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Advancing Parts Circularity: Overview of Mechano-Biocatalytic Approaches for Squander Plastic-type (Re)valorization.
Breast fibroepithelial lesions (FEL) are biphasic tumors which consist of benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). FAs and PTs have overlapping features, but have different clinical management, which makes correct core biopsy diagnosis important. This study used whole-slide images (WSIs) of 187 FA and 100 PT core biopsies, to investigate the potential role of artificial intelligence (AI) in FEL diagnosis. A total of 9228 FA patches and 6443 PT patches was generated from WSIs of the training subset, with each patch being 224 × 224 pixel in size. Our model employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction from the patches, and a recurrent neural network (RNN) component for whole-slide classification using activation values from the global average pooling layer in the CNN model. It achieved an overall slide-level accuracy of 87.5%, with accuracies of 80% and 95% for FA and PT slides respectively. This affirms the potential role of AI in diagnostic discrimination between FA and PT on core biopsies which may be further refined for use in routine practice.Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. Several large-scale projects have aimed to specifically link clinical mutations to resistance phenotypes, but they were limited in both their explanatory and predictive powers. Here, we combine functional genomics and phylogenetic associations using clinical strain genomes to decipher the architecture of isoniazid resistance and search for new resistance determinants. This approach has allowed us to confirm the main target route of the antibiotic, determine the clinical relevance of redox metabolism as an isoniazid resistance mechanism and identify novel candidate genes harboring resistance mutations in strains with previously unexplained isoniazid resistance. This approach can be useful for characterizing how the tuberculosis bacilli acquire resistance to new antibiotics and how to forestall them.A variety of targeted anticancer agents have been successfully introduced into clinical practice, largely reflecting their ability to inhibit specific molecular alterations that are required for disease progression. However, not all malignant cells rely on such alterations to survive, proliferate, disseminate and/or evade anticancer immunity, implying that many tumours are intrinsically resistant to targeted therapies. Radiotherapy is well known for its ability to activate cytotoxic signalling pathways that ultimately promote the death of cancer cells, as well as numerous cytoprotective mechanisms that are elicited by cellular damage. Importantly, many cytoprotective mechanisms elicited by radiotherapy can be abrogated by targeted anticancer agents, suggesting that radiotherapy could be harnessed to enhance the clinical efficacy of these drugs. In this Review, we discuss preclinical and clinical data that introduce radiotherapy as a tool to elicit or amplify clinically actionable signalling pathways in patients with cancer.Mitochondrial decline in ageing robs cells of ATP. However, animal studies show that long wavelength exposure (650-900 nm) over weeks partially restores ATP and improves function. The likely mechanism is via long wavelengths reducing nanoscopic interfacial water viscosity around ATP rota pumps, improving their efficiency. Recently, repeated 670 nm exposures have been used on the aged human retina, which has high-energy demands and significant mitochondrial and functional decline, to improve vision. We show here that single 3 min 670 nm exposures, at much lower energies than previously used, are sufficient to significantly improve for 1 week cone mediated colour contrast thresholds (detection) in ageing populations (37-70 years) to levels associated with younger subjects. But light needs to be delivered at specific times. In environments with artificial lighting humans are rarely dark-adapted, hence cone function becomes critical. This intervention, demonstrated to improve aged mitochondrial function can be applied to enhance colour vision in old age.Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces. But known drugs for IPF are far from meeting clinical demands, validation of drug targets against pulmonary fibrosis is in urgent demand. Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling. In this study we designed and synthesized a new indazole derivative XBLJ-13, and identified XBLJ-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities. We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients. Then we showed that XBLJ-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM, respectively. Among a panel of 34 kinases tested, XBLJ-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1, as well as Abl kinase that had high homology with DDRs. Extensive profiling of XBLJ-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice. Furthermore, pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBLJ-13 (30, 60, 90 mg·kg-1·d-1, i.g.) for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis. Together, this study confirms that DDRs kinase is a potential target for PF, Particularly, compound XBLJ-13 is a highly potent and specific DDRs inhibitor, along with good pharmacokinetics profiles, and preferable in vivo efficacy, suggesting that it is a potential candidate for the treatment of PF.Interpersonal synchrony is a fundamental part of human social interaction, with known effects on facilitating social bonding. Moving in time with another person facilitates prosocial behaviour, however, it is