MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.

DNA double-strand break (DSB) repair via homologous recombination is initiated by end resection. The extent of DNA end resection determines the choice of the DSB repair pathway. Nucleases for end resection have been extensively studied. However, it is still unclear how the potential DNA structures generated by the initial short resection by MRE11-RAD50-NBS1 are recognized and recruit proteins, such as EXO1, to DSB sites to facilitate long-range resection. We found that the MSH2-MSH3 mismatch repair complex is recruited to DSB sites through interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 facilitates the recruitment of EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 also inhibits access of POLθ, which promotes polymerase theta-mediated end-joining (TMEJ). Collectively, we present a direct role of MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing the DSB repair pathway by favoring homologous recombination over TMEJ.

Roles of Human Gut Microbiota in Liver Cirrhosis Risk: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Accumulating evidence suggests that alterations in gut microbiota composition and diversity are associated with liver cirrhosis. But whether gut microbiota promotes or hampers the genesis and development of liver cirrhosis remains vague. OBJECTIVES: This study aimed to establish a causal relationship between gut microbiota and the development of liver fibrosis and cirrhosis. To achieve this, we employed a 2-sample Mendelian randomization (MR) analysis utilizing genome-wide association study (GWAS) summary statistics. This approach enabled us to assess the potential impact of gut microbiota on liver cirrhosis. METHODS: The independent genetic instruments of gut microbiota were obtained from the MiBioGen (up to 18,340 participants), which is a large-scale genome-wide genotype and 16S fecal microbiome dataset. Cirrhosis data were derived from the FinnGen biobank analysis, which included 214,403 individuals of European ancestry (811 patients and 213,592 controls). To assess the causal relationship between gut microbiota and cirrhosis, we applied 4 different methods of MR analysis: the inverse-variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WME), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. RESULTS: Results of MR analyses provided evidence of a causal association between 4 microbiota features and cirrhosis, including 2 family [Lachnosiraceae: odds ratio (OR): 1.82626178; 95% confidence interval (CI): 1.05208209, 3.17012532; P = 0.0323194; Lactobacillaceae : OR: 0.62897502; 95% CI: 0.42513162, 0.93055788; P = 0.02033345] and 2 genus [Butyricicoccus: OR: 0.41432215; 95% CI: 0.22716865, 0.75566257; P = 0.0040564; Lactobacillus: OR: 0.6663767; 95% CI: 0.45679511, 0.97211616; P = 0.03513627]. CONCLUSIONS: Our findings offered compelling evidence of a causal association between gut microbiota and cirrhosis in European population and identified specific bacteria taxa that may regulate the genesis and progression of liver fibrosis and cirrhosis, may offer a new direction for the treatment of cirrhosis.

Age-Related Gut Microbiota Transplantation Disrupts Myocardial Energy Homeostasis and Induces Oxidative Damage.

BACKGROUND: Aging-related energy homeostasis significantly affects normal heart function and disease development. The relationship between the gut microbiota and host energy metabolism has been well established. However, the influence of an aged microbiota on energy metabolism in the heart remains unclear. OBJECTIVE: The objective of this was to explore the effects of age-related microbiota composition on energy metabolism in the heart. METHODS: In this study, we used the fecal microbiota transplantation (FMT) method. The fecal microbiota from young (2-3 mo) and aged (18-22 mo) donor mice were transplanted into separate groups of young (2-3 mo) recipient mice. The analysis utilized whole 16S rRNA sequencing and plasma metabolomics to assess changes in the gut microbiota composition and metabolic potential. Energy changes were monitored by performing an oral glucose tolerance test, biochemical testing, body composition analysis, and metabolic cage measurements. Metabolic markers and markers of DNA damage were assessed in heart samples. RESULTS: FMT of an aged microbiota changed the composition of the recipient's gut microbiota, leading to an elevated Firmicutes-to-Bacteroidetes ratio. It also affected overall energy metabolism, resulting in elevated plasma glucose concentrations, impaired glucose tolerance, and epididymal fat accumulation. Notably, FMT of an aged microbiota increased the heart weight and promoted cardiac hypertrophy. Furthermore, there were significant associations between heart weight and cardiac hypertrophy indicators, epididymal fat weight, and fasting glucose concentrations. Mechanistically, FMT of an aged microbiota modulated the glucose metabolic pathway and induced myocardial oxidative damage. CONCLUSIONS: Our findings suggested that an aged microbiota can modulate metabolism and induce cardiac injury. This highlights the possible role of the gut microbiota in age-related metabolic disorders and cardiac dysfunction.

A Raf-like kinase is required for smoke-induced seed dormancy in Arabidopsis thaliana.

