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Nucleotide metabolism fuels normal DNA replication and is also primarily targeted by the DNA replication checkpoint when replication stalls. To reveal a comprehensive interconnection between genome maintenance and metabolism, we analyzed the metabolomic changes upon replication stress in the budding yeast S. cerevisiae. We found that upon treatment of cells with hydroxyurea, glucose is rapidly diverted to the oxidative pentose phosphate pathway (PPP). This effect is mediated by the AMP-dependent kinase, SNF1, which phosphorylates the transcription factor Mig1, thereby relieving repression of the gene encoding the rate-limiting enzyme of the PPP. Surprisingly, NADPH produced by the PPP is required for efficient recruitment of replication protein A (RPA) to single-stranded DNA, providing the signal for the activation of the Mec1/ATR-Rad53/CHK1 checkpoint signaling kinase cascade. Thus, SNF1, best known as a central energy controller, determines a fast mode of replication checkpoint activation through a redox mechanism. These findings establish that SNF1 provides a hub with direct links to cellular metabolism, redox, and surveillance of DNA replication in eukaryotes.
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Replicação do DNA , Proteínas Serina-Treonina Quinases/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/genética , Quinase do Ponto de Checagem 2/metabolismo , Replicação do DNA/efeitos dos fármacos , DNA de Cadeia Simples/metabolismo , Glucose/genética , Glucose/metabolismo , Glicólise/fisiologia , Hidroxiureia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NADP/metabolismo , Via de Pentose Fosfato , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteína de Replicação A/genética , Proteína de Replicação A/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Heterochromatin is a key feature of eukaryotic genomes and is crucial for maintaining genomic stability. In fission yeast, heterochromatin nucleation is mainly mediated by DNA-binding proteins or the RNA interference (RNAi) pathway. In the filamentous fungus Neurospora crassa, however, the mechanism that causes the initiation of heterochromatin at the relics of repeat-induced point mutation is unknown and independent of the classical RNAi pathway. Here, we show that casein kinase II (CKII) and its kinase activity are required for heterochromatin formation at the well-defined 5-kb heterochromatin of the 5H-cat-3 region and transcriptional repression of its adjacent cat-3 gene. Similarly, mutation of the histone H3 phosphorylation site T11 also impairs heterochromatin formation at the same locus. The catalytic subunit CKA colocalizes with H3T11 phosphorylation (H3pT11) within the 5H-cat-3 domain and the deletion of cka results in a significant decrease in H3T11 phosphorylation. Furthermore, the loss of kinase activity of CKII results in a significant reduction of H3pT11, H3K9me3 (histone H3 lysine 9 trimethylation) and DNA methylation levels, suggesting that CKII regulates heterochromatin formation by promoting H3T11 phosphorylation. Together, our results establish that histone H3 phosphorylation by CKII is a critical event required for heterochromatin formation.
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UPF-1-UPF-2-UPF-3 complex-orchestrated nonsense-mediated mRNA decay (NMD) is a well-characterized eukaryotic cellular surveillance mechanism that not only degrades aberrant transcripts to protect the integrity of the transcriptome but also eliminates normal transcripts to facilitate appropriate cellular responses to physiological and environmental changes. Here, we describe the multifaceted regulatory roles of the Neurospora crassa UPF complex in catalase-3 (cat-3) gene expression, which is essential for scavenging H2O2-induced oxidative stress. First, losing UPF proteins markedly slowed down the decay rate of cat-3 mRNA. Second, UPF proteins indirectly attenuated the transcriptional activity of cat-3 gene by boosting the decay of cpc-1 and ngf-1 mRNAs, which encode a well-studied transcription factor and a histone acetyltransferase, respectively. Further study showed that under oxidative stress condition, UPF proteins were degraded, followed by increased CPC-1 and NGF-1 activity, finally activating cat-3 expression to resist oxidative stress. Together, our data illustrate a sophisticated regulatory network of the cat-3 gene mediated by the UPF complex under physiological and H2O2-induced oxidative stress conditions.
