Palladium-Catalyzed Construction of Quaternary Stereocenters by Enantioselective Arylation of γ-Lactams with Aryl Chlorides and Bromides.

Herein, we report the first Pd-catalyzed enantioselective arylation of α-substituted γ-lactams. Two sets of conditions were developed for this transformation, allowing for the use of either aryl chlorides or bromides as electrophiles. Utilizing a highly electron-rich dialkylphosphine ligand we have been able to construct α-quaternary centers in good yields (up to 91 % yield) and high enantioselectivities (up to 97 % ee).

A surface glycoprotein indispensable for gamete fusion in the social amoeba Dictyostelium discoideum.

Sexual reproduction is essential for the maintenance of species in a wide variety of multicellular organisms, and even unicellular organisms that normally proliferate asexually possess a sexual cycle because of its contribution to increased genetic diversity. Information concerning the molecules involved in fertilization is accumulating for many species of the metazoan, plant, and fungal lineages, and the evolutionary consideration of sexual reproduction systems is now an interesting issue. Macrocyst formation in the social amoeba Dictyostelium discoideum is a sexual process in which cells become sexually mature under dark and submerged conditions and fuse with complementary mating-type cells. In the present study, we isolated D. discoideum insertional mutants defective in sexual cell fusion and identified the relevant gene, macA, which encodes a highly glycosylated, 2,041-amino-acid membrane protein (MacA). Although its overall similarity is restricted to proteins of unknown function within dictyostelids, it contains LamGL and discoidin domains, which are implicated in cell adhesion. The growth and development of macA-null mutants were indistinguishable from those of the parental strain. The overexpression of macA using the V18 promoter in a macA-null mutant completely restored its sexual defects. Although the macA gene encoded exactly the same protein in a complementary mating-type strain, it was expressed at a much lower level. These results suggest that MacA is indispensable for gamete interactions in D. discoideum, probably via cell adhesion. There is a possibility that it is controlled in a mating-type-dependent manner.

Essential motion of metacarpophalangeal joints during activities of daily living.

STUDY DESIGN: Bench research. INTRODUCTION: Although information on the range of motion (ROM) required to perform activities is important when setting ROM goals to enable patients to engage in them, there are few studies reporting the required ROM of fingers. PURPOSE OF THE STUDY: To analyze the range of joint motion required of the finger MCP joint to perform activities and to compare the maximum flexion and maximum extension angle required of the finger MCP joints in the individual fingers. METHODS: We used an electrogoniometer to measure the ROM of four finger MCP joints in the dominant hand in healthy adults (n = 20) performing 19 activities. Finger MCP joint angles were analyzed throughout each of the 19 tasks. RESULTS: The mean ROM of finger MCP joints of the index, middle, ring, and little fingers required to perform all 19 activities ranged from -10 to 60°, -10 to 75°, -10 to 80°, and -10 to 85°, respectively. The mean maximum flexion angle of the finger MCP joints gradually increased as the finger MCP joints were compared moving from the radial to the ulnar side. CONCLUSION: The data obtained in this study on MCP joint motions that are required to perform activities may be beneficial in setting ROM goals for patients with finger MCP joint impairment. LEVEL OF EVIDENCE: NA.

A scalable synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole ((S)-t-BuPyOx) ligand.

An efficient method for the synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole ((S)-t-BuPyOx) ligand has been developed. Inconsistent yields and tedious purification in known routes to (S)-t-BuPyOx suggested the need for an efficient, dependable, and scalable synthetic route. Furthermore, a route suitable for the synthesis of PyOx derivatives is desirable. Herein, we describe the development of a three-step route from inexpensive and commercially available picolinic acid. This short procedure is amenable to multi-gram scale synthesis and provides the target ligand in 64% overall yield.

Limited influence of aspirin intake on mast cell activation in patients with food-dependent exercise-induced anaphylaxis: comparison using skin prick and histamine release tests.

Food-dependent exercise-induced anaphylaxis (FDEIA) is a severe systemic syndrome induced by physical exercise after ingesting causative food. Aspirin is a well-known trigger for anaphylaxis in patients with FDEIA. Possible mechanisms by which symptoms are aggravated by aspirin include enhanced antigen absorption and mast cell activation. The aim of this study was to determine whether aspirin intake has an influence on mast cell/basophil activation in patients with FDEIA. Provocation tests revealed that adding aspirin to the causative food challenge in 7 of 9 (77.8%) patients with FDEIA provoked symptoms. In most cases, pretreatment with aspirin did not enhance skin tests (71.4%) or histamine release tests (88.9%) with food allergen challenges. The study confirms that histamine release and skin prick tests can be adjunctive tools for diagnosing FDEIA. In addition, our results suggest that exacerbation of FDEIA symptoms by aspirin is not mediated by direct effects of aspirin on mast cell/basophil activation.

Dysfunction of melanocytes in photoleukomelanoderma following photosensitivity caused by hydrochlorothiazide.

We report a 68-year-old Japanese man who developed photoleukomelanoderma following prolonged photosensitivity caused by hydrochlorothiazide. He showed complete recovery from the leukomelanoderma with the discontinuation of the responsive drug and with topical application of tacrolimus hydrate and corticosteroid. Histological and immunohistochemical examination revealed that there were no melanin-positive cells in the hypopigmented area, despite the presence of melanocytes. These results and the clinical course indicate that leukomelanoderma is postulated temporary dysfunction of melanocytes. We also conducted a review of previous case reports regarding drug-induced photoleukomelanoderma.

siRNA-based therapy ameliorates glomerulonephritis.

RNA interference by short interfering RNAs (siRNAs) holds promise as a therapeutic strategy, but use of siRNAs in vivo remains limited. Here, we developed a system to target delivery of siRNAs to glomeruli via poly(ethylene glycol)-poly(l-lysine)-based vehicles. The siRNA/nanocarrier complex was approximately 10 to 20 nm in diameter, a size that would allow it to move across the fenestrated endothelium to access to the mesangium. After intraperitoneal injection of fluorescence-labeled siRNA/nanocarrier complexes, we detected siRNAs in the blood circulation for a prolonged time. Repeated intraperitoneal administration of a mitogen-activated protein kinase 1 (MAPK1) siRNA/nanocarrier complex suppressed glomerular MAPK1 mRNA and protein expression in a mouse model of glomerulonephritis; this improved kidney function, reduced proteinuria, and ameliorated glomerular sclerosis. Furthermore, this therapy reduced the expression of the profibrotic markers TGF-beta1, plasminogen activator inhibitor-1, and fibronectin. In conclusion, we successfully silenced intraglomerular genes with siRNA using nanocarriers. This technique could aid the investigation of molecular mechanisms of renal disease and has potential as a molecular therapy of glomerular diseases.

Basal cell carcinoma developed from an epidermal cyst: A case report and review of the literature.

Cutaneous epidermal cysts are common benign cysts derived from the epidermis or epithelium of hair follicles, and malignancy originating from epidermal cysts is uncommon. When a cutaneous epidermal cyst turns malignant, it is mostly squamous cell carcinoma, and basal cell carcinoma is rare. We present the case of a 58-year-old man with basal cell carcinoma originating from an epidermal cyst on the buttocks. Histopathological analysis with hematoxylin- eosin (H&E) staining showed the presence of the cyst, the wall of which was partially replaced by a malignant tumor. Moreover, the cyst was filled with malignant tumor cells in some areas. The tumor cells were basaloid, and extended through the dermis down to the subcutaneous tissue in a solid pattern. Immunoperoxidase staining for Ber-EP4 was positive. To our knowledge, there are 11 reported cases of BCC originating from epidermal cysts in English, and we reviewed these reports and examined potential trends. We estimate that some longstanding epidermal cysts may have the potential of malignant transformation, and chronic and repeated irritation might trigger malignancy from epidermal cysts. We emphasize that benignlooking cystic lesions showing progressive growth should be examined histopathologically.

Event-related potentials for gender discrimination: an examination between differences in gender discrimination between males and females.

The event-related potentials (ERP) following presentation of male and female faces were investigated to study differences in the gender discrimination process. Visual stimuli from four categories including male and female faces were presented. For the male subjects, the P220 amplitude of the T5 area following viewing of a female face was significantly larger than that following viewing of a male face. On the other hand for female subjects, the P170 amplitude of the Cz area following observation of a male face was larger than that for a female face. The results indicate that the neural processes, including responsive brain areas used for gender discrimination by observing faces, are different between males and females.

Effects of temperature, pH and curing on the viability of Sarcocystis, a Japanese sika deer (Cervus Nippon centralis) parasite, and the inactivation of their diarrheal toxin.

Recently, the Sarcocystis parasite in horse and deer meat has been reported to be a causative agent of acute food poisoning, inducing nausea, vomiting and diarrhea. Compared with other causative agents, such as bacteria, viruses and other parasites, in deer meat, the Sarcocystis species parasite, including its stability under various conditions, is poorly understood. In this study, we assessed the viability of Sarcocystis spp. and the activity of their diarrhea toxin (a 15-kDa protein) in deer meat under conditions of freezing, cold storage, pH change and curing. In addition, the heat tolerance was assayed using purified bradyzoites. The results showed that the species lost viability by freezing at -20, -30 and -80°C for <1 hr, heating at 70°C for 1 min, alkaline treatment (pH 10.0) for 4 days and addition of salt at 2.0% for <1 day. Immunoblot assays showed that the diarrhea toxin disappeared together with the loss of viability. However, the parasite survived cooling at 0 and 4°C and acidification (pH 3.0 and 5.0) for more than 7 days with the diarrhea toxin intact. These results provide useful information for developing practical applications for the prevention of food poisoning induced by diarrheal toxin of Sarcocystis spp. in deer meat during cooking and preservation.

