Effects of ingestion of glucose on GH and TSH secretion: evidence for stimulation of somatostatin release from the hypothalamus by acute hyperglycemia in normal man and its impairment in acromegalic patients

Ingestion of glucose is known to induce suppression of GH secretion in normal subjects and this phenomenon is often absent in acromegalic patients. To clarify the mechanism of GH suppression in acute hyperglycemia in normal subjects and disturbed GH response in acromegalic patients, the effects of acute hyperglycemia on plasma GH and TSH levels were examined in normal subjects and acromegalic patients. Plasma GH levels were significantly lowered 45-60 min after ingestion of 75 g glucose and elevated at 210 and 240 min in nine normal subjects. Plasma TSH levels were also significantly lowered between 45 and 120 min after ingestion; levels then gradually rose. Subcutaneous administration of 50 micrograms SMS 201-995, a long acting somatostatin analog, lowered plasma TSH levels in both normal subjects and acromegalic patients, and there was no significant difference in the degree of decrease in plasma TSH levels between the normal subjects and patients. These results, taken together with several reports that somatostatin suppresses TSH secretion as well as GH secretion, suggest that acute hyperglycemia stimulates somatostatin release from the hypothalamus, thus causing inhibition of GH and TSH secretion. However, in ten acromegalic patients, only two showed suppression of plasma GH levels to below 50% of basal level and the degree of suppression of TSH secretion was significantly less than in normal subjects in the glucose tolerance test. It is, therefore, suggested that somatostatin release in response to acute hyperglycemia is impaired in most acromegalic patients and that this abnormality may be one of causes for the absence of the normal GH response to acute hyperglycemia in this disorder.     

Region specificity of rectus femoris muscle for force vectors in vivo

To examine the region specificity within the rectus femoris (RF) for knee extension and hip flexion force directions, three force components around the ankle were measured during intramuscular electrical stimulation applied to six parts of the RF: a proximal and medial part, a proximal and lateral part, a middle and medial part, a middle and lateral part, a distal and medial part, and a distal and lateral part. As a result, the exerted force directions in all of the subjects were variable in all regions, and the proximal region of the RF was the dominant contributor to the hip flexion moment. In addition, the force in the lateral region of the RF, rather than that in the medial region, denoted the lateral direction. These results suggest that divergent regions of muscle fibers within the RF are responsible for different functions in determining the force direction.     

Limonoid compounds inhibit sphingomyelin biosynthesis by preventing CERT protein-dependent extraction of ceramides from the endoplasmic reticulum

To identify novel inhibitors of sphingomyelin (SM) metabolism, a new and selective high throughput microscopy-based screening based on the toxicity of the SM-specific toxin, lysenin, was developed. Out of a library of 2011 natural compounds, the limonoid, 3-chloro-8β-hydroxycarapin-3,8-hemiacetal (CHC), rendered cells resistant to lysenin by decreasing cell surface SM. CHC treatment selectively inhibited the de novo biosynthesis of SM without affecting glycolipid and glycerophospholipid biosynthesis. Pretreatment with brefeldin A abolished the limonoid-induced inhibition of SM synthesis suggesting that the transport of ceramide (Cer) from the endoplasmic reticulum to the Golgi apparatus is affected. Unlike the Cer transporter (CERT) inhibitor HPA-12, CHC did not change the transport of a fluorescent short chain Cer analog to the Golgi apparatus or the formation of fluorescent and short chain SM from the corresponding Cer. Nevertheless, CHC inhibited the conversion of de novo synthesized Cer to SM. We show that CHC specifically inhibited the CERT-mediated extraction of Cer from the endoplasmic reticulum membranes in vitro. Subsequent biochemical screening of 21 limonoids revealed that some of them, such as 8β-hydroxycarapin-3,8-hemiacetal and gedunin, which exhibits anti-cancer activity, inhibited SM biosynthesis and CERT-mediated extraction of Cer from membranes. Model membrane studies suggest that 8β-hydroxycarapin-3,8-hemiacetal reduced the miscibility of Cer with membrane lipids and thus induced the formation of Cer-rich membrane domains. Our study shows that certain limonoids are novel inhibitors of SM biosynthesis and suggests that some biological activities of these limonoids are related to their effect on the ceramide metabolism.     

Alternative biofuel production in non-natural hosts

Global energy and environmental concerns have stimulated increased efforts in synthesizing petroleum-derived products from renewable resources. Biological production of metabolites for fuel is increasingly becoming a feasible, renewable, environmentally sound alternative. However, many of these chemicals are not highly produced in any known native organism. Here we review the current progress of modifying microorganisms with heterogeneous elements for the production of biofuels. This strategy has been extensively employed in a variety of hosts for the development of production of various alcohols, fatty acids, alkenes and alkanes.     