unknown if the degree of synchronisation predicts the degree of social bonding. Similarly, while people readily fall in synchrony even without being instructed to do so, we do not know whether such spontaneous synchronisation elicits similar prosocial effects as instructed synchronisation. Across two studies, we investigated how context (social vs non-social stimulus) and instruction (instructed vs uninstructed) influenced synchronisation accuracy and bonding with the interaction partner in adults and children. The results revealed improved visuomotor synchrony within a social, compared to non-social, context in adults and children. Children, but not adults, synchronised more accurately when instructed to synchronise than when uninstructed. For both children and adults, synchronisation in a social context elicited stronger social bonding towards an interaction partner as compared to synchronisation in a non-social context. Finally, children's, but not adults', degree of synchrony with the partner was significantly associated with their feelings of social closeness. These findings illuminate the interaction of sensorimotor coupling and joint action in social contexts and how these mechanisms facilitate synchronisation ability and social bonding.Sox2 is a core transcription factor in embryonic stem cells (ESCs), and O-GlcNAcylation is a type of post-translational modification of nuclear-cytoplasmic proteins. Although both factors play important roles in the maintenance and differentiation of ESCs and the serine 248 (S248) and threonine 258 (T258) residues of Sox2 are modified by O-GlcNAcylation, the function of Sox2 O-GlcNAcylation is unclear. Here, we show that O-GlcNAcylation of Sox2 at T258 regulates mouse ESC self-renewal and early cell fate. ESCs in which wild-type Sox2 was replaced with the Sox2 T258A mutant exhibited reduced self-renewal, whereas ESCs with the Sox2 S248A point mutation did not. ESCs with the Sox2 T258A mutation heterologously introduced using the CRISPR/Cas9 system, designated E14-Sox2TA/WT, also exhibited reduced self-renewal. RNA sequencing analysis under self-renewal conditions showed that upregulated expression of early differentiation genes, rather than a downregulated expression of self-renewal genes, was responsible for the reduced self-renewal of E14-Sox2TA/WT cells. There was a significant decrease in ectodermal tissue and a marked increase in cartilage tissue in E14-Sox2TA/WT-derived teratomas compared with normal E14 ESC-derived teratomas. RNA sequencing of teratomas revealed that genes related to brain development had generally downregulated expression in the E14-Sox2TA/WT-derived teratomas. Our findings using the Sox2 T258A mutant suggest that Sox2 T258 O-GlcNAc has a positive effect on ESC self-renewal and plays an important role in the proper development of ectodermal lineage cells. Overall, our study directly links O-GlcNAcylation and early cell fate decisions.Exosomes play a vital role in cell-cell communication within the cancer microenvironment. Exosomal long noncoding RNAs (lncRNAs) are important regulators in cancer development and are involved in multiple processes, including cancer cell proliferation, angiogenesis, metastasis, drug resistance, and immunomodulation. Changes in the levels of exosomal lncRNAs often appear with the occurrence and development of cancer. Therefore, exosomal lncRNAs can be used as biomarkers for cancer diagnosis and prognosis. Exosomal lncRNAs can also indicate the treatment response of patients receiving chemotherapy. Moreover, exosomal lncRNAs are potential therapeutic targets for cancer treatment. In this review, we summarize the role of exosomal lncRNAs in cancer biology as well as in clinical management. A more comprehensive and in-depth understanding of the role of exosomal lncRNAs in cancer may help us better understand the mechanism of cancer development and clinically manage cancer patients.The determination of the somatic cell count of a milk sample is one of the most common methods to monitor udder health of a dairy cow. selleck inhibitor However, this procedure does not take into account the fact that cells in milk present a great variety of different cell types. The objective of our study was to establish a high-resolution differential cell count (HRDCC) by means of flow cytometry in blood and milk. We were able to detect ten subpopulations among the three main populations of immune cells and to determine their viability. Additionally, blood samples were analyzed for common laboratory biomarkers, i.e. differential blood counts, haptoglobin levels and several metabolic parameters. In this first feasibility study, we used three different vaccines to stimulate the immune system of five healthy cows each. Samples were collected shortly before, in between and after the vaccinations. Using multivariate statistical methods we saw a diagnostic benefit when HRDCCs were included compared to only the standard laboratory parameters. The impacts of all three vaccinations on the immune system were visible in blood HRDCCs as well as in milk HRDCCs. Cluster of Differentiation 8+ (CD8+) T cells, B cells and monocyte/macrophage subpopulations were among the most important and statistically relevant parameters for all treatments in both biofluids. Moreover, in one of the treatment groups intermediate monocytes showed a significant increase after both vaccinations. Although the use of HRDCC in blood or milk was shown to be highly relevant for early systemic diagnostic, to confirm these subpopulations further investigations in cows of different breed, lactation stage or health status are required.
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