Target Of Action Research Articles

Multicenter Clinical Randomized Controlled Trial and Network Pharmacology Analysis of Zhenzhu Qingyuan Granules for the Treatment of Gastroesophageal Reflux Disease

Abstract Objective To evaluate the clinical efficacy and safety of Zhenzhu Qingyuan Granules through a clinical randomized controlled trial and to analyze the potential action targets and pathways of this formula using network pharmacology. Methods Patients with gastroesophageal reflux disease (GERD) of liver–stomach stagnant heat pattern who met the inclusion and exclusion criteria were randomly divided into the control group and the observation group. The control group received oral rabeprazole, whereas the observation group were given Zhenzhu Qingyuan Granules in addition to the rabeprazole. The treatment duration was 8 weeks. Clinical efficacy was observed in both groups after 8 weeks. Network pharmacology was used to analyze the action targets of Zhenzhu Qingyuan Granules and the genes related to GERD, and core targets were inferred. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted to explore the potential mechanisms of this formula. Results The clinical research results showed that the total effective rate in the treatment group was 92.68%, compared with 70.00% in the control group, with a statistically significant difference (p < 0.05). After treatment, both Chinese medicine syndrome score and endoscopic score improved in both groups compared with before treatment (p < 0.05), and the treatment group showed greater improvement than the control group (p < 0.05). Network pharmacology identified effective components of Zhenzhu Qingyuan Granules for treating GERD, including quercetin, luteolin, and β-sitosterol, with potential action targets such as tumor protein 53 (TP53), protein kinase B (AKT1), and tumor necrosis factor. Conclusion Zhenzhu Qingyuan Granules can significantly improve clinical symptoms in patients with GERD of liver–stomach stagnated heat pattern, enhance clinical efficacy, and have high safety. This formula may exert therapeutic effects through multiple targets and pathways.

Drupacine as a potent SARS-CoV-2 replication inhibitor in vitro

Despite the availability of vaccines and antiviral treatments, the continued emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and breakthrough infections underscores the need for new, potent antiviral therapies. In a previous study, we established a transcription and replication-competent SARS-CoV-2 virus-like particle (trVLP) system that recapitulates the complete viral life cycle. In this study, we combined high-content screening (HCS) with the SARS-CoV-2 trVLP cell culture system, providing a powerful phenotype-oriented approach to assess the antiviral potential of compounds on a large scale. We screened a library of 3,200 natural compounds and identified drupacine as a potential candidate against SARS-CoV-2 infection. Furthermore, we utilized a SARS-CoV-2 replicon system to demonstrate that drupacine could inhibit viral genome transcription and replication. However, in vitro, enzymatic assays revealed that the inhibition could not be attributed to conventional antiviral targets, such as the viral non-structural proteins nsp5 (MPro) or nsp12 (RdRp). In conclusion, our findings position drupacine as a promising antiviral candidate against SARS-CoV-2, providing a novel scaffold for developing anti-coronavirus disease 2019 (COVID-19) therapeutics. Further investigation is required to pinpoint its precise target and mechanism of action.

Farrerol alleviates insulin resistance and hepatic steatosis of metabolic associated fatty liver disease by targeting PTPN1.

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, characterized by excess lipid deposition. Insulin resistance (IR) serves as a fundamental pathogenic factor in MAFLD. However, currently, there are no approved specific agents for its treatment. Farrerol, a novel compound with antioxidant and anti-inflammatory effects, has garnered significant attention in recent years due to its hepatoprotective properties. Despite this, the precise underlying mechanisms of action remain unclear. In this study, a network pharmacology approach predicted protein tyrosine phosphatase non-receptor type 1 (PTPN1) as a potential target for farrerol's action in the liver. Subsequently, the administration of farrerol improved insulin sensitivity and glucose tolerance in MAFLD mice. Furthermore, farrerol alleviated lipid accumulation by binding to PTPN1 and reducing the dephosphorylation of the insulin receptor (INSR) in HepG2 cells and MAFLD mice. Thus, the phosphoinositide 3-kinase/serine/threonine-protein kinases (PI3K/AKT) signalling pathway was active, leading to downstream protein reduction. Overall, the study demonstrates that farrerol alleviates insulin resistance and hepatic steatosis of MAFLD by targeting PTPN1.

