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The rapid emergence of resistance in plant pathogens to the limited number of chemical classes of fungicides challenges sustainability and profitability of crop production worldwide. Understanding mechanisms underlying fungicide resistance facilitates monitoring of resistant populations at large-scale, and can guide and accelerate the development of novel fungicides. A majority of modern fungicides act to disrupt a biochemical function via binding a specific target protein in the pathway. While target-site based mechanisms such as alternation and overexpression of target genes have been commonly found to confer resistance across many fungal species, it is not uncommon to encounter resistant phenotypes without altered or overexpressed target sites. However, such non-target site mechanisms are relatively understudied, due in part to the complexity of the fungal genome network. This type of resistance can oftentimes be transient and noninheritable, further hindering research efforts. In this review, we focused on crop pathogens and summarized reported mechanisms of resistance that are otherwise related to target-sites, including increased activity of efflux pumps, metabolic circumvention, detoxification, standing genetic variations, regulation of stress response pathways, and single nucleotide polymorphisms (SNPs) or mutations. In addition, novel mechanisms of drug resistance recently characterized in human pathogens are reviewed in the context of nontarget-directed resistance.

This study advances the inclusive wealth accounting of human capital (HC) to improve global research on the valuation of HC for sustainability. By innovatively integrating complex population dynamics, including schooling and labor force participation, and using a net present value (NPV) valuation method aligned with capital budgeting principles, we quantitatively measure HC in 165 countries. As a methodological advancement, we use a unified framework that incorporates education, health and economic participation via the measurement of life expectancy in different life stages to inform sustainable development investments. Our analysis from 1990 to 2020 reveals significant differences in HC development across countries. While education is strongly correlated with GDP growth, disparities in health and economic participation are critical barriers to long-term HC accumulation. Our findings argue for a comprehensive policy approach that goes beyond investing in education for its financial benefits and includes substantial improvements in health and economic opportunities to promote more equitable HC growth. We emphasize the need to incorporate complex population dynamics into HC assessments to better understand and strengthen the interdependencies between these critical factors, with the aim of reducing global development gaps.

Lipid metabolism is widely reprogrammed in tumor cells. Lipid droplet is a common organelle existing in most mammal cells, and its complex and dynamic functions in maintaining redox and metabolic balance, regulating endoplasmic reticulum stress, modulating chemoresistance, and providing essential biomolecules and ATP have been well established in tumor cells. The balance between lipid droplet formation and catabolism is critical to maintaining energy metabolism in tumor cells, while the process of energy metabolism affects various functions essential for tumor growth. The imbalance of synthesis and catabolism of fatty acids in tumor cells leads to the alteration of lipid droplet content in tumor cells. Diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2, the enzymes that catalyze the final step of triglyceride synthesis, participate in the formation of lipid droplets in tumor cells and in the regulation of cell proliferation, migration and invasion, chemoresistance, and prognosis in tumor. Several diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 inhibitors have been developed over the past decade and have shown anti-tumor effects in preclinical tumor models and improvement of metabolism in clinical trials. In this review, we highlight key features of fatty acid metabolism and different paradigms of diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 activities on cell proliferation, migration, chemoresistance, and prognosis in tumor, with the hope that these scientific findings will have potential clinical implications.

Background Traumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI. Methods We employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood–brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, sensorimotor function and cognitive function were assessed by a battery of behavioral tests. Results The activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI. Conclusion ASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI. Highlights This study highlights the critical role of ASK1-K716’s site in regulating ASK1 activity during TBI. ASK1-K716R enhances BBB integrity by inhibiting ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. ASK1-K716R suppresses the infiltration of peripheral immune cells and attenuates microglia-mediated neuroinflammation following TBI. ASK1-K716R mitigates white matter injury and facilitates the long-term recovery of neurological function following TBI.

