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The catalytic capabilities of metals in degrading azo dyes have garnered extensive interest; however, selecting highly efficient metals remains a significant challenge. We have developed a Zn-Ca-based metallic glass composite which shows outstanding degradation efficiency for Direct Blue 6. This alloy comprises a Zn2Ca crystalline phase and an amorphous matrix, allowing for the degradation of azo dyes within minutes in a wide temperature range of 0-60 °C. Kinetic calculations reveal an exceptionally low activation energy of 8.99 kJ/mol. The rapid degradation is attributed to the active element Ca and the unique amorphous structure of the matrix, which not only facilitates abundant redox conditions but also minimizes the hydrolysis of the active element. The newly developed metallic glass composite exhibits a notably higher azo dye degradation rate compared to those of general metallic glasses, offering a new avenue for the rapid degradation of azo dyes. This paper holds significant importance for the development of novel azo dye wastewater treatment agents.
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Many reports have presented that in tight formation, the flow mechanism differs from a conventional reservoir, such as molecular diffusion, Pre-Darcy flow behavior, and stress sensitivity. However, for CO2 Huff-n-Puff development, it is a challenge to synthetically research these mechanisms. Considering the above flow mechanisms and offshore engineering background, the development plan optimization becomes a key issue. In this paper, a self-developed simulator that satisfies research needs is introduced. Then, based on experimental results, the simulation is launched to analyze the effects of CO2 diffusion, Huff-n-Puff period, and permeability heterogeneity. The results indicate that molecular diffusion makes a positive contribution to the oil recovery factor. Additionally, for offshore reservoirs, limited to the development cost and CO2 facilities corrosion, when the total Huff-n-Puff time is constant, the ratio of 0.5-1.0 between the Huff period and the Puff period in every cycle performs better. Finally, the greater heterogeneity in permeability is much more favorable for the CO2 Huff-n-Puff because of more intensive transport processes in formation. These different scenarios can increase the understanding of the CO2 Huff-n-Puff in tight oil offshore reservoirs.
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The construction of heterojunctions can reduce the energy barrier for the oxygen evolution reaction (OER), which is crucial for the design of efficient electrocatalysts. A novel OER electrocatalyst, composed of g-C3N4-supported NiFeP spherical nanoclusters, was successfully synthesized using a simple hydrothermal method and a gas-phase precipitation method. Benefiting from its unique spherical nanocluster structure and strong electronic interactions among Ni, Fe, and P, the catalyst exhibited outstanding performance under alkaline conditions, with an overpotential of only 232â¯mV at a current density of 10â¯mAâ¯cm-2 and a Tafel slope of 103â¯mV dec-1. Additionally, the electrical resistance of NiFeP/g-C3N4 (Rctâ¯=â¯5.1â¯Ω) was much lower than that of NiFeP (Rctâ¯=â¯10.8â¯Ω) and layered g-C3N4 (Rctâ¯=â¯44.8â¯Ω). The formation of a Schottky barrier heterojunction efficiently reduced electron transfer impedance during the OER process, accelerating the electron transfer from g-C3N4 to NiFeP, enhancing the carrier concentration, and thereby improving the OER activity. Moreover, The robust g-C3N4 chain-mail protects NiFeP from adverse reaction environments, maintaining a balance between catalytic activity and stability. Furthermore, ab initio molecular dynamics (AIMD) and density functional theory (DFT) were conducted to explore the thermal stability and internal electron transfer behavior of the cluster heterojunction structure. This study offers a broader design strategy for the development of transition metal phosphide (TMPs) materials in the oxygen evolution reaction.
