Combined and rapid detection of anti-Brucella IgG/IgM in clinical samples based on surface-enhanced Raman scattering-lateral flow immunochromatography.

Brucellosis is a bacterial infectious disease caused mainly by Brucella. Transmission is mainly by contact with infected domestic or wild animals or their excreta. Clinical diagnosis of brucellosis is usually based on qualitative total antibody tests, which make it difficult to differentiate between acute and pre-existing infections. In this study, for the simultaneous detection of anti-brucellosis IgG and IgM, we innovatively developed a surface-enhanced Raman scattering (SERS)-lateral flow immunoassay (LFIA) detection system, and evaluated its performance and diagnostic effect by using clinical serum samples. The key design of this biosensor involves the preparation of two immunoprobes using two Raman spheres (R-Sphere) with distinct signals conjugated to mouse anti-human IgG and IgM, respectively. In this design, brucellosis-specific antigens are embedded in the T-line, allowing simultaneous capture of anti-brucellosis IgG and IgM in a specific binding reaction. A portable Raman instrument is used to detect the characteristic signal intensities generated by IgM and IgG on the T-line, which can then be used to analyze the target IgM and IgG antibodies. Based on the analysis of 40 clinical samples, the method has a sensitivity and specificity of 100%, and the detection time is only 15 min. The advantages of this technology are fast speed, convenient use, high sensitivity, and it can distinguish the disease course to achieve precise treatment. These features make it an ideal solution for large-scale brucellosis testing in remote and nomadic areas, where it can play a crucial role in improving public health protection.

A Spatiotemporal Transcriptome Reveals Stalk Development in Pearl Millet.

Pearl millet is a major cereal crop that feeds more than 90 million people worldwide in arid and semi-arid regions. The stalk phenotypes of Poaceous grasses are critical for their productivity and stress tolerance; however, the molecular mechanisms governing stalk development in pearl millet remain to be deciphered. In this study, we spatiotemporally measured 19 transcriptomes for stalk internodes of four different early developmental stages. Data analysis of the transcriptomes defined four developmental zones on the stalks and identified 12 specific gene sets with specific expression patterns across the zones. Using weighted gene co-expression network analysis (WGCNA), we found that two co-expression modules together with candidate genes were involved in stalk elongation and the thickening of pearl millet. Among the elongation-related candidate genes, we established by SELEX that a MYB-family transcription factor PMF7G02448 can bind to the promoters of three cell wall synthases genes (CesAs). In summary, these findings provide insights into stalk development and offer potential targets for future genetic improvement in pearl millet.

Whole genome regulatory effect of MoISW2 and consequences for the evolution of the rice plant pathogenic fungus Magnaporthe oryzae.

Isw2 proteins, ubiquitous across eukaryotes, exhibit a propensity for DNA binding and exert dynamic influences on local chromosome condensation in an ATP-dependent fashion, thereby modulating the accessibility of neighboring genes to transcriptional machinery. Here, we report the deletion of a putative MoISW2 gene, yielding substantial ramifications on plant pathogenicity. Subsequent gene complementation and chromatin immunoprecipitation sequencing (ChIP-seq) analyses were conducted to delineate binding sites. RNA sequencing (RNA-seq) assays revealed discernible impacts on global gene regulation along chromosomes in both mutant and wild-type strains, with comparative analyses against 55 external RNA-seq data sets corroborating these findings. Notably, MoIsw2-mediated binding and activities delineate genomic loci characterized by pronounced gene expression variability proximal to MoIsw2 binding sites, juxtaposed with comparatively stable expression in surrounding regions. The contingent genes influenced by MoIsw2 activity predominantly encompass niche-determinant genes, including those encoding secreted proteins, secondary metabolites, and stress-responsive elements, alongside avirulence genes. Furthermore, our investigations unveil a spatial correlation between MoIsw2 binding motifs and known transposable elements (TEs), suggesting a potential interplay wherein TE transposition at these loci could modulate the transcriptional landscape of Magnaporthe oryzae in a strain-specific manner. Collectively, these findings position MoIsw2 as a plausible master regulator orchestrating the delicate equilibrium between genes vital for biomass proliferation, akin to housekeeping genes, and niche-specific determinants crucial for ecological adaptability. Stress-induced TE transposition, in conjunction with MoIsw2 activity, emerges as a putative mechanism fostering enhanced mutagenesis and accelerated evolution of niche-determinant genes relative to housekeeping counterparts.IMPORTANCEIsw2 proteins are conserved in plants, fungi, animals, and other eukaryotes. We show that a fungal Isw2 protein in the rice pathogen Magnaporthe oryzae binds to retrotransposon (RT) DNA motifs and affects the epigenetic gene expression landscape of the fungal genome. Mainly ecological niche determinant genes close to the binding motifs are affected. RT elements occur frequently in DNA between genes in most organisms. They move place and multiply in the genome, especially under physiological stress. We further discuss the Isw2 and RT combined activities as a possible sought-after mechanism that can cause biased mutation rates and faster evolution of genes necessary for reacting to abiotic and biotic challenges. The most important biotic challenges for plant pathogens are the ones from the host plants' innate immunity. The overall result of these combined activities will be an adaptation-directed evolution of niche-determinant genes.

