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Lithium (Li) metal batteries (LMBs) are the "holy grail" in the energy storage field due to their high energy density (theoretically >500 Wh kg-1 ). Recently, tremendous efforts have been made to promote the research & development (R&D) of pouch-type LMBs toward practical application. This article aims to provide a comprehensive and in-depth review of recent progress on pouch-type LMBs from full cell aspect, and to offer insights to guide its future development. It will review pouch-type LMBs using both liquid and solid-state electrolytes, and cover topics related to both Li and cathode (including LiNix Coy Mn1-x-y O2 , S and O2 ) as both electrodes impact the battery performance. The key performance criteria of pouch-type LMBs and their relationship in between are introduced first, then the major challenges facing the development of pouch-type LMBs are discussed in detail, especially those severely aggravated in pouch cells compared with coin cells. Subsequently, the recent progress on mechanistic understandings of the degradation of pouch-type LMBs is summarized, followed with the practical strategies that have been utilized to address these issues and to improve the key performance criteria of pouch-type LMBs. In the end, it provides perspectives on advancing the R&Ds of pouch-type LMBs towards their application in practice.

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The gut microbiota plays a significant role in influencing human immunity, metabolism, development, and behavior by producing a wide range of metabolites. While there is accumulating data on several microbiota-derived small molecules that contribute to host health and disease, our knowledge regarding the molecular mechanisms underlying metabolite-mediated microbe-host interactions remains limited. This is primarily due to the lack of efficient genetic tools for most commensal bacteria, especially those belonging to the dominant phyla Bacteroides spp. and Clostridium spp., which hinders the application of synthetic biology to these gut commensal bacteria. In this review, we provide an overview of recent advances in synthetic biology tools developed for the two dominant genera, as well as their applications in deciphering the mechanisms of microbe-host interactions mediated by microbiota-derived small molecules. We also discuss the potential biomedical applications of engineering commensal bacteria using these toolboxes. Finally, we share our perspective on the future development of synthetic biology tools for a better understanding of small molecule-mediated microbe-host interactions and their engineering for biomedical purposes.

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The history of the development of the cell transformation assays (CTAs) is described, providing an overview of in vitro cell transformation from its origin to the new transcriptomic-based CTAs. Application of this knowledge is utilized to address how the different types of CTAs, variously addressing initiation and promotion, can be included on a mechanistic basis within the integrated approach to testing and assessment (IATA) for non-genotoxic carcinogens. Building upon assay assessments targeting the key events in the IATA, we identify how the different CTA models can appropriately fit, following preceding steps in the IATA. The preceding steps are the prescreening transcriptomic approaches, and assessment within the earlier key events of inflammation, immune disruption, mitotic signaling and cell injury. The CTA models address the later key events of (sustained) proliferation and change in morphology leading to tumor formation. The complementary key biomarkers with respect to the precursor key events and respective CTAs are mapped, providing a structured mechanistic approach to represent the complexity of the (non-genotoxic) carcinogenesis process, and specifically their capacity to identify non-genotoxic carcinogenic chemicals in a human relevant IATA.

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The Transformics Assay is an in vitro test which combines the BALB/c 3T3 Cell Transformation Assay (CTA) with microarray transcriptomics. It has been shown to improve upon the mechanistic understanding of the CTA, helping to identify mechanisms of action leading to chemical-induced transformation thanks to RNA extractions in specific time points along the process of in vitro transformation. In this study, the lowest transforming concentration of the carcinogenic benzo(a)pyrene (B(a)P) has been tested in order to find molecular signatures of initial events relevant for oncotransformation. Application of Enrichment Analysis (Metacore) to the analyses of the results facilitated key biological interpretations. After 72 h of exposure, as a consequence of the molecular initiating event of aryl hydrocarbon receptor (AhR) activation, there is a cascade of cellular events and microenvironment modification, and the immune and inflammatory responses are the main processes involved in cell response. Furthermore, pathways and processes related to cell cycle regulation, cytoskeletal adhesion and remodeling processes, cell differentiation and transformation were observed.

