A Novel Pharmacological Protective Role for Safranal in an Animal Model of Huntington’s Disease

Neurochemical Research - Huntington’s disease (HD) is a progressive, neurodegenerative and inherited disease and recent years have witnessed the understanding of the cellular and molecular...     

Design of an Interpolyelectrolyte Gastroretentive Matrix for the Site-Specific Zero-Order Delivery of Levodopa in Parkinson’s Disease

This study focused on developing a gastroretentive drug delivery system employing a triple-mechanism interpolyelectrolyte complex (IPEC) matrix comprising high density, swelling, and bioadhesiveness for the enhanced site-specific zero-order delivery of levodopa in Parkinson’s disease. An IPEC was synthesized and directly compressed into a levodopa-loaded matrix employing pharmaceutical technology and evaluated with respect to its physicochemical and physicomechanical properties and in vitro drug release. The IPEC-based matrix displayed superior mechanical properties in terms of matrix hardness (34–39 N/mm) and matrix resilience (44–47%) when different normality’s of solvent and blending ratios were employed. Fourier transform infrared spectroscopy confirmed the formation of the IPEC. The formulations exhibited pH and density dependence with desirable gastro-adhesion with Peak Force of Adhesion ranging between 0.15 and 0.21 N/mm, densities from 1.43 to 1.54 g/cm³ and swellability values of 177–234%. The IPEC-based gastroretentive matrix was capable of providing site-specific levodopa release with zero-order kinetics corroborated by detailed mathematical and molecular modeling studies. Overall, results from this study have shown that the IPEC-based matrix has the potential to improve the absorption and subsequent bioavailability of narrow absorption window drugs, such as levodopa with constant and sustained drug delivery.     

Refined mapping of the Pierce’s disease resistance locus, PdR1, and Sex on an extended genetic map of Vitis rupestris × V. arizonica

A framework genetic map based on genomic DNA-derived SSR, EST-derived SSR, EST-STS and EST-RFLP markers was developed using 181 genotypes generated from D8909-15 (female) × F8909-17 (male), the ‘9621’ population. Both parents are half siblings with a common female parent, Vitis rupestris ‘A. de Serres’, and different male parents (forms of V. arizonica). A total of 542 markers were tested, and 237 of them were polymorphic for the female and male parents. The female map was developed with 159 mapped markers covering 865.0 cM with an average marker distance of 5.4 cM in 18 linkage groups. The male map was constructed with 158 mapped molecular markers covering 1055.0 cM with an average distance of 6.7 cM in 19 linkage groups. The consensus ‘9621’ map covered 1154.0 cM with 210 mapped molecular markers in 19 linkage groups, with average distance of 5.5 cM. Ninety-four of the 210 markers on the consensus map were new. The ‘Sex’ expression locus segregated as single major gene was mapped to linkage group 2 on the consensus and the male map. PdR1, a major gene for resistance to Pierce’s disease, caused by the bacterium Xylella fastidiosa, was mapped to the linkage group 14 between markers VMCNg3h8 and VVIN64, located 4.3 and 2.7 cM away from PdR1, respectively. Differences in segregation distortion of markers were also compared between parents, and three clusters of skewed markers were observed on linkage groups 6, 7 and 14.     

Flower symmetry and flower size variability: an examination of Berg’s hypotheses in an alpine meadow

植物花对称性与传粉系统密切相关, 花特征的变异性受到传粉者的选择作用。由于特化的传粉者对两侧对称的花的稳定选择, Berg假说认为两侧对称植物花大小的变异性比辐射对称植物的更低; 而且, 在传粉者的选择作用下花特征比植物营养特征明显有更低的变异性, 因为后者更易受环境影响。该文对青藏高原东部高山草甸植物群落的50种开花植物(包括19种两侧对称植物和31种辐射对称植物)的花和叶特征进行了测定和分析。结果表明不论是两侧对称植物还是辐射对称植物, 花大小的变异性都显著低于叶片大小的变异性, 表明传粉者对花施加的稳定选择有利于花的稳定性。但是, 辐射对称物种花大小的变异程度和两侧对称物种的相似, 即使在控制物种系统发育的影响后, 也没有发现显著的差异, 这与Berg假说不一致。高山生态系统中传粉者种类相对较少, 以熊蜂和蝇类为主, 传粉者的活动受局域气候环境影响较大, 因此传粉昆虫对植物花的选择作用强度可能有较大的变异性。     

