The rare cause of ST segment elevation in left precordial leads - Diagnostic clues from subtle waveforms.

We report a case of ST segment elevation in left precordial leads with a convex shape caused by a rare etiology. By carefully analyzing the electrocardiogram (leads I, II, V3 to V9) of a patient with convex ST segment elevation in the left-sided chest leads, relevant etiological clues were derived. The findings were further supported by cardiac ultrasound and cardiac magnetic resonance imaging, ruling out other common causes. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) was postulated as the underlying cause, and potential mechanisms were discussed. The diagnosis was further confirmed through a follow-up period of over three years.

Marine-Derived Bisindoles for Potent Selective Cancer Drug Discovery and Development.

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

Construction of Steady Amorphous Colloidal Array Patterns via Infiltration-Driven Assembly of Core-Shell Microparticles followed by Short-Time Heating.

Although core-shell microparticles with a hard core and soft shell are often used to fabricate photonic crystal films, they are rarely applied to construct steady amorphous colloidal array (ACA) patterns. In this work, a series of monodisperse core-shell microparticles with a polystyrene (PS) core and poly(methyl methacrylate-butyl acrylate) (P(MMA-BA)) shell have been successfully synthesized, and the glass transition temperatures (Tg) of the shell layer have been well regulated. The synthesized core-shell microparticles were then used to fabricate ACA patterns via a convenient infiltration-driven assembly method. The results showed that the Tg of the shell significantly affected the microstructure of the amorphous colloidal arrays (ACAs). During the assembly process, the microparticles quickly contacted each other and the lower-Tg shells could merge with each other to form a continuous film. In this situation, the PS core was embedded and ranked in the P(MMA-BA) film, and both the refractive index contrast and order degree of the colloidal array became relatively low, resulting in a poor structural color. However, when the Tg of the shell layer was moderately high, a short-range ordered array was prepared via infiltration-driven assembly, thereby displaying a bright structural color. More importantly, the shell layers could merge with each other to some extent after short-time heating, resulting in fine mechanical stability. In brief, this study provides a facile and environmental approach to construct steady ACA patterns, which is promising in printing and painting industries.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids.

Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs.

Observation of Transient Parity-Time Symmetry in Electronic Systems.

We demonstrate the transient parity-time (PT) symmetry in electronics. It is revealed by equivalent circuit transformation according to the switching states of electronic systems. With the phasor method and Laplace transformation, we derive the hidden PT-symmetric Hamiltonian in the switching oscillation, which are characterized by free oscillation modes. Both spectral and dynamic properties of the PT electronic structure demonstrate the phase transition with eigenmode orthogonality. Importantly, the observed transient PT symmetry enables exceptional-point-induced optimal switching oscillation suppression, which shows the significance of PT symmetry in electronic systems with temporary responses. Our work paves the way for breakthroughs in the PT symmetry theory and has essential applications such as anti-interference in switch-mode electronics.

Identification of four insertion sites for foreign genes in a pseudorabies virus vector.

BACKGROUND: Pseudorabies virus (PRV) is a preferred vector for recombinant vaccine construction. Previously, we generated a TK&gE-deleted PRV (PRVΔTK&gE-AH02) based on a virulent PRV AH02LA strain. It was shown to be safe for 1-day-old piglets with maternal PRV antibodies and 4 ~ 5 week-old PRV antibody negative piglets and provide rapid and 100 % protection in weaned pigs against lethal challenge with the PRV variant strain. It suggests that PRVTK&gE-AH02 may be a promising live vaccine vector for construction of recombinant vaccine in pigs. However, insertion site, as a main factor, may affect foreign gene expression. RESULTS: In this study, we constructed four recombinant PRV-S bacterial artificial chromosomes (BACs) carrying the same spike (S) expression cassette of a variant porcine epidemic diarrhea virus strain in different noncoding regions (UL11-10, UL35-36, UL46-27 or US2-1) from AH02LA BAC with TK, gE and gI deletion. The successful expression of S gene (UL11-10, UL35-36 and UL46-27) in recombinant viruses was confirmed by virus rescue, PCR, real-time PCR and indirect immunofluorescence. We observed higher S gene mRNA expression level in swine testicular cells infected with PRV-S(UL11-10)ΔTK/gE and PRV-S(UL35-36)ΔTK/gE compared to that of PRV-S(UL46-27)ΔTK/gE at 6 h post infection (P < 0.05). Moreover, at 12 h post infection, cells infected with PRV-S(UL11-10)ΔTK/gE exhibited higher S gene mRNA expression than those infected with PRV-S(UL35-36)ΔTK/gE (P = 0.097) and PRV-S(UL46-27)ΔTK/gE (P < 0.05). Recovered vectored mutant PRV-S (UL11-10, UL35-36 and UL46-27) exhibited similar growth kinetics to the parental virus (PRVΔTK&gE-AH02). CONCLUSIONS: This study focuses on identification of suitable sites for insertion of foreign genes in PRV genome, which laids a foundation for future development of recombinant PRV vaccines.

