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Lysine-specific demethylase 1 (LSD1) is the firstly discovered histone demethylase. In recent years, LSD1 has become a hot topic in the study of the development and progression of malignancies, and its expression is closely related to the poor prognosis of malignancies. At present, some studies have showed that LSD1 is strongly related to the proliferation, invasion and metastasis of triple-negative breast cancer (TNBC). However, the specific mechanism is not fully understood. This article summarizes the possible mechanism of the development and progression in LSD1 and TNBC, and reviews the latest progress of LSD1 in the clinical research application of TNBC, so as to provide a reference for drug combination therapy in TNBC patients.

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【Objective】 To explore the correlation between abnormal thalamic functional connectivity (FC) and memory loss in maintenance hemodialysis patients with end-stage renal disease (ESRD). 【Methods】 An auditory verbal learning test (AVLT-H) was conducted on 22 patients with ESRD and 28 age-, sex-, and education-matched healthy controls (HC) to evaluate memory function. After that, resting-state functional magnetic resonance imaging (rs-fMRI) data were gathered, and a whole-brain FC analysis centered on the thalamus was executed to discern variations in thalamic FC between the two groups. Finally, Pearson and Spearman correlation analyses were carried out. 【Results】 Compared to the HC group, the ESRD group exhibited notably lower scores in IR-S (P=0.002), SR-S (P<0.001), and LR-S (P=0.005). Concurrently, the ESRD group demonstrated diminished FC of the right thalamus with the left superior frontal gyrus, the left parietal lobule, the right suproccipital gyrus, the right anterior cuneus, and the right middle frontal gyrus (P<0.05, TFCE correction). Additionally, reduced FC were observed between the left thalamus and the left gyrus rectus, the left parietal lobule, and the right parietal lobule in the ESRD group (P<0.05, TFCE correction). Moreover, the FC values between the left thalamus and the left gyrus rectus in the ESRD group displayed significant negative correlations with IR-S (r=-0.499), SR-S (r=-0.458), and LR-S (r=-0.455) (all P<0.05). 【Conclusion】 Memory impairment is evident in ESRD patients undergoing maintenance hemodialysis, and it appears to be intricately linked to anomalous FC within the left thalamus and the left gyrus rectus. These findings offer potential imaging markers for monitoring memory dysfunction in individuals with ESRD.

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Streptomyces clavuligerus NRRL 3585 is a native producer of clavulanic acid (CA), a clinically used ß-lactamase inhibitor, and is widely used as an industrial strain for the production of antibiotics. Selective random mutagenesis has successfully generated the improved CA-producing S. clavuligerus mutant strains as well as the strain with the loss of CA biosynthesis. To understand the molecular mechanisms associated with the improved CA-production potential, genome-scale RNA-sequencing-based transcriptional data were obtained for the wild-type S. clavuligerus strain and its three mutant strains. Total RNA samples for each strain were collected across four different growth stages, and all 32 sequencing data points exhibited an average Phred score of 36. The high-quality genome-scale transcriptional profile of S. clavuligerus strains with varied CA biosynthetic potential provides valuable insights and new opportunities for discovering efficient metabolic engineering strategies for the development of improved industrial strains.

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Adaptive cellular immunotherapy, especially chimeric antigen receptor-T (CAR-T) cell therapy, has advanced the treatment of hematological malignancy. However, major limitations still remain in the source of cells comes from the patients themselves. The use of human pluripotent stem cells to differentiate into immune cells, such as T cells, NK cells, and macrophages, then arm with chimeric antigen receptor (CAR) to enhance tumor killing has gained major attention. It is expected to solve the low number of immune cells recovery from patients, long waiting periods, and ethical issues(reprogramming somatic cells to produce induced pluripotent stem cells (iPS cells) avoids the ethical issues unique to embryonic stem cells (Lo and Parham, 2009). However, there are still major challenges to be further solved. This review summarizes the progress, challenges, and future direction in human pluripotent stem cell-based immunotherapy.

