Exploring Transformer Model in Longitudinal Pharmacokinetic/Pharmacodynamic Analyses and Comparing with Alternative Natural Language Processing Models.

There remains a substantial need for a comprehensive assessment of various natural language processing (NLP) algorithms in longitudinal pharmacokinetic/pharmacodynamic (PK/PD) modeling despite recent advances in machine learning in the space of quantitative pharmacology. We herein investigated the application of the transformer model and further compared the performance among several different NLP models, including long short-term memory (LSTM) and neural-ODE (Ordinary Differential Equation) in analyzing longitudinal PK/PD data using virtual data containing three different regimens. Results suggested that LSTM and neural-ODE, along with their respective variants provide a strong performance when predicting from training-included (seen) regimens, albeit with slight information loss for training-excluded (unseen) regimens. Similarly, as with neural-ODE, the transformer exhibited superior performance in describing time-series PK/PD data. Nonetheless, when extrapolating to unseen regimens, while outlining the general data trends, it encountered difficulties in precisely capturing data fluctuations. Remarkably, a small integration of unseen data into the training dataset significantly bolsters predictive performance for both seen and unseen regimens. Our study marks a pioneering effort in deploying the transformer model for time-series PK/PD analysis and provides a systematic exploration of the currently available NLP models in this field.

Genomic and Transcriptomic Survey Provides Insights into Molecular Basis of Pathogenicity of the Sunflower Pathogen Phoma macdonaldii.

Phoma macdonaldii (teleomorph Leptosphaeria lindquistii) is the causal agent of sunflower (Helianthus annuus L.) black stem. In order to investigate the molecular basis for the pathogenicity of P. ormacdonaldii, genomic and transcriptomic analyses were performed. The genome size was 38.24 Mb and assembled into 27 contigs with 11,094 putative predicted genes. These include 1133 genes for CAZymes specific for plant polysaccharide degradation, 2356 for the interaction between the pathogen and host, 2167 for virulence factors, and 37 secondary metabolites gene clusters. RNA-seq analysis was conducted at the early and late stages of the fungal spot formation in infected sunflower tissues. A total of 2506, 3035, and 2660 differentially expressed genes (DEGs) between CT and each treatment group (LEAF-2d, LEAF-6d, and STEM) were retrieved, respectively. The most significant pathways of DEGs from these diseased sunflower tissues were the metabolic pathways and biosynthesis of secondary metabolites. Overall, 371 up-regulated DEGs were shared among LEAF-2d, LEAF-6d, and STEM, including 82 mapped to DFVF, 63 mapped to PHI-base, 69 annotated as CAZymes, 33 annotated as transporters, 91 annotated as secretory proteins, and a carbon skeleton biosynthetic gene. The most important DEGs were further confirmed by RT-qPCR. This is the first report on the genome-scale assembly and annotation for P. macdonaldii. Our data provide a framework for further revealing the underlying mechanism of the pathogenesis of P. macdonaldii, and also suggest the potential targets for the diseases caused by this fungal pathogen.

Prevalence of smoking among nurses and its association with blood pressure: A cross-sectional study in 11 cities of China.

AIM: Smoking is harmful to human health. However, the relationship between smoking and blood pressure (BP) has not been consistent. This study aimed to analyse nurses' smoking behaviours and their relationship with BP. METHODS: This cross-sectional study recruited 128 009 nurses in 11 cities in China. They were surveyed with questionnaires including BP measurements. The main contents of the questionnaire included smoking status and other factors that might be associated with hypertension. Multiple linear regression analyses and binary logistic regression analyses were used to analyse the data. RESULTS: The results showed there was a significant difference in the smoking rate among nurses with different characteristics (P < 0.05). For both male and female nurses, smoking was associated with increased diastolic BP and mean arterial pressure, but only with increased systolic BP of male nurses. The prevalence of hypertension among male and female nurses was not related to smoking. CONCLUSION: Despite a relatively low overall smoking rate, rates among some groups are high. Different cities, hospitals, and departments can combine local data and conditions to formulate targeted tobacco control measures to improve nurses' physical and mental health.

RNAi machinery regulates nutrient metabolism and fluconazole resistance in the pathogenic fungus Cryptococcus deneoformans.

