Changes in DNA copy number, whether confined to specific genes or affecting whole chromosomes, have been identified as causes of diseases and developmental abnormalities and as sources of adaptive ...potential. Here, we discuss the costs and benefits of DNA copy-number alterations. Changes in DNA copy number are largely detrimental. Amplifications or deletions of specific genes can elicit discrete defects. Large-scale changes in DNA copy number can also cause detrimental phenotypes that are due to the cumulative effects of copy-number alterations of many genes simultaneously. On the other hand, studies in microorganisms show that DNA copy-number alterations can be beneficial, increasing survival under selective pressure. As DNA copy-number alterations underlie many human diseases, we will end with a discussion of gene copy-number changes as therapeutic targets.
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•TK/TD behavior in mice is MPs particle size-dependent.•Mice-based TK parameters and threshold criteria could be derived.•Assist in designing robust researches to evaluate human MP ...consumption.
While a large body of literature has shown that microplastics (MPs) are highly likely to be accumulated in marine organisms and terrestrial animals, information about toxicity of MPs in mammal from a mechanistic point of view is more limited. Our paper fills this knowledge gap by assessing polystyrene (PS)-MPs-mice system based on toxicity-based toxicokinetic/toxicodynamic (TBTK/TD) modeling to quantify organ-bioaccumulation and biomarker responses appraised with published dataset. The key TBTK-parameters for mice liver, kidney, and gut posed by 5 or 20 μm PS-MPs could be obtained. We found that gut had the highest bioaccumulation factor (BCF) of ∼8 exposed to 5 μm PS-MPs with a mean residence time of ∼17 days. We showed that threshold concentrations of 5 and 20 μm PS-MPs among the most sensitive biomarkers were 8 ± 5 (mean ± SE) and 0.71 ± 0.14 μg g−1 bw, respectively, implicating that particle size was likely to affect TK/TD behavior in mice. The mice-based TK parameters and threshold criteria greatly assist in designing robust researches to evaluate MP consumption by humans. We establish a TBTK/TD framework for mechanistically assessing potential from mice size-specific MPs exposure that would offer a tool-kit for extrapolating to humans from health risk assessment perspective.
•Debris distance is predicted for building damage states.•Haiti earthquake data is used for model calibration.•Fragility curves are developed to predict road section blockage.•Road blockage is ...modeled as a system reliability problem.•Conceptual illustrations are made using two examples.
Transportation infrastructure supports the social and economic activities of communities. One of the impacts of roads’ disruption is the obstruction of emergency services (e.g., ambulance, firefighting, evacuation). Furthermore, the recovery process of a community following an extreme event (e.g., a natural hazard) depends on the functionality of the transportation infrastructure. Therefore, conducting a risk and resilience analysis of transportation infrastructure is critical to help communities minimize the initial impact of hazards and promote a rapid recovery. Current approaches model the probability of road blockage due to building damage using high-resolution optical satellite images and aerial photographs collected after past events. However, the data used by these methods are limited, and few data have been collected before 2010. Besides, data may not be available for specific regions that have not experienced recent earthquakes. Thus, a probabilistic predictive method is needed for risk and resilience analysis of roads. This paper proposes a probabilistic model using the data from the 2010 Haiti Earthquake and calibrated by Bayesian approach to predict the debris distance from undamaged buildings (e.g., the distance debris can reach from the footprint of the undamaged building). The model is then used to construct fragility curves that give the conditional probability of road blockage at a given road section for a given seismic intensity. The proposed model considers the relevant factors affecting the road blockage probability, including building types, damage level, and road characteristics. The probability of road blockage at a given road section is estimated for the four general road section types, considering buildings on only one side of the road or both sides, and with or without a raised traffic median. The probability of road blockage for an entire road is then calculated by system and parallel reliability analysis. The proposed models apply to any general urban area without the dependence on historical data from past earthquakes.
A novel approach for using conjugated rod–coil materials as a floating gate in the fabrication of nonvolatile photonic transistor memory devices, consisting of n‐type Sol‐PDI and p‐type C10‐DNTT, is ...presented. Sol‐PDI and C10‐DNTT are used as dual functions of charge‐trapping (conjugated rod) and tunneling (insulating coil), while n‐type BPE‐PDI and p‐type DNTT are employed as the corresponding transporting layers. By using the same conjugated rod in the memory layer and transporting channel with a self‐assembled structure, both n‐type and p‐type memory devices exhibit a fast response, a high current contrast between “Photo‐On” and “Electrical‐Off” bistable states over 105, and an extremely low programing driving force of 0.1 V. The fabricated photon‐driven memory devices exhibit a quick response to different wavelengths of light and a broadband light response that highlight their promising potential for light‐recorder and synaptic device applications.
