Secofumitremorgins C and D, a pair of atropisomers from saltern-derived fungus Aspergillus fumigatus GXIMD00544.

A pair of atropisomers secofumitremorgins C (1a) and D (1b), together with fifteen known alkaloids (2-16), were isolated from a saltern-derived fungus Aspergillus fumigatus GXIMD00544. The structures of atropisomers 1a and 1b were elucidated by the detailed spectroscopic data, chemical reaction and quantum chemical calculations. Compounds 1 and 8 displayed antifungal spore germination effects against plant pathogenic fungus associated with sugarcane Fusarium sp. with inhibitory rates of 53% and 77% at the concentration of 100 µM, repectively. Atropisomers 1 also exhibited antifouling potential against Balanus amphitrite larval settlement with an inhibitory rate of 96% at the concentration of 100 µM.

Myricetin Acts as an Inhibitor of Type II NADH Dehydrogenase from Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is a common pathogenic microorganism in humans and animals. Type II NADH oxidoreductase (NDH-2) is the only NADH:quinone oxidoreductase present in this organism and represents a promising target for the development of anti-staphylococcal drugs. Recently, myricetin, a natural flavonoid from vegetables and fruits, was found to be a potential inhibitor of NDH-2 of S. aureus. The objective of this study was to evaluate the inhibitory properties of myricetin against NDH-2 and its impact on the growth and expression of virulence factors in S. aureus. RESULTS: A screening method was established to identify effective inhibitors of NDH-2, based on heterologously expressed S. aureus NDH-2. Myricetin was found to be an effective inhibitor of NDH-2 with a half maximal inhibitory concentration (IC50) of 2 µM. In silico predictions and enzyme inhibition kinetics further characterized myricetin as a competitive inhibitor of NDH-2 with respect to the substrate menadione (MK). The minimum inhibitory concentrations (MICs) of myricetin against S. aureus strains ranged from 64 to 128 µg/mL. Time-kill assays showed that myricetin was a bactericidal agent against S. aureus. In line with being a competitive inhibitor of the NDH-2 substrate MK, the anti-staphylococcal activity of myricetin was antagonized by MK-4. In addition, myricetin was found to inhibit the gene expression of enterotoxin SeA and reduce the hemolytic activity induced by S. aureus culture on rabbit erythrocytes in a dose-dependent manner. CONCLUSIONS: Myricetin was newly discovered to be a competitive inhibitor of S. aureus NDH-2 in relation to the substrate MK. This discovery offers a fresh perspective on the anti-staphylococcal activity of myricetin.

Hyperbaric oxygen therapy promotes the browning of white fat and contributes to the healing of diabetic wounds.

Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.

Dissection and integration of bursty transcriptional dynamics for complex systems.

RNA velocity estimation is a potentially powerful tool to reveal the directionality of transcriptional changes in single-cell RNA-sequencing data, but it lacks accuracy, absent advanced metabolic labeling techniques. We developed an approach, TopicVelo, that disentangles simultaneous, yet distinct, dynamics by using a probabilistic topic model, a highly interpretable form of latent space factorization, to infer cells and genes associated with individual processes, thereby capturing cellular pluripotency or multifaceted functionality. Focusing on process-associated cells and genes enables accurate estimation of process-specific velocities via a master equation for a transcriptional burst model accounting for intrinsic stochasticity. The method obtains a global transition matrix by leveraging cell topic weights to integrate process-specific signals. In challenging systems, this method accurately recovers complex transitions and terminal states, while our use of first-passage time analysis provides insights into transient transitions. These results expand the limits of RNA velocity, empowering future studies of cell fate and functional responses.

Size effects and electronic properties of zinc-doped boron clusters Zn B n (n = 1-15).

