E-Nose: Time-Frequency Attention Convolutional Neural Network for Gas Classification and Concentration Prediction.

In the electronic nose (E-nose) systems, gas type recognition and accurate concentration prediction are some of the most challenging issues. This study introduced an innovative pattern recognition method of time-frequency attention convolutional neural network (TFA-CNN). A time-frequency attention block was designed in the network, aiming to excavate and effectively integrate the temporal and frequency domain information in the E-nose signals to enhance the performance of gas classification and concentration prediction tasks. Additionally, a novel data augmentation strategy was developed, manipulating the feature channels and time dimensions to reduce the interference of sensor drift and redundant information, thereby enhancing the model's robustness and adaptability. Utilizing two types of metal-oxide-semiconductor gas sensors, this research conducted qualitative and quantitative analysis on five target gases. The evaluation results showed that the classification accuracy could reach 100%, and the coefficient of the determination (R2) score of the regression task was up to 0.99. The Pearson correlation coefficient (r) was 0.99, and the mean absolute error (MAE) was 1.54 ppm. The experimental test results were almost consistent with the system predictions, and the MAE was 1.39 ppm. This study provides a method of network learning that combines time-frequency domain information, exhibiting high performance in gas classification and concentration prediction within the E-nose system.

Benign prostatic hyperplasia nodules in patients treated with celecoxib and/or finasteride have reduced levels of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, a mitochondrial protein essential for efficient function of the electron transport chain.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS. METHODS: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed. RESULTS: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration. CONCLUSIONS: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.

Robust structural superlubricity under gigapascal pressures.

Structural superlubricity (SSL) is a state of contact with no wear and ultralow friction. SSL has been characterized at contact with van der Waals (vdW) layered materials, while its stability under extreme loading conditions has not been assessed. By designing both self-mated and non-self-mated vdW contacts with materials chosen for their high strengths, we report outstanding robustness of SSL under very high pressures in experiments. The incommensurate self-mated vdW contact between graphite interfaces can maintain the state of SSL under a pressure no lower than 9.45 GPa, and the non-self-mated vdW contact between a tungsten tip and graphite substrate remains stable up to 3.74 GPa. Beyond this critical pressure, wear is activated, signaling the breakdown of vdW contacts and SSL. This unexpectedly strong pressure-resistance and wear-free feature of SSL breaks down the picture of progressive wear. Atomistic simulations show that lattice destruction at the vdW contact by pressure-assisted bonding triggers wear through shear-induced tearing of the single-atomic layers. The correlation between the breakdown pressure and material properties shows that the bulk modulus and the first ionization energy are the most relevant factors, indicating the combined structural and electronic effects. Impressively, the breakdown pressures defined by the SSL interface could even exceed the strength of materials in contact, demonstrating the robustness of SSL. These findings offer a fundamental understanding of wear at the vdW contacts and guide the design of SSL-enabled applications.

Anthropogenic warming is a key climate indicator of rising urban fire activity in China.

China, one of the most populous countries in the world, has suffered the highest number of natural disaster-related deaths from fire. On local scales, the main causes of urban fires are anthropogenic in nature. Yet, on regional to national scales, little is known about the indicators of large-scale co-varying urban fire activity in China. Here, we present the China Fire History Atlas (CFHA), which is based on 19 947 documentary records and represents fires in urban areas of China over the twentieth century (1901-1994). We found that temperature variability is a key indicator of urban fire activity in China, with warmer temperatures being correlated with more urban fires, and that this fire-temperature relationship is seasonally and regionally explicit. In the early twentieth century, however, the fire-temperature relationship was overruled by war-related fires in large urban areas. We further used the fire-temperature relationship and multiple emissions scenarios to project fire activity across China into the twenty-first century. Our projections show a distinct increase in future urban fire activity and fire-related economic loss. Our findings provide insights into fire-climate relationships in China for densely-populated areas and on policy-relevant time scales and they contribute spatial coverage to efforts to improve global fire models.

Adsorption of magnetic manganese ferrites to simulated monomeric mercury in flue gases.

