*2.4. Enzyme Inhibitory Effects*

Low levels of the neurotransmitter acetylcholine, oxidative stress, and inflammation in the central nervous system (CNS) are hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease. To date, patients diagnosed with AD are only offered enzyme inhibitors (acetylcholinesterase/butyrylcholinesterase, or AChE/BChE) for treatment [40]. Hence, as mechanism of pharmacological action, these cholinesterase inhibitors are able to modify cholinergic signalling by disrupting the degradation of acetylcholine [41].

All extracts, except NADES-B and NADES-C extracts, possessed anti-AChE activity (7.32–15.16 mg GALAE/g). Interestingly, the highest anti-AChE activity was revealed for NADES-A. It is particularly important observation, as components of NADES-A choline chloride and urea—are nontoxic; thus, such obtained extracts could be further used without removal of NADES. On the other hand, only the extracts prepared in the traditional way, with solvents hexane, ethyl acetate, dichloromethane, ethanol, and ethanol/water, displayed anti-BChE potential (1.39–2.13 mg GALAE/g). The water extract and the NADES extracts showed no anti-BChE activity. It follows from the ionic nature of the used NADESs, which in this case was not favourable for extraction. The ethanol extract demonstrated relatively higher BChE inhibitory effect compared to the other extracts (Figure 3).

**Figure 3.** Cholinesterase inhibitory effects (**A**), amylase and glucosidase inhibitory effects (**B**), tyrosinase inhibitory effects (**C**), Pearson's correlations between total bioactive compounds and enzyme inhibitory assays (*p* < 0.05) (**D**). na: not active. Different letters in column for same assays indicate significant differences in the extracts (*p* < 0.05).

Tyrosinase is the rate-limiting enzyme in melanin synthesis. Melanin is synthesised in human melanocytes when tyrosine is hydroxylated to l-DOPA, which is then oxidised to dopaquinone and polymerises to form melanin. Melasma, melanoma, and freckles are just some of the dermatological conditions that can develop when melanin production increases too rapidly. However, tyrosinase in plant-based foods oxidises phenolic compounds into quinones. The former reacts with amino acids and proteins to produce brown/black pigments, a process known as enzymatic browning, which is one of the most pressing problems in the food industry and the source of 50 percent of the industry's economic losses. In addition, browning reduces the food's nutritional value and safety because it leads to the loss of vitamin C, antioxidants, and other nutrients, and can even lead to the production of antinutritional and toxic substances. Consequently, tyrosinase inhibition is seen as an efficient method for preventing hyperpigmentation in the pharmaceutical industry and delaying enzymatic browning, which is helpful in the food industry [42].

In the current investigation, all the studied extracts were found to possess antityrosinase activity (49.14–153.97 mg KAE/g). However, NADES-A exhibited the highest inhibitory activity against tyrosinase, while the hexane extract displayed the lowest (Figure 3). On this basis, it is clear that polar NADES-A, as well as other polar solvents, should be preferred for the extraction of bioactive compounds responsible for tyrosinase activity.

Interestingly, in the study by Zucca et al. [2], the ethanolic extract of *C. hypocistis* showed the highest tyrosinase inhibition activity, compared to cyclohexane and water extracts, probably due to being predominantly rich in polyphenols, in most part hydrolysable tannins. *C. hypocistis* aerial part extract was also reported to show tyrosinase inhibition of 80%, when tested at 50 μg/mL [43]. Furthermore, a linear correlation was obtained between enzymatic activities and increasing TPC and TFC. The reason could be a specific class of polyphenols acting against tyrosinase through a competitive inhibition mechanism, thus interfering with the biological function of tyrosinase, which is a polyphenoloxidase [43].

The inhibition of the carbohydrate-digesting enzymes alpha-glucosidase and alphaamylase is an important strategy for controlling blood glucose levels in patients with Type 2 diabetes and borderline diabetes, because it significantly reduces the postprandial rise in blood glucose [44]. Even though drugs such as voglibose, acarbose, and miglitol are commercially available as those enzymes' inhibitors and are also used in practice, they produce undesirous effects such as abdominal discomfort, bloating, and diarrhoea.

In addition, many chronic diseases such as diabetes are associated with oxidative stress, during which reactive oxygen species (O2 −, H2O2 and OH−) are generated. The role of free radicals in the onset and development of diabetes has also been established. Therefore, compounds that possess both antidiabetic and antioxidant properties without causing serious side effects would be of great value [45].

In the present investigation, all extracts were found to inhibit both carbohydrate-hydrolysing enzymes (Amylase: 0.35–2.54 mmol ACAE/g; glucosidase: 0.93–2.20 mmol ACAE/g). Remarkably, the NADES extracts were found to be better inhibitors of amylase and glucosidase compared the other extracts (Figure 3). This could be due to the higher TPC in the NADES extracts, and this fact was also confirmed by Pearson's correlation analysis (Figure 3). In fact, it has been previously suggested that phenolics are involved in the modulation of the activity of starch digestive enzymes [46].

#### *2.5. Data Mining*

To gain more insight into the tested extracts and biological activity assays, we performed PCA analysis. The results are given in Figure 4. Firstly, we examined the relationship between the tested extracts based on the biological activity results. We obtained a good distribution, and the tested extracts were very well-separated based on the biological activity results. Two components (PC1: 47.3% and PC2: 33.8) accounted for 811% of the total components. Two extracts (hexane and dichloromethane) exhibited the lowest biological abilities and were distributed in the same axis. In addition, polar extracts (ethanol, ethanol/water, water) and NADES-A had similar biological abilities and were placed in the

same group. The PCA plot also confirmed a strong correlation between total flavonoid and antioxidant properties, which were very close to each other on the PCA plot. In addition to biological activity results, we investigated the similarities/differences of the tested extracts based on their chemical profiles. Two components were used in the analysis to determine the distribution of the tested solvents (PC1: 60.1% and PC2: 18.8%). In Figure 4b, the used nonpolar and polar solvents and NADESs were clearly separated, and these results were very similar to the distribution from the biological activity results. Taken together, we concluded that there is a good connection between chemical compounds and biological activities of *Cytinus* extracts.

**Figure 4.** Principal component analysis between tested extracts and biological activities (**a**). Distribution of the tested extracts in principal component analysis by using chemical compound peak areas (**b**).


3.4.3. Design Storms

Climatic variables' projections unto 2100 are forecasting within project RESCCUE. This study embraces these rainfall projections to create design storms (using alternating blocks method, according to recommendations produced near the study area [64]). After running the hydrodynamic model for the future expected conditions, including climate change influence, hence obtaining the pluvial floods to assess expected future impacts.

Extreme events analysis is considering return periods of one, five, 10, and 20 years as possible adaptation frameworks. The same rain intensity is distributed over the whole area for these synthetic events, with the rain gauges used for rainfall data acquisition process, and the cumulative rainfall (mm) for an event. These synthetic rains are conceived with a five-minute temporal resolution to reach a high-level accuracy, duration up to 2 h 30 min, and a maximum rainfall intensity as Figure 12 illustrates for each one of the return periods.

**Figure 12.** Synthetic rainfall events characteristics. Five-minute rainfall intensity hyetographs for events under current rainfall conditions: (**a**) A 1-in-1 year event; (**b**) a 1-in-5 year event; (**c**) a 1-in-10 year event; (**d**) a 1-in-20 year event. Five-minute rainfall intensity hyetographs for events under future rainfall conditions: (**e**) A 1-in-1 year event; (**f**) a 1-in-5 year event; (**g**) a 1-in-10 year event; (**h**) a 1-in-20 year event.

### **4. Results**

Section four highlights the research findings, focusing on the three key themes: The calibration and validation results obtained through hydrodynamic modelling of two historical flood events, from which there are real data to carry out the required corroboration; and the outcomes of the simulations under current and future rainfall conditions. This section outlines the modelling process results achieved via the application of the proposed methodology, their interpretation as well as the conclusions that can be drawn for three points: The calibration and validation phase. Besides, it shows the hydraulic modelling outputs from the application of the synthetic rainfall conditions driven by the impact of climate change into the drainage model.

With the results of the projected water depth for the conditions of the historical event used for the calibration of the model and the projected water depth for future flooding events, one of the two fundamental criteria is obtained. Along with the ridership flow to obtain the hazard and vulnerability assessment, the flood risk assessment results for Line 3 Metro stations are obtained, following the methodology introduced in Section 3.

### *4.1. Calibration and Validation Processes*

The first set of analyses examined the real events' pluvial flooding impact; one of them (2018-09-06) caused both surface flooding, along with two stations flooding on Metro Line 3, as indicated in Figure 13. The other flood event (2018-08-07) was merely superficial, comparable to the first event, but it did not generate flooding on Metro stations.

**Figure 13.** Calibration process summary output, for flooding event 2018-09-06: (**a**) Water depth modelling outcome in access 323\_1 that serves the Paral·lel Metro station; (**b**) photograph of the flood event in the Metro access surroundings, corroborating the water depth obtained in the modelling; (**c**) water depth modelling outcome in Paral·lel Metro station tunnel; (**d**) photograph of the flood event in the Paral·lel Metro tunnel, corroborating the water depth obtained in the modelling.

This real-life hydraulic behavior replication in the hydrodynamic modelling output is successful in obtaining similar water depths at the surface level, through the calibration process applying this model for the Barcelona master drainage plan and the executed process for this study. Moreover, for the first event, the model identified water entries to Line 3 surrounding Paral·lel and Drassanes Metro stations areas, including water in their tunnels, as can be seen from the table (below). Then, water depth results in the 2D hydraulic element surrounding the ventilation grates and Metro stations' accesses are summarized, in addition to the water level in the cited Metro stations, are consistent with the flood event records.


**4. Policy application of sense of place**

Application of sense of place to policy questions is relatively new and there have been mixed findings about its utility for informing environmental management [2]. This may have resulted from sense of place studies not being conducted using consistent metrics or methods and the findings have also not always been consistent across places and studies. Researchers are increasingly applying similar quantitative scale questions, most particularly the scales developed by Jorgensen and Stedman [26] and Williams and Vaske [23]. Qualitative investigations of sense of place follow consistent themes investigating place attachment, dependence, identity, and meanings; however, because of the inherent nature of place-based work, these quantitative and qualitative questions often need to be tweaked to be site- or useappropriate. This can make broader interpretation and application of the findings more difficult.

One example is the connection between recreationists and sense of place. A number of studies have found positive relationships between recreation and sense of place values. In several recreation studies (e.g. [25, 33–35]), recreationists did not have particularly high attachment to a place. Further, research that applies mixed qualitative and quantitative methods may help to tease out the reasons for these differences. A high sense of place also does not necessarily translate to actions. Rudestam [36] found a strong sense of place for waters in the Willamette River Basin among water users in their professional capacity (agriculture-related, fisheries-related, recreational outfitters), as well as those involved in agencies and watershed councils. However, that attachment did not motivate intentions for personal sacrifices. For example, interview participants still talked about clearcutting their lands for high timber prices or anglers being unhappy with management actions that would limit their catch. These results point to the importance of using sense of place values along with other social measures, as well as biophysical measures. Although social attitudes and values are complex and subjective, a better understanding of these attitudes and values, including sense of place, could enable better connections between communities and management and conservation of resources.

*Water Quality - Science, Assessments and Policy*

for attributes of a place.

studies of various types of recreation areas and was found to increase with perceived familiarity with a park [23], and with length of residence and education [24]. Several studies have investigated hypotheses that sense of place (e.g., often place dependence, specifically) is different for various types of users but have not always found consistent differences [2]. For example, Bricker and Kerstetter [25] found that, for whitewater recreationists, how particularly specialized recreational users were described in terms of equipment, skills, and activity frequency did not affect place dependence, although it did influence place identity. When applying sense of place metrics to water quality assessments, degree of specialization is important because the acceptable type of recreation may vary considerably for different water quality conditions. For example, someone may still be willing to go for a walk on a beach that is closed to swimming because of bacterial contamination but would not be willing to go diving or swimming. Specialization also matters when connecting the social value of a place to economic values, as people tend to have different values depending on the type of recreational use, and users' individual attributes (e.g., more or less avid, residents or visitors) affect their values

*Place identity* can be described as the emotional counterpart to place dependence. Instead of measuring the dependence on a place for its resources to support an activity or livelihood, place identity captures the dependence on the place for constructing one's self-identity [2, 16]. The specific place builds symbolic importance for an individual's emotions and self-identification [26]. For example, people with high place identity for water areas might express sentiments like "I'm an ocean person," or "Water is a part of who I am." Higher place identity has been identified in those who are more familiar with a recreational site [23]; in those who have a higher degree of recreational specialization [25]; or in those who live in rural areas,

The most studied of the main sub-components of sense of place is *place attachment*. In part this is because, out of the components, it has the broadest breadth of meanings [2, 27]. In some fields and research efforts, place attachment and sense of place are virtually synonymous [23]. In other applications, particularly in recreation-based work, place attachment is a subcomponent of sense of place that captures the emotional bond with a place or how important a place is to someone beyond the resource or identity dependences. Place attachment is rooted in Tuan's [28] seminal work on topophilia which focuses on the connection of an individual

Past studies have shown that local environmental perceptions, as well as the number of local social relationships, increase place attachment [8]. Someone with high attachment may have a lot of fond memories of visiting a place or consider themselves bonded with a location. There is a range of findings associated with place attachment to natural areas. Some researchers have found that place attachment to lands or sites is higher for locals (e.g., [1]). Others (e.g., [29]) have found

A number of researchers (e.g., [5, 15, 20, 30]) have argued the importance of in sense of place is not just the strength of these three sub-components, but also the overall meanings an individual ascribes to a location. These place meanings are often captured through complementary quantitative/qualitative studies or standalone qualitative investigations into people's values, significance, and descriptions of the place [30]. A place may hold diverse meanings for different individuals, such as a recreationist at a site versus an adjacent property owner. For example, in the Midwest, Mullendore et al. [31] argue that farmers' sense of place values have not been captured in most sense of place studies. They explain that most sense of place studies have targeted recreational use in parks, wilderness, or other natural areas

that place attachment is higher for more repetitive users of the area.

have a longer time of residence, and own their homes [24].

**24**

to a place.

