Intraspecific divergence associated with a biogeographic barrier and climatic models show future threats and long-term decline of a rainforest conifer

A capacity to foresee the shift in species’ range and the demographic response to future climate change is integral to effective conservation planning. Here we model the future climate-driven range shift, and compare it with past range shift, along a latitudinal gradient in two population groups of a late-successional rainforest conifer (Podocarpus elatus), genetically differentiated over the Clarence River Corridor biogeographic barrier (Northern NSW, East Australian Rainforests). Climate envelope modelling of the past-current-future distributions of the two groups and a coalescent-based isolation-with-migration model investigated divergence times and effective population sizes among the current genetic disjunctions in the species. This suggests differential range shift (i.e. expansion in the north and contraction in the south) will continue in the future, with a southern range shift also occurring in both climatic models. The origin of the Clarence River Corridor dividing the two population groups was inferred by molecular analysis to be prior to the last glacial maximum (LGM). Another divergence in the south (19 ka) is indicative of slow consistent habitat contractions since the LGM (21 ka). We recommend the southern and Macleay Overlap Zone (far-eastern Australia) populations as priority areas for protection based upon intraspecific diversity and past-current-future habitat suitability. The integrated approach shows that this widely distributed species is more at risk than expected from current climate change and other anthropogenic effects.Rohan Mellick, Maurizio Rossetto, Chris Allen, Peter D. Wilson, Robert S. Hill and Andrew Low

Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

α-Synuclein aggregation inhibitory activity of the bromotyrosine derivatives aerothionin and aerophobin-2 from the subtropical marine sponge Aplysinella sp

The neuronal protein α-synuclein (α-syn) is one of the main constituents of intracellular amyloid aggregations found in the post-mortem brains of Parkinson’s disease (PD) patients. Recently, we screened the MEOH extracts obtained from 300 sub-tropical marine invertebrates for α-syn binding activity using affinity MS and this resulted in the extract of the Verongida marine sponge Aplysinella sp. 1194, (QM G339263) displaying molecules that bind to the protein. The subsequent bioassay-guided separation of the Aplysinella sp. extract led to the isolation of the known bromotyrosine derivatives (+)-aerothionin (1) and (+)-aerophobin-2 (2). Both compounds bind to α-syn as detected by a MS affinity assay and inhibit α-syn aggregation in an assay that uses the fluorescence probe, thioflavin T, to detect aggregation. (+)-Aerothionin (1) was toxic to primary dopaminergic neurons at its expected α-syn aggregation inhibitory concentration and so could not be tested for pSyn aggregates in this functional assay. (+)-Aerophobin-2 (2) was not toxic and shown to weakly inhibit pSyn aggregation in primary dopaminergic neurons at 10 µM.Peer reviewe

Hesperine, a new imidazole alkaloid and α-synuclein binding activity of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine from the marine sponge Clathria (Thalysias) cf. hesperia

During a high-throughput screen of 300 Australian marine invertebrate extracts, the extract of the marine sponge Clathria (Thalysias) cf. hesperia was identified with α-synuclein binding activity. The bioassay-guided purification of this extract resulted in the isolation of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2) as the α-syn binder along with one new compound, hesperine (1), and five known compounds, indole-3-carboxaldehyde (3), (Z)-2'-demethylaplysinopsin (4), 2-amino-4'-hydroxyacetophenone (5), 4-hydroxybenzoic acid (6) and 4-hydroxybenzaldehyde (7). Herein, we report the structure elucidation of hesperine (1) and α-syn binding activity of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2).Peer reviewe

Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization

Tumors build vessels by cooption of pre-existing vasculature and de novo recruitment of bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the contribution and the functional role of EPCs in tumor neoangiogenesis are controversial. Therefore, by using genetically marked BM progenitor cells, we demonstrate the precise spatial and temporal contribution of EPCs to the neovascularization of three transplanted and one spontaneous breast tumor in vivo using high-resolution microscopy and flow cytometry. We show that early tumors recruit BM-derived EPCs that differentiate into mature BM-derived endothelial cells (ECs) and luminally incorporate into a subset of sprouting tumor neovessels. Notably, in later tumors, these BM-derived vessels are diluted with non-BM-derived vessels from the periphery, which accounts for purported differences in previously published reports. Furthermore, we show that specific ablation of BM-derived EPCs with alpha-particle-emitting anti-VE-cadherin antibody markedly impaired tumor growth associated with reduced vascularization. Our results demonstrate that BM-derived EPCs are critical components of the earliest phases of tumor neoangiogenesis

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Two-Generation Reproduction Study of Lewisite in Rats Final Report

Occupational health standards have not been established for Lewisite [bis(2-chlorethyl)arsine], a potent toxic vesicant which reacts with the sulfhydryl groups of proteins through its arsenic group. The purposes of this study were to determine the reproductive consequences and dose~response of continuing Lewisite exposure of parental males and females and their offspring in a 42-week two-generation study. Solutions of Lewisite were prepared for administration by diluting the neat agent with sesame oil. Rats were administered Lewisite (0, 0.10, 0.25 or 0.60 mg/kg/day for 5 days a week) via intragastric intubation prior to mating, during mating and after mating until the birth of their offspring. The dams continued to receive Lewisite during lactation. At weaning, male and female offspring of each group were selected to continue on the study; rece1v1ng Lewisite during adolescence, mating and throughout gestation. Again, the dams continued to receive Lewisite until weaning of the offspring. Lewisite had no adverse effect on reproduction performance, fertility or reproductive organ weights of male or female rats through two consecutive generations. No adverse effect to offspring were attributed to Lewisite exposure. Minor changes in growth was the only maternal effect observed. Lewisite exposure of parental rats caused no gross or microscopic lesions in testes, epididymis, prostrate, seminal vesicles, ovaries, uterus or vagina. Severe inflammation of the lung was observed at necropsy in cases in which Lewisite gained access to the respiratory system from accidental dosing or reflux and aspiration; this usually caused early death of the animal. The NOEL for reproductive effects in this study was greater than 0.60 mg/kg/day

