The qualitative character of consciousness, its “what-it-is-likeness”, is a contested issue, both in philosophy and psychology. I argue that, rather than by conceptual analyses, the status of “what-it-is-likeness” has to be decided by empirical investigation. Pending the outcome, we should maintain an agnostic stance, in order to remove the bias in favor of fictionalism from our study of consciousness,. I illustrate this with the notion of “ownership unity”. People adhere to the belief of a single, unified self as the owner of their experiences, in spite of abundant dis-unities in the informational content of their experience. On one reading, this supports the notion that the unity of experience is no more than a convenient fiction, based on an illusory experience of unity. Cognitive neuroscience is slanted in favor of such understanding, insofar it emphasizes functional specialization and localization. To restore the balance, I present a complementary perspective: the view that the experience of unity is afforded by the intrinsic, multiscale brain dynamics. This approach offers a biological substrate for unity of experience as a regular scenario within certain boundary conditions, as well mechanisms that may let it go astray. To behaviorism, the proposed zombie, who behaves in all possible ways like a normal individual would effectively be identical to that individual. In other words, a zombie, according to behaviorism, cannot exist Kirk, . BehavioThe logical possibility of philosophical zombies permits a principled skepticism, firstly, with respect to other minds. This observation gains practical significance in light of our increasingly frequent conversations with dialog bots, which are rapidly becoming more and more convincing. We may be surrounded by bots, or zombies.The skeptical contagion does not halt at the self. We have seen that our introspections could be misleading; but now even worse, the sum total of our experiences could be delusions. This is hilariously illustrated in a one-page essay by Smullyan . LooselyEven if we were all philosophical zombies, this would have no effect whatsoever on our lives, as all of us will continue to act as if we possess “what-is-it-likeness”, and continue deceiving ourselves and each other about having it. The upshot is that it may be a complete epiphenomenon, i.e., it is completely irrelevant towards the course of events in our lives and at worst a complete fiction. Thereby the philosophical zombie argument appears to be cutting through the ties of psychological explanation and “what-it-is-likeness.”“When scholars study a thing, they strive to kill it first, if it’s alive; then they have the parts and the’be lost the whole, for the link that’s missing was the living soul.”—Johann Wolfgang von Goethe, Faust, Part OneBased on Chalmers’ zombie thought experiment, we may call “what-is-it-likeness” redundant, or so it seems. But this is true only if one buys into the philosophical hubris of it. Remember the definition of a zombie as an individual in all possible psychological functions identical to a person with, yet having no qualitative conscious experience. It uses “all possible psychological functions” as if it were a well-delineated set. But this could be debated. What delineates this set cannot be decided apriori and is to be determined, based on empirical investigation. Such investigation may determine whether the concept of “psychological zombie” turns out to be meaningful, because it is empirically possible that some functions necessitate qualitative consciousness. And so, as far as “what-is-it likeness” is concerned, the ball is in the court of psychology and its sister sciences.Can we envisage any psychological functions that might necessitate qualitative consciousness? We have seen that Georgalis  requiredShould we endorse such a theory, the ball would be back in the philosophers’ court, as the question would now be how “what-it-is-likeness” can exist in a physical world. Psychologists, however, even those who are in the consciousness business, are somewhat reluctant to endorse talk of “what it is likeness”. The problem, however, is, it is closely intertwined with most, if not all, psychological functions and properties. How we experience a color depends on the object the color belongs to, and the context the object is embedded in McCann et al. , includiBut rather, one could argue, this interwovenness underscores how central a role “what-it-is-likeness” play in how we understand ourselves in our everyday lives. This remains true, even if we are all zombies. We might therefore equally proclaim that understanding “what it is likeness” is the ultimate goal of studying consciousness.The interwovenness with so many of our psychological functions could even be considered a defining characteristic of consciousness. According to Baars , 1997, cPerhaps another reason for reluctance in addressing “what-it-is-likeness” is the discrepancy, highlighted by philosophers, between private certainty (Descartes) and public inaccessibility (Wittgenstein). We have seen the philosophical match between them to be undecided.Yet, researchers feel that they may have to take sides with one or the other. we see phenomenological doctrines making private certainty the core of their theoretical commitment vs. mainstream psychology, which seems to have sided with the accessible.agnosticism with respect to the ontological status of “what-is-it-likeness”. Making progress requires suspending judgment. For science to have the last word, we should proceed in understanding consciousness through empirical research, without having in advance either to affirm it as truth or reject it it as myth.But exactly because the minds have become so divided on this issue, an unbiased contribution from science is desparately wanting. Rather than taking sides, we should practice I will argue that our current knowledge of consciousness does not decide the status of “what-is-it-likeness”. In particular, I will illustrate this with the property of ownership unity, i.e., the sense that you possess a self that owns your experiences, is of special interest in this debate, because people hold on to ownership unity despite what appears overwhelming scientific evidence to the contrary. The experience of unity, or what someone calls “self”, may be no more than the product of a number of discrete psychological functions. This might suggest that the experience of unity itself is unreal. I will argue that such a conclusion would be premature: even if the unity of experience is a figment of our imagination, the resilience of of ownership unity may be still have a real basis. I will argue that the basis may exist in the biology of our brain.In me there are two souls, alas, and theirDivision tears my life in two.One loves the world, it clutches her, it bindsItself to her, clinging with furious lust;The other longs to soar beyond the dustInto the realm of high ancestral minds.—Faust, lines 1110–1115self.Some functions that involve conscious experiences, including imagery, predominantly have sensory components, some involve our willful actions and thus appear linked to our motoric abilities, still others appear linguistic or amodal in nature. What binds them together is the tendency of the subject to identify with them: these are my thoughts, my sensations, etc. This is what we experience, and have come to describe, as our Why do we see ourselves as inhabited by a single the arbiter of our experience and chief commander of our actions? In a religiously motivated perspective, unity is provided by the concept of a soul. The precise relation between soul and self may vary according to religious persuasion; in a Christian context the divine aspects of the soul pose certain norms which the self must reflect. As agnosticists, however, we need not take such beliefs for granted. We may wonder: why is it one rather than two, or 20; or, perhaps, wouldn’t a committee do just as well? According to Dennett , the selThe principle that we perceive ourselves as one is hardly ever violated, except in some cases of extremely dissociative identity disorder . Extremely dissociative identity disorder patients show multiple alters, each of which may claim ownership unity for part of a person’s experience and biography. These phenomena may well be controversial. But it is exactly the kinds of controversies  that the agnosticist view has no stake in. What matters is whether they show the symptoms, have a history that could explain them, and whether they have a biological basis. For this, see Perry, .We may wish to distinguish between the self as a persistent unity and the unity of the momentary experience of selfhood. Dissociative personalities may lack persistent unity but each of their alters may still have a unified sense of self at a moment-to-moment basis or, what Stroud  calls thNo matter how richly or sparsely endowed, the minimal self is not indispensable for having a persistent self  sense of self. Welshon  points tThe distinction between unity in the persistent and the minimal sense of self refers to the spatial and temporal scale at which unity is experienced. Based on the double dissociation between, on the one hand, extreme dissociative personalities  and Balint syndrome patients , I propose that both may the product of distinct biological mechanisms.A further distinction is between ownership and content unity Welshon,  In some Schiffer et al.  speculatinformationally based. In most normal situations both hemispheres of split brain patients receive plenty of same information through their senses. Foveal vision goes to both hemispheres, most sounds are binaural, etc. Kim Peek, however, was unusual in many respects; he had savant syndrome, and could read two pages at the same time. His brain had language centers in both hemispheres as well as other anomalies. These anomalies might be strong enough to consider the possibility that also his sense of self was different from ours.We could, however, maintain that the psychological ownership unity is jointly maintained by the two hemispheres even in cases where direct communication between them is reduced. Most of these patients, after all, already had a unitary self before they were lesioned. One notable case of a patient who had the lesion congenitally was Kim Peek  sense of self. Peterson et al. used Necker cubes that were locally disambiguated Figure . When thAs I argued elsewhere  suppression mechanisms ensure that during saccadic eye-movements, the signal from the eye is interrupted and cannot alert us to the change in eye-position. Prior to the eye-movements, a shift in attention takes place that offsets the selectivity in the receptive fields to remain maximally position-invariant. It is clear, therefore, that these mechanisms have adaptive significance. Without them, our perceptual information would constantly suffer from disruptive interference caused by our own oculomotor behavior.Similar mechanisms play a role at higher levels of perception. The high-level analog of blink suppression is the attentional blink; the analog of saccade suppression is change blindness. The origin of these phenomena in our perceptual system are currently under study. See, for instance, , the different forms of unilateral neglect , and dementia (memory) are other pathologies where we may encounter violation of maximal ownership unity. All these syndroms clearly have a biological basis; for instance, brain lesions, even if the precise mechanisms that lead to the symptom are unknown. As for subtler symptoms, usually called “denial” or sometimes “repressed psychological states”, it is reasonable to speculate that these are due to milder forms of the biological mechanisms responsible for the clinical cases. Clearly, a deeper understanding of the brain is required to see what enables a healthy dialectic of ownership unity and content disunity, as well as the various syndroms that emerge when it goes wrong.If ever I to the moment shall say:Beautiful moment, do not pass away!Then you may forge your chains to bind me—Faust, lines 1698–1701We need to understand, however, what enables the experience of unity and the absence of unity in experience to persist within a single individual. I propose that this is a property of brain activity and structure. Cognitive neuroscience has provided ample support for content disunity, by seeking to confirm hypotheses of functional specialization and localization in the brain. Localized modules seem to work independently and in parallel, only coupled through the signals that they pass through to each other through their synapses. Thus the scientific view seems slanted in favor of the conclusion that the experience of unity is illusory. However, I will argue that certain brain states occur at least intermittently that reveal a more global level of organization. These are the biological basis for the experience of unity.What has led cognitive neuroscience to overlook these functions. It has at its disposal two well-established methods for studying brain activity: fMRI and EEG. Whereas the former has great spatial resolution, this is lacking in the second. Conversely, the first lacks the temporal resolution of the second. As a result, fMRI has been preferably used for studying the localization of function, while EEG for studying its temporal aspects. This has helped strengthen the belief that brain function can be studied in the spatial and temporal domains independently. This, researchers localize static sources in the brain with one method, and study the time course of their activity with the other, thinking this is all there is to the brain. However, this may be a mistake; important characteristics of the brain signal are lost when ignoring their spatiotemporal properties, such as traveling wave activity  and periods of instability, where the activity shows more localized and transient patterns. This behavior is called itinerancy Freeman, . Such dyBrains, basically, are networks of diffusively coupled nonlinear oscillators. In such systems, biological as well as artificial ones, itinerant regimes are pervasive. But these do not sustain any global activity pattern long enough to form the basis of our maximal sense of unity. However, their activity may support the evolution of a brain network structure that could do this job. Activity (function) and connectivity (structure) evolve in the brain on different time scales: fast activation dynamics leads to slow, adaptive modifications in connection strength , even though clearly not autistic, including an seeming inability to deal with non-literal speech, prodigious attention to detail, and savant syndrome. Autism patients share with simultagnosia patients an inability to perceive and interpret the overall gestalt of a scene.Glazebrook and Wallace , associaThe mechanism these patients have in common may become clear if we take (re)wiring costs into account. Jarman et al.  applied The property of modularity in small world networks  and modular small-world architecture constitute the biological substrate for our maximum sense of self. Key is that the existence of different modules at various levels allows the system to keep pieces of content separate and relatively isolated from each other. The global connectivity implies that these discrete contents can at times be integrated. Our brains possess the conditions for both the disunity of conscious content, and the persistent ownership unity.As an antidote for the view that uor experience of unity is just a convenient fiction, I offered the hypothesis that its basis lies in the adaptive and dynamic mechanisms of the brain. I reached this view without taking a phenomenological stance, nor studying the brain from a first person perspective. I developed my view as a case for agnosticism with respect to “what-is-it-likeness”.Agnosticism with respect to”what-is-it-likeness” does not constrain our efforts to study it. We may continue to address the question of what are the grounds for ascribing conscious experiences to ourselves, without presumptions about the validity of doing so. We may speak of phenomenal content in, for instance, a psychophysical, functional, or evolutionary perspective. We may study experience in relation to particular physical referents in the world (indirect psychophysics), in the brain (direct psychophysics), in relation to attention (Graziano, But agnosticism does also invite us also to study certain biological mechanisms that could, at least in principle, support the validity of such beliefs, or aliefs. Some of these mechanisms are specific: saccade and blink suppression secure the continuity of our visual experience across perturbations from oculomotor behavior. Some are more generic: traveling waves produce a short-term unity in biological space-time as a pattern activity moves over of the cortical sheet. These patterns have their own, characteristic duration (Nikolaev et al., 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.


