A Small Molecule Modulator of Hsp90 Improves Experimental Diabetic Neuropathy

Background: Current Hsp90 inhibitors are therapeutically problematic. Although they induce a pro-survival heat shock response that promotes the refolding of damaged proteins, a confounding issue is that at these concentrations the inhibitors are cytotoxic, due to their ability to decrease the maturation of newly synthesized client proteins. KU-32 contains a novobiocin-based scaffold that binds to the C-terminal of Hsp90 and induces a pro-survival heat shock response at a concentration ~10,000 fold lower than that needed to induce neurotoxicity. This creates an optimal therapeutic window in which to operate, providing promise towards the development of novel neuroprotective agents. Objective: To evaluate whether the induction of the heat shock response through Hsp90 modulation could decrease or reverse the pathophysiological progression of diabetic peripheral neuropathy in Type-1 diabetic mice. Hypothesis: A small molecule modulator of Hsp90 will improve experimental diabetic neuropathy. Methods: After 8-12 weeks of diabetes induced by streptozotocin, the effects of weekly doses of KU-32 on several standard indices of diabetic neuropathy were measured. Results: Initial toxicity studies employing the weekly intraperitoneal administration of 2 or 20 mg/kg KU-32 to non-diabetic mice over 6 week duration did not alter motor or sensory nerve conduction velocity (MNCV/SNCV), mechanical or thermal sensitivity, or intra-epidermal nerve fiber density. Thus, the drug alone had no effect on altering common measures of neuropathy. In a 12-week intervention study, wild-type C57 Bl/6 animals receiving a weekly treatment regimen of 20 mg/kg KU-32 for 6 weeks exhibited a steady recovery to control levels in thermal and mechanical sensitivity, MNCV, and SNCV. KU-32 did not alter metabolic control. As Hsp70 is hypothesized to be a major target for KU-32, its necessity in neuroprotection was examined using Hsp70 double knockout mice (Hsp70.1/Hsp70.3). In a 12-week intervention study, Hsp70 knockout mice receiving a weekly treatment regimen of 20 mg/kg for 6 weeks displayed no improvements in thermal and mechanical sensitivity, MNCV, and SNCV. In 8-week intervention studies, animals demonstrated recoveries in sensory hypoalgesia and nerve conduction velocity deficits in a dose-dependent manner. KU-32 did not alter sensory nerve fiber innervation. Conclusions: These data suggest that hyperglycemia may adversely impact the ability of neurons to promote refolding or decrease unfolding of mildly damaged proteins. C-terminal Hsp90 modulators can improve several standard clinical indices of negative symptoms associated with small and large fiber dysfunction in the absence of improving overall metabolic control. The affects of KU-32 appear to be dose-dependent and require the presence of inducible Hsp70 for efficacy. Inducible Hsp70 is not required for the pathophysiological progression of diabetic neuropathy

Toward a Framework of Inclusive Social Studies: Obstacles and Opportunities in a Preservice Teacher Education Program

This study explores how one secondary social studies teacher education program prepares prospective teachers for inclusive education. Drawing on theories of democratic citizenship education and Disability Studies in Education, inclusive social studies envisions a socially democratic educational setting that fosters the development of a community of learners, attempts to balance the unity and diversity of democratic citizenship, and adopts a curriculum that is flexible, participatory, and accessible to learners of all abilities. Addressing the dearth of research on the intersection of social studies and inclusive education, as well as the limits of what we know about how prospective social studies teachers are prepared for inclusive schooling, this study answers the research question, How does a preservice social studies teacher education program help prepare prospective teachers for inclusive social studies? In addition, I explore preservice teachers' prior knowledge of and beliefs about disability, inclusion, and democratic citizenship, as well as the teaching and learning that take place within a social studies teacher education program. Over the course of one semester, I employed an instrumental case study design using an introductory questionnaire, multiple interviews and observations, and documents to explore preparation for inclusive social studies in a teacher education program at a New York college. Participants in the study included nine preservice teachers (four undergraduate students and five graduate students), the social studies program director and methods course instructor, and two special education instructors. Major findings indicate that normative structures of contemporary schooling, especially in the current era of standards-based educational reform, have hindered preparation for inclusive social studies, as they run counter to its constituent elements of democratic citizenship education and inclusive education. Although undergraduate and graduate social studies methods courses emphasized knowing and implementing democratic citizenship education, fostering a classroom community of diverse learners, and creating a flexible curriculum for students of all abilities, students in these programs frequently clung to narrow conceptions of democratic citizenship and inclusion. The intransigence of their prior knowledge and initial beliefs was influenced in part by their own experiences in social studies classrooms, both before and during their time in the program, as well as the persistence of ableism and the stigmatizing effects of disability in education. Theoretical and pedagogical incongruence throughout the program, coupled with a lack of critical reflective space, also resulted in students feeling unprepared to teach inclusive social studies. Obstacles to inclusive social studies included students' apprenticeships of observation, the persistence of the traditional special education paradigm, the limits of diversity education in addressing disability, and the lack of space for critical reflection. Opportunities for inclusive social studies, or areas in which there was some consistency and consensus across the disparate components of the program, focused on fostering classroom communities of learners and creating flexible, differentiated curricula. This study has implications for research, practice, and policy in the areas of inclusive education, teacher education, and democratic citizenship education

