Spotlight on USP4: Structure, Function, and Regulation

The deubiquitinating enzyme (DUB)–mediated cleavage of ubiquitin plays a critical role in balancing protein synthesis and degradation. Ubiquitin-specific protease 4 (USP4), a member of the largest subfamily of cysteine protease DUBs, removes monoubiquitinated and polyubiquitinated chains from its target proteins. USP4 contains a DUSP (domain in USP)–UBL (ubiquitin-like) domain and a UBL-insert catalytic domain, sharing a common domain organization with its paralogs USP11 and USP15. USP4 plays a critical role in multiple cellular and biological processes and is tightly regulated under normal physiological conditions. When its expression or activity is aberrant, USP4 is implicated in the progression of a wide range of pathologies, especially cancers. In this review, we comprehensively summarize the current knowledge of USP4 structure, biological functions, pathological roles, and cellular regulation, highlighting the importance of exploring effective therapeutic interventions to target USP4.

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The Diverse Roles of the Global Transcriptional Regulator PhoP in the Lifecycle of Yersinia pestis

Pathogens ◽

10.3390/pathogens9121039 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1039

Author(s):

Hana S. Fukuto ◽

Gloria I. Viboud ◽

Viveka Vadyvaloo

Keyword(s):

Yersinia Pestis ◽

Current Knowledge ◽

Response Regulator ◽

Expression Profiles ◽

Critical Role ◽

Gene Expression Profiles ◽

Acanthamoeba Castellanii ◽

Wide Range

Yersinia pestis, the causative agent of plague, has a complex infectious cycle that alternates between mammalian hosts (rodents and humans) and insect vectors (fleas). Consequently, it must adapt to a wide range of host environments to achieve successful propagation. Y. pestis PhoP is a response regulator of the PhoP/PhoQ two-component signal transduction system that plays a critical role in the pathogen’s adaptation to hostile conditions. PhoP is activated in response to various host-associated stress signals detected by the sensor kinase PhoQ and mediates changes in global gene expression profiles that lead to cellular responses. Y. pestis PhoP is required for resistance to antimicrobial peptides, as well as growth under low Mg2+ and other stress conditions, and controls a number of metabolic pathways, including an alternate carbon catabolism. Loss of phoP function in Y. pestis causes severe defects in survival inside mammalian macrophages and neutrophils in vitro, and a mild attenuation in murine plague models in vivo, suggesting its role in pathogenesis. A Y. pestisphoP mutant also exhibits reduced ability to form biofilm and to block fleas in vivo, indicating that the gene is also important for establishing a transmissible infection in this vector. Additionally, phoP promotes the survival of Y. pestis inside the soil-dwelling amoeba Acanthamoeba castellanii, a potential reservoir while the pathogen is quiescent. In this review, we summarize our current knowledge on the mechanisms of PhoP-mediated gene regulation in Y. pestis and examine the significance of the roles played by the PhoP regulon at each stage of the Y. pestis life cycle.

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PtdIns5P: a little phosphoinositide with big functions?

Biochemical Society Symposium ◽

10.1042/bss2007c11 ◽

2007 ◽

Vol 74 ◽

pp. 117-128 ◽

Cited By ~ 18

Author(s):

Sophie Coronas ◽

Damien Ramel ◽

Caroline Pendaries ◽

Frédérique Gaits-Iacovoni ◽

Hélène Tronchère ◽

...

Keyword(s):

Potential Role ◽

Current Knowledge ◽

Critical Role ◽

Cell Regulation ◽

Cellular Functions ◽

Minor Constituents ◽

Signalling Molecules ◽

Phosphoinositide 3 Kinase ◽

Synthesis And Degradation

Phosphoinositides are minor constituents of cell membranes playing a critical role in the regulation of many cellular functions. Recent discoveries indicate that mutations in several phosphoinositide kinases and phosphatases generate imbalances in the levels of phosphoinositides, thereby leading to the development of human diseases. Although the roles of phosphoinositide 3-kinase products and PtdIns(4,5)P2 were largely studied these last years, the potential role of phosphatidylinositol monophosphates as direct signalling molecules is just emerging. PtdIns5P, the least characterized phosphoinositide, appears to be a new player in cell regulation. This review will summarize the current knowledge on the mechanisms of synthesis and degradation of PtdIns5P as well as its potential roles.

