Shape Effect in the Design of Nanowire Coated Microparticles as Transepithelial Drug Delivery Devices

While the oral drug delivery route has traditionally been the most popular among patients, it is estimated that 90 % of therapeutic compounds possess oral bioavailability limitations. Thus, the development of novel drug carriers for more effective oral delivery of therapeutics is an important goal. Composite particles made by growing nanoscopic silicon wires from the surface of narrowly dispersed, microsized silica beads were previously shown to be able to: (a) adhere well onto the epithelium by interdigitating their nanowires with the apical microvilli; and (b) increase the permeability of Caco-2 cell monolayers with respect to small organic molecules in direct proportion to their concentration. A comparison between the effects of spherical and planar particle morphologies on the permeability of the epithelial cell layer in vitro and in vivo presented the subject of this study. Owing to their larger surface area, the planar particles exhibited a higher drug loading efficiency than their spherical counterparts, while simultaneously increasing the transepithelial permeation of a moderately sized model drug, insulin. The insulin elution profile for planar nanowire-coated particles displayed a continual increase in the cumulative amount of the released drug, approaching a constant release rate for 1 – 4 h period of the elution time. An immunohistochemical study confirmed the ability of planar silica particles coated with nanowires to loosen the tight junction of the epithelial cells to a greater extent than the spherical particles did, thus enabling a more facile transport of the drug across the epithelium. Transepithelial permeability tests conducted for model drugs ranging in size from 0.4 to 150 kDa yielded three categories of molecules depending on their permeation propensities. Insulin belonged to the category of molecules deliverable across the epithelium only with the assistance of nanowire-coated particles. Other groups of drugs, smaller and bigger, respectively, either did not need the carrier to permeate the epithelium or were not able to cross it even with the support from the nanowire-coated particles. Bioavailability of insulin orally administered to rabbits was also found to be increased when delivered in conjunction with the nanowire-coated planar particles

Phenology Effects on Productivity and Hatching-Asynchrony of American Kestrels (\u3cem\u3eFalco sparverius\u3c/em\u3e) Across a Continent

Optimal reproductive performance occurs when birds time reproduction to coincide with peak food availability. Deviation from optimal timing, or mismatch, can affect productivity, though birds may mediate some mismatch effects by altering their incubation behavior. We studied the consequences of nesting timing (i.e., clutch initiation relative to an index of spring start) on productivity across the breeding range of American kestrels (Falco sparverius) in the United States and southern Canada, and associations between nesting timing, incubation behavior, and hatching asynchrony. We used observations from long-term nest box monitoring, remote trail cameras, and community-scientist-based programs to obtain data on clutch initiation, productivity, incubation, and hatching synchrony. Kestrels that initiated clutches after the extended spring index (SI-x, start of spring estimate) had higher rates of nest failure and fewer nestlings than earlier nesters, and effects of nesting timing on productivity were strongest in the Northeast. In contrast, kestrels in the Southwest experienced a more gradual decline in productivity across the season. Spatial effects may be the result of regional differences in growing seasons and temporal nesting windows (duration of nesting season). Specifically, resource availability in the Northeast was highly peaked during the breeding season, potentially resulting in shorter nesting windows. Conversely, resource curves were more prolonged in the Southwest, and growing seasons are becoming longer with climate change, potentially resulting in longer nesting windows. We found an inverse relationship between nesting timing and the onset of male incubation. Males from breeding pairs that initiated clutches after SI-x began incubation sooner than males from breeding pairs that initiated clutches before SI-x. Early-onset of male incubation was positively associated with hatching asynchrony, creating increased age variation in developing young. In sum, nesting phenology relative to the SI-x has consequences for American kestrels’ productivity, and these consequences vary across space. The early onset of incubation may act as a potential adaptive behavior to advance the average hatch date and spread out energetic demands. Given the effects of nesting timing on productivity, kestrels are likely to be sensitive to climate-driven advances in growing seasons and vulnerable to phenological mismatch, particularly in the Northeast

Local Convergence and Global Diversity: From Interpersonal to Social Influence

Axelrod (1997) showed how local convergence in cultural influence can preserve cultural diversity. We argue that central implications of Axelrod's model may change profoundly, if his model is integrated with the assumption of social influence as assumed by an earlier generation of modelers. Axelrod and all follow up studies employed instead the assumption that influence is interpersonal (dyadic). We show how the combination of social influence with homophily allows solving two important problems. Our integration of social influence yields monoculture in small societies and diversity increasing in population size, consistently with empirical evidence but contrary to earlier models. The second problem was identified by Klemm et al.(2003a,b), an extremely narrow window of noise levels in which diversity with local convergence can be obtained at all. Our model with social influence generates stable diversity with local convergence across a much broader interval of noise levels than models based on interpersonal influence.Comment: 20 pages, 3 figures, Paper presented at American Sociological Association 103rd Annual Meeting, August 1-4, 2008, Boston, MA. Session on Mathematical Sociolog

Reconnecting with nature for sustainability

Calls for humanity to ‘reconnect to nature’ have grown increasingly louder from both scholars and civil society. Yet, there is relatively little coherence about what reconnecting to nature means, why it should happen and how it can be achieved. We present a conceptual framework to organise existing literature and direct future research on human–nature connections. Five types of connections to nature are identified: material, experiential, cognitive, emotional, and philosophical. These various types have been presented as causes, consequences, or treatments of social and environmental problems. From this conceptual base, we discuss how reconnecting people with nature can function as a treatment for the global environmental crisis. Adopting a social–ecological systems perspective, we draw upon the emerging concept of ‘leverage points’—places in complex systems to intervene to generate change—and explore examples of how actions to reconnect people with nature can help transform society towards sustainability

Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis

Brain atrophy is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment.Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, putamen, thalamus, ventricles, and brainstem using a validated and completely automated segmentation method. We correlated these volumes with the Expanded Disability Status Scale (EDSS), MS Severity Scale (MSSS), MS Functional Composite (MSFC), and quantitative measures of ankle strength and toe sensation. Normalized volumes of both cortical and subcortical GM structures were abnormally low in the MS group, whereas no abnormality was found in the volume of the cerebral WM. High physical disability was associated with low cerebral WM, thalamus, and brainstem volumes (partial correlation coefficients ~0.3-0.4) but not with low cortical GM volume. Thalamus volumes were inversely correlated with lesion load (r = -0.36, p<0.005).The GM is atrophic in MS. Although lower WM volume is associated with greater disability, as might be expected, WM volume was on average in the normal range. This paradoxical result might be explained by the presence of coexisting pathological processes, such as tissue damage and repair, that cause both atrophy and hypertrophy and that underlie the observed disability

Pet Rodents and Fatal Lymphocytic Choriomeningitis in Transplant Patients

A unique strain of this virus was traced back to hamsters from an Ohio rodent distribution facility

Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells

The adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro-inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs../Akt/COX-2 signalling axis is required for leptin's pro-angiogenic actions and that this is regulated upstream by ObRb-dependent activation of VEGFR2. These studies identify a new function for VEGFR2 as a mediator of leptin-stimulated COX-2 expression and angiogenesis and have implications for understanding leptin's regulation of the vasculature in both non-obese and obese individuals

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n=31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n=30), and with two PPTMs (BSEP3/3; n=77). We compared presentation, native liver survival (NLS), and effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001). Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment