Global change effects on plant communities are magnified by time and the number of global change factors imposed.

Global change drivers (GCDs) are expected to alter community structure and consequently, the services that ecosystems provide. Yet, few experimental investigations have examined effects of GCDs on plant community structure across multiple ecosystem types, and those that do exist present conflicting patterns. In an unprecedented global synthesis of over 100 experiments that manipulated factors linked to GCDs, we show that herbaceous plant community responses depend on experimental manipulation length and number of factors manipulated. We found that plant communities are fairly resistant to experimentally manipulated GCDs in the short term (<10 y). In contrast, long-term (≥10 y) experiments show increasing community divergence of treatments from control conditions. Surprisingly, these community responses occurred with similar frequency across the GCD types manipulated in our database. However, community responses were more common when 3 or more GCDs were simultaneously manipulated, suggesting the emergence of additive or synergistic effects of multiple drivers, particularly over long time periods. In half of the cases, GCD manipulations caused a difference in community composition without a corresponding species richness difference, indicating that species reordering or replacement is an important mechanism of community responses to GCDs and should be given greater consideration when examining consequences of GCDs for the biodiversity-ecosystem function relationship. Human activities are currently driving unparalleled global changes worldwide. Our analyses provide the most comprehensive evidence to date that these human activities may have widespread impacts on plant community composition globally, which will increase in frequency over time and be greater in areas where communities face multiple GCDs simultaneously.

Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice.

BACKGROUND: Mutations of the gene encoding the major component of Lewy bodies (LB), α-synuclein (α-syn), cause autosomal dominant forms of Parkinson's disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against α-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human α-syn (hA30Pα-syn) and with two, one or no parkin knockout alleles. RESULTS: Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to α-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar α-syn species phosphorylated at S129 (PS129α-syn) were the predominant neuropathological feature in hA30Pα-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and α-syn truncated at D135 (α-synD135), indicating that PS129α-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction. CONCLUSIONS: These findings suggest that Parkin deficiency acts as a protective modifier in α-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of α-syn deposits in end-stage disease.

Regional signatures of plant response to drought and elevated temperature across a desert ecosystem.

The performance of many desert plant species in North America may decline with the warmer and drier conditions predicted by climate change models, thereby accelerating land degradation and reducing ecosystem productivity. We paired repeat measurements of plant canopy cover with climate at multiple sites across the Chihuahuan Desert over the last century to determine which plant species and functional types may be the most sensitive to climate change. We found that the dominant perennial grass, Bouteloua eriopoda, and species richness had nonlinear responses to summer precipitation, decreasing more in dry summers than increasing with wet summers. Dominant shrub species responded differently to the seasonality of precipitation and drought, but winter precipitation best explained changes in the cover of woody vegetation in upland grasslands and may contribute to woody-plant encroachment that is widespread throughout the southwestern United States and northern Mexico. Temperature explained additional variability of changes in cover of dominant and subdominant plant species. Using a novel empirically based approach we identified "climate pivot points" that were indicative of shifts from increasing to decreasing plant cover over a range of climatic conditions. Reductions in cover of annual and several perennial plant species, in addition to declines in species richness below the long-term summer precipitation mean across plant communities, indicate a decrease in the productivity for all but the most drought-tolerant perennial grasses and shrubs in the Chihuahuan Desert. Overall, our regional synthesis of long-term data provides a robust foundation for forecasting future shifts in the composition and structure of plant assemblages in the largest North American warm desert.

Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors.

Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.

Landscape characteristics shape surface soil microbiomes in the Chihuahuan Desert.

