Antibody and transcription landscape in peripheral blood mononuclear cells of elderly adults over 70 years of age with third dose of COVID-19 BBIBP-CorV and ZF2001 booster vaccine.

BACKGROUND: In the context of the COVID-19 pandemic and extensive vaccination, it is important to explore the immune response of elderly adults to homologous and heterologous booster vaccines of COVID-19. At this point, we detected serum IgG antibodies and PBMC sample transcriptome profiles in 46 participants under 70 years old and 25 participants over 70 years old who received the third dose of the BBIBP-CorV and ZF2001 vaccines. RESULTS: On day 7, the antibody levels of people over 70 years old after the third dose of booster vaccine were lower than those of young people, and the transcriptional responses of innate and adaptive immunity were also weak. The age of the participants showed a significant negative correlation with functions related to T-cell differentiation and costimulation. Nevertheless, 28 days after the third dose, the IgG antibodies of elderly adults reached equivalence to those of younger adults, and immune-related transcriptional regulation was significantly improved. The age showed a significant positive correlation with functions related to "chemokine receptor binding", "chemokine activity", and "chemokine-mediated signaling pathway". CONCLUSIONS: Our results document that the response of elderly adults to the third dose of the vaccine was delayed, but still able to achieve comparable immune effects compared to younger adults, in regard to antibody responses as well as at the transcript level.

Spatial-temporal drivers and incidence heterogeneity of hemorrhagic fever with renal syndrome transmission in Shandong Province, China, 2016-2022.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) signals a recurring risk in Eurasia in recent years owing to its continued rise in case notifications and the extension of geographical distribution. This study was undertaken to investigate the spatiotemporal drivers and incidence heterogeneity of HFRS transmission in Shandong Province. METHODS: The epidemiological data for HFRS, meteorological data and socioeconomic data were obtained from China Information System for Disease Control and Prevention, China Meteorological Data Sharing Service System, and Shandong Statistical Yearbook, respectively. The spatial-temporal multicomponent model was employed to analyze the values of spatial-temporal components and the heterogeneity of HFRS transmission across distinct regions. RESULTS: The total effect values of the autoregressive, epidemic, and endemic components were 0.451, 0.187, and 0.033, respectively, exhibiting significant heterogeneity across various cities. This suggested a pivotal role of the autoregressive component in propelling HFRS transmission in Shandong Province. The epidemic component of Qingdao, Weifang, Yantai, Weihai, and Jining declined sharply at the onset of 2020. The random effect identified distinct incidence levels associated with Qingdao and Weifang, signifying regional variations in HFRS occurrence. CONCLUSIONS: The autoregressive component emerged as a significant driver in the transmission of HFRS in Shandong Province. Targeted preventive measures should be strategically implemented across various regions, taking into account the predominant component influencing the epidemic.

Natural variations of TFIIAγ gene and LOB1 promoter contribute to citrus canker disease resistance in Atalantia buxifolia.

Citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is one of the most devastating diseases in citrus industry worldwide. Most citrus cultivars such as sweet orange are susceptible to canker disease. Here, we utilized wild citrus to identify canker-resistant germplasms, and found that Atalantia buxifolia, a primitive (distant-wild) citrus, exhibited remarkable resistance to canker disease. Although the susceptibility gene LATERAL ORGAN BOUNDARIES 1 (LOB1) could also be induced in Atalantia after canker infection, the induction extent was far lower than that in sweet orange. In addition, three of amino acids encoded by transcription factor TFIIAγ in Atalantia (AbTFIIAγ) exhibited difference from those in sweet orange (CsTFIIAγ) which could stabilize the interaction between effector PthA4 and effector binding element (EBE) of LOB1 promoter. The mutation of AbTFIIAγ did not change its interaction with transcription factor binding motifs (TFBs). However, the AbTFIIAγ could hardly support the LOB1 expression induced by the PthA4. In addition, the activity of AbLOB1 promoter was significantly lower than that of CsLOB1 under the induction by PthA4. Our results demonstrate that natural variations of AbTFIIAγ and effector binding element (EBE) in the AbLOB1 promoter are crucial for the canker disease resistance of Atalantia. The natural mutations of AbTFIIAγ gene and AbLOB1 promoter in Atalantia provide candidate targets for improving the resistance to citrus canker disease.

