scholarly journals Past, present and future experiments on muscle

2000 ◽  
Vol 355 (1396) ◽  
pp. 539-543 ◽  
Author(s):  
H. E. Huxley
Keyword(s):  
Molecular Motors ◽  
Molecular Mechanisms ◽  
Atp Hydrolysis ◽  
Large Change ◽  
Technical Difficulty ◽  
Definitive Evidence ◽  
Technical Developments ◽  
Mechanical Information ◽  
Cross Bridges

Since the basic outline of the sliding filament mechanism became apparent some 45 years ago, the principal challenge, an experimental one, has been to produce definitive evidence about the detailed molecular mechanisms by which myosin cross–bridges produce force and movement in a muscle. More recently, similar questions could be posed about other molecular motors, in non–muscle cells. This problem proved unexpectedly difficult to solve, in part because of the technical difficulty of obtaining the structural and mechanical information required about rapid events within macromolecules, especially in a working system, and this triggered many remarkable technical developments. There is now very strong evidence for a large change in shape of the myosin heads during ATP hydrolysis, consistent with a leverarm mechanism. Whether this does indeed provide the driving force for contraction and movement— and, if so, exactly how—and whether some other processes could also play a significant role, is discussed in the light of the experimental and theoretical findings presented at this meeting, and other recent and long–term evidence.

scholarly journals Inducible molecular switches for the study of long-term potentiation

2003 ◽  
Vol 358 (1432) ◽  
pp. 797-804 ◽  
Author(s):  
Gaël Hédou ◽  
Isabelle M. Mansuy
Keyword(s):  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Knock Out ◽  
Technical Developments ◽  
Term Potentiation ◽  
Dependent Protein ◽  
Strength And Plasticity ◽  
Regulated Gene Expression ◽  
Molecular Bases

This article reviews technical and conceptual advances in unravelling the molecular bases of long-term potentiation (LTP), learning and memory using genetic approaches. We focus on studies aimed at testing a model suggesting that protein kinases and protein phosphatases balance each other to control synaptic strength and plasticity. We describe how gene ‘knock-out’ technology was initially exploited to disrupt the Ca 2+ /calmodulin-dependent protein kinase II α (CaMKII α ) gene and how refined knock-in techniques later allowed an analysis of the role of distinct phosphorylation sites in CaMKII. Further to gene recombination, regulated gene expression using the tetracycline-controlled transactivator and reverse tetracycline-controlled transactivator systems, a powerful new means for modulating the activity of specific molecules, has been applied to CaMKII α and the opposing protein phosphatase calcineurin. Together with electro-physiological and behavioural evaluation of the engineered mutant animals, these genetic methodologies have helped gain insight into the molecular mechanisms of plasticity and memory. Further technical developments are, however, awaited for an even higher level of finesse.

scholarly journals Molecular mechanisms of substrate-controlled ring dynamics and sub-stepping in a nucleic-acid dependent hexameric motor

2016 ◽  
Author(s):  
Nathan D. Thomsen ◽  
Michael R. Lawson ◽  
Lea B. Witkowsky ◽  
Song Qu ◽  
James M. Berger
Keyword(s):  
Nucleic Acid ◽  
Conformational Changes ◽  
Molecular Motors ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Atp Hydrolysis ◽  
Ring Closure ◽  
Structural Studies ◽  
Saxs Data ◽  
Structural Methods

ABSTRACTRing-shaped hexameric helicases and translocases support essential DNA, RNA, and protein-dependent transactions in all cells and many viruses. How such systems coordinate ATPase activity between multiple subunits to power conformational changes that drive the engagement and movement of client substrates is a fundamental question. Using the E. coli Rho transcription termination factor as a model system, we have employed solution and crystallographic structural methods to delineate the range of conformational changes that accompany distinct substrate and nucleotide cofactor binding events. SAXS data show that Rho preferentially adopts an open-ring state in solution, and that RNA and ATP are both required to cooperatively promote ring closure. Multiple closed-ring structures with different RNA substrates and nucleotide occupancies capture distinct catalytic intermediates accessed during translocation. Our data reveal how RNA-induced ring closure templates a sequential ATP-hydrolysis mechanism, provide a molecular rationale for how the Rho ATPase domains distinguishes between distinct RNA sequences, and establish the first structural snapshots of substepping events in a hexameric helicase/translocase.SIGNIFICANCEHexameric, ring-shaped translocases are molecular motors that convert the chemical energy of ATP hydrolysis into the physical movement of protein and nucleic acid substrates. Structural studies of several distinct hexameric translocases have provided insights into how substrates are loaded and translocated; however, the range of structural changes required for coupling ATP turnover to a full cycle of substrate loading and translocation has not been visualized for any one system. Here, we combine low-and high-resolution structural studies of the Rho helicase, defining for the first time the ensemble of conformational transitions required both for substrate loading in solution and for substrate movement by a processive hexameric translocase.

