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Objective: The objective of this study is to analyze the death characteristics and burden of disease (BOD) in diabetes mellitus (DM) patients in Weifang from 2010 to 2021. The findings will serve as a foundational data source and theoretical framework for public health administrative departments in the formulation of DM-related policies., Methods: The annual percent change (APC) and average annual percent change (AAPC) of the disability-adjusted life years (DALY), years of life lost (YLL), and years lived with disability (YLD) in DM residents from 2010 to 2021 were analyzed using the Joinpoint software to reflect the changing trend of the BOD in DM patients. Additionally, we conducted an analysis of the various causes of death among these patients and compared BOD in diabetic patients with different backgrounds., Results: From 2010 to 2021, the burden of disease, which includes DALY, YL, and YLD, has been increasing among patients with DM in Weifang. It is noteworthy that the burden of disease is particularly pronounced among male patients and those aged 75 or above. Additionally, it is observed that widowed and illiterate DM patients have comparatively longer survival times. Furthermore, among the DM patients who have unfortunately passed away, it has been identified that unspecified DM with ketoacidosis accounts for 10.03% of the deaths as a direct cause of death. In contrast, type 2 diabetes mellitus (T2DM) with kidney complications contributes to 10.23% of the deaths as the fundamental cause of death., Conclusion: The city is faced with a significant challenge of diabetes, which is influenced by factors such as gender, age, cultural background, and marital status. Unspecified diabetes mellitus (DM) with ketoacidosis (10.03%) and T2DM with renal complications (0.23%) are identified as the primary direct and underlying causes of death among diabetic patients, respectively. This study serves as a valuable reference for other regions in terms of diabetes prevention, control, and the management of chronic diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Genome-wide association studies typically considers epistatic interactions as a crucial factor in exploring complex diseases. However, the current methods primarily concentrate on the detection of two-order epistatic interactions, with flaws in accuracy. In this work, we introduce a novel method called Epi-SSA, which can be better utilized to detect high-order epistatic interactions. Epi-SSA draws inspiration from the sparrow search algorithm and optimizes the population based on multiple objective functions in each iteration, in order to be able to more precisely identify epistatic interactions. To evaluate its performance, we conducted a comprehensive comparison between Epi-SSA and seven other methods using five simulation datasets: DME 100, DNME 100, DME 1000, DNME 1000 and DNME3 100. The DME 100 dataset encompasses eight second-order epistasis disease models with marginal effects, each comprising 100 simulated data instances, featuring 100 SNPs per instance, alongside 800 case and 800 control samples. The DNME 100 encompasses eight second-order epistasis disease models without marginal effects and retains other properties consistent with DME 100. Experiments on the DME 100 and DNME 100 datasets were designed to evaluate the algorithms' capacity to detect epistasis across varying disease models. The DME 1000 and DNME 1000 datasets extend the complexity with 1000 SNPs per simulated data instance, while retaining other properties consistent with DME 100 and DNME 100. These experiments aimed to gauge the algorithms' adaptability in detecting epistasis as the number of SNPs in the data increases. The DNME3 100 dataset introduces a higher level of complexity with six third-order epistasis disease models, otherwise paralleling the structure of DNME 100, serving to test the algorithms' proficiency in identifying higher-order epistasis. The highest average F-measures achieved by the seven other existing methods on the five datasets are 0.86, 0.86, 0.41, 0.56, and 0.79 respectively, while the average F-measures of Epi-SSA on the five datasets are 0.92, 0.97, 0.79, 0.86, and 0.97 respectively. The experimental results demonstrate that the Epi-SSA algorithm outperforms other methods in a variety of epistasis detection tasks. As the number of SNPs in the data set increases and the order of epistasis rises, the advantages of the Epi-SSA algorithm become increasingly pronounced. In addition, we applied Epi-SSA to the analysis of the WTCCC dataset, uncovering numerous genes and gene pairs that might play a significant role in the pathogenesis of seven complex diseases. It is worthy of note that some of these genes have been relatedly reported in the Comparative Toxicogenomics Database (CTD). Epi-SSA is a potent tool for detecting epistatic interactions, which aids us in further comprehending the pathogenesis of common and complex diseases. The source code of Epi-SSA can be obtained at https://osf.io/6sqwj/., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: The frequency and characteristics of post-acute sequelae of SARS-CoV-2 infection (PASC) may vary by SARS-CoV-2 variant., Objective: To characterize PASC-related conditions among individuals likely infected by the ancestral strain in 2020 and individuals likely infected by the Delta variant in 2021., Design: Retrospective cohort study of electronic medical record data for approximately 27 million patients from March 1, 2020-November 30, 2021., Setting: Healthcare facilities in New York and Florida., Participants: Patients who were at least 20 years old and had diagnosis codes that included at least one SARS-CoV-2 viral test during the study period., Exposure: Laboratory-confirmed COVID-19 infection, classified by the most common variant prevalent in those regions at the time., Main Outcome(s) and Measure(s): Relative risk (estimated by adjusted hazard ratio [aHR]) and absolute risk difference (estimated by adjusted excess burden) of new conditions, defined as new documentation of symptoms or diagnoses, in persons between 31-180 days after a positive COVID-19 test compared to persons without a COVID-19 test or diagnosis during the 31-180 days after the last negative test., Results: We analyzed data from 560,752 patients. The median age was 57 years; 60.3% were female, 20.0% non-Hispanic Black, and 19.6% Hispanic. During the study period, 57,616 patients had a positive SARS-CoV-2 test; 503,136 did not. For infections during the ancestral strain period, pulmonary fibrosis, edema (excess fluid), and inflammation had the largest aHR, comparing those with a positive test to those without a COVID-19 test or diagnosis (aHR 2.32 [95% CI 2.09 2.57]), and dyspnea (shortness of breath) carried the largest excess burden (47.6 more cases per 1,000 persons). For infections during the Delta period, pulmonary embolism had the largest aHR comparing those with a positive test to a negative test (aHR 2.18 [95% CI 1.57, 3.01]), and abdominal pain carried the largest excess burden (85.3 more cases per 1,000 persons)., Conclusions and Relevance: We documented a substantial relative risk of pulmonary embolism and a large absolute risk difference of abdomen-related symptoms after SARS-CoV-2 infection during the Delta variant period. As new SARS-CoV-2 variants emerge, researchers and clinicians should monitor patients for changing symptoms and conditions that develop after infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Varma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Prior studies have shown disparities in the uptake of cardioprotective newer glucose-lowering drugs (GLDs), including sodium-glucose cotranwsporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1a). This study aimed to characterize geographic variation in the initiation of newer GLDs and the geographic variation in the disparities in initiating these medications., Methods: Using 2017-2018 claims data from a 15% random nationwide sample of Medicare Part D beneficiaries, we identified individuals diagnosed with type 2 diabetes (T2D), who had ≥1 GLD prescriptions, and did not use SGLT2i or GLP1a in the year prior to the index date,1/1/2018. Patients were followed up for a year. The cohort was spatiotemporally linked to Dartmouth hospital-referral regions (HRRs), with each patient assigned to 1 of 306 HRRs. We performed multivariable Poisson regression to estimate adjusted initiation rates, and multivariable logistic regression to assess racial disparities in each HRR., Results: Among 795,469 individuals with T2D included in the analyses, the mean (SD) age was 73 (10) y, 53.3% were women, 12.2% were non-Hispanic Black, and 7.2% initiated a newer GLD in the follow-up year. In the adjusted model including clinical factors, compared to non-Hispanic White patients, non-Hispanic Black (initiation rate ratio, IRR [95% CI]: 0.66 [0.64-0.68]), American Indian/Alaska Native (0.74 [0.66-0.82]), Hispanic (0.85 [0.82-0.87]), and Asian/Pacific islander (0.94 [0.89-0.98]) patients were less likely to initiate newer GLDs. Significant geographic variation was observed across HRRs, with an initiation rate spanning 2.7%-13.6%., Conclusions: This study uncovered substantial geographic variation and the racial disparities in initiating newer GLDs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Preterm birth (PTB) presents a complex challenge in pregnancy, often leading to significant perinatal and long-term morbidities. "While machine learning (ML) algorithms have shown promise in PTB prediction, the lack of interpretability in existing models hinders their clinical utility. This study aimed to predict PTB in a pregnant population using ML models, identify the key risk factors associated with PTB through the SHapley Additive exPlanations (SHAP) algorithm, and provide comprehensive explanations for these predictions to assist clinicians in providing appropriate care. This study analyzed a dataset of 3509 pregnant women in the United Arab Emirates and selected 35 risk factors associated with PTB based on the existing medical and artificial intelligence literature. Six ML algorithms were tested, wherein the XGBoost model exhibited the best performance, with an area under the operator receiving curves of 0.735 and 0.723 for parous and nulliparous women, respectively. The SHAP feature attribution framework was employed to identify the most significant risk factors linked to PTB. Additionally, individual patient analysis was performed using the SHAP and the local interpretable model-agnostic explanation algorithms (LIME). The overall incidence of PTB was 11.23% (11 and 12.1% in parous and nulliparous women, respectively). The main risk factors associated with PTB in parous women are previous PTB, previous cesarean section, preeclampsia during pregnancy, and maternal age. In nulliparous women, body mass index at delivery, maternal age, and the presence of amniotic infection were the most relevant risk factors. The trained ML prediction model developed in this study holds promise as a valuable screening tool for predicting PTB within this specific population. Furthermore, SHAP and LIME analyses can assist clinicians in understanding the individualized impact of each risk factor on their patients and provide appropriate care to reduce morbidity and mortality related to PTB., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Khan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Younger age is an independent risk factor for breast cancer (BC) prognosis, and BC in young women is often considered more aggressive. BC patients with different age and molecular subtypes have different metastasis patterns and survival. Herein, we aim to explore the metastasis patterns, characteristics and treatment methods of young patients with BC, and to compare them with older patients., Methods: Data of young patients (aged ≤40 years old) and older patients (aged >40 years old) with BC were extracted from the Surveillance, Epidemiology, and End Results (SEER) registration database in 2010-2019 in this retrospective cohort study. Univariate and multivariate competing risk models and proportional hazard models were used to explore the association between different metastasis patterns and treatments and BC prognoses in young and older patients. Kaplan-Meier (KM) curves were drawn to reflect the survival probability of patients with BC who have different metastasis patterns. Also, we performed subgroup analysis of different metastasis patterns to explore the association between different treatments and overall survival (OS)/cancer specific survival (CSS) in patients with BC. The evaluation index was hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: Totally, 5,984 patients died, and 92.56% of them died from BC. There were respectively 1,089 young patients and 9,105 older patients, and we found some differences of characteristics and metastasis patterns between them. After adjusting for covariates, young patients who had brain metastasis and multiple sites metastasis seemed to have high risk of both lower OS and CSS. Among older patients with BC, brain metastasis, liver metastasis, and multiple sites metastasis were all positively associated with both lower OS and CSS. In young and older patients, those who not receive radiotherapy or surgery, or received non-surgery combined with radiotherapy seemed to have high risk of both lower OS and CSS. Breast-conserving surgery (BCS) and surgery combined with radiotherapy were associated with higher OS and CSS in young patients, while only older patients received surgery combined with radiotherapy had higher OS and CSS. Results of subgroup analysis indicated that for patients with different metastasis patterns, developing a personalized treatment plan is necessary., Conclusions: Characteristics of BC between young patients and older patients were different. Clinicians should focus on different metastasis sites and choose appropriate treatments in patients with different ages, which may improve the prognoses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Topoisomerases are nuclear enzymes that get to the bottom of topological troubles related with DNA all through a range of genetic procedures. More and more studies have shown that topoisomerase-mediated DNA cleavage plays crucial roles in tumor cell death and carcinogenesis. There is however still a lack of comprehensive multi-omics studies related to topoisomerase family genes from a pan-cancer perspective., Methods: In this study, a multiomics pan-cancer analysis of topoisomerase family genes was conducted by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from The Cancer Genome Atlas (TCGA), 481 small molecule drug response data from cancer therapeutics response portal (CTRP) as well as normal tissue data from Genotype-Tissue Expression (GTEx). Finally, overall activity-level analyses of topoisomerase in pan-cancers were performed by gene set variation analysis (GSVA), together with differential expression, clinical relevancy, immune cell infiltration and regulation of cancer-related pathways., Results: Dysregulated gene expression of topoisomerase family were related to genomic changes and abnormal epigenetic modifications. The expression levels of topoisomerase family genes could significantly impact cancer progression, intratumoral heterogeneity, alterations in the immunological condition and regulation of the cancer marker-related pathways, which in turn caused the differences in potential drugs sensitivity and the distinct prognosis of patients., Conclusion: It was anticipated that topoisomerase family genes would become novel prognostic biomarkers for cancer patients and provide new insights for the diagnosis and treatment of tumors., Competing Interests: The authors have declared that no competing interests exist.

Cancer is a major health problem in the U.S and type 2 diabetes mellitus (T2DM) is known to increase the risk for the development of many cancers. Metformin, a first-line therapy for treating T2DM, is increasingly being used for its anticancer effects; however, the literature is limited on the effect of metformin dose on overall survival in patients with stage IV cancer. Overall survival was defined as the time interval from the date of diagnosis to the last known follow-up or death from any cause. Subjects who were alive on December 31, 2016 were censored. In this cohort study we examined the relationship between metformin dose and overall survival in persons with both T2DM and stage IV lung, breast, colorectal, prostate, or pancreas cancers. We used a retrospective study design with Cox proportional hazards regression analysis of the 2007-2016 of the Surveillance Epidemiology and End Results-Medicare (SEER) dataset. Of the 7,725 patients, 2,981(38.5%) had been prescribed metformin. Patients who used metformin had significantly better overall survival in both unadjusted (Unadjusted HR, 0.73; 95% CI, 0.69-0.76; p < 0.001) and adjusted models (adjusted HR, 0.77; 95% CI, 0.73-0.81; p < 0.001). The overall survival between patients who took metformin with average daily dose ≥ 1000mg or < 1000mg were not statistically significant (aHR, 1.00; 95% CI, 0.93-1.08; p = 0.90). Metformin use regardless of dose is associated with increased overall survival in older adults with stage IV cancer., Competing Interests: The authors have declared that no competing interests exist.

