Enkele aspecten van de ijzeropname door erytroïde cellen

Het menselijk lichaam bevat circa 4 g ijzer; de verdeling van dit ijzer over de verschillende compartimenten en componenten is weergegeven in figuur 1 en tabel I. Het lichaam gaat zeer economisch om met ijzer, getuige het feit dat het ijzerverlies slechts 1-2 mg per dag bedraagt. Dit ijzer verlaat het lichaam via excretie door nieren, darm en zweetklieren: tevens gaat een geringe hoeveelheid ijzer verloren door fysiologisch celverval van huid, haren en nagels. Het lichaam beschikt niet over een actief excretiemechanisme voor ijzer en de ijzerbalans wordt dan ook voornamelijk gehandhaafd door veranderingen in de absorptie, welke vanuit de tractus digestivus plaatsvindt. Vanuit de mucosacel van het duodenum wordt het opgenomen ijzer via de bloedbaan naar de verschillende organen getransporteerd. Gezien het feit dat het oplosbaarheidsprodukt van Fe(OH)3 slechts 4 x 10-38 bedraagt, is de regulatie van de ijzerhuishouding geen eenvoudige taak voor het menselijk lichaam. Onder aërobe omstandigheden zullen in het lichaam ferro(F e 11)-verbindingen gemakkelijk oxyderen tot ferri(Fe 111)-verbindingen. Bij een lichaams-pH van 7,4 kan een concentratie van vrije Fe(lll) ionen voorkomen van slechts 10-17 mol/l, deze uiterst geringe concentratie is onmeetbaar. Uit dit gegeven en het feit dat in het plasma een concentratie van meer dan 20 !'mol/! Fe(lll) kan voorkomen, zal het duidelijk zijn dat het lichaam over verbindingen moet beschikken die een complex kunnen vormen met dit Fe. In het plasma wordt ijzer gebonden door een beta-globuline, siderofiline of transferrille genoemd. Dit transferrillemolecuul is opgebouwd uit een enkele polypeptideketen, met een molecuuhnassa van 81.000, welke twee domains bevat, die de N-tenninale (Nt) en C-tenninale (Ct) genoemd worden. Dit molecuul bevat twee bindingsplaatsen voor Fe(lll), de zogenaamde A· en B-bindingsplaats, respectievelijk gelegen in het Cr en Nrdomain

Isolation of the Two Monoferric Human Transferrins by Preparative Isoelectric Focussing

Peer Reviewe

Maladaptive personality traits in adolescence: Psychometric properties of the Personality Diagnostic Questionnaire-4+

AbstractThe Personality Diagnostic Questionnaire-4+ (PDQ-4+) is a self-report used for the assessment of personality disorder traits, however, its psychometric characteristics have yet to be tested in community samples of adolescents. The main goal was to analyze the psychometric properties of the PDQ-4+ scores in a large sample of non-clinical adolescents (N=1,443; M=15.9 years; SD=1.2). The PDQ-4+ scores showed adequate psychometric properties. Reliability of the subscales, incorporating a Likert-type 5-point response format, ranged from .62 to .85. The study of the internal structure at item level revealed that the PDQ-4+ subscales were essentially one-dimensional. Analysis of the internal structure at the subscale level by means of exploratory factor analysis and exploratory structural equation modeling yielded a possible three-dimensional solution. The PDQ-4+ subscales correlated moderately with emotional and behavioural variables measured by the Strengths and Difficulties Questionnaire. The results have clear implications for the understanding of maladaptive personality traits in adolescents

Development of an International SMA Bulbar Assessment for Inter-professional Administration

BACKGROUND: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. OBJECTIVE: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. METHODS: Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus. RESULTS: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. CONCLUSIONS: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals

大震災が促進したコミュニティ・デベロップメント : 中華系コミュニティにみる「地域化」と「国際化」 (「被災外国人の研究」グループ)

The DNA recombination and repair machinery of Mycoplasma pneumoniae is composed of a limited set of approximately 11 proteins. Two of these proteins were predicted to be encoded by neighboring open reading frames (ORFs) MPN340 and MPN341. Both ORFs were found to have sequence similarity with genes that encode proteins belonging to the DNA helicase superfamily 1 (SF1). Interestingly, while a homolog of the MPN341 ORF is present in the genome of Mycoplasma genitalium (ORF MG244), MPN340 is an M. pneumoniae-specific ORF that is not found in other mycoplasmas. Moreover, the length of MPN340 (1590 base pairs [bp]) is considerably shorter than that of MPN341 (2148 bp). Examination of the MPN340-encoded amino acid sequence indicated that it may lack a so-called 2B subdomain, which is found in most SF1 DNA helicases. Also, the MPN340-encoded amino acid sequence was found to differ between subtype 1 strain M129 and subtype 2 strain FH at three amino acid positions. Both protein variants, which were termed PcrA(s) M129 and PcrA(s) FH, respectively, as well as the MPN341- and MG244-encoded proteins (PcrA Mpn and PcrA Mge , respectively), were purified, and tested for their ability to interact with DNA. While PcrA Mpn and PcrA Mge were found to bind preferentially to single-stranded DNA, both PcrA(s) M129 and PcrA(s) FH did not demonstrate significant DNA binding. However, all four proteins were found to have divalent cation- and ATP-dependent DNA helicase activity. The proteins displayed highest activity on partially double-stranded DNA substrates carrying 3' single-stranded extensions

Lugdunomycin, an Angucycline-Derived Molecule with Unprecedented Chemical Architecture

The angucyclines form the largest family of polycyclic aromatic polyketides, and have been studied extensively. Herein, we report the discovery of lugdunomycin, an angucycline-derived polyketide, produced by Streptomyces species QL37. Lugdunomycin has unique structural characteristics, including a heptacyclic ring system, a spiroatom, two all-carbon stereocenters, and a benzaza-[4,3,3]propellane motif. Considering the structural novelty, we propose that lugdunomycin represents a novel subclass of aromatic polyketides. Metabolomics, combined with MS-based molecular networking analysis of Streptomyces sp. QL37, elucidated 24 other rearranged and non-rearranged angucyclines, 11 of which were previously undescribed. A biosynthetic route for the lugdunomycin and limamycins is also proposed. This work demonstrates that revisiting well-known compound families and their producer strains still is a promising approach for drug discovery

The additional value of TGFβ1 and IL-7 to predict the course of prostate cancer progression

Background: Given the fact that prostate cancer incidence will increase in the coming years, new prognostic biomarkers are needed with regard to the biological aggressiveness of the prostate cancer diagnosed. Since cytokines have been associated with the biology of cancer and its prognosis, we determined whether transforming growth factor beta 1 (TGFβ1), interleukin-7 (IL-7) receptor and IL-7 levels add additional prognostic information with regard to prostate cancer

Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer

<p>Abstract</p> <p>Background</p> <p>Activating mutations of the epidermal growth factor receptor (<it>EGFR</it>) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease.</p> <p>Methods</p> <p>Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples.</p> <p>Results</p> <p>EGFR protein overexpression (EGFR_high) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFR_hightumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFR_low). Microarray analysis did not reveal any differences in gene expression between EGFR_highand EGFR_lowtumours. Conversely, in EGFR_hightumours, we were able to identify a 79 gene signature distinguishing mutated from non-mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFR_high(n=3) and mutated/EGFR_lowtumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression.</p> <p>Conclusions</p> <p>Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.</p

Bypass Mechanisms of the Androgen Receptor Pathway in Therapy-Resistant Prostate Cancer Cell Models

Background: Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. Methodology/Principal Findings: Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentiallyexpressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (,5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10 27). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression