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A new helper cell line designated L3.07, has been used to package spleen necrosis virus (SNV)-based vectors, resulting in the production of high titres of replication defective retroviruses. One of these vectors, vSNO21 has been shown to infect avian primordial germ cells (PGCs).
BACKGROUND: The occurrence of apoptosis in choroidal neovascularizations (CNV) has only been described previously in a few cases. However, little is known about the extent and function of apoptosis. We analyzed the incidence of apoptosis in order to find new options in the therapy of CNV. Particular attention was given to the length of time that the process existed before surgery in patients with age-related macular degeneration (AMD). PATIENTS AND METHODS: In 34 patients (18 women, 16 men) ranging in age from 20 to 91 years (mean 70.3 years), CNV was detected by angiography. The majority of patients (n = 29) with CNV had AMD, which in most patients affected both eyes. In two patients CNV was due to post-traumatic proliferative vitreoretinopathy, in two other patients CNV occurred after a penetrating bulbus injury, and in one patient pseudoxanthoma elasticum was found. Thirty-four CNV membranes were excised by pars plana vitrectomy via retinotomy, fixed in formalin and embedded in paraffin. Sections were stained with PAS and H&E and examined microscopically. The in situ cell-detection kit (TUNEL) was used for immunohistochemical detection of apoptotic cells from fragmented DNA. RESULTS: In 74% (n = 25) of all patients and in 76% (n = 22) of patients with AMD, disseminated or focal apoptotic cells were detectable in the connective tissue, retinal pigment epithelium and in the vascular endothelium. In AMD patients with apoptotic cells, the SNV existed 1-12 months (mean 5.5 months) before surgical intervention. In patients without apoptotic cells, the CNV were present 5-36 months (mean 17 months) before surgery. At the time of surgery, the loss of reading ability had on average been going on 3 months; in patients with apoptotic cells, the mean time from the onset of this symptom was 2.4 months (1 week to 11 months); and in patients without apoptotic cells it was 5 months (1-12 months). CONCLUSION: Programmed cell death as a regulating pathomechanism was observed in all tissue parts of CNV with variable extension. In patients with AMD, a correlation existed between the length of time that CNV existed before surgery and the incidence of apoptotic cells. Apoptosis was found more frequently in recent CNV than in long-standing lesions. The various activity found in CNV suggests that the success of treatment may depend on the moment of intervention. To characterize the role of apoptosis further inducing and inhibiting factors have to be analyzed.
BACKGROUND: Personality-related phenotypes are genetically correlated with psychiatric disorders, but whether these relationships reflect shared genetic loci and differ across individual phenotypes remains unclear. We investigated their shared genetic architecture at the level of specific phenotype-disorder pairs. METHODS: We analyzed genome-wide association study summary statistics for 13 personality-related phenotypes and eight psychiatric disorders in populations of European ancestry. Genetic correlations were evaluated separately for 104 phenotype-disorder pairs using linkage disequilibrium score regression and high-definition likelihood. For pairs supported by both methods, MTAG and CPASSOC were applied separately to identify pleiotropic signals, followed by linkage disequilibrium clumping, Bayesian colocalization, gene prioritization, functional enrichment and bidirectional two-sample Mendelian randomization analyses. No composite personality or psychiatric-disorder phenotype was constructed. RESULTS: Among the 104 evaluated pairs, 77 showed significant positive genetic correlations in both analyses. Joint screening of MTAG and CPASSOC results identified pleiotropic signals in 61 pairs, comprising 1088 independent lead SNV-pair associations and 776 unique SNVs. Bayesian colocalization supported 351 signals across 42 pairs and 284 unique lead SNVs. MAGMA identified 1293 unique genes, of which 379 were prioritized by PoPS and 151 were further supported by SMR. These genes were enriched in brain tissues and biological processes involving nervous system development, synaptic organization and intercellular connectivity. Inverse-variance weighted Mendelian randomization identified 41 forward and 32 reverse associations after false-discovery-rate correction, including 21 pairs with bidirectional evidence. CONCLUSION: These item-resolved analyses identify widespread but heterogeneous genetic sharing between personality-related phenotypes and psychiatric disorders. The findings provide a pair-specific map of shared loci and prioritized genes, while the Mendelian randomization results should be interpreted cautiously because of residual heterogeneity and potential horizontal pleiotropy. Further validation in diverse populations and functional studies is required.
