PA-824 inhibits porcine epidemic diarrhea virus infection in vivo and in vitro by inhibiting p53 activation.

Porcine epidemic diarrhea virus (PEDV) is a type A coronavirus that causes severe watery diarrhea in piglets, resulting in severe economic losses worldwide. Therefore, new approaches to control PEDV infection are essential for a robust and sustainable pig industry. We screened 314 small-molecule drug libraries provided by Selleck and found that four drugs had obviously inhibitory effects on PEDV in Vero cells. PA-824, which had the highest SI index and the most reliable clinical safety, was selected for in vivo experiments. Animal attack tests showed that PA-824 effectively alleviated the clinical signs, intestinal pathological changes, and inflammatory responses in lactating piglets after PEDV infection. To further investigate the antiviral mechanism of PA-824, we measured the inhibitory effect of PA-824 on PEDV proliferation in a dose-dependent manner. By exploring the effect of PA-824 on the PEDV life cycle, we found that PA-824 acted directly on viral particles and hindered the adsorption, internalization, and replication phases of the virus, followed by molecular docking analysis to predict the interaction between PA-824 and PEDV non-structural proteins. Finally, we found that PA-824 could inhibit the apoptotic signaling pathway by suppressing PEDV-induced p53 activation. These results suggest that PA-824 could be protective against PEDV infection in piglets and could be developed as a drug or a feed additive to prevent and control PEDV diseases.IMPORTANCEPEDV is a highly contagious enteric coronavirus that widely spread worldwide, causing serious economic losses. There is no drug or vaccine to effectively control PEDV. In this study, we found that PA-824, a compound of mycobacteria causing pulmonary diseases, inhibited PEDV proliferation in both in vitro and in vivo. We also found that PA-824 directly acted on viral particles and hindered the adsorption, internalization, and replication stages of the virus. In addition, we found that PA-824 could inhibit the apoptotic signaling pathway by inhibiting PEDV-induced p53 activation. In conclusion, it is expected to be developed as a drug or a feed additive to prevent and control PEDV diseases.

Identify gestational diabetes mellitus by deep learning model from cell-free DNA at the early gestation stage.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy, which has significant adverse effects on both the mother and fetus. The incidence of GDM is increasing globally, and early diagnosis is critical for timely treatment and reducing the risk of poor pregnancy outcomes. GDM is usually diagnosed and detected after 24 weeks of gestation, while complications due to GDM can occur much earlier. Copy number variations (CNVs) can be a possible biomarker for GDM diagnosis and screening in the early gestation stage. In this study, we proposed a machine-learning method to screen GDM in the early stage of gestation using cell-free DNA (cfDNA) sequencing data from maternal plasma. Five thousand and eighty-five patients from north regions of Mainland China, including 1942 GDM, were recruited. A non-overlapping sliding window method was applied for CNV coverage screening on low-coverage (~0.2×) sequencing data. The CNV coverage was fed to a convolutional neural network with attention architecture for the binary classification. The model achieved a classification accuracy of 88.14%, precision of 84.07%, recall of 93.04%, F1-score of 88.33% and AUC of 96.49%. The model identified 2190 genes associated with GDM, including DEFA1, DEFA3 and DEFB1. The enriched gene ontology (GO) terms and KEGG pathways showed that many identified genes are associated with diabetes-related pathways. Our study demonstrates the feasibility of using cfDNA sequencing data and machine-learning methods for early diagnosis of GDM, which may aid in early intervention and prevention of adverse pregnancy outcomes.

DNA-Programmed Four-Bit Quaternary Fluorescence Encoding (FLUCO) Enables 51-Colored Bioimaging Analysis.

Color encoding plays a crucial role in painting, digital photography, and spectral analysis. Achieving accurate, target-responsive color encoding at the molecular level has the potential to revolutionize scientific research and technological innovation, but significant challenges persist. Here, we propose a multibit DNA self-assembly system based on computer-aided design (CAD) technology, enabling accurate, target-responsive, amplified color encoding at the molecular level, termed fluorescence encoding (FLUCO). As a model, we establish a quaternary FLUCO system using four-bit DNA self-assembly, which can accurately encode 51 colors, presenting immense potential in applications such as spatial proteomic imaging and multitarget analysis. Notably, FLUCO enables the simultaneous imaging of multiple targets exceeding the limitations of channels using conventional imaging equipment, and marks the integration of computer science for molecular encoding and decoding. Overall, our work paves the way for target-responsive, controllable molecular encoding, facilitating spatial omics analysis, exfoliated cell analysis, and high-throughput liquid biopsy.

Genomic insights into local adaptation and vulnerability of Quercus longinux to climate change.

BACKGROUND: Climate change is expected to alter the factors that drive changes in adaptive variation. This is especially true for species with long life spans and limited dispersal capabilities. Rapid climate changes may disrupt the migration of beneficial genetic variations, making it challenging for them to keep up with changing environments. Understanding adaptive genetic variations in tree species is crucial for conservation and effective forest management. Our study used landscape genomic analyses and phenotypic traits from a thorough sampling across the entire range of Quercus longinux, an oak species native to Taiwan, to investigate the signals of adaptation within this species. RESULTS: Using ecological data, phenotypic traits, and 1,933 single-nucleotide polymorphisms (SNPs) from 205 individuals, we classified three genetic groups, which were also phenotypically and ecologically divergent. Thirty-five genes related to drought and freeze resistance displayed signatures of natural selection. The adaptive variation was driven by diverse environmental pressures such as low spring precipitation, low annual temperature, and soil grid sizes. Using linear-regression-based methods, we identified isolation by environment (IBE) as the optimal model for adaptive SNPs. Redundancy analysis (RDA) further revealed a substantial joint influence of demography, geology, and environments, suggesting a covariation between environmental gradients and colonization history. Lastly, we utilized adaptive signals to estimate the genetic offset for each individual under diverse climate change scenarios. The required genetic changes and migration distance are larger in severe climates. Our prediction also reveals potential threats to edge populations in northern and southeastern Taiwan due to escalating temperatures and precipitation reallocation. CONCLUSIONS: We demonstrate the intricate influence of ecological heterogeneity on genetic and phenotypic adaptation of an oak species. The adaptation is also driven by some rarely studied environmental factors, including wind speed and soil features. Furthermore, the genetic offset analysis predicted that the edge populations of Q. longinux in lower elevations might face higher risks of local extinctions under climate change.

Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition.

BACKGROUND AND AIMS: Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis. APPROACH AND RESULTS: By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus. CONCLUSIONS: ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.

Development and validation of a clinical and ultrasound features-based nomogram for preoperative differentiation of renal urothelial carcinoma and central renal cell carcinoma.

PURPOSE: This study aimed to develop and validate an ultrasound (US)-based nomogram for the preoperative differentiation of renal urothelial carcinoma (rUC) from central renal cell carcinoma (c-RCC). METHODS: Clinical data and US images of 655 patients with 655 histologically confirmed malignant renal tumors (521 c-RCCs and 134 rUCs) were collected and divided into training (n = 455) and validation (n = 200) cohorts according to examination dates. Conventional US and contrast-enhanced US (CEUS) tumor features were analyzed to determine those that could discriminate rUC from c-RCC. Least absolute shrinkage and selection operator regression was applied to screen clinical and US features for the differentiation of rUC from c-RCC. Using multivariate logistic regression analysis, a diagnostic model of rUC was constructed and visualized as a nomogram. The diagnostic model's performance was assessed in the training and validation cohorts by calculating the area under the receiver operating characteristic curve (AUC) and calibration plot. Decision curve analysis (DCA) was used to assess the clinical usefulness of the US-based nomogram. RESULTS: Seven features of both clinical features and ultrasound imaging were selected to build the diagnostic model. The nomogram achieved favorable discrimination in the training (AUC = 0.996, 95% CI: 0.993-0.999) and validation (AUC = 0.995, 95% CI: 0.974, 1.000) cohorts, and good calibration (Brier scores: 0.019 and 0.016, respectively). DCA demonstrated the clinical usefulness of the US-based nomogram. CONCLUSION: A noninvasive clinical and US-based nomogram combining conventional US and CEUS features possesses good predictive value for differentiating rUC from c-RCC.

