Unveiling the dance of evolution: Pla-mediated cleavage of Ymt modulates the virulence dynamics of Yersinia pestis.

Yersinia pestis has recently evolved into a highly lethal flea-borne pathogen through the pseudogenization of extensive genes and the acquisition of exogenous plasmids. Particularly noteworthy are the newly acquired pPCP1 and pMT1 plasmids, which encode the virulence determinants Pla and Yersinia murine toxin (Ymt), crucial for subcutaneous infection and survival within flea vector of Y. pestis, respectively. This study reveals that Pla can cleave Ymt at K299 both in vivo and in vitro. Y. pestis expressing YmtK299A displays enhanced in vitro biofilm formation and increased blood survival, indicating significant roles of Pla-mediated Ymt cleavage in these phenotypes. Intriguingly, although both the ancestral form of Pla and the prevalent Pla-I259T variant in modern Y. pestis strains are capable of cleaving Ymt at K299, the cleavage efficiency of Pla-I259T is only half that of the ancestral variant. In subcutaneous infection, mice infected with Δymt::ymt-K299A show significantly prolonged survival compared to those infected with Δymt::ymt. Similarly, infection with Δpla::pla-I259T also results in extended survival compared to Δpla::pla infection. These data demonstrate that the I259T substitution of Pla mitigates the enhanced virulence of Y. pestis in mice caused by Pla-mediated Ymt cleavage, thereby prolonging the survival period of infected animals and potentially conferring advantages on the transmission of Y. pestis to the next host. These findings deepen our understanding of the intricate interplay between two newly acquired plasmids and shed light on the positive selection of the Pla-I259T mutation, providing new insights into the virulence dynamics and transmission mechanisms of Y. pestis. IMPORTANCE: The emergence of Y. pestis as a highly lethal pathogen is driven by extensive gene pseudogenization and acquisition of exogenous plasmids pPCP1 and pMT1. However, the interplay between these two plasmids during evolution remains largely unexplored. Our study reveals intricate interactions between Ymt and Pla, two crucial virulence determinants encoded on these plasmids. Pla-mediated cleavage of Ymt significantly decreases Y. pestis survival in mouse blood and enhances its virulence in mice. The prevalent Pla-I259T variant in modern strains displays reduced Ymt cleavage, thereby extending the survival of infected animals and potentially increasing strain transmissibility. Our findings shed light on the nuanced evolution of Y. pestis, wherein reduced cleavage efficiency is a positive selection force, shaping the pathogen's natural trajectory.

An artificial intelligence grading system of apical periodontitis in cone-beam computed tomography data.

OBJECTIVES: In order to assist junior doctors in better diagnosing apical periodontitis (AP), an artificial intelligence AP grading system was developed based on deep learning (DL) and its reliability and accuracy were evaluated. METHODS: 120 cone-beam computed tomography (CBCT) images were selected to construct a classification dataset with four categories, which were divided by CBCT periapical index (CBCTPAI), including normal periapical tissue, CBCTPAI 1-2, CBCTPAI 3-5 and young permanent teeth. Three classic algorithms (ResNet50/101/152) as well as one self-invented algorithm (PAINet) were compared with each other. PAINet were also compared with two recent Transformer-based models and three attention models. Their performance was evaluated by accuracy, precision, recall, balanced F score (F1-score) and the area under the macro-average receiver operating curve (AUC). Reliability was evaluated by Cohen's kappa ​​to compare the consistency of model predicted labels with expert opinions. RESULTS: PAINet performed best among the four algorithms. The accuracy, precision, recall, F1-score and AUC on the test set were 0.9333, 0.9415, 0.9333, 0.9336 and 0.9972, respectively. Cohen's kappa was 0.911, which represented almost perfect consistency. CONCLUSIONS: PAINet can accurately distinguish between normal periapical tissues, CBCTPAI 1-2, CBCTPAI 3-5 and young permanent teeth. Its results were highly consistent with expert opinions. It can help junior doctors diagnose and score AP, reducing the burden. It can also be promoted in areas where experts are lacking to provide professional diagnostic opinions.

Pt Loading of Phosphorus-Doped Carbon Nanotube Aerogels in Fuel Cell-Type Gas Sensors for Ultrasensitive H2 Detection.

