Transformation of a Viral Capsid from Nanocages to Nanotubes and Then to Hydrogels: Redirected Self-Assembly and Effects on Immunogenicity.

The ability to manipulate the self-assembly of proteins is essential to understanding the mechanisms of life and beneficial to fabricating advanced nanomaterials. Here, we report the transformation of the MS2 phage capsid from nanocages to nanotubes and then to nanotube hydrogels through simple point mutations guided by interfacial interaction redesign. We demonstrate that site 70, which lies in the flexible FG loop of the capsid protein (CP), is a "magic" site that can largely dictate the final morphology of assemblies. By varying the amino acid at site 70, with the aid of a cysteine-to-alanine mutation at site 46, we achieved the assembly of double-helical or single-helical nanotubes in addition to nanocages. Furthermore, an additional cysteine substitution on the surface of nanotubes mediated their cross-linking to form hydrogels with reducing agent responsiveness. The hierarchical self-assembly system allowed for the investigation of morphology-related immunogenicity of MS2 CPs, which revealed dramatic differences among nanocages, nanotubes, and nanotube hydrogels in terms of immune response types, antibody levels and T cell functions. This study provides insights into the assembly manipulation of protein nanomaterials and the customized design of nanovaccines and drug delivery systems.

A Self-supervised Learning-Based Fine-Grained Classification Model for Distinguishing Malignant From Benign Subcentimeter Solid Pulmonary Nodules.

RATIONALE AND OBJECTIVES: Diagnosing subcentimeter solid pulmonary nodules (SSPNs) remains challenging in clinical practice. Deep learning may perform better than conventional methods in differentiating benign and malignant pulmonary nodules. This study aimed to develop and validate a model for differentiating malignant and benign SSPNs using CT images. MATERIALS AND METHODS: This retrospective study included consecutive patients with SSPNs detected between January 2015 and October 2021 as an internal dataset. Malignancy was confirmed pathologically; benignity was confirmed pathologically or via follow-up evaluations. The SSPNs were segmented manually. A self-supervision pre-training-based fine-grained network was developed for predicting SSPN malignancy. The pre-trained model was established using data from the National Lung Screening Trial, Lung Nodule Analysis 2016, and a database of 5478 pulmonary nodules from the previous study, with subsequent fine-tuning using the internal dataset. The model's efficacy was investigated using an external cohort from another center, and its accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were determined. RESULTS: Overall, 1276 patients (mean age, 56 ± 10 years; 497 males) with 1389 SSPNs (mean diameter, 7.5 ± 2.0 mm; 625 benign) were enrolled. The internal dataset was specifically enriched for malignancy. The model's performance in the internal testing set (316 SSPNs) was: AUC, 0.964 (95% confidence interval (95%CI): 0.942-0.986); accuracy, 0.934; sensitivity, 0.965; and specificity, 0.908. The model's performance in the external test set (202 SSPNs) was: AUC, 0.945 (95% CI: 0.910-0.979); accuracy, 0.911; sensitivity, 0.977; and specificity, 0.860. CONCLUSION: This deep learning model was robust and exhibited good performance in predicting the malignancy of SSPNs, which could help optimize patient management.

Impaired meningeal lymphatic drainage in Listeria monocytogenes infection.

Previous studies have demonstrated an association between lymphatic vessels and diseases caused by bacterial infections. Listeria monocytogenes (LM) bacterial infection can affect multiple organs, including the intestine, brain, liver and spleen, which can be fatal. However, the impacts of LM infection on morphological and functional changes of lymphatic vessels remain unexplored. In this study, we found that LM infection not only induces meningeal and mesenteric lymphangiogenesis in mice, but also impairs meningeal lymphatic vessels (MLVs)-mediated macromolecules drainage. Interestingly, we found that the genes associated with lymphatic vessel development and function, such as Gata2 and Foxc2, were downregulated, suggesting that LM infection may affect cellular polarization and valve development. On the other hand, photodynamic ablation of MLVs exacerbated inflammation and bacterial load in the brain of mice with LM infection. Overall, our findings indicate that LM infection induces lymphangiogenesis and may affect cell polarization, cavity formation, and valve development during lymphangiogenesis, ultimately impairing MLVs drainage.

