Amelioration of Lupus Nephritis by Serum Amyloid P Component Gene Therapy with Distinct Mechanisms Varied from Different Stage of the Disease

BACKGROUND: Our previous study revealed that administration of syngeneic female BALB/c mice with excessive self activated lymphocyte-derived DNA (ALD-DNA) could induce systemic lupus erythematosus (SLE) disease, indicating that overload of self-DNA might exceed normal clearance ability and comprise the major source of autoantigens in lupus mice. Serum amyloid P component (SAP), an acute-phase serum protein with binding reactivity to DNA in mice, was proved to promote the clearance of free DNA and prevent mice against self-antigen induced autoimmune response. It is reasonable to hypothesize that SAP treatment might contribute to alleviation of SLE disease, whereas its role in ALD-DNA-induced lupus nephritis is not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: The ratios of SAP to DNA significantly decreased and were negatively correlated with the titers of anti-dsDNA antibodies in ALD-DNA-induced lupus mice, indicating SAP was relatively insufficient in lupus mice. Herein a pcDNA3-SAP plasmid (pSAP) was genetically constructed and intramuscularly injected into BALB/c mice. It was found that SAP protein purified from the serum of pSAP-treated mice bound efficiently to ALD-DNA and inhibited ALD-DNA-mediated innate immune response in vitro. Treatment of ALD-DNA-induced lupus mice with pSAP in the early stage of SLE disease with the onset of proteinuria reversed lupus nephritis via decreasing anti-dsDNA autoantibody production and immune complex (IC) deposition. Further administration of pSAP in the late stage of SLE disease that had established lupus nephritis alleviated proteinuria and ameliorated lupus nephritis. This therapeutic effect of SAP was not only attributable to the decreased levels of anti-dsDNA autoantibodies, but also associated with the decreased infiltration of lymphocytes and the reduced production of inflammatory markers. CONCLUSION/SIGNIFICANCE: These results suggest that SAP administration could effectively alleviated lupus nephritis via modulating anti-dsDNA antibody production and the inflammation followed IC deposition, and SAP-based intervening strategy may provide new approaches for treating SLE disease

Estimate of the Hadronic Production of the Doubly Charmed Baryon Ξcc\Xi_{cc} under GM-VFN Scheme

Hadronic production of the doubly charmed baryon $\Xi_{cc}$ ($\Xi^{++}_{cc}$ and $\Xi^{+}_{cc}$) is investigated under the general-mass variable-flavor-number (GM-VFN) scheme. The gluon-gluon fusion mechanism and the intrinsic charm mechanisms, i.e. via the sub-processes $g+g\to(cc)[^3S_1]_{\bar 3}+\bar{c}+\bar{c}$, $g+g\to(cc)[^1S_0]_6+\bar{c}+\bar{c}$; $g+c\to (cc)[^3S_1]_{\bar 3}+\bar{c}$, $g+c\to (cc)[^1S_0]_6+\bar{c}$ and $c+c\to (cc)[^3S_1]_{\bar 3}+g$, $c+c\to (cc)[^1S_0]_6+g$, are taken into account in the investigation, where $(cc)[^3S_1]_{\bar 3}$ (in color {\bf $\bar 3$}) and $(cc)[^1S_0]_6$ (in color {\bf 6}) are two possible $S$-wave configurations of the doubly charmed diquark pair $(cc)$ inside the baryon $\Xi_{cc}$. Numerical results for the production at hadornic colliders LHC and TEVATRON show that both the contributions from the doubly charmed diquark pairs $(cc)[^1S_0]_6$ and $(cc)[^3S_1]_{\bar 3}$ are sizable with the assumption that the two NRQCD matrix elements are equal, and the total contributions from the `intrinsic' charm mechanisms are bigger than those of the gluon-gluon fusion mechanism. For the production in the region of small transverse-momentum $p_t$, the intrinsic mechanisms are dominant over the gluon-gluon fusion mechanism and they can raise the theoretical prediction of the $\Xi_{cc}$ by almost one order.Comment: 26 pages, 8 figure

MicroRNA319-mediated gene regulatory network impacts leaf development and morphogenesis in poplar

MicroRNA319 (miR319) has been implicated in leaf development in a number of plant species. Here we study the roles of miR319a and its regulated network in leaf development in poplars. Over-expression of miR319a in Populus alba × Populus glandulosa caused dwarf statures, narrow leaf blades and serrated leaf margins. The vascular bundles and bundle sheaths in transgenic leaves had more layers of cells than those in the leaves of control plants, indicating enhanced lignification in these cells. Among the 93 putative targets of miR319a predicted with the psRNATarget tool, only three genes, TCP (TEOSINTE BRANCHED1, CYCLOIDEA, and PROLIFERATING CELL NUCLEAR ANTIGEN BINDING FACTOR), were differentially expressed in the leaves of MIR319a-over-expression transgenic lines. With the RNA-seq data sets from multiple MIR319a over-expression transgenic lines, we built a three-layered gene regulatory network mediated by miR319a using Top-down graphic Gaussian model (GGM) algorithm that is capable of capturing causal relationships from transcriptomic data. The results support that miR319a primarily regulates the lignin biosynthesis, leaf development and differentiation as well as photosynthesis via miR319-MEE35/TCP4, miR319-TCP2 and miR319-TCP2-1 regulatory modules

The Color-Octet Contributions to PP-wave BcB_c Meson Hadroproduction

The contributions from the color-octet components $|(c\bar b)_{\bf 8}(^{1}S_{0}) g>$ and $|(c\bar b)_{\bf 8}(^{3}S_{1}) g>$ to the $h_{B_c}$ or $\chi_{B_c}^J$ (the $P$-wave $B_c$ meson) hadroproduction are estimated in terms of the complete ${\cal O}(\alpha_s^4)$ calculation. As necessary inputs in the estimate, we take the values of the octet matrix elements according to the NRQCD scaling rules, and as a result, we have found that the contributions to the $P$-wave production may be the same in order of magnitude as those from the color-singlet ones, $|(c\bar b)_{\bf 1}(^{1}P_{1})>$ and $|(c\bar b)_{\bf 1}(^{3}P_{J})>$ ($J=1,2,3$). Especially, our result indicates that the observation of the color-octet contributions to the $P$-wave production in the low transverse momentum region is not very far from the present experimental capability at Tevatron and LHC.Comment: 14 pages, 4 figures (8 eps-files for figures), add references and correct typo

Using combination of lifting wavelet and multiclass SVM based on global optimization class strategy for fault pattern identification

This paper presents a new method based on lifting wavelet for obtaining a fast multiclass SVM classification based on global optimization class strategy for fault diagnosis of roller bearing. Decision making was performed in two stages: feature extraction by computing the lifting wavelet coefficients and classification using the multiclass SVM classifiers trained on the extracted features. Experiments demonstrate that in comparison to discrete wavelet transform the lifting wavelet feature extraction can speed up the identification phase as well as achieve higher accuracy of multiclass SVM that is based on global optimization class strategy. Experimental results also reveal that the proposed multiclass SVM of global optimization is better than strategy of one against one and DAGSVM

Using combination of lifting wavelet and multiclass SVM based on global optimization class strategy for fault pattern identification

This paper presents a new method based on lifting wavelet for obtaining a fast multiclass SVM classification based on global optimization class strategy for fault diagnosis of roller bearing. Decision making was performed in two stages: feature extraction by computing the lifting wavelet coefficients and classification using the multiclass SVM classifiers trained on the extracted features. Experiments demonstrate that in comparison to discrete wavelet transform the lifting wavelet feature extraction can speed up the identification phase as well as achieve higher accuracy of multiclass SVM that is based on global optimization class strategy. Experimental results also reveal that the proposed multiclass SVM of global optimization is better than strategy of one against one and DAGSVM