The RNAi machinery has been extensively studied in plant and animal cells for their crucial roles in the regulation of genome function. However, the potential roles of RNAi in controlling fungal growth and development have been poorly studied, especially in the basidiomycetous yeast Cryptococcus deneoformans. To characterize the biological functions of RNAi in the pathogenic fungus, a comparative analysis of mRNA profiles using high-throughput sequencing technology was performed for the wild type and the RNAi mutants of C. deneoformans. The results revealed a clear difference in the expression of genes associated with metabolic processes in the RNAi mutants. Besides, the growth under nutrient-limited conditions was significantly reduced in the ago2Δ mutant, suggesting the essential roles of Ago2 in nutrient metabolism. Further investigations revealed the differentially expressed transporters in the RNAi mutants, in which transporters involved in fluconazole efflux were significantly up-regulated. More importantly, on account of the upregulated transporters, RNAi mutant strains developed resistance to fluconazole. By disrupting AFR1 gene using the 'suicide' CRISPR-Cas9 system, we verified that the upregulated ABC transporter Afr1 in the RNAi mutants contributed to the fluconazole resistance. In summary, our data demonstrate that in C. deneoformans the RNAi pathway participates in nutrient metabolism and plays a role in the repression of fluconazole resistance, which provides a deep insight into RNAi mechanisms in Cryptococcus and brings great hints for the clinical treatment of cryptococcosis.

Transcriptome sequencing reveals biological functions of RNAi in C. deneoformans. Nutritional metabolism is deficient due to the AGO2 disruption. RNAi mechanism inhibits fluconazole resistance by regulating the expression of transporters.

A cross-sectional study of the interaction between night shift frequency and age on hypertension prevalence among female nurses.

Night shift is a common work schedule. This study aimed to analyze the interaction between age and frequency of night shift on the hypertension prevalence. A census questionnaire was conducted in 512 medical institutions in 11 cities of Hebei Province. One lakh twenty-one thousand nine hundred three female nurses were included in this study. Binary Logistic regression analysis was done by SPSS Version 26.0. The youngest age group without night shift was used as the reference group. The odds ratio was calculated by different combinations of interaction items. Interaction coefficients were calculated by an Excel table designed by Andersson. Compared with the 18-25 year old ones without night shift, there existed an additive interaction between the age of 36-45 and more than 5-10 night shifts per month on hypertension prevalence. Odds ratio, the relative excess risk of interaction, the attributable proportion of interaction, and the synergy index and their 95% confidence intervals were 2.923(2.292-3.727), 0.631(0.309-0.954), 0.216(0.109-0.323), 1.488(1.158-1.913). Additive interaction was also found between the age of 36-45 and more than 10 night shifts per month. OR, RERI, API, SI, and their 95% confidence intervals were 3.430(2.273-5.175) 1.037(0.061-2.013), 0.303(0.089-0.516), and 1.746(1.093-2.788). There also existed an additive interaction between the age of 46-65 and more than 5-10 night shifts per month on hypertension prevalence. OR, RERI, API, SI, and their 95% confidence intervals were 7.398(5.595-9.781) 1.809(0.880-2.739), 0.245(0.148-0.341), and 1.394(1.199-1.622).There existed interaction between specific age groups and night shift frequency on the prevalence of hypertension among female nurses.

Acquiring novel chemicals by overexpression of a transcription factor DibT in the dibenzodioxocinone biosynthetic cluster in Pestalotiopsis microspora.

The endophytic fungus Pestalotiopsis microspora has drawn attention due to its production of dibenzodioxocinones which are a new class of inhibitors of cholesterol ester transfer protein (CETP). Previous studies showed that the pks8 gene cluster is responsible for the biosynthesis of dibenzodioxocinones in P. microspora. Disrupting the gene encoding a transcription factor DibT, which contains a zinc-finger functional domain, led to a significant decrease in the production of dibenzodioxocinones. To further investigate the function of DibT in the expression of pks8 cluster, we constructed dibT-overexpressing strains and found that all genes in the pks8 cluster were upregulated and the yields of dibenzodioxocinones were significantly increased. Moreover, function of DibT was required for the expression of most PKS genes outside of pks8 clusters, i.e., 43 out of 48 defined PKS genes, and boosted pigmentation of the mycelium and conidia. Still, we identified a new dibenzodioxocinone, 1',2'-dimethyl-3'-formyl- 1',2'-dehydropenicillide (6) and a previously known, but conditionally synthesized dibenzodioxocinone, 3'-methoxy-1',2'-dehydropenicillide (4) from the overexpression strains. Our results show that DibT was the key transcription factor in the expression of pks8 cluster and still has a wide effect on the expression of PKS genes in the genome. This work provides information for the regulation of dibenzodioxocinone biosynthesis and may be helpful for the development of new CETP inhibitors.