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Methodological Aspects of Randomized Controlled Trials for Tinnitus: A Systematic Review and How a Decision Support System Could Overcome Barriers

Journal of Clinical Medicine ◽

10.3390/jcm10081737 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1737

Author(s):

Dimitrios Kikidis ◽

Evgenia Vassou ◽

Winfried Schlee ◽

Eleftheria Iliadou ◽

Nikolaos Markatos ◽

...

Keyword(s):

Clinical Trials ◽

Randomized Clinical Trials ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Future Studies ◽

Randomized Controlled ◽

Management Interventions ◽

Wide Range ◽

Tinnitus Treatment ◽

Methodological Aspects

Although a wide range of tinnitus management interventions is currently under research and a variety of therapeutic interventions have already been applied in clinical practice, no optimal and universal tinnitus treatment has been reached yet. This fact is to some extent a consequence of the high heterogeneity of the methodologies used in tinnitus related clinical studies. In this manuscript, we have identified, summarized, and critically appraised tinnitus-related randomized clinical trials since 2010, aiming at systematically mapping the research conducted in this area. The results of our analysis of the 73 included randomized clinical trials provide important insight on the identification of limitations of previous works, methodological pitfalls or gaps in current knowledge, a prerequisite for the adequate interpretation of current literature and execution of future studies.

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Microglial Potassium Channels: From Homeostasis to Neurodegeneration

Biomolecules ◽

10.3390/biom11121774 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1774

Author(s):

Germana Cocozza ◽

Stefano Garofalo ◽

Riccardo Capitani ◽

Giuseppina D’Alessandro ◽

Cristina Limatola

Keyword(s):

Potassium Channels ◽

Neurodegenerative Diseases ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Cns Disorders ◽

Pathological Conditions ◽

Wide Range ◽

Functional Features ◽

Lateral Sclerosis

The growing interest in the role of microglia in the progression of many neurodegenerative diseases is developing in an ever-expedited manner, in part thanks to emergent new tools for studying the morphological and functional features of the CNS. The discovery of specific biomarkers of the microglia phenotype could find application in a wide range of human diseases, and creates opportunities for the discovery and development of tailored therapeutic interventions. Among these, recent studies highlight the pivotal role of the potassium channels in regulating microglial functions in physiological and pathological conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. In this review, we summarize the current knowledge of the involvement of the microglial potassium channels in several neurodegenerative diseases and their role as modulators of microglial homeostasis and dysfunction in CNS disorders.

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Notch3 Targeting: A Novel Weapon against Ovarian Cancer Stem Cells

Stem Cells International ◽

10.1155/2019/6264931 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Simona Ceccarelli ◽

Francesca Megiorni ◽

Diana Bellavia ◽

Cinzia Marchese ◽

Isabella Screpanti ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Notch Signaling ◽

Current Knowledge ◽

Critical Role ◽

Tumor Formation ◽

Therapeutic Interventions ◽

Ovarian Cancer Stem Cells ◽

Promising Tool

Notch signaling is frequently activated in ovarian cancer (OC) and contributes to the proliferation and survival of cultured OC cells as well as to tumor formation and angiogenesis in xenograft models. Several studies demonstrate that Notch3 expression renders cancer cells more resistant to carboplatin, contributing to chemoresistance and poor survival of OC-bearing patients. This suggests that Notch3 can represent both a biomarker and a target for therapeutic interventions in OC patients. Although it is still unclear how chemoresistance arises, different lines of evidence support a critical role of cancer stem cells (CSCs), suggesting that CSC targeting by innovative therapeutic approaches might represent a promising tool to efficiently reduce OC recurrence. To date, CSC-directed therapies in OC tumors are mainly targeted to the inhibition of CSC-related signaling pathways, including Notch. As it is increasingly evident the involvement of Notch signaling, and in particular of Notch3, in regulating stem-like cell maintenance and expansion in several tumors, here we provide an overview of the current knowledge of Notch3 role in CSC-mediated OC chemoresistance, finally exploring the potential design of innovative Notch3 inhibition-based therapies for OC treatment, aimed at eradicating tumor through the suppression of CSCs.