A phosphorus-doped carbon nanotube (CNT) aerogel as the support material was loaded with Pt nanoparticles in fuel cell-type gas sensors for ultrasensitive H2 detection. The high surface area of the CNT scaffold is favorable to providing abundant active sites, and the high electrical conductivity facilitates the transport of carriers generated by electrochemical reactions. In addition, the CNT aerogel was doped with phosphorus (P) to further enhance the conductivity and electrochemical catalytic activity. As a result, the fuel cell-type gas sensor using the Pt/CNT aerogel doped with the optimal P content as the sensing material shows considerable performance for H2 detection at room temperature. The sensor exhibits an ultrahigh response of -921.9 µA to 15,000 ppm of H2. The sensitivity is -0.063 µA/ppm, which is 21 times higher than that of the conventional Pt/CF counterpart. The sensor also exhibits excellent repeatability and humidity resistance, as well as fast response/recovery; the response/recovery times are 31 and 4 s to 3000 ppm of H2, respectively. The modulation of the structure and catalytic properties of the support material is responsible for the improvement of the sensor performance, thus providing a feasible solution for optimizing the performance of fuel cell-type gas sensors.

Combined genome and transcriptome provides insight into the genetic evolution of an edible halophyte Suaeda salsa adaptation to high salinity.

Suaeda salsa L. is a typical halophyte with high value as a vegetable. Here, we report a 447.98 Mb, chromosomal-level genome of S. salsa, assembled into nine pseudomolecules (contig N50 = 1.36 Mb) and annotated with 27,927 annotated protein-coding genes. Most of the assembled S. salsa genome, 58.03%, consists of transposable elements. Some gene families including HKT1, NHX, SOS and CASP related to salt resistance were significantly amplified. We also observed expansion of genes encoding protein that bind the trace elements Zn, Fe, Cu and Mn, and genes related to flavonoid and α-linolenic acid metabolism. Many expanded genes were significantly up-regulated under salinity, which might have contributed to the acquisition of salt tolerance in S. salsa. Transcriptomic data showed that high salinity markedly up-regulated salt-resistance related genes, compared to low salinity. Abundant metabolic pathways of secondary metabolites including flavonoid, unsaturated fatty acids and selenocompound were enriched, which indicates that the species is a nutrient-rich vegetable. Particularly worth mentioning is that there was no significant difference in the numbers of cis-elements in the promoters of salt-related and randomly selected genes in S. salsa when compared with Arabidopsis thaliana, which may affirm that plant salt tolerance is a quantitative rather than a qualitative trait in terms of promoter evolution. Our findings provide deep insight into the adaptation of halophytes to salinity from a genetic evolution perspective.

[Construction and validation of a nomogram for predicting the prognosis of patients with septic shock in department of emergency medicine].

OBJECTIVE: To construct a nomogram model for predicting the 28-day mortality of patients with septic shock in the emergency medicine department and to validate the predictive efficacy. METHODS: Based on the database of the emergency medicine department of Chu Hsien-I Memorial Hospital of Tianjin Medical University, Tianjin Medical University General Hospital and the Second Hospital of Tianjin Medical University, the data of 913 patients with septic shock admitted to the emergency medicine department from January 2017 to October 2020 were collected, including baseline demographic information and clinical characteristics, laboratory indices, and the main endpoints (28-day mortality). The patients were divided into a training set and a validation set based on simple random sampling. All significant variables from the one-way binary Logistic regression analysis of the training set were included in the multivariate Logistic regression analysis to analyze the risk factors for 28-day mortality in patients with septic shock and to construct a column-line graphical model. The predictive efficacy of the nomogram model was assessed using calibration curves and receiver operator characteristic curve (ROC curve). RESULTS: A total of 860 patients with septic shock meeting the criteria were finally enrolled, including 472 in the training set and 388 in the validation set. The 28-day mortalities were 52.5% (248/472) and 54.1% (210/388) for the training and validation sets, respectively. In the training set, age, respiratory rate (RR), the levels of C-reactive protein (CRP), D-dimer, white blood cell count (WBC), neutrophil count (NEU), neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), mean platelet volume (MPV), and platelet count (PLT) in the death group were significantly higher than those in the survival group, and the levels of base remaining (BE), lymphocyte count (LYM), hemoglobin (Hb) and the proportion of chronic obstructive pulmonary diseases (COPD) were significantly lower than those in the survival group (all P < 0.05). Multifactorial Logistic regression analysis showed that NLR [odds ratio (OR) = 0.023 0, 95% confidence interval (95%CI) was -0.204 4 to 0.113 0], MPV (OR = 0.179 8, 95%CI was -0.877 6 to 0.172 7), Hb (OR = 0.007 8, 95%CI was 0.010 3 to 0.040 8), procalcitonin (PCT; OR = 1.957 0, 95%CI was 1.243 0 to 3.081 0), and D-dimer (OR = 0.000 1, 95%CI was -0.000 4 to 0.000 1) were independent predictors of 28-day mortality in patients with septic shock in the emergency department (all P < 0.05). A column-line graph model was established based on the above variables, and the ROC curves showed that the area under the ROC curve (AUC) of the nomogram model in the training set and validation set for predicting the 28-day mortality of patients with septic shock was 0.907 (95%CI was 0.864 to 0.940) and 0.822 (95%CI was 0.781 to 0.863), respectively. The calibration curves showed good agreement between the predicted and observed results for both the training and validation sets. CONCLUSIONS: The nomogram model constructed based on NLR, MPV, Hb, PCT and D-dimer has significant clinical value in predicting the 28-day mortality of patients with septic shock in the emergency medicine department.

Pathogenicity and transmissibility of bovine H5N1 influenza virus.

Highly pathogenic H5N1 avian influenza (HPAI H5N1) viruses occasionally infect, but typically do not transmit, in mammals. In the Spring of 2024, an unprecedented outbreak of HPAI H5N1 in bovine herds occurred in the US, with virus spread within and between herds, infections in poultry and cats, and spillover into humans, collectively indicating an increased public health risk1-4. Here, we characterized an HPAI H5N1 virus isolated from infected cow milk in mice and ferrets. Like other HPAI H5N1 viruses, the bovine H5N1 virus spread systemically, including to the mammary glands of both species; however, this tropism was also observed for an older HPAI H5N1 virus isolate. Importantly, bovine HPAI H5N1 virus bound to sialic acids expressed in human upper airways and inefficiently transmitted to exposed ferrets (one of four exposed ferrets seroconverted without virus detection). Bovine HPAI H5N1 virus thus possesses features that may facilitate infection and transmission in mammals.

Safety evaluation of outpatient vs inpatient unicompartmental knee arthroplasty: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to evaluate the safety of outpatient and inpatient Unicompartmental Knee Arthroplasty (UKA) based on the incidence of adverse events. METHOD: A systematic search of the literature was performed in October 2022 on PubMed, Web of Science, Cochrane library, and Embase. The Meta package for R was used to perform the meta-analysis. RESULT: Five studies with a total of 26,301 patients were included. 5813 patients (22.1%) were treated with outpatient UKA, and 20,488 patients (77.9%) were treated with inpatient UKA. There were no statistically significant differences in the incidence of total complications (RR = 1.36, 95% CI = 0.64-2.89, Z = 0.79, P = 0.43), readmission (RR = 1.02, 95% CI = 0.40-2.60, Z = 0.05, P = 0.96), and venous thrombosis (RR = 1.43, 95% CI = 0.96-2.11, Z = 1.78, P = 0.08). Incidence rates were lower in outpatient UKA regarding urinary tract infection (RR = 1.48, 95% CI = 1.07-2.04, Z = 2.40, P = 0.02), pulmonary embolus (RR = 7.48, 95% CI = 1.80-31.17, Z = 2.76, P < 0.01), and transfusion (RR = 2.77, 95% CI = 1.63-4.71, Z = 3.78, P < 0.01). CONCLUSION: In summary, outpatient UKA shows lower incidences of hospital-acquired complications such urinary tract infection, pulmonary embolus, and transfusion. It's worth noting that the incidences of total complications, readmission, and venous thrombosis in outpatient UKA were not higher than the incidences of inpatient UKA, suggestting that outpatient UKA can be considered a safe alternative to inpatient UKA.

Thrombocytopenia in SFTS due to platelets with altered function undergoing cell death pathways.

BACKGROUND: Thrombocytopenia is the major clinical feature associated with the severity of SFTS, but the mechanism by which it occurs remains unclear. METHODS: RNA transcriptome analyses were performed on platelets purified from SFTS patients and SFTSV-infected mice. The functions of differentially expressed genes (DEGs) in the platelets were characterized. ELISA, flow cytometry, and qRT-PCR were used to measure the levels of platelet activation, SFTSV infection in platelets, formation of neutrophil extracellular traps (NETs), transcription of DEGs and percent of platelets undergoing cell death. RESULTS: Enhanced neutrophil activation and interferon (IFN) signaling involved in the viral life cycle were common platelet responses in SFTS, which may consume increasing numbers of platelets. Other functional changes may be associated with different outcomes of SFTS. SFTSV infection led to platelet destruction by pyroptosis, apoptosis, necroptosis, and autophagy. In contrast to SFTS patients, platelets in SFTSV-infected mice mainly play a role in adaptive immunity, and platelet death was not as severe as in humans. CONCLUSIONS: The altered functions of platelets, such as mediating leukocyte activation and undergoing cell death, contribute to thrombocytopenia in SFTS patients. The different mechanisms of thrombocytopenia in mice, suggest that platelet functions should be considered in experimental animal models.

Transcription factor MdbZIP44 targets the promoter of MdPPO2 to regulate browning in Malus domestica Borkh.

Apple (Malus domestica Borkh.) is among the most widely planted and economically valuable horticultural crops globally. Over time, the apple fruit's cut surface undergoes browning, and the degree of browning varies among different apple varieties. Browning not only affects the appearance of fruits but also adversely affects their taste and flavor. In the present study, we observed browning in different apple varieties over time and analyzed the expression of genes in the polyphenol oxidase gene family. The results indicated a strong correlation between the browning degree of the fruit and the relative expression of the polyphenol oxidase gene MdPPO2. With the MdPPO2 promoter as bait, the basic leucine zipper (bZIP) transcription factor MdbZIP44 was identified using the yeast single-hybrid screening method. Further investigation revealed that the overexpression of MdbZIP44 in 'Orin' callus could enhance the expression of MdPPO2 and promote browning of the callus. However, knocking out MdbZIP44 resulted in a callus with no apparent browning phenotype. In addition, our results confirmed the interaction between MdbZIP44 and MdbZIP11. In conclusion, the results indicated that MdbZIP44 can induce apple fruit browning by activating the MdPPO2 promoter. The results provide a theoretical basis for further clarifying the browning mechanism of apple fruit.

A transcriptional repressor HVA regulates vascular bundle formation through auxin transport in Arabidopsis stem.

Vascular bundles transport water and photosynthate to all organs, and increased bundle number contributes to crop lodging resistance. However, the regulation of vascular bundle formation is poorly understood in the Arabidopsis stem. We report a novel semi-dominant mutant with high vascular activity, hva-d, showing increased vascular bundle number and enhanced cambium proliferation in the stem. The activation of a C2H2 zinc finger transcription factor, AT5G27880/HVA, is responsible for the hva-d phenotype. Genetic, biochemical, and fluorescent microscopic analyses were used to dissect the functions of HVA. HVA functions as a repressor and interacts with TOPLESS via the conserved Ethylene-responsive element binding factor-associated Amphiphilic Repression motif. In contrast to the HVA activation line, knockout of HVA function with a CRISPR-Cas9 approach or expression of HVA fused with an activation domain VP16 (HVA-VP16) resulted in fewer vascular bundles. Further, HVA directly regulates the expression of the auxin transport efflux facilitator PIN1, as a result affecting auxin accumulation. Genetics analysis demonstrated that PIN1 is epistatic to HVA in controlling bundle number. This research identifies HVA as a positive regulator of vascular initiation through negatively modulating auxin transport and sheds new light on the mechanism of bundle formation in the stem.

Comparison of therapeutic agents' short-term effects on facial and scalp actinic keratosis: A network meta-analysis.