Applications of sense of place findings are primarily at a localized level but provide insights about the relative social value of different places. To increase the application of sense of place in environmental management, social data will need to be collected on a broader scale with more consistent means of data collection such as the use of standardized sense of place scales for use across locations. One promising advancement has been an increase in applying spatial techniques in place-based research (e.g., [37–39]). These techniques connect survey or interview data to places and landscapes which allows for the incorporation of spatially defined ecological data to analyze relationships with sense of place.

Beckley [4] calls for research that identifies the environmental attributes for which people develop place attachment; however, a big limitation in the use of sense of place, or many other place-based social indicators, for water quality assessment is the lack of localized biophysical water quality data. Place-based values are site specific and are not always generalizable past that location as testing and monitoring methods are not always consistent. Without corresponding localized water quality data—either perceptions or biophysical measurements—we may be able to capture the social value for that place as a whole but not for its environmental attributes. In the case of water quality valuation, this means that we are limited in our ability to explain changes in the social value for sense of place resulting from changes in water quality due to gaps in our biophysical monitoring and understanding.


However, several challenges for effective collaboration exist with respect to trust, independence, attribution, and intellectual property (Bos et al., 2007; Clark and Kinoshita, 2007). Scientists may prefer to work independently and may be restricted by the boundaries of institutions to freely exchange ideas. Moreover, there is the added complexity of communications across disciplines. Alzforum (http://www*.*alzforum*.*org) (Kinoshita and Clark, 2007)—a community of Alzheimer's disease researchers was successfully able to overcome these challenges with a combination of high quality articles, neutrality, inclusiveness and editorial solicitation/moderation to gain trust and participation (Clark and Kinoshita, 2007). The Schizophrenia Research Forum (SRF) (http://www*.*schizophreniaforum*.*org/) was modeled after Alzforum to focus on schizophrenia research. SRF was built using the same software code as the original Alzforum site, and thus has an identical look, feel, and functionality to the previous version of Alzforum, before its 2013 re-launch. However, tools to rapidly create and customize such communities were not readily available and therefore the software cost to launch one such community could not be effectively amortized across others using a common software model.

To address this need, we decided to create a reusable platform to build biomedical web communities. We developed the Science Collaboration Framework (SCF) to provide the building blocks for these communities. An earlier version of the platform was developed primarily to publish scholarly articles in biomedicine that can be indexed by the National Library of Medicine (NLM) PubMed library (Das et al., 2009). Our newer version has been re-engineered to add social media and community features similar to those available in Alzforum. We also incorporated elements of Semantic Web technologies (Berners-Lee et al., 2001) to facilitate interoperability and interdisciplinary communications. Semantic Web is a technology developed by the World Wide Web Consortium (W3C), which aims to promote interoperability of Web content and creation of a "Web of Data" through the use of machine-readable Web pages. It relies heavily upon the used of agreed common vocabularies to describe objects and relationships in the Web. Biomedical science has developed a very rich set of such vocabularies or "ontologies" (over 300 vocabularies with over 5 million terms registered in the National Center for Biomedical Ontology at Stanford University Medical School). Use of ontologies such as these permits, among other benefits, resolution of the many synonym terms in biomedicine, to single common identifiers. Enabling Semantic Web technologies on our framework is meant as a step toward better integration with biomedical vocabularies and databases.

We chose the research area of chronic pain as the first use case. Chronic pain significantly impacts quality of life and is a substantial, growing, and unmet medical need worldwide. Although researchers have made great strides in understanding the underlying mechanisms and neurobiology of pain, few of these discoveries have been translated into new treatments. According to a recent report from the US Institutes of Medicine, chronic pain affects an estimated 100 million people in the US, and costs \$600 billion annually in health care and lost productivity (National Research Council, 2011); the world-wide toll is unknown. For the most part, chronic pain conditions lack medications that are effective and well tolerated. One of the roadblocks to new treatments is a lack of communication and collaboration between basic, translational, and clinical researchers in the diverse scientific fields and clinical specialties that make up the pain research community. Thus, we developed an online open community, Pain Research Forum (PRF, http://painresearchforum*.*org), for pain researchers to freely exchange ideas and collectively elevate discussion of the causes of chronic pain and how that knowledge can be translated into new treatments and better care.

#### **MATERIALS AND METHODS**

We have developed a reusable platform—SCF—to build science communities in focused biomedical areas. Previous versions of the platform included tools to publish scientific review articles following the NLM Document Type Definition (DTD), which can be indexed in PubMed (Das et al., 2009). The new release, used for PRF, includes a large number of additional community features, including means to publish news articles, forums, member profiles and various community and research resources. These features are described in the following sections.

#### **ARCHITECTURE**

The SCF is developed on an open-source content management system, Drupal 7 1 . Drupal is based on the PHP programming language and MySQL database running in the Linux/Apache web server environment. We chose Drupal because it is easily extensible and there are 30,000 registered Drupal developers continually contributing modules and enhancements to the core features 2 . We developed several custom content types and packaged them as features that can be installed and reused on any science community site. The graphic design (colors, fonts, etc.) is customized for each site using a theme layer (Kumar, 2012). The key content types available in the SCF are described in the next sections. The software is freely available upon request and a complete manual for editors to manage the site is under development.

#### **NEWS ARTICLES AND FORUMS**

The number of papers published in scientific journals continues to grow at a double-exponential rate (Hunter and Cohen, 2006) and it is becoming increasingly difficult for researchers to keep up with the literature. One way to address this problem is to publish news articles that summarize the research and provide context. We have developed a news feature that allows editors of the site to readily publish original news articles on emerging research. The News article has the following main fields: title, subhead, author, and body. The body text is composed in a WYSIWYG editor that allows flexible styling and the ability to add images. News items have references that are implemented as links to bibliographic listings of papers (described in section Papers of the Week). We wanted an easy method for researchers to find relevant news from a certain field, thus news items are categorized with terms from a pre-defined taxonomy. News articles can also be related to other news stories or papers, which appear in a block to the right of the article.

Discussion forums are important social media tools that enable interactions among researchers. Forums have fields similar to those of News. Forums can be Discussions of open research questions, structured Webinars or Journal Clubs. Videos and images can be embedded in Discussion, Webinars, or Journal Clubs. Site editors can specify related items for any Discussion, Webinar, or Journal Club.

Each News article and Forum can be commented on, bookmarked, watched, recommended or shared using social media tools.

#### **PAPERS OF THE WEEK**

Hundreds of papers are published weekly in PubMed for a given biomedical domain such as pain, and editor-curated weekly digests can help researchers stay abreast of the growing literature.

1http://www*.*drupal*.*org

2http://en*.*wikipedia*.*org/wiki/Drupal

Thus, we decided to create a module for curating and annotating papers downloaded from the NLM PubMed library. We use the previously developed PubMed module to import biomedical articles from PubMed using its Application Programming Interface (API) (Sayers, 2008). The Drupal biblio module3 is used to represent papers. We further developed the Journal Stream module that runs nightly queries using the software utility cron and imports the results in batches of 100 items. Complete documentation including a screencast and software for the Journal Stream module is available4 .

