scholarly journals Understanding biological ageing in terms of constitutive signals: Convergence to an average decrease in cellular sensitivity and information transmission

2019 ◽  
Author(s):  
Alvaro Martinez Guimera ◽  
Daryl P. Shanley
Keyword(s):  
Information Transmission ◽  
Biological Function ◽  
Loss Of Function ◽  
Biological Ageing ◽  
Average Decrease ◽  
Network Sensitivity ◽  
Gradual Loss ◽  
Cellular Sensitivity ◽  
Stochastic Damage ◽  
Shed Light

Biological ageing is a process that encompasses observations often too heterogeneous to draw coherent conceptual frameworks that may shed light into the generality of the underlying gradual loss of function. Whilst the concept of stochastic damage is often invoked as the driver of the ageing process, this can be too abstract to understand ageing at a higher mechanistic resolution. However, there do exist general mechanisms that describe how stochastic damage interferes with biological function, such as through genetic mutations. In a similar manner, we argue that a ‘molecular habituation’ phenomenon occurs during biological ageing where constitutive signals arising from damage accumulation drive an average decrease in network sensitivity and information transmission, as well as an increase in noise, across cells and tissue.

scholarly journals MicroRNA-7a2 Regulates Prolactin in Developing Lactotrophs and Prolactinoma Cells

Endocrinology ◽  
2020 ◽  
Vol 162 (2) ◽  
Author(s):  
Mary P LaPierre ◽  
Svenja Godbersen ◽  
Mònica Torres Esteban ◽  
Anaïs Nura Schad ◽  
Mathias Treier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mirna Family ◽  
Dynamic Network ◽  
Loss Of Function ◽  
Gradual Loss ◽  
Prolactin Gene ◽  
Multiple Cell ◽  
Complex Regulation ◽  
Mouse Pituitary ◽  
Shed Light

Abstract Prolactin production is controlled by a complex and temporally dynamic network of factors. Despite this tightly coordinated system, pathological hyperprolactinemia is a common endocrine disorder that is often not understood, thereby highlighting the need to expand our molecular understanding of lactotroph cell regulation. MicroRNA-7 (miR-7) is the most highly expressed miRNA family in the pituitary gland and the loss of the miR-7 family member, miR-7a2, is sufficient to reduce prolactin gene expression in mice. Here, we used conditional loss-of-function and gain-of-function mouse models to characterize the function of miR-7a2 in lactotroph cells. We found that pituitary miR-7a2 expression undergoes developmental and sex hormone–dependent regulation. Unexpectedly, the loss of mir-7a2 induces a premature increase in prolactin expression and lactotroph abundance during embryonic development, followed by a gradual loss of prolactin into adulthood. On the other hand, lactotroph development is delayed in mice overexpressing miR-7a2. This regulation of lactotroph function by miR-7a2 involves complementary mechanisms in multiple cell populations. In mouse pituitary and rat prolactinoma cells, miR-7a2 represses its target Raf1, which promotes prolactin gene expression. These findings shed light on the complex regulation of prolactin production and may have implications for the physiological and pathological mechanisms underlying hyperprolactinemia.

scholarly journals GPR37 promotes the malignancy of lung adenocarcinoma via TGF-β/Smad pathway

Open Medicine ◽  
2020 ◽  
Vol 16 (1) ◽  
pp. 024-032
Author(s):  
Jian Wang ◽  
Min Xu ◽  
Dan-Dan Li ◽  
Wujikenayi Abudukelimu ◽  
Xiu-Hong Zhou
Keyword(s):  
Lung Adenocarcinoma ◽  
Biological Function ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Malignant Phenotype ◽  
Smad Pathway ◽  
Smad3 Phosphorylation ◽  
Poor Outcomes ◽  
Tgf Β1

AbstractThis paper aimed to research the function and in-depth mechanism of GPR37 in lung adenocarcinoma (LUAD). Herein, based on TCGA and Oncomine databases, we revealed that GPR37 was expressed at high levels in LUAD, and upregulation of GPR37 was related to the poor outcomes. Furthermore, biological function experiments in vitro were utilized to assess whether GPR37 impacts malignant phenotype of LUAD cells. Gain- or loss-of-function assays indicated that the upregulation of GPR37 contributed to improving the proliferation, migration, and invasion of LUAD cells in vitro, while knockdown of GPR37 can inhibit the malignant biological behaviors. Then, we found that depletion of GPR37 resulted in a decrease in the expression of TGF-β1 as well as the extents of Smad2 and Smad3 phosphorylation, while overexpression of GPR37 presented opposite outcomes. Altogether, our findings indicated that GPR37 is a potential oncogene of LUAD, and its promoting effects on the malignant progression of LUAD may be realized via TGF-β/Smad pathway.