Molecular data and ecological niche modelling reveal a highly dynamic evolutionary history of the East Asian Tertiary relict Cercidiphyllum (Cercidiphyllaceae)

? East Asia's temperate deciduous forests served as sanctuary for Tertiary relict trees, but their ages and response to past climate change remain largely unknown. To address this issue, we elucidated the evolutionary and population demographic history of Cercdiphyllum, comprising species in China/Japan (Cercdiphyllum?japonicum) and central Japan (Cercdiphyllum magnificum). ? Fifty-three populations were genotyped using chloroplast and ribosomal DNA sequences and microsatellite loci to assess molecular structure and diversity in relation to past (Last Glacial Maximum) and present distributions based on ecological niche modelling. ? Late Tertiary climate cooling was reflected in a relatively recent speciation event, dated at the Mio-/Pliocene boundary. During glacials, the warm-temperate C.?japonicum experienced massive habitat losses in some areas (north-central China/north Japan) but increases in others (southwest/-east China, East China Sea landbridge, south Japan). In China, the Sichuan Basin and/or the middle-Yangtze were source areas of postglacial northward recolonization; in Japan, this may have been facilitated through introgressive hybridization with the cool-temperate C.?magnificum. ? Our findings challenge the notion of relative evolutionary and demographic stability of Tertiary relict trees, and may serve as a guideline for assessing the impact of Neogene climate change on the evolution and distribution of East Asian temperate plants.     

Climate oscillation during the Quaternary associated with landscape heterogeneity promoted allopatric lineage divergence of a temperate tree Kalopanax septemlobus (Araliaceae) in East Asia

We investigated the biogeographic history of Kalopanax septemlobus, one of the most widespread temperate tree species in East Asia, using a combined phylogeographic and palaeodistribution modelling approach. Range-wide genetic differentiation at nuclear microsatellites (G'(ST) = 0.709; 2205 samples genotyped at five loci) and chloroplast DNA (G(ST) = 0.697; 576 samples sequenced for 2055 bp at three fragments) was high. A major phylogeographic break in Central China corresponded with those of other temperate species and the spatial delineation of the two temperate forest subkingdoms of East Asia, consistent with the forests having been isolated within both East and West China for multiple glacial-interglacial cycles. Evidence for multiple glacial refugia was found in most of its current range in China, South Japan and the southernmost part of the Korean Peninsula. In contrast, lineage admixture and absence of private alleles and haplotypes in Hokkaido and the northern Korean Peninsula support a postglacial origin of northernmost populations. Although palaeodistribution modelling predicted suitable climate across a land-bridge extending from South Japan to East China during the Last Glacial Maximum, the genetic differentiation of regional populations indicated a limited role of the exposed sea floor as a dispersal corridor at that time. Overall, this study provides evidence that differential impacts of Quaternary climate oscillation associated with landscape heterogeneity have shaped the genetic structure of a wide-ranging temperate tree in East Asia.     

Major components of the KARRIKIN INSENSITIVE2-dependent signaling pathway are conserved in the liverwort Marchantia polymorpha

KARRIKIN INSENSITIVE2 (KAI2) was first identified as a receptor of karrikins, smoke-derived germination stimulants. KAI2 is also considered a receptor of an unidentified endogenous molecule called the KAI2 ligand. Upon KAI2 activation, signals are transmitted through the degradation of D53/SMXL proteins via MAX2-dependent ubiquitination. Although components in the KAI2-dependent signaling pathway, namely MpKAI2A and MpKAI2B, MpMAX2, and MpSMXL, exist in the genome of the liverwort Marchantia polymorpha, their functions remain unknown. Here, we show that early thallus growth is retarded and gemma dormancy in the dark is suppressed in Mpkai2a and Mpmax2 loss-of-function mutants. These defects are counteracted in Mpkai2a Mpsmxl and Mpmax2 Mpsmxl double mutants indicating that MpKAI2A, MpMAX2, and MpSMXL act in the same genetic pathway. Introduction of MpSMXL^d53, in which a domain required for degradation is mutated, into wild-type plants mimicks Mpkai2a and Mpmax2 plants. In addition, the detection of citrine fluorescence in Nicotiana benthamiana cells transiently expressing a SMXL-Citrine fusion protein requires treatment with MG132, a proteasome inhibitor. These findings imply that MpSMXL is subjected to degradation, and that the degradation of MpSMXL is crucial for MpKAI2A-dependent signaling in M. polymorpha. Therefore, we claim that the basic mechanisms in the KAI2-dependent signaling pathway are conserved in M. polymorpha.

Functions of genes in the KARRIKIN INSENSITIVE2-dependent signaling pathway are conserved in the liverwort Marchantia polymorpha and control early development of the thallus.     

Targeted deletion of the tybe IIb Na-dependent Pi-co-transporter, NaPi-IIb, results in early embryonic lethality

NaPi-IIb encodes a Na⁺-dependent Pi co-transporter, which is expressed in various adult tissues and mediates transport of extracellular Pi ions coupling with Na⁺ ion. To define the role of NaPi-IIbin vivo, NaPi-IIb gene deficient mice were generated utilizing targeted mutagenesis, yielding viable, heterozygous NaPi-IIb mice. In contrast, homozygous NaPi-IIb mice died in utero soon after implantation, indicating that NaPi-IIb was essential for early embryonic development. In situ hybridization revealed NaPi-IIb mRNA expression in the parietal endoderm, followed by the visceral endoderm, at a time point prior to establishment of a functioning chorio-allantoic placenta. At the time point of functional placenta development, the main site of NaPi-IIb production resided in the labyrinthine zone, where embryonic and maternal circulations were in closest contact. Expression patterns of NaPi-IIb suggest that NaPi-IIb plays an important role in Pi absorption from maternal circulation.