Spatiotemporal distribution and environmental influences of severe fever with thrombocytopenia syndrome in Shandong Province, China.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in China in 2009. The purpose of this study was to describe the spatiotemporal distribution of SFTS and to identify its environmental influencing factors and potential high-risk areas in Shandong Province, China. METHODS: Data on the SFTS incidence from 2010 to 2021 were collected. Spatiotemporal scan statistics were used to identify the time and area of SFTS clustering. The maximum entropy (MaxEnt) model was used to analyse environmental influences and predict high-risk areas. RESULTS: From 2010 to 2021, a total of 5705 cases of SFTS were reported in Shandong. The number of SFTS cases increased yearly, with a peak incidence from April to October each year. Spatiotemporal scan statistics showed the existence of one most likely cluster and two secondary likely clusters in Shandong. The most likely cluster was in the eastern region, from May to October 2021. The first secondary cluster was in the central region, from May to October 2021. The second secondary cluster was in the southeastern region, from May to September 2020. The MaxEnt model showed that the mean annual wind speed, NDVI, cattle density and annual cumulative precipitation were the key factors influencing the occurrence of SFTS. The predicted risk map showed that the area of high prevalence was 28,120 km2, accounting for 18.05% of the total area of the province. CONCLUSIONS: The spatiotemporal distribution of SFTS was heterogeneous and influenced by multidimensional environmental factors. This should be considered as a basis for delineating SFTS risk areas and developing SFTS prevention and control measures.

A possible new activator of PI3K-Huayu Qutan Recipe alleviates mitochondrial apoptosis in obesity rats with acute myocardial infarction.

Obesity, which has unknown pathogenesis, can increase the frequency and seriousness of acute myocardial infarction (AMI). This study evaluated effect of Huayu Qutan Recipe (HQR) pretreatment on myocardial apoptosis induced by AMI by regulating mitochondrial function via PI3K/Akt/Bad pathway in rats with obesity. For in vivo experiments, 60 male rats were randomly divided into 6 groups: sham group, AMI group, AMI (obese) group, 4.5, 9.0 and 18.0 g/kg/d HQR groups. The models fed on HQR with different concentrations for 2 weeks before AMI. For in vitro experiments, the cardiomyocytes line (H9c2) was used. Cells were pretreated with palmitic acid (PA) for 24 h, then to build hypoxia model followed by HQR-containing serum for 24 h. Related indicators were also detected. In vivo, HQR can lessen pathohistological damage and apoptosis after AMI. In addition, HQR improves blood fat levels, cardiac function, inflammatory factor, the balance of oxidation and antioxidation, as well as lessen infarction in rats with obesity after AMI. Meanwhile, HQR can diminish myocardial cell death by improving mitochondrial function via PI3K/Akt/Bad pathway activation. In vitro, HQR inhibited H9c2 cells apoptosis, improved mitochondrial function and activated the PI3K/Akt/Bad pathway, but effects can be peripeteiad by LY294002. Myocardial mitochondrial dysfunction occurs following AMI and can lead to myocardial apoptosis, which can be aggravated by obesity. HQR can relieve myocardial apoptosis by improving mitochondrial function via the PI3K/Akt/Bad pathway in rats with obesity.

Z-Scheme Photocarrier Transfer Realized in Tungsten Oxide-Based Photocatalysts by Combining with Bismuth Vanadate Quantum Dots.

