Search

Background/Aims: GBR12909 has been reported to possess anticonvulsant activity with focal brain perfusion to the hippocampus of pilocarpine, although an earlier publication suggested any anticonvulsant effects were only mild. Here we further explored the anticonvulsant potential of GBR12909 with a suite of anticonvulsant assays in both zebrafish and mammals and then explored whether it possessed any QT effects which might limit clinical utility. Methods: We assessed the anticonvulsant effects of GBR12909 in zebrafish pentylenetetrazole (PTZ), mammalian maximal electroshock and PTZ models of generalized epilepsy and a rodent hippocampal kindling model. Cardiac effects were assessed in zebrafish and man. Results: GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy. However, phase 1 human data indicated potential QT effects. Subsequent testing in a zebrafish QT assay confirmed marked arrhythmogenic potential. Conclusion: Further clinical development of GBR12909 in epilepsy was considered inappropriate because of insufficient window between the therapeutic effects and the cardiac arrhythmia problems identified in zebrafish assays. Any further development based on this mechanism of action should avoid the GBR12909 chemical scaffold, or involve structure-activity dissociation of its neurological and cardiac effects.

Aim: To collect clinical and pharmacokinetic (PK) data for QAW039 (fevipiprant), a novel oral CRTh2 receptor antagonist, for asthma treatment. Methods: We assessed efficacy (change in trough FEV 1 from baseline to day 29), ACQ scores, PK of QAW039 and safety vs placebo (PBO). Atopic patients (pts) with mild-to-moderate persistent asthma (ACQ scores ≥1.5) and predicted FEV 1 between 60-85% at baseline were randomised to QAW039 500mg or PBO once-daily for 28 days after a run-in period of up to 28 days where ICS or combinations ICS and LABAs were withdrawn. Results: A total of 170 pts were randomised to QAW039 (n=82) and PBO (n=88). There were no significant differences between QAW039 and PBO groups for trough FEV 1 or ACQ in the whole population. Amongst the various subgroup analyses conducted, positive results were seen in the subgroup of pts (QAW039, n=28; PBO, n=37) with airflow limitation of 1 with significant improvement for both FEV 1 (Δ[QAW-PBO]=+207mL; 90%CI: 96, 319; p=0.002) and ACQ7 (Δ[QAW-PBO]=-0.41; 90%CI: -0.69, -0.13; p=0. 009). QAW039 (n=82) reached a mean maximum concentration (C max ) of 3440ng/mL on day 28 at a median T max of 1h (range 0.5–4h). The AUC tau ratio (day 28 AUC 0-24h –day 1 AUC 0-24h ) of 1.2 indicated modest accumulation of QAW039 upon repeat dosing. Most AEs were mild/moderate and balanced between both groups with no SAEs. Conclusion: QAW039 may improve lung function and asthma control in pts with greater severity of airflow limitation and had a favourable safety profile in all treated pts. Positive results were seen in a post-hoc subgroup analysis and are thus interpreted with caution.

Seed sprouts have been implicated as vehicles for numerous foodborne outbreaks worldwide. Seed sprouts pose a unique food safety concern because of the ease of microbiological seed contamination, the inherent ability of the sprouting process to support microbial growth, and their consumption either raw or lightly cooked. To examine seed sprout safety in the Australian state of Victoria, a survey was conducted to detect specific microbes in seed sprout samples and to investigate food handling practices relating to seed sprouts. A total of 298 seed sprout samples were collected from across 33 local council areas. Escherichia coli was detected in 14.8%, Listeria spp. in 12.3%, and Listeria monocytogenes in 1.3% of samples analyzed. Salmonella spp. were not detected in any of the samples. A range of seed sprout handling practices were identified as potential food safety issues in some food businesses, including temperature control, washing practices, length of storage, and storage in proximity to unpackaged ready-to-eat potentially hazardous foods.

This paper estimates the effect of Chapter 13 bankruptcy protection on post-filing financial outcomes using a new dataset linking bankruptcy filings to credit bureau records. Our empirical strategy uses the leniency of randomly-assigned judges as an instrument for Chapter 13 protection. Over the first five post-filing years, we find that Chapter 13 protection decreases an index measuring adverse financial events such as civil judgments and repossessions by 0.316 standard deviations, increases the probability of being a homeowner by 13.2 percentage points, and increases credit scores by 14.9 points. Chapter 13 protection has little impact on open unsecured debt, but decreases the amount of debt in collections by $1,315.

