Outbreeding Depression Caused by Intraspecific Hybridization Between Local and Nonlocal Genotypes in Abies sachalinensis

To evaluate the effects of intraspecific hybridization of local and nonlocal genotypes on growth traits of progeny in Abies sachalinensis, we performed reciprocal crossing between nonlocal trees in a high‐elevation zone (1,100–1,200 m asl) and local trees in a low‐elevation zone (530 m asl) in Hokkaido, northern Japan, in 1979 and established a common garden experiment using local × local (female × male ), local × nonlocal , nonlocal × local , and nonlocal × nonlocal progeny in the low‐elevation zone in 1986. Survival, height, diameter at breast height (dbh), needle nitrogen content, specific leaf area (SLA), and needle area per shoot diameter (NA) of 25‐year‐old progeny were measured in 2005. The survival rate was consistently high (>85% on average). Reductions in height and dbh were apparent in F1 hybrids compared with local × local progeny. Furthermore, outbreeding depression was significant in height growth of nonlocal × local F1 hybrids and in dbh of both F1 hybrids. Reductions in growth traits may be related to morphological needle traits, such as the low values of SLA and NA. Elevation guidelines for A. sachalinensis seed zones are discussed to ensure the long‐term viability of both restored and native populations.     

Supersaturation-limited and Unlimited Phase Transitions Compete to Produce the Pathway Complexity in Amyloid Fibrillation

Although amyloid fibrils and amorphous aggregates are two types of aggregates formed by denatured proteins, their relationship currently remains unclear. We used β₂-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, to clarify the mechanism by which proteins form either amyloid fibrils or amorphous aggregates. When ultrasonication was used to accelerate the spontaneous fibrillation of β2m at pH 2.0, the effects observed depended on ultrasonic power; although stronger ultrasonic power effectively accelerated fibrillation, excessively strong ultrasonic power decreased the amount of fibrils formed, as monitored by thioflavin T fluorescence. An analysis of the products formed indicated that excessively strong ultrasonic power generated fibrillar aggregates that retained β-structures but without high efficiency as seeds. On the other hand, when the spontaneous fibrillation of β2m was induced at higher concentrations of NaCl at pH 2.0 with stirring, amorphous aggregates became more dominant than amyloid fibrils. These apparent complexities in fibrillation were explained comprehensively by a competitive mechanism in which supersaturation-limited reactions competed with supersaturation-unlimited reactions. We link the kinetics of protein aggregation and a conformational phase diagram, in which supersaturation played important roles.     

Chemical anatomy of hydra nervous system using antibodies against hydra neuropeptides: a review

Polyclonal antibodies against hydra neuropeptides allow us to visualize the hydra nerve net. Chemical anatomy of the hydra nerve net was archived by means of immunocytochemistry with various antibodies to hydra neuropeptides. Our goal is to describe the hydra nerve net both qualitatively and quantitatively. The present chemical anatomy results indicate (1) differences in peptide expression between ganglion cells and sensory cells, (2) large differences in neuropeptide expression between ectodermal nerve cells and endodermal nerve cells, and (3) the usefulness of quantitative chemical anatomy to analyze the entire nervous system of hydra.     

A series of novel indazole derivatives of Sirt 1 activator as osteogenic regulators

A series of indazole derivatives were identified as Sirt 1 activators though high-throughput screening. Optimization of each substituent on the indazole ring led to the identification of compound 13. Compound 13 appeared to give the best Sirt 1 activity of the compounds tested and also showed osteogenesis activity in a cell assay. Sirt 1 activators are therefore potential candidates for the treatment of osteoporosis.     

Synthesis and SAR studies of 3,6-disubstituted indazole derivatives as potent hepcidin production inhibitors

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.     

Design,semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC₅₀, 67.0 nM) and 19b (IC₅₀, 99.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.     

Antitubulin effects of aminobenzothiophene-substituted triethylated chromones

In the course of our continuing studies on the 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (TEDB-TB) series, we designed and synthesized nine amino-TEDB-TB derivatives to improve pharmaceutical properties, identify structure activity relationships, and discover novel antitubulin agents. Among all newly synthesized amino-TEDB-TBs, the 5′- and 6′-amino derivatives, 6 and 7, exhibited significant antiproliferative activity against five human tumor cell lines, including an MDR subline overexpressing P-gp. The IC₅₀ values of 0.50–1.01 µM were 3–6 times better than those of previously reported hydroxy-TEDB-TBs. Compounds 6 and 7 inhibited tubulin polymerization, induced both depolymerization of interphase microtubules and multiple spindle formations, and caused cell arrest at prometaphase. Among all compounds, compound 7 scored best pharmaceutically with LogP 2.11 and biologically with greater antiproliferative activity and induction of cell cycle arrest at prometaphase.     

Time-of-day effects of exposure to solar radiation on thermoregulation during outdoor exercise in the heat

High solar radiation has been recognised as a contributing factor to exertional heat-related illness in individuals exercising outdoors in the heat. Although solar radiation intensity has been known to have similar time-of-day variation as body temperature, the relationship between fluctuations in solar radiation associated with diurnal change in the angle of sunlight and thermoregulatory responses in individuals exercising outdoors in a hot environment remains largely unknown. The present study therefore investigated the time-of-day effects of variations in solar radiation associated with changing solar elevation angle on thermoregulatory responses during moderate-intensity outdoor exercise in the heat of summer. Eight healthy, high school baseball players, heat-acclimatised male volunteers completed a 3-h outdoor baseball trainings under the clear sky in the heat. The trainings were commenced at 0900 h in AM trial and at 1600 h in PM trial each on a separate day. Solar radiation and solar elevation angle during exercise continued to increase in AM (672–1107 W/m² and 44–69°) and decrease in PM (717–0 W/m² and 34–0°) and were higher on AM than on PM (both P < 0.001). Although ambient temperature (AM 32–36°C, PM 36–30°C) and wet-bulb globe temperature (AM 31–33°C, PM 34–27°C) also continued to increase in AM and decrease in PM, there were no differences between trials in these (both P > 0.05). Tympanic temperature measured by an infrared tympanic thermometer and mean skin temperature were higher in AM than PM at 120 and 180 min (P < 0.05). Skin temperature was higher in AM than PM at the upper arm and thigh at 120 min (P < 0.05) and at the calf at 120 and 180 min (both P < 0.05). Body heat gain from the sun was greater during exercise in AM than PM (P < 0.0001), at 0–60 min in PM than AM (P < 0.0001) and at 120–180 min in AM than PM (P < 0.0001). Dry heat loss during exercise was greater at 0–60 min (P < 0.0001), and lower at 60–120 min (P < 0.05) and 120–180 min (P < 0.0001) in AM than PM. Evaporative heat loss during exercise was greater in PM than AM at 120–180 min (P < 0.0001). Total (dry + evaporation) heat loss at the skin was greater during exercise in PM than AM (P < 0.0001), at 0–60 min in AM than PM (P < 0.0001) and at 60–120 and 120–180 min in PM than AM (P < 0.05 and 0.0001). Heart rate at 120–150 min was also higher in AM than PM (P < 0.05). Neither perceived thermal sensation nor rating of perceived exertion was different between trials (both P > 0.05). The current study demonstrates a greater thermoregulatory strain in the morning than in the afternoon resulting from a higher body temperature and heart rate in relation to an increase in environmental heat stress with rising solar radiation and solar elevation angle during moderate-intensity outdoor exercise in the heat. This response is associated with a lesser net heat loss at the skin and a greater body heat gain from the sun in the morning compared with the afternoon.