BACKGROUND: Care for actinic keratosis (AK) can be improved with more knowledge on the relative of effect of indicated therapies. OBJECTIVES: Using network meta-analyses, we quantitatively determined the comparative "short-term" effects of interventions in adults with facial and scalp AK. METHODS: On February 28, 2023, evidence from the peer-reviewed literature was systematically obtained from OVID, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. We analyzed data from studies published in English, of a trial design, and investigating the effect of an actinic keratosis monotherapy. Patient complete clearance, patient partial clearance or lesion-specific clearance across adults were analyzed at 8-12 weeks after therapy. Patient complete clearance pertained to proportion of participants who experienced complete clearance of actinic keratosis lesions; patient partial clearance corresponded to percentage of subjects who achieved at least 75% clearance of actinic keratosis lesions; lesion-specific clearance represented the percentage of all lesions that were cleared. In the main (i.e., base) analyses, nodes were analyzed only at the level of the agent. RESULTS: Data from a total of 84 studies were used-across which 22 active agents were identified. Estimates of interventions' surface under the cumulative ranking curve rankings and (pairwise) relative effects were estimated. Across the three outcomes, fluorouracil 5% was ranked the most effective. CONCLUSIONS: Our work is the first to provide information on covariate-adjusted relative effects of actinic keratosis therapies- including the more recently reported treatments-for the face and scalp; this knowledge may help physicians and patients make more informed decisions.

Association between nonalcoholic steatohepatitis and high serum ferritin levels in type 2 diabetes mellitus.

OBJECTIVE: The aim of this study was to assess the role of elevated serum ferritin levels in the onset, pathological progression and prognosis of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease has been rapidly increasing worldwide. Despite extensive research on the pathogenesis of nonalcoholic fatty liver disease, a lack of sufficient clinical research on the relationship between nonalcoholic fatty liver disease and serum ferritin levels remains. METHODS: We analysed 968 patients with type 2 diabetes mellitus who underwent liver ultrasound examination and had their serum ferritin levels measured. The presence of nonalcoholic fatty liver disease and advanced liver fibrosis was determined through abdominal ultrasound examination and the nonalcoholic fatty liver disease fibrosis score. RESULTS: Compared to that in the non-nonalcoholic fatty liver disease group, the presence of hyperferritinemia was significantly more common in the nonalcoholic fatty liver disease group (83.3 vs. 56.3%, p=0.005). When patients with nonalcoholic fatty liver disease were stratified by the nonalcoholic fatty liver disease fibrosis score, those with advanced liver fibrosis exhibited a higher prevalence of hyperferritinemia (56.3, 78.9, and 88.9% for none, simple steatosis, and advanced fibrosis, respectively; p for trend=0.002). In multivariate logistic regression, liver fibrosis was independently associated with hyperferritinemia (odds ratio [OR] 1.45; 95% confidence interval [CI] 1.18-2.02; p=0.014), and this association remained significant in male patients after adjusting for other risk factors (OR 2.66; 95% CI 1.43-5.48; p=0.026). CONCLUSION: Identifying nonalcoholic fatty liver disease patients at a risk of developing nonalcoholic steatohepatitis and advanced fibrosis is crucial for implementing timely interventions and improving patient outcomes. This study highlights the potential utility of serum ferritin levels as a serum biomarker for identifying nonalcoholic steatohepatitis patients and those at a risk of late-stage fibrosis, particularly in male patients with nonalcoholic fatty liver disease.

Dual-Intermetallic Heterostructure on Hierarchical Nanoporous Metal for Highly Efficient Alkaline Hydrogen Electrocatalysis.

Constructing well-defined active multisites is an effective strategy to break linear scaling relationships to develop high-efficiency catalysts toward multiple-intermediate reactions. Here, dual-intermetallic heterostructure composed of tungsten-bridged Co3W and WNi4 intermetallic compounds seamlessly integrated on hierarchical nanoporous nickel skeleton is reported as a high-performance nonprecious electrocatalyst for alkaline hydrogen evolution and oxidation reactions. By virtue of interfacial tungsten atoms configuring contiguous multisites with proper adsorptions of hydrogen and hydroxyl intermediates to accelerate water dissociation/combination and column-nanostructured nickel skeleton facilitating electron and ion/molecule transportations, nanoporous nickel-supported Co3W-WNi4 heterostructure exhibits exceptional hydrogen electrocatalysis in alkaline media, with outstanding durability and impressive catalytic activities for hydrogen oxidation reaction (geometric exchange current density of ≈6.62 mA cm-2) and hydrogen evolution reaction (current density of ≈1.45 A cm-2 at overpotential of 200 mV). Such atom-ordered intermetallic heterostructure alternative to platinum group metals shows genuine potential for hydrogen production and utilization in hydroxide-exchange-membrane water electrolyzers and fuel cells.

