Bioactive α-Pyrone Analogs from the Endophytic Fungus Diaporthe sp. CB10100: α-Glucosidase Inhibitory Activity, Molecular Docking, and Molecular Dynamics Studies.

Two α-pyrone analogs were isolated from the endophytic fungus Diaporthe sp. CB10100, which is derived from the medicinal plant Sinomenium acutum. These analogs included a new compound, diaporpyrone F (3), and a known compound, diaporpyrone D (4). The structure of 3 was identified by a comprehensive examination of HRESIMS, 1D and 2D NMR spectroscopic data. Bioinformatics analysis revealed that biosynthetic gene clusters for α-pyrone analogs are common in fungi of Diaporthe species. The in vitro α-glucosidase inhibitory activity and antibacterial assay of 4 revealed that it has a 46.40% inhibitory effect on α-glucosidase at 800 µM, while no antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), Mycolicibacterium (Mycobacterium) smegmatis or Klebsiella pneumoniae at 64 µg/mL. Molecular docking and molecular dynamics simulations of 4 with α-glucosidase further suggested that the compounds are potential α-glucosidase inhibitors. Therefore, α-pyrone analogs can be used as lead compounds for α-glucosidase inhibitors in more in-depth studies.

Cardiac Resolvin D2 ameliorates sepsis-induced cardiomyopathy via inhibiting Caspase-11/GSDMD dependent pyroptosis.

BACKGROUND: Sepsis-induced cardiomyopathy (SICM) is common complication in septic patients with a high mortality and is characterized by an abnormal inflammation response, which was precisely regulated by endogenous specialized pro-resolving mediators (SPMs). However, the metabolic changes of cardiac SPMs during SICM and the roles of SPMs subset in the development of SICM remain unknown. METHODS: In this work, the SPMs concentration was assessed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) of SICM mice and SICM patients. The cardiac function was measured by echocardiography after the treatment of a SPMs subset, termed Resolvin D2 (RvD2). Caspase-11-/-, GSDMD-/- and double deficient (Caspase-11-/-GSDMD-/-) mice were used to clarify the mechanisms of RvD2 in SICM. RESULTS: We found that endogenous cardiac SPMs were disorders and RvD2 was decreased significantly and correlated with left ventricular ejection fraction (LVEF) and ß-BNP, cTnT in Lipopolysaccharide/Cecum ligation and puncture (CLP) induced SICM models. Treatment with RvD2 attenuated lethality, cardiac dysfunction and cardiomyocytes death during SICM. Mechanistically, RvD2 alleviated SICM via inhibiting Caspase-11/GSDMD-mediated cardiomyocytes pyroptosis. Finally, the plasma levels of RvD2 were also decreased and significantly correlated with IL-1ß, ß-BNP, cTnT and LVEF in patients with SICM. Of note, plasma RvD2 level is indicator of SICM patients from healthy controls or sepsis patients. CONCLUSION: These findings suggest that decreased cardiac RvD2 may involve in the pathogenesis of SICM. In addition, treatment with RvD2 represents a novel therapeutic strategy for SICM by inhibiting cardiomyocytes pyroptosis.

CdBi2S4-Decorated Aminated Polyacrylonitrile Nanofiber for Photocatalytic Treatment of Cr(VI) and Tetracycline Wastewater.

The significant threat posed by the high toxicity of heavy metals and antibiotics in water pollutants has prompted a growing emphasis on the development of highly efficient removal methods for these pollutants. In this paper, flexible electrospinning polyacrylonitrile (PAN) nanofiber-supported CdBi2S4 was synthesized via a hydrothermal method, followed by amination treatment with diethylenetriamine (DETA). The as-prepared CdBi2S4/NH2-PAN nanofiber, enriched with sulfur vacancies, demonstrated outstanding visible-light trapping ability and a suitable band gap, leading to efficient separation and transport of photogenerated carriers, ultimately resulting in exceptional photocatalytic capability. The optimal 3-CdBi2S4/NH2-PAN nanofiber achieved impressive reduction rates of 92.26% for Cr(VI) and 96.45% for tetracycline hydrochloride (TCH) within 120 min, which were much higher than those for CdS/NH2-PAN, Bi2S3/NH2-PAN, and CdBi2S4/PAN nanofibers. After five cycles, the removal rate of the CdBi2S4/NH2-PAN nanofiber consistently remained above 90%. Their ease of separation and recovery from the application environment contributes to their practicality. Additionally, compared with conventional suspended particle catalyzers, the composite nanofiber exhibited remarkable flexibility and self-supporting properties.

