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Search Results: 1 - 10 of 130441 matches for " Sokol V. Todi "
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An optimal ubiquitin-proteasome pathway in the nervous system: the role of deubiquitinating enzymes
Wei-Ling Tsou,Sokol V. Todi
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00072
Abstract: The Ubiquitin-Proteasome Pathway (UPP), which is critical for normal function in the nervous system and is implicated in various neurological diseases, requires the small modifier protein ubiquitin to accomplish its duty of selectively degrading short-lived, abnormal or misfolded proteins. Over the past decade, a large class of proteases collectively known as deubiquitinating enzymes (DUBs) has increasingly gained attention in all manners related to ubiquitin. By cleaving ubiquitin from another protein, DUBs ensure that the UPP functions properly. DUBs accomplish this task by processing newly translated ubiquitin so that it can be used for conjugation to substrate proteins, by regulating the “where, when, and why” of UPP substrate ubiquitination and subsequent degradation, and by recycling ubiquitin for re-use by the UPP. Because of the reliance of the UPP on DUB activities, it is not surprising that these proteases play important roles in the normal activities of the nervous system and in neurodegenerative diseases. In this review, we summarize recent advances in understanding the functions of DUBs in the nervous system. We focus on their role in the UPP, and make the argument that understanding the UPP from the perspective of DUBs can yield new insight into diseases that result from anomalous intra-cellular processes or inter-cellular networks. Lastly, we discuss the relevance of DUBs as therapeutic options for disorders of the nervous system.
Ubiquitin-Specific Protease 25 Functions in Endoplasmic Reticulum-Associated Degradation
Jessica R. Blount, Aaron A. Burr, Amanda Denuc, Gemma Marfany, Sokol V. Todi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036542
Abstract: Endoplasmic Reticulum (ER)-associated degradation (ERAD) discards abnormal proteins synthesized in the ER. Through coordinated actions of ERAD components, misfolded/anomalous proteins are recognized, ubiquitinated, extracted from the ER and ultimately delivered to the proteasome for degradation. It is not well understood how ubiquitination of ERAD substrates is regulated. Here, we present evidence that the deubiquitinating enzyme Ubiquitin-Specific Protease 25 (USP25) is involved in ERAD. Our data support a model where USP25 counteracts ubiquitination of ERAD substrates by the ubiquitin ligase HRD1, rescuing them from degradation by the proteasome.
Myosin VIIA, Important for Human Auditory Function, Is Necessary for Drosophila Auditory Organ Development
Sokol V. Todi, Elena Sivan-Loukianova, Julie S. Jacobs, Daniel P. Kiehart, Daniel F. Eberl
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002115
Abstract: Background Myosin VIIA (MyoVIIA) is an unconventional myosin necessary for vertebrate audition [1]–[5]. Human auditory transduction occurs in sensory hair cells with a staircase-like arrangement of apical protrusions called stereocilia. In these hair cells, MyoVIIA maintains stereocilia organization [6]. Severe mutations in the Drosophila MyoVIIA orthologue, crinkled (ck), are semi-lethal [7] and lead to deafness by disrupting antennal auditory organ (Johnston's Organ, JO) organization [8]. ck/MyoVIIA mutations result in apical detachment of auditory transduction units (scolopidia) from the cuticle that transmits antennal vibrations as mechanical stimuli to JO. Principal Findings Using flies expressing GFP-tagged NompA, a protein required for auditory organ organization in Drosophila, we examined the role of ck/MyoVIIA in JO development and maintenance through confocal microscopy and extracellular electrophysiology. Here we show that ck/MyoVIIA is necessary early in the developing antenna for initial apical attachment of the scolopidia to the articulating joint. ck/MyoVIIA is also necessary to maintain scolopidial attachment throughout adulthood. Moreover, in the adult JO, ck/MyoVIIA genetically interacts with the non-muscle myosin II (through its regulatory light chain protein and the myosin binding subunit of myosin II phosphatase). Such genetic interactions have not previously been observed in scolopidia. These factors are therefore candidates for modulating MyoVIIA activity in vertebrates. Conclusions Our findings indicate that MyoVIIA plays evolutionarily conserved roles in auditory organ development and maintenance in invertebrates and vertebrates, enhancing our understanding of auditory organ development and function, as well as providing significant clues for future research.