Lost Glory

2018 ◽  
Author(s):  
Sumit K. Majumdar
Keyword(s):  
Positive Impact ◽  
Positive Outcomes ◽  
State Sector ◽  
Definitive Evidence ◽  
Industrial Landscape ◽  
Intellectual Origins ◽  
Automobile Manufacturer ◽  
High Output

Lost Glory: India’s Capitalism Story describes India’s industrialization experiences. Questions about long-term industry and productivity evolution, and their impact on economic growth, lie at the heart of discourses of capitalism. The book is based on detailed empirical analyses of India’s industrialization over a period of almost seven decades, and a case study of Maruti Suzuki, India’s largest automobile manufacturer. The deeply nuanced depiction of the historical political economy that has affected India’s industrialization is a unique feature. This history will enlighten everyone interested in India. The presentation takes readers on a definitive evidence-based survey of India’s industrial landscape. It includes a detailed historical description of the intellectual origins of India’s modern industrialization, anchored in a privileged view of economic policymaking. Grounded in historical and political analyses, the facts derived on India’s long-term economic performance are used to set the record straight. It is unsparing in its assessments where the evidence warrants such conclusions. Its findings will transform debate, and set the agenda for thoughtfully assessing the future course of India’s prosperity. The author overturns the assumptions that India’s much-vaunted private sector firms only engender positive outcomes, finding State-sector firms to have become efficient, and the molecular sector to be as effective overall, while also challenging the notion that privatization is necessary for progress. Conversely, it is found that competition policy innovations to have had positive impact. Practical suggestions are provided and three fundamental reforms, one administrative, one structural, and one behavioral, necessary to regenerate high output, are advocated.

scholarly journals Cardiac Cell Therapy: Insights into the Mechanisms of Tissue Repair

2021 ◽  
Vol 22 (3) ◽  
pp. 1201
Author(s):  
Hsuan Peng ◽  
Kazuhiro Shindo ◽  
Renée R. Donahue ◽  
Ahmed Abdel-Latif
Keyword(s):  
Stem Cell ◽  
Immune Responses ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Cell Delivery ◽  
Cardiac Cell Therapy ◽  
Stem Cell Treatment

Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.

scholarly journals RNAseq Reveals Differential Gene Expression Contributing to Phytophthora nicotianae Adaptation to Partial Resistance in Tobacco

Agronomy ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 656
Author(s):  
Jing Jin ◽  
Rui Shi ◽  
Ramsey Steven Lewis ◽  
Howard David Shew
Keyword(s):  
Partial Resistance ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Effective Means ◽  
Phytophthora Nicotianae ◽  
Economic Losses ◽  
Black Shank ◽  
Differential Gene ◽  
Go Terms

