Publications by authors named "Paulo Tavares"

71 Publications

Biogenesis of a Bacteriophage Long Non-Contractile Tail.

J Mol Biol 2021 Jun 18:167112. Epub 2021 Jun 18.

Unité de Virologie Moléculaire et Structurale, Centre de Recherche de Gif, CNRS UPR 3296 and IFR115, CNRS, Gif-sur-Yvette, France; Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, 91198, Gif-sur-Yvette, France. Electronic address:

Siphoviruses are main killers of bacteria. They use a long non-contractile tail to recognize the host cell and to deliver the genome from the viral capsid to the bacterial cytoplasm. Here, we define the molecular organization of the Bacillus subtilis bacteriophage SPP1 ∼6.8 MDa tail and uncover its biogenesis mechanisms. A complex between gp21 and the tail distal protein (Dit) gp19.1 is assembled first to build the tail cap (gp19.1-gp21Nter) connected by a flexible hinge to the tail fiber (gp21Cter). The tip of the gp21Cter fiber is loosely associated to gp22. The cap provides a platform where tail tube proteins (TTPs) initiate polymerization around the tape measure protein gp18 (TMP), a reaction dependent on the non-structural tail assembly chaperones gp17.5 and gp17.5* (TACs). Gp17.5 is essential for stability of gp18 in the cell. Helical polymerization stops at a precise tube length followed by binding of proteins gp16.1 (TCP) and gp17 (THJP) to build the tail interface for attachment to the capsid portal system. This finding uncovers the function of the extensively conserved gp16.1-homologs in assembly of long tails. All SPP1 tail components, apart from gp22, share homology to conserved proteins whose coding genes' synteny is broadly maintained in siphoviruses. They conceivably represent the minimal essential protein set necessary to build functional long tails. Proteins homologous to SPP1 tail building blocks feature a variety of add-on modules that diversify extensively the tail core structure, expanding its capability to bind host cells and to deliver the viral genome to the bacterial cytoplasm.
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http://dx.doi.org/10.1016/j.jmb.2021.167112DOI Listing
June 2021

Long-Term Response after 94 Cycles of Trabectedin in a Patient with Metastatic Leiomyosarcoma of the Lower Extremity.

Case Rep Oncol 2020 Jan-Apr;13(1):113-119. Epub 2020 Feb 11.

Bone and Soft Tissue Tumor Unit, Coimbra University Hospital, Coimbra, Portugal.

Leiomyosarcomas of the lower extremity are extremely rare disorders and account for 10-15% of limb soft tissue sarcomas. These tumours have poor prognosis and even in early stages, patients persist at high risk for local and distant relapse; consequently, the treatment of advanced leiomyosarcoma of the lower extremity embodies a substantial defy. We present the case of a 73-year-old man diagnosed with metastatic lower extremity leiomyosarcoma of the hallux soft tissue, and with bone, lung and lymph node metastasis. After core needle biopsy confirmation of high-grade fusocellular sarcoma, the patient underwent surgery of the primary tumour and received anthracycline-based chemotherapy. However, after a 7-month progression-free survival period, a CT revealed lung disease progression. Sequentially, the patient was treated with trabectedin (Yondelis®) at a dose of 1.5 mg/m2 resulting in complete remission of the lung metastasis and stable disease of the remaining lesions after 26 months of treatment. Afterwards, the patient started on maintenance therapy with trabectedin, resulting in long-lasting stable disease, as he was able to receive 94 cycles with very acceptable quality of life. Finally, in March 2019, the patient died of community-acquired pneumonia without objective progression disease. This clinical case reports the first patient ever treated with 94 cycles of trabectedin. Our results additionally confirm that trabectedin wields relevant oncostatic benefits with a manageable safety profile and without cumulative toxicities. Trabectedin properties enable a maintenance long-term therapy (until disease progression or unbearable toxicity), with a high impact on survival and with a preserved quality of life.
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http://dx.doi.org/10.1159/000505393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098334PMC
February 2020

Structural transitions during the scaffolding-driven assembly of a viral capsid.

Nat Commun 2019 10 24;10(1):4840. Epub 2019 Oct 24.

Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London, WC1E 7HX, UK.

Assembly of tailed bacteriophages and herpesviruses starts with formation of procapsids (virion precursors without DNA). Scaffolding proteins (SP) drive assembly by chaperoning the major capsid protein (MCP) to build an icosahedral lattice. Here we report near-atomic resolution cryo-EM structures of the bacteriophage SPP1 procapsid, the intermediate expanded procapsid with partially released SPs, and the mature capsid with DNA. In the intermediate state, SPs are bound only to MCP pentons and to adjacent subunits from hexons. SP departure results in the expanded state associated with unfolding of the MCP N-terminus and straightening of E-loops. The newly formed extensive inter-capsomere bonding appears to compensate for release of SPs that clasp MCP capsomeres together. Subsequent DNA packaging instigates bending of MCP A domain loops outwards, closing the hexons central opening and creating the capsid auxiliary protein binding interface. These findings provide a molecular basis for the sequential structural rearrangements during viral capsid maturation.
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http://dx.doi.org/10.1038/s41467-019-12790-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813328PMC
October 2019

Association between endoscopic findings and histopathological confirmation in patients with suspicion of eosinophilic esophagitis.

Arq Gastroenterol 2019 Aug 13;56(2):151-154. Epub 2019 Aug 13.

Hospital Universitário Walter Cantídio, Serviço de Endoscopia Digestiva, Fortaleza, CE, Brasil.

Background: The diagnosis of eosinophilic esophagitis (EoE) is performed by the detection of 15 or more eosinophils per field in an esophageal biopsy sample, but the endoscopic findings alone are not validated for a diagnosis of the disease.