The optimal spacing interval between principal shelterbelts of the farm-shelter forest network.

The farm-shelter forest network is a complex grid protection system, with a windbreak that is distinctly different from that of the single shelterbelt. We selected the farm-shelter forest network of a jujube field in the Tarim Basin of northwest China and used a combination of field measurements and wind tunnel tests to determine the optimal spacing interval between principal shelterbelts. The wind speed reductive curve of the farm-shelter forest network showed a gradual wind speed tendency to stability. Therefore, a model was established based on the energy transfer balance between the upper and the lower airflows for a steady wind speed. The prediction error of the model was found to be < 1%. The model results indicated that increasing the spacing interval between principal shelterbelts from 10 to 20 H, where H is the shelterbelt height, maintained more than 70% of the windbreak effect of the farm-shelter forest network. If the spacing interval between principal shelterbelts were to be increased from 10 to 20 H, the jujube planting area would be increased by 0.54%. Therefore, a thorough consideration of the windbreak effect of each shelterbelt, the synergistic effects of shelterbelts, the windbreak effects of tall crops, and the effects of temperature and humidity in farm-shelter forest networks indicates that increasing the spacing interval will not only maintain the windbreak effect, but it will also reduce the side effects of shelterbelts, increase the planting area, favor mechanized operation, and improve planting efficiency.

[Development of the iGEM high school track].

The international genetically engineered machine (iGEM) competition is a global top college academic competition in synthetic biology. The iGEM competition has exhibited extensive international influence and attracted teams from more than 40 countries and regions around the world to participate in. The annual iGEM outputs have attracted the attention of top academic journals or international media such as Science, Nature, Scientific American, The Economist, British Broadcasting Corporation (BBC), etc. High school teams participated in iGEM since 2011, and the number of high school teams has increased year by year. High school participants are increasingly becoming one of the most important forces to promote the development of iGEM and synthetic biology. IGEM competition has also become an important platform to foster the core literacy of high school students. This paper summarized the track rules, topic selection tendency and awards of high school teams based on data of 2017 to 2021 iGEM competition. In addition, we analyzed the significance of iGEM competition on fostering of high school students' core literacy and discussed the development trend of global high school teams, with the aim to provide a reference for high school team building in the future.

Deletion of a Rare Fungal PKS CgPKS11 Promotes Chaetoglobosin A Biosynthesis, Yet Defers the Growth and Development of Chaetomium globosum.

We previously reported that chaetoglobosin A (ChA) exhibits a great potential in the biocontrol of nematodes and pathogenic fungi. To improve the production of ChA, a CRISPR-Cas9 system was created and applied for eliminating potential competitive polyketide products. One of the polyketide synthase encoding genes, Cgpks11, which is putatively involved in the biosynthesis of chaetoglocin A, was disrupted. Cgpks11 deletion led to the overexpression of the CgcheA gene cluster, which is responsible for ChA biosynthesis, and a 1.6-fold increase of ChA. Transcription of pks-1, a melanin PKS, was simultaneously upregulated. Conversely, the transcription of genes for chaetoglocin A biosynthesis, e.g., CHGG_10646 and CHGG_10649, were significantly downregulated. The deletion also led to growth retardation and seriously impaired ascospore development. This study found a novel regulatory means on the biosynthesis of ChA by CgPKS11. CgPKS11 affects chaetoglobosin A biosynthesis, growth, and development in Chaetomium globosum.

A Rapid, Visible, and Highly Sensitive Method for Recognizing and Distinguishing Invasive Fungal Infections via CCP-FRET Technology.

Invasive fungal infection (IFI) is one of the leading causes of death in the intensive care unit (ICU) due to its high morbidity and mortality among immunocompromised patients. Early diagnosis of IFI is typically infeasible because of the lack of clinical signs and symptoms. By virtue of the cationic conjugated polymer-based fluorescence resonance energy transfer (CCP-FRET) technology, we develop a rapid, visible, simple, and sensitive method for simultaneous detection and discrimination of three types of pathogens, including Candida albicans (C. albicans), Klebsiella pneumoniae (K. pneumoniae), and Cryptococcus neoformans (C. neoformans). The CCP-FRET system contains a CCP fluorescent probe and pathogen-specific DNA labeled with fluorescent dyes. These two components spontaneously self-assemble into the complex under electrostatic attraction, resulting in an efficient FRET from CCP to fluorescent dyes when irradiated with a 380 nm ultraviolet (UV) light. The CCP-FRET method can specifically identify the DNA molecules that are extracted from culture pathogen strains or blood samples via PCR and single base extension (SBE) reactions, without any cross-reactions on the DNA of nonspecific strains. In particular, the sensitivity of this method is down to 0.03125 ng, which is ten times higher than that of real-time PCR. We further evaluate its detection efficiency by testing 15 blood samples from neonatal patients who suffer from pathogen infections, in which some of them have undergone antipathogen treatments. Using the CCP-FRET method, 33.3% (5/15) of samples tested positive for C. albicans and/or K. pneumoniae infections, whereas no pathogen DNAs are recognized with real-time PCR, despite using the same primers. Interestingly, the CCP-FRET method can output unique fluorescent color as well as RGB patterns to different types of pathogen infections, by which the infection type can be conveniently determined. Collectively, the CCP-FRET method is a sensitive and reliable detection platform for rapid identification of fungal and bacterial multiple infections, holding great promise for uses in clinical testing.

