Unveiling the impacts of microplastics on cadmium transfer in the soil-plant-human system: A review.

The co-contamination of soils by microplastics (MPs) and cadmium (Cd), one of the most perilous heavy metals, is emerging as a significant global concern, posing risks to plant productivity and human health. However, there remains a gap in the literature concerning comprehensive evaluations of the combined effects of MPs and Cd on soil-plant-human systems. This review examines the interactions and co-impacts of MPs and Cd in soil-plant-human systems, elucidating their mechanisms and synergistic effects on plant development and health risks. We also review the origins and contamination levels of MPs and Cd, revealing that sewage, atmospheric deposition, and biosolid applications are contributors to the contamination of soil with MPs and Cd. Our meta-analysis demonstrates that MPs significantly (p<0.05) increase the bioavailability of soil Cd and the accumulation of Cd in plant shoots by 6.9 and 9.3 %, respectively. The MPs facilitate Cd desorption from soils through direct adsorption via surface complexation and physical adsorption, as well as indirectly by modifying soil physicochemical properties, such as pH and dissolved organic carbon, and altering soil microbial diversity. These interactions augment the bioavailability of Cd, along with MPs, adversely affect plant growth and its physiological functions. Moreover, the ingestion of MPs and Cd through the food chain significantly enhances the bioaccessibility of Cd and exacerbates histopathological alterations in human tissues, thereby amplifying the associated health risks. This review provides insights into the coexistence of MPs and Cd and their synergistic effects on soil-plant-human systems, emphasizing the need for further research in this critical subject area.

Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer.

There is an urgent need to fully understand the biology of third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, and to develop mechanism-driven strategies to manage their acquired resistance. Transient receptor potential melastatin-2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR-TKIs and acquired resistance to EGFR-TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR-TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy-optimized TRPM2 inhibitors.

Unveiling biochar potential to promote safe crop production in toxic metal(loid) contaminated soil: A meta-analysis.

Biochar application emerges as a promising and sustainable solution for the remediation of soils contaminated with potentially toxic metal (loid)s (PTMs), yet its potential to reduce PTM accumulation in crops remains to be fully elucidated. In our study, a hierarchical meta-analysis based on 276 research articles was conducted to quantify the effects of biochar application on crop growth and PTM accumulation. Meanwhile, a machine learning approach was developed to identify the major contributing features. Our findings revealed that biochar application significantly enhanced crop growth, and reduced PTM concentrations in crop tissues, showing a decrease trend of grains (36.1%, 33.6-38.6%) > shoots (31.1%, 29.3-32.8%) > roots (27.5%, 25.7-29.2%). Furthermore, biochar modifications were found to amplify its remediation potential in PTM-contaminated soils. Biochar application was observed to provide favorable conditions for reducing PTM uptake by crops, primarily through decreasing available PTM concentrations and improving overall soil quality. Employing machine learning techniques, we identified biochar properties, such as surface area and C content as a key factor in decreasing PTM bioavailability in soil-crop systems. Furthermore, our study indicated that biochar application could reduce probabilistic health risks associated with of the presence of PTMs in crop grains, thereby contributing to human health protection. These findings highlighted the essential role of biochar in remediating PTM-contaminated lands and offered guidelines for enhancing safe crop production.

DNA topoisomerase II inhibition potentiates osimertinib's therapeutic efficacy in EGFR-mutant non-small cell lung cancer models.

Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo IIα levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo IIα. Increased Topo IIα levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.

Clay-based 1D-2D halloysite&g-C3N4 nanostructured meat floss for photocatalytic hydrogen evolution.

Graphitic carbon nitride (g-C3N4) has drawn extensive attention with some features including visible-light response as non-metallic semiconductor, low cost in raw material and green pollution-free for environment, but suffers from some issues such as fast charge carriers' recombination, easy aggregation, etc. In this work, the 1D-2D HNTs&g-C3N4-X binary materials similar to meat floss pattern in a series of halloysite loading amounts are designed via a facile electrostatic self-assembly strategy with debris g-C3N4 after cell pulverizing treatment and HNTs that outwardly modified by cetyltrimethylammonium bromide (CTAB) as the building blocks. The halloysite-mediated satellite-core material displays a photocatalytic of H2 evolution performance with the highest evolution rate of 137.0 µmol g-1 h-1 in visible light condition with no co-catalysts, and is ∼3.4 times that of bulk g-C3N4, mainly benefiting from the reduced nanometer size of debris g-C3N4 and enhanced interface dispersion ability by HNTs, resulting in ameliorative separation efficiency of photogenerated charge carriers. This research conclusively provides the new perspective towards the performance enhancement of water splitting of g-C3N4 in raw clay mineral modification mode and broadens the applications of mineral-based composite in the renewable energy utilization field.

