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Mitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber's hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. PAPERCLIP.
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Marcação de Genes , Doenças Mitocondriais/genética , Animais , Fusão Celular , DNA Mitocondrial , Embrião de Mamíferos/metabolismo , Endonucleases/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NZB , Doenças Mitocondriais/prevenção & controle , Mutação , Oócitos/metabolismoRESUMO
Hemi-methylated cytosine dyads widely occur on mammalian genomic DNA, and can be stably inherited across cell divisions, serving as potential epigenetic marks. Previous identification of hemi-methylation relied on harsh bisulfite treatment, leading to extensive DNA degradation and loss of methylation information. Here we introduce Mhemi-seq, a bisulfite-free strategy, to efficiently resolve methylation status of cytosine dyads into unmethylation, strand-specific hemi-methylation, or full-methylation. Mhemi-seq reproduces methylomes from bisulfite-based sequencing (BS-seq & hpBS-seq), including the asymmetric hemi-methylation enrichment flanking CTCF motifs. By avoiding base conversion, Mhemi-seq resolves allele-specific methylation and associated imprinted gene expression more efficiently than BS-seq. Furthermore, we reveal an inhibitory role of hemi-methylation in gene expression and transcription factor (TF)-DNA binding, and some displays a similar extent of inhibition as full-methylation. Finally, we uncover new hemi-methylation patterns within Alu retrotransposon elements. Collectively, Mhemi-seq can accelerate the identification of DNA hemi-methylation and facilitate its integration into the chromatin environment for future studies.
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Metilação de DNA , Análise de Sequência de DNA , Animais , Citosina/metabolismo , Metilação de DNA/genética , Mamíferos/genética , Retroelementos , Análise de Sequência de DNA/métodos , Sulfitos , Regulação da Expressão GênicaRESUMO
Polymer-in-salt solid-state electrolytes (PIS SSEs) are emerging for high room-temperature ionic conductivity and facile handling, but suffer from poor mechanical durability and large thickness. Here, Al2O3-coated PE (PE/AO) separators are proposed as robust and large-scale substrates to trim the thickness of PIS SSEs without compromising mechanical durability. Various characterizations unravel that introducing Al2O3 coating on PE separators efficiently improves the wettability, thermal stability, and Li-dendrite resistance of PIS SSEs. The resulting PE/AO@PIS demonstrates ultra-small thickness (25 µm), exceptional mechanical durability (55.1 MPa), high decomposition temperature (330 °C), and favorable ionic conductivity (0.12 mS cm-1 at 25 °C). Consequently, the symmetrical Li cells remain stable at 0.1 mA cm-2 for 3000 h, without Li dendrite formation. Besides, the LiFePO4|Li full cells showcase excellent rate capability (131.0 mAh g-1 at 10C) and cyclability (93.6% capacity retention at 2C after 400 cycles), and high-mass-loading performance (7.5 mg cm-2). Moreover, the PE/AO@PIS can also pair with nickel-rich layered oxides (NCM811 and NCM9055), showing a remarkable specific capacity of 165.3 and 175.4 mAh g-1 at 0.2C after 100 cycles, respectively. This work presents an effective large-scale preparation approach for mechanically durable and ultrathin PIS SSEs, driving their practical applications for next-generation solid-state Li-metal batteries.