Effects of central injection of angiotensin-converting-enzyme inhibitor and angiotensin type 1 receptor antagonist on the brain NF-kappaB and AP-1 activities of rats given LPS.

Angiotensin II (ANG II) activation of the angiotensin type 1 (AT1) receptor facilitates the production of brain interleukin-1beta (IL-1beta) and contributes to the induction of the fever following the intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS). The purpose of the present study was to investigate whether proinflammatory transcription factors [nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1)] contribute to the ANG II-dependent production of cytokines within the brain. Interestingly, we found that a single i.c.v. injection of LPS had no effect on NF-kappaB and AP-1 activities in the hypothalamus, hippocampus, and cerebellum at either 1 or 3 h post-injection (except for a decrease in hypothalamic AP-1 activity at 1 h). Furthermore, both an angiotensin-converting-enzyme (ACE) inhibitor and an AT1 receptor antagonist enhanced (rather than reduced) the NF-kappaB and AP-1 activities in the hippocampus and/or cerebellum of rats given LPS. In contrast, an i.c.v. injection of ANG II increased the NF-kappaB activity in the hypothalamus. These results suggest that while "endogenous" ANG II exerts (via AT1 receptors) inhibitory effects on the activation of transcription factors in the brain of rats given LPS, a large dose of exogenous ANG II produces effects opposite to those induced by the presumably small amount of endogenous ANG II released locally by LPS. Our results seem not to support the idea that NF-kappaB and AP-1 play key roles in the ANG II-induced enhancement of the production of proinflammatory cytokines that is induced by LPS in the rat's brain.

Endothelin(B) receptor blocker inhibits high glucose-induced synthesis of fibronectin in human peritoneal mesothelial cells.

BACKGROUND: Long-term peritoneal dialysis using glucose-based dialysates is associated with peritoneal fibrosis. The object of this study was to investigate the hypothesis that endothelin (ET)-1, which is known to play an important role in various fibrotic diseases, may also be involved in peritoneal fibrosis using human peritoneal mesothelial cells (HPMC). METHODS: HPMC were cultured with 4% D- or L-glucose, or loaded with 10 nmol/L ET-1. In some experiments, the ETA receptor antagonist BQ-123, the ETB receptor antagonist BQ-788, and antioxidants 4-hydroxy-2,2,6,6-tetramethyl-piperidine 1-oxyl (TEMPOL) and diphenyleneiodium chloride (DPI) were used. mRNA expression of ET-1, ETA receptor, ETB receptor, and fibronectin (FN) was analyzed by real-time polymerase chain reaction (real-time PCR). The protein levels for FN and ET-1 were measured by ELISA. CM-H2DCFDA-sensitive reactive oxygen species (ROS) were evaluated by flow cytometry. RESULTS: D-Glucose significantly induced mRNA expression of ET-1 and the ETB receptor but not the ETA receptor. FN production under high glucose conditions was inhibited by BQ-788. ET-1 directly stimulated H PMC to increase mRNA expression of FN and CM-H2DCFDA-sensitive ROS production. BQ-788, TEMPOL, and DPI inhibited mRNA expression of FN induced by ET-1. CONCLUSION: The present study suggests that high-glucose-induced FN synthesis is mediated by the ET-1/ETB receptor pathway and, therefore, an ETB receptor antagonist may be usefulin preventing FN production in HPMC.

Characteristics of processing for trait adjectives in depressive persons: an event-related potential study.

Event-related potentials (ERP) following emotive words were investigated in 22 healthy subjects with high (HD) or low (LD) depressive scores. The ERP was recorded following a visual presentation of emotive adjectives. The adjectives presented included words that subjects felt to be fit or unfit to their own character or traits, and that they perceived as positive or negative. The latency of P300 (P1) for negative words was significantly longer than that for positive words at Pz in HD subjects. The N400 (N1) in HD subjects showed a longer latency than that in LD subjects (p<0.01) at Cz and Pz. However, there was no difference in amplitude between the fit and unfit category, nor in the positive or negative category of words between the LD and HD groups. The present study suggests that an excessive level of cognitive processing in response to passive stimulation by non-specific emotive words occurs in normal subjects with a depressive condition.

Cognitive mechanism for meaning of emotive words in depressed personality: an event-related potential study.

We investigated the relationship between the ERP modulation of emotive words and the depression score in thirty-five healthy subjects with both high and low Beck Depression Inventory scores. The event-related evoked potentials (ERP) were measured following a visual presentation of emotive adjectives. Each word was classified into two sets of categories by each subject, i.e., positive or negative, and fit or unfit to his/her personality. The ERP signals were then separately averaged according to the subject's classifications. After stimulation, positive and negative ERP components at 200 ms (P2) and 400 ms (N2), respectively, were enhanced in amplitude in subjects with a high depression score. The enhancement of the P2 and N2 components was not related to the subject's categorization of the words. The results suggest that hypersensitivity to non-specific emotive words might be a neurophysiological phenomenon in a depressive state in healthy subjects.