Role of serum B-cell-activating factor and interleukin-17 as biomarkers in the classification of interstitial pneumonia with autoimmune features.

Interstitial pneumonia with autoimmune features (IPAF) is a type of interstitial lung disease (ILD) with immune features that do not meet the diagnostic criteria for specific connective tissue diseases (CTDs). This retrospective case-control study investigated the role of serum B-cell-activating factor of the tumor necrosis factor family (BAFF) and interleukin (IL)-17 as biomarkers for IPAF. The differences in serum BAFF, IL-17, and IL-10 were compared among patients with idiopathic pulmonary fibrosis (IPF), IPAF, ILD associated with CTD (CTD-ILD), and healthy controls. The patients were treatment naïve. The correlations of BAFF with IL-10, IL-17, and pulmonary function were analyzed. The classifiable value of BAFF for IPAF was examined. The results showed that the serum levels of BAFF and IL-17 in the IPAF and CTD-ILD groups were higher than in the IPF group. High BAFF levels and high predicted diffusion capacity of the lungs for carbon monoxide (DLCO) were independent predictive factors for IPAF vs IPF. In the IPAF and CTD-ILD groups, serum BAFF levels were negatively correlated with predicted values of forced vital capacity (FVC%) and diffusing capacity of the lungs for carbon monoxide (DLCO%) and positively correlated with serum IL-17 and IL-10 levels. The cutoff value of combined BAFF and IL-17 was 0.704, and the sensitivity and specificity for classifying IPAF were 78.9 and 95.7%, respectively. In conclusion, combining serum BAFF and IL-17 as a biomarker may have classifiable value in differentiating IPAF from other forms of ILD.

Structural and functional changes on polyhydroxy alcohol-mediated curing pork myofibrillar protein: Experimental and molecular simulation investigations.

This study aimed to investigate the structural and functional changes in polyhydroxy alcohol-mediated curing on pork myofibrillar proteins (MP). The results obtained from total sulfhydryl groups, surface hydrophobicity, fluorescence and Raman spectroscopies, and solubility demonstrated that the polyhydroxy alcohols (especially xylitol) significantly modified the MP tertiary structure, making this structure more hydrophobic and tighter. However, no significant differences were detected in the secondary structure. Furthermore, the thermodynamic analysis revealed that polyhydroxy alcohols could develop an amphiphilic interfacial layer on the MP surface, significantly increasing the denaturation temperature and enthalpy of denaturation (P < 0.05). On the other hand, the molecular docking and dynamics simulations showed that polyhydroxy alcohols interact with actin mainly through hydrogen bonds and van der Waals forces. Therefore, this could help reduce the effect of high-content salt ions on MP denaturation and improve the cured meat quality.

Novel serum proteomic biomarkers for early diagnosis and aggressive grade identification of prostate cancer.

Background: Prostate cancer (PCa) is one of the most common tumors and the second leading cause of cancer-related death in men. The discovery of novel biomarkers for PCa diagnosis in the early stage, as well as discriminating aggressive PCa from non-aggressive PCa continue to pose a challenge. The aim of this study was to identify serum proteins that were sensitive and specific enough to detect early-stage and aggressive PCa. Methods: The serum proteomic profiling of patients with PCa and benign prostatic hyperplasia (BPH) was comprehensively analyzed using data-independent acquisition mass spectrometry (DIA-MS), and the bioinformatics analysis was performed. The differentially expressed proteins (DEPs) of interest were further verified by enzyme-linked immunosorbent assay (ELISA) and immunoturbidimetry assay. Results: Statistically significant difference in abundance showed 56 DEPs between early-stage PCa and BPH and 47 DEPs between aggressive and non-aggressive PCa patients. In addition, the verification results showed that serum L-selectin concentration was significantly higher (p<0.05) in Gleason 6 PCa when compared with BPH, and the concentration of osteopontin (SPP1) and ceruloplasmin (CP) increased with higher Gleason score. Conclusions: DIA-MS has great potential in cancer-related biomarker screening. Our data demonstrated that adding SPP1 and CP to PSA improved the separation of Gleason 7 (4 + 3) or above from Gleason 7 (3 + 4) or below compared with PSA diagnosis alone. Serum SPP1 and CP could be effective biomarkers to differentiate aggressive PCa (especially Gleason 7 (4 + 3) or above) from non-aggressive disease.