scholarly journals lnc-SAMD14-4 can regulate expression of the COL1A1 and COL1A2 in human chondrocytes

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7491 ◽  
Author(s):  
Haibin Zhang ◽  
Cheng Chen ◽  
Yinghong Cui ◽  
Yuqing Li ◽  
Zhaojun Wang ◽  
...  
Keyword(s):  
Biological Function ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Human Chondrocytes ◽  
Loss Of Function ◽  
Knee Oa ◽  
System Disease ◽  
Chondrocyte Death ◽  
Differentially Expressed Mrna ◽  
Gain Loss

Osteoarthritis (OA) is the most common motor system disease in aging people, characterized by matrix degradation, chondrocyte death, and osteophyte formation. OA etiology is unclear, but long noncoding RNAs (lncRNAs) that participate in numerous pathological and physiological processes may be key regulators in the onset and development of OA. Because profiling of lncRNAs and their biological function in OA is not understood, we measured lncRNA and mRNA expression profiles using high-throughput microarray to study human knee OA. We identified 2,042 lncRNAs and 2,011 mRNAs that were significantly differentially expressed in OA compared to non-OA tissue (>2.0- or < − 2.0-fold change; p < 0.5), including 1,137 lncRNAs that were upregulated and 905 lncRNAs that were downregulated. Also, 1,386 mRNA were upregulated and 625 mRNAs were downregulated. QPCR was used to validate chip results. Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes was used to study the biological function enrichment of differentially expressed mRNA. Additionally, coding-non-coding gene co-expression (CNC) network construction was performed to explore the relevance of dysregulated lncRNAs and mRNAs. Finally, the gain/loss of function experiments of lnc-SAMD14-4 was implemented in IL-1β-treated human chondrocytes. In general, this study provides a preliminary database for further exploring lncRNA-related mechnisms in OA.

scholarly journals Converging physiological roles of the anthrax toxin receptors

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1415
Author(s):  
Oksana A. Sergeeva ◽  
F. Gisou van der Goot
Keyword(s):  
Anthrax Toxin ◽  
Loss Of Function ◽  
Disease Symptoms ◽  
Hyaline Fibromatosis Syndrome ◽  
Anthrax Toxins ◽  
The Difference ◽  
Related Proteins ◽  
Tumor Endothelial Marker 8 ◽  
Insight Into ◽  
Shed Light

The anthrax toxin receptors—capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8)—were identified almost 20 years ago, although few studies have moved beyond their roles as receptors for the anthrax toxins to address their physiological functions. In the last few years, insight into their endogenous roles has come from two rare diseases: hyaline fibromatosis syndrome, caused by mutations in CMG2, and growth retardation, alopecia, pseudo-anodontia, and optic atrophy (GAPO) syndrome, caused by loss-of-function mutations in TEM8. Although CMG2 and TEM8 are highly homologous at the protein level, the difference in disease symptoms points to variations in the physiological roles of the two anthrax receptors. Here, we focus on the similarities between these receptors in their ability to regulate extracellular matrix homeostasis, angiogenesis, cell migration, and skin elasticity. In this way, we shed light on how mutations in these two related proteins cause such seemingly different diseases and we highlight the existing knowledge gaps that could form the focus of future studies.

scholarly journals IV. On the changes produced in the circulation and respiration by increase of the intra-cranial pressure or tension

1891 ◽  
Vol 182 ◽  
pp. 201-254 ◽  
Keyword(s):  
Loss Of Function ◽  
Sequence Of Events ◽  
High Tension ◽  
Gradual Loss ◽  
Full Explanation ◽  
Definite Sequence ◽  
The One ◽  
Future Revision ◽  
Low Tension ◽  
Intra Cranial Pressure

For some time we have made intra-cranial pressure the subject of an enquiry. The present paper deals with the effect upon the circulation and respiration of an increase of such intra-cranial pressure. Our object is to indicate how the degree of the intracranial tension may be estimated by changes in the pulse and breathing, whether a prognosis may be formed as to the termination of the condition, and whether the effect is due to gradual loss of function of the lower part of the medulla. Until lately, the pulse and breathing have yielded signs, the meaning of which was uncertain; thus the pulse, it is said, may be slow and of low tension, or again, in severe cases, quicker than normal and of high tension. The respiration also, is sometimes noted as being stertorous, or of the “Cheyne-Stokes” rhythm. But although death frequently comes by arrest of respiration in tumours of the brain, whilst the heart may continue to beat for five, ten, or even thirty minutes after, little has been recorded concerning the abnormal rhythm of respiration preceding its arrest; we therefore arranged our experimental method so as to investigate these phenomena in their entirety. It is impossible to give a full explanation of all the results we have obtained, because the functions of the medulla are not yet fully understood, and therefore, whatever hypotheses we have advanced on these points in this paper, have been inserted merely for the sake of clearness, and are fully open, of course, to future revision. However, the recorded tracings of all the experiments show so clearly that a diminished activity of the medulla occurs as a definite sequence of events contemporaneously with increase in the intra-cranial pressure, that we regard this fundamental fact to be established; therefore the value of the results, as regards the estimation of the effect of increased pressure, is independent of exact knowledge of the mode of their production. Further, we believe that our experiments have an important general bearing, in that they show how the three “centres” regulating the heart rate, the blood pressure, and the respiration, can be impeded or arrested, either together, or almost separately, and consequently the varying influences they have the one on the other can be estimated with an approximation to accuracy.