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The cell size of phytoplankton is an important defining functional trait that can serve as a driver and sentinel of phytoplankton community structure and function. However, the study of the assembly patterns and drivers of phytoplankton metacommunities with different cell sizes has not been widely carried out. In this study, we systematically investigated the biodiversity patterns, drivers, and assembly processes of the three phytoplankton cell sizes (micro: 20-200 µm; nano: 2-20 µm; pico: 0.2-2 µm) in the Za'gya Zangbo River from the source to the estuary using 18S rDNA amplicon sequencing. The results demonstrated that the alpha diversity and co-occurrence network complexity for all three sizes of phytoplankton increased to a peak downstream of the glacier sources and then decreased to the estuary. The nanophytoplankton subcommunity consistently had the highest alpha diversity and co-occurrence network complexity. On the other hand, total beta diversity followed a unimodal trend of decreasing and then increasing from source to estuary, and was dominated by species replacement components. In addition, deterministic processes driven mainly by physiochemical indices (PCIs) and biogenic elements (BGEs) dominated the assembly of micro- and nanophytoplankton subcommunities, whereas stochastic processes driven by geographical factors (GGFs) dominated the assembly of picophytoplankton subcommunities. The results explained the contradictions in previous studies of phytoplankton community assembly processes in highland aquatic ecosystems, elucidating the different contributions of deterministic and stochastic processes, and the complexity of compositional mechanisms in shaping the assembly of micro-, nano-, and picophytoplankton in this highland glacial river. IMPORTANCE: The cell size of phytoplankton is a key life-history trait and key determinant, and phytoplankton of different cell sizes are differentially affected by ecological processes. However, the study of the assembly patterns and drivers of phytoplankton metacommunities with different cell sizes has not been widely carried out. We provide an in-depth analysis of phytoplankton community diversity across three cell sizes in the glacier-fed river, describing how the pattern of phytoplankton communities differs across cell sizes in response to geochemical gradients. The results show that the smaller phytoplankton (picophytoplankton) are relatively more influenced by dispersal-based stochastic processes, whereas larger ones (microphytoplankton and nanophytoplankton) are more structured by selection-based deterministic processes.
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Species adulteration or mislabeling with meat and seafood products could negatively affect the fair trade, wildlife conservation, food safety, religion aspect, and even the public health. While PCR-based methods remain the gold standard for assessment of the species authenticity, there is an urgent need for alternative testing platforms that are rapid, accurate, simple, and portable. Owing to its ease of use, low cost, and rapidity, LAMP is becoming increasingly used method in food analysis for detecting species adulteration or mislabeling. In this review, we outline how the features of LAMP have been leveraged for species authentication test with meat and seafood products. Meanwhile, as the trend of LAMP detection is simple, rapid and instrument-free, it is of great necessity to carry out end-point visual detection, and the principles of various end-point colorimetry methods are also reviewed. Moreover, with the aim to enhance the LAMP reaction, different strategies are summarized to either suppress the nonspecific amplification, or to avoid the results of nonspecific amplification. Finally, microfluidic chip is a promising point-of-care method, which has been the subject of a great deal of research directed toward the development of microfluidic platforms-based LAMP systems for the species authenticity with meat and seafood products.
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As one of the important biodiversity conservation areas in China, the ecosystem in the lower reaches of the Yarlung Zangbo River is fragile, and is particularly sensitive to global changes. To reveal the diversity pattern of phytoplankton, the metabarcode sequencing was employed in the Medog section of the lower reaches of the Yarlung Zangbo River during autumn 2019 in present study. The phytoplankton assemblies can be significantly divided into the main stem and the tributaries; there are significant differences in the phytoplankton biomass, alpha and beta diversity between the main stem and the tributaries. While both the main stem and the tributaries are affected by dispersal limitation, the phytoplankton assemblages in the entire lower reaches are primarily influenced by heterogeneous selection. Community dissimilarity and assembly process were significantly correlated with turbidity, electrical conductivity, and nitrogen nutrition. The tributaries were the main source of the increase in phytoplankton diversity in the lower reaches of the Yarlung Zangbo River. Such diversity pattern of phytoplankton in the lower reach may be caused by the special habitat in Medog, that is, the excessive flow velocity, and the significant spatial heterogeneity in physical and chemical factors between stem and tributaries. Based on the results and conclusions obtained in present study, continuous long-term monitoring is essential to assess and quantify the impact of global changes on phytoplankton.
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Ecossistema , Rios , Biodiversidade , Biomassa , FitoplânctonRESUMO
Plastic additives, represented by plasticizers, are important components of plastic pollution. Biofilms inevitably form on plastic surfaces when plastic enters the aqueous environment. However, little is known about the effect of biofilms on plastic surfaces on the release of additives therein. In this study, PVC plastics with different levels of di(2-ethylhexyl)phthalate (DEHP) content were investigated to study the effect of biofilm growth on DEHP release. The presence of biofilms promoted the migration of DEHP from PVC plastics to the external environment. Relative to biofilm-free controls, although the presence of surface biofilm resulted in 0.8 to 11.6 times lower DEHP concentrations in water, the concentrations of the degradation product, monoethylhexyl phthalate (MEHP) in water, were 2.3 to 57.3 times higher. When the total release amounts of DEHP in the biofilm and in the water were combined, they were increased by 0.6-73 times after biofilm growth. However, most of the released DEHP was adsorbed in the biofilms and was subsequently degraded. The results of this study suggest that the biofilm as a new interface between plastics and the surrounding environment can affect the transport and transformation of plastic additives in the environment through barrier, adsorption, and degradation. Future research endeavors should aim to explore the transport dynamics and fate of plastic additives under various biofilm compositions as well as evaluate the ecological risks associated with their enrichment by biofilms.
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Dietilexilftalato , Dietilexilftalato/metabolismo , Plastificantes , Biofilmes , Poluição Ambiental , Água , PlásticosRESUMO
Understanding the relative role of dispersal dynamics and niche constraints is not only a core task in community ecology, but also becomes an important prerequisite for bioassessment. Despite the recent progress in our knowledge of community assembly in space and time, patterns and processes underlying biotic communities in alpine glacierized catchments remain mostly ignored. To fill this knowledge gap, we combined the recently proposed dispersal-niche continuum index (DNCI) with traditional constrained ordinations and idealized patterns of species distributions to unravel community assembly mechanisms of different key groups of primary producers and consumers (i.e., phytoplankton, epiphytic algae, zooplankton, macroinvertebrates, and fishes) in rivers in the Qinghai-Tibet Plateau, the World's Third Pole. We tested whether organismal groups with contrasting body sizes differed in their assembly processes, and discussed their applicability in bioassessment in alpine zones. We found that community structure of alpine river biotas was always predominantly explained in terms of dispersal dynamics and historical biogeography. These patterns are most likely the result of differences in species-specific functional attributes, the stochastic colonization-extinction dynamics driven by multi-year glacier disturbances and the repeated hydrodynamic separation among alpine catchments after the rising of the Qilian mountains. Additionally, we found that the strength of dispersal dynamics and niche constraints was partially mediated by organismal body sizes, with dispersal processes being more influential for microscopic primary producers. Finding that zooplankton and macroinvertebrate communities followed clumped species replacement structures (i.e., Clementsian gradients) supports the notion that environmental filtering also contributes to the structure of high-altitude animal communities in glacierized catchments. In terms of the applied fields, we argue that freshwater bioassessment in glacierized catchments can benefit from incorporating the metacommunity perspective and applying novel approaches to (i) detect the optimal spatial scale for species sorting and (ii) identify and eliminate the species that are sensitive to dispersal-related processes.
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Rios , Animais , Tibet , Zooplâncton/fisiologia , Zooplâncton/classificação , Invertebrados/fisiologia , Camada de Gelo , Peixes/fisiologia , Ecossistema , Organismos Aquáticos , Biota , Fitoplâncton/fisiologia , Biodiversidade , Distribuição AnimalRESUMO
Carrier mobility in titanium dioxide (TiO2) systems is a key factor for their application as energy materials, especially in solar cells and lithium-ion batteries. Studies on the diffusion of Li-ions and polarons in rutile TiO2 systems have attracted extensive attention. However, how their interaction affects the diffusion of Li-ions and electron polarons is largely unclear and related studies are relatively lacking. By using first-principles calculations, we systematically investigate the interaction between the intercalated Li-ions and electron polarons in rutile TiO2 materials. Our analysis shows that the diffusion barrier of the electron polarons decreases around the Li-ion. The interaction between the Li-ions and polarons would benefit their synergistic diffusion both in the pristine and defective rutile TiO2 systems. Our study reveals the synergistic effects between the ions and polarons, which is important for understanding the carrier properties in TiO2 systems and in further improving the performance of energy materials.