CONTEXT: To gain a deeper understanding of zinc-doped boron clusters, theoretical calculations were performed to investigate the size effects and electronic properties of zinc-doped boron clusters. The study of the electronic properties, spectral characteristics, and geometric structures of Zn B n (n = 1-15) is of great significance in the fields of semiconductor materials science, material detection, and improving catalytic efficiency. The results indicate that Zn B n (n = 1-15) clusters predominantly exhibit planar or quasi-planar structures, with the Zn atom positioned in the outer regions of the B n framework. The second stable structure of Zn B 3 is a three-dimensional configuration, indicating that the structures of zinc-doped boron clusters begin to convert from the planar or quasi-planar structures to the 3D configurations. The second low-energy structure of Zn B 15 is a novel configuration. Relative stability analyses show that the Zn B 12 has better chemical stability than other clusters with a HOMO-LUMO gap of 2.79 eV. Electric charge analysis shows that part electrons on zinc atoms are transferred to boron atoms, and electrons prefer to cluster near the B n framework. According to the electron localization function, it gets harder to localize electrons as the equivalent face value drops, and it's challenging to see covalent bond formation between zinc and boron atoms. The spectrograms of Zn B n (n = 1-15) exhibit distinct properties and notable spectral features, which can be used as a theoretical basis for the identification and confirmation of boron clusters doped with single-atom transition metals. METHODS: The calculations were performed using the ABCluster global search technique combined with density functional theory (DFT) methods. The selected low-energy structures were subjected to geometric optimization and frequency calculations at the PBE0/6-311 + G(d) level to ensure structural stability and eliminate any imaginary frequencies. To acquire more precise relative energies, we performed single-point energies calculations for the low-lying isomers of Zn B n (n = 1-15) at the CCSD(T)/6-311 + G(d)//PBE0/6-311 + G(d) level of theory. All calculations were performed using Gaussian 09 software. To facilitate analysis, we utilized software tools such as Multiwfn, and VMD.

Raman time-delay in attosecond transient absorption of strong-field created krypton vacancy.

Strong field ionization injects a transient vacancy in the atom which is entangled to the outgoing photoelectron. When the electron is finally detached, the ion is populated at different excited states with part of coherence information lost. The preserved coherence of matter after interacting with intense short pulses has important consequences on the subsequent nonequilibrium evolution and energy relaxation. Here we employ attosecond transient absorption spectroscopy to measure the time-delay of resonant transitions of krypton vacancy during their creation. We have observed that the absorptions by the two spin-orbit split states are modulated at different paces when varying the time-delay between the near-infrared pumping pulse and the attosecond probing pulse. It is shown that the coupling of the ions with the remaining field leads to a suppression of ionic coherence. Comparison between theory and experiments uncovers that coherent Raman coupling induces time-delay between the resonant absorptions, which provides insight into laser-ion interactions enriching attosecond chronoscopy.

Distinct microbiota assembly and functional patterns in disease-resistant and susceptible varieties of tobacco.

The plant microbiota is believed to be an accessory genome that extends plant functions, forming holobionts together with the host plant. Plant disease resistance, therefore, is inextricably linked with plant microbiota, which play important roles in plant growth and health. To explore the relationship between plant microbiota and disease resistance, we investigated the tobacco microbiome of two varieties with contrasting disease-resistance levels to bacterial wilt and black shank diseases. Comparative microbiome analysis indicated that the resistant variety assembled a distinct microbiota with higher network complexity and diversity. While Pseudomonas and Ensifer, which contain biocontrol and beneficial members, were enriched in the rhizosphere of the resistant variety, Ralstonia, a genus including the known causative pathogen, was enriched in the susceptible variety. Metagenome sequencing revealed that biocontrol functions, such as hydrogen cyanide synthase, pyochelin biosynthesis, and arthrofactin-type cyclic lipopeptide synthetase, were more abundant in the resistant variety. Further analysis indicated that contigs encoding the corresponding genes were mostly assigned to Pseudomonas. Among all the metagenome-assembled genomes, positive selection was suggested in the genome assigned to Pseudomonas only in the rhizosphere of the resistant variety. The search of biosynthetic gene clusters in the Pseudomonas genome revealed a non-ribosomal peptide synthetase, the compound of which was brabantamide A, with known antimicrobial activity. Collectively, our study suggests that the plant microbiota might be involved in microbe-mediated disease resistance. Particularly, our results highlight Pseudomonas in the rhizosphere of the disease-resistant variety as a promising biocontrol candidate. Our study may facilitate further screening of bacterial isolates and the targeted design of microbial communities.

