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Article ; Online: Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity.

Bhaduri, Utsa / Merla, Giuseppe

2021 Volume 10, Issue 5

Abstract: Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite ...

Abstract	Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.
MeSH term(s)	Biotechnology/economics ; Biotechnology/statistics & numerical data ; Humans ; Industry/economics ; Protein Domains ; Protein Processing, Post-Translational ; Tripartite Motif Proteins/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Tripartite Motif Proteins ; Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2021-04-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10051015
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Rise of TRIM8: A Molecule of Duality.

Bhaduri, Utsa / Merla, Giuseppe

Molecular therapy. Nucleic acids

2020 Volume 22, Page(s) 434–444

Abstract: The human tripartite motif containing protein 8 (TRIM8), a member of TRIM family proteins, is known to play a dual role as both tumor suppressor and oncogene, and to function at the crosstalk of cancer and innate immunity. In this review, in addition to ... ...

Abstract	The human tripartite motif containing protein 8 (TRIM8), a member of TRIM family proteins, is known to play a dual role as both tumor suppressor and oncogene, and to function at the crosstalk of cancer and innate immunity. In this review, in addition to accumulating recent corroborations that endorse this dual character of TRIM8, we appraise the game-changing capacity of TRIM8 under stress conditions against the backdrop of cell proliferation, apoptosis, and cancer, and also highlight the duality of TRIM8 in multiple contexts like cellular localization, stress-induced conditions, and E3 ubiquitin ligase activity. Finally, we discuss the emerging role of TRIM8 during bipolar spindle formation and mitotic progression, and its growing sphere of influence across multiple human cancers and pathologies, and suggest TRIM8-linked axes that can be modulated further for anti-cancer therapeutics development.
Language	English
Publishing date	2020-09-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2020.08.034
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Article: E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis.

Venuto, Santina / Merla, Giuseppe

Cells

2019 Volume 8, Issue 5

Abstract: The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA ... ...

Abstract	The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA replication is confined to a discrete synthesis phase while chromosome segregation occurs during mitosis. During mitosis, the chromosomes are pulled into each of the two daughter cells by the coordination of spindle microtubules, kinetochores, centromeres, and chromatin. These four functional units tie chromosomes to the microtubules, send signals to the cells when the attachment is completed and the division can proceed, and withstand the force generated by pulling the chromosomes to either daughter cell. Protein ubiquitination is a post-translational modification that plays a central role in cellular homeostasis. E3 ubiquitin ligases mediate the transfer of ubiquitin to substrate proteins determining their fate. One of the largest subfamilies of E3 ubiquitin ligases is the family of the tripartite motif (TRIM) proteins, whose dysregulation is associated with a variety of cellular processes and directly involved in human diseases and cancer. In this review we summarize the current knowledge and emerging concepts about TRIMs and their contribution to the correct regulation of cell cycle, describing how TRIMs control the cell cycle transition phases and their involvement in the different functional units of the mitotic process, along with implications in cancer progression.
MeSH term(s)	Autophagy ; Cell Cycle Checkpoints ; Centrosome/metabolism ; Chromosome Segregation ; Gene Expression ; Humans ; Kinetochores/metabolism ; Mitosis/physiology ; Neoplasms/genetics ; Neoplasms/metabolism ; Spindle Poles/metabolism ; Tripartite Motif Proteins/genetics ; Tripartite Motif Proteins/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Tripartite Motif Proteins ; Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2019-05-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8050510
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Article ; Online: DNA Methylation in the Fields of Prenatal Diagnosis and Early Detection of Cancers.

Coppedè, Fabio / Bhaduri, Utsa / Stoccoro, Andrea / Nicolì, Vanessa / Di Venere, Eleonora / Merla, Giuseppe

International journal of molecular sciences

2023 Volume 24, Issue 14

Abstract: The central objective of the metamorphosis of discovery science into biomedical applications is to serve the purpose of patients and curtail the global disease burden. The journey from the discovery of DNA methylation (DNAm) as a biological process to ... ...

