scholarly journals Weak catch bonds make strong networks

2020 ◽  
Author(s):  
Yuval Mulla ◽  
Mario J Avellaneda ◽  
Antoine Roland ◽  
Lucia Baldauf ◽  
Sander J Tans ◽  
...  
Keyword(s):  
Binding Sites ◽  
Fluid Flows ◽  
Actin Networks ◽  
On Demand ◽  
High Tension ◽  
Weak Binding ◽  
Cryptic Binding Sites ◽  
Current Paradigm ◽  
Catch Bonds

Molecular catch bonds are ubiquitous in biology and well-studied in the context of leukocyte extravasion1, cellular mechanosensing2,3, and urinary tract infection4. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this remarkable ability enables cells to increase their adhesion in fast fluid flows1,4, and hence provides ‘strength-on-demand’. Recently, cytoskeletal crosslinkers have been discovered that also display catch bonding5–8. It has been suggested that they strengthen cells, following the strength-on-demand paradigm9,10. However, catch bonds tend to be weaker compared to regular (slip) bonds because they have cryptic binding sites that are often inactive11–13. Therefore, the role of catch bonding in the cytoskeleton remains unclear. Here we reconstitute cytoskeletal actin networks to show that catch bonds render them both stronger and more deformable than slip bonds, even though the bonds themselves are weaker. We develop a model to show that weak binding allows the catch bonds to mitigate crack initiation by moving from low- to high-tension areas in response to mechanical loading. By contrast, slip bonds remain trapped in stress-free areas. We therefore propose that the mechanism of catch bonding is typified by dissociation-on-demand rather than strength-on-demand. Dissociation-on-demand can explain how both cytolinkers5–8,10,14,15 and adhesins1,2,4,12,16–20 exploit continuous redistribution to combine mechanical strength with the adaptability required for movement and proliferation21. Our findings provide a mechanistic understanding of diseases where catch bonding is compromised11,12 such as kidney focal segmental glomerulosclerosis22,23, caused by the α-actinin-4 mutant studied here. Moreover, catch bonds provide a route towards creating life-like materials that combine strength with deformability24.

scholarly journals Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution

2013 ◽  
Vol 368 (1632) ◽  
pp. 20130018 ◽  
Author(s):  
Andrea I. Ramos ◽  
Scott Barolo
Keyword(s):  
Transcription Factor ◽  
Binding Affinity ◽  
Binding Sites ◽  
Target Genes ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Morphogen Gradients ◽  
Weak Binding ◽  
Initial Hypothesis

In the era of functional genomics, the role of transcription factor (TF)–DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients . We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp , wingless and stripe , by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.

scholarly journals Role of the Transcription Activator Ste12p as a Repressor of PRY3 Expression

2006 ◽  
Vol 26 (21) ◽  
pp. 7901-7912 ◽  
Author(s):  
Kellie S. Bickel ◽  
David R. Morris
Keyword(s):  
Binding Sites ◽  
Full Length ◽  
Transcription Activator ◽  
Pheromone Response ◽  
Reading Frame ◽  
Short Transcript ◽  
Cryptic Binding Sites ◽  
Full Length Transcript ◽  
Transcript Evidence

ABSTRACT Mating pheromone represses synthesis of full-length PRY3 mRNA, and a new transcript appears simultaneously with its 5′ terminus 452 nucleotides inside the open reading frame (ORF). Synthesis of this shorter transcript results from activation of a promoter within the PRY3 locus, and its production is concomitant with the rapid disappearance of the full-length transcript. Evidence is consistent with the pheromone-induced transcription factor Ste12p binding two pheromone response elements within the PRY3 promoter, directly impeding transcription of the full-length mRNA while simultaneously inducing initiation of the short transcript. This process depends on a TATA box within the PRY3 ORF. Expression of full-length PRY3 inhibited mating, while no disadvantage was detectable for cells unable to make the short transcript. Therefore, Ste12p is utilized as a repressor of full-length PRY3 transcription, ensuring efficient mating. There is no evidence that production of the short PRY3 transcript is anything more than an adventitious by-product of this mechanism. It is possible that cryptic binding sites for transcriptional activators may occur frequently within genomes and have the potential of evolving for rapid, gene-specific repression by mechanisms analogous to PRY3. PRY3 regulation provides a model for the coordination of both inductive and repressive activities within a regulatory network.

Participation of ABCA1 transporter in development of chronic obstructive pulmonary disease

2020 ◽  
Vol 28 (3) ◽  
pp. 360-370
Author(s):  
Stanislav N. Kotlyarov ◽  
Anna A. Kotlyarova
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Significant Contribution ◽  
Modern Medicine ◽  
Lipid Homeostasis ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Reverse Transport ◽  
Current Paradigm

Despite all achievements of the modern medicine, the problem of chronic obstructive pulmonary disease (COPD) does not lose its relevance. The current paradigm suggests a key role of macrophages in inflammation in COPD. Macrophages are known to be heterogeneous in their functions. This heterogeneity is determined by their immunometabolic profile and also by peculiarities of lipid homeostasis of cells. Aim. To analyze the role of the ABCA1 transporter, a member of the ABC A subfamily, in the pathogenesis of COPD. The expression of ABCA1 in lung tissues is on the second place after the liver, which shows the important role of the carrier and of lipid homeostasis in the function of lungs. Analysis of the literature shows that participation of the transporter in inflammation consists in regulation of the content of cholesterol in the lipid rafts of the membranes, in phagocytosis and apoptosis. Conclusion. Through regulation of the process of reverse transport of cholesterol in macrophages of lungs, ABCA1 can change their inflammatory response, which makes a significant contribution to the pathogenesis of COPD.

Prawne aspekty eutanazji w Holandii

2016 ◽  
Vol 14 (3) ◽  
pp. 243-253
Author(s):  
Grzegorz Stefanowicz
Keyword(s):  
The Netherlands ◽  
Assisted Suicide ◽  
Public Authority ◽  
Dutch Society ◽  
On Demand ◽  
Limited Length ◽  
The Law ◽  
Death On Demand ◽  
The Way

This article undertakes to show the way that has led to the statutory decriminalization of euthanasia-related murder and assisted suicide in the Kingdom of the Netherlands. It presents the evolution of the views held by Dutch society on the euthanasia related practice, in the consequence of which death on demand has become legal after less than thirty years. Due attention is paid to the role of organs of public authority in these changes, with a particular emphasis put on the role of the Dutch Parliament – the States General. Because of scarcity of space and limited length of the article, the change in the attitudes toward euthanasia, which has taken place in the Netherlands, is presented in a synthetic way – from the first discussions on admissibility of a euthanasia-related murder carried out in the 1970s, through the practice of killing patients at their request, which was against the law at that time, but with years began more and more acceptable, up to the statutory decriminalization of euthanasia by the Dutch Parliament, made with the support of the majority of society.

scholarly journals The MarR-Type Regulator PA3458 Is Involved in Osmoadaptation Control in Pseudomonas aeruginosa

2021 ◽  
Vol 22 (8) ◽  
pp. 3982
Author(s):  
Karolina Kotecka ◽  
Adam Kawalek ◽  
Kamil Kobylecki ◽  
Aneta Agnieszka Bartosik
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Binding Sites ◽  
Transcriptional Profiling ◽  
Mrna Level ◽  
Transcriptional Regulators ◽  
Resistance Mechanisms ◽  
Chronic Infections ◽  
Environmental Signals ◽  
Regulatory Systems