Osteoporosis and diseases of bone loss are a major public health problem for the present and the future since longevity and prevalence of the disease are increasing in all parts of the world. The bisphosphonates, widely used in the treatment of osteoporosis, act by inhibiting bone resorption. However, there are few agents that promote or increase bone formation in patients who have suffered substantial bone loss. To facilitate the identification of novel anabolic therapies, the authors have developed a rapid, high-throughput in vivo screen using larval zebrafish (Danio rerio) in which they are able to identify agents with anabolic effects in the skeleton within a 6-day time period. Vitamin D3 analogs and intermittent parathyroid hormone (PTH) result in dose-dependent increases in the formation of mineralized bone, whereas continuous exposure to PTH results in net bone loss. Because this model is fast, economical, and genetically tractable, it provides a powerful adjunct to mammalian models for the identification of new anabolic bone agents and offers the potential for genetic elucidation of pathways important in osteoblastic activity.

Zebrafish offer a tractable system for the study of retinal development and degeneration, to provide insights into human retinal degeneration. We have begun to dissect the question of neighborhood effects on photoreceptor differentiation and survival through the isolation and characterization of mutants with retinal degeneration. We describe two mutants, ebony and ivory, isolated through a behavioral screen for blind mutants induced by ethyl nitrosourea mutagenesis. Chimeric analysis was conducted to attempt to rescue the photoreceptor degeneration. In ebony, the photoreceptor cell death was both cell autonomous and nonautonomous in nature, whilst the photoreceptor cell death was strikingly nonautonomous in ivory. The rescue at a distance is in keeping with a putative diffusible survival factor. We propose a density-dependent nonautonomous neighborhood effect to explain these findings. © 2003 Wiley Periodicals, Inc. J Neurobiol 57: 235–245, 2003

This is a white paper for project ngVLA This paper discusses compelling science cases for a future long-baseline interferometer operating at millimeter and centimeter wavelengths, like the proposed Next Generation Vary Large Array (ngVLA). We report on the activities of the Cradle of Life science working group, which focused on the formation of low- and high-mass stars, the formation of planets and evolution of protoplanetary disks, the physical and compositional study of Solar System bodies, and the possible detection of radio signals from extraterrestrial civilizations. We propose 19 scientific projects based on the current specification of the ngVLA. Five of them are highlighted as possible Key Science Projects: (1) Resolving the density structure and dynamics of the youngest HII regions and high-mass protostellar jets, (2) Unveiling binary/multiple protostars at higher resolution, (3) Mapping planet formation regions in nearby disks on scales down to 1 AU, (4) Studying the formation of complex molecules, and (5) Deep atmospheric mapping of giant planets in the Solar System. For each of these projects, we discuss the scientific importance and feasibility. The results presented here should be considered as the beginning of a more in-depth analysis of the science enabled by such a facility, and are by no means complete or exhaustive.

Background: Current treatments for schizophrenia generally have significant side effects and show limited efficacy across symptom domains. TAK-063 is a novel, potent, and selective inhibitor of phosphodiesterase 10A, an intracellular enzyme selectively expressed in the medium spiny neurons of the striatum. TAK-063 has shown efficacy in animal models of schizophrenia, and was shown to be safe and well tolerated in Phase 1 studies of healthy subjects and subjects with stable schizophrenia. This study evaluated the efficacy and safety of 20-mg daily TAK-063 vs placebo in subjects with acutely exacerbated symptoms of schizophrenia.

