In recent years, a wealth of bioinformatics applications in the fields of basic and applied life sciences has changed the paradigm of both research and exploitation of knowledge. The development of novel and powerful bioinformatics tools dedicated to biological data acquisition, data mining, and analysis empowered both the basic and applied life sciences research. These bioinformatics developments span from tools for genome annotation and function prediction, gene expression analyses, and databases of biological information, to the emerging fields of biomedical applications of research, including the development of new bioinformatics-based devices and predictive applications.Life sciences researchers collect and analyse a high amount of different types of scientific data, including DNA, RNA, and amino acid sequences,This special issue is composed of five original research papers selected after in-depth peer review. Selected papers describe novel bioinformatics tools and/or databases for fundamental and/or applied research in the broad range of biological and biomedical sciences.Understanding the genetic control of complex dynamic traits is of fundamental importance to agricultural, evolutionary, and biomedical genetic research. A statistical mapping framework, called functional mapping, has been developed and extensively used to characterize the quantitative trait loci (QTLs) or nucleotides (QTNs) that underlie a complex dynamic trait. However, this tool is not well suited when the curves are complex, especially in the case of nonmonotonic curves. Therefore, to overcome this problem, in their work J. Qi and colleagues propose the earliness index (E-index) to cumulatively measure the earliness degree to which a variable (or dynamic trait) increases or decreases its value. The authors show by both theoretical proofs and simulation studies that E-index is more general than functional mapping and can be applied to any complex dynamic trait, even those with nonmonotonic curves.RNA-Seq experiments are nowadays extensively used in a wide range of studies, spanning from genome-wide gene expression and regulatory mechanisms underlying basic physiological traits to human pathologies, including cancer. However, RNA-Seq data analyses are complex and require the use of several different tools to manipulate and process the retrieved data. The work presented by F. Russo and collaborators shows recent advancements and novelties introduced in RNASeqGUI, a graphical interface that allows the user to handle and analyse big data sets (collected from RNA-Seq experiments) in a fast, efficient, and reproducible way. The here presented version of RNASeqGUI combines graphical interfaces with tools for reproducible research, such as literate statistical programming, human readable report, parallel executions, caching, and interactive and web-exploitable tables of results.The Cancer Genome Atlas (TCGA) data portal is a platform containing tumor gene expression data, together with clinical information, enabling researchers to gather information on significant genomic alterations that occur during the development and metastasis of a tumor. To help biomedical researchers to identify gene expression patterns related to breast cancer survival, H. Zhenzhen et al. developed a web-based TCGA data analysis platform called TCGA4U, providing a visualization solution for the analysis of the relationships of genomic changes with the available clinical data. The authors believe that the use of TCGA4U will inspire more biomedical researchers to explore the biological mechanisms of those genes and more precisely explain their role in breast cancer development, paving the way for the discover of more targeted therapies and help more breast cancer patients. in silico screening methods have been introduced to assist in the development of central nervous system active drugs. In their paper, D. Zhang and colleagues describe the design and implementation of a genetic algorithm to predict the BBB permeation ability of a given molecule, achieving more accurate results than currently available models.Predicting blood-brain barrier (BBB) permeation is essential for drug design of molecules that act in the central nervous system (CNS). On the other hand, peripherally acting drugs must show limited ability to cross the BBB and therefore be devoid of action in the CNS. However, understanding the process of permeation is complicated, since compounds can cross the BBB by passive diffusion and/or active transport. As an alternative to invasive animal experiments,A single nucleotide polymorphism (SNP) is the result of the variation of a single nucleotide at a specific position in the genome. Besides introducing some degree of genetic variation within a population, certain SNPs have been associated with the susceptibility of the individual to specific diseases. The accumulated knowledge resulting from the availability of human genome sequences and the association of specific SNPs with certain diseases prompted the development of the so-called predictive preventive personalized medicine. In their article, P. Ponomarenko and colleagues analysed the effects of SNPs occurring at the promotor region of specific genes on the affinity of the TATA-binding proteins to the promoter region using their web-service SNP_TATA_Comparator. Throughout their work, the authors provide some examples and discuss how to use the bioinformatics application SNP_TATA_Comparator to analyse and extract unannotated SNPs from the database “1000 genomes.” Seventeen novel candidate SNP markers, putatively associated with several diseases, are reported.The development of bioinformatics tools have changed the paradigm of research in both basic and applied biological sciences, as illustrated by the papers published in this special issue. While these tools enable scientists to gain knowledge of complex biological systems, they also allow envisioning the exploitation of results towards novel developments in biomedical applications, thus contributing to promote both individuals and populations welfare.Sílvia A. SousaJorge H. LeitãoRaul C. MartinsJoão M. SanchesJasjit S. SuriAlejandro Giorgetti


Arthropods may be ectoparasites of dogs, representing a nuisance and causing direct damage such as blood loss, irritation, skin lesions, hypersensitivity reactions, toxicosis and even paralysis. Many of those invertebrates are also a potential indirect threat to their vertebrate hosts due to the transmission, mainly while feeding on blood, of a range of vector-borne pathogens, including bacteria, protozoa, helminths and viruses, many of which are of zoonotic concern. Ticks, together with fleas, mosquitoes, sand flies and other insects, are among the haematophagous ectoparasites that have a major impact on the well-being and health not only of dogs but also of humans, thus providing factual examples of the “One Health” concept. The vector-borne diseases of dogs include anaplasmosis, babesiosis, bartonellosis, borreliosis, dipylidiosis, dirofilariosis, ehrlichiosis, leishmaniosis and rickettsiosis, most of which represent emergent veterinary medical and public health problems in many geographical regions worldwide.Prevention of canine vector-borne diseases largely relies on ectoparasite control, aiming at protecting dogs and simultaneously limiting the risk of zoonotic infections. Due to changes in the distribution of arthropods, along with those in the lifestyle of pets, it is advisable to maintain protection against ectoparasites year-round. Regular application of effective anti-vector products on dogs remains the best approach to control infestations and associated diseases. The range of ectoparasiticides has expanded in recent years with the development of new active ingredients and formulations. Many active ingredients are available on the market as insecticides/acaricides, supplying veterinarians and dog owners with a wide variety of products to choose from, such as sprays, spot-on pipettes, impregnated collars and orally administered preparations. One current approach in the development of tools for parasite control is the use of existing molecules in combinations.Parasites & Vectors article collection represents a series of seven papers describing studies conducted on the efficacy of a novel combination of fipronil and permethrin in a spot-on formulation for dogs . Fipronil is a phenylpyrazole with both insecticidal and acaricidal properties; permethrin is a pyrethroid which combines insecticidal, acaricidal and repellent activities; both diffuse across the skin and accumulate in sebaceous glands and cutaneous lipids, remaining active for weeks. Although there is substantial available scientific literature on the efficacy of fipronil and permethrin as separate molecules, no previous study has been published on the performance of their combination. The efficacy of the current formulation has been demonstrated in controlled studies in dogs.This Ctenocephalides felis, a single application of fipronil and permethrin provided excellent levels of efficacy against fleas on dogs at 24 and 48 hours post-treatment or post-infestation, during one month. In two of those studies, efficacy was maintained at 100% during a full month after treatment in dogs that underwent either three water immersions or one shampooing, simulating an outdoor lifestyle. One of the articles presents interesting results on the repellency of the product against Ctenocephalides canis fleas at one hour post-infestation, which is a less investigated parameter of insecticide preparations. A successful flea control program aims at eliminating fleas quickly after infestation and preventing re-infestation from the environment. For fleas, insecticides should have rapid killing or repellent activity. Adult fleas infesting the host must be eliminated, and further infestations by latent environmental stages should be prevented.In five different studies with adult Ixodes ricinus and Rhipicephalus sanguineus. Regarding Dermacentor reticulatus, the new product demonstrated high repellency and prevention of attachment, at 12 and 24 hours after re-infestation, and excellent acaricidal efficacy, within 48 hours, with the effects persisting up to four weeks after treatment. Transmission of most pathogens from tick species to dogs usually requires an initial pre-activation period of about 24 to 48 hours after attachment. Taking these times into account, the results suggest that the application to dogs of the new combination can significantly reduce the potential for transmission of Babesia canis as well as other agents of tick-borne diseases.The new ectoparasiticide had the ability of killing ticks when administered to infested dogs (immediate or curative efficacy) and to prevent tick re-infestations for at least four weeks after treatment (persistent or protective efficacy). A single topical treatment with the fipronil and permethrin combination provided excellent acaricidal efficacy against both i.e., an anti-feeding effect) against the bites of Phlebotomus perniciosus sand flies, which lasted for three to four weeks. A single topical administration of the product also provided high repellency against mosquitoes  on dogs for at least four weeks. High protection  of the combination of fipronil and permethrin was also found against the biting stable fly Stomoxys calcitrans on dogs for at least five weeks after a single treatment. This overall repellent efficacy by inhibition of blood-feeding may contribute to the protection of dogs from sequelae of bites by mosquitoes and biting flies, as well as from major pathogens transmitted by mosquitoes and sand flies, i.e., Dirofilaria spp. and Leishmania infantum, respectively.The new fipronil and permethrin combination demonstrated a high repellency (In conclusion, a long lasting repellent effect against mosquitoes, sand flies and stable flies has been demonstrated, along with a long lasting efficacy against fleas and the main tick species infesting dogs in Europe. For one month following a single topical application, the new fipronil and permethrin ectoparasiticide combination offers a broad spectrum protection against the major canine ectoparasites, protecting the dogs themselves and also minimizing the risk of zoonotic pathogen transmission.