Ilex dabieshanensis K. Yao & M. B. Deng is not only a highly valued tree species for landscaping, it is also a good material for making kuding tea due to its anti-inflammatory and lipid-lowering medicinal properties. Utilizing next-generation and long-read sequencing technologies, we assembled the whole chloroplast genome of I. dabieshanensis. The genome was 157,218 bp in length, exhibiting a typical quadripartite structure with a large single copy (LSC: 86,607 bp), a small single copy (SSC: 18,427 bp) and a pair of inverted repeat regions (IRA and IRB: each of 26,092 bp). A total of 121 predicted genes were encoded, including 113 distinctive (79 protein-coding genes, 30 tRNAs, and 4 rRNAs) and 8 duplicated (8 protein-coding genes) located in the IR regions. Overall, 132 SSRs and 43 long repeats were detected and could be used as potential molecular markers. Comparative analyses of four traditional Ilex tea species (I. dabieshanensis, I. paraguariensis, I. latifolia and I. cornuta) revealed seven divergent regions: matK-rps16, trnS-psbZ, trnT-trnL, atpB-rbcL, petB-petD, rpl14-rpl16, and rpl32-trnL. These variations might be applicable for distinguishing different species within the genus Ilex. Phylogenetic reconstruction strongly suggested that I. dabieshanensis formed a sister clade to I. cornuta and also showed a close relationship to I. latifolia. The generated chloroplast genome information in our study is significant for Ilex tea germplasm identification, phylogeny and genetic improvement., Competing Interests: The authors have declared that no competing interests exist.

