Vitamin B12 deficiency-induced increase of osteoclastic bone resorption caused by abnormal renal resorption of inorganic phosphorus via Napi2a

Vitamin B₁₂ deficiency is a risk factor for bone disorders via mechanisms not fully understood. In this study, an increase in serum inorganic phosphorus (Pi) concentrations was associated with a vitamin B₁₂ deficiency. Napi2a, a renal cotransporter for Pi reabsorption, accumulated on plasma membranes in a vitamin B₁₂ deficiency suggests that vitamin B₁₂ plays an important role in Pi homeostasis.     

Single‐Walled Carbon Nanotubes in Emerging Solar Cells: Synthesis and Electrode Applications

Emerging solar cells, namely, organic solar cells and perovskite solar cells, are the thin‐film photovoltaics that have light to electricity conversion efficiencies close to that of silicon solar cells while possessing advantages in having additional functionalities, facile‐processability, and low fabrication cost. To maximize these advantages, the electrode components must be replaced by materials that are more flexible and cost‐effective. Researchers around the globe have been looking for the new electrodes that meet these requirements. Among many candidates, single‐walled carbon nanotubes have demonstrated their feasibility as the new alternative to conventional electrodes, such as indium tin oxide and metals. This review discusses various growth methods of single‐walled carbon nanotubes and their electrode applications in thin‐film photovoltaics.     

Acoustic emissions of Sorex unguiculatus (Mammalia: Soricidae): Assessing the echo‐based orientation hypothesis

Shrew species have been proposed to utilize an echo‐based orientation system to obtain additional acoustic information while surveying their environments. This system has been supported by changes in vocal emission rates when shrews encounter different habitats of varying complexity, although detailed acoustic features in this system have not been reported. In this study, behavioral experiments were conducted using the long‐clawed shrew (Sorex unguiculatus) to assess this orientation system. Three experimental conditions were set, two of which contained obstacles. Short‐click, noisy, and different types of tonal calls in the audible‐to‐ultrasonic frequency range were recorded under all experimental conditions. The results indicated that shrews emit calls more frequently when they are facing obstacles or exploring the experimental environment. Shrews emitted clicks and several different types of tonal calls while exploring, and modified the use of different types of calls for varying behavior. Furthermore, shrews modified the dominant frequency and duration of squeak calls for different types of obstacles, that is, plants and acrylic barriers. The vocalizations emitted at short inter‐pulse intervals could not be observed when shrews approached these obstacles. These results are consistent with the echo‐based orientation hypothesis according to which shrews use a simple echo‐orientation system to obtain information from their surrounding environments, although further studies are needed to confirm this hypothesis.     

Mutant analyses reveal different functions of fgfr1 in medaka and zebrafish despite conserved ligand-receptor relationships

Medaka (Oryzias latipes) is a small freshwater teleost that provides an excellent developmental genetic model complementary to zebrafish. Our recent mutagenesis screening using medaka identified headfish (hdf) which is characterized by the absence of trunk and tail structures with nearly normal head including the midbrain-hindbrain boundary (MHB). Positional-candidate cloning revealed that the hdf mutation causes a functionally null form of Fgfr1. The fgfr1hdf is thus the first fgf receptor mutant in fish. Although FGF signaling has been implicated in mesoderm induction, mesoderm is induced normally in the fgfr1hdf mutant, but subsequently, mutant embryos fail to maintain the mesoderm, leading to defects in mesoderm derivatives, especially in trunk and tail. Furthermore, we found that morpholino knockdown of medaka fgf8 resulted in a phenotype identical to the fgfr1hdf mutant, suggesting that like its mouse counterpart, Fgf8 is a major ligand for Fgfr1 in medaka early embryogenesis. Intriguingly, Fgf8 and Fgfr1 in zebrafish are also suggested to form a major ligand-receptor pair, but their function is much diverged, as the zebrafish fgfr1 morphant and zebrafish fgf8 mutant acerebellar (ace) only fail to develop the MHB, but develop nearly unaffected trunk and tail. These results provide evidence that teleost fish have evolved divergent functions of Fgf8-Fgfr1 while maintaining the ligand-receptor relationships. Comparative analysis using different fish is thus invaluable for shedding light on evolutionary diversification of gene function.     

Six1 is essential for early neurogenesis in the development of olfactory epithelium

The olfactory epithelium (OE) is derived from the olfactory placode (OP) during mouse development. At embryonic day (E) 10.0-E10.5, “early neurogenesis” occurs in the OE, which includes production of pioneer neurons that emigrate out of the OE and other early-differentiated neurons. Around E12.5, the OE becomes organized into mature pseudostratified epithelium and shows “established neurogenesis,” in which olfactory receptor neurons (ORNs) are differentiated from basal progenitors. Little is known about the molecular pathway of early neurogenesis. The homeodomain protein Six1 is expressed in all OP cells and neurogenic precursors in the OE. Here we show that early neurogenesis is severely disturbed despite the unaltered expression of Mash1 at E10.5 in the Six1-deficient mice (Six1^−/−). Expression levels of neurogenin1 (Ngn1) and NeuroD are reduced and those of Hes1 and Hes5 are augmented in the OE of Six1^−/− at E10.5. Pioneer neurons and cellular aggregates, which are derived from the OP/OE and situated in the mesenchyme between the OE and forebrain, are completely absent in Six1^−/−. Moreover, ORN axons and the gonadotropin-releasing hormone-positive neurons fail to extend and migrate to the forebrain, respectively. Our study indicates that Six1 plays critical roles in early neurogenesis by regulating Ngn1, NeuroD, Hes1, and Hes5.     