Predicting epidermal growth factor receptor mutations in non-small cell lung cancer through dual-layer spectral CT: a prospective study.

OBJECTIVE: To determine whether quantitative parameters of detector-derived dual-layer spectral computed tomography (DLCT) can reliably identify epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with NSCLC who underwent arterial phase (AP) and venous phase (VP) DLCT between December 2021 and November 2022 were subdivided into the mutated and wild-type EGFR groups following EGFR mutation testing. Their baseline clinical data, conventional CT images, and spectral images were obtained. Iodine concentration (IC), iodine no water (INW), effective atomic number (Zeff), virtual monoenergetic images, the slope of the spectral attenuation curve (λHU), enhancement degree (ED), arterial enhancement fraction (AEF), and normalized AEF (NAEF) were measured for each lesion. RESULTS: Ninety-two patients (median age, 61 years, interquartile range [51, 67]; 33 men) were evaluated. The univariate analysis indicated that IC, normalized IC (NIC), INW and ED for the AP and VP, as well as Zeff and λHU for the VP were significantly associated with EGFR mutation status (all p < 0.05). INW(VP) showed the best diagnostic performance (AUC, 0.892 [95% confidence interval {CI}: 0.823, 0.960]). However, neither AEF (p = 0.156) nor NAEF (p = 0.567) showed significant differences between the two groups. The multivariate analysis showed that INW(AP) and NIC(VP) were significant predictors of EGFR mutation status, with the latter showing better performance (p = 0.029; AUC, 0.897 [95% CI: 0.816, 0.951] vs. 0.774 [95% CI: 0.675, 0.855]). CONCLUSION: Quantitative parameters of DLCT can help predict EGFR mutation status in patients with NSCLC. CRITICAL RELEVANCE STATEMENT: Quantitative parameters of DLCT, especially NIC(VP), can help predict EGFR mutation status in patients with NSCLC, facilitating appropriate and individualized treatment for them. KEY POINTS: Determining EGFR mutation status in patients with NSCLC before starting therapy is essential. Quantitative parameters of DLCT can predict EGFR mutation status in NSCLC patients. NIC in venous phase is an important parameter to guide individualized treatment selection for NSCLC patients.

Radiological and clinical features of large consolidative-type pulmonary invasive mucinous adenocarcinoma.

BACKGROUND: This study aimed to investigate the radiological, pathological, and prognostic characteristics of large consolidative-type pulmonary invasive mucinous adenocarcinomas (IMA). METHODS: We retrospectively reviewed 738 patients who confirmed IMA between January 2010 and August 2022, and two radiologists reviewed imaging data to determine subtypes. We included 41 patients with pathologically large consolidative-type IMA. We analyzed their radiological, pathological, and prognostic characteristics. The recurrence-free survival (RFS) and overall survival (OS) were determined using the Kaplan-Meier method. RESULTS: Most lesions were located in the lower lobe, with 46.3% patients showing multiple lesions. Halo, angiogram, vacuole, air bronchogram, and dead branch sign were observed in 97.6%, 73.2%, 63.4%, 61.0%, and 61.0% of the cases, respectively. Unevenly low enhancement was observed in 88.89% of patients. T3 and T4 pathological stages were observed in 50.0% and 30.6% of patients, respectively. Lymph node metastasis was observed in 16.7% patients, with no distant metastasis. Spread-through air spaces and intrapulmonary dissemination were observed in 27.8% and 19.4% patients, respectively. Moreover, Kirsten rat sarcoma viral oncogene mutations were found in 68.6% of cases, and no epidermal growth factor receptor mutations were seen. Among all mutation sites, G12V mutation is the most common, accounting for 40%. The average RFS and OS were 19.4 and 66.4 months, respectively, with 3-year RFS and OS rates of 30.0% and 75.0%, respectively. Pleural invasion and lymph node metastasis were independent risk factors for diagnosis. CONCLUSION: Halo, vacuole, angiogram, and dead branch signs were frequently observed in consolidative-type IMA. Kirsten rat sarcoma viral oncogene mutations are common in consolidative-type IMA, especially site G12V, whereas epidermal growth factor receptor mutations were rare; therefore, gene immunotherapy was more difficult. Most patients were in stage T3-T4; however, lymph node metastasis was rare.

Rapid translocation of NGR proteins driving polarization of PIN-activating D6 protein kinase during root gravitropism.

Root gravitropic bending represents a fundamental aspect of terrestrial plant physiology. Gravity is perceived by sedimentation of starch-rich plastids (statoliths) to the bottom of the central root cap cells. Following gravity perception, intercellular auxin transport is redirected downwards leading to an asymmetric auxin accumulation at the lower root side causing inhibition of cell expansion, ultimately resulting in downwards bending. How gravity-induced statoliths repositioning is translated into asymmetric auxin distribution remains unclear despite PIN auxin efflux carriers and the Negative Gravitropic Response of roots (NGR) proteins polarize along statolith sedimentation, thus providing a plausible mechanism for auxin flow redirection. In this study, using a functional NGR1-GFP construct, we visualized the NGR1 localization on the statolith surface and plasma membrane (PM) domains in close proximity to the statoliths, correlating with their movements. We determined that NGR1 binding to these PM domains is indispensable for NGR1 functionality and relies on cysteine acylation and adjacent polybasic regions as well as on lipid and sterol PM composition. Detailed timing of the early events following graviperception suggested that both NGR1 repolarization and initial auxin asymmetry precede the visible PIN3 polarization. This discrepancy motivated us to unveil a rapid, NGR-dependent translocation of PIN-activating AGCVIII kinase D6PK towards lower PMs of gravity-perceiving cells, thus providing an attractive model for rapid redirection of auxin fluxes following gravistimulation.

Dual-energy CT-based radiomics in predicting EGFR mutation status non-invasively in lung adenocarcinoma.

Objectives: Patients with epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD) can benefit from individualized targeted therapy. This study aims to develop, compare, analyse prediction models based on dual-energy spectral computed tomography (DESCT) and CT-based radiomic features to non-invasively predict EGFR mutation status in LUAD. Materials and methods: Patients with LUAD (n = 175), including 111 patients with and 64 patients without EGFR mutations, were enrolled in the current study. All patients were randomly divided into a training dataset (122 cases) and validation dataset (53 cases) at a ratio of 7:3. After extracting CT-based radiomic, DESCT and clinical features, we built seven prediction models and a nomogram of the best prediction. Receiver operating characteristic (ROC) curves and the mean area under the curve (AUC) values were used for comparisons among the models to obtain the best prediction model for predicting EGFR mutations. Results: The best distinguishing ability is the combined model incorporating radiomic, DESCT and clinical features for predicting the EGFR mutation status with an AUC of 0.86 (95 % CI: 0.79-0.92) in the training group and an AUC value of 0.83 (95 % CI: 0.73, 0.96) in the validation group. Conclusions: Our study provides a predictive nomogram non-invasively with a combination of CT-based radiomic, DESCT and clinical features, which can provide image-based biological information for targeted therapy of LUAD with EGFR mutations.

Development of a combined radiomics and CT feature-based model for differentiating malignant from benign subcentimeter solid pulmonary nodules.

BACKGROUND: We aimed to develop a combined model based on radiomics and computed tomography (CT) imaging features for use in differential diagnosis of benign and malignant subcentimeter (≤ 10 mm) solid pulmonary nodules (SSPNs). METHODS: A total of 324 patients with SSPNs were analyzed retrospectively between May 2016 and June 2022. Malignant nodules (n = 158) were confirmed by pathology, and benign nodules (n = 166) were confirmed by follow-up or pathology. SSPNs were divided into training (n = 226) and testing (n = 98) cohorts. A total of 2107 radiomics features were extracted from contrast-enhanced CT. The clinical and CT characteristics retained after univariate and multivariable logistic regression analyses were used to develop the clinical model. The combined model was established by associating radiomics features with CT imaging features using logistic regression. The performance of each model was evaluated using the area under the receiver-operating characteristic curve (AUC). RESULTS: Six CT imaging features were independent predictors of SSPNs, and four radiomics features were selected after a dimensionality reduction. The combined model constructed by the logistic regression method had the best performance in differentiating malignant from benign SSPNs, with an AUC of 0.942 (95% confidence interval 0.918-0.966) in the training group and an AUC of 0.930 (0.902-0.957) in the testing group. The decision curve analysis showed that the combined model had clinical application value. CONCLUSIONS: The combined model incorporating radiomics and CT imaging features had excellent discriminative ability and can potentially aid radiologists in diagnosing malignant from benign SSPNs. RELEVANCE STATEMENT: The model combined radiomics features and clinical features achieved good efficiency in predicting malignant from benign SSPNs, having the potential to assist in early diagnosis of lung cancer and improving follow-up strategies in clinical work. KEY POINTS: • We developed a pulmonary nodule diagnostic model including radiomics and CT features. • The model yielded the best performance in differentiating malignant from benign nodules. • The combined model had clinical application value and excellent discriminative ability. • The model can assist radiologists in diagnosing malignant from benign pulmonary nodules.