The interactome mappings of different time points also found the down-regulated trend of gene expression existed across the whole duration, which brought a possibility to introduce the myogenesis related miRNAs into the interactome regulatory networks of skeletal muscle in pigs.The regulatory relationship and connectivity among genes involved in myogenesis and hypertrophy of skeletal muscle in pigs still remain large challenges. Presentation of gene interactions is a potential way to understand the mechanisms of developmental events in skeletal muscle. In this study, genome-wide transcripts and miRNA profiling was determined for Landrace pigs at four time points using microarray chips. A comprehensive method integrating gene ontology annotation and interactome network mapping was conducted to analyze the biological patterns and interaction modules of muscle development events based on differentially expressed genes and miRNAs. Our results showed that in total 484 genes and 34 miRNAs were detected for the duration from embryonic stage to adult in pigs, which composed two linear expression patterns with consensus changes. Moreover, the gene ontology analysis also disclosed that there were three typical biological events  Muscle growth and development is of central importance for porcine carcass mass weight and quality. Skeletal muscle cells arise from embryonic mesoderm during embryonic development ,2. MultimiR-1, miR-133, miR-206 and miR-208, which are responsible for the transcriptional networks involving SRF, MyoD, MEF2 and myocardin, and play central regulatory roles in myoblast proliferation and differentiation during myogenesis [The previous studies showed that the non-coding RNA, especially microRNAs (miRNAs), are widely considered as a type of regulator, associated with muscle growth and development, and play an important role in various regulatory mechanisms and interaction networks . The musogenesis ,10. Aberogenesis . TogetheIt is generally acknowledged that there are two distinctive periods in the development of skeletal muscle of pigs, the prenatal period composed of early, middle and late embryonic stages and postnatal period from neonatal to adult . Also, tAlthough, recent studies involving skeletal muscle development in pigs largely converged functional characterization and regulatory networks based on RNA-Seq or microarray data, the core questions of the relationship and biological events behind the genes or miRNAs remain to be investigated ,16. MoreIn the present study, we undertook the chip-based expression profiling for the DEGs and DEMs at four time points of skeletal muscle in pigs. The gene ontology annotation (GOA) analysis combined with interactome networks mapping was conducted on the DEGs to build the interaction networks for the four time points of skeletal muscle development in pigs. Our results disclosed that 484 DEGs and 34 DEMs constituted two linear expression patters (LEPs) responsible for the biological events in the development of skeletal muscles. Moreover, the interaction maps were created based on the DEGs and their GOA items, which revealed more detailed relationship and key nodes about the DEGs. Thus, on the basis of the interaction maps about porcine skeletal muscle, this work provided a new insight into understanding the interactions or modulation mechanisms of the development of skeletal muscle in pigs. Also, the study is likely to shed light on genes and gene networks that during 4 time points from embryo to adult can be involved to influence growth and development of porcine skeletal muscle.Myogenesis and hypertrophy are two vital topics in muscle development of pigs, which are turned on by different genes and miRNAs at different time points. Compared to the E33 time point, there were in total 484 DEGs composed of 175 up-regulated genes and 309 down-regulated genes from the E65, E90 to ADU time points . InteresThe linear expression patterns (LEPs) of DEGs was defined to indicate consensus change in the developmental procedures and showed the sustained roles of involved genes in the whole durations. Two LEP blocks at the four time points were constituted by 32 linear up-regulated DEGs  were determined by the normalized relative percentages at four time points. In total 34 DEMs were significant at different time points, which constituted three category patterns of DEMs for the developmental stages . There wet al., forming 3 GOs including striated muscle cell development, actin-myosin filament sliding and sarcomere to contribute the biological event of sarcomere microstructure assembly  was widely used to identify the genes responsible for the roles in a specific biological process, such as a disease. In order to construct the relationship of DEGs at different time points, the interactome networks were mapped according to the pathway designation  and the e points a. HoweveMRFs) was considered to regulate muscle differentiation, and also downstream effectors, the target genes, were easy to identify using microarray or sequencing technology, how to dissect the biological meaning and the relationship underneath the DEGs or DEMs is still a challenge in the data mining area [Embryonic differentiation and postnatal hypertrophy are two distinct events in skeletal muscle development in pigs, which dominates the commercial value of carcass. Although a family of proteins knows as myogenic regulatory factors  with corresponding services  followed manufacturer’s procedures. Generally, the porcine gene chip contains 23,937 probe sets that interrogate approximately 23,256 transcripts from 20,201 porcine genes. In order to detect the expression level of porcine miRNAs, a new miRNA array contained 1551 porcine miRNA probes including 988 miRNA for human, 350 for rat, 627 for mouse and 546 for pig was designed according to the conservation of miRNAs among mammalian kingdom. The detailed information of the miRNA array was as noted in a previous study . In totavs. the E33, were obtained by using standard t-test with adjusted p-value for multiple comparisons, which was controlled under 0.05 false discovery rate (FDR) using Benjamini-Hochberg method.The intensity of probes in gene chips and miRNA arrays was converted to the expression levels by using limma package in R and Bioconductor software ,27. The Pig genome Sscrofa10.2 was retrieved from Ensembl website  and the The GOA of genes was functionally annotated based on GO database using AmiGO tools. The annotation enrichment analysis, functional clustering, KEGG pathway mapping and homologue match were utilized the DAVID tools ,38. The The protein-protein interaction (PPI) network (PIN) was constructed by using CCSB interactome database, and the DEGs were homologous converted to human genes based on Ensembl BioMart homologs database before inputting to the networks. Note that the pre-defined PIN in human may lose some corresponding nodes in pigs because there is not one-to-one mapping in two species and these nodes will be removed before constructing maps. The R packages, GeneAnswers and BioNet, were used to construct the interaction maps among genes, and Cytoscape software was used to refine the maps ,40,41. TOur results demonstrated that there were in total 484 DEGs and 34 DEMs detected in the period from embryonic stage to adult in pigs, which consisted of two LEPs with consensus changes. Moreover, myogenesis events, microstructure assembly of sarcomere and myofibril formation of muscle fibers, were presented based on the GOA analysis, resulting in the interaction networks of DEGs. The interactome mapping may provide extra clues and widen our search for more candidates for further research on the relationship between DEGs and interactions, as well as shedding light on genes and gene networks involved in influencing the growth and development of porcine skeletal muscle.