Enhancing boreal forest resilience: A four-year impact of biochar on soil quality and fungal communities.

Boreal forests commonly suffer from nutrient deficiency due to restricted biological activity and decomposition. Biochar has been used as a promising strategy to improve soil quality, yet its impacts on forest soil microbes, particularly in cold environment, remains poorly understood. In this study, we investigated the effects of biochar, produced at different pyrolysis temperatures (500 °C and 650 °C) and applied at different amounts (0.5 kg·m-2 and 1.0 kg·m-2), on soil property, soil enzyme activity, and fungal community dynamics in a boreal forest over a span of two to four years. Our results showed that, four-year post-application of biochar produced at 650 °C and applied at 1.0 kg·m-2, significantly increased the relative abundance of Mortierellomycota and enhanced fungal species richness, α-diversity and evenness compared to the control (CK) (P < 0.05). Notably, the abundance of Phialocephala fortinii increased with the application of biochar produced at 500 °C and applied at 0.5 kg·m-2, exhibiting a positively correlation with the carbon cycling-related enzyme ß-cellobiosidase. Functionally, distinct fungal gene structures were formed between different biochar pyrolysis temperatures, and between application amounts in four-year post-biochar application (P < 0.05). Additionally, correlation analyses revealed the significance of the duration post-biochar application on the soil properties, soil extracellular enzymes, soil fungal dominant phyla, fungal community and gene structures (P < 0.01). The interaction between biochar pyrolysis temperature and application amount significantly influenced fungal α-diversity (P < 0.01). Overall, these findings provide theoretical insights and practical application for biochar as soil amendment in boreal forest ecosystems.

T2WI-based MRI radiomics for the prediction of preoperative extranodal extension and prognosis in resectable rectal cancer.

OBJECTIVE: To investigate whether T2-weighted imaging (T2WI)-based intratumoral and peritumoral radiomics can predict extranodal extension (ENE) and prognosis in patients with resectable rectal cancer. METHODS: One hundred sixty-seven patients with resectable rectal cancer including T3T4N + cases were prospectively included. Radiomics features were extracted from intratumoral, peritumoral 3 mm, and peritumoral-mesorectal fat on T2WI images. Least absolute shrinkage and selection operator regression were used for feature selection. A radiomics signature score (Radscore) was built with logistic regression analysis. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of each Radscore. A clinical-radiomics nomogram was constructed by the most predictive radiomics signature and clinical risk factors. A prognostic model was constructed by Cox regression analysis to identify 3-year recurrence-free survival (RFS). RESULTS: Age, cT stage, and lymph node-irregular border and/or adjacent fat invasion were identified as independent clinical risk factors to construct a clinical model. The nomogram incorporating intratumoral and peritumoral 3 mm Radscore and independent clinical risk factors achieved a better AUC than the clinical model in the training (0.799 vs. 0.736) and validation cohorts (0.723 vs. 0.667). Nomogram-based ENE (hazard ratio [HR] = 2.625, 95% CI = 1.233-5.586, p = 0.012) and extramural vascular invasion (EMVI) (HR = 2.523, 95% CI = 1.247-5.106, p = 0.010) were independent risk factors for predicting 3-year RFS. The prognostic model constructed by these two indicators showed good performance for predicting 3-year RFS in the training (AUC = 0.761) and validation cohorts (AUC = 0.710). CONCLUSION: The nomogram incorporating intratumoral and peritumoral 3 mm Radscore and clinical risk factors could predict preoperative ENE. Combining nomogram-based ENE and MRI-reported EMVI may be useful in predicting 3-year RFS. CRITICAL RELEVANCE STATEMENT: A clinical-radiomics nomogram could help preoperative predict ENE, and a prognostic model constructed by the nomogram-based ENE and MRI-reported EMVI could predict 3-year RFS in patients with resectable rectal cancer. KEY POINTS: • Intratumoral and peritumoral 3 mm Radscore showed the most capability for predicting ENE. • Clinical-radiomics nomogram achieved the best predictive performance for predicting ENE. • Combining clinical-radiomics based-ENE and EMVI showed good performance for 3-year RFS.