Epigenetic regulation of virulence and the transcription of ribosomal protein genes involves a YEATS family protein in Cryptococcus deneoformans.

Epigenetic marks or post-translational modifications on histones have important regulatory roles in gene expression in eukaryotic organisms. The epigenetic regulation of gene expression in the pathogenic yeast Cryptococcus deneoformans remains largely undetermined. The YEATS domain proteins are readers of crotonylated lysine residues in histones. Here, we reported the identification of a single-copy gene putatively coding for a YEATS domain protein (Yst1) in C. deneoformans. To define its function, we created a mutant strain, yst1Δ, using CRISPR-Cas9 editing. yst1Δ exhibited defects in phenotype, for instance, it was hypersensitive to osmotic stress in the presence of 1.3 M NaCl or KCl. Furthermore, it was hypersensitive to 1% Congo red, suggesting defects in the cell wall. Interestingly, RNA-seq data revealed that Yst1p was critical for the expression of genes encoding the ribosomal proteins, that is, most were expressed with significantly lower levels of mRNA in yst1Δ than in the wild-type strain. The mutant strain was hypersensitive to low temperature and anti-ribosomal drugs, which we putatively attribute to the impairment in ribosomal function. In addition, the yst1Δ strain was less virulent to Galleria mellonella. These results generally suggest that Yst1, as a histone modification reader, might be a key coordinator of the transcriptome of this human pathogen. Yst1 could be a potential target for novel antifungal drugs, which might lead to significant developments in the clinical treatment of cryptococcosis.

Effect of frequency and pattern of night shift on hypertension risk in female nurses: a cross-sectional study.

OBJECTIVES: Understanding the effect of night shift on hypertension risk in nurses is important to improve the health of nurses and ensure patient safety. This study aimed to evaluate the effect of the frequency and pattern of night shift on hypertension risk and the interaction of them in female nurses. METHODS: This cross-sectional study constituted 84 697 female nurses in 13 cities in China. The main contents of the survey included SBP, DBP, the frequency and pattern of night shift, and some other factors that might be associated with hypertension. Logistic regression analyses were used to calculate ORs and 95% CIs to estimate the effect of the frequency and pattern of night shift on hypertension risk and the interaction of them in relation to hypertension risk. RESULTS: Having more than 5 to 10 or more than 10 night shifts per month were significantly more likely to be hypertensive (OR 1.19, 95% CI 1.10-1.28; OR 1.32, 95% CI 1.13-1.54), whereas having less than or equal to 5 night shifts per month was not (OR 1.05, 95% CI 0.95-1.16). The patterns of night shift were all associated with a higher probability of hypertension and participants engaging in rapidly rotating night shift had a lower OR (1.14) than those having slowly rotating night shift (1.23) and permanent night shift (1.46). No significant interaction was observed between the frequency and the pattern of night shift (Pinteraction = 0.281). CONCLUSION: The frequency and pattern of night shift were associated with hypertension risk in female nurses and no significant interaction was observed between them.

A Putative C2H2 Transcription Factor CgTF6, Controlled by CgTF1, Negatively Regulates Chaetoglobosin A Biosynthesis in Chaetomium globosum.