Each imported item is presented to the editors in a moderation queue and can then be "accepted" or "rejected." A screen shot of the moderation queue is shown in **Figure 1**. The abstract of each paper is displayed so that editors can determine whether the paper should be accepted or rejected. Key papers can be selected as Editors' Picks, and editors can choose to highlight the paper with a few sentences. The accepted papers are published as weekly collections; the periodicity of posting the collections can be configured per site. Once the collection is published, each

3https://drupal*.*org/project/biblio

paper can be individually commented on, bookmarked, watched, recommended or shared using social media tools. Users may download paper citations into the EndNote reference management software using the Endnote XML format. Currently, only EndNote is available to PRF users, but the Drupal biblio module allows site administrators to enable the BibTeX format if desired, for import into various other reference management tools such as Mendeley, Reference Manager, or Papers.

The citation and Medline Subject Headings (MeSH) terms associated with each paper are automatically updated periodically, as new information is posted in PubMed.

#### **MEMBERS AND REGISTRATION**

Members are the most important component of an online scientific community. We developed tools for members to join the site and publish their profile. While much of the content on the site is freely accessible without registration, only members can post comments on the site and have access to other members' profiles. The registration process starts with the members signing up online using a form. Research credentials including affiliation, position and research interest fields are required. The full name, email, city, and country are also required. Members agree to terms and conditions of membership on the site. The editor is

4http://scf*.*github*.*io/journalstream/

notified when a member signs up and once the registration has been reviewed and approved, the new member receives an email informing them of the approval. Email authentication is required for membership activation and reminder emails are sent if members have not responded to the authentication request by 1 week after approval.

Members can publish detailed research profiles on the site, upload their biography, and have the opportunity to import a list of publications directly from PubMed. A member's contributions to the site are also listed on his or her profile page. Members can choose to allow other members to contact them via email functionality provided on the member profile page. Finally, members can subscribe to receive email alerts on new content by type (News, Webinars, Jobs, etc.).

#### **COMMUNITY AND RESEARCH RESOURCES**

We provide a variety of structured resources for members: Meetings and Events, Jobs, Funding Opportunities and Bulletin Board. Meetings and Events allows researchers to quickly find upcoming meetings of interest. These are listed automatically in reverse chronological order. Meetings can be linked to PRF Blogs and News stories on the event, allowing researchers to "catch-up" if they missed the actual event. Jobs provide networking between hiring institutions and applicants; Funding Opportunities highlights grants in the field and Bulletin Board is for posting *ad hoc* announcements. Together, these community resources provide content tailored to the professional needs of researchers in the pain field. All community resource items have social media tools and can be individually commented on, bookmarked, shared or recommended.

We also provide a variety of tools for creating and publishing research resources. Some are simply pages of information or collections of links to other useful resources. We also developed a structured database for genes associated with a disease or biological condition such as pain. Fields include data to fully describe the gene and details of data on variants associated with pain, with literature references. For studies using research models, the type of model is described, thus presenting a detailed overview of the research done to associate the gene with the disease. In the future, we would also like to create other resources, such as a drugs database that would serve as a central repository for information on new drugs in development and associated clinical trials.

#### **SOCIAL MEDIA TOOLS**

Social media tools are important for online collaboration. We developed or customized a large number of social media tools and incorporated them in our framework. Members can comment on or invite others to comment, share, bookmark, and recommend most content throughout the site. All content on PRF can be emailed and shared on all the popular social network tools (Facebook, Twitter, etc.) by using standard "email" and "share" modules present on every page. RSS news and Twitter feeds are available as well as an email newsletter.

To accommodate the needs of our scientific community, we made a large number of enhancements to the comment feature in Drupal. Scientific commentaries often have attachments or figures, so we developed capabilities for attaching images or documents. The comments can be formatted with a WYSIWYG editor and can be associated with more than one content item if applicable.

#### **WEB SITE USE AND TRACKING**

Websites are tracked using Google Analytics 5 , which provides extensive data on how users interact with the site. We analyze data on number of visits, unique visitors, total pageviews, and views of individual pages. We also look at selected demographic data (country and city of origin), system information, and source of traffic to the site.

#### **SEARCH AND SEMANTIC WEB**

Search is implemented using the open-source enterprise Apache Lucene Solr 6 search platform. We also implemented sectionspecific searches. Search results can be sorted by date, relevance, number of comments or the date of the last comment. The number of search results per page can be configured by the user. Search results can be filtered using facets. The content type, date, categories etc. are presented as facets.

Semantic Web technologies enable publication of structured documents that can be processed by machines, thus allowing interoperability with the Web of Data (Berners-Lee et al., 2001). We use the Drupal Resource Description Framework Modules (RDF) modules (Corlosquet et al., 2009) to publish RDF of News and Forums. The RDF is indexed and stored in a SPARQL endpoint using the PHP ARC2 libraries 7 . The Dublin Core (Weibel et al., 1998) and Semantically-Interlinked Online Communities (SIOC) (Breslin et al., 2006) ontologies are used to express the RDF. SPARQL queries enable us to perform flexible queries and integrate with other knowledge repositories. Thus, incorporation of Semantic Web technologies in the SCF platform will allow us to network additional online communities built with SCF and identify relevant information across multiple sites.

# **RESULTS**

#### **PAIN RESEARCH FORUM**

The SCF platform, originally used for publishing scholarly articles for StemBook (http://stembook*.*org), was reengineered to create an online community of chronic pain researchers. The goal was to accelerate pain research by enabling free discussion and faster sharing of information between academia, industry, and the clinic, to foster new collaborations and to raise interest in pain research among the wider community of neuroscientists and clinicians. The PRF 8 was launched in June 2011; a screenshot of the home page is shown in **Figure 2**. As of December 2013, PRF has attracted ∼1400 registered members and has published more than 150 News stories and 25 Discussion forums, facilitated five Webinars and published four Journal Clubs features. There are more than 200 member-authored comments on News, Papers, and other content. Papers of the Week are published every Friday and 2–6 papers are highlighted each week as Editors'

5http://www*.*google*.*com/analytics/

6http://lucene*.*apache*.*org/solr/

7https://github*.*com/semsol/arc2

8http://www*.*painresearchforum*.*org/

logged-in).

Picks. Curated and frequently updated lists of Meetings and Events, Jobs, Funding Opportunities, and Bulletin Board items are posted. The site editors actively curate and maintain several research resources. All content is licensed for reuse under Creative Commons license BY-ND-NC9 .

#### **NEWS**

PRF publishes 1–2 news stories each week; a screen shot of the News section is shown in **Figure 3**. News stories are categorized as "Research," "Drug Development," "People" or "Conferences." PRF's news coverage helps researchers stay abreast of the latest findings in the field. For example, PRF was one of the first media outlets to publish a news story about a study of how "high-dose opioid reverses synaptic potentiation in the spinal cord in rats" (Talkington, 2012). The research paper was published in Science on January 13, 2012 and the PRF news story came out 3 days later. Four prominent pain researchers presented their opinions on the work in the form of comments to the story.

Often several related stories are published on an individual topic, and SCF is engineered to allow integration of this material.