Trypanosoma cruzi infection of human induced pluripotent stem cell-derived cardiomyocytes: an in vitro model for drug screening for Chagas disease

Chagas disease, caused by Trypanosoma cruzi, is an important global public health problem which, despite partial efficacy of benznidazole (Bz) in acute phase, urgently needs an effective treatment. Cardiotoxicity is a major safety concern for conduction of more accurate preclinical drug screening platforms. Human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CM) are a reliable model to study genetic and infectious cardiac alterations and may improve drug development. Herein, we introduce hiPSC-CM as a suitable model to study T. cruzi heart infection and to predict the safety and efficacy of anti-T. cruzi drugs.     

BioBanking: an environmental scientist’s view of the role of biodiversity banking offsets in conservation

Offsets, first formalised in the United States of America in the 1970s for wetland mitigation, are now widely used globally with the aim to mitigate loss of biodiversity due to development. Embracing biodiversity offsets is one method of governments to meet their commitments under the Millennium Development Goals and the Convention on Biological Diversity. Resource extraction companies see them as a method of gaining access to land, while the community may perceive them as a way of enhancing environmental outcomes. In New South Wales, Australia, BioBanking legislation was introduced in late 2006 with the aim of ‘no net loss’ of biodiversity associated with development, particularly expanding urban and coastal development. The strengths of the legislation are that it aims to enhance threatened species conservation, and raise the profile of conservation of threatened species and habitats. Weaknesses include (1) the narrowness of the definition of biodiversity; (2) the concepts are based on a flawed logic and immature, imprecise and complex science which results in difficulties in determining biodiversity values; (3) likely problems with management and compliance; and (4) an overall lack of resources for implementation and long-term monitoring. It is concluded that the legislation is a concerted effort to deal with biodiversity loss, however, stakeholders have concerns with the process, and it is unworkable with the complexity of such ecosystems (compared for example to carbon credit trading), and underdeveloped disciplines such as restoration biology and ecology. Despite these criticisms, there is a need for all stakeholders to work to improve the outcomes.     

Greenhouse gas fluxes from Atacama Desert soils: a test of biogeochemical potential at the Earth’s arid extreme

Most terrestrial ecosystems support a similar suite of biogeochemical processes largely dependent on the availability of water and labile carbon (C). Here, we explored the biogeochemical potential of soils from Earth’s driest ecosystem, the Atacama Desert, characterized by extremely low moisture and organic C. We sampled surface soil horizons from sites ranging from the Atacama’s hyper-arid core to less-arid locations at higher elevation that supported sparse vegetation. We performed laboratory incubations and measured fluxes of the greenhouse gases carbon dioxide (CO₂), nitrous oxide (N₂O), and methane (CH₄) as indices of potential biogeochemical activity across this gradient. We were able to stimulate trace gas production at all sites, and treatment responses often suggested the influence of microbial processes. Sites with extant vegetation had higher C concentrations (0.13–0.68%) and produced more CO₂ under oxic than sub-oxic conditions, suggesting the presence of aerobic microbial decomposers. In contrast, abiotic CO₂ production appeared to predominate in the most arid and C-poor (<0.08% C) sites without plants, with one notable exception. Soils were either a weak source or sink of CH₄ under oxic conditions, whereas anoxia stimulated CH₄ production across all sites. Several sites were rich in nitrate, and we stimulated N₂O fluxes in all soils by headspace manipulation or dissolved organic matter addition. Peak N₂O fluxes in the most C-poor soil (0.02% C) were very high, exceeding 3 ng nitrogen g^?1 h^?1 under anoxic conditions. These results provide evidence of resilience of at least some soil biogeochemical capacity to long-term water and C deprivation in the world’s driest ecosystem. Atacama soils appear capable of responding biogeochemically to moisture inputs, and could conceivably constitute a regionally-important source of N₂O under altered rainfall regimes, analogous to other temperate deserts.     