Tumor-associated antigen-specific cell imaging based on upconversion luminescence and nucleic acid rolling circle amplification.

Tumor-associated antigen (TAA)-based diagnosis has gained prominence for early tumor screening, treatment monitoring, prognostic assessment, and minimal residual disease detection. However, limitations such as low sensitivity and difficulty in extracting non-specific binding membrane proteins still exist in traditional detection methods. Upconversion luminescence (UCL) exhibits unique physical and chemical properties under wavelength near-infrared light excitation. Rolling circle amplification (RCA) is an efficient DNA amplification technique with amplification factors as high as 105. Therefore, the above two excellent techniques can be employed for highly accurate imaging analysis of tumor cells. Herein, we developed a novel nanoplatform for TAA-specific cell imaging based on UCL and RCA technology. An aptamer-primer complex selectively binds to Mucin 1 (MUC1), one of TAA on cell surface, to trigger RCA reaction, generating a large number of repetitive sequences. These sequences provide lots of binding sites for complementary signal probes, producing UCL from lanthanide-doped upconversion nanoparticles (UCNPs) after releasing quencher group. The experimental results demonstrate the specific attachment of upconversion nanomaterials to cancer cells which express a high level of MUC1, indicating the potential of UCNPs and RCA in tumor imaging.

Mice deficient in poly(C)-binding protein 4 are susceptible to spontaneous tumors through increased expression of ZFP871 that targets p53 for degradation.

Poly(C)-binding protein 4 (PCBP4), also called MCG10 and a target of p53, plays a role in the cell cycle and is implicated in lung tumor suppression. Here, we found that PCBP4-deficient mice are prone to lung adenocarcinoma, lymphoma, and kidney tumor and that PCBP4-deficient mouse embryo fibroblasts (MEFs) exhibit enhanced cell proliferation but decreased cellular senescence. We also found that p53 expression is markedly reduced in PCBP4-deficient MEFs and mouse tissues, suggesting that PCBP4 in turn regulates p53 expression. To determine how PCBP4 regulates p53 expression, PCBP4 targets were identified by RNA immunoprecipitation followed by RNA sequencing (RNA-seq). We found that the transcript encoding ZFP871 (zinc finger protein 871; also called ZNF709 in humans) interacts with and is regulated by PCBP4 via mRNA stability. Additionally, we found that ZFP871 physically interacts with p53 and MDM2 proteins. Consistently, ectopic expression of ZFP871 decreases-whereas knockdown of ZFP871 increases-p53 protein stability through a proteasome-dependent degradation pathway. Moreover, loss of ZFP871 reverses the reduction of p53 expression by lack of PCBP4, and thus increased expression of ZFP871 is responsible for decreased expression of p53 in the PCBP4-deficient MEFs and mouse tissues. Interestingly, we found that, like PCBP4, ZFP871 is also regulated by DNA damage and p53. Finally, we showed that knockdown of ZFP871 markedly enhances p53 expression, leading to growth suppression and apoptosis in a p53-dependent manner. Thus, the p53-PCBP4-ZFP871 axis represents a novel feedback loop in the p53 pathway. Together, we hypothesize that PCBP4 is a potential tissue-specific tumor suppressor and that ZFP871 is part of MDM2 and possibly other ubiquitin E3 ligases that target p53 for degradation.

Nannizzia polymorpha as Rare Cause of Skin Dermatophytosis.

Nannizzia polymorpha is a dermatophyte that rarely infects humans. We describe 2 case-patients from Asia who had an inflammatory type of tinea capitis and tinea manuum caused by infection with this fungus. The diagnosis was confirmed on the basis of the morphologic and molecular characteristics of the microorganism.