Introduction: Soil microbial communities, including biological soil crust microbiomes, play key roles in water, carbon and nitrogen cycling, biological weathering, and other nutrient releasing processes of desert ecosystems. However, our knowledge of microbial distribution patterns and ecological drivers is still poor, especially so for the Chihuahuan Desert. Methods: This project investigated the effects of trampling disturbance on surface soil microbiomes, explored community composition and structure, and related patterns to abiotic and biotic landscape characteristics within the Chihuahuan Desert biome. Composite soil samples were collected in disturbed and undisturbed areas of 15 long-term ecological research plots in the Jornada Basin, New Mexico. Microbial diversity of cross-domain microbial groups (total Bacteria, Cyanobacteria, Archaea, and Fungi) was obtained via DNA amplicon metabarcode sequencing. Sequence data were related to landscape characteristics including vegetation type, landforms, ecological site and state as well as soil properties including gravel content, soil texture, pH, and electrical conductivity. Results: Filamentous Cyanobacteria dominated the photoautotrophic community while Proteobacteria and Actinobacteria dominated among the heterotrophic bacteria. Thaumarchaeota were the most abundant Archaea and drought adapted taxa in Dothideomycetes and Agaricomycetes were most abundant fungi in the soil surface microbiomes. Apart from richness within Archaea (p = 0.0124), disturbed samples did not differ from undisturbed samples with respect to alpha diversity and community composition (p ≥ 0.05), possibly due to a lack of frequent or impactful disturbance. Vegetation type and landform showed differences in richness of Bacteria, Archaea, and Cyanobacteria but not in Fungi. Richness lacked strong relationships with soil variables. Landscape features including parent material, vegetation type, landform type, and ecological sites and states, exhibited stronger influence on relative abundances and microbial community composition than on alpha diversity, especially for Cyanobacteria and Fungi. Soil texture, moisture, pH, electrical conductivity, lichen cover, and perennial plant biomass correlated strongly with microbial community gradients detected in NMDS ordinations. Discussion: Our study provides first comprehensive insights into the relationships between landscape characteristics, associated soil properties, and cross-domain soil microbiomes in the Chihuahuan Desert. Our findings will inform land management and restoration efforts and aid in the understanding of processes such as desertification and state transitioning, which represent urgent ecological and economical challenges in drylands around the world.

Changes in the solubility and phosphorylation of α-synuclein over the course of Parkinson's disease.

Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue samples from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories; S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson's disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson's disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson's disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.

Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration.

In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-ß in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.

Postinjury depression is a serious complication in adolescents after major trauma: injury severity and injury-event factors predict depression and long-term quality of life deficits.

BACKGROUND: Little is known about the impact of postinjury depression after major trauma in adolescents. A prospective epidemiologic study was conducted to examine depression in injured adolescents. Specific objectives of this report are to identify risk factors for depression onset and the impact of depression on quality of life (QoL) outcomes. METHODS: Four hundred one trauma patients were enrolled in this study (age, 12-19 years; injury severity score [ISS] ≥4). Depression diagnosis was based on the Children's Depression Inventory. QoL outcomes were measured using the Quality of Well-being Scale at 3-, 6-, 12-, 18-, and 24-month follow-up. RESULTS: Depression at discharge was diagnosed in 41% of 399 adolescent trauma survivors with complete Children's Depression Inventory data. Multivariate logistic regression identified ISS, >3 body regions injured, low socioeconomic status, family members injured at the scene, and suicidal ideology or attempted suicide before injury as strong and independent predictors of depression risk. ISS and three or more body regions injured predicted depression risk. Patients with severe injury (ISS ≥17) were twice more likely to have depressive symptoms than patients with moderate injury (ISS <17; odds ratio [OR] = 2.0; p < 0.01). Patients with three or more body regions injured were more likely to have depressive symptoms than patients with less than three body regions injured (OR = 2.1; p < 0.01). Adolescents from low socioeconomic status families were more likely to be depressed (OR = 2.2; p < 0.05). Adolescent patients who witnessed family injured at the trauma event were also more likely to be depressed (OR = 2.4; p < 0.01). Patients who experienced suicidal ideology or attempted suicide preinjury were more likely to be depressed than adolescent patients who did not (OR = 2.87; p < 0.05). Quality of well-being scores were significantly and markedly lesser for patients with depression across the 24-month follow-up (3-18 months follow-up, p < 0.0001; 24 months: with depression = 0.738 vs. without depression = 0.784, p < 0.0001). Patients with depression were also significantly more likely to develop acute stress disorder and long-term posttraumatic stress disorder (OR = 1.8, p < 0.001). CONCLUSIONS: Postinjury depression is a major and an important complication in seriously injured adolescents. Adolescent trauma survivors have high rates of predischarge depression. Depression severely impacts QoL outcomes and is associated with injury severity, injury event-related factors, social factors, acute stress disorder, and posttraumatic stress disorder. Early recognition and treatment of DEPR in seriously injured adolescents will improve acute trauma care and long-term QoL outcomes.