Pseudomonas aeruginosa is a facultative human pathogen, causing acute and chronic infections that are especially dangerous for immunocompromised patients. The eradication of P. aeruginosa is difficult due to its intrinsic antibiotic resistance mechanisms, high adaptability, and genetic plasticity. The bacterium possesses multilevel regulatory systems engaging a huge repertoire of transcriptional regulators (TRs). Among these, the MarR family encompasses a number of proteins, mainly acting as repressors, which are involved in response to various environmental signals. In this work, we aimed to decipher the role of PA3458, a putative MarR-type TR from P. aeruginosa. Transcriptional profiling of P. aeruginosa PAO1161 overexpressing PA3458 showed changes in the mRNA level of 133 genes; among them, 100 were down-regulated, suggesting the repressor function of PA3458. Concomitantly, ChIP-seq analysis identified more than 300 PA3458 binding sites in P. aeruginosa. The PA3458 regulon encompasses genes involved in stress response, including the PA3459–PA3461 operon, which is divergent to PA3458. This operon encodes an asparagine synthase, a GNAT-family acetyltransferase, and a glutamyl aminopeptidase engaged in the production of N-acetylglutaminylglutamine amide (NAGGN), which is a potent bacterial osmoprotectant. We showed that PA3458-mediated control of PA3459–PA3461 expression is required for the adaptation of P. aeruginosa growth in high osmolarity. Overall, our data indicate that PA3458 plays a role in osmoadaptation control in P. aeruginosa.

scholarly journals The Role of Putative Fibrinogen Aα-, Bβ-, and γA-chain Integrin Binding Sites in Endothelial Cell-mediated Clot Retraction

1997 ◽  
Vol 272 (35) ◽  
pp. 22080-22085 ◽  
Author(s):  
Richard A. Smith ◽  
M. W. Mosesson ◽  
Michael M. Rooney ◽  
Susan T. Lord ◽  
A.U. Daniels ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Binding Sites ◽  
Clot Retraction

Role of Reynolds and Archimedes numbers in particle-fluid flows

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Haim Kalman
Keyword(s):  
Flow Regime ◽  
Power Function ◽  
Fluid Flows ◽  
Limited Range ◽  
Operating Conditions ◽  
Pneumatic Conveying ◽  
Particulate Materials ◽  
Simple Power ◽  
Simple Power Function

AbstractAny scientific behavior is best represented by nondimensional numbers. However, in many cases, for pneumatic conveying systems, dimensional equations are developed and used. In some cases, many of the nondimensional equations include Reynolds (Re) and Froude (Fr) numbers; they are usually defined for a limited range of materials and operating conditions. This study demonstrates that most of the relevant flow types, whether in horizontal or vertical pipes, can be better described by Re and Archimedes (Ar) numbers. Ar can also be used in hydraulic conveying systems. This paper presents many threshold velocities that are accurately defined by Re as a simple power function of Ar. Many particulate materials are considered by Ar, thereby linking them to a common behavior. Using various threshold velocities, a flow regime chart for horizontal conveying is presented in this paper.

scholarly journals The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside

Diagnostics ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 7
Author(s):  
Tomislav Meštrović ◽  
Mario Matijašić ◽  
Mihaela Perić ◽  
Hana Čipčić Paljetak ◽  
Anja Barešić ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Infections ◽  
Subsequent Development ◽  
Potential Influence ◽  
Urinary Microbiome ◽  
Important Field ◽  
Tract Infections ◽  
The Relationship ◽  
Current Paradigm

The current paradigm of urinary tract infection (UTI) pathogenesis takes into account the contamination of the periurethral space by specific uropathogens residing in the gut, which is followed by urethral colonization and pathogen ascension to the urinary bladder. Consequently, studying the relationship between gut microbiota and the subsequent development of bacteriuria and UTI represents an important field of research. However, the well-established diagnostic and therapeutic paradigm for urinary tract infections (UTIs) has come into question with the discovery of a multifaceted, symbiotic microbiome in the healthy urogenital tract. More specifically, emerging data suggest that vaginal dysbiosis may result in Escherichia coli colonization and prompt recurrent UTIs, while urinary microbiome perturbations may precede the development of UTIs and other pathologic conditions of the urinary system. The question is whether these findings can be exploited for risk reduction and treatment purposes. This review aimed to appraise the three aforementioned specific microbiomes regarding their potential influence on UTI development by focusing on the recent studies in the field and assessing the potential linkages between these different niches, as well as evaluating the state of translational research for novel therapeutic and preventative approaches.

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