Rabies screen reveals GPe control of cocaine-triggered plasticity.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations

Developing serious games for cultural heritage: a state-of-the-art review

Although the widespread use of gaming for leisure purposes has been well documented, the use of games to support cultural heritage purposes, such as historical teaching and learning, or for enhancing museum visits, has been less well considered. The state-of-the-art in serious game technology is identical to that of the state-of-the-art in entertainment games technology. As a result, the field of serious heritage games concerns itself with recent advances in computer games, real-time computer graphics, virtual and augmented reality and artificial intelligence. On the other hand, the main strengths of serious gaming applications may be generalised as being in the areas of communication, visual expression of information, collaboration mechanisms, interactivity and entertainment. In this report, we will focus on the state-of-the-art with respect to the theories, methods and technologies used in serious heritage games. We provide an overview of existing literature of relevance to the domain, discuss the strengths and weaknesses of the described methods and point out unsolved problems and challenges. In addition, several case studies illustrating the application of methods and technologies used in cultural heritage are presented

ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype

Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1 + subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders

Inhibition of Osteoclastogenesis by Mechanically Loaded Osteocytes: Involvement of MEPE

In regions of high bone loading, the mechanoresponsive osteocytes inhibit osteoclastic bone resorption by producing signaling molecules. One possible candidate is matrix extracellular phosphoglycoprotein (MEPE) because acidic serine- and aspartate-rich MEPE-associated motif peptides upregulate osteoprotegerin (OPG) gene expression, a negative regulator of osteoclastogenesis. These peptides are cleaved from MEPE when relatively more MEPE than PHEX (phosphate-regulating gene with homology to endopeptidases on the X chromosome) is present. We investigated whether mechanical loading of osteocytes affects osteocyte-stimulated osteoclastogenesis by involvement of MEPE. MLO-Y4 osteocytes were mechanically loaded by 1-h pulsating fluid flow (PFF; 0.7 ± 0.3 Pa, 5 Hz) or kept under static control conditions. Recombinant MEPE (0.05, 0.5, or 5 μg/ml) was added to some static cultures. Mouse bone marrow cells were seeded on top of the osteocytes to determine osteoclastogenesis. Gene expression of MEPE, PHEX, receptor activator of nuclear factor kappa-B ligand (RANKL), and OPG by osteocytes was determined after PFF. Osteocytes supported osteoclast formation under static control conditions. Both PFF and recombinant MEPE inhibited osteocyte-stimulated osteoclastogenesis. PFF upregulated MEPE gene expression by 2.5-fold, but not PHEX expression. PFF decreased the RANKL/OPG ratio at 1-h PFF treatment. Our data suggest that mechanical loading induces changes in gene expression by osteocytes, which likely contributes to the inhibition of osteoclastogenesis after mechanical loading of bone. Because mechanical loading upregulated gene expression of MEPE but not PHEX, possibly resulting in the upregulation of OPG gene expression, we speculate that MEPE is a soluble factor involved in the inhibition of osteoclastogenesis by osteocytes

Emergence of Variability in Isogenic Escherichia coli Populations Infected by a Filamentous Virus

The spread of epidemics not only depends on the average number of parasites produced per host, but also on the existence of highly infectious individuals. It is widely accepted that infectiousness depends on genetic and environmental determinants. However, even in clonal populations of host and viruses growing in homogeneous conditions, high variability can exist. Here we show that Escherichia coli cells commonly display high differentials in viral burst size, and address the kinetics of emergence of such variability with the non-lytic filamentous virus M13. By single-cell imaging of a virally-encoded fluorescent reporter, we monitor the viral charge distribution in infected bacterial populations at different time following infection. A mathematical model assuming autocatalytic virus replication and inheritance of bacterial growth rates quantitatively reproduces the experimental distributions, demonstrating that deterministic amplification of small host inhomogeneities is a mechanism sufficient to explain large and highly skewed distributions. This mechanism of amplification is general and may occur whenever a parasite has an initial phase of exponential growth within its host. Moreover, it naturally reproduces the shift towards higher virulence when the host is experimenting poor conditions, as observed commonly in host-parasite systems

Differential sensitivity of Src-family kinases to activation by SH3 domain displacement

Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. © 2014 Moroco et al

Self-Reported Functional Status as Predictor of Observed Functional Capacity in Subjects with Early Osteoarthritis of the Hip and Knee: A Diagnostic Study in the CHECK Cohort