Objective: To evaluate the association between the endoscopic findings and histopathological diagnosis in patients with suspected EoE in endoscopy.

Methods: A retrospective study of 24 patients with suspicion of EoE during endoscopy was held. The information was collected from databases of Endoscopy and Pathology services of the Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, from March 2012 to April 2018. The patients were divided into a group with positive biopsy (>15 Eosinophils/field, N=8) and a group with negative biopsy (<15 Eosinophils/field, N=16), and the endoscopic findings were compared between the two groups.

Results: From a total of 24 patients, 79.1% had longitudinal grooves, 20.8% white exudates, 33.3% mucosal pallor or loss of vascularity and 45.8% had more than one endoscopic finding. There was a significant difference (P<0.05) in the evaluation of the finding of mucosal pallor or decreased vasculature alone among the groups. The positive predictive value and negative predictive value of the presence of more than one endoscopic findings for the diagnosis of EoE was 54% and 84%, respectively.

Conclusion: There was a low association between the presence of endoscopic findings and histopathological confirmation of the disease, which indicates that endoscopic findings alone are not reliable for the diagnosis of EoE.
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http://dx.doi.org/10.1590/S0004-2803.201900000-30DOI Listing
August 2019

Restoration of shoulder external rotation by means of the infraspinatus muscle reinnervation with a radial nerve branch transfer.

Br J Neurosurg 2020 Oct 19;34(5):552-558. Epub 2019 Jun 19.

Peripheral Nerve Surgery Unit, Division of Functional Neurosurgery, Institute of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil.

Although reinnervation of the suprascapular nerve is frequently obtained through brachial plexus surgery, reestablishment of infraspinatus muscle function is rarely achieved. The viability of transfer of the radial nerve to the nerve branch to the infraspinatus muscle was determined anatomically, including histomorphometrical analysis on 30 adult cadavers. Eleven adult patients were then treated using the proposed nerve transfer. The branch to the medial head was more suitable for the nerve transfer. In one cadaver, nerve transfer was impossible because there was no donor of sufficient length. According to axon counts, the branches to the lateral and medial heads had sufficient numbers of axons (means = 994.2 ± 447.6 and 1030.8 ± 258.5, respectively) for reinnervation of the branch to the infraspinatus (means = 830.2 ± 241.2 axons). In the surgical series, one patient was lost in the follow-up and only two patients achieved a good result from the transfer. Recovery of external shoulder rotation started 14 months after surgery in one patient and 8 months in the other. The first patient reached 90° of external rotation 6 months later and the second, achieved 120°of shoulder external rotation 6 months after surgery . Four other patients recovered small amounts of movement: 20, 35, 40 and 45°. Although anatomically feasible, the proposed nerve transfer resulted in a small number of good clinical outcomes.
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http://dx.doi.org/10.1080/02688697.2019.1630549DOI Listing
October 2020

Integration of Sentinel-1 and Sentinel-2 for Classification and LULC Mapping in the Urban Area of Belém, Eastern Brazilian Amazon.

Sensors (Basel) 2019 Mar 6;19(5). Epub 2019 Mar 6.

Earth Sciences Institute (ICT) and Faculty of Sciences (FCUP), University of Porto, 4169-007 Porto, Portugal.

In tropical regions, such as in the Amazon, the use of optical sensors is limited by high cloud coverage throughout the year. As an alternative, Synthetic Aperture Radar (SAR) products could be used, alone or in combination with optical images, to monitor tropical areas. In this sense, we aimed to select the best Land Use and Land Cover (LULC) classification approach for tropical regions using Sentinel family products. We choose the city of Belém, Brazil, as the study area. Images of close dates from Sentinel-1 (S-1) and Sentinel-2 (S-2) were selected, preprocessed, segmented, and integrated to develop a machine learning LULC classification through a Random Forest (RF) classifier. We also combined textural image analysis (S-1) and vegetation indexes (S-2). A total of six LULC classifications were made. Results showed that the best overall accuracy (OA) was found for the integration of S-1 and S-2 (91.07%) data, followed by S-2 only (89.53%), and S-2 with radiometric indexes (89.45%). The worse result was for S-1 data only (56.01). For our analysis the integration of optical products in the stacking increased de OA in all classifications. However, we suggest the development of more investigations with S-1 products due to its importance for tropical regions.
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http://dx.doi.org/10.3390/s19051140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427458PMC
March 2019

The Revisited Genome of Bacillus subtilis Bacteriophage SPP1.

Viruses 2018 12 11;10(12). Epub 2018 Dec 11.

Institut de Biologie Intégrative de la Cellule (I2BC), French Alternative Energies and Atomic Energy Commission (CEA), Centre National de la Recherche Scientifique (CNRS), Univ Paris-Sud, Université Paris-Saclay, 91190 Gif-sur-Yvette, France.

bacteriophage SPP1 is a lytic siphovirus first described 50 years ago [1]. Its complete DNA sequence was reported in 1997 [2]. Here we present an updated annotation of the 44,016 bp SPP1 genome and its correlation to different steps of the viral multiplication process. Five early polycistronic transcriptional units encode phage DNA replication proteins and lysis functions together with less characterized, mostly non- as the reference species for a new SPP1-like viruses genus of the family.
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http://dx.doi.org/10.3390/v10120705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316719PMC
December 2018

Neoadjuvant Trabectedin plus Radiotherapy in High-Grade Sarcoma of the Leg: A Case Report.

Case Rep Oncol 2018 May-Aug;11(2):499-504. Epub 2018 Jul 18.

Bone and Soft Tissue Tumor Unit, Coimbra University Hospital, Coimbra, Portugal.

Here, we present the case of a 78-year-old male patient with undifferentiated spindle cell sarcoma on the posteromedial surface of the right leg who experienced a long-lasting progression-free survival. Due to an underlying cardiac disease, the patient was not suitable for anthracyclines. In September 2015, he received first-line chemotherapy with trabectedin (Yondelis®) at the approved dosage and regimen - concomitant with external radiotherapy (RT). After the first 9 cycles of trabectedin plus RT given in the neoadjuvant setting, the patient underwent surgical resection. At that stage, we observed a very good pathological response with 80% of necrotic area. The patient resumed the therapy with trabectedin; however, approximately 5 months later, we observed a new nodular heterogeneous lesion with ill-defined margins in the right leg and suggestive of tumor relapse. Subsequently an above-the-knee amputation was performed, and the patient resumed his trabectedin therapy with the same dosage and regimen. In January 2018, almost 2 1/2 years after the start of trabectedin treatment and 30+ cycles of trabectedin, the patient is locoregionally and distant metastatically disease-free. Currently, the treatment with trabectedin is maintained without any significant serious toxicity. Future clinical trials are needed to gain additional insights into the role of trabectedin maintenance therapy until disease progression in the neoadjuvant setting and to identify predictive and prognostic criteria for response to trabectedin in patients with advanced sarcoma.
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http://dx.doi.org/10.1159/000490849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103334PMC
July 2018

The Bacteriophage Head-to-Tail Interface.

Authors:
Paulo Tavares

Subcell Biochem 2018;88:305-328

Department of Virology, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.

Many icosahedral viruses use a specialized portal vertex for genome encapsidation in the viral capsid (or head). This structure then controls release of the viral genetic information to the host cell at the beginning of infection. In tailed bacteriophages, the portal system is connected to a tail device that delivers their genome to the bacterial cytoplasm. The head-to-tail interface is a multiprotein complex that locks the viral DNA inside the phage capsid correctly positioned for egress and that controls its ejection when the viral particle interacts with the host cell receptor. Here we review the molecular mechanisms how this interface is assembled and how it carries out those two critical steps in the life cycle of tailed phages.
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http://dx.doi.org/10.1007/978-981-10-8456-0_14DOI Listing
November 2018

"French Phage Network"-Third Meeting Report.

Viruses 2018 03 10;10(3). Epub 2018 Mar 10.

Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 91190 Gif-sur-Yvette CEDEX, France.

In its third year of existence, the French Phage Network (Phages.fr) is pursuing its expansion. With more than 25 groups, mostly based in France, working on the various aspects of phage research, the network has increased its visibility, interactivity, and activity. The third meeting of the Phages.fr network, held on November 2017 at the Gif-sur-Yvette Centre National de la Recherche Scientifique (CNRS) campus, was a great opportunity for many young scientists to present their work and interact with more senior scientists, amongst which several were invited from abroad. Here we provide a summary of the work presented at this occasion during the oral presentations and poster sessions.
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http://dx.doi.org/10.3390/v10030123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869516PMC
March 2018

Bacteriophage SPP1 pac Cleavage: A Precise Cut without Sequence Specificity Requirement.

J Mol Biol 2017 05 9;429(9):1381-1395. Epub 2017 Jan 9.

Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette, France. Electronic address:

In many tailed bacteriophages, DNA packaging is initiated by recognition and cleavage of a specific sequence pac by the small (TerS) and large (TerL) terminase subunits. It was previously shown that the SPP1 pac region has two sequences where TerS binds (pacR and pacL), flanking the segment where TerL cleaves the SPP1 DNA (pacC). However, the pac-specific sequences required to achieve this endonucleolytic cut were not established. Their characterization is essential to understand the underlying mechanism. We show that the pacR sequence localized within 35bp downstream of the pac cut can be extensively degenerated, including its c1 and c2 repeats, and that only a disruption of a 5-bp polyadenine tract impairs the pac cleavage. This result together with deletion analysis of pacL shows that the specific DNA sequences required for targeting the terminase for pac cleavage are considerably shorter than the large region bound by TerS. Furthermore, extensive degeneration of the 6-bp target sequence within pacC where pac cleavage occurs reveals that TerL maintains, remarkably, its precise position of cleavage. Studies with SPP1-related phages show the conservation of the cut position, irrespective of the sequence variation in pacC and in pacR or the changes in pacL-pacC distance. Mechanistically, our data are compatible with a model in which TerS interactions with part of the pacL sequence and a poly-A tract in pacR are sufficient to orient very accurately the TerL nuclease to a defined pacC position. They also demonstrate that the resulting precise cut at pacC is independent of the targeted DNA sequence.
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http://dx.doi.org/10.1016/j.jmb.2017.01.005DOI Listing
May 2017

Structures of biomolecular complexes by combination of NMR and cryoEM methods.

Curr Opin Struct Biol 2017 04 2;43:104-113. Epub 2017 Jan 2.

Institut de Biologie Intégrative de la Cellule (I2BC), CEA, CNRS, Univ. Paris Sud, Université Paris-Saclay, F-91198 Gif-sur-Yvette, France; Institut de Biologie et de Technologies de Saclay, CEA, F-91191 Gif-sur-Yvette, France. Electronic address:

CryoEM is presently providing structures of biocomplexes considered intractable to analysis by other structural techniques. NMR is playing an important role in delivering structural information on dynamics events and conformational heterogeneity. Impressive results were obtained by combining cryoEM and either liquid- or solid-state NMR, revealing the structures of cellular machines, filaments and amyloid fibrils. NMR solution structures of proteins and nucleic acids were fitted, together with crystallographic structures, into cryoEM maps of large complexes, to decipher their assembly mechanisms and describe their functional dynamics. Modelling based on solid-state NMR and cryoEM data provided 3D structure of filaments and fibrils. These NMR approaches validated, but also corrected, atomic models built de novo in cryoEM maps, and provided new structural data on flexible or structurally heterogeneous systems. Combination of cryoEM and NMR became an established hybrid approach in structural biology that significantly contributes to our understanding of functional mechanisms in supramolecular assemblies.
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http://dx.doi.org/10.1016/j.sbi.2016.12.008DOI Listing
April 2017

Action of Ants on Vertebrate Carcasses and Blow Flies (Calliphoridae).