Magnetic MnFe2O4 nanoparticles were successfully prepared by the rapid combustion method at 500 °C for 2 h with 30 mL absolute ethanol, and were characterized by SEM, TEM, XRD, VSM, and XPS techniques, their average particle size and the saturation magnetization were about 25.3 nm and 79.53 A·m2/kg, respectively. The magnetic MnFe2O4 nanoparticles were employed in a fixed bed experimental system to investigate the adsorption capacity of Hg0 from air. The MnFe2O4 nanoparticles exhibited the large adsorption performance on Hg0 with the adsorption capacity of 16.27 µg/g at the adsorption temperature of 50 °C with the space velocity of 4.8×104 h-1. The VSM and EDS results illustrated that the prepared MnFe2O4 nanoparticles were stable before and after adsorption and successfully adsorbed Hg0. The TG curves demonstrated that the mercury compound formed after adsorption was HgO, and both physical and chemical adsorption processes were observed. Magnetic MnFe2O4 nanoparticles revealed excellent adsorbance of Hg0 in air, which suggested that MnFe2O4 nanoparticles be promising for the removal of Hg0.

Spatiotemporal multi-omics: exploring molecular landscapes in aging and regenerative medicine.

Aging and regeneration represent complex biological phenomena that have long captivated the scientific community. To fully comprehend these processes, it is essential to investigate molecular dynamics through a lens that encompasses both spatial and temporal dimensions. Conventional omics methodologies, such as genomics and transcriptomics, have been instrumental in identifying critical molecular facets of aging and regeneration. However, these methods are somewhat limited, constrained by their spatial resolution and their lack of capacity to dynamically represent tissue alterations. The advent of emerging spatiotemporal multi-omics approaches, encompassing transcriptomics, proteomics, metabolomics, and epigenomics, furnishes comprehensive insights into these intricate molecular dynamics. These sophisticated techniques facilitate accurate delineation of molecular patterns across an array of cells, tissues, and organs, thereby offering an in-depth understanding of the fundamental mechanisms at play. This review meticulously examines the significance of spatiotemporal multi-omics in the realms of aging and regeneration research. It underscores how these methodologies augment our comprehension of molecular dynamics, cellular interactions, and signaling pathways. Initially, the review delineates the foundational principles underpinning these methods, followed by an evaluation of their recent applications within the field. The review ultimately concludes by addressing the prevailing challenges and projecting future advancements in the field. Indubitably, spatiotemporal multi-omics are instrumental in deciphering the complexities inherent in aging and regeneration, thus charting a course toward potential therapeutic innovations.

Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

BACKGROUND: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. RESULTS: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. CONCLUSIONS: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Clays and Wound Healing.

Aluminosilicates, such as montmorillonite, kaolinite, halloysite, and diatomite, have a uniform bidimensional structure, a high surface-to-volume ratio, inherent stiffness, a dual charge distribution, chemical inertness, biocompatibility, abundant active groups on the surface, such as silanol (Si-OH) and/or aluminol (Al-OH) groups. These compounds are on the list of U.S. Food and Drug Administration-approved active compounds and excipients and are used for various medicinal products, such as wound healing agents, antidiarrheals, and cosmetics. This review summarizes the wound healing mechanisms related to the material characteristics and the chemical components. Numerous wound dressings with different active components and multiple forms have been studied. Then, medicinal mineral resources for use in hemostatic materials can be developed.

MOF-Mediated Construction of NiCoMn-LDH Nanoflakes Assembled Co(OH)F Nanorods for Improved Supercapacitive Performance.

The application of transition metal hydroxides has long been plagued by its poor conductivity and stability as well as severe aggregation tendency. In this paper, a novel hierarchical core-shell architecture, using an F-doped Co(OH)2 nanorod array (Co(OH)F) as the core and Mn/Ni co-doped Co(OH)2 nanosheets (NiCoMn-LDH) as the shell, was constructed via an MOF-mediated in situ generation method. The obtained Co(OH)F@ NiCoMn-LDH composites exhibited excellent supercapacitive performance with large specific capacitance as well as improved rate capability and long-term stability. The effect of the Ni/Mn ratio on the supercapacitive performance and energy storage kinetics was systematically investigated and the related mechanism was revealed.

Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene.

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

Biological and physiological effects in Bemisia tabaci feeding on tomatoes endophytically colonized by Beauveria bassiana.

BACKGROUND: Entomopathogenic fungi (EPF) treatment of plants may affect the survival and feeding preferences of herbivorous pests. However, comprehensive studies on the fitness across their entire life cycle, feeding behavior, and physiological changes in herbivores consuming EPF-treated plants within the tripartite interactions of EPF, plants, and pests are still limited. In this study, we utilized life tables, electrical penetration graph (EPG), and metabolomics to uncover the biological and physiological characteristics of Bemisia tabaci on tomato plants inoculated with Beauveria bassiana through root irrigation. RESULTS: Our study indicated that Beauveria bassiana Bb252 can penetrate the entire tissue from the point of inoculation, primarily colonizing the intercellular spaces and vascular tissue. However, this colonization is temporary, lasting no more than 35 days. Moreover, the population fitness and feeding behavior of Bemisia tabaci on tomato plants treated with Beauveria bassiana via root irrigation were significantly affected, showing a substantial 41.4% decrease in net reproductive rate (R0), a notable reduction in watery salivation, and shortened phloem ingestion. Lastly, we observed a significant decrease in hormones and amino acids of whiteflies that fed on Beauveria bassiana-treated tomato plants by root irrigation. CONCLUSIONS: Our results indicated that the endophyte, Beauveria bassiana Bb252, reduced demographic fitness of Bemisia tabaci by altering its hormones and amino acids levels. These findings enhance our understanding of multitrophic interactions in integrated pest management. © 2024 Society of Chemical Industry.

Novel small multidrug resistance protein Tmt endows the Escherichia coli with triphenylmethane dyes bioremediation capability.

Dye contamination in printing and dyeing wastewater has long been a major concern due to its serious impact on both the environment and human health. In the quest for bioremediation of these hazardous dyes, biological resources such as biodegradation bacteria and enzymes have been investigated in severely polluted environments. In this context, the triphenylmethane transporter gene (tmt) was identified in six distinct clones from a metagenomic library of the printing and dyeing wastewater treatment system. Escherichia coli expressing tmt revealed 98.1% decolorization efficiency of triphenylmethane dye malachite green within 24 h under shaking culture condition. The tolerance to malachite green was improved over eightfold in the Tmt strain compared of the none-Tmt expressed strain. Similarly, the tolerance of Tmt strain to other triphenylmethane dyes like crystal violet and brilliant green, was improved by at least fourfold. Site-directed mutations, including A75G, A75S and V100G, were found to reinforce the tolerance of malachite green, and double mutations of these even further improve the tolerance. Therefore, the tmt has been demonstrated to be a specific efflux pump for triphenylmethane dyes, particularly the malachite green. By actively pumping out toxic triphenylmethane dyes, it significantly extends the cells tolerance in a triphenylmethane dye-rich environment, which may provide a promising strategy for bioremediation of triphenylmethane dye pollutants in the environments.

Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including ß3-Adrenoceptor Agonists -Basic Research Perspectives.

Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. ß3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a ß3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial ß3-AR.

Bladder-cancer-derived exosomal circRNA_0013936 promotes suppressive immunity by up-regulating fatty acid transporter protein 2 and down-regulating receptor-interacting protein kinase 3 in PMN-MDSCs.

