Septin-microtubule association via a motif unique to isoform 1 of septin 9 tunes stress fibers.

Septins, a family of GTP-binding proteins that assemble into higher order structures, interface with the membrane, actin filaments and microtubules, and are thus important regulators of cytoarchitecture. Septin 9 (SEPT9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short microtubule-associated protein (MAP)-like motif unique to SEPT9 isoform 1 (SEPT9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring SEPT9_i1. Although outside of the MAP-like motif, HNA mutations abrogate this association, identifying a putative regulatory domain. Removal of this domain from SEPT9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering the mechanisms underlying septin-associated pathologies. This article has an associated First Person interview with the first author of the paper.

trans-Cyclooctenes as Scavengers of Bromine Involved in Catalytic Bromination.

Scavengers that capture reactive chemical substances are used to prevent the decomposition of materials. However, in the field of catalysis, the development of scavengers that inhibit background pathways has attracted little attention, although the concept will open up an otherwise inaccessible reaction space. In catalytic bromination, fast non-catalyzed background reactions disturb the catalytic control of the selectivity, even when using N-bromoamide reagents, which have a milder reactivity than bromine (Br2 ). Here, we developed a trans-cyclooctene (TCO) bearing a 2-pyridylethyl group to efficiently retard background reactions by capturing Br2 in bromocyclization using N-bromosuccinimide. The use of less than a stoichiometric amount of the TCO was sufficient to inhibit non-catalyzed reactions, and mechanistic studies using the TCO revealed that in situ-generated Br2 provides non-catalyzed reaction pathways based on a chain mechanism. The TCO is useful as an additive for improving enantioselectivity and regioselectivity in catalytic reactions. Cooperative systems using the TCO with selective catalysts offer an alternative strategy for optimizing catalyst-controlled selectivity during bromination. Moreover, it also served as an indicator of Br2 involved in catalytic reaction pathways; thus, the TCO was useful as a probe for mechanistic investigations into the involvement of Br2 in bromination reactions of interest.

Organocatalytic Access to Tetrasubstituted Chiral Carbons Integrating Functional Groups.

Three-dimensional organic structures containing sp3 carbons bearing four non-hydrogen substituents can provide drug-like molecules. Although such complex structures are challenging targets in synthetic organic chemistry, efficient synthetic approaches will open a new chemical space for pharmaceutical candidates. This review provides an account of our recent achievements in developing organocatalytic approaches to attractive molecular platforms based on optically active sp3 carbons integrating four different functional groups. These methodologies include asymmetric cycloetherification and cyanation of multifunctional ketones, both of which take advantage of the mild characteristics of organocatalytic activation. Enzyme-like but non-enzymatic organocatalytic systems can be used to precisely manufacture molecules containing complex chiral structures without substrate specificity problems. In addition, these catalytic systems control not only stereoselectivity but also site-selectivity and do not induce side reactions even from substrates with rich functionality.

The effects of cognitive tasks on the frequency of non-MTC gait cycle during walking in healthy older and young adults.

[Purpose] To investigate the effects of cognitive tasks on the non-minimum toe clearance gait cycles (nMTC) frequency during walking in healthy older and young adults. [Participants and Methods] This study included 20 healthy older and 20 young adults. The participants performed 3 min preferred-speed walking under a single-task and three dual-tasks (DTs) consisting of verbal, subtraction, and recall tasks. We determined the nMTC, which could not detect a trough in the toe trajectory during the swing phase. We evaluated the nMTC frequency (the cases of nMTC / total gait cycles) and compared them among the tasks and between groups. [Results] The results of the two-way analysis of variance revealed that there were no differences among the tasks, while the nMTC frequency in the older group was higher than that in the young group. The DT cost (DTc), which was used as an indicator of cognitive-motor interference (CMI), was higher in the subtraction and recall tasks in the older group than those in the young group. [Conclusion] This study showed that adding a cognitive task while walking increased in the nMTC frequency in older adults. These results suggest that the nMTC frequency under DT would reflect the increased CMI in healthy older adults.

Effects of cognitive tasks on center-of-foot pressure displacements and brain activity during single leg stance: comparison in community-dwelling healthy older and young people.

