scholarly journals Dermatophyte Virulence Factors: Identifying and Analyzing Genes That May Contribute to Chronic or Acute Skin Infections

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Rebecca Rashid Achterman ◽  
Theodore C. White
Keyword(s):  
Virulence Factors ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Sequence Information ◽  
Skin Infections ◽  
Future Directions ◽  
Keratinized Tissue ◽  
Genome Sequence Information

Dermatophytes are prevalent causes of cutaneous mycoses and, unlike many other fungal pathogens, are able to cause disease in immunocompetent individuals. They infect keratinized tissue such as skin, hair, and nails, resulting in tinea infections, including ringworm. Little is known about the molecular mechanisms that underlie the ability of these organisms to establish and maintain infection. The recent availability of genome sequence information and improved genetic manipulation have enabled researchers to begin to identify and study the role of virulence factors of dermatophytes. This paper will summarize our current understanding of dermatophyte virulence factors and discuss future directions for identifying and testing virulence factors.

scholarly journals L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Marco Giordano ◽  
Alessandra Decio ◽  
Chiara Battistini ◽  
Micol Baronio ◽  
Fabrizio Bianchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Tumor Formation ◽  
In Vitro Assays ◽  
Tumor Initiation ◽  
Loss Of Function ◽  
Stat3 Signaling

Abstract Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. Methods The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. Results We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. Conclusions Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

Future Directions for Pharmacogenetics

1993 ◽  
Vol 6 (1) ◽  
pp. 44-46
Author(s):  
Michael W. Jann ◽  
Y.W. Francis Lam
Keyword(s):  
Molecular Mechanisms ◽  
Regulatory Control ◽  
Ethnic Variation ◽  
Metabolizing Enzymes ◽  
Future Directions ◽  
Clinical Investigations ◽  
Length Polymorphisms ◽  
Polymerase Chain

The discipline of pharmacogenetics will continue to expand as scientific and clinical investigations increase our understanding of genetic variabilities in drug metabolism and response. These research efforts will include determination of molecular mechanisms for the different polymorphisms and evaluation of their clinical significance. The availability of molecular methodologies such as restriction fragment length polymorphisms analysis, polymerase chain reaction, and expression of cDNAs in cell cultures will further the investigative work in detection of normal and mutant alleles, identification of new substrates for different polymorphic metabolizing enzymes, and evaluation of mechanisms of individual susceptibility to biological disorders. Other areas such as the role of pharmacogenetics in drug development and regulatory control, in evaluation of potential drug-drug interactions, ethnic variation in polymorphic metabolism, and response, also need to be evaluated.

Acquired cholesteatoma: summary of the cascade of molecular events

2013 ◽  
Vol 127 (6) ◽  
pp. 542-549 ◽  
Author(s):  
L Louw
Keyword(s):  
Molecular Mechanisms ◽  
Bone Erosion ◽  
Chronic Otitis Media ◽  
Future Directions ◽  
Molecular Events ◽  
Matrix Interactions ◽  
Proliferation And Apoptosis ◽  
Acquired Cholesteatoma ◽  
Role Players

AbstractBackground:Cholesteatoma is considered a benign, gradually expanding and destructive epithelial lesion of the temporal bone. The pathogenesis of different classifications of cholesteatoma is marked by similar underlying cellular and molecular processes. Stepwise explanations of the histopathogenesis have been described previously. The current paper focuses on expounding the molecular events of cholesteatoma.Method and results:Cholesteatoma pathogenesis encompasses a complex network of signalling pathways during: epidermal hyperplasia, perimatrix–matrix interactions and mucosal disease. This paper presents a review of the molecular events driven by inflammatory mediators and enzymes during: cholesteatoma growth (cell proliferation and apoptosis); maintenance and deterioration (angiogenesis and hypoxia, oxidative stress and toxicity); and complications (bone erosion and hearing loss). The cascade of molecular events applicable to atelectasis and cholesteatoma that coexist with chronic otitis media and bone erosion as sequelae is summarised.Conclusion:The role of lipids in this disease is relatively unexplored, but there is evidence in support of fatty acid role-players that needs confirmation. Future directions in lipid research to delineate molecular mechanisms are proposed.

scholarly journals Functional genomics of pathogenic bacteria

2002 ◽  
Vol 357 (1417) ◽  
pp. 109-116 ◽  
Author(s):  
E. R. Moxon ◽  
D. W. Hood ◽  
N. J. Saunders ◽  
E. K. H. Schweda ◽  
J. C. Richards
Keyword(s):  
Pathogenic Bacteria ◽  
Whole Genome Sequence ◽  
Sequence Information ◽  
Microbial Diseases ◽  
Mortality And Morbidity ◽  
Automated Dna Sequencing ◽  
Genome Sequence Information ◽  
Pathogenic Microbes