Taking early preventive interventions to manage the challenging issue of acquired resistance to third-generation EGFR inhibitors.

Although the clinical efficacies of third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as osimertinib in the treatment of non-small cell lung cancer (NSCLC) with EGFR-activating mutations are promising, drug-acquired resistance inevitably occurs whether they are used as first-line or second-line treatment. Therefore, managing the acquired resistance to third-generation EGFR-TKIs is crucial in the clinic for improving patient survival. Great efforts have been made to develop potentially effective strategies or regimens for the treatment of EGFR-mutant NSCLC patients after relapse following these TKIs therapies with the hope that patients will continue to benefit from treatment through overcoming acquired resistance. Although this approach, which aims to overcome drug-acquired resistance, is necessary and important, it is a passive practice. Taking preventive action early before disease progression to manage the unavoidable development of acquired resistance offers an equally important and efficient approach. We strongly believe that early preventive interventions using effective and tolerable combination regimens that interfere with the process of developing acquired resistance may substantially improve the outcomes of EGFR-mutant NSCLC treatment with third-generation EGFR-TKIs. Thus, this review focuses on discussing the scientific rationale and mechanism-driven strategies for delaying and even preventing the emergence of acquired resistance to third-generation EGFR-TKIs, particularly osimertinib.

Effects of four amendments on cadmium and arsenic immobilization and their exposure risks from pakchoi consumption.

Exposure to heavy metal(loid)s (HM) through contaminated food chains poses significant health risks to humans. While soil amendments are known to reduce HM bioavailability, their effects on bioaccessibility and health risks in soil-pakchoi-human systems remain unclear. To address this knowledge gap, we conducted a greenhouse pot experiment coupling soil immobilization with bioaccessibility-based health risk assessment for Cd and As exposure from pakchoi consumption. Four amendments (attapulgite, shell powder, nanoscale zero-valent iron, and biochar) were applied to soil, resulting in changes to soil characteristics (pH and organic matter), plant dry weight, and exchangeable fractions of As and Cd. Among the tested amendments, biochar exhibited the highest effectiveness in reducing the risk of Cd and As exposure from pakchoi consumption. The bioaccessibility-based health risk assessment revealed that the application of 5% biochar resulted in the lowest hazard index, significantly decreasing it from 1.36 to 0.33 in contaminated soil. Furthermore, the structural equation model demonstrated that pH played a critical role in influencing remediation efficiency, impacting the exposure of the human body to Cd and As. In conclusion, our study offers a new perspective on mitigating exposure risks of soil HM and promoting safe crop production. The results underscore the importance of considering bioaccessibility in health risk assessment and highlight the potential of biochar as a promising amendment for reducing Cd and As exposure from pakchoi consumption.

ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant lung cancer cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression.

The successful treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which are approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which functions as a pro-apoptotic protein that transduces TRAIL death signaling to trigger apoptosis. DR4 expression is positively regulated by MEK/ERK signaling and thus can be downregulated by MEK/ERK inhibition. This study thus focused on determining the effects of AKL-TKIs on DR4 expression and the underlying mechanisms. Three tested ALK-TKIs including APG-2449, brigatinib and alectinib effectively and preferentially inhibited Akt/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. This was also true for DR4 downregulation, which occurred even at 2 h post treatment. These ALK-TKIs did not affect DR4 protein stability, rather decreased DR4 mRNA expression. In parallel, they promoted degradation and reduced the levels of Fra-1 and c-Jun, two critical components of AP-1, and suppressed AP-1 (Fra-1/c-Jun)-dependent transcription/expression of DR4. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation of the biological significance of DR4 downregulation in ALK-targeted cancer therapy.