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BACKGROUND: Understanding genome organization and evolution is important for species involved in transmission of human diseases, such as mosquitoes. Anophelinae and Culicinae subfamilies of mosquitoes show striking differences in genome sizes, sex chromosome arrangements, behavior, and ability to transmit pathogens. However, the genomic basis of these differences is not fully understood. METHODS: In this study, we used a combination of advanced genome technologies such as Oxford Nanopore Technology sequencing, Hi-C scaffolding, Bionano, and cytogenetic mapping to develop an improved chromosome-scale genome assembly for the West Nile vector Culex quinquefasciatus. RESULTS: We then used this assembly to annotate odorant receptors, odorant binding proteins, and transposable elements. A genomic region containing male-specific sequences on chromosome 1 and a polymorphic inversion on chromosome 3 were identified in the Cx. quinquefasciatus genome. In addition, the genome of Cx. quinquefasciatus was compared with the genomes of other mosquitoes such as malaria vectors An. coluzzi and An. albimanus, and the vector of arboviruses Ae. aegypti. Our work confirms significant expansion of the two chemosensory gene families in Cx. quinquefasciatus, as well as a significant increase and relocation of the transposable elements in both Cx. quinquefasciatus and Ae. aegypti relative to the Anophelines. Phylogenetic analysis clarifies the divergence time between the mosquito species. Our study provides new insights into chromosomal evolution in mosquitoes and finds that the X chromosome of Anophelinae and the sex-determining chromosome 1 of Culicinae have a significantly higher rate of evolution than autosomes. CONCLUSION: The improved Cx. quinquefasciatus genome assembly uncovered new details of mosquito genome evolution and has the potential to speed up the development of novel vector control strategies.
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Aedes , Culex , Animales , Humanos , Masculino , Filogenia , Elementos Transponibles de ADN/genética , Mosquitos Vectores/genética , Culex/genética , Aedes/genética , Cromosomas , Evolución MolecularRESUMEN
The mosquito family Culicidae is divided into 2 subfamilies named the Culicinae and Anophelinae. Nix, the dominant male-determining factor, has only been found in the culicines Aedes aegypti and Aedes albopictus, 2 important arboviral vectors that belong to the subgenus Stegomyia. Here we performed sex-specific whole-genome sequencing and RNAseq of divergent mosquito species and explored additional male-inclusive datasets to investigate the distribution of Nix. Except for the Culex genus, Nix homologs were found in all species surveyed from the Culicinae subfamily, including 12 additional species from 3 highly divergent tribes comprising 4 genera, suggesting Nix originated at least 133 to 165 million years ago (MYA). Heterologous expression of 1 of 3 divergent Nix open reading frames (ORFs) in Ae. aegypti resulted in partial masculinization of genetic females as evidenced by morphology and doublesex splicing. Phylogenetic analysis suggests Nix is related to femaleless (fle), a recently described intermediate sex-determining factor found exclusively in anopheline mosquitoes. Nix from all species has a conserved structure, including 3 RNA-recognition motifs (RRMs), as does fle. However, Nix has evolved at a much faster rate than fle. The RRM3 of both Nix and fle are distantly related to the single RRM of a widely distributed and conserved splicing factor transformer-2 (tra2). The RRM3-based phylogenetic analysis suggests this domain in Nix and fle may have evolved from tra2 or a tra2-related gene in a common ancestor of mosquitoes. Our results provide insights into the evolution of sex determination in mosquitoes and will inform broad applications of mosquito-control strategies based on manipulating sex ratios toward nonbiting males.