Understanding the Role of the Josephin Domain in the PolyUb Binding and Cleavage Properties of Ataxin-3
Giuseppe Nicastro,Sokol V. Todi,Ezgi Karaca,Alexandre M. J. J. Bonvin,Henry L. Paulson,Annalisa Pastore
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012430
Abstract: Ataxin-3, the disease protein in the neurodegenerative disorder Spinocerebellar Ataxia Type 3 or Machado Joseph disease, is a cysteine protease implicated in the ubiquitin proteasome pathway. It contains multiple ubiquitin binding sites through which it anchors polyubiquitin chains of different linkages that are then cleaved by the N-terminal catalytic (Josephin) domain. The properties of the ubiquitin interacting motifs (UIMs) in the C-terminus of ataxin-3 are well established. Very little is known, however, about how two recently identified ubiquitin-binding sites in the Josephin domain contribute to ubiquitin chain binding and cleavage. In the current study, we sought to define the specific contribution of the Josephin domain to the catalytic properties of ataxin-3 and assess how the topology and affinity of these binding sites modulate ataxin-3 activity. Using NMR we modeled the structure of diUb/Josephin complexes and showed that linkage preferences are imposed by the topology of the two binding sites. Enzymatic studies further helped us to determine a precise hierarchy between the sites. We establish that the structure of Josephin dictates specificity for K48-linked chains. Site 1, which is close to the active site, is indispensable for cleavage. Our studies open the way to understand better the cellular function of ataxin-3 and its link to pathology.
Systematic Analysis of the Physiological Importance of Deubiquitinating Enzymes
Wei-Ling Tsou, Michael J. Sheedlo, Marie E. Morrow, Jessica R. Blount, Kelly M. McGregor, Chittaranjan Das, Sokol V. Todi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043112
Abstract: Deubiquitinating enzymes (DUBs) are proteases that control the post-translational modification of proteins by ubiquitin and in turn regulate diverse cellular pathways. Despite a growing understanding of DUB biology at the structural and molecular level, little is known about the physiological importance of most DUBs. Here, we systematically identify DUBs encoded by the genome of Drosophila melanogaster and examine their physiological importance in vivo. Through domain analyses we uncovered 41 Drosophila DUBs, most of which have human orthologues. Systematic knockdown of the vast majority of DUBs throughout the fly or in specific cell types had dramatic consequences for Drosophila development, adult motility or longevity. Specific DUB subclasses proved to be particularly necessary during development, while others were important in adults. Several DUBs were indispensable in neurons or glial cells during developmental stages; knockdown of others perturbed the homeostasis of ubiquitinated proteins in adult flies, or had adverse effects on wing positioning as a result of neuronal requirements. We demonstrate the physiological significance of the DUB family of enzymes in intact animals, find that there is little functional redundancy among members of this family of proteases, and provide insight for future investigations to understand DUB biology at the molecular, cellular and organismal levels.
Surgical treatment of chronic hidradenitis suppurativa in the gluteal and perianal regions
Bilali Sokol,Todi Vangjel,Lila Ali,Bilali Valbona
Acta Chirurgica Iugoslavica , 2012, DOI: 10.2298/aci1202091b
Abstract: Introduction: Verneuil disease, or perianal hidradenitis suppurativa (HS), is a chronic suppurative disease with a tendency to develop sinus formation, fibrosis, and sclerosis, having a great impact on quality of life. HS affect the apocrine sweat glands or sebaceous glands and may arise in each of the regions where the apocrine glands are prominent: the axilla, breast aureole, umbilicus, perineum, groin, and buttocks. We present here moderate and extensive HS cases, with their respective treatment methods and outcomes. Methods: A retrospective re-view of 6 patients’ medical records from January 2001 to December 2010. Results: The 6 patients underwent treatment for HS in the gluteal and perianal regions with surgical excision. Five of the patients were male (83%). The median age was 42.5 years. We performed a total of 8 operations on these patients. In 3 patients, the wound was left open for secondary healing, and the mean time for complete wound healing was 11.3 weeks (range: 9.5-19 weeks). Delayed skin grafting was used for 2 patients in whom the wounds had been left open after the first operation. In this group, complete wound healing took 2 months in total. One patient underwent primary wound closure using rotation flaps, with a complete healing time of 2 weeks. Successful treatment without recurrence was accomplished in 5 (83.3%) of the patients. Conclusion: The conservative treatment methods had little effect, particularly on gluteal and perianal/perineal HS. The only successful treatment was wide surgical excision. Management of the wound after wide excision should be tailored to the individual patient.