Assessment of the Characteristics of Patent Foramen Ovale Associated with Cryptogenic Stroke.

OBJECTIVE: This study aims to comprehensively assess the characteristics of patent foramen ovale (PFO) in relation to Cryptogenic Strok (CS) by utilizing transesophageal echocardiography (TEE) and contrast transthoracic echocardiography (c-TTE) and to identify high-risk factors associated with PFO-related CS. BACKGROUND: Transcatheter PFO closure has demonstrated its effectiveness in preventing PFO-related CS. Therefore, understanding the specific structural attributes of PFO associated with CS is imperative. METHODS: Enrollment comprised 113 test patients who experienced CS in conjunction with PFO and 117 control patients diagnosed with migraine with PFO but without a history of stroke. The characteristics of the PFO were observed by TEE and c-TTE. A comparative analysis was undertaken to assess the variations in PFO characteristics between the test patients and controls, and to uncover the independent factors relevant to CS. RESULTS: The patients in the test group were older than the controls. Both the height and length of the PFO during Valsalva exhibited greater dimensions in the test group when contrasted with controls. Notably, the test group presented higher incidence rates of low-angle PFO (defined as an angle between the inferior vena cava (IVC) and PFO ≤ 10°) and atrial septal aneurysm (ASA) as contrasted with the control group. Right-to-left shunt (RLS) III during Valsalva demonstrated a significantly elevated occurrence within the test group as opposed to the controls. Conversely, RLS II during Valsalva exhibited a significantly higher frequency in the controls in contrast to the tests. No significant disparities were observed between the two groups with respect to RLS I during Valsalva and all grades of RLS at rest. Multivariate analysis revealed that the length of the PFO during Valsalva, the presence of ASA, RLS III during Valsalva and low-angle PFO were independent relevant factors associated with CS. CONCLUSIONS: The length of the PFO tunnel, low-angle PFO, RLS III during Valsalva and the presence of ASA were independent risk factors for CS. The combined utilization of TEE and c-TTE may prove valuable in identifying PFO patients at a heightened risk of CS and in facilitating the screening process for transcatheter PFO closure.

Using Multi-phase CT Radiomics Features to Predict EGFR Mutation Status in Lung Adenocarcinoma Patients.

RATIONALE AND OBJECTIVES: This study aimed to non-invasively predict epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma using multi-phase computed tomography (CT) radiomics features. MATERIALS AND METHODS: A total of 424 patients with lung adenocarcinoma were recruited from two hospitals who underwent preoperative non-enhanced CT (NE-CT) and enhanced CT (including arterial phase CT [AP-CT], and venous phase CT [VP-CT]). Patients were divided into training (n = 297) and external validation (n = 127) cohorts according to hospital. Radiomics features were extracted from the NE-CT, AP-CT, and VP-CT images, respectively. The Wilcoxon test, correlation analysis, and simulated annealing were used for feature screening. A clinical model and eight radiomics models were established. Furthermore, a clinical-radiomics model was constructed by incorporating multi-phase CT features and clinical risk factors. Receiver operating characteristic curves were used to evaluate the predictive performance of the models. RESULTS: The predictive performance of multi-phase CT radiomics model (AUC of 0.925 [95% CI, 0.879-0.971] in the validation cohort) was higher than that of NE-CT, AP-CT, VP-CT, and clinical models (AUCs of 0.860 [95% CI,0.794-0.927], 0.792 [95% CI, 0.713-0.871], 0.753 [95% CI, 0.669-0.838], and 0.706 [95% CI, 0.620-0.791] in the validation cohort, respectively) (all P < 0.05). The predictive performance of the clinical-radiomics model (AUC of 0.927 [95% CI, 0.882-0.971] in the validation cohort) was comparable to that of multi-phase CT radiomics model (P > 0.05). CONCLUSION: Our multi-phase CT radiomics model showed good performance in identifying the EGFR mutation status in patients with lung adenocarcinoma, which may assist personalized treatment decisions.