Optimizing Adsorption of 17α-Ethinylestradiol from Water by Magnetic MXene Using Response Surface Methodology and Adsorption Kinetics, Isotherm, and Thermodynamics Studies.

Magnetic MXene composite Fe3O4@Ti3C2 was successfully prepared and employed as 17α-ethinylestradiol (EE2) adsorbent from water solution. The response surface methodology was employed to investigate the interactive effects of adsorption parameters (adsorption time, pH of the solution, initial concentration, and the adsorbent dose) and optimize these parameters for obtaining maximum adsorption efficiency of EE2. The significance of independent variables and their interactions were tested by the analysis of variance (ANOVA) and t-test statistics. Optimization of the process variables for maximum adsorption of EE2 by Fe3O4@Ti3C2 was performed using the quadratic model. The model predicted maximum adsorption of 97.08% under the optimum conditions of the independent variables (adsorption time 6.7 h, pH of the solution 6.4, initial EE2 concentration 0.98 mg L-1, and the adsorbent dose 88.9 mg L-1) was very close to the experimental value (95.34%). pH showed the highest level of significance with the percent contribution (63.86%) as compared to other factors. The interactive influences of pH and initial concentration on EE2 adsorption efficiency were significant (p < 0.05). The goodness of fit of the model was checked by the coefficient of determination (R2) between the experimental and predicted values of the response variable. The response surface methodology successfully reflects the impact of various factors and optimized the process variables for EE2 adsorption. The kinetic adsorption data for EE2 fitted well with a pseudo-second-order model, while the equilibrium data followed Langmuir isotherms. Thermodynamic analysis indicated that the adsorption was a spontaneous and endothermic process. Therefore, Fe3O4@Ti3C2 composite present the outstanding capacity to be employed in the remediation of EE2 contaminated wastewaters.

A gD&gC-substituted pseudorabies virus vaccine strain provides complete clinical protection and is helpful to prevent virus shedding against challenge by a Chinese pseudorabies variant.

BACKGROUND: Since 2011, pseudorabies caused by a variant PRV has re-emerged in many Chinese Bartha-K61-vaccinated pig farms. An efficacious vaccine is necessary to control this disease. We described the construction of a gD&gC-substituted pseudorabies virus (PRV B-gD&gCS) from the Bartha-K61 (as backbone) and AH02LA strain (as template for gD and gC genes) through bacterial artificial chromosome (BAC) technology using homologous recombination. The growth kinetics of PRV B-gD&gCS was compared with Bartha-K61. Its safety was evaluated in 28-day-old piglets. Protection efficacy was tested in piglets by lethal challenge with AH02LA at 7 days post vaccination, including body temperature, clinical symptoms, virus shedding, mortality rate, and lung lesions. RESULTS: The results showed that a BAC clone of Bartha-K61 and a B-gD&gCS clone were successfully generated. The growth kinetics of PRV B-gD&gCS strain on ST (Swine testicular) cells was similar to that of the Bartha-K61 strain. No piglets inoculated intramuscularly with PRV B-gD&gCS strain exhibited any clinical symptoms or virus shedding. After AH02LA challenge, all piglets in PRV B-gD&gCS and Bartha-K61 groups (n = 5 each) survived without exhibiting any clinical symptoms and high body temperature. More importantly, PRV B-gD&gCS strain completely prevented virus shedding in 2 piglets and reduced virus shedding post challenge in the other 3 piglets as compared with Bartha-K61 group. CONCLUSIONS: Our results suggest that PRV B-gD&gCS strain is a promising vaccine candidate for the effective control of current severe epidemic pseudorabies in China.

Safety and immunogenicity of an attenuated Chinese pseudorabies variant by dual deletion of TK&gE genes.