Multicomponent photocatalysts with a Z-scheme charge transfer are promising in converting solar to hydrogen fuel because of their significantly improved light absorption and restrained photocarrier recombination while keeping their redox capacity. In this work, a composite photocatalyst of BiVO4 quantum dot-decorated WO3 nanosheet arrays was synthesized and investigated. The existence of the Z-scheme charge transfer behavior was confirmed by the redox probe technique. Such a Z-scheme charge transfer makes it possible to generate hydrogen without bias. An optimized photocatalyst produces a hydrogen generation rate of 0.75 µmol/h without bias and a photocurrent of 1.91 mA/cm2 at 1.23 V versus RHE, which is about 70% higher than that of pure WO3. We attributed these improvements to the enhanced light absorption, extended conduction band level of BiVO4, as well as the unique charge transfer behavior in the Z-scheme structure. This work presents a generalizable method to improve the redox capacity of a variety of semiconductors through rationally selecting the building material blocks in view of energy levels.

Enhancing energy storage capacity of iron oxide-based anodes by adjusting Fe (II/III) ratio in spinel crystalline.

Supercapacitors, as promising energy storage candidates, are limited by their unsatisfactory anodes. Herein, we proposed a strategy to improve the electrochemical performance of iron oxide anodes by spinel-framework constraining. We have optimized the anode performance by adjusting the doping ratio of Fe (II/III) self-redox pairs. Structure and electronic state characterizations reveal that the NixFe3-xO4was composed of Fe (II/III) and Ni (II/III) pairs in lattice, ensuring a flexible framework for the reversible reaction of Fe (II/III). Typically, when the ratio of Fe (II/III) is 0.91:1 (Fe (II/III)-0.91/1), the NixFe3-xO4anode shows a remarkable electrochemical performance with a high specific capacitance of 1694 F g-1at the current density of 2 A g-1and capacitance retention of 81.58%, even at a large current density of 50 A g-1. In addition, the obtained material presents an ultra-stable electrochemical performance, and there is no observable degradation after 5000 cycles. Moreover, an assembled asymmetric supercapacitor of Ni-Co-S@CC//NixFe3-xO4@CC presents a maximum energy density of 136.82 Wh kg-1at the power density of 850.02 W kg-1. When the power density was close to 42 500 W kg-1, the energy density was still maintained 63.75 Wh kg-1. The study indicates that inherent performance of anode material can be improved by tuning the valence charge of active ions.

QTL mapping of yield-related traits in sesame.

Improving yield is one of the most important targets of sesame breeding. Identifying quantitative trait loci (QTLs) of yield-related traits is a prerequisite for marker-assisted selection (MAS) and QTL/gene cloning. In this study, a BC1 population was developed and genotyped with the specific-locus amplified fragment (SLAF) sequencing technology, and a high-density genetic map was constructed. The map consisted of 13 linkage groups, contained 3528 SLAF markers, and covered a total of 1312.52 cM genetic distance, with an average distance of 0.37 cM between adjacent markers. Based on the map, 46 significant QTLs were identified for seven yield-related traits across three environments. These QTLs distributed on 11 linkage groups, each explaining 2.34-71.41% of the phenotypic variation. Of the QTLs, 23 were stable QTLs that were detected in more than one environment, and 20 were major QTLs that explained more than 10% of the corresponding phenotypic variation in at least one environment. Favorable alleles of 38 QTLs originated from the locally adapted variety, Yuzhi 4; the exotic germplasm line, BS, contributed favorable alleles to only 8 QTLs. The results should provide useful information for future molecular breeding and functional gene cloning. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01236-x.

LAMC1 is related to the poor prognosis of patients with gastric cancer and facilitates cancer cell malignancies.

