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Journal PLOS ONE

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Pagna Sok, Sciprofile linkPhilip J. Lupo, Melissa A. Richard, Karen R. Rabin, Sciprofile linkErik A. Ehli, Noah A. Kallsen, Gareth E. Davies, Michael E. Scheurer, Sciprofile linkAustin L. Brown
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0229352

Abstract:Heel pricks are performed on newborns for diagnostic screenings of various pre-symptomatic metabolic and genetic diseases. Excess blood is spotted on Guthrie cards and archived by many states in biobanks for follow-up diagnoses and public health research. However, storage environment may vary across biobanks and across time within biobanks. With increased applications of DNA extracted from spots for genetic studies, identifying factors associated with genotyping success is critical to maximize DNA quality for future studies. We evaluated 399 blood spots, which were part of a genome-wide association study of childhood leukemia risk in children with Down syndrome, archived at the Michigan Neonatal Biobank between 1992 and 2008. High quality DNA was defined as having post-quality control call rate ≥ 99.0% based on the Illumina GenomeStudio 2.0 GenCall algorithm after processing the samples on the Illumina Infinium Global Screening Array. Bivariate analyses and multivariable logistic regression models were applied to evaluate effects of storage environment and storage duration on DNA genotyping quality. Both storage environment and duration were associated with sample genotyping call rates (p-values < 0.001). Sample call rates were associated with storage duration independent of storage environment (p-trend = 0.006 for DBS archived in an uncontrolled environment and p-trend = 0.002 in a controlled environment). However, 95% of the total sample had high genotyping quality with a call rate ≥ 95.0%, a standard threshold for acceptable sample quality in many genetic studies. Blood spot DNA quality was lower in samples archived in uncontrolled storage environments and for samples archived for longer durations. Still, regardless of storage environment or duration, neonatal biobanks including the Michigan Neonatal Biobanks can provide access to large collections of spots with DNA quality acceptable for most genotyping studies.
Qiao Ke, Nanping Lin, Manjun Deng, Lei Wang, Yongyi Zeng, Jingfeng Liu
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0229292

Abstract:Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. However, the benefit of adjuvant therapy (AT) remains controversial, although it has been conducted prevalently. Hence, a meta-analysis was warranted to evaluate the effect of AT for patients with ICC after resection. PubMed, MedLine, Embase, the Cochrane Library, Web of Science were used to identify potentially eligible studies from Jan.1st 1990 to Aug. 31st 2019, investigating the effect of AT for patients with ICC after resection. Primary endpoint was overall survival (OS), and secondary endpoints was recurrence-free survival (RFS). Hazard ratio (HR) with 95% confidence interval (CI) was used to determine the effect size. 22 studies with 10181 patients were enrolled in this meta-analysis, including 832 patients in the chemotherapy group, 309 patients in the transarterial chemoembolization (TACE) group, 1192 patients in the radiotherapy group, 235 patients in the chemoradiotherapy group, and 6424 patients in the non-AT group. The pooled HR for the OS rate and RFS rate in the AT group were 0.63 (95%CI 0.52~0.74), 0.74 (95%CI 0.58~0.90), compared with the non-AT group. Subgroup analysis showed that the pooled HR for the OS rate in the AT group compared with non-AT group were as follows: chemotherapy group was 0.57 (95%CI = 0.44~0.70), TACE group was 0.56 (95%CI = 0.31~0.82), radiotherapy group was 0.71 (95%CI = 0.39~1.03), chemoradiotherapy group was 0.73 (95%CI = 0.57~0.89), positive resection margin group was 0.60 (95%CI = 0.51~0.69), and lymph node metastasis (LNM) group was 0.67 (95%CI = 0.57~0.76). With the current data, we concluded that AT such as chemotherapy, TACE and chemoradiotherapy could benefit patients with ICC after resection, especially those with positive resection margin and LNM, but the conclusion needed to be furtherly confirmed.
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0219648