BACKGROUND: Since the outbreak of a new emerging virulent pseudorabies virus mutant in Chinese pig herds, intensive research has been focused on the construction of novel gene deletion vaccine based on the variant virulent viruses. An ideal vaccine candidate is expected to have a balanced safety and immunogenicity. RESULTS: From the infectious clone of PRV AH02LA strain, a TK deletion mutant was generated through two-step Red mutagenesis. After homologous recombination with a transfer vector, a TK&gE dual deficient mutant PRV (PRVΔTK&gE-AH02) was generated, and its structure verified by PCR, RFLP and sequencing. Growth kinetics test showed that PRVΔTK&gE-AH02 reached a titer of 107.5 TCID50 /mL on ST cells. The PRVΔTK&gE-AH02 at a dose of 106.0 TCID50 /animal was not virulent in mice or 1-day-old piglets with maternal PRV antibodies. No clinical signs or virus shedding were detected in 28~ 35-day-old piglets without maternal PRV antibodies after nasal or intramuscular administration with a dose of 106.0 TCID50, although it caused one death of four 1-day-old piglets without maternal PRV antibodies. In the efficiency test of PRVΔTK&gE-AH02, all four 28~ 35-day-old piglets without PRV antibody in the challenge control showed typical clinical symptoms and virus shedding, and two died at 4~ 5 days post challenge. All piglets in 105.0, 104.0 and 103.0 TCID50/dose PRVΔTK&gE-AH02 groups provided complete protection against challenge at only 7 days post intramuscular vaccination. More importantly, PRVΔTK&gE-AH02 stopped virus shedding in these piglets. In contrast, all four piglets in PRV Bartha K61 vaccine group developed high body temperature (≥40.5 °C) and viral shedding, despite they had mild or even no clinical symptoms. CONCLUSIONS: The constructed TK&gE dual deletion mutant PRVΔTK&gE-AH02 can reach high titers on ST cells. The live vaccine of PRVΔTK&gE-AH02 is highly safe, and can not only provide clinical protection but also stops virus shedding. This study suggests that PRVΔTK&gE-AH02 might work as a promising vaccine candidate to combat the PRV variant emerging in Chinese herds since 2011.

An inactivated gE-deleted pseudorabies vaccine provides complete clinical protection and reduces virus shedding against challenge by a Chinese pseudorabies variant.

BACKGROUND: Since the end of 2011 an outbreak of pseudorabies affected Chinese pig herds that had been vaccinated with the commercial vaccine made of Bartha K61 strain. It is now clear that the outbreak was caused by an emergent PRV variant. Even though vaccines made of PRV Bartha K61 strain can confer certain cross protection against PRV variants based on experimental data, less than optimal clinical protection and virus shedding reduction were observed, making the control or eradication of this disease difficult. RESULTS: An infectious clone of PRV AH02LA strain was constructed to generate a gE deletion mutant PRV(LA-AB) strain. PRV(LA-AB) strain can reach a titer of 108.43 TCID50 /mL (50% tissue culture infectious dose) on BHK-21 cells. To evaluate the efficiency of the inactivated vaccine made of PRV(LA-AB) strain, thirty 3-week-old PRV-negative piglets were divided randomly into six groups for vaccination and challenge test. All five piglets in the challenge control showed typical clinical symptoms of pseudorabies post challenge. Sneezing and nasal discharge were observed in four and three piglets in groups C(vaccinated with inactivated PRV Bartha K61 strain vaccine) and D(vaccinated with live PRV Bartha K61 strain vaccine) respectively. In contrast, piglets in both groups A(vaccinated with inactivated PRV LA-AB strain vaccine) and B(vaccinated with inactivated PRV LA-AB strain vaccine with adjuvant) presented mild or no clinical symptoms. Moreover, viral titers detected via nasal swabs were approximately 100 times lower in group B than in the challenge control, and the duration of virus shedding (3-4 days) was shorter than in either the challenge control (5-10 days) or groups C and D (5-6 days). CONCLUSIONS: The infectious clone constructed in this study harbors the whole genome of the PRV variant AH02LA strain. The gE deletion mutant PRV(LA-AB)strain generated from PRV AH02LA strain can reach a high titer on BHK-21 cells. An inactivated vaccine of PRV LA-AB provides clinical protection and significantly reduces virus shedding post challenge, especially if accompanied by the adjuvant CVC1302. While Inactivated or live vaccines made of PRV Barth K61 strain can provide only partial protection in this test.

Construction of a recombinant duck enteritis virus (DEV) expressing hemagglutinin of H5N1 avian influenza virus based on an infectious clone of DEV vaccine strain and evaluation of its efficacy in ducks and chickens.