The role of dopamine oxidation in mitochondrial dysfunction: implications for Parkinson’s disease

The etiology of sporadic Parkinson’s disease (PD) is unknown, although mitochondrial dysfunction and oxidative stress have been implicated in the mechanisms associated with PD pathogenesis. Dopamine (DA) neurons of the substantia nigra pars compacta have been shown to degenerate to a greater extent in PD than other neurons suggesting the possibility that DA itself may be contributing to the neurodegenerative process. This review discusses our work on the effects of DA oxidation and reactive DA quinones on mitochondrial function and protein modification and the potential for exacerbating toxicity associated with mitochondrial dysfunction in PD.     

Earth Mover’s Distance (EMD): A True Metric for Comparing Biomarker Expression Levels in Cell Populations

Changes in the frequencies of cell subsets that (co)express characteristic biomarkers, or levels of the biomarkers on the subsets, are widely used as indices of drug response, disease prognosis, stem cell reconstitution, etc. However, although the currently available computational “gating” tools accurately reveal subset frequencies and marker expression levels, they fail to enable statistically reliable judgements as to whether these frequencies and expression levels differ significantly between/among subject groups. Here we introduce flow cytometry data analysis pipeline which includes the Earth Mover’s Distance (EMD) metric as solution to this problem. Well known as an informative quantitative measure of differences between distributions, we present three exemplary studies showing that EMD 1) reveals clinically-relevant shifts in two markers on blood basophils responding to an offending allergen; 2) shows that ablative tumor radiation induces significant changes in the murine colon cancer tumor microenvironment; and, 3) ranks immunological differences in mouse peritoneal cavity cells harvested from three genetically distinct mouse strains.     

The Limitations of Kim’s Reductive Physicalism in Accounting for Living Systems and an Alternative Nonreductionist Ontology

Jaegwon Kim's exclusion argument is a general ontological argument, applicable to any properties deemed supervenient on a microproperty basis, including biological properties. It implies that the causal power of any higher-level property must be reducible to the subset of the causal powers of its lower-level properties. Moreover, as Kim's recent version of the argument indicates, a higher-level property can be causally efficient only to the extent of the efficiency of its micro-basis. In response, I argue that the ontology that aims to capture experimentally based explanations of metabolic control systems and morphogenetic systems must involve causally relevant contextual properties. Such an ontology challenges the exclusiveness of micro-based causal efficiency that grounds Kim's reductionism, since configurations themselves are inherently causally efficient constituents. I anticipate and respond to the reductionist's objection that the nonreductionist ontology's account of causes and inter-level causal relations is incoherent. I also argue that such an ontology is not open to Kim's overdetermination objection.     

Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sj?gren’s syndrome

Introduction

Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab.

Methods

To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period.

Results

Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection.

Conclusions

For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B-cell populations in humans.     

Valproate Improves Memory Deficits in an Alzheimer’s disease Mouse Model: Investigation of Possible Mechanisms of Action

Alzheimer’s disease (AD) is a very common progressive neurodegenerative disorder affecting the learning and memory abilities in the brain. Key findings from recent studies of epigenetic mechanisms of memory suggest chromatin remodeling disorders via histone hypoacetylation of the lysine residue contribute to the cognitive impairment in AD. Therefore, the deinhibition of histone acetylation induced by histone deacetylases (HDACs) inhibitors contributes to recovery of learning and memory. We show here that the antiepileptic drug sodium valproate (VPA) potently enhanced long-term recognition memory and spatial learning and memory in AD transgenic mice. Possible mechanisms showed VPA could significantly elevate histone acetylation through HDACs activity inhibition and increase plasticity-associated gene expression within the hippocampi of mice. Our study suggests that VPA, serving as a HDACs inhibitor, can be considered as a potential pharmaceutical agent for the improvement of cognitive function in AD.     

Design,synthesis, and evaluation of Trolox-conjugated amyloid-β C-terminal peptides for therapeutic intervention in an in vitro model of Alzheimer’s disease

Two hallmarks of Alzheimer’s disease (AD) observed in the brains of patients with the disease include oxidative injury and deposition of protein aggregates comprised of amyloid-β (Aβ) variants. To inhibit these toxic processes, we synthesized antioxidant-conjugated peptides comprised of Trolox and various C-terminal motifs of Aβ variants, TxAβ_x–n (x = 34, 36, 38, 40; n = 40, 42, 43). Most of these compounds were found to exhibit anti-aggregation activities. Among them, TxAβ_36–42 significantly inhibited Aβ_1–42 aggregation, showed potent antioxidant activity, and protected SH-SY5Y cells from Aβ_1–42-induced cytotoxicity. Thus, this method represents a promising strategy for developing multifunctional AD therapeutic agents.     

