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Molecular determinants of acute inflammatory responses to biomaterials

Molecular determinants of acute inflammatory responses to biomaterials

Thus, this is by no means the first indication of a possible causal connection between the deposition of fibrin(ogen) and promotion of inflammation. However, to the best of our knowledge the present results constitute the first clear in vivo evidence of the possible molecular determinants of this inter- relationship. At least in the case of biomaterial implants, it ap- pears that phagocyte accumulation is mediated by interactions between fibrinogen g190–202 and the phagocyte integrin Mac-1 (CD11b/CD18). Further knowledge of the interplay between biomaterials, adsorbed proteins, and host cells may permit the rational design of surfaces which discourage adverse inflam- matory and/or fibrotic reactions. In a broader context, under- standing of such interactions may lead to the development of new therapeutic strategies for the moderation of other types of pathogenic inflammatory responses.
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Molecular Determinants of Virulence, Cell Tropism, and Pathogenic Phenotype of Infectious Bursal Disease Virus

Molecular Determinants of Virulence, Cell Tropism, and Pathogenic Phenotype of Infectious Bursal Disease Virus

Infectious bursal disease viruses (IBDVs), belonging to the family Birnaviridae, exhibit a wide range of immunosuppressive potential, pathogenicity, and virulence for chickens. The genomic segment A encodes all the structural (VP2, VP4, and VP3) and nonstructural proteins, whereas segment B encodes the viral RNA- dependent RNA polymerase (VP1). To identify the molecular determinants for the virulence, pathogenic phenotype, and cell tropism of IBDV, we prepared full-length cDNA clones of a virulent strain, Irwin Moulthrop (IM), and constructed several chimeric cDNA clones of segments A and B between the attenuated vaccine strain (D78) and the virulent IM or GLS variant strain. Using the cRNA-based reverse-genetics system developed for IBDV, we generated five chimeric viruses after transfection by electroporation procedures in Vero or chicken embryo fibroblast (CEF) cells, one of which was recovered after propagation in embryonated eggs. To evaluate the characteristics of the recovered viruses in vivo, we inoculated 3-week-old chickens with D78, IM, GLS, or chimeric viruses and analyzed their bursae for pathological lesions 3 days postinfection. Viruses in which VP4, VP4-VP3, and VP1 coding sequences of the virulent strain IM were substituted for the corresponding region in the vaccine strain failed to induce hemorrhagic lesions in the bursa. In contrast, viruses in which the VP2 coding region of the vaccine strain was replaced with the variant GLS or virulent IM strain caused rapid bursal atrophy or hemorrhagic lesions in the bursa, as seen with the variant or classical virulent strain, respectively. These results show that the virulence and pathogenic-phenotype markers of IBDV reside in VP2. Moreover, one of the chimeric viruses containing VP2 sequences of the virulent strain could not be recovered in Vero or CEF cells but was recovered in embryonated eggs, suggesting that VP2 contains the determinants for cell tropism. Similarly, one of the chimeric viruses containing the VP1 segment of the virulent strain could not be recovered in Vero cells but was recovered in CEF cells, suggesting that VP1 contains the determinants for cell-specific replication in Vero cells. By comparing the deduced amino acid sequences of the D78 and IM strains and their reactivities with monoclonal antibody 21, which binds specifically to virulent IBDV, the putative amino acids involved in virulence and cell tropism were identified. Our results indicate that residues Gln at position 253 (Gln253), Asp279, and Ala284 of VP2 are involved in the virulence, cell tropism, and pathogenic phenotype of virulent IBDV.
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Molecular determinants of uterine receptivity

Molecular determinants of uterine receptivity

Molecular determinants of uterine receptivity ZHAOWEI TU#,1,2, HAO RAN#,1,3, SHUANG ZHANG1, GUOLIANG XIA3, BINGYAN WANG*,1 and HAIBIN WANG*,1 1State Key Laboratory of Reproductive Biology, Institute o[.]