Maxillary osteomyelitis is a rare condition defined as inflammation of the bone primarily caused by odontogenic bacteria, with trauma being the second leading cause. The present report documents a rare case of maxillary osteomyelitis in a 38-year-old female who was the victim of domestic violence approximately a year prior to presentation. Intraoral examination revealed a lesion appearing as exposed bony sequestrum, with significant destruction of gingiva and alveolar mucosa in the maxillary right quadrant, accompanied by significant pain, local edema, and continued purulence. Teeth numbers 11, 12, 13, 14, and 15 were mobile, not responsive to percussion, and nonvital. Treatment included antibiotic therapy for seven days followed by total enucleation of the necrotic bone tissue and extraction of the involved teeth. Microscopic findings confirmed the clinical diagnosis of chronic suppurative osteomyelitis. Six months postoperatively, the treated area presented complete healing and there was no sign of recurrence of the lesion. Maxillofacial trauma is a form of injury that can affect males and females of all ages and can result in facial bone fractures, dentoalveolar trauma, and soft tissue lesions, occurring in isolation or in association with other lesions in the body . The maiAccording to Gassner et al. , males aMaxillofacial injuries are commonly seen in victims of domestic violence , 8. A woA possible complication of maxillofacial trauma may be chronic osteomyelitis, defined as inflammation of the bone primarily caused by odontogenic bacteria; trauma is the second leading cause of chronic osteomyelitis . ChronicThe aim of this report is to present a case of chronic suppurative osteomyelitis occurring in the maxilla of a female patient as a result of maxillofacial trauma caused by domestic violence, to emphasize the lesion characteristics , the treatment rendered, and the impact on the patient's quality of life.A 38-year-old female was referred (May 2011) to the stomatology clinic with a lesion on the anterior right maxilla. Her medical history was unremarkable, she denied taking any medications, and she reported being a cigarette smoker (20-pack-year exposure). Approximately a year prior to presentation, she was victim of domestic violence. Her husband had punched her in the face. The patient did not report complaints to the police and did not seek medical attention after the incident. After a few months, she noticed the appearance of purulent exudate from the attached gingiva in the area between teeth 11 and 12. Since the original appearance of the fistula, the lesion increased in size and was accompanied by significant pain, local edema, and continued purulence.Extraoral examination revealed slight facial asymmetry, caused by elevation of the right wing of the nose and edema in the midface. The overlying skin color was normal. Head and neck lymph nodes were normal to palpation. Intraoral examination revealed a lesion appearing as exposed bony sequestrum, with significant destruction of gingiva and alveolar mucosa in the maxillary right quadrant . Edema . Based oIn addition to the lesion in the anterior maxilla, clinical and radiographic examination revealed poor dental health, with periodontal, endodontic, and restorative treatment needs.Initial treatment consisted of oral antibiotic prescription (amoxicillin 500 mg tid and metronidazole 400 mg tid) and antimicrobial mouthwash (chlorhexidine digluconate 0.12% bid) for seven days. Following this regimen, the patient reported improvement of symptoms; however, the clinical appearance of the lesion remained unchanged. Surgical enucleation of the lesion was treatment planned and requested preoperative hematological exams were all within normal ranges.The surgical intervention, performed under local anesthesia, consisted of total enucleation of the necrotic bone tissue and extraction of teeth 11, 12, 13, 14, and 15 . The palThe surgical specimen, including the extracted teeth, was submitted for routine histopathology (hematoxylin and eosin stain). Histopathologic analysis identified the presence of acellular, avascular bone tissue, with reversal lines, irregular surface, extensive marrow spaces, and Haversian canals. An amorphous material, acellular and slightly basophilic, suggesting microbial colonies, was also observed . The micAt the first postoperative visit (7 days) the surgical site exhibited partial healing and sutures were removed. The patient was subsequently referred to the integrated clinic for follow-up and for continuation of required additional dental treatment (including restorative work). At the 6-month postoperative visit the surgical site had completely healed and there was no sign of recurrence .This report presented a case of chronic suppurative osteomyelitis in the anterior maxilla associated with maxillofacial trauma resulting from domestic violence. To the best of our knowledge, this is the first reported case of maxillary osteomyelitis in a context of domestic violence.The majority of osteomyelitis cases of the jaws involve the mandible while maxillary cases are much less common, due to differences in vascularization . The posRegarding management of the reported maxillary osteomyelitis case, therapy was initiated with oral antibiotics (amoxicillin and metronidazole combination) and followed by surgical removal of the necrotic bone tissue and extraction of associated teeth; this approach achieved good results with no signs of recurrence at the 6-month follow-up. Combination of antibiotic therapy and surgical debridement is effective for the treatment of chronic suppurative osteomyelitis of the jaws , 11. AltLocal and systemic host factors are important in the pathogenesis of osteomyelitis . OsteomyA partially healed fracture and osteomyelitis of the radius in a victim of child abuse have been previously reported ; the ostInterpersonal physical violence (IPV), which encompasses domestic violence, is a major cause of craniomaxillofacial injury occurring in females aged 15–50 years, with most injuries located in the middle third of the face . Soft tiMost maxillofacial IPV injuries are caused by punching, followed by kicking and slapping . Female Maxillofacial trauma caused by domestic violence can lead to chronic osteomyelitis of the maxilla. The recognition of the injury pattern caused by interpersonal physical violence is important for the diagnosis and management of such cases.


Osteoarthritis of the thumb CMC joint is the most frequent degenerative arthritis in the upper limb. It is a very common cause of pain, loss of strength and functional impairment of the hand, reported in approximately one in three postmenopausal females. Conservative treatment  can be helpful, but fail to provide long term relief in many patients. Surgery is indicated in these cases.Many different surgical techniques have been advocated, including simple (Wilson) or double (Goubeau) osteotomy, trapeziectomy alone or combined with suspensionplasty and / or tendon interposition (LRTI: the Burton- Pellegrini technique), implant arthroplasty, and arthrodesis. Although each of these treatments have their specific limitations, most of the results published in the literature have indicated a satisfactory pain relief, and varied degrees of decrease in pinch strength and in range of motion.The suspensionplasty techniques aim at maintaining the trapezial height after trapeziectomy. They involve a ligamentoplasty utilizing part of the flexor carpi radialis or of the abductor pollicis longus. A new technique of suspensionplasty has been developed by Yao in 2010, which suspends the first metacarpal to the second by means of a strong suture material (fiberwire) introduced through both bones’ metaphyses, and tied with a suture button (Mini-TightRope).This technique is less invasive and less time consuming than the previous ligamentoplasties, because there is no need to harvest a nearby tendon. Furthermore, active motion is initiated early on after surgery. A bulky dressing is applied for ten days, then gentle auto-exercises are performed by the patient him(her)self once a day. Rehabilitation is started after one month.Results of this technique have been published at two years follow-up by Wells (25 cases), and by Yao (21 cases), showing excellent pain relief, pinch strength amounting to 80% of the contralateral side, and conservation of the range of motion. Radiological follow-up shows some degree of subsidence of the trapezial height over the first year, without any incidence on the clinical outcome.Clinical results continue to improve over the first two years.The rare specific complications reported with this technique are second metacarpal fractures, and subcutaneous prominence of the suture button on the second metacarpal shaft.


Domain-specific databases are essential resources for the biomedical community, leveraging expert knowledge to curate published literature and provide access to referenced data and knowledge. The limited scope of these databases, however, poses important challenges on their infrastructure, visibility, funding and usefulness to the broader scientific community. CollecTF is a community-oriented database documenting experimentally validated transcription factor (TF)-binding sites in the Bacteria domain. In its quest to become a community resource for the annotation of transcriptional regulatory elements in bacterial genomes, CollecTF aims to move away from the conventional data-repository paradigm of domain-specific databases. Through the adoption of well-established ontologies, identifiers and collaborations, CollecTF has progressively become also a portal for the annotation and submission of information on transcriptional regulatory elements to major biological sequence resources . This fundamental change in database conception capitalizes on the domain-specific knowledge of contributing communities to provide high-quality annotations, while leveraging the availability of stable information hubs to promote long-term access and provide high-visibility to the data. As a submission portal, CollecTF generates TF-binding site information through direct annotation of RefSeq genome records, definition of TF-based regulatory networks in UniProtKB entries and submission of functional annotations to the Gene Ontology. As a database, CollecTF provides enhanced search and browsing, targeted data exports, binding motif analysis tools and integration with motif discovery and search platforms. This innovative approach will allow CollecTF to focus its limited resources on the generation of high-quality information and the provision of specialized access to the data.Database URL:http://www.collectf.org/ Biological databases have rapidly become a cornerstone of modern biology, centralizing access to knowledge and data to facilitate and often guide experimental and computational research across all biological science disciplines. Beyond major coordinated resources hosted by federal institutions, such as the National Center for Biotechnological Information (NCBI) or the European Bioinformatics Institute (EMBL-EBI), the biological database arena is dominated by domain-specific databases . These dProposed models for database financial sustainability are difficult to adopt for databases addressing topics unattractive to private funders. They also tend to restrict data sharing and limit community participation , 11. HenHere we report on the ongoing effort to rethink CollecTF, a database on experimentally validated transcription factor (TF)-binding sites across Bacteria, envisioning its transition from data repository to submission portal. CollecTF compiles data on TF-binding sites reported in the literature, capturing both the interaction of the TF with its target sites and their downstream regulatory effects, and placing a strong emphasis on the experimental support for reported sites . Since iIn silico evidence is also compiled when providing complementary support, but TF-binding sites supported only by in silico approaches are not reported. Since its inception in 2013, CollecTF has compiled over 9750 experimentally validated TF-binding sites, mapping to >390 unique TF instances from over 240 TFs in over 100 bacterial species. This has situated CollecTF at the forefront of transcriptional regulation databases in Bacteria, rivaling the content and breadth of comparable initiatives, such as the Escherichia coli-centered RegulonDB , which egulonDB  or the pegulonDB .Validated data entry is an essential component of a domain-specific database. CollecTF was born as a community-oriented initiative that aims at combining in-house curation of published literature with direct submission by authors . To accoTF-binding sites can be submitted to CollecTF as sequences or coordinates. For submissions involving high-throughput binding assays, such as ChIP-seq, CollecTF has developed a dedicated pipeline that captures experimental details of the high-throughput methods and extracts, when available, quantitative information from enriched DNA fragments (e.g. ChIP-seq peaks), automatically mapping it to reported sites. Submitted TF-binding sites are mapped to the reference chromosomes directly through coordinates or sequence search, and the submitter is next asked to validate that identified sites in the reference chromosomes map to reported sites by means of a graphical interface displaying the sequence and genomic environment of each mapped site . In the protein_bind feature identifier. The fields under this feature detail the location of the TF-binding site, the protein accession for the TF, the experimental evidence for the annotation including PubMed identifiers for the supporting publications and a db_xref link to the original CollecTF record . The CollecTF records implemented for UniProtKB entries contain detailed information on the sites bound by the TF, including their genomic location, the experimental evidence and literature sources, the genes regulated through the binding event and links to external databases providing additional information on the binding mechanism (e.g. the Protein Data Bank), the bound sites or their regulatory role (e.g. Gene Expression Omnibus)  , 26  . The duaBy construction, the curation process in CollecTF defines relationships between a gene product (the TF), the genomic DNA it binds to and the genes upon which such binding has a transcriptional regulatory effect. These well-defined interactions can be captured by ontological statements using the GO formalism. A prerequisite for the generation of GO annotations is the use of standardized terms for the experimental evidence supporting them. To this end, CollecTF has worked in close collaboration with the ECO team to map its controlled vocabulary of experimental techniques to standardized ECO terms. This synergistic effort has been extremely productive for both initiatives, increasing the interoperability of CollecTF and leading to the creation and collaborative revision of new and existing ECO terms.Supplementary Material 2). TF-centric GO annotations are generated automatically by the CollecTF curation pipeline, using the information provided by the submitter during the curation process  to specific methods (e.g. DNAse footprinting), allowing them to generate fully customized collections of binding sites for a TF of interest .An important feature of domain-specific databases is the ability to provide customized access and services for the community they serve. CollecTF has several specialized properties that make it a particularly useful resource for the community. A key element of CollecTF is the dynamic integration of experimental evidence supporting multiple TF-binding site instances mapping to a particular genomic location . This feinterest . These dinterest , as wellA significant amount of work on transcriptional regulation mechanisms in Bacteria focuses on the analysis of TF-binding motifs and their evolution. CollecTF provides specialized tools to analyse TF-binding motifs in different contexts. Pairs of TF-binding motifs, resulting from two independent custom searches by the user, can be compared using a wide variety of methods, such as an analysis of the pair-wise site Levenshtein distance within and between motifs, the Kullback-Leibler divergence or the Pearson correlation coefficient between motifs , 31. ThiThis article reports the work made on CollecTF to facilitate its gradual transition from a conventional domain- specific biological database towards a submission portal for reference databases. This strategic move stems from two complementary facts: the availability of large centralized repositories for curated sequence information and the realization that the biggest asset of domain-specific databases originates in the combined expertise and will of the contributing community. Our experience reveals that shifting the emphasis towards the submission of information to reference repositories yields several benefits for domain-specific databases. An immediate advantage stems from the need for standardization in data identifiers required to submit to reference repositories, as well as the development and/or adoption of ontologies. Both efforts intrinsically increase the interoperability of the database and greatly enhance the ability of third parties to recover curated information in the event of database demise. Beyond these direct advantages, the development and/or adoption of ontologies also forces database developers to reassess structural and functional schemas, and provides the opportunity for productive interactions within and beyond the community.The submission of curated information to reference repositories yields further important benefits. First, and foremost, it mitigates the data tomb effect, by simultaneously promoting long-term data accessibility and making the information highly accessible to a broad range of users. The resulting increased visibility and accountability, together with the adoption of well-established standards, provide an incentive for authors to directly submit their information and for publishing houses to consider recommending or enforcing author submission . The parSupplementary Material 3). The database has established a successful training and peer-mentoring program that enables undergraduate students to participate in the curation effort. However, the sheer volume of data generated yearly on the specific subject targeted by the database makes this approach untenable as the primary mechanism for curation, motivating the work reported here. Direct author submissions require internal validation, but submitting authors have unrivaled knowledge of the data being deposited and a vested interest in its accuracy, expediting greatly the internal review process.This article reports the successful implementation of necessary structural and technical changes in CollecTF, a domain-specific database, in order to enable its gradual transition towards a portal for the submission of high-quality annotated data on bacterial transcriptional regulatory systems. Even though the introduction of these changes yields immediate benefits for domain-specific databases, such as increased interoperability and robustness through the adoption of supporting ontologies, the ultimate success of the shift towards submission portal depends on its adoption by a sizeable community of users. To date, CollecTF relies primarily on internal curations to populate its contents (A fundamental issue in the development of community-based approaches for the annotation of scientific data is the lack of clear incentives for authors to submit their results. In this setting, the structural changes undertaken in CollecTF to automate the submission of data to large reference repositories address two important elements. On the one hand, they provide a centralized and guided resource for the submission of relevant data, decreasing the apparent complexity of the data submission process as perceived by authors. On the other hand, the deposition of data linked to original publications in highly accessed repositories results in increased visibility and accountability for authors, providing a basic incentive for submission. Having established the structural mechanisms to become a community-oriented resource, CollecTF is actively working on a two-pronged outreach effort to elicit direct submissions by authors. Beyond maintaining an active presence in scientific meetings, CollecTF is developing scripts to automatically identify newly published literature sources in PubMed and request author contributions, and plans to periodically issue contribution requests to the authors of publications already present in the database. In parallel, CollecTF is actively engaging publishing companies to include submission recommendations in their author guidelines and contributing opinion pieces to relevant journals in the field. As these efforts fructify, CollecTF aims at engaging the community in the evolution of this resource, adapting the submission process and the underlying database structure to better serve the needs of authors and the community at large.Supplementary data are available at Database Online.


Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system’s (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted. Depression is a common neuropsychiatric disorder constituting one of the leading causes of disability worldwide, estimated to affect 350 million people, and projected to be the leading cause of disease burden by 2030  has been extensively studied, rates of depression have not decreased over the past decades. According to a review comparing cases of mental disorders between 2004 and 2010 in the European Union, rates in this period remained more or less stable with the increase in better detection and health care systems. However, in a previous study the prevalence of persons affected each year was estimated to be 38.2%, depression being the second most prevalent form of mental disorders  resistance, and excess of glutamate, corticotrophin-releasing hormone and cortisol levels, therefore compromising the monoaminergic and glutamatergic neurotransmission along with the hypothalamus-pituitary-adrenal (HPA) axis activity  can lead to MDD. However, this depends on the genetic susceptibility, gender, family history, and personality traits of the person affected  in the different neuropsychiatric disorders, the evidence presented so far suggests that dysfunctional glia play an active role in the abrogation of the monoaminergic and glutamatergic neurotransmission systems, contributing to cognitive deficits and behavioral changes in mood disorders.The inflammatory hypothesis of depression has gained momentum since it first appeared two decades ago, proposing MDD as a cytokine-mediated disorder  and TBX21 (T bet) that result in T-cell dysfunction, were reported to contribute to the pathology of MDD , physical inactivity, smoking habits, and vitamin D deficiency , and serotonin-norepinephrine re-uptake inhibitors are some of the most common types to be prescribed , minocycline, omega-3 fatty acids, and vitamin D, among others. Usage of selective cyclooxygenase (COX)-2 and non-selective COX inhibitors NSAIDs, namely celecoxib and aspirin, to treat MDD has yielded varied results. A recent meta-analysis of 11 studies evaluating the use of selective COX-2 or non-selective COX inhibitors, including seven randomized clinical trials (RCTs) and four cohort studies, found no overall significant changes in the response to either type of NSAIDs , a recent meta-analysis of 13 separate RCTs demonstrated no significant effect on MDD 2D3, also known as calcitriol. However, other natural sources include cod-liver oil, oily fish, butter, cream, and egg yolk  and CNS cells (e.g., neurons, astrocytes, and microglia; Di Rosa et al., Escherichia coli were also observed (Djukic et al., Despite the substantial amount of evidence linking VDR and the immune response, its role in the regulation of the inflammatory response in mood disorders remains to be elucidated. Only two studies to date have reported an association between VDR gene variant and susceptibility to develop depressive symptoms in old age (Kuningas et al., Hence, the potential role of VDR influencing the peripheral and/or CNS immune response makes it an attractive target of study in the cytokine-mediated model of MDD Figure . In addiIt is noteworthy that vitamin D and omega-3 fatty acids also take part in pathways other than the inflammatory network influencing the development of neuropsychiatric illnesses. It was proposed that deficiencies of vitamin D and omega-3 fatty acids in the brain affect serotonin-related mechanisms (Patrick and Ames, Depression constitutes a distressing health concern topic. In the last decades, the importance of treating MDD has been accentuated, attracting public interest due to its increasing worldwide prevalence, particularly in high-income countries, threatening to become the leading cause of global disability. Moreover, currently available pharmacological antidepressants do not achieve desired results, producing severe side effects with high relapse rates. Increasing evidence suggests the involvement of the immune response. Cytokine-induced sickness behavior is proposed to culminate in MDD by promoting the activation of the KYN pathway and GR resistance, hence compromising the monoaminergic and glutamatergic neurotransmission along with the HPA axis hyperactivation. Therefore, new alternative options targeting the inflammatory response in mood disorders are being tested. Vitamin D appears to be a plausible candidate although current results from RCTs do not provide sufficient evidence to encourage its supplementation in MDD. It is, however, arguable that the intervention of vitamin D-VDR in different molecular mechanisms affecting the immune system is not fully understood. Research directed towards investigating the role of VDR in regulating the periphery and CNS immune response in relation to mood disorders is suggested. Moreover, another important issue raised in this review is the active participation of glial cells in the dysregulation of relevant mechanisms in the pathology of depression. Microglia and astrocytes are important CNS-immune mediators. However, interactions between VDR and glia have hardly been studied.In view of the global importance of MDD and the gaps in knowledge that still exist concerning its pathophysiology, further pursuit of knowledge in regards to the glio-pathogenesis of the inflammatory system activation aiming to find better treatment options is highly warranted.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.