A MnO2 nanosheet-mediated photo-controlled DNAzyme for intracellular miRNA cleavage to suppress cell growth.

Certain miRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed, thus, representing a potential new class of targets for therapeutic intervention. RNA-cleaving DNAzymes, mainly aimed at mRNA, have shown potential as therapeutic agents for various diseases. However, it's rarely reported that a DNAzyme was used for intracellular miRNA cleavage to suppress cell growth. Herein, we have developed a MnO2 nanosheet-mediated photo-controlled DNAzyme (NPD) for intracellular miRNA cleavage to suppress cell growth. MnO2 nanosheets adsorb photocaged DNAzymes, protect them from enzymatic digestion, and efficiently deliver them into cells. In the presence of intracellular glutathione (GSH), MnO2 nanosheets are reduced to Mn2+ ions, which serve as cofactors of the 8-17 DNAzyme for miRNA cleavage. Once the DNAzyme is activated by light, it can cyclically cleave endogenous miR-21 inside cells, which would suppress cancer cell migration and invasion, and finally induce cancer cell apoptosis.

Genomic insights into evolution of pathogenicity and resistance of multidrug-resistant Raoultella ornithinolytica WM1.

Raoultella ornithinolytica is a poorly understood opportunistic pathogen, and the underlying mechanisms of its multidrug resistance and pathogenicity have not yet been comprehensively investigated. The multidrug-resistant (MDR) strain WM1 was isolated from the blood of a male patient in Tianjin, China, in 2018. Here, we describe the complete genome and provide a genomic analysis of R. ornithinolytica WM1. The isolate was resistant to all tested antimicrobials except amikacin, tobramycin, and tigecycline. Two plasmids, pWM1-1 (IncHI5) and pWM1-2 (IncR), carried multidrug-resistance regions. A large antimicrobial resistance island region resided on pWM1-1 and exhibited mosaic structures resulting from the acquisition of complex integrations of variable regions, including genes conferring resistance to multiple classes of antimicrobials. Moreover, WM1 possessed virulence-related elements that encode several virulence factors, including type I fimbriae, Escherichia coli common pilus, type II and VI secretion systems, yersiniabactin, enterobactin, and surface polysaccharide, indicating pathogenic potential. Furthermore, the core genome phylogeny and pan-genome analyses revealed extensive genetic diversity. Our analysis indicates the need for stringent infection control, antimicrobial stewardship, periodic resistance monitoring, and rational medication to address potential threats posed by MDR R. ornithinolytica strains.

Neural Belief-Propagation Decoders for Quantum Error-Correcting Codes.

Belief-propagation (BP) decoders play a vital role in modern coding theory, but they are not suitable to decode quantum error-correcting codes because of a unique quantum feature called error degeneracy. Inspired by an exact mapping between BP and deep neural networks, we train neural BP decoders for quantum low-density parity-check codes with a loss function tailored to error degeneracy. Training substantially improves the performance of BP decoders for all families of codes we tested and may solve the degeneracy problem which plagues the decoding of quantum low-density parity-check codes.

Discriminative Cooperative Networks for Detecting Phase Transitions.

The classification of states of matter and their corresponding phase transitions is a special kind of machine-learning task, where physical data allow for the analysis of new algorithms, which have not been considered in the general computer-science setting so far. Here we introduce an unsupervised machine-learning scheme for detecting phase transitions with a pair of discriminative cooperative networks (DCNs). In this scheme, a guesser network and a learner network cooperate to detect phase transitions from fully unlabeled data. The new scheme is efficient enough for dealing with phase diagrams in two-dimensional parameter spaces, where we can utilize an active contour model-the snake-from computer vision to host the two networks. The snake, with a DCN "brain," moves and learns actively in the parameter space, and locates phase boundaries automatically.

Giant phonon anomaly associated with superconducting fluctuations in the pseudogap phase of cuprates.

The pseudogap in underdoped cuprates leads to significant changes in the electronic structure, and was later found to be accompanied by anomalous fluctuations of superconductivity and certain lattice phonons. Here we propose that the Fermi surface breakup due to the pseudogap, leads to a breakup of the pairing order into two weakly coupled sub-band amplitudes, and a concomitant low energy Leggett mode due to phase fluctuations between them. This increases the temperature range of superconducting fluctuations containing an overdamped Leggett mode. In this range inter-sub-band phonons show strong damping due to resonant scattering into an intermediate state with a pair of overdamped Leggett modes. In the ordered state, the Leggett mode develops a finite energy, changing the anomalous phonon damping into an anomaly in the dispersion. This proposal explains the intrinsic connection between the anomalous pseudogap phase, enhanced superconducting fluctuations and giant anomalies in the phonon spectra.

Polymorphisms of NFκB1 and IκBα and Their Synergistic Effect on Nasopharyngeal Carcinoma Susceptibility.

Nasopharyngeal carcinoma (NPC) is a multifactoral and polygenic disease with high prevalence in Southeast Asia and Southern China. Environmental factors and genetic susceptibility play important roles in NPC pathogenesis. In the present study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in nuclear factor-kappa B (NFκB) and its inhibitor (IκBα) conferred consistent risks for NPC. Four putatively functional SNPs (NFκB1: rs28362491del>ins ATTG; NFκB2: rs12769316G>A; IκBα: rs2233406C>T and rs696G>A) were analyzed to evaluate their associations with NPC risk in total 1590 NPC cases and 1979 cancer-free controls. We found that the rs28362491 insATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of NPC (odds ratio [OR] = 1.30, 95% confidence interval [CI] = 1.09-1.55, and P = 2.80 × 10(-3)) compared with the del/del homozygous genotype. The rs696AA variant in IκBα had an increased risk of NPC (OR = 1.41, 95% CI = 1.20-1.66, and P = 2.28 × 10(-5)) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a. Furthermore, both adverse genotypes of NFκB/IκBα and their interaction also exerted an increased risk on NPC. Taken together, Our findings indicated that genetic variants in NFκB1 (rs28362491del>ins ATTG) and IκBα (rs696G>A) and their synergistic effect might contribute to NPC predisposition.

Split Orthogonal Group: A Guiding Principle for Sign-Problem-Free Fermionic Simulations.

We present a guiding principle for designing fermionic Hamiltonians and quantum Monte Carlo (QMC) methods that are free from the infamous sign problem by exploiting the Lie groups and Lie algebras that appear naturally in the Monte Carlo weight of fermionic QMC simulations. Specifically, rigorous mathematical constraints on the determinants involving matrices that lie in the split orthogonal group provide a guideline for sign-free simulations of fermionic models on bipartite lattices. This guiding principle not only unifies the recent solutions of the sign problem based on the continuous-time quantum Monte Carlo methods and the Majorana representation, but also suggests new efficient algorithms to simulate physical systems that were previously prohibitive because of the sign problem.

[The Clumping factor B gene typing in discriminating the strains of nosocomial-acquired methicillin-resistant Staphylococcus aureus].

