Exposure to particles from laser printers operating within office workplaces

While recent research has provided valuable information as to the composition of laser printer particles, their formation mechanisms, and explained why some printers are emitters whilst others are low emitters, fundamental questions relating to the potential exposure of office workers remained unanswered. In particular, (i) what impact does the operation of laser printers have on the background particle number concentration (PNC) of an office environment over the duration of a typical working day?; (ii) what is the airborne particle exposure to office workers in the vicinity of laser printers; (iii) what influence does the office ventilation have upon the transport and concentration of particles?; (iv) is there a need to control the generation of, and/or transport of particles arising from the operation of laser printers within an office environment?; (v) what instrumentation and methodology is relevant for characterising such particles within an office location? We present experimental evidence on printer temporal and spatial PNC during the operation of 107 laser printers within open plan offices of five buildings. We show for the first time that the eight-hour time-weighted average printer particle exposure is significantly less than the eight-hour time-weighted local background particle exposure, but that peak printer particle exposure can be greater than two orders of magnitude higher than local background particle exposure. The particle size range is predominantly ultrafine (< 100nm diameter). In addition we have established that office workers are constantly exposed to non-printer derived particle concentrations, with up to an order of magnitude difference in such exposure amongst offices, and propose that such exposure be controlled along with exposure to printer derived particles. We also propose, for the first time, that peak particle reference values be calculated for each office area analogous to the criteria used in Australia and elsewhere for evaluating exposure excursion above occupational hazardous chemical exposure standards. A universal peak particle reference value of 2.0 x 104 particles cm-3 has been proposed

Comparative Effectiveness of Structural versus Regulatory Protein Gene Transfer on Articular Chondrocyte Matrix Gene Expression

OBJECTIVE: The production of extracellular matrix is a necessary component of articular cartilage repair. Gene transfer is a promising method to improve matrix biosynthesis by articular chondrocytes. Gene transfer may employ transgenes encoding regulatory factors that stimulate the production of matrix proteins, or may employ transgenes that encode the proteins themselves. The objective of this study was to determine which of these 2 approaches would be the better choice for further development. We compared these 2 approaches using the transgenes encoding the structural matrix proteins, aggrecan or type II collagen, and the transgene encoding the anabolic factor, insulin-like growth factor I (IGF-I). METHODS: We transfected adult bovine articular chondrocytes with constructs encoding type II collagen, aggrecan, or IGF-I, and measured the expression of type II collagen ( COL2A1) and aggrecan ( ACAN) from their native genes and from their transgenes. RESULTS: IGF-I gene ( IGF1) transfer increased the expression of the native chondrocyte COL2A1 and ACAN genes 2.4 and 2.9 times control, respectively. COL2A1 gene transfer did not significantly increase COL2A1 transcripts, even when the transgene included the genomic COL2A1 regulatory sequences stimulated by chondrogenic growth factors. In contrast, ACAN gene transfer increased ACAN transcripts up to 3.4 times control levels. IGF1, but not ACAN, gene transfer increased aggrecan protein production. CONCLUSION: Taken together, these results suggest that the type II collagen and aggrecan production required for articular cartilage repair will be more effectively achieved by genes that encode anabolic regulatory factors than by genes that encode the matrix molecules themselves

