Tetrahydrobiopterin Availability in Parkinson’s and Alzheimer’s Disease; Potential Pathogenic Mechanisms

Within the central nervous system, tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis. In addition, BH4 is now established to be an essential cofactor for all isoforms of nitric oxide synthase (NOS). Inborn errors of metabolism affecting BH4 availability are well documented and the clinical presentation can be attributed to a paucity of dopamine, serotonin, and nitric oxide (NO) generation. In this article, we have focussed upon the sensitivity of BH4 to oxidative catabolism and the observation that when BH4 is limiting some cellular sources of NOS may generate superoxide whilst other BH4 saturated NOS enzymes may be generating NO. Such a scenario could favor peroxynitrite generation. If peroxynitrite is not scavenged, e.g., by antioxidants such as reduced glutathione, irreversible damage to critical cellular enzymes could ensue. Such targets include components of the mitochondrial electron transport chain, alpha ketoglutarate dehydrogenase and possibly pyruvate dehydrogenase. Such a cascade of events is hypothesized, in this article, to occur in neurodegerative conditions such as Parkinson’s and Alzheimer’s disease.     

Vitellogenin’s putative role in <Emphasis Type="Italic">Tegillarca granosa</Emphasis>’s cadmium detoxification

The bloody clam, Tegillarca granosa, is a commercial benthic bivalve, having a strong accumulation ability and torrelence to cadmium. To investigate whether vitellogenin (Vg) is involved in cadmium (Cd) detoxification, the full-length cDNA of T. granosa Vg was cloned, and its expression pattern in response to cadmium exposure was studied compared with the reference metallothionein (MT) gene. The full T. granosa Vg sequence consisted of 8988 bp, including a 6930-bp open reading frame that encoded a 2309 amino acid polypeptide. The deduced Vg protein contained a Vg N-terminal domain, domain of unknown function (DUF1943), SbcC domain, and von Willebrand factor type D domain (VWD). Multiple metal-binding sites were predicted in the deduced T. granosa Vg protein, suggesting its potential in functioning as a metal-binding protein. In addition, Vg expression increased in the T. granosa digestive gland and hemolymph in time-dependent manner after exposure to 1, 3, 6 and 9 μg/L Cd for 28 days. MT expression was measured in parallel with Vg expression, and the latter was more sensitive to Cd induction than the former. Together, results of the present research suggested that Vg may play an important role in T. granosa metal detoxification.     

Impact of Women’s Harvest Practices on <Emphasis Type="Italic">Pandanus guillaumetii</Emphasis> in Madagascar’s Lowland Rainforests<Superscript>1</Superscript>

Impact of Women’s Harvest Practices on Pandanus guillaumetii in Madagascar’s Lowland Rainforests. Pandanus guillaumetii B.C. Stone is endemic to the east coast rainforests of Madagascar. The plant is an important non-timber forest product (NTFP) for the local population living near these forests, and its leaves are collected by women to be woven into mats. These mats have economic value and are also used for daily activities. At present, little is known about how local harvesting practices impact this plant species. In this study, we describe women’s local harvest practices and quantify their impact on the P. guillaumetii population. We carried out plant inventories as well as interviews and participatory observations with local people harvesting P. guillaumetii in two villages with different population densities in the Manompana region. Inventories were conducted at varying distances from the villages in order to better understand the influence of human pressure on the plant population. The results suggest that local communities apply practices that tend to minimize the harvest impact on the plant. Harvesting seems to have no effect on the actual density of P. guillaumetii. However, the availability of plants with leaves of sufficient quality for mat production is influenced by human pressure. Considering the decreasing number of plants suitable for handicraft, we assume that their availability in the long term may not fulfill the needs of the local people.     

Adenosine A<Subscript>2A</Subscript> receptors in Parkinson’s disease treatment

Latest results on the action of adenosine A_2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A_2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A_2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A_2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A_2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A_2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A_2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A_2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A_2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A_2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A_2A receptors, as an anti-Parkinson drug.     