BACKGROUND: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is one of the causes of tumor immune tolerance and failure of cancer immunotherapy. Here, we found that bladder cancer (BCa)-derived exosomal circRNA_0013936 could enhance the immunosuppressive activity of PMN-MDSCs by regulating the expression of fatty acid transporter protein 2 (FATP2) and receptor-interacting protein kinase 3 (RIPK3). However, the underlying mechanism remains largely unknown. METHODS: BCa-derived exosomes was isolated and used for a series of experiments. RNA sequencing was used to identify the differentially expressed circRNAs. Western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, ELISA and Flow cytometry were performed to reveal the potential mechanism of circRNA_0013936 promoting the immunosuppressive activity of PMN-MDSC. RESULTS: CircRNA_0013936 enriched in BCa-derived exosomes could promote the expression of FATP2 and inhibit the expression of RIPK3 in PMN-MDSCs. Mechanistically, circRNA_0013936 promoted the expression of FATP2 and inhibited the expression of RIPK3 expression via sponging miR-320a and miR-301b, which directly targeted JAK2 and CREB1 respectively. Ultimately, circRNA_0013936 significantly inhibited the functions of CD8+ T cells by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway, and down-regulating RIPK3 through the circRNA_0013936/miR-301b/CREB1 pathway in PMN-MDSCs. CONCLUSIONS: BCa-derived exosomal circRNA_0013936 promotes suppressive immunity by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway and down-regulating RIPK3 through the circRNA_0013936/miR-301b-3p/CREB1 pathway in PMN-MDSCs. These findings help to find new targets for clinical treatment of human bladder cancer.

Multilevel Micronanoscale Texture Effects on Fly Wing Membrane-Water Droplet Interaction.

The wettable surface or nonwettable surface that is derived from a multilevel micronanoscale structure is abundant in nature and biomimetic commodities. Those hoverflies with the seta-coated wing membrane detached from impacting free-falling raindrops were observed in static states. A hoverfly wing membrane with well-ordered setae was identified as a robust nonwettable surface, and the static water contact angle θ on the wing membrane at the microscopic scale is 136.84 ± 0.98°. Hoverfly wing membrane-water droplet interaction with the actual truth and the theoretical models was discussed and indicated that the theoretical calculation might not state the actual situation, arising from the membrane or seta-drop-bubble interaction and those multilevel micronanoscale structure characteristics on the wing membrane. Detailed investigation on nonwettable surface-wettable surface transformation with surface CaCO3 accumulation in a carbonization reaction and the characteristic transformation toward the hoverfly wing membrane with the multilevel micronanoscale structure was carried out. Then, the CaCO3 accumulation on PDMS texture films was carried out and the static water contact angle θ was tested. Those observations offer ideas to fabricate artificial films with a multilevel micronanoscale structure that could obtain some characteristics, i.e., nonwettable surface-wettable surface transformation.

Toxicological Evaluation toward Refined Montmorillonite with Human Colon Associated Cells and Human Skin Associated Cells.

Montmorillonite has been refined to overcome uncertainties originating from different sources, which offers opportunities for addressing various health issues, e.g., cosmetics, wound dressings, and antidiarrheal medicines. Herein, three commercial montmorillonite samples were obtained from different sources and labeled M1, M2, and M3 for Ca-montmorillonite, magnesium-enriched Ca-montmorillonite, and silicon-enriched Na-montmorillonite, respectively. Commercial montmorillonite was refined via ultrasonic scission-differential centrifugation and labeled S, M, or L according to the particle sizes (small, medium, or large, respectively). The size distribution decreased from 2000 nm to 250 nm with increasing centrifugation rates from 3000 rpm to 12,000 rpm. Toxicological evaluations with human colon-associated cells and human skin-associated cells indicated that side effects were correlated with excess dosages and silica sand. These side effects were more obvious with human colon-associated cells. The microscopic interactions between micro/nanosized montmorillonite and human colon-associated cells or human skin-associated cells indicated that those interactions were correlated with the size distributions. The interactions of the M1 series with the human cells were attributed to size effects because montmorillonite with a broad size distribution was stored in the M1 series. The M2 series interactions with human cells did not seem to be correlated with size effects because large montmorillonite particles were retained after refining. The M3 series interactions with human cells were attributed to size effects because small montmorillonite particles were retained after refining. This illustrates that toxicological evaluations with refined montmorillonite must be performed in accordance with clinical medical practices.

[Effects of different surgical methods on the application of topical hormones in the sinus after operation].