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Peróxido de Hidrogênio , Neurospora , Peróxido de Hidrogênio/farmacologia , Catalase/genética , Degradação do RNAm Mediada por Códon sem Sentido , Estresse Oxidativo/genéticaRESUMO
In recent years, there has been significant interest in the development of two-dimensional (2D) nanomaterials with unique physicochemical properties for various energy applications. These properties are often derived from the phase structures established through a range of physical and chemical design strategies. A concrete analysis of the phase structures and real reaction mechanisms of 2D energy nanomaterials requires advanced characterization methods that offer valuable information as much as possible. Here, we present a comprehensive review on the phase engineering of typical 2D nanomaterials with the focus of synchrotron radiation characterizations. In particular, the intrinsic defects, atomic doping, intercalation, and heterogeneous interfaces on 2D nanomaterials are introduced, together with their applications in energy-related fields. Among them, synchrotron-based multiple spectroscopic techniques are emphasized to reveal their intrinsic phases and structures. More importantly, various in situ methods are employed to provide deep insights into their structural evolutions under working conditions or reaction processes of 2D energy nanomaterials. Finally, conclusions and research perspectives on the future outlook for the further development of 2D energy nanomaterials and synchrotron radiation light sources and integrated techniques are discussed.
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Although the coupling between circadian and cell cycles allows circadian clocks to gate cell division and DNA replication in many organisms, circadian clocks were thought to function independently of cell cycle. Here, we show that DNA replication is required for circadian clock function in Neurospora. Genetic and pharmacological inhibition of DNA replication abolished both overt and molecular rhythmicities by repressing frequency (frq) gene transcription. DNA replication is essential for the rhythmic changes of nucleosome composition at the frq promoter. The FACT complex, known to be involved in histone disassembly/reassembly, is required for clock function and is recruited to the frq promoter in a replication-dependent manner to promote replacement of histone H2A.Z by H2A. Finally, deletion of H2A.Z uncoupled the dependence of the circadian clock on DNA replication. Together, these results establish circadian clock and cell cycle as interdependent coupled oscillators and identify DNA replication as a critical process in the circadian mechanism.
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Relógios Circadianos , Ritmo Circadiano , Replicação do DNA , DNA Fúngico/metabolismo , Neurospora/metabolismo , Nucleossomos/metabolismo , Animais , DNA Fúngico/química , DNA Fúngico/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Histonas/genética , Histonas/metabolismo , Neurospora/genética , Conformação de Ácido Nucleico , Nucleossomos/química , Nucleossomos/genética , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Regiões Promotoras Genéticas , Conformação Proteica , Relação Estrutura-Atividade , Fatores de Tempo , Transcrição Gênica , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismoRESUMO
The spindle assembly checkpoint factors Bub3 and BuGZ play critical roles in mitotic process, but little is known about their roles in other cellular processes in eukaryotes. In aerobic organisms, transcriptional regulation of catalase genes in response to developmental or environmental stimuli is necessary for redox homeostasis. Here, we demonstrate that Bub3 and BuGZ negatively regulate cat-3 transcription in the model filamentous fungus Neurospora crassa. The absence of Bub3 caused a significant decrease in BuGZ protein levels. Our data indicate that BuGZ and Bub3 interact directly via the GLEBS domain of BuGZ. Despite loss of the interaction, the amount of BuGZ mutant protein negatively correlated with the cat-3 expression level, indicating that BuGZ amount rather than Bub3-BuGZ interaction determines cat-3 transcription level. Further experiments demonstrated that BuGZ binds directly to the cat-3 gene and responses to cat-3 overexpression induced by oxidative stresses. However, the zinc finger domains of BuGZ have no effects on DNA binding, although mutations of these highly conserved domains lead to loss of cat-3 repression. The deposition of BuGZ along cat-3 chromatin hindered the recruitment of transcription activators GCN4/CPC1 and NC2 complex, thereby preventing the assembly of the transcriptional machinery. Taken together, our results establish a mechanism for how mitotic proteins Bub3 and BuGZ functions in transcriptional regulation in a eukaryotic organism.
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Proteínas de Ciclo Celular , Mitose , Catalase/genética , Proteínas de Ciclo Celular/genética , Pontos de Checagem da Fase M do Ciclo Celular , Proteínas Associadas aos Microtúbulos/genética , Mitose/genética , Proteínas de Ligação a Poli-ADP-Ribose/genéticaRESUMO
The synergistic interaction between the isolated metal sites promoted the electrocatalytic activity of the catalysts. However, the structural heterogeneity of the isolated sites makes it challenging to evaluate this effect accurately. In this work, metal-coordinated polyphthalocyanine molecules (Fe-PPc, Co-PPc, FeCo-PPc) with long-range ordered and precise coordination structures are used as a platform to study the synergies of different isolated metal sites in the electrochemical CO2 reduction reaction. The combination means of experimental and theoretical calculation clearly reveal that the coexistence of Fe and Co sites in PPc significantly enhances the conjugation effect of the macrocycle. This enhancement subsequently causes the metal sites to lose more electrons, thereby improving their adsorption of CO2 and facilitating the formation of intermediate *COOH on them. As a result, FeCo-PPc achieves a CO partial current density of about 57.4 mA/cm2 with a high turnover frequency of over 49000 site-1 h-1 at -0.9 V (vs RHE).
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Enterovirus A71 (EV-A71) is one of the major causative agents of hand, foot, and mouth disease (HFMD) that majorly affects children. Most of the time, HFMD is a mild disease but can progress to severe complications, such as meningitis, brain stem encephalitis, acute flaccid paralysis, and even death. HFMD caused by EV-A71 has emerged as an acutely infectious disease of highly pathogenic potential in the Asia-Pacific region. In this review, we introduced the properties and life cycle of EV-A71, and the pathogenesis and the pathophysiology of EV-A71 infection, including tissue tropism and host range of virus infection, the diseases caused by the virus, as well as the genes and host cell immune mechanisms of major diseases caused by enterovirus 71 (EV-A71) infection, such as encephalitis and neurologic pulmonary edema. At the same time, clinicopathologic characteristics of EV-A71 infection were introduced. There is currently no specific medication for EV-A71 infection, highlighting the urgency and significance of developing suitable anti-EV-A71 agents. This overview also summarizes the targets of existing anti-EV-A71 agents, including virus entry, translation, polyprotein processing, replication, assembly and release; interferons; interleukins; the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase B signaling pathways; the oxidative stress pathway; the ubiquitin-proteasome system; and so on. Furthermore, it overviews the effects of natural products, monoclonal antibodies, and RNA interference against EV-A71. It also discusses issues limiting the research of antiviral drugs. This review is a systematic and comprehensive summary of the mechanism and pathological characteristics of EV-A71 infection, the latest progress of existing anti-EV-A71 agents. It would provide better understanding and guidance for the research and application of EV-A71 infection and antiviral inhibitors.
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Encefalite , Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Criança , Humanos , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêuticoRESUMO
Determining the functional consequences of karyotypic changes is invariably challenging because evolution tends to obscure many of its own footprints, such as accumulated mutations, recombination events, and demographic perturbations. Here, we describe the assembly of a chromosome-level reference genome of the gayal (Bos frontalis) thereby revealing the structure, at base-pair-level resolution, of a telo/acrocentric-to-telo/acrocentric Robertsonian translocation (2;28) (T/A-to-T/A rob[2;28]). The absence of any reduction in the recombination rate or genetic introgression within the fusion region of gayal served to challenge the long-standing view of a role for fusion-induced meiotic dysfunction in speciation. The disproportionate increase noted in the distant interactions across pro-chr2 and pro-chr28, and the change in open-chromatin accessibility following rob(2;28), may, however, have led to the various gene expression irregularities observed in the gayal. Indeed, we found that many muscle-related genes, located synthetically on pro-chr2 and pro-chr28, exhibited significant changes in expression. This, combined with genome-scale structural variants and expression alterations in genes involved in myofibril composition, may have driven the rapid sarcomere adaptation of gayal to its rugged mountain habitat. Our findings not only suggest that large-scale chromosomal changes can lead to alterations in genome-level expression, thereby promoting both adaptation and speciation, but also illuminate novel avenues for studying the relationship between karyotype evolution and speciation.