Identification of a novel thermostable transaminase and its application in L-phosphinothricin biosynthesis.

Transaminase (TA) is a crucial biocatalyst for enantioselective production of the herbicide L-phosphinothricin (L-PPT). The use of enzymatic cascades has been shown to effectively overcome the unfavorable thermodynamic equilibrium of TA-catalyzed transamination reaction, also increasing demand for TA stability. In this work, a novel thermostable transaminase (PtTA) from Pseudomonas thermotolerans was mined and characterized. The PtTA showed a high specific activity (28.63 U/mg) towards 2-oxo-4-[(hydroxy)(methyl)phosphinoyl]butyric acid (PPO), with excellent thermostability and substrate tolerance. Two cascade systems driven by PtTA were developed for L-PPT biosynthesis, including asymmetric synthesis of L-PPT from PPO and deracemization of D, L-PPT. For the asymmetric synthesis of L-PPT from PPO, a three-enzyme cascade was constructed as a recombinant Escherichia coli (E. coli G), by co-expressing PtTA, glutamate dehydrogenase (GluDH) and D-glucose dehydrogenase (GDH). Complete conversion of 400 mM PPO was achieved using only 40 mM amino donor L-glutamate. Furthermore, by coupling D-amino acid aminotransferase (Ym DAAT) from Bacillus sp. YM-1 and PtTA, a two-transaminase cascade was developed for the one-pot deracemization of D, L-PPT. Under the highest reported substrate concentration (800 mM D, L-PPT), a 90.43% L-PPT yield was realized. The superior catalytic performance of the PtTA-driven cascade demonstrated that the thermodynamic limitation was overcome, highlighting its application prospect for L-PPT biosynthesis. KEY POINTS: • A novel thermostable transaminase was mined for L-phosphinothricin biosynthesis. • The asymmetric synthesis of L-phosphinothricin was achieved via a three-enzyme cascade. • Development of a two-transaminase cascade for D, L-phosphinothricin deracemization.

Cervical vertebral Hounsfield units are a better predictor of Zero-P subsidence than the T-score of DXA in patients following single-level anterior cervical discectomy and fusion with zero-profile anchored spacer.

OBJECTIVES: To determine the predictive effect of Hounsfield unit (HU) values in the cervical vertebral body measured by computed tomography (CT) and T-scores measured by dual-energy X-ray absorptiometry (DXA) on Zero-P subsidence after anterior cervical discectomy and fusion (ACDF)with Zero-P. In addition, we evaluated the most reliable measurement of cervical HU values. METHODS: We reviewed 76 patients who underwent single-level Zero-P fusion for cervical spondylosis. HU values were measured on CT images according to previous studies. Univariate analysis was used to screen the influencing factors of Zero-P subsidence, and then, logistic regression was used to determine the independent risk factors. The area under the receiver operating characteristic curve (AUC) was used to evaluate the ability to predict Zero-P subsidence. RESULTS: Twelve patients (15.8%) developed Zero-P subsidence. There were significant differences between subsidence group and non-subsidence group in terms of age, axial HU value, and HU value of midsagittal, midcoronal, and midaxial (MSCD), but there were no significant differences in lowest T-score and lowest BMD. The axial HU value (OR = 0.925) and HU value of MSCD (OR = 0.892) were independent risk factors for Zero-P subsidence, and the lowest T-score was not (OR = 1.186). The AUC of predicting Zero-P subsidence was 0.798 for axial HU value, 0.861 for HU value of MSCD, and 0.656 for T-score. CONCLUSIONS: Lower cervical HU value indicates a higher risk of subsidence in patients following Zero-P fusion for single-level cervical spondylosis. HU values were better predictors of Zero-P subsidence than DXA T-scores. In addition, the measurement of HU value in the midsagittal, midcoronal, and midaxial planes of the cervical vertebral body provides an effective method for predicting Zero-P subsidence.

Efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS.

The lymphatic vasculature is the natural pathway for the resolution of inflammation, yet the role of pulmonary lymphatic drainage function in sepsis-induced acute respiratory distress syndrome (ARDS) remains poorly characterized. In this study, indocyanine green-near infrared lymphatic living imaging was performed to examine pulmonary lymphatic drainage function in septic mouse models. We found that the pulmonary lymphatic drainage was impaired owing to the damaged lymphatic structure in sepsis-induced ARDS. Moreover, prior lymphatic defects by blocking vascular endothelial growth factor receptor-3 (VEGFR-3) worsened sepsis-induced lymphatic dysfunction and inflammation. Posttreatment with vascular endothelial growth factor-C (Cys156Ser) (VEGF-C156S), a ligand of VEGFR-3, ameliorated lymphatic drainage by rejuvenating lymphatics to reduce the pulmonary edema and promote draining of pulmonary macrophages and neutrophils to pretracheal lymph nodes. Meanwhile, VEGF-C156S posttreatment reversed sepsis-inhibited CC chemokine ligand 21 (CCL21), which colocalizes with pulmonary lymphatic vessels. Furthermore, the advantages of VEGF-C156S on the drainage of inflammatory cells and edema fluid were abolished by blocking VEGFR-3 or CCL21. These results suggest that efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS. Our findings offer a therapeutic approach to sepsis-induced ARDS by promoting lymphatic drainage function.

Fast and Sensitive Detection of CO by Bi-MOF-Derived Porous In2O3/Fe2O3 Core-Shell Nanotubes.

In2O3 is an optimal material for sensitive detection of carbon monoxide (CO) gas due to its low resistivity and high catalytic activity. Yet, the gas response dynamics between the CO gas molecules and the surface of In2O3 is limited by its solid structure, resulting in a weak gas response value and sluggish electron transport. Herein, we report a strategy to synthesize porous In2O3/Fe2O3 core-shell nanotubes derived from In/Fe bimetallic organic frameworks. The fabricated porous In2O3/Fe2O3-4 core-shell nanotubes present outstanding gas sensitivities, including a response value 3.8 times (33.7 to 200 ppm CO at 260 °C) higher than that of monometallic-derived In2O3 (8.7), ultrashort response and recovery times (23/76 s) to 200 ppm CO, low detection limit (1 ppm), promising selectivity, and long-term stability. The enhanced sensing mechanisms are clarified by the combination of experiment and first-principles calculations, showing that the synergetic strategy of higher adsorption energy, increased electrical conductivity, higher electron transfer numbers, and larger specific surface area of porous core-shell structures promotes the surface activity and charge transfer efficiency. The present work paves a way to tune gas-sensing materials with special morphologies for the development of high-performance CO sensors.

Computed Tomography Manifestations in Patients with Rifampin Primary Drug-Resistant Tuberculosis in an Infectious Disease Hospital in the Yi Autonomous Prefecture, China.