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Identification of molecular determinants of cell culture growth characteristics of Enterovirus 71

Identification of molecular determinants of cell culture growth characteristics of Enterovirus 71

However, there were only 2 nt. substitutions found in the Sabin 2 strain that appeared at position 481 within the IRES region and at position 2909 within the VP1. For Sabin 3, a total of 10 nt. substitutions were found to differ from its parent strain, but only 3 substitutions appeared to be the main determinants for the attenuated phenotype (C274U in IRES, C2034U in VP3, and U2493C in VP1) [25]. Sabin 3 strain was also found to be the most genetically unstable of the three Sabin strains. As a result of the analysis of the molecular deter- minants of cell culture growth, in vitro construction of polioviruses with reduced-virulence could be performed via the introduction of mutations in the 5′-NTR to reduce the efficiency of viral replication. The EV-A71 strains had 46% amino acid identity with the polioviral P1 capsid region and 55% with the entire polyprotein. In addition, EV-A71 and PV share high sequence homology especially in the 5′-NTR region [22]. For example, EV- A71 carried the same C nt. at position 475 which corre- sponds to position 472 in the PV genome.
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Molecular Determinants for Subcellular Localization of the Severe Acute Respiratory Syndrome Coronavirus Open Reading Frame 3b Protein

Molecular Determinants for Subcellular Localization of the Severe Acute Respiratory Syndrome Coronavirus Open Reading Frame 3b Protein

The molecular mechanism regulating the timing of nucleo- mitochondrial translocation of ORF 3b protein remains to be determined. We have been unable to detect any evidence of posttranslational modifications of ORF 3b that could explain the localization behavior; ORF 3b isolated from a nuclear fraction has the same electrophoretic mobility as ORF 3b obtained from mitochondrial purification and does not appear to be phosphorylated (data not shown). We favor the hypoth- esis that ORF 3b undergoes a conformational change in the nucleus that exposes the MTS and nuclear export signal, which are encompassed in the same region of the protein, allowing for translocation out of the nucleus and to mitochondria. Our evidence would seem to suggest that a feature of the newly synthesized ORF 3b causes its continual uptake and inhibited egress from the nucleus since it appears to be mobile rather than tethered in the nucleus. Alternatively, it may be released in a time-dependent fashion from a fluid nuclear retention factor or acquire a mitochondrial location protein and thereby assume its specific localization via a partner protein(s). Al- though ORF 3b is sufficiently small to diffuse passively through the nuclear pore complex, the presence of active transport domains suggests that the SARS-CoV ORF 3b may act as a virally encoded chaperone and thus may bind and remove a host-encoded protein from the nucleus to modulate host re- sponses during infection. The literature includes numerous examples of RNA viruses whose replication cycle occurs ex- clusively in the cytoplasm, like that of SARS-CoV, but that target the nucleus to facilitate replication or alter host cell function (18, 36).
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Molecular determinants for virulence in coxsackievirus B1 infection.

Molecular determinants for virulence in coxsackievirus B1 infection.

In 1979, Ray et al. reported the isolation of a CVB1 strain which causes myositis in certain mouse strains (22); this isolate has become known as the Tucson strain of CVB1 (CVB1T). CVB1T has been used by several laboratories in order to investigate an experimental model of enterovirus-induced my- ositis (26). Our studies demonstrated that CVB1T was more virulent following intraperitoneal (i.p.) inoculation than virus produced from an infectious cDNA clone of CVB1 (CVB1N). To identify the molecular determinant(s) for the difference in virulence between these two viruses, we prepared chimeras between the cDNAs and investigated the 50% lethal dose (LD 50 ) of the recombinant viruses. We focused on recombi-
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Clinical and molecular determinants of extrahepatic disease progression in patients with metastatic colorectal cancer with liver-limited metastases deemed initially unresectable

Clinical and molecular determinants of extrahepatic disease progression in patients with metastatic colorectal cancer with liver-limited metastases deemed initially unresectable