Health state preferences are equivalent in the United States and Trinidad and Tobago.

PURPOSE: To derive preference weights in Trinidad and Tobago for Quality of Well-being Scale (QWB) health states in order to calculate QWB scores that can be compared to scores calculated from US-derived preference weights. The comparison was to determine whether the QWB scores from these different preference weights would lead to similar conclusions. METHODS: We conducted in-person household interviews to elicit preferences for 65 health states using a probability sample of 235 adults from Port of Spain, Chaguanas and San Fernando, Trinidad and Tobago. A regression model with correction for within-person clustering of observations was used to obtain preference weights based on case judgments on a 0 (dead) to 10 ("perfect health") scale. The independent variables were the components of the QWB entered as indicator (0, 1) variables. RESULTS: One hundred and nineteen (51%) respondents provided ratings. The respondents that provided ratings were demographically no different from those that did not. The QWB response patterns were very similar using Trinidad and US weights. The mean (SD) QWB score was 0.750 (0.130) for female respondents and 0.784 (0.125) for male respondents using Trinidad coefficients (t2, 233=-2.05, P=0.04) and 0.747 (0.131) for female respondents and 0.783 (0.126) for male respondents using US weights (t2, 233=-2.17, P=0.03). CONCLUSIONS: Overall, we found the US and Trinidad and Tobago weights were highly similar and that the choice of either set of weights would lead to similar conclusions.

Modifying connectivity to promote state change reversal: the importance of geomorphic context and plant-soil feedbacks.

Alternative states maintained by feedbacks are notoriously difficult, if not impossible, to reverse. Although positive interactions that modify soil conditions may have the greatest potential to alter self-reinforcing feedbacks, the conditions leading to these state change reversals have not been resolved. In a 9-yr study, we modified horizontal connectivity of resources by wind or water on different geomorphic surfaces in an attempt to alter plant-soil feedbacks and shift woody-plant-dominated states back toward perennial grass dominance. Modifying connectivity resulted in an increase in litter cover regardless of the vector of transport (wind, water) followed by an increase in perennial grass cover 2 yr later. Modifying connectivity was most effective on sandy soils where wind is the dominant vector, and least effective on gravelly soils on stable surfaces with low sediment movement by water. We found that grass cover was related to precipitation in the first 5 yr of our study, and plant-soil feedbacks developed following 6 yr of modified connectivity to overwhelm effects of precipitation on sandy, wind-blown soils. These feedbacks persisted through time under variable annual rainfall. On alluvial soils, either plant-soil feedbacks developed after 7 yr that were not persistent (active soils) or did not develop (stable soils). This novel approach has application to drylands globally where desertified lands have suffered losses in ecosystem services, and to other ecosystems where connectivity-mediated feedbacks modified at fine scales can be expected to impact plant recovery and state change reversals at larger scales, in particular for wind-impacted sites.

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions.

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.

Red blood cells are the major source of alpha-synuclein in blood.

BACKGROUND: Alpha-synuclein has been directly linked to Parkinson's disease etiology by mutations in and multiplication of its gene that result in a familial form of Parkinson's disease. Alpha-synuclein has been detected in blood, and was found to be elevated in the blood of those individuals with the alpha-synuclein gene multiplication. OBJECTIVE: A complete analysis of the level of alpha-synuclein in blood has not been performed. In this report, we determine the quantitative distribution of alpha-synuclein in the plasma and different cellular fractions of human blood. The levels of alpha-synuclein in human and mouse blood are compared. METHODS: Alpha-synuclein levels in the different fractions of blood were quantified by a sandwich ELISA with purified recombinant alpha-synuclein as an assay standard. Samples were further characterized by Western immunoblot analysis. RESULTS: More than 99% of the alpha-synuclein resides in the red blood cells (RBCs) with less than 1% of the total detected in the plasma, platelets and peripheral blood mononuclear cells. CONCLUSIONS: More than 99% of the alpha-synuclein in human blood is present in the peripheral blood cells, with the remainder in plasma. Fractionation of peripheral blood cells from human blood and quantification of alpha-synuclein revealed that only a very small amount of the total alpha-synuclein is present in peripheral blood mononuclear cells, and platelets, with the majority of alpha-synuclein in blood being present in RBCs. Considering the abundance and fragility of RBCs, alpha-synuclein levels in these other blood fractions or other bodily fluids such as cerebrospinal fluid may be artificially elevated by contamination with intact or lysed RBCs.

