A common transcriptional mechanism involving R-loop and RNA abasic site regulates an enhancer RNA of APOE.

RNA is modified by hundreds of chemical reactions and folds into innumerable shapes. However, the regulatory role of RNA sequence and structure and how dysregulation leads to diseases remain largely unknown. Here, we uncovered a mechanism where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We found an enhancer RNA, AANCR, that regulates the transcription and expression of apolipoprotein E (APOE). In some human cells such as fibroblasts, AANCR is folded into an R-loop and modified by N-glycosidic cleavage; in this form, AANCR is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in other cell types including hepatocytes and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. DNA sequence variants in AANCR are associated significantly with APOE expression and Alzheimer's Disease, thus AANCR is a modifier of Alzheimer's Disease. Besides AANCR, thousands of noncoding RNAs are regulated by abasic sites in R-loops. Together our data reveal the essentiality of the folding and modification of RNA in cellular regulation and demonstrate that dysregulation underlies common complex diseases such as Alzheimer's disease.

A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia.

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) type 2, caused by MDS1 and EVI1 complex locus (MECOM) gene mutations, is a rare inherited bone marrow failure syndrome (IBMFS) with skeletal anomalies, characterized by varying presentation of congenital thrombocytopenia (progressing to pancytopenia), bilateral proximal radioulnar synostosis, and other skeletal abnormalities. Due to limited knowledge and heterogenous manifestations, clinical diagnosis of the disease is challenging. Here we reported a novel MECOM mutation in a Chinese boy with typical clinical features for RUSAT-2. Trio-based whole exome sequencing of buccal swab revealed a novel heterozygous missense mutation in exon 11 of the MECOM gene (chr3:168818673; NM_001105078.3:c.2285G > A). The results strongly suggest that the variant was a germline mutation and disease-causing mutation. The patient received matched unrelated donor hematopoetic stem cell transplantation (HSCT). This finding was not only expanded the pathogenic mutation spectrum of MECOM gene, but also provided key information for clinical diagnosis and treatment of RUSAT-2.

Total and simulated keratometry measurements using IOLMaster 700 and Pentacam AXL after small incision lenticule extraction.

PURPOSE: Calculating the intraocular lens (IOL) in patients after corneal refractive surgery presents a challenge. Because an overestimation of corneal power in cases undergone this surgery leading to a subsequent under-correction of IOL power. However, recent advancements in technology have eliable measurement of total corneal power. The aim of this research was to assess the agreement in simulated keratometry (SimK) and total keratometry (TK) values between IOLMaster 700 and Pentacam AXL. METHODS: The study involved 99 patients (99 eyes) undergone small incision lenticule extraction (SMILE) surgery. Each patient underwent scans using IOL Master 700 and Pentacam AXL. The following parameters were recorded: SimK1, SimK2, Total K1 (TK1), and Total K2 (TK2) for IOLMaster 700; and SimK1, SimK2, True Net Power (TNP) K1, TNPK2, Total Corneal Refractive Power (TCRP) K1, and TCRP K2 for Pentacam AXL. Agreement between the two devices was evaluated using Bland-Altman plot, while paired t-test was utilized to compare any differences in the same parameter by both instruments. RESULTS: The results revealed a strong correlation between the two devices.Noticeable comparability was identified for all SimK variables. However, there were noticeable differences in TK measurements as well as TK1-TNPK1, TK2-TNP K2, TK1-TCRP K1, and TK2-TCRP K2 parameters when comparing the two devices. The IOLMaster 700 consistently measured steeper values than the Pentacam AXL, with significant and clinically relevant differences of 1.34, 1.37, 0.87, and 0.95 diopters, respectively. CONCLUSION: While there was a noticeable correlation between the IOLMaster 700 and Pentacam AXL in SimK measurements, a marked difference was noted in TK values. The two devices cannot be used interchangeably when quantifying TK values.

Inhaled Lipid Nanoparticles Alleviate Established Pulmonary Fibrosis.

