Kinetic stability of Fe-based nanoparticles with rheological modification by xanthan gum: A critical stabilization concentration and the underlying mechanism.

Enhanced kinetic stability of Fe-NPs in groundwater is a focus in application of Fe-NPs for groundwater remediation. The effect of surfactants (Triton X-100 and SDBS) and polymers (XG, SA, CCS, PSS and PVP) on the kinetic stability of Fe-NPs were studied with sedimentation experiments. Polymers improved stability of nFe3O4 and XG had the best effect, while surfactants had minimal effect. There was a critical concentration (CSC) for XG to stabilize nFe3O4, which was 2.0 g/L. At such a concentration nFe3O4, nFe2O3, and nCuO did not settled in 10 h, while the settlement occurred below the concentration and increased with decreasing XG concentration. At CSC XG could stabilize 20 g/L of nFe3O4 for >30 days and 8.0 g/L of nZVI for 13 days. Rheology studies indicated that the enhanced stability was due to the entanglement of XG molecules in the concentration range of 0.5-2.8 g/L and the formation of a uniform entangled network at CSC concentration was responsible for non-sedimentation of Fe-NPs. At hyper-CSC concentrations under the regime of concentrated network (>2.8 g/L), the stability of nFe3O4 and nFe2O3 decreased due to depletion interaction. The rules for XG to stabilize particles and information about the critical concentration will improve XG application in groundwater remediation using Fe-NPs.

Cotransport of fullerene nanoparticles and montmorillonite colloids in porous media: Critical role of divalent cations of montmorillonite.

While the cotransport of carbon nanoparticles (CNPs) and clay colloids in porous media has been widely studied, the influence of the cation exchange capacity (CEC) of clay colloids on the transport process remains unclear. In this study, batch adsorption and column transport experiments were conducted to investigate the fate and transport of CNPs and clay colloids in quartz sand, with respect to the effect of monovalent-cation exchange capacity (mono-CEC), divalent-cation exchange capacity (di-CEC) and total CEC of clays. Fullerene nanoparticles (nC60) and six types of montmorillonite (ML) with different CEC were selected as modeled CNPs and clay colloids, respectively. Transport behavior of nC60 and ML was characterized using breakthrough curves (BTCs) and fitted with two-kinetic-sites colloid transport model. Results of the adsorption experiments showed a good linear correlation between the deposition of nC60 on the sand surface and the di-CEC of ML. Transport of ML and nC60 was inhibited by each other. The calculated mass recovery of nC60, as well as the fitted maximum deposition capacity and attachment rate coefficients of nC60 exhibited a strong linear relationship with the di-CEC of ML. These results indicate that divalent cations in ML interlayers play a significant role in aggregation between nC60 and ML and their cotransport. Through measurements of the particle size and zeta potentials of sole nC60 and mixtures of ML and nC60, FTIR and XPS analysis of nC60 under different conditions, and a release experiment of nC60 in a sand column, it demonstrated cation bridging (Ca2+-π) between nC60 and ML mediated by the divalent cations in ML interlayers. The study highlighted the potential of using di-CEC of clays as an indicator to predict the mobility of nC60 in clay-containing porous media and added insights to the transport behavior of CNPs in porous media.

Rheological behavior of xanthan gum suspensions with Fe-based nanoparticles: the effect of nanoparticles and the mechanism.

The rheological behavior of a xanthan gum (XG) suspension with Fe-based nanoparticles (Fe-NPs), e.g., nanoparticles of zerovalent iron (nZVI) and Fe3O4 (nFe3O4), needs to be understood for better injection of Fe-NPs for groundwater remediation. In this study, the rheological behavior of a XG suspension of nZVI and nFe3O4 was investigated at different particle concentrations. The Ostwald, Sisko, Williamson, and Cross models were employed to fit the rheological behavior of the suspensions for quantitatively describing the effect of the particles. The results showed that the viscosity of the XG solutions decreased with increasing particle concentrations and they maintained shear thinning properties. The Cross model was the best among the four models to describe the shear thinning behavior of the XG solution in the presence of the particles. According to Cross model analysis, increasing particle concentrations increased the degree of shear thinning behavior, as indicated by the increase of the power index (n). Also, the relaxation time (λ) decreased with increasing particle concentrations, which indicated an increase of molecule movement of XG. Compared with nFe3O4, nZVI resulted in a larger decrease in viscosity and a larger increase in the degree of shear thinning behavior. There was a good linear relation between n and λ for the suspensions (R2 = 0.85), which indicated that increasing molecule movement of XG was an important mechanism for the particles to intensify the shear thinning rheological behavior of the XG suspension of Fe-NPs. This study added insight into the knowledge of the rheological properties of the XG suspension of Fe-NPs, which is of importance for the field injection effort.

FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements.

On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.

Anti-SARS-CoV-2 Repurposing Drug Database: Clinical Pharmacology Considerations.

A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti-SARS-CoV-2 Repurposing Drug Database is a database that includes both in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti-SARS-CoV-2 drugs. Continuous development and expansion are feasible with the public availability of this database.

Production, functional stability, and effect of rhamnolipid biosurfactant from Klebsiella sp. on phenanthrene degradation in various medium systems.

The present study investigated the stability and efficacy of a biosurfactant produced by Klebsiella sp. KOD36 under extreme conditions and its potential for enhancing the solubilization and degradation of phenanthrene in various environmental matrices. Klebsiella sp. KOD36 produced a mono-rhamnolipids biosurfactant with a low critical micelle concentration (CMC) value. The biosurfactant was stable under extreme conditions (60 °C, pH 10 and 10% salinity) and could lower surface tension by 30% and maintained an emulsification index of > 40%. The emulsion index was also higher (17-43%) in the presence of petroleum hydrocarbons compared to synthetic surfactant Triton X-100. Investigation on phenanthrene degradation in three different environmental matrices (aqueous, soil-slurry and soil) confirmed that the biosurfactant enhanced the solubilization and biodegradation of phenanthrene in all matrices. The high functional stability and performance of the biosurfactant under extreme conditions on phenanthrene degradation show the great potential of the biosurfactant for remediation applications under harsh environmental conditions.

Sub-CMC solubilization of n-alkanes by rhamnolipid biosurfactant: the Influence of rhamnolipid molecular structure.

Solubilization of n-alkanes by dirhamnolipid (diRL) biosurfactant at sub-critical micelle concentrations (sub-CMC) was studied and the results were compared to that for monorhamnolipid (monoRL) obtained in our prior study. The results show that the apparent solubility of the four alkanes (decane, dodecane, tetradecane and hexadecane) increases linearly with the increase of diRL concentration at diRL concentrations below CMC. The solubilization potential of diRL indicated by molar solubilization ratio (MSR) is higher at sub-CMC than at hyper-CMC concentrations (0.43 vs 0.03, 7.91 vs 0.02, 5.16 vs 1.98 and 3.71 vs 1.26 for decane, dodecane, tetradecane and hexadecane, respectively). The maximum access at the surface of the alkane-rhamnolipid aggregates (Гmax) is smaller for diRL than for monoRL (2.47 vs 3.09, 2.35 vs 2.86, 2.26 vs 3.60, and 2.01 vs 4.09 mol/m2 for decane, dodecane, tetradecane and hexadecane, respectively). In addition, more significant impact of surface access change on the size of the aggregates were observed for diRL, indicating that the difference in the structure of polar group between diRL and monoRL (one more rhamnose ring in diRL polar group) has influence on alkane-solubilization behavior. Due to the smaller access at the surface of the aggregates, diRL can produce larger number of aggregates than monoRL in the solution and thus show higher solubilization efficiency of dodecane, tetradecane and hexadecane. The findings of the study add to the knowledge of solubilization of hydrophobic organic compounds by surfactants and contribute to application of rhamnolipid biosurfactant in the area of remediation.

Surfactant-enhanced aquifer remediation: Mechanisms, influences, limitations and the countermeasures.

In recent years, surfactant-enhanced aquifer remediation (SEAR) has attracted increasing interest duo to the high efficiency of removing non-aqueous phase liquids (NAPLs) from aquifer. A thorough understanding of SEAR is necessary for its successful implementation in field remediation. This paper reviewed the SEAR technology in a comprehensive way based on the recent research advances. Firstly, an overview of the basic processes and mechanisms underlying the technology was presented. Secondly, applications of SEAR and the factors that influence the performance were summarized. Thirdly, the key limitations of SEAR, which are downward migration of dense-NAPLs, secondary pollution of surfactants, adsorptive, precipitative and partitioning loss of surfactants, and heterogeneity of the aquifer, were reviewed. Finally, the recent advances in modifying SEAR to overcome the limitations were discussed in detail. The review will promote our understanding of SEAR technology and provide some useful information to improve the performance of SEAR in applications.

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy.

Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.

Designing combination therapies with modeling chaperoned machine learning.

Chemotherapy resistance is a major challenge to the effective treatment of cancer. Thus, a systematic pipeline for the efficient identification of effective combination treatments could bring huge biomedical benefit. In order to facilitate rational design of combination therapies, we developed a comprehensive computational model that incorporates the available biological knowledge and relevant experimental data on the life-and-death response of individual cancer cells to cisplatin or cisplatin combined with the TNF-related apoptosis-inducing ligand (TRAIL). The model's predictions, that a combination treatment of cisplatin and TRAIL would enhance cancer cell death and exhibit a "two-wave killing" temporal pattern, was validated by measuring the dynamics of p53 accumulation, cell fate, and cell death in single cells. The validated model was then subjected to a systematic analysis with an ensemble of diverse machine learning methods. Though each method is characterized by a different algorithm, they collectively identified several molecular players that can sensitize tumor cells to cisplatin-induced apoptosis (sensitizers). The identified sensitizers are consistent with previous experimental observations. Overall, we have illustrated that machine learning analysis of an experimentally validated mechanistic model can convert our available knowledge into the identity of biologically meaningful sensitizers. This knowledge can then be leveraged to design treatment strategies that could improve the efficacy of chemotherapy.

Correction to: A quantitative systems pharmacology (QSP) model for Pneumocystis treatment in mice.

It was highlighted that the original article [1] contained errors in the figures and their legends and by extension the in-text figure citations. This Corrections article shows the correct figures and correct figure legends.

Phosphorylation of Hsp20 Promotes Fibrotic Remodeling and Heart Failure.

Cardiomyocyte-specific increases in phosphorylated Hsp20 (S16D-Hsp20) to levels similar to those observed in human failing hearts are associated with early fibrotic remodeling and depressed left ventricular function, symptoms which progress to heart failure and early death. The underlying mechanisms appear to involve translocation of phosphorylated Hsp20 to the nucleus and upregulation of interleukin (IL)-6, which subsequently activates cardiac fibroblasts in a paracrine fashion through transcription factor STAT3 signaling. Accordingly, treatment of S16D-Hsp20 mice with a rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) attenuated interstitial fibrosis and preserved cardiac function. These findings suggest that phosphorylated Hsp20 may be a potential therapeutic target in heart failure.

A quantitative systems pharmacology (QSP) model for Pneumocystis treatment in mice.

BACKGROUND: The yeast-like fungi Pneumocystis, resides in lung alveoli and can cause a lethal infection known as Pneumocystis pneumonia (PCP) in hosts with impaired immune systems. Current therapies for PCP, such as trimethoprim-sulfamethoxazole (TMP-SMX), suffer from significant treatment failures and a multitude of serious side effects. Novel therapeutic approaches (i.e. newly developed drugs or novel combinations of available drugs) are needed to treat this potentially lethal opportunistic infection. Quantitative Systems Pharmacological (QSP) models promise to aid in the development of novel therapies by integrating available pharmacokinetic (PK) and pharmacodynamic (PD) knowledge to predict the effects of new treatment regimens. RESULTS: In this work, we constructed and independently validated PK modules of a number of drugs with available pharmacokinetic data. Characterized by simple structures and well constrained parameters, these PK modules could serve as a convenient tool to summarize and predict pharmacokinetic profiles. With the currently accepted hypotheses on the life stages of Pneumocystis, we also constructed a PD module to describe the proliferation, transformation, and death of Pneumocystis. By integrating the PK module and the PD module, the QSP model was constrained with observed levels of asci and trophic forms following treatments with multiple drugs. Furthermore, the temporal dynamics of the QSP model were validated with corresponding data. CONCLUSIONS: We developed and validated a QSP model that integrates available data and promises to facilitate the design of future therapies against PCP.