Change in dominance determines herbivore effects on plant biodiversity.

Herbivores alter plant biodiversity (species richness) in many of the world's ecosystems, but the magnitude and the direction of herbivore effects on biodiversity vary widely within and among ecosystems. One current theory predicts that herbivores enhance plant biodiversity at high productivity but have the opposite effect at low productivity. Yet, empirical support for the importance of site productivity as a mediator of these herbivore impacts is equivocal. Here, we synthesize data from 252 large-herbivore exclusion studies, spanning a 20-fold range in site productivity, to test an alternative hypothesis-that herbivore-induced changes in the competitive environment determine the response of plant biodiversity to herbivory irrespective of productivity. Under this hypothesis, when herbivores reduce the abundance (biomass, cover) of dominant species (for example, because the dominant plant is palatable), additional resources become available to support new species, thereby increasing biodiversity. By contrast, if herbivores promote high dominance by increasing the abundance of herbivory-resistant, unpalatable species, then resource availability for other species decreases reducing biodiversity. We show that herbivore-induced change in dominance, independent of site productivity or precipitation (a proxy for productivity), is the best predictor of herbivore effects on biodiversity in grassland and savannah sites. Given that most herbaceous ecosystems are dominated by one or a few species, altering the competitive environment via herbivores or by other means may be an effective strategy for conserving biodiversity in grasslands and savannahs globally.

Quality of Well-being profiles followed paths of health status change at micro- and meso-levels in trauma patients.

OBJECTIVE: The objective of this study is to analyze Quality of Well-being Scale scores and profiles tracing Trauma Recovery Project (TRP) patient scores over time. STUDY DESIGN AND SETTING: A total of 787 TRP patients had complete preinjury and injury day data. Of these 787, 574 patients were followed up 6 months after hospital release. Analyses include persons with head injury vs. long bone and pelvic injury. RESULTS: Paired t-tests found significant differences for scores between each measurement point. Means analyses found significant variation on first day of hospitalization vs. 6-month recovery scores by injury site--head worse off than long bone and pelvic injury at first, but becoming better off 6 months after release from hospital. These effects were traced to specific symptom/problem complexes and functional limitations. CONCLUSION: Examination of such profiles can add significant information about health implications not obvious from overall scores. The size and direction of such contributions to overall scores may be reliably traced over time.

Report of nationally representative values for the noninstitutionalized US adult population for 7 health-related quality-of-life scores.

BACKGROUND: Despite widespread use of generic health-related quality-of-life (HRQoL) scores, few have publicly published nationally representative US values. PURPOSE: To create current nationally representative values for 7 of the most common HRQoL scores, stratified by age and sex. METHODS: The authors used data from the 2001 Medical Expenditures Panel Survey (MEPS) and the 2001 National Health Interview Survey (NHIS), nationally representative surveys of the US noninstitutionalized civilian population: The MEPS was used to calculate 6 HRQoL scores: categorical self-rated health, EuroQoL-5D with US scoring, EuroQoL-5D with UK scoring, EuroQol Visual Analog Scale, mental and physical component summaries from the SF-12, and the SF-6D. The authors estimated Quality of Well-being scale scores from the NHIS. RESULTS: They included 22,523 subjects from MEPS 2001 and 32,472 subjects from NHIS 2001. Most age and sex categories had instrument completion rates above 85%. Females reported lower scores than males across all ages and instruments. In general, those in older age groups reported lower scores than younger age groups, with the exception of the mental component summary from the SF-12. CONCLUSION: This is one of the first sets of publicly available, nationally representative US values for any standardized HRQoL measure. These values are important for use in both generalized comparisons of health status and in cost-effectiveness analyses.

Development of a Luminex Bead Based Assay for Diagnosis of Toxocariasis Using Recombinant Antigens Tc-CTL-1 and Tc-TES-26.