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Aedes , Mosquitos Vectores , Animales , Femenino , Masculino , Filogenia , Mosquitos Vectores/genética , Aedes/genética , Aedes/metabolismo , Empalme del ARNRESUMEN
Ferroptosis, a form of cell death mediated by lipid peroxidation, is implicated in various pathological processes. Although monounsaturated fatty acids (MUFAs) can inhibit ferroptotic lipid peroxidation, the underlying structural mechanism of this antagonistic effect remains poorly understood. We hypothesized that MUFAs with different structures (including chain length, conformation, and double bond position) may affect their regulatory effect on ferroptosis. In this study, 11 MUFAs with varying structures were screened to identify those with an inhibitory effect on ferroptosis. Results from 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide assays indicated that only exogenous MUFAs with cis-conformation and centered double bond could inhibit ferroptosis. Meanwhile, it was found that suppressing the expression of SCD1 and SCD5 genes could sensitize cells to ferroptosis indicating the protective role of endogenous MUFA against ferroptosis. Additionally, western blot analysis revealed that cis-MUFAs with centered double bond downregulated the protein levels of transferrin receptor 1. Flow cytometry confirmed that these MUFAs led to decreases in intracellular iron, reactive oxygen species, and lipid peroxides. It was also found that SCD1 inhibitor could enhance ferroptosis inducer-mediated tumor suppression both in vivo and in vitro. Overall, these findings shed light on the particular structural features of MUFAs that contribute to their ferroptosis-resistant properties and suggest the potential therapeutic relevance of natural MUFAs in a range of ferroptosis-related diseases.
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Ácidos Grasos Monoinsaturados , Ferroptosis , Ácidos Grasos Monoinsaturados/farmacología , Regulación hacia Abajo , Muerte Celular , Receptores de Transferrina/metabolismo , Ácidos Grasos/farmacologíaRESUMEN
Ferroptosis due to polyunsaturated fatty acid (PUFA) peroxidation has been implicated in the pathogenesis of acute kidney injury (AKI), suggesting the risk of dietary intake of PUFA for people susceptible to AKI. Clinically, however, in addition to ferroptosis, other mechanisms also contribute to different types of AKI such as inflammation associated necroptosis and pyroptosis. Therefore, the role of PUFA, especially ω3 PUFA which is a common food supplement, in various AKIs deserves further evaluation. In this study, rhabdomyolysis- and folic acid-induced AKI (Rha-AKI and FA-AKI) were established in mice fed with different fatty acids Histology of kidney, blood urea nitrogen and creatinine, lipid peroxidation, and inflammatory factors were examined. Results showed that these two types of AKIs had diametrically different pathogenesis indicated by that ferrostatin-1 (Fer-1), a lipid antioxidant, can attenuate FA-AKI rather than Rha-AKI. Further, dietary DHA (provided by fish oil) reduced tubular injury and renal lesion by inhibiting peroxidation and inflammation in mice with Rha-AKI while increasing cell death, tissue damage, peroxidation and inflammation in mice with FA-AKI. In human renal tubular epithelial cell line HK-2, MTT assay and DHE staining showed that both myoglobin and ferroptosis inducers can cause cell death and oxidative stress. Ferroptosis inducer-induced cell death was promoted by DHA, while such result was not observed in myoglobin-induced cell death when adding DHA. This study illustrates that the mechanisms of AKI might be either ferroptosis dependent or -independent and the deterioration effect of dietary DHA depends on whether ferroptosis is involved.
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Lesión Renal Aguda , Ácidos Grasos Omega-3 , Humanos , Ratones , Animales , Ácidos Docosahexaenoicos/farmacología , Mioglobina/efectos adversos , Lesión Renal Aguda/inducido químicamente , Ácidos Grasos Omega-3/efectos adversos , Ácidos Grasos Insaturados/metabolismo , InflamaciónRESUMEN
Mg-based metallic glass (MG) has attracted extensive attention in the field of wastewater treatment due to its high decolorization rate in degrading azo dyes. However, the azo dye degradation rate of Mg-based MGs is strongly dependent on the particle size. Improving the intrinsic degradation efficiency using large particles is of great interest for future applications. In this work, in-situ metallic glass matrix composites (MGMCs) with high Mg content were successfully prepared by melt spinning. It is found that when the Mg content is 79-82%, the as-spun sample shows typical glassy characteristics. The SEM and XRD tests confirm that the as-spun sample is composed of α-Mg dendrite, multiple Mg-Zn intermetallic particles and an MG matrix. The degradation experiment using Direct Blue 6 and a 500 µm particle sample demonstrate that the Mg82Zn14Ca3Sr1 MGMC sample degrades azo dyes faster than typical Mg-Zn-Ca MG alloy. It can be attributed to the galvanic cell effect on the α-Mg/MG interface, which reduces the waste of active Mg atoms in the MG matrix according to the corrosion protection mechanism by the α-Mg anode sacrifice. This result provides a new perspective and insight into the design of azo dye degradation alloys and the understanding of degradation mechanisms.