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Circadian clocks are an intrinsic element of life that orchestrate appropriately timed daily physiological and behavioural rhythms entrained to the solar cycle, thereby conferring increased fitness. However, it is thought that the first archaic 'proto-clocks' evolved in ancient cyanobacteria in a marine environment, where the dominant time cues (zeitgebers) probably would have been lunar-driven and included tidal cycles. To date, non-circadian 'marine clocks' have been described with circatidal (~12.4 h), circasemilunar (~14.8 days), and circalunar (~29.5 days) periodicity, mostly studied in accessible but temporally complex intertidal habitats. In contrast to the well-described circadian clock, their molecular machinery is poorly understood, and fundamental mechanisms remain unclear. We propose that a multi-species approach is the most apposite strategy to resolve the divergence that arose from non-circadian clockwork forged in an evolutionary environment with multiple zeitgebers. We review circatidal clock models with a focus on intertidal organisms, for which robust behavioural, physiological, or genetic underpinnings have been explicated, and discuss their relative experimental merits. Developing a comprehensive mechanistic understanding of circatidal clocks should be a priority because it will ultimately contribute to a more holistic understanding of the origins and evolution of chronobiology itself.

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The "Sigma plan" https://www.sigmaplan.be/en/ aims to create in Belgium inundation zones along the Grote Nete river to prevent Antwerp from flooding in extreme weather conditions. The riverbanks of the Grote Nete are at some hotspots historically contaminated by the phosphate industry resulting in Naturally Occurring Radionuclides (NOR) legacy. 226Ra is from a radiation protection point of view one of the most important radionuclides present at the hot spot under study, with a local soil activity concentration higher than 3000 Bq/kg 226Ra. In this paper, we identify the most relevant mechanisms governing the mobility of 226Ra. We selected for this study the role of CaSO4.2H2O, clay minerals and humic acids as the main contributors determining the speciation of Ra, due to their presence at the hot spot, their cation exchange capacity and their functional group density, respectively. Various novel analytical chemistry approaches were developed to study the prevailing reaction mechanisms that impact the solid-liquid distribution of 226Ra. We show that 226Ra coprecipitates in a (Ca,Ra)SO4 solid solution due to the high Ca2+ and SO42- concentrations in the local hot spot. If CaSO4.2H2O is not saturated in the soil solution, 226Ra adsorption to clay minerals counteracts the tendency of 226Ra partitioning to the liquid phase by interactions with humic and fulvic acids. Interactions between different soil compounds may further alter the partitioning of Ra. As, Cd, Pb and Zn in the hot spot are significantly above background values in Flemish sediments. Pb may be coprecipitated as sulphate salts, whereas Cd and Zn are most probably partially present as arsenate salts. The excess of Zn may interact with humic acids. The observed reaction mechanisms suggest that Ca2+ might play a key role in the immobilisation of Ra. The role of Ca2+ as immobilisation agent of the other contaminants is discussed.

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Since the discovery of 2D materials, 2D material nanofiltration (NF) membranes have attracted great attention and are being developed with a tremendously fast pace, due to their energy efficiency and cost effectiveness for water purification. The most attractive aspect for 2D material NF membranes is that, anomalous water and ion permeation phenomena have been constantly observed because of the presence of the severely confined nanocapillaries (<2 nm) in the membrane, leading to its great potential in achieving superior overall performance, e.g., high water flux, high rejection rates of ions, and high resistance to swelling. Hence, fundamental understandings of such water and ion transport behaviors are of great significance for the continuous development of 2D material NF membranes. In this work, the microscopic understandings developed up to date on 2D material NF membranes regarding the abnormal transport phenomena are reviewed, including ultrafast water and ion permeation rates with the magnitude several orders higher than that predicted by conventional diffusion behavior, ion dehydration, ionic Coulomb blockade, ion-ion correlations, etc. The state-of-the-art structural designs for 2D material NF membranes are also reviewed. Discussion and future perspectives are provided highlighting the rational design of 2D material membrane structures in the future.