MTID) based on traces acquired from historic information. We decompose the influential scores of users into two parts: the direct influence determined by information propagation along the link structure and indirect influence that extends beyond the restrictions of direct follower relationships. To model the network from a multi-topical viewpoint, we introduce topic pools, each of which represents a particular topic information source. Then, we extract the topic distributions from the traces of tweets, determining the influence propagation probability and content generation probability. In the network, we adopt multiple ground nodes representing topic pools to connect every user through bidirectional links. Based on this multi-topical view of the network, we further introduce the topic-dependent rank (TD-Rank) algorithm to identify the multi-topic influential users. Our algorithm not only effectively overcomes the shortages of PageRank but also effectively produces a measure of topic-related rank. Extensive experiments on a Weibo dataset show that our model is both effective and robust.Recently, increasing numbers of users have adopted microblogging services as their main information source. However, most of them find themselves drowning in the millions of posts produced by other users every day. To cope with this, identifying a set of the most influential people is paramount. Moreover, finding a set of related influential users to expand the coverage of one particular topic is required in real world scenarios. Most of the existing algorithms in this area focus on topology-related methods such as PageRank. These methods mine link structures to find the expected influential rank of users. However, because they ignore the interaction data, these methods turn out to be less effective in social networks. In reality, a variety of topics exist within the information diffusing through the network. Because they have different interests, users play different roles in the diffusion of information related to different topics. As a result, distinguishing influential leaders according to different topics is also worthy of research. In this paper, we propose a multi-topic influence diffusion model ( Online social networks provide a medium through which millions of users interact with each other; their members diffuse information and exhibit influence . InfluenTwitter-like social networks employ a network model called “following”, in which each user is allowed to follow anyone without requiring permission. Based on these established social relations, a user will be alerted whenever a user they are following posts tweet updates . Hence, In total, users generate an enormous number of tweets everyday on social media. Topic-mixed tweets propagate through the same network, and these various tweets contain the topic-related information. Faced with this flood of information, information seekers  are eageMTID) model to discover topic-related influential leaders. Specifically, the influence of these users in our model consists of both direct and indirect influence. The direct influence follows the information propagation trace along the links. Meanwhile, users can retweet tweets posted by people they are not following, giving the original posters further indirect influence. Notice that both types of influence are related to different topics. Based on MTID, we further propose a topic-dependent rank algorithm, namely TD-Rank. Different from setting one ground node to make the network strongly connected, as in LeaderRank  and  and 4] aOur work is different from all the studies described above in that we propose a novel influence diffusion model, to which we further add a novel topic-dependent rank algorithm. We introduce several ground nodes to decompose the total influence into direct influence and indirect influence. The adoption of ground nodes allows the construction of multiple-topic views of the whole network. Moreover, this is helpful in finding topic-related influence. Meanwhile, it also overcomes the shortages of PageRank. In addition, we adopt a data-based approach to define the transition probability, which makes the model more accurate.G = {V, E} is formed consisting of users and their following relationships, where V is the set of users and E represents the edge set of their followings. We denote e = <i, j> in E as a directed edge starting from i to j. Meanwhile users have traces of tweets D = {d1, d2, …, dN}, where di is trace of user i, and N is the number of users. We separate these tweets into two types: original tweets, those that are created originally by that user, and retweets, which are re-posted tweets created by others.First, a directed social network LDA) model D with LDA according to the topic number T process fort = 1 TO Tdo   end for  connect ground nodes to users with bidirectional edges set the weights on edgesfori = 1 TO Ndo TDS[i] = Si =   end for whileerr > ϵ or k < Itermaxdo Temp = TDSk    Update every ground node score according to Eq (6)  Update every user score according to Eq (7)err = Temp − TDSk  find the max error: end while PR(i) is the rank value of node i, α is the decay factor (i.e. the return probability), and pj,i is the transition probability matrix defined by the specific algorithm.In other algorithms akin to Pagerank, the final ranking equation can be defined as:MTID effectively overcomes these shortages. Due to the adoption of ground nodes, TD-Rank extends the advantage of LeaderRank on every topic view. Moreover, we further adopt a data-driven approach to divide the transition probability into original and retweet probability. Finally, we reconstruct the network into a strongly connected network using the ground nodes and adopt a data-based approach to deal with the transition probability between users and ground nodes, aiming to discover an actual influence score.There are several drawbacks in applying this algorithm to social networks. First, the return probability is essential. Convergence is guaranteed only on strongly connected networks. In addition, the probability on every edge is identical for all users—irrespective of each user’s tweet history. In comparison, our proposed TD-Rank based on the To validate the effectiveness of the TD-Rank algorithm, we test it on crawled data from Weibo, the largest twitter-like social network in China. We start by randomly choosing several active seed users to avoid “Zombie users”—those who have registered but have not posted any tweets. Specifically, we include active users who retweeted more than 20 tweets between May 24th 2013 and May 24th, 2014. With these users, we crawl a network with 211,000 users, 1,612,289 following relationships and 47,002,906 total tweets. The detaileded statistics for this dataset are are listed in α, β and topic number T. In this paper, these parameters are set as T = 20, α = 50/T + 1, and β = 0.1 + 1 in Spark [D for every user. The only parameters that must be set are the LDA parameters, which reflect the number of ground nodes selected. The LDA is tuned by three parameters: the Dirichlet hyper-parameters in Spark . ObviousPageRank, which measures the influence by taking the link structure of the network into account. The experiment setting in the comparison is set as follows: the return probability is 0.15 and the transition probability is i goes to j, while i.LeaderRank, which introduced a ground node to connect all of the nodes, setting the transition probability as TwitterRank, which first studied topic-related ranking. In this comparison, we extract the same topics using LDA in TD-Rank.In this section, we make comparisons against related algorithms using the above dataset with Spark. The related algorithms studied include:The first experiment discusses the topic property of the rank result. We introduce the entropy on topic distribution. The entropy is calculated by:Notice that we use the topic distribution on the original tweets here because original tweets are posted by a user to express his or her own interests. Then, we obtain the average entropy of users grouped in ranking list order as 1-10, 11-20, 21-30, 31-40 and 41-50. The comparison results are demonstrated in From the results, it is obvious that the users ranked by TD-Rank and TwitterRank have far less entropy compared with PageRank and LeaderRank, indicating that our proposed algorithm finds topic-related influential leaders similarly to TwitterRank. Moreover, in v edges which link v fake followers to every user and observe the positional changes in the ranking.Another issue concerning the ranking results is the problem of robustness. Many spammers exist in social networks who attempt to gain reputation for advertising purposes . To invev fake spammers and compare the positional changes in both ranking results. The whole process is described as follows. Suppose the user is i, we randomly select v users denoting as {u1, u2, …, uv}. Then following directed links are created to disturb the algorithm: { < u1, i >, < u2, i >, …, < uv, i >}. The results are reported in Specifically, we simulate the situation where a user creates v spammers. As result, the diagonal line is the baseline, which indicates the rank is invariant. Vertical shift from the diagonal line corresponds to the change of ranking results. In addition, for ease of visualization, we select the ranking list on topic #1 as an example to show the comparative performance of TwitterRank and TD-Rank. As shown, TD-Rank is the most robust against spammers because the changes in ranking positions are much smaller than those of the other algorithms, and TwitterRank is more robust than PageRank and LeaderRank. Therefore, the results are mainly due to the distinguishing topics. In all, TD-Rank is a better algorithm for creating robust rankings in social network.The horizontal axis of The next issue is influence maximization. We first consider two information-diffusing models in previous work .Independent Cascade (IC) Model: This model begins with an initial set of active nodes. The process unfolds in discrete steps. When node v first becomes active in step t, it has a single chance to activate each currently inactive neighbor w based on parameter pv,w. In our experiment, we set the parameter pv,w uniformly to 0.1.Topic Independent Cascade (TIC) Model: This model uses the same process as IC, but its the parameter pv,w is related to topic. Specifically, the probability of diffusion is defined as:v on topic t, and v on w on topic t.We conduct experiments on IC and TIC with the top 10 users in every ranking results consisting of the initial set of active nodes. In addition, the top 10 users in TD-Rank and TwitterRank are also selected from the ranking list of topic #1 as additional experiments. The results are shown in Because it ignores the effects of topic distribution, the IC model is more suitable for a comprehensive ranking algorithm. However, it is worth noting that TD-Rank converges to a stable number faster than the others, which indicates that TD-Rank is more inclined to measure the influence of users on one particular topic with a smaller population. Compared to TIC, TD-Rank and TwitterRank calculate the influence on more users by considering topic effects. In all, this experiment shows the essential value of taking the topic factor into account.i is denoted by di, we then evaluate the influence-predicting performances of all the algorithms using the mean squared error (MSE) as the evaluation metric:k posted by user i, N is the number of users, and Vi(k) is the real value.We also extracted the number of retweets for several tweets posted by the top 50 users in the whole dataset. Then, we investigated the differences between this true retweet number and the number obtained by TIC. Assuming that the set of tweets posted by user The predictions’ MSEs are presented in As shown in MTID) model, which decomposes the influence of a particular user into two parts: direct influence, which is influence related to that user’s followers, and indirect influence, which is influence that is not restricted to direct followers. To cope with the definition of indirect influence, we introduced topic ground nodes that represent topic pools for establishing links between users. Moreover, to deal with the transition probability, we adopted a data-based approach that extracts the topic distribution from traces of tweets. Based on MTID, we further proposed a topic-dependent rank (TD-Rank) algorithm to identify the topic aware influential leaders. Finally, we conducted extensive experiments comparing the existing ranking algorithms using the Spark platform. The experimental results demonstrated that our proposed algorithm is more robust, more accurate and more sensitive to topic than previous algorithms.In this paper, we focused on discovering multi-topic influential leaders in social network. We proposed a multi-topic influence diffusion (Our plans for future work include dealing with the dynamic structure of a following social network by incorporating a time factor into our model. We will also consider other influence measures in the future.