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Constructing metal-semiconductor interfaces by loading metal atoms onto two-dimensional material to build atomically dispersed single-atom catalysts (SACs) has emerged as a new frontier for improving atom utilization and designing multifunctional electrocatalysts. Nowadays, studies on black phosphorus nanosheets in electrocatalysis have received much attention and the successful preparation of metal nanoparticle/black phosphorus (BP) hybrid electrocatalysts indicates BP nanosheets can serve as a potential support platform for SACs. Herein, by using large-scale ab initio calculations, we explored a large composition space of SACs with transition metal atoms supported on BP monolayer (M-BP) and built a comprehensive picture of activity trend, stability, and electronic origin towards oxygen reduction and evolution reaction (ORR and OER) and hydrogen evolution reaction (HER). The results show that the catalytic activity can be widely tuned by reasonable regulation of metal atoms. Ni-, Pd-, and Pt-BP could effectively balance the binding strength of the target intermediates, thus achieving efficient bifunctional activity for OER and ORR. Favorable bifunctional catalytic performance for OER and HER can be realized on Rh-BP. Especially, Pt-BP exhibits promising trifunctional activity towards OER, ORR, and HER. Multiple-level corrections among overpotential, Gibbs free energy, orbital population, and d-band center reveal that the trend and origin of catalytic activity are intrinsically determined by the d-band center of metal sites. The thermodynamic and dynamic stability simulations demonstrate that the active metal centers are firmly anchored on BP substrate with intact M-P bonds. These findings provide a theoretical basis for the rational design of BP-based SACs toward promising multifunctional activity.
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Understanding the origin of charge-density wave (CDW) instability is important for manipulating novel collective electronic states. Many layered transition metal dichalcogenides (TMDs) share similarity in the structural and electronic instability, giving rise to diverse CDW phases and superconductivity. It is still puzzling that even isostructural and isoelectronic TMDs show distinct CDW features. For instance, bulk NbSe2 exhibits CDW order at low temperature, while bulk NbS2 displays no CDW instability. The CDW transitions in single-layer NbS2 and NbSe2 are also different. In the classic limit, we investigate the electron correlation effects on the dimensionality dependence of the CDW ordering. By performing ab initio path integral molecular dynamics simulations and comparative analyses, we further revealed significant nuclear quantum effects in these systems. Specifically, the quantum motion of sulfur anions significantly reduces the CDW transition temperature in both bulk and single-layer NbS2, resulting in distinct CDW features in the NbS2 and NbSe2 systems.
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Carbon catabolite repression (CCR) is a very important mechanism for efficient use of carbon sources in the environment and is necessary for the regulation of fungal growth, development, and pathogenesis. Although there have been extensive studies conducted regarding this mechanism in fungi, little is yet known about the effects of CreA genes on Valsa mali. However, based on the results obtained in this study for the identification of the VmCreA gene in V. mali, it was determined that the gene was expressed at all stages of fungal growth, with self-repression observed at the transcriptional level. Furthermore, the functional analysis results of the gene deletion mutants (ΔVmCreA) and complements (CTΔVmCreA) showed that the VmCreA gene played an important role in the growth, development, pathogenicity, and carbon source utilization of V. mali.
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Ascomicetos , Proteínas Fúngicas , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Carbono/metabolismo , Virulência/genéticaRESUMO
Microplastics in remote areas has received increasing concern in recent years. However, studies on microplastics in alpine rivers and their affecting factors are still limited. In this study, we investigate the abundance and characteristics of microplastic in the surface water of five alpine rivers in Qilian Mountain, China. Utilizing sieve collection, digestion and density separation, along with microscopy and Raman spectroscopy analyses, microplastics were observed in all the water samples and the average abundance of microplastics was 0.48 ± 0.28 items/L, which was lower than in other freshwaters. Transparent (37.3%) and fibrous (72.1%) microplastics were predominant. Polypropylene (53.8%) was the most frequently identified polymer type. Analysis of similarities (ANOSIM) and linear discriminant analysis (LDA) based on microplastic shape, color, and polymer type showed that there was no significant difference in the microplastic characteristics among rivers of Qilian Mountain. The distance decay models revealed that the similarity in microplastics characteristics was not affected by changes in watershed characteristics, such as geographical distance, elevation, water quality, and land use. This finding suggests that the primary source of microplastics in Qilian Mountain rivers could be from dispersed origins. The results of this study indicated that despite remote alpine rivers suffering limited anthropogenic impacts, they were not immune to microplastics. However, in watersheds with lower intensity of human activity, the abundance and characteristics of microplastics in water bodies may be more uniformly distributed and controlled by diffusion conditions such as atmospheric transport or riverine transport. Our investigation unveils novel understanding of microplastic dispersion in secluded alpine territories, emphasizing the crucial need for managing atmospheric transport of microplastics within conservation areas.