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Beryllium has applications in fission and fusion reactors, and it is present in specific streams of radioactive waste. Accordingly, the environmental mobility of beryllium needs to be assessed in the context of repositories for nuclear waste. Although cement is widely used in these facilities, Be(II) uptake by cementitious materials was not previously investigated and was hence assumed negligible. Sorption experiments were performed under Ar-atmosphere. Ordinary Portland cement, low pH cement, calcium silicate hydrated (C-S-H) phases and the model system TiO2 were investigated. Sorption kinetics, sorption isotherms and distribution ratios (Rd, in kg⋅L-1) were determined for these systems. Molecular dynamics were used to characterize the surface processes driving Be(II) uptake. A strong uptake (5 ≤ log Rd ≤ 7) is quantified for all investigated cementitious systems. Linear sorption isotherms are observed over three orders of magnitude in [Be(II)]aq, confirming that the uptake is controlled by sorption processes and that solubility phenomena is not relevant within the investigated conditions. The analogous behaviour observed for cement and C-S-H support that the latter are the main sink of beryllium. The two step sorption kinetics is explained by a fast surface complexation process, followed by the slow incorporation of Be(II) in C-S-H. Molecular dynamics indicate that Be(OH)3- and Be(OH)42- are sorbed to the C-S-H surface through Ca-bridges. This work provides a comprehensive quantitative and mechanistic description of Be(II) uptake by cementitious materials, whose retention properties can be now reliably assessed for a wide range of boundary conditions of relevance in nuclear waste disposal.

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Dual-atom catalysts have the potential to outperform the well-established single-atom catalysts for the electrochemical conversion of CO2 . However, the lack of understanding regarding the mechanism of this enhanced catalytic process prevents the rational design of high-performance catalysts. Herein, an obvious synergistic effect in atomically dispersed Ni-Zn bimetal sites is observed. In situ characterization combined with density functional theory (DFT) calculations reveals that heteronuclear coordination modifies the d-states of the metal atom, narrowing the gap between the d-band centre (εd ) of the Ni (3d) orbitals and the Fermi energy level (EF ) to strengthen the electronic interaction at the reaction interface, resulting in a lower free energy barrier (ΔG) in the thermodynamic pathway and a reduced activation energy (Ea ) as well as fortified metal-C bonding in the kinetic pathway. Consequently, a CO faradaic efficiency of >90% is obtained across a broad potential window from -0.5 to -1.0 V (vs RHE), reaching a maximum of 99% at -0.8 V, superior to that of the Ni/Zn single-metal sites.

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Manufacturing of recombinant adeno-associated virus (rAAV) viral vectors remains challenging, with low yields and low full:empty capsid ratios in the harvest. To elucidate the dynamics of recombinant viral production, we develop a mechanistic model for the synthesis of rAAV viral vectors by triple plasmid transfection based on the underlying biological processes derived from wild-type AAV. The model covers major steps starting from exogenous DNA delivery to the reaction cascade that forms viral proteins and DNA, which subsequently result in filled capsids, and the complex functions of the Rep protein as a regulator of the packaging plasmid gene expression and a catalyst for viral DNA packaging. We estimate kinetic parameters using dynamic data from literature and in-house triple transient transfection experiments. Model predictions of productivity changes as a result of the varied input plasmid ratio are benchmarked against transfection data from the literature. Sensitivity analysis suggests that (1) the poorly coordinated timeline of capsid synthesis and viral DNA replication results in a low ratio of full virions in harvest, and (2) repressive function of the Rep protein could be impeding capsid production at a later phase. The analyses from the mathematical model provide testable hypotheses for evaluation and reveal potential process bottlenecks that can be investigated.