China’s foreign oil policy: genesis, deployment and selected effects

China is a rising global power with a growing role and impact on the world’s energy markets as well as on the Earth’s climate system. China pursues its development in an essentially non-confrontational manner, a vision encapsulated by the notion of peaceful rise which is viewed positively in the world’s major capitals. Nevertheless, China’s rapid growth represents a genuine global challenge and raises many questions. How is China dealing with its growing need for imported crude oil? What is the impact of China’s rise on the global oil market, notably in terms of oil price developments? Are Chinese actions on oil markets different from those of other major importers? What opportunities and risks arise as a result of china’s growing role on the global oil market from the viewpoint of other global players? In this report we seek to offer some answers to those questions with a review of China’s developing energy policy, of the actions and revealed preferences of its national oil companies, and of broader economic and geopolitical analyses of the impact of China’s growing oil consumption on other global players.Crude oil, energy security, oil security, China, foreign oil policy

Monitoring and Modeling Hot Water Consumption in Hotels for Solar Thermal Water Heating System Optimization

In this study, hot water consumption was monitored at two hotels in Boone, North Carolina. A typical hot water profile was created for each hotel, and the profiles were then used to size a solar thermal water heating system for each of them. The systems were modeled and optimized with TRNSYS 16. Then, the effect of altering the hot water draw profile on solar thermal system performance was investigated. The effect of hotel occupancy on hot water consumption was also explored. The optimal collector tilt angle (a few degrees below latitude) and collector flow rate (1 to 1.5 gpm per square foot of collector area) are similar to the values found in literature, but it was found that the optimal flow rate decreases with increasing collector area. The optimal storage volume was found to be 3 to 4 gallons per square foot of collector area, which is roughly twice the size recommended for residential solar thermal water heating systems. The hot water draw profile was found to have little effect on a properly-sized system’s life-cycle savings (2.7 to 3.8 percent). No correlation was found between hotel occupancy and hot water consumption

The evolutionary transition from reptiles to mammals: analyses of body size reduction and separation of middle ear elements from the jaw