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Nucleophosmin1 (NPM1) abnormality in hematologic malignancies, and therapeutic targeting of mutant NPM1 in acute myeloid leukemia

Therapeutic Advances in Hematology ◽

10.1177/2040620719899818 ◽

2020 ◽

Vol 11 ◽

pp. 204062071989981 ◽

Cited By ~ 2

Author(s):

Yingyu Chen ◽

Jianda Hu

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Catalytic Domain ◽

Critical Role ◽

Normal Karyotype ◽

Hematologic Malignancies ◽

Therapeutic Interventions ◽

Anaplastic Lymphoma ◽

Hodgkin's Lymphomas ◽

Acute Myeloid

Nucleophosmin ( NPM1) is an abundant nucleolar protein that is implicated in a variety of biological processes and in the pathogenesis of several human malignancies. For hematologic malignancies, approximately one-third of anaplastic large-cell non-Hodgkin’s lymphomas were found to express a fusion between NPM1 and the catalytic domain of anaplastic lymphoma receptor tyrosine kinase. About 50–60% of acute myeloid leukemia patients with normal karyotype carry NPM1 mutations, which are characterized by cytoplasmic dislocation of the NPM1 protein. Nevertheless, NPM1 is overexpressed in various hematologic and solid tumor malignancies. NPM1 overexpression is considered a prognostic marker of recurrence and progression of cancer. Thus, NPM1 abnormalities play a critical role in several types of hematologic malignancies. This has led to intense interest in the development of an NPM1 targeting strategy for cancer therapy. The aim of this review is to summarize present knowledge on NPM1 origin, pathogenesis, and therapeutic interventions in hematologic malignancies.

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Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

Current Vascular Pharmacology ◽

10.2174/1570161118666200616144512 ◽

2020 ◽

Vol 19 (2) ◽

pp. 176-192

Author(s):

Samantha Bedell ◽

Janine Hutson ◽

Barbra de Vrijer ◽

Genevieve Eastabrook

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Obesity ◽

Environmental Changes ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Placental Development ◽

Exchange Site ◽

And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

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Cognitive Impact of Cerebellar Damage: Is There a Future for Cognitive Rehabilitation?

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180110125043 ◽

2018 ◽

Vol 17 (3) ◽

pp. 199-206 ◽

Cited By ~ 8

Author(s):

Kim van Dun ◽

Frank V. Overwalle ◽

Mario Manto ◽

Peter Marien

Keyword(s):

Affective Disorders ◽

Cognitive Rehabilitation ◽

Therapeutic Interventions ◽

Posterior Fossa Surgery ◽

Daily Life Activities ◽

Wide Range ◽

Affective Deficits ◽

Cerebellar Injury ◽

Cognitive Therapies ◽

The Impact

Background & Objective: During the past 3 decades, numerous neurophysiological, neuroimaging, experimental and clinical studies have evidenced a crucial role for the cerebellum in cognitive, affective and behavioral functions. As a result of the acknowledged modulatory role of the cerebellum upon remote structures such as the cerebral cortex, cerebellar injury may give rise to a constellation of behavioral, affective and cognitive symptoms (Schmahmann's Syndrome). In sharp contrast to the wide range of therapeutic interventions to treat cognitive and affective disorders following cerebral cortical lesions and despite the consequences of Schmahmann’s syndrome upon daily life activities, the literature is surprisingly only scantly documented with studies investigating the impact of cognitive therapies on cerebellar induced cognitive and affective disorders. This survey aims to present an overview of the therapeutic interventions available in the literature as a possible treatment for Schmahmann’s Syndrome after cerebellar injury, after posterior fossa surgery in children, and in children with neurodevelopmental disorders. Although systematical studies are clearly warranted, available evidence suggests that cerebellar-induced cognitive and affective disorders should be treated in a specific way. Approaches where the patients are explicitly made aware of their deficits and are considered to act as an “external cerebellum” are the most promising. Conclusion: The study of the anatomical connectivity of the cerebellar microcomplexes involved in cognitive/affective deficits is likely to play a major-role in the future.

