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2021 ◽  
Vol 28 ◽  
Author(s):  
Mona Sheta ◽  
Martin Götte

: The successive stages of breast cancer growth and dissemination depend on cell-autonomous factors and the communication between tumor cells and their surrounding cellular and extracellular matrix microenvironment. The cell surface heparan sulfate proteoglycan Syndecan-1 is dysregulated both in tumor cells and cells of the breast tumor stroma, indicating a potential role in the pathogenesis of this most frequent malignancy in women. Indeed, Syndecan-1 interacts with numerous ligands and receptors relevant to tumor progression, affecting processes as diverse as cancer stem cell function, cell proliferation, apoptosis, cell adhesion, migration and invasion, tumor angiogenesis, and leukocyte function the tumor stroma. The present review summarizes the current understanding of breast carcinogenesis in correlation with their Syndecan-1 expression, involved mechanisms, and proposed therapeutic strategies against Syndecan-1-related malignancy.


2021 ◽  
Author(s):  
Yongchan Lee ◽  
Pattama Wiriyasermkul ◽  
Satomi Moriyama ◽  
Deryck J Mills ◽  
Werner Kühlbrandt ◽  
...  

Cystinuria is a genetic disorder characterized by overexcretion of dibasic amino acids and cystine, which causes recurrent kidney stones and occasionally severe kidney failure. Mutations of the two responsible proteins, rBAT and b0,+AT, which comprise system b0,+, are linked to type I and non-type I cystinuria respectively and they exhibit distinct phenotypes due to protein trafficking defects or catalytic inactivation. Although recent structural insights into human b0,+AT-rBAT suggested a model for transport-inactivating mutations, the mechanisms by which type I mutations trigger trafficking deficiencies are not well understood. Here, using electron cryo-microscopy and biochemistry, we discover that Ca2+-mediated higher-order assembly of system b0,+ is the key to its trafficking on the cell surface. We show that Ca2+ stabilizes the interface between two rBAT molecules to mediate super-dimerization, and this in turn facilitates the N-glycan maturation of system b0,+. A common cystinuria mutant T216M and mutations that disrupt the Ca2+ site in rBAT cause the loss of higher-order assemblies, resulting in protein trafficking deficiency. Mutations at the super-dimer interface reproduce the mis-trafficking phenotype, demonstrating that super-dimerization is essential for cellular function. Cell-based transport assays confirmed the importance of the Ca2+ site and super-dimerization, and additionally suggested which residues are involved in cationic amino acid recognition. Taken together, our results provide the molecular basis of type I cystinuria and serve as a guide to develop new therapeutic strategies against it. More broadly, our findings reveal an unprecedented link between transporter oligomeric assembly and trafficking diseases in general.


Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1627-1637
Author(s):  
Xiaoqing Pan ◽  
Xuemei Geng ◽  
Yong Liu ◽  
Mengqian Yu ◽  
Manoj K. Mishra ◽  
...  

Small noncoding RNAs (sncRNAs) are important regulators of gene expression. In contrast with well-studied microRNAs, transfer RNA-derived RNA fragments (tRFs) are a new class of sncRNAs that has not been studied in hypertension. This study aims to characterize renal tRFs and identify dysregulation and potential role of renal tRFs in hypertension. We analyzed sncRNA-sequencing and mRNA-sequencing data from the kidneys of Dahl salt-sensitive rats and sncRNA-sequencing data from kidney biopsy specimens from hypertensive nephrosclerosis patients. Over 300 tRFs were identified in the rat renal outer medulla, several of which were differentially expressed between rats with different levels of salt sensitivity or between rats on low- and high-salt diets. The number and abundance of these tRFs were comparable with those of well-known microRNAs. Multiple tRFs were potentially involved in the regulation of immune function, cell cycle, ion transport, and metabolic pathways based on an integrative analysis of sncRNA-sequencing and mRNA-sequencing data from the same set of rats. As a proof of concept, we experimentally validated the gene regulatory effect of a 3′-tRF (3′-tRF-ProTGG-19) that was dysregulated in both salt-induced hypertension in rats ( P =0.002) and hypertensive nephrosclerosis in humans ( P =1.7×10 −05 ). To our knowledge, our study represents the first characterization of tRFs in hypertension. These findings demonstrate the abundant expression of tRFs in human and rat kidneys and pave the way for studies to investigate novel roles of renal tRFs in the development of hypertension and renal injury.


2021 ◽  
Vol 26 (2) ◽  
pp. 154-161
Author(s):  
S.O. Belostotskaya ◽  
◽  
A.A. Lukyanov ◽  
A.S. Roslyakov ◽  
A.N. Semenov ◽  
...  

