Search Results (12)

Estimating the sparse covariance matrix can effectively identify important features and patterns, and traditional estimation methods require complete data vectors on all subjects. When data are left-censored due to detection limits, common strategies such as excluding censored individuals or replacing censored values with suitable constants may result in large biases. In this paper, we propose two penalized log-likelihood estimators, incorporating the $L_1$ penalty and SCAD penalty, for estimating the sparse covariance matrix of a multivariate normal distribution in the presence of left-censored data. However, the fitting of these penalized estimators poses challenges due to the observed log-likelihood involving high-dimensional integration over the censored variables. To address this issue, we treat censored data as a special case of incomplete data and employ the Expectation Maximization algorithm combined with the coordinate descent algorithm to efficiently fit the two penalized estimators. Through simulation studies, we demonstrate that both penalized estimators achieve greater estimation accuracy compared to methods that replace censored values with constants. Moreover, the SCAD penalized estimator generally outperforms the $L_1$ penalized estimator. Our method is used to analyze the proteomic datasets. Full article

In the clinical diagnosis of pneumonia, particularly during the COVID-19 pandemic, individuals who progress to a critical stage requiring mechanical ventilation are classified as mechanically ventilated critically ill patients. Accurately predicting the discharge outcomes for this specific cohort, especially those with COVID-19, is of paramount clinical importance. Missing data, a common issue in medical research, can significantly impact the validity of analyses. In this work, we address this challenge by employing two missing data imputation techniques: multiple imputation and missForest, to enhance data completeness. Additionally, we utilize the smoothly clipped absolute deviation (SCAD) penalized logistic regression method to select significant features. Our real data analysis compares the predictive performances of extreme learning machines, random forests, support vector machines, and XGBoost using 10-fold cross-validation. The results consistently show that XGBoost outperforms the other methods in predicting discharge outcomes, making it a reliable tool for clinical decision-making in the treatment of severe pneumonia, including COVID-19 cases. Within this context, the random forest imputation method generally enhances performance, underscoring its effectiveness in managing missing data compared to multiple imputation. Full article

Data security and privacy have become essential due to the increasingly advanced interconnectivity in today’s world, hence the reliance on cryptography. This paper introduces a new algorithm that uses a novel hybrid Tent–May chaotic map to generate pseudo-random numbers, as well as block encryption. We design a robust S-box by combining the Tent and May Maps, which yields a chaotic system with improved cryptographic properties. This S-box is a critical cryptographic primitive that significantly improves encryption security and leverages the strengths of both maps. The encryption process involves two key steps: block-wise substitution and permutation. First, we divide the image into $16\times 16$ blocks, then substitute each pixel with the $8-byte$ key and S-box. Next, we convert the encrypted image back into vector form, reorganize it using the permutation vector based on the subgroups of $S_{16}$, and finally return it to its original form. This approach greatly improves block cipher security when used, especially to protect medical images by guaranteeing their confidentiality and noninterference. Performance measures like PSNR, UACI, MSE, NCC, AD, SC, MD, and NAE prove how immune our method is to various cryptographic and statistical attacks, making it more accurate and more secure than the existing techniques. Full article

Adenovirus vectors possess a good safety profile, an extensive genome, a range of host cells, high viral yield, and the ability to elicit broad humoral and cellular immune responses. Adenovirus vectors are widely used in infectious disease research for future vaccine development and gene therapy. In this study, we obtained a fowl adenovirus serotype 4 (FAdV-4) isolate from sick chickens with hepatitis–hydropericardium syndrome (HHS) and conducted animal regression text to clarify biological pathology. We amplified the transfer vector and extracted viral genomic DNA from infected LMH cells, then recombined the mixtures via the Gibson assembly method in vitro and electroporated them into EZ10 competent cells to construct the FAdV-4 infectious clone. The infectious clones were successfully rescued in LMH cells within 15 days of transfection. The typical cytopathic effect (CPE) and propagation titer of FAdV-4 infectious clones were also similar to those for wild-type FAdV-4. To further construct the single-cycle adenovirus (SC-Ad) vector, we constructed SC-Ad vectors by deleting the gene for IIIa capsid cement protein. The FAdV4 infectious clone vector was introduced into the ccdB cm expression cassette to replace the IIIa gene using a λ-red homologous recombination technique, and then the ccdB cm expression cassette was excised by PmeI digestion and self-ligation to obtain the resulting plasmids as SC-Ad vectors. Full article