Endoplasmic reticulum stress promotes hepatocellular carcinoma by modulating immunity: a study based on artificial neural networks and single-cell sequencing.

INTRODUCTION: Hepatocellular carcinoma (HCC) is characterized by the complex pathogenesis, limited therapeutic methods, and poor prognosis. Endoplasmic reticulum stress (ERS) plays an important role in the development of HCC, therefore, we still need further study of molecular mechanism of HCC and ERS for early diagnosis and promising treatment targets. METHOD: The GEO datasets (GSE25097, GSE62232, and GSE65372) were integrated to identify differentially expressed genes related to HCC (ERSRGs). Random Forest (RF) and Support Vector Machine (SVM) machine learning techniques were applied to screen ERSRGs associated with endoplasmic reticulum stress, and an artificial neural network (ANN) diagnostic prediction model was constructed. The ESTIMATE algorithm was utilized to analyze the correlation between ERSRGs and the immune microenvironment. The potential therapeutic agents for ERSRGs were explored using the Drug Signature Database (DSigDB). The immunological landscape of the ERSRGs central gene PPP1R16A was assessed through single-cell sequencing and cell communication, and its biological function was validated using cytological experiments. RESULTS: An ANN related to the ERS model was constructed based on SRPX, THBS4, CTH, PPP1R16A, CLGN, and THBS1. The area under the curve (AUC) of the model in the training set was 0.979, and the AUC values in three validation sets were 0.958, 0.936, and 0.970, respectively, indicating high reliability and effectiveness. Spearman correlation analysis suggests that the expression levels of ERSRGs are significantly correlated with immune cell infiltration and immune-related pathways, indicating their potential as important targets for immunotherapy. Mometasone was predicted to be the most promising treatment drug based on its highest binding score. Among the six ERSRGs, PPP1R16A had the highest mutation rate, predominantly copy number mutations, which may be the core gene of the ERSRGs model. Single-cell analysis and cell communication indicated that PPP1R16A is predominantly distributed in liver malignant parenchymal cells and may reshape the tumor microenvironment by enhancing macrophage migration inhibitory factor (MIF)/CD74 + CXCR4 signaling pathways. Functional experiments revealed that after siRNA knockdown, the expression of PPP1R16A was downregulated, which inhibited the proliferation, migration, and invasion capabilities of HCCLM3 and Hep3B cells in vitro. CONCLUSION: The consensus of various machine learning algorithms and artificial intelligence neural networks has established a novel predictive model for the diagnosis of liver cancer associated with ERS. This study offers a new direction for the diagnosis and treatment of HCC.

Synthesis of N-N Axially Chiral Pyrrolyl-oxoisoindolin via Isothiourea-Catalyzed Acylative Dynamic Kinetic Resolution.

The development of methods for the asymmetric synthesis of N-N axial chirality remains elusive and challenging. Here, we disclose a method for the construction of N-N axially chiral pyrrolyl-oxoisoindolins along with central chirality via the isothiourea (ITU)-catalyzed acylative dynamic kinetic resolution (DKR). Axial chirality was introduced into the acylative DKR of hemiaminals for the first time. This protocol features mild conditions with excellent yields and enantioselectivities.

Innovative biomaterials for food packaging: Unlocking the potential of polyhydroxyalkanoate (PHA) biopolymers.

Polyhydroxyalkanoate (PHA) biopolyesters show a good balance between sustainability and performance, making them a competitive alternative to conventional plastics for ecofriendly food packaging. With an emphasis on developments over the last decade (2014-2024), this review examines the revolutionary potential of PHAs as a sustainable food packaging material option. It also delves into the current state of commercial development, competitiveness, and the carbon footprint associated with PHA-based products. First, a critical examination of the challenges experienced by PHAs in terms of food packaging requirements is undertaken, followed by an assessment of contemporary strategies addressing permeability, mechanical properties, and processing considerations. The various PHA packaging end-of-life options, including a comprehensive overview of the environmental impact and potential solutions will also be discussed. Finally, conclusions and future perspectives are elucidated with a view of prospecting PHAs as future green materials, with a blend of performance and sustainability of food packaging solutions.

