Forces and torques in the nucleus: chromatin under mechanical constraintsThis paper is one of a selection of papers published in this Special Issue, entitled 29th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 87 (1) ◽  
pp. 307-322 ◽  
Author(s):  
Christophe Lavelle
Keyword(s):  
Single Molecule ◽  
Ad Hoc ◽  
Peer Review Process ◽  
Critical Role ◽  
Experimental Studies ◽  
Dynamic Changes ◽  
Physical Constraints ◽  
Mechanical Constraints ◽  
Selection Of

Genomic DNA in eukaryotic cells is organized in discrete chromosome territories, each consisting of a single huge hierarchically supercoiled nucleosomal fiber. Through dynamic changes in structure, resulting from chemical modifications and mechanical constraints imposed by numerous factors in vivo, chromatin plays a critical role in the regulation of DNA metabolism processes, including replication and transcription. Indeed, DNA-translocating enzymes, such as polymerases, produce physical constraints that chromatin has to overcome. Recent techniques, in particular single-molecule micromanipulation, have allowed precise quantization of forces and torques at work in the nucleus and have greatly improved our understanding of chromatin behavior under physiological mechanical constraints. These new biophysical approaches should enable us to build realistic mechanistic models and progressively specify the ad hoc and hazy “because of chromatin structure” argument often used to interpret experimental studies of biological function in the context of chromatin.

scholarly journals The Anti-Neuroinflammatory Effect of Fuzi and Ganjiang Extraction on LPS-Induced BV2 Microglia and Its Intervention Function on Depression-Like Behavior of Cancer-Related Fatigue Model Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Songwei Yang ◽  
Yantao Yang ◽  
Cong Chen ◽  
Huiqin Wang ◽  
Qidi Ai ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Inflammatory Mediators ◽  
Critical Role ◽  
Chinese Herb ◽  
Experimental Studies ◽  
Research Results ◽  
Cancer Related Fatigue

The Chinese herb couple Fuzi and Ganjiang (FG) has been a classic combination of traditional Chinese medicine that is commonly used clinically in China for nearly 2000 years. Traditional Chinese medicine suggests that FG can treat various ailments, including heart failure, fatigue, gastrointestinal upset, and depression. Neuroinflammation is one of the main pathogenesis of many neurodegenerative diseases in which microglia cells play a critical role in the occurrence and development of neuroinflammation. FG has been clinically proven to have an efficient therapeutic effect on depression and other neurological disorders, but its mechanism remains unknown. Cancer-related fatigue (CRF) is a serious threat to the quality of life of cancer patients and is characterized by both physical and psychological fatigue. Recent studies have found that neuroinflammation is a key inducement leading to the occurrence and development of CRF. Traditional Chinese medicine theory believes that extreme fatigue and depressive symptoms of CRF are related to Yang deficiency, and the application of Yang tonic drugs such as Fuzi and Ganjiang can relieve CRF symptoms, but the underlying mechanisms remain unknown. In order to define whether FG can inhibit CRF depression-like behavior by suppressing neuroinflammation, we conducted a series of experimental studies in vitro and in vivo. According to the UPLC-Q-TOF/MSE results, we speculated that there were 49 compounds in the FG extraction, among which 30 compounds were derived from Fuzi and 19 compounds were derived from Ganjiang. Our research data showed that FG can effectively reduce the production of pro-inflammatory mediators IL-6, TNF-α, ROS, NO, and PGE2 and suppress the expression of iNOS and COX2, which were related to the inhibition of NF-κB/activation of Nrf2/HO-1 signaling pathways. In addition, our research results revealed that FG can improve the depression-like behavior performance of CRF model mice in the tail suspension test, open field test, elevated plus maze test, and forced swimming test, which were associated with the inhibition of the expression of inflammatory mediators iNOS and COX2 in the prefrontal cortex and hippocampus of CRF model mice. Those research results suggested that FG has a satisfactory effect on depression-like behavior of CRF, which was related to the inhibition of neuroinflammation.

scholarly journals Can Hypoxic Conditioning Improve Bone Metabolism? A Systematic Review