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The development of novel antibacterial nano-materials with synergistic biological effects has attracted extensive interest of the researchers. In the study, 0.5 mol% Ag and 0.5 mol% Cu co-doped K2Ti6O13(0.5 Ag-0.5 Cu-KTO) nanomaterial was successfully synthesized using two-step method of sol-gel and hydrothermal synthesis. The crystal structure of 0.5 Ag-0.5 Cu-KTO was the same as that of monoclinic K2Ti6O13. Ag ions and Cu ions were uniformly loaded on K2Ti6O13by replacing partial Ti ions, so that these antibacterial ions could be slowly released. High specific surface area of 0.5 Ag-0.5 Cu-KTO (337.6 m2g-1) provided more surface active sites for Ag-Cu doping and adsorption. More negative surface zeta potential (-32.83 mV in phosphate buffer solution and -21.45 mV in physiological saline solution, respectively) would be beneficial to prevent the aggregation of the nanowires in physiological environment. Under the same doping amount, compared to 1.0 mol% Cu doped K2Ti6O13, 0.5 Ag-0.5 Cu-KTO exhibited better antibacterial performance against gram-positive and gram-negative bacteria at only 100 µg ml-1dose concentration, near to 1.0 mol% Ag doped K2Ti6O13(1.0 Ag-KTO). And 0.5 Ag-0.5 Cu-KTO showed more excellent biocompatibility than 1.0 Ag-KTO, which was attribute to the introduction of Cu ions effectively decreasing the hemolytic and cytotoxic risks from Ag ions. As expected, the synthesized 0.5 Ag-0.5 Cu-KTO nanowires demonstrated excellent structural stability, high antibacterial activity, good hemocompatibility and cytocompatibility owing to the synergistic effects of Cu and Ag ions. 0.5 Ag-0.5 Cu-KTO nanowires will be a promising antimicrobial candidate for biomedical applications.
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Antibacterianos , Nanocables , Antibacterianos/química , Titanio/química , Bacterias Gramnegativas , Bacterias Grampositivas , IonesRESUMEN
Aedes aegypti is a major vector of arboviruses that cause dengue, chikungunya, yellow fever, and Zika. Although recent success in reverse genetics has facilitated rapid progress in basic and applied research, integration of forward genetics with modern technologies remains challenging in this important species, as up to 47% of its chromosome is refractory to genetic mapping due to extremely low rate of recombination. Here, we report the development of a marker-assisted mapping strategy to readily screen for and genotype only the rare but informative recombinants, drastically increasing both the resolution and signal-to-noise ratio. Using marker-assisted mapping, we mapped a transgene that was inserted in a >100-Mb recombination desert and a sex-linked spontaneous red-eye (re) mutation just outside the region. We subsequently determined, by CRISPR/Cas9-mediated knockout, that cardinal is the causal gene of re, which is the first forward genetic identification of a causal gene in Ae. aegypti. The identification of the causal gene of the sex-linked re mutation provides the molecular foundation for using gene editing to develop versatile and stable genetic sexing methods. To facilitate genome-wide forward genetics in Ae. aegypti, we generated and compiled a number of lines with markers throughout the genome. Thus, by overcoming the challenges presented by the vast recombination deserts and the scarcity of markers, we have shown that effective forward genetic analysis is increasingly feasible in this important arboviral vector species.