Plants sense and integrate diverse stimuli to determine the timing for germination. A smoke compound, 3,4,5-trimethylfuran-2(5H)-one (trimethylbutenolide, TMB), has been identified to inhibit the seed germination of higher plants. To understand the mode of action, we examined various physiological and molecular aspects of the TMB-dependent inhibition of seed germination in Arabidopsis thaliana The results indicated that the effect of TMB is due to the enhanced physiological dormancy, which is modulated by other dormancy regulatory cues such as after-ripening, stratification, and ABA/GA signaling. In addition, gene expression profiling showed that TMB caused genome-wide transcriptional changes, altering the expression of a series of dormancy-related genes. Based on the TMB-responsive physiological contexts in Arabidopsis, we performed mutant screening to isolate genetic components that underpin the TMB-induced seed dormancy. As a result, the TMB-RESISTANT1 (TES1) gene in Arabidopsis, encoding a B2 group Raf-like kinase, was identified. Phenotypic analysis of the tes1 mutant implicated that TES1 has a critical role in the TMB-responsive gene expression and the inhibition of seed germination. Taken together, we propose that plants have been equipped with a TMB sensory pathway through which the TMB induces the seed dormancy in a TES1-dependent way.

Eight-year trajectories and predictors of cognitive function in community-dwelling Korean older adults with cardiovascular diseases.

PURPOSE: This study aims to identify longitudinal patterns and predictors of cognitive function trajectories among Korean older adults with cardiovascular diseases. DESIGN: This study is a longitudinal panel analysis based on secondary data. Data from the the Korean Longitudinal Study of Ageing (KLoSA) were used for analysis. METHODS: The KLoSA is a representative panel survey of older Koreans. We analyzed responses from 301 participants aged ≥65 years who completed the same survey more than three times out of five waves between 2012 and 2020. FINDINGS: Latent class growth modeling identified two trajectories of cognitive function in older people with cardiovascular diseases: "low and declining" (n = 81, 26.9%) and "high and declining" (n = 220, 73.1%). Participants in "the low and declining trajectory group" were more likely to have a low educational level, weak handgrip strength, depression, and low social participation at baseline than those in "the high and declining trajectory group." CONCLUSIONS: Our results indicate a need to develop community-based tailored interventions for improving handgrip strength, mental health, and social participation in delaying cognitive decline in older people with cardiovascular diseases considering their educational level. CLINICAL RELEVANCE: Healthcare providers should be more concerned about older people with a weaker handgrip, depression, and low social activities as a high-risk group for cognitive decline over time in cardiovascular care. Therefore, it is necessary to evaluate them early with standardized tools and make subsequent strategies for the older population with cardiovascular diseases.

In Addition to Stigma: Cognitive and Autism-Related Predictors of Mental Health in Transgender Adolescents.

OBJECTIVE: Autism spectrum disorder (ASD) is significantly over-represented among transgender adolescents. Independently, ASD and gender diversity are associated with increased mental health risks. Yet, mental health in autistic-transgender adolescents is poorly understood. This study investigates mental health in the largest matched sample to date of autistic-transgender, non-autistic (allistic) transgender, and autistic-cisgender adolescents diagnosed using gold-standard ASD diagnostic procedures. In accordance with advancing understanding of sex/gender-related autism phenotypes, slightly subthreshold autistic diagnostic presentations (common in autistic girls/women) are modeled. METHOD: This study includes 93 adolescents aged 13-21, evenly divided between autistic-transgender, autistic-cisgender, and allistic-transgender groups; 13 transgender adolescents were at the margin of ASD diagnosis and included within a larger "broad-ASD" grouping. Psychological and neuropsychological evaluation included assessment of mental health, IQ, LGBT stigma, ASD-related social symptoms, executive functioning (EF), and EF-related barriers to achieving gender-related needs. RESULTS: Autistic-transgender adolescents experienced significantly greater internalizing symptoms compared to allistic-transgender and autistic-cisgender groups. In addition to stigma-related associations with mental health, ASD-related cognitive/neurodevelopmental factors (i.e., poorer EF and greater social symptoms) were associated with worse mental health: specifically, social symptoms and EF gender barriers with greater internalizing and EF problems and EF gender barriers with greater suicidality. Comparing across all ASD and gender-related groups, female gender identity was associated with greater suicidality. CONCLUSIONS: Parsing the heterogeneity of mental health risks among transgender youth is critical for developing targeted assessments and interventions. This study identifies ASD diagnosis, ASD phenotypic characteristics, and EF-related gender barriers as potential risks for poorer mental health in transgender adolescents.

Longitudinal patterns and predictors of self-care behavior trajectories among Korean patients with heart failure: A 6-month prospective study.

