Transfer learning improves predictions in lignin content of Chinese fir based on Raman spectra.

Lignin in biomass plays significant role in substitution of synthetic polymer and reduction of energy expenditure, and the lignin content was usually determined by wet chemical methods. However, the methods' heavy workload, low efficiency, huge consumption of chemicals and use of toxic reagents render them unsuitable for sustainable development and environmental protection. Chinese fir, a prevalent angiosperm tree, holds immense importance for various industries. Since our previous work found that Raman spectroscopy could accurately predict the lignin content in poplar, we propose that the lignin content of Chinese fir can be estimated by similar strategy. The results suggested that the peak at 2895 cm-1 is the optimal choice of internal standard peak and algorithm of XGBoost demonstrates the highest accuracy among all algorithms. Furthermore, transfer learning was successfully introduced to enhance the accuracy and robustness of the model. Ultimately, we report that a machine learning algorithm, combining transfer learning with XGBoost or LightGBM, offers an accurate, high-efficiency and environmental friendly method for predicting the lignin content of Chinese fir using Raman spectra.

A portable colorimetric sensing platform for rapid and sensitive quantification of dichlorvos pesticide based on Fe-Mn bimetallic oxide nanozyme-participated highly efficient chromogenic catalysis.

BACKGROUND: Dichlorvos (DDVP), as a highly effective insecticide, is widely used in agricultural production. However, DDVP residue in foodstuffs adversely affects human health. Conventional instrumental analysis can provide highly sensitive and accurate detection of DDVP, while the need of bulky and expensive equipment limits their application in resource-poor areas and on-site detection. Therefore, the development of easily portable sensing platforms for convenient, rapid and sensitive quantification of DDVP is very essential for ensuring food safety. RESULT: A portable colorimetric sensing platform for rapid and sensitive quantification of DDVP is developed based on nanozyme-participated highly efficient chromogenic catalysis. The Fe-Mn bimetallic oxide (FeMnOx) nanozyme possesses excellently oxidase-like activity and can efficiently catalyze oxidation of 3, 3', 5, 5'-tetramethylbenzidine (TMB) into a blue oxide with a very low Michaelis constant (Km) of 0.0522 mM. The nanozyme-catalyzed chromogenic reaction can be mediated by DDVP via inhibiting the acetylcholinesterase (AChE) activity. Thus, trace DDVP concentration-dependent color evolution is achieved and DDVP can be sensitively detected by spectrophotometry. Furthermore, a smartphone-integrated 3D-printed miniature lightbox is fabricated as the colorimetric signal acquisition and processing device. Based on the FeMnOx nanozyme and smartphone-integrated lightbox system, the portable colorimetric sensing platform of DDVP is obtained and it has a wide linear range from 1 to 3000 ng mL-1 with a low limit of detection (LOD) of 0.267 ng mL-1 for DDVP quantification. SIGNIFICANCE: This represents a new portable colorimetric sensing platform that can perform detection of DDVP in foodstuffs with simplicity, sensitivity, and low cost. The work not only offers an alternative to rapid and sensitive detection of DDVP, but also provides a new insight for the development of advanced sensors by the combination of nanozyme, 3D-printing and information technologies.

Simulation of ultrafast electron diffraction intensity under coherent acoustic phonons.

Ultrafast electron diffraction has been proven to be a powerful tool for the study of coherent acoustic phonons owing to its high sensitivity to crystal structures. However, this sensitivity leads to complicated behavior of the diffraction intensity, which complicates the analysis process of phonons, especially higher harmonics. Here, we theoretically analyze the effects of photoinduced coherent transverse and longitudinal acoustic phonons on electron diffraction to provide a guide for the exploitation and modulation of coherent phonons. The simulation of the electron diffraction was performed in 30-nm films with different optical penetration depths based on the atomic displacements obtained by solving the wave equation. The simulation results exhibit a complex relationship between the frequencies of the phonons and diffraction signals, which highly depends on the laser penetration depth, sample thickness, and temporal stress distribution. In addition, an intensity decomposition method is proposed to account for the in-phase oscillation and high harmonics caused by inhomogeneous excitation. These results can provide new perspectives and insights for a comprehensive and accurate understanding of the lattice response under coherent phonons.