Spinal Cathepsin S promotes visceral hypersensitivity via FKN/CX3CR1/p38 MAPK signaling pathways.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the typical representatives of chronic functional visceral pain that lacks effective treatment. Recently, attention has been given to the role of microglia in IBS, particularly the activation of spinal microglia and the subsequent release of Cathepsin S (Cat S), a proteolytic enzyme. However, the specific role of spinal Cat S in IBS remains to be elucidated. The purpose of this study is to investigate the mechanisms underlying the regulation of visceral hypersensitivity in IBS-like rats by Cat S. METHODS: An IBS-like rat model was developed, and visceral sensitivity was tested via the electromyographic (EMG) response to colorectal distention (CRD) and pain threshold. Western blot and immunofluorescence were used to examine the expressions of proteins. The effects of inhibitors or neutralizing antibodies on visceral pain and the downstream molecular expressions were detected. The open-field test was performed to evaluate locomotor activity and anxiety-like behaviors in rats. RESULTS: We discovered that spinal Cat S was upregulated and colocalized with microglia in IBS-like rats. Treatment with LY3000328, a selective inhibitor of Cat S, dose-dependently down-regulated EMG amplitude and Fractalkine (FKN) expression, indicating that Cat S regulated visceral hypersensitivity via activating FKN in IBS-like rats. Furthermore, the expressions of FKN, CX3CR1, and p-p38 MAPK were elevated in IBS-like rats whereas inhibition of these molecules could alleviate visceral pain. Moreover, pharmacological inhibitor experiments suggested the activation of CX3CR1 by FKN facilitated p38 MAPK phosphorylation, which in turn promoted Cat S expression in IBS-like rats. CONCLUSIONS: Neonatal adverse stimulation might enhance the expression of spinal microglial Cat S, thereby activating the FKN/CX3CR1/p38 MAPK pathway and lead to visceral hypersensitivity in IBS-like rats. As a selective inhibitor of Cat S, LY3000328 could become a potential therapeutic option for IBS.

The causal role of gut microbiota in susceptibility and severity of COVID-19: A bidirectional Mendelian randomization study.

Growing evidence has shown that altered gut microbiota is associated with the pathogenesis of COVID-19, but their causal effects are still unclear. We conducted a bidirectional Mendelian randomization (MR) study to assess the causal effects of gut microbiota on COVID-19 susceptibility or severity, and vice versa. The microbiome genome-wide association studies (GWAS) data of 18 340 individuals and GWAS statistics from the COVID-19 host genetics initiative (38 984 European patients and 1 644 784 controls) were used as exposure and outcomes. The inverse variance weighted (IVW) was used as the primary MR analysis. Sensitivity analyses were performed to validate the robustness, pleiotropy, and heterogeneity of results. In the forward MR, we identified several microbial genera with causal effects on COVID-19 susceptibility (p < 0.05 and FDR < 0.1): Alloprevotella (odds ratio [OR]: 1.088, 95% confidence interval [CI]: 1.021-1.160), Coprococcus (OR: 1.159, 95% CI: 1.030-1.304), Parasutterella (OR: 0.902, 95% CI: 0.836-0.973), and Ruminococcaceae UCG014 (OR: 0.878, 95% CI: 0.777-0.992). The Reverse MR identified that exposure to COVID-19 had causal effects on the depletion of the families Lactobacillaceae (Beta [SE]: -0.220 [0.101]) and Lachnospiraceae (-0.129 [0.062]), the genera Flavonifractor (-0.180 [0.081]) and Lachnoclostridium [-0.181 [0.063]). Our findings supported the causal effect of gut microbiota on the pathogenesis of COVID-19, and infection of COVID-19 might further causally induce gut microbiota dysbiosis.

IL-33/ST2 antagonizes STING signal transduction via autophagy in response to acetaminophen-mediated toxicological immunity.