Objectives Patients with hip or knee osteoarthritis (OA) may experience functional limitations in work settings. In the Cohort Hip and Cohort Knee study (CHECK) physical function was both self-reported and measured performance-based, using Functional Capacity Evaluation (FCE). Relations between self-reported scores on SF-36 and WOMAC (Western Ontario and McMaster Arthritis Index, function scales) and FCE performance were studied, and their diagnostic value for clinicians in predicting observed physical work limitations was assessed. Methods Ninety-two subjects scored physical function on SF-36 (scale 0–100, 100 indicating the best health level) and WOMAC (scale 0–68, 68 indicates maximum restriction) and performed the FCE. Correlations were calculated between all scores. Cross-tables were constructed using both questionnaires as diagnostic tests to identify work limitations. Subjects lifting <22.5 kg on the FCE-test ‘lifting-low’ were labeled as having physical work limitations. Diagnostic aspects at different cut-off scores for both questionnaires were analysed. Results Statistically significant correlations (Spearman’s ρ 0.34–0.49) were found between questionnaire scores and lifting and carrying tests. Results of a diagnostic cross-table with cut-off point <60 on SF-36 ‘physical functioning’ were: sensitivity 0.34, specificity 0.97 and positive predictive value (PV+) 0.95. Cut-off point ≥21 on WOMAC ‘function’ resulted in sensitivity 0.51, specificity 0.88 and PV+ 0.88. Conclusion Low self-reported function scores on SF-36 and WOMAC diagnosed subjects with limitations on the FCE. However, high scores did not guarantee performance without physical work limitations. These results are specific to the tested persons with early OA, in populations with a different prevalence of limitations, different diagnostic values will be found. FCE may be indicated to help clinicians to assess actual work capacity

Social capital of venture capitalists and start-up funding

How does the social capital of venture capitalists (VCs) affect the funding of start-ups? By building on the rich social capital literature, we hypothesize a positive effect of VCs' social capital, derived from past syndication, on the amount of money that start-ups receive. Specifically, we argue that both structural and relational aspects of VCs' social networks provide VCs with superior access to information about current investment objects and opportunities to leverage them in the future, increasing their willingness to invest in these firms. Our empirical results, derived from a novel dataset containing more than 1,500 first funding rounds in the Internet and IT sector, strongly confirm our hypotheses. We discuss the implications of our findings for theories of venture capital and entrepreneurship, showing that the role and effect of VCs' social capital on start-up firms may be more complex than previously argued in the literature

Surgical perspectives from a prospective, nonrandomized, multicenter study of breast conserving surgery and adjuvant electronic brachytherapy for the treatment of breast cancer

<p>Abstract</p> <p>Background</p> <p>Accelerated partial breast irradiation (APBI) may be used to deliver radiation to the tumor bed post-lumpectomy in eligible patients with breast cancer. Patient and tumor characteristics as well as the lumpectomy technique can influence patient eligibility for APBI. This report describes a lumpectomy procedure and examines patient, tumor, and surgical characteristics from a prospective, multicenter study of electronic brachytherapy.</p> <p>Methods</p> <p>The study enrolled 65 patients of age 45-84 years with ductal carcinoma or ductal carcinoma in situ, and 44 patients, who met the inclusion and exclusion criteria, were treated with APBI using the Axxent^®electronic brachytherapy system following lumpectomy. The prescription dose was 34 Gy in 10 fractions over 5 days.</p> <p>Results</p> <p>The lumpectomy technique as described herein varied by site and patient characteristics. The balloon applicator was implanted by the surgeon (91%) or a radiation oncologist (9%) during or up to 61 days post-lumpectomy (mean 22 days). A lateral approach was most commonly used (59%) for insertion of the applicator followed by an incision site approach in 27% of cases, a medial approach in 5%, and an inferior approach in 7%. A trocar was used during applicator insertion in 27% of cases. Local anesthetic, sedation, both or neither were administered in 45%, 2%, 41% and 11% of cases, respectively, during applicator placement. The prescription dose was delivered in 42 of 44 treated patients.</p> <p>Conclusions</p> <p>Early stage breast cancer can be treated with breast conserving surgery and APBI using electronic brachytherapy. Treatment was well tolerated, and these early outcomes were similar to the early outcomes with iridium-based balloon brachytherapy.</p