Body size generally decreased during synapsid evolution until the origin of mammals, and this decrease has often been linked to the evolution of mammal-like characteristics. Despite the importance of these patterns to our understanding of mammalian evolution, the particular evolutionary mechanisms that underlie them are less clear. Previous studies have tested models across synapsid phylogeny prior to the origin of mammals and found little evidence for a pervasive direction bias in body size evolution. However, whether the rate or mode of body size evolution changed among particular subclades, or after the origin of mammals, has not been explored quantitatively. In this study we constructed a phylogenetic framework and used two proxies for body size (humerus and femur length) to model the pattern of body size evolution in a diverse suite of non-mammalian synapsids and Mesozoic mammals. Specifically, we statistically tested for shifts in the rates or modes of body size evolution at specific times or nodes of the phylogeny. Results confirm that passive processes are responsible for body size reduction when viewing the phylogeny as a whole. However, there is evidence of multiple rate changes along the way, as well as a significant period of stasis in the small early mammals. Body size also tended to evolve at a slower rate in mammals than in their ancestors. These results suggest that mammals exhibited significantly different evolutionary dynamics than their synapsid ancestors, consistent with a selective advantage for small body size in these groups. The evolutionary transition from reptiles to mammals is characterized by many remarkable changes, perhaps none more dramatic than the conversion of postdentary elements from the reptilian jaw into the middle ear of mammals. Reptiles and early synapsids possess multiple bones in the jaw but only a single bone in the middle ear, the columella (stapes). Additionally, they conduct jaw abduction via a joint between the articular and the quadrate. Conversely, mammals all possess a single bone in the jaw, the dentary, and multiple bones in the middle ear. Mammalian jaw articulation takes place between the dentary and squamosal. Throughout evolutionary history mammals have formed a new jaw joint and extended the middle ear into a three-ossicle chain. The articular and quadrate of the reptilian jaw have become the malleus and incus of the mammalian middle ear, respectively, adding to the pre-existing stapes. Another homologous element in this transition is the ectotympanic ring, which originated from the angular in the mandible. The historical transformation of these bones is documented in the fossil record, though gaps remain. In order to help elucidate some of the existing gaps, we studied the transition of these elements in the development of an extant mammal. Modern marsupials are born in an extremely premature state. In fact, at the time of birth they still exhibit a reptilian-style jaw joint between the articular and quadrate. Not until postnatally does the new jaw joint form and the original elements transition to the typical mammalian positioning within the middle ear. We utilized micro-CT scans of neonatal Monodelphis domestica taken at five-day intervals throughout the first month and a half of postnatal development to use as comparisons with exceptional fossil specimens from the past 250 million years. Three-dimensional reconstructions from these developmental time points line up quite well with the fossil record. Each five-day increment in early development equates with an approximate 40-million year jump in the fossil record. We also find that the Meckel’s cartilage, connecting the dentary to malleus, begins to separate at 20 days postnatal. This marks a significant milestone in development, as it is the point at which the middle ear ossicles gain independence from the jaw and can become specialized for hearing. Derived elements, such as the manubrium of the malleus, develop much later, consistent with their subsequent appearance in the fossil record after the origin of mammals. Overall, marsupial development appears to recapitulate evolutionary transitions within the synapsid lineage leading to mammals. The middle ear ossicles did not separate from the jaw in a single step, but rather underwent a distinct two-step process. Several exceptionally preserved fossils from ~120mya, Yanoconodon and Liaoconodon, show us that the first step consisted of a mediolateral separation of the elements from the dentary while they maintained an anterior connection via an ossified Meckel's cartilage. Only in later organisms did the MC become absorbed, completing the second step of the separation. It was this final degeneration of the Meckel’s cartilage that fully freed the middle ear elements from their association with the jaw and allowed unconstrained evolution for improvement hearing functionality. While the fossil record documents the middle ear transition through time, it only gives us a view of the patterns of change, leaving the underlying processes as a mystery. In order to fully understand the mechanistic drivers of such a dramatic shift, we need to examine the transition in an extant organism. Marsupials offer an opportunity for just such an analysis as their postnatal development essentially recapitulates the entire transition as observed in the fossil record. Thus, using Monodelphis we strove to uncover the underlying cellular and genetic drivers that are responsible for the separation of middle ear elements from the jaw. As we previously noted, the timeframe of Meckel’s disconnection from the malleus at postnatal day 20 served as a starting point for this work. Immunohistochemical staining revealed, that contrary to what is observed in placental mammals, apoptosis places an essential role in degenerating MC at the point of connection with the malleus. Programmed cell death has been ruled out as a factor in Meckel's breakdown for placentals, making it a comparatively novel method for marsupials to complete the same process. Interestingly, RNA-sequencing revealed significant upregulation in a handful of key genes (including Tgfbr2, Wisp1, Mmp9 and Ctsk) responsible for promoting apoptosis, bone breakdown, and cartilage resorption. Through verification with fluorescent in situ hybridization (FISH), all of these factors were shown to increase in expression level as they approached day 20. Inhibiting gene expression through anti-TGFb and alendronate injections, in order to prohibit apoptosis and osteoclast formation, resulted in maintenance of the Meckel's cartilage connection beyond the 20-day mark, and indications of MC ossification as well. An ossified MC was also evident in several ancestral lineages, indicating that changes in expression level of just a few genes may have been all that was required for independence of the middle ear elements

Intervention with the Hsp90 Modulator KU-32 Improves Chronic Experimental Diabetic Neuropathy

Inducing the heat shock response (HSR) through Hsp90 inhibition augments heat shock protein (Hsp) support and may improve several aspects of neurodegenerative phenotypes. Several Hsps serve as molecular chaperones that assist in the folding of nascent polypeptides (client proteins) into their mature conformations. They also act as intracellular triage units that refold damaged proteins, stabilize protein complexes, solubilize protein aggregates, and help clear irreparable proteins. A confounding issue surrounding Hsp90 inhibitors is their inability to generate therapeutic windows that dissociate cytotoxic client protein degradation from HSR induction. Our novel C-terminal Hsp90 inhibitor, KU-32, induces the HSR while divesting client protein degradation, thus expanding the dose range for neuroprotection. After 16 weeks of streptozotocin (STZ)-induced Type 1 diabetes in Swiss-Webster mice, KU-32 was intraperitoneally injected weekly at a dose of 20 mg/kg KU-32 (~ 43 mM Captisol/saline vehicle) for 10 weeks. Untreated diabetic mice developed significant reductions in motor and sensory nerve conduction velocities and worsening thermal and mechanical hypoalgesia. KU-32 intervention time-dependently restored these deficits back to untreated non-diabetic levels, without adversely affecting non-diabetic mice. Further, untreated diabetic mice exhibited a 31% reduction in hindpaw intraepidermal nerve fiber (iENF) density by 16 weeks, which remained consistent until study completion. KU-32 improved diabetic iENF density to within 11% of non-diabetic levels by 26 weeks. To assess mitochondrial function, a 96-well Extracellular Flux (XF96) Analyzer was used to measure oxygen consumption rates (OCRs) for lumbar (L4-L6) dorsal root ganglia (DRG) isolated and cultured upon study completion at 26 weeks. Treatment with the ATP synthase inhibitor oligomycin reduced diabetic OCRs by ~ 80%, indicating that diabetic DRG devote most of their basal oxygen consumption to ATP synthesis. This is over twice that of untreated non-diabetic DRG at ~ 35%. KU-32 treatment in STZ-diabetes improved OCR reductions to ~ 40%, signifying vast improvements to ATP synthesis efficiency. Upon protonophore injection, DRG from KU-32-treated diabetic mice exhibited a much higher rebound in OCRs compared to diabetes alone, suggesting possible improvements in resiliency to prolonged metabolic stress. Overall, these data suggest that the neuroprotective effects of KU-32 at more chronic stages of diabetic peripheral neuropathy (DPN) may stem from the drug’s ability to improve mitochondrial function and nerve fiber innervation. KU-32 pharmacokinetic (PK) analyses were also performed on DPN-relevant tissues to verify successful drug distribution and elimination from these tissues after intraperitoneal (IP) or oral gavage (OG) treatments. The results showed that KU-32 was rapidly absorbed and distributed to DPN-relevant tissues within 30 minutes of IP treatment and one hour of gavage. Temporal PK analyses suggested that 99.9% of KU-32 distributed to these tissues was eliminated within ~ 30 hours of treatment. This was consistent with findings from an 8 week intervention study, which showed virtually no detectable levels of KU-32 present in diabetic and non-diabetic tissues one week after final treatment. In support of the ongoing hypothesis that inducible Hsp70 is essential for KU-32’s neuroprotective effects in DPN, we showed that drug distribution to DPN-relevant tissues were indistinguishable between wild type C57BL/6 and Hsp70 KO mice. OG also increased drug elimination half-lives for all examined tissues compared to IP treatments, suggesting that OG drug delivery may beneficially increase drug exposure duration

Colour vision of the citrus psylla Trioza erytreae (Del Guercio) (Homoptera: Psyllidae) in relation to alightment colour preferences