Potential emergence of terbinafine resistance by squalene epoxidase gene mutations: An 18-month cohort study of onychomycosis patients in the United States.

BACKGROUND: There is a concerning rise in antifungal-resistant dermatophytosis globally, with resistance to terbinafine conferred by point mutations in the squalene epoxidase (SQLE) gene. OBJECTIVES: Report changes in the prevalence and profile of SQLE mutations in onychomycosis patients in the United States. METHODS: A longitudinal cohort study of toenail samples was collected from suspected onychomycosis patients over an 18-month period from 2022 to 2023. Samples were submitted from across the United States and subjected to multiplex real-time polymerase chain reactions for dermatophyte detection, with further screening of SQLE mutations at four known hotspots (393Leu, 397Phe, 415Phe and 440His). RESULTS: A total of 62,056 samples were submitted (mean age: 57.5 years; female: 60.4%). Dermatophytes were detected in 38.5% of samples, primarily Trichophyton rubrum complex (83.6%) and T. mentagrophytes complex (10.7%). A survey of SQLE mutations was carried out in 22,610 dermatophyte samples; there was a significant increase in the prevalence of SQLE mutations between the first quarter of 2022 and the second quarter of 2023 (29.0 to 61.9 per 1000 persons). The Phe397Leu substitution was the predominant mutation; Phe415Ser and His440Tyr have also emerged which were previously reported as minor mutations in skin samples. The temporal change in mutation rates can be primarily attributed to the Phe415Ser substitution. Samples from elderly patients (>70 years) are more likely to be infected with the T. mentagrophytes complex including strains harbouring the Phe415Ser substitution. CONCLUSION: The prevalence of SQLE mutations among onychomycosis patients with Trichophyton infections may be underestimated. Older individuals may have a higher risk.

Establishment of epidemiological cut-off values for eravacycline, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus.

OBJECTIVES: To establish the epidemiology cut-off (ECOFF) values of eravacycline against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus, from a multi-centre study in China. METHODS: We collected 2500 clinical isolates from five hospitals in China from 2017 to 2020. The MICs of eravacycline were determined using broth microdilution. The ECOFF values of eravacycline against the five species commonly causing cIAIs were calculated using visual estimation and ECOFFinder following the EUCAST guideline. RESULTS: The MICs of eravacycline against all the strains were in the range of 0.004-16 mg/L. The ECOFF values of eravacycline were 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus, consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations. No discrepancy was found between the visually estimated and 99.00% ECOFF values calculated using ECOFFinder. CONCLUSIONS: The determined ECOFF values of eravacycline against the five species can assist in distinguishing wild-type from non-wild-type strains. Given its promising activity, eravacycline may represent a member of the tetracycline class in treating cIAIs caused by commonly encountered Gram-negative and Gram-positive pathogens.

Sotagliflozin attenuates cardiac dysfunction and depression-like behaviors in mice with myocardial infarction through the gut-heart-brain axis.

Myocardial infarction (MI) and depression are leading causes of mortality and morbidity globally, and these conditions are increasing recognized as being fundamentally interconnected. The recently recognized gut-heart-brain axis offers insights into depression following MI, but effective treatments for this comorbidity remain lacking. To address this medical need, we employed an animal model of MI to investigate the potential repurposing of sotagliflozin (SOTA), an approved sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor for diabetes, for managing depression following MI and identifying potential SOTA-associated microbial mechanisms. SOTA treatment improved cardiac dysfunction and alleviated depression-like behaviors induced by MI, accompanied by alterations in gut microbiota composition, such as changes in the Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001. Moreover, fecal microbiota transplantation (FMT) using fecal samples from SOTA-treated MI mice demonstrated that gut microbiota contributed to the beneficial effects of SOTA on cardiac dysfunction and depression-like behaviors in MI mice. Intriguingly, FMT-based intervention and concordance analysis of gut microbiota before and after FMT suggested that Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001 were associated with the beneficial effects of SOTA. Furthermore, functional prediction of gut microbiota and correlation analysis support the significance of these dynamic microbial communities. In conclusion, these findings suggest that SOTA could serve as a potential drug to ameliorate cardiac dysfunction and depressive symptoms in MI patients via through the gut-heart-brain axis.