BACKGROUND: Interleukin-33 (IL-33), defined as "alarming", exert diverse functions through signaling via the suppression of tumorigenicity 2 (ST2). However, the physiological roles of IL-33/ST2 signaling during acetaminophen (APAP)-induced liver injury are still poorly understood by modern medicine (AILI). This research aims to explore the relationship between IL-33/ST2 and stimulator of interferon (IFN) response cGAMP interactor 1 (STING)-mediated signal transduction. METHODS: C57BL/6N mice (WT) and IL-33-deficient mice (KO) were intraperitoneally injected with APAP (250 mg/kg). Recombinant IL-33 (500 ng/mouse) and the cGAS/STING inhibitor RU.521 (200 g/kg) were combined to treat AILI. For mechanistic research in vitro, CRISPR-mediated KD technology, immunoprecipitation, mass spectrometry, and immunofluorescence were utilized. RESULTS: We discovered that IL-33 deficient mice had increased APAP-induced hepatotoxicity, DNA accumulation, and type 1 IFN production. Mechanistic analysis revealed that IL-33/ST2 enhanced the interaction between Beclin-1 and STING, disrupting STING dimerization, IRF3 phosphorylation, nuclear transport, and IFN-1 gene transcription in HepaRG and Huh7 cells. Beclin-1 interacted with the C-terminus of STING, causing Lys338 acetylation and autophagy degradation of STING. ST2 depletion increased STING signal transduction and IFN-1 promoter activity. Surprisingly, the cGAS/STING inhibitor RU.521 and recombinant IL-33 together improved AILI in vivo. CONCLUSIONS: These results shed insight on the potential of inhibiting cGAS/STING as a therapy for AILI and emphasize the crucial role of IL-33/ST2 signaling in the regulation of APAP-induced STING signaling. Video Abstract.

Spinal P2X4 Receptors Involved in Visceral Hypersensitivity of Neonatal Maternal Separation Rats.

Recent studies have demonstrated the vital role of P2X4 receptors (a family of ATP-gated non-selective cation channels) in the transmission of neuropathic and inflammatory pain. In this study, we investigated the role of spinal P2X4 receptors in chronic functional visceral hypersensitivity of neonatal maternal separation (NMS) rats. A rat model of irritable bowel syndrome was established by neonatal maternal separation. Visceral sensitivity was assessed by recording the response of the external oblique abdominal muscle to colorectal distension. P2X4 receptor antagonist and agonist were administrated intrathecally. The expression of P2X4 receptor was examined by Western Blot and immunofluorescence. The effect of P2X4 receptor antagonist on expression of brain-derived neurotrophic factor (BDNF) was assessed by Western Blot. We found neonatal maternal separation enhanced visceral hypersensitivity and increased the expression of P2X4 receptor in spinal thoracolumbar and lumbosacral segments of rats. Pharmacological results showed that visceral sensitivity was attenuated after intrathecal injection of P2X4 receptor antagonist, 5-BDBD, at doses of 10 nM or 100 nM, while visceral sensitivity was enhanced after intrathecal injection of P2X4 receptor agonist C5-TDS at doses of 10 µM or 15 µM. In addition, the spinal expression of BDNF significantly increased in NMS rats and intrathecal injection of 5-BDBD significantly decreased the expression of BDNF especially in NMS rats. C5-TDS failed to increase EMG amplitude in the presence of ANA-12 in control rats. Our results suggested the spinal P2X4 receptors played an important role in visceral hypersensitivity of NMS rats through BDNF.

The high diversity of Scedosporium and Lomentospora species and their prevalence in human-disturbed areas in Taiwan.

