Successful use of axonal transport for drug delivery by synthetic molecular vehicles

We report the use of axonal transport to achieve intraneural drug delivery. We constructed a novel tripartite complex of an axonal transport facilitator conjugated to a linker molecule bearing up to a hundred reversibly attached drug molecules. The complex efficiently enters nerve terminals after intramuscular or intradermal administration and travels within axonal processes to neuron cell bodies. The tripartite agent provided 100-fold amplification of saturable neural uptake events, delivering multiple drug molecules per complex. _In vivo_, analgesic drug delivery to systemic and to non-targeted neural tissues was greatly reduced compared to existing routes of administration, thus exemplifying the possibility of specific nerve root targeting and effectively increasing the potency of the candidate drug gabapentin 300-fold relative to oral administration

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Freedom, Servitude and Voluntary Labor

We present an economic framework to revisit and reframe some important debates over the nature of free versus unfree labor and the economic consequences of emancipation. We use a simple general equilibrium model in which labor can be either free or coerced and where land and labor will be exchanged on markets that can be competitive or manipulated or via other non-market collusive arrangements. By working with variants of the same basic model under different assumptions about initial economy-wide factor endowments and asset ownership we can compare equilibrium distributional outcomes under different institutional and contractual arrangements including markets with free labor and free tenancy, slavery, and tenancy arrangements with tied labor-service obligations. Analysis of these different contractual and organizational forms yields insights that accord with common sense, but that are often overlooked or downplayed in academic debates, particularly amongst economists

Search for rare or forbidden decays of the D0 meson

We present a search for nine lepton-number-violating and three lepton-flavor-violating neutral charm decays of the type D0→h'−h−ℓ'+ℓ+ and D0→h'−h+ℓ'±ℓ∓, where h and h′ represent a K or π meson and ℓ and ℓ′ an electron or muon. The analysis is based on 468 fb−1 of e+e− annihilation data collected at or close to the Υ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signal is observed for any of the twelve modes, and we establish 90% confidence level upper limits on the branching fractions in the range (1.0–30.6)×10−7. The limits are between 1 and 3 orders of magnitude more stringent than previous measurements.publishedVersio

Light meson spectroscopy from Dalitz plot analyses of ηc decays to η0 K+K− , η0 π + π − , and ηπ + π − produced in two-photon interactions

We study the processes γγ→ηc→η′K+K−, η′π+π−, and ηπ+π− using a data sample of 519  fb−1 recorded with the BABAR detector operating at the SLAC PEP-II asymmetric-energy e+e− collider at center-of-mass energies at and near the Υ(nS) (n=2, 3, 4) resonances. This is the first observation of the decay ηc→η′K+K− and we measure the branching fraction Γ(ηc→η′K+K−)/(Γ(ηc→η′π+π−)=0.644±0.039stat±0.032sys. Significant interference is observed between γγ→ηc→ηπ+π− and the nonresonant two-photon process γγ→ηπ+π−. A Dalitz plot analysis is performed of ηc decays to η′K+K−, η′π+π−, and ηπ+π−. Combined with our previous analysis of ηc→K¯Kπ, we measure the K∗0(1430) parameters and the ratio between its η′K and πK couplings. The decay ηc→η′π+π− is dominated by the f0(2100) resonance, also observed in J/ψ radiative decays. A new a0(1700)→ηπ resonance is observed in the ηc→ηπ+π− channel. We also compare ηc decays to η and η′ final states in association with scalar mesons as they relate to the identification of the scalar glueball.publishedVersio

Measurements of the absolute branching fractions of B± →k±Xc c

A study of the two-body decays B±→Xc¯cK±, where Xc¯c refers to one charmonium state, is reported by the BABAR Collaboration using a data sample of 424 fb−1. The absolute determination of branching fractions for these decays are significantly improved compared to previous BABAR measurements. Evidence is found for the decay B+→X(3872)K+ at the 3σ level. The absolute branching fraction B[B+→X(3872)K+]=[2.1±0.6(stat)±0.3(syst)]×10−4 is measured for the first time. It follows that B[X(3872)→J/ψπ+π−]=(4.1±1.3)%, supporting the hypothesis of a molecular component for this resonance.publishedVersio