Hantaviruses cause two diseases of man, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Pathogenic and non-pathogenic hantaviruses use beta3 and beta1 integrins, respectively, to enter endothelial cells. Beta3 integrins were recently reported to bind receptors that regulate vascular permeability suggesting that hantavirus beta3 integrin interactions may regulate endothelial cell function and contribute to viral pathogenesis. In this study we investigated the ability of pathogenic and non-pathogenic hantaviruses to regulate beta3 and beta1 integrin directed endothelial cell functions. We found that pathogenic NY-1, SNV, HTN, SEO and PUU viruses blocked endothelial cell migration on beta3, but not beta1, integrin ligands. Migration is similarly inhibited by antibodies to beta3 integrins which selectively block vitronectin directed endothelial cell migration. As a result, the ability of endothelial cells to migrate on integrin ligands was selectively inhibited by only pathogenic hantaviruses. Infection by NY-1 virus inhibited endothelial cell migration as early as 24-48 h post-infection. In contrast, non-pathogenic PH and TUL viruses had no effect on the ability of endothelial cells to migrate on either beta3 or beta1 integrin ligands from 1 to 5 days post-infection. These findings indicate that only hantaviruses which use beta3 integrins, and are associated with HPS and HFRS diseases, functionally dysregulate endothelial cell migration. These findings further demonstrate that hantaviruses regulate only beta3 integrin directed endothelial cell functions and have no effect on beta1 integrin functions. Since beta3 integrins are linked to changes in vascular permeability and the maintenance of vascular integrity, these findings suggest a means by which hantavirus usage and regulation of beta3 integrins may contribute to hantavirus pathogenesis.
This study aims to investigate the prognostic significance and potential biological functions of the MTORC1 signaling pathway-associated gene POLR3G in Hepatocellular carcinoma (HCC). A prognostic risk model for HCC was developed by integrating HCC-related datasets and associated clinical data obtained from The Cancer Genome Atlas (TCGA) database. The GSVA website was employed to analyze the model genes across pan-cancer datasets, focusing on copy number variations (CNV), single nucleotide variations (SNV), methylation differences, drug sensitivity and immune cell infiltration profiles. Subsequently, we examined the expression levels and prognostic significance of POLR3G in HCC. Utilizing Spearman correlation analysis, we identified genes associated with POLR3G. Furthermore, Gene Set Enrichment Analysis (GSEA) was employed to elucidate the potential signaling pathways in which POLR3G may be involved. The relationship between POLR3G expression and immune cell abundance in HCC samples was assessed using the ssGSEA algorithm. Finally, the impact of POLR3G on HCC cell proliferation was validated through CCK-8 and EDU cell proliferation assays. Through univariate Cox regression analysis and LASSO regression analysis, we established a prognostic risk model for HCC comprising 13 genes. The analysis revealed that individuals categorized in the low-risk group had a markedly improved overall survival probability relative to those in the high-risk group. POLR3G exhibited a markedly elevated expression in HCC tissues when compared to adjacent normal tissues. The expression of POLR3G was correlated with tumor grade, and elevated POLR3G expression was associated with poor prognosis in HCC patients. Furthermore, the expression level of POLR3G was found to be correlated with the level of immune cell infiltration. Knockdown of POLR3G significantly inhibited the proliferative capacity of hepatocellular carcinoma cells. The findings suggest that POLR3G may serve as a potential biomarker influencing the prognosis of hepatocellular carcinoma patients by modulating the tumor immune microenvironment.
