Keynote Address | Residential Research and Bilateral Knowledge Translation Supporting Community-based Actions

地域環境知プロジェクト第1回国際シンポジウム，総合地球環境学研究所 講演室，2014-09-13，総合地球環境学研究所 地域環境知プロジェク

Pica and refractory iron deficiency anaemia: a case report

INTRODUCTION: Iron deficiency is the most common cause of anaemia worldwide. Pica, the ingestion of substances that are inappropriate for consumption, is associated with iron deficiency and may be under-diagnosed. CASE PRESENTATION: A 34-year-old woman presented with iron deficiency anaemia refractory to treatment for more than a decade. The clinical presentation, endoscopic findings and laboratory investigations were consistent with pica. Subsequent geophysical analysis confirmed that the ingested material was kaolin, a negatively charged silicate. CONCLUSION: Prolonged unexplained iron deficiency anaemia should prompt clinicians to remember and inquire about pica. In our patient, this would have averted numerous unnecessary investigations and prevented a decade-long suffering

The Determinants of Activity and Specificity in Actinorhodin Type II Polyketide Ketoreductase

SummaryIn the actinorhodin type II polyketide synthase, the first polyketide modification is a regiospecific C9-carbonyl reduction, catalyzed by the ketoreductase (actKR). Our previous studies identified the actKR 94-PGG-96 motif as a determinant of stereospecificity. The molecular basis for reduction regiospecificity is, however, not well understood. In this study, we examined the activities of 20 actKR mutants through a combination of kinetic studies, PKS reconstitution, and structural analyses. Residues have been identified that are necessary for substrate interaction, and these observations have suggested a structural model for this reaction. Polyketides dock at the KR surface and are steered into the enzyme pocket where C7–C12 cyclization is mediated by the KR before C9-ketoreduction can occur. These molecular features can potentially serve as engineering targets for the biosynthesis of novel, reduced polyketides

Pounds Off Digitally Study: A Randomized Podcasting Weight Loss Intervention

As obesity rates rise, new weight loss methods are needed. Little is known about the use of podcasting (audio files for a portable music player or computer) to promote weight loss, despite its growing popularity

A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse

Asthma and mouse models of allergic respiratory inflammation are invariably associated with a pulmonary eosinophilia; however, this association has remained correlative. In this report, a causative relationship between eosinophils and allergen-provoked pathologies was established using eosinophil adoptive transfer. Eosinophils were transferred directly into the lungs of either naive or OVA-treated IL-5-/- mice. This strategy resulted in a pulmonary eosinophilia equivalent to that observed in OVA-treated wild-type animals. A concomitant consequence of this eosinophil transfer was an increase in Th2 bronchoalveolar lavage cytokine levels and the restoration of intracellular epithelial mucus in OVA-treated IL-5-/- mice equivalent to OVA-treated wild-type levels. Moreover, the transfer also resulted in the development of airway hyperresponsiveness. These pulmonary changes did not occur when eosinophils were transferred into naive IL-5-/- mice, eliminating nonspecific consequences of the eosinophil transfer as a possible explanation. Significantly, administration of OVA-treated IL-5-/- mice with GK1.5 (anti-CD4) Abs abolished the increases in mucus accumulation and airway hyperresponsiveness following adoptive transfer of eosinophils. Thus, CD4+ T cell-mediated inflammatory signals as well as signals derived from eosinophils are each necessary, yet alone insufficient, for the development of allergic pulmonary pathology. These data support an expanded view of T cell and eosinophil activities and suggest that eosinophil effector functions impinge directly on lung function

Transformed non‐Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100290/1/bjh12570.pd

Next-generation sequencing identifies the natural killer cell microRNA transcriptome

Natural killer (NK) cells are innate lymphocytes important for early host defense against infectious pathogens and surveillance against malignant transformation. Resting murine NK cells regulate the translation of effector molecule mRNAs (e.g., granzyme B, GzmB) through unclear molecular mechanisms. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate the translation of their mRNA targets, and are therefore candidates for mediating this control process. While the expression and importance of miRNAs in T and B lymphocytes have been established, little is known about miRNAs in NK cells. Here, we used two next-generation sequencing (NGS) platforms to define the miRNA transcriptomes of resting and cytokine-activated primary murine NK cells, with confirmation by quantitative real-time PCR (qRT-PCR) and microarrays. We delineate a bioinformatics analysis pipeline that identified 302 known and 21 novel mature miRNAs from sequences obtained from NK cell small RNA libraries. These miRNAs are expressed over a broad range and exhibit isomiR complexity, and a subset is differentially expressed following cytokine activation. Using these miRNA NGS data, miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following cytokine activation. Furthermore, we demonstrate that miR-223 specifically targets the 3′ untranslated region of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. Thus, the sequenced NK cell miRNA transcriptome provides a valuable framework for further elucidation of miRNA expression and function in NK cell biology

Hypomorphic PCNA mutation underlies a novel human DNA repair disorder

A number of human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a novel syndrome in which the cardinal clinical features include postnatal growth retardation, hearing loss, premature aging, telangiectasia, neurological signs and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appears to have no effect on protein levels or DNA replication, patient cells exhibit significant abnormalities in response to UV irradiation displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly alters PCNA’s interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Taken together our findings detail the first mutation of PCNA in humans, associated with a unique neurodegenerative disease displaying clinical and molecular features common to other DNA repair disorders, which we show to be attributable to a hypomorphic amino acid alteration

Methamphetamine and Viagra Use: Relationship to Sexual Risk Behaviors

Recent studies show that Viagra and methamphetamine use are associated with unprotected anal intercourse among men who have sex with men (MSM). In Long Beach, California, we have reported on an association between Viagra use and the use of amphetamines during sex. The current research investigated the use of both Viagra and amphetamine in men in Long Beach, California. Data on 1,839 men recruited into HIV prevention and testing programs were collected using the Risk Behavior Assessment. A generalized logit model was constructed comparing ever having used both amphetamine and Viagra together and separately, as compared to never having used either (referent). Men who used both methamphetamine and Viagra showed a significantly higher prevalence of hepatitis B, syphilis, and HIV compared to those who used only one or neither drug. Of the 1,794 complete cases, 11.1% (199/1794) had used both amphetamine and Viagra. Of 20 potential risk and protective factors for use of amphetamine and Viagra, 12 were significant predictors: ever used gamma-hydroxybutyrate (GHB), ever used cocaine, ever used ecstasy, being infected with HIV, race = White compared to other, ever having hepatitis B, ever using crack, ever given money to have sex, living in a hotel, ever been in drug treatment, and ever using heroin. The protective factor was being heterosexual. Viagra use was associated with insertive, and methamphetamine was associated with receptive, anal intercourse. GHB use appears to play a more important role than previously thought

Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel.

BACKGROUND: CMT-2 is a clinically and genetically heterogeneous group of peripheral axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical giant axonal neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of "kinky" hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN, encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation. METHODS: An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair. RESULTS: Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement. CONCLUSIONS: Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone