Multi-omic analysis tools for microbial metabolites prediction.

How to resolve the metabolic dark matter of microorganisms has long been a challenging problem in discovering active molecules. Diverse omics tools have been developed to guide the discovery and characterization of various microbial metabolites, which make it gradually possible to predict the overall metabolites for individual strains. The combinations of multi-omic analysis tools effectively compensates for the shortcomings of current studies that focus only on single omics or a broad class of metabolites. In this review, we systematically update, categorize and sort out different analysis tools for microbial metabolites prediction in the last five years to appeal for the multi-omic combination on the understanding of the metabolic nature of microbes. First, we provide the general survey on different updated prediction databases, webservers, or software that based on genomics, transcriptomics, proteomics, and metabolomics, respectively. Then, we discuss the essentiality on the integration of multi-omics data to predict metabolites of different microbial strains and communities, as well as stressing the combination of other techniques, such as systems biology methods and data-driven algorithms. Finally, we identify key challenges and trends in developing multi-omic analysis tools for more comprehensive prediction on diverse microbial metabolites that contribute to human health and disease treatment.

AcrR1, a novel TetR/AcrR family repressor, mediates acid and antibiotic resistance and nisin biosynthesis in Lactococcus lactis F44.

Lactococcus lactis, widely used in the manufacture of dairy products, encounters various environmental stresses both in natural habitats and during industrial processes. It has evolved intricate machinery of stress sensing and defense to survive harsh stress conditions. Here, we identified a novel TetR/AcrR family transcription regulator, designated AcrR1, to be a repressor for acid and antibiotic tolerance that was derepressed in the presence of vancomycin or under acid stress. The survival rates of acrR1 deletion strain ΔAcrR1 under acid and vancomycin stresses were about 28.7-fold (pH 3.0, HCl), 8.57-fold (pH 4.0, lactic acid) and 2.73-fold (300 ng/mL vancomycin) as that of original strain F44. We also demonstrated that ΔAcrR1 was better able to maintain intracellular pH homeostasis and had a lower affinity to vancomycin. No evident effects of AcrR1 deletion on the growth and morphology of strain F44 were observed. Subsequently, we characterized that the transcription level of genes associated with amino acids biosynthesis, carbohydrate transport and metabolism, multiple drug resistance and DNA repair proteins significantly upregulated in ΔAcrR1 using transcriptome analysis and quantitative reverse transcription-PCR (qRT-PCR) assays. Additionally, AcrR1 could repress the transcription of nisin post-translational modification gene, nisC, leading to a 16.3% increase in nisin yield after AcrR1 deletion. Our results not only refined the knowledge of the regulatory mechanism of TetR/AcrR family regulator in L. lactis, but presented a potential strategy to enhance industrial production of nisin.

Deciphering and designing microbial communities by genome-scale metabolic modelling.

Microbial communities are shaped by the complex interactions among organisms and the environment. Genome-scale metabolic models (GEMs) can provide deeper insights into the complexity and ecological properties of various microbial communities, revealing their intricate interactions. Many researchers have modified GEMs for the microbial communities based on specific needs. Thus, GEMs need to be comprehensively summarized to better understand the trends in their development. In this review, we summarized the key developments in deciphering and designing microbial communities using different GEMs. A timeline of selected highlights in GEMs indicated that this area is evolving from the single-strain level to the microbial community level. Then, we outlined a framework for constructing GEMs of microbial communities. We also summarized the models and resources of static and dynamic community-level GEMs. We focused on the role of external environmental and intracellular resources in shaping the assembly of microbial communities. Finally, we discussed the key challenges and future directions of GEMs, focusing on the integration of GEMs with quorum sensing mechanisms, microbial ecology interactions, machine learning algorithms, and automatic modeling, all of which contribute to consortia-based applications in different fields.

Tofacitinib Treatment for Pretibial Myxedema.

This case report describes tofacitinib treatment for 2 patients with pretibial myxedema.

Catalytic Mechanism and Heterologous Biosynthesis Application of Sesquiterpene Synthases.