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Aedes , Arbovirus , Fiebre Chikungunya , Infección por el Virus Zika , Virus Zika , Animales , Aedes/genética , Arbovirus/genética , Mosquitos Vectores/genética , Recombinación GenéticaRESUMEN
PURPOSE: Ferroptosis is a form of regulated cell death that has the potential to be targeted as a cancer therapeutic strategy. But cancer cells have a wide range of sensitivities to ferroptosis, which limits its therapeutic potential. Accumulation of lipid peroxides determines the occurrence of ferroptosis. However, the type of lipid involved in peroxidation and the mechanism of lipid peroxide accumulation are less studied. METHODS: The effects of fatty acids (10 µM) with different carbon chain length and unsaturation on ferroptosis were evaluated by MTT and LDH release assay in cell lines derived from prostate cancer (PC3, 22RV1, DU145 and LNCaP), colorectal cancer (HT-29), cervical cancer (HeLa) and liver cancer (HepG2). Inhibitors of apoptosis, necroptosis, autophagy and ferroptosis were used to determine the type of cell death. Then the regulation of reactive oxygen species (ROS) and lipid peroxidation by docosahexaenoic acid (DHA) was measured by HPLC-MS and flow cytometry. The avtive form of DHA was determined by siRNA mediated gene silencing. The role of lipoxygenases was checked by inhibitors and gene silencing. Finally, the effect of DHA on ferroptosis-mediated tumor killing was verified in xenografts. RESULTS: The sensitivity of ferroptosis was positively correlated with the unsaturation of exogenously added fatty acid. DHA (22:6 n-3) sensitized cancer cells to ferroptosis-inducing reagents (FINs) at the highest level in vitro and in vivo. In this process, DHA increased ROS accumulation, lipid peroxidation and protein oxidation independent of its membrane receptor, GPR120. Inhibition of long chain fatty acid-CoA ligases and lysophosphatidylcholine acyltransferases didn't affect the role of DHA. DHA-involved ferroptosis can be induced in both arachidonate lipoxygenase 5 (ALOX5) negative and positive cells. Down regulation of ALOX5 inhibited ferroptosis, while overexpression of ALOX5 promoted ferroptosis. CONCLUSION: DHA can effectively promote ferroptosis-mediated tumor killing by increasing intracellular lipid peroxidation. Both ALOX5 dependent and independent pathways are involved in DHA-FIN induced ferroptosis. And during this process, free DHA plays an important role.
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Ácidos Docosahexaenoicos , Neoplasias , Masculino , Humanos , Ácidos Docosahexaenoicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Peróxidos Lipídicos , Lipooxigenasa/metabolismo , Lipooxigenasa/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Lisofosfatidilcolinas/farmacología , Línea Celular Tumoral , Muerte Celular , Peroxidación de Lípido , Lipooxigenasas/metabolismo , Araquidonato Lipooxigenasas/metabolismo , Araquidonato Lipooxigenasas/farmacología , Aciltransferasas/metabolismo , Aciltransferasas/farmacología , Carbono , Coenzima A/metabolismo , Coenzima A/farmacologíaRESUMEN
Skeletal muscle from meat-producing livestock such as cattle is a major source of food for humans. To improve skeletal muscle growth efficiency or quality in cattle, it is necessary to understand the genetic and physiological mechanisms that govern skeletal muscle composition, development, and growth. Satellite cells are the myogenic progenitor cells in postnatal skeletal muscle. In this study we analyzed the composition of bovine satellite cells with single-cell RNA sequencing (scRNA-seq). We isolated satellite cells from a 2-week-old male calf, cultured them in growth medium for a week, and performed scRNA-seq using the 10x Genomics platform. Deep sequencing of two scRNA-seq libraries constructed from cultured bovine satellite cells yielded 860 million reads. Cell calling analyses revealed that these reads were sequenced from 19,096 individual cells. Clustering analyses indicated that these reads represented 15 cell clusters that differed in gene expression profile. Based on the enriched expression of markers of satellite cells (PAX7 and PAX3), markers of myoblasts (MYOD1, MYF5), and markers of differentiated myoblasts or myocytes (MYOG), three clusters were determined to be satellite cells, two clusters myoblasts, and two clusters myocytes. Gene ontology and trajectory inference analyses indicated that cells in these myogenic clusters differed in proliferation rate and differentiation stage. Two of the remaining clusters were enriched with PDGFRA, a marker of fibro-adipogenic (FAP) cells, the progenitor cells for intramuscular fat, and are therefore considered to be FAP cells. Gene ontology analyses indicated active lipogenesis in one of these two clusters. The identity of the remaining six clusters could not be defined. Overall, the results of this study support the hypothesis that bovine satellite cells are composed of subpopulations that differ in transcriptional and myogenic state. The results of this study also support the hypothesis that intramuscular fat in cattle originates from fibro-adipogenic cells.