[Purpose] This study aimed to investigate the effect of cognitive tasks on the center-of-foot pressure (COP) displacements and brain activity during single leg stance (SLS) in older people. [Participants and Methods] This study included 25 healthy older (age, 68.8 ± 4.9 years) and 25 young (age, 21.0 ± 0.9 years) participants. Participants performed SLS for 35 s under a single-task (ST) and three dual-tasks (DTs), namely verbal, subtraction, and recall tasks. We measured the total length of COP (COP_ TL ) and change in oxygenated hemoglobin (HbO2) levels during SLS under four tasks. [Results] There were no differences in COP_ TL and HbO2 levels in the young group, whereas COP_ TL in the recall task was significantly longer than in ST in the older group. In the comparisons of the DTc (the relative change of DT to ST), no differences were found among three DTs in the young group, whereas the DTc of COP_ TL in the recall task was significantly higher than that in the verbal task in the older group. Regarding HbO2, no differences were observed among the four tasks in both groups. [Conclusion] These results suggest that SLS combined with a recall task may be useful for fall risk screening in healthy older individuals.

Validation of Intraoperative Catheter Phase Mapping Using a Simultaneous Optical Measurement System in Rabbit Ventricular Myocardium.

BACKGROUND: Recently, an interoperative catheter electrode mapping system, termed ExTRa Mapping (EXT), was developed for precise diagnosis and effective treatment of non-paroxysmal atrial fibrillations (non-PAF). However, the mapping accuracy of EXT is still unclear.Methods and Results:In this study, the reliability of the EXT in comparison with that of high-resolution optical membrane potential mapping was compared. Spiral wave re-entries (SWRs) were induced in the excised rabbit hearts (n=8, 42 episodes). Electrical signals were measured by electrodes on a transparent silicone plate, with the same arrangement as in the clinical catheter, and fluorescence signals were recorded simultaneously across the plate. Based on the phase maps derived by EXT, activation patterns (one-directed propagations: 26, rotational activities: 16) were identified correctly with 95% accuracy (40/42), and the correlation coefficient of the ratio of the non-passive period was 0.95. In the rotational episodes (15), the mean position error of the centers of gravity of the SWR trajectory (2,000 ms) was 2.0 mm. For the one-directional episodes (25), the correlation coefficient of the directions of one-way propagation was 0.99. CONCLUSIONS: The phase map sequence by EXT is consistent with that by the analyses of high-resolution optical mapping. EXT is reliable for analyzing the activation pattern in the region of interest.

CreA-independent carbon catabolite repression of cellulase genes by trimeric G-protein and protein kinase A in Aspergillus nidulans.

Cellulase production in filamentous fungi is repressed by various carbon sources. In our preliminary survey in Aspergillus nidulans, degree of de-repression differed depending on carbon sources in a mutant of creA, encoding the transcriptional repressor for carbon catabolite repression (CCR). To further understand mechanisms of CCR of cellulase production, we compared the effects of creA deletion with deletion of protein kinase A (pkaA) and G (ganB) genes, which constitute a nutrient sensing and signaling pathway. In plate culture with carboxymethyl cellulose and D-glucose, deletion of pkaA and ganB, but not creA, led to significant de-repression of cellulase production. In submerged culture with cellobiose and D-glucose or 2-deoxyglucose, both creA or pkaA single deletion led to partial de-repression of cellulase genes with the highest level by their double deletion, while ganB deletion caused de-repression comparable to that of the creA/pkaA double deletion. With ball-milled cellulose and D-glucose, partial de-repression was detected by deletion of creA but not of pkaA or ganB. The creA/pkaA or creA/ganB double deletion led to earlier expression than the creA deletion. Furthermore, the effect of each deletion with D-xylose or L-arabinose as the repressing carbon source was significantly different from that with D-glucose, D-fructose, and D-mannose. Consequently, this study revealed that PkaA and GanB participate in CreA-independent CCR and that contribution of CreA, PkaA, and GanB in CCR differs depending on the inducers, repressing carbon sources, and culture conditions (plate or submerged). Further study of CreA-independent mechanisms is needed to fully understand CCR in filamentous fungi.

trans-Cyclooctenes as Halolactonization Catalysts.

The strained olefins in trans-cyclooctenes serve as efficient catalysts for halolactonizations, including bromolactonizations and iodolactonizations. The trans-cyclooctene framework is essential for excellent catalytic performance, and the substituents also play important roles in determining efficiency. These results are the first demonstration of catalysis by a trans-cyclooctene.

Induction of Axial Chirality in 8-Arylquinolines through Halogenation Reactions Using Bifunctional Organocatalysts.