Association between novel TARDBP mutations and Chinese patients with amyotrophic lateral sclerosis

<p>Abstract</p> <p>Background</p> <p><it>TARDBP </it>mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations except Chinese. The present aim is to investigate the association between <it>TARDBP </it>mutations and Chinese patients with ALS.</p> <p>Methods</p> <p>71 SALS patients and 5 FALS families with non-<it>SOD1 </it>mutations were screened for <it>TARDBP </it>mutations via direct sequencing.</p> <p>Results</p> <p>A novel heterozygous variation, Ser292Asn (875G>A), was identified in the proband and 4 asymptomatic relatives including the children of the dead patient from a FALS family. Thus the dead patient, the proband's brother, was speculated to carry Ser292Asn though his sample was unavailable to the detection. This variation was not found in 200 unrelated control subjects. A homology search of the TDP-43 protein in different species demonstrated that it was highly conserved. Also, it was predicted to be deleterious to protein function with SIFT-calculated probabilities of 0.00. Therefore, Ser292Asn is predicted to be a pathogenic mutation. In addition, we have found two silent mutations (Gly40Gly and Ala366Ala) and one novel polymorphism (239-18t>c).</p> <p>Conclusions</p> <p>The present data have extended the spectrum of <it>TARDBP </it>mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.</p

Association between genetically proxied glucosamine and risk of cancer and non-neoplastic disease: A Mendelian randomization study

IntroductionObservational investigations have examined the impact of glucosamine use on the risk of cancer and non-neoplastic diseases. However, the findings from these studies face limitations arising from confounding variables, reverse causation, and conflicting reports. Consequently, the establishment of a causal relationship between habitual glucosamine consumption and the risk of cancer and non-neoplastic diseases necessitates further investigation.MethodsFor Mendelian randomization (MR) investigation, we opted to employ single-nucleotide polymorphisms (SNPs) as instruments that exhibit robust associations with habitual glucosamine consumption. We obtained the corresponding effect estimates of these SNPs on the risk of cancer and non-neoplastic diseases by extracting summary data for genetic instruments linked to 49 varied cancer types amounting to 378,284 cases and 533,969 controls, as well as 20 non-neoplastic diseases encompassing 292,270 cases and 842,829 controls. Apart from the primary analysis utilizing inverse-variance weighted MR, we conducted two supplementary approaches to account for potential pleiotropy (MR-Egger and weighted median) and assessed their respective MR estimates. Furthermore, the results of the leave-one-out analysis revealed that there were no outlying instruments.ResultsOur results suggest divergence from accepted biological understanding, suggesting that genetically predicted glucosamine utilization may be linked to an increased vulnerability to specific illnesses, as evidenced by increased odds ratios and confidence intervals (95% CI) for diseases, such as malignant neoplasm of the eye and adnexa (2.47 [1.34–4.55]), benign neoplasm of the liver/bile ducts (2.12 [1.32–3.43]), benign neoplasm of the larynx (2.01 [1.36–2.96]), melanoma (1.74 [1.17–2.59]), follicular lymphoma (1.50 [1.06–2.11]), autoimmune thyroiditis (2.47 [1.49–4.08]), and autoimmune hyperthyroidism (1.93 [1.17–3.18]). In contrast to prior observational research, our genetic investigations demonstrate a positive correlation between habitual glucosamine consumption and an elevated risk of sigmoid colon cancer, lung adenocarcinoma, and benign neoplasm of the thyroid gland.ConclusionCasting doubt on the purported purely beneficial association between glucosamine ingestion and prevention of neoplastic and non-neoplastic diseases, habitual glucosamine ingestion exhibits dichotomous effects on disease outcomes. Endorsing the habitual consumption of glucosamine as a preventative measure against neoplastic and non-neoplastic diseases cannot be supported