Modification of a loop sequence between α-helices 6 and 7 of virus capsid (CA) protein in a human immunodeficiency virus type 1 (HIV-1) derivative that has simian immunodeficiency virus (SIVmac239) vif and CA α-helices 4 and 5 loop improves replication in cynomolgus monkey cells

<p>Abstract</p> <p>Background</p> <p>Human immunodeficiency virus type 1 (HIV-1) productively infects only humans and chimpanzees but not cynomolgus or rhesus monkeys while simian immunodeficiency virus isolated from macaque (SIVmac) readily establishes infection in those monkeys. Several HIV-1 and SIVmac chimeric viruses have been constructed in order to develop an animal model for HIV-1 infection. Construction of an HIV-1 derivative which contains sequences of a SIVmac239 loop between α-helices 4 and 5 (L4/5) of capsid protein (CA) and the entire SIVmac239 <it>vif </it>gene was previously reported. Although this chimeric virus could grow in cynomolgus monkey cells, it did so much more slowly than did SIVmac. It was also reported that intrinsic TRIM5α restricts the post-entry step of HIV-1 replication in rhesus and cynomolgus monkey cells, and we previously demonstrated that a single amino acid in a loop between α-helices 6 and 7 (L6/7) of HIV type 2 (HIV-2) CA determines the susceptibility of HIV-2 to cynomolgus monkey TRIM5α.</p> <p>Results</p> <p>In the study presented here, we replaced L6/7 of HIV-1 CA in addition to L4/5 and <it>vif </it>with the corresponding segments of SIVmac. The resultant HIV-1 derivatives showed enhanced replication capability in established T cell lines as well as in CD8+ cell-depleted primary peripheral blood mononuclear cells from cynomolgus monkey. Compared with the wild type HIV-1 particles, the viral particles produced from a chimeric HIV-1 genome with those two SIVmac loops were less able to saturate the intrinsic restriction in rhesus monkey cells.</p> <p>Conclusion</p> <p>We have succeeded in making the replication of simian-tropic HIV-1 in cynomolgus monkey cells more efficient by introducing into HIV-1 the L6/7 CA loop from SIVmac. It would be of interest to determine whether HIV-1 derivatives with SIVmac CA L4/5 and L6/7 can establish infection of cynomolgus monkeys <it>in vivo</it>.</p

Efficacy of Corrected Rapid Turnover Protein Increment Index (CRII) for Early Detection of Improvement of Nutrition Status in Patients with Malnutrition

Serum prealbumin level is useful for assessment of changes in nutritional status but it is markedly affected by the inflammation. In this study, we examined the efficacy of the corrected rapid turnover protein increment index (CRII) for prealbumin, which is calculated as [prealbumin level/C-reactive protein (CRP) level on the assessment day]/[prealbumin level/CRP level on the day of starting nutritional care], for prediction of improvement of nutritional status in patients with malnutrition. The subjects were 50 hospitalized patients with low albuminemia, who were receiving nutritional care. Serum concentrations of albumin, prealbumin and CRP were measured every week for 5 weeks. We defined patients whose serum albumin level was elevated by more than 0.2 g/dl after 5 weeks as those showing improved nutritional status. There was a significant difference in the prealbumin level between improved and unimproved patients at 5 weeks after the start of nutritional support. On the other hand, the prealbumin CRII value showed a significant difference between the groups at 1 and 2 weeks after the start of nutritional support. In conclusion, assessment of prealbumin CRII is useful for early prediction of improved nutritional status in patients with malnutrition

Geographical, genetic and functional diversity of antiretroviral host factor TRIMCyp in cynomolgus macaque (Macaca fascicularis)

The antiretroviral factor tripartite motif protein 5 (TRIM5) gene-derived isoform (TRIMCyp) has been found in at least three species of Old World monkey: rhesus (Macaca mulatta), pig-tailed (Macaca nemestrina) and cynomolgus (Macaca fascicularis) macaques. Although the frequency of TRIMCyp has been well studied in rhesus and pig-tailed macaques, the frequency and prevalence of TRIMCyp in cynomolgus macaques remain to be definitively elucidated. Here, the geographical and genetic diversity of TRIM5α/TRIMCyp in cynomolgus macaques was studied in comparison with their anti-lentiviral activity. It was found that the frequency of TRIMCyp in a population in the Philippines was significantly higher than those in Indonesian and Malaysian populations. Major and minor haplotypes of cynomolgus macaque TRIMCyp with single nucleotide polymorphisms in the cyclophilin A domain were also found. The functional significance of the polymorphism in TRIMCyp was examined, and it was demonstrated that the major haplotype of TRIMCyp suppressed human immunodeficiency virus type 1 (HIV-1) but not HIV-2, whilst the minor haplotype of TRIMCyp suppressed HIV-2 but not HIV-1. The major haplotype of TRIMCyp did not restrict a monkey-tropic HIV-1 clone, NL-DT5R, which contains a capsid with the simian immunodeficiency virus-derived loop between α-helices 4 and 5 and the entire vif gene. These results indicate that polymorphisms of TRIMCyp affect its anti-lentiviral activity. Overall, the results of this study will help our understanding of the genetic background of cynomolgus macaque TRIMCyp, as well as the host factors composing species barriers of primate lentiviruses

Clinical Characteristics of Fragile X Syndrome Patients in Japan

[Background] Fragile X syndrome (FXS) is a well-known X-linked disorder clinically characterized by intellectual disability and autistic features. However, diagnosed Japanese FXS cases have been fewer than expected, and clinical features of Japanese FXS patients remain unknown. [Methods] We evaluated the clinical features of Japanese FXS patients using the results of a questionnaire-based survey. [Results] We presented the characteristics of seven patients aged 6 to 20 years. Long face and large ears were observed in five of seven patients. Macrocephaly was observed in four of five patients. The meaningful word was first seen at a certain time point between 18 and 72 months (median = 60 months). Developmental quotient or intellectual quotient ranged between 20 and 48 (median = 29). Behavioral disorders were seen in all patients (autistic spectrum disorder in six patients, hyperactivity in five patients). Five patients were diagnosed by polymerase chain reaction analysis, and two patients were diagnosed by the cytogenetic study. All physicians ordered FXS genetic testing for suspicious cases because of clinical manifestations. [Conclusion] In the present study, a long face, large ears, macrocephaly, autistic spectrum disorder, and hyperactivity were observed in almost cases, and these characteristics might be common features in Japanese FXS patients. Our finding indicated the importance of clinical manifestations to diagnosis FXS. However, the sample size of the present study is small, and these features are also seen to patients with other disorders. We consider that genetic testing for FXS should be performed on a wider range of intellectually disabled cases

Cynomolgus macaque TRIMCyp-resistant HIV-1

Old World monkey TRIM5α strongly suppresses human immunodeficiency virus type 1 (HIV-1) replication. A fusion protein comprising cynomolgus macaque (CM) TRIM5 and cyclophilin A (CM TRIMCyp) also potently suppresses HIV-1 replication. However, CM TRIMCyp fails to suppress a mutant HIV-1 that encodes a mutant capsid protein containing a SIVmac239-derived loop between α-helices 4 and 5 (L4/5). There are seven amino acid differences between L4/5 of HIV-1 and SIVmac239. Here, we investigated the minimum numbers of amino acid substitutions that would allow HIV-1 to evade CM TRIMCyp-mediated suppression. We performed random PCR mutagenesis to construct a library of HIV-1 variants containing mutations in L4/5, and then we recovered replication-competent viruses from CD4+ MT4 cells that expressed high levels of CM TRIMCyp. CM TRIMCyp-resistant viruses were obtained after three rounds of selection in MT4 cells expressing CM TRIMCyp and these were found to contain four amino acid substitutions (H87R, A88G, P90D and P93A) in L4/5. We then confirmed that these substitutions were sufficient to confer CM TRIMCyp resistance to HIV-1. In a separate experiment using a similar method, we obtained novel CM TRIM5α-resistant HIV-1 strains after six rounds of selection and rescue. Analysis of these mutants revealed that V86A and G116E mutations in the capsid region conferred partial resistance to CM TRIM5α without substantial fitness cost when propagated in MT4 cells expressing CM TRIM5α. These results confirmed and further extended the previous notion that CM TRIMCyp and CM TRIM5α recognize the HIV-1 capsid in different manners

The MAXI Mission on the ISS: Science and Instruments for Monitoring All Sky X-Ray Images

The MAXI (Monitor of All-sky X-ray Image) mission is the first astronomical payload to be installed on the Japanese Experiment Module-Exposed Facility (JEM-EF) on the ISS. It is scheduled for launch in the middle of 2009 to monitor all-sky X-ray objects on every ISS orbit. MAXI will be more powerful than any previous X-ray All Sky Monitor (ASM) payloads, being able to monitor hundreds of AGN. MAXI will provide all sky images of X-ray sources of about 20 mCrab in the energy band of 2-30 keV from observation on one ISS orbit (90 min), about 4.5 mCrab for one day, and about 1 mCrab for one month. A final detectability of MAXI could be 0.2 mCrab for 2 year observations.Comment: 12 pages, 11 figures, accepted for publication in Publications of the Astronomical Society of Japa

K0(K0ˉ)K^0(\bar{K^0}) Production in Two-Photon Processes at TRISTAN

We have carried out an inclusive measurement of $K^0(\bar{K^0})$ production in two-photon processes at TRISTAN. The mean $\sqrt{s}$ was 58 GeV and the integrated luminosity was 199 pb$^{-1}$. High-statistics $K_s$ samples were obtained under such conditions as no-, anti-electron, and remnant-jet tags. The remnant-jet tag, in particular, allowed us, for the first time, to measure the cross sections separately for the resolved-photon and direct processes.Comment: 20 pages, Latex format, 4 figures and KEK-mark included. Table 1 revised. To be published in Phys. Lett.

A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair.

When DNA replication is stalled at sites of DNA damage, a cascade of responses is activated in the cell to halt cell cycle progression and promote DNA repair. A pathway initiated by the kinase Ataxia teleangiectasia and Rad3 related (ATR) and its partner ATR interacting protein (ATRIP) plays an important role in this response. The Fanconi anemia (FA) pathway is also activated following genomic stress, and defects in this pathway cause a cancer-prone hematologic disorder in humans. Little is known about how these two pathways are coordinated. We report here that following cellular exposure to DNA cross-linking damage, the FA core complex enhances binding and localization of ATRIP within damaged chromatin. In cells lacking the core complex, ATR-mediated phosphorylation of two functional response targets, ATRIP and FANCI, is defective. We also provide evidence that the canonical ATR activation pathway involving RAD17 and TOPBP1 is largely dispensable for the FA pathway activation. Indeed DT40 mutant cells lacking both RAD17 and FANCD2 were synergistically more sensitive to cisplatin compared with either single mutant. Collectively, these data reveal new aspects of the interplay between regulation of ATR-ATRIP kinase and activation of the FA pathway

Measurement of the forward-backward asymmetries for charm- and bottom-quark pair productions at <s><\sqrt{s}>=58GeV with electron tagging

We have measured, with electron tagging, the forward-backward asymmetries of charm- and bottom-quark pair productions at $$=58.01GeV, based on 23,783 hadronic events selected from a data sample of 197pb$^{-1}$ taken with the TOPAZ detector at TRISTAN. The measured forward-backward asymmetries are $A_{FB}^c = -0.49 \pm 0.20(stat.) \pm 0.08 (sys.)$ and $A_{FB}^b = -0.64 \pm 0.35(stat.) \pm 0.13 (sys.)$, which are consistent with the standard model predictions.Comment: 19 pages, Latex format (article), 5 figures included. to be published in Phys. Lett.