Human bocavirus (HBoV) is a member of the genus Bocavirus, family Parvoviridae, and subfamily Parvovirus and was first identified in nasopharyngeal aspirates of Swedish children with acute respiratory tract infection (ARTI) in 2005. It is the causative agent of nasopharyngeal aspirate disease and death in children. The HboV genomic structure is a linear single-stranded DNA (ssDNA). Its clinical pathogenic characteristics have been extensively studied, however, at present the molecular mechanism underlying the pathogenesis of HBoV infection is not completely clear. In this study, a total of 293 differentially expressed proteins (DEPs) between ARTI cases and healthy plasma samples were characterized using isobaric tags for relative and absolute quantitation (iTRAQ)-coupled bioinformatics analysis, among which 148 were up-regulated and 135 were down-regulated. Gene Ontology (GO) and Cluster of Orthologous Groups of proteins (COG) annotated an enrichment of DEPs in complement activation and biological processes like immunity, inflammation, signal transduction, substance synthesis, and metabolism. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis enriched DEPs mainly in the Wnt signaling pathway (ko04310), PPAR signaling pathway (ko03320), intestinal immune network for IgA production (ko04672), complement and coagulation cascades (ko04610), Toll-like receptor signaling pathway (ko04620) and B cell receptor signaling pathway (ko04662). Further, expression levels of three candidate proteins (upregulated PPP2R1A and CUL1, and downregulated CETP) were validated using western blotting. Our investigation is the first analysis of the proteomic profile of HBoV-infected ARTI cases using the iTRAQ approach, providing a foundation for a better molecular understanding of the pathogenesis of ARTI in children., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To examine the morbidities associated with workplace injury and to explore how clinical variables modify the risk of injury recurrence., Methods: A case-control study was designed using Florida's statewide inpatient, outpatient, and emergency visits data obtained from the Healthcare Cost and Utilization Project. We included adults who were admitted for a workplace injury (WPI) or injury at other places (IOP), and a matched population of random controls without WPI/IOP. The associations between WPI and clinical morbidities were assessed by univariate and multivariable regression, ranking predictors by information gain, area under the receiver operating characteristic (AUROC), and odds ratios. We analyzed WPI recurrence using survival methods (Kaplan-Meier, Cox regression, survival decision trees) and developed prediction models via regularized logistic regression, random forest, and AdTree. Performance was assessed by 10-fold cross-validation comparing AUROC, sensitivity, specificity, and Harrell's c-index., Results: A total of 80,712 WPI, 161,424 IOP, and 161,424 control patients were included; 485 distinct clinical diagnostic and 160 procedure codes were analyzed after filtering. Acute bronchitis and bronchiolitis, sprains and strains of shoulder and upper arm, ankle and foot, or other and unspecified parts of back, accidents caused by cutting and piercing instruments or objects, and overexertion and strenuous movements were identified as important consequences of WPI. The prediction models of injury recurrence identified several key factors, such as insurance type and prior injury events, although none of the models exhibited high predictive performance (best AUROC = 0.60, best c-index = 0.62)., Conclusions: WPI is associated to diverse serious physical comorbidity burden. There are demographic, social and clinical comorbidity components associated to the risk of WPI recurrence, although their predictive value is moderate, which warrants future investigation in other information source domains, e.g. deepening into the environmental and societal sphere., Competing Interests: The authors have declared that no competing interests exist.

The propensity for differentiation varies substantially across human pluripotent stem cell (hPSC) lines, greatly restricting the use of hPSCs for cell replacement therapy or disease modeling. Here, we investigate the underlying mechanisms and demonstrate that activation of the retinoblastoma (Rb) pathway in a transient manner is important for differentiation. In prior work, we demonstrated that pre-treating hPSCs with dimethylsulfoxide (DMSO) before directed differentiation enhanced differentiation potential across all three germ layers. Here, we show that exposure to DMSO improves the efficiency of hPSC differentiation through Rb and by repressing downstream E2F-target genes. While transient inactivation of the Rb family members (including Rb, p107, and p130) suppresses DMSO's capacity to enhance differentiation across all germ layers, transient expression of a constitutively active (non-phosphorylatable) form of Rb increases the differentiation efficiency similar to DMSO. Inhibition of downstream targets of Rb, such as E2F signaling, also promotes differentiation of hPSCs. More generally, we demonstrate that the duration of Rb activation plays an important role in regulating differentiation capacity., Competing Interests: The authors have declared that no competing interests exist.

Unclassified tailings are the main backfilling aggregates in mines and their settling is the first step in the utilization of tailings; thus, it is very important to determine their settling behavior. The aim of this study was to understand the flocculating settling behavior of unclassified tailings with different factors. The combination of property detection, laboratory experiments and industrial tests were used to assess the flocculating settling behavior of unclassified tailings; the orthogonal experimental design and the control variate method were used for an experimental design. The results show that the flocculating settling velocity of unclassified tailings decreases with the increase of slurry concentration and that this settling velocity increases first and then decreases with the increase of flocculant unit consumption. The underflow concentration is positively correlated with the slurry concentration and negatively correlated with the flocculant unit consumption and flocculant concentration. Slower feed velocity could produce higher concentration underflow but lower clarity overflow water. The greater the mud height, the higher the underflow concentration and the suspended solids concentration in the overflow water. The underflow concentration has a maximum at the rake speed of 0.3 r/min, and the rake speed has little effect on the suspended solids concentration in the overflow water. By analyzing the settling velocity, the underflow concentration, the suspended solids concentration in the overflow water and the solid flux, the following parameters of the flocculating settling experiments were determined: the flocculant type is APAM with a molecular weight of 12 million, the flocculant unit consumption is 30 g/t, the slurry concentration is 6 vol.%, the flocculant concentration is 0.1 wt.%, the rake speed is 0.3 r/min, and the feed velocity is 0.4 L/min (its solid flux is 0.523 t/(m2·h)). The industrial tests were carried out based on the laboratory settling data, and the appropriate selection parameters of the industrial tests were estimated., Competing Interests: We have the following interests: During the study period, Chongchun Xiao conducted an internship in the Feny Corporation Limited. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Background: Cardiorespiratory fitness (CRF) is the only major risk factor that is not routinely assessed in the clinical setting, for preventive medicine. A valid and practical CRF test is needed for use in the clinics. The objective of this study is to demonstrate the validity of a 3-minute squat test to assess CRF in primary care., Methods: A cross-sectional study in which the participants performed both the Ruffier squat test and the Balke maximal treadmill test. The study was conducted in a clinical setting from September 2016 to March 2017. We recruited a convenient sample of 40 adults between 18 and 64 years from the general U.S. population. Participants completed 30 squats in 45 seconds, paced by a metronome. Heart rate was measured at rest (P1), immediately after the test (P2), one minute after the test (P3). [Formula: see text] was measured using the Balke maximal treadmill fitness test., Results: Of the 40 participants, there were 18 men and 22 women. Mean age was 31.2 years (SD = 9.9). We found that the best [Formula: see text] predictors were HR features P1/height and (P2-P3)/age3. Our best-performing model using these two features predicted individuals' CRF levels with an adjusted R2 of 0.637, sensitivity of 0.79, and specificity of 0.56., Conclusions: The study provided strong evidence for the validity of the squat test in the clinical setting. Further, the equation of our model along with [Formula: see text] normative tables provides an efficient and easy way to assess CRF in a primary care setting., Competing Interests: The authors have declared that no competing interests exist.