Puumala virus (PUUV) is a hantavirus that causes a mild form of hemorrhagic fever with renal syndrome in northern and central Europe, and in large parts of Russia. The nucleocapsid (N) protein encoded by hantaviruses plays an important role in the life-cycle of these viruses, and one important function for the N-protein is to oligomerize, surround and protect the viral RNAs. We have identified amino- and carboxy-terminal regions involved in PUUV N-N interactions, which comprise amino acids 100-120 and 330-405. Our findings strengthen the hypothesis that the amino-terminus of the N-protein of hantaviruses holds a more regulatory function regarding N-N interactions, while conserved residues in the carboxy-terminal region, F335 together with F336 and W392, in concert with Y388 and/or F400 seems to play a more critical role in the PUUV N-N formation. This study provides evidence that the amino-terminal regions involved in the N-N interaction of Puumala virus are similar to those reported for Seoul virus (SEOV) and to some extent Hantaan virus (HTNV), even though the identity between PUUV N and SEOV/HTNV N is markedly lower than between PUUV N and Tula virus (TULV) N or Sin Nombre virus (SNV) N.
The genomic DNA extracted from chicken embryo fibroblast (CEF) infected with a Chinese field isolate HA9901 of reticuloendotheliosis virus (REV) was used as the template to amplify the REV proviral genomic cDNA by PCR with 6 pairs of primers according to published sequences. Six overlapping fragments were amplified, cloned into the TA vector and sequenced, including a fragment which was amplified from the circular proviral cDNA and covering both 5'- and 3'-ends. The complete sequence of the whole genome was established and analyzed with a DNAstar software. Comparisons of the sequence with two other strains demonstrated that the genomes of REV were relatively conservative, the homogenecity for all genes or LTR fragments of the 3 strains was over 92%, no matter whether they were isolated from different species and regions in different years. But, the homology of Chinese strain HA9901 to a fowl pox virus-associated strain from Chickens was higher than that to strain SNV isolated from ducks.
A retrospective investigation of soft-tissue changes following two types of maxillary surgical procedure (anterior alveolar segmental, LeForte I) in nineteen adult patients was undertaken. Several hard-tissue coordinates were correlated to each coordinate of eleven soft-tissue points by multivariate regression analysis. This new method was compared to a previously derived nonsurgical prediction method (Ricketts). The following results were observed: 1. For eight horizontal and vertical coordinates (Glh, Glv, Nah, Av, Nch, Ncv, Pnh, and Pnv), neither method was accurate. 2. For ten horizontal and vertical coordinates (Snh, Snv, Ah, Av, ULh, ULv, Stv, LLh, Bv, and Pogv), the mean prediction residuals for the multivariate method were significantly smaller than those for the modified nonsurgical method. 3. For three horizontal and vertical coordinates (LLv, Bh, and Pogh), there were no significant differences between the mean prediction residuals of both methods. Two additional cases were used to test the new method for general applicability. Visual examination reveals that the predictions for these cases are clinicallly acceptable. Only further testing can establish the true validity of the new method.
To obtain a replication-defective retrovirus vector well suited for cell lineage marking in early avian embryos, we have constructed and tested a derivative of the avian spleen necrosis virus (SNV) carrying the marker gene lacZ. Consistently high titers of this virus, designated CXL, were produced from retroviral packaging cells with no evidence of contaminating helper virus even after 12 months of continuous culture. CXL expresses lacZ strongly and stably in avian cells and has a host range that extends to other avian and some mammalian species. We show that CXL has the potential to mark a wide variety of chick embryo cell types by infection in ovo. The high titers obtainable with this virus can provide a significant advantage over alternative lacZ vectors, especially in lineage marking of early stage embryos. As an example of this, we show that CXL can be used to mark cells of the precardiac mesoderm in stage 4-5 chick embryos.
Mesenchymal cells isolated from stage 24 embryonic chicken limb buds were infected with the temperature-sensitive transformation mutants of Rous sarcoma virus tsNY68, tsNY10 and tsLA25 at the nonpermissive temperature for transformation (41 degrees C). Virus infection greatly inhibited subsequent limb bud chondrogenesis under nontransforming conditions, as indicated by a reduction in the rate of 35SO4 incorporation into cell-associated proteoglycans. The inhibition of chondrogenesis was directly related to the percentage of cells infected with tsNY68 at 41 degrees C. The observed inhibition of chondrogenesis was independent of src gene expression since this effect was also caused by many viruses which lack the src gene, including the leukosis viruses RAV-1, RAV-2 and MAV-2(0); the src deletion mutant RSVtd107; and the reticuloendotheliosis viruses REV-T and SNV. Infection of mesenchymal cells with tsNY68 under nontransforming conditions did not cause changes in parameters such as the rate of thymidine incorporation, total cell DNA and total cell protein. Infection with tsNY68 at 41 degrees C resulted in altered kinetics of 35SO4 incorporation into cell-associated proteoglycans and a corresponding reduction in 35SO4-labeled proteoglycans extracted from the cell layer. There were no apparent quantitative effects on the rate of accumulation of proteoglycans in the culture medium. The proteoglycans extracted from the cells and the collected medium of tsNY68-infected cultures were smaller than those of uninfected cultures, as shown by agarose gel chromatography.
The vaginal microbiome is key for women's health. However, its establishment, interindividual variation and dynamics remain poorly understood. Here, we investigate bacterial relatedness at species and strain level in adult mother-daughter pairs from the large-scale citizen-science program Isala. Using metagenomic sequencing with quality control including 16S rRNA profile comparison, along with targeted culturing, we assess intergenerational microbiome sharing. At species level, daughters' vaginal microbiomes are significantly more similar to their mothers' than to those of unrelated mothers, with a strong mother-daughter correlation in Lactobacillus crispatus dominance. Strain-level analyses of metagenomes and isolate genomes reveal intraspecies diversity in L. crispatus, with up to two strains observed within the same host, and support intergenerational vaginal bacteria sharing. SNV counts in shared L. crispatus strains show no correlation with daughters' ages. Together, these findings suggest that maternal transmission, host factors, and (shared) environment collectively shape the vaginal microbiome, providing fundamental ecological insights into vaginal microbiome dynamics and perspectives toward lactobacilli-based applications.
This work is part of a study in which the possibility of NIR combined with some chemometrical methods is investigated as a suitable technique to classify clinical study samples of a cream. In this study, the influence of different preprocessing methods on the removal of spectral variations due to some variance sources has been investigated. The applied preprocessing methods are standard normal variate (SNV), detrend correction, offset correction, and first and second derivation. The investigated variance sources are different batches of ingredients, different samples of the same batch, different days and different positions of the sample cup in the sample drawer of the instrument. A nested ANOVA design has been applied in order to quantify the variances introduced by these variance sources. Since ANOVA is a univariate technique, the necessary variable (wavelength) selection has been performed by the Fisher criterion. The best results, i.e. largest reduction of interfering variability and clearest distinction between different clinical study samples, are obtained with the second derivative spectra.
The two components (paracetamol and amantadine hydrochloride) were simultaneously determined in combined paracetamol and amantadine hydrochloride tablets and powder by using near-infrared (NIR) spectroscopy and artificial neural networks (ANNs). The ANN models of three pretreated spectra (first-derivative, second-derivative and standard normal variate (SNV), respectively) were established. The mathematical corrected models of tablets were compared with those of the powder. In the models, the concentrations of paracetamol and amantadine hydrochloride as the active components were determined simultaneously and compared with the results of their separate determination. The parameters that affected the network were studied and the concentrations of the test set samples were predicted. The degree of approximation, a new evaluation criterion of the network was employed to prove the accuracy of the predicted results.
We report new results suggesting the feasibility of Raman spectrometry as a tool by which to examine the variability of tablet coatings. Our experiments feature a probe that can operate with a revolving laser focus to average content and coating non-uniformity. Raman spectral changes are correlated with tablet exposure times in a pan coater by means of partial least squares (PLS) multivariate analysis. Statistical models are found to be improved by pre-processing schemes that emphasize spectral changes while minimizing the effects of background light scattering and fluorescence. These pre-processing techniques include multiplicative scatter correction (MSC) and standard normal variate (SNV) transformation, used in concert with Savitzky-Golay second derivative smoothing (SGSD). The two approaches give comparable results yielding R2 values for PLS calibration and cross-calibrated prediction variance regression of 0.999 and 0.997, respectively. Correlation results and model residual values demonstrate that Raman spectroscopy serves sensitively to reflect the coating thickness of the tablets studied.