J Med Entomol 2016 11 29;53(6):1283-1291. Epub 2016 Jul 29.

Programa de Pós-graduação em Entomologia e Conservação da Biodiversidade, Universidade Federal da Grande Dourados, Dourados, MS, Brazil

Forensic entomology is a science that uses insect fauna as a tool to assist in criminal investigations and civil proceedings. Although the most researched insects are the Diptera and Coleoptera, ants may be present in all stages of decomposition. The aim of this study was to evaluate the role of ants and their action on blow flies during the decomposition process. Experiments were performed in which four pig carcasses were exposed in the cold and dry season (November/2012 and March/2013) and four in the hot and wet season (May/2013 and August/2013). Flies were the first insects to detect and interact with the carcasses, and six species of the Calliphoridae family were identified. Ants (Hymenoptera: Formicidae) were the second group, with six subfamilies identified. Myrmycinae represented 42% of the species, followed by Formicinae (28%), Ectatominae and Ponerinae (both 10%), and Ecitoninae and Dolichoderinae (both 5%). The ants acted on the carcasses as predators of visiting species, omnivores, and necrophagous, in all cases significantly affecting the decomposition time, slowing it down when the ants preyed on adult and immature insects consuming the carcass, or accelerating it by consuming the carcass and creating holes that could serve as gateways for the action of other organisms. The ants also generated artifacts that could lead to forensic misinterpretation.
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http://dx.doi.org/10.1093/jme/tjw119DOI Listing
November 2016

A non-invasive method for studying viral DNA delivery to bacteria reveals key requirements for phage SPP1 DNA entry in Bacillus subtilis cells.

Virology 2016 08 12;495:79-91. Epub 2016 May 12.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address:

Bacteriophages use most frequently a tail apparatus to create a channel across the entire bacterial cell envelope to transfer the viral genome to the host cell cytoplasm, initiating infection. Characterization of this critical step remains a major challenge due to the difficulty to monitor DNA entry in the bacterium and its requirements. In this work we developed a new method to study phage DNA entry that has the potential to be extended to many tailed phages. Its application to study genome delivery of bacteriophage SPP1 into Bacillus subtilis disclosed a key role of the host cell membrane potential in the DNA entry process. An energized B. subtilis membrane and a millimolar concentration of calcium ions are shown to be major requirements for SPP1 DNA entry following the irreversible binding of phage particles to the receptor YueB.
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http://dx.doi.org/10.1016/j.virol.2016.05.004DOI Listing
August 2016

Suppressing activity of tributyrin on hepatocarcinogenesis is associated with inhibiting the p53-CRM1 interaction and changing the cellular compartmentalization of p53 protein.

Oncotarget 2016 Apr;7(17):24339-47

Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.

Hepatocellular carcinoma (HCC), an aggressive and the fastest growing life-threatening cancer worldwide, is often diagnosed at intermediate or advanced stages of the disease, which substantially limits therapeutic approaches for its successful treatment. This indicates that the prevention of hepatocarcinogenesis is probably the most promising approach to reduce both the HCC incidence and cancer-related mortality. In previous studies, we demonstrated a potent chemopreventive effect of tributyrin, a butyric acid prodrug, on experimental hepatocarcinogenesis. The cancer-inhibitory effect of tributyrin was linked to the suppression of sustained cell proliferation and induction of apoptotic cell death driven by an activation of the p53 apoptotic signaling pathway. The goal of the present study was to investigate the underlying molecular mechanisms linked to tributyrin-mediated p53 activation. Using in vivo and in vitro models of liver cancer, we demonstrate that an increase in the level of p53 protein in nuclei, a decrease in the level of cytoplasmic p53, and, consequently, an increase in the ratio of nuclear/cytoplasmic p53 in rat preneoplastic livers and in rat and human HCC cell lines caused by tributyrin or sodium butyrate treatments was associated with a marked increase in the level of nuclear chromosome region maintenance 1 (CRM1) protein. Mechanistically, the increase in the level of nuclear p53 protein was associated with a substantially reduced binding interaction between CRM1 and p53. The results demonstrate that the cancer-inhibitory activity of sodium butyrate and its derivatives on liver carcinogenesis may be attributed to retention of p53 and CRM1 proteins in the nucleus, an event that may trigger activation of p53-mediated apoptotic cell death in neoplastic cells.
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http://dx.doi.org/10.18632/oncotarget.8248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029705PMC
April 2016

Balance Impairments after Brachial Plexus Injury as Assessed through Clinical and Posturographic Evaluation.

Front Hum Neurosci 2015 25;9:715. Epub 2016 Jan 25.

Laboratório de Neurobiologia II, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil; Núcleo de Pesquisa em Neurociência e Reabilitação, Instituto de Neurologia Deolindo Couto, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil.

Objective: To investigate whether a sensorimotor deficit of the upper limb following a brachial plexus injury (BPI) affects the upright balance.

Design: Eleven patients with a unilateral BPI and 11 healthy subjects were recruited. The balance assessment included the Berg Balance Scale (BBS), the number of feet touches on the ground while performing a 60 s single-leg stance and posturographic assessment (eyes open and feet placed hip-width apart during a single 60 s trial). The body weight distribution (BWD) between the legs was estimated from the center of pressure (COP) lateral position. The COP variability was quantified in the anterior-posterior and lateral directions.