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Cromatina , Genoma , Animais , BovinosRESUMO
OBJECTIVES: Microwave ablation (MWA) has achieved excellent long-term efficacy in treating unifocal papillary thyroid microcarcinoma (UPTMC). The therapeutic effect of this treatment on multifocal papillary thyroid microcarcinoma (MPTMC) is unknown. Therefore, we evaluated the long-term efficacy of MWA for low-risk MPTMC and to provide evidence-based medicine for the revision of clinical guidelines. METHODS: This study included 66 MPTMC patients with a total of 158 lesions, all of whom received MWA. We collected and retrospectively analyzed the patients' follow-up data before MWA, at 1, 3, 6, and 12 months posttreatment and every 6 months thereafter until 5 years posttreatment. We evaluated the MWA complication rate, technical success rate (TSR), lesion volume reduction rate (VRR), and complete disappearance rate (CDR) during follow-up and in those patients with tumor progression and delayed surgery. RESULTS: After 60 months of follow-up, all 158 lesions disappeared in 66 patients, and the volume was reduced from 43.82 mm3 to 0.00 mm3. The TSR and VRR were both 100%. The CDRs at 1 year, 2 years, and 3 years were 57.59%, 93.67%, and 100%, respectively. The complication rate was 3.03% (2/66), and the incidence of tumor progression was 3.03% (2/66), including one new intrathyroidal lesion and one cervical lymph node metastasis (LNM). These lesions were retreated with MWA, and the lesions disappeared during the follow-up period. CONCLUSIONS: Ultrasound-guided MWA for low-risk MPTMC is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance (AS). CLINICAL RELEVANCE STATEMENT: This study concludes that ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance. KEY POINTS: ⢠Ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective. ⢠During 5 years of follow-up, multifocal papillary thyroid microcarcinoma patients treated with microwave ablation had a favorable prognosis. ⢠To provide evidence-based medicine for the revision of clinical guidelines.
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Carcinoma Papilar , Micro-Ondas , Neoplasias da Glândula Tireoide , Humanos , Seguimentos , Micro-Ondas/uso terapêutico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
Crucial mechanisms are required to restrict self-propagating heterochromatin spreading within defined boundaries and prevent euchromatic gene silencing. In the filamentous fungus Neurospora crassa, the JmjC domain protein DNA METHYLATION MODULATOR-1 (DMM-1) prevents aberrant spreading of heterochromatin, but the molecular details remain unknown. Here, we revealed that DMM-1 is highly enriched in a well-defined 5-kb heterochromatin domain upstream of the cat-3 gene, hereby called 5H-cat-3 domain, to constrain aberrant heterochromatin spreading. Interestingly, aberrant spreading of the 5H-cat-3 domain observed in the dmm-1KO strain is accompanied by robust deposition of histone variant H2A.Z, and deletion of H2A.Z abolishes aberrant spreading of the 5H-cat-3 domain into adjacent euchromatin. Furthermore, lysine 56 of histone H3 is deacetylated at the expanded heterochromatin regions, and mimicking H3K56 acetylation with an H3K56Q mutation effectively blocks H2A.Z-mediated aberrant spreading of the 5H-cat-3 domain. Importantly, genome-wide analyses demonstrated the general roles of H3K56 deacetylation and H2A.Z deposition in aberrant spreading of heterochromatin. Together, our results illustrate a previously unappreciated regulatory process that mediates aberrant heterochromatin spreading.
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Heterocromatina , Histonas , Neurospora crassa/metabolismo , Metilação de DNA , Eucromatina/genética , Estudo de Associação Genômica Ampla , Heterocromatina/genética , Histonas/genética , Histonas/metabolismoRESUMO
Electrochemical formic acid oxidation reaction (FAOR) is a pivotal model for understanding organic fuel oxidation and advancing sustainable energy technologies. Here, we present mechanistic insights into a novel molecular-like iridium catalyst (Ir-N4-C) for FAOR. Our studies reveal that isolated sites facilitate a preferential dehydrogenation pathway, circumventing catalyst poisoning and exhibiting high inherent activity. In-situ spectroscopic analyses elucidate that weakly adsorbed intermediates mediate the FAOR and are dynamically regulated by potential-dependent redox transitions. Theoretical and experimental investigations demonstrate a parallel mechanism involving two key intermediates with distinct pH and potential sensitivities. The rate-determining step is identified as the adsorption of formate via coupled or sequential proton-electron transfer, which aligns well with the observed kinetic properties, pH dependence, and hydrogen/deuterium isotope effects in experiments. These findings provide valuable insights into the reaction mechanism of FAOR, advancing our understanding at the molecular level and potentially guiding the design of efficient catalysts for fuel cells and electrolyzers.