The enantioselective syntheses of axially chiral heterobiaryls were accomplished through the aromatic electrophilic halogenation of 3-(quinolin-8-yl)phenols with bifunctional organocatalysts that control the molecular conformations during successive halogenations. Axially chiral quinoline derivatives, which have rarely been synthesized in an enantioselective catalytic manner, were afforded in moderate-to-good enantioselectivities through bromination, and an analogous protocol also enabled enantioselective iodination. In addition, this catalytic reaction, which allows enantioselective control through the use of mono-ortho-substituted substrates, allowed the asymmetric synthesis of 8-arylquinoline derivatives bearing two different halogen groups in high enantioselectivities.

Asymmetric Net Cycloaddition for Access to Diverse Substituted 1,5-Benzothiazepines.

In this study, the isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,ß-unsaturated carboxylic acid derivatives with 2-aminothiophenols was developed. Mechanistic studies suggested that the reaction proceeds via a reversible sulfa-Michael addition to α,ß-unsaturated acylammonium intermediates, followed by the enantioselective formation of a seven-membered ring, enabling the facile and divergent synthesis of optically active 2- and 3-substituted 1,5-benzothiazepines. This process was demonstrated to be highly versatile, affording the corresponding products in excellent regioselectivities and high enantioselectivities. Furthermore, this method enabled the synthesis of chiral 2,3-disubstituted 1,5-benzothiazepines in high regio-, enantio-, and diastereoselectivities. Hence, this protocol can be applied for the construction of a library of useful pharmaceutical candidates.

Ultra-Low-Dose Fetal CT With Model-Based Iterative Reconstruction: A Prospective Pilot Study.

OBJECTIVE: Prenatal diagnosis of skeletal dysplasia by means of 3D skeletal CT examination is highly accurate. However, it carries a risk of fetal exposure to radiation. Model-based iterative reconstruction (MBIR) technology can reduce radiation exposure; however, to our knowledge, the lower limit of an optimal dose is currently unknown. The objectives of this study are to establish ultra-low-dose fetal CT as a method for prenatal diagnosis of skeletal dysplasia and to evaluate the appropriate radiation dose for ultra-low-dose fetal CT. SUBJECTS AND METHODS: Relationships between tube current and image noise in adaptive statistical iterative reconstruction and MBIR were examined using a 32-cm CT dose index (CTDI) phantom. On the basis of the results of this examination and the recommended methods for the MBIR option and the known relationship between noise and tube current for filtered back projection, as represented by the expression SD = (milliamperes)-0.5, the lower limit of the optimal dose in ultra-low-dose fetal CT with MBIR was set. The diagnostic power of the CT images obtained using the aforementioned scanning conditions was evaluated, and the radiation exposure associated with ultra-low-dose fetal CT was compared with that noted in previous reports. RESULTS: Noise increased in nearly inverse proportion to the square root of the dose in adaptive statistical iterative reconstruction and in inverse proportion to the fourth root of the dose in MBIR. Ultra-low-dose fetal CT was found to have a volume CTDI of 0.5 mGy. Prenatal diagnosis was accurately performed on the basis of ultra-low-dose fetal CT images that were obtained using this protocol. The level of fetal exposure to radiation was 0.7 mSv. CONCLUSION: The use of ultra-low-dose fetal CT with MBIR led to a substantial reduction in radiation exposure, compared with the CT imaging method currently used at our institution, but it still enabled diagnosis of skeletal dysplasia without reducing diagnostic power.

Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides.

Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantioselective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatility of bifunctional organocatalysts for the enantioselective construction of axially chiral compounds. Moderate to good enantioselectivities were afforded with a range of benzamide substrates. Mechanistic investigations were also carried out.

Facile net cycloaddition approach to optically active 1,5-benzothiazepines.

The 1,5-benzothiazepine moiety is well-known as a versatile pharmacophore, and its derivatives are expected to have antagonism against numerous diseases. Thus, it is desirable to develop a synthetic route that enables facile enantioselective preparation of a wide range of such derivatives. Although the cycloaddition approach could be considered a possible route to these compounds, to date, there has been no precedent of such a protocol. We therefore present the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5-benzothiazepines by utilizing α,ß-unsaturated acylammonium intermediates generated by chiral isothiourea catalysts, which undergo two sequential chemoselective nucleophilic attacks by 2-aminothiophenols. This protocol provided cycloadducts in extremely high regioselectivity, with a good-to-excellent stereoselectivity being achieved regardless of the steric and electronic properties of the substrates. This method therefore offers promising synthetic routes for the construction of a library of optically active 1,5-benzothiazepines for assay evaluation.