Gα signaling pathway as well as the global regulator LaeA were demonstrated to positively regulate the biosynthesis of chaetoglobosin A (ChA), a promising biotic pesticide produced by Chaetomium globosum. Recently, the regulatory function of Zn2Cys6 binuclear finger transcription factor CgcheR that lies within the ChA biosynthesis gene cluster has been confirmed. However, CgcheR was not merely a pathway specific regulator. In this study, we showed that the homologs gene of CgcheR (designated as Cgtf1) regulate ChA biosynthesis and sporulation in C. globosum NK102. More importantly, RNA-seq profiling demonstrated that 1,388 genes were significant differentially expressed as Cgtf1 deleted. Among them, a putative C2H2 transcription factor, named Cgtf6, showed the highest gene expression variation in zinc-binding proteins encoding genes as Cgtf1 deleted. qRT-PCR analysis confirmed that expression of Cgtf6 was significantly reduced in CgTF1 null mutants. Whereas, deletion of Cgtf6 resulted in the transcriptional activation and consequent increase in the expression of ChA biosynthesis gene cluster and ChA production in C. globosum. These data suggested that CgTF6 probably acted as an end product feedback effector, and interacted with CgTF1 to maintain a tolerable concentration of ChA for cell survival.

Transcription Factors Pmr1 and Pmr2 Cooperatively Regulate Melanin Biosynthesis, Conidia Development and Secondary Metabolism in Pestalotiopsis microspora.

Melanins are the common fungal pigment, which contribute to stress resistance and pathogenesis. However, few studies have explored the regulation mechanism of its synthesis in filamentous fungi. In this study, we identified two transcription factors, Pmr1 and Pmr2, in the filamentous fungus Pestalotiopsis microspora. Computational and phylogenetic analyses revealed that Pmr1 and Pmr2 were located in the gene cluster for melanin biosynthesis. The targeted deletion mutant strain Δpmr1 displayed defects in biosynthesis of conidia pigment and morphological integrity. The deletion of pmr2 resulted in reduced conidia pigment, but the mycelial morphology had little change. Moreover, Δpmr2 produced decreased conidia. RT-qPCR data revealed that expression levels of genes in the melanin biosynthesis gene cluster were downregulated from the loss of Pmr1 and Pmr2. Interestingly, the yield of secondary metabolites in the mutant strains Δpmr1 and Δpmr2 increased, comparing with the wild type, and additionally, Pmr1 played a larger regulatory role in secondary metabolism. Taken together, our results revealed the crucial roles of the transcription factors Pmr1 and Pmr2 in melanin synthesis, asexual development and secondary metabolism in the filamentous fungus P. microspora.

A Fungal Diterpene Synthase Is Responsible for Sterol Biosynthesis for Growth.

A conserved open reading frame, dps, is described in Pestalotiopsis microspora, sharing a remarkable similarity with fungal diterpene synthases whose function is less studied. Loss-of-function approach manifested that dps was necessary for the growth and the development of the fungus. A deletion strain, dpsΔ, showed a fundamental retardation in growth, which could deliberately be restored by the addition of exogenous sterols to the media. Gas chromatography-mass spectrometry analysis confirmed the loss of the ability to produce certain sterols. Thus, the tolerance and the resistance of dpsΔ to several stress conditions were impaired. Secondary metabolites, such as the polyketide derivative dibenzodioxocinones, were significantly diminished. At the molecular level, the deletion of dps even affected the expression of genes in the mevalonate pathway. This report adds knowledge about fungal diterpene synthases in Pestalitiopsis microspora.

An effective method to produce 7-epitaxol from taxol in HCO3.

It is known that 7-epitaxol has much stronger cytotoxicity than taxol does. However, the content of 7-epitaxol in yew is much less than taxol, which makes it more costly to obtain. We describe here a method to effectively convert taxol to 7-epitaxol. The key condition for reaction needs NaHCO3 in solvent acetonitrile (ACN). The conversion rate can be over 82%.

A Gene Cluster for the Biosynthesis of Dibenzodioxocinons in the Endophyte Pestalotiopsis microspora, a Taxol Producer.

The fungal products dibenzodioxocinones promise a novel class of inhibitors against cholesterol ester transfer protein (CEPT). Knowledge as to their biosynthesis is scarce. In this report, we characterized four more dibenzodioxocinones, which along with a previously described member pestalotiollide B, delimit the dominant spectrum of secondary metabolites in P. microspora. Through mRNA-seq profiling in gα1Δ, a process that halts the production of the dibenzodioxocinones, a gene cluster harboring 21 genes including a polyketide synthase, designated as pks8, was defined. Disruption of genes in the cluster led to loss of the compounds, concluding the anticipated role in the biosynthesis of the chemicals. The biosynthetic route to dibenzodioxocinones was temporarily speculated. This study reveals the genetic basis underlying the biosynthesis of dibenzodioxocinone in fungi, and may facilitate the practice for yield improvement in the drug development arena.