Kirstie N Anderson, Paul Goldsmith, Alison Gardiner Regional Sleep Service, Freeman Hospital, Newcastle upon Tyne, UK Introduction: Computerized or online cognitive behavioral therapies (CBTs) are increasingly being developed to deliver insomnia therapy (CBT-i). They seek to address the difficulty of delivering an evidence-based technology to a large number of patients at low cost. Previous online applications have shown significant but variable improvements in sleep efficiency and a decrease in insomnia severity when compared with control groups. The best online methodology remains debated, and there are no such applications currently available within the UK National Health Service. Method: Evaluation of treatment outcomes in 75 participants with insomnia disorder using an open-access, novel, interactive online therapy. Rigorous screening was first undertaken to exclude those with probable sleep apnea, restless legs, circadian rhythm disorder, or significant anxiety or depression prior to commencing therapy. A modern interactive video-based website was used to encourage compliance by personalizing therapy based on response. Sleep efficiency, sleep latency, total sleep time, and sleep quality were all assessed prior to and after intervention. Results: Of those who accessed therapy, 62% were excluded based on a likely diagnosis of another sleep disorder (788/1281). Participants who completed therapy all had severe insomnia disorder, with a group mean sleep efficiency of 55%. After intervention there was a significant increase in sleep efficiency and sleep latency, with modest nonsignificant improvements in total sleep time. The majority of users reported improved sleep quality, and compliance with therapy was very good, with over 64/75 completing >90% of sleep diary entries. Conclusion: Online CBT-i can be designed to deliver personalized therapy with good reported outcomes and high compliance rates in those who start therapy. This initial evaluation also suggests that screening for other sleep disorders and mental health problems is necessary as many other sleep disorders are detected in those who self-refer with insomnia. This would inform the development of any larger-scale applications within the psychological therapies used in the health care system. Keywords: CBT, online applications, sleep efficiency, sleep latency, total sleep time, sleep quality, compliance

Cross-listing on a U.S. exchange does not bond foreign firms to follow the corporate governance rules of that exchange. Hand-collected data show that 80% of cross-listed firms opt out of at least one exchange governance rule, instead committing to observe the rules of their home country. Relative to firms that comply, firms that opt out have weaker governance practices in that they have a smaller share of independent directors. The decision to opt out reflects the relative costs and benefits of doing so. Cross-listed firms opt out more when coming from countries with weak corporate governance rules, but if firms based in such countries are growing and have a need for external finance, they are more likely to comply. Finally, opting out affects the value of cash holdings. For cross-listed firms based in countries with weak governance rules, a dollar of cash held inside the firm is worth $1.52 if the firm fully complies with U.S. exchange rules but just $0.32 if it is non-compliant.

Summary Tumor necrosis factor α (TNFα)-initiated biological responses are regulated by internalization of the receptor signaling complex and its fusion with components of several endocytic compartments [1]. We have recently reported that CARP2 is constitutively associated with cytosolic membrane vesicles that fuse with the internalized TNF receptor 1 (TNFR1) signaling complex, and that it functions as a ubiquitin protein ligase (E3) for RIP1, an obligate signaling intermediary for NF-κB activation [2]. It has also been shown that CARP2 and its homolog CARP1 function as E3s for caspase-8 and -10, and that knockdown via short hairpin RNAs (shRNAs) of CARP1 or CARP2 expression enhances TNFα-induced caspase activation and cell death [3].

Due to changes in the economic, political and educational landscape in Thailand over the past 15 years, higher education institu tions are being mandated to shift from fully public, civil service entities to autonomous, quasi-public universities that require significant management changes. This research considers the likely challenges associated with future educational impacts and utilizes a case study at the College of Arts, Media and Technology, Chiang Mai University to show the current ‘as-is’ and desired ‘to-be’ management scenarios. The paper investigates potential solutions through the lens of a Governance, Risk Management and Compliance (GRC) framework to facilitate sustainability within Thailand’s affiliated universities. While the management challenges of higher education are specific to individual faculties and universities, the case study presented in this paper acts as a microcosm of Thailand’s higher education challenges. The aim of this paper is to promote discussion and consideration of the likely challenges and solutions to Thailand’s changing higher education.

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kβ. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.

e-Tourism or e-tourism business, represents the development of tourism to integrate ICT tools and has significantly changed the infrastructure of the tourism industry and tourists' behavior over the last decade. In order to meet the needs of new tourists, service supplier (i.e. the university) most meet the requirements of e-tourism industries. Research suggests that higher education, as one of the most important knowledge providers, is not currently meeting the needs of the e-tourism industry, especially in GMS developing countries. The quality of e-tourism curriculum provision depends largely on the curriculum quality and its subsequent implementation. This research focuses on two major problems, which represent a gap between the knowledge needs of the e-tourism industry and the knowledge provided by tourism curricula in higher education. The research investigates how to fill the gap between knowledge demand and that supplied by higher education through an analysis of the “as-is” situation and the desired “to-be” situation as related to e-tourism curriculum design. A solution is proposed through an integration of the tools of supply chain management and knowledge management.

We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.