9http://creativecommons*.*org/licenses/by-nc-nd/3*.*0/

For instance, PRF recently covered three high-profile brainimaging studies (Ahmed, 2013; Talkington, 2013; Talkington and McCaffrey, 2013). A screen shot of one of the stories is shown in **Figure 4**. The forms used to create and publish the story are shown in **Figure 5**. Related stories are listed in a block on the right. In addition, PRF conducted a webinar in December 2013, featuring one of the principal investigators on the brain imaging papers, along with several panelists including authors of the other papers mentioned in the news coverage. The webinar is also listed as related content to the news story. By hyperlinking, using the References function, cross-posting comments on both news stories and papers, and using the Related Content feature, PRF is able to provide a contextualized, intelligent overview of fast-moving developments in this corner of the larger field. Social media tools

**FIGURE 4 | News story on brain imaging.**  Study was led by Tor Wager, University of Colorado, Boulder, US and describes a new functional MRI-based test for measuring pain. Related stories are listed on a block on the right. The article has 3 comments.

such as Twitter feeds and newsletters disseminate the information quickly and effectively to members.

Brain imaging in the context of understanding and detecting pain is a popular but controversial topic, and the three stories cited above (Ahmed, 2013; Talkington, 2013; Talkington and McCaffrey, 2013) elicited several comments from PRF members. It is significant that many of the researchers commenting on PRF are junior people, including graduate students or postdoctoral fellows. Often the study authors participate in the discussion: for example, on the news story by Talkington and McCaffrey (2013), the study authors responded to two previous comments from researchers not involved with the study. Thus, the commenting feature on PRF news stories serves a function similar to the "letters to the editor" sections of journals, with key differences: it is faster, has a lower barrier to entry, and welcomes contributions from junior researchers.

Currently, the most accessed news story is one that discusses the new research on the use of antibiotics to relieve some forms of chronic lower back pain (Morton, 2013). The PRF news story covers two published research studies: one suggests that pain may be caused by a low-grade bacterial infection in the discs and the other finds that antibiotics can effectively treat the pain and prevent further tissue degeneration. Both studies have implications for patients with long-standing low back pain, and they elicited a lot of attention and controversy including in the popular press. In a Google search for the query "antibiotics for back pain," the PRF news story is the number one hit. This shows that PRF news stories can be highly ranked in Google searches for general pain terms, giving many readers access to the site. This high ranking may contribute to the unusually high number of page views for this article, which are three times more than the second most viewed news article.

#### **FORUMS**

The PRF Forums category includes Discussions, Webinars, and Journal Clubs. PRF editors have moderated several online discussions. The most-accessed Discussion is a debate on how the human brain processes stimuli, initiated by a well known pain researcher and PRF Science Advisory Board member (Basbaum, 2011). A Discussion on the challenges associated with translating pain research discoveries into clinical developments, presented by another researcher and science advisor, attracted many follow-on comments (Mogil, 2011). In 2013, PRF conducted five Webinars, each typically attracting ∼150 registered attendees, plus an unknown number of additional viewers who watched the event in groups under one registration. Each Webinar is conducted online using a webinar-hosting service and a recording is subsequently posted to PRF with a written introduction. This archives the presentation for future viewing and enables an ongoing, online conversation beyond the duration of the actual presentation. The Journal Club is a venue for disseminating the results of discussions that occur in individual lab groups about recently published scientific articles. For example, a graduate student and postdoctoral fellow studying pediatric pain presented a journal club at their institution on Walker et al. (2012; Birnie and Caes, 2012). They then wrote for PRF a brief synopsis of the study and the discussion that took place in their meeting. They also posed questions to the author of the original paper, who responded with her own online comment. A screenshot of the Journal Club is shown in **Figure 6**.

### **PAPERS OF THE WEEK**

Papers of the Week are published every Friday and provide a curated digest of recent and noteworthy pain-relevant articles published in academic journals. For example, for the November 2–8, 2013 collection10 , 61 papers were identified and listed. Two were further highlighted as Editors' Picks. Highlighted papers are often commented on by PRF-registered members, sometimes resulting in vibrant back-and-forth discussions between the authors and other PRF members11 . Related papers are listed in a block on the right as shown in **Figure 7**; a news story on the paper

10http://www*.*painresearchforum*.*org/node/33603

11http://www.painresearchforum.org/papers/22720-activation-5-ht2areceptors-upregulates-function-neuronal-k-cl-cotransporter-kcc2

is listed under the paper citation. Papers of the Week are archived as weekly lists, and the database of all papers can be searched with a detailed section-specific search. Members can also search for other papers using links provided on the paper page to Google Scholar or PubMed.

#### **PRF MEMBERSHIP AND USAGE STATISTICS**

As of December 17, 2013, PRF has just over 1400 registered members, of whom 1143 have published profiles in the member directory. Member demographics are shown in **Figure 8**. A variety of professionals sectors are represented including universities, hospitals, industry, government, and non-profit foundations, with the majority of members coming from academia (**Figure 8A**). Most members are research scientists and academicians including graduate students and postdoctoral fellows (**Figure 8B**). Twothirds (67%) of PRF members have an advanced degree, 41% have earned a PhD and 20% have an MD or DDS.

**FIGURE 6 | Journal Club on recently published paper.** Screenshot of journal club featuring a recently published paper in the journal PAIN (http://www. painresearchforum.org/forums/journal-club/21586-predicting-adult-outcomes-childhood-pain-profiles). Featured forums are highlighted in a block on the right.

Although promotional efforts—emails, conference attendance, printed literature, etc.—have been responsible for attracting many members (**Figure 8C**), more than half of members found PRF either via a Web search, word of mouth or were directly invited to join by an existing member. Social media tools played an important role in recruiting members ("Other" Category).

We found that a significant proportion (about one-third) of newly registered members failed to respond to the email validation message, which asked them to click a link and return to the site to complete the registration process. We installed a module to automatically send reminder emails to these new members, and have recovered about half of the non-responders.

Google Analytics shows that in October 2013, PRF had ∼8000 unique visitors, ∼11,000 visits and over 25,000 page views. PRF has visitors from all over the world, with the majority from the USA, UK, Canada, and Australia. The most popular browsers are Chrome, Safari, and Firefox. The Papers of the Week and News are the most popular sections; popular community pages include Jobs and Meetings & Events. Some of the news stories mentioned above are among the top pages visited on the site.

### **COMMUNITY AND RESEARCH RESOURCES**

PRF lists community and research resources of interest to the community, and the software automatically highlights new listings on the home page and section landing pages. Currently users

can access information on more than 30 upcoming meetings and read coverage of past meetings. Job postings 12, funding opportunities 13, and bulletin board 14 items are posted. In addition, several research resources are also provided including a curated pain gene resource consisting of about 25 genes that are associated with pain, according to peer reviewed, published studies, and a collection of "Pain 101" articles covering basic questions in pain research. A collection of useful links is planned.

#### **SEARCH AND SEMANTIC WEB**

We have implemented a general as well as section-specific search for PRF using the Apace Solr module as described in the Methods section. The search results can be further filtered by content type, date, news topic or whether an item is recommended or has comments (**Figure 9**). The search term is highlighted in the results and users have the option to sort the results by type, date, number of comments or last comment date.

We have created Linked data and RDF for News, Forums, and Papers using the Drupal RDF modules along with the SIOC and DC ontologies. A sample RDF15 illustrates the use of these ontologies to describe the News article. The RDF is indexed using the ARC2 PHP libraries and is available at http://www*.* painresearchforum*.*org/sparql*.* The SPARQL endpoint allows us to perform flexible queries such as "all News articles published with greater than 2 comments" (see **Table 1**). In the future, we could perform federated queries across endpoints from multiple communities.