Diagnostic performance of a deep learning-based method in differentiating malignant from benign subcentimeter (≤10 mm) solid pulmonary nodules.

Background: This study assessed the diagnostic performance of a deep learning (DL)-based model for differentiating malignant subcentimeter (≤10 mm) solid pulmonary nodules (SSPNs) from benign ones in computed tomography (CT) images compared against radiologists with 10 and 15 years of experience in thoracic imaging (medium-senior seniority). Methods: Overall, 200 SSPNs (100 benign and 100 malignant) were retrospectively collected. Malignancy was confirmed by pathology, and benignity was confirmed by follow-up or pathology. CT images were fed into the DL model to obtain the probability of malignancy (range, 0-100%) for each nodule. According to the diagnostic results, enrolled nodules were classified into benign, malignant, or indeterminate. The accuracy and diagnostic composition of the model were compared with those of the radiologists using the McNemar-Bowker test. Enrolled nodules were divided into 3-6-, 6-8-, and 8-10-mm subgroups. For each subgroup, the diagnostic results of the model were compared with those of the radiologists. Results: The accuracy of the DL model, in differentiating malignant and benign SSPNs, was significantly higher than that of the radiologists (71.5% vs. 38.5%, P<0.001). The DL model reported more benign or malignant deterministic results and fewer indeterminate results. In subgroup analysis of nodule size, the DL model also yielded higher performance in comparison with that of the radiologists, providing fewer indeterminate results. The accuracy of the two methods in the 3-6-, 6-8-, and 8-10-mm subgroups was 75.5% vs. 28.3% (P<0.001), 62.0% vs. 28.2% (P<0.001), and 77.6% vs. 55.3% (P=0.001), respectively, and the indeterminate results were 3.8% vs. 66.0%, 8.5% vs. 66.2%, and 2.6% vs. 35.5% (all P<0.001), respectively. Conclusions: The DL-based method yielded higher performance in comparison with that of the radiologists in differentiating malignant and benign SSPNs. This DL model may reduce uncertainty in diagnosis and improve diagnostic accuracy, especially for SSPNs smaller than 8 mm.

ZNT1 and Zn 2+ control TLR4 and PD-L1 endocytosis in macrophages to improve chemotherapy efficacy against liver tumor.

BACKGROUND AND AIMS: HCC is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc (Zn) deficiency. This study aims to understand how Zn could affect macrophage function and its application for HCC therapy. APPROACH AND RESULTS: Zn 2+ and the Zn transporter 1 (ZNT1, solute carrier family 30 member 1) were markedly reduced in intrahepatic macrophages from patients with HCC and from mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in patients with HCC. Critically, ZNT1 regulated endosomal Zn 2+ levels for endocytosis of toll-like receptor 4 and programmed cell death ligand 1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, Zn supplementation could reduce inflammation and surface programmed cell death ligand 1 expression in macrophages with the increased CD8 + T cell cytotoxicity, which synergized the antitumor efficacy of Sorafenib/Lenvatinib. CONCLUSIONS: Our study proposes a new concept that ZNT1 and Zn regulate endosome endocytosis to maintain surface receptors, and Zn supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing programmed cell death ligand 1 + myeloid cells.

Investigating the influence of bentonite colloids on strontium sorption in granite under various hydrogeochemical conditions.