Role of the fungus-specific flavin carrier Flc1 in antifungal resistance in the fungal pathogen Cryptococcus neoformans.

FLC family, a conserved fungus-specific family of integral membrane proteins, has been demonstrated to play important roles in flavin transport, growth, and virulence in several fungi but not yet in Cryptococcus neoformans. In this study, we have identified the single homologue of flavin adenine dinucleotide transporter in the opportunistic pathogen C. neoformans. The computational and phylogenetic analysis confirmed the fungal specificity of cryptococcal Flc1 protein, thus providing a promising drug target for clinical treatment of cryptococcosis. Disruption of FLC1 conferred sensitivity to 1% Congo red and 0.02% SDS, as well as leading to impaired chitin distribution in cell wall as observed with Calcofluor White staining, which collectively indicated the roles of FLC1 in maintenance of cell wall integrity. Further investigations revealed the defects of flc1Δ mutant in resistance to poor nutrition and elevated temperatures, and the ability to undergo invasive growth under nutrient-depleted conditions was reduced as well in flc1Δ mutant, suggesting the roles of Flc1 in response to environmental stresses. More importantly, our results showed that flc1Δ mutant exhibited severe susceptibility to antifungal aminoglycosides (hygromycin B and geneticin) and amphotericin B, but developed multidrug resistance to flucytosine and rapamycin, which provided great hints for therapeutic failure of cryptococcosis in clinic with the standard combination therapy. Finally, typical virulence factors including melanin biosynthesis and capsule formation in flc1Δ mutant were reduced as well, indicating the possible involvement of Flc1 in virulence.

Regulation of the Gα-cAMP/PKA signaling pathway in cellulose utilization of Chaetomium globosum.

BACKGROUND: The canonical heterotrimeric G protein-cAMP/PKA pathway regulates numerous cellular processes in filamentous fungi. Chaetomium globosum, a saprophytic fungus, is known for producing many secondary metabolites, including cytotoxic chaetoglobosin A (ChA), as well as abundant cellulase and xylanase. RESULTS: Here we report on the functional characterization of this signaling pathway in C. globosum. We blocked the pathway by knocking down the putative Gα-encoding gene gna1 (in the pG14 mutant). This led to impaired cellulase production and significantly decreased transcription of the major cellulase and xylanase genes. Almost all the glycohydrolase family genes involved in cellulose degradation were downregulated, including the major cellulase genes, cel7a, cel6a, egl1, and egl2. Importantly, the expression of transcription factors was also found to be regulated by gna1, especially Ace1, Clr1/2 and Hap2/3/5 complex. Additionally, carbon metabolic processes including the starch and sucrose metabolism pathway were substantially diminished, as evidenced by RNA-Seq profiling and quantitative reverse transcription (qRT)-PCR. Interestingly, these defects could be restored by simultaneous knockdown of the pkaR gene encoding the regulatory subunit of cAMP-dependent PKA (in the pGP6 mutant) or supplement of the cAMP analog, 8-Br-cAMP. Moreover, the Gα-cAMP/PKA pathway regulating cellulase production is modulated by environmental signals including carbon sources and light, in which VelB/VeA/LaeA complex and ENVOY probably work as downstream effectors. CONCLUSION: These results revealed, for the first time, the positive role of the heterotrimeric Gα-cAMP/PKA pathway in the regulation of cellulase and xylanase utilization in C. globosum.

A MYST Histone Acetyltransferase Modulates Conidia Development and Secondary Metabolism in Pestalotiopsis microspora, a Taxol Producer.

Reverse genetics is a promising strategy for elucidating the regulatory mechanisms involved in secondary metabolism and development in fungi. Previous studies have demonstrated the key role of histone acetyltransferases in transcriptional regulation. Here, we identified a MYST family histone acetyltransferase encoding gene, mst2, in the filamentous fungus Pestalotiopsis microspora NK17 and revealed its role in development and secondary metabolism. The gene mst2 showed temporal expression that corresponded to the conidiation process in the wild-type strain. Deletion of mst2 resulted in serious growth retardation and impaired conidial development, e.g., a delay and reduced capacity of conidiation and aberrant conidia. Overexpression of mst2 triggered earlier conidiation and higher conidial production. Additionally, deletion of mst2 led to abnormal germination of the conidia and caused cell wall defects. Most significantly, by HPLC profiling, we found that loss of mst2 diminished the production of secondary metabolites in the fungus. Our data suggest that mst2 may function as a general mediator in growth, secondary metabolism and morphological development.