Comparison of Modular Control during Side Cutting before and after Fatigue.

The purpose of this study was to clarify the coordination between the trunk and lower limb muscles during sidestep and to compare this coordination before and after fatigue intervention. The intervention was lateral jump until exhaustion. Nonnegative matrix factorization (NMF) was used to extract muscle synergies from electromyography. Subsequently, to compare the muscle synergies, a scalar product that evaluates the coincidence of synergies was calculated. Three muscle synergies were extracted before and after the intervention from the NMF analysis. In accordance with the evaluation of the scalar product, these synergies were the same before and after the intervention. One of these synergies that engaged the internal oblique/transversus abdominis, rectus femoris, and adductor muscle was activated from before landing to midstance during sidestep motion; therefore, this synergy is thought to suppress excessive hip abduction. However, the activation timing of this synergy was delayed after the intervention (P = 0.028, effect size: 0.54, Wilcoxon test). This delay is considered to decrease hip stability. Thus, this change may induce a reduction in hip control function.

Design and synthesis of novel and potent GPR119 agonists with a spirocyclic structure.

Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50 = 4 nM) with no CYP inhibitory activity (IC50 >10 µM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats.

Inducible De Novo Biosynthesis of Isoflavonoids in Soybean Leaves by Spodoptera litura Derived Elicitors: Tracer Techniques Aided by High Resolution LCMS.

Isoflavonoids are a characteristic family of natural products in legumes known to mediate a range of plant-biotic interactions. For example, in soybean (Glycine max: Fabaceae) multiple isoflavones are induced and accumulate in leaves following attack by Spodoptera litura (Lepidoptera: Noctuidae) larvae. To quantitatively examine patterns of activated de novo biosynthesis, soybean (Var. Enrei) leaves were treated with a combination of plant defense elicitors present in S. litura gut content extracts and L-α-[13C9, 15N]phenylalanine as a traceable isoflavonoid precursor. Combined treatments promoted significant increases in 13C-labeled isoflavone aglycones (daidzein, formononetin, and genistein), 13C-labeled isoflavone 7-O-glucosides (daidzin, ononin, and genistin), and 13C-labeled isoflavone 7-O-(6″-O-malonyl-ß-glucosides) (malonyldaidzin, malonylononin, and malonylgenistin). In contrast levels of 13C-labeled flavones and flavonol (4',7-dihydroxyflavone, kaempferol, and apigenin) were not significantly altered. Curiously, application of fatty acid-amino acid conjugate (FAC) elicitors present in S. litura gut contents, namely N-linolenoyl-L-glutamine and N-linoleoyl-L-glutamine, both promoted the induced accumulation of isoflavone 7-O-glucosides and isoflavone 7-O-(6″-O-malonyl-ß-glucosides), but not isoflavone aglycones in the leaves. These results demonstrate that at least two separate reactions are involved in elicitor-induced soybean leaf responses to the S. litura gut contents: one is the de novo biosynthesis of isoflavone conjugates induced by FACs, and the other is the hydrolysis of the isoflavone conjugates to yield isoflavone aglycones. Gut content extracts alone displayed no hydrolytic activity. The quantitative analysis of isoflavone de novo biosynthesis, with respect to both aglycones and conjugates, affords a useful bioassay system for the discovery of additional plant defense elicitor(s) in S. litura gut contents that specifically promote hydrolysis of isoflavone conjugates.

Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors.

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.

Synthetic studies toward 13-oxyingenol: construction of the fully substituted tetracyclic compound.

13-Oxyingenol and its derivatives have high levels of anti-HIV activity. A fully substituted tetracyclic skeleton of 13-oxyingenol is constructed by using spiro-cyclization and ring-closing olefin metathesis as key steps.

[Support for a cancer-suffering mother's desire to live].

We consider the case of a woman in her 50s with thyroid cancer, lung metastasis and dyspnea; living with her high-school student son, she had a strong wish to live to see him graduate and was deeply troubled by her inability to fulfill her role as a mother in practice. The palliative care team provided support during her time in the hospital with the aim of allowing her to still feel like a mother. As her condition worsened and the prospect of death became clear, the patient expressed to staff her feelings as a mother of not wishing her son to see her suffering and dying as she approached the end. It is believed that the support for the patient's feelings helped her to maintain her sense of autonomy and self-worth.