The disposal of high-level radioactive waste in deep geological repositories is a critical environmental issue. The presence of bentonite colloids generated in the engineering barrier can significantly impact the transport of radionuclides, but their effect on radionuclide sorption in granite remains poorly understood. This study aimed to investigate the sorption characteristics of strontium (Sr) on granite as well as on the coexistence system of granite and colloids under various hydrogeochemical conditions, through batch experiments. Fourier transform infrared spectroscopy was employed to analyze the sorption forms of Sr on granite before and after sorption. Several hydrogeochemical factors were examined, including contact time, pH, ionic strength, coexisting ions, and bentonite and humic acid colloid concentration. Among these factors, the concentration of bentonite colloids exhibited a significant effect on Sr sorption. Within a specific range of colloid concentration, the sorption of Sr on the solid system increased linearly with the bentonite colloid concentration. pH and ionic strength were also found to play crucial roles in the sorption process. At low pH, Sr sorption primarily occurred through the outer sphere's surface complexation and Na+/H+ ion exchange. However, at high pH, inner sphere surface complexation dominated the process. As the ionic strength increased, electrostatic repulsion gradually increased, resulting in fewer binding sites for particle aggregation and Sr sorption on bentonite colloids. The results also indicate that with increasing pH, the predominant forms of Sr in the solution transitioned from SrHCO3+ and SrCl+ to SrCO3 and SrCl+. This was mainly due to the ion exchange of Ca2+/Mg2+ in plagioclase and biotite, forming SrCO3 precipitation. These findings provide valuable insights into the transport behavior of radionuclides in the subsurface environment of the repository and highlight the importance of considering bentonite colloids and other hydrogeochemical factors when assessing the environmental impact of high-level radioactive waste disposal.

Tale of cAMP as a second messenger in auxin signaling and beyond.

The 3',5'-cyclic adenosine monophosphate (cAMP) is a versatile second messenger in many mammalian signaling pathways. However, its role in plants remains not well-recognized. Recent discovery of adenylate cyclase (AC) activity for transport inhibitor response 1/auxin-signaling F-box proteins (TIR1/AFB) auxin receptors and the demonstration of its importance for canonical auxin signaling put plant cAMP research back into spotlight. This insight briefly summarizes the well-established cAMP signaling pathways in mammalian cells and describes the turbulent and controversial history of plant cAMP research highlighting the major progress and the unresolved points. We also briefly review the current paradigm of auxin signaling to provide a background for the discussion on the AC activity of TIR1/AFB auxin receptors and its potential role in transcriptional auxin signaling as well as impact of these discoveries on plant cAMP research in general.

The Oxysterol Receptor EBI2 Links Innate and Adaptive Immunity to Limit IFN Response and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid and cholesterol metabolism is linked together with type I interferon (IFN-I) signaling in the regulation of the pathogenesis of SLE. Here, a metabonomic analysis is performed and increased plasma concentrations of oxysterols, especially 7α, 25-dihydroxycholesterol (7α, 25-OHC), are identified in SLE patients. The authors find that 7α, 25-OHC binding to its receptor Epstein-Barr virus-induced gene 2 (EBI2) in macrophages can suppress STAT activation and the production of IFN-ß, chemokines, and cytokines. Importantly, monocytes/macrophages from SLE patients and mice show significantly reduced EBI2 expression, which can be triggered by IFN-γ produced in activated T cells. Previous findings suggest that EBI2 enhances immune cell migration. Opposite to this effect, the authors demonstrate that EBI2-deficient macrophages produce higher levels of chemokines and cytokines, which recruits and activates myeloid cells,T and B lymphocytes to exacerbate tetramethylpentadecane-induced SLE. Together, via sensing the oxysterol 7α, 25-OHC, EBI2 in macrophages can modulate innate and adaptive immune responses, which may be used as a potential diagnostic marker and therapeutic target for SLE.

VEGFR-3 signaling restrains the neuron-macrophage crosstalk during neurotropic viral infection.

