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.

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.

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.

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.

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.

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.

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 Aβ 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.

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.

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.

Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease.

Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo.

Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce α-synuclein phosphorylation in rat brain.

Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo.

Tenuigenin attenuates α-synuclein-induced cytotoxicity by down-regulating polo-like kinase 3.

Background And Aims: Tenuigenin (Ten) is a Chinese herbal extract with antioxidative and antiinflammatory effects on toxin-induced cell models of Parkinson's disease (PD); however, its effects on α-synuclein toxicity-based PD models remain unknown. α-synuclein hyperphosphorylation is a key event in PD pathogenesis and potential target of therapeutic interventions. We tested whether Ten alleviates α-synuclein-induced cytotoxicity via reducing kinases that phosphorylate α-synuclein.

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.

Conserved C-terminal charge exerts a profound influence on the aggregation rate of α-synuclein.

α-Synuclein (α-syn) is the major component of filamentous Lewy bodies found in the brains of patients diagnosed with Parkinson's disease (PD). Recent studies demonstrate that, in addition to the wild-type sequence, α-syn is found in several modified forms, including truncated and phosphorylated species. Although the mechanism by which the neuronal loss in PD occurs is unknown, aggregation and fibril formation of α-syn are considered to be key pathological features.

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.

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.

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.

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.

Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system.

Several neurological diseases, including Parkinson disease and dementia with Lewy bodies, are characterized by the accumulation of alpha-synuclein phosphorylated at Ser-129 (p-Ser-129). The kinase or kinases responsible for this phosphorylation have been the subject of intense investigation. Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons.

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.

Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice.

The aspartyl protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid beta (Abeta) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of Abeta-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(-/-) mice demonstrated that BACE1 is absolutely required for both Abeta generation and the development of age-associated plaque pathology.

Trauma in adolescents causes long-term marked deficits in quality of life: adolescent children do not recover preinjury quality of life or function up to two years postinjury compared to national norms.

Background: Injury is a leading cause of death and preventable morbidity in adolescents. Little is known about long-term quality of life (QoL) outcomes in injured adolescents. The objectives of the present report are to describe long-term QoL outcomes and compare posttrauma QoL to national norms for QoL in uninjured adolescents from the National Health Interview Survey (NHIS).

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.

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.

Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease.

A comprehensive, unbiased inventory of synuclein forms present in Lewy bodies from patients with dementia with Lewy bodies was carried out using two-dimensional immunoblot analysis, novel sandwich enzyme-linked immunosorbent assays with modification-specific synuclein antibodies, and mass spectroscopy. The predominant modification of alpha-synuclein in Lewy bodies is a single phosphorylation at Ser-129. In addition, there is a set of characteristic modifications that are present to a lesser extent, including ubiquitination at Lys residues 12, 21, and 23 and specific truncations at Asp-115, Asp-119, Asn-122, Tyr-133, and Asp-135.