During the analog signals processing one of the key factors is the reduction of power consumption with high accuracy of signal processing. One way of solving this problem is the implementation of analog IP-blocks. PLLs, AGC, modulators often include the analog signal multipliers. In the paper, the principle of quadratic function cell operation has been described in detail. The analog signal multiplier has been constructed on the basis of the difference of squares arithmetic formula and the considered cell of the quadratic current function. On the basis of the elements of 5529 series structured ASIC, the analog signal multiplier has been simulated and its accuracy has been assessed. The resulting analog complex functional IP-block for signal multiplication is a part of the development strategy for 5529 series structured ASIC library.


Life ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 28
Author(s):  
Grazyna Niewiadomska ◽  
Wiktor Niewiadomski ◽  
Marta Steczkowska ◽  
Anna Gasiorowska

Although the mechanisms of toxic activity of tau are not fully recognized, it is supposed that the tau toxicity is related rather not to insoluble tau aggregates but to its intermediate forms. It seems that neurofibrillar tangles (NFTs) themselves, despite being composed of toxic tau, are probably neither necessary nor sufficient for tau-induced neuronal dysfunction and toxicity. Tau oligomers (TauOs) formed during the early stages of tau aggregation are the pathological forms that play a key role in eliciting the loss of neurons and behavioral impairments in several neurodegenerative disorders called tauopathies. They can be found in tauopathic diseases, the most common of which is Alzheimer’s disease (AD). Evidence of co-occurrence of b-amyloid, α-synuclein, and tau into their most toxic forms, i.e., oligomers, suggests that these species interact and influence each other’s aggregation in several tauopathies. The mechanism responsible for oligomeric tau neurotoxicity is a subject of intensive investigation. In this review, we summarize the most recent literature on the damaging effect of TauOs on the stability of the genome and the function of the nucleus, energy production and mitochondrial function, cell signaling and synaptic plasticity, the microtubule assembly, neuronal cytoskeleton and axonal transport, and the effectiveness of the protein degradation system.


The chapter describes the existing approach to modeling dynamic systems. The rules of the transfer of properties and conditions from cell to cell in cellular automata of various organizations are considered. The basic cell structures are presented in the transfer of only states, as well as properties of cell activity and states. The options are considered when the cell itself selects a cell among the cells in the neighborhood that will become active in the next time step. Also is considered is the option when the cell analyzes the state of neighboring cells and, based on the results of the local state function, makes a decision about the transition to the active state or not. An embodiment of a cell for transmitting an active state is described, only to cells with a given local logical function. Cell structures and their CAD models are constructed.


2020 ◽  
Author(s):  
Juan A. Sánchez ◽  
Ana L. Gil-Martinez ◽  
Alejandro Cisterna ◽  
Sonia García-Ruíz ◽  
Alicia Gómez ◽  
...  

AbstractMotivationCo-expression networks are a powerful gene expression analysis method to study how genes co-express together in clusters with functional coherence that usually resemble specific cell type behaviour for the genes involved. They can be applied to bulk-tissue gene expression profiling and assign function, and usually cell type specificity, to a high percentage of the gene pool used to construct the network. One of the limitations of this method is that each gene is predicted to play a role in a specific set of coherent functions in a single cell type (i.e. at most we get a single <gene, function, cell type> for each gene). We present here GMSCA (Gene Multifunctionality Secondary Co-expression Analysis), a software tool that exploits the co-expression paradigm to increase the number of functions and cell types ascribed to a gene in bulk-tissue co-expression networks.ResultsWe applied GMSCA to 27 co-expression networks derived from bulk-tissue gene expression profiling of a variety of brain tissues. Neurons and glial cells (microglia, astrocytes and oligodendrocytes) were considered the main cell types. Applying this approach, we increase the overall number of predicted triplets <gene, function, cell type> by 46.73%. Moreover, GMSCA predicts that the SNCA gene, traditionally associated to work mainly in neurons, also plays a relevant function in oligodendrocytes.AvailabilityThe tool is available at GitHub,https://github.com/drlaguna/GMSCA as open source software.ImplementationGSMCA is implemented in R.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hemanth R. Nelvagal ◽  
Maica Llavero Hurtado ◽  
Samantha L. Eaton ◽  
Rachel A. Kline ◽  
Douglas J. Lamont ◽  
...  

Abstract CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl protein thioesterase-1 (PPT-1). We recently found significant spinal pathology in Ppt1-deficient (Ppt1−/−) mice and human CLN1 disease that contributes to clinical outcome and precedes the onset of brain pathology. Here, we quantified this spinal pathology at 3 and 7 months of age revealing significant and progressive glial activation and vulnerability of spinal interneurons. Tandem mass tagged proteomic analysis of the spinal cord of Ppt1−/−and control mice at these timepoints revealed a significant neuroimmune response and changes in mitochondrial function, cell-signalling pathways and developmental processes. Comparing proteomic changes in the spinal cord and cortex at 3 months revealed many similarly affected processes, except the inflammatory response. These proteomic and pathological data from this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies. These data also fundamentally change our understanding of the progressive, site-specific nature of CLN1 disease pathogenesis, and highlight the importance of the neuroimmune response. This should greatly impact our approach to the timing and targeting of future therapeutic trials for this and similar disorders.


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