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Although metal-containing polymers have been widely studied as a novel class of functional soft materials, the microphase separation between polymeric segments and metal-ligand complexes has been less addressed, which is critical to control their structures and functions. To do this, short-chain polystyrenes (PSs) have been end-functionalized with nanosized square-planar platinum(II) complexes. The platinum(II)-comprising polymers were found to show significant luminescence enhancement in chloroform/methanol solvent mixtures upon increasing the methanol composition. By modulating both the PS length and solvent quality, various self-assembled morphologies formed controllably in the mixed solvents and typical examples include nanofibers, nanoellipsoids, and nanospheres. More interestingly, the inside structures of these polymer particles are shown to be lamellar with sub-10 nm spacings, wherein the PS blocks are alternatively aligned with the platinum(II) units. Such a luminescence enhancement and hierarchical nanostructured particles originate from a subtle combination of directional Pt(II)â¯Pt(II) and/or π-π stacking interactions between the platinum(II) units and the solvophobic effect between the PS blocks. This work suggests that by microphase separating polymer chains with nanosized metal-ligand complexes, metal-containing polymers can self-assemble to form sub-10 nm scale nanostructures showcasing desired properties and functions.
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Amino accelerators and antioxidants (AAL/Os), as well as their degradation derivatives, are industrial additives of emerging concern due to their massive production and use (particularly in rubber tires), pervasiveness in the environment, and documented adverse effects. This study delineated their inter-regional variations in road dust collected from urban/suburb, agricultural, and forest areas, and screened for less-studied AAL/O analogues with high-resolution mass spectrometry. 1,3-Diphenylguanidine (DPG; median concentration: 121 ng/g) and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q; 9.75 ng/g) are the most abundant congeners, constituting 69.7% and 41.4% of the total concentrations of AAL/Os (192 ng/g) and those of AAO transformation products (22.3 ng/g), respectively. The spatial distribution across the studied sites suggests evident human impacts, reflected by the pronounced urban signature and vehicle-originated pollution. Our nontargeted analysis of the most-contaminated road dust identified 16 AAL/O-related chemicals, many of which have received little investigation. Particularly, environmental and toxicological information remains extremely scarce for five out of the 10 most concerning compounds prioritized in terms of their dusty residues and toxicity including 1,2-diphenyl-3-cyclohexylguanidine (DPCG), N,N''-bis[2-(propan-2-yl)phenyl]guanidine (BPPG), and N-(4-anilinophenyl)formamide (PPD-CHO). Additionally, dicyclohexylamine (DChA), broadly applied as an antioxidant in automobile products, had an even greater median level than DPG. Therefore, future research on their health risks and (eco)toxic potential is of high importance.