First Report of Apiospora arundinis Causing Wet Root Rot of Pseudostellaria heterophylla in China.

Pseudostellaria heterophylla is one of the traditional medicines in China. From 2020 to 2022, postharvest wet root rot disease was observed with an incidence of 2~5% on the tuberous roots of the harvested P. heterophylla in Zherong county, Fujian province, China, which usually occurs under damp and unventilated conditions. The symptoms of the disease were as follows: white mycelia grew on the surface of tuberous root initially and gradually wrapped around the roots, the internal root tissue turned yellow and became wet decay finally. To identify the causal agent, a total of 20 samples with symptomatic tuberous roots were collected. Small pieces (3 mm2) were treated by surface disinfection with 75% ethanol and 1% NaOCl, then rinsed 3 times with sterile water. These treated pieces were transferred onto potato dextrose agar (PDA) and incubated at 25°C in the dark for 7 d. Ten pure cultures were obtained using single-spore isolation method. The fungus colonies initially produced white aerial mycelium, subsequently exhibited yellow pigmentation. Mycelia were consisted of smooth, hyaline, branched, and septate hyphae. The conidia were solitary or clustered, brown or dark brown, smooth, ellipsoidal to spherical, 6.66 (5.50-7.81)×5.65 (4.17-7.22) µm (n=50) in size. The conidiophores were hyaline or pale brown and produced conidiogenous cells, which were pale brown, smooth, ampulliform, and 10.14 (8.82-15.30) um long (n=50). Based on these morphological characteristics, the fungus was identified as the genus Apiospora (Arthrinium). The rDNA-ITS region and partial ß-tubulin gene (BenA) were amplified using the primers ITS1/ITS4 (White et al. 1990) and Bt2a/Bt2b (Glass and Donaldson 1995), respectively. The sequences of isolates FJAT-32563 and FJAT-32564 were deposited in GenBank (ITS, OM920984 and OM920985; BenA, OM953823 and OM953824). All sequences had more than 99% similarity with those of A. arundinis strain CBS:106.12 (ITS, KF144883; BenA, KF144973). In the multilocus phylogenetic analysis (ITS + BenA), the two isolates clustered together with other strains of A. arundinis with 100% bootstrap support. The isolates were therefore identified as A. arundinis based on both morphological and molecular characteristics. To confirm the pathogenicity, fresh tuberous roots were selected and surface disinfected, then the roots were immersed with a quarter length in the conidial suspension (106/mL) for 30 min, whereas the control roots were immersed with sterile water (n=30). They were placed in petri dish with wet filter paper at 25±2℃, maintaining 80% relative humidity in the dark. The white aerial mycelium appeared at 5 days after inoculation, and wet root rot decaying occurred after inoculation for 21 days. The symptoms were similar to those described above, whereas the control roots were asymptomatic. The same fungus was re-isolated from the infected roots, showing similar morphological characteristics and molecular traits. Koch's postulates were completed and the pathogenicity test for the isolates has been repeated thrice. Previously, A. arundinis was reported to infect peach and sugarcane (Ji et al. 2020; Liao et al. 2022). To our knowledge, this is the first report of A. arundinis causing wet root rot of P. heterophylla in China. The disease would be a potentially new threat to this medicinal plant.

Daptomycin production enhancement by ARTP mutagenesis and fermentation optimization in Streptomyces roseosporus.