Exploring the functional role of tRF-39-8HM2OSRNLNKSEKH9 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality globally. tRNA-derived small RNAs (tsRNAs) have emerged as potential targets for cancer treatment. However, the specific impact of tsRNAs on HCC remains undiscovered. In this study, we aimed to investigate the biological significance of tsRNAs in HCC. First, we screened the differentially expressed tsRNAs in HCC tissues and normal tissues adjacent to the tumor (NAT) using high-throughput sequencing and the results showed that tRF-39-8HM2OSRNLNKSEKH9 was more highly expressed in HCC tissues than NATs. Agarose gel electrophoresis (AGE), nuclear-cytoplasmic separation assays and fluorescence in situ hybridization (FISH) were employed to assess the characterization of tRF-39-8HM2OSRNLNKSEKH9. The relationship between the expression of tRF-39-8HM2OSRNLNKSEKH9 and clinicopathological parameters was evaluated and we found that it was positively associated with tumor size. The cell counting kit-8 (CCK8) assay, colony formation assay and EdU staining assay were employed to investigate the role of tRF-39-8HM2OSRNLNKSEKH9 in the proliferation of HCC cells. Additionally, transwell assays demonstrated that overexpression of tRF-39-8HM2OSRNLNKSEKH9 could accelerate cell migration capability. Taken together, tRF-39-8HM2OSRNLNKSEKH9 was highly expressed in HCC cells, serum and tissues, and it may play an oncogenic role in HCC cells through interacting with downstream mRNA targets.

Austin-Type Meroterpenoids from Fungi Reported in the Last Five Decades: A Review.

Austin was first isolated as a novel polyisoprenoid mycotoxin from Aspergillus ustus in 1976. Subsequently, some new austin-type meroterpenoids (ATMTs) have been continually found. This review attempts to give a comprehensive summary of progress on the isolation, chemical structural features, biological activities, and fungal biodiversity of 104 novel ATMTs from 5 genera of terrestrial- and marine-derived fungi reported from October 1976 to January 2023. The genera of Penicillium and Aspergillus are the two dominant producers, producing 63.5% and 30.8% of ATMTs, respectively. Moreover, about 26.9% of ATMTs display various pronounced bioactivities, including insecticidal, anti-inflammatory, cytotoxicity, antibacterial, and PTP1B inhibitory activities. The chemical diversity and potential activities of these novel fungal ATMTs are reviewed for a better understanding, and a relevant summary focusing on the source fungi and their taxonomy is provided to shed light on the future development and research of austin-type meroterpenoids.

Carneusones A-F, Benzophenone Derivatives from Sponge-Derived Fungus Aspergillus carneus GXIMD00543.

Six benzophenone derivatives, carneusones A-F (1-6), along with seven known compounds (7-13) were isolated from a strain of sponge-derived marine fungus Aspergillus carneus GXIMD00543. Their chemical structures were elucidated by detailed spectroscopic data and quantum chemical calculations. Compounds 5, 6, and 8 exhibited moderate anti-inflammatory activity on NO secretion using lipopolysaccharide (LPS)-induced RAW 264.7 cells with EC50 values of 34.6 ± 0.9, 20.2 ± 1.8, and 26.8 ± 1.7 µM, while 11 showed potent effect with an EC50 value of 2.9 ± 0.1 µM.

Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2 O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

MAIVeSS: streamlined selection of antigenically matched, high-yield viruses for seasonal influenza vaccine production.

Vaccines are the main pharmaceutical intervention used against the global public health threat posed by influenza viruses. Timely selection of optimal seed viruses with matched antigenicity between vaccine antigen and circulating viruses and with high yield underscore vaccine efficacy and supply, respectively. Current methods for selecting influenza seed vaccines are labor intensive and time-consuming. Here, we report the Machine-learning Assisted Influenza VaccinE Strain Selection framework, MAIVeSS, that enables streamlined selection of naturally circulating, antigenically matched, and high-yield influenza vaccine strains directly from clinical samples by using molecular signatures of antigenicity and yield to support optimal candidate vaccine virus selection. We apply our framework on publicly available sequences to select A(H1N1)pdm09 vaccine candidates and experimentally confirm that these candidates have optimal antigenicity and growth in cells and eggs. Our framework can potentially reduce the optimal vaccine candidate selection time from months to days and thus facilitate timely supply of seasonal vaccines.

A ferroptosis-reinforced nanocatalyst enhances chemodynamic therapy through dual H2O2 production and oxidative stress amplification.