The rhetoric of Islamophobia: an analysis of the means of persuasion in Hege Storhaug’s writings on Islam and Muslims

Few actors have had a greater impact on the “framing of Muslims” as a social and political “problem” in Norway since 2001 than Hege Storhaug of the government- and corporate billionaire funded civil society organization Human Rights Service (HRS). Using the methodological tools of the “rhetorical branch” of Critical Discourse Analysis (CDA), and applying the Aristotelian concepts of ethos, logos and pathos, we analyze the bestselling popular title on Islam and Muslims ever published in Norway, namely Storhaug’s self-published 2015 title “Islam – The Eleventh Plague”. We argue that Storhaug’s popular success must be understood in light of her rhetorical appeals to femonationalism, the critique of religion and “Enlightenment” values. We show how she in her writings incites fear of the Muslim “Other” through specific rhetorical devices and a positioning of herself as a defender of the “nation” and the “people” – against national and international “elites”.     

Phylogeography of Fischer’s blue,Tongeia fischeri,in Japan: Evidence for introgressive hybridization

The widespread lycaenid butterfly Tongeia fischeri is distributed from eastern Europe to northeastern Asia and represented by three geographically isolated populations in Japan. In order to clarify the phylogeographic history of the species, we used sequences of three mitochondrial (COI, Cyt b and ND5) and two nuclear (Rpl5 and Ldh) genes of 207 individuals collected from 55 sites throughout Japan and five sites on the Asian continent. Phylogenetic trees and the median-joining network revealed six evolutionary mitochondrial haplotype clades, which corresponded to the geographic distribution of the species. Common ancestors of Japanese T. fischeri might have come to Japan during the mid-Pleistocene by multiple dispersals of continental populations, probably via a land bridge or narrow channel between western Japan and the Korean Peninsula. The geographical patterns of variation of mitochondrial and nuclear markers are discordant in northeastern Kyushu, possibly as a result of introgressive hybridization during the ancient contact between the Kyushu and Shikoku populations in the last glacial maximum. The phylogeographic pattern of T. fischeri in Japan are probably related to the geological history, Pleistocene climatic oscillations and distribution of the host plant.     

Effectiveness of Traditional Chinese Medicine as an Adjunct Therapy for Parkinson’s Disease: A Systematic Review and Meta-Analysis

Background

Idiopathic Parkinson disease (PD) is a common neurodegenerative disease that seriously hinders limb activities and affects patients’ lives. We performed a meta-analysis aiming to systematically review and quantitatively synthesize the efficacy and safety of traditional Chinese medicine (TCM) as an adjunct therapy for clinical PD patients.

Methods

An electronic search was conducted in PubMed, Cochrane Controlled Trials Register, China National Knowledge Infrastructure, Chinese Scientific Journals Database and Wanfang data to identify randomized trials evaluating TCM adjuvant therapy versus conventional treatment. The change from baseline of the Unified Parkinson’s Disease Rating Scale score (UPDRS) was used to estimate the effectiveness of the therapies.

Results

Twenty-seven articles involving 2314 patients from 1999 to 2013 were included. Potentially marked improvements were shown in UPDRS I (SMD 0.68, 95%CI 0.38, 0.98), II (WMD 2.41, 95%CI 1.66, 2.62), III (WMD 2.45, 95%CI 2.03, 2.86), IV (WMD 0.32, 95%CI 0.15, 049) and I-IV total scores (WMD 6.18, 95%CI 5.06, 7.31) in patients with TCM plus dopamine replacement therapy (DRT) compared to DRT alone. Acupuncture add-on therapy was markedly beneficial for improving the UPDRS I–IV total score of PD patients (WMD 10.96, 95%CI 5.85, 16.07). However, TCM monotherapy did not improve the score. The effectiveness seemed to be more obvious in PD patients with longer adjunct durations. TCM adjuvant therapy was generally safe and well tolerated.

Conclusions

Although the data were limited by methodological flaws in many studies, the evidence indicates the potential superiority of TCM as an alternative therapeutic for PD treatment and justifies further high-quality studies.