Scedosporium and Lomentospora are important opportunistic pathogens causing localized or disseminated infection in humans. Understanding their environmental distribution is critical for public hygiene and clinical management. We carried out the first environmental survey in urbanized and natural regions in Taiwan. Overall, Scedosporium and Lomentospora species were recovered in 132 out of 273 soil samples (48.4%) across Taiwan. We morphologically and molecularly identified six Scedosporium and one Lomentospora species. All four major clinical relevant species were isolated with high frequency, i.e., Scedosporium apiospermum (42.4%), S. boydii (21.8%), Lomentosporaprolificans (14.5%), S. aurantiacum (8.5%); two clinically minor species, Pseudallescheria angusta (6.7%) and S. dehoogii (5.6%), and a saprobic species, S. haikouense (0.6%), had moderate to rare incidence. These fungal species had high incidence in urban (48.6%) and hospital (67.4%) soil samples, and had limited distribution in samples from natural regions (5%). Multivariate analysis of the fungal composition revealed strong evidence of the preferential distribution of these fungi in urban and hospital regions compared with natural sites. In addition, strong evidence suggested that the distribution and abundance of these fungal species were highly heterogeneous in the environment; samples in vicinity often yielded varied fungal communities. We concluded that these fungal species were prevalent in soil in Taiwan and their occurrences were associated with human activities. Although, hygiene sensitive sites such as hospitals were not harboring heavier fungal burdens than other urban facilities in our survey, still, aware should be taken for the high frequency of these clinical relevant species around hospital regions.

Scedosporium and Lomentospora are two fungal genera that can cause infections to wildlife and humans. Our experiment demonstrated that these fungi are ubiquitous in the soil in Taiwan. Their proximity to human-dwelling regions raises our awareness of their exposure to those who are susceptible.

Ubiquity of Amino Accelerators and Antioxidants in Road Dust from Multiple Land Types: Targeted and Nontargeted Analysis.

Amino accelerators and antioxidants (AAL/Os), as well as their degradation derivatives, are industrial additives of emerging concern due to their massive production and use (particularly in rubber tires), pervasiveness in the environment, and documented adverse effects. This study delineated their inter-regional variations in road dust collected from urban/suburb, agricultural, and forest areas, and screened for less-studied AAL/O analogues with high-resolution mass spectrometry. 1,3-Diphenylguanidine (DPG; median concentration: 121 ng/g) and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q; 9.75 ng/g) are the most abundant congeners, constituting 69.7% and 41.4% of the total concentrations of AAL/Os (192 ng/g) and those of AAO transformation products (22.3 ng/g), respectively. The spatial distribution across the studied sites suggests evident human impacts, reflected by the pronounced urban signature and vehicle-originated pollution. Our nontargeted analysis of the most-contaminated road dust identified 16 AAL/O-related chemicals, many of which have received little investigation. Particularly, environmental and toxicological information remains extremely scarce for five out of the 10 most concerning compounds prioritized in terms of their dusty residues and toxicity including 1,2-diphenyl-3-cyclohexylguanidine (DPCG), N,N''-bis[2-(propan-2-yl)phenyl]guanidine (BPPG), and N-(4-anilinophenyl)formamide (PPD-CHO). Additionally, dicyclohexylamine (DChA), broadly applied as an antioxidant in automobile products, had an even greater median level than DPG. Therefore, future research on their health risks and (eco)toxic potential is of high importance.

Simulated microgravity altered the proliferation, apoptosis, and extracellular matrix formation of L929 fibroblasts and the transforming growth factor-ß1/Smad3 signaling pathway.

Exposure to microgravity can adversely affect the fitness of astronauts. The integrity of the skin plays a crucial role in protecting against mechanical forces and infections, fluid imbalance, and thermal dysregulation. In brief, the skin wound may cause unknown challenges to the implementation of space missions. Wound healing is a physiological process that relies on the synergistic action of inflammatory cells, extracellular matrix (ECM), and various growth factors to maintain the integrity of skin after trauma. Fibroblasts are present almost throughout the entire process of wound repair, especially in the scar formation at the endpoint of wound healing. However, there is limited knowledge about the extent to which fibroblasts are affected by the lack of gravity during wound healing. In this study, we utilized the rotary cell culture system, a ground-based facility that mimics the weightless condition, to study the alterations of L929 fibroblast cells under simulated microgravity (SMG). Our results demonstrated that the SM condition exerted negative influences on the proliferation and ECM formation of the L929 fibroblast. Whereas, the apoptosis of fibroblast was significantly upregulated upon exposure to SMG conditions. Moreover, the transforming growth factor-ß1/Smad3 (TGF-ß1/smad3) signaling pathway of L929 fibroblast related to wound repair was also altered significantly under a weightless environment. Overall, our study provided evidence that fibroblasts are strongly sensitive to SMG and elucidated the potential value of the TGF-ß1/Smad3 signaling pathway modulating wound healing in the future practice of space medicine.