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The differentiation of natural killer (NK) cells from human pluripotent stem cells allows for research on and the manufacture of clinical-grade cellular products for immunotherapy. Described here is a two-phase protocol that uses a serum-free commercial medium and a cocktail of cytokines (interleukin [IL]-3, IL-7, IL-15, stem cell factor [SCF], and FMS-like tyrosine kinase 3 ligand [Ftl3L]) to differentiate human expanded potential stem cells (hEPSCs) into cells that possess NK cell properties in vitro with both 3-dimensional (3D) and 2-dimensional (2D) culture technology. Following this protocol, CD3-CD56+ or CD45+CD56+ NK cells are consistently generated. When cocultured with tumor targets for 3 h, the differentiated products display mild cytotoxicity as compared to an IL-2-independent permanent cell line, NK92mi cells. The protocol preserves the complexity of the differentiation microenvironment by the generation of 3D structures, thus facilitating the study of the spatial relationships between immune cells and their niches. Meanwhile, the 2D culture system enables the routine phenotypical validation of cell differentiation without harming the delicate differentiation niche.

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OBJECTIVE To evaluate the cost-effectiveness of sugemalimab in patients with stage Ⅲ non-small cell lung cancer （NSCLC） whose disease had not progressed after concurrent or sequential chemoradiotherapy from the perspective of the Chinese healthcare system. METHODS Based on the GEMSTONE-301 clinical trial，a three-health state partitioned survival model （PartSA） was developed to simulate the progression of disease，with model cycle of 3 weeks and a lifetime time range； the main output indicators of the model were total cost，quality-adjusted life year （QALY），and incremental cost-effectiveness ratio （ICER）； the cost and health output were discounted using 5% discount rate. Using 1-3 times China’s per capita gross domestic product （GDP） in 2022 as the willingness-to-pay （WTP） threshold，the cost-utility analysis method was used for analysis，and sensitivity analysis and scenario analysis were conducted to assess model robustness. RESULTS Compared with placebo，ICER for sugemalimab consolidation therapy was 59 872.57 yuan/QALY，which was less than one time China’s per capita GDP in 2022 （85 698 yuan） as the WTP threshold. The scenario analysis results further confirmed the robustness of the model. The results of single factor sensitivity analysis indicated that the cost of drugs （pembrolizumab，sugemalimab，docetaxel） and the utility value of disease progression status had a significant impact on ICER； the results of the probabilistic sensitivity analysis showed that sugemalimab had 67.2% probability of being cost-effective at one time China’s GDP per capita in 2022 as the WTP threshold； when 20 000 yuan （less than 3 times GDP per capita in China of 257 094 yuan） was used as the WTP threshold，the probability of sugemalimab consolidation therapy being cost-effective was greater than 98%. CONCLUSIONS The consolidation therapy with sugemalimab is cost-effective for stage Ⅲ NSCLC whose disease had not progressed after concurrent or sequential chemoradiotherapy.