Role of sox9 in growth factor regulation of articular chondrocytes

Chondrogenic polypeptide growth factors influence articular chondrocyte functions that are required for articular cartilage repair. Sox9 is a transcription factor that regulates chondrogenesis, but its role in the growth factor regulation of chondrocyte proliferation and matrix synthesis is poorly understood. We tested the hypotheses that selected chondrogenic growth factors regulate sox9 gene expression and protein production by adult articular chondrocytes and that sox9 modulates the actions of these growth factors. To test these hypotheses, we delivered insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), bone morphogenetic protein-2 (BMP-2) and/or bone morphogenetic protein-7 (BMP-7), or their respective transgenes to adult bovine articular chondrocytes, and measured changes in sox9 gene expression and protein production. We then knocked down sox9 gene expression with sox9 siRNA, and measured changes in the expression of the genes encoding aggrecan and types I and II collagen, and in the production of glycosaminoglycan, collagen and DNA. We found that FGF-2 or the combination of IGF-I, BMP-2, and BMP-7 increased sox9 gene expression and protein production and that sox9 knockdown modulated growth factor actions in a complex fashion that differed both with growth factors and with chondrocyte function. The data suggest that sox9 mediates the stimulation of matrix production by the combined growth factors and the stimulation of chondrocyte proliferation by FGF-2. The mitogenic effect of the combined growth factors and the catabolic effect of FGF-2 appear to involve sox9-independent mechanisms. Control of these molecular mechanisms may contribute to the treatment of cartilage damage

An evaluation of the performance of HapMap SNP data in a Shanghai Chinese population: Analyses of allele frequency, linkage disequilibrium pattern and tagging SNPs transferability on chromosome 1q21-q25

<p>Abstract</p> <p>Background</p> <p>The HapMap project aimed to catalog millions of common single nucleotide polymorphisms (SNPs) in the human genome in four major populations, in order to facilitate association studies of complex diseases. To examine the transferability of Han Chinese in Beijing HapMap data to the Southern Han Chinese in Shanghai, we performed comparative analyses between genotypes from over 4,500 SNPs in a 21 Mb region on chromosome 1q21-q25 in 80 unrelated Shanghai Chinese and 45 HapMap Chinese data.</p> <p>Results</p> <p>Three thousand and forty-two SNPs were analyzed after removal of SNPs that failed quality control and those not in the HapMap panel. We compared the allele frequency distributions, linkage disequilibrium patterns, haplotype frequency distributions and tagging SNP sets transferability between the HapMap population and Shanghai Chinese population. Among the four HapMap populations, Beijing Chinese showed the best correlation with Shanghai population on allele frequencies, linkage disequilibrium and haplotype frequencies. Tagging SNP sets selected from four HapMap populations at different thresholds were evaluated in the Shanghai sample. Under the threshold of r²equal to 0.8 or 0.5, both HapMap Chinese and Japanese data showed better coverage and tagging efficiency than Caucasian and African data.</p> <p>Conclusion</p> <p>Our study supported the applicability of HapMap Beijing Chinese SNP data to the study of complex diseases among southern Chinese population.</p

Human IGF-I propeptide A promotes articular chondrocyte biosynthesis and employs glycosylation-dependent heparin binding

Background Insulin-like growth factor I (IGF-I) is a key regulator of chondrogenesis, but its therapeutic application to articular cartilage damage is limited by rapid elimination from the repair site. The human IGF-I gene gives rise to three IGF-I propeptides (proIGF-IA, proIGF-IB and proIGF-IC) that are cleaved to create mature IGF-I. In this study, we elucidate the processing of IGF-I precursors by articular chondrocytes, and test the hypotheses that proIGF-I isoforms bind to heparin and regulate articular chondrocyte biosynthesis. Methods Human IGF-I propeptides and mutants were overexpressed in bovine articular chondrocytes. IGF-I products were characterized by ELISA, western blot and FPLC using a heparin column. The biosynthetic activity of IGF-I products on articular chondrocytes was assayed for DNA and glycosaminoglycan that the cells produced. Results Secreted IGF-I propeptides stimulated articular chondrocyte biosynthetic activity to the same degree as mature IGF-I. Of the three IGF-I propeptides, only one, proIGF-IA, strongly bound to heparin. Interestingly, heparin binding of proIGF-IA depended on N-glycosylation at Asn92 in the EA peptide. To our knowledge, this is the first demonstration that N-glycosylation determines the binding of a heparin-binding protein to heparin. Conclusion The biosynthetic and heparin binding abilities of proIGF-IA, coupled with its generation of IGF-I, suggest that proIGF-IA may have therapeutic value for articular cartilage repair. General significance These data identify human pro-insulin-like growth factor IA as a bifunctional protein. Its combined ability to bind heparin and augment chondrocyte biosynthesis makes it a promising therapeutic agent for cartilage damage due to trauma and osteoarthritis