Gabapentin for complex regional pain syndrome in Machado-Joseph disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chronic pain is a common problem for patients with Machado-Joseph disease. Most of the chronic pain in Machado-Joseph disease has been reported to be of musculoskeletal origin, but now there seems to be different chronic pain in patients with Machado-Joseph disease.</p> <p>Case presentation</p> <p>A 29-year-old man (Han Chinese, Hoklo) with Machado-Joseph disease experienced severe chronic pain in both feet, cutaneous thermal change, thermal hypersensitivity, focal edema, and sweating and had a history of bone fracture. These symptoms were compatible with a diagnosis of complex regional pain syndrome. After common analgesics failed to relieve his pain, gabapentin was added and titrated to 2000 mg/day (500 mg every six hours) in less than two weeks. This relieved 40% of his pain and led to significant clinical improvement.</p> <p>Conclusions</p> <p>The pathophysiology of complex regional pain syndrome includes peripheral and central sensitizations, the latter of which might be associated with the neurodegeneration in Machado-Joseph disease. In this report, we suggest that gabapentin could inhibit central sensitization as an adjunct for complex regional pain syndrome in patients with Machado-Joseph disease.</p

The accuracy and precision of radiostereometric analysis in monitoring tibial plateau fractures

Background and purpose: The application of radiostereometric analysis (RSA) to monitor stability of tibial plateau fractures during healing is both limited and yet to be validated. We therefore evaluated the accuracy and precision of RSA in a tibial plateau fracture model. Methods: Combinations of 3, 6, and 9 markers in a lateral condyle fracture were evaluated with reference to 6 proximal tibial arrangements. Translation and rotation accuracy was assessed with displacement-controlled stages, while precision was assessed with dynamic double examinations. A comparison of error according to marker number and arrangement was completed with 2-way ANOVA models. Results: The results were improved using more tantalum markers in each segment. In the fracture fragment, marker scatter in all axes was achieved by a circumferential arrangement (medial, anterior, and lateral) of the tantalum markers above the fixation devices. Markers placed on either side of the tibial tuberosity and in the medial aspect of the fracture split represented the proximal tibial reference segment best. Using 6 markers with this distribution in each segment, the translation accuracy (root mean square error) was less than 37 μm in all axes. The precision (95% confidence interval) was less than ± 16 μm in all axes in vitro. Rotation, tested around the x-axis, had an accuracy of less than 0.123° and a precision of ± 0.024°. Interpretation: RSA is highly accurate and precise in the assessment of lateral tibial plateau fracture fragment movement. The validation of our center's RSA system provides evidence to support future clinical RSA fracture studies.Lucian B Solomon, Aaron W Stevenson, Stuart A Callary, Thomas R Sullivan, Donald W Howie, and Mellick J Chehad

Evaluation of a Medium Chain Fatty Acid-Based Additive for Nursery Pigs

A total of 350 pigs (DNA 400 × 200, initial BW = 13.8 lb) were used in a 34-d growth trial to evaluate the effects of increasing a medium chain fatty acid (MCFA)-based feed additive in nursery pig diets. Following arrival to the nursery research facility, pigs were randomized to pens (5 pigs per pen) and allowed a 4-d acclimation period. Thereafter, pens of pigs were blocked by body weight (BW) and randomized to 1 of 5 dietary treatments (14 pens per treatment). Treatments were constructed such that a dose response was created including 0, 0.5, 1.0, and 2.0% MCFA-based additive (CaptiSURE, Kemin Industries, Inc., Des Moines, IA) as well as a treatment including a 1.0% MCFA blend of C6, C8, and C10 (1:1:1 ratio; Sigma Aldrich, St. Louis, MO). Treatment diets were formulated and manufactured in two dietary phases (d 0 to 13 and 13 to 34). Overall (d 0 to 34), increasing CaptiSURE increased (linear, P ≤ 0.014) average daily gain (ADG) and average daily feed intake (ADFI). Feed efficiency improved (quadratic, P = 0.002) with increasing CaptiSURE up to 1% of the diet with no benefit thereafter. As a result of these linear improvements in ADG, pigs fed 2.0% CaptiSURE were 4 lb heavier (P = 0.05) than pigs consuming diets without MCFA at d 34. There was no evidence for differences between the pigs fed 1.0% CaptiSURE and the 1.0% MCFA blend of C6, C8, and C10 in phase 1, phase 2, or in overall performance. In summary, the addition of this MCFA-based additive in nursery pig diets resulted in a linear improvement in ADG and ADFI. Based on these results, this MCFA feed additive appears to result in a similar improvement in growth performance as the C6, C8, and C10 MCFA blend when both are added at 1% of the diet. Additional research is warranted under commercial conditions to determine if similar advantages in growth performance are observed and if they provide an economic return