Microbial diseases remain the commonest cause of global mortality and morbidity. Automated–DNA sequencing has revolutionized the investigation of pathogenic microbes by making the immense fund of information contained in their genomes available at reasonable cost. The challenge is how this information can be used to increase current understanding of the biology of commensal and virulence behaviour of pathogens with particular emphasis on in vivo function and novel approaches to prevention. One example of the application of whole–genome–sequence information is afforded by investigations of the pathogenic role of Haemophilus influenzae lipopolysaccharide and its candidacy as a vaccine.

scholarly journals New Insights Into the Role of Aberrant Hippocampal Neurogenesis in Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Chen ◽  
Fuchao Chen ◽  
Yue Wu ◽  
Benhong Zhou
Keyword(s):  
Molecular Mechanisms ◽  
Wide Spectrum ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Future Directions ◽  
The Past ◽  
The Central Nervous System ◽  
Spontaneous Recurrent Seizures ◽  
Patients With Epilepsy

Data accumulated over the past four decades have confirmed that adult hippocampal neurogenesis (HN) plays a key role in the wide spectrum of hippocampal pathology. Epilepsy is a disorder of the central nervous system characterized by spontaneous recurrent seizures. Although neurogenesis in persistent germinative zones is altered in the adult rodent models of epilepsy, the effects of seizure-induced neurogenesis in the epileptic brain, in terms of either a pathological or reparative role, are only beginning to be explored. In this review, we described the most recent advances in neurogenesis in epilepsy and outlooked future directions for neural stem cells (NSCs) and epilepsy-in-a-dish models. We proposed that it may help in refining the underlying molecular mechanisms of epilepsy and improving the therapies and precision medicine for patients with epilepsy.

scholarly journals Dnj1 Promotes Virulence in Cryptococcus neoformans by Maintaining Robust Endoplasmic Reticulum Homeostasis Under Temperature Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Linda C. Horianopoulos ◽  
Christopher W. J. Lee ◽  
Guanggan Hu ◽  
Mélissa Caza ◽  
James W. Kronstad
Keyword(s):  
Endoplasmic Reticulum ◽  
Cryptococcus Neoformans ◽  
Virulence Factors ◽  
Fungal Pathogens ◽  
Elevated Temperatures ◽  
Mammalian Host ◽  
Human Body Temperature ◽  
J Domain ◽  
Er Homeostasis

The capacity of opportunistic fungal pathogens such as Cryptococcus neoformans to cause disease is dependent on their ability to overcome an onslaught of stresses including elevated temperature under mammalian host conditions. Protein chaperones and co-chaperones play key roles in thermotolerance. In this study, we characterized the role of the endoplasmic reticulum (ER) J-domain containing co-chaperone, Dnj1, in the virulence of C. neoformans. A strain expressing a Dnj1-GFP fusion protein was used to confirm localization to the ER, and a dnj1∆ deletion mutant was shown to be hypersensitive to the ER stress caused by tunicamycin (TM) or 4μ8C. Dnj1 and another ER chaperone, calnexin were found to coordinately maintain ER homeostasis and contribute to maintenance of cell wall architecture. Dnj1 also contributed to thermotolerance and increased in abundance at elevated temperatures representative of febrile patients (e.g., 39°C) thus highlighting its role as a temperature-responsive J domain protein. The elaboration of virulence factors such as the polysaccharide capsule and extracellular urease activity were also markedly impaired in the dnj1∆ mutant when induced at human body temperature (i.e., 37°C). These virulence factors are immunomodulatory and, indeed, infection with the dnj1∆ mutant revealed impaired induction of the cytokines IL-6, IL-10, and MCP-1 in the lungs of mice compared to infection with wild type or complemented strains. The dnj1∆ mutant also had attenuated virulence in an intranasal murine model of cryptococcosis. Altogether, our data indicate that Dnj1 is crucial for survival and virulence factor production at elevated temperatures. The characterization of this co-chaperone also highlights the importance of maintaining homeostasis in the ER for the pathogenesis of C. neoformans.

scholarly journals Norovirus Attachment and Entry

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 495 ◽  
Author(s):  
Vincent R. Graziano ◽  
Jin Wei ◽  
Craig B. Wilen
Keyword(s):  
Viral Entry ◽  
Molecular Mechanisms ◽  
Viral Gastroenteritis ◽  
Blood Group Antigens ◽  
Cell Tropism ◽  
Murine Norovirus ◽  
Human Norovirus ◽  
Future Directions ◽  
Minor Capsid Protein

Human norovirus is a major human pathogen causing the majority of cases of viral gastroenteritis globally. Viral entry is the first step of the viral life cycle and is a significant determinant of cell tropism, host range, immune interactions, and pathogenesis. Bile salts and histo-blood group antigens are key mediators of norovirus entry; however, the molecular mechanisms by which these molecules promote infection and the identity of a potential human norovirus receptor remain unknown. Recently, there have been several important advances in norovirus entry biology including the identification of CD300lf as the receptor for murine norovirus and of the role of the minor capsid protein VP2 in viral genome release. Here, we will review the current understanding about norovirus attachment and entry and highlight important future directions.

The regulatory role of the kinase-homology domain in receptor guanylyl cyclases: nothing ‘pseudo’ about it!