Joint Screening and Identification of Potential Targets of Nitazoxanide by Affinity Chromatography and Label-Free Techniques.

Nitazoxanide not only exhibits a broad spectrum of activities against various pathogens infecting animals and humans but also induces cellular autophagy. Currently, the pattern of action and subcellular targets of nitazoxanide-induced cellular autophagy are still unclear. To identify potential targets of nitazoxanide in mammalian cells, we developed an af-finity chromatography system using tizoxanide, a deacetyl derivative of nitazoxanide, as a ligand. Affinity chromatography was performed using VERO cell extracts on tizoxanide-biotin, and the isolated binding proteins were identified by mass spectrometry. Candidate target proteins ob-tained using affinity chromatography were co-analysed with the drug affinity response target sta-bility method. Fluorescent probes obtained by coupling rhodamine B to nitazoxanide were used for intracellular localisation of the binding targets. Solvent-induced protein precipitation profiling and thermal proteome profiling were used to further validate the binding proteins. The joint analysis of the drug affinity response target stability method and affinity chro-matography resulted in the screening of six possible candidate target proteins. Fluorescent probes localised the nitazoxanide-binding protein around the nuclear membrane. Molecular docking re-vealed that the binding proteins mainly formed hydrogen bonds with the nitro group of nitazoxa-nide. Solvent-induced protein precipitation profiling and thermal proteome profiling further vali-dated SEC61A, PSMD12, and PRKAG1 as potential target proteins of nitazoxanide. The data supports the idea that nitazoxanide is a multifunctional compound with multiple targets.

170 Collective creativity; promoting physical activity. Outlining a Co-design process for the development of Digital Physical Activity promotion initiatives for Autistic Adults

Abstract Purpose Autistic students at higher education institutions in Ireland have reported feelings of isolation, depression, and disengagement, all of which contribute to health disparities in this population. It is critical to address these issues, given the recent significant increase in the number of Autistic youths enrolling in higher education. To inform the development of acceptable and effective physical activity promotion programmes, we utilized a co-design process with the aim of co-creating a digital health intervention to promote physical activity among Autistic university students. Methods A co-design process [Design Thinking] was utilized for the development of the intervention. First, to empathize with participants, semi-structured interviews were held with Autistic adults. Interviews were recorded, transcribed verbatim, and analysed via reflexive thematic analysis. Actionable intervention targets were defined, and potential solutions ideated. The findings from the interviews informed the exploration and refinement of intervention ideas during co-design workshops. Workshops featured a multidisciplinary development team, including Autistic adults and experts in technology, physical activity promotion, and digital health. Results Three central themes were developed during analysis of the interview data: (1) “Psychological Factors” describing participants’ experiences and needs relating to routines, motivation, and self-consciousness/anxiety; (2), “E-Health Ideas and Needs” encapsulated the participants’ preferences and suggestions for digital health intervention components; and (3) “Supportive Spaces” encompassing the participants’ preferences relating to physical and social environments for physical activity. Individual interviews findings informed the ideation of digital health solutions for refinement in co-design workshops; these included interventions focusing on enhancing e-communication about physical activity opportunities on campus, the use of AI Chatbots for physical activity promotion; and the use of online social support groups. Conclusions Findings suggest Autistic adults face a variety of interrelated barriers to physical activity. The co-design process enabled the collective design of digital health interventions with the potential to overcome these barriers and support Autistic students to enjoy and more active, engaged University experience. Support/Funding Source Erasmus+ Sport grant

To Explore the Rule and Mechanism of Traditional Chinese Medicine in the Treatment of Postmenopausal Osteoporosis Based on Data Mining, Network Pharmacology and Molecular Docking Technology