Microplastics may increase the environmental risks of Cd via promoting Cd uptake by plants: A meta-analysis.

Microplastics (MPs) and cadmium (Cd) are widely distributed in soil ecosystems, posing a potential threat to agricultural production and human health. However, the coupled effects of MPs and Cd in soil-plant systems remain largely unknown, especially on a large scale. In this study, a meta-analysis was conducted to evaluate the influence of MPs on plant growth and Cd accumulation under the Cd contamination conditions. Our results showed that MPs had significantly negative effects on shoot biomass (a decrease of 11.8 %) and root biomass (a decrease of 8.79 %). MPs also significantly increased Cd accumulation in the shoots and roots by 14.6 % and 13.5 %, respectively, revealing that MPs promote plant Cd uptake. Notably, polyethylene displayed a stronger promoting effect (an increase of 29.4 %) on Cd accumulation among these MP types. MPs induced a significantly increase (9.75 %) in concentration of soil available Cd and a slight decrease in soil pH, which may be the main driver promoting plant Cd uptake. MP addition posed physiological toxicity risks to plants by inhibiting photosynthesis and enhancing oxidative damage, directly demonstrating that MPs in combination with Cd can pose synergetic toxicity risks to plants. We further noted that MPs altered microbial diversity, likely influencing Cd bioavailability in soil-plant systems. Overall, our study has important implications for the combined impacts of Cd and MPs on plants and provides new insights into developing guidelines for the sustainable use of MPs in agriculture.

Design and preparation of highly active TiO2 photocatalysts by modulating their band structure.

Titanium dioxide photocatalysts with high reduction potential and visible light response hold great promise in photochemical conversion. Here, we used a simple glycine doping method to synthesize novel N-TiO2@C photocatalysts with upward shifted conduction bands and narrowed band gaps as well as inhibited recombination of photoinduced electron-hole pairs. The N-TiO2@C photocatalysts exhibited higher visible light response and remarkably enhanced photocatalytic activity in the production of nicotinamide adenine dinucleotide (NADH) by photomediated reduction of NAD+ without any electron mediator. The yield of NADH was up to 70.3 % far greater than that of the undoped TiO2 (11.3 %), and it stabilized at ca. 60 % after 10 cycles. The viability of coupling NADH regeneration with enzymatic reaction (alcohol dehydrogenase) was established in aldehyde reduction where formaldehyde was specifically reduced to methanol. These findings shed new light on the modulation of the band structure of semiconductors and develop an electron mediator free strategy for NADH-dependent artificial photosynthesis through coupled photocatalytic and enzymatic approaches.

A multi-trait GWAS-based genetic association network controlling soybean architecture and seed traits.

Ideal plant architecture is essential for enhancing crop yields. Ideal soybean (Glycine max) architecture encompasses an appropriate plant height, increased node number, moderate seed weight, and compact architecture with smaller branch angles for growth under high-density planting. However, the functional genes regulating plant architecture are far not fully understood in soybean. In this study, we investigated the genetic basis of 12 agronomic traits in a panel of 496 soybean accessions with a wide geographical distribution in China. Analysis of phenotypic changes in 148 historical elite soybean varieties indicated that seed-related traits have mainly been improved over the past 60 years, with targeting plant architecture traits having the potential to further improve yields in future soybean breeding programs. In a genome-wide association study (GWAS) of 12 traits, we detected 169 significantly associated loci, of which 61 overlapped with previously reported loci and 108 new loci. By integrating the GWAS loci for different traits, we constructed a genetic association network and identified 90 loci that were associated with a single trait and 79 loci with pleiotropic effects. Of these 79 loci, 7 hub-nodes were strongly linked to at least three related agronomic traits. qHub_5, containing the previously characterized Determinate 1 (Dt1) locus, was associated not only with plant height and node number (as determined previously), but also with internode length and pod range. Furthermore, we identified qHub_7, which controls three branch angle-related traits; the candidate genes in this locus may be beneficial for breeding soybean with compact architecture. These findings provide insights into the genetic relationships among 12 important agronomic traits in soybean. In addition, these studies uncover valuable loci for further functional gene studies and will facilitate molecular design breeding of soybean architecture.