2018 ◽  
Vol 46 (6) ◽  
pp. 1729-1742 ◽  
Author(s):  
Vishwas Mishra ◽  
Ridhima Goel ◽  
Sandhya S. Visweswariah
Keyword(s):  
Protein Structures ◽  
Sequence Information ◽  
Guanylyl Cyclases ◽  
Downstream Signaling ◽  
Cyclase Domain ◽  
Interesting Possibility ◽  
Genome Sequence Information ◽  
Kinase Homology Domain ◽  
Kinase Homology

The availability of genome sequence information and a large number of protein structures has allowed the cataloging of genes into various families, based on their function and predicted biochemical activity. Intriguingly, a number of proteins harbor changes in the amino acid sequence at residues, that from structural elucidation, are critical for catalytic activity. Such proteins have been categorized as ‘pseudoenzymes’. Here, we review the role of the pseudokinase (or kinase-homology) domain in receptor guanylyl cyclases. These are multidomain single-pass, transmembrane proteins harboring an extracellular ligand-binding domain, and an intracellular domain composed of a kinase-homology domain that regulates the activity of the associated guanylyl cyclase domain. Mutations that lie in the kinase-homology domain of these receptors are associated with human disease, and either abolish or enhance cGMP production by these receptors to alter downstream signaling events. This raises the interesting possibility that one could identify molecules that bind to the pseudokinase domain and regulate the activities of these receptors, in order to alleviate symptoms in patients harboring these mutations.

scholarly journals Circular RNAs as Competing Endogenous RNAs in Cardiovascular and Cerebrovascular Diseases: Molecular Mechanisms and Clinical Implications

2021 ◽  
Vol 8 ◽  
Author(s):  
Xue Min ◽  
Dong-liang Liu ◽  
Xing-dong Xiong
Keyword(s):  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Suppressive Effect ◽  
Cerebrovascular Diseases ◽  
Circular Rnas ◽  
Clinical Implications ◽  
Future Directions ◽  
Rna Molecules ◽  
Competing Endogenous Rnas

Circular RNAs (circRNAs) represent a novel class of widespread and diverse endogenous RNA molecules. This unusual class of RNA species is generated by a back-splicing event of exons or introns, resulting in a covalently closed circRNA molecule. Accumulating evidence indicates that circRNA plays an important role in the biological functions of a network of competing endogenous RNA (ceRNA). CircRNAs can competitively bind to miRNAs and abolish the suppressive effect of miRNAs on target RNAs, thus regulating gene expression at the posttranscriptional level. The role of circRNAs as ceRNAs in the pathogenesis of cardiovascular and cerebrovascular diseases (CVDs) has been recently reported and highlighted. Understanding the underlying molecular mechanism could aid the discovery of therapeutic targets or strategies against CVDs. Here, we review the progress in studying the role of circRNAs as ceRNAs in CVDs, with emphasis on the molecular mechanism, and discuss future directions and possible clinical implications.

The role of TRAF3IP2 in obesity-associated vascular insulin resistance and dysfunction

2020 ◽  
Author(s):  
◽  
Zachary I. Grunewald
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Vascular Dysfunction ◽  
Reactive Hyperemia ◽  
Causal Role ◽  
Wild Type ◽  
Vascular Control

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI-COLUMBIA AT REQUEST OF AUTHOR.] Insulin resistance in the vasculature is a characteristic feature of obesity and contributes to the pathogenesis of vascular dysfunction and disease. However, the molecular mechanisms underlying obesity-associated vascular insulin resistance and dysfunction remain poorly understood. We hypothesized that TRAF3 Interacting Protein 2 (TRAF3IP2), a pro-inflammatory adaptor molecule known to activate pathological stress pathways and implicated in cardiovascular disease, plays a causal role in obesity-associated vascular insulin resistance and dysfunction. We tested this hypothesis by employing genetic-manipulation in endothelial cells in vitro and in isolated arteries ex vivo, and by using a mouse model of TRAF3IP2 ablation and diet-induced obesity in vivo. We show that forced expression of TRAF3IP2 blunts insulin signaling in endothelial cells and diminishes endothelium-dependent vasorelaxation in isolated aortic rings. Further, 16 weeks of high fructose/high sucrose (HFHS) feeding impaired glucose tolerance, aortic insulin-induced vasorelaxation, and hindlimb postocclusive reactive hyperemia, while increasing blood pressure and arterial stiffness in wild-type male mice. Notably, TRAF3IP2 gene ablation protected mice against such metabolic and vascular defects caused by HFHS feeding. Interestingly, wild-type female mice expressed markedly reduced levels of TRAF3IP2 mRNA independent of diet and were protected against HFHS diet-induced vascular dysfunction. These data indicate that TRAF3IP2 plays a causal role in vascular insulin resistance and dysfunction. Specifically, the present findings highlight a sexual dimorphic role of TRAF3IP2 in vascular control and identify it as a promising therapeutic target in vasculometabolic derangements associated with obesity, particularly in males.

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