A novel human S10F-Hsp20 mutation induces lethal peripartum cardiomyopathy.

Heat shock protein 20 (Hsp20) has been shown to be a critical regulator of cardiomyocyte survival upon cardiac stress. In this study, we investigated the functional significance of a novel human Hsp20 mutation (S10F) in peripartum cardiomyopathy. Previous findings showed that cardiac-specific overexpression of this mutant were associated with reduced autophagy, left ventricular dysfunction and early death in male mice. However, this study indicates that females have normal function with no alterations in autophagy but died within a week after 1-4 pregnancies. Further examination of mutant females revealed left ventricular chamber dilation and hypertrophic remodelling. Echocardiography demonstrated increases in left ventricular end-systolic volume and left ventricular end-diastolic volume, while ejection fraction and fractional shortening were depressed following pregnancy. Subsequent studies revealed that cardiomyocyte apoptosis was elevated in mutant female hearts after the third delivery, associated with decreases in the levels of Bcl-2/Bax and Akt phosphorylation. These results indicate that the human S10F mutant is associated with dysregulation of cell survival signalling, accelerated heart failure and early death post-partum.

Mechanisms for rhamnolipids-mediated biodegradation of hydrophobic organic compounds.

The widespread existence of hydrophobic organic compounds (HOCs) in soil and water poses a potential health hazard to human, such as skin diseases, heart diseases, carcinogenesis, etc. Surfactant-enhanced bioremediation has been regarded as one of the most viable technologies to treat HOCs contaminated soil and groundwater. As a biosurfactant that has been intensively studied, rhamnolipids have shown to enhance biodegradation of HOCs in the environment, however, the underlying mechanisms are not fully disclosed. In this paper, properties and production of rhamnolipids are summarized. Then effects of rhamnolipids on the biodegradation of HOCs, including solubilization, altering cell affinity to HOCs, and facilitating microbial uptake are reviewed in detail. Special attention is paid to how rhamnolipids change the bioavailability of HOCs, which are crucial for understanding the mechanism of rhamnolipids-mediated biodegradation. The biodegradation and toxicity of rhamnolipids are also discussed. Finally, perspectives and future research directions are proposed. This review adds insight to rhamnolipids-enhanced biodegradation process, and helps in application of rhamnolipids in bioremediation.

Identification of the Functional Autophagy-Regulatory Domain in HCLS1-Associated Protein X-1 That Resists Against Oxidative Stress.

HCLS1 Associated Protein X-1 (HAX1) promotes cell survival through attenuation of the damaged signals from endoplasmic reticulum and mitochondria, which are known as prominent intracellular compartments for the autophagic process under stress conditions. This study investigates whether autophagy can be upregulated in response to HAX1 overexpression and identifies the functional motif in HAX1 responsible for the autophagic induction. Autophagosome accumulation, mitochondrial membrane potential (Δψm), and apoptosis were assessed in HEK293 cells post transduction with full-length or truncated HAX1-encoding genes, while empty vector-transduced cells served as control. Upon the oxidative stress, the enhanced autophagy induction was observed in cells overexpressing HAX1, as well as HAX1 truncations that encode peptide segments ranging from amino acids 127-180 (AA127-180). This protective response was further supported by flow cytometry and Western Blot results, in which oxidative stress-induced Δψm dissipation and the programmed cell death were suppressed in HAX1-overexpressing cells, associated with reduced DNA fragmentation and decreased Caspase-9 cleavage. Interestingly, the HAX1-induced autophagy response was abrogated when AA127-180 was removed, compromising the antiapoptotic effects upon oxidative stress. Overall, these data indicate that autophagy induction is involved in HAX1-induced cell protective mechanism, and AA127-180 serves as the functional autophagy-regulatory domain of this antiapoptotic protein.