AIMS: We evaluated whether the randomness of mutation breeding can be regulated through a double-reporter system. We hope that by establishing a new precursor feeding strategy, the production capacity of industrial microorganisms after pilot scale-up can be further improved. METHODS AND RESULTS: In this study, the industrial strain Streptomyces roseosporus L2796 was used as the starter strain for daptomycin production, and a double-reporter system with the kanamycin resistance gene Neo and the chromogenic gene gusA was constructed to screen for high-yield strain L2201 through atmospheric and room temperature plasma (ARTP). Furthermore, the composition of the culture medium and the parameters of precursor replenishment were optimized, resulting in a significant enhancement of the daptomycin yield of the mutant strain L2201(752.67 mg/l). CONCLUSIONS: This study successfully screened a high-yield strain of daptomycin through a double-reporter system combined with ARTP mutation. The expression level of two reporter genes can evaluate the strength of dptEp promoter, which can stimulate the expression level of dptE in the biosynthesis of daptomycin, thus producing more daptomycin. The developed multi-stage feeding rate strategy provides a novel way to increase daptomycin in industrial fermentation.

Humanoid Intelligent Display Platform for Audiovisual Interaction and Sound Identification.

This study proposes a rational strategy for the design, fabrication and system integration of the humanoid intelligent display platform (HIDP) to meet the requirements of highly humanized mechanical properties and intelligence for human-machine interfaces. The platform's sandwich structure comprises a middle light-emitting layer and surface electrodes, which consists of silicon elastomer embedded with phosphor and silk fibroin ionoelastomer, respectively. Both materials are highly stretchable and resilient, endowing the HIDP with skin-like mechanical properties and applicability in various extreme environments and complex mechanical stimulations. Furthermore, by establishing the numerical correlation between the amplitude change of animal sounds and the brightness variation, the HIDP realizes audiovisual interaction and successful identification of animal species with the aid of Internet of Things (IoT) and machine learning techniques. The accuracy of species identification reaches about 100% for 200 rounds of random testing. Additionally, the HIDP can recognize animal species and their corresponding frequencies by analyzing sound characteristics, displaying real-time results with an accuracy of approximately 99% and 93%, respectively. In sum, this study offers a rational route to designing intelligent display devices for audiovisual interaction, which can expedite the application of smart display devices in human-machine interaction, soft robotics, wearable sound-vision system and medical devices for hearing-impaired patients.

Mechanochemically assisted morphing of shape shifting polymers.

Morphing in creatures has inspired various synthetic polymer materials that are capable of shape shifting. The morphing of polymers generally relies on stimuli-active (typically heat and light active) units that fix the shape after a mechanical load-based shape programming. Herein, we report a strategy that uses a mechanochemically active 2,2'-bis(2-phenylindan-1,3-dione) (BPID) mechanophore as a switching unit for mechanochemical morphing. The mechanical load on the polymer triggers the dissociation of the BPID moiety into stable 2-phenylindan-1,3-dione (PID) radicals, whose subsequent spontaneous dimerization regenerates BPID and fixes the temporary shapes that can be effectively recovered to the permanent shapes by heating. A greater extent of BPID activation, through a higher BPID content or mechanical load, leads to higher mechanochemical shape fixity. By contrast, a relatively mechanochemically less active hexaarylbiimidazole (HABI) mechanophore shows a lower fixing efficiency when subjected to the same programing conditions. Another control system without a mechanophore shows a low fixing efficiency comparable to the HABI system. Additionally, the introduction of the BPID moiety also manifests remarkable mechanochromic behavior during the shape programing process, offering a visualizable indicator for the pre-evaluation of morphing efficiency. Unlike conventional mechanical mechanisms that simultaneously induce morphing, such as strain-induced plastic deformation or crystallization, our mechanochemical method allows for shape programming after the mechanical treatment. Our concept has potential for the design of mechanochemically programmable and mechanoresponsive shape shifting polymers.

A fluorescent method for bisphenol A detection based on enzymatic oxidation-mediated emission quenching of silicon nanoparticles.