Gastric cancer is a common malignancy in the alimentary system. The laminin subunit gamma 1 (LAMC1) is an important oncogene in human cancers. However, how and whether LAMC1 takes part in gastric cancer progression is largely uncertain. This study analyzed the association between clinical factors of patients and LAMC1 expression and explored the influence of LAMC1 silencing on cell proliferation, migration, invasion, the Warburg effect, protein kinase B (AKT) pathway, and mitogen-activated protein kinase (MEK)/extracellular regulated protein kinase (ERK) pathway in gastric cancer cells. Our results showed LAMC1 abundance was enhanced in gastric cancer samples and cells. LAMC1 was related to the clinical stage, tumor depth, lymph node metastasis, and distant metastasis of patients. LAMC1 silencing inhibited cell proliferation, migration, and invasion. Moreover, LAMC1 knockdown suppressed the Warburg effect via decreasing lactate production, lactate dehydrogenase (LDH) activity, and glucose uptake. LAMC1 interference blocked the activation of the AKT and MEK/ERK signaling. Collectively, LAMC1 knockdown constrained cell proliferation, migration, invasion, and the Warburg effect in gastric cancer cells via inactivating the AKT and MEK/ERK pathway.

Transmission Potential of Asymptomatic and Paucisymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections: A 3-Family Cluster Study in China.

Data concerning the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in asymptomatic and paucisymptomatic patients are lacking. We report a 3-family cluster of infections involving asymptomatic and paucisymptomatic transmission. Eight of 15 (53%) members from 3 families were confirmed with SARS-CoV-2 infection. Of 8 patients, 3 were asymptomatic and 1 was paucisymptomatic. An asymptomatic mother transmitted the virus to her son, and a paucisymptomatic father transmitted the virus to his 3-month-old daughter. SARS-CoV-2 was detected in the environment of 1 household. The complete genomes of SARS-CoV-2 from the patients were > 99.9% identical and were clustered with other SARS-CoV-2 sequences reported from China and other countries.

[Screening of plant growth-promoting rhizobacteria and its effect on seed germination of Polygonum multiflorum].

In this study, the rhizobacteria and actinomycetes of Polygonum multiflorum were screened for the strains with indole acetic acid(IAA)-producing capacity by Salkowski method, the siderophore-producing strains by Chrome Azurol S(CAS) assay, and the strains with inorganic phosphorus-solubilizing capacity by PKO inorganic phosphorus medium. The strains were identified by morphological identification, physiological and biochemical characteristics, and 16 S rDNA sequences. Furthermore, the effect of growth-promoting strains on the seed germination and development of P. multiflorum was tested. The results showed that among 196 strains, two strains F17 and F42 were found to be capable of producing IAA and siderophore and solubilizing inorganic phosphorus simulta-neously. For F17 and F42, the results are listed below: 38.65 and 33.64 mg·L~(-1) for IAA production, 0.85 and 0.49 for siderophore-producing capacities(A_s/A_r), and 1.35 and 1.70 for inorganic phosphorus-solubilizing capacities(D/d), respectively. Comprehensive analysis revealed that strains F17 and F42 were identified as Pseudochrobactrum asacharolyticum and Bacillus aryabhattai, respectively, and both could significantly promote the seed germination of P. multiflorum.

Detection of Severe Acute Respiratory Syndrome Coronavirus 2 RNA on Surfaces in Quarantine Rooms.

We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) environmental contamination in 2 rooms of a quarantine hotel after 2 presymptomatic persons who stayed there were laboratory-confirmed as having coronavirus disease. We detected SARS-CoV-2 RNA on 8 (36%) of 22 surfaces, as well as on the pillow cover, sheet, and duvet cover.

General Construction of 2D Ordered Mesoporous Iron-Based Metal-Organic Nanomeshes.

Nanomeshes with highly regular, permeable pores in plane, combining the exceptional porous architectures with intrinsic properties of 2D materials, have attracted increasing attention in recent years. Herein, a series of 2D ultrathin metal-organic nanomeshes with ordered mesopores is obtained by a self-assembly method, including metal phosphate and metal phosphonate. The resultant mesoporous ferric phytate nanomeshes feature unique 2D ultrathin monolayer morphologies (≈9 nm thickness), hexagonally ordered, permeable mesopores of ≈16 nm, as well as improved surface area and pore volume. Notably, the obtained ferric phytate nanomeshes can directly in situ convert into mesoporous sulfur-doped metal phosphonate nanomeshes by serving as an unprecedented reactive self-template. Furthermore, as advanced anode materials for Li-ion batteries, they deliver excellent capacity, good rate capability, and cycling performance, greatly exceeding the similar metal phosphate-based materials reported previously, resulting from their unique 2D ultrathin mesoporous structure. Therefore, the work will pave an avenue for constructing the other 2D ordered mesoporous materials, and thus offer new opportunities for them in diverse areas.

