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Background Negative symptoms in schizophrenia (SCZ) are poorly treated and interfere with the function of patients. Studies focusing on structural and functional imaging and non-invasive electrophysiology implicate perturbations of the frontocortico-temporal circuits and disruption of cortico-striatal loops to negative symptoms in SCZ. GPR139 is an orphan GPCR that is specifically expressed in the CNS and enriched in the habenula, a brain structure involved in reward and motivation. Structural and functional alterations of the habenula have been found in SCZ patients, who show deficits in feedback processing and lack habenula activation in response to negative outcomes. Rodent experiments demonstrate the involvement of direct projection from the cortex to the habenula controlling social behavior. Alteration in habenula activity have been correlated with depression, and normalization of aberrant habenula activity has been proposed as therapeutic strategy to reverse anhedonia. Building on data previously reported at SIRS2018, we further explored modulation of GPR139 receptors and habenula circuitry in vivo as a novel mechanism to treat negative symptoms in SCZ. Methods Animals were submitted to an unpredictable chronic mild stress (uCMS) protocol, an animal model of depression that produces deficits in several behavioral domains affected in depressed patients. The three-chamber (Crawley’s) paradigm has been used to study social interaction in rodents. Induction of the immediate early gene c-fos expression was studied as marker for habenula neuron activation in vivo. Dopamine release in the nucleus accumbens (NAc) was studied by standard in vivo microdialysis in freely moving rats. Results The selective GPR139 agonist TAK-041 increased cFOS expression in the habenula in wild type mice, but not in GPR139 knock out mice. No desensitization of cFOS in the habenula was observed after chronic dosing of TAK-041. Microdialysis studies showed that TAK-041 reduced amphetamine- and nicotine-induced dopamine release in the NAc in rats. TAK-041 dosed acutely and chronically reversed anhedonia caused by uCMS in rats. TAK-041 also reversed anxiety related behavior assessed in the novelty suppressed feeding test and depressive-like behavior in the forced swim test in the uCMS model. uCMS-exposed animals develop a disrupted circadian regulation of corticosterone secretion, which was also normalized by TAK-041 treatment. Furthermore, TAK-041 reversed the uCMS-induced atrophy in the basal dendrites of pyramidal neurons in the hippocampus and the uCMS-induced hypertrophy of medium-spiny neurons in the NAc. These results suggest a potential benefit of TAK-041 in the treatment of anhedonia and possibly depression. TAK-041 also completely reversed social interaction (SI) deficits in the maternal immune activation poly-I:C model of SCZ, the subchronic PCP-SI model and in Balb/C and BTBR mice. Discussion The GPR139 agonist TAK-041 is proposed as a modulator of habenula circuitry to treat negative symptoms in SCZ based on efficacy in reversing anhedonia and social interaction deficits in multiple rodent models related to negative symptoms in SCZ. *Employed by Takeda when the study was done.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (ext-link ext-link-type="uri" xlink:href="https://openscienceprobes.sgc-frankfurt.de"https://openscienceprobes.sgc-frankfurt.de/ext-linkext-link ext-link-type="uri" xlink:href="https://openscienceprobes.sgc-frankfurt.de/"//ext-link). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.

Background Individuals with schizophrenia fail to appropriately use negative feedback to guide learning. These learning deficits are thought to arise from abnormalities in midbrain dopamine activity. The habenula is a well conserved paired structure that sits in the midline, adjacent to the third ventricle, and dorsal and posterior to the thalamus. Classic studies have shown that it is part of the reward pathway and functions with dopamine neurons in the ventral tegmental area (VTA) to mediate reward related signals, specifically aversive and negative stimulus (Hikosaka, 2010). Several studies point to pathology in the habenula as contributing to schizophrenia (Sandyk, 1992; Caputo et al., 1998; Shepard et al., 2006). Despite the many studies on the habenula, the precise function of the habenula remains unclear. Here we describe functional consequences of regulation of GPR139 an orphan GPCR that is specifically expressed in the CNS and enriched in the habenula (Matsuo et al., 2005) in mouse models of domain of schizophrenia. Methods Specific expression of mouse GPR139 in the habenula was evaluated using bacterial artificial chromosome translating ribosome affinity purification (bacTRAP) and confirmed by immunohistochemistry. GPR139-/- mice were generated by removal of a 736bp region encoding the seven transmembrane domain (7TM) domain. Knockout animals were maintained inbred on a 129/SvEv background and evaluated in behavioral models that reflect aspects of negative symptoms. High throughput screen (HTS) for small molecules was performed. We expressed full length GPR139 into CHO cells and screened a 600K library using a calcium assay to identify small molecule agonist. Hits were identified and physical properties optimized to produce a molecule suitable for in vivo evaluation. GPR139 agonist was testedin vivo in social interaction in Poly(I:C) and cognitive test in subchronic PCP, models of schizophrenia. Results Using bacTRAP we observed enriched expression of GPR139 in substance P positive- cells of the medial habenula. This expression was confirmed with immunohistochemistry. To determine if GPR139 regulates the known role of the habenula in learning, motivation, and social behaviour, GPR139 -/- animals were generated and phenotyped. These animals appeared normal and performed comparably to wild-type animals in a range of standard tasks. However, they were significantly impaired in models that reflect aspects of negative symptoms such as progressive ratio (Killeen et al., 2009; Heath et al., 2016), a measure of motivation and nest-building (Pedersen et al., 2014; Nakajima et al., 2013), a model of self-neglect. Furthermore, these animals showed deficits in novel object recognition model of working memory (Antunes and Biala, 2012). The small molecule agonist was observed to reverse deficits in models of schizophrenia including cognition in a subchronic PCP induced attentional set-shifting paradigm (Birrell and Brown, 2000) and social interaction in the Poly(I:C) maternal model (Meyer et al., 2008; Bitanihirwe et al., 2010). Discussion These findings identify an orphan receptor that plays an important role in habenular function. Modulation of this receptor may provide an opportunity to address an important unmet need in schizophrenia.