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The Agency for Toxic Substances and Disease Registry (ATSDR) develops interaction profiles using binary weight of evidence (BINWOE) methodology to determine interaction directions of common environmental mixtures. We collected direction of interactions, BINWOE score determination, and BINWOE score confidence rating from 13 interaction profiles along with toxicodynamic and toxicokinetic influences on interaction direction. By doing so, we quantified the 1) direction of interaction and indeterminate evaluations; 2) characterized confidence in the BINWOE determinations; and 3) quantified toxicokinetic/toxicodynamic, and other influences on projected BINWOE interaction directions. Thirty-nine percent (130/336) of the attempts to make a BINWOE were indeterminate due to no interaction data or inadequate or conflicting evidence. Out of remaining BINWOEs, 25% were additive, 9% were greater-than-additive, and 27% were less-than-additive interactions. Fifty-five percent of BINWOEs were explained by toxicokinetic interactions, 12% and 5% were explained by toxicodynamic and other explanations, respectively. High quality mixture toxicology in vivo studies along with mixture in vitro and in silico studies will lead to greater confidence in interaction directions and influences. Limitations for interpretation of the data were also included.

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Recombinant adeno-associated viruses (rAAVs) are among the most important vectors for in vivo gene therapies. With the rapid development of gene therapy, current rAAV manufacturing capacity faces a challenge to meet the emerging demand for these therapies in the future. To examine the bottlenecks in rAAV production during cell culture, we focus here on an analysis of cellular pathways of rAAV production, based on an overview of assembly mechanisms first in the wild-type (wt) AAV replication and then in the common methods of rAAV production. The differences analyzed between the wild-type and recombinant systems provide insights into the mechanistic differences that may correlate with viral productivity. Based on these analyses, we identify potential barriers to high productivity of rAAV and discuss future directions for improvement to meet the emerging needs set by the growth of rAAV-based therapy and the needs of patients.

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Black phosphorus (BP)-based nanomaterials have distinguished advantages and potential applications in various biomedical fields. However, their biological effects in physiological systems remain largely unexplored. Here, we systematically revealed a reactive oxygen species (ROS)-mediated mechanism for the selective killing of cancer cells by BP-based nanosheets. The treatment with BP-based materials can induce higher levels of ROS in cancer cells than in normal cells, leading to significant changes in the cytoskeleton, cell cycle arrest, DNA damage, and apoptosis in tumor cell lines. We revealed that the decreased superoxide dismutase activity by lipid peroxides could be an essential mechanism of the selectively higher ROS generation induced by BP-based nanosheets in cancer cells. In addition, the selective killing effect only occurred within a certain dosage range (named "SK range" in this study). Once exceeding the SK range, BP-based materials could also induce a high ROS production in normal tissues, leading to detectable DNA damage and pathological characteristics in normal organs and raising safety concerns. These findings not only shed light on a new mechanism for the selective killing of cancer cells by BP-based materials but also provide deep insights into the safe use of BP-based therapies.

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For solving the drawbacks of low conductivity and the shuttle effect in a sulfur cathode, various nonpolar carbon and polar metal compounds with strong chemical absorption ability are applied as sulfur host materials for lithium-sulfur (Li-S) batteries. Nevertheless, previous research simply attributed the performance improvement of sulfur cathodes to the chemical adsorption ability of polar metal compounds toward lithium polysulfides (LPS), while a deep understanding of the enhanced electrochemical performance in these various sulfur hosts, especially at the molecular levels, is still unclear. Herein, for a mechanistic understanding of superior metal phosphide host in Li-S battery chemistry, an integrated phosphide-based host of CF/FeP@C (carbon cloth with grown FeP@C nanotube arrays) is chosen as the model, and this binder-free cathode can exclude interference from the binder and conductive additives. With a systematic electrochemical investigation of the loading sulfur in such oxide- and phosphide-based hosts (CF/Fe3O4@C and CF/FeP@C), it is found that CF/FeP@C@S shows much superior Li-S performances. The greatly enhanced performance of CF/FeP@C@S suggests that FeP can well suppress the shuttle effect of LPS and accelerate their transformation during the charge-discharge process. The first-principles calculations reveal the performance variations of Fe3O4 and FeP in Li-S batteries mainly because the shifts of the p band of the FeP could accelerate the interfacial electronics transfer dynamics by increasing the electronic concentration in the Fermi level of adsorbed Li2S4. The current work sheds light on the promising design of superior Li-S batteries from both theoretical and experimental aspects.