Purpose: This study aimed to investigate clinical features and computed tomography (CT) manifestations of rifampicin primary drug-resistant pulmonary tuberculosis in Liangshan Yi Autonomous Prefecture. Patients and Methods: A total of 100 inpatients with confirmed primary rifampicin-resistant pulmonary tuberculosis were recruited from January 2020 to December 2022 at an infectious disease hospital located in the Liangshan Yi Autonomous Prefecture. Additionally, 100 inpatients with confirmed drug-susceptible pulmonary tuberculosis during the same period were matched to the rifampicin-resistant group based on gender, age, and ethnicity. The clinical characteristics of the two groups were recorded separately. Furthermore, the CT manifestations in these patients were independently analyzed by three radiologists. Results: The results showed that comorbid diabetes mellitus was more prevalent in the drug-resistant tuberculosis (DR-TB) group than in the drug-susceptible tuberculosis (DS-TB) group (9% vs 0%, p=0.0032). In terms of imaging presentation, DR-TB patients exhibited a higher frequency of calcifications (55% vs 35.00%, p=0.0068), greater median number of cavities (5 vs 2, p=0.0027), and larger maximum cavity diameter (52.08±25.55 mm vs 42.72±17.48 mm, p=0.0097). Additionally, bilateral involvement was more common in DR-TB patients at the site of the lesion (89% vs 76%, p=0.0246), with a higher prevalence in the right middle (82% vs 68%, p=0.0332), right lower (82% vs 68%, p=0.0332), left upper (91% vs 77%, p=0.0113), and left lower lobes (92% vs 66%, p<0.0001). Conversely, the involvement of only one lobe was less frequent in patients with DR-TB than in those with DS-TB (4% vs 13%, p=0.0398), whereas the involvement of all five lobes was more common (68% vs 51%, p=0.0209). Conclusion: Patients with DR-TB exhibit a higher prevalence of severe imaging manifestations, highlighting the importance of CT in the early detection and diagnosis of DR-TB.

Modifiable risk factors for ventilator associated diaphragmatic dysfunction: a multicenter observational study.

BACKGROUND: Diaphragmatic dysfunction is known to be associated with difficulties weaning from invasive mechanical ventilation and is related to worse patient outcomes yet our understanding of how to prevent diaphragmatic dysfunction remains incomplete. We examined potentially modifiable risk factors for diaphragmatic dysfunction and attempted to estimate benefits attributable to altering these modifiable risk factors. METHODS: This prospective multicenter observational study was undertaken in the general ICUs of two tertiary care teaching hospitals. Critically ill adults expected to receive invasive mechanical ventilation for at least 48 h were enrolled. Diaphragm function was assessed by ultrasound each study day, with dysfunction defined as thickening fraction less than 20%. RESULTS: From January to December 2019, 856 patients were screened and 126 patients were enrolled. Overall, 40.5% (51/126) of patients experienced diaphragmatic dysfunction during invasive mechanical ventilation. Patients with diaphragmatic dysfunction were more likely to develop ventilator associated pneumonia (risk difference [RD] + 12.9%, 95% Confidence Interval [CI] 1.4 to 24.4%, P = 0.028), were more likely to experience extubation failure (RD + 8.5%, 95% CI 0.4 to 16.6%, P = 0.039) and required a longer duration of invasive mechanical ventilation (RD + 1.3 days, 95% CI 0.1 to 2.5 days, P = 0.035). They also required a longer hospital stay (RD + 1.2 days, 95% CI 0.04 to 2.4 days, P = 0.041) and were more likely to die before hospital discharge (RD + 18.1%, 95% CI 3.7 to 32.5%, P = 0.014). Multivariable analysis considered the impact of age, sex, pre-existing nutritional status, caloric intake, amino acid intake, acute disease severity, modes of mechanical ventilation, measures of respiratory status, sedation, pain control and baseline diaphragm thickness. Only SOFA score (P = 0.008) and early amino acid intake (P = 0.001) remained significant independent risk factors for the onset of diaphragmatic dysfunction. Causal path modeling suggested early amino acid intake may significantly reduce diaphragmatic dysfunction (RRR 29%, 95% CI 10% to 48%, P = 0.003) and may also reduce mortality (RRR 49%, 95% CI 25% to 73%, P < 0.0001). CONCLUSIONS: Amino acid intake during the first 24 h of ICU stay may represent an important, modifiable risk factor for diaphragmatic dysfunction and may have a direct causal effect on mortality. We recommend additional research on this topic.

Interaction Between Blood Vasculatures and Lymphatic Vasculatures During Inflammation.