A fifty-three year old highway maintenance worker was referred to the Movement Disorders clinic because he could not walk backward. In the months before presentation he had begun to feel unsteady when standing and found that he could no longer do his job (placing traffic cones), because whenever he walked backward he would fall over. Over the following three years he developed a hoarse voice, mild emotional lability and micrographia. He had no significant past medical history and was taking no regular medications. His mother had been diagnosed with Parkinson's disease aged fifty-five and died two years later. One of his two siblings developed chorea in her early fifties and was diagnosed with neuroferritinopathy (FTL1 460InsA mutation). Neurological examination revealed hypomimia, hypophonia and dysphonia. Cranial nerve examination was normal. There was no visible or palpable tremor of the lower limbs. There was bilateral bradykinesia and mild bilateral upper limb cogwheel rigidity. There was no muscle weakness, tendon jerks were normal and plantar responses were flexor. There was no ataxia. Romberg's sign was negative. On walking forwards there was bilaterally reduced arm swing and instability on turning, particularly when making rapid turns. Tandem gait was normal. Antepulsion was normal but there was marked postural instability on retropulsion (pull test). On attempting to walk backward a few shuffling steps were taken before falling backward (see video). Brain MRI (gradient echo sequences) revealed a pattern of iron deposition typical of that seen in neuroferritinopathy. Genetic testing revealed the FTL1 460InsA mutation, the commonest of the four mutations of the ferritin light chain identified in neuroferritinopathy1. Electromyography (EMG) showed no evidence of leg tremor while seated, either at rest or with co-contraction, but as the patient stood synchronous 9Hz tremor bursts of 40-80ms duration appeared in the EMG bilaterally, therefore fulfilling diagnostic criteria for slow orthostatic tremor (OT)2. Raw rectified EMG recorded using adhesive electrodes from right and left tibialis anterior (TA) muscles (gain 5000; band pass filtered 30Hz-2kHz; 5kHz digitization) whilst standing is shown in Figure 1A. Frequency domain analysis (see power spectra in Figure 1B) confirmed that the dominant frequency was 8-10Hz. Coherence analysis was performed as previously published3 and confirmed significant unilateral and bilateral EMG-EMG coherence at 8-10Hz (see Figure 1C). As previously described in OT, when the patient walked forwards (1-2 steps/second) the 9Hz EMG bursts disappeared (see Figure 1D), unilateral 8-10Hz intermuscular coherence was reduced and there was no significant bilateral 8-10Hz intermuscular coherence (grey line; Figure 1E). However, although ~8Hz EMG bursts persisted when the patient tried to walk backwards, the bursts became desynchronized (Figure 1 D). Coherence analysis confirmed that bilateral EMG bursts were asynchronous (black line; Figure 1E) but that significant unilateral 8-10Hz coherence persisted. Figure 1 A. Raw rectified EMG recorded simultaneously from right and left tibialis anterior (TA) during stance. B. EMG power spectra obtained from right and left TA and left and right gastrocnemius-soleus (GS) during stance (black line) and while the patient was ... Direction specific or task specific gait disorders are rare and, because of their often bizarre appearance, frequently dismissed as functional or psychogenic4. Problems with forward gait initiation can occur after pallidotomy and can be seen in patients with cerebrovascular disease, progressive supranuclear palsy, corticobasal degeneration, pallidonigroluysian degeneration, Orthostatic Myoclonus (OM)5 and OT6; problems with forward ambulation can be a feature of dystonia4. Transient failure of gait initiation (or transient gait arrest) with shuffling and trembling are also features of Freezing of Gait (FOG) in Parkinson's disease, vascular parkinsonism and neurodegenerative parkinsonian syndromes7. FOG has not previously been described in neuroferritinopathy, but could explain the task specific gait disorder we observed, particularly given the presence of other parkinsonian features. Orthostatic Tremor has not previously been reported in neuroferritinopathy1. OT is a rare task specific tremor affecting the legs and trunk, which only appears on standing, is associated with a profound and disabling sense of unsteadiness and is relieved by sitting, walking or the use of a support. Two types of OT are recognized: fast OT, characterized by bursts of muscle activity at 13-18 Hz8; and slow OT, with EMG bursts at frequencies

Dopa responsive dystonia results from abnormalities in the dopamine synthesis pathway which produces an array of phenotypic presentations with equally numerous genotypes. First documented in children in 1971, the ‘classic’ phenotype is childhood onset, predominantly lower limb dystonia which gradually progresses to generalised dystonia. Other hallmarks of ‘classical’ dopa responsive dystonia include marked diurnal variation in symptom severity (worse in the evening), subsequent development of parkinsonism and an excellent, sustained response to levodopa. More recently, adult onset variants have been reported. Here we discuss two siblings with dopa responsive dystonia caused by a mutation in the GTP cyclohydrolase 1 gene. Both presented in adulthood with tremor rather than the ‘classic’ phenotype. A video is presented (available online) followed by a brief discussion of the literature.

