Two-pole structures demystified: chiral dynamics at work

In the past two decades, one of the most puzzling phenomena discovered in hadron physics is that a nominal hadronic state can actually correspond to two poles on the complex energy plane. This phenomenon was first noticed for the $\Lambda(1405)$, and then for $K_1(1270)$ and to a less extent for $D_0^*(2300)$. In this Letter, we show explicitly how the two-pole structures emerge from the underlying chiral dynamics describing the coupled-channel interactions between heavy matter particles and Nambu-Goldstone bosons. In particular, the fact that two poles appear between the two dominant coupled channels can be attributed to the particular form of the leading order chiral potentials of the Weinberg-Tomozawa form. Their lineshapes overlap with each other because the degeneracy of the two coupled channels is only broken by explicit chiral symmetry breaking of higher order. We predict that for light-quark~(pion) masses heavier than their physical values, the two-pole structures disappear, which can be easily verified by future lattice QCD simulations. Furthermore, we anticipate similar two-pole structures in other systems, such as the isopin $1/2$ $\bar{K}\Sigma_c-\pi\Xi'_c$ coupled channel, which await for experimental discoveries.Comment: 5 pages, 4 figure

Novel potential therapeutic targets of alopecia areata

Alopecia areata (AA) is a non-scarring hair loss disorder caused by autoimmunity. The immune collapse of the hair follicle, where interferon-gamma (IFN-γ) and CD8+ T cells accumulate, is a key factor in AA. However, the exact functional mechanism remains unclear. Therefore, AA treatment has poor efficacy maintenance and high relapse rate after drug withdrawal. Recent studies show that immune-related cells and molecules affect AA. These cells communicate through autocrine and paracrine signals. Various cytokines, chemokines and growth factors mediate this crosstalk. In addition, adipose-derived stem cells (ADSCs), gut microbiota, hair follicle melanocytes, non-coding RNAs and specific regulatory factors have crucial roles in intercellular communication without a clear cause, suggesting potential new targets for AA therapy. This review discusses the latest research on the possible pathogenesis and therapeutic targets of AA

Understanding variation in transcription factor binding by modeling transcription factor genome-epigenome interactions

Despite explosive growth in genomic datasets, the methods for studying epigenomic mechanisms of gene regulation remain primitive. Here we present a model-based approach to systematically analyze the epigenomic functions in modulating transcription factor-DNA binding. Based on the first principles of statistical mechanics, this model considers the interactions between epigenomic modifications and a cis-regulatory module, which contains multiple binding sites arranged in any configurations. We compiled a comprehensive epigenomic dataset in mouse embryonic stem (mES) cells, including DNA methylation (MeDIP-seq and MRE-seq), DNA hydroxymethylation (5-hmC-seq), and histone modifications (ChIP-seq). We discovered correlations of transcription factors (TFs) for specific combinations of epigenomic modifications, which we term epigenomic motifs. Epigenomic motifs explained why some TFs appeared to have different DNA binding motifs derived from in vivo (ChIP-seq) and in vitro experiments. Theoretical analyses suggested that the epigenome can modulate transcriptional noise and boost the cooperativity of weak TF binding sites. ChIP-seq data suggested that epigenomic boost of binding affinities in weak TF binding sites can function in mES cells. We showed in theory that the epigenome should suppress the TF binding differences on SNP-containing binding sites in two people. Using personal data, we identified strong associations between H3K4me2/H3K9ac and the degree of personal differences in NFκB binding in SNP-containing binding sites, which may explain why some SNPs introduce much smaller personal variations on TF binding than other SNPs. In summary, this model presents a powerful approach to analyze the functions of epigenomic modifications. This model was implemented into an open source program APEG (Affinity Prediction by Epigenome and Genome, http://systemsbio.ucsd.edu/apeg)

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD

Magnesium Lithospermate B Protects Cardiomyocytes from Ischemic Injury Via Inhibition of TAB1–p38 Apoptosis Signaling

Danshen has been used in traditional Chinese medicine for hundreds of years to treat cardiovascular diseases. However, its precise cardioprotective components and the underlying mechanism are still unclear. In the present study, we demonstrated that in a rat model of acute myocardial infarction, the treatment with magnesium lithospermate B (MLB), the representative component of phenolic acids in Danshen, significantly reduced the infarct size and the blood lactate dehydrogenase level. In contrast, tanshinone IIA, the representative component of lipophilic tanshinones in Danshen, had no such protective effects. Moreover, in the simulated ischemia cell model, MLB treatment considerably increased the cell viability and reduced the sub-G1 population and the apoptotic nuclei, indicating its anti-apoptotic effect. Further mechanism study revealed that the ischemia-induced p38 phosphorylation was abolished by MLB treatment. Interestingly, MLB specifically inhibited the TGFβ-activated protein kinase 1-binding protein 1 (TAB1) mediated p38 phosphorylation through disrupting the interaction between TAB1 and p38, but it did not affect the mitogen-activated protein kinase 3/6 mediated p38 phosphorylation. In conclusion, the present study identifies MLB as an active component of Danshen in protecting cardiomyocytes from ischemic injury through specific inhibition of TAB1–p38 apoptosis signaling. These results indicate TAB1–p38 interaction as a putative drug target in treating ischemic heart diseases

Understanding Variation in Transcription Factor Binding by Modeling Transcription Factor Genome-Epigenome Interactions