High‐performance photonic transistor memory devices are fabricated using conjugated rod–coil materials as a photoactive floating gate, in which the conjugated rods and side‐chain coils act as charge‐trapping and tunneling moieties, respectively. By inheriting their self‐assembled structure, both n‐type and p‐type memory devices exhibit a fast response, a current contrast over 105, and an extremely low programing driving force of 0.1 V.
Donor–acceptor type polymers and supramolecules are promising electrets in photonic field‐effect transistor (FET)‐type memory because of their diversified polymer‐structure design and favorable ...mechanical tolerance. Using intermolecular association, supramolecule electrets can surpass donor–acceptor type polymers with versatile facile combining processes. Currently, there has been no application of charge‐transfer (CT) supramolecules in electrets of photonic FET memory devices. Herein, a novel series of CT‐based supramolecular electrets comprising poly(1‐pyrenemethyl methacrylate) (PPyMA) and 7,7,8,8‐tetracyanoquinodimethane (TCNQ) is used to elucidate the effect of CT on photonic FET memory. Accordingly, memory devices based on the supramolecular electret with an equimolar content of pyrene and TCNQ exhibit superior bistable memory switchability using electrical/photoprograming with UV (365 nm) and green light (525 nm). This shows a broad memory window of 34 V and favorable memory ratio of over 106 after 104 s. The memory performance can be attributed to the favorable molecular association and dispersion between pyrene and TCNQ in the solid state. The results provide evidence that CT‐based supramolecular electrets warrant applications in optoelectronic applications.
A series of charge transfer‐based supramolecular electrets comprising poly(1‐pyrenemethyl methacrylate) and 7,7,8,8‐tetracyanoquinodimethane are applied to elucidate the effect of charge transfer on photonic field‐effect transistor memory. Accordingly, the devices based on the supramolecular electret exhibit superior memory switchability using electrical/photoprograming under UV (365 nm) and green light, showing a broad memory window of 34 V and memory ratio of over 106 after 104 s.
•Toxicokinetic (TK) data of microplastics (MPs) and nanoplastics (NPs) are compiled.•TK properties and mechanisms of MPs and NPs are thoroughly discussed.•Several conceptual PBTK model structures are ...proposed for MPs and NPs in mammals.•Challenges and implication of PBTK modeling for MPs and NPs are discussed.
Microplastics (MPs) and nanoplastics (NPs) pollution has emerged as a significant and widespread environmental issue. Humans are inevitably exposed to MPs and NPs via ingestion, inhalation, and dermal contacts from various sources. However, mechanistic knowledge of their distribution, interaction, and potency in the body is still lacking. To address this knowledge gap, we have undertaken the task of elucidating the toxicokinetic (TK) behaviors of MPs and NPs, aiming to provide mechanistic information for constructing a conceptual physiologically based toxicokinetic (PBTK) model to support in silico modeling approaches. Our effort involved a thorough examination of the existing literature and data collation on the presence of MPs in the human body and in vitro/ex vivo/in vivo biodistribution across various cells and tissues. By comprehending the absorption, distribution, metabolism, and excretion mechanisms of MPs and NPs in relation to their physicochemical attributes, we established a foundational understanding of the link between external exposure and internal tissue dosimetry. We observed that particle size and surface chemistry have been thoroughly explored in previous experimental studies. However, certain attributes, such as polymer type, shape, and biofilm/biocorona, warrant attention and further examination. We discussed the fundamental disparities in TK properties of MPs/NPs from those of engineered nanoparticles. We proposed a preliminary PBTK framework with several possible modeling approaches and discussed existing challenges for further investigation. Overall, this article provides a comprehensive compilation of existing TK data of MPs/NPs, a critical overview of TK processes and mechanisms, and proposes potential PBTK modeling approaches, particularly regarding their applicability to the human system, and outlines future perspectives for developing PBTK models and their integration into human health risk assessment of MPs and NPs.
PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential ...regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor EGF through Ca2+/Calmodulin-dependent kinase and is essential for EGF-mediated Akt activation and biological functions. AMPK phosphorylates Skp2 at S256 and promotes the integrity and E3 ligase activity of Skp2 SCF complex leading to K63-linked ubiquitination and activation of Akt and subsequent oncogenic processes. Importantly, AMPK-mediated Skp2 S256 phosphorylation promotes breast cancer progression in mouse tumor models, correlates with Akt and AMPK activation in breast cancer patients, and predicts poor survival outcomes. Finally, targeting AMPK-mediated Skp2 S256 phosphorylation sensitizes cells to anti-EGF receptor targeted therapy. Our study sheds light on how stress and EGF induce Akt activation and new mechanisms for AMPK-mediated oncogenesis and drug resistance.
Rotation around a specific bond after photoexcitation is central to vision and emerging opportunities in optogenetics, super-resolution microscopy, and photoactive molecular devices. Competing roles ...for steric and electrostatic effects that govern bond-specific photoisomerization have been widely discussed, the latter originating from chromophore charge transfer upon excitation. We systematically altered the electrostatic properties of the green fluorescent protein chromophore in a photoswitchable variant, Dronpa2, using amber suppression to introduce electron-donating and electron-withdrawing groups to the phenolate ring. Through analysis of the absorption (color), fluorescence quantum yield, and energy barriers to ground- and excited-state isomerization, we evaluate the contributions of sterics and electrostatics quantitatively and demonstrate how electrostatic effects bias the pathway of chromophore photoisomerization, leading to a generalized framework to guide protein design.
One year of treatment with entecavir (0.5 mg daily) in nucleoside‐naive patients with hepatitis B e antigen (HBeAg)‐positive or HBeAg‐negative chronic hepatitis B (CHB) resulted in significantly ...improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long‐term rollover study and underwent long‐term liver biopsy were evaluated for improvements in histological appearance. Sixty‐nine patients 50 HBeAg‐positive and 19 HBeAg‐negative receiving entecavir therapy underwent long‐term liver biopsy (median time of biopsy = 6 years, range = 3‐7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ≥2, and adequate long‐term biopsy samples. At the time of long‐term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (≥2‐point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ≥1‐point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside‐naive patients with CHB who were treated with entecavir in this long‐term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010)
Meat and poultry are prone to contamination with foodborne pathogens sourced from the livestock or introduced from the processing environments. In this study, for retention of meat quality while ...assuring microbial food safety, mild levels of high hydrostatic pressure were hurdled with food‐grade additives (i.e., allyl isothiocyanate AITC and acetic acid AA, functioned as antimicrobials) to inactivate pathogenic Escherichia coli in ground chicken. The reductions of Shiga toxin‐producing E. coli (STEC) O157:H7 and uropathogenic E. coli (UPEC) were described as a function of high hydrostatic pressure (200–350 MPa), process‐holding time (10–25 min), AITC concentration (0.05–0.20% w/w), and AA concentration (0.10‐–0.30% w/w) using a full factorial design. The antimicrobials had little influence on bacterial inactivation without high pressure. Without the antimicrobials, a high‐pressure treatment at 300 MPa and 4°C for 15 min reduced E. coli O157:H7 and UPEC by 1.52 and 2.52 log, respectively. A 5‐log reduction was achieved when AITC and AA were combined with high pressure, indicating a synergistic effect. The survivors were further reduced to below the detection limit of 1 log CFU/g after subsequent storage tests at 4 and 10°C for 10 days. The STEC O157:H7 was found slightly more resistant than UPEC in our test matrix. The developed models showed good fits with experimental data (R2 > 0.95 for linear models; Pr > F (<0.0001) for dimensionless nonlinear models); which may help processors find/optimize the processing parameters to achieve target foodborne pathogens reduction for food safety requirement.
Practical Application
Models were developed to predict the inactivation of pathogenic Escherichia coli in ground chicken by high‐pressure processing (HPP) in combination with natural antimicrobial compounds. These models can be used to estimate/determine the HPP operation parameters and antimicrobial usage levels (i.e., allyl isothiocyanate and acetic acid) needed to achieve a specific microbial log reduction within the selected factor ranges. The operation parameters and clean‐label ingredients are of interest in the food industry, which may benefit from the application of the models in achieving microbial safety, process optimization, and operation cost reduction.
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