Glycopolymeric Micellar Nanoparticles for Platelet-Mediated Tumor-Targeted Delivery of Docetaxel for Cancer Therapy.

The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.

A novel Pik allele confers extended resistance to rice blast.

In the ongoing arms race between rice and Magnaporthe oryzae, the pathogen employs effectors to evade the immune response, while the host develops resistance genes to recognise these effectors and confer resistance. In this study, we identified a novel Pik allele, Pik-W25, from wild rice WR25 through bulked-segregant analysis, creating the Pik-W25 NIL (Near-isogenic Lines) named G9. Pik-W25 conferred resistance to isolates expressing AvrPik-C/D/E alleles. CRISPR-Cas9 editing was used to generate transgenic lines with a loss of function in Pik-W25-1 and Pik-W25-2, resulting in loss of resistance in G9 to isolates expressing the three alleles, confirming that Pik-W25-induced immunity required both Pik-W25-1 and Pik-W25-2. Yeast two-hybrid (Y2H) and split luciferase complementation assays showed interactions between Pik-W25-1 and the three alleles, while Pik-W25-2 could not interact with AvrPik-C, -D, and -E alleles with Y2H assay, indicating Pik-W25-1 acts as an adaptor and Pik-W25-2 transduces the signal to trigger resistance. The Pik-W25 NIL exhibited enhanced field resistance to leaf and panicle blast without significant changes in morphology or development compared to the parent variety CO39, suggesting its potential for resistance breeding. These findings advance our knowledge of rice blast resistance mechanisms and offer valuable resources for effective and sustainable control strategies.

A mechanistic analysis of metformin's biphasic effects on lifespan and healthspan in C. elegans: Elixir in youth, poison in elder.

Aging, a complex biological process influenced by genetic, environmental, and pharmacological factors, presents a significant challenge in understanding its underlying mechanisms. In this study, we explored the divergent impacts of metformin treatment on the lifespan and healthspan of young and old C. elegans, demonstrating a intriguing "elixir in youth, poison in elder" phenomenon. By scrutinizing the gene expression changes in response to metformin in young (day 1 of adulthood) and old (days 8) groups, we identified nhr-57 and C46G7.1 as potential modulators of age-specific responses. Notably, nhr-57 and C46G7.1 exhibit contrasting regulation patterns, being up-regulated in young worms but down-regulated in old counterparts following metformin treatment. Functional studies employing knockdown approaches targeting nhr-57, a gene under the control of hif-1 with a documented protective function against pore-forming toxins in C. elegans, and C46G7.1, unveiled their critical roles in modulating lifespan and healthspan, as well as in mediating the biphasic effects of metformin. Furthermore, deletion of hif-1 retarded the influence of metformin, implicating the involvement of hif-1/nhr-57 in age-specific drug responses. These findings underscored the necessity of deciphering the mechanisms governing age-related susceptibility to pharmacological agents to tailor interventions for promoting successful aging.

Differential impacts of nonsteroidal anti-inflammatory drugs on lifespan and healthspan in aged Caenorhabditis elegans.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

Magnaporthe oryzae Effector AvrPik-D Targets Rice Rubisco Small Subunit OsRBCS4 to Suppress Immunity.