The existence of a delicate redox balance in tumors usually leads to cancer treatment failure. Breaking redox homeostasis by amplifying oxidative stress and reducing glutathione (GSH) can accelerate cancer cell death. Herein, we construct a ferroptosis-reinforced nanocatalyst (denoted as HBGL) to amplify intracellular oxidative stress via dual H2O2 production-assisted chemodynamic therapy (CDT). Specifically, a long-circulating liposome is employed to deliver hemin (a natural iron-containing substrate for Fenton reaction and ferroptosis), ß-lapachone (a DNA topoisomerase inhibitor with H2O2 generation capacity for chemotherapy), and glucose oxidase (which can consume glucose for starvation therapy and generate H2O2). HBGL can achieve rapid, continuous, and massive H2O2 and •OH production and GSH depletion in cancer cells, resulting in increased intracellular oxidative stress. Additionally, hemin can reinforce the ferroptosis-inducing ability of HBGL, which is reflected in the downregulation of glutathione peroxidase-4 and the accumulation of lipid peroxide. Notably, HBGL can disrupt endo/lysosomes and impair mitochondrial function in cancer cells. HBGL exhibits effective tumor-killing ability without eliciting obvious side effects, indicating its clinical translation potential for synergistic starvation therapy, chemotherapy, ferroptosis therapy, and CDT. Overall, this nanocatalytic liposome may be a promising candidate for achieving potentiated cancer treatment.

Discovering Social Determinant of Health Risk Factors for Perinatal Morbidity Through Real World Data.

Gestational diabetes and preterm birth are perinatal morbidities that significantly impact women and infants' health. While clinical factors like cesarean delivery, multiple gestation, preeclampsia, and hypertensive disorder are associated with these conditions, it is increasingly recognized that social determinants of health play a crucial role. This study aims to measure the associations between the social vulnerability index (SVI) and these perinatal morbidities using multivariate logistic regression models. The results indicate that factors across all four themes in SVI are significantly associated with these conditions. These findings suggest that interventions targeting these areas are needed to achieve better reproductive health.

Targeted therapies of inflammatory diseases with intracellularly gelated macrophages in mice and rats.

Membrane-camouflaged nanomedicines often suffer from reduced efficacy caused by membrane protein disintegration and spatial disorder caused by separation and reassembly of membrane fragments during the coating process. Here we show that intracellularly gelated macrophages (GMs) preserve cell membrane structures, including protein content, integration and fluidity, as well as the membrane lipid order. Consequently, in our testing GMs act as cellular sponges to efficiently neutralize various inflammatory cytokines via receptor-ligand interactions, and serve as immune cell-like carriers to selectively bind inflammatory cells in culture medium, even under a flow condition. In a rat model of collagen-induced arthritis, GMs alleviate the joint injury, and suppress the overall arthritis severity. Upon intravenous injection, GMs efficiently accumulate in the inflammatory lungs of acute pneumonia mice for anti-inflammatory therapy. Conveniently, GMs are amenable to lyophilization and can be stored at ambient temperatures for at least 1 month without loss of integrity and bio-activity. This intracellular gelation technology provides a universal platform for targeted inflammation neutralization treatment.

J24335 exerts neuroprotective effects against 6-hydroxydopamine-induced lesions in PC12 cells and mice.

Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged >60 years. Meanwhile, single-target drugs becoming inapplicable as PD pathogenesis diversifies. Mitochondrial dysfunction and neurotoxicity have been shown to be relevant to the pathogenesis of PD. The novel synthetic compound J24335 (11-Hydroxy-1-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-one oxime), which has been researched similarly to J2326, has the potential to be a multi-targeted drug and alleviate these lesions. Therefore, we investigated the mechanism of action and potential neuroprotective function of J24335 against 6-OHDA-induced neurotoxicity in mice, and in PC12 cell models. The key target of action of J24335 was also screened. MTT assay, LDH assay, flow cytometry, RT-PCR, LC-MS, OCR and ECAR detection, and Western Blot analysis were performed to characterize the neuroprotective effects of J24335 on PC12 cells and its potential mechanism. Behavioral tests and immunohistochemistry were used to evaluate behavioral changes and brain lesions in mice. Moreover, bioinformatics was employed to assess the drug-likeness of J24335 and screen its potential targets. J24335 attenuated the degradation of mitochondrial membrane potential and enhanced glucose metabolism and mitochondrial biosynthesis to ameliorate 6-OHDA-induced mitochondrial dysfunction. Animal behavioral tests demonstrated that J24335 markedly improved motor function and loss of TH-positive neurons and dopaminergic nerve fibers, and contributed to an increase in the levels of dopamine and its metabolites in brain tissue. The activation of both the CREB/PGC-1α/NRF-1/TFAM and PKA/Akt/GSK-3ß pathways was a major contributor to the neuroprotective effects of J24335. Furthermore, bioinformatics predictions revealed that J24335 is a low toxicity and highly BBB permeable compound targeting 8 key genes (SRC, EGFR, ERBB2, SYK, MAPK14, LYN, NTRK1 and PTPN1). Molecular docking suggested a strong and stable binding between J24335 and the 8 core targets. Taken together, our results indicated that J24335, as a multi-targeted neuroprotective agent with promising therapeutic potential for PD, could protect against 6-OHDA-induced neurotoxicity via two potential pathways in mice and PC12 cells.

