipid peroxidation, which is covalently bound to proteins forming MDA-protein adducts. The spatial distribution of MDA-protein adducts in Arabidopsis leaves shows that MDA-protein adducts are located in the chloroplasts, uniformly spread out over the thylakoid membrane. At the lumenal side of thylakoid membrane, MDA interacts with PsbP, an extrinsic subunit of the photosystem II (PSII), which is in electrostatic interaction with the PSII core proteins. Under heat stress, when MDA is moderately enhanced, the electrostatic interaction between PsbP and PSII core proteins is weakened, and PsbP with bound MDA is released in the lumen. It is proposed here that the electrophilic MDA is bound to the nucleophilic lysine residues of PsbP, which are involved in electrostatic interactions with the negatively charged glutamate of the PSII core protein. Our data provide crucial information about the MDA binding topology in the higher plant PSII complex, which is necessary to understand better the physiological functions of MDA for plant survival under stress.

DNA structural properties of DNA binding sites for 21 transcription factors in the mycobacterial genome.

Mycobacterium tuberculosis, the causative agent of tuberculosis, has evolved over time into a multidrug resistance strain that poses a serious global pandemic health threat. The ability to survive and remain dormant within the host macrophage relies on multiple transcription factors contributing to virulence. To date, very limited structural insights from crystallographic and NMR studies are available for TFs and TF-DNA binding events. Understanding the role of DNA structure in TF binding is critical to deciphering MTB pathogenicity and has yet to be resolved at the genome scale. In this work, we analyzed the compositional and conformational preference of 21 mycobacterial TFs, evident at their DNA binding sites, in local and global scales. Results suggest that most TFs prefer binding to genomic regions characterized by unique DNA structural signatures, namely, high electrostatic potential, narrow minor grooves, high propeller twist, helical twist, intrinsic curvature, and DNA rigidity compared to the flanking sequences. Additionally, preference for specific trinucleotide motifs, with clear periodic signals of tetranucleotide motifs, are observed in the vicinity of the TF-DNA interactions. Altogether, our study reports nuanced DNA shape and structural preferences of 21 TFs.

Electrosteric Control of the Aggregation and Yielding Behavior of Concentrated Portlandite Suspensions.

Portlandite (calcium hydroxide: CH: Ca(OH)2) suspensions aggregate spontaneously and form percolated fractal aggregate networks when dispersed in water. Consequently, the viscosity and yield stress of portlandite suspensions diverge at low particle loadings, adversely affecting their processability. Even though polycarboxylate ether (PCE)-based comb polyelectrolytes are routinely used to alter the particle dispersion state, water demand, and rheology of similar suspensions (e.g., ordinary portland cement suspensions) that feature a high pH and high ionic strength, their use to control portlandite suspension rheology has not been elucidated. This study combines adsorption isotherms and rheological measurements to elucidate the role of PCE composition (i.e., charge density, side chain length, and grafting density) in controlling the extent of PCE adsorption, particle flocculation, suspension yield stress, and thermal response of portlandite suspensions. We show that longer side-chain PCEs are more effective in affecting suspension viscosity and yield stress, in spite of their lower adsorption saturation limit and fractional adsorption. The superior steric hindrance induced by the longer side chain PCEs results in better efficacy in mitigating particle aggregation even at low dosages. However, when dosed at optimal dosages (i.e., a dosage that induces a dynamically equilibrated dispersion state of particle aggregates), different PCE-dosed portlandite suspensions exhibit identical fractal structuring and rheological behavior regardless of the side chain length. Furthermore, it is shown that the unusual evolution of the rheological response of portlandite suspensions with temperature can be tailored by adjusting the PCE dosage. The ability of PCEs to modulate the rheology of aggregating charged particle suspensions can be generally extended to any colloidal suspension with a strong screening of repulsive electrostatic interactions.

Understanding the Mechanism and Extent of Transplacental Transfer of (-)-∆9 -Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure.

Cannabis use during pregnancy may cause fetal toxicity driven by in utero exposure to (-)-∆9 -tetrahydrocannabinol (THC) and its psychoactive metabolite, (±)-11-hydroxy-∆9 -THC (11-OH-THC). THC concentrations in the human term fetal plasma appear to be lower than the corresponding maternal concentrations. Therefore, we investigated whether THC and its metabolites are effluxed by placental transporters using the dual cotyledon, dual perfusion, term human placenta. The perfusates contained THC alone (5 µM) or in combination (100-250 nM) with its metabolites (100 nM or 250 nM 11-OH-THC, 100 nM COOH-THC), plus a marker of P-glycoprotein (P-gp) efflux (1 or 10 µM saquinavir), and a passive diffusion marker (106 µM antipyrine). All perfusions were conducted with (n = 7) or without (n = 16) a P-gp/BCRP (breast-cancer resistance protein) inhibitor, 4 µM valspodar. The maternal-fetal and fetal-maternal unbound cotyledon clearance indexes (m-f-CLu,c,i and f-m-CLu,c,i ) were normalized for transplacental antipyrine clearance. At 5 µM THC, the m-f-CLu,c,i , 5.1 ± 2.1, was significantly lower than the f-m-CLu,c,i , 13 ± 6.1 (P = 0.004). This difference remained in the presence of valspodar or when the lower THC concentrations were perfused. In contrast, neither metabolite, 11-OH-THC/COOH-THC, had significantly different m-f-CLu,c,i vs. f-m-CLu,c,i . Therefore, THC appears to be effluxed by placental transporter(s) not inhibitable by the P-gp/BCRP antagonist, valspodar, while 11-OH-THC and COOH-THC appear to passively diffuse across the placenta. These findings plus our previously quantified human fetal liver clearance, extrapolated to in vivo, yielded a THC fetal/maternal steady-state plasma concentration ratio of 0.28 ± 0.09, comparable to that observed in vivo, 0.26 ± 0.10.