Distal pancreatectomy (DP) is a surgical procedure performed to remove the pancreatic tail jointly with a variable part of the pancreatic body and including a spleen resection in the case of conventional distal pancreatectomy or not in the spleen-preserving distal pancreatectomy.In this article, we describe a standardized operative technique for fully robotic distal pancreatectomy.In the last decade, the use of robotic systems has become increasingly common as an approach for benign and malignant pancreatic disease treatment. Robotic Distal Pancreatectomy (RDP) is an emerging technology for which sufficient data to draw definitive conclusions in surgical oncology are still not available because the follow-up period after surgery is too short (less than 2 years).RDP is an emerging technology for which sufficient data to draw definitive conclusions of value in surgical oncology are still not available, however this techniques is safe and reproducible by surgeons that possess adequate skills. Distal pancreatectomy (DP) is a surgical procedure performed to remove the pancreatic tail jointly with a variable part of the pancreatic body and including a spleen resection in the case of conventional distal pancreatectomy or not in the spleen-preserving distal pancreatectomy. In this article we describe a technical note on RDP.After the induction of general anesthesia, the patient’s arms are abducted and his legs are spread apart in order to allow the placement of the assistant surgeon. A nasogastric tube and urinary catheter are also applied. After preparation of the skin with povidone-iodine is completed, the abdomen is insufflated with CO2 using a veress needle through a one millimeter diameter periumbilical incision. The ınsufflator is set to a constant pressure of 12 mmHg. The trocars are placed following a concave and arcuate line Figure . In thiset al., who presented their experience on this topic [In 1913, Mayo standardized the surgical procedure for DP . Currentis topic –13. LDP is topic , 15, a sis topic , flexibiis topic , and thuis topic . HoweverRDP is an emerging technology for which sufficient data to draw definitive conclusions of value in surgical oncology are still not available and for which the follow-up period after surgery is too short (less than 2 years) ; howeverWritten informed consent was obtained from the patient for the publication of this report and any accompanying images.


Molecular Neurodegeneration: Basic Biology and Disease Pathways" in a number of state-of-the-art manuscripts that cover themes presented at the Third International Conference on Molecular Neurodegeneration: "Basic biology and disease pathways" held in Cannes, France, September, 2013.The field of neurodegeneration research has been advancing rapidly over the past few years, and has provided intriguing new insights into the normal physiological functions and pathogenic roles of a wide range of molecules associated with several devastating neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, and Down syndrome. Recent developments have also facilitated initial efforts to translate preclinical discoveries toward novel therapeutic approaches and clinical trials in humans. These recent developments are reviewed in the current Review Series on " Basic biology and disease pathways" was held in Cannes, France. The three-day conference brought together scientists from around the world to present and discuss the results of their most recent research on the normal physiological functions and pathological mechanisms of molecular pathways that are relevant to neurodegenerative diseases (Figure Molecular Neurodegeneration: Basic Biology and Disease Pathways", is intended to represent not only the scientific findings presented during the conference, but to also reflect the state-of-the-art in a given field. The review series will consist of a "rolling submission" format in which manuscripts by presenters at the conference will appear at regular intervals in the journal.In September 2013, the Third International Conference on Molecular Neurodegeneration: "The conference covered a wide array of topics concerning neurodegeneration at the genetic, molecular, cellular, physiological, behavioral, and systems levels, and with a translational perspective of moving discoveries from preclinical models into human clinical trials. Sessions discussed the following areas of neurodegeneration research: The genetics of AD and other neurodegenerative diseases The structure and normal physiological functions of molecules involved in neurodegeneration Novel molecular mechanisms of AD, PD, ALS, FTD, DS, and HD Mechanisms of neurotoxicity in PD, AD and other tauopathies Novel therapeutic approaches for neurodegenerative diseasesMolecular mechanisms of neurodegeneration were dominant themes of the conference. Some highlights included novel insights into AD pathogenesis provided by genetic analyses revealing new AD risk factor genes like CD33 and TREM2 involved in innate immunity–4. DeepeIn summary, this review series aims to encapsulate the themes discussed at the Third International Conference on Molecular Neurodegeneration and provide state-of-the-art knowledge of a wide range of fields in neurodegeneration research. It is the hope of the editors that the knowledge conveyed in the review series will provide quality information to readers and stimulate further scientific advances in molecular neurodegeneration that may someday bring an end to these devastating neurodegenerative disorders.