We acknowledge some limitations of our work, including the relatively small sample size and the retro- spective collection of clinical data. Moreover, given the strong impact of a post-baseline variable, such as surgical resection, on the natural history of the disease and its progression patterns, this study did not allow developing and validating a score or a nomogram able to predict the risk of ePD at baseline. When focusing on the subgroup of patients who underwent at least one liver-directed procedure, the smaller sample size prevented to derive robust conclusions on ePD determinants, though high- lighting the positive impact of subsequent liver re-treat- ments on the extrahepatic spread. The clinical relevance of locoregional tools in the therapeutic route of patients with oligometastatic CRC is well described in the latest version of the European Society for Medical Oncology guidelines 20 underlining the contribution of disease local-
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Molecular Determinants of Antiviral Potency of Paramyxovirus Entry Inhibitors

Molecular Determinants of Antiviral Potency of Paramyxovirus Entry Inhibitors

Hendra virus (HeV) and Nipah virus (NiV) constitute the Henipavirus genus of paramyxoviruses, both fatal in humans and with the potential for subversion as agents of bioterrorism. Binding of the HeV/NiV attachment protein (G) to its receptor triggers a series of conformational changes in the fusion protein (F), ultimately leading to formation of a postfusion six-helix bundle (6HB) structure and fusion of the viral and cellular membranes. The ectodomain of paramyxovirus F proteins contains two conserved heptad repeat regions, the first (the N-terminal heptad repeat [HRN]) adjacent to the fusion peptide and the second (the C-terminal heptad repeat [HRC]) immediately preceding the transmembrane domain. Peptides derived from the HRN and HRC regions of F are proposed to inhibit fusion by preventing activated F molecules from forming the 6HB structure that is required for fusion. We previously reported that a human parainfluenza virus 3 (HPIV3) F peptide effectively inhibits infection mediated by the HeV glycoproteins in pseudotyped-HeV entry assays more effectively than the comparable HeV-derived peptide, and we now show that this peptide inhibits live-HeV and -NiV infection. HPIV3 F peptides were also effective in inhibiting HeV pseudotype virus entry in a new assay that mimics multicycle replication. This anti-HeV/NiV efficacy can be correlated with the greater potential of the HPIV3 C peptide to interact with the HeV F N peptide coiled-coil trimer, as evaluated by thermal unfolding experiments. Furthermore, replacement of a buried glutamic acid (glutamic acid 459) in the C peptide with valine enhances antiviral potency and stabilizes the 6HB conformation. Our results strongly suggest that conserved interhelical packing interactions in the F protein fusion core are important determinants of C peptide inhibitory activity and offer a strategy for the development of more-potent analogs of F peptide inhibitors.
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Unravelling the molecular determinants of bee sensitivity to neonicotinoid insecticides

Unravelling the molecular determinants of bee sensitivity to neonicotinoid insecticides

In conclusion, these data demonstrate that the CYP9Q family of both honeybees and bumble bees contains critically important enzymes that define their sensitivity to neonicotinoids. This finding illustrates the importance of considering bee xenobiotic biotransformation pathways to predict, and potentially influence, the pharmacological and toxicological outcomes of insecticide use. For example, the knowledge and tools developed in this study can be harnessed to avoid negative pesticide-pesticide in- teractions [24] due to inhibition of these key defense systems. Furthermore, our findings, and those of previous studies that have uncovered the molecular and biochemical basis of pesti- cide selectivity [15, 25–29], can facilitate the development of compounds that show high efficacy against crop pests but low toxicity to nontarget beneficial insects. In this regard, the recom- binant enzymes and transgenic Drosophila lines developed in our study can be used as screening tools to assess the metabolic liability of future insecticidal lead compounds and so ensure that they are rapidly broken down by these major xenobiotic detoxi- fying enzymes.
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The molecular determinants and consequences of recombination in the evolution of human enteroviruses

The molecular determinants and consequences of recombination in the evolution of human enteroviruses

precursor protein before cleavage to make VP2 and VP4 capsid protein capsid protein capsid protein capsid protein virus protease precursor protein, interacts with cellular membranes inte[r]