# **DISCUSSION**

Our reusable platform, SCF, was successfully deployed to create a vibrant online community of chronic pain researchers: PRF. In a little over 2 years, PRF has attracted a large community of registered users and contributors including members from academia, industry, government, and non-profit organizations. Scientists engaged in laboratory research, clinicians, students, and fellows are all represented. PRF is a network of investigators from various sectors and disciplines and a venue for discussing, critiquing, and advancing pain research. The response to PRF in terms of member registrations and site use indicates a pent-up demand for such online communities that provide researchers in diseasecircumscribed fields of biomedical research with news, forums, and resources that are most relevant to them in one place.

In our experience, editorial involvement is crucial to keep the site active and vibrant with user interactions. Reporting news, moderating discussions, soliciting comments and producing webinars and journal club pieces is labor intensive but necessary to maintain high quality interactions within the user community. On PRF, this is accomplished by a staff of professional editors and writers with backgrounds in research and neurobiology, whose primary responsibility is to create and moderate content. Assembling an active and engaged Scientific Advisory Board made up of leading researchers and clinicians from a variety of disciplines is also important to ensure the highest quality content, provide community outreach and promote community involvement.

PRF is publicized in the pain research community by several avenues. The launch was announced with a press release and with a direct email to several thousand pain researchers, identified through meeting rosters, publications, and a existing pain research listserve. In addition, fliers were distributed at pain meetings and neuroscience meetings, including 7000 postcards placed in meeting bags at the most recent World Congress on Pain in Milan (2012), the largest gathering of pain researchers in the world. Several pain professional groups promote the site to their members on their websites or in member newsletters. PRF editors have given talks and posters at pain conferences. The PRF science advisors promote the site to their colleagues using slides and other materials provided by PRF. The site is also marketed through word of mouth, a monthly email newsletter, and RSS and Twitter (@PainResForum) feeds.

12http://www.painresearchforum.org/members/jobs

13http://www.painresearchforum.org/members/funding-opportunities

14http://www.painresearchforum.org/members/bulletin-board

15http://www*.*painresearchforum*.*org/node/34289*.*rdf

**FIGURE 9 | Search Results.** This figure displays the search results for the term MRI. The search results can be filtered using various facets on the left and sorted by content type, date, number of comments or date of last comment.

#### **Table 1 | Example SPARQL Query.**

PREFIX schema: *<*http://schema.org/*>* PREFIX sioc: *<*http://rdfs.org/sioc/ns#*>* SELECT ?post ?title ?replies WHERE { ?post a schema:NewsArticle; schema:name ?title; sioc:num\_replies ?replies. FILTER (\$replies *>* 2) } ORDER BY DESC(?replies)

*Query to find news articles with > 2 comments.*

One barrier to progress in research is the reticence of researchers to divulge unpublished or other preliminary work, or to publicly criticize the work of others. Web communities like PRF provide a new model of open communication that will help change this culture and promote faster and freer information exchange. A barrier to achieving more researcher involvement in and contributions to communities like PRF is the lack of incentives for scientists to contribute comments or other materials that do not add to their official publication record. In the future, sites like PRF should aim to provide incentives for contribution, for example by indexing content on PubMed or by arranging to provide continuing medical education (CME) credits for physicians who contribute.

All content on PRF is provided free of charge to the research community, and funding of shared resources like PRF is an ongoing challenge. To attract donors and other sponsors of the site we must continually demonstrate both scientific credibility in all of the content presented, and constant, lively and intellectually valuable interactions. Consistent outreach to and education of potential funders in the philanthropic area, professional societies, relevant pharmaceutical and biotech companies and the academic sector is also required. At the same time, editorial independence from sponsors must be strictly maintained. PRF does not accept paid advertisements and does not intend to do so.

In terms of technology, the SCF platform consists of a comprehensive set of building blocks for an online community. We have effectively used the SCF platform to create other communities: the Multiple Sclerosis Discovery Forum (msdiscovery.org) and StemBook (stembook.org). The platform incorporates elements of Semantic Web technologies, which have the potential to accelerate the pace of inter-disciplinary research by defining a common language and improving interoperability between various resources on the Web (Hendler, 2003). In the future, we plan to leverage these Semantic Web technologies to enable us to do cross-site queries and find relevant information on other sites. Interoperability between these multiple communities involved in neurobiology and neurology research will, we hope, identify common biological mechanisms behind complex neurological diseases and accelerate translation of science to new treatments.

#### **ACKNOWLEDGMENTS**

We gratefully acknowledge essential funding from the Curvey Family Foundation, the Mayday Fund, the Guthart Family Foundation, Purdue Pharma L.P. and Genentech. We thank Alzforum and PDOnline editors for their feedback and ideas, Nick Maloney, Paul Northup, Jake Strawn, and Chris Akeley for their contributions to software development, and Stoltze Design for graphic design.

#### **REFERENCES**

Kumar, K. (2012). *Drupal 7 Theming Cookbook.* Birmingham: Packt Publishing Ltd.

**Conflict of Interest Statement:** 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.

*Received: 24 December 2013; accepted: 19 February 2014; published online: 11 March 2014.*

*Citation: Das S, McCaffrey PG, Talkington MWT, Andrews NA, Corlosquet S, Ivinson AJ and Clark T (2014) Pain Research Forum: application of scientific social media frameworks in neuroscience. Front. Neuroinform. 8:21. doi: 10.3389/fninf.2014.00021 This article was submitted to the journal Frontiers in Neuroinformatics.*

*Copyright © 2014 Das, McCaffrey, Talkington, Andrews, Corlosquet, Ivinson and Clark. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Growing a garden of neurons

# *Rebekah C. Evans\* and Sridevi Polavaram*

*Center for Neural Informatics, Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, USA \*Correspondence<EMAIL_ADDRESS>
*Edited by:*

*John Van Horn, University of California at Los Angeles, USA*

**Keywords: morphology, dendrites, growth algorithm, computational model, neural networks**

#### **A commentary on**

**Self-referential forces are sufficient to explain different dendritic morphologies** *by Memelli, H., Torben-Nielsen, B., and Kozloski, J. (2013). Front. Neuroinform. 7:1. doi: 10.3389/fninf.2013.00001*

Computational models of biologically realistic neuronal networks have advanced neuroscience in the past 20 years. With an ultimate goal of simulating a whole brain, these networks must become larger and more complex. However, a sheer massive number of neurons do not make a brain. Neurons are all different, with different kinetics, neurotransmitters, and importantly different morphologies. A network can be made by connecting copies of the same cell together, but this kind of *homogenous* network can only explain so much. Real neuronal networks are *heterogeneous* and are made up of neurons that follow both intrinsic and extrinsic cues to grow their unique dendritic arbors (Scott and Luo, 2001). In addition to *homogenous* and *heterogeneous* network models, *hybrid* network models have been implemented by creating a small heterogeneous network and replicating it to establish a larger network (Kozloski, 2011). However, modeling studies have shown that homogenous networks act differently than realistic heterogeneous ones (Mäki-Marttunen et al., 2011).