OBJECTIVE: To evaluate the clfB typing method in discriminating the ST239 methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients under nosocomial infection in Tianjin first central hospital so as to access the clinical risk factors and outcomes of the MRSA nosocomial infection from ICU and non-ICU departments. METHODS: Forty-two stains of MRSA with known SCCmec type were chosen in both ICU (n = 35) and non-ICU (n = 7) wards, from 2006 to 2012, of which MLST genotype was ST239. Clinical risk factors and rates on drug resistant to MRSA were counted, respectively. RESULTS: All the isolates of MRSA belonged to the same lineage 3 and 6 haplotypes, based on clfB variable-number tandom repeats typing. Thirty-five isolates from ICU belonged to 6 haplotypes, among which clfB3-52, 3-52E, 3-50, 3-52C, 3-50A and 3-50E were accouted for 42.9%, 37.1%, 8.6%, 5.7%, 2.9% and 2.9%, respectively. Seven isolates from non-ICU belonged to 3 haplotypes, in which 3-52, 3-52E and 3-50 were accouted for 42.8%, 28.6%, 28.6%, respectively. When clfB typing was combined with SCCmec typing in use, results showed that the index of discrimination as 0.767, better than clfB (ID = 0.688) or SCCmec (ID = 0.303) used alone. SCCmec III -clfB3-52E seemed as the major clone among the 10 haplotypes of clfB/SCCmec typing, which was accounted for 40.4% . There were significant differences on the length of hospitalization (P < 0.005) and the duration of antibiotics use (P < 0.05) between ICU and non-ICU. CONCLUSION: The clfB typing method which was based on variable-numbers of tandom repeats showed powerful ability of resolution. It could also be combined with MLST and SCCmec typing to be used in local epidemiological investigations.

A mechanism to pin skyrmions in chiral magnets.

We propose a mechanism to pin skyrmions in chiral magnetic thin films by introducing local maxima of magnetic exchange strength as pinning centers. The local maxima can be realized by engineering the local density of itinerant electrons. The stationary properties and the dynamical pinning and depinning processes of an isolated skyrmion around a pinning center are studied. We carry out numerical simulations of the Landau-Lifshitz-Gilbert (LLG) equation and find a way to control the position of an isolated skyrmion in a pinning center lattice using electric current pulses. The results are verified by a Thiele equation analysis. We also find that the critical current to depin a skyrmion, which is estimated to have order of magnitude 10(7)-10(8) A m(-2), has linear dependence on the pinning strength.

Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese.

Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: -94del>insATTG; NFκB2: -2966G>A; IκBα: -826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the -94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95% CI 1.06-1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95% CI 1.30-1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the -94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for -2966G>A and -826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (-94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.

Recombinant M. smegmatis vaccine targeted delivering IL-12/GLS into macrophages can induce specific cellular immunity against M. tuberculosis in BALB/c mice.

In the present study, we constructed a viable therapeutic vaccine of recombinant M. smegmatis mediated IL-12/GLS (granulysin) gene transfer into murine macrophages to exert the immunotherapy effects on the Mycobacterium tuberculosis infection. We tested this recombinant therapeutic vaccine in an in vivo study to determine its capability of stimulating host specific immune responses against M. tuberculosis. BALB/c mice intranasally immunized with the therapeutic vaccine developed an efficient Th1 protective immune response against M. tuberculosis which was equal to that of the BCG strain. Inoculation intranasally with this viable vaccine induced high level of serum IFN-gamma, IL-12 and IgG2a. The viable vaccine was capable of inducing purified protein derivative (PPD) antigen-specific splenocytes proliferation and IFN-gamma production from T cells in spleens of the immunized mice. In addition, intranasally inoculation with the viable vaccine can induce PPD antigen-specific sIgA production in the broncho-alveolar lavage fluid (BALF) of the immunized mice. No change of IL-4 level was found in all groups. The therapeutic mechanism of this viable vaccine against M. tuberculosis infection observed here appeared to be a result of the specific Th1 immune response activated by mycobacterium antigen from M. smegmatis and the expression of sIL-12/GLS in alveolar macrophages via the M. smegmatis-mediated gene transfer method. This research demonstrates that the therapeutic gene can be introduced into a host by viable mycobacteria works to induce the host specific immune response against M. tuberculosis infection in vivo. Since this therapeutic vaccine can strongly induce specific Th1 responses against M. tuberculosis in BALB/c mice and has no obviously harmfulness to the host simultaneously, the recombinant vaccine might be a potential candidate therapeutic vaccine against tuberculosis.