HAX-1 regulates SERCA2a oxidation and degradation.

Ischemia/reperfusion injury is associated with contractile dysfunction and increased cardiomyocyte death. Overexpression of the hematopoietic lineage substrate-1-associated protein X-1 (HAX-1) has been shown to protect from cellular injury but the function of endogenous HAX-1 remains obscure due to early lethality of the knockout mouse. Herein we generated a cardiac-specific and inducible HAX-1 deficient model, which uncovered an unexpected role of HAX-1 in regulation of sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) in ischemia/reperfusion injury. Although ablation of HAX-1 in the adult heart elicited no morphological alterations under non-stress conditions, it diminished contractile recovery and increased infarct size upon ischemia/reperfusion injury. These detrimental effects were associated with increased loss of SERCA2a. Enhanced SERCA2a degradation was not due to alterations in calpain and calpastatin levels or calpain activity. Conversely, HAX-1 overexpression improved contractile recovery and maintained SERCA2a levels. The regulatory effects of HAX-1 on SERCA2a degradation were observed at multiple levels, including intact hearts, isolated cardiomyocytes and sarcoplasmic reticulum microsomes. Mechanistically, HAX-1 ablation elicited increased production of reactive oxygen species at the sarco/endoplasic reticulum compartment, resulting in SERCA2a oxidation and a predisposition to its proteolysis. This effect may be mediated by NAPDH oxidase 4 (NOX4), a novel binding partner of HAX-1. Accordingly, NOX inhibition with apocynin abrogated the effects of HAX-1 ablation in hearts subjected to ischemia/reperfusion injury. Taken together, our findings reveal a role of HAX-1 in the regulation of oxidative stress and SERCA2a degradation, implicating its importance in calcium homeostasis and cell survival pathways.

Regulation of BECN1-mediated autophagy by HSPB6: Insights from a human HSPB6S10F mutant.

HSPB6/Hsp20 (heat shock protein family B [small] member 6) has emerged as a novel cardioprotector against stress-induced injury. We identified a human mutant of HSPB6 (HSPB6S10F) exclusively present in dilated cardiomyopathy (DCM) patients. Cardiac expression of this mutant in mouse hearts resulted in remodeling and dysfunction, which progressed to heart failure and early death. These detrimental effects were associated with reduced interaction of mutant HSPB6S10F with BECN1/Beclin 1, leading to BECN1 ubiquitination and its proteosomal degradation. As a result, autophagy flux was substantially inhibited and apoptosis was increased in HSPB6S10F-mutant hearts. In contrast, overexpression of wild-type HSPB6 (HSPB6 WT) not only increased BECN1 levels, but also competitively suppressed binding of BECN1 to BCL2, resulting in stimulated autophagy. Indeed, preinhibition of autophagy attenuated the cardioprotective effects of HSPB6 WT. Taken together, these findings reveal a new regulatory mechanism of HSPB6 in cell survival through its interaction with BECN1. Furthermore, Ser10 appears to be crucial for the protective effects of HSPB6 and transversion of this amino acid to Phe contributes to cardiomyopathy.

Advances in applications of rhamnolipids biosurfactant in environmental remediation: A review.

The objective of this review is to provide a comprehensive overview of the advances in the applications of rhamnolipids biosurfactants in soil and ground water remediation for removal of petroleum hydrocarbon and heavy metal contaminants. The properties of rhamnolipids associated with the contaminant removal, that is, solubilization, emulsification, dispersion, foaming, wetting, complexation, and the ability to modify bacterial cell surface properties, were reviewed in the first place. Then current remediation technologies with integration of rhamnolipid were summarized, and the effects and mechanisms for rhamnolipid to facilitate contaminant removal for these technologies were discussed. Finally rhamnolipid-based methods for remediation of the sites co-contaminated by petroleum hydrocarbons and heavy metals were presented and discussed. The review is expected to enhance our understanding on environmental aspects of rhamnolipid and provide some important information to guide the extending use of this fascinating chemical in remediation applications.