Phytophthora nicotianae is a devastating oomycete plant pathogen with a wide host range. On tobacco, it causes black shank, a disease that can result in severe economic losses. Deployment of host resistance is one of the most effective means of controlling tobacco black shank, but adaptation to complete and partial resistance by P. nicotianae can limit the long-term effectiveness of the resistance. The molecular basis of adaptation to partial resistance is largely unknown. RNAseq was performed on two isolates of P. nicotianae (adapted to either the susceptible tobacco genotype Hicks or the partially resistant genotype K 326 Wz/Wz) to identify differentially expressed genes (DEGs) during their pathogenic interactions with K 326 Wz/Wz and Hicks. Approximately 69% of the up-regulated DEGs were associated with pathogenicity in the K 326 Wz/Wz-adapted isolate when sampled following infection of its adapted host K 326 Wz/Wz. Thirty-one percent of the up-regulated DEGs were associated with pathogenicity in the Hicks-adapted isolate on K 326 Wz/Wz. A broad spectrum of over-represented gene ontology (GO) terms were assigned to down-regulated genes in the Hicks-adapted isolate. In the host, a series of GO terms involved in nuclear biosynthesis processes were assigned to the down-regulated genes in K 326 Wz/Wz inoculated with K 326 Wz/Wz-adapted isolate. This study enhances our understanding of the molecular mechanisms of P. nicotianae adaptation to partial resistance in tobacco by elucidating how the pathogen recruits pathogenicity-associated genes that impact host biological activities.

scholarly journals Vitamin D Deficiency in Testicular Cancer Survivors: A Systematic Review

2021 ◽  
Vol 22 (10) ◽  
pp. 5145
Author(s):  
Giuseppe Schepisi ◽  
Caterina Gianni ◽  
Sara Bleve ◽  
Silvia De Padova ◽  
Cecilia Menna ◽  
...  
Keyword(s):  
Vitamin D ◽  
Testicular Cancer ◽  
Vitamin D Deficiency ◽  
Molecular Mechanisms ◽  
Hypovitaminosis D ◽  
Young Males ◽  
Report Data ◽  
Testicular Cancer Survivors ◽  
Patients Experience

Testicular cancer (TC) is the most frequent tumor in young males. In the vast majority of cases, it is a curable disease; therefore, very often patients experience a long survival, also due to their young age at diagnosis. In the last decades, the role of the vitamin D deficiency related to orchiectomy has become an increasingly debated topic. Indeed, vitamin D is essential in bone metabolism and many other metabolic pathways, so its deficiency could lead to various metabolic disorders especially in long-term TC survivors. In our article, we report data from studies that evaluated the incidence of hypovitaminosis D in TC survivors compared with cohorts of healthy peers and we discuss molecular mechanisms and clinical implications.

scholarly journals Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 25
Author(s):  
Lara Macchioni ◽  
Davide Chiasserini ◽  
Letizia Mezzasoma ◽  
Magdalena Davidescu ◽  
Pier Luigi Orvietani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Nuclear Factor ◽  
Rpe Cells ◽  
Age Related ◽  
Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

scholarly journals Expression Profile of New Marker Genes Involved in Differentiation of Canine Adipose-Derived Stem Cells into Osteoblasts

2021 ◽  
Vol 22 (13) ◽  
pp. 6663
Author(s):  
Maurycy Jankowski ◽  
Mariusz Kaczmarek ◽  
Grzegorz Wąsiatycz ◽  
Claudia Dompe ◽  
Paul Mozdziak ◽  
...  
Keyword(s):  
Stem Cells ◽  
In Vitro Culture ◽  
Osteogenic Differentiation ◽  
Molecular Mechanisms ◽  
Marker Genes ◽  
P Value ◽  
Illumina Platform

Next-generation sequencing (RNAseq) analysis of gene expression changes during the long-term in vitro culture and osteogenic differentiation of ASCs remains to be important, as the analysis provides important clues toward employing stem cells as a therapeutic intervention. In this study, the cells were isolated from adipose tissue obtained during routine surgical procedures and subjected to 14-day in vitro culture and differentiation. The mRNA transcript levels were evaluated using the Illumina platform, resulting in the detection of 19,856 gene transcripts. The most differentially expressed genes (fold change >|2|, adjusted p value < 0.05), between day 1, day 14 and differentiated cell cultures were extracted and subjected to bioinformatical analysis based on the R programming language. The results of this study provide molecular insight into the processes that occur during long-term in vitro culture and osteogenic differentiation of ASCs, allowing the re-evaluation of the roles of some genes in MSC progression towards a range of lineages. The results improve the knowledge of the molecular mechanisms associated with long-term in vitro culture and differentiation of ASCs, as well as providing a point of reference for potential in vivo and clinical studies regarding these cells’ application in regenerative medicine.

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