Pre-Polymerization Enables Controllable Synthesis of Nanosheet-Based Porphyrin Polymers towards High-Performance Li-Ion Batteries.

The precise regulation of nucleation growth and assembly of polymers is still an intriguing goal but an enormous challenge. In this study, we proposed a pre-polymerization strategy to regulate the assembly and growth of polymers by facilely controlling the concentration of polymerization initiator, and thus obtained two kinds of different nanosheet-based porphyrin polymer materials using tetrakis-5,10,15,20-(4-aminophenyl) porphyrin (TAPP) as the precursor. Notably, due to the π-π stacking and doping of TAPP during the preparation process, the obtained PTAPP-nanocube material exhibits a high intrinsic bulk conductivity reaching 1.49×10-4  S m-1 . Profiting from the large π-conjugated structure of porphyrin units, closely stacked layer structure and excellent conductivity, the resultant porphyrin polymers, as electrode materials for lithium ion batteries, deliver high specific capacity (≈650 mAh g-1 at the current density of 100 mA g-1 ), excellent rate performance and long-cycle stability, which are among the best reports of porphyrin polymer-based electrode materials for lithium-ion batteries, to the best of our knowledge. Therefore, such a pre-polymerization approach would provide a new insight for the controllable synthesis of polymers towards custom-made architecture and function.

Antibacterial effect of Blumea balsamifera DC. essential oil against Haemophilus parasuis.

Haemophilus parasuis (H. parasuis), the cause of the Glasser's disease, is a potentially pathogenic gram-negative organism that colonizes the upper respiratory tract of pigs. The extraction of Blumea balsamifera DC., as a traditional Chinese herb, has shown great bacteriostatic effect against several common bacteria. To study the antibacterial effect on H. parasuis in vitro, this study evaluated the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Blumea balsamifera DC. essential oil (BBO) as well as morphological changes in H. parasuis treated with it. Furthermore, changes in expression of total protein and key virulence factors were also assessed. Results showed that the MIC and MBC were 0.625 and 1.25 µg/mL, respectively. As the concentration of BBO increased, the growth curve inhibition became stronger. H. parasuis cells were damaged severely after treatment with BBO for 4 h, demonstrating plasmolysis and enlarged vacuoles, along with broken cell walls and membranes. Total protein and virulence factor expression in H. parasuis was significantly downregulated by BBO. Taken together, these results indicated a substantial antibacterial effect of BBO on H. parasuis.

Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma.

Although the genotype-phenotype for familial medullary thyroid carcinoma (FMTC) is well studied, only few low susceptibility risk loci were identified for familial non-medullary thyroid carcinoma (FNMTC). The aim of this study is to screen and identify high-penetrate genes for FNMTC. A total of 34 families with more than two first-degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of MAP2K5 variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of MAP2K5 c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P < 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5-ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1/2(MEK1/2)-ERK1/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of MAP2K5 for molecular diagnosis as well as early prevention.