Postmenopausal osteoporosis (PMOP) is an important part of primary osteoporosis, and the current clinical treatment program for PMOP is easily limited by side effects and adverse reactions, so it is particularly important to seek more efficient, safe, and economical drug treatment for PMOP. In recent years, with the change of disease treatment mode and the gradual deepening of Traditional Chinese medicine (TCM) research on PMOP, a review of the literature reveals that there is a huge number of studies on the use of TCM in the treatment of PMOP, but there are no relevant systematic studies on the rules of its formulas and the specific mechanisms by which the core drugs exert their therapeutic effects. Therefore, in this study, we collected a total of 141 formulas used by TCM clinicians to treat PMOP, statistically analyzed their high-frequency medications, Four Qi, Five Flavors, meridians, and efficacies, and analyzed the core medications based on the association rules, which were Rehmanniae Radix Praeparata, Epimedium, Eucommia ulmoides, Rhizoma Drynariae, Angelica sinensis, Achyranthes, Astragalus propinquus, Psoralen, Cornus officinalis and licorice. A total of 87 drug pairs were obtained from the correlation analysis, and a total of 8 groups of potential core combination drugs and 4 potential new prescriptions were derived based on the cluster analysis. Subsequently, a network pharmacological analysis of the core drugs was conducted to obtain 173 active ingredients in the core drugs, including kaempferol, β-sitosterol, quercetin, etc. 298 targets of action, including MAPK3, STAT1, HSP90AA1, etc. 170 signaling pathways including AGE-RAGE, PI3 K/Akt, TNF, HIF-1 and others. The molecular docking results showed that 11 key active ingredients in the core drugs had stable binding to the target targets. This study showed that TCM treatment of PMOP is mainly based on “reinforcing liver and kidney, warmly invigorating spleen and stomach, activating blood and resolving stasis.” Core drugs therapy for PMOP is a comprehensive intervention through multi-component, multi-target, and multi-pathway approaches. The minimum binding energies between the 11 key active ingredients and the 11 key targets were calculated in a comprehensive analysis, which shows that the core drugs have good binding activities to their therapeutic targets, proving that the predictions of this study are reliable. In the future, it will provide certain medication basis and data support for TCM treatment of PMOP.

Embedding net zero ambition at Dublin Airport : A world to connect and a future to protect

Irish legislation on climate change has driven transformative measures across the public sector in Ireland. For Dublin Airport, this has pushed sustainability to the forefront of how we operate our airport and the impact it has had on our ability to grow. This paper explores how Dublin Airport has adapted its capital investment plans and strategy to achieve these new climate action targets as well as its plans to invest in sustainability to achieve its ambition to facilitate the growth of passengers while also meeting its net zero target by 2050. The paper takes a deep dive into the airport’s carbon footprint, providing detail on Scope 1, 2 and 3 emissions, evaluating the current challenges of decarbonisation across each scope and the opportunities for collaboration with key stakeholders to reduce Scope 3 emissions.

GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI

Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.

Potential Targets for the Protective Effect of Astaxanthin on Ethanolinduced Damage in Rat Liver Mitochondria.

Alcohol intoxication leads to multiple degenerative disorders in the structure and function of mitochondria. The mechanisms underlying these disorders, as well as ways to prevent them, are an urgent task in biomedicine. We investigate the mechanism of the positive effect of AX on rat liver mitochondria after chronic alcohol administration and suggest the targets of its effects. In this work, we continued our studies of astaxanthin (AX) as a possible protector of mitochondria from the toxic effects of ethanol. In our experiments, we used the Lieber-DeCarly model of chronic alcohol intoxication, which allows high-dose alcohol intake. Four groups of animals were used in the experiments: group 1 (control), group 2 (treated with AX), group 3 (treated with ethanol), and group 4 (treated with ethanol and AX together). Rat liver mitochondria (RLM) were isolated by the standard method modified in our laboratory. A multifunctional chamber with built-in electrodes was used to determine mitochondrial functions. Electrophoresis followed by Western blot analysis was used to detect mitochondrial proteins. Statistical significance was calculated using t-test Student-Newman- Keuls test. AX has been shown to have a positive effect on the functioning of the mitochondrial permeability transition pore (mPTP), the regulation of signaling pathways, as well as mitochondrial dynamics. It was found that AX is able to suppress the degenerative effect of alcohol on liver mitochondria. Targets for the protective action of AX in rat liver mitochondria (RLM) have been proposed. The discovered protective effect of AX on liver mitochondria during alcohol damage may contribute to the development of new strategies for the treatment of alcohol- induced damage.