Mycobacterium bovis alone or together with other acid fast bacilli (AFB).This study was aimed to determine the prevalence of bovine tuberculosis (bTB) in slaughtered cattle in Bauchi State, Nigeria. The cause (s) of grossly suspected bTB lesions encountered at the abattoirs during post-mortem (PM), as whether due to A cross-sectional abattoir based study was conducted on 800 cattle slaughtered in the Northern, Central and Southern zonal abattoirs of Bauchi State, Nigeria, from June to August 2013; using PM meat inspection, Ziehl-Neelsen staining (ZN) and confirmatory polymerase chain reaction (PCR) techniques.The occurrence of bTB lesions from the organs of slaughtered cattle in Bauchi State, showed that the lungs had the highest number of suspected tissues 65 (54.20%), followed by the lymph nodes 28 (23.30%) while the heart, liver, spleen, intestines and mammary glands had the other 8.3%, 6.7%, 5.0%, 1.7%, and 0.8%, suspected tissues respectively. By ZN microscopic staining all 100% (2/2) of the intestines were positive for bTB, followed by the heart with 50% (5/10), then the lungs 29.23% (19/65); while the liver, lymph nodes, and spleen had 25%, 21.43% and 16.67% respectively were tested positive for bTB. It was only the mammary gland that tested negative for bTB in all the suspected tissues sampled. By PCR, the intestines had the highest positive bTB with 100% (2/2), followed by the liver with 12.5% (1/8), and then the lungs with 7.8% (5/65). The lymph nodes had 7.14% (2/28) tissues that tested positive for bTB. However, the spleen, heart and mammary gland were all tested negative with 0%; indicating that the false positive for bTB detected by ZN were confirmed by PCR. While based on the location of the abattoirs in the three senatorial zones of Bauchi State, Bauchi zonal abattoir had the highest number of suspected bTB cases 75 (62.50%), followed by Katagum zonal slaughter house with 32 (26.7%) and then Misau with 13 (10.8%). By the ZN staining technique, there were 25 (33.33%) positivity in Bauchi Zonal abattoir, while Katagum and Misau abattoirs had 9 (28.13%) and 1 (7.72%) positive respectively. By the PCR technique, 9 (12.00%), 1 (3.13%) and 0 (0.00%) positive cases were recorded for Bauchi, Katagum and Misau abattoirs respectively.M. bovis alone, as other MTBC and AFB organisms may cause bTB-like lesions that were excluded by PCR specific primers. The prevalence of bTB was higher in Bauchi abattoir that supplies larger population of the state with beef. These findings also demonstrate the urgent need for public health authorities in the state to intervene in the control of the zoonotic bTB.The present study estimated the prevalence rate of bTB in Bauchi State, using PM, ZN and PCR techniques at 15.0%, 29.16% and 8.33%, respectively. Bovine TB lesions found at PM were not all due to  Mycobacterium TB complex (MTBC) from humans in industrialized countries [Tuberculosis (TB) remains a major global public health problem. The World Health Organization (WHO) estimates that there are 8 million new cases and 3 million deaths directly attributed to the disease each year . This maountries .Bovine TB (bTB) is a chronic infectious and contagious zoonotic disease of domestic animals, wild animals and humans . It alsoMycobacterium bovis that is a member of MTBC [Mycobacterium TB complex (MTBC), include: Mycobacterium TB, Mycobacterium bovis, Mycobacterium microti, Mycobacterium caprae, Mycobacterium africanum, Mycobacterium canettii, and Mycobacterium pinnipedii. Mycobacterium africanum consists of a rather heterogeneous group of strains isolated from humans in Africa [. Mycobacterium bovis, otherwise known as the bovine tubercle bacillus is the cause of bTB, and the organism may be transmitted by aerosol or droplets of exudates containing the bacilli. It can be transmitted by ingestion of feed and water contaminated with urine, fecal material or exudates that contain the tubercle bacilli from diseased animals [Bovine TB is caused by  of MTBC ,13. The n Africa . Mycobac animals . The bov animals . Cattle  animals .M. bovis via direct inoculation . Referred to as the Butcher’s Wart , this skin lesion can occur in persons handling infected meat. It is very rare and generally self-limiting. Because M. bovis is either enzootic or found sporadically in much of the developing world, there is clearly a risk of cow to human transmission by either ingestion or inhalation [In rare cases, humans can become infected with halation .M. bovis) to retail markets and finally to the consumers (public).As a result of the lack of surveillance data, the actual scope of the problem is unknown. However, our abattoir settings in Nigeria could always be a hazard and critical control points where thorough examination are needed to control the entry of foodborne pathogens  examination of carcasses, as a diagnostic technique, Ziehl-Neelsen (Z-N) staining and polymerase chain reaction (PCR) were used to determine the prevalence of bTB in some Local Government Areas in the State while questionnaire administration was used to determine the public health awareness of the people at risk  were carried out. The three major slaughter houses namely Bauchi, Misau, and Katagum (Azare) in each of the three senatorial zones of Bauchi State were selected for the study for sampling purposes, based on their daily slaughter capacity and socio-economic impact of the abattoir. Accordingly, out of the 800 cattle examined (sample size), a proportionate distribution was employed, given a share of 50% (400) to Bauchi abattoir and 25% (200) each to Katagum and Misau slaughter houses. This was based on their daily slaughter capacity of 40-60, 20-30 and 20-25 cattle from Bauchi abattoir, Katagum, and Misau slaughter houses, respectively.Cattle slaughtered at Bauchi, Katagum and Misau abattoirs were the subjects of the study. Their respective breeds, sexes, and ages were recorded during sampling.Abattoir selection was based on convenient and the daily slaughter capacity of the abattoirs, accessibility of the abattoir to the public and its socio-economic impact on the State. The Bauchi abattoir along with Katagum and Misau abattoirs were therefore selected.2 PQ/d2 - Ass described by [N=Zribed by Where: N = sample sizeZ = value for the corresponding confidence level P = estimated value for the proportion of a sample/expected prevalenceQ= 1-P, d= is the margin of error A sample size of 730 cattle was estimated from the expected prevalence rate of 1.72%  as descrM. bovis diagnosis was confirmed following proper meat inspection by microbiological identification and characterization of the etiological agent using ZN stain and PCR, respectively.Cattle brought in for slaughter were routinely subjected to procedures such as ante-mortem inspection and PM examination (by meat inspectors), before the carcasses were conveyed to the market. PM examinations of the carcasses were carried out by carefully inspecting the lymph nodes of the head, tonsils, thoracic cavity, and abdomen, including deep and superficial cervical, popliteal and sacral lymph nodes. The meat inspection procedures employed visual examination and palpation of the lungs, liver, kidneys, lymph nodes of the carcass including the mesenteric lymph nodes and intestines. For this study, diagnosis of bovine TB was based on gross detection of typical tubercle, yellowish granulomatous caseated lesions or sometimes ‘gritty’ calcification in carcasses in the above-mentioned organs on incision and with the use of protective clothing. In addition, all nodular lungs were carefully inspected visually, palpated and incised -26. AginAll suspected tissue samples from cattle with suspected bTB-lesions were collected into sterile screw capped containers  and transported inside a cooler containing ice pack to the Department Veterinary Public Health and Preventive Medicine, Bacterial Zoonoses Laboratory, Ahmadu Bello University, Zaria and stored at −20°C until analyzed. Stored samples were processed for microscopic examination (Modified ZN staining technique).All suspected tissues that were collected from the abattoirs and stored at −20°C were thawed to room temperature and then processed for ZN Staining technique according to the method of , to deteThe tissue samples positive by ZN were collected into a 1.5 ml microfuge tube containing lysis buffer, stored at room temperature and transported on ice pack to DNA-Labs, Kaduna. About 1 g of the tissue sample was homogenized with pestle and mortar for chromosomal DNA extraction using a phenol-chloroform technique as described by ,30. The 2 was used. All amplification reactions were performed using a Perkin Elmer Thermocycler (Perkin Elmer Cetus) programed for 40 amplification cycles. The reaction was performed in a final volume of 50 μl containing 10 μl of DNA Template, ×1 TE reaction buffer (containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.3mM MgCl2, and 0.001% of gelatin), 2.5 U Taq polymerase, 0.2 mM of each deoxynucleoside triphosphate, and 75 pmol of each primer . DNA from M. bovis ATCC 19210 and BCG Pasteur 27291 and sterile nuclease-free water were used as positive and negative PCR controls, respectively. After an initial denaturation step , 40 amplification cycles were performed as follows: Denaturation at 94°C for 1 min, annealing at 58°C for 30 s and extension at 72°C for 30 s; with an increment of 1 s per cycle for the denaturation and extension segment. A final extension was performed at e72°C for 15 min [A volume of 10 µl suspended DNA was used as a template for PCR amplification under standard conditions as described by . A commer 15 min .The occurrence of bTB lesions from the organs of slaughtered cattle in Bauchi State, showed that the lungs had the highest number of suspected tissues 65 (54.20%), followed by the lymph nodes 28 (23.30%) while the heart, liver, spleen, intestines and mammary glands had the other 8.3%, 6.7%, 5.0%, 1.7%, and 0.8%, suspected tissues respectively . By ZN mM. bovis and other MTBC) identified from suspected tissue sample after the Ziehl-Neelsen (ZN) staining.In The findings that, 120 (15%) bTB suspected lesions were observed in the 800 slaughtered cattle examined in Bauchi State abattoirs had emphasized the importance of PM meat inspection. This agrees with the report of , as PM eM. bovis alone as MTBC and other AFB organisms, like Norcardia asteroides may be involved while 35 (29.16%) of the 120 suspected bTB lesions were positive by ZN.The present study also showed that, the highest number of suspected bTB cases was recorded in Bauchi abattoir, followed by Katagum, and then Misau with the least number. This could be due to the socio-economic impact, as a result of high patronage with the resultant increase in daily slaughter capacity associated with the Bauchi metropolitan abattoir than the other two abattoirs. Many researchers have reported relatively higher prevalence rates of bTB in various parts of Africa. In Chad, about 9% of the inspected cattle were condemned because of bTB in slaughter houses as reported by Maho et al . IbrahimThe prevalence rates shown in this study is much higher in female cattle than in male cattle. However, there was no statistically significant association between sex of cattle with bTB by ZN technique as earlier observed by  and alsoThe age-related increase in the prevalence rate shown in this study by both ZN and PCR was consistent with the chronic pattern of TB in cattle reported by ,40. AnimM. bovis alone, as other MTBC and AFB organisms may cause bTB-like lesions that were excluded by PCR specific primers. The study recommended that, a proper PM meat inspection should be practiced efficiently at the abattoirs and slaughter houses, before taking beef to the retail markets and thereby to the public. The emergence MDR and XDR-TB strains are also a major concern in Nigeria. Thus, further molecular epidemiological studies with more improved techniques, like MIRU-VNTR and Spoligotyping, should be carried out on isolates from the state to look for other zoonotics, like M. africanum.The present study estimated the prevalence rate of bTB in Bauchi State, using PM, ZN and PCR techniques at . Bovine TB lesions found at PM were not all due to ASS: Designed the study, did the sampling, run the laboratory techniques including the Ziehl-Neelsen staining technique and wrote the first draft of the manuscript. ECO: Supervised the whole research and reviewed the manuscript. AAG and MB: Contributed in the data collation and managed the data analyses of the study. NAB: Did the literature searches, part of data analyses and financial contribution. All authors read and approved the final manuscript.