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Antioxidantes , Benzoquinonas , Poeira , Guanidinas , Fenilenodiaminas , Humanos , Agricultura , Antioxidantes/análise , Poeira/análise , Monitoramento Ambiental , Espectrometria de Massas , Guanidinas/análise , Fenilenodiaminas/análise , Benzoquinonas/análiseRESUMO
INTRODUCTION: Acute kidney injury (AKI) is a clinical emergency caused by the rapid decline of renal function caused by various etiologies. Growth differentiation factor 11 (GDF11) can promote renal tubular regeneration and improve kidney function in AKI, but the specific mechanism remains unclear. Herein, we investigated the effect and mechanisms of GDF11 in ameliorating AKI induced by ischemia-reperfusion (I/R). METHODS: An animal model of AKI was established by I/R method, and the changes of serum urea nitrogen and creatinine were measured to evaluate the AKI. Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokines, malondialdehyde, superoxide dismutase, nitric oxide synthase, and arginase 1 levels. Flow cytometry was used to count the M1/M2 macrophages. IHC, WB, and q-PCR experiments were used to evaluate the expression of GDF11. RESULTS: The changes in serum levels of urea nitrogen and creatinine after I/R suggest that an animal model of AKI induced by I/R was successfully established. AKI caused by I/R significantly changed the M1/M2 macrophage polarization balance, with an increase in M2 being significantly higher than M1 as well as increased oxidative stress. Treatment with GDF11 after I/R significantly increased the differentiation of M2 cells and inhibited the differentiation of M1 macrophages, as well as decreased oxidative stress. CONCLUSION: GDF11 can promote the repair of AKI caused by I/R by regulating the balance of M1/M2 polarization in macrophages and oxidative stress.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Animais , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Creatinina/metabolismo , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Isquemia/complicações , Rim/metabolismo , Macrófagos/metabolismo , Nitrogênio/metabolismo , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Ureia/metabolismoRESUMO
Background: Rhinitis, allergic rhinitis in particular, and urticaria are both common diseases globally. However, there is controversy with regard to the correlation between rhinitis and urticaria. Objective: To examine the accurate association between rhinitis and urticaria. Methods: Three medical literature data bases were searched from data base inception until January 11, 2022. The prevalence and association between rhinitis and urticaria were estimated by meta-analysis. Quality assessment was performed by using the Newcastle-Ottawa Scale. Pooled odds ratios (OR) with 95% confidence intervals (CI) and pooled prevalence were calculated by using random-effects models. Results: Urticaria prevalence in patients with rhinitis was 17.6% (95% CI, 13.2%-21.9%). The pooled prevalence of rhinitis was 31.3% (95% CI, 24.2%-38.4%) in patients with urticaria, and rhinitis prevalence in patients with acute urticaria and chronic urticaria was 31.6% (95% CI, 7.4%-55.8%) and 28.7% (95% CI, 20.4%-36.9%), respectively. Rhinitis occurrence was significantly associated with urticaria (OR 2.67 [95% CI, 2.625-2.715]). Urticaria and rhinitis were diagnosed based on different criteria, possibly resulting in a potential error of misclassification. Conclusion: Rhinitis and urticaria were significantly correlated. Physicians should be cognizant with regard to this relationship and address nasal or skin symptoms in patients.
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Rinite Alérgica Perene , Rinite Alérgica , Rinite , Urticária , Humanos , Rinite/epidemiologia , Prevalência , Urticária/epidemiologia , Rinite Alérgica/epidemiologiaRESUMO
Enhancing activity and stability of iridium- (Ir-) based oxygen evolution reaction (OER) catalysts is of great significance in practice. Here, we report a vacancy-rich nickel hydroxide stabilized Ir single-atom catalyst (Ir1-Ni(OH)2), which achieves long-term OER stability over 260 h and much higher mass activity than commercial IrO2 in alkaline media. In situ X-ray absorption spectroscopy analysis certifies the obvious structure reconstruction of catalyst in OER. As a result, an active structure in which high-valence and peripheral oxygen ligands-rich Ir sites are confined onto the nickel oxyhydroxide surface is formed. In addition, the precise introduction of atomized Ir not only surmounts the large-range dissolution and agglomeration of Ir but also suppresses the dissolution of substrate in OER. Theoretical calculations further account for the activation of Ir single atoms and the promotion of oxygen generation by high-valence Ir, and they reveal that the deprotonation process of adsorbed OH is rate-determining.
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Negative cofactor 2 (NC2), including two subunits NC2α and NC2ß, is a conserved positive/negative regulator of class II gene transcription in eukaryotes. It is known that NC2 functions by regulating the assembly of the transcription preinitiation complex. However, the exact role of NC2 in transcriptional regulation is still unclear. Here, we reveal that, in Neurospora crassa, NC2 activates catalase-3 (cat-3) gene transcription in the form of heterodimer mediated by histone fold (HF) domains of two subunits. Deletion of HF domain in either of two subunits disrupts the NC2α-NC2ß interaction and the binding of intact NC2 heterodimer to cat-3 locus. Loss of NC2 dramatically increases histone variant H2A.Z deposition at cat-3 locus. Further studies show that NC2 recruits chromatin remodeling complex INO80C to remove H2A.Z from the nucleosomes around cat-3 locus, resulting in transcriptional activation of cat-3. Besides HF domains of two subunits, interestingly, C-terminal repression domain of NC2ß is required not only for NC2 binding to cat-3 locus, but also for the recruitment of INO80C to cat-3 locus and removal of H2A.Z from the nucleosomes. Collectively, our findings reveal a novel mechanism of NC2 in transcription activation through recruiting INO80C to remove H2A.Z from special H2A.Z-containing nucleosomes.