Pulmonary fibrosis, a sequela of lung injury resulting from severe infection such as severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) infection, is a kind of life-threatening lung disease with limited therapeutic options. Herein, inhalable liposomes encapsulating metformin, a first-line antidiabetic drug that has been reported to effectively reverse pulmonary fibrosis by modulating multiple metabolic pathways, and nintedanib, a well-known antifibrotic drug that has been widely used in the clinic, are developed for pulmonary fibrosis treatment. The composition of liposomes made of neutral, cationic or anionic lipids, and poly(ethylene glycol) (PEG) is optimized by evaluating their retention in the lung after inhalation. Neutral liposomes with suitable PEG shielding are found to be ideal delivery carriers for metformin and nintedanib with significantly prolonged retention in the lung. Moreover, repeated noninvasive aerosol inhalation delivery of metformin and nintedanib loaded liposomes can effectively diminish the development of fibrosis and improve pulmonary function in bleomycin-induced pulmonary fibrosis by promoting myofibroblast deactivation and apoptosis, inhibiting transforming growth factor 1 (TGFß1) action, suppressing collagen formation, and inducing lipogenic differentiation. Therefore, this work presents a versatile platform with promising clinical translation potential for the noninvasive inhalation delivery of drugs for respiratory disease treatment.

Comparative analysis of ultrasonic elastosonography and contrast-enhanced ultrasonography in the diagnosis of benign and malignant intraocular tumors.

PURPOSE: To compare the diagnostic value of ultrasonic elastosonography (UE) and contrast-enhanced ultrasonography (CEUS) for benign and malignant intraocular tumors. METHODS: This retrospective study enrolled patients with intraocular tumors at Beijing Tongren Hospital, Capital Medical University (August 2016 to January 2020). The strain rate ratio (strain rate of tumor tissue divided by strain rate of surrounding normal tissue) was measured by UE. CEUS was performed using SonoVue® contrast agent. The performance of each method at differentiating benign from malignant intraocular tumors was evaluated by receiver operating characteristic curve analysis. RESULTS: The analysis included 147 eyes in 145 patients (45.6 ± 13.4 years-old; 66 males): 117 patients (119 eyes) with malignant tumors and 28 patients (28 eyes) with benign tumors. At an optimal cutoff of 22.67 for the strain rate ratio, UE distinguished benign from malignant tumors with a sensitivity of 86.6% and a specificity of 96.4%. CEUS showed that 117 eyes with malignant tumors had a fast-in, fast-out time-intensity curve, and only two eyes with malignant tumors had a fast-in, slow-out curve, while all 28 eyes with benign tumors had a fast-in, slow-out curve. CEUS differentiated benign from malignant tumors with a sensitivity of 98.3% and a specificity of 100%. The diagnostic results differed significantly between the two methods (P = 0.004, McNemar test). The diagnostic performances of the two tests were moderately consistent (κ = 0.657, P < 0.001). CONCLUSION: Both CEUS and UE have good diagnostic value in the differentiation of benign intraocular tumors from malignant intraocular tumors.

RNA abasic sites in yeast and human cells.

RNA abasic sites and the mechanisms involved in their regulation are mostly unknown; in contrast, DNA abasic sites are well-studied. We found surprisingly that, in yeast and human cells, RNA abasic sites are prevalent. When a base is lost from RNA, the remaining ribose is found as a closed-ring or an open-ring sugar with a reactive C1' aldehyde group. Using primary amine-based reagents that react with the aldehyde group, we uncovered evidence for abasic sites in nascent RNA, messenger RNA, and ribosomal RNA from yeast and human cells. Mass spectroscopic analysis confirmed the presence of RNA abasic sites. The RNA abasic sites were found to be coupled to R-loops. We show that human methylpurine DNA glycosylase cleaves N-glycosidic bonds on RNA and that human apurinic/apyrimidinic endonuclease 1 incises RNA abasic sites in RNA-DNA hybrids. Our results reveal that, in yeast and human cells, there are RNA abasic sites, and we identify a glycosylase that generates these sites and an AP endonuclease that processes them.