Objective. To evaluate the efficacy and safety of Kushenin (KS) combined with nucleoside analogues (NAs) for chronic hepatitis B (CHB). Methods. Randomized controlled trials (RCTs) of KS combined with NAs for CHB were identified through 7 databases. Frequencies of loss of serum HBeAg, HBeAg seroconversion, undetectable serum HBV-DNA, ALT normalization, and adverse events at 48 weeks were abstracted by two reviewers. The Cochrane software was performed to assess the risk of bias in the included trials. Data were analyzed with Review Manager 5.3 software. Results. 18 RCTs involving 1684 subjects with CHB were included in the analysis. KS combined with NAs including lamivudine (LAM), entecavir (ETV), adefovir dipivoxil (ADV), and telbivudine (TLV) showed different degree of improvement in CHB indices. KS combined with NAs increased the frequency of loss of serum HBeAg, HBeAg seroconversion, undetectable HBV-DNA levels, and ALT normalization compared with single agents. It also decreased serum ALT and AST level after one-year treatment. However, KS combined with TLV did not show a significant difference in CHB indices. The side-effects of KS combined with NAs were light and of low frequency. Conclusion. KS combined with NAs improves the efficacy of NAs in CHB. Chronic hepatitis B (CHB) is a global health problem with an estimated 400 billion people worldwide being chronically infected with the virus (HBV) . ChronicCurrently, available treatments include interferon-alfa, nucleos(t)ide analogue polymerase inhibitors, such as lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine, and tenofovir (TLV), used alone or in combination with 2 or more agents . Interfe Yellow Emperor's Internal Classic, an ancient book containing records of TCM, indicates that TCM was used to treat chronic liver disease in China since 475 BCE at least [Traditional Chinese medicine (TCM), one of the complementary and alternative therapies, is often used in cholestasis treatment in China . The Yelat least . The objat least . Sophora flavescens Alt. (Kushen in Chinese). Evidence-backed studies reveal its effectiveness in treating hepatocyte injury, chronic hepatitis B, liver fibrosis, and tissue inflammation [Kushenin (KS) is a mixture of the alkaloids oxymatrine (the main content > 98%) and oxysophocarpine, extracted from the root ofammation . It has ammation . Under tammation –17. It hammation .Nowadays, the combinations of KS with NAs for CHB treatment have attracted more and more attention. It demonstrates a promising therapy of the combinations of KS with NAs for CHB treatment in clinic. Therefore, this meta-analysis of RCTs was conducted to assess the clinical value of KS combined with NAs for the treatment of CHB, which provides a possible complementary and alternative therapy for global application.Comprehensive searches of English and Chinese databases were performed by two researchers. The databases included PubMed, Embase, Cochrane Library, Chinese Biomedical Database (CBM), Wanfang, VIP medicine information system (VMIS), and China National Knowledge Infrastructure (CNKI), and the dates ranged from the establishment of the different databases through 2015. Search terms included Kushenin, chronic hepatitis B, HBV, CHB, and randomized controlled trial. The first author, year of publication, title, and journal name of the articles were recorded for further screening.The inclusion criteria were as follows. (1) There are randomized controlled trials (RCTs). (2) The diagnostic criteria for CHB were serum hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive for more than 6 months, with elevating levels of serum alanine aminotransferase (ALT). (3) Studies were selected for analysis if there was an objective outcome, including ALT normalization, loss of serum HBeAg, and/or undetectable serum HBV-DNA. (4) Intervention therapies with combinations of KS with NAs or single application were included.The exclusion criteria were as follows. (1) There are studies of patients who were coinfected with HIV, HCV, or HDV. (2) Patients did not present any severe complications, such as hepatic failure and cirrhosis. (3) Studies did not report any efficacy measures or not conveying sufficient statistical information. (4) There are studies without equal baseline or endpoint of outcome measure.Data extraction and quality assessment were independently performed by two researchers and disagreements were resolved by consensus. Detailed data such as data source, eligibility, methods, participants, interventions, and study results were imported into Cochrane Review Manager 5.3  for further analysis.The Cochrane risk of bias tool was used to assess the methodological quality of included RCTs. The six domains of this tool include random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome data (attrition bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). The judgment was marked as “high risk,” “unclear risk,” or “low risk.” Trials that met all the criteria were categorized as low risk of bias, whereas those that met none were categorized as high risk of bias. The others were classified as unclear risk of bias if the information was insufficient to make a judgment.Q test. Only data with low heterogeneity (P ≥ 0.10 and I2 ≤ 50%) were assessed as a fixed-effects model whereas others were assessed as a random-effects model. A funnel plot was used for assessing the potential publication bias.Statistical analysis was performed by Cochrane Review Manager 5.3 . Dichotomous data were presented as odds ratio (OR) and continuous variables as mean difference (MD), with 95% confidence intervals (95% CI). Statistical heterogeneity was assessed by Cochrane's A total of 891 records were identified for initial screening and 18 eligible articles were included in this meta-analysis . There wAccording to Cochrane risk of bias estimation, randomized allocation of participants was mentioned in all trials. All the trials were classified using a random number table –29. ThreP < 0.00001). KS + ETV and KS + ADV group also suggested a significant effect on it and their values were OR = 2.04, 95%  CI = 1.37–3.04, P = 0.0005 and OR = 2.08, 95%  CI = 1.33–3.27, P = 0.001, respectively. However, there was no significance in KS + TLV group, which could be caused by the small scale of the patients   .P = 0.001). KS + ETV group showed a significant effect on HBeAg seroconversion rate compared with ETV group . KS + ADV group also exhibited a significant effect on it and the values were OR = 2.84, 95%  CI = 1.49–5.43, and P = 0.002. However, there was no significance in KS + TLV group, which could be caused by small scale of the patients   .P = 0.002). 69.3% of patients in KS + ETV group and 51.5% of patients in ETV group reached undetectable serum HBV-DNA levels, and there was also a significant difference between two groups . Moreover, 54.5% of patients in KS + ADV group and 43.5% of patients in ADV group reached the undetectable levels, and KS + ADV group showed a significant effect on undetectable serum HBV-DNA rate at 48 weeks , whereas there was no significance in KS + TLV and TLV group , which could be caused by small scale of the patients . After 48-week treatment, 83.1% of patients in KS + LAM group and 73.5% of patients in LAM group reached undetectable serum HBV-DNA levels, and there was a significant difference between two groups . ALT normalization rate of KS + ADV reached 87.1% and ADV alone reached 64.7% at 48 weeks, indicating a significant difference between two groups . However, 81.8% of patients in KS + ETV group and 75.9% of patients in ETV group got ALT normalization. There was no significant difference between two groups  . After 48-week treatment, 94.3% of patients in KS + LAM group and 85.9% of patients in LAM group got ALT normalization. There was a significant difference between those two groups  .P < 0.00001 in ALT; MD = −10.26, 95%  CI = −12.57– − 7.95; P < 0.00001 in AST). Serum ALT and AST level also decreased lower in KS + TLV group than in TLV group at 48 weeks . Both of KS + LAM and KS + TLV groups indicated a good favorable curative effect on decreasing serum ALT and AST levels (Serum biochemical indices such as serum ALT, AST levels were detected. The results indicated that serum level of ALT and AST decreased lower in KS + LAM group than in LAM group at 48 weeks (MD = −7.12, 95%  CI = −8.89–−5.27; T levels .It was worth noting that no serious adverse event happened in the clinical trials. Among 18 RCTs, 5 trials displayed light digestive tract symptom and 2 trials showed dizziness or fatigue during treatment, but all the symptoms disappeared later. In spite of no difference between trial and control group, further investigation is needed for a systematic safety assessment of combinations of KS with NAs .In this study, 18 RCTs involving 891 subjects with CHB were included. The combinations of KS with the main NAs therapy medicine including LAM, ETV, ADV, and TLV were conducted to explore the curative effect. Some CHB indices were selected to represent the curative effect. The loss of serum HBeAg and HBeAg seroconversion rate are considered as indicators of the patients transition to a state of substantially lower HBV replication, which when maintained is likely to be associated with improved long-term clinical outcomes and so are undetectable serum HBV-DNA and ALT normalization rate . The indIn the meta-analysis, KS combined with LAM, ETV, or ADV showed a good curative effect after one-year treatment, which indicated that different improvement of chronic hepatitis B indices included loss of serum HBeAg, HBeAg seroconversion rate, and undetectable serum HBV-DNA. However, KS combined with TLV could enhance the loss of serum HBeAg, HBeAg seroconversion rate, undetectable serum HBV-DNA rate, and ALT normalization rate but did not show a significant difference. Serum ALT and AST level obviously decreased in combination therapy in meta-analysis, which suggested the hepatoprotective effects. This could be caused by small sample size and multicenter and large-scale randomized trials of KS combined with TLV needed are further carried out.It is still difficult to draw firm conclusions since the studies reviewed here are flawed in some areas. First, the quality of the studies determines the quality of such analyses, and the studies included in this investigation had shortcomings in methodology. Second, the present meta-analysis was based on 18 published RCTs. The relatively small size of the study was a limitation since it restricts statistical power and may explain why some of the changes did not reach statistical significance. Furthermore, only one of the RCTs in this meta-analysis measured follow-up beyond 24 weeks and most of the RCTs did not measure follow-up. Due to this, statistical power of this analysis cannot define the long-term efficacy of combinations of KS with NAs.Therefore, the methodological quality of clinical trials with KS combined with NAs for chronic hepatitis B needs to be improved. Rigorously designed, large randomized, double blind, placebo-controlled trials are required to confirm the efficacy of KS combined with NAs in chronic hepatitis B. The outcome measures should include logical changes, liver pathology, and endpoint events. Adverse events should be monitored by a standardized effective reporting system in clinical trials and rare serious adverse events can be observed through epidemiological studies.The systematic review and meta-analysis indicate that the combinations of KS with NAs not only enhance the indexes of loss of serum HBeAg and HBeAg seroconversion, but also improve the undetectable serum HBV-DNA rate and ALT normalization rate to a certain degree. Meanwhile, there is no obvious adverse effect. In summary, KS combined with NAs could be a beneficial and safe treatment approach for patients to improve the comprehensive efficacy of CHB. Considering being accepted by more and more practitioners, further rigorously designed, multicenter, large-scale trials with higher quality worldwide are required.