PERK/eIF2α pathway affected the thyroid hormone synthetic in hypertensive disorders of pregnancy rats

BackgroundClinical research has identified a correlation between hypertensive disorders of pregnancy (HDP) and subclinical hypothyroidism during gestation. But the potential influence of HDP on thyroid hormone synthesis remains undetermined.AimsThis study aims to elucidate the impact of HDP on thyroid hormone synthesis and to delineate the underlying mechanisms.Methods20 pregnancy SD rats were stratified at random into the HDP group and the Control group. The HDP group was subjected to NG-Nitro-L-arginine-methylester administration from gestational days 13 to 20, while the Control group received saline. Subsequent assessments encompassed serum FT4, FT3, and TSH concentrations, morphological examination of the thyroid, as well as quantification of essential proteins pivotal to thyroid hormone synthesis and markers indicative of endoplasmic reticulum stress.ResultsThe HDP group exhibited a statistically significant augmentation in serum TSH concentrations (p&lt;0.05), while FT3 and FT4 levels manifested no discernible statistical variations. H&amp;E staining highlighted a pronounced hyperplasia of the follicular epithelial cells and a diminution in the follicle lumen area. Electron microscopy unveiled pronounced endoplasmic reticulum markedly swelling and expansion within the HDP group. Molecular evaluations revealed a decrement in Tg expression within thyroid tissue, concomitant with an upregulated expression of p-PERK, P-eIF2α, and ATF4.ConclusionThis investigation suggests that HDP might modulate Tg expression within thyroid tissue, possibly mediated through the PERK/eIF2α signaling cascade. This perturbation may compromise thyroid hormone synthesis, thereby predisposing pregnant rats to subclinical hypothyroidism

Rapid Detection of the mt3243A > G Mutation Using Urine Sediment in Elderly Chinese Type 2 Diabetic Patients

Objective. In this study, we aimed to identify mt3243A > G mutation carriers in a group of Chinese elderly type 2 diabetic patients by a rapid and noninvasive diagnostic system. Methods. DNA was extracted from blood, saliva, and urine sediment samples. The mutation screening and quantitation of heteroplasmy were performed by high-resolution melting (HRM) curve and pyrosequencing, respectively. Patients with mt3243A > G mutation underwent a detailed audiometric, ophthalmologic, neurological, and cardiac examination. Results. Two patients (2/1041) carrying the mt3243A > G mutation were detected among all type 2 diabetic patients. In patient 1, the heteroplasmy was 0.8%, 2.8%, and 14.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. In patient 2, the heteroplasmy was 5.3%, 8.4%, and 37.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. Both of the two patients showed hearing impairment. Abnormal ophthalmologic conditions and hyperintensity on T2-weighted magnetic resonance images were showed in patient 1. Conclusion. The occurrence of mt3243 A > G mutation was 0.2% in Chinese elderly type 2 diabetic patients. Moreover, detection of mt3243 A > G mutation in urine sediment with high-resolution melting (HRM) curve and pyrosequencing is feasible in molecular genetic diagnosis

Random Forest in Clinical Metabolomics for Phenotypic Discrimination and Biomarker Selection