Analysis of the relationship between lens morphology and aberrations in patients with myopia: a cross-sectional study.

PURPOSE: To investigate the relationship between lens morphology and aberrations in patients with myopia. METHODS: This cross-sectional study included 155 patients with myopia in their right eyes. Spherical power and cylindrical power were achieved by cycloplegic autorefraction. The eyes were divided into three groups for analysis based on their spherical equivalent (SE) values. The 4 mm and 6 mm ocular and internal aberrations were measured using the OPD-scan III. Lens parameters were measured using CASIA2, including lens thickness (LT), radius of anterior/posterior lens surface curvature (RAL/RPL), lens decentration (DEC), and lens tilt (TILT). The differences of lenticular parameters and aberration parameters among the three groups analyzed with ANOVA or Kruskal Wallis test. Pearson correlation or Spearman correlation analysis was performed to evaluate the relationships between the lens parameters and aberrations. A p value < 0.05 indicated statistical significance. RESULTS: The difference in LT, RAL, DEC and TITL among the three groups was statistically significant (p < 0.05). And there were differences among differences in internal high-order aberrations, spherical aberration, and coma aberration(p < 0.05).Spherical power was positively correlated with LT and TITL (p < 0.05) and negatively correlated with DEC, RAL, and RPL (p < 0.05). Cylindrical power was positively correlated with LT (p < 0.05) and negatively correlated DEC (p < 0.05); The lenticular parameters (LT, RAL, DEC, and TILT) were mainly correlated with the ocular and internal spherical aberration. LT and DEC were correlated with ocular and internal higher-order aberrations and coma aberration. CONCLUSION: DEC and LT were the main factors affecting aberrations in patients with myopia.

Quantitative Analysis of Perfusion Characteristics Using Contrast-Enhanced Ultrasound in Patients with Choroidal Metastasis.

PURPOSE: The aim of the study was to quantitatively analyze the perfusion characteristics of choroidal metastasis using contrast-enhanced ultrasound (CEUS) and compare its perfusion characteristics with these of choroidal hemangioma and choroidal melanoma. METHODS: The patients who were clinically diagnosed with choroidal metastasis were classified as the study group, and the patients who were diagnosed with choroidal hemangioma and choroidal melanoma during the same period were classified as the comparison group. All patients underwent CEUS examination, and Sonoliver was used to obtain the data on quantitative parameters of the tumor and the adjacent normal orbital tissues, including maximum of intensity (IMAX), rise time (RT), time to peak (TTP), and mean transit time (mTT). Wilcoxon signed rank test was performed to compare the quantitative parameters of choroidal metastasis and normal orbital tissues. Kruskal-Wallis test was adopted to compare the quantitative parameters of the 3 types of tumors, and Bonferroni was used to correct the results of the multiple comparisons. Receiver operating characteristic (ROC) curve analysis was used to identify valuable parameters. RESULTS: Twenty-six patients (26 eyes) with choroidal metastasis, 55 patients (55 eyes) with choroidal hemangioma, and 49 patients (49 eyes) with choroidal melanoma were enrolled in this study. The IMAX of choroidal metastasis was significantly higher than that of normal orbital tissues, while RT, TTP, and mTT were significantly shorter than these of normal orbital tissues (all p values were <0.001). The IMAX of choroidal metastasis was lower than that of choroidal hemangioma, and RT, TTP, and mTT were shorter than these of choroidal hemangioma and choroidal melanoma (p = 0.002, p = 0.004, p = 0.007). ROC curve analysis showed that areas under the ROC curves (AUCs) of RT and mTT (AUC = 0.851, 95% CI 0.783-0.918 and 0.849, 95% CI 0.783-0.915) were larger. CONCLUSION: Quantitative analysis with CEUS can reflect the perfusion characteristics of choroidal metastasis and can exhibit the difference between its perfusion characteristics and these of choroidal hemangioma and choroidal melanoma. RT and mTT may serve as useful parameters for differentiating choroidal metastasis from choroidal hemangioma and choroidal melanoma.

Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4.