Concern has been raised regarding the potential contributions of veterinary antimicrobial use to increasing levels of resistance in bacteria critically important to human health. Canine pyoderma is a frequent, often recurrent diagnosis in pet dogs, usually attributable to secondary bacterial infection of the skin. Lesions can range in severity based on the location, total area and depth of tissue affected and antimicrobial therapy is recommended for resolution. This study aimed to describe patient signalment, disease characteristics and treatment prescribed in a large number of UK, primary-care canine pyoderma cases and to estimate pyoderma prevalence in the UK vet-visiting canine population.Of 54,600 dogs presented to 73 participating practices in 2010, 683 (1.3%) had a pyoderma diagnosis recorded in available electronic patient record (EPR) data. Antimicrobials were dispensed in 97% of cases and most dogs were prescribed systemic therapy (92%). Agents most frequently prescribed were amoxicillin-clavulanate, cefalexin, clindamycin and cefovecin. Systemic antimicrobials were prescribed for fewer than 14 days in around 40% of study cases reviewed in detail. Prescribed daily doses were below minimum recommended daily dose (MRDD) in 26% of 43 dogs with sufficient information for calculation of minimum dose.Antimicrobial prescribing behaviour for treatment of canine pyoderma was variable but frequently appeared inconsistent with current recommendations. Use of clinical data from primary practice EPRs can provide valuable insight into common clinical conditions and associated prescribing.The online version of this article (doi:10.1186/s12917-014-0240-5) contains supplementary material, which is available to authorized users. S. pseudintermedius. Other staphylococcal  and non-staphylococcal bacteria  can also be isolated from affected skin in some cases. While these species can act as primary pyoderma pathogens, particularly in immune-compromised patients, they are usually secondary infectious agents or simply lesion contaminants ) was used to select a subset sample of at least 10% of the dogs identified as pyoderma cases by the initial search criteria. These selected cases were reviewed in depth, including evaluation of disease and treatment details, follow-up of clinical progression and validation of the initial case-finding approach. Queries were designed to extract all clinical entries associated with these dogs from the original database on dates up to and including the 31st December 2011. Chronological review of all available free-text clinical history was undertaken for each dog to assess the validity of selection as a pyoderma case and to describe pyoderma lesion depth, underlying cause and treatment-related information in greater detail.Pyoderma depth was categorised as either ‘surface’ , ‘superficial’ , ‘deep’ , or ‘mixed’ based on lesion description statements recorded by the examining clinician . Cases wAdditional treatment-related data extracted for this subset included the daily dosing instructions and total number of units (tablets/capsules/volume of injectable formulation) of any initially prescribed systemic antimicrobial agent dispensed across all consecutive prescribing events during the studied pyoderma episode. Based on calculations using patient weight (as recorded on the date of diagnosis) and drug manufacturers’ recommended daily dose (MRDD) rates for treatment of canine pyoderma , dogs wed. Concurrent prescription of shampoos or liquid washes (including non-medicated products) was noted to reflect the intention for regular physical bathing of the skin and coat.Non-antimicrobial treatments prescribed or administered to study dogs concurrently with the systemic antimicrobial agent of interest were also recorded. Where appropriate, prescribed products were classified  into one or more of the following categories, highlighted due to their potential relevance in cases of skin infection: Systemic steroids, antifungal agents and anti-ectoparasitic agentsData were cleaned in Microsoft Excel . Statistical analysis was carried out using Stata . Variables were categorised where required. Descriptive statistics were calculated for all study dogs with respect to signalment factors and antimicrobial product/s prescribed within 24 hours of recorded diagnosis of the pyoderma episode of interest.Additional descriptive statistics were calculated for the randomly selected subset of pyoderma cases described in greater detail, including lesion depth, duration of systemic antimicrobial treatment prescribed and adequacy of prescribed daily dose compared with MRDD. The extent of missing or insufficiently specific data was summarized. Mean and standard deviation or median and range were used for the description of quantitative data as appropriate while qualitative data were described using frequencies with percentage of stated totals.aRVC Ethics Committee, March 2009.bThe recording format of the PMS used by participating practices included opportunities for standardised terminology based on the VeNom codes.cStudy protocol included a list of terminology accepted as compatible with pyoderma for study purposes, based on clinical codes defined by the VeNom Coding group. Some notable exceptions were also specified, e.g. pyotraumatic dermatitis.dFull category listings are provided in Additional file


AbstractHirudisoma roseum , is still in use, yet requiring a neotype designation, whereas the remaining few myriapod names he proposed are either nomina dubia or nomina nuda. The former include Scolopendra pentagramma Motschoulsky, 1866  and Strongylosoma carinulatum Motschoulsky, 1866 , both from Japan, as well as Julus costulatus Motschoulsky, 1851 , from Montenegro, because their type material is either inadequate or missing.The little that remains of Motschoulsky’s myriapodological legacy in the collection of Moscow’s Zoological Museum proves to be of very limited value. Only one species of Diplopoda described by Motschoulsky, the Caucasian  With the recent publication of V. I. Motschoulsky’s memoirs  and sevePageBreakMotschoulsky’s published contributions to myriapodology are very few, but even these have largely remained neglected. To my knowledge, no-one has ever attempted to revise any of Motschoulsky’s myriapod types.Myriapoda still contains Motschoulsky’s original wooden box full of dry pinned animals , and only a couple of larger Scolopendridae specimens. Much of the material is in poor condition, damaged by dermestid beetle larvae.The Moscow Museum collection of  animals ! There aPageBreakPolydesmus complanatus (L.)” or “Scolopendra spinula Brandt”) or bear provisional names marked as “mihi”. These latter specimens must be considered as nomina nuda. One such name has even been published: Julus melanocephalus Motschoulsky, 1851, said to be very common across Montenegro, even though specimens were clearly smaller near Cattaro  Victor, 1839, from eastern Georgia, Caucasus    , most ofeum e.g.  are inco39) e.g. . Even thJulus costulatus Motschoulsky, 1851, from the environs of Cattaro (= Kotor), Montenegro, has long been considered as a putative synonym of either Apfelbeckia insculpta  or Acanthopetalum carinatum   . Since nn dubium .Scolopendra pentagramma Motschoulsky, 1866 (ZMUM ρ7449) and 3 syntypes of Strongylosoma carinulata (recte: -tum) Motschoulsky, 1866 (ZMUM ρ2376), both species coming from unknown localities in Japan. As their original descriptions . NB: Only three species of Scolopendra are currently known to occur in Japan, Scolopendra morsitans Linnaeus, 1758, Scolopendra subspinipes  and Scolopendra multidens Newport, 1844 . In this case, Motschoulsky’s Scolopendra pentagramma, if identifiable, would anyway represent a junior synonym of one of the above three species.A careful search for type material has revealed two type series only: the holotype of riptions  are anecriptions , they hariptions . UnfortuStrongylosoma carinulatum  are later juvenile instars of a paradoxosomatid millipede, thus being absolutely inapt for revealing the species’ identity. In other words, both Scolopendra pentagramma Motschoulsky, 1866 and Strongylosoma carinulatum Motschoulsky, 1866 are also doomed to remain nomina dubia.Similarly, all 3 syntypes of Diplopoda described by Motschoulsky, the Caucasian Hirudisoma roseum , is still in use, yet requiring a neotype designation, whereas the remaining few myriapod names he proposed are either nomina dubia or nomina nuda.To summarize, the little that remains of Motschoulsky’s myriapodological legacy in the collection of the Moscow Museum proves to be of very limited value. However, even the negative result is a result. Only one species of PageBreak


We sought to design a free energy calculation scheme with the hope of saving cost for generating dynamical information that is inherent in trajectories. We demonstrated that snapshots in a converged trajectory set are associated with implicit conformers that have invariant statistical weight distribution (ISWD). Since infinite number of sets of implicit conformers with ISWD may be created through independent converged trajectory sets, we hypothesized that explicit conformers with ISWD may be constructed for complex molecular systems through systematic increase of conformer fineness, and tested the hypothesis in lipid molecule palmitoyloleoylphosphatidylcholine (POPC). Furthermore, when explicit conformers with ISWD were utilized as basic states to define conformational entropy, change of which between two given macrostates was found to be equivalent to change of free energy except a mere difference of a negative temperature factor, and change of enthalpy essentially cancels corresponding change of average intra-conformer entropy. By implicitly taking advantage of entropy enthalpy compensation and forgoing all dynamical information, constructing explicit conformers with ISWD and counting thermally accessible number of which for interested end macrostates is likely to be an efficient and reliable alternative end point free energy calculation strategy. A and B visited in a set of converged molecular dynamics (MD) simulation trajectories, the free energy difference may be expressed as:For two arbitrary macrostates invariant statistical weight distribution (ISWD) across the whole configurational space , if with pace see . More impace see . TherefoFor ECISWD, It was demonstrated that sequential Monte Carlo (SMC) in combination with importance sampling1Conformers associated with MD snapshots are implicit with no information available for their shapes or sizes, we consequently may not directly learn from MD trajectories. One principal consideration for defining ECISWD is sufficient fineness since statistical weight of complex molecular systems are in general exponentially different for different macrostatesa priori in a real complex molecular system. Nonetheless, complex molecular systems are very different from a double well system. As shown in This hypothesis is immediately disproved by a simple double well system shown in Sufficiently well-converged MD trajectory sets of specific molecular systems provide ideal test grounds for ISWD property of given explicit conformers based on the following two arguments. Firstly, trajectory sets are generated by known force fields, and therefore no convolution of force fields inaccuracy and experimental error exists as in the case of comparing computational results with experimental ones; Secondly, we may arbitrarily partition configurational space visited in a trajectory set, and a hypothesis tested for arbitrarily given partitions should remain true for the whole configurational space. This is an important logic since traversing configurational space for complex molecular systems is practically impossible. The symbolic equivalence between eqs Methods for details).We chose lipid POPC to carry out such tests based on the fact that large MD trajectory sets are available for this molecule. Specifically, we firstly extracted MD trajectories of POPC from trajectories of M2 muscarinic acetylcholine receptor studyMethods for details), which essentially measures differences between our constructed set of explicit conformers and implicit conformers associated with snapshots. Distributions of a priori to divide otherwise. To test further the hypothesis that any sufficiently fine conformers should have similarly good approximation of ISWD, we defined a few more different set of conformers with similar fineness to CONF1 through CONF4 respectively, and similar observations were made . To this end, we plotted Typical molecular systems in chemical, materials and biological studies, when treated quantum mechanically, present intractable complexity. Classical (continuous) representation of atomic DOFs, however, presents an awkward situation for the definition of microstates and entropyIt is well established in the informational theory fieldwith The first terms on the right hand side of eqs With a simple algebraic manipulation shown below:Conformational entropy of macrostate Similarly, denote probability distribution of conformer statistical weights in macrostate For ECISWD, if we denote the corresponding ISWD with a continuous probability density Note that  eq.  is equiveq.  eq.  except aet CONF1  matches gh CONF4  match ouIn canonical ensemble, we have:with While the derivation is carried out in canonical ensemble, it should be applicable for many isobaric-isothermal processes  where change of the In summary, we presented the idea that snapshots in a converged MD trajectory set map directly to implicit thermally accessible conformers with ISWD. Based on the thought that infinite number of ways exist for defining implicit conformers with ISWD for a given molecular system, we hypothesized that any sufficiently fine set of conformers should have sufficiently good approximate ISWD. This hypothesis, while being disproved by a double well potential, tested successfully on extensive MD trajectories of lipid POPC. We think that competition of many DOFs, each allowed to vary significantly in both potential energy and spatial position within a conformer, constitutes the foundation for the observed validity of the hypothesis. Considering the moderate complexity of lipid POPC, it is likely that the hypothesis holds for complex molecular systems in general. This is a useful demonstration of the idea that “More is different”1Trajectory sets TSA1, TSA2 and TSA3 are constructed from snapshots of POPC collected in simulation condition A in the To define conformers, we first take a given set of nal DOFs , with eaTo prepare macrostates, all snapshots in a given trajectory set were projected onto a selected backbone dihedral that was partitioned into 20 18°-windows, snapshots fall within each of which constitute an observed macrostate. Such projections were performed for each of 43 dihedrals  and we hFor a given pair of macrostates .


In this article, we advocate a bottom-up direction for the methodological modeling of interdisciplinary research based on concrete interactions among individuals within interdisciplinary projects. Drawing on our experience in Hearing the Voice , we focus on the dynamic if also problematic integration of cognitive science , phenomenology, and humanistic disciplines . We propose a new model for disciplinary integration which brings to the fore an under-investigated dynamic of interdisciplinary projects, namely their being processes of distributed cognition and cognitive integration. Instead of assessing potential intersections in the theoretical realms of each discipline we suggest that a model for cross-disciplinary work should be derived from (and embrace) concrete interactions among individuals within interdisciplinary projects. By drawing on our experience in a cross-disciplinary project on auditory verbal hallucinations (AVHs) running at Durham University, we focus on the dynamic if also problematic integration of the cognitive sciences , phenomenology, and humanistic disciplines . In the final section, we propose a new model for disciplinary integration which adds depth and complexity to otherwise flat, two-dimensional representations of disciplinary intersections. Importantly, this model brings to the fore an under-investigated dynamic of interdisciplinary projects, namely their being processes of distributed cognition and cognitive integration.2In the last two decades interdisciplinary research has been pursued with increasing vigor within universities, centers, and laboratories all over the globe. However, methodological reflections on interdisciplinary research have not kept pace with this flourishing of cross-disciplinary projects and agendas, and the articulation of a transferable methodology for interdisciplinary work remains the ‘great challenge’ Ref , p. 18. 4 policy,5 and as an object of scholarly inquiry.8 While some have argued for the retention of broad, flexible, and even ‘slippery’ definitions of the term ; interdisciplinary approaches emphasize integration as well as interaction, effecting disciplinary transformation at methodological as well as theoretical levels; finally, in transdisciplinary approaches, research questions and practices are framed by problems arising from the life-world and addressed by academics in partnership with other stakeholders.Although in 1989 it was possible to dismiss interdisciplinarity as ‘the most seriously underthought critical, pedagogical, and institutional concept in the modern academy’ Ref , p. 743,term Ref , p. 14 J11 Advocates argue that interdisciplinary approaches are essential to solving complex real-world problems such as climate change or poverty.12 In sharp opposition to those who would uncritically celebrate interdisciplinarity as the dismantling of disciplinary boundaries in the rapacious pursuit of new knowledge, Robert Frodeman has suggested that interdisciplinary research should be conceptualized in environmental terms as research which ‘recognizes limits—to people’s capacity for understanding, to time and money, and to research itself’  has an important role to play in advancing our capacity to understand and address these challenges from a ‘bottom-up’ perspective.17 For this reason we turn now to the analysis of an interdisciplinary project based at Durham University in the UK: Hearing the Voice (HtV).The practical and institutional challenges of conducting interdisciplinary research are many, ranging from those located at the level of research funding and evaluationa The core research team of 18 Durham-based academics, ranging from postgraduate to professorial level, have primary disciplinary affiliations in the arts, neuroscience, psychology, philosophy of mind, psychiatry, cultural studies, geography, history, literary studies and theology, and work with an extended research team of clinicians, mental health advocates, and people with lived experience of hearing voices. University support for the project in material as well as conceptual terms has been strong: the majority of academic researchers meet fortnightly at the Durham Institute of Advanced Study and work in offices co-located with the interdisciplinary Centre for Medical Humanities.HtV is an ambitious interdisciplinary study of the phenomenon of voice-hearing, or AVH, funded by a 3-year Wellcome Trust Strategic Award .18) their phenomenology is complex, heterogeneous, and not yet well-understood.20 AVHs are reported in nonclinical populations and by patients with a wide variety of diagnoses, they are measured and investigated using a range of empirical methods, as well as variously interpreted and valued in people’s lives across cultures and religious contexts, and as ‘talkative acts’ they are symptoms or experiences which are distinctively amenable to hermeneutic and linguistic analysis. For these reasons, HtV integrates scientific and humanities approaches to voice-hearing to achieve two high-level objectives. First, the project is pursuing multiple interdisciplinary lines of inquiry to attain a new holistic understanding of the phenomenon of voice-hearing, examining its significance as an aspect of personal narrative and as psychiatric symptom, conducting empirical studies into its cognitive and neuroscientific mechanisms, performing culturally sensitive investigations of its personal, social, and historical significance, and leading translational research into its therapeutic management. By drawing on and synthesizing multiple disciplinary perspectives and methodologies, the project seeks to move beyond the limitations inherent in approaching AVHs as discrete objects abstracted from the wider context of human experience or assigning biological psychiatry priority in their explanation. The second high-level objective is to develop a transferable methodology for interdisciplinary research into human experience which can be generalized to other areas of inquiry.Despite the common misperception in clinical and cultural contexts that AVHs are inherently pathological , but rather their recruitment by disciplines such as literary studies,28 narratology,30 esthetics,31 or theology.32 While psychology, phenomenology, and philosophy of mind have exerted an influence on esthetic and cultural theory for over a century, only recently have experimental cognitive disciplines stimulated in the humanities such an array of enthusiasms, biases, and perplexities. Critiques of what has been termed ‘neuromania’33 are two-pronged. On the one hand, it is argued that the proliferation of ‘neuro-labels’  is a fashionable trend and signals no substantial innovation on research hypotheses and outcomes that could have been framed or obtained by already existing disciplines. On the other hand, there is a suspicion concerning the methodological ground of these new ‘interdisciplines’. To what extent should neuroscientific methods inform humanistic research? Is this best conceptualized as a largely one-way interaction? And if not, how can the explanatory and interpretive toolkits of the humanities and social sciences modify the empirical and causal frameworks of cognitive sciences?If the historical separation of the humanities from the ‘hard’ sciences has been extensively theorized,34 has suggested that the cognitive sciences should provide a constraining function for humanistic research. This ‘vertical integration’—according to which hypotheses and method within the humanities should be vertically limited by what the cognitive sciences say can be a testable truth—clearly assigns a hierarchical priority to the scientific field. In what follows we aim to provide a different definition of disciplinary integration based on individuals’ interaction in the HtV project; a definition which can fully accommodate a mutual, more ‘horizontal’ exchange of methods and hypothesis between the cognitive sciences and humanities.Among the supporters of the importance of the cognitive sciences for the esthetic field, Edward Slingerland9 taxonomy of interdisciplinary research assigns to multi- and interdisciplinarity a different degree of disciplinary involvement and plasticity . Through juxtaposition and alignment, multidisciplinarity increases knowledge through encyclopedic additions that leave unaltered the contributing disciplines. The distinguishing feature of a strong interdisciplinarity is instead the proactive processes of interaction and integration. When deep interdisciplinary takes place we have, in Burns’ terms . On the other hand, we want to advocate the importance of considering interdisciplinarity not (only) as a disembodied interaction of disciplines on a theoretical level, but as concrete processes involving individuals’ entanglements in space and time . To put it succinctly, what is missing from Klein’s categorization is a cognitive description of interdisciplinary research. We suggest that looking at what cognitive sciences and cognitively informed phenomenology say about distributed cognition can and should profitably inform models of interdisciplinary research, complementing sociological and ethnographic approaches to the study of actors and agents in contexts of scientific investigation.At the beginning of our project we started by visualizing the project’s four largely discipline-based and one methodological workpackage through a classic Venn diagram .41 and enactive43 cognition.This diagram has proven to be an effective heuristic tool for a preliminary project planning, and for communicating key areas of research to funders and others stakeholders. Yet, after the first year of the project, its limitations have become clear. The Venn diagram has its historical and disciplinary roots in the mathematical branch of set theory. Loosely speaking, its function is to display logical intersections between classes (finite sets) of objects; its explanatory potential therefore resides in assessing possible  relations between them. The problem in using Venn diagrams for the description of interdisciplinary projects is twofold: first, disciplines are not finite sets but historically evolving organisms with uncertain boundaries; related to this is presentation of relations between them as fixed and static in time. To the extent that disciplines are not simply aligned, but not yet dynamically integrating and interacting, the Venn diagram appears to describe, in Klein’s taxonomy, something in between multidisciplinarity and interdisciplinarity. The plasticity of each discipline, which is a necessary condition for a proper integration, requires and occurs in time, a factor that is completely absent from this model of intersection. In the case of HtV, the Venn diagram is unable to capture the disciplinary interrogation and (re)definition, conceptual exchanges, emergent alliances, and problematic frictions of the project’s first year. The time factor in disciplinary plasticity is not the only dynamic aspect missing from intersecting and taxonomical models. Relatedly and, we argue, more importantly, disciplines are always considered as disembodied entities with definite boundaries. Our view is that dynamic processes of integration and interaction must take account of the fact that individuals are the bearers and beholders of knowledge and methods. Prioritizing the embodied and social components of interdisciplinarity projects, we propose an account of disciplinary encounters in terms of extended44 This monstrosity can be detected also in disciplinary umbrella terms such as ‘literary studies’, ‘medical humanities’, and ‘cognitive sciences’. So varied are its contributing disciplines, and so heterogeneous are its approaches, that to treat the field of ‘cognitive sciences’ as a unitary agent in the interdisciplinary exchange is problematic, to say the least. The habit of speaking of disciplines as unified agents relates to our functional tendency to simplify and to anthropomorphize. But if disciplines are not individual, they are embodied in (and their existence and development rely on) individual human agents. Instead of approaching interdisciplinarity in the abstract terms of a theoretical integration, we propose to ground analysis in the actual interaction of what we can call individuals’ disciplinary minds. This methodological turnaround, from a top-down categorization of interdisciplinarity to a bottom-up account, complements formulations of disciplinary actors and agents within science and technology studies, and has two important benefits. First, it reconceptualizes the abstract problem of disciplinary boundaries in terms of the boundaries of human minds and in terms thus amenable to cognitive inquiry. Secondly, by drawing on contemporary accounts of extended, embodied, and enactive cognition, it enables us to understand the ‘unbounding’2 of disciplinary minds in interdisciplinary projects.In referring to the mutual ‘cannibalization’ of theories and their unsystematic incorporation of sometimes conflicting claims, Jacques Derrida defined theories as ‘monsters’.just ‘in the head’.45 According to this new framework in the science of the mind,46 cognitive processes are instead partially extending into the world through the interaction with the environment and cognitive tools.40 The extended mind (EM) thesis assumes that the boundaries of the mind  become under certain conditions ‘porous’.47 This porosity takes place when the mind interacts, manipulates and exploits external tools; when the mind couples with these externalities and constituting what EM theorists call a ‘coupled system’. By drawing on recent expansions of this thesis into the social domain,49 in the next section, we want to suggest that, once we consider interdisciplinarity as the embodied and enactive interaction of individuals  the same ‘porosity’ is activated in what we called ‘disciplinary minds’. Furthermore, we propose a model that accommodates the same causal reciprocity and agency distribution between disciplinary minds that the EM thesis attributes to the mind–world interaction.Cognitive sciences now strongly challenge the Cartesian idea that cognition is something that happens is (so we claim) part of the cognitive process’  remains untouched due to the activation of ‘inextricable tangles of feedback, feedforward, and feedaround loops that promiscuously criss-cross the boundaries of brain, body, and the world’ , but recently this thesis has been tentatively applied also to social cognition—an application that appears particularly warranted if viewed in relation to earlier social theories of cognition such as Vygotsky’s.ce”’ Ref , p. 643. project .actually be transformed into a physical building. Even without this concretizing operation, however, the model is not entirely conceptual and metaphorical. In HtV, we do have a central meeting space, a social ‘we-space’ constituted by a physical room where we have our fortnight meetings (‘Voice Club’) structured and facilitated by artist Mary Robson. The concentric circles emanating from this physical ‘we-space’ are the ever-changing research questions generated within it. Touching on every discipline in the project, these questions open up specific, temporally contingent spaces in which individual researchers interact. The model accommodates two temporal dimensions: synchronic entanglements (in the immediate ‘we-space’ of ‘Voice Club’), as well as the diachronic or longer-term entanglements emerging from prolonged engagements as participants move together in a common problem space, slowly adjusting to—and integrating with—other disciplines’ ways of thinking, speaking, and framing problems.cWe called this a ‘blueprint model’ because it can Two criteria guide the disposition of disciplines in the angular dimensions—read clockwise they show (1) a contiguity of methods and research topics and (2) a major toward minor reliance on empirical experimental data. In this respect, phenomenology is significantly a boundary discipline between the scientific and humanistic semi-circles. The radial axes are generated by different research questions and hence change throughout the project. This model could be easily be manipulated and modified to accommodate a larger or smaller numbers of disciplines and research questions, but our illustration focuses on three aspects of AVH to which all disciplines are called to contribute: (RQ1) the relationship between inner speech and AVHs (discussed in more detail below); (RQ2) the degree to which voice-hearers’ recognize their voices as agents over which they have various degrees of control; and (RQ3) the developmental trajectory of AVH across the lifespan. Black dots are people involved in the project, or what we have called ‘disciplinary minds’. The model makes clear that people are not just positioned by their main discipline of expertise, but can be located in a greater or less proximity to the contiguous field. Furthermore, along the project their location can vary both in the angular dimension and radial axis, following their role in the new research questions  and their disciplinary polarization for those specific topics. Another important aspect to underline is that the concentric circles are all dashed, emphasizing movement and exchange including with actors ‘outside’ the project, and avoiding a hierarchical orientation of the model in terms of center versus periphery.all the disciplinary minds interact; interactions which activate what we might call ‘enhancing loops’  These include:Intuition Pumps: In Dennett’s terms, intuition pumps are tools which stimulate specific kinds of thinking. These ‘imagination extenders’ and ‘focus holders’  but a form of ‘know-how’ (enactive exploration).56 Disciplinary minds discover in the interaction and extension with other minds what is possible to do and what is not. There is a mutual constraining or, in Gallagher’s words, each disciplinary mind provides a specific and limited kind of affordance.Emergent Properties: The phenomenon to be investigated and explored by interdisciplinary projects  has probably already distinct features and properties in many discipline involved. The coupled interdisciplinary extension of disciplinary minds allows the emergence of unpredicted  properties.Constructive Failures: Failures are rarely in the spotlight of interdisciplinary debate, but we regard them as telling signs of resisting integrations. Understanding why feedbacks loops are not generated or the reasons for the impossibility of front-loading experimental designs is a constructive form of enactive disciplinary exploration. These failures, in fact, affect further interactions as well as successful integrations.Although subgroups form and interact throughout the project space, the central physical we-space of ‘Voice Club’ offers the starkest presentation of the interdisciplinary project as a cognitively integrated system of extended disciplinary minds. This is the space in which 59 we have conducted close reading and narratological analyses of the varieties of inner speech in literary texts by Samuel Beckett and Hilary Mantel; in-depth discussion in small groups of the scales and measures used to investigate inner experience, and the subsequent development and implementation of new tools for phenomenological research; and simulation of the meditative practices used by monks in the middle ages to quiet turbulent inner voices. We have also used these investigations to cast, confront and reciprocally constrain hypotheses for empirical research  While the findings and quantifiable outputs of many these entanglements (which began in late 2012) have yet to be published, their effects are evident in the questions and directions now being explored by researchers within the project, as well as in the qualitative data gathered through formal and informal evaluations of ‘Voice Club’.This is a partial list of the kind of activities creating/generated by enhancing loops within the project. Among the several examples we are collecting throughout the project, we can briefly refer to the interaction of disciplinary minds in addressing (RQ1) the relationship between inner speech and AVHs. Together with the formal presentation of existing research in psychology and philosophy,unthinkable or unpredictable before, even if subtly so. All these cognitive practices between disciplinary minds follow a horizontal ‘parity principle’ and loops of ‘CRC’; every interaction is at the same time a coupled system in itself and part of the larger cognitive system, which is the project as a whole. The model, then, allows us to trace the holistic understanding of a phenomenon at issue (AVHs) by portraying the cognitive unity of the project as a whole as well as the small-scale integrated and integrating couple systems constituted by individuals’ interactions. It also allows us to grasp the complexity of potential what Fitzgerald and Callard have termed ‘experimental entanglements’.60 ‘To be entangled’, they write, ‘is precisely not simply to labour together, or to compare - or engage in “dialogue” about – our different disciplinary perspectives. It is to proceed, instead, on the assumption that entanglements – of bodies, epistemologies, apparatuses, elements of experimental systems, operationalizations of terms – might produce something new in the world, even as the forms that that newness might take are undecided, and undecidable, prior to the moments of experimentation’.60Although not an exhaustive list, the enhancing loops at operation within HtV all function to produce thoughts and outcomes that, as the EM thesis indicates, were 62 or Docherty’s fear that interdisciplinarity lets ‘our disciplines overflow into each other like anarchic lava lamps’63 spatial and particularly architectural metaphors have dominated the conceptualization of disciplinary distinction and interdisciplinary integration. In this article, we offered an account of interdisciplinarity as a form of cognitive integration grounded in an analysis of the HtV project. The model  we proposed allows us to (1) move from an idea of ‘vertical integration’ to horizontal nonhierarchical interactions; (2) reintegrate the extended, embodied, and enactive factors of interdisciplinarity by focusing on individual disciplinary agents; (3) treat interdisciplinary as cognitive process of socially extended ‘disciplinary minds’; (4) better represent the dynamic temporal and spatial dimensions of interdisciplinary research (the position and relation of disciplinary minds will change with each new research question). In essence, the model puts the onus on the cognitive dynamics among individuals engaged in interdisciplinary projects, and therefore can be consistently applied also to other projects even when cognitive sciences are not involved.Whether in Kant’s call to view every science ‘as a separate and independent building … a self-subsisting whole’ Ref , p. 31, 13? Shifting the debate on interdisciplinarity from a disembodied abstract level to an account of its extended, embodied, and enactive processes discloses a complexity which calls for more sophisticated models. Our article provides the ground for future advances in this direction.We believe that this cognitive account of interdisciplinarity has great potential for further development in at least two directions. First, we have not accounted here for the emotional dimensions of social cognition, or the training, motivation, skills, attitudes, and even ‘virtues’ Ref , p. 34 w