Despite explosive growth in genomic datasets, the methods for studying epigenomic mechanisms of gene regulation remain primitive. Here we present a model-based approach to systematically analyze the epigenomic functions in modulating transcription factor-DNA binding. Based on the first principles of statistical mechanics, this model considers the interactions between epigenomic modifications and a cis-regulatory module, which contains multiple binding sites arranged in any configurations. We compiled a comprehensive epigenomic dataset in mouse embryonic stem (mES) cells, including DNA methylation (MeDIP-seq and MRE-seq), DNA hydroxymethylation (5-hmC-seq), and histone modifications (ChIP-seq). We discovered correlations of transcription factors (TFs) for specific combinations of epigenomic modifications, which we term epigenomic motifs. Epigenomic motifs explained why some TFs appeared to have different DNA binding motifs derived from in vivo (ChIP-seq) and in vitro experiments. Theoretical analyses suggested that the epigenome can modulate transcriptional noise and boost the cooperativity of weak TF binding sites. ChIP-seq data suggested that epigenomic boost of binding affinities in weak TF binding sites can function in mES cells. We showed in theory that the epigenome should suppress the TF binding differences on SNP-containing binding sites in two people. Using personal data, we identified strong associations between H3K4me2/H3K9ac and the degree of personal differences in NFκB binding in SNP-containing binding sites, which may explain why some SNPs introduce much smaller personal variations on TF binding than other SNPs. In summary, this model presents a powerful approach to analyze the functions of epigenomic modifications. This model was implemented into an open source program APEG (Affinity Prediction by Epigenome and Genome, http://systemsbio.ucsd.edu/apeg).</p

A Comparison of Murine Smooth Muscle Cells Generated from Embryonic versus Induced Pluripotent Stem Cells

Smooth muscle cell (SMC) differentiation and dedifferentiation play a critical role in the pathogenesis of cardiovascular diseases. The lack of a good and simple in vitro SMC differentiation system has hampered the progress of SMC field for years. The generation of such an in vitro system would be invaluable for exploring molecular mechanisms of SMC differentiation and dedifferentiation. Recently, the establishment of induced pluripotent stem (iPS) cells has offered a novel therapeutic strategy to generate patient-specific stem cell lines. Here we have investigated whether iPS cells are able to differentiate into SMCs in vitro. Mouse iPS cell (O9 and TT025) monolayers were treated with 105 mol/L all-trans retinoid acid (RA). After 8 days of RA treatment, we found that >40% of the O9 iPS cells expressed the SMC-markers including SMα-actin and SM myosin heavy chain. Also, we documented that iPS-derived SMCs acquired SMC functional characteristics including contraction and calcium influx in response to stimuli. Moreover, our results indicated that there were differences in SMC-specific gene expression patterns between SMCs derived from O9 and TT025 iPS as well as normal embryonic stem cells. These differences might be due to disparity in the current iPS technology. Taken together, our data have established a simple iPS-SMC system to generate SMCs in vitro, which has tremendous potential to generate individualized SMCs for vascular tissue engineering and personalized drug screening.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78153/1/scd.2008.0179.pd

A Hybrid Artificial Bee Colony Algorithm for Flexible Job Shop Scheduling Problems

In this paper, we propose a hybrid Pareto-based artificial bee colony (HABC) algorithm for solving the multi-objective flexible job shop scheduling problem. In the hybrid algorithm, each food sources is represented by two vectors, i.e., the machine assignment vector and the operation scheduling vector. The artificial bee is divided into three groups, namely, employed bees, onlookers, and scouts bees. Furthermore, an external Pareto archive set is introduced to record non-dominated solutions found so far. To balance the exploration and exploitation capability of the algorithm, the scout bees in the hybrid algorithm are divided into two parts. The scout bees in one part perform randomly search in the predefined region while each scout bee in another part randomly select one non-dominated solution from the Pareto archive set. Experimental results on the well-known benchmark instances and comparisons with other recently published algorithms show the efficiency and effectiveness of the proposed algorithm

Reconfigurable Dual Peptide Tethered Polymer System Offers a Synergistic Solution for Next Generation Dental Adhesives

Resin-based composite materials have been widely used in restorative dental materials due to their aesthetic, mechanical, and physical properties. However, they still encounter clinical shortcomings mainly due to recurrent decay that develops at the composite-tooth interface. The low-viscosity adhesive that bonds the composite to the tooth is intended to seal this interface, but the adhesive seal is inherently defective and readily damaged by acids, enzymes, and oral fluids. Bacteria infiltrate the resulting gaps at the composite-tooth interface and bacterial by-products demineralize the tooth and erode the adhesive. These activities lead to wider and deeper gaps that provide an ideal environment for bacteria to proliferate. This complex degradation process mediated by several biological and environmental factors damages the tooth, destroys the adhesive seal, and ultimately, leads to failure of the composite restoration. This paper describes a co-tethered dual peptide-polymer system to address composite-tooth interface vulnerability. The adhesive system incorporates an antimicrobial peptide to inhibit bacterial attack and a hydroxyapatite-binding peptide to promote remineralization of damaged tooth structure. A designer spacer sequence was incorporated into each peptide sequence to not only provide a conjugation site for methacrylate (MA) monomer but also to retain active peptide conformations and enhance the display of the peptides in the material. The resulting MA-antimicrobial peptides and MA-remineralization peptides were copolymerized into dental adhesives formulations. The results on the adhesive system composed of co-tethered peptides demonstrated both strong metabolic inhibition of S. mutans and localized calcium phosphate remineralization. Overall, the result offers a reconfigurable and tunable peptide-polymer hybrid system as next-generation adhesives to address composite-tooth interface vulnerability