Photochemical Deoxygenative Hydroalkylation of Unactivated Alkenes Promoted by a Nucleophilic Organocatalyst.

The direct utilization of simple and abundant feedstocks in carbon-carbon bond-forming reactions to embellish sp3 -enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid-, alcohol-, ester-, ketone-, amide-, silane-, and boronic ester groups, as well as nitrile-containing substrates. The reaction is operationally simple, mild, and water-tolerant, and can be carried out on multigram-scale, which highlights the utility of the method to prepare value-added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T-cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.

Interaction of genetic and environmental factors for body fat mass control: observational study for lifestyle modification and genotyping.

Previous studies suggested that genetic, environmental factors and their interactions could affect body fat mass (BFM). However, studies describing these effects were performed at a single time point in a population. In this study, we investigated the interaction between genetic and environmental factors in affecting BFM and implicate the healthcare utilization of lifestyle modifications from a personalized and genomic perspective. We examined how nutritional intake or physical activity changes in the individuals affect BFM concerning the genetic composition. We conducted an observational study including 259 adult participants with single nucleotide polymorphism (SNP) genotyping and longitudinal lifestyle monitoring, including food consumption and physical activities, by following lifestyle modification guidance. The participants' lifelog data on exercise and diet were collected through a wearable device for 3 months. Moreover, we measured anthropometric and serologic markers to monitor their potential changes through lifestyle modification. We examined the influence of genetic composition on body fat reduction induced by lifestyle changes using genetic risk scores (GRSs) of three phenotypes: GRS-carbohydrate (GRS-C), GRS-fat (GRS-F), and GRS-exercise (GRS-E). Our results showed that lifestyle modifications affected BFM more significantly in the high GRS class compared to the low GRS class, indicating the role of genetic factors affecting the efficiency of the lifestyle modification-induced BFM changes. Interestingly, the influence of exercise modification in the low GRS class with active lifestyle change was lower than that in the high GRS class with inactive lifestyle change (P = 0.022), suggesting the implication of genetic factors for efficient body fat control.

Effects of Intramuscular Alfaxalone/Acepromazine on Echocardiographic, Biochemical, and Blood Gas Measurements in Healthy Cats.

The effects of intramuscular injection of alfaxalone ([ALF] 5 mg/kg), acepromazine ([ACE] 0.05 mg/kg), and an ALF-ACE combination ([AA] 0.025 mg/kg ACE followed by 2.5 mg/kg ALF) on the sedation, echocardiographic, biochemical, and blood gas indexes and recovery were evaluated in seven cats. No sedation was obtained with ACE, and sedation scores were higher with ALF than with AA treatment. Compared with baseline, an increase in heart rate occurred after ACE, and all treatments caused a decrease in systemic arterial pressure. Decreased left ventricular internal dimension in diastole, end-diastolic volume of the left ventricle, stroke volume, and left atrial dimension were identified after AA. There were minimal changes in echocardiographic variables after ALF. Biochemical and blood gas analysis showed no significant changes after all treatments. Although the difference in quality of recovery between the AA and ALF treatment groups was insignificant, all cats treated with AA or ALF showed ataxia. The AA combination did not change the recovery score, and tremor and twitching were identified more frequently with AA than ALF. ALF had no significant effects on echocardiographic, biochemical, or blood gas variables. ALF could be considered a useful sedative option for diagnostic procedures and echocardiography in cats.

Amino acid position 37 of HLA-DRß1 affects susceptibility to Crohn's disease in Asians.

Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRß1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).

C(sp3)-H amination of 8-methylquinolines with azodicarboxylates under Rh(iii) catalysis: cytotoxic evaluation of quinolin-8-ylmethanamines.

The rhodium(iii)-catalyzed C(sp3)-H amination reaction of 8-methylquinolines and azodicarboxylates is described. A cationic rhodium catalyst in the presence of lithium acetate and lithium carbonate was found to be an optimal catalytic system for the construction of quinolin-8-ylmethanamine derivatives, which were evaluated for in vitro cytotoxicity against human breast adenocarcinoma cells (MCF-7) and human prostate adenocarcinoma cells (LNCaP).

X Chromosome-wide Association Study Identifies a Susceptibility Locus for Inflammatory Bowel Disease in Koreans.