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Shooting a Tiger

10.1093/oso/9780199489381.001.0001 ◽

2018 ◽

Author(s):

Vijaya Ramadas Mandala

Keyword(s):

Critical Role ◽

Late Nineteenth Century ◽

Way Of Life ◽

Colonial India ◽

British Raj ◽

Early Colonial ◽

Wide Range ◽

Forest Legislation ◽

Imperial Governance ◽

North And South

The main contention of Shooting a Tiger is that hunting during the colonial period was not merely a recreational activity, but a practice intimately connected with imperial governance. The book positions shikar or hunting at the heart of colonial rule by demonstrating that, for the British in India, it served as a political, practical, and symbolic apparatus in the consolidation of power and rule during the nineteenth and early twentieth centuries. The book analyses early colonial hunting during the Company period, and then surveys different aspects of hunting during the high imperial decades in the later nineteenth and early twentieth centuries. The book draws upon an impressive array of archival material and uses a wide range of evidence to support its contentions. It examines hunting at a variety of social and ethnic levels—military, administrative, elite, princely India, Indian professional hunters, and in terms of Indian auxiliaries and (sometimes) resisters. It also deals with different geographical contexts—the plains, the mountains, north and south India. The exclusive privilege of hunting exercised by the ruling classes, following colonial forest legislation, continued to be extended to the Indian princes who played a critical role in sustaining the lavish hunts that became the hallmark of the late nineteenth-century British Raj. Hunting was also a way of life in colonial India, undertaken by officials and soldiers alike alongside their everyday duties, necessary for their mental sustenance and vital for the smooth operation of the colonial administration. There are also two final chapters on conservation, particularly the last chapter focusing on two British hunter-turned-conservationists, Jim Corbett and Colonel Richard Burton.

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Fitness of Herbicide-Resistant Weeds: Current Knowledge and Implications for Management

Plants ◽

10.3390/plants8110469 ◽

2019 ◽

Vol 8 (11) ◽

pp. 469 ◽

Cited By ~ 5

Author(s):

Vila-Aiub

Keyword(s):

Life History ◽

Herbicide Resistance ◽

Management Practices ◽

Current Knowledge ◽

Resistance Management ◽

Fitness Cost ◽

Plant Fitness ◽

Resistance Mutations ◽

Fitness Costs ◽

Wide Range

Herbicide resistance is the ultimate evidence of the extraordinary capacity of weeds to evolve under stressful conditions. Despite the extraordinary plant fitness advantage endowed by herbicide resistance mutations in agroecosystems under herbicide selection, resistance mutations are predicted to exhibit an adaptation cost (i.e., fitness cost), relative to the susceptible wild-type, in herbicide untreated conditions. Fitness costs associated with herbicide resistance mutations are not universal and their expression depends on the particular mutation, genetic background, dominance of the fitness cost, and environmental conditions. The detrimental effects of herbicide resistance mutations on plant fitness may arise as a direct impact on fitness-related traits and/or coevolution with changes in other life history traits that ultimately may lead to fitness costs under particular ecological conditions. This brings the idea that a “lower adaptive value” of herbicide resistance mutations represents an opportunity for the design of resistance management practices that could minimize the evolution of herbicide resistance. It is evident that the challenge for weed management practices aiming to control, minimize, or even reverse the frequency of resistance mutations in the agricultural landscape is to “create” those agroecological conditions that could expose, exploit, and exacerbate those life history and/or fitness traits affecting the evolution of herbicide resistance mutations. Ideally, resistance management should implement a wide range of cultural practices leading to environmentally mediated fitness costs associated with herbicide resistance mutations.

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