Abstract	The central objective of the metamorphosis of discovery science into biomedical applications is to serve the purpose of patients and curtail the global disease burden. The journey from the discovery of DNA methylation (DNAm) as a biological process to its emergence as a diagnostic tool is one of the finest examples of such metamorphosis and has taken nearly a century. Particularly in the last decade, the application of DNA methylation studies in the clinic has been standardized more than ever before, with great potential to diagnose a multitude of diseases that are associated with a burgeoning number of genes with this epigenetic alteration. Fetal DNAm detection is becoming useful for noninvasive prenatal testing, whereas, in very preterm infants, DNAm is also shown to be a potential biological indicator of prenatal risk factors. In the context of cancer, liquid biopsy-based DNA-methylation profiling is offering valuable epigenetic biomarkers for noninvasive early-stage diagnosis. In this review, we focus on the applications of DNA methylation in prenatal diagnosis for delivering timely therapy before or after birth and in detecting early-stage cancers for better clinical outcomes. Furthermore, we also provide an up-to-date commercial landscape of DNAm biomarkers for cancer detection and screening of cancers of unknown origin.
MeSH term(s)	Pregnancy ; Female ; Humans ; Infant, Newborn ; DNA Methylation ; Infant, Premature ; Early Detection of Cancer ; Prenatal Diagnosis ; Biomarkers ; Neoplasms/diagnosis ; Neoplasms/genetics ; Epigenesis, Genetic
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-07-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241411715
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: In Vitro

De Leonardis, Francesco / Barile, Simona Nicole / Cianci, Claudia / Pisano, Isabella / Merla, Giuseppe / Pappalettera, Giovanni / Casavola, Caterina / Pappalettere, Carmine

Journal of Cancer

2023 Volume 14, Issue 7, Page(s) 1088–1106

Abstract: The study of the biological effects of low-energy ultrasound and its applications is a rapidly expanding research area. Low-energy ultrasound could be used as anti-tumoral therapy with or without the pharmacological combination even if the second ... ...

Abstract	The study of the biological effects of low-energy ultrasound and its applications is a rapidly expanding research area. Low-energy ultrasound could be used as anti-tumoral therapy with or without the pharmacological combination even if the second situation has been scarcely investigated up to now. Very little information is available about the ultrasound effects on healthy red blood cells, CD3, and mainly CD8 subset lymphocytes which is the main subset cell having cytotoxic function towards cancer cells. In this study, we investigated
Language	English
Publishing date	2023-04-24
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2573318-7
ISSN	1837-9664
ISSN	1837-9664
DOI	10.7150/jca.83050
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Article ; Online: The Emerging Role of Gβ Subunits in Human Genetic Diseases.

Malerba, Natascia / De Nittis, Pasquelena / Merla, Giuseppe

Cells

2019 Volume 8, Issue 12

Abstract: Environmental stimuli are perceived and transduced inside the cell through the activation of signaling pathways. One common type of cell signaling transduction network is initiated by G-proteins. G-proteins are activated by G-protein-coupled receptors ( ... ...

Abstract	Environmental stimuli are perceived and transduced inside the cell through the activation of signaling pathways. One common type of cell signaling transduction network is initiated by G-proteins. G-proteins are activated by G-protein-coupled receptors (GPCRs) and transmit signals from hormones, neurotransmitters, and other signaling factors, thus controlling a number of biological processes that include synaptic transmission, visual photoreception, hormone and growth factors release, regulation of cell contraction and migration, as well as cell growth and differentiation. G-proteins mainly act as heterotrimeric complexes, composed of alpha, beta, and gamma subunits. In the last few years, whole exome sequencing and biochemical studies have shown causality of disease-causing variants in genes encoding G-proteins and human genetic diseases. This review focuses on the G-protein β subunits and their emerging role in the etiology of genetically inherited rare diseases in humans.
MeSH term(s)	GTP-Binding Protein beta Subunits/chemistry ; GTP-Binding Protein beta Subunits/genetics ; GTP-Binding Protein beta Subunits/metabolism ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/metabolism ; Humans ; Neurodevelopmental Disorders/genetics ; Neurodevelopmental Disorders/metabolism ; Signal Transduction
Chemical Substances	GTP-Binding Protein beta Subunits
Language	English
Publishing date	2019-12-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8121567
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors.