PURPOSE: This study aimed to identify distinct trajectories of self-care behaviors over 6 months after hospital discharge in patients with heart failure, including the baseline predictors affecting these trajectories. DESIGN: This was a prospective longitudinal observational cohort study with a 6-month follow-up. METHODS: A total of 158 patients with heart failure (mean age = 66.75 years, 62.7% men) were included in this study. Patients' characteristics, including cognitive function, health literacy, and social support were collected as possible baseline predictors of self-care behavior trajectories using a structured questionnaire and an electronic medical record review. Self-care behaviors were evaluated using the Korean version of the nine-item European Heart Failure Self-care Behavior Scale at baseline, 1, 3, and 6 months after hospital discharge. Latent growth model analysis was conducted to identify the homogeneous subgroups with distinct trajectories of self-care behaviors. Subsequently, multinomial logistic regression was used to assess whether baseline predictors were associated with these trajectories in patients with heart failure. RESULTS: Three distinct self-care behavior trajectory groups were identified: "low-decreased" (n = 33, 20.9%), "middle-increased" (n = 93, 58.9%), and "high-sustained" (n = 32, 20.2%). The multinomial logistic regression analysis showed that baseline adequate health literacy and positive social support significantly predicted patients' belonging to both the middle-increased and high-sustained self-care behavior trajectory groups compared to the low-decreased group. Importantly, better cognitive function at baseline was only significantly associated with the high-sustained self-care behavior trajectory compared to the low-decreased trajectory. CONCLUSION: Our study revealed that only one-fifth of the patients belonged to the high-sustained self-care behavior group 6 months after hospital discharge. Strategies aimed at improving cognitive function, health literacy, and social support should be developed to sustain satisfactory self-care behaviors in patients with heart failure. Further studies with long-term follow-ups are required to identify other possible factors, as well as the baseline predictors of this study affecting longitudinal trajectories of self-care behaviors. CLINICAL RELEVANCE: Healthcare providers should recognize and evaluate the distinct patterns of self-care behaviors over time in patients with heart failure. Importantly, assessing baseline cognitive function, health literacy, and social support before hospital discharge may be necessary to prevent a decline in self-care behaviors over time.

Inflammatory molecular endotypes of nasal polyps derived from White and Japanese populations.

BACKGROUND: Emerging evidence suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with disparate inflammatory characteristics between different racial groups and geographies. Currently, little is known about possible underlying distinguishing factors between these inflammatory differences. OBJECTIVE: Our aim was to interrogate differences in CRSwNP disease between White/non-Asian patients and Japanese patients by using whole transcriptome and single-cell RNA gene expression profiling of nasal polyps (NPs). METHODS: We performed whole transcriptome RNA sequencing with endotype stratification of NPs from 8 White patients (residing in the United States) and 9 Japanese patients (residing in Japan). Reproducibility was confirmed by quantitative PCR in an independent validation set of 46 White and 31 Japanese patients. Single-cell RNA sequencing (scRNAseq) was used to stratify key cell types for contributory transcriptional signatures. RESULTS: Unsupervised clustering analysis identified 2 major endotypes that were present within both cohorts of patients with NPs and had previously been reported at the cytokine level: (1) type 2 endotype and (2) non-type 2 endotype. Importantly, there was a statistically significant difference in the proportion of these endotypes between these geographically distinct subgroups with NPs (P = .03). Droplet-based single-cell RNA sequencing further identified prominent type 2 inflammatory transcript expression: C-C motif chemokine ligand 13 (CCL13) and CCL18 in M2 macrophages, as well as cystatin SN (CST1) and CCL26 in basal, suprabasal, and secretory epithelial cells. CONCLUSION: NPs from both racial groups harbor the same 2 major endotypes, which we have determined to be present in differing ratios between each cohort with CRSwNP disease. Distinct inflammatory and epithelial cells contribute to the type 2 inflammatory profiles observed.

A Pilot Study of Autonomic Function Screening Tests for Differentiating Complex Regional Pain Syndrome Type II and Traumatic Neuropathic Pain.

Background and Objectives: One of the most challenging tasks in a clinical setting is to differentiate between complex regional pain syndrome (CRPS) type II and traumatic neuropathic pain (NeP). CRPS is characterized by several dysautonomic manifestations, such as edema, hyper/hypohidrosis, skin color change, and tachycardia. This study compared the outcomes of autonomic function screening tests in patients with CRPS type II and traumatic NeP for diagnostic differentiation. Materials and Methods: CRPS type II was diagnosed according to the Budapest research criteria, while NeP was diagnosed according to the updated grading system suggested by the International Association for the Study of Pain Special Interest Group on Neuropathic Pain in 2016. Twenty patients with CRPS type II and twenty-five with traumatic NeP were investigated. Results: Twelve patients with CRPS type II presented abnormal results for the quantitative sudomotor axon reflex test (QSART). Abnormal QSART results were more common in the CRPS type II group. Conclusions: Analysis of QSART combined with other ancillary tests can help in the differential diagnosis of CRPS type II and traumatic NeP if factors influencing abnormal QSART are sufficiently controlled.