Sesquiterpenes comprise a diverse group of natural products with a wide range of applications in cosmetics, food, medicine, agriculture, and biofuels. Heterologous biosynthesis is increasingly employed for sesquiterpene production, aiming to overcome the limitations associated with chemical synthesis and natural extraction. Sesquiterpene synthases (STSs) play a crucial role in the heterologous biosynthesis of sesquiterpene. Under the catalysis of STSs, over 300 skeletons are produced through various cyclization processes (C1-C10 closure, C1-C11 closure, C1-C6 closure, and C1-C7 closure), which are responsible for the diversity of sesquiterpenes. According to the cyclization types, we gave an overview of advances in understanding the mechanism of STSs cyclization from the aspects of protein crystal structures and site-directed mutagenesis. We also summarized the applications of engineering STSs in the heterologous biosynthesis of sesquiterpene. Finally, the bottlenecks and potential research directions related to the STSs cyclization mechanism and application of modified STSs were presented.

Heterologous Biosynthesis of Kauralexin A1 in Saccharomyces cerevisiae through Metabolic and Enzyme Engineering.

Kauralexin A1 (KA1) is a key intermediate of the kauralexin A series metabolites of maize phytoalexins. However, their application is severely limited by their low abundance in maize. In this study, an efficient biosynthetic pathway was constructed to produce KA1 in Saccharomyces cerevisiae. Also, metabolic and enzyme engineering strategies were applied to construct the high-titer strains, such as chassis modification, screening synthases, the colocalization of enzymes, and multiple genomic integrations. First, the KA1 precursor ent-kaurene was synthesized using the efficient diterpene synthase GfCPS/KS from Fusarium fujikuroi, and optimized to reach 244.36 mg/L in shake flasks, which displayed a 200-fold increase compared to the initial strain. Then, the KA1 was produced under the catalysis of ZmCYP71Z18 from Zea mays and SmCPR1 from Salvia miltiorrhiza, and the titer was further improved by integrating the fusion protein into the genome. Finally, an ent-kaurene titer of 763.23 mg/L and a KA1 titer of 42.22 mg/L were achieved through a single-stage fed-batch fermentation in a 5 L bioreactor. This is the first report of the heterologous biosynthesis of maize diterpene phytoalexins in S. cerevisiae, which lays a foundation for further pathway reconstruction and biosynthesis of the kauralexin A series maize phytoalexins.

Neutrophil extracellular traps and neutrophilic dermatosis: an update review.

Neutrophils have both antimicrobial ability and pathogenic effect in the immune system, neutrophil extracellular traps (NETs) formation is one of the representative behaviors of their dual role. NETs formation was triggered by pathogen-related components and pathogen non-related proteins as cytokines to exert its effector functions. Recent studies indicate that the pathogenicity of NETs contributed to several skin diseases such as psoriasis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and neutrophilic dermatosis. Especially in neutrophilic dermatosis, a heterogeneous group of inflammatory skin disorders characterized with sterile neutrophilic infiltrate on dermis, NETs formation was reported as the way of participation of neutrophils in the pathogenesis of these diseases. In this review, we describe the different processes of NETs formation, then summarized the most recent updates about the pathogenesis of neutrophilic dermatosis and the participation of NETs, including pyoderma gangrenosum and PAPA syndrome, Behçet syndrome, hidradenitis suppurativa, Sweet Syndrome, pustular dermatosis and other neutrophilic dermatosis. Furthermore, we discuss the link between NETs formation and the development of neutrophilic dermatosis.

Clinical features of macrophage activation syndrome in adult dermatomyositis: A single-center retrospective case-control study.