An important question to address relates to the relationship between MSCs and FLSs. MSCs and FLSs could be the same cell type with functional specialisation or represent different functional stages of the same stromal lineage. This review will discuss the roles of MSCs in RA and will address current knowledge of the relative identity between MSCs and FLSs. It will also examine the immunomodulatory properties of the MSCs and the potential to harness such properties for the treatment of RA.The advancements in our understanding of the inflammatory and immune mechanisms in rheumatoid arthritis (RA) have fuelled the development of targeted therapies that block cytokine networks and pathogenic immune cells, leading to a considerable improvement in the management of RA patients. Nonetheless, no therapy is curative and clinical remission does not necessarily correspond to non-progression of joint damage. Hence, the biomedical community has redirected scientific efforts and resources towards the investigation of other biological aspects of the disease, including the mechanisms driving tissue remodelling and repair. In this regard, stem cell research has attracted extraordinary attention, with the ultimate goal to develop interventions for the biological repair of damaged tissues in joint disorders, including RA. The recent evidence that mesenchymal stem cells (MSCs) with the ability to differentiate into cartilage are present in joint tissues raises an opportunity for therapeutic interventions via targeting intrinsic repair mechanisms. Under physiological conditions, MSCs in the joint are believed to contribute to the maintenance and repair of joint tissues. In RA, however, the repair function of MSCs appears to be repressed by the inflammatory milieu. In addition to being passive targets, MSCs could interact with the immune system and play an active role in the perpetuation of arthritis and progression of joint damage. Like MSCs, fibroblast-like synoviocytes (FLSs) are part of the stroma of the synovial membrane. During RA, FLSs undergo proliferation and contribute to the formation of the deleterious pannus, which mediates damage to articular cartilage and bone. Both FLSs and MSCs are contained within the mononuclear cell fraction  Extensive investigations of the pathogenetic mechanisms of inflammation and autoimmunity and the resulting increased understanding of cytokine networks and cellular players in rheumatoid arthritis (RA) have led to the development of agents that block tumour necrosis factor (TNF)α, interleukin (IL)-1 and IL-6 signalling, or target pathogenic cells such as B cells and osteoclasts . DespiteA hallmark of RA joint pathology is chronic inflammation of the synovium (synovitis), which causes cartilage and bone erosion via interplay between infiltrating inflammatory/immune cells and the resident fibroblast-like synoviocytes (FLSs). Once established, the erosions do not heal, posing considerable risks for joint damage progression towards secondary osteoarthritis and joint failure. The synovium is also home to mesenchymal stromal/stem cells (MSCs) -9. Thesein vitro and in vivo [in vitro with similarity to the synovial lining in vivo [in vitro, indicating that lining layer condensation is an inherent feature of FLSs that requires cadherin-11 [A key tissue in RA is the synovium, a membrane that lines the cavity of synovial joints. The synovium lubricates the joint surfaces and provides nutrients to the articular cartilage. It consists of a lining layer of macrophage-like (type A) synoviocytes and FLSs (type B synoviocytes), and a sublining of loose connective tissue containing fibroblasts interspersed between endothelium (with juxtaposed pericytes) of small blood vessels. The fibroblasts appear to be functionally distinct depending on their location. FLSs in the synovial lining share with the common fibroblasts many characteristics, including expression of type IV and V collagens, vimentin and CD90 (Thy-1). However, they have distinctive features from other fibroblasts, including the fibroblasts resident in the synovial sublining whose main function is thought to be production and remodelling of extracellular matrix . The FLS in vivo ,12. FLSs in vivo . CadheriRecent lineage tracing studies in mice have unveiled that, like articular cartilage, the synovium derives from the embryonic joint interzone ,15, a stin vitro are fibroblast-like cells capable of plastic adherence, form colonies derived from single cells (colony forming unit fibroblasts) and can differentiate into mature cells of mesenchymal lineages such as osteoblasts and chondrocytes [MSCs were originally isolated from bone marrow . In 2001drocytes -22. The drocytes . Of notedrocytes , suggestin vitro, from which they can be culture-expanded as fibroblast-like cells. Cultures of FLSs and MSCs are therefore indistinguishable, and at present no markers permit selective identification of either cell type from culture-expanded synovial stromal cell populations. It is not known, therefore, whether FLS and MSC properties reside in the same individual cell or in distinct cell types.Following enzymatic release from the synovium, MSCs and FLSs are both contained within the plastic-adherent mononuclear cell fraction in vitro culture expansion. However, the extensive culture expansion required to perform all the necessary tests to investigate the mesenchymal potency may have selected for MSC clones, while FLSs or other fibroblasts were left behind. In addition, primary fibroblasts derived from various human tissues, including skin, were reported to contain cells that were able to differentiate into osteoblasts, chondrocytes and adipocytes [To shed light on the relationship between these two cell types, we carried out studies at the single cell level. Culture-expanded synovial clonal cell populations from normal or osteoarthritic donors displayed a phenotype compatible with conventional bone marrow MSCs . Howeveripocytes .in vitro is yet to be clarified, and studies using single cell-derived clonal populations will be needed to determine whether FLS invasiveness and MSC differentiation potency are inherent in individual cells from the RA synovium.Primary cultures of plastic-adherent cells from RA synovium (commonly regarded as FLSs) have been shown to contain cells with the functional ability, typical of RA FLSs, to erode cartilage through matrix metalloproteinases ,26, as win vivo identification and location of MSCs in mouse synovium [in situ in the knee joints of mice [Recently, we reported the synovium . We deve of mice  to overc of mice , therebyIn synovium, MSCs are located mainly in two niches Figure : the linin vivo, or after isolation and culture expansion in vitro. The existence of cell plasticity and dedifferentiation has long been controversial, but the induced pluripotent cell technology [in vivo, it could allow cells to swing between the perhaps imprinted embryonic memories of MSCs and the tissue-specific, functionally specialised cells like the FLSs.Meanwhile, the relationship between the MSCs and the FLSs in the lining layer remains unclear. In our study , label-rchnology  has provOur current knowledge of the roles of MSCs in RA is limited. MSCs appear to be passive targets of the inflammatory process but they could also play an active pathogenic role. While under homeostatic conditions the synovium contributes to joint maintenance, in RA this tissue exerts a deleterious, damaging action on the joint, and the FLSs are known to be major pathogenic cell players. During RA, the synovium forms a 'pannus' that invades and erodes cartilage and bone. The pannus is a pathological outgrowth of synovial tissue sustained mainly by proliferation of FLSs, with infiltration of blood-borne inflammatory/immune cells. There is also evidence suggesting an influx of mesenchymal cells from bone marrow into synovium. In this regard, primary FLS cultures established from RA-like arthritic joints of mice carrying GFP-positive bone marrow contained over 30% of GFP-positive (bone marrow-derived) cells, significantly higher than the approximately 1% observed in FLS cultures obtained from normal joints . The molin vitro multilineage potential, was significantly lower in the synovial fluid of RA patients than osteoarthritis patients [in vitro [The erosive changes that occur in association with the inflammatory synovitis in RA indicate prevalence of cartilage/bone loss over repair. FLSs are well known to produce inflammatory cytokines and to develop an invasive phenotype with release of proteases that cause cartilage and bone destruction . At the patients . In addipatients , suggestin vitro ,38. Thusin vitro , TNFα siin vitro .in vitro to induce the immunosuppressive and anti-inflammatory functions in cultured MSCs [in vivo exert such functions remains unknown. An intriguing possibility is that arthritic FLSs could be 'diseased' MSCs with a differentiation arrested at early stages, thereby becoming pathogenic cells actively contributing to RA chronicity and progression. A major downstream target of inflammatory cytokines is the transcription factor nuclear factor-κB, and its sustained activation in FLS/MSC cultures was sufficient to inhibit osteogenic and adipogenic differentiation and at the same time to enhance proliferation, motility, and matrix-degrading activity [in vivo in mice [In addition to being 'innocent bystanders' repressed in their stem cell function by the inflammatory milieu, MSCs in the joint could be active players contributing to the pathogenesis of arthritis. Inflammatory cytokines such as interferon (IFN)-γ are required red MSCs , but wheactivity . These f in mice . Notably in mice . Thus, m in mice .Alongside their stem cell properties, culture-expanded MSCs possess immunomodulatory properties. Studies predominantly using bone marrow-derived MSCs have demonstrated that MSC-mediated immunomodulation is dependent on IFN-γ , and is The immunosuppressive and anti-inflammatory properties of cultured MSCs have led to these cells being tested for their therapeutic potential in preclinical models of RA-like inflammatory arthritis (reviewed in ). SeveraMeanwhile, clinical studies have also been carried out. Intravenous infusion of allogeneic bone marrow or umbilical cord MSCs into four patients with established RA resistant to disease-modifying antirheumatic drugs (DMARDs) and at least one anti-TNFα agent was safe and resulted in only partial and transient clinical improvement . More reIt is tempting to speculate that MSC treatment would control disease activity in RA patients not only through the immunosuppressive and anti-inflammatory functions but also