Results: BPI patients presented lower BBS scores (p = 0.048) and a higher frequency of feet touches during the single-leg stance (p = 0.042) compared with those of the healthy subjects. An asymmetric BWD toward the side opposite the affected arm was shown by 73% of BPI patients. Finally, higher COP variability was observed in BPI patients compared with healthy subjects for anterior-posterior (p = 0.020), but not for lateral direction (p = 0.818).

Conclusions: This study demonstrates that upper limb sensorimotor deficits following BPI affect body balance, serving as a warning for the clinical community about the need to prevent and treat the secondary outcomes of this condition.
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http://dx.doi.org/10.3389/fnhum.2015.00715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724713PMC
February 2016

The chemopreventive activity of butyrate-containing structured lipids in experimental rat hepatocarcinogenesis.

Mol Nutr Food Res 2016 Feb 2;60(2):420-9. Epub 2015 Dec 2.

Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.

Scope: Emerging evidence indicates that the use of bioactive food components is a promising strategy to prevent the development of liver cancer. The goal of this study was to examine the chemopreventive effect of butyrate-containing structured lipids (STLs) produced by an enzymatic interesterification of tributyrin and flaxseed oil on rat hepatocarcinogenesis.

Methods And Results: Male Wistar rats were subjected to a classic "resistant hepatocyte" model of liver carcinogenesis and treated with STLs, tributyrin or flaxseed oil during the initial phases of hepatocarcinogenesis. Treatment with STLs and tributyrin strongly inhibited the development of preneoplastic liver lesions. The chemopreventive activity of tributyrin was associated with the induction of apoptosis and reduction of the expression of major activated hepatocarcinogenesis-related oncogenes. Treatment with STLs caused substantially greater inhibitory effects than tributyrin on oncogene expression.

Conclusion: These results demonstrate that the tumor-suppressing activity of butyrate-containing STLs is associated with its ability to prevent and inhibit activation of major hepatocarcinogenesis-related oncogenes. Enrichment of histone H3K9me3 and H3K27me3 at the promoter of Myc and Ccnd1 genes may be related to the inhibitory effect on oncogene expression in the livers of STL-treated rats.
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http://dx.doi.org/10.1002/mnfr.201500643DOI Listing
February 2016

Structural rearrangements in the phage head-to-tail interface during assembly and infection.

Proc Natl Acad Sci U S A 2015 Jun 19;112(22):7009-14. Epub 2015 May 19.

Institute of Structural and Molecular Biology, Birkbeck College, London WC1E 7HX, United Kingdom;

Many icosahedral viruses use a specialized portal vertex to control genome encapsidation and release from the viral capsid. In tailed bacteriophages, the portal system is connected to a tail structure that provides the pipeline for genome delivery to the host cell. We report the first, to our knowledge, subnanometer structures of the complete portal-phage tail interface that mimic the states before and after DNA release during phage infection. They uncover structural rearrangements associated with intimate protein-DNA interactions. The portal protein gp6 of bacteriophage SPP1 undergoes a concerted reorganization of the structural elements of its central channel during interaction with DNA. A network of protein-protein interactions primes consecutive binding of proteins gp15 and gp16 to extend and close the channel. This critical step that prevents genome leakage from the capsid is achieved by a previously unidentified allosteric mechanism: gp16 binding to two different regions of gp15 drives correct positioning and folding of an inner gp16 loop to interact with equivalent loops of the other gp16 subunits. Together, these loops build a plug that closes the channel. Gp16 then fastens the tail to yield the infectious virion. The gatekeeper system opens for viral genome exit at the beginning of infection but recloses afterward, suggesting a molecular diaphragm-like mechanism to control DNA efflux. The mechanisms described here, controlling the essential steps of phage genome movements during virus assembly and infection, are likely to be conserved among long-tailed phages, the largest group of viruses in the Biosphere.
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http://dx.doi.org/10.1073/pnas.1504039112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460457PMC
June 2015

Virus evolution toward limited dependence on nonessential functions of the host: the case of bacteriophage SPP1.

J Virol 2015 Mar 24;89(5):2875-83. Epub 2014 Dec 24.

Unité de Virologie Moléculaire et Structurale, CNRS UPR3296, Centre de Recherche de Gif, Gif-sur-Yvette, France

Unlabelled: All viruses are obligate intracellular parasites and depend on certain host cell functions for multiplication. However, the extent of such dependence and the exact nature of the functions provided by the host cell remain poorly understood. Here, we investigated if nonessential Bacillus subtilis genes are necessary for multiplication of bacteriophage SPP1. Screening of a collection of 2,514 single-gene knockouts of nonessential B. subtilis genes yielded only a few genes necessary for efficient SPP1 propagation. Among these were genes belonging to the yuk operon, which codes for the Esat-6-like secretion system, including the SPP1 receptor protein YueB. In addition, we found that SPP1 multiplication was negatively affected by the absence of two other genes, putB and efp. The gene efp encodes elongation factor P, which enhances ribosome activity by alleviating translational stalling during the synthesis of polyproline-containing proteins. PutB is an enzyme involved in the proline degradation pathway that is required for infection in the post-exponential growth phase of B. subtilis, when the bacterium undergoes a complex genetic reprogramming. The putB knockout shortens significantly the window of opportunity for SPP1 infection during the host cell life cycle. This window is a critical parameter for competitive phage multiplication in the soil environment, where B. subtilis rarely meets conditions for exponential growth. Our results in combination with those reported for other virus-host systems suggest that bacterial viruses have evolved toward limited dependence on nonessential host functions.

Importance: A successful viral infection largely depends on the ability of the virus to hijack cellular machineries and to redirect the flow of building blocks and energy resources toward viral progeny production. However, the specific virus-host interactions underlying this fundamental transformation are poorly understood. Here, we report on the first systematic analysis of virus-host cross talk during bacteriophage infection in Gram-positive bacteria. We show that lytic bacteriophage SPP1 is remarkably independent of nonessential genes of its host, Bacillus subtilis, with only a few cellular genes being necessary for efficient phage propagation. We hypothesize that such limited dependence of the virus on its host results from a constant "evolutionary arms race" and might be much more widespread than currently thought.
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http://dx.doi.org/10.1128/JVI.03540-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325756PMC
March 2015

Bacteriophage SPP1 tail tube protein self-assembles into β-structure-rich tubes.

J Biol Chem 2015 Feb 17;290(6):3836-49. Epub 2014 Dec 17.

From the Laboratoire de Biologie Structurale et Radiobiologie, UMR CNRS 8221 and CEA IBITECS, Commissariat à l'Energie Atomique, Saclay 91191 Gif-sur-Yvette Cedex, France,

The majority of known bacteriophages have long tails that serve for bacterial target recognition and viral DNA delivery into the host. These structures form a tube from the viral capsid to the bacterial cell. The tube is formed primarily by a helical array of tail tube protein (TTP) subunits. In phages with a contractile tail, the TTP tube is surrounded by a sheath structure. Here, we report the first evidence that a phage TTP, gp17.1 of siphophage SPP1, self-assembles into long tubes in the absence of other viral proteins. gp17.1 does not exhibit a stable globular structure when monomeric in solution, even if it was confidently predicted to adopt the β-sandwich fold of phage λ TTP. However, Fourier transform infrared and nuclear magnetic resonance spectroscopy analyses showed that its β-sheet content increases significantly during tube assembly, suggesting that gp17.1 acquires a stable β-sandwich fold only after self-assembly. EM analyses revealed that the tube is formed by hexameric rings stacked helicoidally with the same organization and helical parameters found for the tail of SPP1 virions. These parameters were used to build a pseudo-atomic model of the TTP tube. The large loop spanning residues 40-56 is located on the inner surface of the tube, at the interface between adjacent monomers and hexamers. In line with our structural predictions, deletion of this loop hinders gp17.1 tube assembly in vitro and interferes with SPP1 tail assembly during phage particle morphogenesis in bacteria.
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http://dx.doi.org/10.1074/jbc.M114.613166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319047PMC
February 2015

Automated classification of tailed bacteriophages according to their neck organization.

BMC Genomics 2014 Nov 27;15:1027. Epub 2014 Nov 27.

CEA, iBiTecS, Gif-sur-Yvette, F-91191 Paris, France.

Background: The genetic diversity observed among bacteriophages remains a major obstacle for the identification of homologs and the comparison of their functional modules. In the structural module, although several classes of homologous proteins contributing to the head and tail structure can be detected, proteins of the head-to-tail connection (or neck) are generally more divergent. Yet, molecular analyses of a few tailed phages belonging to different morphological classes suggested that only a limited number of structural solutions are used in order to produce a functional virion. To challenge this hypothesis and analyze proteins diversity at the virion neck, we developed a specific computational strategy to cope with sequence divergence in phage proteins. We searched for homologs of a set of proteins encoded in the structural module using a phage learning database.

Results: We show that using a combination of iterative profile-profile comparison and gene context analyses, we can identify a set of head, neck and tail proteins in most tailed bacteriophages of our database. Classification of phages based on neck protein sequences delineates 4 Types corresponding to known morphological subfamilies. Further analysis of the most abundant Type 1 yields 10 Clusters characterized by consistent sets of head, neck and tail proteins. We developed Virfam, a webserver that automatically identifies proteins of the phage head-neck-tail module and assign phages to the most closely related cluster of phages. This server was tested against 624 new phages from the NCBI database. 93% of the tailed and unclassified phages could be assigned to our head-neck-tail based categories, thus highlighting the large representativeness of the identified virion architectures. Types and Clusters delineate consistent subgroups of Caudovirales, which correlate with several virion properties.

Conclusions: Our method and webserver have the capacity to automatically classify most tailed phages, detect their structural module, assign a function to a set of their head, neck and tail genes, provide their morphologic subtype and localize these phages within a "head-neck-tail" based classification. It should enable analysis of large sets of phage genomes. In particular, it should contribute to the classification of the abundant unknown viruses found on assembled contigs of metagenomic samples.
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http://dx.doi.org/10.1186/1471-2164-15-1027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362835PMC
November 2014

The collagen-like protein gp12 is a temperature-dependent reversible binder of SPP1 viral capsids.

J Biol Chem 2014 Sep 29;289(39):27169-27181. Epub 2014 Jul 29.

Unité de Virologie Moléculaire et Structurale, UPR 3296 CNRS, Centre de Recherche de Gif, 91190 Gif-sur-Yvette, France,. Electronic address:

Icosahedral capsids of viruses are lattices of defined geometry and homogeneous size. The (quasi-)equivalent organization of their protein building blocks provides, in numerous systems, the binding sites to assemble arrays of viral polypeptides organized with nanometer precision that protrude from the capsid surface. The capsid of bacterial virus (bacteriophage) SPP1 exposes, at its surface, the 6.6-kDa viral polypeptide gp12 that binds to the center of hexamers of the major capsid protein. Gp12 forms an elongated trimer with collagen-like properties. This is consistent with the fold of eight internal GXY repeats of gp12 to build a stable intersubunit triple helix in a prokaryotic setting. The trimer dissociates and unfolds at near physiological temperatures, as reported for eukaryotic collagen. Its structural organization is reacquired within seconds upon cooling. Interaction with the SPP1 capsid hexamers strongly stabilizes gp12, increasing its Tm to 54 °C. Above this temperature, gp12 dissociates from its binding sites and unfolds reversibly. Multivalent binding of gp12 trimers to the capsid is highly cooperative. The capsid lattice also provides a platform to assist folding and association of unfolded gp12 polypeptides. The original physicochemical properties of gp12 offer a thermoswitchable system for multivalent binding of the polypeptide to the SPP1 capsid surface.
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http://dx.doi.org/10.1074/jbc.M114.590877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175352PMC
September 2014

The chemopreventive activity of the histone deacetylase inhibitor tributyrin in colon carcinogenesis involves the induction of apoptosis and reduction of DNA damage.