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Molecular determinants of rotavirus virulence

Molecular determinants of rotavirus virulence

Diarrhoea produced by B223 strain of rotavirus in 7 day old suckling pups of various mice strains... Replication of OSU strain of rotavirus in 7 day X..[r]

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Discovering early molecular determinants of leukemogenesis

Discovering early molecular determinants of leukemogenesis

demonstrate that these mutations confer a competitive clonal advantage upon HSCs in mice and that the advantage is conditional because it is observed only in the presence of the ligand G-CSF (see the related article beginning on page 946). Once activated, the mutant receptor requires the function of Stat5 in order to effect clonal expansion of this stem cell population. The results support the notion that early molecular steps in this and other neoplastic processes represent adaptations in which, through somatic mutations, “unfit” stem cells gain a measure of fitness by altering their relationships with their
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Molecular Determinants of Sporulation in Ashbya gossypii

Molecular Determinants of Sporulation in Ashbya gossypii

In kar3 mutants sporulation is severely reduced, while deletion of KAR4 as well as of homologs of central Saccharomyces cerevisiae regulators of sporulation, IME1 , IME2 , IME4 , and NDT[r]

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A review of soft-tissue sarcomas: translation of biological advances into treatment measures

A review of soft-tissue sarcomas: translation of biological advances into treatment measures

Abstract: Soft-tissue sarcomas are rare malignant tumors arising from connective tissues and have an overall incidence of about five per 100,000 per year. While this diverse family of malignancies comprises over 100 histological subtypes and many molecular aberrations are prevalent within specific sarcomas, very few are therapeutically targeted. Instead of utilizing molecular signatures, first-line sarcoma treatment options are still limited to traditional surgery and chemotherapy, and many of the latter remain largely ineffective and are plagued by disease resistance. Currently, the mechanism of sarcoma oncogenesis remains largely unknown, thus necessitating a better understanding of pathogenesis. Although substantial progress has not occurred with molecularly targeted therapies over the past 30 years, increased knowledge about sarcoma biology could lead to new and more effective treatment strategies to move the field forward. Here, we discuss biological advances in the core molecular determinants in some of the most common soft-tissue sarcomas – liposarcoma, angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, Ewing’s sarcoma, and synovial sarcoma – with an emphasis on emerging genomic and molecular pathway targets and immunotherapeutic treatment strategies to combat this confounding disease.
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Molecular Analysis of an Echovirus 3 Strain Isolated from an Individual Concurrently with Appearance of Islet Cell and IA 2 Autoantibodies

Molecular Analysis of an Echovirus 3 Strain Isolated from an Individual Concurrently with Appearance of Islet Cell and IA 2 Autoantibodies

of islet cells. Over the past few years, a number of studies have reported an association between enteroviruses and diabetes on the basis of reverse transcription (RT)-PCR amplification from clinical material, using specific sequences from the well-con- served 5 ⬘ UTR (1, 8, 10). However, these studies have provided limited information on the precise nature of the enterovirus present, as frequent recombination means that 5 ⬘ -UTR se- quences do not correlate with other regions of the genome, notably, the capsid-encoding region, which determines the se- rotype and receptor binding properties of the virus (19, 25, 27, 39, 44). Virus propagation from diabetic subjects has been another approach. CBV4 and E9 strains isolated in this way have been studied, and attempts to identify diabetic determi- nants have been made (21, 37, 48, 52). Other studies have identified sequences in enteroviruses that could be involved in autoimmunity through molecular mimicry (13, 14, 36, 53). Re- cently, enterovirus RNA has been demonstrated in islet cells of some diabetic patients, and these cells were shown to express several receptors recognized by enteroviruses (55). In addition, work on a strain of CBV4 indicated that changes close to the canyon, the site of receptor binding in enteroviruses, corre- lated with persistent infection in pancreatic islet cells, empha- sizing a potential role for receptor interactions in T1D (54). However, our understanding of the role of enteroviruses in diabetes and potential molecular determinants is still very in- complete.
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Viral determinants of simian immunodeficiency virus (SIV) virulence in rhesus macaques assessed by using attenuated and pathogenic molecular clones of SIVmac.