through contribution to joint tissue repair, thereby preventing tissue damage, once established, from continuing to trigger inflammation. MSC therapeutic approaches to enhance joint tissue repair have been trialled in patients with joint surface defects and/or osteoarthritis with results that appear promising -61, suppin vivo functions of FLSs/MSCs in the regulation of immune homeostasis in physiology and their contribution to immune deregulation in RA. It is possible that stromal cells in the synovium, particularly FLSs and MSCs, would be involved in the modulation of immune homeostasis within the healthy joint and that failure of such immunomodulation is the basis of RA development. While FLSs can inhibit T-cell proliferation [While immune cells have been extensively investigated in the pathogenesis of RA, little is known about the feration  and the feration , similarferation . They caferation . RA FLSsferation  and induferation . These fHaving discussed the multiple facets of MSCs in RA, from their potential role in the pathogenesis of RA, including their relationship with FLSs, to the possibility of using MSCs as immunomodulators for the treatment of RA, it becomes apparent that MSCs could be good or bad depending on the context.per se (and therefore a subset of the MSC pool) or are distinct specialised cells, likely down in the MSC lineage pathway. It will be interesting to determine whether FLSs/MSCs are descendants of the embryonic joint interzone; FLSs and MSCs could have distinct ancestors. These are some of the fundamental scientific questions that we and others are trying to address.Elucidation of the relationship between MSCs and FLSs will not only be an important scientific advancement, but will also lay the foundations for devising tailored therapeutic interventions for RA aiming at stopping the FLSs (bad MSCs) while stimulating the residual good MSC activity in the joint to achieve repair of damaged tissues such as cartilage and bone and restore joint homeostasis. The combination of modern research tools and technologies with pre-clinical mouse models of RA will be pivotal in addressing whether the FLSs are MSCs in vivo between FLSs/MSCs and immune cells in health and inflammatory arthritis also warrants further investigation. In normal conditions, FLSs/MSCs would control the degree of immune responses. Instead, during RA, due to the inflammatory environmental cues and the interplay with inflammatory/immune cells, the immunomodulatory functions of FLSs/MSCs are perturbed. FLSs/MSCs then proliferate, leading to the formation of the deleterious pannus with inflammatory and aggressive functions, thereby contributing to chronic disease maintenance and progression. Aberrant crosstalk between FLSs/MSCs and immune cells could be the basis of the vicious cycle underpinning RA chronicity and progression. An increased understanding of such crosstalk will be crucial to advance our targeted therapeutic armamentarium for RA patients to stop the vicious cycle sustaining chronicity and perhaps even achieve a cure for RA.The interplay in vitro showed that the addition of TNFα, a key mediator in RA and one of the main targets of biological agents [The immunosuppressive properties of MSCs are being exploited for the treatment of RA. It will be important to identify the RA patient subset most likely to respond to MSC therapy. Considering the presumed mechanism of action of MSCs to reset the immune system, an early intervention could be desirable. If patients receiving MSC-based therapy are already on conventional therapy such as DMARDs or biologics, then it will be essential to determine how these medications will alter MSC function. Experiments l agents , reversel agents ,72. MSC-in vitro assays of immunomodulatory function predictive of in vivo clinical outcomes will allow standardisation of MSC therapy and direct comparison between clinical studies. Other challenges relate to the biodistribution of the MSCs and their long-term fate in the body, which remain to be fully determined. Genetic engineering of MSCs for targeted migration to arthritic joints could be envisaged, for example, by MSCs expressing antibodies on their cell membrane that recognise epitopes specific to the damaged articular cartilage [Systemically administered MSCs would represent a source of multipotent stem cells that could be available for the repair of damaged tissues while exerting their immunomodulation/suppression. The conflicting results in studies using MSCs emphasise the need for standardised and robust bioprocessing to obtain consistent and reliable MSC products. The development of artilage . UltimatThe success of the biologic agents targeting specific cytokines or cell types in the control of the inflammatory component of RA has made the biomedical community realise that other aspects of joint biology deserve more attention, such as the mechanisms driving tissue remodelling and repair. Established damage requires repair approaches and regenerative medicine offers potential for a lifelong solution. In orthopaedics, cell-based tissue repair has entered daily clinical practice, and there is anticipation that the development of injectable regenerative biologics will soon introduce this practice into rheumatology. Regenerative treatments will find applications for post-traumatic damaged joints, osteoarthritic and (post)-inflammatory joints and will include the repair of damaged joint surfaces or joint structures such as ligaments and menisci, or the implantation of off-the-shelf skeletal bio-structures, such as viable ligaments, menisci and other joint tissues.In conclusion, MSC-based therapies via administration of exogenous MSCs or targeting of the endogenous MSCs in the joint are strategies that are being pursued to trigger/enhance repair of the damaged joint tissues, with the ultimate aim to restore joint homeostasis. With their wide range of functions, including immunomodulatory and anti-inflammatory properties, MSCs offer ample opportunities for the development of novel treatments for RA. This is an exciting journey in rheumatology and we are just at the beginning of it.Biology and clinical applications of stem cells for autoimmune and musculoskeletal disorders, edited by Christian Jorgensen and Anthony Hollander. Other articles in this series can be found at http://www.biomedcentral.com/series/MSCThis article is part of a thematic series on


Primary sclerosing cholangitis is a cholestatic condition with unknown etiology and long-standing, progressive course, leading to cirrhosis and requiring orthotropic liver transplant. In approximately 80%, primary sclerosing cholangitis is accompanied by inflammatory bowel disease, and in most cases the recognition of bowel disease precedes the diagnosis of primary sclerosing cholangitis. We describe a case of 22-year-old male diagnosed simultaneously with primary sclerosing cholangitis and ulcerative colitis, with a medical history suggesting uncommon prior development of the liver disease. Five months after the initial diagnosis, we observed advanced lesions of bile tree due to progression of primary sclerosing cholangitis, which led to the unusually fast necessity for the orthotopic liver transplant. Primary sclerosing cholangitis (PSC) is a chronic cholestatic condition with unknown etiology. The outcome of the progressive fibrosis and destruction of bile ducts is a persistent cholestasis leading to the development of liver cirrhosis. It is estimated that, in approximately 80%, PSC is accompanied by inflammatory bowel disease (IBD), mostly ulcerative colitis (UC). However, UC may remain clinically silent; therefore, the course of PSC usually does not correlate with intestinal activity. In most cases, the recognition of IBD precedes the PSC diagnosis by several years. The natural history of PSC is long-standing and variable and frequently progressive, leading to cirrhosis, requiring orthotropic liver transplant (OLT). The most ominous adverse event of PSC is the development of cholangiocarcinoma (CC) –6.A 22-year-old male was referred to the Department of Internal Medicine due to periodic abdominal pain accompanied by loose stools and rectal bleeding lasting for a couple of weeks. General weakness, pruritus, and weight loss were also noticeable. He had no noteworthy medical or family history, including IBD and liver diseases; however, abnormal liver function tests were first noted approximately 1 year earlier. He had no history of drug abuse or significant alcohol consumption prior to admission. Physical examination showed grey-sallow colour of the skin, yellowness of the sclera, singular mutilations in the skin area of the abdominal cavity and thighs, and hepatomegaly. Laboratory tests showed anaemia as well as elevated levels of total bilirubin and hepatobiliary enzymes. Other clinical tests, including those for infectious diseases, were normal .Abdominal ultrasound examination showed hepatosplenomegaly and slight dilatations of bile ducts in the area of the left liver lobe. Enhanced computerized tomography (CT) demonstrated hepatomegaly and splenomegaly, lymphadenopathy, and changes suggesting the presence of inflammation in the area of intrahepatic bile ducts. Magnetic resonance cholangiopancreatography (MRCP) revealed the presence of irregular dilatations and constrictions of the intrahepatic bile ducts , suggesting the recognition of PSC Figures .Endoscopic examination of the large bowel showed erythema and friability of the mucosa and loss of vascular pattern in the whole colon. More intensive inflammatory changes with additional superficial erosions and ulcers were visible within the sigmoid colon (Mayo UC score: 2/3). Histology confirmed inflammatory changes of the mucosa which are characteristic for UC. The presence of the hiatus hernia and slight superficial inflammation of the antral mucosa was diagnosed during esophagogastroduodenoscopy. The patient received typical treatment with glucocorticosteroids p.o. (prednisone 30 mg/day) and mesalazine p.o. (3 g/day) and p.r. (4 g/day) with good tolerance and satisfactory clinical response.Three months later, the patient was hospitalized due to elevation of aminotransferases, total bilirubin, alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGTP). Endoscopic retrograde cholangiopancreatography (ERCP) showed significant constrictions of bile ducts , a sphincterotomy was performed, and a plastic stent was implanted in the common bile duct. During hospitalization, PSC-AIH (autoimmune hepatitis) overlap syndrome was also considered; however, on the basis of all available clinical data, its probability was estimated as very low. It is