To establish 24-h urinary creatinine excretion reference ranges based on anthropometry in healthy Chinese children, a cross-sectional survey was conducted using twice-sampled 24-h urine and anthropometric variables. Age- and sex-specific 24-h creatinine excretion reference ranges (crude and related to individual anthropometric variables) were derived. During October 2013 and May 2014, urine samples were collected. Anthropometric variables were measured in the first survey. Data of 710 children (377 boys and 333 girls) aged 8-13 years who completed the study were analyzed. No significant difference was observed in 24-h urine volumes between the two samples (median [interquartile range): 855.0 [600.0-1272.0) mL vs. 900.0 [660.0-1220.0) mL, P = 0.277). The mean 24-h urine creatinine excretion was regarded as representative of absolute daily creatinine excretion in children. Sex-specific, body-weight-adjusted creatinine excretion reference values were 15.3 mg/kg/day (0.1353 mmol/kg/day) for boys and 14.3 mg/kg/day (0.1264 mmol/kg/day) for girls. Differences were significant between boys and girls within the same age group but not across different age groups within the same sex. Ideal 24-h creatinine excretion values for height were derived for potential determination of the creatinine height index. These data can serve as reference ranges to calculate ratios of analyte to creatinine. The creatinine height index can be used to assess somatic protein status., Competing Interests: The authors have declared that no competing interests exist.

The agent responsible for prion diseases is a misfolded form of a normal protein (PrPC). The prion hypothesis stipulates that PrPC must be present for the disease to manifest. Cervid populations across the world are infected with chronic wasting disease, a horizontally-transmissible prion disease that is likely spread via oral exposure to infectious prions (PrPCWD). Though PrPCWD has been identified in many tissues, there has been little effort to characterize the overall PrPC expression in cervids and its relationship to PrPCWD accumulation. We used immunohistochemistry (IHC), western blot and enzyme-linked immunosorbent assay to describe PrPC expression in naïve white-tailed deer. We used real-time, quaking-induced conversion (RT-QuIC) to detect prion seeding activity in CWD-infected deer. We assessed tissues comprising the alimentary tract, alimentary-associated lymphoid tissue and systemic lymphoid tissue from 5 naïve deer. PrPC was expressed in all tissues, though expression was often very low compared to the level in the CNS. IHC identified specific cell types wherein PrPC expression is very high. To compare the distribution of PrPC to PrPCWD, we examined 5 deer with advanced CWD infection. Using RT-QuIC, we detected prion seeding activity in all 21 tissues. In 3 subclinical deer sacrificed 4 months post-inoculation, we detected PrPCWD consistently in alimentary-associated lymphoid tissue, irregularly in alimentary tract tissues, and not at all in the brain. Contrary to our hypothesis that PrPC levels dictate prion accumulation, PrPC expression was higher in the lower gastrointestinal tissues than in the alimentary-associated lymphoid system and was higher in salivary glands than in the oropharyngeal lymphoid tissue. These data suggest that PrPC expression is not the sole driver of prion accumulation and that alimentary tract tissues accumulate prions before centrifugal spread from the brain occurs.

We designed this study to investigate whether cadmium induces caspase-independent apoptosis and to investigate the relationship between the caspase-dependent and caspase-independent apoptotic pathways. Cadmium (1.25-2.5 μM) induced oxidative stress in rat proximal tubular (rPT) cells, as seen in the reactive oxygen species levels; N-acetylcysteine prevented this. Cyclosporin A (CsA) prevented mitochondrial permeability transition pore opening and apoptosis; there was mitochondrial ultrastructural disruption, mitochondrial cytochrome c (cyt c) translocation to the cytoplasm, and subsequent caspase-9 and caspase-3 activation. Z-VAD-FMK prevented caspase-3 activation and apoptosis and decreased BNIP-3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) expression levels and apoptosis-inducing factor/endonuclease G (AIF/Endo G) translocation. Simultaneously, cadmium induced prominent BNIP-3 expression in the mitochondria and cytoplasmic AIF/Endo G translocation to the nucleus. BNIP-3 silencing significantly prevented AIF and Endo G translocation and decreased the apoptosis rate, cyt c release, and caspase-9 and caspase-3 activation. These results suggest that BNIP-3 is involved in the caspase-independent apoptotic pathway and is located upstream of AIF/Endo G; both the caspase-dependent and caspase-independent pathways are involved in cadmium-induced rPT cell apoptosis and act synergistically., Competing Interests: The authors have declared that no competing interests exist.

Social media analysis has shown tremendous potential to understand public's opinion on a wide variety of topics. In this paper, we have mined Twitter to understand the public's perception of the Internet of Things (IoT). We first generated the discussion trends of the IoT from multiple Twitter data sources and validated these trends with Google Trends. We then performed sentiment analysis to gain insights of the public's attitude towards the IoT. As anticipated, our analysis indicates that the public's perception of the IoT is predominantly positive. Further, through topic modeling, we learned that public tweets discussing the IoT were often focused on business and technology. However, the public has great concerns about privacy and security issues toward the IoT based on the frequent appearance of related terms. Nevertheless, no unexpected perceptions were identified through our analysis. Our analysis was challenged by the limited fraction of tweets relevant to our study. Also, the user demographics of Twitter users may not be strongly representative of the population of the general public.