Dehydroevodiamine targeting IKKβ to alleviate acute gastric injury via inhibiting the p65/NLRP3 axis

BackgroundAcute gastric injury, a common and recurring global digestive disorder, significantly impairs patient quality of life and overall health. Dehydroevodiamine (DHE), a bioactive natural product derived from Tetradium ruticarpum (A. Juss.) Hartley, shows potential therapeutic effects on acute gastric injury. This study investigates the underlying mechanisms of DHE's alleviating effects on acute gastric injury. MethodsThe gastric mucosal protective effect of DHE was confirmed through in vivo and in vitro acute gastric injury models. Biotin pulldown MS and molecular dynamics simulations identified DHE's target. CETSA and SPR assays validated DHE's affinity for IKKβ. Protein site mutation validation and MST pinpointed the direct binding sites of DHE on IKKβ. Additionally, the potential mechanism by which DHE ameliorates acute gastric injury was elucidated using WB, IHC, and IF methods, and further confirmed by rescue experiments. ResultsDHE effectively ameliorated IDO-induced gastric injury in GES-1 cells and rat gastric mucosa, both in vitro and in vivo. Biotin pulldown MS identified IKKβ as the target of DHE in alleviating gastric injury. CETSA and SPR assays confirmed DHE's direct binding to IKKβ. Molecular dynamics simulations, protein mutation experiments, and MST results pinpointed GLU-149, GLU-49, and ASP-103 in the ATP-binding pocket as the binding sites of DHE on IKKβ. Notably, DHE was found to competitively bind to IKKβ with ATP. Mechanistically, DHE attenuated IDO-induced gastric injury by inhibiting the IKKβ-p65/NLRP3 signaling pathway. Importantly, exogenous activation of IKKβ reversed the therapeutic effect of DHE, indicating that DHE's efficacy depends on IKKβ. ConclusionDHE attenuated IDO-induced gastric injury by inhibiting the IKKβ-p65/NLRP3 signaling pathway. Notably, DHE is a novel ATP-competitive IKKβ inhibitor that prevents phosphorylation by targeting GLU-149, GLU-49, and ASP-103 in the ATP-binding pocket. This study reveals new targets of action for DHE, providing a new molecular basis for using DHE in treating inflammation-related diseases.

Cordycepin ameliorates kidney injury by inhibiting gasdermin D-mediated pyroptosis of renal macrophages through nuclear factor kappa-B.

To explain the effect and mechanism of cordycepin (COR) in resisting acute kidney injury (AKI). Network pharmacology was employed to analyze the correlations between COR, AKI, and pyroptosis, as well as the action target of COR. A mouse model of AKI was established by ischemia reperfusion injury (IRI), andafter treatment with COR, the renal function, tissue inflammatory cytokine levels, and pyroptosis-related signals were detected in mice. In in-vitro experiments, damage of renal macrophages was caused bythe oxygen-glucose deprivationmodel, and pyroptosis indicators and inflammatory cytokine levels were assayed after COR treatment. Network pharmacological analysis revealed that nuclear factor kappa-B (NF-κB) was the primary action target of CORand that COR could inhibit kidney injury and tissue inflammation during IRI by inhibiting NF-κB-mediated gasdermin D cleavage. When NF-κB was inhibited, the effect of COR was weakened. COR in renal macrophages could inhibit pyroptosis and lower the levels of inflammatory cytokines, whose effect was associated with NF-κB. Our study finds that COR can play an anti-inflammatory role and inhibit the progression of AKI through the NF-κB-mediated pyroptosis, which represents its nephroprotective mechanism.

Urolithin A Ameliorates the TGF Beta-Dependent Impairment of Podocytes Exposed to High Glucose.

Increased activity of transforming growth factor-beta (TGF-β) is a key factor mediating kidney impairment in diabetes. Glomerular podocytes, the crucial component of the renal filter, are a direct target of TGF-β action, resulting in irreversible cell loss and progression of chronic kidney disease (CKD). Urolithin A (UA) is a member of the family of polyphenol metabolites produced by gut microbiota from ellagitannins and ellagic acid-rich foods. The broad spectrum of biological activities of UA makes it a promising candidate for the treatment of podocyte disorders. In this in vitro study, we investigated whether UA influences the changes exerted in podocytes by TGF-β and high glucose. Following a 7-day incubation in normal (NG, 5.5 mM) or high (HG, 25 mM) glucose, the cells were treated with UA and/or TGF-β1 for 24 h. HG and TGF-β1, each independent and in concert reduced expression of nephrin, increased podocyte motility, and up-regulated expression of b3 integrin and fibronectin. These typical-for-epithelial-to-mesenchymal transition (EMT) effects were inhibited by UA in both HG and NG conditions. UA also reduced the typically elevated HG expression of TGF-β receptors and activation of the TGF-β signal transducer Smad2. Our results indicate that in podocytes cultured in conditions mimicking the diabetic milieu, UA inhibits and reverses changes underlying podocytopenia in diabetic kidneys. Hence, UA should be considered as a potential therapeutic agent in podocytopathies.

Multi-omics combined to investigate potential druggable therapeutic targets for stroke: A systematic Mendelian randomization study and transcriptome verification

ObjectiveStroke is a highly prevalent and disabling disease whose disease mechanisms are not fully understood. The discovery of disease-associated proteins with genetic evidence of pathogenicity provides an opportunity to identify new therapeutic targets. MethodWe examined the observed and causal associations of thousands of plasma and inflammatory proteins that were measured using affinity-based proteomic assays. First, we pooled >3000 relevant proteins using a fixed-effects meta-analysis of 2 population-based studies involving 48,383 participants, then investigated the causal effects of stroke and its subtype-associated proteins by forward Mendelian randomization using cis-protein quantitative locus genetic tools identified from genome-wide association studies of these >48,000 individuals. To improve the accuracy of causal estimation, we implemented a systematic Mendelian randomization model that accounts for cascading imbalances between instruments and tested the robustness of causal estimation through multi-method analyses. To further validate the hypothesis that ginsenoside Rg1 monomer acts on the five protein targets screened for drug-targeted regulation, we conducted a comparative analysis of the mRNA (gene) expression levels of a limited number of genes in the brain tissues of different groups of SD rats. The druggability of the candidate proteins was investigated and the mechanism of action and potential targeting side effects were explored by Phenome-wide MR. ResultsSix circulating proteins were identified to have a significant genetic association with stroke (PFDR < 0.05). For example, in patients with cardioembolic stroke, higher genetically predicted APRT was associated with a lower risk of cardioembolic stroke (ORivw [95 % CI] = 0.641 [0.517, 0.795]; P = 5.25 × 10−5, ORSMR [95 % CI] = 0.572, [0.397, 0.825], PSMR = 0.003). Mediation analyses suggested that atrial fibrillation, angina pectoris, and heart failure may mediate the association of CD40L, LIFR, and UPA with stroke. Molecular docking revealed promising interactions between the identified proteins and glycosides. Transcriptomic sequencing in animal models indicated that ginsenoside Rg1 may act through APRT, IL15RA, and VSIR pathways, with APRT showing significant variability in mRNA sequencing expression. Phenome-wide MR of the six target proteins showed an overwhelming predominance of PFDR > 0.05, indicating less toxicity. ConclusionsThe present study provides genetic evidence to support the potential efficacy of targeting the three druggable protein targets for the treatment of stroke. This is achieved by triangulating population genomic and proteomic data. Furthermore, the study validates the pathway mechanisms by which APRT, IL15RA, and VSIR dock ginsenoside Rg1 in animal models. This will help to prioritize stroke drug development.

Dehydroevodiamine Alleviates Ulcerative Colitis by Inhibiting the PI3K/AKT/NF-κB Signaling Pathway via Targeting AKT1 and Regulating Gut Microbes and Serum Metabolism.

Ulcerative colitis (UC) is a typical inflammatory bowel disease (IBD), impairing the quality of life of patients. Dehydroevodiamine (DHE) is an active alkaloid isolated from Tetradium ruticarpum that exerts significant anti-inflammatory effects in gastrointestinal diseases. However, the effect and mechanisms of DHE on UC remain unclear. We performed a DSS-induced experimental UC rat model to reveal the efficacy and potential mechanisms of DHE on UC. HE and AB-PAS staining were used for the evaluation of pathologies, and 16S rRNA sequencing was used to detect changes in gut microbes. Metabolomics was used to detect changes in serum metabolites. Network pharmacology and transcriptomics were conducted to reveal the underlying mechanisms of DHE for UC. HuProt proteome microarrays, molecular docking, and SPR were used to reveal the targets of action of DHE. WB, RT-qPCR, and IHC were used to assess the action effects of DHE. DHE demonstrated significant alleviation of DSS-induced colitis symptoms in rats by suppressing inflammatory and oxidative stress responses, amending colonic barrier injury, and inhibiting apoptosis. In terms of gut microbial modulation, DHE decreased the abundance of Allobaculum, Clostridium, Escherichia, Enterococcus, and Barnesiella and increased the abundance of Lactobacillus, Bifidobacterium, and SMB5. Moreover, metabolomics suggested that the regulation of DHE in DSS-induced UC rats mainly involved aminoacyl-tRNA biosynthesis, vitamin B6 metabolism, phenylalanine, tyrosine, and so on. Mechanically, DHE alleviated UC in rats by targeting AKT1, thereby inhibiting the PI3K/AKT/NF-κB signaling pathway.

Leveraging local habitat suitability models to enhance restoration benefits for species of conservation concern

AbstractEfforts to restore habitats and conserve wildlife species face many challenges that are exacerbated by limited funding and resources. Habitat restoration actions are often conducted across a range of habitat conditions, with limited information available to predict potential outcomes among local sites and identify those that may lead to the greatest returns on investment. Using the Gunnison sage-grouse (Centrocercus minimus) as a case study, we leveraged existing resource selection function models to identify areas of high restoration potential across landscapes with variable habitat conditions and habitat-use responses. We also tested how this information could be used to improve restoration planning. We simulated change in model covariates across crucial habitats for a suite of restoration actions to generate heatmaps of relative habitat suitability improvement potential, then assessed the degree to which use of these heatmaps to guide placement of restoration actions could improve suitability outcomes. We also simulated new or worsening plant invasions and projected the resulting loss or degradation of habitats across space. We found substantial spatial variation in projected changes to habitat suitability and new habitat created, both across and among crucial habitats. Use of our heatmaps to target placement of restoration actions improved habitat suitability nearly fourfold and increased new habitat created more than 15-fold, compared to placements unguided by heatmaps. Our decision-support products identified areas of high restoration potential across landscapes with variable habitat conditions and habitat-use responses. We demonstrate their utility for strategic targeting of habitat restoration actions, facilitating optimal allocation of limited management resources to benefit species of conservation concern.

Antifungal Activity of Disalt of Epipyrone A from Epicoccum nigrum Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis.

Multidrug-resistant fungal pathogens and antifungal drug toxicity have challenged our current ability to fight fungal infections. Therefore, there is a strong global demand for novel antifungal molecules with the distinct mode of action and specificity to service the medical and agricultural sectors. Polyenes are a class of antifungal drugs with the broadest spectrum of activity among the current antifungal drugs. Epipyrone A, a water-soluble antifungal molecule with a unique, linear polyene structure, was isolated from the fungus Epiccocum nigrum. Since small changes in a compound structure can significantly alter its cell target and mode of action, we present here a study on the antifungal mode of action of the disalt of epipyrone A (DEA) using chemical-genetic profiling, fluorescence microscopy, and metabolomics. Our results suggest the disruption of sphingolipid/fatty acid biosynthesis to be the primary mode of action of DEA, followed by the intracellular accumulation of toxic phenolic compounds, in particular p-toluic acid (4-methylbenzoic acid). Although membrane ergosterol is known to be the main cell target for polyene antifungal drugs, we found little evidence to support that is the case for DEA. Sphingolipids, on the other hand, are known for their important roles in fungal cell physiology, and their biosynthesis has been recognized as a potential fungal-specific cell target for the development of new antifungal drugs.

Network pharmacology and molecular docking reveal potential mechanisms of ginseng in the treatment of diabetes mellitus-induced erectile dysfunction and asthenospermia.

Diabetes mellitus (DM) is a chronic metabolic disease that predisposes to chronic damage and dysfunction of various organs, including leading to erectile dysfunction (ED) and asthenospermia. Literature suggests that ginseng plays an important role in the treatment and management of DM. Ginseng may have a therapeutic effect on the complications of DM-induced ED and asthenospermia. The study aimed to explore the mechanisms of ginseng in the treatment of DM-induced ED and asthenospermia following the Traditional Chinese Medicine (TCM) theory of "treating different diseases with the same treatment." This study used network pharmacology and molecular docking to examine the potential targets and pharmacological mechanism of Ginseng for the treatment of DM-induced ED and asthenospermia. The chemical ingredients and targets of ginseng were acquired using the Traditional Chinese Medicine Systems Pharmacology database and analysis platform. The targets of DM, ED, and asthenospermia were extracted with the GeneCards and Online Mendelian Inheritance in Man databases. A protein-protein interaction network analysis was constructed. The Metascape platform was applied for analyzing the gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways. AutoDock Vina was used to perform molecular docking. Network pharmacology revealed that the main active components of the target of action were kaempferol, beta-sitosterol, ginsenoside rh2, stigmasterol, and fumarine. Core targets of the protein-protein interaction network included TNF, IL-1β, AKT1, PTGS2, BCL2, and JUN. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that they were mainly involved in AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, Lipid and atherosclerosis. The interactions of core active components and targets were analyzed by molecular docking. Ginseng may play a comprehensive therapeutic role in the treatment of DM-induced ED and asthenospermia through "multicomponent, multi-target, and multi-pathway" biological mechanisms such as inflammation and oxidative stress.

Health professionals’ presence and attributes in connecting with parents of children with cancer: A qualitative study through the lens of compassion

PurposeThroughout a child's cancer treatment, health professionals (HPs) constitute an important source of support for the entire family. However, the understanding of their presence and essential attributes is unclear. This study explored HPs' presence and attributes in connecting with parents and identified facilitators and barriers for connectedness. MethodsThis qualitative study was undertaken in a compassion paradigm, designed and guided by Heidegger's and Gadamer's philosophical concepts, and employed compassionate methods. Data were generated through ethnographic fieldwork (144 h), parent interviews (n = 16), and focus group interviews with parents of cancer survivors (n = 2) and HPs (n = 3). Inductive content analysis was utilised to analyse data. ResultsMany HP-parent contacts developed into close, genuine connections based on HPs' great commitment and ability to balance the act of closeness and distance. This involved HPs’ sensitivity, humanity, humility, honest communication, genuine interest, and high clinical competencies; all promoting trust. Adapting and ending close relationships when approaching the end of treatment had little attention and was difficult for families, making some find ways of keeping contact on a personal level. Barriers disclosed were structural work changes, busyness, dishonest, poor, or lack of communication, and poor or lack of interpersonal chemistry. ConclusionHuman interconnectedness is powerful in long-term professional relationships and strengthens the parents. More research and clinical attention are needed to develop the understanding and help target actions toward building, maintaining, and ending relationships. Further, cultivating being present in the moment, through mindfulness and compassion, may support HPs in maintaining a receptive mind and a caring role.

Clinical value of guideline recommended molecular targets and genome targeted cancer therapies: cross sectional study

ObjectiveTo assess the clinical benefit and actionability of molecular targets for genome targeted cancer drugs recommended for clinical practice by the National Comprehensive Cancer Network (NCCN).DesignCross sectional study.Participants/settingGenome targeted cancer...