important to note that abdominal ultrasound, due to parietal solid lesion of uncertain etiology in the gallbladder, raised the suspicion of malignancy, which was subsequently excluded. However, given rapidly progressing PSC which would require transplantation in the future, the patient was transferred to the hepatology referential centre for cholecystectomy. UC was in remission and none of the intestinal symptoms were present at the time.Five months later, the patient was once more referred to the transplantology centre. The general condition of the patient was poor, and laboratory tests showed impaired liver function (with cholestasis and jaundice), additionally complicated by local symptoms suggesting bacterial inflammation. ECPW was performed, and further exacerbation of lesions characteristic for PSC combined with the inflammatory changes was seen. A common bile duct free passage was restored by the reimplantation of a new stent (the previous stent was expelled prior to admission). After completion of all the tests included in the OLT qualification protocol, the patient was enrolled on the liver recipient's waiting list.OLT was performed three months later. Histopathological examination of excised liver showed preserved architecture of the organ and severe fibrosis in the majority of the portobiliary sinuses, with bands of connective tissue penetrating into the parenchyma and separating more clearly demarcated nodules. Within the portobiliary sinuses and in some bands of connective tissue were found mainly chronic inflammatory infiltration and multifocally devastation of the wall of the bile canaliculus. Multifocally, within the walls of large interlobular and hilum bile ducts, massive inflammatory infiltrations, almost complete disappearance of the epithelium, and numerous mucosal ulceration were found. In addition, locally, in the portobiliary sinuses exacerbated growth of neocholangioli was present. Characteristic periductal fibrosis was found around the walls of some bile ducts. Hepatocytes were without significant abnormalities; in the gallbladder, chronic inflammation was found. The above result supported the diagnosis of PSC.The patient's postoperative course was complicated by bleeding from the vascular anastomosis approximately one month after OLT and provided with surgical treatment. The patient is well 15 months after transplantation.It is commonly believed that the PSC has a long-standing course; however, the dynamics of the destruction of the biliary duct system is highly variable, although usually leading to liver-related morbidity, mortality, and the need for liver transplantation , 4–7. UsClinical symptoms of PSC usually develop together with progression of the inflammation, fibrosis, and strictures of the biliary tree , 4, 6. TPatients with PSC are at increased risk for malignancy of the gallbladder; therefore, any change within the gallbladder found on imaging studies should be an indication for an urgent cholecystectomy , 17.In the presented case, 5 months after the initial diagnosis, very fast progression of bile tree destruction due to PSC was noted, with bacterial cholangitis, chronic symptoms , and lesion of uncertain etiology within the gallbladder, which raised the suspicion of malignancy. The coexistence of these factors with poor efficacy of the endoscopic treatment resulted in the unusually fast necessity for the OLT which, in fact, shortened the natural history of PSC in this patient to less than 12 months.To the best of our knowledge, this is only description of a very rapid course of PSC which finally led to the OLT. However, in the cited case the OLT was performed 3 years after the initial diagnosis, mainly due to the suspicion of CC (which was subsequently confirmed) .We describe an example of a particularly rare and fast progression of PSC, which led to the OLT in less than 12 months from establishing the initial diagnosis. Moreover, PSC was diagnosed simultaneously with UC and the patient's medical history suggested uncommon, previous to UC, development of the liver disease. This report highlights that patients with an atypical course of the PSC may benefit from early referral to the hepatology referential centre.


Properly evaluating the overall performance of tubular scraper conveyors (TSCs) can increase their overall efficiency and reduce economic investments, but such methods have rarely been studied. This study evaluated the overall performance of TSCs based on the technique for order of preference by similarity to ideal solution (TOPSIS). Three conveyors of the same type produced in the same factory were investigated. Their scraper space, material filling coefficient, and vibration coefficient of the traction components were evaluated. A mathematical model of the multiattribute decision matrix was constructed; a weighted judgment matrix was obtained using the DELPHI method. The linguistic positive-ideal solution (LPIS), the linguistic negative-ideal solution (LNIS), and the distance from each solution to the LPIS and the LNIS, that is, the approximation degrees, were calculated. The optimal solution was determined by ordering the approximation degrees for each solution. The TOPSIS-based results were compared with the measurement results provided by the manufacturer. The ordering result based on the three evaluated parameters was highly consistent with the result provided by the manufacturer. The TOPSIS-based method serves as a suitable evaluation tool for the overall performance of TSCs. It facilitates the optimal deployment of TSCs for industrial purposes. Tubular scraper conveyors are a new type of granular material conveyance equipment that utilizes flexible traction components. These conveyors have a number of advantages, including their compact construction, airtight conveyance, low energy consumption, low noise levels, good environmental performance, easy manipulation and maintenance, and long service life. In the production of nuclear fuel elements, the use of a tubular scraper conveyor eliminates the disadvantages from using either a screw conveyor or an air conveyor. A screw conveyor has a long conveying distance, a low conveying capacity, and severe machine-part wear. An air conveyor requires a substantial amount of power and multiple gas purification treatment devices. Moreover, a tubular scraper conveyor reduces radioactive environmental contamination by sealing the source materials in the equipment, thereby satisfying the requirements for technological developments in nuclear fuel element manufacturing .Tubular scraper conveyors are primarily composed of traction components, a driving device, tensioner, pipeline system, feeding gate, and a discharge gate. The traction components (a chain or a wire rope equipped with disc scrapers) move inside the sealed-in pipeline, and scrapers convey the materials forward. The scraper space, material filling coefficient, and the dynamic load of the traction components affect the scraper force on the materials, stress upon the traction components, and the overall conveying efficiency. Both inaccurately specified parameters and a design that does not address all issues increase the driving power and accident rate of tubular scraper conveyors, which affects the overall efficiency of the conveyor and increases costs , 3. TherX  to the linguistic positive-ideal solution (LPIS) and the linguistic negative-ideal solution (LNIS) for multiattribute decision analyses to determine the optimal solution . A value of yi close to 1 indicates that the evaluated target is a degree closer to the optimal level, whereas the evaluated target is a degree closer to the least optimal level when yi is close to 0. The evaluated targets were ordered according to the obtained yi values: the overall performance of the evaluated target increases as yi increases.Furthermore, the approximation degree of each evaluated target to the optimal solution (t), material filling coefficient (η), and the vibration coefficient of the traction components (k) when the overall performance reached optimal levels  was obtained using the DELPHI expert group method; the weighted judgment matrix (P) was determined to beThe information-weighted matrix   8) are sFurthermore, our results demonstrate that, among the different influential factors, the vibration of the traction components had the greatest effect on the overall performance of the tubular scraper conveyors, followed by the material filling coefficient and the scraper space.To validate the results obtained from the TOPSIS-based method, we used the measurement data supplied by the manufacturer for comparison. The results are summarized in The overall performance of tubular scraper conveyors is affected by a variety of factors. To date, a reasonable evaluation method for the overall performance of tubular scraper conveyors has not been proposed. In this study, we used the TOPSIS method to establish an ideal model for the overall performance evaluation of tubular scraper conveyors based on the scraper space, material filling coefficient, and the dynamic load of the traction components, which are the primary factors that affect the overall performance of tubular scraper conveyors. To test the validity of our results, we compared the TOPSIS-based results with those provided by the manufacturer, which indicated that the TOPSIS-based results were consistent with those provided by the manufacturer. Although previous studies on tubular scraper conveyors using dynamic analyses and three-dimensional models have optimized machine parts, these studies failed to optimize the overall performance of tubular scraper conveyors based on human factors . The appThis study has a number of limitations. Fierce market competition makes data collection a challenging task. Consequently, we only considered three major factors that affect the overall performance of tubular scraper conveyors, namely, the scraper space, material filling coefficient, and the dynamic load of the traction components. Other factors, such as characteristics of the granular materials, the interspace between the scraper and the trough, and the thickness of the scraper, also affect the overall performance of tubular scraper conveyors. Therefore, additional associated data must be collected in the future. Furthermore, the TOPSIS-based method for evaluating the overall performance of tubular scraper conveyors can be improved. A more ideal and more rational mathematical model that better reflects the weights of different influencing factors on the overall performance is still needed and will benefit the design of energy-saving and highly efficient tubular scraper conveyors.