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Recent developments have prompted the transition of empirically based testing of late stage toxicity in animals for a range of different endpoints including neurotoxicity to more efficient and predictive mechanistically based approaches with greater emphasis on measurable key events early in the progression of disease. The adverse outcome pathway (AOP) has been proposed as a simplified organizational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organization to disease outcomes. As such, AOPs are anticipated to facilitate the compilation of information to increase mechanistic understanding of pathophysiological pathways that are responsible for human disease. In this review, the sequence of key events resulting in adverse outcome (AO) defined as parkinsonian motor impairment and learning and memory deficit in children, triggered by exposure to environmental chemicals has been briefly described using the AOP framework. These AOPs follow convention adopted in an Organization for Economic Cooperation and Development (OECD) AOP development program, publically available, to permit tailored application of AOPs for a range of different purposes. Due to the complexity of disease pathways, including neurodegenerative disorders, a specific symptom of the disease (e.g. parkinsonian motor deficit) is considered as the AO in a developed AOP. Though the description is necessarily limited by the extent of current knowledge, additional characterization of involved pathways through description of related AOPs interlinked into networks for the same disease has potential to contribute to more holistic and mechanistic understanding of the pathophysiological pathways involved, possibly leading to the mechanism-based reclassification of diseases, thus facilitating more personalized treatment.

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BACKGROUND: The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization. However, these events have not been organized in a sequence of related events that is plausible to result in sensitization, and useful to challenge current hypotheses. The aim of this manuscript was to collect and structure the current mechanistic understanding of sensitization induction to food proteins by applying the concept of adverse outcome pathway (AOP). MAIN BODY: The proposed AOP for food sensitization is based on information on molecular and cellular mechanisms and pathways evidenced to be involved in sensitization by food and food proteins and uses the AOPs for chemical skin sensitization and respiratory sensitization induction as templates. Available mechanistic data on protein respiratory sensitization were included to fill out gaps in the understanding of how proteins may affect cells, cell-cell interactions and tissue homeostasis. Analysis revealed several key events (KE) and biomarkers that may have potential use in testing and assessment of proteins for their sensitizing potential. CONCLUSION: The application of the AOP concept to structure mechanistic in vivo and in vitro knowledge has made it possible to identify a number of methods, each addressing a specific KE, that provide information about the food allergenic potential of new proteins. When applied in the context of an integrated strategy these methods may reduce, if not replace, current animal testing approaches. The proposed AOP will be shared at the www.aopwiki.org platform to expand the mechanistic data, improve the confidence in each of the proposed KE and key event relations (KERs), and allow for the identification of new, or refinement of established KE and KERs.

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The objectives of the present study were to develop a controlled-release bilayered tablet of aceclofenac (AFN) 200mg with dual release and to gain a mechanistic understanding of the enhanced sustained release capability achieved by utilizing a binary mixture of the sustained release materials. Different formulations of the sustained-release layer were formulated by employing hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) as the major retarding polymers. The in vitro dissolution studies of AFN bilayered tablets were carried out in intestinal fluid (pH 6.8 buffer). The mechanism of the synergistic rate-retarding effect of the polymer mixture containing HPC and carbomer was elucidated by the rate of swelling and erosion in intestinal fluid and the molecular interactions in the polymer network. The optimized bilayered tablets had similar in vitro dissolution profiles to the marketed tablet Clanza®CR based on the similarity factor (f2) in combination with their satisfactory micromeritic, physicochemical properties, and stability profiles. Drug release from HPMC-based matrix was controlled by non-Fickian transport, while drug release from HPC-based matrix was solely governed by drug diffusion. The swelling and erosion data exhibited a dramatic increase of water uptake and a reduction of weight loss in the polymer mixture-loaded tablet. Fourier transform infrared (FTIR) spectra revealed strong hydrogen bonding between HPC and carbomer in the polymer mixture. Regarding spatial distribution of polymers in the polymer mixture-loaded tablet, carbomer was found to be the main component of the gel layer during the first 2h of the hydration process, which was responsible for retarding drug release at initial stage. This process was then followed by a gradual transition of HPC from the glassy core to the gel layer for further increasing gel strength.

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