Examination of Wear Resistance of Polymer – Basalt Composites
A. Todi,D. ?ikara,V. Lazi?,T. Todi
Tribology in Industry , 2013,
Abstract: Olivine basalt, as a natural material, has excellent physical and mechanical properties such as hardness, compressive strength, wear resistance, color and gloss. On the other hand it is difficult for processing, because of its high values of mechanical properties. Retention of physical and mechanical properties of basaltand its formation is only possible by mixing basalt powder with polymers, which would enable the composite material that can be formed by the casting process into complex shapes. The mechanical properties of the obtained composites andproduction technologies are, to a great extent, unknown in both, local and foreignliterature. Researches conducted and presented in this paper show an overview oftribological behavior of the basaltic composite material, and some technologicalparameters of the production process. Based on the obtained results, it can bedetermine the best ratio of components in the composite. These data areimportant for the development of new composite materials based on basalt, which will have significant application in the future.
Achievement of Real Paying Capacity in the Context of Analysis of Provision of Obligations of an Insurance Company by Means of its Resources Достижение реальной платежеспособности в разрезе анализа обеспечения обязательств страховой компании за счёт её ресурсов
Sokol Sergey V.
Business Inform , 2013,
Abstract: The article describes requirements to real paying capacity of insurers from the point of view of Ukrainian legislation. It analyses provision of obligations of an insurer by means of its resources. It specifies forms of provision of obligations of an insurance company, which facilitate development of a basis for compensation of losses and satisfaction of creditors’ requirements. It draws a conclusion of a contradiction relevant to paying capacity, which lies in worsening paying capacity in the event of increase of insurance payments and reserves of unearned premiums. В статье изложены требования к реальной платежеспособности страховщиков с позиции законодательства Украины. Проанализировано обеспечение обязательств страховщика за счёт его ресурсов. Определены формы обеспечения обязательств страховой компании, которые способствуют созданию основания для возмещения убытков и удовлетворения требований кредиторов. Подытожено соответствующее платежеспособности противоречие, которое заключается в ухудшении платежеспособности при увеличении страховых платежей и резервов незаработанных премий.
Theory of p-wave Pairing for $^3$He on Grafoil
A. V. Chubukov,A. Sokol
Physics , 1993, DOI: 10.1103/PhysRevB.49.678
Abstract: The specific heat and susceptibility data for $^3$He on Grafoil are analyzed in the framework of the Landau Fermi liquid theory. The dominant interaction between $^3$He quasiparticles is found to be in the p-wave channel for most experimentally accessible areal densities of $^{3}$He. This interaction is attractive and gives rise to the p-wave transition temperature which for moderate areal densities is estimated to be on the scale of several millikelvin. The relevance of these results to the anomaly in the specific heat observed at $ T_k = 3.2 \, \mbox{mK} $ is discussed.
Modular system design for plastic euro pallets
J. Tepi?,V. Todi,I. Tanackov,D. Luki?
Metalurgija , 2012,
Abstract: Although pallet, as a tool, yields significant and widely recognized economic effects in production and distribution systems, it is still not fully utilized, indicating that it needs to be defined and developed as a specific product. Euro pallet product was designed using PRO/ENGINEER software system CAD module, as one of the most popular Cax systems, yielding a pallet of novel modular design that meets all the operational requirements of the existing range. The chosen material ensures high pallet longevity and durability, in line with the concept of sustainable development.
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