BACKGROUND: Little is known about the features of macrophage activation syndrome (MAS) in dermatomyositis, especially the association between rapidly progressive interstitial lung disease (RP-ILD) and MAS. OBJECTIVE: To determine the characteristics of MAS in patients with dermatomyositis and their association with RP-ILD. METHODS: This was a retrospective cohort study of 201 dermatomyositis patients at the First Affiliated Hospital of Zhejiang University over a 10-year period. RESULTS: A total of 22 (10.9%) patients were diagnosed with MAS. The rate of RP-ILD was significantly higher in patients with MAS than in those without MAS (81.8% vs. 17.4%, respectively, p < .001). Multivariate analysis indicated that RP-ILD (p = .019), ferritin level > 1685 ng/mL (p = .007) and hemoglobin < 100 g/L (p = .001) were independent risk factors for MAS. Furthermore, RP-ILD patients with MAS presented more cardiac injury (50.0% vs. 13.3%, respectively, p < .009), central nervous system dysfunction (42.8% vs. 3.4%, respectively, p < .001) and hemorrhage (38.9% vs. 3.3%, respectively, p = .003) than RP-ILD patients without MAS. The 90-day cumulative survival rate for patients with MAS was significantly lower than for those without MAS (18.2% vs. 82.1%, respectively, p < .001). CONCLUSION: MAS was a common and fatal complication of dermatomyositis in our cohort. MAS is closely related to RP-ILD in patients with dermatomyositis. When RP-ILD is present in dermatomyositis patients with abnormal laboratory findings, such as cytopenia and hyperferritinemia, the presence of MAS should be considered.

Basal cell carcinoma arising within nevus sebaceous on the right scalp in a 55-year-old male: A case report and review of literature.

We report here a case of nevus sebaceous in a 55-year-old male, who presented with a 50-year history of an asymptomatic swelling in his right scalp. The solitary, yellowish, expansile plaque over the scalp gradually became lobulated and turned dark-pigmented with spontaneous bleeding, itching discomfort, and occasional ulceration after scratching. The male's clinical presentation and histopathological findings were compatible with basal cell carcinoma arising in nevus sebaceous. At present, 5-aminolevulinic acid photodynamic therapy (ALA-PDT) emerges as a novel treatment modality which has proved safe and effective. In this case, three sessions of photodynamic therapy in combination with surgical excision were performed, leaving mild pigmentation within 3 weeks. The patient showed good cosmetic outcome, minimal scarring on the right scalp without further complications, disease recurrence or metastasis after ALA-PDT within six months.

Multiple Umbilicated Papules on the Face.

A man in his 20s presented to the dermatology department with a monthlong history of gradually progressing papules and nodules on the face, accompanied by fever, fatigue, and weight loss. What is your diagnosis?

Molecular and Functional Analyses of Characterized Sesquiterpene Synthases in Mushroom-Forming Fungi.

Sesquiterpenes are a type of abundant natural product with widespread applications in several industries. They are biosynthesized by sesquiterpene synthases (STSs). As valuable and abundant biological resources, mushroom-forming fungi are rich in new sesquiterpenes and STSs, which remain largely unexploited. In the present study, we collected information on 172 STSs from mushroom-forming fungi with experimentally characterized products from the literature and sorted them to develop a dataset. Furthermore, we analyzed and discussed the phylogenetic tree, catalytic products, and conserved motifs of STSs. Phylogenetic analysis revealed that the STSs were clustered into four clades. Furthermore, their cyclization reaction mechanism was divided into four corresponding categories. This database was used to predict 12 putative STS genes from the edible fungi Flammulina velutipes. Finally, three FvSTSs were selected to experimentally characterize their functions. FvSTS03 predominantly produced Δ-cadinol and FvSTS08 synthesized ß-barbatene as the main product; these findings were consistent with those of the functional prediction analysis. A product titer of 78.8 mg/L ß-barbatene was achieved in Saccharomyces cerevisiae via metabolic engineering. Our study findings will help screen or design STSs from fungi with specific product profiles as functional elements for applications in synthetic biology.

Monkeypox presenting as a chancre-like rash: A case report.

BACKGROUND: Since May 2022, outbreaks of monkeypox have occurred in many countries around the world, and several cases have been reported in China. CASE SUMMARY: A 38-year-old man presented with a small, painless, shallow ulcer on the coronary groove for 8 d. One day after the rash appeared, the patient developed inguinal lymphadenopathy with fever. The patient had a history of male-male sexual activity and denied a recent history of travel abroad. Monkeypox virus was detected by quantitative polymerase chain reaction from the rash site and throat swab. Based on the epidemiological history, clinical manifestations and nucleic acid test results, the patient was diagnosed with monkeypox. CONCLUSION: Monkeypox is an emerging infectious disease in China. Monkeypox presenting as a chancre-like rash is easily misdiagnosed. Diagnosis can be made based on exposure history, clinical manifestations and nucleic acid test results.