Structure of the antitumour enzyme L-methionine gamma-lyase from Pseudomonas putida at 1.8 A resolution

l-Methionine gamma-lyase (EC 4.4.1.11, MGL_Pp) from Pseudomonas putida is a multifunctional enzyme, which belongs to the gamma-family of pyridoxal-5'-phosphate (PLP) dependent enzymes. In this report, we demonstrate that the three-dimensional structure of MGL_Pp has been completely solved by the molecular replacement method to an R-factor of 20.4% at 1.8 A resolution. Detailed information of the overall structure of MGL_Pp supplies a clear picture of the substrate- and PLP-binding pockets. Tyr59 and Arg61 of neighbouring subunits, which are strongly conserved in other gamma-family enzymes, contact the phosphate group of PLP. These residues are important as the main anchor within the active site. Lys240, Asp241 and Arg61 of one partner monomer and Tyr114 and Cys116 of the other partner monomer form a hydrogen-bond network in the MGL active site which is specific for MGLs. It is also suggested that electrostatic interactions at the subunit interface are involved in the stabilization of the structural conformation. The detailed structure will facilitate the development of MGL_Pp as an anticancer drug.     

Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach

Colonization of the gastric pits in the stomach by Helicobacter pylori (Hp) is a major risk factor for gastritis, gastric ulcers, and cancer. Normally, rapid self-renewal of gut epithelia, which occurs by a balance of progenitor proliferation and pit cell apoptosis, serves as a host defense mechanism to limit bacterial colonization. To investigate how Hp overcomes this host defense, we use the Mongolian gerbil model of Hp infection. Apoptotic loss of pit cells induced by a proapoptotic agent is suppressed by Hp. The ability of Hp to suppress apoptosis contributed to pit hyperplasia and persistent bacterial colonization of the stomach. Infection with WT Hp but not with a mutant in the virulence effector cagA increased levels of the prosurvival factor phospho-ERK and antiapoptotic protein MCL1 in the gastric pits. Thus, CagA activates host cell survival and antiapoptotic pathways to overcome self-renewal of the gastric epithelium and help sustain Hp infection.     

Polyglutamine expansion mutation yields a pathological epitope linked to nucleation of protein aggregate: determinant of Huntington's disease onset

Polyglutamine (polyQ) expansion mutation causes conformational, neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. These diseases are characterized by the aggregation of misfolded proteins, such as amyloid fibrils, which are toxic to cells. Amyloid fibrils are formed by a nucleated growth polymerization reaction. Unexpectedly, the critical nucleus of polyQ aggregation was found to be a monomer, suggesting that the rate-limiting nucleation process of polyQ aggregation involves the folding of mutated protein monomers. The monoclonal antibody 1C2 selectively recognizes expanded pathogenic and aggregate-prone glutamine repeats in polyQ diseases, including Huntington's disease (HD), as well as binding to polyleucine. We have therefore assayed the in vitro and in vivo aggregation kinetics of these monomeric proteins. We found that the repeat-length-dependent differences in aggregation lag times of variable lengths of polyQ and polyleucine tracts were consistently related to the integration of the length-dependent intensity of anti-1C2 signal on soluble monomers of these proteins. Surprisingly, the correlation between the aggregation lag times of polyQ tracts and the intensity of anti-1C2 signal on soluble monomers of huntingtin precisely reflected the repeat-length dependent age-of-onset of HD patients. These data suggest that the alterations in protein surface structure due to polyQ expansion mutation in soluble monomers of the mutated proteins act as an amyloid-precursor epitope. This, in turn, leads to nucleation, a key process in protein aggregation, thereby determining HD onset. These findings provide new insight into the gain-of-function mechanisms of polyQ diseases, in which polyQ expansion leads to nucleation rather than having toxic effects on the cells.     

Effect of electrical stimulation of antagonist muscles for voluntary motor drive

Voluntary motor drive is an important central command that descends via the corticospinal tract to initiate muscle contraction. When electrical stimulation (ES) is applied to an antagonist or agonist muscle, it changes the agonist muscle’s representative motor cortex and thus its voluntary motor drive. In this study, we used a reaction time task to compare the effects of weak and strong ES of the antagonist or agonist muscle during the premotor period of a wrist extension. We recorded motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) that was applied to the extensor carpi radialis (ECR; agonist) and flexor carpi radialis (FCR; antagonist). When stronger ES intensities were applied to the antagonist, the MEP control ratio in the ECR significantly increased during the premotor time. Furthermore, the MEP control ratio with stronger antagonist ES intensity was significantly larger than that in the agonist for the same ES intensity. In the FCR, the MEP control ratio was also significantly greater at the strong ES intensity than at the weak ES intensity. Furthermore, the MEP control ratio in the antagonist with a strong ES intensity was significantly larger than that in the agonist with the same ES intensity. These results suggest that agonist corticomotor excitability might be enhanced by ES of the antagonist, which in turn strongly activates the descending motor system in the preparation of agonist contraction.