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Microplásticos , Poluentes Químicos da Água , Humanos , Plásticos , Monitoramento Ambiental , Poluentes Químicos da Água/análise , Rios/química , ChinaRESUMO
BACKGROUND: Incorporation of polysaccharide-based nanofillers is an effective strategy to fabricate bio-nanocomposite films with preferable mechanical, barrier, and surface hydrophobicity properties compared to pure biopolymer films. The objective of this research is to investigate the influence of starch nanocrystals obtained from native (NSNC) and waxy rice starch (WSNC) on the physical-chemical properties of pullulan-based nanocomposite films and their preservation performance on fresh beef. RESULTS: Continuous SNCs network structure was observed for pullulan-10% SNCs nanocomposite films, whereas the percolation network of SNCs was destroyed and became no longer continuous with increasing SNCs concentration up to 20% in pullulan films. Among the tested films, pullulan-10% SNCs films showed the highest TS values, lowest WVP and OTR values, due to the formation of percolating SNCs network in pullulan matrix. It is noteworthy that the WVP and OTR values of pullulan-10% WSNC films were significantly lower than that of pullulan-10% NSNC films, probably due to higher hydrophobicity and crystallinity of WSNC compared with NSNC. Beef pieces coated with pullulan-SNCs films had higher L* and a* values, lower TVB-N, TBARS, and TVC values during 7 days' storage at 4 °C compared with samples coated with pullulan films. CONCLUSION: Pullulan-SNCs nanocomposite films, especially pullulan-WSNC films, could be potentially used as a coating material for fresh beef due to their desirable oxygen and water barrier properties. © 2022 Society of Chemical Industry.
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Nanocompostos , Nanopartículas , Animais , Bovinos , Amido/química , Glucanos/química , Nanopartículas/química , Nanocompostos/químicaRESUMO
BACKGROUND: Species adulteration has been widely revealed around the world, and the possible reasons include declining stocks in most source areas of the world, poor transparency in the global supply chain, and difficulty in distinguishing the features of processed products. The present work selected Atlantic cod (Gadus morhua) as a case study, and developed a novel loop-mediated isothermal amplification (LAMP) assay for Atlantic cod authentication, where a self-quenched primer and a newly designed reaction vessel were used to realize the endpoint visual detection of the target-specific products. RESULTS: A novel LAMP primer set was designed for Atlantic cod, and the inner primer BIP was selected to label the self-quenched fluorogenic element. The fluorophore's dequenching only occurred along with LAMP elongation for the target species. No fluorescence could be observed with both single-stranded DNA and partially complementary dsDNA of the non-target species. With the novel reaction vessel, both amplification as well as detection were operated in an enclosed device, and visual differentiation of Atlantic cod, negative control, and false positive generated from primer dimers was achieved. The novel assay has proved its specificity and applicability, and could detect as little as 1 pg of Atlantic cod DNA. Moreover, Atlantic cod adulteration as low as 10% could be detected in haddock (Melanogrammus aeglefinus), and no cross-reactivity was observed. CONCLUSION: The established assay could be a useful tool to detect mislabeling incidents involving Atlantic cod considering the advantages of speed, simplicity and accuracy. © 2023 Society of Chemical Industry.