Background: Recent advances in stem cell technology afford an unlimited source of neural progenitors and glial cells for cell based therapy in central nervous system (CNS) disorders. However, current differentiation strategies still need to be improved due to time-consuming processes, poorly defined culture conditions, and low yield of target cell populations., Methodology/principle Findings: This study aimed to provide a precise sequential differentiation to capture two transient stages: neural epithelia-like stem cells (NESCs) and oligodendrocytes progenitor cells (OPCs) derived from mouse embryonic stem cells (ESCs). CHIR99021, a glycogen synthase kinase 3 (GSK-3) inhibitor, in combination with dual SMAD inhibitors, could induce ESCs to rapidly differentiate into neural rosette-like colonies, which facilitated robust generation of NESCs that had a high self-renewal capability and stable neuronal and glial differentiation potentials. Furthermore, SHH combined with FGF-2 and PDGF-AA could induce NESCs to differentiate into highly expandable OPCs. These OPCs not only robustly differentiated into oligodendrocytes, but also displayed an increased migratory activity in vitro., Conclusions/significance: We developed a precise and reliable strategy for sequential differentiation to capture NESCs and OPCs derived from ESCs, thus providing unlimited cell source for cell transplantation and drug screening towards CNS repair.

The United States Constitution protects the right of citizens to petition the government for "a redress of grievances." This right has important implications for citizens desiring to advance the public health by petitioning administrative agencies, such as the Food and Drug Administration, to take safety actions. We examined a total of 1,915 petitions filed between 2001 and 2013 to investigate the outcomes of citizen petitions that address public health concerns. We found that most petitions were filed by manufacturers against other manufacturers. Only 346 (18%) of all petitions were submitted by individuals and non-profit organizations, and 178 (87.3%) of these petitions with a final response were denied. On average, these petitions required 2.85 years for a final agency decision, and many decisions remain pending 10-13 years after their initial submission. The great majority of the approved requests included some form of risk communication, such as labeling changes, boxed warnings or placement of a drug into a Risk Evaluation and Mitigation Strategy. As a policy instrument to improve the safety of medical and food products, the citizen petition process requires sophisticated legal and scientific expertise, and may not represent a viable route for ordinary citizens to petition the FDA to "redress grievances."

Rice reproductive development is sensitive to high temperature and soil nitrogen supply, both of which are predicted to be increased threats to rice crop yield. Rice spikelet development is a critical process that determines yield, yet little is known about the transcriptional regulation of rice spikelet development in response to the combination of heat stress and low nitrogen availability. Here, we profiled gene expression of rice spikelet development during meiosis under heat stress and different nitrogen levels using RNA-seq. We subjected plants to four treatments: 1) NN: normal nitrogen level (165 kg ha-1) with normal temperature (30°C); 2) HH: high nitrogen level (264 kg ha-1) with high temperature (37°C); 3) NH: normal nitrogen level and high temperature; and 4) HN: high nitrogen level and normal temperature. The de novo transcriptome assembly resulted in 52,250,482 clean reads aligned with 76,103 unigenes, which were then used to compare differentially expressed genes (DEGs) in the different treatments. Comparing gene expression in samples with the same nitrogen levels but different temperatures, we identified 70 temperature-responsive DEGs in normal nitrogen levels (NN vs NH) and 135 DEGs in high nitrogen levels (HN vs HH), with 27 overlapping DEGs. We identified 17 and seven nitrogen-responsive DEGs by comparing changes in nitrogen levels in lower temperature (NN vs HN) and higher temperature (NH vs HH), with one common DEG. The temperature-responsive genes were principally associated with cytochrome, heat shock protein, peroxidase, and ubiquitin, while the nitrogen-responsive genes were mainly involved in glutamine synthetase, amino acid transporter, pollen development, and plant hormone. Rice spikelet fertility was significantly reduced under high temperature, but less reduced under high-nitrogen treatment. In the high temperature treatments, we observed downregulation of genes involved in spikelet development, such as pollen tube growth, pollen maturation, especially sporopollenin biosynthetic process, and pollen exine formation. Moreover, we observed higher expression levels of the co-expressed DEGs in HN vs HH compared to NN vs NH. These included the six downregulated genes (one pollen maturation and five pollen exine formation genes), as well as the four upregulated DEGs in response to heat. This suggests that high-nitrogen treatment may enhance the gene expression levels to mitigate aspects of heat-stress. The spikelet genes identified in this study may play important roles in response to the combined effects of high temperature and high nitrogen, and may serve as candidates for crop improvement.

Osteoprotegerin (OPG) is known to inhibit differentiation and activation of osteoclasts (OCs) by functioning as a decoy receptor blocking interactions between RANK and RANKL. However, the exact role of OPG in the survival/apoptosis of OCs remains unclear. OPG caused increased rates of apoptosis of both OCs and osteoclast precursor cells (OPCs). The expression of Fas and activated caspase-8 was increased by both 20 ng/mL and 40 ng/mL of OPG, but was markedly decreased at 80 ng/mL. Interestingly, we noted that while levels of Fas ligand (FasL) increased with increasing doses of OPG, the soluble form of FasL in the supernatant decreased. The results of a co-immunoprecipitation assay suggested that the decrease of sFasL might be caused by the binding of OPG. This would block the inhibition of the apoptosis of OCs and OPCs. Furthermore, changes in expression levels of Bax/Bcl-2, cleaved-caspase-9, cleaved-caspased-3 and the translocation of cytochrome c, illustrated that OPG induced apoptosis of OCs and OPCs via the classic Fas/FasL apoptosis pathway, and was mediated by mitochondria. Altogether, our results demonstrate that OPG induces OCs and OPCs apoptosis partly by the Fas/FasL signaling pathway.