Viral determinants of simian immunodeficiency virus (SIV) virulence in rhesus macaques assessed by using attenuated and pathogenic molecular clones of SIVmac.

In this study, infection of rhesus macaques with recombinant viruses showed a spectrum of virulence between the parent viruses, SIVmaclA1l and SIVmac239; thus, molecular determinants of [r]

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Roles Played by Capsid-Dependent Induction of Membrane Curvature and Gag-ESCRT Interactions in Tetherin Recruitment to HIV-1 Assembly Sites

Roles Played by Capsid-Dependent Induction of Membrane Curvature and Gag-ESCRT Interactions in Tetherin Recruitment to HIV-1 Assembly Sites

HIV-1 encodes four accessory genes that have been implicated in combating host defense responses (Vif, Vpr, Vpu, and Nef) (82), exemplifying the necessity for immune evasion by successful viral pathogens. Such evolutionary interplay between virus and host is epitomized by the relationship between HIV-1 Vpu and human tetherin. Tetherin appears to have arisen early in mammalian evo- lution and remains a potent inhibitor of many enveloped viruses (20). Considering the broad range of susceptible viruses, it is un- likely that tetherin recruitment is mediated by a direct interaction between tetherin and the Gag polyprotein. In support of this no- tion, we and others have observed that tetherin potently inhibited release of Gag derivatives lacking the juxta-membrane MA do- main, which could potentially interact with the short cytoplasmic tail of tetherin (83) (unpublished data). Instead of the MA se- quence, this study identified amino acid residues in the CA N-ter- minal domain and late domain motifs as molecular determinants for recruitment of tetherin to HIV-1 assembly sites at the plasma membrane. Importantly, mutations in the former impair Gag- induced membrane curvature, whereas those in the latter disrupt
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Stimulation of histamine release from human basophils by human platelet factor 4

Stimulation of histamine release from human basophils by human platelet factor 4

That a similar maximal release of histamine from human basophils was evoked by PF4 and PF459-70 suggested that the molecular determinants critical for basophil activation are located in [r]

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Identification of a single amino acid residue in the capsid protein VP1 of coxsackievirus B4 that determines the virulent phenotype.

Identification of a single amino acid residue in the capsid protein VP1 of coxsackievirus B4 that determines the virulent phenotype.

4797 Downloaded from http://jvi.asm.org/ on November 9, 2019 by guest To identify the molecular determinants of virulence for coxsackievirus B4, a panel of recombinant, chimeric viruses [r]

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Characterization of the Self-Resistance Mechanism to Dityromycin in the Streptomyces Producer Strain

Characterization of the Self-Resistance Mechanism to Dityromycin in the Streptomyces Producer Strain

ABSTRACT Dityromycin is a peptide antibiotic isolated from the culture broth of the soil microorganism Streptomyces sp. strain AM-2504. Recent structural studies have shown that dityromycin targets the ribosomal protein S12 in the 30S ribosomal subunit, inhibiting translocation. Herein, by using in vitro protein synthesis assays, we identified the resistance mechanism of the producer strain to the secondary me- tabolite dityromycin. The results show that the self-resistance mechanism of the Streptomyces sp. strain AM-2504 is due to a specific modification of the ribosome. In particular, two amino acid substitutions, located in a highly conserved region of the S12 protein corresponding to the binding site of the antibiotic, were found. These mutations cause a substantial loss of affinity of the dityromycin for the 30S ribo- somal subunit, protecting the producer strain from the toxic effect of the antibiotic. In addition to providing a detailed description of the first mechanism of self- resistance based on a mutated ribosomal protein, this work demonstrates that the molecular determinants of the dityromycin resistance identified in Streptomyces can be transferred to Escherichia coli ribosomes, where they can trigger the same antibi- otic resistance mechanism found in the producer strain.
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