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OBJECTIVE@#To observe the effects of electroacupuncture (EA) on cardiac function and local field potential (LFP) in sensory and motor cortices in mice with stress cardiomyopathy (SC), and to explore the possible mechanism of EA in improving SC.@*METHODS@#Twenty-seven female C57BL/6 mice were randomized into a blank group, a model group and an EA group, 9 mice in each group. In the model group and the EA group, SC model was established by continuous intraperitoneal injection of isoproterenol (ISO) for 14 days. At the same time of modeling, EA was applied at "Neiguan" (PC 6) and "Shenmen" (HT 7) in the EA group, with disperse-dense wave, in frequency of 2 Hz/15 Hz, 15 min each time, once a day for 14 days. After intervention, the total movement distance, the number of crossing grid and the number of crossing central grid of open field test within 5 minutes were observed; the left ventricular function indexes (left ventricular diameter of end-diastole [LVIDd], left ventricular diameter of end-systole [LVIDs], left ventricular volume of end-diastole [LVEDV], left ventricular volume of end-systole [LVESV], ejection fraction [EF] and fraction shortening [FS]) were detected by echocardiography; the changes in ST-segment amplitude and PR interval of electrocardiogram were observed; the morphology of myocardial tissue was observed by HE staining; the serum levels of cortisol (CORT), cardiac troponin T (cTnT) and brain natriuretic peptide (BNP) were detected by ELISA; the changes of LFP in sensory and motor cortices were recorded by Plexon multi-channel acquisition system.@*RESULTS@#Compared with the blank group, in the model group, the total movement distance, the number of crossing grid and the number of crossing central grid of open field test were decreased (P<0.05); LVIDd, LVIDs, LVEDV and LVESV were increased (P<0.05), EF and FS were decreased (P<0.05); ST-segment amplitude was increased (P<0.05) and PR interval was prolonged (P<0.05); irregular myocardial fiber arrangement, interstitial edema and inflammatory cell infiltration were observed; the serum levels of CORT, cTnT and BNP were increased (P<0.05); in the sensory cortex, the ratios of delta, theta, alpha and beta frequency bands were increased (P<0.05), the maximum energy spectrum of theta and beta frequency bands was increased (P<0.05), the power spectral density (PSD) of delta, theta, alpha, beta and gamma frequency bands was increased (P<0.05); in the motor cortex, the ratios of delta, theta, alpha and beta frequency bands were increased (P<0.05), the maximum energy spectrum as well as PSD of delta, theta, alpha, beta and gamma frequency bands were increased (P<0.05). Compared with model group, in the EA group, the total movement distance, the number of crossing grid and the number of crossing central grid of open field test were increased (P<0.05); LVIDd, LVIDs, LVEDV and LVESV were decreased (P<0.05), EF and FS were increased (P<0.05); ST-segment amplitude was decreased (P<0.05), and the PR interval was shortened (P<0.05); myocardial fiber injury and inflammatory cell infiltration were reduced; the serum levels of CORT, cTnT and BNP were decreased (P<0.05); in the sensory cortex, the ratios of theta, alpha and beta frequency bands were decreased (P<0.05), the ratio of gamma frequency band was increased (P<0.05), the maximum energy spectrum of theta frequency band as well as the PSD of theta, alpha, beta and gamma frequency bands were decreased (P<0.05); in the motor cortex, the ratios of theta, alpha and beta frequency bands were decreased (P<0.05) and the ratio of gamma frequency band was increased (P<0.05), the maximum energy spectrum of delta frequency band was increased (P<0.05), the maximum energy spectrum of theta frequency band as well as the PSD of theta and gamma frequency bands were decreased (P<0.05).@*CONCLUSION@#EA can improve cardiac function in mice with stress cardiomyopathy, and its mechanism may be related to the regulation of local field potentials in sensory and motor cortices.

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OBJECTIVES@#To study the clinical features of children with coronavirus disease 2019 (COVID-19) caused by Delta variant infection in different ages groups.@*METHODS@#A total of 45 children with COVID-19 caused by Delta variant infection who were hospitalized in the designated hospital in Henan Province, China, from November 17 to December 17, 2021, were included. They were divided into three groups: <6 years group (n=16), 6-13 years group (n=16), and >13 years group (n=13). The three groups were compared in clinical features and laboratory examination data.@*RESULTS@#COVID-19 in all age groups was mainly mild. Main manifestations included cough and expectoration in the three groups, and fever was only observed in the 6-13 years group. The <6 years group had significantly higher serum levels of aspartate aminotransferase, lactate dehydrogenase, and creatine kinase isoenzymes than the other two groups (P<0.05). The 6-13 years group had the highest proportion of children with elevated serum creatinine levels (50%). Among the three groups, only 4 children in the >13 years group had an increase in serum C-reactive protein levels. The 6-13 years group had the lowest counts of CD3+CD4+ lymphocytes, CD3+CD8+ lymphocytes, and natural killer cells in the peripheral blood among the three groups. The >13 years group had a significantly higher positive rate of SARS-CoV-2 IgG on admission than the other two groups (P<0.05). There was no significant difference in the imaging findings on chest CT among the three groups (P>0.05).@*CONCLUSIONS@#The clinical features of COVID-19 caused by Delta variant infection in children of different age groups may be different: children aged <6 years tend to develop myocardial injury, and those aged 6-13 years have fever except cough and expectoration and tend to develop renal and immune dysfunction.