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Alternative polarization of macrophages regulates multiple biological processes. While M1-polarized macrophages generally mediate rapid immune responses, M2-polarized macrophages induce chronic and mild immune responses. In either case, polyunsaturated fatty acid (PUFA)-derived lipid mediators act as both products and regulators of macrophages. Prostaglandin E3 (PGE3 ) is an eicosanoid derived from eicosapentaenoic acid, which is converted by cyclooxygenase, followed by prostaglandin E synthase successively. We found that PGE3 played an anti-inflammatory role by inhibiting LPS and interferon-γ-induced M1 polarization and promoting interleukin-4-mediated M2 polarization (M2a). Further, we found that although PGE3 had no direct effect on the growth of prostate cancer cells in vitro, PGE3 could inhibit prostate cancer in vivo in a nude mouse model of neoplasia. Notably, we found that PGE3 significantly inhibited prostate cancer cell growth in a cancer cell-macrophage co-culture system. Experimental results showed that PGE3 inhibited the polarization of tumour-associated M2 macrophages (TAM), consequently producing indirect anti-tumour activity. Mechanistically, we identified that PGE3 regulated the expression and activation of protein kinase A, which is critical for macrophage polarization. In summary, this study indicates that PGE3 can selectively promote M2a polarization, while inhibiting M1 and TAM polarization, thus exerting an anti-inflammatory effect and anti-tumour effect in prostate cancer.
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Alprostadil/análogos & derivados , Antiinflamatorios/farmacología , Diferenciación Celular , Inflamación/tratamiento farmacológico , Activación de Macrófagos/inmunología , Neoplasias de la Próstata/tratamiento farmacológico , Alprostadil/farmacología , Animales , Polaridad Celular , Humanos , Inflamación/inmunología , Inflamación/patología , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Transducción de SeñalRESUMEN
Fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, is an attractive therapeutic target for diseases characterized by excessive lipid accumulation. Many FASN inhibitors have failed in the clinical trial phase, largely because of poor solubility and safety. In this study, we generated a novel small-molecule FASN inhibitor by structure-based virtual screening. PFI09, the lead compound, is easy to synthesize, and inhibits the lipid synthesis in OP9 mammalian cell line and Caenorhabditis elegans as well as the proliferation of several cancer cell lines via the blockade of FASN. Mechanistic investigations show that PFI09 induces S-phase arrest, cell division reduction and apoptosis. We also develop a chemically stable analog of PFI09, MFI03, which reduces the proliferation of PC3 tumor cells both in vitro and in vivo, without toxicity to mice. In summary, our data suggest that MFI03 is an effective FASN inhibitor and a promising antineoplastic drug candidate.