The colour vision of adult citrus psylla, Trioza erytreae, was investigated in the laboratory using the behavioural parameters: alightment and walking. Light green flushing leaves (under which the nymphs develop) were significantly preferred, visually, to dark green mature leaves for alightment. Diffuse reflectance spectroscopy showed (when expressed in the parameters of human colour vision) that flush has a very slightly longer dominant wavelength, and roughly double the reflectance and purity. Alightrnent frequency correlated almost equally well with "purity" (as noted by Moericke, 1952 et seq., in "yellow-sensitive" aphids) as with the aphidological colour parameter "long/short ratio" developed by Kennedy et al. (1961). Elucidation of the mechanism underlying the citrus psylla's alightment colour preference was initially attempted with a printed spectrum and several paint series of measured spectral characteristics. It was clear that T.erytreae belongs to the "yellow-sensitive" group of Homoptera, but it was impossible to distinguish which pararneter(s) of colour the psyllids were responding to. Phototactic (walking) response to the individual parameters of colour was therefore measured using a monochromator. The phototactic action spectrum (against wavelength) was tri-modal, with peaks in the yellow-green (YG), blue (B), and ultra= violet (UV). Rate of phototaxis was not influenced by bandwidth (roughly equivalent to purity), but was proportional to intensity (roughly equivalent to reflectance). To investigate the influence of the above three wavelength regions on alightment, use was made of a very simple flight chamber incorporating a target of coloured light. Yellow-green and UV light both independently stimulated alightment . Their effect was additive. Different thresholds indicated distinct YG and UV receptor systems. Blue light alone did not stimulate alightment, and was strongly alightment-inhibitory in combination both with YG and with UV light. On the basis of the above physiological/behavioural findings, a new alightment formula was drawn up for describing the hamopteran's apparent manner of alightment determining integration of surface reflectance. The flush preference and alightment distributions on the series of artificial surfaces were found to correlate slightly more accurately, on average, as well as more consistently, with the new formula than with previously-available colour parameters. These findings are placed in perspective to the literature, and their possible economic relevance is discussed

Heat shock response and insulin-associated neurodegeneration

Dysfunctional insulin and insulin-like growth factor-I (IGF-I) signaling contributes to the pathological progression of diabetes, diabetic peripheral neuropathy (DPN), Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD). Despite their prevalence, there are limited therapeutic options available for the treatment of these neurodegenerative disorders. Therefore, establishing a link between insulin/IGF-I and the pathoetiology of these diseases may provide alternative approaches toward their management. Many of the heat shock proteins (Hsps) are well-known molecular chaperones that solubilize and clear damaged proteins and protein aggregates. Recent studies suggest that modulating Hsps may represent a promising therapeutic avenue for improving insulin and IGF-I signaling. Pharmacological induction of the heat shock response (HSR) may intersect with insulin/IGF-I signaling to improve aspects of neurodegenerative phenotypes. Herein, we review the intersection between Hsps and the insulin/IGF systems under normal and pathological conditions. The discussion will emphasize the potential of non-toxic HSR inducers as viable therapeutic agents

Housing Issues in Boston: Guidelines for New Policy and Program Perspectives

Urban stagnation and turbulence, the roller-coaster trends In the national and local economy and the vicissitudes of national, state and local public policies have left their mark on Boston\u27s residential neighborhoods and housing markets. Boston\u27s response to the new opportunities of public policy during the sixties and seventies was to take full advantage of urban renewal, assis ted-housing production and housing rehabilitation. Large-scale activities reshaped the occupancy patterns and market strengths of residential neighborhoods. By mid-1975, however, except for continuing growth in the City\u27s subsidized housing stock, Boston\u27s housing future looked bleak. There was pervasive evidence of a growing housing problem—physical neglect in public housing, exacerbated by major changes in tenant occupancy and acknowledged powerlessness of the tenant constituency to effect improvements; an increasing number of mortgage defaults, assignments or foreclosures in the large inventory of HUD-assisted multifamily rental housing; and the eroding effects on conventionally-financed private rental housing of rent regulation, inflation and high interest costs. Boston was experiencing relative stagnation in its housing markets. Residential property values in the strongest neighborhoods were barely able to keep pace with inflation while those in transitional and weak housing markets seemed to face an uncertain future