Multiplexed protein profiling reveals spatial subcellular signaling networks.

Protein-protein interaction networks are altered in multi-gene dysregulations in many disorders. Image-based protein multiplexing sheds light on signaling pathways to dissect cell-to-cell heterogeneity, previously masked by the bulk assays. Herein, we present a rapid multiplexed immunofluorescence (RapMIF) method measuring up to 25-plex spatial protein maps from cultures and tissues at subcellular resolution, providing combinatorial 272 pairwise and 1,360 tri-protein signaling states across 33 multiplexed pixel-level clusters. The RapMIF pipeline automated staining, bleaching, and imaging of the biospecimens in a single platform. RapMIF showed that WNT/ß-catenin signaling upregulated upon the inhibition of the AKT/mTOR pathway. Subcellular protein images demonstrated translocation patterns, spatial receptor discontinuity, and subcellular signaling clusters in single cells. Signaling networks exhibited spatial redistribution of signaling proteins in drug-responsive cultures. Machine learning analysis predicted the phosphorylated ß-catenin expression from interconnected signaling protein images. RapMIF is an ideal signaling discovery approach for precision therapy design.

Response to osimertinib plus trametinib in a heavily treated epidermal growth factor receptor (EGFR)-positive NSCLC harboring a rare, acquired rapidly accelerated fibrosarcoma B-type (BRAF) p.D594N mutation: a case report.

Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEK/ERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors.

A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations, in order to achieve maximal response duration or treatment remission. Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment. Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy. It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs, particularly osimertinib, to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance. Hence, restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.

Therapeutic potential of the novel Bcl-2/Bcl-XL dual inhibitor, APG1252, alone or in combination against non-small cell lung cancer.

Targeting the induction of apoptosis is a promising cancer therapeutic strategy with some clinical success. This study focused on evaluating the therapeutic efficacy of the novel Bcl-2/Bcl-XL dual inhibitor, APG1252-M1 (also named APG-1244; an in vivo active metabolite of APG1252 or pelcitoclax), as a single agent or in combination, against non-small cell lung cancer (NSCLC) cells. APG1252-M1 effectively decreased the survival of some NSCLC cell lines expressing low levels of Mcl-1 and induced apoptosis. Overexpression of ectopic Mcl-1 in the sensitive cells substantially compromised APG1252-M1's cell-killing effects, whereas inhibition of Mcl-1 greatly sensitized insensitive cell lines to APG1252-M1, indicating the critical role of Mcl-1 levels in impacting cell response to APG1252-M1. Moreover, APG1252-M1, when combined with the third generation epidermal growth factor receptor (EGFR) inhibitor, osimertinib, synergistically decreased the survival of EGFR-mutant NSCLC cell lines including those resistant to osimertinib with enhanced induction of apoptosis and abrogated emergence of acquired resistance to osimertinib. Importantly, the combination was effective in inhibiting the growth of osimertinib-resistant tumors in vivo. Collectively, these results demonstrate the efficacy of APG1252 alone or in combination against human NSCLC cells.

Brassinosteroids promote thermotolerance through releasing BIN2-mediated phosphorylation and suppression of HsfA1 transcription factors in Arabidopsis.

High temperature adversely affects plant growth and development. The steroid phytohormones brassinosteroids (BRs) are recognized to play important roles in plant heat stress responses and thermotolerance, but the underlying mechanisms remain obscure. Here, we demonstrate that the glycogen synthase kinase 3 (GSK3)-like kinase BRASSINOSTEROID INSENSITIVE2 (BIN2), a negative component in the BR signaling pathway, interacts with the master heat-responsive transcription factors CLASS A1 HEAT SHOCK TRANSCRIPTION FACTORS (HsfA1s). Furthermore, BIN2 phosphorylates HsfA1d on T263 and S56 to suppress its nuclear localization and inhibit its DNA-binding ability, respectively. BR signaling promotes plant thermotolerance by releasing the BIN2 suppression of HsfA1d to facilitate its nuclear localization and DNA binding. Our study provides insights into the molecular mechanisms by which BRs promote plant thermotolerance by strongly regulating HsfA1d through BIN2 and suggests potential ways to improve crop yield under extreme high temperatures.