The clinical spectrum of human disease caused by the roundworms Toxocara canis and Toxocara cati ranges from visceral and ocular larva migrans to covert toxocariasis. The parasite is not typically recovered in affected tissues, so detection of parasite-specific antibodies is usually necessary for establishing a diagnosis. The most reliable immunodiagnostic methods use the Toxocara excretory-secretory antigens (TES-Ag) in ELISA formats to detect Toxocara-specific antibodies. To eliminate the need for native parasite materials, we identified and purified immunodiagnostic antigens using 2D gel electrophoresis followed by electrospray ionization mass spectrometry. Three predominant immunoreactive proteins were found in the TES; all three had been previously described in the literature: Tc-CTL-1, Tc-TES-26, and Tc-MUC-3. We generated Escherichia coli expressed recombinant proteins for evaluation in Luminex based immunoassays. We were unable to produce a functional assay with the Tc-MUC-3 recombinant protein. Tc-CTL-1 and Tc-TES-26 were successfully coupled and tested using defined serum batteries. The use of both proteins together generated better results than if the proteins were used individually. The sensitivity and specificity of the assay for detecting visceral larval migrans using Tc-CTL-1 plus Tc-TES-26 was 99% and 94%, respectively; the sensitivity for detecting ocular larval migrans was 64%. The combined performance of the new assay was superior to the currently available EIA and could potentially be employed to replace current assays that rely on native TES-Ag.

Design of substrate-based inhibitors of human beta-secretase.

By use of the effectively cleaved beta-secretase (BACE) substrate (1), incorporation of a statine in P(1) resulted in a weak inhibitor 13 of the enzyme. Further substitution of P(1)'-Asp by P(1)'-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P(10)-P(5) residues on the N-terminal part of inhibitor 22 resulted in no loss of potency (23). C-terminal truncations of inhibitor 22 generally led to significant loss of potency.

Design and synthesis of statine-based cell-permeable peptidomimetic inhibitors of human beta-secretase.

We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.

Intratympanic gentamicin therapy for Ménière's disease: a meta-analysis.

OBJECTIVE: This study compared the effectiveness of five different techniques of intratympanic gentamicin administration for Ménière's disease. DATA SOURCES: A MEDLINE search of the English language literature from 1978 to 2002 was performed using the key words "intratympanic," "gentamicin," "therapy," "Ménière's," and "disease." STUDY SELECTION: Inclusion criteria to select articles for meta-analysis were clear description of gentamicin delivery technique, clearly reported vertigo control results, and report of hearing loss posttreatment. Seven studies (n = 218) describing the multiple daily dosing technique (delivery three times per day for >or=4 d), two studies (n = 84) describing the weekly dosing technique (weekly injections for four total doses), eight studies (n = 253) of the low-dose technique (one to two injections with retreatment for recurrent vertigo), four studies (n =156) of continuous microcatheter delivery, and six studies (n =269) of the titration technique (daily or weekly doses until onset of vestibular symptoms, change in vertigo, or hearing loss) were entered into the model. DATA EXTRACTION: Vertigo control results were stratified into complete, substantial, or poor control. Hearing results were separated by profound, partial, or no hearing loss. Individuals undergoing caloric testing were separated by degree of vestibular ablation (complete versus partial) and analyzed for vertigo control (n = 301) and hearing loss (n = 333) after treatment. DATA SYNTHESIS: Comparisons between the rates of complete vertigo control, effective vertigo control (complete plus substantial control), overall hearing loss (partial plus profound), and profound hearing loss by delivery method were based on a parametric empirical Bayes analysis using binomial generalized linear models and backward variable selection (joining). Relative risk for vertigo control and hearing loss by partial or complete ablation was examined study by study using residual maximum likelihood to carry out a parametric empirical Bayes analysis. CONCLUSION: The titration method of gentamicin delivery demonstrated significantly better complete (81.7%, p = 0.001) and effective (96.3%, p < 0.05) vertigo control compared with other methods. The low-dose method of delivery demonstrated significantly worse complete vertigo control (66.7%, p < 0.001) and trends toward worse effective vertigo control (86.8%, p = 0.05) compared with other methods. The weekly method of delivery trends toward less overall hearing loss (13.1%, p = 0.08), and the multiple daily method demonstrated significantly more overall hearing loss (34.7%, p < 0.01) compared with other groups. No significant difference in profound hearing loss was found between groups. Degree of vestibular ablation after gentamicin therapy is not significantly correlated with the resulting vertigo control or hearing loss status.

Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease.

The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aß peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets α-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions.