Botulinum neurotoxin A subtype 2 reduces pathological behaviors more effectively than subtype 1 in a rat Parkinson’s disease model

Recent reports indicate that interruption of acetylcholine release by intrastriatal injection of botulinum neurotoxin type A (BoNT/A) in a rat Parkinson’s disease model reduces pathogenic behavior without adverse side effects such as memory dysfunction. Current knowledge suggests that BoNT/A subtype 1 (BoNT/A1) and BoNT/A subtype 2 (BoNT/A2) exert different effects. In the present study, we compared the effects of BoNT/A1 and BoNT/A2 on rotation behavior and in vivo cleavage of presynaptic protein SNAP-25 in a rat unilateral 6-hydroxydopamine-induced Parkinson’s disease model. BoNT/A2 more effectively reduced pathogenic behavior by efficiently cleaving SNAP-25 in the striatum compared with that of BoNT/A1. Our results suggest that BoNT/A2 has greater clinical therapeutic value for treating subjects with Parkinson’s disease compared to that of BoNT/A1.     

Social buffering reduces male rats' behavioral and corticosterone responses to a conditioned stimulus

In social species, the presence of an affiliative same-sex conspecific ameliorates acute stress responses in threatening conditions. We previously found that the presence of an unfamiliar male rat separated by a wire mesh barrier blocks the behavioral responses and Fos expression in the paraventricular nucleus of the hypothalamus (PVN) in a male subject rat that had previously been exposed to an auditory conditioned stimulus (CS) paired with foot shocks. Based on the Fos expression in the PVN, we hypothesized that the presence of a conspecific ameliorated the hypothalamic–pituitary–adrenal (HPA) axis activation and induced social buffering of conditioned fear responses. The direct evidence for this hypothesis, however, is still lacking. To clarify this point, we exposed fear-conditioned and non-conditioned subjects to the CS either alone or with a conspecific separated by a wire mesh barrier. When the fear-conditioned subject alone was re-exposed to the CS, it exhibited increased freezing, decreased sniffing, and elevated corticosterone levels. In contrast, the presence of the conspecific suppressed these behavioral and HPA axis responses to a level similar to those observed in the non-conditioned subjects. These results suggest that the presence of a conspecific suppressed the behavioral responses and HPA axis activation to the CS. The present results provide direct evidence for the existence of social buffering of conditioned fear responses in male rats.     

Ablation of Elovl6 protects pancreatic islets from high-fat diet-induced impairment of insulin secretion

ELOVL family member 6, elongation of very long-chain fatty acids (Elovl6) is a microsomal enzyme that regulates the elongation of C12–16 saturated and monounsaturated fatty acids and is related to the development of obesity-induced insulin resistance via the modification of the fatty acid composition. In this study, we investigated the role of systemic Elovl6 in the pancreatic islet and β-cell function. Elovl6 is expressed in both islets and β-cell lines. In mice fed with chow, islets of the Elovl6^−/− mice displayed normal architecture and β-cell mass compared with those of the wild-type mice. However, when fed a high-fat, high-sucrose (HFHS) diet, the islet hypertrophy in response to insulin resistance observed in normal mice was attenuated and glucose-stimulated insulin secretion (GSIS) increased in the islets of Elovl6^−/− mice compared with those of the wild-type mice. Enhanced GSIS in the HFHS Elovl6^−/− islets was associated with an increased ATP/ADP ratio and the suppression of ATF-3 expression. Our findings suggest that Elovl6 could be involved in insulin secretory capacity per β-cell and diabetes.     

Ideal Osmotic Spaces for Chlorobionts or Cyanobionts Are Differentially Realized by Lichenized Fungi

Lichens result from symbioses between a fungus and either a green alga or a cyanobacterium. They are known to exhibit extreme desiccation tolerance. We investigated the mechanism that makes photobionts biologically active under severe desiccation using green algal lichens (chlorolichens), cyanobacterial lichens (cyanolichens), a cephalodia-possessing lichen composed of green algal and cyanobacterial parts within the same thallus, a green algal photobiont, an aerial green alga, and a terrestrial cyanobacterium. The photosynthetic response to dehydration by the cyanolichen was almost the same as that of the terrestrial cyanobacterium but was more sensitive than that of the chlorolichen or the chlorobiont. Different responses to dehydration were closely related to cellular osmolarity; osmolarity was comparable between the cyanolichen and a cyanobacterium as well as between a chlorolichen and a green alga. In the cephalodium-possessing lichen, osmolarity and the effect of dehydration on cephalodia were similar to those exhibited by cyanolichens. The green algal part response was similar to those exhibited by chlorolichens. Through the analysis of cellular osmolarity, it was clearly shown that photobionts retain their original properties as free-living organisms even after lichenization.Lichens are ubiquitously found in all terrestrial environments, including those with extreme climates such as Antarctica and deserts; they are pioneer organisms in primary succession (Longton, 1988; Ahmadjian, 1993). Colonization ability is largely owed to lichens’ extreme tolerance for desiccation (Ahmadjian, 1993). Although lichens harbor photosynthetic green algae or cyanobacteria (blue-green algae) within their thalli, they show metabolic activity even when dried at 20°C and under conditions of 54% relative humidity (Cowan et al., 1979). This desiccation tolerance partially results from drought resistance originally exhibited by the photobiont. It is further strengthened by lichen symbiosis (Kosugi et al., 2009). Cyanolichens (symbiosis between a fungus and a cyanobacterium) are desiccation-tolerant organisms that favor humid and shady environments, whereas chlorolichens (symbiosis between a fungus and a green alga) tolerate dry and high-light environments (James and Henssen, 1976; Lange et al., 1988). Chlorolichens can perform photosynthesis when the surrounding humidity is high, but cyanolichens require some water in a liquid state (Lange et al., 1986, 2001; Nash et al., 1990; Ahmadjian, 1993).Most poikilohydric photosynthetic organisms can tolerate rapid drying. Biological activity during desiccation and recovery following drought are scarcely affected by protein synthesis inhibitors (Proctor and Smirnoff, 2000). Moderate drought tolerance is attained by increasing compatible solutes (amino acids, sugars, and sugar alcohols) as protective agents during drought stress (Mazur, 1968; Parker, 1968; Hoekstra et al., 2001). An increase in compatible solutes prevents water loss or increases water uptake from the air when humidity is high (Lange et al., 1988). It has been observed, however, that the intracellular solute concentration is low (corresponding to a sorbitol concentration of approximately 0.22 m) in the desiccation-tolerant terrestrial cyanobacterium Nostoc commune (Satoh et al., 2002; Hirai et al., 2004). N. commune photosynthetic activity is lost when incubated in low sorbitol concentrations (Hirai et al., 2004), whereas a Trebouxia spp. chlorobiont freshly isolated from the desiccation-tolerant chlorolichen Ramalina yasudae remains active under the same conditions (Kosugi et al., 2009).Different solute concentrations in photobionts may dictate habitat preferences for chlorolichens and cyanolichens (James and Henssen, 1976; Lange et al., 1988). One might expect that the ideal cellular osmotic pressure (or cellular solute concentration) of a lichenized fungus is problematic, as both the fungus and the photobiont are closely associated in the thallus (Kranner et al., 2005). Thus, we may be able to further hypothesize that the solute concentration itself in original photobionts determines the nature of desiccation tolerance in chlorolichens and cyanolichens.To better understand symbiosis in lichens, it is important to examine how the cellular osmotic pressures of both symbionts contribute to lichen photosynthesis. In this study, cellular osmotic pressures of lichens and photobionts were determined by assessing water potential. The cephalodia-possessing lichen Stereocaulon sorediiferum was chosen as a desiccation-tolerant model organism because it separately harbors a green alga and a cyanobacterium in different compartments of the lichen body. The green algal photobiont is contained in the stem- and branch-like structures, whereas the cyanobacterial photobiont (cyanobiont) is contained in the organism’s cephalodia. For comparison, several chlorolichens (R. yasudae, Parmotrema tinctorum, and Graphis spp.), cyanolichens (Collema subflaccidum and Peltigera degenii), green algae (Prasiola crispa, Trebouxia spp., and Trentepohlia aurea), and cyanobacteria (N. commune, Scytonema spp., and Stigonema spp.) were also analyzed (Fig. 1). The cyanobiont of C. subflaccidum is closely related to N. commune (Ahmadjian, 1993), and the cyanobiont of S. sorediiferum belongs to the genus Stigonema (Kurina and Vitousek, 1999). Green algal photobionts of R. yasudae and S. sorediiferum are Trebouxia spp. (Bergman and Huss-Danell, 1983). For the measurements of water potential, we had to use specimens larger than 0.1 g dry weight for one measurement. Furthermore, the specimens should cover approximately 70% of the surface area of a sample cup with 4 cm diameter that was equipped in our dewpoint potentiometer. Considering the statistical analyses, we needed large amounts of lichen and algal samples for the measurement of water potential. To conduct this study, we wanted to use free-living green algae and cyanobacteria, not the photobionts isolated from a lichen body. This is because inconsistent results were reported previously for chlorobionts liberated from lichens (Brock, 1975; Lange et al., 1990). Three major photobionts of lichens, Trebouxia, Trentepohlia, and Nostoc spp., were considered for inclusion. Until now, free-living Trebouxia spp. were not observed convincingly in nature. Therefore, cultivated Trebouxia spp. were used. Other green algae and cyanobacteria were chosen from among free-living species that (1) are closely related to some photobionts, (2) form large communities sufficient to cover the required quantity that will not destroy the local ecosystem by our sampling, (3) are easy to remove from other attached algae/microorganisms, and (4) are tolerant to desiccation. P. crispa forms large communities in nature, and the closely related species Prasiola borealis is known to be a photobiont of Mastodia tessellata. Only two freshwater species of genus Prasiola are found in Japan; P. crispa inhabits a limited area of Hokkaido Island, and Prasiola japonica is a rare species. P. crispa harvested in Antarctica and shown to be desiccation tolerant in our previous work (Kosugi et al., 2010b) was used in this study.Open in a separate windowFigure 1.Lichens analyzed in this study. A, Cyanolichen C. subflaccidum on a rock. B, Wet (left) and dry (right) thalli of cyanolichen Peltigera degenii with green moss. C, Chlorolichen R. yasudae on a rock. D, Chlorolichen Graphis spp. on a Zelkova serrata tree trunk. The grayish basal part of Graphis spp. is the site where the photobiont resides, and the dark-colored streaks are the apothecia. E, Chlorolichen Parmotrema tinctorum on a Z. serrata tree trunk. F, Cephalodia-possessing lichen S. sorediiferum. Some cephalodia are indicated by arrows. The stem- and branch-like structures are the green algae-containing compartments.     

Hypermethylated-capped selenoprotein mRNAs in mammals

Mammalian mRNAs are generated by complex and coordinated biogenesis pathways and acquire 5′-end m⁷G caps that play fundamental roles in processing and translation. Here we show that several selenoprotein mRNAs are not recognized efficiently by translation initiation factor eIF4E because they bear a hypermethylated cap. This cap modification is acquired via a 5′-end maturation pathway similar to that of the small nucle(ol)ar RNAs (sn- and snoRNAs). Our findings also establish that the trimethylguanosine synthase 1 (Tgs1) interacts with selenoprotein mRNAs for cap hypermethylation and that assembly chaperones and core proteins devoted to sn- and snoRNP maturation contribute to recruiting Tgs1 to selenoprotein mRNPs. We further demonstrate that the hypermethylated-capped selenoprotein mRNAs localize to the cytoplasm, are associated with polysomes and thus translated. Moreover, we found that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo.     

From ‘third pole’ to north pole: a Himalayan origin for the arctic fox

The ‘third pole’ of the world is a fitting metaphor for the Himalayan–Tibetan Plateau, in allusion to its vast frozen terrain, rivalling the Arctic and Antarctic, at high altitude but low latitude. Living Tibetan and arctic mammals share adaptations to freezing temperatures such as long and thick winter fur in arctic muskox and Tibetan yak, and for carnivorans, a more predatory niche. Here, we report, to our knowledge, the first evolutionary link between an Early Pliocene (3.60–5.08 Myr ago) fox, Vulpes qiuzhudingi new species, from the Himalaya (Zanda Basin) and Kunlun Mountain (Kunlun Pass Basin) and the modern arctic fox Vulpes lagopus in the polar region. A highly hypercarnivorous dentition of the new fox bears a striking resemblance to that of V. lagopus and substantially predates the previous oldest records of the arctic fox by 3–4 Myr. The low latitude, high-altitude Tibetan Plateau is separated from the nearest modern arctic fox geographical range by at least 2000 km. The apparent connection between an ancestral high-elevation species and its modern polar descendant is consistent with our ‘Out-of-Tibet’ hypothesis postulating that high-altitude Tibet was a training ground for cold-environment adaptations well before the start of the Ice Age.