Targeting the choroid plexus-CSF-brain nexus using peptides identified by phage display.

Drug delivery to the central nervous system requires the use of specific portals to enable drug entry into the brain and, as such, there is a growing need to identify processes that can enable drug transfer across both blood-brain and blood-cerebrospinal fluid barriers. Phage display is a powerful combinatorial technique that identifies specific peptides that can confer new activities to inactive particles. Identification of these peptides is directly dependent on the specific screening strategies used for their selection and retrieval. This chapter describes three selection strategies, which can be used to identify peptides that target the choroid plexus (CP) directly or for drug translocation across the CP and into cerebrospinal fluid

Functional responses of methanogenic archaea to syntrophic growth.

Methanococcus maripaludis grown syntrophically with Desulfovibrio vulgaris was compared with M. maripaludis monocultures grown under hydrogen limitation using transcriptional, proteomic and metabolite analyses. These measurements indicate a decrease in transcript abundance for energy-consuming biosynthetic functions in syntrophically grown M. maripaludis, with an increase in transcript abundance for genes involved in the energy-generating central pathway for methanogenesis. Compared with growth in monoculture under hydrogen limitation, the response of paralogous genes, such as those coding for hydrogenases, often diverged, with transcripts of one variant increasing in relative abundance, whereas the other was little changed or significantly decreased in abundance. A common theme was an apparent increase in transcripts for functions using H(2) directly as reductant, versus those using the reduced deazaflavin (coenzyme F(420)). The greater importance of direct reduction by H(2) was supported by improved syntrophic growth of a deletion mutant in an F(420)-dependent dehydrogenase of M. maripaludis. These data suggest that paralogous genes enable the methanogen to adapt to changing substrate availability, sustaining it under environmental conditions that are often near the thermodynamic threshold for growth. Additionally, the discovery of interspecies alanine transfer adds another metabolic dimension to this environmentally relevant mutualism

Interseismic quiescence and triggered slip of active normal faults of Kīlauea Volcano's south flank during 2001-2018

The mobile south flank of Kīlauea Volcano hosts two normal fault systems, the Koa'e fault system (KFS) and the Hilina fault system (HFS). In historical time, at least three M>6.5 earthquakes have occurred on the basal detachment of the Kīlauea Volcano's south flank, with the most recent being the 4 May 2018 M6.9 earthquake. Here we analyze kinematic Global Positioning System data collected from 2001 to 2017 and interferometric synthetic aperture radar data before, during, and after the 2018 M6.9 earthquake to determine the crustal motion across the HFS and KFS faults. Our results indicate that the HFS faults did not significantly slip during the interseismic period from 2007 to 2011. Despite its substantial magnitude, interferometric synthetic aperture radar (InSAR) data show that the 2018 M6.9 earthquake triggered subcentimeter level slip along sections of the previously mapped HFS branches. Up to 20 cm of offset occurred on what appears to be a newly formed (or previously unknown) fault near the eastern end of the HFS. During the 3 months following the M6.9 earthquake, up to ~30 cm of slip occurred along the KFS, which helps accommodate rapid large‐scale subsidence of Kīlauea's summit region as large volumes of summit reservoir magma fed the lower East Rift Zone eruption. The HFS appears to activate only in concert with large earthquakes on the basal detachment. The KFS, on the other hand, moves both seismically during small local earthquakes and aseismically in response to nearby earthquakes and caldera subsidence

Single-photon tunneling

Strong evidence of a single-photon tunneling effect, a direct analog of single-electron tunneling, has been obtained in the measurements of light tunneling through individual subwavelength pinholes in a thick gold film covered with a layer of polydiacetylene. The transmission of some pinholes reached saturation because of the optical nonlinearity of polydiacetylene at a very low light intensity of a few thousands photons per second. This result is explained theoretically in terms of "photon blockade", similar to the Coulomb blockade phenomenon observed in single-electron tunneling experiments. The single-photon tunneling effect may find many applications in the emerging fields of quantum communication and information processing.Comment: 4 pages, 4figure

Targeting choroid plexus epithelia and ventricular ependyma for drug delivery to the central nervous system

