Overcoming the blood-brain barrier to taxane delivery for brain tumors and neurodegenerative diseases and brain tumors

The original publication is available at www.springerlink.comThe blood-brain barrier (BBB) effectively prevents microtubule stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for microtubule stabilizing drug permeation across the BBB is the active efflux back into the circulation by the over-expression of the multidrug resistant gene product (MDR1) or P-glycoprotein (P-gp). This study has focused on strategies to overcome P-gp-mediated efflux of taxol analogues, microtubule (MT) stabilizing agents that could be used to treat brain tumors and, potentially, neurodegenerative diseases such as Alzheimer’s disease. However, taxol is a strong P-gp substrate which limits its distribution across the BBB and therapeutic potential in the CNS. We have found that addition of a succinate group to the C-10 position of taxol results in an agent, Tx-67, with reduced interactions with P-gp and enhanced permeation across the BBB in both in vitro and in situ models. Our studies demonstrate the feasibility of making small chemical modifications to taxol to generate analogues with reduced affinity for the P-gp but retention of MT-stabilizing properties, i.e., a taxane that may reach and treat therapeutic targets in the CNS

Discovery of Two Nearby, Peculiar L Dwarfs from the 2MASS Proper Motion Survey: Young or Metal-Rich?

We present the discovery of two nearby L dwarfs from our 2MASS proper motion search, which uses multi-epoch 2MASS observations covering ~4700 square degrees of sky. 2MASS J18212815+1414010 and 2MASS J21481628+4003593 were overlooked by earlier surveys due to their faint optical magnitudes and their proximity to the Galactic Plane (10 degrees < |b| < 15 degrees). Assuming that both dwarfs are single, we derive spectrophotometric distances of ~10 pc, thus increasing the number of known L dwarfs within 10 pc to 10. In the near-infrared, 2MASS J21481628+4003593 shows a triangular-shaped H-band spectrum, strong CO absorption, and a markedly red J-Ks color (2.38+/-0.06) for its L6 optical spectral type. 2MASS J18212815+1414010 also shows a triangular-shaped H-band spectrum and a slightly red J-Ks color (1.78+/-0.05) for its L4.5 optical spectral type. Both objects show strong silicate absorption at 9-11 microns. Cumulatively, these features imply an unusually dusty photosphere for both of these objects. We examine several scenarios to explain the underlying cause for their enhanced dust content and find that a metal-rich atmosphere or a low-surface gravity are consistent with these results. 2MASS J18212815+1414010 may be young (and therefore have a low-surface gravity) based on its low tangential velocity of 10 km/s. On the other hand, 2MASS J21481628+4003593 has a high tangential velocity of 62 km/s and is therefore likely old. Hence, high metallicity and low-surface gravity may lead to similar effects.Comment: 9 pages, 4 tables, 13 figures. Accepted to Ap

Drift as a Force of Evolution: A Manipulationist Account

Can evolutionary theory be properly characterised as a “theory of forces”, like Newtonian mechanics? One common criticism to this claim concerns the possibility to conceive genetic drift as a causal process endowed by a specific magnitude and direction. In this article, we aim to offer an original response to this criticism by pointing out a connection between the notion of force and the notion of explanatory depth, as depicted in Hitchcock and Woodward’s manipulationist account of causal explanation. In a nutshell, our argument is that, since force-explanations can be consistently reframed as deep explanations and vice versa, and the notion of drift can be characterised in manipulationist terms as constitutively intervening in evolutionary deep explanations, then drift-explanations can be consistently reframed as force-explanations, and drift can be properly considered as a force of evolution. Insofar as similar considerations may be extended also to other evolutionary factors – chiefly selection –, our analysis offers an important support to the claim that evolutionary theory is a theory of forces.info:eu-repo/semantics/publishedVersio

TOI-1670 c, a 40-day Orbital Period Warm Jupiter in a Compact System, is Well-aligned