[Inhibitory effects of 10-23 deoxyribozyme targeting ICL gene on the expression of isocitrate lyase and the infection of Mycobacterium tuberculosis in macrophages].

OBJECTIVE: To investigate the inhibitory effects of the 10-23 deoxyribozyme (DRZ) targeting ICL gene on the expression of isocitrate lyase (ICL) and the survival of Mycobacterium tuberculosis in macrophages. METHODS: Five 10-23 DRZ targeting ICL genes (DZ1-DZ5) were designed according to the predicted secondary structure of Mycobacterium tuberculosis ICL mRNA. Their cleavage activity and specificity were identified in cell free conditions. Then Mycobacterium tuberculosis pretreated with DZ4 with or without subinhibitory concentration of isoniazid (INH) were used to infect THP-1 cells. The bacterial burden of the infected THP-1 cells was monitored at indicated times after infection. The effect of 10-23 DRZ on the growth of Mycobacterium tuberculosis in vitro was also assayed by plating Mycobacterium tuberculosis treated with INH alone or DZ4 plus INH on M7H10 agar directly. RESULTS: Four of the five designed 10-23 DRZ, DZ1, DZ3, DZ4 and DZ5 could cleavage ICL mRNA efficiently and specifically. Treating Mycobacterium tuberculosis with 5 micromol/L DZ4 plus subinhibitory concentration of INH decreased the expression of ICL dramatically, by 34.9% - 46.7% (10 microg/L INH, P < 0.01) or 21.9% - 36.9% (5 microg/L INH, P < 0.01) when compared with corresponding concentration of INH alone. The survival of Mycobacterium tuberculosis in THP-1 cells was decreased significantly when Mycobacterium tuberculosis was pretreated with 5 micromol/L DZ4 plus subinhibitory concentration of INH. 4 or 7 days after infection, the bacteria burden in macrophages was decreased from 126.5 x 10(4) CFU, 307.5 x 10(4) CFU to 54.6 x 10(4) CFU, 114.3 x 10(4) CFU (when 10 microg/L INH used) or from 133.0 x 10(4) CFU, 325.4 x 10(4) CFU to 71.7 x 10(4) CFU, 174.4 x 10(4) CFU (when 5 microg/L INH used). 10-23 DRZ showed no obvious effect on the growth of Mycobacterium tuberculosis in M7H10 agar. CONCLUSIONS: INH at the subinhibitory concentration can improve the entry of 10-23 DRZ in Mycobacterium tuberculosis. In the presence of subinhibitory concentration of INH, 10-23 DRZ targeting ICL gene can strongly inhibit the expression of ICL and decrease the survival of Mycobacterium tuberculosis in macrophages.

DNAzymes targeting the icl gene inhibit ICL expression and decrease Mycobacterium tuberculosis survival in macrophages.

Latent infection with Mycobacterium tuberculosis presents a big obstacle for tuberculosis therapy. In this study, we investigated the effects of sequence-specific DNAzymes targeting the mRNA of isocitrate lyase (ICL), an enzyme playing a pivotal role in the metabolism of M. tuberculosis in the latent state, on the expression of ICL and survival of M. tuberculosis. In vitro studies showed that four of five designed DNAzymes, DZ1, DZ3, DZ4, and DZ5 could cleave icl mRNA efficiently and specifically. Treatment of virulent M. tuberculosis with 5microM DZ4 plus a subinhibitory concentration of isoniazid (INH) decreased ICL expression and the survival of M. tuberculosis in macrophages but had no obvious influence on the growth of M. tuberculosis in vitro. This study demonstrates that using INH to soften the cell wall of M. tuberculosis and help the entry of biomolecules is an efficient method of improving the uptake of DNAzymes. Silencing the icl gene by DNAzyme is a promising method to combat latent infection of tuberculosis.