scholarly journals Mechanistic Insights into Axenfeld–Rieger Syndrome from Zebrafish foxc1 and pitx2 Mutants

2021 ◽  
Vol 22 (18) ◽  
pp. 10001
Author(s):  
Curtis R. French
Keyword(s):  
Transcription Factors ◽  
Developmental Disorders ◽  
Anterior Segment ◽  
Therapeutic Interventions ◽  
Loss Of Function ◽  
Cardiovascular Malformations ◽  
Developmental Defects ◽  
Rieger Syndrome ◽  
Function Models ◽  
Shed Light

Axenfeld–Rieger syndrome (ARS) encompasses a group of developmental disorders that affect the anterior segment of the eye, as well as systemic developmental defects in some patients. Malformation of the ocular anterior segment often leads to secondary glaucoma, while some patients also present with cardiovascular malformations, craniofacial and dental abnormalities and additional periumbilical skin. Genes that encode two transcription factors, FOXC1 and PITX2, account for almost half of known cases, while the genetic lesions in the remaining cases remain unresolved. Given the genetic similarity between zebrafish and humans, as well as robust antisense inhibition and gene editing technologies available for use in these animals, loss of function zebrafish models for ARS have been created and shed light on the mechanism(s) whereby mutations in these two transcription factors cause such a wide array of developmental phenotypes. This review summarizes the published phenotypes in zebrafish foxc1 and pitx2 loss of function models and discusses possible mechanisms that may be used to target pharmaceutical development and therapeutic interventions.

scholarly journals PEA15 loss of function and defective cerebral development in the domestic cat

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1008671
Author(s):  
Emily C. Graff ◽  
J. Nicholas Cochran ◽  
Christopher B. Kaelin ◽  
Kenneth Day ◽  
Heather L. Gray-Edwards ◽  
...  
Keyword(s):  
White Matter ◽  
Internal Capsule ◽  
Immunohistochemical Analysis ◽  
Domestic Cat ◽  
Anterior Cingulate ◽  
Model Organisms ◽  
Loss Of Function ◽  
Average Decrease ◽  
Targeted Mutation ◽  
Underlying Pathophysiology

Cerebral cortical size and organization are critical features of neurodevelopment and human evolution, for which genetic investigation in model organisms can provide insight into developmental mechanisms and the causes of cerebral malformations. However, some abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an intracellular adapter protein, and suggesting an underlying pathophysiology in which increased death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal organization of neuronal layers and loss of white matter. Taken together, our work points to a new role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic species.

scholarly journals Biological function of cobalamin: causes and effects of hypocobalaminemia at the molecular, cellular, tissue and organism level

2020 ◽  
Vol 74 ◽  
pp. 443-451
Author(s):  
Zuzanna Rzepka ◽  
Mateusz Maszczyk ◽  
Dorota Wrześniok
Keyword(s):  
Vitamin B12 ◽  
Biological Function ◽  
Clinical Symptoms ◽  
Tricarboxylic Acid Cycle ◽  
Megaloblastic Anemia ◽  
Vitamin B12 Deficiency ◽  
Cellular Tissue ◽  
Water Soluble ◽  
Cobalamin Deficiency ◽  
Loss Of Function

Cobalamin (vitamin B12) is a complex compound, which is classified as a water-soluble vitamin. Absorption of cobalamin in the gut and its transport to cells is a unique process, in which many proteins are involved. The loss of function of these proteins causes serious cell homeostasis disturbance, which may result in the dysfunction of many tissues and organs. Vitamin B12, a cofactor of methionine synthase, provides methylation process and nucleic acid synthesis. Cobalamin is also necessary for methylmalonyl-CoA mutase activity. The enzyme synthesizes succinyl-CoA, an intermediate in tricarboxylic acid cycle. Vitamin B12 deficiency is an important and current health problem. It may be caused by insufficient dietary intake, age, or disease-related malabsorption and genetic defects of mechanisms involved in the absorption, transport and metabolism of cobalamin. Hypocobalaminemia can also result from long-term pharmacotherapy with medicines: metformin, proton pump inhibitors (e.g. omeprazole) and H2-receptor antagonists (e.g. ranitidine). Significant clinical symptoms of cobalamin deficiency include hematological abnormalities, mainly megaloblastic anemia, as well as neurological disorders resulting from degeneration within the nervous system. Early diagnosis and starting treatment with vitamin B12 increase chances for a complete cure. Therefore, the diagnostically important symptom of hypocobalaminemia may be skin manifestations, mainly hyperpigmentations, but also premature graying of hair. The aim of this review article was to summarize the current state of knowledge on the biological function of cobalamin, as well as the causes and consequences of its deficiency at the molecular, cellular, tissue and organism level.