Selective interference of liking and beauty judgements on affective working memory and visual working memory.

Aesthetic processing has profound implications for everyday life. Although liking and beauty judgements are outcomes of aesthetic processing and derive from a common hedonic value, there may be some differences in how they engage working memory. This study used maintenance and aesthetic judgement tasks to examine whether liking and beauty judgements make different demands on domain-specific working memory resources. Sixty participants (30 males) were instructed to rate picture for liking or beauty while maintaining the subjective affect or brightness of the presented pictures. Results indicated that liking judgements selectively impaired participants' performance in the affect maintenance task, and beauty judgements selectively impaired their performance in the brightness maintenance task. In addition, maintaining affect and brightness feelings in the mind increased image ratings on beauty but not on liking. Our findings provide evidence that liking judgements draw more on affective working memory resources than beauty judgements, and beauty judgements draw more on visual working memory resources than liking judgements.

Coupling the measures of pollution source control and water replenishment to improve water quality in the catchment scale of Qianshan River Basin.

With the development of the economy, the problem of urban black odorous water bodies has become increasingly significant, having a serious impact on the environment. As important means of remediating aquatic environments, pollution source control and water replenishment are of great significance in improving water quality. This study takes the Qianshan River Basin in Zhuhai City as its study area to simulate their effects on the improvement of water quality. A coupled model of water quantity and quality in Qianshan River Basin was constructed using MIKE11to analyze the water quality compliance rate, with sewage interception rates of 85%, 90%, and 95%, and to investigate the effect of pollution source control on the improvement of the aquatic environment. Using different sewage interception rates, the amount of water replenishment was calculated in order to meet water quality standards, the water replenishment scheme was determined via river-specific and time-specific methods, and the model was used to analyze the replenishment effect of the scheme. The results show that increasing the sewage interception rate can significantly improve the COD compliance rate, and improve the NH3-N and TP compliance rate; however, the enhancement effect is not sufficiently significant. When a sewage interception rate of 95% is implemented, there are still five rivers with a low NH3-N compliance rate, and six rivers with low a TP compliance rate. Comparing the water replenishment effect under different sewage interception rates of 85% and 95%, the water replenishment program alongside a sewage interception rate of 95% can effectively improve the aquatic environment and the water quality essentially meets the standard under different rainfall conditions; this demonstrates that the program presented herein can be used as the aquatic environment remediation program of choice for the Qianshan River Basin.

IAR4 mutation enhances cadmium toxicity by disturbing auxin homeostasis in Arabidopsis thaliana.

Cadmium (Cd) is highly toxic to plants, but the targets and modes of toxicity remain unclear. We isolated a Cd-hypersensitive mutant of Arabidopsis thaliana, Cd-induced short root 2 (cdsr2), in the background of the phytochelatin synthase-defective mutant cad1-3. Both cdsr2 and cdsr2 cad1-3 displayed shorter roots and were more sensitive to Cd than their respective wild type. Using genomic resequencing and complementation, IAR4 was identified as the causal gene, which encodes a putative mitochondrial pyruvate dehydrogenase E1α subunit. cdsr2 showed decreased pyruvate dehydrogenase activity and NADH content, but markedly increased concentrations of pyruvate and alanine in roots. Both Cd stress and IAR4 mutation decreased auxin level in the root tips, and the effect was additive. A higher growth temperature rescued the phenotypes in cdsr2. Exogenous alanine inhibited root growth and decreased auxin level in the wild type. Cadmium stress suppressed the expression of genes involved in auxin biosynthesis, hydrolysis of auxin-conjugates and auxin polar transport. Our results suggest that auxin homeostasis is a key target of Cd toxicity, which is aggravated by IAR4 mutation due to decreased pyruvate dehydrogenase activity. Decreased auxin level in cdsr2 is likely caused by increased auxin-alanine conjugation and decreased energy status in roots.