Clinical manifestations and susceptibility of Scedosporium/Lomentospora infections at a tertiary medical centre in Taiwan from 2014 to 2021: A retrospective cohort study.

BACKGROUND: Scedosporiosis/lomentosporiosis is a globally emerging and crucial fungal infection. However, clinical data on Scedosporium/Lomentospora infections in Taiwan are scarce. OBJECTIVES: This study aimed to explore the clinical characteristics of Scedosporium/Lomentospora-infected patients and evaluate the susceptibility of these isolates to antifungal agents. METHODS: The clinical features of Scedosporium/Lomentospora-infected patients at a tertiary teaching hospital in Northern Taiwan between 2014 and 2021 were retrospectively reviewed; isolates from these patients were identified to species level for antifungal susceptibility testing. RESULTS: Among 44 patients, 27 (61.4%) had scedosporiosis/lomentosporiosis, whereas 17 (38.6%) were colonised with Scedosporium/Lomentospora species. Scedosporium apiospermum was the main coloniser; scedosporiosis was primarily caused by S. boydii. Trauma history, steroid and immunosuppressant use were the most common risk factors for developing these infections. Among 27 patients with scedosporiosis/lomentosporiosis, one was lost to follow-up and seven (7/26, 26.9%) died. Most patients with S. apiospermum infection have a history of trauma, leading to cutaneous, bone and ocular infections. Pulmonary, sinus and disseminated infections and mortality were frequently reported in patients with S. boydii infection. Voriconazole's minimum inhibitory concentration was low for S. boydii, S. apiospermum and S. aurantiacum. Caspofungin, micafungin and anidulafungin were active against S. boydii and S. apiospermum. A potentially novel Scedosporium species was identified in this study, with distinct clinical manifestations and antifungal susceptibility. CONCLUSIONS: At our centre, S. boydii is the main causative species of scedosporiosis; voriconazole could be the first-line treatment in Taiwan. Our study supports the importance of speciation, rather than only categorising these isolates into S. apiospermum species complex.

Comparative genomic and transcriptomic analyses of trans-kingdom pathogen Fusarium solani species complex reveal degrees of compartmentalization.

BACKGROUND: The Fusarium solani species complex (FSSC) comprises fungal pathogens responsible for mortality in a diverse range of animals and plants, but their genome diversity and transcriptome responses in animal pathogenicity remain to be elucidated. We sequenced, assembled and annotated six chromosome-level FSSC clade 3 genomes of aquatic animal and plant host origins. We established a pathosystem and investigated the expression data of F. falciforme and F. keratoplasticum in Chinese softshell turtle (Pelodiscus sinensis) host. RESULTS: Comparative analyses between the FSSC genomes revealed a spectrum of conservation patterns in chromosomes categorised into three compartments: core, fast-core (FC), and lineage-specific (LS). LS chromosomes contribute to variations in genomes size, with up to 42.2% of variations between F. vanettenii strains. Each chromosome compartment varied in structural architectures, with FC and LS chromosomes contain higher proportions of repetitive elements with genes enriched in functions related to pathogenicity and niche expansion. We identified differences in both selection in the coding sequences and DNA methylation levels between genome features and chromosome compartments which suggest a multi-speed evolution that can be traced back to the last common ancestor of Fusarium. We further demonstrated that F. falciforme and F. keratoplasticum are opportunistic pathogens by inoculating P. sinensis eggs and identified differentially expressed genes also associated with plant pathogenicity. These included the most upregulated genes encoding the CFEM (Common in Fungal Extracellular Membrane) domain. CONCLUSIONS: The high-quality genome assemblies provided new insights into the evolution of FSSC chromosomes, which also serve as a resource for studies of fungal genome evolution and pathogenesis. This study also establishes an animal model for fungal pathogens of trans-kingdom hosts.