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Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Ácido Graso Sintasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Ácido Graso Sintasas/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pirrolidinas/química , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Pirrolidinas/uso terapéuticoRESUMEN
Chromosome level assemblies are accumulating in various taxonomic groups including mosquitoes. However, even in the few reference-quality mosquito assemblies, a significant portion of the heterochromatic regions including telomeres remain unresolved. Here we produce a de novo assembly of the New World malaria mosquito, Anopheles albimanus by integrating Oxford Nanopore sequencing, Illumina, Hi-C and optical mapping. This 172.6 Mbps female assembly, which we call AalbS3, is obtained by scaffolding polished large contigs (contig N50 = 13.7 Mbps) into three chromosomes. All chromosome arms end with telomeric repeats, which is the first in mosquito assemblies and represents a significant step toward the completion of a genome assembly. These telomeres consist of tandem repeats of a novel 30-32 bp Telomeric Repeat Unit (TRU) and are confirmed by analyzing the termini of long reads and through both chromosomal in situ hybridization and a Bal31 sensitivity assay. The AalbS3 assembly included previously uncharacterized centromeric and rDNA clusters and more than doubled the content of transposable elements and other repetitive sequences. This telomere-to-telomere assembly, although still containing gaps, represents a significant step toward resolving biologically important but previously hidden genomic components. The comparison of different scaffolding methods will also inform future efforts to obtain reference-quality genomes for other mosquito species.
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Anopheles , Malaria , Animales , Anopheles/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Malaria/genética , Secuencias Repetitivas de Ácidos Nucleicos , Telómero/genéticaRESUMEN
A dominant male-determining locus (M-locus) establishes the male sex (M/m) in the yellow fever mosquito, Aedes aegyptiNix, a gene in the M-locus, was shown to be a male-determining factor (M factor) as somatic knockout of Nix led to feminized males (M/m) while transient expression of Nix resulted in partially masculinized females (m/m), with male reproductive organs but retained female antennae. It was not clear whether any of the other 29 genes in the 1.3-Mb M-locus are also needed for complete sex-conversion. Here, we report the generation of multiple transgenic lines that express Nix under the control of its own promoter. Genetic and molecular analyses of these lines provided insights unattainable from previous transient experiments. We show that the Nix transgene alone, in the absence of the M-locus, was sufficient to convert females into males with all male-specific sexually dimorphic features and male-like gene expression. The converted m/m males are flightless, unable to perform the nuptial flight required for mating. However, they were able to father sex-converted progeny when presented with cold-anesthetized wild-type females. We show that myo-sex, a myosin heavy-chain gene also in the M-locus, was required for male flight as knockout of myo-sex rendered wild-type males flightless. We also show that Nix-mediated female-to-male conversion was 100% penetrant and stable over many generations. Therefore, Nix has great potential for developing mosquito control strategies to reduce vector populations by female-to-male sex conversion, or to aid in a sterile insect technique that requires releasing only non-biting males.
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Aedes/genética , Vuelo Animal , Genes de Insecto , Estudios de Asociación Genética , Proteínas de la Membrana/genética , Procesos de Determinación del Sexo/genética , Animales , Animales Modificados Genéticamente , Sistemas CRISPR-Cas , Femenino , Sitios Genéticos , Genotipo , Patrón de Herencia , Masculino , Penetrancia , Fenotipo , Regiones Promotoras GenéticasRESUMEN
Plastic polarization of macrophage is involved in tumorigenesis. M1-polarized macrophage mediates rapid inflammation, entity clearance and may also cause inflammation-induced mutagenesis. M2-polarized macrophage inhibits rapid inflammation but can promote tumour aggravation. ω-3 long-chain polyunsaturated fatty acid (PUFA)-derived metabolites show a strong anti-inflammatory effect because they can skew macrophage polarization from M1 to M2. However, their role in tumour promotive M2 macrophage is still unknown. Resolvin D1 and D2 (RvD1 and RvD2) are docosahexaenoic acid (DHA)-derived docosanoids converted by 15-lipoxygenase then 5-lipoxygenase successively. We found that although dietary DHA can inhibit prostate cancer in vivo, neither DHA (10 µmol/L) nor RvD (100 nmol/L) can directly inhibit the proliferation of prostate cancer cells in vitro. Unexpectedly, in a cancer cell-macrophage co-culture system, both DHA and RvD significantly inhibited cancer cell proliferation. RvD1 and RvD2 inhibited tumour-associated macrophage (TAM or M2d) polarization. Meanwhile, RvD1 and RvD2 also exhibited anti-inflammatory effects by inhibiting LPS-interferon (IFN)-γ-induced M1 polarization as well as promoting interleukin-4 (IL-4)-mediated M2a polarization. These differential polarization processes were mediated, at least in part, by protein kinase A. These results suggest that regulation of macrophage polarization using RvDs may be a potential therapeutic approach in the management of prostate cancer.