Upon recognizing danger signals produced by virally infected neurons, macrophages in the central nervous system (CNS) secrete multiple inflammatory cytokines to accelerate neuron apoptosis. The understanding is limited about which key effectors regulate macrophage-neuron crosstalk upon infection. We have used neurotropic-virus-infected murine models to identify that vascular endothelial growth factor receptor 3 (VEGFR-3) is upregulated in the CNS macrophages and that virally infected neurons secrete the ligand VEGF-C. When cultured with VEGF-C-containing supernatants from virally infected neurons, VEGFR-3+ macrophages suppress tumor necrosis factor α (TNF-α) secretion to reduce neuron apoptosis. Vegfr-3ΔLBD/ΔLBD (deletion of ligand-binding domain in myeloid cells) mice or mice treated with the VEGFR-3 kinase inhibitor exacerbate the severity of encephalitis, TNF-α production, and neuron apoptosis post Japanese encephalitis virus (JEV) infection. Activating VEGFR-3 or blocking TNF-α can reduce encephalitis and neuronal damage upon JEV infection. Altogether, we show that the inducible VEGF-C/VEGFR-3 module generates protective crosstalk between neurons and macrophages to alleviate CNS viral infection.

Longitudinal assessment of cardiac parameters through MRI in breast cancer patients treated with anti-HER2 therapy.

BACKGROUND: We evaluated the early changes in left ventricular (LV) volumetric, functional, and tissue characteristics in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients treated with trastuzumab and/or pertuzumab at cardiac magnetic resonance imaging (MRI). METHODS: HER2-positive breast cancer patients undergoing planned anti-HER2 therapy and nonanthracycline-based chemotherapy were enrolled and subdivided into dual anti-HER2 (trastuzumab plus pertuzumab) group and trastuzumab group. Cardiac MRI was performed before treatment and three months after starting, covering ventricular volumes, cardiac function, systolic myocardial strain, myocardial oedema, and T1 and T2 relaxation times. Cardiac dysfunction was primarily defined as a > 10% reduction in LV ejection fraction (LVEF) to < 55% and/or a > 15% global longitudinal strain (GLS) change at the follow-up MRI examination. RESULTS: Twenty-four HER2-positive patients were evaluated (16 in the dual anti-HER2 group, 8 in the trastuzumab group). Six patients developed cardiac dysfunction at follow-up, five of them in the dual anti-HER2 group. One patient developed symptomatic heart failure, and five patients developed asymptomatic cardiac dysfunction. Patients displayed significantly decreased systolic function and increased T1 and T2 relaxation time at follow-up (p ≤ 0.031). Systolic dysfunction remained significant in the dual anti-HER2 group. The decrease in GLS in the trastuzumab group was not significant (p = 0.169). T1 and T2 relaxation times tended to increase, but this was not significant at subgroup analysis. CONCLUSIONS: Cardiac MRI scans showed frequent signs of subclinical cardiotoxicity after short-term anti-HER2 therapy and nonanthracycline-based chemotherapy; the effect was slightly stronger in patients treated with dual therapy. KEY POINTS: • A frequent subclinical cardiotoxicity was detected by cardiac magnetic resonance imaging after short-term anti-human epidermal growth factor receptor 2 (HER2) therapy. • The change in myocardial strain was more marked in patients treated with dual (trastuzumab plus pertuzumab) than with trastuzumab only anti-HER2 therapy. • Cardiotoxicity surveillance through MRI is an interesting option particularly in patients treated with dual anti-HER2 therapy.

Upscaling dispersivity for conservative solute transport in naturally fractured media.

Physical heterogeneities are prevalent features of fracture systems and significantly impact transport processes in aquifers across different spatiotemporal scales. Upscaling solute transport parameter is an effective way of quantifying parameter variability in heterogeneous aquifers including fractured media. This paper develops conceptual models for upscaling conservative transport parameters in fracture media. The focus is on upscaling dispersivity. Lagrangian-based transport model (LBTM) for dispersivity upscaling are derived for the solute transport in two-dimensional fractures surrounded by an impermeable matrix. The LBTM is validated against the random walk particle tracking (RWPT) model, which enables highly efficient and accurate predictions of conservative solute transport. The results show that the derived scale-dependent analytical expressions are in excellent agreement with RWPT model results. In addition, LBTM results are also compared to experimental results from the observed breakthrough curve of a conservative solute transport through a single natural fracture within a granite core. Comparing results from the LBTM and transport experiment shows that LBTM based estimated dispersivity is 10.55% higher than the measured value. Errors introduced by the experiments, the conceptual assumptions in deriving models, and the heterogeneities of fracture apertures not fully sampled by measuring instruments are main factor for such discrepancy. The sensitivity analysis indicates that the longitudinal and transverse dispersivities are positively related to the integral scale and the variance of the log-fracture aperture. The longitudinal dispersivity is strongly contolled by the variance of the log-fracture aperture. The LBTM may be useful for directly predicting solute transports, requiring only the acquisition of fractured geostatistical data. This work provides a better understanding of transport processes in fractured media which ultimately control water quality across scales.