Abstract:External loading of the ligamentous tissues induces mechanical creep, which modifies neuromuscular response to perturbations. It is not well understood how ligamentous creep affects athletic performance and contributes to modifications of knee biomechanics during functional tasks. The purpose of this study was to examine the mechanical and neuromuscular responses to single leg drop landing perturbations before and after passive loading of the knee joint. Descriptive laboratory study. Male (n = 7) and female (n = 14) participants’ (21.3 ± 2.1 yrs., 1.69 ± 0.09 m, 69.3 ± 13.0 kg) right hip, knee, and ankle kinematics were assessed during drop landings performed from a 30 cm height onto a force platform before and after a 10 min creep protocol. Electromyography (EMG) signals were recorded from rectus femoris (RF), vastus lateralis (VL), vastus medialis (VM), semimembranosus (SM), and biceps femoris (BF) muscles. The creep protocol involved fixing the knee joint at 35° during static loading with perpendicular loads of either 200 N (males) or 150 N (females). Maximum, minimum, range of motion (ROM), and angular velocities were assessed for the hip, knee, and ankle joints, while normalized EMG (NEMG), vertical ground reaction forces (VGRF), and rate of force development (RFD) were assessed at landing using ANOVAs. Alpha was set at 0.05. Maximum hip flexion velocity decreased (p < 0.01). Minimum knee flexion velocity increased (p < 0.02). Minimum knee ad/abduction velocity decreased (p < 0.001). Ankle ROM decreased (p < 0.001). aVGRF decreased (p < 0.02). RFD had a non-significant trend (p = 0.076). NAEMG was significant between muscle groups (p < 0.02). Distinct changes in velocity parameters are attributed to the altered mechanical behavior of the knee joint tissues and may contribute to changes in the loading of the leg during landing.
Markus Schneider, Carina Trummer, Andreas Stengl, Peng Zhang, Aleksandra Szwagierczak, M. Cristina Cardoso, Heinrich Leonhardt, Christina Bauer, Sciprofile linkIris Antes
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0229144

Abstract:The multi-domain protein UHRF1 is essential for DNA methylation maintenance and binds DNA via a base-flipping mechanism with a preference for hemi-methylated CpG sites. We investigated its binding to hemi- and symmetrically modified DNA containing either 5-methylcytosine (mC), 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), or 5-carboxylcytosine (caC). Our experimental results indicate that UHRF1 binds symmetrically carboxylated and hybrid methylated/carboxylated CpG dyads in addition to its previously reported substrates. Complementary molecular dynamics simulations provide a possible mechanistic explanation of how the protein could differentiate between modification patterns. First, we observe different local binding modes in the nucleotide binding pocket as well as the protein’s NKR finger. Second, both DNA modification sites are coupled through key residues within the NKR finger, suggesting a communication pathway affecting protein-DNA binding for carboxylcytosine modifications. Our results suggest a possible additional function of the hemi-methylation reader UHRF1 through binding of carboxylated CpG sites. This opens the possibility of new biological roles of UHRF1 beyond DNA methylation maintenance and of oxidised methylcytosine derivates in epigenetic regulation.
Jillian Schneider, Woo Hyun Han, Rebecca Matthew, Yves Sauvé, Sciprofile linkHélène Lemieux
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0228710

Abstract:Our study revisits the role of cardiac mitochondrial adjustments during the progression of type 2 diabetes mellitus (T2DM), while considering age and sex as potential confounding factors. We used the Nile Grass rats (NRs) as the animal model. After weaning, animals were fed either a Standard Rodent Chow Diet (SRCD group) or a Mazuri Chinchilla Diet (MCD group) consisting of high-fiber and low-fat content. Both males and females in the SRCD group, exhibited increased body mass, body mass index, and plasma insulin compared to the MCD group animals. However, the females were able to preserve their fasting blood glucose throughout the age range on both diets, while the males showed significant hyperglycemia starting at 6 months in the SRCD group. In the males, a higher citrate synthase activity—a marker of mitochondrial content—was measured at 2 months in the SRCD compared to the MCD group, and this was followed by a decline with age in the SRCD group only. In contrast, females preserved their mitochondrial content throughout the age range. In the males exclusively, the complex IV capacity expressed independently of mitochondrial content varied with age in a diet-specific pattern; the capacity was elevated at 2 months in the SRCD group, and at 6 months in the MCD group. In addition, females, but not males, were able to adjust their capacity to oxidize long-chain fatty acid in accordance with the fat content of the diet. Our results show clear sexual dimorphism in the variation of mitochondrial content and oxidative phosphorylation capacity with diet and age. The SRCD not only leads to T2DM but also exacerbates age-related cardiac mitochondrial defects. These observations, specific to male NRs, might reflect deleterious dietary-induced changes on their metabolism making them more prone to the cardiovascular consequences of aging and T2DM.
Sciprofile linkAdriana Aránguiz-Acuña, José A. Luque, Héctor Pizarro, Mauricio Cerda, Inger Heine-Fuster, Jorge Valdés, Emma Fernández-Galego, Sciprofile linkVolker Wennrich
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0229453