BACKGROUND: Highly pathogenic avian influenza virus (AIV) subtype H5N1 remains a threat to poultry. Duck enteritis virus (DEV)-vectored vaccines expressing AIV H5N1 hemagglutinin (HA) may be viable AIV and DEV vaccine candidates. METHODS: To facilitate the generation and further improvement of DEV-vectored HA(H5) vaccines, we first constructed an infectious clone of DEV Chinese vaccine strain C-KCE (DEV(C-KCE)). Then, we generated a DEV-vectored HA(H5) vaccine (DEV-H5(UL55)) based on the bacterial artificial chromosome (BAC) by inserting a synthesized HA(H5) expression cassette with a pMCMV IE promoter and a consensus HA sequence into the noncoding area between UL55 and LORF11. The immunogenicity and protective efficacy of the resulting recombinant vaccine against DEV and AIV H5N1 were evaluated in both ducks and chickens. RESULTS: The successful construction of DEV BAC and DEV-H5(UL55) was verified by restriction fragment length polymorphism analysis. Recovered virus from the BAC or mutants showed similar growth kinetics to their parental viruses. The robust expression of HA in chicken embryo fibroblasts infected with the DEV-vectored vaccine was confirmed by indirect immunofluorescence and western blotting analyses. A single dose of 10(6) TCID50 DEV-vectored vaccine provided 100 % protection against duck viral enteritis in ducks, and the hemagglutination inhibition (HI) antibody titer of AIV H5N1 with a peak of 8.2 log2 was detected in 3-week-old layer chickens. In contrast, only very weak HI titers were observed in ducks immunized with 10(7) TCID50 DEV-vectored vaccine. A mortality rate of 60 % (6/10) was observed in 1-week-old specific pathogen free chickens inoculated with 10(6) TCID50 DEV-vectored vaccine. CONCLUSIONS: We demonstrate the following in this study. (i) The constructed BAC is a whole genome clone of DEV(C-KCE). (ii) The insertion of an HA expression cassette sequence into the noncoding area between UL55 and LORF11 of DEV(C-KCE) affects neither the growth kinetics of the virus nor its protection against DEV. (iii) DEV-H5(UL55) can generate a strong humoral immune response in 3-week-old chickens, despite the virulence of this virus observed in 1-week-old chickens. (iv) DEV-H5(UL55) induces a weak HI titer in ducks. An increase in the HI titers induced by DEV-vectored HA(H5) will be required prior to its wide application.

Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman's disease: A case report.

Multicentric Castleman disease (MCD) is a heterogeneous, life-threatening disease. A subgroup of HIV-negative and HHV-8-negative MCD is defined as idiopathic MCD (iMCD) with a poor prognosis. Here we report an unusual case of a 47-year-old male patient with iMCD who experienced multiple treatment regimens such as chemotherapy, immunomodulatory therapy, and targeted therapy, all of which were considered ineffective. Subsequently, he was started on bortezomib in combination with dexamethasone for six cycles and he was in complete remission. The patient has survived nearly 13 years to date - the longest survival of any iMCD patient treated with bortezomib in combination with dexamethasone. Bortezomib combined with dexamethasone may be an effective salvage strategy for severe and refractory iMCD.

Molecular mechanism of miRNA mediated biosynthesis of secondary metabolites in medicinal plants.

Plant secondary metabolites are important raw materials for the pharmaceutical industry, and their biosynthetic processes are subject to diverse and precise regulation by miRNA. The identification of miRNA molecules in medicinal plants and exploration of their mechanisms not only contribute to a deeper understanding of the molecular genetic mechanisms of plant growth, development and resistance to stress, but also provide a theoretical basis for elucidating the pharmacological effects of authentic medicinal materials and constructing bioreactors for the synthesis of medicinal secondary metabolite components. This paper summarizes the research reports on the discovery of miRNA in medicinal plants and their regulatory mechanisms on the synthesis of secondary metabolites by searching the relevant literature in public databases. It summarizes the currently discovered miRNA and their functions in medicinal plants, and summarizes the molecular mechanisms regulating the synthesis and degradation of secondary metabolites. Furthermore, it provides a prospect for the research and development of medicinal plant miRNA. The compiled information contributes to a comprehensive understanding of the research progress on miRNA in medicinal plants and provides a reference for the industrial development of related secondary metabolite biosynthesis.

Advances in militarine: Pharmacology, synthesis, molecular regulation and regulatory mechanisms.

Militarine is the lead member of secondary metabolites found in multiple medicinal plants of the orchid family. It acts as not only an important inhibitor on plant growth, but also functions as the quality marker for medicinal materials. In addition, Militarine has been shown to possess remarkably medicinal value, with a definite potential for finding widespread adoption of treating various diseases, including lung injury, brain nerve injury, cognitive impairment, aging, tumors, inflammation, peptic ulcers, and more. Thus, it can serve as a material carrier for pharmacophore upon, so much so that it probes as natural source of lead compounds in the research and development of medication. The study reported herein makes an overview on the physicochemical properties and pharmacological mechanisms of Militarine compounds, summarizes the biogenic pathways of Militarine and organically integrates the biological characteristics of Militarine with multiple omics techniques. Besides, this review also constructs a regulatory system for the biological accumulation of Militarine around its precursor compounds, characteristic gene elements, key enzymes, important metabolic products, and critical steps and links. Exceptionally, emphasis on the biosynthesis of Militarine under both abiotic and biotic stress, as well as an elaboration of the signaling pathways and critical regulatory mechanisms that govern the metabolic flow of Militarine have been represented accordingly in this paper. These findings are expected to provide reference schemes and theoretical foundations for acquiring high-quality resources of Militarine and advancing its large-scale industrial production, drug development, and clinical applications to comprehensively elucidate the biosynthetic and metabolic pathways.

Research overview on the genetic mechanism underlying the biosynthesis of polysaccharide in tuber plants.

Tuber plants are of great significance in the world as human food crops. Polysaccharides, important metabolites in tuber plants, also serve as a source of innovative drugs with significant pharmacological effects. These drugs are particularly known for their immunomodulation and antitumor properties. To fully exploit the potential value of tuber plant polysaccharides and establish a synthetic system for their targeted synthesis, it is crucial to dissect their metabolic processes and genetic regulatory mechanisms. In this article, we provide a comprehensive summary of the basic pathways involved in the synthesis of various types of tuber plant polysaccharides. We also outline the key research progress that has been made in this area in recent years. We classify the main types and functions of tuber plant polysaccharides and analyze the biosynthetic processes and genetic regulation mechanisms of key enzymes involved in the metabolic pathways of starch, cellulose, pectin, and fructan in tuber plants. We have identified hexokinase and glycosyltransferase as the key enzymes involved in the polysaccharide synthesis process. By elucidating the synthesis pathway of polysaccharides in tuber plants and understanding the underlying mechanism of action of key enzymes in the metabolic pathway, we can provide a theoretical framework for enhancing the yield of polysaccharides and other metabolites in plant culture cells. This will ultimately lead to increased production efficiency.

Digital non-Foster-inspired electronics for broadband impedance matching.

Narrow bandwidths are a general bottleneck for applications relying on passive, linear, subwavelength resonators. In the past decades, several efforts have been devoted to overcoming this challenge, broadening the bandwidth of small resonators by the means of analog non-Foster matching networks for radiators, antennas and metamaterials. However, most non-Foster approaches present challenges in terms of tunability, stability and power limitations. Here, by tuning a subwavelength acoustic transducer with digital non-Foster-inspired electronics, we demonstrate five-fold bandwidth enhancement compared to conventional analog non-Foster matching. Long-distance transmission over airborne acoustic channels, with approximately three orders of magnitude increase in power level, validates the performance of the proposed approach. We also demonstrate convenient reconfigurability of our non-Foster-inspired electronics. This implementation provides a viable solution to enhance the bandwidth of sub-wavelength resonance-based systems, extendable to the electromagnetic domain, and enables the practical implementation of airborne and underwater acoustic radiators.

The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target.

Liver disease is a common and serious threat to human health. The progression of liver diseases is influenced by many physiologic processes, including oxidative stress, inflammation, bile acid metabolism, and autophagy. Various factors lead to the dysfunction of these processes and basing on the different pathogeny, pathology, clinical manifestation, and pathogenesis, liver diseases are grouped into different categories. Specifically, Sirtuin1 (SIRT1), a member of the sirtuin protein family, has been extensively studied in the context of liver injury in recent years and are confirmed the significant role in liver disease. SIRT1 has been found to play a critical role in regulating key processes in liver injury. Further, SIRT1 seems to cause divers outcomes in different types of liver diseases. Recent studies have showed some therapeutic strategies involving modulating SIRT1, which may bring a novel therapeutic target. To elucidate the mechanisms underlying the role of sirtuin1 in liver injury and its potentiality as a therapeutic target, this review outlines the key signaling pathways associated with sirtuin1 and liver injury, and discusses recent advances in therapeutic strategies targeting sirtuin1 in liver diseases.