OBJECTIVE: To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants. METHODS: Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual-energy x-ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. RESULTS: We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R2 = 0.35, p = 0.01; lower leg fat fraction R2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. INTERPRETATION: We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R-loop levels in patient-derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547-555.

[Genetic analysis of a child with co-commitment progressive multifocal leukoencephalopathy and X-linked hyper IgM syndrome].

OBJECTIVE: To detect variant of the CD40L gene and infection of Jamestown Canyon virus (JCV) in a 7-year-and-9-month-old boy with co-commitment progressive multifocal leukoencephalopathy (PML) and X-linked hyper IgM syndrome (XHIGM). METHODS: Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA. The 5 exons and exon/intronic boundaries of the CD40L gene were subjected to PCR amplification and sequencing. Suspected variants were analyzed by using bioinformatic software. The JCV gene was amplified from genomic DNA by nested PCR and sequenced. RESULTS: The child was found to harbor a hemizygous c.506 A>C (p.Y169S) missense variant in exon 5 of the CD40L gene. The variant may affect the TNFH domain of the CD40L protein and result in structural instability and loss of hydrophobic interaction between CD40L and CD40. As predicted by PolyPhen2 and SIFT software, the variant was probably damaging (score = 1.00) and deleterious (score= -8.868). His mother was found to be a heterozygous carrier, while the same variant was not found in his father. Gel electrophoresis of the nested PCR product revealed presence of target JCV band, which was confirmed to be 99% identical with the JCV gene by sequencing. CONCLUSION: The patient was diagnosed with co-commitment XHIGM and PML based on the testing of the CD40L gene and JCV infection.

Straightforward Approach toward Multifunctionalized Aziridines via Catalyst-Free Three-Component Reactions of α-Diazoesters, Nitrosoarenes, and Alkynes.

A straightforward, catalyst-free atom- and step-economical approach for the synthesis of multisubstituted 1-arylaziridine-2-carboxylates via one-pot three-component reactions of α-diazoesters, nitrosoarenes, and alkynes has been described. This method could provide facile access to a variety of multifunctionalized aziridines in up to 91% yields under mild reaction conditions and features the catalyst-free strategy and use of cheap and readily accessible starting materials.

KOAc-Catalyzed One-Pot Three-Component 1,3-Dipolar Cycloaddition of α-Diazo Compounds, Nitrosoarenes, and Alkenes: An Approach to Functionalized Isoxazolidines.

A direct, highly efficient KOAc-catalyzed one-pot three-component approach for the preparation of various functionalized isoxazolidines via the 1,3-dipolar cycloaddition reactions of readily accessible diazo compounds, nitrosoarenes, and alkenes has been reported. The cheap and readily available catalyst and starting materials, excellent functional group compatibility, wide substrate scope, high yields, and excellent chemo-, regio-, and diastereoselectivities make this protocol an attractive alternative.

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer.

BACKGROUND: Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity. OBJECTIVE: The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment. METHODS: Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours. RESULTS: Depletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner. CONCLUSION: Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.

The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation.

It is now well accepted that protease activated receptor (PAR) 1 and PAR4 have differential roles in platelet activation. PAR4, a low-affinity thrombin receptor in human platelets, participates in sustained platelet activation in a P2Y12-dependent manner; however, the mechanisms are not defined. Our previous studies demonstrated that thrombin induces the association of PAR4 with P2Y12, together with arrestin recruitment to the complex. Here we show that PAR4 and P2Y12 directly interact to coregulate Akt signaling after PAR4 activation. We observed direct and specific interaction of P2Y12 with PAR4 but not PAR1 by bioluminescent resonance energy transfer when the receptors were coexpressed in human embryonic kidney 293T cells. PAR4-P2Y12 dimerization was promoted by PAR4-AP and inhibited by P2Y12 antagonist. By using sequence comparison of the transmembrane domains of PAR1 and PAR4, we designed a mutant form of PAR4, "PAR4SFT," by replacing LGL194-196 at the base of transmembrane domain 4 with the corresponding aligned PAR1 residues SFT 220-222. PAR4SFT supported only 8.74% of PAR4-P2Y12 interaction, abolishing P2Y12-dependent arrestin recruitment to PAR4 and Akt activation. Nonetheless, PAR4SFT still supported homodimerization with PAR4. PAR4SFT failed to induce a calcium flux when expressed independently; however, coexpression of increasing concentrations of PAR4SFT, together with PAR4 potentiated PAR4-mediated calcium flux, suggested that PAR4 act as homodimers to signal to Gq-coupled calcium responses. In conclusion, PAR4 LGL (194-196) governs agonist-dependent association of PAR4 with P2Y12 and contributes to Gq-coupled calcium responses. PAR4-P2Y12 association supports arrestin-mediated sustained signaling to Akt. Hence, PAR4-P2Y12 dimerization is likely to be important for the PAR4-P2Y12 dependent stabilization of platelet thrombi.