We report the measurement of the sky-projected obliquity angle $\lambda$ of the Warm Jovian exoplanet TOI-1670 c via the Rossiter-McLaughlin effect as part of the Stellar Obliquities in Long-period Exoplanet Systems (SOLES) project. We observed the transit window during UT 20 April 2023 for 7 continuous hours with NEID on the 3.5 m WIYN Telescope at Kitt Peak National Observatory. TOI-1670 hosts a sub-Neptune (P ~11 days; planet b) interior to the Warm Jovian (P ~40 days; planet c), which presents an opportunity to investigate the dynamics of a Warm Jupiter with an inner companion. Additionally, TOI-1670 c is now among the longest-period planets to date to have its sky-projected obliquity angle measured. We find planet c is well-aligned to the host star, with $\lambda$ = -0.3 +/- 2.2 degrees. TOI-1670 c joins a growing census of aligned Warm Jupiters around single stars and aligned planets in multi-planet systems.Comment: 11 pages, 2 figures, 1 table. Accepted to ApJ Letter

Natural selection shaped the rise and fall of passenger pigeon genomic diversity.

The extinct passenger pigeon was once the most abundant bird in North America, and possibly the world. Although theory predicts that large populations will be more genetically diverse, passenger pigeon genetic diversity was surprisingly low. To investigate this disconnect, we analyzed 41 mitochondrial and 4 nuclear genomes from passenger pigeons and 2 genomes from band-tailed pigeons, which are passenger pigeons' closest living relatives. Passenger pigeons' large population size appears to have allowed for faster adaptive evolution and removal of harmful mutations, driving a huge loss in their neutral genetic diversity. These results demonstrate the effect that selection can have on a vertebrate genome and contradict results that suggested that population instability contributed to this species's surprisingly rapid extinction

Alcator C-Mod: research in support of ITER and steps beyond

This paper presents an overview of recent highlights from research on Alcator C-Mod. Significant progress has been made across all research areas over the last two years, with particular emphasis on divertor physics and power handling, plasma–material interaction studies, edge localized mode-suppressed pedestal dynamics, core transport and turbulence, and RF heating and current drive utilizing ion cyclotron and lower hybrid tools. Specific results of particular relevance to ITER include: inner wall SOL transport studies that have led, together with results from other experiments, to the change of the detailed shape of the inner wall in ITER; runaway electron studies showing that the critical electric field required for runaway generation is much higher than predicted from collisional theory; core tungsten impurity transport studies reveal that tungsten accumulation is naturally avoided in typical C-Mod conditions.United States. Department of Energy (DE-FC02-99ER54512-CMOD)United States. Department of Energy (DE-AC02-09CH11466)United States. Department of Energy (DE-FG02-96ER-54373)United States. Department of Energy (DE-FG02-94ER54235

A typology of practice narratives during the implementation of a preventive, community intervention trial

<p>Abstract</p> <p>Background</p> <p>Traditional methods of process evaluation encompass what components were delivered, but rarely uncover how practitioners position themselves and act relative to an intervention being tested. This could be crucial for expanding our understanding of implementation and its contribution to intervention effectiveness.</p> <p>Methods</p> <p>We undertook a narrative analysis of in-depth, unstructured field diaries kept by nine community development practitioners for two years. The practitioners were responsible for implementing a multi-component, preventive, community-level intervention for mothers of new babies in eight communities, as part of a cluster randomised community intervention trial. We constructed a narrative typology of approaches to practice, drawing on the phenomenology of Alfred Schutz and Max Weber's Ideal Type theory.</p> <p>Results</p> <p>Five types of practice emerged, from a highly 'technology-based' type that was faithful to intervention specifications, through to a 'romantic' type that held relationships to be central to daily operations, with intact relationships being the final arbiter of intervention success. The five types also differed in terms of how others involved in the intervention were characterized, the narrative form (<it>e.g</it>., tragedy, satire) and where and how transformative change in communities was best created. This meant that different types traded-off or managed the priorities of the intervention differently, according to the deeply held values of their type.</p> <p>Conclusions</p> <p>The data set constructed for this analysis is unique. It revealed that practitioners not only exercise their agency within interventions, they do so systematically, that is, according to a pattern. The typology is the first of its kind and, if verified through replication, may have value for anticipating intervention dynamics and explaining implementation variation in community interventions.</p