Toxicol Appl Pharmacol 2014 Apr 25;276(2):129-35. Epub 2014 Feb 25.

Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil; Advanced Research Center in Food Science and Nutrition (NAPAN) and Food Research Center (FoRC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil. Electronic address:

The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200mg/100g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week. After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p<0.05) as well as the ACF with ≥4 crypts (p<0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p<0.05) and reduced DNA damage (p<0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p<0.05). TB administration resulted in increased colonic tissue concentrations of BA (p<0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those that were more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB.
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http://dx.doi.org/10.1016/j.taap.2014.02.004DOI Listing
April 2014

Bacterial detection using unlabeled phage amplification and mass spectrometry through structural and nonstructural phage markers.

J Proteome Res 2014 Mar 19;13(3):1450-65. Epub 2014 Feb 19.

bioMérieux S.A. , 376, Chemin de l'Orme, 69280 Marcy-l'Etoile, France.

According to the World Health Organization, food safety is an essential public health priority. In this context, we report a relevant proof of feasibility for the indirect specific detection of bacteria in food samples using unlabeled phage amplification coupled to ESI mass spectrometry analysis and illustrated with the model phage systems T4 and SPP1. High-resolving power mass spectrometry analysis (including bottom-up and top-down protein analysis) was used for the discovery of specific markers of phage infection. Structural components of the viral particle and nonstructural proteins encoded by the phage genome were identified. Then, targeted detection of these markers was performed on a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode. E. coli at 1 × 10(5), 5 × 10(5), and 1 × 10(6) CFU/mL concentrations was successfully detected after only a 2 h infection time by monitoring phage T4 structural markers in Luria-Bertani broth, orange juice, and French bean stew ("cassoulet") matrices. Reproducible detection of nonstructural markers was also demonstrated, particularly when a high titer of input phages was required to achieve successful amplification. This strategy provides a highly time-effective and sensitive assay for bacterial detection.
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http://dx.doi.org/10.1021/pr400991tDOI Listing
March 2014

A touch of glue to complete bacteriophage assembly: the tail-to-head joining protein (THJP) family.

Mol Microbiol 2014 Mar 17;91(6):1164-78. Epub 2014 Feb 17.

Laboratoire de Virologie Moléculaire et Structurale, Centre de Recherche de Gif, CNRS UPR 3296 and IFR115, 91198, Gif-sur-Yvette, France.

Bacteriophage SPP1 is a nanomachine built to infect the bacterium Bacillus subtilis. The phage particle is composed of an icosahedric capsid, which contains the viral DNA, and a long non-contractile tail. Capsids and tails are produced in infected cells by two distinct morphogenetic pathways. Characterization of the suppressor-sensitive mutant SPP1sus82 showed that it produces DNA-filled capsids and tails but is unable to assemble complete virions. Its purified tails have a normal length but lack a narrow ring that tapers the tail end found at the tail-to-head interface. The mutant is defective in production of gp17. The gp17 ring is exposed in free tails competent for viral assembly but becomes shielded in the final virion structure. Recombinant gp17 is active in an in vitro assay to stick together capsids and tails present in extracts of SPP1sus82-infected cells, leading to formation of infectious particles. Gp17 thus plays a fundamental role in the tail-to-head joining reaction, the ultimate step of virus particle assembly. This is the conserved function of gp17 and its structurally related proteins like lambda gpU. This family of proteins can also provide fidelity to termination of the tail tube elongation reaction in a subset of phages including coliphage lambda.
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http://dx.doi.org/10.1111/mmi.12526DOI Listing
March 2014

Headful DNA packaging: bacteriophage SPP1 as a model system.

Virus Res 2013 May 16;173(2):247-59. Epub 2013 Feb 16.

Unité de Virologie Moléculaire et Structurale, CNRS UPR3296 and IFR 115, Bâtiment 14B, CNRS, 91198 Gif-sur-Yvette, France.

Tailed bacteriophages and herpesviruses package DNA inside the viral capsid by a powerful molecular motor. This packaging machine is composed of the portal protein, which provides a gate for DNA entry, the large terminase subunit whose ATPase activity fuels DNA translocation, and most frequently, a small terminase subunit that recognizes the viral packaging site. Here we review the mechanisms how the virulent Bacillus subtilis phage SPP1 packages DNA into a preformed procapsid. Encapsidation of the SPP1 DNA follows a processive unidirectional headful mechanism that starts with the recognition and cleavage of a unique genomic sequence (pac) by the viral terminase. The viral genome is then translocated through the central channel of the portal protein found at a single vertex of the procapsid. Packaging is terminated by an endonucleolytic cleavage of the concatemeric DNA substrate, following by disassembly of the packaging motor and closure of the portal system by the gatekeepers preventing leakage of the viral genome. Recent advances are providing new molecular insights on the mechanisms that ensure precise coordination of these critical steps required to accomplish the packaging encapsidation cycle.
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http://dx.doi.org/10.1016/j.virusres.2013.01.021DOI Listing
May 2013

Tumors of the foot and ankle: a single-institution experience.

J Foot Ankle Surg 2013 Mar-Apr;52(2):147-52. Epub 2013 Jan 16.

Department of Medical Oncology, Portuguese Oncology Institute of Coimbra, Coimbra, Portugal.

Tumors of the foot and ankle are rare, and the particular clinicopathologic features, therapeutic approach, and outcomes in this setting are not well established. From January 2000 to December 2010, 72 patients with primary musculoskeletal tumors of the foot and ankle, both benign and malignant, were treated at a single institution. Of the 72 patients, 56% were female. The median age was 52 years. Of the 72 tumors, 62 (86.11%) were located in the foot and 10 were located in the ankle; 63 (87.5%) were soft tissue tumors and 9 (12.5%) were bone tumors. Overall, 56 (78%) were benign tumors and 16 (22%) were malignant tumors. The most frequent soft tissue and bone diagnosis was giant cell tumor. The median follow-up period was 49 months. The vast majority of the tumors were located in the foot. Benign tumors were dominant, outnumbering malignant tumors by more than 3 to 1. The diversity of the histologic benign types was evident, with giant cell tumor, angiomyoma, and lipoma the most frequent. Regarding the malignant tumors, a clear male predominance was present, the median age was 45 years, and the most frequent tumor was synoviosarcoma. The 9-year overall and disease-free survival rate was 65% and 40%, respectively.
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http://dx.doi.org/10.1053/j.jfas.2012.12.004DOI Listing
August 2013

The use of dual-energy X-ray absorptiometry in the evaluation of obesity in women with obstructive sleep apnea-hypopnea syndrome.

Eur Arch Otorhinolaryngol 2013 Mar 27;270(4):1539-45. Epub 2012 Nov 27.

Department of Medicine, University of Brasilia, Brasília, DF, Brazil.

The inflammatory state caused by obesity increases the level of adipokines, such as leptin, with a direct impact on the central respiratory regulation. The present study addresses this problem by evaluation of the association of sleep apnea diagnosis in relation to body fat measured by dual-energy X-ray absorptiometry (DXA), anthropometric parameters and biochemical variables. All patients carried out overnight polysomnography, anthropometric evaluations [Body Mass Index (BMI), neck and waist circumference], body composition analyzed by DXA and blood sample collection (lipid profile, fasting glycemia, insulin, glycated hemoglobin, C-reactive protein and serum leptin levels). Obstructive sleep apnea-hypopnea syndrome (OSAHS) was defined by the apnea-hypopnea index (AHI) from the overnight polysomnography. According to the AHI, the women were divided into two groups: with and without apnea. Twenty-seven of them had OSAHS (AHI = 22.04 ± 17.55). The main results are the following: (a) BMI was not capable of predicting OSAHS in this study (p = 0.204); (b) for each 1 % increase in TBF %, the probability of having sleep apnea increased by 12.8 %; (c) comparing all variables (anthropometrics, DXA and blood sample), serum leptin was the only variable with a significant difference between the groups (p = 0.0257). The results reinforce the role of total body fat and leptin in the etiology of OSAHS and the need to include the evaluation of corporal composition measures by DXA in studies of sleep apnea.
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http://dx.doi.org/10.1007/s00405-012-2291-1DOI Listing
March 2013

The nuclease domain of the SPP1 packaging motor coordinates DNA cleavage and encapsidation.

Nucleic Acids Res 2013 Jan 30;41(1):340-54. Epub 2012 Oct 30.

Unité de Virologie Moléculaire et Structurale, UPR 3296 CNRS, 91190 Gif-sur-Yvette, France.

The large terminase subunit is a central component of the genome packaging motor from tailed bacteriophages and herpes viruses. This two-domain enzyme has an N-terminal ATPase activity that fuels DNA translocation during packaging and a C-terminal nuclease activity required for initiation and termination of the packaging cycle. Here, we report that bacteriophage SPP1 large terminase (gp2) is a metal-dependent nuclease whose stability and activity are strongly and preferentially enhanced by Mn(2+) ions. Mutation of conserved residues that coordinate Mn(2+) ions in the nuclease catalytic site affect the metal-induced gp2 stabilization and impair both gp2-specific cleavage at the packaging initiation site pac and unspecific nuclease activity. Several of these mutations block also DNA encapsidation without affecting ATP hydrolysis or gp2 C-terminus binding to the procapsid portal vertex. The data are consistent with a mechanism in which the nuclease domain bound to the portal switches between nuclease activity and a coordinated action with the ATPase domain for DNA translocation. This switch of activities of the nuclease domain is critical to achieve the viral chromosome packaging cycle.
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http://dx.doi.org/10.1093/nar/gks974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592435PMC
January 2013

Management of desmoid-type fibromatosis involving peripheral nerves.

Arq Neuropsiquiatr 2012 Jul;70(7):514-9

Peripheral Nerve Surgery Unit, Department of Neurosurgery, Medical School, University of São Paulo, Rua Maestro Cardim 592, São Paulo, SP, Brazil.

Desmoid-type fibromatosis is an uncommon and aggressive neoplasia, associated with a high rate of recurrence. It is characterized by an infiltrative but benign fibroblastic proliferation occurring within the deep soft tissues. There is no consensus about the treatment of those tumors. We present a surgical series of four cases, involving the brachial plexus (two cases), the median nerve and the medial brachial cutaneous nerve. Except for the last case, they were submitted to multiple surgical procedures and showed repeated recurrences. The diagnosis, the different ways of treatment and the prognosis of these tumoral lesions are discussed. Our results support the indication of radical surgery followed by radiotherapy as probably one of the best ways to treat those controversial lesions.
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http://dx.doi.org/10.1590/s0004-282x2012000700008DOI Listing
July 2012