CCT6A alleviates pulmonary fibrosis by inhibiting HIF-1α-mediated lactate production.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive fibrotic lung disease. The development of IPF involves different molecular and cellular processes, and recent studies indicate that lactate plays a significant role in promoting the progression of the disease. Nevertheless, the mechanism by which lactate metabolism is regulated and the downstream effects remain unclear. The molecular chaperone CCT6A performs multiple functions in a variety of biological processes. Our research has identified a potential association between CCT6A and serum lactate levels in IPF patients. Herein, we found that CCT6A was highly expressed in type 2 alveolar epithelial cells (AEC2s) of fibrotic lung tissues and correlated with disease severity. Lactate increases the accumulation of lipid droplets in epithelial cells. CCT6A inhibits lipid synthesis by blocking the production of lactate in AEC2s and alleviates bleomycin-induced pulmonary fibrosis in mice. In addition, our results revealed that CCT6A blocks HIF-1α-mediated lactate production by driving the VHL-dependent ubiquitination and degradation of HIF-1α and further inhibits lipid accumulation in fibrotic lungs. In conclusion, we propose that there is a pivotal regulatory role of CCT6A in lactate metabolism in pulmonary fibrosis, and strategies aimed at targeting these key molecules could represent potential therapeutic approaches for pulmonary fibrosis.

A nanoluciferase SFTSV for rapid screening antivirals and real-time visualization of virus infection in mice.

BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes severe hemorrhagic fever in humans, but no FDA-approved specific antivirals or vaccines are available to treat or prevent SFTS. METHODS: The plasmids construction and transfection were performed to generate the recombinant SFTSV harboring the nanoluciferase gene (SFTSV-Nluc). Immunostaining plaque assay was performed to measure viral titers, and DNA electrophoresis and Sanger sequencing were performed to evaluate the genetic stability. Luciferase assay and quantitative RT-PCR were performed to evaluate the efficacy of antivirals in vitro. Bioluminescence imaging, titration of virus from excised organs, hematology, and histopathology and immunohistochemistry were performed to evaluate the efficacy of antivirals in vivo. FINDINGS: SFTSV-Nluc exhibited high genetic stability and replication kinetics similar to those of wild-type virus (SFTSVwt), then a rapid high-throughput screening system for identifying inhibitors to treat SFTS was developed, and a nucleoside analog, 4-FlU, was identified to effectively inhibit SFTSV in vitro. SFTSV-Nluc mimicked the replication characteristics and localization of SFTSVwt in counterpart model mice. Bioluminescence imaging of SFTSV-Nluc allowed real-time visualization and quantification of SFTSV replication in the mice. 4-FlU was demonstrated to inhibit the replication of SFTSV with more efficiency than T-705 and without obvious adverse effect in vivo. INTERPRETATION: The high-throughput screening system based on SFTSV-Nluc for use in vitro and in vivo revealed that a safe and effective antiviral nucleoside analog, 4-FlU, may be a basis for the strategic treatment of SFTSV and other bunyavirus infections, paving the way for the discovery of antivirals. FUNDING: This work was supported by grants from the National Key Research and Development Plan of China (2021YFC2300700 to L. Zhang, 2022YFC2303300 to L. Zhang), Strategic Priority Research Program of Chinese Academy of Sciences (XDB0490000 to L. Zhang), National Natural Science Foundation of China (31970165 to L. Zhang, U22A20379 to G. Xiao), the Science and Technology Commission of Shanghai Municipality (21S11903100 to Y. Xie), Hubei Natural Science Foundation for Distinguished Young Scholars (2022CFA099 to L. Zhang).

Identification, Biological Function Profiling and Biosynthesis of Secondary Metabolites in Medicinal Orchids.

The secondary metabolites present in medicinal orchids are diverse and possess a vast array of biological activities. They represent valuable raw materials for modern pharmaceuticals and clinical medicine and have tremendous potential for future development. A systematic collation of secondary metabolites' composition and a summary of the biological activities of medicinal orchids represent a crucial step in unlocking the potential of these valuable resources in drug development. Furthermore, such information can provide essential guidance for comprehensively analyzing the pharmacological and therapeutic mechanisms of these valuable herbs in traditional Chinese herbal medicine. This review article presents an overview of the types and main biological functions of the secondary metabolites found in medicinal orchids, as well as the conventional synthesis methods for these compounds. Our aim is to provide a useful reference for future research and the drug development of secondary metabolic products of medicinal orchids.