A new paper by Memelli et al. (2013) joins the field of papers providing algorithms for growing digital neurons. Their algorithm can be used to build a network consisting of millions of neurons each with a unique morphology. The current models, L-Neuron (Ascoli et al., 2001), NeuGen2.0 (Wolf et al., 2013), NetMorph (Koene et al., 2009), and CD3X (Zubler and Douglas, 2009) have made great strides in advancing the process of generating digital neurons. These models are all publicly available, and can be used to generate large networks of neurons. Recently L-Neuron was used to generate a 0.5 million cell model of the dentate gyrus (Schneider et al., 2012). Each algorithm has its own specific advantages. NetMorph has a synapse-generating algorithm, NeuGen2.0 is modular and adaptable to new data, and CD3X can isolate intrinsic and extrinsic factors of neuron development by growing the same neurons in different model environments. In combination with the parallelization of simulation software [such as NEURON (Migliore et al., 2006)], these neuron generators are laying the groundwork for enabling massive biologically realistic simulations.

Memelli et al. (2013) do not attempt to model the molecular mechanisms of dendritic growth, but instead work to make a concise, computationally efficient model that can capture the structure and variability of realistic morphologies. Their work adds two elements to this field. First, it simplifies the neural growth algorithm to contain a combination of three biologically inspired intrinsic parameters: somaoriented tropism, dendritic self-avoidance, and membrane stiffness. The three parameters of their growth algorithm are all intrinsic to the cell itself and do not take into account any extrinsic signals that could come from other neurons or physical constraints. Each of these parameters has been previously described, but Memelli et al. are the first to combine them in one simple model. Second, their algorithm is written to be fast and massively parallel, creating the possibility for generating billions of neurons on the IBM Bluegene computer. Their algorithm can generate a neuron in less than two seconds, and when run on parallel cores is capable of generating enough neurons to simulate an entire brain region. Together, these elements fit the need to have morphological diversity within a network as well as the need to have extremely large networks.

Each of the current morphology simulators has their particular strengths. The ideal situation would be for Memelli's new algorithm to be incorporated into one of the existing ready-to-use packages. For example, the application of this algorithm within the external constraints of CX3D could help isolate the extrinsic and intrinsic aspects of dendritic arborization. When used together these simulators can help create massive-scale heterogeneous networks for computational modelers and can help investigate how dendrites actually grow.

# **REFERENCES**

explain different dendritic morphologies. *Front. Neuroinform.* 7:1. doi: 10.3389/fninf.2013.00001

*Received: 02 August 2013; accepted: 02 August 2013; published online: 26 August 2013.*

*Citation: Evans RC and Polavaram S (2013) Growing a garden of neurons. Front. Neuroinform. 7:17. doi: 10.3389/fninf.2013.00017*

*This article was submitted to the journal Frontiers in Neuroinformatics.*

*Copyright © 2013 Evans and Polavaram. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Corrigendum: Harnessing modern web application technology to create intuitive and efficient data visualization and sharing tools

# Dylan Wood\*

*The Mind Research Network, Albuquerque, NM, USA*

Keywords: neuroinformatics, NeuroDebian, COINS, data sharing, open neuroscience

# **A corrigendum on**

# **Harnessing modern web application technology to create intuitive and efficient data visualization and sharing tools.**

by Wood, D., King, M., Landis, D., Courtney, W., Wang, R., Kelly, R., et al. (2014). Front. Neuroinformatics 8:71. doi: 10.3389/fninf.2014.00071

# Edited and reviewed by:

*Xi Cheng, Lieber Institue for Brain Development, USA*

\*Correspondence:

*Dylan Wood<EMAIL_ADDRESS>
Received: *24 April 2015* Accepted: *12 May 2015* Published: *05 June 2015*

#### Citation:

*Wood D (2015) Corrigendum: Harnessing modern web application technology to create intuitive and efficient data visualization and sharing tools. Front. Neuroinform. 9:14. doi: 10.3389/fninf.2015.00014*

#### **Footnotes 6 and 7:**

Should both refer to the ABIDE dataset: http://fcon\_1000.projects.nitrc.org/indi/abide/

# **Footnote 8:**

Should reference the article below, in addition to the NeuroDebian website: http://neuro.debian. net.

Halchenko, Y. O., and Hanke, M. (2012). Open is not enough. Let's take the next step: an integrated, community-driven computing platform for neuroscience. Front. Neuroinform. **6**:22. doi: 10.3389/fninf.2012.00022. http://journal.frontiersin.org/article/10.3389/fninf.2012.00022/pdf

**Conflict of Interest Statement:** 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.

Copyright © 2015 Wood. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Corrigendum: Impact of functional MRI data preprocessing pipeline on default-mode network detectability in patients with disorders of consciousness

#### *Adrian S. Andronache1, Cristina Rosazza1,2, Davide Sattin3, Matilde Leonardi 3, Ludovico D'Incerti 1 and Ludovico Minati 2 \**

*1 Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy*

*2 Scientific Department, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy*

*3 Neurology, Public Health, Disability Unit, Scientific Department, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy*

*\*Correspondence<EMAIL_ADDRESS>
#### *Edited and reviewed by:*

*Daniel Marcus, Washington University in St. Louis, USA*

**Keywords: functional MRI (fMRI), resting-state, functional connectivity, disorders of consciousness, vegetative state, minimally-conscious state, data preprocessing**

**A corrigendum on**

# **Impact of functional MRI data preprocessing pipeline on default-mode network detectability in patients with disorders of consciousness**

*by Andronache, A., Rosazza, C., Sattin, D., Leonardi, M., D'Incerti, L., Minati, L., et al. (2013) Front. Neuroinform. 7:16. doi: 10.3389/fninf.2013.00016*

The authors of the article by Andronache et al. apologize that the funding acknowledgment "*The Start-up Coma Research Centre (CRC) project was also supported by the European Foundation for Biomedical* *Research (FERB)*" was omitted from the original publication.

# **REFERENCES**

Andronache, A., Rosazza, C., Sattin, D., Leonardi, M., D'Incerti, L., Minati, L., et al. (2013). Impact of functional MRI data preprocessing pipeline on default-mode network detectability in patients with disorders of consciousness. *Front. Neuroinform*. 7:16. doi: 10.3389/fninf.2013.00016

**Conflict of Interest Statement:** 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.

*Received: 14 April 2014; accepted: 24 April 2014; published online: 16 May 2014.*

*Citation: Andronache AS, Rosazza C, Sattin D, Leonardi M, D'Incerti L and Minati L (2014) Corrigendum: Impact of functional MRI data preprocessing pipeline on default-mode network detectability in patients with disorders of consciousness. Front. Neuroinform. 8:50. doi: 10.3389/fninf.2014.00050*

*This article was submitted to the journal Frontiers in Neuroinformatics.*

*Copyright © 2014 Andronache, Rosazza, Sattin, Leonardi, D'Incerti and Minati. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Corrigendum: Software and hardware infrastructure for research in electrophysiology

# *Roman Moucek ˇ 1,2\**

*1 Department of Computer Science and Engineering, University of West Bohemia, Plzen, Czech Republic*

*2 New Technologies for the Information Society, University of West Bohemia, Plzen, Czech Republic*

*\*Correspondence<EMAIL_ADDRESS>
#### *Edited by:*

*Xi Cheng, Lieber Institute for Brain Development, USA*

#### *Reviewed by:*

*Sam Neymotin, State University of New York, Downstate Medical Center, USA Juliana A. Knocikova, Université de Nice Sophia-Antipolis, France*

**Keywords: electrophysiology, event related potentials, infrastructure, neuroinformatics, workflow, portal, signal processing methods, stimulator**

# **A corrigendum on**

# **Software and hardware infrastructure for research in electrophysiology**

*by Mouˇcek, R., Ježek, P., Vaˇreka, L., Rondík, T., Br˚uha, P., Papež, V., et al. ˇ (2014). Front. Neuroinform. 8:20. doi: 10.3389/fninf.2014.00020*

This article adds Yann Le Franc as a coauthor of the technology report article "Software and Hardware Infrastructure for Research in Electrophysiology," describes his individual contribution to the article, and presents changes in two paragraphs in Section 2.4, where an additional reference is also provided. Moreover, the members from the OEN group who work and cooperate on building OEN are personally acknowledged.