Bifunctional organocatalysts for the enantioselective synthesis of axially chiral isoquinoline N-oxides.

Bifunctional catalysts bearing amino and urea functional groups have been applied for a novel, highly enantioselective synthesis of axially chiral isoquinoline N-oxides, which are promising chiral ligands or organocatalysts in organic synthesis. This is the first example of highly enantioselective synthesis of axially chiral biaryls by bifunctional organocatalysts. Good-to-excellent enantioselectivities were obtained with a range of substrates.

Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts.

Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy-Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2-position, which are prevalent in insect pheromones. Optically active (2S,5S)-chalcogran, a pheromone of the six-spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.

Asymmetric chroman synthesis via an intramolecular oxy-Michael addition by bifunctional organocatalysts.

Cinchona-alkaloid-urea-based bifunctional organocatalysts facilitate the catalytic asymmetric synthesis of chroman derivatives via an intramolecular oxy-Michael addition reaction. Phenol derivatives bearing an easily available (E)-α,ß-unsaturated ketone or a thioester moiety are useful substrates for the title transformation. This method represents a facile synthesis of various optically active 2-substituted chromans in high yield.

Procedure-controlled enantioselectivity switch in organocatalytic 2-oxazolidinone synthesis.

In a novel organocatalytic formal [3 + 2] cycloaddition to afford chiral 2-oxazolidinones, an enantioselectivity switch could be induced by changing the manner of addition of the reactants, even when the reaction components (cinchona-alkaloid-derived aminothiourea catalyst, substrates, and solvent) were the same.

New-onset addictions in patients with alcohol dependence: A cross-sectional study.

BACKGROUND: Individuals who are addicted to one addiction are at an increased risk for developing another new addiction. New-onset addictions among patients with alcohol dependence needs to be considered for more effective treatment of alcohol dependence. METHODS: In this cross-sectional study, Japanese outpatients with alcohol dependence were assessed using a comprehensive, originally designed questionnaire to determine whether they were addicted to substances or behaviors other than alcohol. The prevalence rates of new-onset addictions were compared between alcohol-dependent patients who had abstained from alcohol for a year or more and those who had not. Multiple regression analysis was performed to examine the association between the number of new-onset addictions and the demographic and clinical characteristics. RESULTS: One hundred and nine outpatients with alcohol dependence (54.6±11.0 years; 97 men) participated in the study. The prevalence of new-onset addictions was 41.3%. No significant differences were found in the prevalence of new-onset addictions between the patients who had abstained for a year or more and those who had not. Multiple regression analysis revealed that the number of new-onset addictions was positively associated with the presence of psychiatric comorbidity (ß = 0.24; p = 0.02) and use of benzodiazepines (ß = 0.20; p = 0.04) with a R2 of 0.153. CONCLUSION: Alcohol dependent patients with characteristics such as psychiatric comorbidity and use of benzodiazepines should be given more attention to the development of new-onset addictive behaviors. On the other hand, those behaviors could be acceptable for harm-reduction unless excessive and loss of control.

Impact of directed movement on invasive spread in periodic patchy environments.

To address the effect of taxis of invasive animals on their spreading speed in heterogeneous environments, we deal with an advection-diffusion-reaction equation (ADR) in a periodic patchy environment. Two-types of advection that spatially vary depending on environmental heterogeneity are taken into consideration: a stepwise taxis function and a saw-like taxis function. We first analyze the ADR with the stepwise taxis advection, and derive an invasion criterion. When the invasion criterion holds, an initially localized population evolves to a traveling periodic wave (TPW). The asymptotic speed of the TPW is found to be equal to the minimal speed of the TPW analytically derived. Thus, we examine how the minimal speed is influenced by the taxis. The major results are: (1) As the magnitude of the taxis toward favorable patches increases, invasion becomes more feasible. However, the spreading speed increases at first, and then decreases to show a one-humped curve against the magnitude of the taxis; (2) As the scale of fragmentation in the patchy environment is increased, the spreading speed increases when the magnitude of the taxis is small, while it decreases when the magnitude of the taxis becomes sufficiently large. These characteristic features qualitatively apply to the ADR model with the saw-like taxis function.