Cillo, Francesca / Coppola, Emma / Habetswallner, Federico / Cecere, Francesco / Pignata, Laura / Toriello, Elisabetta / De Rosa, Antonio / Grilli, Laura / Ammendola, Antonio / Salerno, Paolo / Romano, Roberta / Cirillo, Emilia / Merla, Giuseppe / Riccio, Andrea / Pignata, Claudio / Giardino, Giuliana

Genes

2024 Volume 15, Issue 3

Abstract: Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a ... ...

Abstract	Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to "dual diagnosis", have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation.
MeSH term(s)	Humans ; DiGeorge Syndrome/genetics ; Epigenesis, Genetic ; Phenotype ; Heart Defects, Congenital/genetics ; MicroRNAs
Chemical Substances	MicroRNAs
Language	English
Publishing date	2024-02-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes15030321
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The ubiquitin ligase TRIM32 promotes the autophagic response to Mycobacterium tuberculosis infection in macrophages.

Romagnoli, Alessandra / Di Rienzo, Martina / Petruccioli, Elisa / Fusco, Carmela / Palucci, Ivana / Micale, Lucia / Mazza, Tommaso / Delogu, Giovanni / Merla, Giuseppe / Goletti, Delia / Piacentini, Mauro / Fimia, Gian Maria

Cell death & disease

2023 Volume 14, Issue 8, Page(s) 505

Abstract: Mycobacterium tuberculosis (Mtb) is known to evade host immune responses and persist in macrophages for long periods. A mechanism that the host uses to combat Mtb is xenophagy, a selective form of autophagy that targets intracellular pathogens for ... ...

Abstract	Mycobacterium tuberculosis (Mtb) is known to evade host immune responses and persist in macrophages for long periods. A mechanism that the host uses to combat Mtb is xenophagy, a selective form of autophagy that targets intracellular pathogens for degradation. Ubiquitination of Mtb or Mtb-containing compartments is a key event to recruit the autophagy machinery and mediate the bacterial delivery to the lysosome. This event relies on the coordinated and complementary activity of different ubiquitin ligases, including PARKIN, SMURF1, and TRIM16. Because each of these factors is responsible for the ubiquitination of a subset of the Mtb population, it is likely that additional ubiquitin ligases are employed by macrophages to trigger a full xenophagic response during Mtb infection. In this study, we investigated the role TRIM proteins whose expression is modulated in response to Mtb or BCG infection of primary macrophages. These TRIMs were ectopically expressed in THP1 macrophage cell line to assess their impact on Mtb replication. This screening identified TRIM32 as a novel player involved in the intracellular response to Mtb infection, which promotes autophagy-mediated Mtb degradation. The role of TRIM32 in xenophagy was further confirmed by silencing TRIM32 expression in THP1 cells, which causes increased intracellular growth of Mtb associated to impaired Mtb ubiquitination, reduced recruitment of the autophagy proteins NDP52/CALCOCO2 and BECLIN 1/BECN1 to Mtb and autophagosome formation. Overall, these findings suggest that TRIM32 plays an important role in the host response to Mtb infection through the induction of autophagy, representing a promising target for host-directed tuberculosis therapies.
MeSH term(s)	Humans ; Ubiquitin/metabolism ; Macrophages/metabolism ; Tuberculosis/genetics ; Autophagy/physiology ; Mycobacterium tuberculosis ; Tripartite Motif Proteins/genetics ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Transcription Factors/metabolism
Chemical Substances	Ubiquitin ; TRIM16 protein, human (EC 2.3.2.27) ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; TRIM32 protein, human (EC 2.3.2.27) ; Transcription Factors ; SMURF1 protein, human (EC 2.3.2.26)
Language	English
Publishing date	2023-08-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-023-06026-1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Clinical Genetics Can Solve the Pitfalls of Genome-Wide Investigations: Lesson from Mismapping a Loss-of-Function Variant in KANSL1

Bigoni, Stefania / Marangi, Giuseppe / Frangella, Silvia / Panfili, Arianna / Ognibene, Davide / Squeo, Gabriella Maria / Merla, Giuseppe / Zollino, Marcella

Genes. 2020 Oct. 09, v. 11, no. 10

2020

Abstract: Massive parallel sequencing of 70 genes in a girl with a suspicion of chromatinopathy detected the (NM_015443.4:)c.985_986delTT variant in exon 2 of KANSL1, which led to a diagnostic consideration of Koolen De Vries syndrome. The same variant was present ...