As a common raw material of industrial products, bisphenol A (BPA) is widely used in the production of food contact materials, and there is a high risk of exposure in food. However, BPA is a well-known endocrine disruptor and poses a serious threat to human health. Herein, a fluorescent sensing platform of BPA based on enzymatic oxidation-mediated fluorescence quenching of silicon nanoparticles (SiNPs) is established and used to the detection of BPA in food species. The SiNPs are prepared with a facile one-step synthesis and emit bright green fluorescence. BPA can be oxidized by horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) to form a product which can quench the fluorescence of SiNPs through electron transfer. There is a good linear relationship between the fluorescence intensity and BPA concentration in the range of 1-100 µM. Therefore, a fluorometry of BPA is established with a low limit of detection (LOD) of 0.69 µM. This method has been applied to the determination of BPA in mineral drinking water, orange juice, and milk with satisfactory results. The fluorescent sensor of BPA based on SiNPs has favorable application foreground in the field of food safety analysis.

An Unusual Case of Lung Adenocarcinoma Metastasis to the Tricep Muscle: Four Years Disease-Free After Surgical Resection and Radiotherapy.

Lung cancer is one of the leading causes of cancer-related death worldwide. Lung cancer commonly metastasizes to the liver, bone, and brain, but metastasis to skeletal muscles is rare. The development of metastasis in skeletal muscles indicates stage IV disease with a poor prognosis. The most effective treatment strategy is unclear. Palliative radiotherapy is often used to treat skeletal muscle metastases, and patient survival is poor, with an average survival of one year. Here we discuss the case of a 76-year-old female diagnosed with lung adenocarcinoma with metastasis to the trapezius muscle. Initially, she was treated with stereotactic body radiotherapy for stage T1 lung adenocarcinoma. Her follow-up surveillance positron emission tomography (PET) scan in 11 months showed an abnormal focal area of increased activity localizing to the long head of the right triceps muscle. The diagnosis was confirmed with an ultrasound-guided biopsy of the trapezius muscle. Following that, the patient underwent wedge resection of the right middle and upper lobe of the lung and partial right trapezius resection. Afterward, she was given radiation therapy at the tricep resection site. She remained disease-free for four years after excision and radiation therapy.

Identification and Characterization of a New Regulator, TagR, for Environmental Stress Resistance Based on the DNA Methylome of Streptomyces roseosporus.

DNA methylation is a defense that microorganisms use against extreme environmental stress, and improving resistance against environmental stress is essential for industrial actinomycetes. However, research on strain optimization utilizing DNA methylation for breakthroughs is rare. Based on DNA methylome analysis and KEGG pathway assignment in Streptomyces roseosporus, we discovered an environmental stress resistance regulator, TagR. A series of in vivo and in vitro experiments identified TagR as a negative regulator, and it is the first reported regulator of the wall teichoic acid (WTA) ABC transport system. Further study showed that TagR had a positive self-regulatory loop and m4C methylation in the promoter improved its expression. The ΔtagR mutant exhibited better hyperosmotic resistance and higher decanoic acid tolerance than the wild type, which led to a 100% increase in the yield of daptomycin. Moreover, enhancing the expression of the WTA transporter resulted in better osmotic stress resistance in Streptomyces lividans TK24, indicating the potential for wide application of the TagR-WTA transporter regulatory pathway. This research confirmed the feasibility and effectiveness of mining regulators of environmental stress resistance based on the DNA methylome, characterized the mechanism of TagR, and improved the resistance and daptomycin yield of strains. Furthermore, this research provides a new perspective on the optimization of industrial actinomycetes. IMPORTANCE This study established a novel strategy for screening regulators of environmental stress resistance based on the DNA methylome and discovered a new regulator, TagR. The TagR-WTA transporter regulatory pathway improved the resistance and antibiotic yield of strains and has the potential for wide application. Our research provides a new perspective on the optimization and reconstruction of industrial actinomycetes.

The effect of FMT and vitamin C on immunity-related genes in antibiotic-induced dysbiosis in mice.

