Gene expression microarrays' analyses provide a description of long noncoding RNAs (lncRNAs) with lack of coding protein function that is often important in human cancer.A number of lncRNAs that have been well characterized in hepatocellular carcinoma (HCC) have been scheduled in this study to discuss for protein–lncRNA interaction.The identified lncRNAs were analyzed by bioinformatics tools, starBase and lncRNA db, to anticipate the RNA-binding proteins (RBPs) that tend to interact to HCC-related lncRNAs. The most important predicted RBPs in interaction with well-known lncRNAs in HCC were briefly discussed.The lncRNAs HOTTIP, H19, HOTAIR, MALAT1, antisense Igf2r (AIR), HOXA13, GTL2  and uc002mb have been reported in association with HCC. Besides, this study predicted that eIF4AIII, PTB and FUS were the most involved RBPs in interaction with HCC-related lncRNAs.This information provides an explanation for the previously valuable literature on the functions of lncRNAs and suggest for the novel therapeutic targeting. Progresses in whole genome expression profiling and transcriptome sequencing have been revealed new type of RNAs and their specific functions in eukaryotic cells . Long noRecent study showed that lncRNAs are associated with cancer subtypes or may have a tumor-promoting or suppressing function . GeneticIn this study HCC-related lncRNAs were extracted from literature to evaluate their possible interactions with RBPs by performing computational programs. Prediction of lncRNAs–RBPs interactions will be potentially useful to explore the molecular mechanisms that are regulated by lncRNAs and influence on the function of proteins in HCC. PubMed and reference lists of relevant review articles were searched to retrieve HCC-related lncRNAs. All searches were updated in December 2013. Searching results were listed in StarBase v 2.0 (http://starbase.sysu.edu.cn/) has distinctive features and improved as Database, Visualizer, and Analyzer. This server was used to discover the lncRNAs- RBPs interactions. Included lncRNAs from published studies was administered to identify the possible RBP binding sites among them.StarBase has provided promising information of predicted RBPs for each lncRNA target. This server provides functional insights on target sites within RBP-lncRNA interaction, shows the target location on chromosomes and the number of transcripts by Ensembl ID. LncRNAdb (http://www.lncrnadb.org/) is a valuable database to provide information of annotated lncRNAs including sequences, structural information, genomic context, expression, subcellular localization, conservation and functional evidence. The summarized information of lncRNAs and related RBPs were indicated in Experimental data showed the achievement of lncRNAs in regulation of gene expression and most often, they are poor prognostic biomarker in patients with hepatocellular carcinoma (HCC) , 25, 26.The next generation sequencing techniques, RNA immunoprecipitation and deletion mapping, quantitative real-time PCR and DNA microarray were the used methods in literature for the identification and potential function assessment of cancer-related lncRNAs. However, predicting RNA target proteins has been a topic of active research. Calculating the sequence similarity average between transcripts and their putative target protein sequences are the base of predicting tools. StarBase is the first database that provides the RNA-protein interaction networks to identify the most popular RBPs. It has been well documented that at least 90 % of the human genome is actively transcribed. Currently, it has been documented that non-protein coding transcripts have regulatory function in cancer biology mainly through their relationships with RNA-binding proteins (RBP) in a sequence-specific manner , 25, 36.These data demonstrated that the interaction of lncRNAs with RBPs might effect on the epigenetic regulatory function of lncRNAs molecules in mRNA inactivation and therefore, influence in common cellular functions. Furthermore, RBPs interacting with mRNA for biological function are probably blocked in lncRNAs-RBPs interactions. These finding suggest for oncogenic role of HCC-related lncRNAs. Analyses of human genome have revealed prevalent large RNA transcripts that are long non-coding RNAs (lncRNAs). These molecules have regulatory impact on gene expression in interaction with human genome and RNAs. LncRNAs are also organized in close relationship with RBPs regulatory proteins that suggest the importance of regulatory binding proteins in biological role of lncRNAs. The present study has been focused on well-defined lncRNAs in HCC and their interaction with regulatory proteins. H19, HOTAIR, MALAT1 and HOTTIP are most common lncRNAs in HCC. These lncRNAs are essential in many biological events for instance cell-proliferation and differentiation, apoptosis and tumorigenesis via their impact on RBPs. A few approaches are available for predicting interactions between lncRNAs and proteins. Here, the StarBase database showed that eIF4AIII, PTB and FUS were the most implicated RBPs in interaction with HCC related lncRNAs. Engagements of these RBPs by lncRNAs probably explain the tumorigenicity in HCC and opens new opportunities for novel therapeutic targets in HCC.


Cell therapy has achieved tremendous success in regenerative medicine in the past several decades. However, challenges such as cell loss, death and immune-rejection after transplantation still persist. Biomaterials have been designed as carriers to deliver cells to desirable region for local tissue regeneration; as barriers to protect transplanted cells from host immune attack; or as reactors to stimulate host cell recruitment, homing and differentiation. With the assistance of biomaterials, improvement in treatment efficiency has been demonstrated in numerous animal models of degenerative diseases compared with routine free cell-based therapy. Emerging clinical applications of biomaterial assisted cell therapies further highlight their great promise in regenerative therapy and even cure for complex diseases, which have been failed to realize by conventional therapeutic approaches. Besides, comprehensive characterizations of biomaterials, varying in geometrical structure, physical form, chemical properties, and biocompatibility, should be assessed prior to their applications. In this review, functions of biomaterials as carriers, barriers, or reactors during cell-based regenerative medicine are discussed respectively to shed light on directions for future development of optimally functional biomaterials in regenerative medicine.Cell-based therapy has emerged as a central strategy in regenerative medicine and tissue engineering. Over the past few decades, various cell types, including primary cells  microenvironment  derived from autologous or allogeneic origin have been seeded in these carriers, cultured y et al. , skin Coy et al. , and cary et al. . These cin vivo, thus recellularized ECM imitating natural organs could be a promising alternative for organ transplantation and regeneration. Successful trials have been established in animal disease models of bladder  produced by organ decellularization provides ideal carrier for cell transplantation, which retains almost intact vasculature system and complex architecture of the original organ. ECM is the major component of the naturally occurring cellular microenvironment, which is secreted and remodeled by the resident cells. Major components of ECM, regardless of tissue origin, includes proteins  and polysaccharides  , polyglycolide (PGA), and their copolymer (PLGA), as well as hydroxyapatite, can be functionalized with serum proteins (e.g. fibronectin or vitronectin), to provide binding sites for cell adhesion  were delivered in scaffolds to bone defective models which demonstrated osteogenic potential  and myoblasts was transplanted into mice with hind limb ischemia. Controlled release of VEGF and IGF-1 and improved myoblast engraftment in injured skeletal muscle resulted in rapid regeneration and limited fibrosis  and gelatin microcryogel systems (from 200–800 μm in diameter) that could be site-directed injected in vivo without significant damage to loaded fibroblasts or MSCs  where host antibodies target antigens on the surfaces of the transplanted cells  and microencapsulation . Whichever technique used, the basic principle is to produce cell-laden droplets with controlled size, followed by stabilization of the droplets via interfacial processing and subsequent generation of solid capsule membrane surrounding the droplets. A central principle for choosing biomaterials for encapsulation is that crosslinking agents should be non-cytotoxic before and after gelation. Immunoisolation devices used in pre- and clinical trials can be classified as intracorporeal cell/tissue transplantation (e.g. islets transplantation) and extracorporeal functional assisted devices .Microcapsules, characterized by dimensions in the order of hundreds of microns or less, are spherical in shape to take advantage of the optimal surface-to-volume ratio for improved protein and nutrient diffusion which can maintain good cell viability. The microscale size makes microcapsule ideal barriers for transplantation into microvascularized and deep tissue sites. Natural polymers derived from non-animal sources or synthetic polymers that do not contain cell binding sites are superior materials for use as barriers. Cells are generally encapsulated within nanoporous biodegradable hydrogels, such as hyaluronic acid, fibrin, or gelatin, or nondegradable hydrogels such as alginate, or PEG, which regulate cross-membrane diffusion of nutrients, oxygen, waste and therapeutic agents produced by the encapsulated cells  to provide biotransformative or synthetic functions. For example, artificial liver devices essentially use non-living components to remove the toxins accumulated due to liver failure, and several systems have been approved by Food and Drug Administration (FDA) and are Council of Europe (CE) labeled . Meanwhile, bio-artificial liver devices contain a cell-housing bioreactor, whose role is to replace the primary liver functions   have been successfully applied in clinic to compensate for loss of mechanical functions in injured tissues such as teeth, hips, knees, heart valves, and intervertebral discs. But they rarely modulate the host to repair and regenerate neotissues , and fibrin) can be potentially less immunogenic with similar biochemical and structural moieties to natural ECM  have been extensively investigated in tissue engineering  could also be preferentially enriched to the damage sites  via growth factors, such as PDGF, FGF, VEGF, and EGF  is among the earliest cell-based skin regenerative products used in clinic, which comprises thin autologous keratinocytes sheets (2–3 cell layers thick) cultured on a xenogeneic mouse feeder layer. A layer of irradiated immortal mouse fibroblasts provides autologous cells of patients with support matrix for cell attachment and growth  biomaterials as cell carriers for efficient and targeted cell delivery to therapeutic sites; (2) biomaterials as semipermeable barriers to protect transplanted cells from host immune system; and (3) biomaterials as cell reactors to activate and recruit host cells for regeneration. Recent progress, clinical applications and emerging trends in these three aspects have also been summarized, which highlight great potentials of future biomaterial development with integration of multi-functionalities. Despite the tremendous improvement in efficiency and efficacy of biomaterials-assisted regenerative medicine, underlying therapeutic mechanisms have not been clearly understood, which renders safety a main concern for large-scale clinical application. Future endeavors can develop injectable biomaterial assisted cell therapy for minimally invasive treatment, and minimize cell damage during the entire procedure , hence fully realize the synergistic effects of biomaterials for cell delivery, protection, and induction. We believe that deeper explorations in the mechanism will potentiate further development in regenerative medicine.


Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are “hotspots” for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS . Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation . Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease. Leu gene [mitochondrial tRNA Leu (L)] (MTTL1) , III (one subunit), IV (three subunits), and V (two subunits). The remaining subunits of the respiratory chain complex are encoded by genes located in the nuclear genome. Two mitochondrial genes encode for ribosomal RNAs (rRNAs) 16S and 12S and the remaining 22 genes encode for the set of mitochondrial transfer RNAs (mt-tRNA). All of the RNA molecules necessary for mitochondrial translation are provided for by the mitochondrial genome. However, many proteins necessary to perform protein synthesis, including mitochondrial aminoacyl tRNA synthetases (mt-ARS), ribosomal proteins, and tRNA processing enzymes are encoded in the nuclear genome. These are synthesized in the cytoplasm and subsequently imported into the mitochondria.It is well established that many different mt-tRNA mutations can cause a wide range of human diseases. High-energy consuming tissues such as muscular and nervous systems are particularly affected by mitochondrial defects. Unlike chromosomal DNA localized to the nucleus and subject to Mendelian inheritance, mitochondrial DNA is inherited solely from the mother and thousands of identical copies can exist per cell. Cells that carry a homogeneous population of the mitochondrial genome, wild type or mutated, are referred to as homoplasmic. A condition in which more than one type of mitochondrial genome exists, either in a cell, tissue or in an individual, is referred to as heteroplasmy. Should a mutation spontaneously arise or be maternally inherited, mitochondria carrying the pathogenic mutated mtDNA can accumulate over the course of organismal development. When the mutational load of a certain tissue type reaches a particular threshold, disease symptoms can become evident. Depending on the mutation and the tissue, this threshold can vary from 50 to 90%. Mitochondrial diseases and their respective tRNA mutations have been extensively cataloged, and the information is available in a variety of useful databases  and myoclonic epilepsy with ragged red fibers (MERRF). These are linked to mutations in mt-tRNALeu A3243G and mt-tRNALys A8344G mutations were initially studied in cybrid cell lines . The G12147A mutation in the D-arm of the mt-tRNAHis molecule would be expected to alter tRNA folding and abundance, leading to a specific decrease in the his-rich COXIII polypeptide, as well as a general decrease in mitochondrial protein synthesis. Additionally, a homoplasmic A12146G mutation was identified in another MELAS patient  activity did not convincingly demonstrate a complete COX deficiency.In addition to the classic MELAS and MERRF cases, mutations in other mt-tRNAs are also linked to sensorineural defects. A number of reports suggest that inner ear hair cells and their connecting neuronal circuitry may be specifically affected by mt-tRNA mutations. In one report, a late onset hearing impairment in a Chinese family was linked to a T12201C mutation in the acceptor arm of mt-tRNAy Figure . For thiHis often present with a pigmentary retinopathy that leads to photoreceptor degeneration, pigmentary deposits in the retina, and ultimately progressive loss of vision. Specific muscles responsible for ocular movement are another target in the visual system susceptible to mt-tRNA mutations. Chronic progressive external ophthalmoplegia (CPEO) is a neuromuscular disorder characterized by the loss of extraocular muscle mobility, which results in the inability to move the eyes.Like the auditory system, the visual system is similarly sensitive to mutations in mt-tRNA. For example, carriers of G12183A mutation in mt-tRNAIle; this substitution disrupts a conserved GC base pair .In some systems, a tRNA-linked disorder that is primarily a sensory defect may exert negative effects on additional brain and motor neuron functions. One recent study reported that the pathogenic G14685A mutation in mt-tRNAWhile most cells are roughly spherical structures with diameters in the range of micrometers to tens of micrometers, neurons possess irregular structures with long dendrites and axons that extend out from the soma at distances from millimeters to a meter. The synapse has the highest energy consumption of the neuron, and mitochondria are responsible for meeting this major energy demand. Among the important ATP dependent processes occurring at the synapse are vesicle exocytosis and endocytosis, maintenance of membrane potential by ion channels, and actin rearrangements of the cytoskeleton. Accordingly, synaptic mitochondria may be docked or anchored in these specialized compartments in order to execute these essential functions  technology. iPScs can be challenging to develop if only specific tissues of affected patients carry the mt-tRNA mutation. Mito-mouse models have been generated to recapitulate pathogenic mitochondrial DNA mutations , is encoded by as many as 32 paralogous genes  is a heterogeneous neurodegenerative disorder characterized by defective growth, development, and function of the brainstem and cerebellum. Symptoms of PCH include microcephaly, seizures, hypotonia, hyper-reflexia, and optic atrophy. Magnetic resonance imaging (MRI) of patient brain tissue shows immature development of the cerebellum as well as mild structural defects  is a mammalian RNA kinase capable of phosphorylating the 5′hydroxyl of double and single stranded RNA and has a role in mRNA 3′-end formation , a major component of synaptic plasticity associated with the enhancement of signaling between neurons. The late phase of LTP (L-LTP) is dependent on gene expression and de novo protein synthesis. A key factor in long term memory in general and LTP in particular is the repressor of cAMP responsive element binding protein (CREB), which plays a direct role in L-LTP, learning, and memory , which is characterized by obstruction and blockage of pulmonary veins by fibrous, collagen rich tissue. PVOD is characterized by low diffusing capacity for carbon monoxide, septal line and lymph node enlargement, as well as occult alveolar hemorrhage , a progressive and eventually fatal disease characterized by capillary proliferation and invasion into alveolar septa and the bronchial wall. Symptoms included pulmonary hypertension, fatigue, cough, weight loss, and dyspnea. Exome sequencing between related individuals of patients with PCH determined that mutations in EIFAK4 are responsible for the autosomal recessive PCH phenotype. Both affected siblings carried the same compound heterozygous mutations for which the parents were heterozygous carries, a nonsense 3438C>T (Arg1150X) mutation and frameshift 1153dupG  mutation  showed that β-actin mRNA and ribosome mobilization to axons is stimulus induced, and that the β-actin mRNA becomes more available to translation machinery after synaptic stimulation  protein IFIT5 was recently shown to have tRNA binding properties  catalyze the attachment of amino acids to cognate tRNA, a key reaction that contributes to the accuracy of protein synthesis. ARSs can be divided into two distinct classes Carter, , 2004. CDARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase  is a hereditary peripheral neuropathy that manifests as progressive degeneration of distal motor and sensory neurons, leading ultimately to muscle weakness and atrophy of the legs and hands/arms. The various forms of CMT can be further categorized into either demyelinating type 1, which features defects in the myelin sheath surrounding peripheral nerves, and axonal type 2, which results in abnormalities in the axon of the peripheral nerve. Nerve conduction studies and electromyography (EMG) examination of patients with CMT are typically abnormal. While more than 80 genes have been linked to CMT   , reduced axon diameter, and sensory and peripheral axonal loss but no myelination defects. Importantly, this mutation does not cause a substantial loss of primary aminoacylation function  is also linked to CMT. In particular, the mutant substitutions G41R and E196K, and deletion Δ153–156, are associated with dominant intermediate Charcot-Marie-Tooth C (DI-CMTC)  lysyl-tRNA synthetase (KARS) represents another targeted gene in CMT. One interesting CMT patient was found to be a compound heterozygote with mutations encoding both a L133H missense and a Y173SX7-frame shift mutation  with uncharacteristic CMT phenotype, a progressive neurogeneration and a coat defect, suggested a link between these properties and an editing defect in AARS . In an earlier study, characterization of the mouse strain AARSHARS gene failed to support growth. When introduced in C. elegans, the mutant HARS gene bearing the R137Q mutation caused aberrant motor neuron axonal growth and a progressive loss of motor coordination. In a fashion reminiscent of the some of the GARS-linked CMT mutants, the R137Q substitution eliminates a salt bridge at the dimer interface with D64 of the opposite monomer  gene  heterozygous mutation, R137Q, was found in a 54-year-old patient with peripheral neuropathy  and T629M compound heterozygous mutations found in another Perrault syndrome patient localizes to the poorly conserved leucine-specific C-terminal domain. Yeast complementation assays showed that T522N LARS2 did not support growth, while T629M LARS2 did. Notably, C. elegans models carrying the mutations were completely sterile, recapitulating at least one component of the disease phenotype.Sensorineural deafness is characterized by defects in either the inner ear or the connecting auditory neural circuitry. Perrault Syndrome is described clinically as an ovarian dysgenesis with sensory hearing loss. Genetic studies indicate that mutations in mitochondrial HARS2 and LARS2 are both linked to Perrault Syndrome  linked to mutations in KARS in the known ARNSHI-associated locus DFNB89  represents the first well-characterized CNS disease associated with an ARS. Genetic analysis of some 30 different families helped link the disease to mutations in the DARS gene encoding cytoplasmic AspRS were identified in patients with hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), an inherited white matter disease  gene in a patient with a homozygous frameshift mutation predicted to generate a truncated protein   was linked to the MARS) was identified in an exome sequencing study as one of 15 genes linked to hereditary spastic paraplegias (HSP)  and familial Parkinson's disease. Initially, AIMP2 was reported to be deposited in Lewy bodies, and its accumulation had been noted in some familial cases of Parkinson's disease (Corti et al., Given the emerging role of mRNA transport and localization in neuronal function (Wang et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


More bases in a personal genome are affected by SVs than by single nucleotide polymorphisms (SNPs), suggesting that SV have a larger or comparable effect on personal phenotype than SNPs. SVs frequently occur in tumor genomes, with several tumor types  having SVs as the dominant type of genomic alteration. Numerous Because of their size and enrichment in repeat regions, these are the most challenging variants to discover and analyze. Even more challenging is the precise identification of SV breakpoints at a single base pair resolution. But reward is huge, as precise breakpoints hold invaluable information about the origin of each SV; i.e., about the mutational process that created it. The main mechanisms of SV mutagenesis are largely known or hypothesized based on existing evidence : Non-AllThe 1,000 Genomes Project, specifically aimed at the analysis of genomic variants across 2,504 individuals from 26 diverse human sub-populations, provided one of the largest data resources to date. Analysis of the data allowed precise reconstruction of breakpoints for over 30 thousand germline SVs, while, in turn, analyses of their breakpoints revealed details of mutation mechanisms generating SVs [The classical NAHR mechanism postulates meiotic cell division as a requirement for generating a germline SV, which happens during chromosomal crossover. Interestingly, breakpoints with a signature of NAHR  found by the project were associated with open chromatin, higher DNA accessibility, and active histone marks in mitotically dividing cells . Such asBreakpoints of SVs generated by NHEJ and replicative mechanisms were known to often be non-blunt; i.e., to include a few extra bases at sequence junctions and sometimes being rather complex. Analysis of 1,651 complex deletions, which are thought to be exclusively created by replicative mechanisms, allowed classifying patterns of rearrangements around breakpoints into few but inclusive classes : deletioMechanism for insertions of retrotransposable elements through reverse transcription of their mRNA is well characterized. Still, large-scale analysis revealed peculiar preference of transposon integration complexes for hypomethylated DNA . Additio


Images embedded in biomedical publications carry rich information that oftenconcisely summarize key hypotheses adopted, methods employed, or results obtainedin a published study. Therefore, they offer valuable clues for understanding maincontent in a biomedical publication. Prior studies have pointed out the potentialof mining images embedded in biomedical publications for automaticallyunderstanding and retrieving such images' associated source documents. Within thebroad area of biomedical image processing, categorizing biomedical images is afundamental step for building many advanced image analysis, retrieval, and miningapplications. Similar to any automatic categorization effort, discriminative imagefeatures can provide the most crucial aid in the process.We observe that many images embedded in biomedical publications carry versatileannotation text. Based on the locations of and the spatial relationships betweenthese text elements in an image, we thus propose some novel image features forimage categorization purpose, which quantitatively characterize the spatialpositions and distributions of text elements inside a biomedical image. We furtheradopt a sparse coding representation (SCR) based technique to categorize imagesembedded in biomedical publications by leveraging our newly proposed imagefeatures.we randomly selected 990 images of the JPG format for use in our experiments where310 images were used as training samples and the rest were used as the testingcases. We first segmented 310 sample images following the our proposed procedure.This step produced a total of 1035 sub-images. We then manually labeled all thesesub-images according to the two-level hierarchical image taxonomy proposed by [Compared with conventional image features that do not exploit characteristicsregarding text positions and distributions inside images embedded in biomedicalpublications, our proposed image features coupled with the SR based representationmodel exhibit superior performance for classifying biomedical images asdemonstrated in our comparative benchmark study. The literature in the broader biomedical domain presents abundant image content. Forexample, a significant number of biomedical articles carry multiple images or graphs intheir main text. Popular types of embedded image content include microscopy images, gelelectrophoresis images, graphical tables, diagrams, and charts, which are adopted forvisually communicating the key research ideas pursued, main theses argued, primaryexperimental results produced, and central findings derived in a study. Compared totheir text counterpart, images and graphs carried in biomedical articles can greatlyfacilitate the intuitive grasp of an article's main content through quick browsing andnavigation--a popular practice by many researchers in reality to cope with the explodingvolume of the literature published in their fields at an ever accelerating rate. Inaddition to being able to summarize and highlight key content of a study, an image canalso report a comprehensive set of results beyond the scope of discussion by text in apaper, e.g. the use of heatmap images to report hundreds or thousands of records ofexperimental results simultaneously at one place. For both types of communicationpurposes, an image is indeed worth a thousand words.Despite the tremendous importance of images and graphs in biomedical publications,previously only limited efforts have been dedicated to mining such rich graphicalcontent, in contrast to the counterpart problem of mining text content in the biomedicalliterature where an overwhelmingly abundant body of studies have been contributed -4. FortuTwo important problems of biomedical image mining are: 1) extracting image features tocharacterize the content of a biomedical image and 2) biomedical image categorization,both of which can help computer gain deeper understanding into the content of an image.Overall, enhancing automatic image content understanding can benefit a collection ofapplications in biomedical image processing, such as content-based image retrieval,recommendation, thematic topic detection, mining for trend discovery, as well asimage-based or facilitated biomedical literature retrieval, navigation, contentclustering, topic extraction, and literature mining-based knowledge discovery. It isnoted that the image content characterizing features can directly help categorizebiomedical images more accurately and reliably; while the machine learning proceduredeployed at the heart of an image categorization method can also work with other imagefeatures for accomplishing the same goal of image categorization as well as otherhigh-level, semantically-oriented image processing tasks that involve machine learningtechniques. Therefore, the algorithmic advancements in overcoming the two problems aremutually supportive.Traditional image features, such as texture, color, and shape-based features, only offerlimited discriminative power for characterizing the content of biomedical images; whilecurrent general-purpose image classification methods do not achieve satisfactoryprecision in dealing with biomedical images. Recognizing the technical limitations ofthe-state-of-the-art regarding the above two important problems, we conducted thisstudy. To address the first problem of designing effective features for characterizingbiomedical images, we propose a set of novel image features that quantitatively exploreand exploit the spatial distributions of text elements appearing inside a biomedicalimage. To the best of our knowledge, none of these features has been previously studiedin the biomedical image literature. To address the second problem of introducingadvanced categorization methods for biomedical images, we propose an improved SparseCoding Representation (SCR) based technique to classify biomedical images using ournewly proposed image features. By using the novel image features and the improvedSCR-based classification method both introduced at this paper, we can categorizebiomedical images with better accuracy and reliability than the peer state-of-the-artpractice, the conclusion of which shall be verified through the experimental resultsreported later in this paper.The rest of the paper is organized as follows. We first briefly review some work closelyrelated to this study. Next, we present the novel image features that we propose forcharacterizing the categories of biomedical images. To extract these image features, wethen introduce some algorithmic pre-processing procedures. In the next, we present ourimproved SCR method and apply the method for categorizing biomedical images using thenovel image features introduced earlier. To explore the effectiveness of the newlyproposed image features and the improved SCR method based image categorization approachusing these features, we report results of benchmark experiments that measure andcompare the performance of the new approach with that of the state-of-the-art peerpractice. After presenting the positive comparative experimental results confirming theadvantages of the new biomedical image features and the companion categorization methodfor biomedical images using these features, we conclude the paper in the end.In this section, we will briefly overview some previous studies that closely relate toour work here, including the design of image features and methods for imagecategorization.HistogramIntersection, which allows real-time indexing in a large multicolored imagedatabase. Stricker  ∈RK × n where K is thetotal number of image features considered and n is the total number oftraining images available. The goal is to optimize the following function  associated with the sparse decomposition. Thenewly formulated problem becomes convex concerning either one of the two variablesD and α under the condition that the other variable amongthe two is fixed. Formally, we can write the new optimization objective functionas (4):In our aforementioned optimization problem, the empirical cost functionD to solve αand then updating the dictionary D with the derived value assignmentfor α, we can solve the problem iteratively. In our work, we employthe iterative procedure proposed by Mairal et al. [D and α.By alternatively using the sparse coding on a given l et al.  to obtaiXj)  is a specific class of images andDj)  improved distribution of text region entropy, (2)structural patterns oftext region distribution, and (3)distance distribution closest neighbours. From Tableimproved microscopy images, 126 are gel electrophoresis images, 135 areline charts, 156 are bar charts, 52 are spot charts, 25are tables, 70 are flow charts, and the remaining 155 images aretype of others. In our experiment, parameter λ is set to0.10.To acquire images to be used in our experimental work, we obtain all materialsprovided by PMC by the enflow chart owns more number of true positive image.Table flow chartclass. Table flow chartstill remains the good performance.We employ standard metrics such as recall, precision, and F-score for measuring imagecategorization performance. Confusion matrix result first demonstrates in Table precision, recall, F-score.To verify our extracting novel features, we employing both traditional image featuresand our proposed novel features to implement the test. Traditional image feature inour experiment consists of edge-direction histogram, intensity histogram and texture.Using our proposed improved SCR categorization method, we first only use thetraditional image features to conduct categorizing image task. Then, we add our novelimage features with traditional image features to carry out the experiment. Theresults of our comparative experiments are exciting. Table To more thoroughly evaluate the performance of our proposed weighted sparse codingrepresentation (SCR), we conduct a case-control experiment where in controlexperimental setting, we employ the traditional SVM based method for imagecategorization; while in the case experimental setting, we apply our proposedweighted SCR method for image categorization. In the experimental process, we alsoexplore the impact on image categorization performance by using different imagefeatures through a second case-control comparative setting. More specifically, in thecontrol setting, we employ the conventional image features such as edge-directionhistograms, texture-features, and intensity histograms for biomedical imagecategorization using the SVM method and the weighted SCR method respectively; in thecase setting, we apply our proposed image features alone as well as apply bothconventional image features and our new features to categorize biomedical imagesusing the SVM method and the weighted SCR method respectively. Table Table To accurately categorize biomedical images, in this paper, we propose a novel type ofbiomedical image features that exploit the spatial distributions of text informationinside an image for image content representation and semantics characterization. We alsointroduce a new weighted sparse coding based representation method for imagecategorization. By jointly leveraging merits of the new image features and the imagecategorization method, we can significantly improve the performance of biomedical imagecategorization task, whose effectiveness is confirmed by the results of all ourexperimental results. According to the results of comparative studies reported in TableOur method is designed for categorizing biomedical images, for which we notice that oneof the salient characteristics of such images is their abundant embedded textinformation. By exploring and quantifying the spatial distributions of these textelements embedded inside an image, we can effectively boost the performance of imagecategorization. We, however, notice that for more common categories of images, whichonly carry sparse or no text information, the new image features proposed in this paperdo not possess advantages than the traditional features. In our future research, we planto investigate dynamic feature selection and weighted classification method toadaptively engage proper types of image features for categorizing images in a broaderdomain.The authors declare that they have no competing interests.Sheng proposed the image categorization method and conducted the experiments. Xuproposed the novel image features used in this paper, directed the whole researcheffort, and prepared the manuscript. Sheng and Xu also jointly performed data analysis,interpreted the results, and drafted the manuscript. Luo provided the experimentplatform and supported the paper works. All authors read and approved the finalmanuscript.


Chronic obstructive pulmonary disease (COPD) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation. In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers. Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues. Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease. Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder involving both airways and lung parenchyma, usually characterized by progressive and poorly reversible airflow limitation and largely caused by tobacco smoke and air pollutants. Nowadays, there is a continuous increase in the prevalence of this common disease, which affects more than 200 million patients mainly including elder people, and current epidemiological projections foresee that by 2020 COPD will become the third leading cause of death worldwide . HoweverIn every body fluid or sample such as plasma or serum, the overall protein content can be assayed and qualified via sequential technical steps, starting from protein separation. For proteomic analysis, protein separation is usually performed by two-dimensional electrophoresis (2-DE), based on a pH gradient (first dimension) within an electric field, where protein migration is dependent on the isoelectric point. The second dimension depends on protein size (molecular weight) that is responsible for migration speed through the electrophoretic field of a dodecyl sulfate polyacrylamide gel (PAGE). Proteins can be then excised from the gel, denatured to their primary, linear structure, and digested with a protease such as trypsin, which produces predictable protein fragments . ProteinAfter fractionation and proteolytic digestion, protein identification mostly relies on mass spectrometry (MS), based on separation of gaseous ions according to their different mass and charge . TherefoTherefore, we can summarize that proteomic-based strategies are largely dominated by two-dimensional polyacrylamide gel electrophoresis  or liquid chromatography (LC) coupled to MS or tandem MS and MALDI-TOF -MS (or its variant SELDI-TOF-MS). The latter is mainly finalized to target a restricted window of the proteome, consisting of peptides and small proteins not easily manageable by conventional gel electrophoresis.α2-macroglobulin, haptoglobin, ceruloplasmin, and hemopexin, were able to significantly discriminate the three study groups. These data suggest that proteins involved in iron metabolism pathways and acute-phase responses can be implicated in the pathogenesis of chronic obstructive respiratory diseases [1 (forced expiratory volume in one second) [Analysis of plasma proteome may contribute to identifying interesting COPD biomarkers. For example, 2-DE and MALDI-TOF technologies have been used to delineate the plasma proteomic profiles of three different people groups, represented by healthy control subjects, patients with COPD, and individuals with asthma, respectively . The difdiseases . Microardiseases . Indeed,diseases . Moreovediseases . High-re second) . In part second) ; howeverThe main problem related to the application of proteomic/peptidomic analysis to blood in COPD arises from the very high abundance of proteins and peptides detectable in this body fluid, which hinders the attempts of really identifying suitable biomarkers directly correlated to COPD pathobiology.Sputum is a complex secretion originating from both proximal and distal airways, which can be induced by inhalation of hypertonic saline. Induced sputum (IS) provides information about both inflammatory cells and mediators present in the airways, potentially relevant for phenotypic characterization of patients with chronic respiratory disorders such as COPD and asthma . Due to 1/FVC  ratio, thus demonstrating their relationship to disease severity [However, to overcome the “mucins” problem, Nicholas et al. combined a 2D gel proteomics approach with GeLC-MS/MS, thus identifying more than 250 proteins in human sputum and demonstrating that proteomics can be applied to IS . Recentlseverity . A furthseverity . In partseverity .Switching from 2-DE-MS- to LC-MS-based strategies, Casado et al. tried to differentiate, on the basis of distinct COPD phenotypic features and disease severity stages, the expression of more than 200 identified proteins by CapLC-ESI-Q-TOF technology . Applyinα-defensins [α-defensins into the airways can be elicited by infectious agents [Given the type of the abovementioned studies, it is quite evident that the low-molecular-weight components of IS are still underrepresented, and new approaches and fractionation techniques are required to extract and to characterize IS peptidome. MS profiling of peptidome for disease-associated patterns is a relatively new concept in clinical diagnostics. In this regard, peptidomic-based strategies have been used to discover disease biomarkers in a wide range of disorders, with a special focus on cancer . Peptidoefensins . Defensiefensins , 32. Secs agents , therebys agents .Therefore, high-throughput screening MS-based platforms can be usefully utilized to detect key peptide biomarkers in IS samples obtained from COPD patients. However, potential drawbacks related to the use of such a source for proteomic/peptidomic purposes include contamination by saliva and the presence of substances recovered from lower airways, which sometimes make it difficult to interpret the data obtained from analyzing this sample. These problems can thus reduce the relevance of IS for periodical monitoring of COPD patients.α1-antitrypsin (α1-AT) deficiency, compared with healthy controls [α1-AT-deficient, emphysematous patients were characterized by higher EBC levels of some cytokines  and cytokeratins  than control [α1-AT deficiency [Exhaled breath condensate (EBC), obtained by cooling exhaled breath collected through a noninvasive procedure, is currently considered as a suitable source of COPD biomarkers present in the lower respiratory tract , 36. Howcontrols . By usin control . Therefoficiency . The resficiency . Of courIn contrast with collection of blood, IS, and EBC, bronchoalveolar lavage fluid (BALF) is recovered through an invasive procedure requiring bronchoscopic manoeuvres. Despite these limitations, SELDI-MS and reverse-phase LC followed by MALDI-MS have been used to delineate the BALF proteome of both healthy smokers and COPD patients . In partAvailability of lung tissues requires very invasive procedures such as endoscopy or surgery, necessarily restricted to research purposes and not applicable to daily clinical setting in real life. With regard to proteomic studies, the main limitation of this approach concerns the small numbers of lung specimens sampled, when related to the overall population of COPD patients. However, highly valuable information can be obtained by profiling protein expression in a real biological context directly reflecting lung pathology. By analogy with IS and EBC, for example, high levels of surfactant protein A were also detected in COPD lung, but not in normal and fibrotic lungs . Using MThe main aim of applying proteomics and peptidomics to biological samples obtained from COPD patients refers to the discovery of potential diagnostic and prognostic biomarkers, hopefully useful to characterize different pathological phenotypes as well as unravel new underlying molecular pathways and therapeutic targets . Within In particular, IS and EBC can be valuable sources of candidate COPD biomarkers, because these samples reflect the real airway biological environment and can be obtained by noninvasive procedures. Peptidomic profiling of IS is very attractive, given the crucial role played by peptides in many pathologic conditions, also including inflammatory and oxidative processes underlying the development and progression of COPD. Within this context, research efforts will be greatly facilitated by the continuous advances in standardization of protein fractionation techniques and mass spectrometric platforms, complemented by more efficient methods of peptide enrichment. In order to achieve the main goals of proteomic/peptidomic applications to COPD, it will be always very important to extend these studies to smokers and nonsmoking controls, thus pursuing in such a way the aim of discovering the cellular and molecular pathways responsible for individual susceptibility to this widespread disease.Furthermore, the search for phenotype-specific biomarkers could help to better understand the individual driving mechanisms of disease as well as identify drug targets possibly useful for personalized treatments of COPD. However, the translational process consisting of information transfer from basic research to the real-life clinical setting is still in its infancy, and many years will be needed to perform larger investigations capable of validating and extending the utility for each COPD patient of the proteomic/peptidomic approaches.


The technology platform of Solazyme: Solazyme´s biotechnology platform transforms a wide variety of sugars into renewable oils with high added value, using microalgae, microorganisms that are naturally capable of storing energy in the form of oil. Solazyme's technology enables the conversion of this feedstock into oils for a variety of applications including chemical, cosmetic, food and fuel. Unique to Solazyme's process is their proprietary ability to tailor oils, meaning that for the first time in the history, Solazyme has the ability to design oil profiles rather than simply use what's available in nature today. Through its world class tailoring capabilities, Solazyme is coupling proprietary strains of algae with standard industrial biotechnology; converting what the earth produces naturally- carbohydrate sugars- into what society needs most - oil.• The existing source of oils × new source of oil: While the physical and chemical characteristics of conventional oils have traditionally been dictated by oils found in nature, or blends derived from them, this is no longer the case. Solazyme has created a new paradigm that enables the company to design and produce novel tailored oils that cannot be achieved through blending of existing oils alone. This core competency has created an incredible market opportunity. Solazyme´s platform enables the production of renewable oils with different carbon chain lengths, saturation levels and profiles simply by changing the microalgae strain used in the fermenter.• Solazyme renewable oils - the microalgae: Through Solazyme's industrial biotechnology platform, the company is able to harness the oil-producing capability of microalgae, an organism that has evolved naturally to produce oil prolifically and efficiently, making it an ideal organism for industrial fermentation. The company's technology allows for the optimization of oil profiles with different carbon lengths, saturation levels and functional groups to modify important oil characteristics, such as flash point, pour point, cloud point, oxidative stability, smoke point, and viscosity, thus enabling much more stable and sustainable end products. Solazyme's platform is also feedstock flexible and can utilize a wide variety of renewable plant-based sugars, such as sucrose, dextrose, and sugar from other sustainable biomass sources including cellulosics. Utilizing standard industrial fermentation equipment to efficiently scale and accelerate microalgae's natural oil production time to a few days, Solazyme feeds their proprietary, oil-producing microalgae plant-based sugars in enclosed fermentation tanks, where they are in effect utilizing "indirect photosynthesis," in contrast to the traditional open-pond approach.• Markets: Solazyme leverages their proprietary biotechnology platform to tailor oils that address major markets served by conventional oils: transportation fuels, chemicals, skin and personal care products, nutritionals, among many others.• Sustainability and safety - breaking paradigms: Solazyme oils address many of the challenges associated with traditional oils, such as supply constraints, volatile pricing, and potentially negative and irreversible environmental effects. The "drop-in" nature of Solazyme's tailored oils enables compatibility with existing production, refining, and distribution infrastructures in each of its target markets. Solazyme´s algal oil are fully traceable back to their source of origin and are more sustainable than any other plant-based or petroleum-based oil. They are produced locally and therefore environmental and logistic costs are lower; feedstock comes from the sugar/alcohol industry, a closed carbon system; Solazyme's oil has the lowest GHG profile as compared to any other plant-based and petroleum-based oils.•


Synthesis. The transition from non-invasive to invasive is not related to phylogenetic distinctiveness to the native community, but instead to their environmental preferences. Therefore, combating biological invasions in the Britain and other industrialized countries need entirely different strategies than in more natural environments.Darwin's naturalization hypothesis predicts that invasive species should perform better in their novel range in the absence of close relatives in the native flora due to reduced competition. Evidence from recent taxonomic and phylogenetic-based studies, however, is equivocal. We test Darwin's naturalization hypothesis at two different spatial scales using a fossil-dated molecular phylogenetic tree of the British native and alien flora (ca. 1600 species) and extensive, fine-scale survey data from the 1998 Countryside Survey. At both landscape and local scales, invasive species were neither significantly more nor less related to the native flora than their non-invasive alien counterparts. Species invasiveness was instead correlated with higher nitrogen and moisture preference, but not other life history traits such as life-form and height. We argue that invasive species spread in Britain is hence more likely determined by changes in land use and other anthropogenic factors, rather than evolutionary history.  Invasive species are considered one of the major threats to ecosystems worldwide Sala  and haveOne approach has been to focus on predicting species invasiveness either by comparing the functional traits or performance of invasive species to that of either non-invasive alien or native species . The Countryside Survey consists of vegetation plot surveys conducted within stratified, randomly chosen 1 km squares, and designed to representatively cover all landscape types in Great Britain . The change index was only calculated for species recorded in both time periods and hence excludes the most recent introductions. One caveat, however, is that because botanical records have improved, some of the apparent expansion in ranges of alien taxa, particularly of recent arrivals, may be due in part to changes in recorder effort, although such changes in recorder effort should affect both groups similarly. Nevertheless, we believe that our classification is robust and hence capture both aspects (“impact” and “geographic”) of their dynamics.The classification of invasiveness status is a difficult task  based on PLANTATT . A combination of portions of rbcL and matK has been recommended as the plant barcode based on assessments of recoverability, sequence quality and discriminatory power among species  of the 1729 species considered  and 1362 (78.7%) sequences were obtained from GenBank/EBI for ered see . A largeered see . Of the ered see . We alsorbcL in two overlapping fragments using the primer pairs: rbcL-1F, rbcL-700R; and rbcL-600F, rbcL-1460R   .rbcL and matK sequences were aligned separately using MAFFT .Due to the size of the data set, we were limited with regard to the methods that can be used to date the tree. We estimated divergence times in the phylogeny using nonparametric rate smoothing (Sanderson L), moisture (F), soil fertility (N), soil pH (R), and salt tolerance (S) were obtained from PLANTATT , clonality, and Ellenberg indicator values for light  across Britain  and mean phylogenetic distance (MPD). PNND was calculated by summing up the total intervening branch length between each alien species and the native taxa to which it is most closely related in the phylogeny, whereas MPD was calculated as the mean pairwise phylogenetic distance between the alien species and all native taxa. We performed these calculations at two spatial scales: at the country scale and the local scale (Countryside Survey plots).., PNND or MPD ˜ invasiveness + (1 | species/square)).Linear models for PNND and MPD were used to test whether phylogenetic relatedness to the native flora differed between invasive alien and non-invasive alien species. For local-scale analyses, we instead used linear mixed effects models, fitting invasiveness as a fixed effect. To account for the nonindependence of PNND and MPD of alien species among plots within the same sampled 1 × 1 km square, square identity was fitted as a nested random effect within species identity , differences in ecological variables between the alien taxa and its most closely related native, as well as absolute ecological trait values as explanatory variables. For continuous traits, the trait value of the alien species was subtracted from the trait value of the most closely related native species. For categorical traits, a value of 1 was assigned if both alien and the closest native species had different trait classes, whereas a value of 0 was assigned if both taxa shared a trait class. Ellenberg indicator values and plant height were treated as continuous variables, while life-form and clonality were treated as categorical variables in our model. To obtain uncertainty estimates for parameters, a model-averaging approach was adopted  for 1612 species , just over 93% of the total British taxa considered in PLANTATT  and MPD  are not significantly different between invasive and non-invasive aliens . The CouN) and moisture preferences (Ellenberg F)  Table . PNND, aF) Table . Model aF) Table .While it has been argued that the lack of consensus in support for Darwin's naturalization hypothesis may be attributed to differences in spatial scale  across the British countryside, where competition is expected to dominate . This was also true at finer scales , our results are consistent with other studies that looked at plot scale trait associations as well as changes in species composition across habitats in Britain (Smart et al. In particular, invasive aliens in Britain appear to have a preference for more fertile and wetter conditions compared with non-invasive aliens. Invasive alien species performance has long been associated with nutrient-rich conditions where changes in resource availability may alter competitive hierarchies in local communities (Burke and Grime Furthermore, there is some evidence that landscape-scale environmental changes in Britain may be favouring invasive species with high nutrient and moisture preferences. Decreases in species richness has been observed in infertile habitats such as calcareous grasslands (Braithwaite et al. In conclusion, our study calls for further evaluation of the role of phylogenetic relatedness in predicting invasiveness (Lambdon and Hulme


Staphylococcus aureus and Staphylococcus epidermidis are the most important etiological agents of biofilm associated-infections on indwelling medical devices. Biofilm infections may also develop independently of indwelling devices, e.g., in native valve endocarditis, bone tissue, and open wounds. After attachment to tissue or indwelling medical devices that have been conditioned with host plasma proteins, staphylococcal biofilms grow, and produce a specific environment which provides the conditions for cell–cell interaction and formation of multicellular communities. Bacteria living in biofilms express a variety of macromolecules, including exopolysaccharides, proteins, extracellular eDNA, and other polymers. The S. aureus surface protein C and G (SasC and SasG), clumping factor B (ClfB), serine aspartate repeat protein (SdrC), the biofilm-associated protein (Bap), and the fibronectin/fibrinogen-binding proteins (FnBPA and FnBPB) are individually implicated in biofilm matrix formation. In S. epidermidis, a protein named accumulation-associated protein (Aap) contributes to both the primary attachment phase and the establishment of intercellular connections by forming fibrils on the cell surface. In S. epidermidis, proteinaceous biofilm formation can also be mediated by the extracellular matrix binding protein (Embp) and S. epidermidis surface protein C (SesC). Additionally, multifunctional proteins such as extracellular adherence protein (Eap) and extracellular matrix protein binding protein (Emp) of S. aureus and the iron-regulated surface determinant protein C (IsdC) of S. lugdunensis can promote biofilm formation in iron-depleted conditions. This multitude of proteins intervene at different stages of biofilm formation with certain proteins contributing to biofilm accumulation and others mediating primary attachment to surfaces. This review examines the contribution of proteins to biofilm formation in Staphylococci. The potential to develop vaccines to prevent protein-dependent biofilm formation during staphylococcal infection is discussed. Staphylococcus aureus and Staphylococcus epidermidis cause a broad spectrum of diseases in humans ranging from soft tissue infections and abscesses in organ tissues to osteomyelitis, endocarditis, and toxic shock syndrome. It is not surprising that these bacteria, especially S. aureus, encode a large array of virulence factors that enable the organisms to infect different tissues within the host. Both species display a strong capacity to form biofilms, which are functional multilayered communities of microrganisms adhering to a surface embedded in a self-synthesized extracellular matrix. Biofilm infections are important clinically because bacteria in biofilms exhibit recalcitrance to antimicrobial compounds and persistence in spite of sustained host defenses. The development of a bacterial biofilm is a complex, multifactorial process and can be divided into three phases which involve specific molecular factors: attachment, accumulation/maturation, and detachment/dispersal  apparatus in the membrane and are cleaved during secretion. At their carboxyl termini, each of these proteins has a characteristic sorting signal, which facilitates their covalent anchorage to peptidoglycan. The housekeeping sortase A anchors the majority of CWA proteins which have the LPXTG motif within their sorting signal. In contrast, sortase B of It has been proposed recently  motif proteins are involved in heme capture from hemoglobin and help bacteria to survive in the host, where iron is restricted. The defining characteristic of Isd CWA proteins is the presence of one or more NEAT motifs, which bind either hemoglobin or heme , each of which consists of single separately folded three-helical bundles that can bind to several distinct ligands. Located between this region and the cell surface is region Xr, which is composed of octapeptide repeats that are highly variable in number, followed by a constant region Xc  that is subdivided into four subdomains, a legume-like (L-type) lectin domain that is responsible for adhesion to glycoproteins containing N-acetyl neuraminic acid, a β-grasp fold domain and two cadherin-like domains  is closely related to Aap of S. epidermidis. Both proteins have repeated G5 domains separated by 50-residue sequences known as E regions . A mutant defective in a single CWA protein might not give a completely defective phenotype because two or more proteins might contribute. For example, in the case of FnBP-dependent biofilm, inactivation of both FnBPA and FnBPB was required to eliminate biofilm formation completely  region of Embp mediates binding of S. epidermidis to surface attached fibronectin, while the binding site in fibronectin for Embp was assigned to the fibronectin domain type III12  combined with antibiotic therapy and demonstrated reduced S. aureus biofilm formation on infected tibias using a chronic osteomyelitis model  is dependent on FnBPs (O'Neill et al., Several staphylococcal surface proteins can support biofilm formation. Representative isolates from the major lineages of MRSA form protein-dependent biofilm Further insights into the mechanistic basis of surface protein-mediated biofilm formation will inform the design of specific inhibitors of the protein–protein interactions involved in biofilm accumulation. Small molecules or peptides could be used to prevent or treat biofilm-associated infection.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Although a variety of new drugs have been developed for HIV, HCV and influenza virus, the optimal combinations of multiple drugs are incompletely understood. To optimize the benefits of multi-drugs combinations, we must investigate the interactions between the combined drugs and their target viruses. Mathematical models of viral infection dynamics provide an ideal tool for this purpose. Additionally, whether drug combinations computed by these models are synergistic can be assessed by two prominent drug combination theories, Loewe additivity and Bliss independence. By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect. Here, we describe the theoretical aspects of multi-drugs therapy and discuss their application to antiviral research. Several landmark mathematical modeling studies of anti-retroviral therapy were reported in 1995. ThereafTo accelerate the above benefits of drug combinations, we need to know whether or not a drug combination exerts a synergistic effect . A Here we discuss two primary concepts of drug combination theory: Loewe additivity and Bliss independence. We apply these models to viral replication in a host cell, and discuss their utility for understanding two-drug interactions and viral dynamics. Finally, we discuss how drug combination theory might be applied to cancer chemotherapies and antiviral therapies. Combining mathematical models of viral replication with drug combination theory, we can establish an efficient framework for optimizing drug combinations.Loewe additivity is regarded as a primary criterion for evaluating drug combination effects. To concCA and CB are the respective concentrations of drugs A and B that produce the same effect as the drug combination. That is, the Loewe additivity specifies the concentration ratio of a single drug and its combination with another drug. Note that Loewe additivity assumes that two drugs target the same molecule or pathway. If two drugs do not mutually interact, they can be related through the combination index (CI) based on the mass action law derived by Chou and Talalay. Th. Th41]. fWT and fCI respectively, in terms of the unaffected fractions of viral infectivity by reverse transcription inhibition and C-to-U mutation, fRT and fMu, as follows:The Bliss independence measure can predict antiviral effects as well as evaluate drug combinations. To illustrate this idea, we estimate the anti-HIV effect of a well-known antiviral host factor by Bliss independence. Apolipoandx is the expression level of APOBEC3G, hRT and hMu are Hill coefficients, andhRT, hMu,where  Figure B. Thus, et al.[ERBB2-amplified breast cancer. They adopted Bliss independence as a synergy criterion. Supplementing this computational approach with experimental data is useful for developing theoretically effective novel drugs. Regarding point (2), the biological networks of signaling pathways constructed by various components can be predicted from the dose–response shapes of drug combinations . Lehar n[et al. used sevet al.[in vitro experiments, they identified a rational inhibitor combination as a novel drug candidate. Mathematical models of HCV dynamics during drug therapy have also been investigated at the intracellular level[et al.[The above research potentially benefits not only cancer chemotherapy, but also antiviral therapy development. For instance, Owens et al. showed har level, the intar level, 50, 51,ar level. These sl[et al. derived We have reviewed two major drug combination theories, Loewe additivity and Bliss independence, and discussed how combining these theories with mathematical modeling of viral dynamics might assist antiviral drug therapy. In addition, we have proposed an efficient framework for optimizing drug combinations and quantifying the anti-viral effect. Based on previous studies of computational virology, the integration of drug combination theory and dynamic modeling is a new approach with great potential for showing viral responses to drug combinations, and accelerating novel antiviral drug discovery.


Accumulation of the microtubule associated protein tau occurs in several neurodegenerative diseases including Alzheimer's disease (AD). The tau protein is intrinsically disordered, giving it unique structural properties that can be dynamically altered by post-translational modifications such as phosphorylation and cleavage. Over the last decade, technological advances in nuclear magnetic resonance (NMR) spectroscopy and structural modeling have permitted more in-depth insights into the nature of tau. These studies have helped elucidate how metamorphism of tau makes it ideally suited for dynamic microtubule regulation, but how it also facilitates tau self-assembly, oligomerization, and neurotoxicity. This review will focus on how the distinct structure of tau governs its function, accumulation, and toxicity as well as how other cellular factors such as molecular chaperones control these processes. MAPT gene coding for tau, while several others are caused by environmental factors: chronic traumatic encephalopathy (CTE) is a sequelae of traumatic brain injury (TBI), postencephalitic parkinsonism (PEP) results from infection, while the cause of age-related AD is unknown. The sheer diversity of the factors that ultimately lead to tauopathy and neurodegeneration is quite remarkable and suggestive of a broad neurological reaction in response to a variety of insults. Because the disordered structure of tau lends itself to heavy post-translational modifications, signaling events caused by these environmental factors can have a multitude of effects on tau structural dynamics.The microtubule-associated protein tau accumulates in a number of neurodegenerative diseases termed tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and several others. Many of these diseases are caused by missense mutations in the Tau aggregates into ß-sheet fibrils in tauopathies, leading to the formation of neurofibrillary tangles (NFTs) and subsequent cell death. Although precisely what triggers tau assembly into these ß-sheet structures in the brain is unclear, it is known that a number of post-translational modifications can regulate this process, including phosphorylation, acetylation, cleavage, ubiquitination, and misfolding. This mini-review will reveal what has been recently discovered about tau structure and how distinct cellular mechanisms such as molecular chaperones can control tau folding to promote or block its toxic assembly [for more comprehensive reviews on tau structure and pathology, we direct readers to Kolarova et al.  and WangMAPT gene and post-translational modifications such as phosphorylation and acetylation  theorized a “paper clip” model of tau wherein the N and C termini transiently fold onto the microtubule-binding repeat domains as well as each other  and AT180 (T231) sites, it loses the ability to drive microtubule assembly, but can still associate with preformed microtubules  is a major co-chaperone of Hsp90 and Hsc70. Tau phosphorylation is required for the Hsc70-CHIP complex to shuttle tau to the proteasome for ubiquitination, an event that mitigates cell death induced by tau hyperphosphorylation .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Muscle performance might be temporarily impaired by high-intensity exercise performed during a competition or training session. The attenuation in muscular strength may be transitory, lasting minutes, hours, or several days following training or competition Barnett, . Longer-Different modalities have been used to improve recovery from a damaging bout of exercise Barnett, . Among tThe “popping-sarcomere” hypothesis, first proposed by Morgan in , provideImmediately after sarcomeres are disrupted, leukocytes are mobilized to the injured tissue via soluble intercellular adhesion molecule 1 (sICAM-1). Thereafter, pro-inflammatory cytokines and reactive oxygen species are produced in muscle by neutrophils, lymphocytes, and monocytes  from blood circulation to the damaged tissue. It is known that leukocytes initiate the acute inflammatory process following EIMD  in athletes decreased adhesion molecule sICAM-I, blood concentrations of muscular enzymes (creatine kinase and lactate dehydrogenase), and the pro-inflammatory response  to 5 days of high intensity training (Banfi et al., We wish to suggest that the attenuation in serum sICAM-1 caused by WBC exposure immediately following EIMD may be responsible for the decreased acute inflammatory response to muscle damage. In addition, repeated bouts of WBC may also further reduce the secondary inflammation occurring days after the damaging bout of exercise. However, the mechanisms in which the thermoregulatory effects of WBC exposure lead to a reduction in sICAM-1 remain unknown. Thus, further studies on this topic are necessary in order to better understand the thermoregulatory effects of WBC on muscle inflammatory process caused by EIMD. Future research could investigate this hypothesis assessing sICAM-1, oxidative stress, neutrophils, lymphocytes, monocytes, and cytokines cells following WBC applied immediately after EIMD. In addition, future work could investigate the effects of repeated WBC on long term muscle adaptation. Although potentially beneficial in the short term, it is unknown if suppressing the acute inflammatory response may negatively affect the muscles ability to adapt to exercise.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Multicellularity evolved multiple times in eukaryotes. In all cases, this required an elaboration of the regulatory mechanisms controlling gene expression. Amongst the conserved eukaryotic transcription factor families, the basic leucine zipper (bZIP) superfamily is one of the most ancient and best characterised. This gene family plays a diversity of roles in the specification, differentiation and maintenance of cell types in plants and animals. bZIPs are also involved in stress responses and the regulation of cell proliferation in fungi, amoebozoans and heterokonts.Using 49 sequenced genomes from across the Eukaryota, we demonstrate that the bZIP superfamily has evolved from a single ancestral eukaryotic gene and undergone multiple independent expansions. bZIP family diversification is largely restricted to multicellular lineages, consistent with bZIPs contributing to the complex regulatory networks underlying differential and cell type-specific gene expression in these lineages. Analyses focused on the Metazoa suggest an elaborate bZIP network was in place in the most recent shared ancestor of all extant animals that was comprised of 11 of the 12 previously recognized families present in modern taxa. In addition this analysis identifies three bZIP families that appear to have been lost in mammals. Thus the ancestral metazoan and eumetazoan bZIP repertoire consists of 12 and 16 bZIPs, respectively. These diversified from 7 founder genes present in the holozoan ancestor.Our results reveal the ancestral opisthokont, holozoan and metazoan bZIP repertoire and provide insights into the progressive expansion and divergence of bZIPs in the five main eukaryotic kingdoms, suggesting that the early diversification of bZIPs in multiple eukaryotic lineages was a prerequisite for the evolution of complex multicellular organisms.The online version of this article (doi:10.1186/s12862-016-0598-z) contains supplementary material, which is available to authorized users. Increasing evidence suggests that the evolution of complex multicellular organisms arose from the expansion and diversification of gene regulatory networks (reviewed in ). In eukThe basic leucine zipper (bZIP) superfamily of transcription factors appears to have originated early in eukaryotic evolution . bZIPs sbZIP transcription factors take their name from a highly conserved 60–80 amino acid bZIP domain, which has a bipartite organisation consisting of an N-terminal basic region, responsible for DNA binding, and a leucine zipper, which mediates homo- and hetero-dimerization between bZIPs. As dimers, they regulate transcription by binding short DNA target sites, often in the form of 8 base pair palindromes. In recent years, the bZIP network of several eukaryotes has been described, and their evolution has been, to some extent, investigated in animals , 8, fungSalpingoeca rosetta [Capsaspora owczarzaki [Here, we analysed the bZIP gene repertoires from a wide range of eukaryote genomes, focusing on the lineage with the widest coverage of draft genomes, the holozoans. We traced back metazoan bZIP families to their origin in the holozoan last common ancestor, opisthokont last common ancestor and beyond. By comparing bZIPs diversification in the main eukaryotic clades, we demonstrate that bZIPs originated from a single protein and then evolved independently in each major eukaryotic lineage. bZIP family complexity appears to increase incrementally over long evolutionary periods, prior to evolutionary transitions into a complex multicellular condition. Early in eukaryotic evolution, a first expansion phase occurred independently in each of the four main eukaryotic lineages - Opistokonta, Amoebozoa, Planta and Heterokonta- yielding to 3 or 4 bZIP families. These families constitute the core of the bZIP complement in extant fungi, heterokonts and amoebozoans. A second expansion phase occurred in holozoans and early plants, prior to the emergence of complex multicellularity in either lineage. In holozoans, it occurred in two main steps: one before the divergence of unicellular holozoans, which display numerous examples of colonial forms with life cycles comprised of more than one cell type (e.g. in  rosetta  and Capsczarzaki ), and onHomo, Branchiostoma and poriferans, which is a composite of the bZIPs found in the genomes of a representative demosponge, calcisponge and homoscleromorph), we identified 12 bZIP families that were comprised of at least one human orthologue, and one family (REPTOR) and two sub-families (PAR-Like and OASIS-Like) that appear to have been lost in humans  and two unicellular holozoan (a choanoflagellate and a filasterean) genomes, using an iterative process that included (i) screening predicted proteomes using PFAM, (ii) interrogating the coding sequences in the genome by blastP and (iii) then using hidden Markov models (HMMs) constructed using the bZIP sequences identified in each clade to re-interrogate each of the proteomes  the foundational bZIP family present prior to the evolution of metazoan multicellularity, (ii) the origin of metazoan bZIP families  and bilaterian subfamilies , (iii) the expansion and loss of specific family members in particular lineages, and (iv) uncovered three uncharacterised bZIP families  and a microsporidial fungus (Antonospora locustae), consistent with bZIPs being present in the most recent shared ancestor of extant eukaryotes.Based on our observation that many bilaterian and indeed metazoan bZIPs originated early in holozoan evolution, well prior to the diversification of the Metazoa, we attempted to retrace bZIP evolution beyond the opisthokont last common ancestor. A total of 896 bZIPs were identified from 49 eukaryotic genomes, including opisthokont , amoebozoan, plant , heterokont  and excavate representatives. bZIP genes were recovered in all species surveyed  is not always accompanied with an increase in gene family number. Indeed, bZIP family complexity appears to increase incrementally over long evolutionary periods, probably being one of a number of prerequisites for the evolution of networks underlying complex gene regulation.The phylogenetic analysis of metazoan bZIPs highlights three major periods in the evolution of bZIPs Fig. . The firDrosophila member [The OASIS family of bZIPs form three orthology groups  than simpler fungi and unicellular algae , bZIPs We compiled a dataset of 896 bZIPs from 49 sequenced genomes from across the Eukaryota. The depth of this dataset permits an assessment of the evolution of this family of transcription factors in relation to the timing of the major evolutionary transitions in eukaryotes, including the evolution of multicellularity. We demonstrated that bZIPs underwent an early expansion and diversification, independently in each of the five main eukaryotic lineages, and was likely a contributing prerequisite for the evolution of organisms with complex life cycles and multiple cell types. Focusing on metazoans, we reconstructed the duplication events that shaped bZIP sub-families and identified three previously uncharacterised bZIP sub-families that appear to have been lost in mammals. Our analysis identified the ancestral metazoan and holozan bZIP repertoire, which comprise 7 and 12 founder genes, respectively.Homo sapiens, Branchiostoma floridae and Ciona intestinalis (Chordata); Strongylocentrotus purpuratus (Echinodermata); Drosophila melanogaster, Tribolium castaneum and Daphnia pulex (Arthropoda): Lottia gigantea (Mollusca), Capitella telata (Polychaeta); Nematostella vectensis, Acropora digitifera and Hydra magnipapillata (Cnidaria); Trichoplax adherans (Placozoa); Mnemiopsis leydi and Pleurobrachia bachei (Ctenophora); and Amphimedon queenslandica, Oscarella carmela and Sycon ciliatum (Porifera). Non-metazoan opisthokonts include: Monosiga brevicollis (Choanoflagellata); Capsaspora owczarzaki (Filasterea); and Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida albicans, Aspergillus nidulans, Magnaporthe grisea, Ustilago maydis, Cryptococcus neoformans, Mucor circinelloides, Rhizophagus irregularis, Antonospora locustae and Encephalitozoon cuniculi (Fungi). Plants include: Arabidopsis thaliana (Planta); Chlamydomonas reinhardtii ; and Galdieria sulphuraria and Chondrus Crispus . Amoebozoans include: Entamoeba histolica, Dictyostelium discoideum, Acanthamoeba castellanii, Hartmannella vermiformis and Physarum polycephalum. Heterokonts include: Thalassiosira pseudonana, Phytophthora sojae, Pythium ultimum, Phytophthora infectans, Ectocarpus sliculosus , Hyaloperonospora arabidopsidis, and Phaeodactylum tricornutum; Excavates include: Giardia lamblia and Naeglaria gruberi. As there are few published analyses of heterokont bZIPs, we sampled several species in this lineage. Subsequent phylogenetic analyses in this study were restricted to Phytophthora infectans (oocmycete), Thalassiosira pseudonana (diatom) and Ectocarpus siliculosus . Species and data sources information can be found in Additional file The sequences of the full complement of bZIP genes were retrieved from the fully sequenced genomes of 31 non-metazoan eukaryotes and 18 metazoan representatives. Metazoan opisthokonts include: -4 was used but proteins with higher e-value were also manually selected against the identification criteria listed below. When possible, we interrogated our dataset with previously published data to assess completeness  building an initial set of bZIP proteins using PFAM, (ii) interrogating the proteome by BlastP in several databases  and We defined the N-terminal domain boundary of the bZIP domain as the N-terminal end of the crystal structure of GCN4 in complex with DNA  and to aTo determine orthologue assignments, we looked at each species independently.Homo, Branchiostoma and poriferans , respectively. We made multiple alignments comprising the putative bZIPs of each species and one of the reference set; the bZIPs identified in each phylum; and the bZIPs identified in each clade. Phylogenetic trees were inferred by maximum likelihood and Bayesian analyses.For holozoan bZIPs, we constructed three bZIP reference sets including the sequences from We considered two sequences as orthologues if their grouping was supported by bootstrap values and posterior marginal probabilities superior to 80 % and 90 %, respectively. We then manually inspected each protein for conserved amino acids peculiar to each bZIP family (described in  (CEBP); Using a similar method, we sought to identify groups of orthologues within and between six eukaryotic kingdoms: animals, fungi, plants, amoebozans, heterokonts and excavates. Our classification was compared with previous studies that have focused on a specific clade (in fungi  and planHomo sapiens; Drosophila melanogaster; Hydra magnipapillata; Amphimedon queenslandica; Mnemiopsis leydii; Monosiga brevicollis; and Capsaspora owczarzaki. The minimal and maximal width for a motif was set to 6 and 50 residues, respectively. The motifs found to be conserved between orthologues were investigated further by building HMM for these motifs/domains and searching the entire derived bZIP proteome of all holozoan species.The complete set of full-length bZIP sequences from the following representative holozoan species was searched for the presence of conserved motifs using the MEME suite : Homo saThe data sets supporting the results of this article are included within the article and its additional files. Protein sequences can be found in Additional file


Mesenchymal stem cells (MSCs) hold great promise for therapeutic use in regenerative medicine and tissue engineering. A detailed understanding of the molecular processes governing MSC fate determination will be instrumental in the application of MSCs. Much progress has been made in recent years in defining the epigenetic events that control the differentiation of MSCs into different lineages. A complex network of transcription factors and histone modifiers, in concert with specific transcriptional co-activators and co-repressors, activates or represses MSC differentiation. In this review, we summarize recent progress in determining the effects of histone-modifying enzymes on the multilineage differentiation of MSCs. In addition, we propose that the manipulation of histone signatures associated with lineage-specific differentiation by small molecules has immense potential for the advancement of MSC-based regenerative medicine. Mesenchymal stem cells (MSCs) have been emerging as an extremely promising therapeutic agent for tissue regeneration and diseases largely because of their multi-potent properties and capacity for self-renewal. Stem cell self-renewal and differentiation require selective activation or silencing of specific transcription programs in response to environmental cues. This is achieved by intensive crosstalk between transcription factors and epigenetic modulators regulating the chromatin conformation that affects access of the transcriptional machinery to specific gene promoters. In contrast to growing information concerning transcriptional regulation, the epigenetic mechanisms governing MSC identity and fate determination are not well understood and remain an active area of investigation.Within the context of chromatin, numerous histone-modifying enzymes reciprocally collaborate to establish and maintain a heritable epigenetic code by addition or removal of an array of covalent modifications in the core histones and other chromatin proteins. These modifications regulate gene expression as well as other genomic functions, and have been implicated in the defining of cell identity and fate. In this review, we summarize our current understanding of how histone-modifying enzymes modulate multi-lineage differentiation of MSCs. In addition, we discuss how an advanced understanding of epigenetic regulatory mechanisms will provide novel avenues for MSC-based therapy.Epigenetic mechanisms play a pivotal role in the promotion of divergent transcriptional pathways during both embryonic development and adult tissue maintenance. Regulation of gene expression at the epigenetic level occurs via modifications of chromatin architecture by facilitating the opening of DNA (euchromatin) to permit transcription, or the condensing of DNA (heterochromatin) to repress transcription . TherefoMSCs, also referred to as multipotent stromal cells or mesenchymal stromal cells, are one of the most intensively studied adult stem cell types, holding significant promise for regenerative therapies. At present, a large number of studies are focusing on identifying extrinsic regulators and their intrinsic target transcription factors that regulate MSC properties and functions, whereas very little is known regarding the epigenetic events that control MSC identity and/or functions. Indeed, accumulating evidence indicates that cell fate and function are determined by DNA-binding transcription factors that are regulated more specifically at the epigenetic level, as we learned from pluripotent stem cells such as embryonic stem (ES) cells and induced-pluripotent stem cells ,8. FurthLike ES cells, several adult tissues, including sperm, testis, cerebellum, and the hematopoietic compartment, have been reported to contain bivalent chromatin domains as well -13. For MSCs can be readily differentiated into osteoblasts, adipocytes or chondrocytes, while directed differentiation strictly relies on an orchestrated balance among these three lineages. Growing evidence suggests that, upon differentiation of MSCs, various histone modifications change to facilitate the activation or repression of key transcription factors, guiding development towards specified cell lineages Figure . Among tHoxA10, a gene necessary for the embryonic patterning of skeletal elements, contributed to osteogenic lineage determination through enrichment of H3K4me3 at the promoter region [Furthermore, histone methylation has a role in osteogenic differentiation from MSCs. It has been shown that r region . Increasr region . While tr region . Overexpr region . Genome-r region . In addir region . It was r region . This idr region . Apart fr region .Recently, distinct HDMs have been identified as critical regulators of MSCs differentiation ,21-24. DHistone acetylation is one of the most abundant and dynamic histone modifications. The actual level of histone acetylation is dependent on highly orchestrated interplay between HATs and HDACs. Numerous studies have reported the involvement of histone acetylation in regulating lineage-specific gene expression in MSCs. Shen and colleagues  observedOn the other hand, HDACs, a conserved family of chromatin-modifying enzymes that repress transcription by deacetylating nucleosomal histones, are also associated with key transcription factors, counteracting the functions of HATs. For instance, through the systematic genetic deletion of HDAC genes in cultured mesenchymal precursor cells, Haberland and colleagues showed that deletion of HDAC1 and HDAC2 led to reduced lipid accumulation, validating the redundant and requisite roles of class I HDACs in adipogenesis . The reg2+ level via the PI3-kinase/Akt signaling pathway, which ultimately leads to the neuronal differentiation of MSCs both in vitro and in vivo [MSCs have the ability to cross oligolineage boundaries and differentiate into different kinds of cell types, such as neurons, cardiomyocytes, hepatocytes and endothelial cells, under appropriate culture conditions, indicating that they are more plastic than we previously thought. While the molecular mechanisms underlying MSC transdifferentiation are largely unknown, it is plausible that epigenetic plasticity is one of the major factors contributing to this unique feature of MSCs. Indeed, increasing evidence has shown that both histone methylation and acetylation are involved in the regulation of MSC transdifferentiation Figure . For exa in vivo . Interes in vivo . Valproi in vivo . Histone in vivo . In cont in vivo . Moreove in vivo . Taken tThe knowledge obtained from epigenetic studies on MSC differentiation could be applied to regenerative medicine. Indeed, it is conceivable that manipulation of the epigenetic signatures associated with lineage-specific differentiation can direct patient-specific therapy. For instance, as chemically modifiable enzymes, KDM4B and KDM6B could be activated or deactivated to regulate specific lineage decisions of MSCs, thereby holding promising potential as therapeutic targets for stem cell-mediated regenerative medicine as well as the treatment of human metabolic diseases such as osteoporosis and obesity . In thisIt is quite apparent that significant progress has been made during the past few years in identifying the histone-modifying enzymes involved in the fate determination processes of MSCs. These functional enzymes fine-tune epigenetic environments at regulatory regions of multiple transcriptional factors and are closely related to gene activation/repression. The challenge for the future is to gain more insights into the global epigenetic regulatory mechanisms governing the commitment of MSCs to specified lineages. In this regard, research into MSCs lags far behind that of pluripotent stem cells since a very limited number of studies have been designed to determine epigenetic signatures during MSC lineage commitment. While one analysis of genes regulating adipogenic differentiation of human MSCs has revealed dynamic changes in histone marks reminiscent of those seen in ES cells , other s