Adenylate cyclase activity of TIR1/AFB auxin receptors in plants.

The phytohormone auxin is the major coordinative signal in plant development1, mediating transcriptional reprogramming by a well-established canonical signalling pathway. TRANSPORT INHIBITOR RESPONSE 1 (TIR1)/AUXIN-SIGNALING F-BOX (AFB) auxin receptors are F-box subunits of ubiquitin ligase complexes. In response to auxin, they associate with Aux/IAA transcriptional repressors and target them for degradation via ubiquitination2,3. Here we identify adenylate cyclase (AC) activity as an additional function of TIR1/AFB receptors across land plants. Auxin, together with Aux/IAAs, stimulates cAMP production. Three separate mutations in the AC motif of the TIR1 C-terminal region, all of which abolish the AC activity, each render TIR1 ineffective in mediating gravitropism and sustained auxin-induced root growth inhibition, and also affect auxin-induced transcriptional regulation. These results highlight the importance of TIR1/AFB AC activity in canonical auxin signalling. They also identify a unique phytohormone receptor cassette combining F-box and AC motifs, and the role of cAMP as a second messenger in plants.

Micronodular thymoma with lymphoid stroma: Contrast-enhanced CT features with histopathological correlation in 10 patients.

Objectives: This study aimed to evaluate and summarize the contrast-enhanced computed tomography (CECT) imaging features of micronodular thymoma with lymphoid stroma (MTWLS) based on all MTWLS patients at our institution and was the first imaging study of MTWLS worldwide. Methods: This retrospective study included 10 MTWLS patients who underwent CECT between April 2012 and November 2021. We collected and analyzed the CECT imaging features, including the location, size, shape, tumor density, classification, and CT value of the solid component. Descriptive statistical analysis was performed using the SPSS software (version 26.0; IBM). Results: Ten patients (five males [50%], five females [50%]; median age, 61.4 years; range, 54-72 years) underwent CECT. Of the 10 cases, one case was purely cystic, seven cases were cystic-solid, and two cases were purely solid. Six cases were round/oval in shape, and four cases were irregularly shaped. Excluding a purely cystic tumor with an unmeasurable degree of enhancement, two cases showed moderate enhancement, and seven cases showed significant enhancement. Among the solid or cystic-solid cases, the mean CT value of the measurable solid component on the enhanced scan was 93.9 HU. Nine masses were located adjacent to the mediastinal pleura, pericardium, or large vessels. Additionally, there were no malignant tumor signs in any patient, including penetration of the mediastinal pleura or involvement of the pericardium, pleural effusion, elevation of the diaphragm, or direct vascular invasion. Conclusion: MTWLS demonstrates certain features on CECT, such as a high rate of cystic change, significant solid component enhancement, and no malignant, invasive imaging features. These CECT features are helpful for diagnosing MTWLS.

Meningeal lymphatic vessels mediate neurotropic viral drainage from the central nervous system.

Recent studies have demonstrated that brain meningeal lymphatic vessels (MLVs) act as a drainage path directly into the cervical lymph nodes (CLNs) for macromolecules contained in the cerebrospinal fluid (CSF). However, the role of MLVs during CNS viral infection remains unexplored. Here, we found that infection with several neurotropic viruses in mice promotes MLV expansion but also causes impaired MLV-mediated drainage of macromolecules. Notably, MLVs could drain virus from the CNS to CLNs. Surgical ligation of the lymph vessels or photodynamic ablation of dorsal MLVs increased neurological damage and mortality of virus-infected mice. By contrast, pretreatment with vascular endothelial growth factor C promoted expansion of functional MLVs and alleviated the effects of viral infection. Together, these data indicate that functional MLVs facilitate virus clearance, and MLVs represent a critical path for virus spreading from the CNS to the CLNs. MLV-based therapeutic strategies may thus be useful for alleviating infection-induced neurological damage.