Metabolomic data analysis becomes increasingly challenging when dealing with clinical samples with diverse demographic and genetic backgrounds and various pathological conditions or treatments. Although many classification tools, such as projection to latent structures (PLS), support vector machine (SVM), linear discriminant analysis (LDA), and random forest (RF), have been successfully used in metabolomics, their performance including strengths and limitations in clinical data analysis has not been clear to researchers due to the lack of systematic evaluation of these tools. In this paper we comparatively evaluated the four classifiers, PLS, SVM, LDA, and RF, in the analysis of clinical metabolomic data derived from gas chromatography mass spectrometry platform of healthy subjects and patients diagnosed with colorectal cancer, where cross-validation, R2/Q2 plot, receiver operating characteristic curve, variable reduction, and Pearson correlation were performed. RF outperforms the other three classifiers in the given clinical data sets, highlighting its comparative advantages as a suitable classification and biomarker selection tool for clinical metabolomic data analysis

Urinary peptidomic profiles to address age-related disabilities: a prospective population study

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 called for innovation in addressing age-related disabilities. Our study aimed to identify and validate a urinary peptidomic profile (UPP) differentiating healthy from unhealthy ageing in the general population, to test the UPP predictor in independent patient cohorts, and to search for targetable molecular pathways underlying age-related chronic diseases. Methods: In this prospective population study, we used data from participants in the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO), done in northern Belgium from 1985 to 2019, and invited participants to a follow-up examination in 2005-10. Participants were eligible if their address was within 15 km of the examination centre and if they had not withdrawn consent in any of the previous examination cycles (1985-2004). All participants (2005-10) were also invited to an additional follow-up examination in 2009-13. Participants who took part in both the 2005-10 follow-up examination and in the additional 2009-13 follow-up visit constituted the derivation dataset, which included their 2005-10 data, and the time-shifted internal validation dataset, which included their 2009-13 data. The remaining participants who only had 2005-10 data constituted the synchronous internal validation dataset. Participants were excluded from analyses if they were incapacitated, had not undergone UPP, or had either missing or outlying (three SDs greater than the mean of all consenting participants) values of body-mass index, plasma glucose, or serum creatinine. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. The multidimensional UPP signature reflecting ageing was generated from the derivation dataset and validated in the time-shifted internal validation dataset and the synchronous validation dataset. It was further validated in patients with diabetes, COVID-19, or chronic kidney disease (CKD). In FLEMENGHO, the mortality endpoints were all-cause, cardiovascular, and non-cardiovascular mortality; other endpoints were fatal or non-fatal cancer and musculoskeletal disorders. Molecular pathway exploration was done using the Reactome and Kyoto Encyclopedia of Genes and Genomes databases. Findings: 778 individuals (395 [51%] women and 383 [49%] men; aged 16·2-82·1 years; mean age 50·9 years [SD 15·8]) from the FLEMENGHO cohort had a follow-up examination between 2005 and 2010, of whom 559 participants had a further follow-up from Oct 28, 2009, to March 19, 2013, and made up the derivation (2005-10) and time-shifted internal validation (2009-13) datasets. 219 were examined once and constituted the synchronous internal validation dataset (2005-10). With correction for multiple testing and multivariable adjustment, chronological age was associated with 210 sequenced peptides mainly showing downregulation of collagen fragments. The trained model relating chronological age to UPP, derived by elastic net regression, included 54 peptides from 17 proteins. The UPP-age prediction model explained 76·3% (r=0·87) of chronological age in the derivation dataset, 54·4% (r=0·74) in the time-shifted validation dataset, and 65·3% (r=0·81) in the synchronous internal validation dataset. Compared with chronological age, the predicted UPP-age was greater in patients with diabetes (chronological age 50·8 years [SE 0·37] vs UPP-age 56·9 years [0·30]), COVID‑19 (53·2 years [1·80] vs 58·5 years [1·67]), or CKD (54·6 years [0·97] vs62·3 years [0·85]; all p Interpretation: The UPP signature indicative of ageing reflects fibrosis and extracellular matrix remodelling and was associated with risk factors and adverse health outcomes in the population and with accelerated ageing in patients. Innovation in addressing disability should shift focus from the ontology of diseases to shared disease mechanisms, in particular ageing-related fibrotic degeneration