Patents and Industrialisation. An Historical Overview of the British Case, 1624-1907

A Report to the Strategic Advisory Board on Intellectual Property Policy (SABIP), U

Recruitment of Triceps Surae Motor Units in the Decerebrate Cat. II. Heterogeneity Among Soleus Motor Units

1. On the basis of the orderly activation of motoneurons in a pool, one would predict that motor unit activity and whole muscle force will change at least roughly in parallel: active motor units should continue to fire as net muscle force increases and quiescent motor units should remain inactive as muscle force decreases. We have consistently observed this relationship in our studies of the medial gastrocnemius (MG) muscle, but here we report an uncoupling of the soleus muscle and some of its motor units. 2. Physiological properties and firing behaviors of 20 soleus motor units were characterized in five decerebrate cats with the use of intra-axonal stimulation and recording. Motor unit firing was elicited in reflexes initiated by muscle stretch, nerve stimulation, and mechanical stimulation of the heel. Particular emphasis was placed on the heterogenic reflexes produced in soleus by ramphold- release stretches of the MC muscle. In agreement with previous reports, either net heterogenic excitation or inhibition of the soleus muscle was produced in separate trials of MG stretch. 3. During excitation of soleus in autogenic stretch reflexes and in crossed-extension reflexes, all 20 units were recruited or increased firing, i.e., unit firing was coupled with soleus force. In the other reflexes, however, unit firing and muscle force were uncoupled for 10 of these units. Six tonically active motor units were inhibited during an increase in soleus force produced by MG stretch or by mechanical stimulation of the heel. Four motor units were activated during a decrease in soleus force produced by the same stimuli. 4. Six motor units were studied during both soleus inhibition and excitation evoked by MG stretches. One motor unit was consistently coupled to the soleus muscle response; firing increased during soleus excitation and decreased during inhibition. However, four soleus motor units were inhibited under both conditions, and one unit was excited under both conditions. Thus the firing behavior of five of these six motor units was the same in response to MG stretch, irrespective of the soleus response. 5. The uncoupling was most clearly recognized when tonically active units ceased firing during net excitation of the soleus muscle and when silent units began firing during net inhibition of the soleus muscle. Unit responses were not as striking in all trials of MG stretch (spike number increased or decreased relative to prestretch values by 1-4 spikes), but the responses were consistent across trials; in multiple stretches, spike number commonly either increased or decreased. Intertrial regularity was also observed in units for which firing was coupled with the net reflex response of the soleus muscle. 6. Divergence in the firing of soleus motor units was also observed in three cases in which records were taken simultaneously from two motor units. In one pair, one unit increased and the other decreased firing during MG stretch-evoked inhibition of soleus. In the other two pairs, one unit increased and the other decreased firing when soleus was excited by heel stimulation. In all pairs, the unit that decreased firing under these conditions had the lowest recruitment threshold in response to the soleus stretch. 7. Although all soleus motor units were classified as slow-twitch (type S), variation in their physiological properties bore some relation to firing behavior. Those units recruited during periods of soleus inhibition exhibited among the fastest conduction velocities and contraction times in our sample. In all three unit pairs sampled, the unit expressing decreases in firing had the slower conduction velocity and contraction time. 8. These findings demonstrate that soleus motor units are differentially activated and deactivated by peripheral afferents. Because the soleus is a uniarticulate muscle composed entirely of type S motor units, these differential effects do not depend on heterogeneity in motor unit type or muscle joint action. Because cats were decerebrated, the differential effects on motor unit firing do not rely on neural structures rostral to the brain stem