2019 ◽  
Vol 16 (10) ◽  
pp. 1799 ◽  
Author(s):  
Marta Camacho-Cardenosa ◽  
Alba Camacho-Cardenosa ◽  
Rafael Timón ◽  
Guillermo Olcina ◽  
Pablo Tomas-Carus ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Experimental Studies ◽  
Hormonal Responses ◽  
Hypoxia Exposure ◽  
Ambient Oxygen ◽  
The Impact

Among other functions, hypoxia-inducible factor plays a critical role in bone–vascular coupling and bone formation. Studies have suggested that hypoxic conditioning could be a potential nonpharmacological strategy for treating skeletal diseases. However, there is no clear consensus regarding the bone metabolism response to hypoxia. Therefore, this review aims to examine the impact of different modes of hypoxia conditioning on bone metabolism. The PubMed and Web of Science databases were searched for experimental studies written in English that investigated the effects of modification of ambient oxygen on bone remodelling parameters of healthy organisms. Thirty-nine studies analysed the effect of sustained or cyclic hypoxia exposure on genetic and protein expression and mineralisation capacity of different cell models; three studies carried out in animal models implemented sustained or cyclic hypoxia; ten studies examined the effect of sustained, intermittent or cyclic hypoxia on bone health and hormonal responses in humans. Different modes of hypoxic conditioning may have different impacts on bone metabolism both in vivo and in vitro. Additional research is necessary to establish the optimal cyclical dose of oxygen concentration and exposure time.

CSPα: the neuroprotective J proteinThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 157-165 ◽  
Author(s):  
Jadah N. Johnson ◽  
Eva Ahrendt ◽  
Janice E.A. Braun
Keyword(s):  
Peer Review Process ◽  
Secretory Granules ◽  
Critical Role ◽  
Premature Death ◽  
Cysteine String Protein ◽  
J Proteins ◽  
Progressive Neurodegeneration ◽  
Client Proteins ◽  
Shock Proteins ◽  
Selection Of

Cysteine string protein (CSPα, also called DnaJC5) is unique among J proteins. Similar to other J proteins, CSPα interacts with and activates the ATPase of Hsc70s (heat shock proteins of 70 kDa), thereby harnessing the ATPase activity for conformational work on client proteins. In contrast to other J proteins, CSPα is anchored to synaptic vesicles, as well as to exocrine, endocrine and neuroendocrine secretory granules, and has been shown to have an essential anti-neurodegenerative role. CSPα-null organisms exhibit progressive neurodegeneration, behavioural deficits, and premature death, most likely due to the progressive misfolding of one or more client proteins. Here we highlight recent advances in our understanding of the critical role that CSPα plays in governing exocytotic secretory functions.

scholarly journals Normal Thymocyte Negative Selection in TRAIL-deficient Mice

2003 ◽  
Vol 198 (3) ◽  
pp. 491-496 ◽  
Author(s):  
Erika Cretney ◽  
Adam P. Uldrich ◽  
Stuart P. Berzins ◽  
Andreas Strasser ◽  
Dale I. Godfrey ◽  
...  
Keyword(s):  
Negative Selection ◽  
Fas Ligand ◽  
Critical Role ◽  
Death Receptor ◽  
Critical Factor ◽  
Immunological Tolerance ◽  
Trail Signaling ◽  
Selection Of

The molecular basis of thymocyte negative selection, which plays a critical role in establishing and maintaining immunological tolerance, is not yet resolved. In particular, the importance of the death receptor subgroup of the tumor necrosis factor (TNF)-family has been the subject of many investigations, with equivocal results. A recent report suggested that TRAIL was a critical factor in this process, a result that does not fit well with previous studies that excluded a role for the FADD-caspase 8 pathway, which is essential for TRAIL and Fas ligand (FasL) signaling, in negative selection. We have investigated intrathymic negative selection of TRAIL-deficient thymocytes, using four well-established models, including antibody-mediated TCR/CD3 ligation in vitro, stimulation with endogenous superantigen in vitro and in vivo, and treatment with exogenous superantigen in vitro. We were unable to demonstrate a role for TRAIL signaling in any of these models, suggesting that this pathway is not a critical factor for thymocyte negative selection.

scholarly journals Integral methods for automatic quantification of fast-scan-cyclic-voltammetry detected neurotransmitters

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254594
Author(s):  
Leonardo X. Espín ◽  
Anders J. Asp ◽  
James K. Trevathan ◽  
Kip A. Ludwig ◽  
J. Luis Lujan
Keyword(s):  
Ad Hoc ◽  
Time Integration ◽  
Large Data ◽  
Data Sets ◽  
Oxidation Reactions ◽  
Fast Scan Cyclic Voltammetry ◽  
Integral Methods ◽  
Selection Of

Modern techniques for estimating basal levels of electroactive neurotransmitters rely on the measurement of oxidative charges. This requires time integration of oxidation currents at certain intervals. Unfortunately, the selection of integration intervals relies on ad-hoc visual identification of peaks on the oxidation currents, which introduces sources of error and precludes the development of automated procedures necessary for analysis and quantification of neurotransmitter levels in large data sets. In an effort to improve charge quantification techniques, here we present novel methods for automatic selection of integration boundaries. Our results show that these methods allow quantification of oxidation reactions both in vitro and in vivo and of multiple analytes in vitro.

Impact and mechanistic role of MicroRNA-1291 on pancreatic tumorigenesis.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 243-243 ◽  
Author(s):  
Mei-Juan Tu ◽  
Yu-Zhuo Pan ◽  
Jing-Xin Qiu ◽  
Edward Jae-hoon Kim ◽  
Aiming Yu
Keyword(s):  
Cell Cycle ◽  
Cancer Biology ◽  
Critical Role ◽  
Experimental Studies ◽  
Mass Spectrometry Analysis ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Spectrometry Analysis

243 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Better understanding of pancreatic cancer biology and identification of new targets are highly warranted. MicroRNAs (miRs or miRNAs) play a critical role in the control of tumor progression via crosstalk with cancer signaling pathways. Our recent studies showed that miR-1291 improved chemosensitivity through targeting of efflux transporter ABCC1. This current study investigated the mechanistic role of miR-1291 in the suppression of pancreatic tumorigenesis. Methods: PANC-1 and AsPC-1 cell lines were stably transfected with miR-1291. Cell cycle status and apoptosis of stable miR-1291-expressing cells were tested against control cells using flow cytometry. Cells were injected subcutaneously into nude mice and tumorigenesis was measured in vivo. Proteomic studies were performed by two-dimensional difference gel electrophoresis, matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis. Computationally predicted miR-1291 targets were assessed by luciferase reporter assay and Western blot. Primary PDAC and control samples were tested for miR-1291 and target gene expression levels. Results: Our data showed that stable miR-1291-expressing PANC-1 and AsPC-1 cells both showed a significantly lower rate of proliferation than the control cells, which was associated with a cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 suppressed the tumorigenesis of PANC-1 cells in mouse models in vivo. Proteomic studies revealed the protein level of several cancer-related genes were downregulated by miR-1291, including a pancreatic tumor promoting protein AGR2 which was reduced ~10-fold. Through computational and experimental studies we further identified that FOXA2, a transcription factor governing AGR2 expression, was a direct target of miR-1291. In addition, we found a significant down-regulation of miR-1291 in a set of PDAC patient tumor samples overexpressing AGR2. Conclusions: These results indicate that miR-1291 suppresses pancreatic tumorigenesis via targeting of FOXA2-AGR regulatory pathway providing new insight supporting development of miR-1291-based therapy for PDAC.

In vitro chromatin self-association and its relevance to genome architectureThis paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

2006 ◽  
Vol 84 (4) ◽  
pp. 411-417 ◽  
Author(s):  
Xu Lu ◽  
Joshua M. Klonoski ◽  
Michael G. Resch ◽  
Jeffrey C. Hansen
Keyword(s):  
Peer Review ◽  
West Coast ◽  
Review Process ◽  
Peer Review Process ◽  
Special Issue ◽  
Eukaryotic Nucleus ◽  
Self Association ◽  
Selection Of

Chromatin in a eukaryotic nucleus is condensed through 3 hierarchies: primary, secondary, and tertiary chromatin structures. In vitro, when induced with cations, chromatin can self-associate and form large oligomers. This self-association process has been proposed to mimic processes involved in the assembly and maintenance of tertiary chromatin structures in vivo. In this article, we review 30 years of studies of chromatin self-association, with an emphasis on the evidence suggesting that this in vitro process is physiologically relevant.

scholarly journals Charge, hydrophobicity, and confined water: putting past simulations into a simple theoretical frameworkThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 359-369 ◽  
Author(s):  
Jeremy L. England ◽  
Vijay S. Pande
Keyword(s):  
Protein Folding ◽  
Self Assembly ◽  
Peer Review Process ◽  
Cellular Biology ◽  
Confined Water ◽  
Wide Range ◽  
Statistical Mechanical Model ◽  
Statistical Mechanical ◽  
Selection Of

Water permeates all life, and mediates forces that are essential to the process of macromolecular self-assembly. Predicting these forces in a given biological context is challenging, since water organizes itself differently next to charged and hydrophobic surfaces, both of which are typically at play on the nanoscale in vivo. In this work, we present a simple statistical mechanical model for the forces water mediates between different confining surfaces, and demonstrate that the model qualitatively unifies a wide range of phenomena known in the simulation literature, including several cases of protein folding under confinement.

Ribosomal synthesis of nonstandard peptidesThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Systems and Chemical Biology, and has undergone the Journal's usual peer review process.

2008 ◽  
Vol 86 (2) ◽  
pp. 92-99 ◽  
Author(s):  
Taek Jin Kang ◽  
Hiroaki Suga
Keyword(s):  
Peer Review Process ◽  
Integrated System ◽  
Historical Background ◽  
Cell Permeability ◽  
Specific Chemical ◽  
Free Translation ◽  
Therapeutic Peptides ◽  
Drug Leads ◽  
Selection Of

It is well known that standard peptides, which comprise proteinogenic amino acids, can act as specific chemical probes to target proteins with high affinity. Despite this fact, a number of peptide drug leads have been abandoned because of their poor cell permeability and protease instability. On the other hand, nonstandard peptides isolated as natural products often exhibit remarkable pharmaco-behavior and stability in vivo. Although it is likely that numerous nonstandard therapeutic peptides capable of recognizing various targets could have been synthesized, enzymes for nonribosomal peptide syntheses are complex; therefore, it is difficult to engineer such modular enzymes to build nonstandard peptide libraries. Here we describe an emerging technology for the synthesis of nonstandard peptides that employs an integrated system of reconstituted cell-free translation and flexizymes. We summarize the historical background of this technology and discuss its current and future applications to the synthesis of nonstandard peptides and drug discovery.

scholarly journals Biased localization of actin binding proteins by actin filament conformation

2020 ◽  
Author(s):  
Andrew R Harris ◽  
Pamela Jreij ◽  
Brian Belardi ◽  
Andreas Bausch ◽  
Daniel A Fletcher
Keyword(s):  
Actin Filament ◽  
Single Molecule ◽  
Conformational Changes ◽  
Actin Filaments ◽  
Binding Proteins ◽  
Critical Role ◽  
Actin Binding ◽  
Cell Physiology ◽  
Physical Constraints

ABSTRACTThe assembly of actin filaments into distinct cytoskeletal structures plays a critical role in cell physiology, but how proteins localize differentially to these structures within a shared cytoplasm remains unclear. Here, we show that the actin-binding domains of accessory proteins can be sensitive to filament conformational changes. Using a combination of live cell imaging and in vitro single molecule binding measurements, we show that tandem calponin homology domains (CH1-CH2) can be mutated to preferentially bind actin networks at the front or rear of motile cells, and we demonstrate that the affinity of CH1-CH2 domain mutants varies as actin filament conformation is altered by perturbations that include stabilizing drugs, physical constraints, and other binding proteins. These findings suggest that conformational heterogeneity of actin filaments in cells could help to direct accessory binding proteins to different actin cytoskeletal structures through a biophysical feedback loop.

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