Intuitively, if a product is useful and has both a priced and a free version its total usage rate would be expected to be higher than if there is only a priced version. Evidence is emerging that this is true for online research journal papers. Authors need accessible online sites in which to deposit their published papers, and users need a means of discovering and evaluating those papers. The Open Archives Initiative (OAI) has now produced free software packages for building OAI-compliant institutional archives and OAI search services, including a citation-ranked search and impact discovery service. New data from this service shows that higher usage of free papers leads directly to a higher number of citations and thus greater research impact. Institutional archives need far more papers to be deposited, and one way of bringing this about is to implement institutional and national policies mandating the self-archiving of all funded research output in open access archives. This paper outlines why such policies are beneficial to researchers, their institutions, funders, and to research itself.

We describe “digitometric” services and tools that add value to open-access eprint archives using the Open Archives Initiative (OAI) Protocol for Metadata Harvesting. Celestial is an OAI cache and gateway tool. Citebase Search enhances OAI-harvested metadata with linked references harvested from the full-text to provide a web service for citation navigation and research impact analysis. Digitometrics builds on data harvested using OAI to provide advanced visualisation and hypertext navigation for the research community. Together these services provide a modular, distributed architecture for building a “semantic web” for the research literature.

The speed of scientific communication — the rate of ideas affecting other researchers' ideas — is increasing dramatically. The factor driving this is free, unrestricted access to research papers. Measurements of user activity in mature eprint archives of research papers such as arXiv have shown, for the first time, the degree to which such services support an evolving network of texts commenting on, citing, classifying, abstracting, listing and revising other texts. The Open Citation project has built tools to measure this activity, to build new archives, and has been closely involved with the development of the infrastructure to support open access on which these new services depend. This is the story of the project, intertwined with the concurrent emergence of the Open Archives Initiative (OAI). The paper describes the broad scope of the project's work, showing how it has progressed from early demonstrators of reference linking to produce Citebase, a Web-based citation and impact-ranked search service, and how it has supported the development of the EPrints.org software for building OAI-compliant archives. The work has been underpinned by analysis and experiments on the semantics of documents (digital objects) to determine the features required for formally perfect linking — instantiated as an application programming interface (API) for reference linking — that will enable other applications to build on this work in broader digital library information environments.

Based on an empirical analysis of author usage of CoRR, and of its predecessor in the Los Alamos eprint archives, it is shown that CoRR has not yet been able to match the early growth of the Los Alamos physics archives. Some of the reasons are implicit in Halpern's paper, and we explore them further here. In particular we refer to the need to promote CoRR more effectively for its intended community - computer scientists in universities, industrial research labs and in government. We take up some points of detail on this new world of open archiving concerning central versus distributed self-archiving, publication, the restructuring of the journal publishers' niche, peer review and copyright., Comment: This is a commentary on "CoRR: A Computing Research Repository" by Joseph Y. Halpern (cs.DL/0005003). See also Halpern's response to this and other commentaries (cs.DL/0005004)

The rapid growth of scholarly information resources available in electronic form and their organisation by digital libraries is proving fertile ground for the development of sophisticated new services, of which citation linking will be one indispensable example. Many new projects, partnerships and commercial agreements have been announced to build citation linking applications. This paper describes the Open Citation (OpCit) project, which will focus on linking papers held in freely accessible eprint archives such as the Los Alamos physics archives and the other distributed archives, and which will build on the work of the Open Archives initiative to make the data held in such archives available to compliant services. The paper emphasises the work of the project in the context of emerging digital library information environments, explores how a range of new linking tools might be combined and identifies ways in which different linking applications might converge. Some early results of linked pages from the OpCit project are reported.

The Open Journal project has completed its three year period of funding by the UK Electronic Libraries (eLib) programme (Rusbridge 1998). During that time, the number of journals that are available electronically leapt from a few tens to a few thousand. Some of these journals are now developing the sort of features the project has been advocating, in particular the use of links within journals, between different primary journals, with secondary journals data, and to non-journal sources. Assessing the achievements of the project and considering some of the difficulties it faced, we report on the different approaches to linking that the project developed, and summarise the important user responses that indicate what works and what does not. Looking ahead, there are signs of change, not just to simple linking within journals but to schemes in which links are the basis of "distributed" journals, where information may be shared and documents built from different sources. The significance has yet to be appreciated, but this would be a major change from printed journals. If projects such as this and others have provided the initial impetus, the motivation for distributed journals comes, perhaps surprisingly, from within certain parts of the industry, as the paper shows.