Rice blast, caused by the fungal pathogen Magnaporthe oryzae (M. oryzae), is a highly destructive disease that significantly impacts rice yield and quality. During the infection, M. oryzae secretes effector proteins to subvert the host immune response. However, the interaction between the effector protein AvrPik-D and its target proteins in rice, and the mechanism by which AvrPik-D exacerbates disease severity to facilitate infection, remains poorly understood. In this study, we found that the M. oryzae effector AvrPik-D interacts with the Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase) small subunit OsRBCS4. The overexpression of the OsRBCS4 gene in transgenic rice not only enhances resistance to M. oryzae but also induces more reactive oxygen species following chitin treatment. OsRBCS4 localizes to chloroplasts and co-localizes with AvrPik-D within these organelles. AvrPik-D suppresses the transcriptional expression of OsRBCS4 and inhibits Rubisco activity in rice. In conclusion, our results demonstrate that the M. oryzae effector AvrPik-D targets the Rubisco small subunit OsRBCS4 and inhibits its carboxylase and oxygenase activity, thereby suppressing rice innate immunity to facilitate infection. This provides a novel mechanism for the M. oryzae effector to subvert the host immunity to promote infection.

A combined nanotherapeutic approach targeting farnesoid X receptor, ferroptosis, and fibrosis for nonalcoholic steatohepatitis treatment.

Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist with favorable effects on fatty and glucose metabolism, has been considered the leading candidate drug for nonalcoholic steatohepatitis (NASH) treatment. However, its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback. Ferroptosis, a newly recognized form of cell death characterized by uncontrolled lipid peroxidation, is involved in the progression of NASH. Nitric oxide (NO) is a versatile biological molecule that can degrade extracellular matrix. In this study, we developed a PEGylated thiolated hollow mesoporous silica nanoparticles (MSN) loaded with OCA, as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol (ONL@MSN). Biochemical analyses, histology, multiplexed flow cytometry, bulk-tissue RNA sequencing, and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle (ONL@MSN) in a mouse NASH model. Compared with the OCA-loaded nanoparticles (O@MSN), ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis. ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis, inhibition of immune response/lipid peroxidation, and correction of microbiota dysbiosis. These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR, ferroptosis, and fibrosis.

sCD155 as a potential marker for diagnosing the vascular invasion in hepatic alveolar echinococcosis.

BACKGROUND: Alveolar Echinococcosis (AE) is a malignant zoonotic disease caused by Echinococcus multilocularis infection. Considering whether the lesion is accompanied by vascular invasion (VI) is crucial for treatment strategies. A cost-effective and convenient clinical diagnostic method is urgently needed to supplement current techniques. Consequently, we detected soluble CD155 (sCD155) as a potential biomarker for diagnosing VI in hepatic alveolar echinococcosis (HAE). METHODS: Blood samples were from 42 AE patients and 49 healthy controls (HCs). Based on the computed tomography (CT) and contrast-enhanced CT, AE patients were further categorized into HAE with VI (VIAE; 27 cases) and HAE without VI (NVAE; 15 cases). The sCD155 concentration was measured by an enzyme-linked immunosorbent assay (ELISA). Correlations between sCD155 expression levels and clinicopathological features of AE patients were analyzed using SPSS and GraphPad Prism software. RESULTS: The sCD155 concentrations in AE patients were significantly higher than in HCs. The serum sCD155 level significantly differed between the VIAE and NVAE groups. The univariate analysis showed that VI of AE was significantly correlated with the sCD155 level when the sCD155 was greater than 11 ng/mL. After adjusting for potential confounding factors, the multivariable analysis showed that sCD155 had an independent effect on VI of HAE. The receiver operating characteristic (ROC) curve showed that sCD155 could differentially diagnose VI of HAE at the cut-off value of 11.08 ng/mL with an area under the curve (AUC) value of 0.75. The sensitivity and specificity were 74.07 % and 66.67 %, respectively; the positive and negative predictive values were 74.07 % and 60.00 %, respectively. CONCLUSION: The sCD155 could be a VI biomarker for HAE. Elevated sCD155 levels are indicative of an increased likelihood of concomitant VI in HAE patients, necessitating a thorough evaluation of vascular impairment and the formulation of individualized management strategies.

Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

Phosphorylation of Mad1 at serine 18 by Mps1 is required for the full virulence of rice blast fungus, Magnaporthe oryzae.