## **Co-author:** Yann Le Franc

**Affiliation:** e-Science Data Factory S.A.S.U., Paris, France; Ludwig-Maxim ilians-Universität München, Planegg-Mart insried, Germany; University of Antwerp, Antwerpen, Belgium

# **Authors' Contributions**

Yann Le Franc contributed to the **Figures 3, 4** and **8** and to the work on the Ontology for describing Experimental Neurophysiology (OEN).

# **Section 2.4**

#### Old version:

The group follows the best practices for creating ontologies, for example, it cooperates with community of researchers who design and create ontologies, uses existing data formats and repositories (odML, HDF5), and reuses existing resources (terms, ontologies—NEMO, OBI). For the general description of experimental neurophysiology, the terms from ontologies NEMO and OBI are relevant. However, the set of the domain terms is still not complete in these ontologies (information stored in the EEG/ERP Portal cannot be fully described by these ontologies) and OEN will be finally an extension of OBI (e.g., the granularity of OBI for devices and related information will be extended).

# New version:

The group follows the best practices for creating ontologies, for example, it cooperates with community of researchers who design and create ontologies, uses existing data formats and repositories (odML, HDF5), and reuses existing resources (terms, ontologies—NEMO, OBI). For the general description of experimental neurophysiology, the terms from ontologies NEMO and OBI are relevant. However, the set of the domain terms needed to describe the information stored in the EEG/ERP Portal is not yet complete in these ontologies. OEN aims at defining these missing terms and at term, should be used to propose an extension of OBI's neurophysiology model (e.g., the granularity of OBI for devices and related information will be extended).

# Old version:

Terminologies within OEN have been primarily developed in the odML format. Subsequently, an OWL file has been constructed aided by Ontofox (Xiang et al., 2010). The current developer's version of OEN is available at https://github*.*com/ G-Node/OEN.

#### New version:

The OEN device branch development is based on the odML terminology (Grewe et al., 2011), concepts gathered by the Neuroscience Information Framework (NIF) and concepts used in the EEGBase data model to describe setups and setup configurations. The gathered terms are currently mapped with the aforementioned ontologies. Subsequently, an OWL file has been constructed to contain OEN terms and the mapped terms. Existing terms in other ontologies will be imported using the MIREOT approach (Courtot et al., 2011), aided by Ontofox (Xiang et al., 2010). The current developer's version of OEN is available at https://github*.* com/G-Node/OEN.

# **ACKNOWLEDGMENTS**

We thank the members of the OEN group Anita Bandrowski, Jan Grewe, Shreejoy Tripathy, and Thomas Wachtler for their work and long-term cooperation on building OEN.

# **REFERENCES**

**Conflict of Interest Statement:** 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.

*Received: 31 July 2014; accepted: 20 August 2014; published online: 05 September 2014.*

*Citation: Mouˇcek R (2014) Corrigendum: Software and hardware infrastructure for research in electrophysiology. Front. Neuroinform. 8:75. doi: 10.3389/fninf. 2014.00075*

*This article was submitted to the journal Frontiers in Neuroinformatics.*

*Copyright © 2014 Mouˇcek. This is an open-access article distributed under the terms of the Creative* *Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

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**1. Introduction**

The finite nature and rapid depletion of fossil fuels due to growing global energy demands have negatively impacted the environment as their combustion entails have led to the search for alternative ways of producing fuels from sustainable, renewable, green, and economical energy sources [1–5]. One source of renewable energy production is biomass, which can be transformed into biofuels, which provide many advantages over fossil fuels in terms of mitigating residues generation and greenhouse gas (GHG), increasing energy independence, and improving the economy of agriculturalists [1,2,6,7].

The term biofuel refers to any liquid, gas, or solid fuel predominantly produced from a renewable biomass feedstock. Biofuel examples are bioethanol, biomethanol, biosynthetic gas (biosyngas), biodiesel, biogas (biomethane), biochar, bio-oil, biohydrogen, and Fischer\_Tropsch produced liquids [1,8]. Biofuels serve as a bridge between the agricultural and energy markets as agricultural commodities are the significant feedstocks in biofuel production [9].

Recently, crop residues as a potential source of feedstock to produce bioenergy have been gaining importance as they are not in competition with food production for human consumption. They have high availability, wide distribution, and almost zero cost [1,10,11]. Crop residues are generally the waste generated in the harvesting of any agricultural crop. These are typically the parts of the products that are often of no value, including the stem, empty fruit bunches, leaves, and stalks. The amount of agricultural waste is variable and reaches 50% for specific crops [12]. In the production of commodities like sugar, rice, flour, starch, and oil, only a fraction of the main crop is recovered and used. The leftover fraction of the processed products are referred to as agro-industrial crop residue. Generally, these residues are either bagasse, molasses, the spent fibrous pulp left behind from stalks of crops, or seed coats, shells, and husks [1,12]. The optimal use of agricultural wastes has excellent economic and ecological advantages due to the possibility of recycling and producing materials with added value [2]. Wheat straw, rice straw, corn straw, and sugarcane bagasse are the agricultural residues available in the approximate amounts of 354.34, 731.30, 128.02, and 180.73 million tons, respectively. The primary composition of these residues is cellulose (20 to 60%), hemicellulose (20 to 40%), and lignin (10 to 25%) [1,13].

Production and use of biofuels made from crop residues could prevent the over-exploitation of fossil fuel and low waste management problems in the field. However, this potential can only be unlocked if they are cost-competitive to petroleum and starch and sucrose-based biofuels. To reduce capital and processing costs, simplifying the process scheme, and integrating as many unit operations as possible is necessary. Therefore, the consolidated bioprocessing CBP is a strategy where all four steps occur in a single reactor. A single microorganism or microbial consortium converts pretreated biomass to a commodity product such as ethanol without adding saccharolytic enzymes, which would represent an innovative breakthrough for low-cost biomass processing. In principle, a CBP strategy can be applied to produce a broad range of chemicals from natural biomass. It requires degrading recalcitrant biomass substrates into solubilized sugars and metabolic intervention to direct metabolic flux toward desired products at high yield and titer [14–16].

The increase in population brought a greater demand for food and energy; this requires an increase in agricultural production and an increase in agricultural waste, which presents enormous challenges for its proper management. Although crop residues represent a potential source for the generation of biofuels, the environmental impacts that their use could cause must also be critically evaluated [16]. Therefore, this work aims to briefly describe the current situation of biofuels, available raw materials, and their production strategies, especially the CBP approach, a strategy that is aimed at the best option for the sustainable production of biofuels.