AKT plays a pivotal role in the acquisition of resistance to 5-fluorouracil in human squamous carcinoma cells.

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that inhibits the growth and initiates the apoptosis of epithelial tumors, including squamous cell carcinoma of the head and neck region. However, resistance to this drug is often observed in a clinical setting. The primary mode of action of 5-FU is believed to be the inhibition of thymidylate synthase. Overexpression of the enzymes involved in thymidine synthesis has been shown in some cases to be associated with resistance. However, the detailed mechanisms of resistance of squamous cell carcinoma are not fully understood. In the present study, we examined the involvement of survival signaling pathways in the resistance of squamous carcinoma cells to 5-FU. 5-FU induced the activation of the ERK and Akt kinases in UM-SCC-23 human squamous carcinoma cells, indicating that this anticancer drug activates survival signaling pathways as well as apoptotic signals. In 5-FU-resistant UM-SCC-23 cells established by our group, ERK and Akt signals were constitutively activated. U0126 is an inhibitor of MEK, which is an upstream activator for ERK. U0126 failed to sensitize resistant UM-SCC-23 cells to 5-FU-induced apoptotic cell death. This is in sharp contrast to LY294002, which is an inhibitor of phosphatidylinositol 3-kinase, an upstream activator for Akt. LY294002 drastically enhanced 5-FU-induced apoptotic cell death in resistant UM-SCC-23 cells. These results indicate that the Akt survival signal plays an important role in the resistance of squamous carcinoma cells to 5-FU treatment, and suggest that the modification of Akt activity might provide a new strategy for human 5-FU-resistant squamous carcinoma therapy.

[Controversial points in cochlear implantation for patients with cochlear otosclerosis].

Most cases of otosclerosis show pathological changes only around the oval window. On the other hand, it is known that cavernous changes extending to the cochlea induce progressive sensorineural deafness. Three patients with severe bilateral deafness and severe cochlear otosclerosis as diagnosed by CT underwent cochlear implantation. The postoperative hearing abilities were satisfactory in two of the three patients at one year after the operation. However, one patient with advanced otosclerosis suffered from the complication of facial nerve stimulation two months later after the cochlear implantation. His available cochlear implant electrodes gradually decreased due to the facial nerve stimulation and at last the cochlear implant was no longer beneficial for reacquisition of his hearing ability. His CT densitometry revealed marked degradation of the CT value in the cochlear basal turn circumference in comparison with that in other patients showing good courses after the cochlear implantation. In conclusion, a cochlear implant operation is valuable in patients with severe sensorineural deafness with cochlear otosclerosis. However, we should cautious in performing cochlear implantation in patients with severe demineralization of the cochlear optic capsule.

Formal synthesis of optically active ingenol via ring-closing olefin metathesis.

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma.

cis-Diaminodichloroplatinum (II) (cisplatin) is one of the most effective anticancer drugs and is widely used for the treatment of squamous cell carcinoma (SCC). However, its efficacy is often limited due to the development of resistance. Although several factors implicated in cisplatin resistance have been identified, the resistance mechanisms in detail are not fully understood yet. In the present study, we have examined the implication of survival signaling pathways in cisplatin-resistance. Cisplatin induced activation of Ras and its downstream effector kinases, Raf/MEK/ERK in UM-SCC-23 human squamous cell carcinoma, suggesting that this anticancer drug activates survival signal pathway in addition to apoptosis signals. In cisplatin-resistant UM-SCC-23 in culture, which we have established, the protein levels of Ras, Raf-1 and MEK were drastically elevated compared to parent UM-SCC-23, and ERK and Akt signals were constitutively activated. U0126, an inhibitor for MEK and LY294002, an inhibitor for phosphatidylinositol 3-kinase (PI3K), sensitized resistant UM-SCC-23 to cisplatin-induced cell death. These results indicate that Raf/MEK/ERK and PI3K/Akt signal cascades may play a considerable role in cisplatin resistance in SCC.