Objective: Higher selenium level has been hypothesized to have the potential to reduce the risk of cardiovascular diseases including dyslipidemia. However, results from previous studies are inconsistent. This study aims to determine the association between selenium level and dyslipidemia in elderly Chinese with relatively low selenium status., Methods: A cross-sectional study of 1859 participants aged 65 or older from four rural counties in China was conducted. Serum total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDLC) and low-density lipoprotein-cholesterol (LDLC), nail selenium concentration and APOE genotype were measured in all subjects. The four types of dyslipidemia were defined as >5.17 mmol/L for High-TC, >1.69 mmol/L for High-TG, >3.36 mmol/L for High-LDLC, and <1.04 mmol/L for Low-HDLC according to Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults. Logistic models adjusting for age, gender, APOE genotype, body mass index, alcohol consumption, smoking, physical activity, medication use for cardiovascular diseases were used to examine the relationship between selenium levels and the risk of dyslipidemia., Results: Mean nail selenium concentration was 0.465 μg/gin this sample. Rates for High-TC, High-LDLC, High-TG, Low-HDLC were 18.13%, 13.23%, 12.21% and 32.76% respectively. Results from logistic models indicated that higher selenium levels were significantly associated with higher risk of High-TC, High-LDLC and lower risk of Low-HDLC adjusting for covariates (p < 0.0001). Compared with the lowest selenium quartile group, participants in selenium quartile groups 2, 3 and 4 had significantly higher rates of High-TC, High-LDLC, High-TG, and lower rate of Low-HDLC adjusting for covariates. No significant association was observed between selenium level and the risk of High-TG. APOEε4 carriers had higher rates of High-TC and High-LDLC. There was no interaction between selenium level and APOE with the rates of dyslipidemia., Conclusions: Our results suggest long-term selenium exposure level may be associated with the risk of dyslipidemia in elderly population. Future studies are needed to examine the underlying mechanism of the association.

It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways.

Social network analysis (SNA) helps us understand patterns of interaction between social entities. A number of SNA studies have shed light on the characteristics of research collaboration networks (RCNs). Especially, in the Clinical Translational Science Award (CTSA) community, SNA provides us a set of effective tools to quantitatively assess research collaborations and the impact of CTSA. However, descriptive network statistics are difficult for non-experts to understand. In this article, we present our experiences of building meaningful network visualizations to facilitate a series of visual analysis tasks. The basis of our design is multidimensional, visual aggregation of network dynamics. The resulting visualizations can help uncover hidden structures in the networks, elicit new observations of the network dynamics, compare different investigators and investigator groups, determine critical factors to the network evolution, and help direct further analyses. We applied our visualization techniques to explore the biomedical RCNs at the University of Arkansas for Medical Sciences--a CTSA institution. And, we created CollaborationViz, an open-source visual analytical tool to help network researchers and administration apprehend the network dynamics of research collaborations through interactive visualization.

Aim: To investigate the differentiation potential of human umbilical mesenchymal stem cells (HuMSCs) and the key factors that facilitate hepatic differentiation., Methods: HuMSCs were induced to become hepatocyte-like cells according to a previously published protocol. The differentiation status of the hepatocyte-like cells was examined by observing the morphological changes under an inverted microscope and by immunofluorescence analysis. Hepatocyte nuclear factor 4 alpha (HNF4α) overexpression was achieved by plasmid transfection of the hepatocyte-like cells. The expression of proteins and genes of interest was then examined by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) or real-time RT-PCR methods., Results: Our results demonstrated that HuMSCs can easily be induced into hepatocyte-like cells using a published differentiation protocol. The overexpression of HNF4α in the induced HuMSCs significantly enhanced the expression levels of hepatic-specific proteins and genes. HNF4α overexpression may be associated with liver-enriched transcription factor networks and the Wnt/β-Catenin pathway., Conclusion: The overexpression of HNF4α improves the hepatic differentiation of HuMSCs and is a simple way to improve cellular sources for clinical applications.

Aim: The aim of this study was to determine the possibility of improving erectile dysfunction using cell therapy with either human urine-derived stem cells (USCs) or USCs genetically-modified with FGF2 in a type 2 diabetic rat model., Methods: Human USCs were collected from 3 healthy donors. USCs were transfected with FGF2 (USCs-FGF2). Sixty-five SD male rats were divided into five groups (G). A control group of normal rats (G1, n = 10), and four other test groups of type 2 diabetic erectile dysfunction rats: PBS as a negative control (G2, n = 10), USCs (G3, n = 15), lentivirus-FGF2 (G4, n = 15), and USCs-FGF2 (G5, n = 15). Diabetes was induced in the rats via a high fat diet for 28 days and a subsequent intraperitoneal injection of streptozotocin (35 mg/kg). Erectile dysfunction was screened with apomorphine (100 μg/kg). Cell injections in the test groups (G2-G5) occurred directly into the corpora cavernosa. The implanted cells were tracked at 7 days (n = 5 animals/G) and 28 days (n = 10 animals/G) post injection. Mean arterial pressure (MAP), intracavernosal pressure (ICP), expression of endothelial markers (CD31, VEGF and eNOS), smooth muscle markers (desmin and smoothelin), histological changes and erectile function were assessed for each group., Results: USCs expressed mesenchymal stem cell markers, and secreted a number of proangiogenic growth factors. USCs expressed endothelial cell markers (CD31 and vWF) after transfection with FGF2. Implanted USCs or USCs-FGF2 displayed a significantly raised ICP and ICP/MAP ratio (p<0.01) 28 days after intracavernous injection. Although few cell were detected within the implanted sites, histological and western blot analysis demonstrated an increased expression of endothelial and smooth muscle markers within the cavernous tissue following USC or USC-FGF2 injection., Conclusions: The paracrine effect of USCs or USCs-FGF2 induced improvement of erectile function in type 2 diabetic rats by recruiting resident cells and increasing the endothelial expression and contents of smooth muscle.