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Gadiformes , Gadus morhua , Animais , Gadus morhua/genética , Técnicas de Amplificação de Ácido Nucleico , Gadiformes/genética , Técnicas de Diagnóstico MolecularRESUMO
Financial literacy has become increasingly crucial in today's complex financial markets. This paper explores the impact of financial literacy on the stock market by establishing an artificial financial market that aligns with the characteristics of the Chinese A-share market using agent-based modeling. The study incorporates financial literacy into investors' mixed beliefs and simulates their behavior in the market. The results show that improving individual investors' financial literacy can improve market quality and investor performance, as well as reduce the unequal distribution of wealth to some extent. However, the phenomenon of speculative trading and irrational behavior in the market can pose potential risks that require regulatory measures. Thus, policy recommendations to improve individual investors' financial literacy and establish corresponding regulatory measures are proposed.
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Using 1-min data, we explore the dynamic variation of the intraday lead-lag relations between stock indices and their derivatives through a comprehensive study with broader coverage of research objectives and methodologies. This paper provides explicit evidence that the futures and options exhibit price leadership over the spot market, and the options is ahead of the futures on most trading days in all three markets. This paper also reports a new finding that the relation between the derivative and its underlying index reverses when the index return has a significantly larger mean value, and the reversal phenomenon is also observed in the relations between the futures and the options, which enriches the empirical results of intraday lead-lag relations. Moreover, these conclusions still hold under the impact of extreme events, e.g., the outbreak of the Covid-19. Finally, we construct a pair trading strategy based on the intraday lead-lag relationships, which can get better performance than the corresponding spot index. Our findings can potentially help regulators understand the price discovery process between the index and its derivatives, and also be of great value for timely adjustment of investors intraday trading strategies.
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Rechargeable batteries and supercapacitors are currently considered as promising electrochemical energy storage (EES) systems to address the energy and environment issues. Self-supported transition metal (Ni, Co, Mn, Mo, Cu, V)-based materials are promising electrodes for EES devices, which offer highly efficient charge transfer kinetics. This review summarizes the latest development of transition metal-based materials with self-supported structures for EES systems. Special focus has been taken on the synthetic methods, the selection of substrates, architectures and chemical compositions of different self-supported nanoarrays in energy storage systems. Finally, the challenges and opportunities of these materials for future development in this field are briefly discussed. We believe that the advancement in self-supported electrode materials would pave the way towards next-generation EES.
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The traditional manual analysis of microplastics has been criticized for its labor-intensive, inaccurate identification of small microplastics, and the lack of uniformity. There are already three automated analysis strategies for microplastics based on vibrational spectroscopy: laser direct infrared (LDIR)-based particle analysis, Raman-based particle analysis, and focal plane array-Fourier transform infrared (FPA-FTIR) imaging. We compared their performances in terms of quantification, detection limit, size measurement, and material identification accuracy and speed by analyzing the same standard and environmental samples. LDIR-based particle analysis provides the fastest analysis speed, but potentially questionable material identification and quantification results. The number of particles smaller than 60 µm recognized by LDIR-based particle analysis is much less than that recognized by Raman-based particle analysis. Misidentification could occur due to the narrow tuning range from 1800 to 975 cm-1 and dispersive artifact distortion of infrared spectra collected in reflection mode. Raman-based particle analysis has a submicrometer detection limit but should be cautiously used in the automated analysis of microplastics in environmental samples because of the strong fluorescence interference. FPA-FTIR imaging provides relatively reliable quantification and material identification for microplastics in environmental samples greater than 20 µm but might provide an imprecise description of the particle shapes. Optical photothermal infrared (O-PTIR) spectroscopy can detect submicron-sized environmental microplastics (0.5-5 µm) intermingled with a substantial amount of biological matrix; the resulting spectra are searchable in infrared databases without the influence of fluorescence interference, but the process would need to be fully automated.
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Microplásticos , Poluentes Químicos da Água , Benchmarking , Monitoramento Ambiental/métodos , Plásticos , Espectroscopia de Infravermelho com Transformada de Fourier , Poluentes Químicos da Água/análiseRESUMO
Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided "proof of concept" for the potential application of metabolic treatment in clinical practice.