Creation of signatures and identification of molecular subtypes based on disulfidptosis-related genes for glioblastoma patients' prognosis and immunological activity.

BACKGROUND: In recent times, disulfidptosis, an intricate form of cellular demise, has garnered attention due to its impact on prognosis, tumor progression and treatment response. Nevertheless, the exact significance of disulfidptosis-related genes (DisRGs) in glioblastoma (GBM) remains enigmatic. METHODS: The GEO and TCGA databases provided transcriptional and clinically relevant data on tumor samples, while the GTEx database provided data on healthy tissues. Disulfidptosis-related genes (DisRGs) were procured from previous scholarly investigations. The expression profile of DisRGs was initially scrutinized among patients diagnosed with GBM, subsequent to which their prognostic value was explored. Through consensus clustering, we constructed DisRGs-related clusters and gene subtypes. Our results established that the DisRG-related clusters had differentially expressed genes, resulting in a DisulfidptosisScore model, which had a positive prognostic value. RESULTS: The differential expression profile of 24 DisRGs between GBM samples and healthy samples was acquired. Through consensus cluster analysis, two distinct disulfidptosis subtypes, namely DisRGcluster A and DisRGcluster B, were identified. Then, the DisulfidptosisScore model including 4 characteristic genes was constructed.Notably, patients with GBM assigned with lower score demonstrated a considerably longer overall survival (OS) compared to those with higher score. CONCLUSION: We have effectively devised a prognostic model associated with disulfidptosis, presenting autonomous prognostic predictions for patients with GBM. These findings serve as a valuable addition to the current comprehension of disulfidptosis and offer fresh theoretical substantiation for the development of enhanced treatment strategies.

Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging.

ABSTRACT: Cancer and other acute and chronic diseases are results of perturbations of common molecular determinants in key biological and signaling processes. Imaging is critical for characterizing dynamic changes in tumors and metastases, the tumor microenvironment, tumor-stroma interactions, and drug targets, at multiscale levels. Magnetic resonance imaging (MRI) has emerged to be a primary imaging modality for both clinical and preclinical applications due to its advantages over other modalities, including sensitivity to soft tissues, nondepth limitations, and the use of nonionizing radiation. However, extending the application of MRI to achieve both qualitative and quantitative precise molecular imaging with the capability to quantify molecular biomarkers for early detection, staging, and monitoring therapeutic treatment requires the capacity to overcome several major challenges including the trade-off between metal-binding affinity and relaxivity, which is an issue frequently associated with small chelator contrast agents. In this review, we will introduce the criteria of ideal contrast agents for precision molecular imaging and discuss the relaxivity of current contrast agents with defined first shell coordination water molecules. We will then report our advances in creating a new class of protein-targeted MRI contrast agents (ProCAs) with contributions to relaxivity largely derived from the secondary sphere and correlation time. We will summarize our rationale, design strategy, and approaches to the development and optimization of our pioneering ProCAs with desired high relaxivity, metal stability, and molecular biomarker-targeting capability, for precision MRI. From first generation (ProCA1) to third generation (ProCA32), we have achieved dual high r1 and r2 values that are 6- to 10-fold higher than clinically approved contrast agents at magnetic fields of 1.5 T, and their relaxivity values at high field are also significantly higher, which enables high resolution during small animal imaging. Further engineering of multiple targeting moieties enables ProCA32 agents that have strong biomarker-binding affinity and specificity for an array of key molecular biomarkers associated with various chronic diseases, while maintaining relaxation and exceptional metal-binding and selectivity, serum stability, and resistance to transmetallation, which are critical in mitigating risks associated with metal toxicity. Our leading product ProCA32.collagen has enabled the first early detection of liver metastasis from multiple cancers at early stages by mapping the tumor environment and early stage of fibrosis from liver and lung in vivo, with strong translational potential to extend to precision MRI for preclinical and clinical applications for precision diagnosis and treatment.