The aim of this study was to determine whether adipose derived stem cells (ADSCs) expressing vascular endothelial growth factor (VEGF) gene can improve endothelial function, recover the impaired VEGF signaling pathway and enhance smooth muscle contents in a rat diabetic erectile dysfunction (DED) model. DED rats were induced via intraperitoneal injection of streptozotocin (40 mg/kg), and then screened by apomorphine (100 µg/kg). Five groups were used (n = 12/group)-Group 1 (G1): intracavernous injection of lentivirus-VEGF; G2: ADSCs injection; G3: VEGF-expressing ADSCs injection; G4: Phosphate buffered saline injection; G1-G4 were DED rats; G5: normal rats. The mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured at days 7 and 28 after the injections. The components of the VEGF system, endothelial, smooth muscle, pericytes markers in cavernoursal tissue were assessed. On day 28 after injection, the group with intracavernosum injection of ADSCs expressing VEGF displayed more efficiently and significantly raised ICP and ICP/MAP (p<0.01) than those with ADSCs or lentivirus-VEGF injection. Western blot and immunofluorescent analysis demonstrated that improved erectile function by ADSCs-VEGF was associated with increased expression of endothelial markers (VEGF, VEGF R1, VEGF R2, eNOS, CD31 and vWF), smooth muscle markers (a-actin and smoothelin), and pericyte markers (CD146 and NG2). ADSCs expressing VEGF produced a therapeutic effect and restored erectile function in diabetic rats by enhancing VEGF-stimulated endothelial function and increasing the contents of smooth muscle and pericytes.

Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure.

Background: MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism (SNP) in the MDM2 promoter region SNP309 has been demonstrated to be associated with an increased MDM2 expression and a significantly earlier age of onset of several tumors, including gastric cancer. Several studies were published to evaluate the association between SNP309 and gastric cancer risk. However, the results remain conflicting rather than conclusive., Objective: The aim of this study was to assess the association between the MDM2 SNP309 polymorphism and gastric risk., Methods: We performed a meta-analysis to investigate this relationship. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively., Results: Five published case-control studies, including 1,621 gastric cancer cases and 2,639 controls were identified. We found that the MDM2 SNP309 polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR = 1.54; 95%CI = 1.04-2.29, and GG versus GT/TT, OR = 1.49, 95%CI = 1.30-1.72). Furthermore, Egger's test did not show any evidence of publication bias (P = 0.799 for GG versus TT)., Conclusion: Our results suggest that the MDM2 SNP309 polymorphism may be a low-penetrant risk factor for the development of gastric cancer.

Background: Associations between interleukin-13 (IL-13) polymorphisms and asthma risk remained controversial and ambiguous. Therefore, we performed a meta-analysis to assess the associations between IL-13 polymorphisms and asthma susceptibility., Methods: Pubmed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wangfang databases were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the random-effects model., Results: Thirty-four studies were included in this meta-analysis. The results indicated that IL13 -1112C/T polymorphism was significantly associated with asthma risk (OR=1.20, 95% CI 1.08-1.34, P=0.0009) in a dominant genetic model. When stratifying for race, IL13 -1112C/T polymorphism exhibited increased asthma risk in Caucasians (OR=1.30, 95% CI 1.09-1.55, P=0.003), while no significant association was found in Asians and African Americans. In the subgroup analysis based on atopic status, significant association was observed in atopic patients (OR=1.25, 95% CI 1.07-1.45, P=0.004) but not in the non-atopic patients. In addition, a significant association between IL13+2044A/G polymorphism and asthma risk was observed (OR=1.18, 95% CI 1.08-1.28, P=0.0002). In the subgroup analysis by ethnicity, there were significant associations between IL13+2044A/G polymorphism and asthma risk in Asians (OR=1.19, 95% CI 1.04-1.36, P=0.01) and Caucasians (OR=1.22, 95% CI 1.06-1.40, P=0.005) but not in African Americans. In the subgroup analysis stratified by atopic status, a marginal significant association was found in atopic patients (OR=1.12, 95% CI 1.00-1.26, P=0.05)., Conclusions: This meta-analysis suggested that the IL13 -1112C/T and +2044A/G polymorphisms were risk factors for asthma.

Protein misfolding cyclic amplification (PMCA) recapitulates the prion protein (PrP) conversion process under cell-free conditions. PMCA was initially established with brain material and then with further simplified constituents such as partially purified and recombinant PrP. However, availability of brain material from some species or brain material from animals with certain mutations or polymorphisms within the PrP gene is often limited. Moreover, preparation of native PrP from mammalian cells and tissues, as well as recombinant PrP from bacterial cells, involves time-consuming purification steps. To establish a convenient and versatile PMCA procedure unrestricted to the availability of substrate sources, we attempted to conduct PMCA with the lysate of cells that express cellular PrP (PrP(C)). PrP(Sc) was efficiently amplified with lysate of rabbit kidney epithelial RK13 cells stably transfected with the mouse or Syrian hamster PrP gene. Furthermore, PMCA was also successful with lysate of other established cell lines of neuronal or non-neuronal origins. Together with the data showing that the abundance of PrP(C) in cell lysate was a critical factor to drive efficient PrP(Sc) amplification, our results demonstrate that cell lysate in which PrP(C) is present abundantly serves as an excellent substrate source for PMCA.