We study credit ratings on subprime and Alt-A mortgage-backed-securities (MBS) deals issued between 2001 and 2007, the period leading up to the subprime crisis. The fraction of highly rated securities in each deal is decreasing in mortgage credit risk (measured either ex ante or ex post), suggesting that ratings contain useful information for investors. However, we also find evidence of significant time variation in risk-adjusted credit ratings, including a progressive decline in standards around the MBS market peak between the start of 2005 and mid-2007. Conditional on initial ratings, we observe underperformance (high mortgage defaults and losses and large rating downgrades) among deals with observably higher risk mortgages based on a simple ex ante model and deals with a high fraction of opaque low-documentation loans. These findings hold over the entire sample period, not just for deal cohorts most affected by the crisis.

Flexible membrane liners (FMLs) have grown, and must continue to grow, in importance across the solid and hazardous waste management industry. Their study has increased in importance as their applications have increased. This paper develops new criteria for testing, as well as discussing the implications. Current test procedures are based upon standard materials tests that do not combine the many stress factors acting on a liner under a landfill. There are no field data against which to calibrate tests that must predict service lives far longer than experience. The anticipated service life of these materials as liners makes it critical to enhance the representation of field conditions in laboratory testing.

A series of 3-amino-6-aryl-pyridazines have been identified as CB2 agonists with high efficacy and selectivity against the CB1 receptor. Details of the investigation of structure–activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain.

There is a growing momentum to use in vitro methods, nestled in in silico physiologically based pharmacokinetic models as the primary source of prediction of human clearance. This represents a shift in the paradigm for predictions in humans, which has been traditionally based on in vivo empirical approaches involving allometric scaling. For hepatic clearance of lipophilic metabolised compounds, methodology for scaling based on in vitro data is well established and approaches based on in vitro data alone seem to be the most accurate. However, limitations in in vitro methods exist for compounds cleared by other mechanisms, such as those for which active transport is a major determinant of the hepatobiliary and renal elimination processes. A major challenge for any clearance prediction is the assessment of variability and uncertainty. Integrative and mechanistic approaches such as physiologically based scaling provide the most promising way of dealing with these aspects. In this review, the authors assess advances in in vitro methods for hepatic and renal clearance predictions with particular emphasis on mechanistic approaches.

Background The condensation of chromosomes and correct sister chromatid segregation during cell division is an essential feature of all proliferative cells. Structural maintenance of chromosomes (SMC) and non-SMC proteins form the condensin I complex and regulate chromosome condensation and segregation during mitosis. However, due to the lack of appropriate mutants, the function of the condensin I complex during vertebrate development has not been described. Results Here, we report the positional cloning and detailed characterization of retinal phenotypes of a zebrafish mutation at the cap-g locus. High resolution live imaging reveals that the progression of mitosis between prometa- to telophase is delayed and that sister chromatid segregation is impaired upon loss of CAP-G. CAP-G associates with chromosomes between prometa- and telophase of the cell cycle. Loss of the interaction partners CAP-H and CAP-D2 causes cytoplasmic mislocalization of CAP-G throughout mitosis. DNA content analysis reveals increased genomic imbalances upon loss of non-SMC condensin I subunits. Within the retina, loss of condensin I function causes increased rates of apoptosis among cells within the proliferative ciliary marginal zone (CMZ) whereas postmitotic retinal cells are viable. Inhibition of p53-mediated apoptosis partially rescues cell numbers in cap-g mutant retinae and allows normal layering of retinal cell types without alleviating their aberrant nuclear sizes. Conclusion Our findings indicate that the condensin I complex is particularly important within rapidly amplifying progenitor cell populations to ensure faithful chromosome segregation. In contrast, differentiation of postmitotic retinal cells is not impaired upon polyploidization.

We describe the medicinal chemistry programme that led to the identification of the EP1 receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.