[Characteristics of choroidal melanoma in contrast-enhanced ultrasonography].

OBJECTIVE: To investigate the characteristics of choroidal melanoma in contrast-enhanced ultrasonography. METHODS: Case-control study.From October 2007 to December 2008, 21 choroidal melanoma patients (21 eyes) were treated in Beijing Tongren Hospital,including 13 males and 8 females with average age at 57 years (ranged from 18 to 76 years).Fourteen cases (14 eyes) of choroidal hemangioma treated during the same period, including 9 males and 5 females, with average age at 51 years(ranged from 24 to 71 years) were selected for the comparison.All patients were examined with contrast-enhance ultrasound, the contrast agent (sulfur hexafluoride) was injected into elbow vein,continuous recording of contrast agent in the lesions was conducted from filling to subside stages. Sonoliver software was used to analyze the imaging process.Logistic regression was used to compare the data collected from choroidal melanoma and hemangioma to develop a differential diagnosis equation for the diagnosis of choroidal melanoma. RESULTS: Contrast-enhanced ultrasonography in choroidal melanoma showed the following characteristics: the lesions were completely filled with the contrast reagent,the typical filling process began from the peripheral area to the center,filling defects were found in some cases,filling time in the melanoma was later than that in the normal tissues and faded early than that in the normal tissues. Quantitative analysis in choroidal melanoma lesions showed that the time to peak of contrast material [(22.80 ± 9.85)s] was less than that in the control group [(29.57 ± 24.76)s], maximum intensity [(191.31 ± 146.90)%] was greater than that in the control group [(100.00 ± 0.00)%]; rising time [(18.52 ± 7.09)s] was less than that in the control group [(26.45 ± 21.83)s] and mean transit time [(63.56 ± 26.04)s] was less than that in the control group [(149.87 ± 182.68)s]. The differences of maximum intensity and mean transit time between the melanoma and the controls were statistically significant (t = -2.848,2.197; P < 0.01). Logistic regression equation using the maximum intensity and mean transit time parameters could distinguish choroidal melanoma and hemangioma with a sensitivity at 90.5% (19/21) and specificity at 12/14. CONCLUSIONS: Contrast-enhanced ultrasonography is a new method for the diagnosis of malignant tumors in the eye. Contrast-enhanced ultrasonography combining with quantitative analysis can be helpful for the diagnosis and different diagnosis of choroidal melanoma.

Advances in Electrochemical Energy Storage over Metallic Bismuth-Based Materials.

Bismuth (Bi) has been prompted many investigations into the development of next-generation energy storage systems on account of its unique physicochemical properties. Although there are still some challenges, the application of metallic Bi-based materials in the field of energy storage still has good prospects. Herein, we systematically review the application and development of metallic Bi-based anode in lithium ion batteries and beyond-lithium ion batteries. The reaction mechanism, modification methodologies and their relationship with electrochemical performance are discussed in detail. Additionally, owing to the unique physicochemical properties of Bi and Bi-based alloys, some innovative investigations of metallic Bi-based materials in alkali metal anode modification and sulfur cathodes are systematically summarized for the first time. Following the obtained insights, the main unsolved challenges and research directions are pointed out on the research trend and potential applications of the Bi-based materials in various energy storage fields in the future.