Nasal Sinus Mucoceles Manifesting Ocular Symptoms.

INTRODUCTION: To describe the ocular symptoms in a series of patients with nasal sinus mucoceles of different locations. METHODS: The authors analyzed the diagnosis and treatment of patients with sinus mucoceles and ocular symptoms who presented to the hospital from February 2010 to April 2020. A total of 61 patients were included in the study. The locations of the mucoceles were the frontal sinus (8 patients), ethmoid sinus (25 patients), and sphenoid sinus (28 patients). The authors selected 1 typical mucocele case from each of the sinuses, including the frontal, ethmoid, and sphenoid sinuses, and analyzed the history, diagnosis, and treatment of mucoceles in each location. RESULTS: The main clinical manifestations were ophthalmic symptoms, such as exophthalmos or displacement, eye pain, blindness or decreased vision, blepharoptosis, and diplopia; no obvious nasal symptoms were noted. Most patients with these symptoms went to an ophthalmologist first. All lesions in this study were found through imaging examinations. Most symptoms improved after surgical interventions. Only 2 of the 61 patients had no improvement in vision because of the long period of vision loss. CONCLUSIONS: Although sinus mucoceles are located in the sinuses, ocular symptoms are more prevalent than nasal symptoms. The earlier the imaging examinations are performed; the sooner lesions are detected, and the patients can be treated.

Bedside nurses' antimicrobial stewardship practice scope and competencies in acute hospital settings: A scoping review.

AIM: To identify and map bedside nurses' practice scope and competencies regarding antimicrobial stewardship in acute hospital settings, and develop a competency framework for them. BACKGROUND: Antimicrobial stewardship requires multidisciplinary engagement including nursing. However, bedside nurses' antimicrobial stewardship practice scope and competencies in acute hospital settings remain unclear. DESIGN: Scoping review. METHODS: Using a five-stage framework proposed by Arksey and O'Malley and following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. RESULTS: A total of 1422 records were retrieved, and 41 studies were included. In addition to the six practices recommended, this review summarized bedside nurses' contributions to five additional fields as well. Correspondingly, the competencies required by bedside nurses were summarized into eight domains: specialized knowledge, safety medication administration, leadership, education, diagnostic stewardship, infection prevention and control, professional development and professional quality. CONCLUSION: Nurses' practice scope overlaps greatly with routine nursing practice in antimicrobial stewardship, confirming the evidence that nurses are ideal partners in antimicrobial stewardship. This review developed a competency framework at both basic and advanced levels. Among them, professional knowledge is the foundation, while professional quality motivates nurses to participate. In addition to competency assessment, it can also be used for training and human resource deployment based on seniority or professional level. This could bridge the knowledge gap and improve the engagement of nurses in heavy workload situations. RELEVANCE TO CLINICAL PRACTICE: This practice scope will provide opportunities for nurses to engage in antimicrobial stewardship. Moreover, nursing competencies identified in this field could facilitate the development of competency-based education interventions, talent assessments, training and recruitment programs. DATA RESOURCES: PubMed, EMBASE, Web of Science, CINHAL, PsycINFO, Cochrane Library, ProQuest and Scopus were searched from inception to November 2022, with an updated search in March 2023. IMPACT: This scoping review provides evidence for best nursing practice scope and competency in antimicrobial stewardship in hospitals. However, it is also in line with the commitment of all nurses in the global community to combat antimicrobial resistance, which has become a global threat. An antimicrobial stewardship competency framework for bedside nurses was developed at both the basic and advanced levels. It would facilitate talent assessment, training, recruitment and human resource management by guiding the development of competency-based education interventions. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.