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Objective:To explore the effects of game addiction disorders on brain cognitive control functions based on near-infrared spectroscopy.Methods:Thirteen subjects were screened according to the Online Game Addiction (OGA) Scale. The experimental paradigm was the stop-signal task. The relative concentration levels of oxyhemoglobin (HbO 2) and deoxyhemoglobin (Hb) in the prefrontal region of the brain during cognitive activity were collected using near-infrared spectroscopy to assess the cognitive control function of the subjects. Results:The game-addicted patients had lower keystroke accuracy in the stop-signal task than healthy subjects, and the difference was statistically significant ( P<0.05). Compared to healthy subjects, game-addicted patients had less activation in prefrontal areas and showed uncontrolled behavior and brain activity. Conclusions:Game addiction disorders impair brain cognitive control, which in turn triggers a weakening of cognitive control. The results of this study provide a reference for the prevention and treatment of game addiction.

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S100A9 is a calcium-binding protein that plays an important role in the progression of malignant tumors. Related studies have confirmed that the abnormal expression of S100A9 is closely related to the proliferation, metastasis and prognosis of breast cancer, while whether S100A9 can be used as a marker for the diagnosis and treatment of breast cancer is still controversial. This article reviews the current research status of S100A9 and its application prospect in the development, progression, diagnosis and treatment of breast cancer.

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Stress cardiomyopathy (SC) is an acute cardiomyopathy caused by intense mental stimulation or physical stress. Currently, few interventions are effective in reducing mortality, improving prognosis, or preventing recurrence in acute or chronic stages of SC. Therefore, it is particularly important to establish a reliable and effective SC animal model to study the pathogenesis and prevention of SC. In this paper, the preparation methods and evaluation indexes of SC models at home and abroad were reviewed, including the operation details of catecholamine hormone injection method, binding method, binding combined with electroshock method, binding combined with dehydration method, vagus nerve electrical stimulation and other modeling methods, as well as evaluation indexes such as open field test, cardiac ultrasound, electrocardiogram and ELISA, striving to provide useful reference for model selection and establishment of SC research.

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【Objective】 To investigate dynamic regional homogeneity (dReHo) abnormality in end-stage renal disease (ESRD) patients by using resting-state functional magnetic resonance imaging (rs-fMRI). 【Methods】 A total of 26 ESRD patients and 26 healthy controls (HC) matched in gender, education level and age were included. Rs-fMRI scanning was performed in all subjects. All the subjects were tested by using auditory verbal learning test Huashan version (AVLT-H) and Montreal Cognitive Assessment (MoCA) to assess cognitive function before collection of MRI data. T-test was used to observe the difference in dReHo at global level between the two groups. Pearson and Spearman correlation analyses were made to estimate the correlation between abnormal brain regions and clinical scales. 【Results】 Compared with HC group, the dReHo value in ESRD patients reduced on the bilateral superior margin gyrus, left insula, left posterior central gyrus, and left putamen (P<0.05, replacement test correction). The dReHo values of left superior margin gyrus (r=-0.534, P=0.005) and left insula in ESRD patients (r=-0.422, P=0.032) were negatively correlated with the LR-S score, and the dReHo value of the left margin was negatively correlated with the SR-S score (r=-0.468, P=0.016). 【Conclusion】 There are abnormal dReHo values in several brain regions in ESRD patients during resting state, which is related to the patients’ cognitive function. The variation of dReHo value provides a new objective imaging basis for evaluating the cognitive function of ESRD patients.

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The paper summarizes the definition, location and main indication of qicimai points recorded in Huangdi Neijing (Yellow Emperor 's Inner Classic). It is found that qicimai points are the "upward moving points" in reference to the meridian distribution rule of "rooting, running, infusing and moving"; and corresponding to the sites of "running outwards and inwards" of the meridians' "separating, meeting and running outwards and inwards". It also includes the infusing points for the sea of qi and marrow. The new idea, "selecting qicimai points for the treatment of qi obstruction in the neck gate", is proposed. Based on the systematic application of the acupoints on the nape region, it is anticipated that a new approach will be provided to the treatment of the diseases in the neck, shoulder, head, face, the five sensory organs, mental disorders and zangfu qi dysfunction.