Measuring a country’s sustainable development by its gross domestic product (GDP) is insufficient to capture the loss of capital that determines future human welfare. To address this, we propose the inclusive wealth index, which integrates biophysical quantities and monetary values of natural, human, and produced capital. We analyzed the level of Inclusive Wealth in 163 countries over the past 30 years to assess sustainable development goals (SDGs) going beyond GDP. Global wealth has suffered significant losses in natural capital, with the biased accumulation of capital assets leading to unsustainable and unequal development. In low-income countries, soaring population levels and biased capital investments exacerbate the depletion of natural capital. Our results underscore the critical role of natural capital and inclusive capital management in sustainable development. Policymakers can use this information to make capital investments in their economies and promote recovery from COVID-19 that aligns with the SDGs, the Paris Climate Agreement, and initiatives beyond GDP.

Spinal cord injury (SCI) is a severe neurological disorder, with glucocorticoids like methylprednisolone commonly used for treatment. However, their efficacy and risks remain controversial. Programmed cell death (PCD) mechanisms have been increasingly implicated in SCI pathology. This study aimed to identify differentially expressed genes (DEGs) related to glucocorticoid receptors and PCD and to construct a diagnostic model to guide glucocorticoid use in SCI treatment. SCI datasets (GSE5296, GSE47681, GSE151371, and GSE45550) were analyzed using protein-protein interaction networks, consensus clustering, GSVA for PCD pathway enrichment, and WGCNA. A total of 113 diagnostic models were developed through 12 machine learning algorithms, with the optimal model, “Lasso + Stepglm[both],” featuring six genes: Abca1, Cdh1, Glipr1, Glt8d2, Il10ra, and Pde5a. Validation through qRT-PCR confirmed the differential expression of four genes (Abca1, Glipr1, Il10ra, and Cdh1), which demonstrated strong predictive performance. Pathway enrichment of GRRDEGs was analyzed using GO, KEGG, and Bayesian network methods, and immune cell infiltration was assessed via CIBERSORT. In this study, we identified GR- and PCD-related DEGs in SCI and constructed a diagnostic model that may improve understanding of SCI molecular mechanisms and inform future investigations of glucocorticoid use.

Background Homocysteine (HCY) is a sulfur-containing amino acid that is an independent or important risk factor for the occurrence of many chronic diseases and is one of the most important indicators for determining health risks. However, existing HCY detection methods do not meet the requirements of clinical diagnosis. Therefore, there is an urgent need to establish new detection methods to meet the needs of clinical detection. Results In this study, we used the principle of competitive method to establish a new method for the determination of HCY in human serum using a chemiluminescent enzyme immunoassay in conjunction with a chemiluminescent assay instrument that uses magnetic microparticles as the solid phase of the immunoreaction. The established method achieved satisfactory results in terms of minimum detection limit, specificity, accuracy, and clinical application. The limit of detection was 0.03 ng/mL. The intra-assay coefficient of variation (CV) was 1.94–5.05%, the inter-assay CV was 2.29–6.88%, and the recovery rate was 88.60–93.27%. Cross-reactivity with L-cysteine ranged from 0.0100 to 0.0200 μmol/L, and cross-reactivity with glutathione ranged from 0.0100 to 0.200 μmol/L, all of which were less than the limit of detection (LoD) of this method. The linear factor R of this method was greater than 0.99. Conclusions In summary, the developed method showed a good correlation with the product from Abbott. A total of 996 clinical patients with cardiovascular diseases were evaluated using the method developed in this study.