Detection of SFTS virus RNA and antibodies in severe fever with thrombocytopenia syndrome surveillance cases in endemic areas of China.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a newly identified severe infectious disease caused by SFTS phlebovirus (SFTSV). SFTS monitoring has been carried out since 2010 in mainland China. We analysed the detection results of SFTSV RNA and antibody in SFTS surveillance cases to provide basic data for SFTS diagnosis. METHODS: This study was conducted in Shandong Province. Sera of SFTS surveillance cases were collected to detect SFTSV RNA and antibody by real-time RT-PCR and enzyme-linked immunosorbent assay, respectively. Detection rates were calculated. SPSS 18.0 (Chicago, IL, USA) was used for statistical analysis to compare the detection rates of SFTSV RNA and antibodies among different sera groups. RESULTS: A total of 374 SFTS surveillance cases were enrolled. Overall, 93.3% (349/374) of the sera samples were collected within 2 weeks after onset, and 6.7% (25/374) were collected between 15 days and 45 days. Of these, 183 (48.9%) were positive for SFTSV RNA. The SFTSV RNA-positive rate peaked (52.2%) in samples collected ≤7 days after onset and then showed a decreasing trend. The detection rate of SFTSV-specific IgM antibody was 30.5% (46/151) and was highest in samples collected between 8 and 14 days (43.3%, 26/60). The positive rate of SFTSV-specific IgG antibody (17.9%, 27/151) showed an increasing trend with the specimen collection time. In total, 74.8% (113/151) of sera samples had the same SFTSV RNA and IgM antibody detection results. However, 23.2% (29/125) of SFTSV RNA-negative cases were IgM antibody-positive, and 8.6% (9/105) of IgM antibody-negative cases were SFTSV RNA-positive. CONCLUSIONS: SFTSV RNA detection was preferred for SFTSV infection during disease surveillance. For highly suspected SFTS cases, IgM antibody is suggested to make a comprehensive judgement.

Kaempferol alleviates LPS-ATP mediated inflammatory injury in splenic lymphocytes via regulation of the pyroptosis pathway in mice.

Background: The pharmacological application of kaempferol, a natural flavonol present in different plant species, has been demonstrated to have extensive anti-inflammatory, anti-apoptotic, anti-oxidative, and anti-cancer effects. Pyroptosis is an inflammatory form of programed cell death by membranolysis and associated leakage of cytoplasm. This study investigated the molecular mechanism of kaempferol-induced effects on the pyroptosis in splenic lymphocytes (SLCs) isolated from mice. Methods: Lipopolysaccharide (LPS)-primed and adenosine triphosphate (ATP)-stimulated SLCs were used to establish the pyroptosis model. The kaempferol pretreatment was tested in the model. Results: The results show that kaempferol alleviates LPS-ATP mediated damage by increasing cell viability, improving membrane integrity, and decreasing the release of IL1b and IL-18. Kaempferol reduces pyroptosis by suppressing the expression and activity of caspase-1, increasing the protein expression of Toll-like receptor 4 (TLR4) and NOD-like receptor 3 (NLRP3), and inhibition of the decomposition of gasdermin D (GSDMD). Conclusions: Our data suggest that kaempferol exhibits anti-pyroptosis activities, which warrants further detailed investigation.

[BRAF V600E Mutation and TERT Promoter Mutation in Papillary Thyroid Carcinomas and Their Association with Clinicopathological Characteristics].

OBJECTIVE: To explore the relationships of BRAF V600E and TERT promoter mutations with the clinicopathological features in papillary thyroid carcinoma (PTC). METHODS: The mutations of BRAF V600E and TERT promoters were examined by PCR-direct sequencing in tumor tissues from 326 PTC patients, while the relationships between the gene mutations and clinicopathological features were analyzed. RESULTS: BRAF V600E mutation was found in 269/326 (82.52%), and TERT promoter mutation in 11/326 (3.37%) of PTC patients. In site mutations of TERT promoter, 9 cases were C228T and 2 cases were C250T. Single factor analysis showed that BRAF V600E mutations were significantly associated with age and recurrence/distant metastasis of tumor (P < 0.05), while TERT promoter mutations were significantly associated with age, tumor size, extrathyroidal extension, T stage, AJCC stage and recurrence/distant metastasis of tumor (P < 0.05). Coexistence of BRAF V600E and TERT promoter mutations (BRAF+/TERT+) were particularly associated with age, tumor size, extrathyroidal extension, T stage and AJCC stage (P < 0.05). CONCLUSION: Coexistence of BRAF V600E and TERT promoter mutations in PTC shows more aggressive tumor behavior.

Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51.

To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC-MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.