Molecular Mechanisms
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Physiology ◽  
2021 ◽  
Vol 36 (6) ◽  
pp. 382-391
Author(s):  
Paul A. Janmey ◽  
Boris Hinz ◽  
Christopher A. McCulloch

Cells spread on surfaces and within three-dimensional (3-D) matrixes as they grow, divide, and move. Both chemical and physical signals orchestrate spreading during normal development, wound healing, and pathological states such as fibrosis and tumor growth. Diverse molecular mechanisms drive different forms of cell spreading. This article discusses mechanisms by which cells spread in 2-D and 3-D and illustrates new directions in studies of this aspect of cell function.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Wei Wei ◽  
Wenqiang Xin ◽  
Yufeng Tang ◽  
Zhonglun Chen ◽  
Yue Heng ◽  
...  

Stroke is an acute cerebrovascular disease, including ischemic and hemorrhagic stroke. Stroke is the second leading cause of death after ischemic heart disease, which accounts for 9% of the global death toll. To explore the molecular mechanisms of the effects of the dysregulated factors, in the GEO database, we obtained transcriptome data from 24 h/72 h of mice with ischemic stroke and 24 h/72 h of normal mice. We then performed differential gene analysis, coexpression analysis, enrichment analysis, and regulator prediction bioinformatics analysis to identify the potential genes. We made a comparison between the ischemic stroke 72 h and the ischemic stroke for 24 h, and 5103 differential genes were obtained ( p < 0.05 ). Four functional barrier modules were obtained by weighted gene coexpression network analysis. The critical genes of each module were ASTL, Zfp472, Fmr1 gene, and Nap1l1. The results of the enrichment analysis showed ncRNA metabolism, microRNAs in cancer, and biosynthesis of amino acids. These three functions and pathways have the most considerable count value. The regulators of the regulatory dysfunction module were predicted by pivotal analysis of TF and noncoding RNA, and critical regulators including NFKB1 (NF-κB1), NFKBIA, CTNNB1, and SP1 were obtained. Finally, the pivotal target gene found that CTNNB1, NFKB1, NFKBia, and Sp1 are involved in 18, 32, 2, and 60 target genes, respectively. Therefore, we believe that NFKB1 and Sp1 have a potential role in the progression of ischemic stroke. The NFKB signaling pathway promotes inflammatory cytokines and regulates the progression of ischemic stroke.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhao ◽  
Zineng Huang ◽  
Hongling Peng

Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia–reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lieke E. Vlaar ◽  
Andre Bertran ◽  
Mehran Rahimi ◽  
Lemeng Dong ◽  
Jan E. Kammenga ◽  
...  

AbstractNematodes are presumably the most abundant Metazoa on Earth, and can even be found in some of the most hostile environments of our planet. Various types of hypobiosis evolved to adapt their life cycles to such harsh environmental conditions. The five most distal major clades of the phylum Nematoda (Clades 8–12), formerly referred to as the Secernentea, contain many economically relevant parasitic nematodes. In this group, a special type of hypobiosis, dauer, has evolved. The dauer signalling pathway, which culminates in the biosynthesis of dafachronic acid (DA), is intensively studied in the free-living nematode Caenorhabditis elegans, and it has been hypothesized that the dauer stage may have been a prerequisite for the evolution of a wide range of parasitic lifestyles among other nematode species. Biosynthesis of DA is not specific for hypobiosis, but if it results in exit of the hypobiotic state, it is one of the main criteria to define certain behaviour as dauer. Within Clades 9 and 10, the involvement of DA has been validated experimentally, and dauer is therefore generally accepted to occur in those clades. However, for other clades, such as Clade 12, this has hardly been explored. In this review, we provide clarity on the nomenclature associated with hypobiosis and dauer across different nematological subfields. We discuss evidence for dauer-like stages in Clades 8 to 12 and support this with a meta-analysis of available genomic data. Furthermore, we discuss indications for a simplified dauer signalling pathway in parasitic nematodes. Finally, we zoom in on the host cues that induce exit from the hypobiotic stage and introduce two hypotheses on how these signals might feed into the dauer signalling pathway for plant-parasitic nematodes. With this work, we contribute to the deeper understanding of the molecular mechanisms underlying hypobiosis in parasitic nematodes. Based on this, novel strategies for the control of parasitic nematodes can be developed.