BACKGROUND AND AIMS: Genome-wide association studies of inflammatory bowel disease identified > 200 susceptibility loci only in autosomes. This study aimed to identify inflammatory bowel disease susceptibility loci on the X chromosome. METHODS: We performed an X chromosome-wide association study in Korean patients with inflammatory bowel disease. We analysed X chromosome data from our recent genome-wide association studies, including 1505 cases [922 Crohn's disease and 583 ulcerative colitis] and 4041 controls during the discovery phase, followed by replication in additional 1989 cases [993 Crohn's disease, 996 ulcerative colitis] and 3491 controls. Sex-related differential effects of single nucleotide polymorphisms on disease were also evaluated. RESULTS: We confirmed a significant association of a previously reported inflammatory bowel disease susceptibility locus at chromosome Xq26.3 [CD40LG-ARHGEF6; odds ratio, 1.22; 95% confidence interval, 1.16-1.28; combined p = 3.79 × 10-15]. This locus accounted for 0.18% and 0.12% of genetic variance in Crohn's disease and ulcerative colitis, respectively, and increased the total autosomal chromosome genetic variance from 6.65% to 6.83% and from 5.47% to 5.59% for Crohn's disease and ulcerative colitis risk, respectively, in the Korean population. Sex-stratified analyses did not reveal sex-related differences in effect sizes. CONCLUSIONS: We confirmed the association of rs2427870 at the CD40LG-ARHGEF6 locus with an inflammatory bowel disease through an X chromosome-wide association study in a Korean population. Our data suggest that the CD40LG-ARHGEF6 locus on the X chromosome might play a role in inflammatory bowel disease pathogenesis in the Korean population.

Identification of Loci at 1q21 and 16q23 That Affect Susceptibility to Inflammatory Bowel Disease in Koreans.

Recent genome-wide association studies have identified more than 200 regions that affect susceptibility to inflammatory bowel disease (IBD). However, identified common variants account for only a fraction of IBD heritability and largely have been identified in populations of European ancestry. We performed a genome-wide association study of susceptibility loci in Korean individuals, comprising a total of 1505 IBD patients and 4041 controls. We identified 2 new susceptibility loci for IBD at genome-wide significance: rs3766920 near PYGO2-SHC1 at 1q21 and rs16953946 in CDYL2 at 16q23. In addition, we confirmed associations, in Koreans, with 28 established IBD loci (P < 2.16 × 10-4). Our findings support the complementary value of genetic studies in different populations.

CPNE7, a preameloblast-derived factor, regulates odontoblastic differentiation of mesenchymal stem cells.

Tooth development involves sequential interactions between dental epithelial and mesenchymal cells. Our previous studies demonstrated that preameloblast-conditioned medium (PA-CM) induces the odontogenic differentiation of human dental pulp cells (hDPCs), and the novel protein Cpne7 in PA-CM was suggested as a candidate signaling molecule. In the present study, we investigated biological function and mechanisms of Cpne7 in regulation of odontoblast differentiation. Cpne7 was expressed in preameloblasts and secreted extracellularly during ameloblast differentiation. After secretion, Cpne7 protein was translocated to differentiating odontoblasts. In odontoblasts, Cpne7 promoted odontoblastic markers and the expression of Dspp in vitro. Cpne7 also induced odontoblast differentiation and promoted dentin/pulp-like tissue formation in hDPCs in vivo. Moreover, Cpne7 induced differentiation into odontoblasts of non-dental mesenchymal stem cells in vitro, and promoted formation of dentin-like tissues including the structure of dentinal tubules in vivo. Mechanistically, Cpne7 interacted with Nucleolin and modulated odontoblast differentiation via the control of Dspp expression. These results suggest Cpne7 is a diffusible signaling molecule that is secreted by preameloblasts, and regulates the differentiation of mesenchymal cells of dental or non-dental origin into odontoblasts.

Purification of a novel peptide derived from Mytilus coruscus and in vitro/in vivo evaluation of its bioactive properties.

Excess oxidant can promote inflammatory responses. Moreover, chronic inflammation accompanied by oxidative stress is connected various steps involved in many diseases. From the aspect, we investigated an antioxidant peptide to prevent inflammatory response against oxidant overexpression. To prepare the peptide, eight proteases were employed for enzymatic hydrolysis, and the antioxidant properties of the hydrolysates were investigated using free radical scavenging activity by electron spin resonance (ESR) spectrometry. Papain hydrolysates, which showed clearly superior free radical scavenging activity, were further purified using consecutive chromatographic methods. Finally, a novel antioxidant peptide was obtained, and the sequence was identified as Ser-Leu-Pro-Ile-Gly-Leu-Met-Ile-Ala-Met at N-terminal. Oral administration of the peptide to mice effectively inhibited malondialdehyde (MDA) levels in a thiobarbituric acid reactive substances (TBARS) assay, and we also confirmed the antioxidative enzyme activities in superoxide dismutase (SOD) and glutathione-s-transferase (GST) assays. This is the first report of an antioxidant peptide derived from the hydrolysate of Mytilus coruscus, and also these results suggest that the peptide possesses potent antioxidant activity, and potential to enhance anti-inflammatory response.

Expression pattern, subcellular localization, and functional implications of ODAM in ameloblasts, odontoblasts, osteoblasts, and various cancer cells.

During tooth development and tumorigenesis, the odontogenic ameloblast-associated protein (ODAM) is involved in cellular differentiation and matrix protein production. However, the precise function of ODAM remains largely unknown. To suggest new functional roles of ODAM, we investigated the cellular expression and subcellular localization of ODAM in tooth and cancer cells. ODAM was expressed in ameloblasts, odontoblasts, and osteoblasts in vivo and in vitro. Furthermore, ODAM was localized in both the nucleus and cytoplasm of MMP-20 expressing ameloblasts and odontoblasts, but only in the cytoplasm of non-MMP-20 expressing osteoblasts. The extracellular secretion of ODAM was not observed in odontoblasts and osteoblasts, but was seen in ameloblasts. In addition, ODAM was discovered in the nucleus, cytoplasm, and extracellular matrix of various cancer cells. These results suggest that the expression pattern and subcellular localization of ODAM is highly variable and dependent on cell types and their differentiation states, and that functional correlations exist between ODAM and MMP-20. This study provides the first evidence for ODAM in multiple cellular compartments of differentiating odontogenic and cancer cell lines with important functional implications.

Let-7 microRNA inhibits the proliferation of human glioblastoma cells.

MicroRNAs (miRNAs) are small noncoding RNAs comprising 21-23 nucleotides that regulate gene expression by transcriptionally repressing their complementary mRNAs. In particular, let-7 miRNA has been postulated to function as a tumor suppressor in various cancer cells, but not yet in glioblastoma. In this study, we investigated the anti-tumorigenic effect of let-7 miRNA in glioblastoma cells. Human glioblastoma cells (U251 or U87 cells) were transfected with let-7 miRNA and assayed for in-vitro proliferation, migration, and in-vivo tumor formation. Transfection of let-7 miRNA reduced expression of pan-RAS, N-RAS, and K-RAS in the glioblastoma cells. Let-7 miRNA also reduced the in-vitro proliferation and migration of the cells, and reduced the sizes of the tumors produced after transplantation into nude mice. However, let-7 miRNA exerted no effect on the proliferation of normal human astrocytes. These results indicate that let-7 miRNA has an anti-tumorigenic effect on glioblastoma cells, and suggest possible use of let-7 miRNA for treating glioblastoma.

A crucial role of WW45 in developing epithelial tissues in the mouse.

The role and molecular mechanisms of a new Hippo signalling pathway are not fully understood in mammals. Here, we generated mice that lack WW45 and revealed a crucial role for WW45 in cell-cycle exit and epithelial terminal differentiation. Many organs in the mutant mouse embryos displayed hyperplasia accompanied by defects in terminal differentiation of epithelial progenitor cells owing to impaired proliferation arrest rather than intrinsic acceleration of proliferation during differentiation. Importantly, the MST1 signalling pathway is specifically activated in differentiating epithelial cells. Moreover, WW45 is required for MST1 activation and translocation to the nucleus for subsequent LATS1/2 activation upon differentiation signal. LATS1/2 phosphorylates YAP, which, in turn, translocates from the nucleus into the cytoplasm, resulting in cell-cycle exit and terminal differentiation of epithelial progenitor cells. Collectively, these data provide compelling evidence that WW45 is a key mediator of MST1 signalling in the coordinate coupling of proliferation arrest with terminal differentiation for proper epithelial tissue development in mammals.

[Effects of hand massage and hand holding on the anxiety in patients with local infiltration anesthesia].

PURPOSE: This study was to examine the effects of hand massage and hand holding as nursing interventions on the anxiety in patients with local infiltration anesthesia. METHOD: The design of this study was a nonequivalent, control group, non- synchronized design. The subjects of this study consisted of 15 patients for the hand group, 15 patients for the hand holding group and 17 patients for the control group awaiting surgery in the operation room of a general hospital in Daegu. As an experimental treatment, hand massage was carried out by the Hand Massage Protocol developed by Snyder (1995) and interpreted by Cho (1998) and hand holding developed by Cho (1998). The data were analyzed by SPSS/WIN, T-test, ANOVA, Cronbach's alpha, and the Scheffe test. RESULTS: The hand massage group and hand holding group were more effective than the control group in reducing anxiety, VAS score, systolic blood pressure and pulse rate. CONCLUSION: Hand massage and hand holding are effective nursing interventions that alleviates the psychological and physiological anxiety of patients with local infiltration anesthesia. In particular, the simple contact of hand holding is regarded as an effective and easily accessible nursing intervention in the operating room.