Huntington's disease (HD) is an autosomal dominant, neurodegenerative condition caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract in the protein huntingtin. Genetic and transgenic studies suggest that the mutation causes disease predominantly via gain-of-function mechanisms. However, loss of normal huntingtin function resulting from the polyglutamine expansion might also contribute to the pathogenesis of HD. Here, we have studied the effects of huntingtin knockdown in zebrafish using morpholino antisense oligonucleotides, as its huntingtin orthologue has 70% amino acid identity with the human protein. Reduced huntingtin levels did not impact on gastrulation and early development, but caused massive apoptosis of neuronal cells by 24 hpf. This was accompanied by impaired neuronal development, resulting in small eyes and heads and enlargement of brain ventricles. Older huntingtin knockdown fish developed lower jaw abnormalities with most branchial arches missing. Molecular analysis revealed that BDNF expression was reduced by ∼50%. Reduction of BDNF levels by injection of a BDNF morpholino resulted in phenotypes very similar to those seen in huntingtin knockdown zebrafish. The phenotypes of both huntingtin- and BDNF-knockdown zebrafish showed significant rescue when treated with exogenous BDNF protein. This underscores the physiological importance of huntingtin as a regulator of BDNF production and suggests that loss of BDNF is a major cause of the developmental abnormalities seen with huntingtin knockdown in zebrafish. Increasing BDNF expression may represent a useful strategy for Huntington's disease treatment.

We report the case of a 70-year-old man reporting with headache and visual disturbances who was being treated for prostate cancer. Investigations showed him to have intracranial hypertension caused by venous sinus obstruction. Patients with metastatic disease and raised intracranial pressure in the absence of focal signs should be considered as possible cases of venous outflow obstruction. Keywords: intracranial hypertension; venous sinus thrombosis; malignancy

We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB2 receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the Western world. PTEN (phosphatase/tensin homolog on chromosome 10)-induced putative kinase 1 (PINK1), a putative kinase that is mutated in autosomal recessive forms of PD, is also implicated in sporadic cases of the disease. Although the mutations appear to result in a loss of function, the roles of this protein and the pathways involved in PINK1 PD are poorly understood. Here, we generated a vertebrate model of PINK1 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio). PINK1 knockdown results in a severe developmental phenotype that is rescued by wild-type human PINK1 mRNA. Morphants display a moderate decrease in the numbers of central dopaminergic neurons and alterations of mitochondrial function, including increases in caspase-3 activity and reactive oxygen species (ROS) levels. When the morphants were exposed to several drugs with antioxidant properties, ROS levels were normalized and the associated phenotype improved. In addition, GSK3β-related mechanisms can account for some of the effects of PINK1 knockdown, as morphant fish show elevated GSK3β activity and their phenotype is partially abrogated by GSK3β inhibitors, such as LiCl and SB216763 [3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)1H-pyrrole-2,5-dione]. This provides new insights into the biology of PINK1 and a possible therapeutic avenue for further investigation.

Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases such as Huntington's disease. Autophagy induction with the mTOR inhibitor rapamycin accelerates clearance of these toxic substrates. As rapamycin has nontrivial side effects, we screened FDA-approved drugs to identify new autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the G(i) signaling activator clonidine induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, in which cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating G(s)alpha, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced, and we provide proof of principle for therapeutic relevance in Huntington's disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+ (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins.

Goal scoring in sports such as hockey and soccer is often modeled as a Poisson process. We work with a Poisson model where the mean goals scored by the home team is the sum of parameters for the home team's offense, the road team's defense, and a home advantage. The mean goals for the road team is the sum of parameters for the road team's offense and for the home team's defense. The best teams have a large offensive parameter value and a small defensive parameter value. A level-2 model connects the offensive and defensive parameters for the k teams. Parameter inference is made by imagining that goals can be classified as being strictly due to offense, to (lack of) defense, or to home-field advantage. Though not a realistic description, such a breakdown is consistent with our model assumptions and the literature, and we can work out the conditional distributions and generate random partitions to facilitate inference about the team parameters. We use the conditional Binomial distribution, given the Poisson totals and the current parameter values, to partition each observed goal total at each iteration in an MCMC algorithm.

Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.

The discovery, synthesis and structure–activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.

The commonest interaction of industry with academia is as the passive recipient of intellectual property. A much deeper and productive interaction is possible with the creation of closely knit collaborations. Here the barriers to achieving this and how they may be overcome are explored.