Eye-tracking women’s preferences for men’s somatotypes

Judging physical attractiveness involves sight, touch, sound and smells. Where visual judgments are concerned, attentional processes may have evolved to prioritize sex-typical traits that reflect cues signaling direct or indirect (i.e. genetic) benefits. Behavioral techniques that measure response times or eye movements provide a powerful test of this assumption by directly assessing how attractiveness influences the deployment of attention. We used eye-tracking to characterize women’s visual attention to men’s back-posed bodies, which varied in overall fat and muscle distribution, while they judged the potential of each model for a short- or long-term relationship. We hypothesized that when judging male bodily attractiveness women would focus more on the upper body musculature of all somatotypes, as it is a signal of metabolic health, immunocompetence and underlying endocrine function. Results showed that mesomorphs (muscular men) received the highest attractiveness ratings, followed by ectomorphs (lean men) and endomorphs (heavily-set men). For eye movements, attention was evenly distributed to the upper and lower back of both ectomorphs and mesomorphs. In contrast, for endomorphs the lower back, including the waist, captured more attention over the viewing period. These patterns in visual attention were evident in the first second of viewing, suggesting that body composition is identified early in viewing and guides attention to body regions that provide salient biological information during judgments of men’s bodily attractiveness.     

Molecular pharming’s foot in the FDA’s door: Protalix’s trailblazing story

Objectives

This short commentary examines the factors that led to Food and Drug Administration’s approval of the first plant-derived biologic.

Results

In 2012, the first plant-derived protein pharmaceutical (biologic) was approved for commercial use in humans. The product, a recombinant form of human β-glucocerebrosidase marketed as ELELYSO, was developed by Protalix Biotherapeutics (Carmiel, Israel). The foresight to select this particular therapeutic product for development, flawless production pipeline, and serendipity seem to provide the key in explaining how ELELYSO became the first plant-derived biologic to achieve approval by Food and Drug Administration.

Conclusions

While the circumstances that enabled Protalix and its scientists to become the first to arrive at this historic milestone are perhaps unique, it is anticipated that more biologics will follow suit in winning regulatory endorsement.

     

Africa’s highest mountain harbours Africa’s tallest trees

While world records of tree heights were set by American, Australian and Asian tree species, Africa seemed to play no role here. In our study we show that Entandrophragma excelsum (Meliaceae) found in a remote valley at Kilimanjaro has to be included in the list of the world’s superlative trees. Estimating tree age from growth rates monitored by high resolution dendrometry indicates that tall individuals may reach more than 470 years of age. A unique combination of anatomical peculiarities and favorable site conditions might explain their enormous size. The late date of this discovery of Africa’s tallest trees may be due to the comparably low study efforts at Kilimanjaro compared with other biodiversity hotspots. Since only a few square kilometers of this habitat of Entandrophragma are left, Kilimanjaro (and Africa) is about to lose not only a unique biogeographical archive with highly diverse vegetation, but also its tallest trees. The inclusion of these valleys into the immediately neighboring Kilimanjaro National Park would be an excellent and urgent possibility of protection.     

Thudichum’s Successors

This paper describes the work of five scientists who, among others, carried on the work of J. L. W. Thudichum, the pre-eminent investigator of brain chemistry in the latter half of the 19th century, after his death in 1901. This paper is dedicated to my friend Moussa Ben-Hur Youdim, who spent three years (1963–1966) in my laboratory, as a graduate student in the Department of Biochemistry, McGill University. During this time, Moussa purified monoamine oxidase of rat liver, and provided the first evidence of its multiplicity. He also contributed to the recognition of iron and riboflavin as constituents of the enzyme.     

Survivin’s Dual Role: An Export’s View

Survivin is proposed to function as a mitotic regulator and an apoptosis inhibitor duringdevelopment and pathogenesis. As such, survivin has aroused keen interest in disparateareas of basic and translational research. Survivin acts as a subunit of the chromosomalpassenger complex (CPC), composed of the mitotic kinase Aurora-B, Borealin 5 and INCENP,and is essential for proper chromosome segregation and cytokinesis. Our recent findingsindicate that the nuclear export receptor Crm1 is critically involved in tethering the CPC to thecentromere by interacting with a leucine-rich nuclear export signal (NES), evolutionaryconserved in all mammalian survivin proteins. In addition, the survivin/Crm1 interaction10 seems to be required for the cytoprotective activity of survivin, because export deficientsurvivin fails to protect tumor cells against cancer therapy-induced apoptosis. These findingsappear of clinical relevance since preferential nuclear localization of survivin turned out to bea favorable prognostic factor in cancer patients. Besides emphasizing the functionalsignificance of the Crm1/survivin interface, we suggest to exploit the pharmacogenetic15 interference with survivin’s export as a novel strategy to antagonize survivin’s activity.