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Antineoplásicos/farmacología , Ácidos Docosahexaenoicos/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Animales , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Humanos , Inmunohistoquímica , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Transducción de Señal/efectos de los fármacos , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
Gut microbiota play important roles in host metabolism, especially in diabetes. However, why different diets lead to similar diabetic states despite being associated with different microbiota is not clear. Mice were fed two high-energy diets (HED) with the same energy density but different fat-to-sugar ratios to determine the associations between the microbiota and early-stage metabolic syndrome. The two diets resulted in different microbiota but similar diabetic states. Interestingly, the microbial gene profiles were not significantly different, and many common metabolites were identified, including l-aspartic acid, cholestan-3-ol (5ß, 3α), and campesterol, which have been associated with lipogenesis and inflammation. Our study suggests that different metabolic-syndrome-inducing diets may result in different microbiota but similar microbiomes and metabolomes. This suggests that the metagenome and metabolome are crucial for the prognosis and pathogenesis of obesity and metabolic syndrome.IMPORTANCE Various types of diet can lead to type 2 diabetes. The gut microbiota in type 2 diabetic patients are also different. So, two questions arise: whether there are any commonalities between gut microbiota induced by different pro-obese diets and whether these commonalities lead to disease. Here we found that high-energy diets with two different fat-to-sugar ratios can both cause obesity and prediabetes but enrich different gut microbiota. Still, these different gut microbiota have similar genetic and metabolite compositions. The microbial metabolites in common between the diets modulate lipid accumulation and macrophage inflammation in vivo and in vitro This work suggests that studies that only use 16S rRNA amplicon sequencing to determine how the microbes respond to diet and associate with diabetic state are missing vital information.
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We previously showed that Guy1, a primary signal expressed from the Y chromosome, is a strong candidate for a male-determining factor that confers female-specific lethality in Anopheles stephensi (Criscione et al., 2016). Here, we present evidence that Guy1 increases X gene expression in Guy1-transgenic females from two independent lines, providing a mechanism underlying the Guy1-conferred female lethality. The median level gene expression (MGE) of X-linked genes is significantly higher than autosomal genes in Guy1-transgenic females while there is no significant difference in MGE between X and autosomal genes in wild-type females. Furthermore, Guy1 significantly upregulates at least 40% of the 996 genes across the X chromosome in transgenic females. Guy1-conferred female-specific lethality is remarkably stable and completely penetrant. These findings indicate that Guy1 regulates dosage compensation in An. stephensi and components of dosage compensation may be explored to develop novel strategies to control mosquito-borne diseases.
Asunto(s)
Anopheles/genética , Compensación de Dosificación (Genética) , Genes Ligados a X , Proteínas de Insectos/metabolismo , Animales , Animales Modificados Genéticamente , FemeninoRESUMEN
Despite their importance in sexual differentiation and reproduction, Y chromosome genes are rarely described because they reside in repeat-rich regions that are difficult to study. Here, we show that Guy1, a unique Y chromosome gene of a major urban malaria mosquito Anopheles stephensi, confers 100% female lethality when placed on the autosomes. We show that the small GUY1 protein (56 amino acids in length) causes female lethality and that males carrying the transgene are reproductively more competitive than their non-transgenic siblings under laboratory conditions. The GUY1 protein is a primary signal from the Y chromosome that affects embryonic development in a sex-specific manner. Our results have demonstrated, for the first time in mosquitoes, the feasibility of stable transgenic manipulation of sex ratios using an endogenous gene from the male-determining chromosome. These results provide insights into the elusive M factor and suggest exciting opportunities to reduce mosquito populations and disease transmission.