To increase the safety of adenovirus vector (AdV)-based therapy without reducing its efficacy, a single-cycle adenovirus vector (SC-AdV) with a deletion in the protease gene (PS) was developed in order to be used as a substitute for the replication-competent adenovirus (RC-AdV). Since no infectious viral particles are assembled, there is no risk of viral shedding. The complementary cell lines for this developed AdV proved to be suboptimal for the production of viral particles and require the presence of fetal bovine serum (FBS) to grow. In the current study, we produced both stable pools and clones using adherent and suspension cells expressing the PS gene. The best adherent cell pool can be used in the early stages for the generation of protease-deleted adenovirus, plaque purification, and titration. Using this, we produced over 3400 infectious viral particles per cell. Additionally, the best suspension subclone that was cultured in the absence of FBS yielded over 4000 infectious viral particles per cell. Harvesting time, culture media, and concentration of the inducer for the best suspension subclone were further characterized. With these two types of stable cells (pool and subclone), we successfully improved the titer of protease-deleted adenovirus in adherent and suspension cultures and eliminated the need for FBS during the scale-up production. Eight lots of SC-AdV were produced in the best suspension subclone at a scale of 2 to 8.2 L. The viral and infectious particle titers were influenced by the virus backbone and expressed transgene. Full article

The Po River Basin (PRB) is Italy’s largest river system and provides a vital water supply source for varying demands, including agriculture, energy (hydropower), and water supply. The current (2022) drought has been associated with low winter–early spring (2021–2022) snow accumulation in higher elevations (European Alps) and a lack of late spring–early summer (2022) precipitation, resulting in deficit PRB streamflow. Many local scientists are now estimating a 50- to 100-year (return period) drought for 2022. Given the importance of this river system, information about past (paleo) drought and pluvial periods would provide important information to water managers and planners. Annual streamflow data were obtained for thirteen gauges that were spatially located across the PRB. The Old World Drought Atlas (OWDA) provides annual June–July–August (JJA) self-calibrating Palmer Drought Severity Index (scPDSI) data for 5414 grid points across Europe from 0 to 2012 AD. In lieu of tree-ring chronologies, this dataset was used as a proxy to reconstruct PRB regional streamflow. Singular value decomposition (SVD) was applied to PRB streamflow gauges and gridded scPDSI data for two periods of record, referred to as the short period of record (SPOR), 1980 to 2012 (33 years), and the long period of record (LPOR), 1967 to 2012 (46 years). SVD serves as both a data reduction technique, identifying significant scPDSI grid points within the selected 450 km search radius, and develops a single vector that represents the regional PRB streamflow variability. Due to the high intercorrelations of PRB streamflow gauges, the SVD-generated PRB regional streamflow vector was used as the dependent variable in regression models for both the SPOR and LPOR, while the significant scPDSI grid points (cells) identified by SVD were used as the independent variables. This resulted in two highly skillful regional reconstructions of PRB streamflow from 0 to 2012. Multiple drought and pluvial periods were identified in the paleo record that exceed those observed in the recent historical record, and several of these droughts aligned with paleo streamflow reconstructions of neighboring European watersheds. Future research will utilize the PRB reconstructions to quantify the current (2022) drought, providing a first-time paleo-perspective of drought frequency in the watershed. Full article

The Adige River Basin (ARB) provides a vital water supply source for varying demands including agriculture (wine production), energy (hydropower) and municipal water supply. Given the importance of this river system, information about past (paleo) drought and pluvial (wet) periods would quantity risk to water managers and planners. Annual streamflow data were obtained for four gauges that were spatially located within the upper ARB. The Old World Drought Atlas (OWDA) provides an annual June–July–August (JJA) self-calibrating Palmer Drought Severity Index (scPDSI) derived from 106 tree-ring chronologies for 5414 grid points across Europe from 0 to 2012 AD. In lieu of tree-ring chronologies, the OWDA dataset was used as a proxy to reconstruct both individual gauge and ARB regional streamflow from 0 to 2012. Principal component analysis (PCA) was applied to the four ARB streamflow gauges to generate one representative vector of regional streamflow. This regional streamflow vector was highly correlated with the four individual gauges, as coefficient of determination (R²) values ranged from 85% to 96%. Prescreening methods included correlating annual streamflow and scPDSI cells (within a 450 km radius) in which significant (p ≤ 0.01 or 99% significance) scPDSI cells were identified. The significant scPDSI cells were then evaluated for temporal stability to ensure practical and reliable reconstructions. Statistically significant and temporally stable scPDSI cells were used as predictors (independent variables) to reconstruct streamflow (predictand or dependent variable) for both individual gauges and at the regional scale. This resulted in highly skillful reconstructions of upper ARB streamflow from 0 to 2012 AD. Multiple drought and pluvial periods were identified in the paleo record that exceed those observed in the recent, historic record. Moreover, this study concurred with streamflow reconstructions in nearby European watersheds. Full article

The embryonal rhabdomyosarcoma (eRMS) is a soft tissue sarcoma commonly affecting the head and neck, the extremities and the genitourinary tract. To contribute to revealing the cell types that may originate this tumor, we exploited mass cytometry, a single-cell technique that, by using heavy-metal-tagged antibodies, allows the accurate monitoring of the changes occurring in the mononuclear cell composition of skeletal muscle tissue during tumor development. To this end, we compared cell populations of healthy muscles with those from spatiotemporal-induced eRMS tumors in a mouse model (LSL-Kras^G12D/+;Tp53^Fl/Fl) that can be used to develop rhabdomyosarcoma by means of infection with an adenovirus vector expressing Cre (Ad-Cre) recombinase. By monitoring different time points after tumor induction, we were able to analyze tumor progression and composition, identifying fibro/adipogenic progenitors (FAPs) as the cell type that, in this model system, had a pivotal role in tumor development. In vitro studies highlighted that both FAPs and satellite cells (SCs), upon infection with the Ad-Cre, acquired the potential to develop rhabdomyosarcomas when transplanted into immunocompromised mice. However, only infected FAPs had an antigen profile that was similar to embryonal rhabdomyosarcoma cells. Overall, our analysis supports the involvement of FAPs in eRMS development. Full article

Simultaneous feature selection and classification have been explored in the literature to extend the support vector machine (SVM) techniques by adding penalty terms to the loss function directly. However, it is the kernel function that controls the performance of the SVM, and an imbalance in the data will deteriorate the performance of an SVM. In this paper, we examine a new method of simultaneous feature selection and binary classification. Instead of incorporating the standard loss function of the SVM, a penalty is added to the data-adaptive kernel function directly to control the performance of the SVM, by firstly conformally transforming the kernel functions of the SVM, and then re-conducting an SVM classifier based on the sparse features selected. Both convex and non-convex penalties, such as least absolute shrinkage and selection (LASSO), moothly clipped absolute deviation (SCAD) and minimax concave penalty (MCP) are explored, and the oracle property of the estimator is established accordingly. An iterative optimization procedure is applied as there is no analytic form of the estimated coefficients available. Numerical comparisons show that the proposed method outperforms the competitors considered when data are imbalanced, and it performs similarly to the competitors when data are balanced. The method can be easily applied in medical images from different platforms. Full article

Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before the age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g.; anticancer treatment, genetic disorders, and enzymatic defects) could be identified. Although hormone-replacement therapy, the principal therapeutic approach for POI, helps alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, an effective approach to manage patients with POI is highly warranted. Several mechanisms associated with POI have been identified, including the lack of function of the follicle-stimulating hormone (FSH) receptor, alterations in apoptosis control, mutations in Sal-like 4 genes, and thymulin or basonuclin-1 deficiency. The above mentioned may be good targets for gene therapy in order to correct defects leading to POI. The goal of this review is to summarize current experiences on POI studies that employed gene therapy, and to discuss possible future directions in this field. Full article

Most adenovirus (Ad) vectors are E1 gene deleted replication defective (RD-Ad) vectors that deliver one transgene to the cell and all expression is based on that one gene. In contrast, E1-intact replication-competent Ad (RC-Ad) vectors replicate their DNA and their transgenes up to 10,000-fold, amplifying transgene expression markedly higher than RD-Ad vectors. While RC-Ad are more potent, they run the real risk of causing adenovirus infections in vector recipients and those that administer them. To gain the benefits of transgene amplification, but avoid the risk of Ad infections, we developed “single cycle” Ad (SC-Ad) vectors. SC-Ads amplify transgene expression and generated markedly stronger and more persistent immune responses than RD-Ad as expected. However, they also unexpectedly generated stronger immune responses than RC-Ad vectors. To explore the basis of this potency here, we compared gene expression and the cellular responses to infection to these vectors in vitro and in vivo. In vitro, in primary human lung epithelial cells, SC- and RC-Ad amplified their genomes more than 400-fold relative to RD-Ad with higher replication by SC-Ad. This replication translated into higher green fluorescent protein (GFP) expression for 48 h by SC- and RC-Ad than by RD-Ad. In vitro, in the absence of an immune system, RD-Ad expression became higher by 72 h coincident with cell death mediated by SC- and RC-Ad and release of transgene product from the dying cells. When the vectors were compared in human THP-1 Lucia- interferon-stimulated gene (ISG) cells, which are a human monocyte cell line that have been modified to quantify ISG activity, RC-Ad6 provoked significantly stronger ISG responses than RD- or SC-Ad. In mice, intravenous or intranasal injection produced up to 100-fold genome replication. Under these in vivo conditions in the presence of the immune system, luciferase expression by RC and SC-Ad was markedly higher than that by RD-Ad. In immunodeficient mice, SC-Ad drove stronger luciferase expression than RC- or RD-Ad. These data demonstrate better transgene expression by SC- and RC-Ad in vitro and in vivo than RD-Ad. This higher expression by the replicating vectors results in a peak of expression within 1 to 2 days followed by cell death of infected cells and release of transgene products. While SC- and RC-Ad expression were similar in mice and in Syrian hamsters, RC-Ad provoked much stronger ISG induction which may explain in part SC-Ad′s ability to generate stronger and more persistent immune responses than RC-Ad in Ad permissive hamsters. Full article

Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated “stealth” vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications. Full article