Patients with colorectal cancer (CRC) carrying KRAS mutations face a challenging prognosis, especially due to their reduced response to EGFR inhibitor therapies. Despite the use of drugs targeting the KRAS G12C mutation, the KRAS G12V mutation is more common in CRC, and unfortunately, there are currently no effective targeted treatments for it. Our study shows that patients harboring KRAS G12V mutation often have larger tumors, increased lymph node metastasis, elevated EGFR expression, and a tendency for right-sided colon tumors. This indicates distinct clinical and pathological traits in CRC patients with KRAS G12V . Cellular studies reveal increased proliferation and decreased cell apoptosis in KRAS G12V CRC cells. Bioinformatics analysis revealed a notable decrease of aquaporin 9 (AQP9) in KRAS G12V CRC, confirmed by immunohistochemistry and Western blot tests. These tests showed a consistent AQP9 decrease in tissue and cell samples, linked to an increased risk of lymph node metastasis in patients with low AQP9. Importantly, AQP9 overexpression was found to hinder CRC cell proliferation and encourage apoptosis, thereby implying a potential therapeutic role for AQP9 modulation. Our study finds a link between ZHX2 and AQP9 in CRC cells, confirmed by histopathological and in vitro evidence. Increased ZHX2 expression elevates AQP9 levels, reduces CRC cell growth, and boosts apoptosis. CO-IP experiments further prove the interaction between ZHX2 and AQP9 proteins. Molecular docking studies reveal that ZHX2 can form stable complexes with AQP9, involving multiple residues. This research enhances our understanding of the molecular mechanisms regulating the growth and death of KRAS G12V CRC cells, paving the way for new therapeutic strategies.

Photodynamic therapy (PDT), sonodynamic therapy (SDT), and oxaliplatin (OXP) can induce immunogenic cell death (ICD) following damage-associated molecular patterns (DAMPs) exposure or release and can be united via the use of nanoplatforms to deliver drugs that can impart anti-tumor effects. The aim of this study was to develop phase-transition nanoparticles (OI_NPs) loaded with perfluoropentane (PFP), indocyanine green (ICG), and oxaliplatin (OXP), to augment anti-tumor efficacy and the immunological effects of chemotherapy, photodynamic therapy and sonodynamic therapy (PSDT). OI_NPs were fabricated by a double emulsion method and a range of physicochemical and dual-modal imaging features were characterized. Confocal microscopy and flow cytometry were used to determine the cellular uptake of OI_NPs by ID8 cells. The viability and apoptotic rate of ID8 cells were investigated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. Flow cytometry, Western blotting, and luminometric assays were then used to investigate the exposure or release of crucial DAMPs such as calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine-5'-triphosphate (ATP). Tumor rechallenge experiments were then used to investigate whether treated ID8 cells underwent ICD. Finally, cytotoxic T lymphocyte (CTL) activity was determined by a lactate dehydrogenase (LDH) assay. Spherical OI_NPs were able to carry OXP, ICG and PFP and were successfully internalized by ID8 cells. The application of OI_NPs significantly enhanced the phase shift ability of PFP and the optical characteristics of ICG, thus leading to a significant improvement in photoacoustic and ultrasonic imaging. When combined with near-infrared light and ultrasound, the application of OI_NPs led to improved anti-tumor effects on cancer cells, and significantly enhanced the expression of DAMPs, thus generating a long-term anti-tumor effect. The application of OI_NPs, loaded with appropriate cargo, may represent a novel strategy with which to increase anti-tumor effects, enhance immunological potency, and improve dual-mode imaging.

The TGF-β1/Smad3-signaling pathway and gender differences were investigated in alcoholic liver fibrosis. Mice were divided into female normal, female model, male normal, and male model groups. Liver injury and fibrosis were assessed using histopathology and serology. Western blotting was performed to analyze the expression of relevant factors. HSC-T6 cells were divided into estradiol + saline, estradiol + ethanol, testosterone + saline, and testosterone + ethanol groups, and similar assessments were conducted in vitro. Compared with the female model group, the male model group exhibited significantly increased GPT, GOT, TNF-α, IL-6, and testosterone levels, fibrosis rate, and TGF-β1, Smad3, and PCNA expression, and significantly decreased estradiol levels and Caspase-3 expression. The apoptosis rate was higher in the estradiol + ethanol group than in the testosterone + ethanol group, although the testosterone + ethanol group exhibited significantly increased TNF-α, IL-6, Collagen-I, α-SMA, TGF-β1, Smad3, and PCNA expression, and significantly decreased Caspase-3 expression. Alcoholic liver fibrosis showed significant gender differences associated with the TGF-β1/Smad3-signaling pathway.