The spindle assembly checkpoint (SAC) proteins are conserved among eukaryotes safeguarding chromosome segregation fidelity during mitosis. However, their biological functions in plant-pathogenic fungi remain largely unknown. In this study, we found that the SAC protein MoMad1 in rice blast fungus (Magnaporthe oryzae) localizes on the nuclear envelope and is dispensable for M. oryzae vegetative growth and tolerance to microtubule depolymerizing agent treatment. MoMad1 plays an important role in M. oryzae infection-related development and pathogenicity. The monopolar spindle 1 homologue in M. oryzae (MoMps1) interacts with MoMad1 through its N-terminal domain and phosphorylates MoMad1 at Ser-18, which is conserved within the extended N termini of Mad1s from fungal plant pathogens. This phosphorylation is required for maintaining MoMad1 protein abundance and M. oryzae full virulence. Similar to the deletion of MoMad1, treatment with Mps1-IN-1 (an Mps1 inhibitor) caused compromised appressorium formation and decreased M. oryzae virulence, and these defects were dependent on its attenuating MoMad1 Ser-18 phosphorylation. Therefore, our study indicates the function of Mad1 in rice blast fungal pathogenicity and sheds light on the potential of blocking Mad1 phosphorylation by Mps1 to control crop fungal diseases.

Sulfated glyco-based hydrogels as self-healing, adhesive, and anti-inflammatory dressings for wound healing.

Hydrogels have emerged as a new type of wound dressing materials that involved in different stages of the healing processes. However, most of the existing wound dressings mainly offer a protective and moisturizing layer to prevent cross-infection, while the anti-inflammatory and anti-oxidative properties are frequently induced by extra addition of other bioactive molecules. Here, a novel type of sulfated glyco-functionalized hydrogels for wound dressing was prepared through the hybrid supramolecular co-assembly of carbohydrate segments (FG, FGS and FG3S), fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF), and diphenylalanine-dopamine (FFD). Implanting sulfated carbohydrates can mimic the structure of glycosaminoglycans (GAGs), promoting cell proliferation and migration, along with anti-inflammatory effects. In situ polymerization of FFD introduced a secondary covalent network to the hydrogel, meanwhile, providing anti-oxidation and adhesion properties to wound surfaces. Furthermore, the dynamic supramolecular interactions within the hydrogels also confer self-healing capabilities to the wound dressing materials. In vivo experiments further demonstrated significantly accelerated healing rates with the multifunctional hydrogel FG3S-FFD, indicating high application potential.

Comprehensive Analysis of Autophagy-Related Genes in Rice Immunity against Magnaporthe oryzae.

Rice blast disease, caused by the fungus Magnaporthe oryzae, is a significant threat to rice production. Resistant cultivars can effectively resist the invasion of M. oryzae. Thus, the identification of disease-resistant genes is of utmost importance for improving rice production. Autophagy, a cellular process that recycles damaged components, plays a vital role in plant growth, development, senescence, stress response, and immunity. To understand the involvement of autophagy-related genes (ATGs) in rice immune response against M. oryzae, we conducted a comprehensive analysis of 37 OsATGs, including bioinformatic analysis, transcriptome analysis, disease resistance analysis, and protein interaction analysis. Bioinformatic analysis revealed that the promoter regions of 33 OsATGs contained cis-acting elements responsive to salicylic acid (SA) or jasmonic acid (JA), two key hormones involved in plant defense responses. Transcriptome data showed that 21 OsATGs were upregulated during M. oryzae infection. Loss-of-function experiments demonstrated that OsATG6c, OsATG8a, OsATG9b, and OsATG13a contribute to rice blast resistance. Additionally, through protein interaction analysis, we identified five proteins that may interact with OsATG13a and potentially contribute to plant immunity. Our study highlights the important role of autophagy in rice immunity and suggests that OsATGs may enhance resistance to rice blast fungus through the involvement of SA, JA, or immune-related proteins. These findings provide valuable insights for future efforts in improving rice production through the identification and utilization of autophagy-related genes.

Fitness difference between two synonymous mutations of Phytophthora infestans ATP6 gene.