Antibiotics are double-edged swords. Although antibiotics are used to inhibit pathogenic bacteria, they also run the risk of destroying some of the healthy bacteria in our bodies. We examined the effect of penicillin on the organism through a microarray dataset, after which 12 genes related to immuno-inflammatory pathways were selected by reading the literature and validated using neomycin and ampicillin. The expression of genes was measured using qRT-PCR. Several genes were significantly overexpressed in antibiotic-treated mice, including CD74 and SAA2 in intestinal tissues that remained extremely expressed after natural recovery. Moreover, transplantation of fecal microbiota from healthy mice to antibiotic-treated mice was made, where GZMB, CD3G, H2-AA, PSMB9, CD74, and SAA1 were greatly expressed; however, SAA2 was downregulated and normal expression was restored, and in liver tissue, SAA1, SAA2, SAA3 were extremely expressed. After the addition of vitamin C, which has positive effects in several aspects, to the fecal microbiota transplantation, in the intestinal tissues, the genes that were highly expressed after the fecal microbiota transplantation effectively reduced their expression, and the unaffected genes remained normally expressed, but the CD74 gene remained highly expressed. In liver tissues, normally expressed genes were not affected, but the expression of SAA1 was reduced and the expression of SAA3 was increased. In other words, fecal microbiota transplantation did not necessarily bring about a positive effect of gene expression restoration, but the addition of vitamin C effectively reduced the effects of fecal microbiota transplantation and regulated the balance of the immune system.

A Rare Case of Relapsed Sarcoidosis Presenting As Severe Thrombocytopenia Associated With Intracerebral Hemorrhage Due to Bone Marrow Involvement.

Sarcoidosis is a systemic granulomatous disease characterized by the hyperactivation of CD4 T cells, CD8 T cells, and macrophages. Clinical presentations of sarcoidosis are highly variable. Sarcoidosis is unknown in its etiology, but it suggests it may result from exposure to specific environmental agents in genetically susceptible people. Sarcoidosis commonly involves the lungs and lymphoid system. Bone marrow involvement in sarcoidosis is uncommon. Sarcoidosis rarely results in intracerebral hemorrhage due to severe thrombocytopenia secondary to bone marrow involvement. We present the case of a 72-year-old woman who has been in remission from sarcoidosis for 15 years and developed intracerebral hemorrhage secondary to severe thrombocytopenia due to sarcoidosis recurrence in the bone marrow. The patient presented to the emergency department with a generalized, non-blanching petechiae rash and nose and gum bleeding. Her labs showed a platelet count of less than 10.000/mcL, and computed tomography (CT) showed intracerebral hemorrhage. A bone marrow biopsy revealed a small, non-caseating granuloma indicative of a sarcoidosis relapse in the bone marrow.

Case Report of Painless Obstructive Jaundice: A Rare First Presentation of Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is a very aggressive type of lung cancer that is of neuroendocrine origin. Because of the high levels of circulating tumor cells, it has a very high rate of metastasis. Obstructive jaundice as the initial manifestation of small cell lung carcinoma is rare. Most of the cases are due to extrahepatic cholestasis by biliary duct obstruction. The biliary duct obstruction may be secondary to metastasis to lymph nodes or pancreatic head metastasis. Obstructive jaundice secondary to intrahepatic cholestasis is even rarer. A 75-year-old male presented to the emergency department (ED) with a complaint of new-onset painless jaundice that his dentist incidentally detected. Examination revealed a mass in the right upper quadrant (RUQ) of the abdomen. Computed tomography (CT) angiography of the abdomen, pancreas, and pelvis shows innumerable hepatic hypodensities highly suspicious for metastatic disease. However, there was no extrahepatic dilatation or pancreatic mass. He was diagnosed with diffuse metastasis of small cell lung carcinoma (SCLC) by needle biopsy of the liver. He developed acute kidney injury and liver damage and thus compromised chemotherapy for SCLC. Later, the patient chose comfort care and passed away the next day. To our knowledge, this is the second reported case of SCLC initially presenting as obstructive jaundice secondary intrahepatic cholestasis by diffuse liver metastases.