Chronic rhinosinusitis （CRS） is a common chronic inflammatory disease in otorhinolaryngology, in which eosinophilic chronic rhinosinusitis with nasal polyps represents the difficult-to-treat chronic rhinosinusitis （DTCRS） with poor prognosis. DTCRS has a poor prognosis, which seriously affects people's physical and mental health, and is treated with various means, including medication, biotherapy and surgery. In recent years, endoscopic sinus surgery and postoperative local administration of nasal hormones as one of its treatment methods have achieved good results. In this paper, we review the relevant literature at home and abroad and give an overview for the treatment means of surgery, focusing on the effect of endoscopic sinus surgery on the distributable range of postoperative nasal glucocorticosteroids in patients with DTCRS, and then on the postoperative efficacy of the treatment, with a view to providing a reference for the clinical treatment of DTCRS.

Topological Structure Realized in Cove-Edged Graphene Nanoribbons via Incorporation of Periodic Pentagon Rings.

Cove-edged zigzag graphene nanoribbons are predicted to show metallic, topological, or trivial semiconducting band structures, which are precisely determined by their cove offset positions at both edges as well as the ribbon width. However, due to the challenge of introducing coves into zigzag-edged graphene nanoribbons, only a few cove-edged graphene nanoribbons with trivial semiconducting bandgaps have been realized experimentally. Here, we report that the topological band structure can be realized in cove-edged graphene nanoribbons by embedding periodic pentagon rings on the cove edges through on-surface synthesis. Upon noncontact atomic force microscopy and scanning tunneling spectroscopy measurements, the chemical and electronic structures of cove-edged graphene nanoribbons with periodic pentagon rings have been characterized for different lengths. Combined with theoretical calculations, we find that upon inducing periodic pentagon rings the cove-edged graphene nanoribbons exhibit nontrivial topological structures. Our results provide insights for the design and understanding of the topological character in cove-edged graphene nanoribbons.

5-Hydroxypyrroloindoline Affords Tryptathionine and 2,2'-bis-Indole Peptide Staples: Application to Melanotan-II.

With peptides increasingly favored as drugs, natural product motifs, namely the tryptathionine staple, found in amatoxins and phallotoxins, and the 2,2'-bis-indole found in staurosporine represent unexplored staples for unnatural peptide macrocycles. We disclose the efficient condensation of a 5-hydroxypyrroloindoline with either a cysteine-thiol or a tryptophan-indole to form a tryptathionine or 2-2'-bis-indole staple. Judicious use of protecting groups provides for chemoselective stapling using α-MSH, which provides a basis for investigating both chemoselectivity and affinity. Both classes of stapled peptides show nanomolar Ki's, with one showing a sub-nanomolar Ki value.

New Polyene Macrolide Compounds from Mangrove-Derived Strain Streptomyces hiroshimensis GXIMD 06359: Isolation, Antifungal Activity, and Mechanism against Talaromyces marneffei.

Mangrove-derived actinomycetes represent a rich source of novel bioactive natural products in drug discovery. In this study, four new polyene macrolide antibiotics antifungalmycin B-E (1-4), along with seven known analogs (5-11), were isolated from the fermentation broth of the mangrove strain Streptomyces hiroshimensis GXIMD 06359. All compounds from this strain were purified using semi-preparative HPLC and Sephadex LH-20 gel filtration while following an antifungal activity-guided fractionation. Their structures were elucidated through spectroscopic techniques including UV, HR-ESI-MS, and NMR. These compounds exhibited broad-spectrum antifungal activity against Talaromyces marneffei with minimum inhibitory concentration (MIC) values being in the range of 2-128 µg/mL except compound 2. This is the first report of polyene derivatives produced by S. hiroshimensis as bioactive compounds against T. marneffei. In vitro studies showed that compound 1 exerted a significantly stronger antifungal activity against T. marneffei than other new compounds, and the antifungal mechanism of compound 1 may be related to the disrupted cell membrane, which causes mitochondrial dysfunction, resulting in leakage of intracellular biological components, and subsequently, cell death. Taken together, this study provides a basis for compound 1 preventing and controlling talaromycosis.