BACKGROUND: Sequence variation produced by mutation provides the ultimate source of natural selection for species adaptation. Unlike nonsynonymous mutation, synonymous mutations are generally considered to be selectively neutral but accumulating evidence suggests they also contribute to species adaptation by regulating the flow of genetic information and the development of functional traits. In this study, we analysed sequence characteristics of ATP6, a housekeeping gene from 139 Phytophthora infestans isolates, and compared the fitness components including metabolic rate, temperature sensitivity, aggressiveness, and fungicide tolerance among synonymous mutations. RESULTS: We found that the housekeeping gene exhibited low genetic variation and was represented by two major synonymous mutants at similar frequency (0.496 and 0.468, respectively). The two synonymous mutants were generated by a single nucleotide substitution but differed significantly in fitness as well as temperature-mediated spatial distribution and expression. The synonymous mutant ending in AT was more common in cold regions and was more expressed at lower experimental temperature than the synonymous mutant ending in GC and vice versa. CONCLUSION: Our results are consistent with the argument that synonymous mutations can modulate the adaptive evolution of species including pathogens and have important implications for sustainable disease management, especially under climate change.

Pharmacological approaches for targeting lysosomes to induce ferroptotic cell death in cancer.

Lysosomes are crucial organelles responsible for the degradation of cytosolic materials and bulky organelles, thereby facilitating nutrient recycling and cell survival. However, lysosome also acts as an executioner of cell death, including ferroptosis, a distinctive form of regulated cell death that hinges on iron-dependent phospholipid peroxidation. The initiation of ferroptosis necessitates three key components: substrates (membrane phospholipids enriched with polyunsaturated fatty acids), triggers (redox-active irons), and compromised defence mechanisms (GPX4-dependent and -independent antioxidant systems). Notably, iron assumes a pivotal role in ferroptotic cell death, particularly in the context of cancer, where iron and oncogenic signaling pathways reciprocally reinforce each other. Given the lysosomes' central role in iron metabolism, various strategies have been devised to harness lysosome-mediated iron metabolism to induce ferroptosis. These include the re-mobilization of iron from intracellular storage sites such as ferritin complex and mitochondria through ferritinophagy and mitophagy, respectively. Additionally, transcriptional regulation of lysosomal and autophagy genes by TFEB enhances lysosomal function. Moreover, the induction of lysosomal iron overload can lead to lysosomal membrane permeabilization and subsequent cell death. Extensive screening and individually studies have explored pharmacological interventions using clinically available drugs and phytochemical agents. Furthermore, a drug delivery system involving ferritin-coated nanoparticles has been specifically tailored to target cancer cells overexpressing TFRC. With the rapid advancements in understandings the mechanistic underpinnings of ferroptosis and iron metabolism, it is increasingly evident that lysosomes represent a promising target for inducing ferroptosis and combating cancer.

Reconstructing Complex Shaped Clothing from a Single Image with Feature Stable Unsigned Distance Fields.

Single-view clothing reconstruction usually relies on topologically fixed clothing templates to reduce the problem complexity, but this strategy also makes the reconstructed clothing shape contours simple and lack diversity. In this paper, we propose a novel clothing reconstruction method to generate complex shape contours and open clothing mesh from a single image. At the heart of our work is an implicit unsigned distance field condition on clothing-oriented and pose-stable spatial shape features to represent the clothing from the image. This feature can provide spatially aligned clothing shape priors to improve the pose robustness. It is based on a type-generic clothing template derived from the mainstream clothing generative model to avoid tedious template design and switching. To output open clothing mesh results from noisy clothing unsigned distance fields, we develop a two-stage clothing mesh extraction method. It takes the point clouds as an intermediate representation and produces smooth, plausible and editable clothing mesh results. To provide effective supervision, we construct a pose-rich and shape-complete clothing scan dataset by enhancing clothing pose diversity and complementing missing clothing geometry caused by occlusion. Extensive experiments demonstrate that our method achieves state-of-the-art levels. More importantly, we provide a simple but effective, and low-cost way to reconstruct complex shape contours clothing from a single image.

Transposable elements impact the population divergence of rice blast fungus Magnaporthe oryzae.