Resolvin D1 attenuates depressive-like behavior in LPS-challenged mice by promoting microglial autophagy.

It has been proven that neuroinflammation triggered by microglial activation is the pathogenesis of depression associated with sepsis. An endogenous lipid mediator known as resolvin D1 (RvD1) is known to have anti-inflammatory effects in a sepsis model. However, it remains unknown if the effects of RvD1 on inflammatory responses are regulated by microglial autophagy. The current study investigated the role of RvD1-induced microglial autophagy in neuroinflammation. The findings showed that RvD1 reverses LPS-induced autophagy inhibition in microglia. RvD1 treatment significantly inhibits inflammatory responses by preventing NF-κB nuclear translocation and microglial M1 phenotypic transition. RvD1 exhibits an attenuation of neurotoxicity in both in vivo and in vitro models of sepsis. Following RvD1 injection, depressive-like behaviors in SAE mice were significantly improved. Notably, the aforesaid effects of RvD1 were eliminated by 3-MA, demonstrating that microglial autophagy was modulated. In conclusion, our findings shed new light on the involvement of microglial autophagy in SAE and emphasize the potential benefits of RvD1 as a promising therapeutic agent in the treatment of depression.

Degradation mechanism of AtrA mediated by ClpXP and its application in daptomycin production in Streptomyces roseosporus.

The efficiency of drug biosynthesis depends on different transcriptional regulatory pathways in Streptomyces, and the protein degradation system adds another layer of complexity to the regulatory processes. AtrA, a transcriptional regulator in the A-factor regulatory cascade, stimulates the production of daptomycin by binding to the dptE promoter in Streptomyces roseosporus. Using pull-down assays, bacterial two-hybrid system and knockout verification, we demonstrated that AtrA is a substrate for ClpP protease. Furthermore, we showed that ClpX is necessary for AtrA recognition and subsequent degradation. Bioinformatics analysis, truncating mutation, and overexpression proved that the AAA motifs of AtrA were essential for initial recognition in the degradation process. Finally, overexpression of mutated atrA (AAA-QQQ) in S. roseosporus increased the yield of daptomycin by 225% in shake flask and by 164% in the 15 L bioreactor. Thus, improving the stability of key regulators is an effective method to promote the ability of antibiotic synthesis.

Degradation Mechanism of AAA+ Proteases and Regulation of Streptomyces Metabolism.

Hundreds of proteins work together in microorganisms to coordinate and control normal activity in cells. Their degradation is not only the last step in the cell's lifespan but also the starting point for its recycling. In recent years, protein degradation has been extensively studied in both eukaryotic and prokaryotic organisms. Understanding the degradation process is essential for revealing the complex regulatory network in microorganisms, as well as further artificial reconstructions and applications. This review will discuss several studies on protein quality-control family members Lon, FtsH, ClpP, the proteasome in Streptomyces, and a few classical model organisms, mainly focusing on their structure, recognition mechanisms, and metabolic influences.

A fluorescent and scattering dual-mode probe based on a carbon dot@cerium-guanosine monophosphate coordination polymer network for tetracycline detection.

Dual-mode sensing with a two-signal read-out is conducive to the improvement of detection accuracy. Herein, a fluorescent and scattering dual-mode chemosensor for tetracycline (TC) is proposed based on a carbon dot@cerium-guanosine monophosphate (CD@GMP-Ce) coordination polymer network. The inexpensive CD@GMP-Ce was prepared by exploiting the adaptive inclusion capability of coordination polymers and possessed remarkable fluorescence and strong Rayleigh scattering. The functional CD@GMP-Ce demonstrated fluorescence and scattering, the two optical-signal responses to TC simultaneously. Based on TC-specific fluorescence and scattering decline, the dual-mode detection of TC was established and the probe's detection limits were 43 nM in the fluorescence mode and 77 nM in the scattering mode, respectively. Furthermore, the potential application of the dual-mode sensor was verified by measuring TC in milk and tap-water samples. The study not only provides a new perspective for the development of assay methods for TC but also expands the applications of cerium coordination polymers.

Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.

Without an effective strategy for targeted therapy, glioblastoma is still incurable with a median survival of only 15 months. Both chronic inflammation and epigenetic reprogramming are hallmarks of cancer. However, the mechanisms and consequences of their cooperation in glioblastoma remain unknown. Here, we discover that chronic inflammation governs H3K27me3 reprogramming in glioblastoma through the canonical NF-κB pathway to target EZH2. Being a crucial mediator of chronic inflammation, the canonical NF-κB signalling specifically directs the expression and redistribution of H3K27me3 but not H3K4me3, H3K9me3 and H3K36me3. Using RNA-seq screening to focus on genes encoding methyltransferases and demethylases of histone, we identify EZH2 as a key methyltransferase to control inflammation-triggered epigenetic reprogramming in gliomagenesis. Mechanistically, NF-κB selectively drives the expression of EZH2 by activating its transcription, consequently resulting in a global change in H3K27me3 expression and distribution. Furthermore, we find that co-activation of NF-κB and EZH2 confers the poorest clinical outcome, and that the risk for glioblastoma can be accurately molecularly stratified by NF-κB and EZH2. It is notable that NF-κB can potentially cooperate with EZH2 in more than one way, and most importantly, we demonstrate a Synergistic effect of cancer cells induced by combinatory inhibition of NF-κB and EZH2, which both are frequently over-activated in glioblastoma. In summary, we uncover a functional cooperation between chronic inflammation and epigenetic reprogramming in glioblastoma, combined targeting of which by inhibitors guaranteed in safety and availability furnishes a potent strategy for effective treatment of this fatal disease.

Sp1 induced gene TIMP1 is related to immune cell infiltration in glioblastoma.

Tumor immune microenvironment exerts a profound effect on the population of infiltrating immune cells. Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) is frequently overexpressed in a variety of cells, particularly during inflammation and tissue injury. However, its function in cancer and immunity remains enigmatic. In this study, we find that TIMP1 is substantially up-regulated during tumorigenesis through analyzing cancer bioinformatics databases, which is further confirmed by IHC tissue microarrays of clinical samples. The TIMP1 level is significantly increased in lymphocytes infiltrating the tumors and correlated with cancer progression, particularly in GBM. Notably, we find that the transcriptional factor Sp1 binds to the promoter of TIMP1 and triggers its expression in GBM. Together, our findings suggest that the Sp1-TIMP1 axis can be a potent biomarker for evaluating immune cell infiltration at the tumor sites and therefore, the malignant progression of GBM.

m4C DNA methylation regulates biosynthesis of daptomycin in Streptomyces roseosporus L30.

Despite numerous studies on transcriptional level regulation by single genes in drug producing Actinomyces, the global regulation based on epigenetic modification is not well explored. N4-methylcytosine (m4C), an abundant epigenetic marker in Actinomycetes' genome, but its regulatory mechanism remains unclear. In this study, we identify a m4C methyltransferase (SroLm3) in Streptomyces roseosporus L30 and multi-omics studies were performed and revealed SroLm3 as a global regulator of secondary metabolism. Notably, three BGCs in ΔsroLm3 strain exhibited decreased expression compared to wild type. In-frame deletion of sroLm3 in S.roseosporus L30 further revealed its role in enhancing daptomycin production. In summary, we characterized a m4C methyltransferase, revealed the function of m4C in secondary metabolism regulation and biosynthesis of red pigment, and mapped a series of novel regulators for daptomycin biosynthesis dominated by m4C methylation. Our research further indicated that m4C DNA methylation may contribute to a metabolic switch from primary to secondary metabolism in Actinomyces.