scholarly journals TMED3/RPS15A Axis promotes the development and progression of osteosarcoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Xu ◽  
Yifan Li ◽  
Xiaojian Ye ◽  
Yunhan Ji ◽  
Yu Chen ◽  
...  
Keyword(s):  
Biological Function ◽  
Profile Analysis ◽  
Tumor Model ◽  
Underlying Mechanism ◽  
Molecular Therapy ◽  
Loss Of Function ◽  
Osteosarcoma Cells ◽  
Downstream Target

Abstract Background Osteosarcoma is a primary malignant tumor that mainly affects children and young adults. Transmembrane emp24 trafficking protein 3 (TMED3) may be involved in the regulation of malignant cancer behaviors. However, the role of TMED3 in osteosarcoma remains mysterious. In this study, the potential biological function and underlying mechanism of TMED3 in progression of osteosarcoma was elaborated. Methods The expression of TMED3 in osteosarcoma was analyzed by immunohistochemical staining. The biological function of TMED3 in osteosarcoma was determined through loss-of-function assays in vitro. The effect of TMED3 downregulation on osteosarcoma was further explored by xenograft tumor model. The molecular mechanism of the regulation of TMED3 on osteosarcoma was determined by gene expression profile analysis. Results The expression of TMED3 in osteosarcoma tissues was significantly greater than that in matched adjacent normal tissues. Knockdown of TMED3 inhibited the progression of osteosarcoma by suppressing proliferation, impeding migration and enhancing apoptosis in vitro. We further validated that knockdown of TMED3 inhibited osteosarcoma generation in vivo. Additionally, ribosomal protein S15A (RPS15A) was determined as a potential downstream target for TMED3 involved in the progression of osteosarcoma. Further investigations elucidated that the simultaneous knockdown of RPS15A and TMED3 intensified the inhibitory effects on osteosarcoma cells. Importantly, knockdown of RPS15A alleviated the promotion effects of TMED3 overexpression in osteosarcoma cells. Conclusions In summary, these findings emphasized the importance of TMED3/RPS15A axis in promoting tumor progression, which may be a promising candidate for molecular therapy of osteosarcoma.

scholarly journals MiR-16-1*and miR-16-2*possess strong tumor suppressive and anti-metastatic properties in osteosarcoma

2018 ◽  
Author(s):  
Vadim V. Maximov ◽  
Saleh Khawaled ◽  
Zaidoun Salah ◽  
Lina Jaber ◽  
Nataly Bengaiev ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Ectopic Expression ◽  
Loss Of Function ◽  
Primary Tumor Growth ◽  
Fatal Disease ◽  
Passenger Strand ◽  
Rna Immunoprecipitation ◽  
Direct Target ◽  
Shed Light ◽  
Validation Experiments

AbstractOsteosarcoma (OS) is an aggressive malignancy affecting mostly children and adolescents. MicroRNAs (miRNAs) play important roles in OS development and progression. Here we found that miR-16-1* and miR-16-2* “passenger” strands as well as the “lead” miR-16 strand possess strong tumor suppressive functions in human OS. We report different although strongly overlapping functions for miR-16-1* and miR-16-2* in OS cells. Ectopic expression of these miRNAs affected primary tumor growth, metastasis seeding, and chemoresistance and invasiveness of human OS cells. Loss-of-function experiments verified tumor suppressive functions of these miRNAs at endogenous levels of expression. Using RNA immunoprecipitation (RIP) assays, we identify direct targets of miR-16-1* and miR-16-2* in OS cells. Furthermore, validation experiments identifiedFGFR2as a direct target for miR-16-1* and miR-16-2*. Overall, our findings underscore the importance of passenger strand miRNAs in osteosarcomagenesis.Novelty and ImpactOsteosarcoma (OS) can be a fatal disease. MicroRNAs (miRNAs) play crucial roles in osteosarcomagenesis. In this study, we identify miR-16-1* and miR-16-2* as strong tumor suppressors and anti-metastatic genes in OS. This is the first report demonstrating tumor suppressive functions of passenger strands of these miRNAs in OS. Given thatMIR-16-1is located in 13q14 region that is commonly deleted in several human malignancies, our findings shed light on oncogenic mechanisms triggered by 13q14 deletion.

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