Dynamic transposition of transposable elements (TEs) in fungal pathogens has significant impact on genome stability, gene expression, and virulence to the host. In Magnaporthe oryzae, genome plasticity resulting from TE insertion is a major driving force leading to the rapid evolution and diversification of this fungus. Despite their importance in M. oryzae population evolution and divergence, our understanding of TEs in this context remains limited. Here, we conducted a genome-wide analysis of TE transposition dynamics in the 11 most abundant TE families in M. oryzae populations. Our results show that these TEs have specifically expanded in recently isolated M. oryzae rice populations, with the presence/absence polymorphism of TE insertions highly concordant with population divergence on Geng/Japonica and Xian/Indica rice cultivars. Notably, the genes targeted by clade-specific TEs showed clade-specific expression patterns and are involved in the pathogenic process, suggesting a transcriptional regulation of TEs on targeted genes. Our study provides a comprehensive analysis of TEs in M. oryzae populations and demonstrates a crucial role of recent TE bursts in adaptive evolution and diversification of the M. oryzae rice-infecting lineage. IMPORTANCE: Magnaporthe oryzae is the causal agent of the destructive blast disease, which caused massive loss of yield annually worldwide. The fungus diverged into distinct clades during adaptation toward the two rice subspecies, Xian/Indica and Geng/Japonica. Although the role of TEs in the adaptive evolution was well established, mechanisms underlying how TEs promote the population divergence of M. oryzae remain largely unknown. In this study, we reported that TEs shape the population divergence of M. oryzae by differentially regulating gene expression between Xian/Indica-infecting and Geng/Japonica-infecting populations. Our results revealed a TE insertion-mediated gene expression adaption that led to the divergence of M. oryzae population infecting different rice subspecies.

Inhibition of AMPK activation in Echinococcus granulosus sensu stricto limits the parasite's glucose metabolism and survival.

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by larvae of the Echinococcus granulosus sensu lato (s.l.) cluster. There is an urgent need to develop new drug targets and drug molecules to treat CE. Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a serine/threonine protein kinase consisting of α, ß, and γ subunits, plays a key role in the regulation of energy metabolism. However, the role of AMPK in regulating glucose metabolism in E. granulosus s.l. and its effects on parasite viability is unknown. In this study, we found that targeted knockdown of EgAMPKα or a small-molecule AMPK inhibitor inhibited the viability of E. granulosus sensu stricto (s.s.) and disrupted the ultrastructure. The results of in vivo experiments showed that the AMPK inhibitor had a significant therapeutic effect on E. granulosus s.s.-infected mice and resulted in the loss of cellular structures of the germinal layer. In addition, the inhibition of the EgAMPK/EgGLUT1 pathway limited glucose uptake and glucose metabolism functions in E. granulosus s.s.. Overall, our results suggest that EgAMPK can be a potential drug target for CE and that inhibition of EgAMPK activation is an effective strategy for the treatment of disease.

FvKex2 is required for development, virulence, and mycotoxin production in Fusarium verticillioides.

Fusarium verticillioides is one of the most important fungal pathogens causing maize ear and stalk rots, thereby undermining global food security. Infected seeds are usually unhealthy for consumption due to contamination with fumonisin B1 (FB1) mycotoxin produced by the fungus as a virulence factor. Unveiling the molecular factors that determine fungal development and pathogenesis will help in the control and management of the diseases. Kex2 is a kexin-like Golgi-resident proprotein convertase that is involved in the activation of some important proproteins. Herein, we identified and functionally characterized FvKex2 in relation to F. verticillioides development and virulence by bioinformatics and functional genomics approaches. We found that FvKex2 is required for the fungal normal vegetative growth, because the growth of the ∆Fvkex2 mutant was significantly reduced on culture media compared to the wild-type and complemented strains. The mutant also produced very few conidia with morphologically abnormal shapes when compared with those from the wild type. However, the kexin-like protein was dispensable for the male role in sexual reproduction in F. verticillioides. In contrast, pathogenicity was nearly abolished on wounded maize stalks and sugarcane leaves in the absence of FvKEX2 gene, suggesting an essential role of Fvkex2 in the virulence of F. verticillioides. Furthermore, high-performance liquid chromatography analysis revealed that the ∆Fvkex2 mutant produced a significantly lower level of FB1 mycotoxin compared to the wild-type and complemented strains, consistent with the loss of virulence observed in the mutant. Taken together, our results indicate that FvKex2 is critical for vegetative growth, FB1 biosynthesis, and virulence, but dispensable for sexual reproduction in F. verticillioides. The study presents the kexin-like protein as a potential drug target for the management of the devastating maize ear and stalk rot diseases. Further studies should aim at uncovering the link between FvKex2 activity and FB1 biosynthesis genes. KEY POINTS: •The kexin-like protein FvKex2 contributes significantly to the vegetative growth of Fusarium verticillioides. •The conserved protein is required for fungal conidiation and conidial morphology, but dispensable for sexual reproduction. •Deletion of FvKEX2 greatly attenuates the virulence and mycotoxin production potential of F. verticillioides.