It seems that with climatic and geoecologic changes, Hantaviruses have re-emerged as human pathogens related to increases in interaction between humans and rodent reservoirs. Infection with SNV in North America and the Andes virus in South America can produce infection manifest initially as a flu-like illness. In the setting of a history of possible exposure to rodents or their excreta, clinical symptoms and laboratory clues such as thrombocytopenia should raise the suspicion of HPS. Clinical deterioration can be rapid, so patients should be hospitalized and transported to tertiary care centers where mechanical ventilation is available if necessary. Presumptive treatment for other forms of sepsis should be considered before confirmation of diagnosis. Survival seems to be determined in part by viral and host factors. Canadian and South American data suggest that there may be species variations influencing clinical manifestations and course of disease. Because the pathogenesis seems to be based on immunologic injury, future treatments will likely focus on interventions other than antiviral medications. Prevention strategies should be emphasized, particularly when recognized climatic conditions favor rodent abundance. Physicians should remain alert to the possibility of such a diagnosis when evaluating a patient with CAP and should request appropriate serology while supporting the patient in a closely monitored setting. The declining mortality rates seen over the past decade may be a consequence of improved medical management or better recognition of cases, including those less severe than originally described.
The application of the second most popular artificial neural networks (ANNs), namely, the radial basis function (RBF) networks, has been developed for quantitative analysis of drugs during the last decade. In this paper, the two components (aspirin and phenacetin) were simultaneously determined in compound aspirin tablets by using near-infrared (NIR) spectroscopy and RBF networks. The total database was randomly divided into a training set (50) and a testing set (17). Different preprocessing methods (standard normal variate (SNV), multiplicative scatter correction (MSC), first-derivative and second-derivative) were applied to two sets of NIR spectra of compound aspirin tablets with different concentrations of two active components and compared each other. After that, the performance of RBF learning algorithm adopted the nearest neighbor clustering algorithm (NNCA) and the criterion for selection used a cross-validation technique. Results show that using RBF networks to quantificationally analyze tablets is reliable, and the best RBF model was obtained by first-derivative spectra.
The present study aimed at providing a new method in sight into short-wavelength near-infrared (NIR) spectroscopy of in pharmaceutical quantitative analysis. To do that, 124 experimental samples of metronidazole powder were analyzed using artificial neural networks (ANNs) in the 780-1100 nm region of short-wavelength NIR spectra. In this paper, metronidazole was as active component and other two components (magnesium stearate and starch) were as excipients. Different preprocessing spectral data (first-derivative, second-derivative, standard normal variate (SNV) and multiplicative scatter correction (MSC)) were applied to establish the ANNs models of metronidazole powder. The degree of approximation, a new evaluation criterion of the networks was employed to prove the accuracy of the predicted results. The results presented here demonstrate that the short-wavelength NIR region is promising for the fast and reliable determination of major component in pharmaceutical analysis.
The potential of near infrared spectroscopy (NIRS) for determining the total arsenic (As) content in the prostrate amaranth (Amaranthus blitoides S. Watson) was assessed. Seventy-four samples belonging to this species, were harvested at different maturity stages along the polluted area, and then were scanned by NIRS. Their As reference values were obtained by atomic absorption spectrometry and they were regressed against different spectral transformations using modified partial least square (MPLS) regression. First derivative transformation equation of the raw optical data, previously standardized by standard normal variate (SNV) and De-trending (DT) transformations, resulted in a coefficient of determination (r(2)) in the external validation of 0.63, indicative of equations that can be used for a correct separation of the samples into low, medium and high groups. The standard deviation to standard error of prediction ratio (RPD) and range to standard error of prediction ratio (RER) for the first derivative equation were similar to those obtained for other trace metal calibrations reported in NIRS reflectance. Major cell components such as chlorophyll, lipids, starch and proteins were used by MPLS for modeling the equations. The use of NIRS for the determination of the As content in A. blitoides plants offers an important saving of time and cost of analysis.