Physiological activity cannot be regulated without the blood and lymphatic vasculatures, which play complementary roles in maintaining the body's homeostasis and immune responses. Inflammation is the body's initial response to pathological injury and is responsible for protecting the body, removing damaged tissues, and restoring and maintaining homeostasis in the body. A growing number of researches have shown that blood and lymphatic vessels play an essential role in a variety of inflammatory diseases. In the inflammatory state, the permeability of blood vessels and lymphatic vessels is altered, and angiogenesis and lymphangiogenesis subsequently occur. The blood vascular and lymphatic vascular systems interact to determine the development or resolution of inflammation. In this review, we discuss the changes that occur in the blood vascular and lymphatic vascular systems of several organs during inflammation, describe the different scenarios of angiogenesis and lymphangiogenesis at different sites of inflammation, and demonstrate the prospect of targeting the blood vasculature and lymphatic vasculature systems to limit the development of inflammation and promote the resolution of inflammation in inflammatory diseases.

Diaporpyrone E, an undescribed α-pyrone from the endophytic fungus Diaporthe sp. CB10100.

An undescribed α-pyrone diaporpyrone E (1), and three known nucleotides, 5'-O-acetyl uridine (2), 5'-O-acetyl thymidine (3), and adenine (4), were identified from Diaporthe sp. CB10100, an endophytic fungus isolated from the medicinal plant Sinomenium acutum. The structure of 1 was determined by extensive analysis of its HRMS, 1D and 2D NMR spectroscopic data, as well as electronic circular dichroism calculations and comparison. The in vitro cytotoxic and antibacterial assays of 1 revealed that it has a 30.2% inhibitory effect on HepG2 cells at 50 µM, while no antibacterial activities against Staphylococcus aureus and Klebsiella pneumoniae at 64 µg/mL.

MRI-based multiregional radiomics for preoperative prediction of tumor deposit and prognosis in resectable rectal cancer: a bicenter study.

OBJECTIVE: To build T2WI-based multiregional radiomics for predicting tumor deposit (TD) and prognosis in patients with resectable rectal cancer. MATERIALS AND METHODS: A total of 208 patients with pathologically confirmed rectal cancer from two hospitals were prospectively enrolled. Intra- and peritumoral features were extracted separately from T2WI images and the least absolute shrinkage and selection operator was used to screen the most valuable radiomics features. Clinical-radiomics nomogram was developed by radiomics signatures and the most predictive clinical parameters. Prognostic model for 3-year recurrence-free survival (RFS) was constructed using univariate and multivariate Cox analysis. RESULTS: For TD, the area under the receiver operating characteristic curve (AUC) for intratumoral radiomics model was 0.956, 0.823, and 0.860 in the training cohort, test cohort, and external validation cohort, respectively. AUC for the peritumoral radiomics model was 0.929, 0.906, and 0.773 in the training cohort, test cohort, and external validation cohort, respectively. The AUC for combined intra- and peritumoral radiomics model was 0.976, 0.918, and 0.874 in the training cohort, test cohort, and external validation cohort, respectively. The AUC for clinical-radiomics nomogram was 0.989, 0.777, and 0.870 in the training cohort, test cohort, and external validation cohort, respectively. The prognostic model constructed by combining intra- and peritumoral radiomics signature score (radscore)-based TD and MRI-reported lymph nodes metastasis (LNM) indicated good performance for predicting 3-year RFS, with AUC of 0.824, 0.865, and 0.738 in the training cohort, test cohort and external validation cohort, respectively. CONCLUSION: Combined intra- and peritumoral radiomics model showed good performance for predicting TD. Combining intra- and peritumoral radscore-based TD and MRI-reported LNM indicated the recurrence risk. CLINICAL RELEVANCE STATEMENT: Combined intra- and peritumoral radiomics model could help accurately predict tumor deposits. Combining this predictive model-based tumor deposits with MRI-reported lymph node metastasis was associated with relapse risk of rectal cancer after surgery. KEY POINTS: • Combined intra- and peritumoral radiomics model provided better diagnostic performance than that of intratumoral and peritumoral radiomics model alone for predicting TD in rectal cancer. • The predictive performance of the clinical-radiomics nomogram was not improved compared with the combined intra- and peritumoral radiomics model for predicting TD. • The prognostic model constructed by combining intra- and peritumoral radscore-based TD and MRI-reported LNM showed good performance for assessing 3-year RFS.

Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation.

cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways-the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway-affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype affects sAC-dependent regulation of melanin synthesis. Although sAC loss of function in wild-type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R nonfunctional human and mouse melanocytes or skin and hair melanin in e/e mice. Interestingly, activation of transmembrane adenylyl cyclases, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC-knockout mice relative to that in sAC wild-type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation.

Development of an aminotransferase-driven biocatalytic cascade for deracemization of d,l-phosphinothricin.

2-oxo-4-[(hydroxy)(methyl)phosphinoyl]butyric acid (PPO) is the essential precursor keto acid for the asymmetric biosynthesis of herbicide l-phosphinothricin (l-PPT). Developing a biocatalytic cascade for PPO production with high efficiency and low cost is highly desired. Herein, a d-amino acid aminotransferase from Bacillus sp. YM-1 (Ym DAAT) with high activity (48.95 U/mg) and affinity (Km = 27.49 mM) toward d-PPT was evaluated. To circumvent the inhibition of by-product d-glutamate (d-Glu), an amino acceptor (α-ketoglutarate) regeneration cascade was constructed as a recombinant Escherichia coli (E. coli D), by coupling Ym d-AAT, d-aspartate oxidase from Thermomyces dupontii (TdDDO) and catalase from Geobacillus sp. CHB1. Moreover, the regulation of the ribosome binding site was employed to overcome the limiting step of expression toxic protein TdDDO in E. coli BL21(DE3). The aminotransferase-driven whole-cell biocatalytic cascade (E. coli D) showed superior catalytic efficiency for the synthesis of PPO from d,l-phosphinothricin (d,l-PPT). It revealed the production of PPO exhibited high space-time yield (2.59 g L-1 h-1 ) with complete conversion of d-PPT to PPO at high substrate concentration (600 mM d,l-PPT) in 1.5 L reaction system. This study first provides the synthesis of PPO from d,l-PPT employing an aminotransferase-driven biocatalytic cascade.

MRI radiomics signature to predict lymph node metastasis after neoadjuvant chemoradiation therapy in locally advanced rectal cancer.

PURPOSE: To investigative the performance of MRI-radiomics analysis derived from T2WI and apparent diffusion coefficients (ADC) images before and after neoadjuvant chemoradiation therapy (nCRT) separately or simultaneously for predicting post-nCRT lymph node status in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Eighty-three patients (training cohort, n = 57; validation cohort, n = 26) with LARC between June 2017 and December 2022 were retrospectively enrolled. All the radiomics features were extracted from volume of interest on T2WI and ADC images from baseline and post-nCRT MRI. Delta-radiomics features were defined as the difference between radiomics features before and after nCRT. Seven clinical-radiomics models were constructed by combining the most predictive radiomics signatures and clinical parameters selected from support vector machine. Receiver operating characteristic curve (ROC) was used to evaluate the performance of models. The optimum model-based LNM was applied to assess 5-years disease-free survival (DFS) using Kaplan-Meier analysis. The end point was clinical or radiological locoregional recurrence or distant metastasis during postoperative follow-up. RESULTS: Clinical-deltaADC radiomics combined model presented good performance for predicting post-CRT LNM in the training (AUC = 0.895,95%CI:0.838-0.953) and validation cohort (AUC = 0.900,95%CI:0.771-1.000). Clinical-deltaADC radiomics-postT2WI radiomics combined model also showed good performances (AUC = 0.913,95%CI:0.838-0.953) in the training and (AUC = 0.912,95%CI:0.771-1.000) validation cohort. As for subgroup analysis, clinical-deltaADC radiomics combined model showed good performance predicting LNM in ypT0-T2 (AUC = 0.827;95%CI:0.649-1.000) and ypT3-T4 stage (AUC = 0.934;95%CI:0.864-1.000). In ypT0-T2 stage, clinical-deltaADC radiomics combined model-based LNM could assess 5-years DFS (P = 0.030). CONCLUSION: Clinical-deltaADC radiomics combined model could predict post-nCRT LNM, and this combined model-based LNM was associated with 5-years DFS in ypT0-T2 stage.