Abstract:The Atacama Desert (21–26°S) is currently one of the driest places on Earth and metal(loid)s are of special concern for this region, which hosts the largest-known porphyry copper deposits produced in Chile. Evidence of past environmental conditions is commonly preserved in natural archives, such as lacustrine sediments. Sediment records obtained from Inca Coya Lake (22°20’S-68°35’W, 2534 m.a.s.l.), a small lake located in the Atacama Desert, reflected the evolution of regional mining activity during the 20th century and sedimentation associated with decadal climate variability. We studied the aquatic community structure changes recorded in sediment records from Inca Coya Lake. By analysis of magnetic properties (susceptibility, hysteresis curves and Curie temperatures), grain size and geochemical composition of the sediments, we identified environmental periods and changes in the community of benthic and planktonic organisms (diatoms and diapausing egg bank). We identified three detrital episodes that we interpret as dry/wet phases during the last 90 years associated with the increase of flash flood events promoting hypoxia oscillations; anthropogenic (mining activity) signals were also identified. Invertebrate community structure (primary consumers) reflected the metal exposure, measured as changes in assemblage composition through species turnover. Diatom community composition was best associated with variables related to wetter/drier alternation and consequent changes in oxygen availability. Bioindicators analyzed (diatoms, diapausing egg bank and invertebrate community) demonstrated to be excellent indicators of the bioavailability of compounds in the aquatic ecosystem of Inca Coya Lake, allowing the environmental impact assessment of the water resources due to flash floods and mining activity in the driest desert of the world.
Sciprofile linkZeyu Peng, Maria D. R. Peralta, Daniel L. Cox, Michael D. Toney
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0229319

Abstract:Biomolecular self-assembly is an emerging bottom-up approach for the synthesis of novel nanomaterials. DNA and viruses have both been used to create scaffolds but the former lacks chemical diversity and the latter lack spatial control. To date, the use of protein scaffolds to template materials on the nanoscale has focused on amyloidogenic proteins that are known to form fibrils or two-protein systems where a second protein acts as a cross-linker. We previously developed a unique approach for self-assembly of nanomaterials based on engineering β-solenoid proteins (BSPs) to polymerize into micrometer-length fibrils. BSPs have highly regular geometries, tunable lengths, and flat surfaces that are amenable to engineering and functionalization. Here, we present a newly engineered BSP based on the antifreeze protein of the beetle Rhagium inquisitor (RiAFP-m9), which polymerizes into stable fibrils under benign conditions. Gold nanoparticles were used to functionalize the RiAFP-m9 fibrils as well as those assembled from the previously described SBAFP-m1 protein. Cysteines incorporated into the sequences provide site-specific gold attachment. Additionally, silver was deposited on the gold-labelled fibrils by electroless plating to create nanowires. These results bolster prospects for programable self-assembly of BSPs to create scaffolds for functional nanomaterials.
Akiko Fujita, Takaya Okuno, Mika Oda, Sciprofile linkKeiko Kato
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0229269

Abstract:Psychiatric disorders including depression and anxiety comprise a broad range of conditions with different symptoms. We have developed a mouse model of depression/anxiety in mice deficient in the St3gal4 gene. In this study, we performed a comparative analysis of urinary volatile organic compounds (VOCs) in St3gal4-deficient (St3gal4-KO) and wild-type mice using gas chromatography-mass spectrometry, and we screened 18 putative VOCs. Principal component analysis (PCA) based on these VOCs identified a major group of 11 VOCs, from which two groups were clarified by hierarchical clustering analysis. One group including six VOCs (pentanoic acid, 4-methyl-, ethyl ester; 3-heptanone, 6-methyl; benzaldehyde; 5,9-undecadien-2-ol, 6,10-dimethyl; and unknown compounds RI1291 and RI1237) was correlated with the startle response (r = 0.620), which is related to an unconscious defensive response. The other group including two VOCs (beta-farnesene and alpha-farnesene) comprised pheromones which increased in KO mice. Next, male mice underwent a social behavior test with female mice in the estrus stage, showing reduced access of KO male mice to female mice. Comparative analysis of urinary VOCs before and after encounters revealed that the six VOCs were not changed by these encounters. However, in WT mice, the two farnesenes increased after the encounters, reaching the level observed in KO mice, which was not altered following the encounter. Taken together, these results indicated that St3gal4 was involved in modulating urinary VOCs. Moreover, VOC clusters discovered by comparison of St3gal4-KO mice with WT mice were correlated with differential emotional behaviors.
Michael Graner, Tiffany Pointon, Sean Manton, Miyoko Green, Kathryn Dennison, Mollie Davis, Gino Braiotta, Julia Craft, Taylor Edwards, Bailey Polonsky, et al.
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0228883

Abstract:IgG oligoclonal bands (OCBs) are present in the cerebrospinal fluid (CSF) of more than 95% of patients with multiple sclerosis (MS), and are considered to be the immunological hallmark of disease. However, the target specificities of the IgG in MS OCBs have remained undiscovered. Nevertheless, evidence that OCBs are associated with increased levels of disease activity and disability support their probable pathological role in MS. We investigated the antigen specificity of individual MS CSF IgG from 20 OCB-positive patients and identified 40 unique peptides by panning phage-displayed random peptide libraries. Utilizing our unique techniques of phage-mediated real-time Immuno-PCR and phage-probed isoelectric focusing immunoblots, we demonstrated that these peptides were targeted by intrathecal oligoclonal IgG antibodies of IgG1 and IgG3 subclasses. In addition, we showed that these peptides represent epitopes sharing sequence homologies with proteins of viral origin, and proteins involved in cell stress, apoptosis, and inflammatory processes. Although homologous peptides were found within individual patients, no shared peptide sequences were found among any of the 42 MS and 13 inflammatory CSF control specimens. The distinct sets of oligoclonal IgG-reactive peptides identified by individual MS CSF suggest that the elevated intrathecal antibodies may target patient-specific antigens.
Jaakko Leskelä, Milla Pietiäinen, Anton Safer, Markku Lehto, Jari Metso, Ernst Malle, Florian Buggle, Heiko Becher, Jouko Sundvall, Armin J. Grau, et al.
Published: 21 February 2020
PLOS ONE, Volume 15; doi:10.1371/journal.pone.0228806

Abstract:Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated. The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined. LPS-NC values ranged between 51–83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (β = -0.68, p<0.001), and ii) HDL cholesterol (0.260, <0.001), LDL cholesterol (-0.265, <0.001), PLTP (-0.196, 0.011), and IgG against A. actinomycetemcomitans (0.174, 0.011). Saliva A. actinomycetemcomitans concentration was higher [log mean (95% CI), 4.39 (2.35–8.19) vs. 10.7 (5.45–21) genomes/ml, p = 0.023) and serotype D more frequent (4 vs. 0%, p = 0.043) in cases than controls. Serotypeablity or serotypes did not, however, relate to the LPS-NC. Serum LPS-NC comprised low PLTP-activity, triglyceride and LDL cholesterol concentrations, as well as high HDL cholesterol and IgG against A. actinomycetemcomitans. The present findings let us to conclude that LPS-NC did not associate with stroke.
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