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BACKGROUND: Nematodes are parasitic animals that cause over 100 billion US dollars loss in agricultural business. The whole-genomes of two Streptomyces strains, Streptomyces spectabilis KCTC9218T and Streptomyces sp. AN091965, were sequenced. Both strains produce spectinabilin, an antinematode drug. Its secondary metabolism was examined to aid the development of an efficient nematicidal drug-producing host strain. RESULTS: The whole-genome sequences of S. spectabilis KCTC9218T and Streptomyces sp. AN091965 were analyzed using PacBio and Illumina sequencing platforms, and assembled using hybrid methodology. The total contig lengths for KCTC9218T and AN091965 were 9.97 Mb and 9.84 Mb, respectively. A total of 8,374 and 8,054 protein-coding genes, as well as 39 and 45 secondary metabolite biosynthetic gene clusters were identified in KCTC9218T and AN091965, respectively. 18.4 ± 6.45 mg/L and 213.89 ± 21.30 mg/L of spectinabilin were produced by S. spectabilis KCTC9218T and Streptomyces sp. AN091965, respectively. Pine wilt disease caused by nematode was successfully prevented by lower concentration of spectinabilin injection than that of abamectin recommended by its manufacturer. Production of multiple antinematode drugs, including spectinabilin, streptorubin B, and undecylprodigiosin was observed in both strains using high-resolution liquid chromatography mass spectrometry (LC-MS) analysis. CONCLUSIONS: Whole-genome sequencing of spectinabilin-producing strains, coupled with bioinformatics and mass spectrometry analyses, revealed the production of multiple nematicidal drugs in the KCTC9218T and AN091965 strains. Especially, Streptomyces sp. AN091965 showed high production level of spectinabilin, and this study provides crucial information for the development of potential nematicidal drug producers.

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One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)2 design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.

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@#Lung cancer is the most common cancer and the leading cause of cancer-related death in China. Early screening of lung cancer proves to be effective in improving its prognosis. The National Comprehensive Cancer Network (NCCN) has updated and released version 2, 2022 NCCN clinical practice guidelines for lung cancer screening in July, 2022. Based on high-quality clinical evidence and the latest research progress, the guidelines have developed and updated criteria for lung cancer screening which have been widely recognized by clinicians around the world. Compared with Chinese lung cancer screening guidelines, this article will interpret the updated content of the brand new 2022 NCCN screening guidelines, providing some reference for the current lung cancer screening practice in our country.

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OBJECTIVES@#To study the clinical features of children with coronavirus disease 2019 (COVID-19) Delta variant infection vaccinated or not vaccinated with inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine.@*METHODS@#A total of 11 children with COVID-19 Delta variant infection who were vaccinated with inactivated SARS-CoV-2 vaccine and were hospitalized in the designated hospital in Henan Province, China, from November 3 to December 17, 2021 were enrolled as the vaccinated group. Thirty-one children with COVID-19 Delta variant infection who were not vaccinated and were hospitalized during the same period were enrolled as the unvaccinated group. A retrospective analysis was performed on their epidemiological data, clinical features, and laboratory examination results.@*RESULTS@#There was no significant difference in gender composition and disease classification between the two groups (P>0.05), and there was also no significant difference in the incidence rates of the clinical symptoms such as cough, expectoration, and fever between the two groups (P>0.05). No significant difference was found between the two groups in leukocyte count, lymphocyte percentage, alanine aminotransferase, and serum creatinine (P>0.05). Compared with the unvaccinated group, the vaccinated group had significantly lower levels of aspartate aminotransferase, lactate dehydrogenase, and creatine kinase-MB (P<0.05). There was no significant difference between the two groups in the proportion of children with elevated C-reactive protein or procalcitonin and the levels of peripheral blood cytokines (P>0.05). The vaccinated group had significantly lower counts of B lymphocytes and total T lymphocytes (CD3+) than the unvaccinated group (P<0.05). Compared with the unvaccinated group, the vaccinated group had a significantly higher positive rate of IgG on admission and at week 2 of the course of disease (P<0.05), as well as a significantly higher Ct value of nucleic acid at weeks 1 and 2 of the course of disease (P<0.05).@*CONCLUSIONS@#Vaccination with inactivated SARS-CoV-2 vaccine may reduce myocardial injury caused by SARS-CoV-2 Delta variant. For children with SARS-CoV-2 Delta variant infection after the vaccination, more attention should be paid to their immune function.

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@#To analyze the characteristics of mental symptoms in patients with autoimmune encephalitis with different antibody types. Methods The clinical characteristics of patients with autoimmune encephalitis were retrospectively studied. The mental symptoms of patients with autoimmune brain were analyzed. Subjects：Patients diagnosed with autoimmune encephalitis admitted to the Department of Neurology，the First Affiliated Hospital of China Medical University from September 2019 to December 2020.Results There were 20 cases with positive antibody，and the most common clinical manifestations were convulsion，mental symptoms，consciousness disorder and memory decline. One tumor was found in NMDAR AE，which was teratoma of ovary. Conclusion The mental symptoms of patients with subtypes of autoimmune encephalitis have no significant difference，that is，the type of autoimmune brain antibodies can not be determined by the patients’ major mental symptoms.

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BackgroundThe public and scientific discourse on how to mitigate the COVID-19 pandemic is often focused on the impact of individual protective measures, in particular on vaccination. In view of changing virus variants and conditions, however, it seems not clear if vaccination or any other protective measure alone may suffice to contain the transmission of SARS-CoV-2. MethodsHere, we investigate the effectiveness and synergies of vaccination and non-pharmaceutical interventions like masking, distancing & ventilation, testing & isolation, and contact reduction as a function of compliance in the population. Our new analysis accounts for the practical compliance in the population and for both droplet transmission and aerosol transmission. FindingsFor realistic conditions, we find that it would be difficult to contain highly contagious SARS-CoV-2 variants by any individual measure. Instead, we show how multiple synergetic measures have to be combined to reduce the effective reproduction number (Re) below unity for different basic reproduction numbers ranging from the SARS-CoV-2 ancestral strain up to measles-like values (R0 = 3 to 18). For R0 = 5 as reported for the Delta variant and [~]70% vaccination rate, the synergies of masking and distancing & ventilation with compliances around 30% appear sufficient to keep Re < 1. In combination with 2-3 tests per week, this would work also at lower vaccination rates, e.g., in schools. InterpretationIf the Omicron variant were to reach R0 = 8, it could still be contained with the synergetic measures outlined above. In case of measles-like transmissibilities (R0 = 12 to 18), higher compliances and testing rates or additional measures like general contact reductions would be required. The presented findings and approach can be used to design and communicate efficient strategies for mitigating the COVID-19 pandemic. FundingMax Planck Society. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSStudies on how to mitigate the COVID-19 pandemic are often focused on the impact of individual protective measures, in particular on vaccination. The effectiveness of non-pharmaceutical interventions (NPIs) like masking or distancing & ventilation are often under debate due to a lack of understanding of different transmission pathways (droplet versus aerosol transmission) and protective measures, in particular for the efficacy of masking and contrasting randomized trial results under different conditions (virus-limited vs. virus-rich) and at different levels of practical compliance. Thus, in view of more contagious variants such as Delta or Omicron, it is not clear if vaccination or any other protective measure alone may suffice to contain the transmission of SARS-CoV-2. Added value of this studyOur analysis explicitly accounts for both droplet and aerosol transmission as well as for practical compliance in the population, which is the main reason for divergent results on the effectiveness of the same NPIs in different regions. This was not fully considered before and may have led to misunderstandings and misinformation about the actual effects of preventive measures. For realistic conditions, we find that it would be difficult to contain highly contagious SARS-CoV-2 variants by any individual measure. Instead, we show that combining multiple synergetic measures with realistic compliances can reduce Re below unity without lockdown. Implications of all the available evidenceOur findings and the presented scientific approach can be used to design and communicate efficient strategies for mitigating the COVID-19 pandemic for specific environments like schools as well as on a population level.

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Clavulanic acid (CA) produced by Streptomyces clavuligerus is a clinically important ß-lactamase inhibitor. It is known that glycerol utilization can significantly improve cell growth and CA production of S. clavuligerus. We found that the industrial CA-producing S. clavuligerus strain OR generated by random mutagenesis consumes less glycerol than the wild-type strain; we then developed a mutant strain in which the glycerol utilization operon is overexpressed, as compared to the parent OR strain, through iterative random mutagenesis and reporter-guided selection. The CA production of the resulting S. clavuligerus ORUN strain was increased by approximately 31.3% (5.21 ± 0.26 g/l) in a flask culture and 17.4% (6.11 ± 0.36 g/l) in a fermenter culture, as compared to that of the starting OR strain. These results confirmed the important role of glycerol utilization in CA production and demonstrated that reporter-guided mutant selection is an efficient method for further improvement of randomly mutagenized industrial strains.

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