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Catalase/genética , Fosfoproteínas/genética , Fatores de Transcrição/genética , Transcrição Gênica , Núcleo Celular/genética , Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica/genética , Genes MHC da Classe II/genética , Histonas/genética , Neurospora crassa/genética , Nucleossomos/genética , Nucleossomos/ultraestrutura , Fosfoproteínas/ultraestrutura , Ligação Proteica/genética , Fatores de Transcrição/ultraestrutura , Ativação Transcricional/genéticaRESUMO
Cellulolytic fungi have evolved a complex regulatory network to maintain the precise balance of nutrients required for growth and hydrolytic enzyme production. When fungi are exposed to cellulose, the transcript levels of cellulase genes rapidly increase and then decline. However, the mechanisms underlying this bell-shaped expression pattern are unclear. We systematically screened a protein kinase deletion set in the filamentous fungus Neurospora crassa to search for mutants exhibiting aberrant expression patterns of cellulase genes. We observed that the loss of stk-12 (NCU07378) caused a dramatic increase in cellulase production and an extended period of high transcript abundance of major cellulase genes. These results suggested that stk-12 plays a critical role as a brake to turn down the transcription of cellulase genes to repress the overexpression of hydrolytic enzymes and prevent energy wastage. Transcriptional profiling analyses revealed that cellulase gene expression levels were maintained at high levels for 56 h in the Δstk-12 mutant, compared to only 8 h in the wild-type (WT) strain. After growth on cellulose for 3 days, the transcript levels of cellulase genes in the Δstk-12 mutant were 3.3-fold over WT, and clr-2 (encoding a transcriptional activator) was up-regulated in Δstk-12 while res-1 and rca-1 (encoding two cellulase repressors) were down-regulated. Consequently, total cellulase production in the Δstk-12 mutant was 7-fold higher than in the WT. These results strongly suggest that stk-12 deletion results in dysregulation of the cellulase expression machinery. Further analyses showed that STK-12 directly targets IGO-1 to regulate cellulase production. The TORC1 pathway promoted cellulase production, at least partly, by inhibiting STK-12 function, and STK-12 and CRE-1 functioned in parallel pathways to repress cellulase gene expression. Our results clarify how cellulase genes are repressed at the transcriptional level during cellulose induction, and highlight a new strategy to improve industrial fungal strains.
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Celulase/genética , Proteínas Fúngicas/genética , Fatores de Transcrição/genética , Celulose/genética , Regulação Fúngica da Expressão Gênica/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Neurospora crassa/enzimologia , Neurospora crassa/genéticaRESUMO
Auxin is unique among plant hormones in that its function requires polarized transport across plant cells. A chemiosmotic model was proposed to explain how polar auxin transport is derived by the H+ gradient across the plasma membrane (PM) established by PM H+ -adenosine triphosphatases (ATPases). However, a classical genetic approach by mutations in PM H+ -ATPase members did not result in the ablation of polar auxin distribution, possibly due to functional redundancy in this gene family. To confirm the crucial role of PM H+ -ATPases in the polar auxin transport model, we employed a chemical genetic approach. Through a chemical screen, we identified protonstatin-1 (PS-1), a selective small-molecule inhibitor of PM H+ -ATPase activity that inhibits auxin transport. Assays with transgenic plants and yeast strains showed that the activity of PM H+ -ATPases affects auxin uptake as well as acropetal and basipetal polar auxin transport. We propose that PS-1 can be used as a tool to interrogate the function of PM H+ -ATPases. Our results support the chemiosmotic model in which PM H+ -ATPase itself plays a fundamental role in polar auxin transport.