2021 ◽  
Vol 12 ◽  
Author(s):  
Tapan Kumar Mohanta ◽  
Awdhesh Kumar Mishra ◽  
Yugal Kishore Mohanta ◽  
Ahmed Al-Harrasi

Since the beginning of space exploration, researchers have been exploring the role of microgravity, cosmic radiation, and other aspects of the space environment on plant growth and development. To create superior crop varieties and achieve noticeable success in the space environment, several types of research have been conducted thus far. Space-grown plants have been exposed to cosmic radiation and microgravity, which has led to the generation of crop varieties with diverse genotypes and phenotypes arising from different cellular, subcellular, genomic, chromosomal, and biochemical changes. DNA damage and chromosomal aberrations due to cosmic radiation are the major factors responsible for genetic polymorphism and the generation of crops with modified genetic combinations. These changes can be used to produce next-generation crop varieties capable of surviving diverse environmental conditions. This review aims to elucidate the detailed molecular mechanisms and genetic mutations found in plants used in recent space crop projects and how these can be applied in space breeding programmes in the future.


2021 ◽  
Author(s):  
Chao Ma ◽  
Xiaobo Wang ◽  
Wanli W Smith ◽  
Zhaohui Liu

Abstract BackgroundRecently, four Parkinson’s disease (PD)-linked mutations (Y92C, R141L, 184PGext*5 and 184Wext*5) in transmembrane protein 230 (TMEM230) were identified in PD patients, and these mutations have implications in protein trafficking and neurodegeneration. However, there is a lack of in vivo studies on the roles of PD-related variants of TMEM230 in PD pathogenesis.MethodsIn this study, we generated human wild-type (WT) and mutant TMEM230 (Y92C, R141L, 184PGext*5 and 184Wext*5) transgenic Drosophila using isoform Ⅱ cDNA. ResultsWe found that the expression of TMEM230 184PGext*5 in pan-neurons or dopaminergic neurons in Drosophila induced PD-like phenotypes, which included impaired locomotor ability, a shortened lifespan, reduced TH levels, and increased phosphorylated JNK and cleaved caspase-3 levels. Moreover, rotenone, a common pesticide, enhanced TMEM230-184PGext*5-induced PD-like phenotypes. In contrast, the overexpression of wild-type (WT) VPS35 rescued TMEM230-184PGext*5-induced PD-like phenotypes, while the knockdown of VPS35 by RNA interference (RNAi) or the expression of mutant VPS35 D620N worsened PD-like phenotypes. ConclusionThese results indicate that VPS35, as a downstream effector of TMEM230, plays a critical role in TMEM230-linked JNK/caspase-3 signalling pathways and that mutations in TMEM230 and VPS35 disrupt these pathways, resulting in dopaminergic neurodegeneration and PD-like phenotypes. These findings provide novel insight into the molecular mechanisms of mutant TME230- and VPS35-induced abnormalities underlying the pathogenesis of PD.


Author(s):  
Stephen R Lantz ◽  
Robert A. Adair ◽  
Jon J Amberg ◽  
Roger A. Bergstedt ◽  
Michael A Boogaard ◽  
...  

Successful integrated management of the invasive predatory sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes of North America is owed largely to the long history of beneficial use of two lampricides: 3 trifluoromethyl 4 nitrophenol (TFM) and 2’,5-dichloro-4’-nitrosalicylanilide (niclosamide). Ensuring continued successful sea lamprey control necessitates consideration of possible next-generation lampricides to supplement or replace current lampricides. This review identifies fifteen hallmarks of success for current lampricides to be used as design criteria in a search for next-generation lampricides. A three-stage research approach is outlined. Targeted research using omics, computer modelling, and high-throughput technology to define molecular mechanisms and high probability molecular targets for sea lamprey selective toxic action is crucial to prioritizing chemical candidates. Targeted delivery or identifying synergists to existing or new lampricides can provide increased efficiency and reduced environmental impact. Ultimate development of next-generation lampricides will rely on traditional toxicity testing methodologies to ensure safety and regulatory compliance.


Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fernando A. Vicentini ◽  
Catherine M. Keenan ◽  
Laurie E. Wallace ◽  
Crystal Woods ◽  
Jean-Baptiste Cavin ◽  
...  

Abstract Background The intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and ENS. Microbiota-dependent molecular mechanisms of ENS neuronal survival and neurogenesis were also assessed. Results Adult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion secretion, and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia was only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion, but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, short-chain fatty acids (SCFA) were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo. Conclusions Our results demonstrate a role for the gut microbiota in regulating the structure and function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies.


2021 ◽  
Vol 12 ◽  
Author(s):  
Kun Cheng ◽  
Yi-Fan Pan ◽  
Lü-Meng Liu ◽  
Han-Qing Zhang ◽  
Yuan-Ming Zhang

The seed oil and starch content of soybean are significantly different from that of chickpea. However, there are limited studies on its molecular mechanisms. To address this issue, we conducted integrated transcriptomic and bioinformatics analyses for species-specific genes and acyl-lipid-, starch-, and carbon metabolism-related genes. Among seven expressional patterns of soybean-specific genes, four were highly expressed at the middle- and late oil accumulation stages; these genes significantly enriched fatty acid synthesis and carbon metabolism, and along with common acetyl CoA carboxylase (ACCase) highly expressed at soybean middle seed development stage, common starch-degrading enzyme beta-amylase-5 (BAM5) was highly expressed at soybean early seed development stage and oil synthesis-related genes ACCase, KAS, KAR, ACP, and long-chain acyl-CoA synthetase (LACS) were co-expressed with WRI1, which may result in high seed oil content and low seed starch content in soybean. The common ADP-glucose pyrophosphorylase (AGPase) was highly expressed at chickpea middle seed development stage, along with more starch biosynthesis genes co-expressed with four-transcription-factor homologous genes in chickpea than in soybean, and the common WRI1 was not co-expressed with oil synthesis genes in chickpea, which may result in high seed starch content and low seed oil content in chickpea. The above results may be used to improve chickpea seed oil content in two ways. One is to edit CaWRI1 to co-express with oil synthesis-related genes, which may increase carbon metabolites flowing to oil synthesis, and another is to increase the expression levels of miRNA159 and miRNA319 to inhibit the expression of MYB33, which may downregulate starch synthesis-related genes, making more carbon metabolites flow into oil synthesis. Our study will provide a basis for future breeding efforts to increase the oil content of chickpea seeds.


2021 ◽  
Vol 11 ◽  
Author(s):  
Sarah Morice ◽  
Geoffroy Danieau ◽  
Robel Tesfaye ◽  
Mathilde Mullard ◽  
Régis Brion ◽  
...  

BackgroundThe poor survival rate of patients with osteosarcoma (OS), specifically with metastases at diagnosis, undergoes the urgency to develop new therapeutic strategies. Although we recently demonstrated the key role of YAP/TEAD signaling in the growth of OS primary tumor, the molecular mechanisms by which YAP regulates metastases development remain poorly understood.MethodsThe molecular mechanisms by which YAP regulates metastases development were studied using an overexpression of mutated forms of YAP able or not able to interact with TEAD. Molecular signatures were identified using RNA-sequencing analysis and gene set enrichment. Interactions between YAP and Smad3 were studied using proximity ligation assay (PLA), immunoprecipitation, and promoter/specific gene assays. The involvement of the TGF-β pathway in the ability of YAP to stimulate metastatic development in vivo was studied using an inhibitor of the TGF-β cascade in a preclinical model of OS and in vitro on the ability of OS cells to migrate and invade.ResultsOur work shows that a high YAP expression is associated with the presence of lung metastases which predicts a poor prognosis. Molecular analysis indicates that TGF-β signaling is involved in YAP-driven osteosarcoma cell pro-migratory phenotype, epithelial mesenchymal transition, cell migration, and in vivo lung metastasis development. Regardless of its ability to bind to TEAD, YAP interacts with Smad3 and stimulates the transcriptional activity of TGF-β/Smad3, thereby enhancing the ability of TGF-β to stimulate lung metastasis development.ConclusionsWe demonstrated the crucial involvement of the TGF-β/Smad3 signaling pathway in YAP-driven lung metastasis development in OS.


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