Mutations in the SARS-CoV-2 genome can alter the virus' fitness, leading to the emergence of variants of concern (VOC). In Brazil, the Gamma variant dominated the pandemic in the first half of 2021, ...and from June onwards, the first cases of Delta infection were documented. Here, we investigate the introduction and dispersal of the Delta variant in the RS state by sequencing 1077 SARS-CoV-2-positive samples from June to October 2021. Of these samples, 34.7% were identified as Gamma and 65.3% as Delta. Notably, 99.2% of Delta sequences were clustered within the 21J lineage, forming a significant Brazilian clade. The estimated clock rate was 5.97 × 10
substitutions per site per year. The Delta variant was first reported on 17 June in the Vinhedos Basalto microregion and rapidly spread, accounting for over 70% of cases within nine weeks. Despite this, the number of cases and deaths remained stable, possibly due to vaccination, prior infections, and the continued mandatory mask use. In conclusion, our study provides insights into the Delta variant circulating in the RS state, highlighting the importance of genomic surveillance for monitoring viral evolution, even when the impact of new variants may be less severe in a given region.
Trisomy of chromosome 21 is associated to congenital heart defects in ∼50% of affected newborns. Transcriptome analysis of hearts from trisomic human foeti demonstrated that genes involved in ...mitochondrial function are globally downregulated with respect to controls, suggesting an impairment of mitochondrial function. We investigated here the properties of mitochondria in fibroblasts from trisomic foeti with and without cardiac defects. Together with the upregulation of Hsa21 genes and the downregulation of nuclear encoded mitochondrial genes, an abnormal mitochondrial cristae morphology was observed in trisomic samples. Furthermore, impairment of mitochondrial respiratory activity, specific inhibition of complex I, enhanced reactive oxygen species production and increased levels of intra-mitochondrial calcium were demonstrated. Seemingly, mitochondrial dysfunction was more severe in fibroblasts from cardiopathic trisomic foeti that presented a more pronounced pro-oxidative state. The data suggest that an altered bioenergetic background in trisomy 21 foeti might be among the factors responsible for a more severe phenotype. Since the mitochondrial functional alterations might be rescued following pharmacological treatments, these results are of interest in the light of potential therapeutic interventions.
The parameters of the Nakagami distribution have been utilized in the past to classify lesions in breast tissue as benign or malignant. To avoid the effect of operator-gain settings on the parameters ...of the Nakagami distribution, normalized parameters were utilized for the classification. The normalized parameter was defined as the ratio of the parameter at the site of the lesion to its average value over several regions away from the site. This technique, however, was very time consuming. In this paper, the application of frequency diversity and compounding is explored to achieve this normalization. Lesions are classified using these normalized parameters at the site. A receiver operating characteristic (ROC) analysis of the parameters of the Nakagami distribution has been conducted before and after compounding on a data set of 60 benign and 65 malignant lesions. The ROC results indicate that this technique can reasonably classify lesions in breast tissue as benign or malignant.
Up to 10% of women with a diagnosis of unilateral breast cancer have cancer in the contralateral breast, despite negative clinical and mammographic examinations. This study investigated the use of ...MRI examination of the contralateral breast in women with a diagnosis of unilateral breast cancer and negative clinical and mammographic examinations. MRI detected occult cancer in the contralateral breast in about 3% of these women. All of the cancers were early stage, without evidence of spread to the lymph nodes or beyond.
MRI detected occult cancer in the contralateral breast in about 3% of women with a diagnosis of unilateral breast cancer and negative clinical and mammographic examinations.
A woman with unilateral breast cancer has an increased risk of having cancer in the contralateral breast.
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In the 1990s, the role of mammography in improving the detection of contralateral cancers at the time of the initial diagnosis of breast cancer was firmly established; as compared with clinical breast examination alone, mammography resulted in a 1 to 3% increase in the number of cancers detected.
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Despite normal findings on clinical and mammographic examination of the contralateral breast at the time of the initial breast-cancer diagnosis, however, contralateral cancer was subsequently detected in up to 10% of women.
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A new series of 3,6‐disubstituted 2‐(methylthio)‐4‐(trifluoromethyl)‐3,4‐dihydropyrimidin‐4‐ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6‐position; and methyl, ethyl, allyl, and ...phenyl groups at the 3‐position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC50 values in the lower micromolar range. The compound 4‐trifluoromethyl‐6‐(4‐fluorophenyl)‐3‐methyl‐2‐methylthio‐3,4‐dihydropyrimidin‐4‐ol (6e) had the best inhibitory activity (IC50 2.2 ± 0.9 μm) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: π–π stacking interactions between the aromatic ring of the ligand's 4‐fluorophenyl moiety and the aromatic rings of the electron‐rich Trp84; and H‐bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin‐4‐ols was also investigated.
A series of 3,6‐disubstituted 2‐(methylthio)‐4‐(trifluoromethyl)‐3,4‐dihydropyrimidin‐4‐ols derivatives were synthesized and screened for acetylcholinesterase (AChE) inhibition. Many of the new compounds were capable to inhibit the AChE, among them, compound 6e was identified to be the most potent (IC50 = 2.2 ± 0.9 µm, in vitro), and its inhibition was characterized as competitive. The molecular docking study showed that the compound 6e accommodates in the catalytic site of AChE enzyme. In addition, some dihydropyrimidin‐4‐ols exhibited significant antioxidant effect.
Back-scattered ultrasonic signals provide scatterer structure information. Large-scale structures, such as tissue and tumor boundaries, typically create significant amplitude differences that reveal ...boundaries in conventional intensity images. Small-scale structures typically result in textures observed over regions of the intensity image. This paper describes the generalized spectrum (GS) for characterizing small-scale scatterer structures and applies it to analyze scatterer structures in a class of malignant and benign breast masses. Methods are presented for scaling and normalizing the GS to reduce effects from system response, overlaying tissue, and variability from noncritical structures. Results from a limited clinical study demonstrate an application of using the GS to discriminate between benign and malignant breast masses that contain internal echoes. Sections of rf A-scans in 41 breast mass regions were taken from 26 patients. A GS analysis was applied to determine critical structural properties between a class of fibroadenoma and carcinoma masses. Classifiers designed using significant structure differences identified by the GS analysis achieved approximately 82% true-positive and 10% false-positive rates.
Gap junctional intercellular communication (GJIC) of cultured mouse epidermal cells is mediated by a gap junction protein, connexin 43, and is dependent on the calcium concentration in the medium, ...with higher GJIC in a high-calcium (1.2 mM) medium. In several mouse epidermal cell lines, we found a good correlation between the level of GJIC and that of immunohistochemical staining of E-cadherin, a calcium-dependent cell adhesion molecule, at cell-cell contact areas. The variant cell line P3/22 showed both low GJIC and E-cadherin protein expression in low- and high-Ca2+media. P3/22 cells showed very low E-cadherin mRNA expression. To test directly whether E-cadherin is involved in the Ca2+-dependent regulation of GJIC, we transfected the E-cadherin expression vector into P3/22 cells and obtained several stable clones which expressed high levels of E-cadherin mRNA. All transfectants expressed E-cadherin molecules at cell-cell contact areas in a calcium-dependent manner. GJIC was also observed in these transfectants and was calcium dependent. These results suggest that Ca2+-dependent regulation of GJIC in mouse epidermal cells is directly controlled by a calcium-dependent cell adhesion molecule, E-cadherin. Furthermore, several lines of evidence suggest that GJIC control by E-cadherin involves posttranslational regulation (assembly and/or function) of the gap junction protein connexin 43.
This study was aimed to characterize the mitochondrial and extra-mitochondrial oxygen consuming reactions in human CD34+ hematopoietic stem cells. Cell samples were collected by apheresis following ...pre-conditioning by granulocyte colony-stimulating factor and isolated by anti-CD34 positive immunoselection. Polarographic analysis of the CN-sensitive endogenous cell respiration revealed a low mitochondrial oxygen consumption rate. Differential absorbance spectrometry on whole cell lysate and two-dimensional blue native-PAGE analysis of mitoplast proteins confirmed a low amount of mitochondrial respiratory chain complexes thus qualifying the hematopoietic stem cell as a poor oxidative phosphorylating cell type. Confocal microscopy imaging showed, however, that the intracellular content of mitochondria was not homogeneously distributed in the CD34+ hematopoietic stem cell sample displaying a clear inverse correlation of their density with the expression of the CD34 commitment marker. About half of the endogenous oxygen consumption was extra-mitochondrial and completely inhibitable by enzymatic scavengers of reactive oxygen species and by diphenylene iodinium. By spectral analysis, flow cytometry, reverse transcriptase-PCR, immunocytochemistry, and immunoprecipitation it was shown that the extra-mitochondrial oxygen consumption was contributed by the NOX2 and NOX4 isoforms of the O2-*. producer plasma membrane NAD(P)H oxidase with low constitutive activity. A model is proposed suggesting for the NAD(P)H oxidase a role of O2 sensor and/or ROS source serving as redox messengers in the activation of intracellular signaling pathways leading (or contributing) to mitochondriogenesis, cell survival, and differentiation in hematopoietic stem cells.
Gap junction intercellular communication (GJIC) or cell coupling has an important function in maintaining tissue homeostasis and is thus a critical factor in the life and death balance of cells. ...While the role of GJIC in cell growth regulation has been much studied, its involvement in apoptosis remains unclear. In this study we elucidated the possibility that cell death is propagated via gap junctions, employing the rat bladder carcinoma cell line BC31. BC31 cells proliferate quickly, are tumorigenic, and are well-coupled via gap junctions that contain the gap junction protein Connexin43 (Cx43). In addition, these cells are predisposed to spontaneous death by apoptosis, particularly upon achieving confluency. We found that many dying BC31 cells express Cx43 just as their non-apoptotic counterparts do. Furthermore, Cx43 in apoptotic cells could be functionally competent, supporting coupling of these cells with their non-apoptotic neighbors, and as a result, clusters of coordinately dying cells were observed. The role of Cx43 and GJIC in propagating cell death was shown by analysing clones of BC31 cells expressing a mutant of Cx43 that is a dominant negative inhibitor of GJIC, and by using beta-glycyrrhetinic acid to inhibit intrinsic cell coupling in BC31 cells: in both cases the formation of clusters of dying cells was abrogated, and the intensity of cell death was considerably decreased. These results suggest that GJIC spreads cell-killing signals initially generated by a single cell that spontaneously initiates apoptosis, into healthy surrounding cells, thus increasing the level of cell death. Treatment of BC31 cells with the sleep-inducing lipid Oleamide, which selectively restricts gap junction permeability to Ca(2+) ions, did not abrogate coordinated cell death by clusters, indicating that Ca(2+) ions are the most probable cell-killing signals spread through gap junctions.
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