Abstract	Massive parallel sequencing of 70 genes in a girl with a suspicion of chromatinopathy detected the (NM_015443.4:)c.985_986delTT variant in exon 2 of KANSL1, which led to a diagnostic consideration of Koolen De Vries syndrome. The same variant was present in the healthy mother, consistent with either incomplete penetrance or variant mismapping. A network of second opinion was implemented among clinical geneticists first, and a diagnosis of Koolen De Vries syndrome was considered unlikely. By MLPA, a duplication spanning exons 1-3 of KANSL1 was detected in both the mother and the daughter. On cDNA sequencing, biallelic wild type mRNA was observed. We concluded that the variant affects the noncoding duplicated gene region in our family, and we finally classified it as benign. Parallel wide genomic sequencing is increasingly the first genetic investigation in individuals with intellectual disability. The c.985_986delTT variant in KANSL1 was described both in individuals with typical KdVS and in a limited number of healthy subjects. This report highlights the role of clinical genetics to correctly classify variants and to define proper clinical and diagnostic correlations.
Keywords	exons ; gene duplication ; genomics ; girls ; loss-of-function mutation ; penetrance
Language	English
Dates of publication	2020-1009
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes11101177
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: DNA methylation profiling in Kabuki syndrome: reclassification of germline KMT2D VUS and sensitivity in validating postzygotic mosaicism.

Niceta, Marcello / Ciolfi, Andrea / Ferilli, Marco / Pedace, Lucia / Cappelletti, Camilla / Nardini, Claudia / Hildonen, Mathis / Chiriatti, Luigi / Miele, Evelina / Dentici, Maria Lisa / Gnazzo, Maria / Cesario, Claudia / Pisaneschi, Elisa / Baban, Anwar / Novelli, Antonio / Maitz, Silvia / Selicorni, Angelo / Squeo, Gabriella Maria / Merla, Giuseppe /

Dallapiccola, Bruno / Tumer, Zeynep / Digilio, Maria Cristina / Priolo, Manuela / Tartaglia, Marco

European journal of human genetics : EJHG

2024

Abstract: Autosomal dominant Kabuki syndrome (KS) is a rare multiple congenital anomalies/neurodevelopmental disorder caused by heterozygous inactivating variants or structural rearrangements of the lysine-specific methyltransferase 2D (KMT2D) gene. While it is ... ...

Abstract	Autosomal dominant Kabuki syndrome (KS) is a rare multiple congenital anomalies/neurodevelopmental disorder caused by heterozygous inactivating variants or structural rearrangements of the lysine-specific methyltransferase 2D (KMT2D) gene. While it is often recognizable due to a distinctive gestalt, the disorder is clinically variable, and a phenotypic scoring system has been introduced to help clinicians to reach a clinical diagnosis. The phenotype, however, can be less pronounced in some patients, including those carrying postzygotic mutations. The full spectrum of pathogenic variation in KMT2D has not fully been characterized, which may hamper the clinical classification of a portion of these variants. DNA methylation (DNAm) profiling has successfully been used as a tool to classify variants in genes associated with several neurodevelopmental disorders, including KS. In this work, we applied a KS-specific DNAm signature in a cohort of 13 individuals with KMT2D VUS and clinical features suggestive or overlapping with KS. We succeeded in correctly classifying all the tested individuals, confirming diagnosis for three subjects and rejecting the pathogenic role of 10 VUS in the context of KS. In the latter group, exome sequencing allowed to identify the genetic cause underlying the disorder in three subjects. By testing five individuals with postzygotic pathogenic KMT2D variants, we also provide evidence that DNAm profiling has power to recognize pathogenic variants at different levels of mosaicism, identifying 15% as the minimum threshold for which DNAm profiling can be applied as an informative diagnostic tool in KS mosaics.
Language	English
Publishing date	2024-03-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-024-01597-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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