Increasing evidence has shown that the pathophysiology of neuropsychiatric disorders, including mood disorders, is associated with abnormal function and regulation of the glutamatergic system. Consistently, preclinical studies on stress-based animal models of pathology showed that glucocorticoids and stress exert crucial effects on neuronal excitability and function, especially in cortical and limbic areas. In prefrontal and frontal cortex, acute stress was shown to induce enhancement of glutamate release/transmission dependent on activation of corticosterone receptors. Although the mechanisms whereby stress affects glutamate transmission have not yet been fully understood, it was shown that synaptic, non-genomic action of corticosterone is required to increase the readily releasable pool of glutamate vesicles, but is not sufficient to enhance transmission in prefrontal and frontal cortex. Slower, partly genomic mechanisms are probably necessary for the enhancement of glutamate transmission induced by stress. Combined evidence has suggested that the changes in glutamate release and transmission are responsible for the dendritic remodeling and morphological changes induced by stress and it has been argued that sustained alterations of glutamate transmission may play a key role in the long-term structural/functional changes associated with mood disorders in patients. Intriguingly, modifications of the glutamatergic system induced by stress in the prefrontal cortex seem to be biphasic. Indeed, while the fast response to stress suggests an enhancement in the number of excitatory synapses, synaptic transmission and working memory, long-term adaptive changes – including those consequent to chronic stress – induce opposite effects. Better knowledge of the cellular effectors involved in this biphasic effect of stress may be useful to understand the pathophysiology of stress-related disorders, and open new paths for the development of therapeutic approaches. Starting from the evidence of the antidepressant properties of drugs increasing the availability of monoamines, the pathophysiology of mood and anxiety disorders has been linked for many years to alterations in monoaminergic transmission , 2. HoweIn the present review, we focus on the functional alterations in the glutamate system and in dendritic reorganization and neuronal connectivity in the PFC , reportEvidence collected from clinical studies showed alterations in the levels of glutamate and of its metabolites in plasma, cerebrospinal fluid, and selected brain areas of patients affected by mood and anxiety disorders.In particular, increased glutamate levels were measured both in the plasma of depressed patients compared with healthy controls  and in pIn vivo proton magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate-related metabolites in the brain of depressed patients. Despite some inconsistencies, a large number of studies provided evidence for reduction in Glx levels, a composite measure of glutamate and glutamine, with a minor contribution from GABA and other metabolites, in FC and cingulate regions of depressed subjects in the midst of a current depressive episode, and in non-responders patients  in medial PFC , 65. TheThese studies strongly suggest that the structural remodeling induced by chronic stress in PFC is accompanied by dysfunctions in neurotransmission and plasticity.N-acetyl aspartate, and taurine was reported in the PFC of social defeated mice -stress to rats, and then purified synaptic terminals (synaptosomes) from PFC and FC with Percoll gradients . Basal ain vitro application of corticosterone to purified PFC and FC synaptosomes were shown to increase the RRP size of glutamate vesicles (assessed in synaptosomes superfused with hypertonic sucrose). In line with this evidence, FS-stress increased the number of synaptic vesicles docked onto presynaptic membranes of excitatory perforated synapses, measured with electron microscopy stereology in medial PFC (in vitro of corticosterone to synaptosomes for up to 10 min rapidly increased trafficking of FM1-43 labeled synaptic vesicles toward the presynaptic membrane. The increase of vesicle mobilization and RRP induced by both acute stress and in vitro corticosterone application was demonstrated to be dependent on the activation of synaptic corticosterone receptors and downstream increase of site 1 (Ser9) synapsin I phosphorylation in presynaptic membranes  enhancement of trafficking of glutamate synaptic vesicles into the so-called readily releasable pool (RRP), through the activation of synaptic glucocorticoid/mineralocorticoid receptors . Indeed,dial PFC , 84. Simembranes . Indeed,However, while corticosterone rapidly primes synapses for enhanced release, it does not likewise rapidly enhance glutamate release and transmission. Indeed, acute application of corticosterone failed to reproduce the stress-induced increase of depolarization-evoked release of glutamate in purified PFC and FC synaptosomes, and to induce any change in intracellular EPSCs amplitude or paired-pulse ratio in acute medial PFC slices , 85, sugin vitro treatment of both PFC neuronal cultures and acute PFC slices was shown to induce synaptic potentiation at least 1 h and up to 24 h after corticosterone application , less is known about the effects of acute stress on PFC synaptic plasticity and memory. Neurons in cortical and limbic areas are highly plastic and undergo rapid activity-dependent morphological transformations, including modulation of neuronal excitability and connectivity , 91. Howex novo in PFC, as early as 40 min after a severe stressful event, confirming the remarkable dynamics of synapse structure in response to stressful events in this brain area.In a recent study, we have shown that both acute FS-stress and restraint stress induce marked effects on synaptic plasticity, increasing the total number of asymmetric  non-perforated synapses in pyramidal neurons of prelimbic PFC layers II/III . FS-streIn line with these data, the plasticity enhancing effect induced by acute forced swim stress and elevated-platform stress in PFC glutamate transmission was associated with enhanced working memory in the T-maze delayed alternation task when examined 4 h or 1 day after stress, but not 2 days after stress . The enhFinally, in a separate study, acute forced swim stress was found to induce a significant retraction of apical  branches, measured 3 days after stress . HoweverCompelling evidence strongly suggests that long-term changes in brain areas and circuits, mediating complex cognitive and emotional behaviors, represent the biological underpinnings of mood and anxiety disorders. Stressful life events deeply affect brain function and, especially when stress exposure is intense, chronic, uncontrollable, or overwhelming, it represents a major risk factor for many diseases, including neuropsychiatric disorders.The stress response is a complex physiological process involving hormonal, neurochemical, and metabolic mechanisms. Indeed, although PFC was consistently reported to be a brain area particularly sensitive to stress, it is important to notice that stress induces changes in connectivity and plasticity, not only within PFC but also in other areas, such as hippocampus and amygdala, and between different areas . IntrigAs shown above, although the evidence is far from conclusive, the acute and delayed  outcome on structural and functional features of the glutamate system could be different and often opposite, at least in the PFC. On one side, stressful events rapidly enhance glutamate release and excitatory transmission and may facilitate plasticity and PFC-dependent behavior, while chronic stress and long-term effects of some acute stressors induce a reduction of excitatory transmission, atrophy/remodeling of dendrites and loss of synapses, accompanied by behavioral impairment. Therefore, the structural and functional changes in excitatory circuitry may follow a biphasic process, during which, at some unknown points, the stress response turns from increased excitatory activation into its opposite [Figure Understanding what regulates the turning point between a physiological adaptive stress response and the beginning of maladaptive remodeling will be crucial in the study of pathophysiology of neuropsychiatric stress-related disorders. In this context, considering that a high majority of individuals, although exposed to traumatic experiences during lifespan, do not develop stress-related neuropsychiatric disorders, a better knowledge of the molecular/cellular effectors regulating the individual susceptibility to stress could be of great help to mitigate the detrimental effects of external threats and/or to increase the resilience of individuals to stressful events .All authors contributed to the design and content of the manuscript as well as the first draft of the manuscript and all subsequent revisions. All authors have approved the final version of the manuscript.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 last decade, various clinical trials proved the capability of visual prostheses, in particular retinal implants, to restore a useful form of vision. These encouraging results promoted the emerging of several strategies for neuronal stimulation aiming at the restoration of sight. Besides the traditional approach based on electrical stimulation through metal electrodes in the different areas of the visual path , novel concepts for neuronal stimulation have been mostly exploited as building blocks of the next generation of retinal implants. This review is focused on critically discussing recent major advancements in the field of retinal stimulation with particular attention to the findings in the application of novel concepts and materials. Last, the major challenges in the field and their clinical implications will be outlined. Retinitis pigmentosa  is altered or sustains damage. In the recent years, a great attention has been dedicated to inherited retinal dystrophies, one of the major causes of adult blindness in industrialized countries, causing the malformation or progressive degeneration, and death of retinal photoreceptors  or micro-electrode arrays (MEAs). MEA-based devices consist of an implanted electrode array physically connected to a multichannel stimulator. Images are collected by a digital camera and processed by an image-processing unit, which in turn develops and generates a specific stimulation pattern wirelessly transmitted to the implanted chip. Recently, these retinal implants have been developed mainly by three research consortium: Boston Retinal Implant Project , Second Sight® Medical Products Inc. , and Pixium Visium SA . The first targets the subretinal implant location, while the latter two target an epiretinal implant location. On the contrary, MPDAs have been exploited mainly by two consortiums: Optobionics  and Retina Implant AG . In this configuration, the light impinging the retina is converted by the photodiodes in electrical stimuli delivered to the inner retina through metal electrodes. In general, they are designed to be positioned in the sub-retinal space, thus providing functional replacement of photoreceptors, representing the earliest possible level, thus reducing the level of signal processing needed. On the same framework, the unit of Grabiel A. Silva is developing a new photo-detector technology approaching the natural photoreceptors with nanoscale control of topography  and 18 months (3 patients)  has been recently introduced has alternative to optogenetic methods for light-tissue interaction . In general, the pure biocompatibility of implants described so fare are good. However, in addition to biocompatibility issues related to the use of foreign materials in the host eye, toxic effects at the pixel level must be considered. In fact, cellular-electrode interface is an argument of intense research in the recent years, in terms of chemical composition, physical, and mechanical properties, long-term stability, and charge transfer from the electrode to the target tissue. Material selection plays a critical role. As an example, carbon-based materials  have now been explored as the working element in a vast array of bionic devices, thus becoming a valuable solution for the next generation of implants . Other prostheses typically are in the range of 1-3 mm. Investigation on normal individuals under pixelated vision condition indicated that 30° of visual field could provide adequate mobility skills (Cha et al., Complementary to the enlargement of the visual field, the design of retinal prosthesis with high pixel density matches the need of restoring a useful visual acuity in the blind patient. However, increasing coverage together with pixel density leads to the increase of the number of pixels, possibly introducing significant technological problems (Palanker et al., Retinal stimulation represents a real solution for restoring vision in blind people. The clinical trials with conventional retinal prostheses already demonstrated that tangible results can be obtained in everyday life. However, the goal of “restoring vision” is still unreached. The challenges behind making retinal stimulation a valuable solution for blindness must be faced by an interdisciplinary activity including experts in material science, micro-fabrication, neuroscientists, and clinicians.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.