Background: Because the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions. To this end, we sought to identify peptides capable of ligand-mediated targeting to CP epithelial cells reasoning that they could be exploited to deliver drugs, biotherapeutics and genes to the CNS.Methods: A peptide library displayed on M13 bacteriophage was screened for ligands capable of internalizing into CP epithelial cells by incubating phage with CP explants for 2 hours at 37C and recovering particles with targeting capacity.Results: Three peptides, identified after four rounds of screening, were analyzed for specific and dose dependant binding and internalization. Binding was deemed specific because internalization was prevented by co-incubation with cognate synthetic peptides. Furthermore, after i.c.v. injection into rat brains, each peptide was found to target phage to epithelial cells in CP and to ependyma lining the ventricles.Conclusion: These data demonstrate that ligand-mediated targeting can be used as a strategy for drug delivery to the central nervous system and opens the possibility of using the choroid plexus as a portal of entry into the brain

The No-Hair Conjecture in 2D Dilaton Supergravity

We study two dimensional dilaton gravity and supergravity following hamiltonian methods. Firstly, we consider the structure of constraints of 2D dilaton gravity and then the 2D dilaton supergravity is obtained taking the squere root of the bosonic constraints. We integrate exactly the equations of motion in both cases and we show that the solutions of the equation of motion of 2D dilaton supergravity differs from the solutions of 2D dilaton gravity only by boundary conditions on the fermionic variables, i.e. the black holes of 2D dilaton supergravity theory are exactly the same black holes of 2D bosonic dilaton gravity modulo supersymmetry transformations. This result is the bidimensional analogue of the no-hair theorem for supergravity.Comment: Plain Tex, 19pp, IPNO-TH 93/2

Long-range potential fluctuations and 1/f noise in hydrogenated amorphous silicon

We present a microscopic theory of the low-frequency voltage noise (known as "1/f" noise) in micrometer-thick films of hydrogenated amorphous silicon. This theory traces the noise back to the long-range fluctuations of the Coulomb potential produced by deep defects, thereby predicting the absolute noise intensity as a function of the distribution of defect activation energies. The predictions of this theory are in very good agreement with our own experiments in terms of both the absolute intensity and the temperature dependence of the noise spectra.Comment: 8 pages, 3 figures, several new parts and one new figure are added, but no conceptual revision

A decision analytical cost analysis of offering ECV in a UK district general hospital

OBJECTIVE: To determine the care pathways and implications of offering mothers the choice of external cephalic version (ECV) at term for singleton babies who present with an uncomplicated breech pregnancy versus assisted breech delivery or elective caesarean. DESIGN: A prospective observational audit to construct a decision analysis of uncomplicated full term breech presentations. SETTING: The North Staffordshire NHS Trust. SUBJECTS: All women (n = 176) who presented at full term with a breech baby without complications during July 1995 and June 1997. MAIN OUTCOME MEASURES: The study determined to compare the outcome in terms of the costs and cost consequences for the care pathways that resulted from whether a women chose to accept the offer of ECV or not. All the associated events were then mapped for the two possible pathways. The costs were considered only within the hospital setting, from the perspective of the health care provider up to the point of delivery. RESULTS: The additional costs for ECV, assisted breech delivery and elective caesarean over and above a normal birth were £186.70, £425.36 and £1,955.22 respectively. The total expected cost of the respective care pathways for "ECV accepted" and "ECV not accepted" (including the probability of adverse events) were £1,452 and £1,828 respectively, that is the cost of delivery through the ECV care pathways is less costly than the non ECV delivery care pathway. CONCLUSIONS: Implementing an ECV service may yield cost savings in secondary care over and above the traditional delivery methods for breech birth of assisted delivery or caesarean section. The scale of these expected cost savings are in the range of £248 to £376 per patient. This converts to a total expected cost saving of between £43,616 and £44,544 for the patient cohort considered in this study

Organizational-Social-Capital, Time and International Family SMEs:An Empirical Study from the East of England

Previous studies on family-SME internationalization have largely focused on what resources are needed to drive an incremental process rather than how resource management occurs in historical time. This paper focuses on the latter, adopting a social capital perspective (capturing both internal, i.e. among family-SME board members, and external, cross border agent dyads, relations) in order to decipher case study data from the East of England. Findings show that it is not the presence or absence of organizational-social-capital that affects family-SME internationalization success but rather its variable use over the years driven by the future pursuit of longevity, not growth. Key within this context is the variable use of the international expertise and management capability of non-family managers in the family SME intra-organizational context. Ultimately this may lead to change and learning that occurs erratically, often including reversals, without causing family-SME progression across a sequence of incremental stages