Site-Selective C8-Alkylation of Quinoline N-Oxides with Maleimides under Rh(III) Catalysis.

The site-selective modification of quinolines and their analogs has emerged as a pivotal topic in medicinal chemistry and drug discovery. Herein, we describe the rhodium(III)-catalyzed C8-alkylation of quinoline N-oxides with maleimides as alkylating agents, resulting in the formation of bioactive succinimide-containing quinoline derivatives. The reaction proceeds under mild conditions with complete functional group tolerance.

Application of deep learning to the diagnosis of cervical lymph node metastasis from thyroid cancer with CT: external validation and clinical utility for resident training.

PURPOSE: This study aimed to validate a deep learning model's diagnostic performance in using computed tomography (CT) to diagnose cervical lymph node metastasis (LNM) from thyroid cancer in a large clinical cohort and to evaluate the model's clinical utility for resident training. METHODS: The performance of eight deep learning models was validated using 3838 axial CT images from 698 consecutive patients with thyroid cancer who underwent preoperative CT imaging between January and August 2018 (3606 and 232 images from benign and malignant lymph nodes, respectively). Six trainees viewed the same patient images (n = 242), and their diagnostic performance and confidence level (5-point scale) were assessed before and after computer-aided diagnosis (CAD) was included. RESULTS: The overall area under the receiver operating characteristics (AUROC) of the eight deep learning algorithms was 0.846 (range 0.784-0.884). The best performing model was Xception, with an AUROC of 0.884. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of Xception were 82.8%, 80.2%, 83.0%, 83.0%, and 80.2%, respectively. After introducing the CAD system, underperforming trainees received more help from artificial intelligence than the higher performing trainees (p = 0.046), and overall confidence levels significantly increased from 3.90 to 4.30 (p < 0.001). CONCLUSION: The deep learning-based CAD system used in this study for CT diagnosis of cervical LNM from thyroid cancer was clinically validated with an AUROC of 0.884. This approach may serve as a training tool to help resident physicians to gain confidence in diagnosis. KEY POINTS: • A deep learning-based CAD system for CT diagnosis of cervical LNM from thyroid cancer was validated using data from a clinical cohort. The AUROC for the eight tested algorithms ranged from 0.784 to 0.884. • Of the eight models, the Xception algorithm was the best performing model for the external validation dataset with 0.884 AUROC. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 82.8%, 80.2%, 83.0%, 83.0%, and 80.2%, respectively. • The CAD system exhibited potential to improve diagnostic specificity and accuracy in underperforming trainees (3 of 6 trainees, 50.0%). This approach may have clinical utility as a training tool to help trainees to gain confidence in diagnoses.

CoMnO2-Decorated Polyimide-Based Carbon Fiber Electrodes for Wire-Type Asymmetric Supercapacitor Applications.

In this work, we report the carbon fiber-based wire-type asymmetric supercapacitors (ASCs). The highly conductive carbon fibers were prepared by the carbonized and graphitized process using the polyimide (PI) as a carbon fiber precursor. To assemble the ASC device, the CoMnO2-coated and Fe2O3-coated carbon fibers were used as the cathode and the anode materials, respectively. Herein, the nanostructured CoMnO2 were directly deposited onto carbon fibers by a chemical oxidation route without high temperature treatment in presence of ammonium persulfate (APS) as an oxidizing agent. FE-SEM analysis confirmed that the CoMnO2-coated carbon fiber electrode exhibited the porous hierarchical interconnected nanosheet structures, depending on the added amount of APS, and Fe2O3-coated carbon fiber electrode showed a uniform distribution of porous Fe2O3 nanorods over the surface of carbon fibers. The electrochemical properties of the CoMnO2-coated carbon fiber with the concentration of 6 mmol APS presented the enhanced electrochemical activity, probably due to its porous morphologies and good conductivity. Further, to reduce the interfacial contact resistance as well as improve the adhesion between transition metal nanostructures and carbon fibers, the carbon fibers were pre-coated with the Ni layer as a seed layer using an electrochemical deposition method. The fabricated ASC device delivered a specific capacitance of 221 F g-1 at 0.7 A g-1 and good rate capability of 34.8% at 4.9 A g-1. Moreover, the wire-type device displayed the superior energy density of 60.2 Wh kg-1 at a power density of 490 W kg-1 and excellent capacitance retention of 95% up to 3000 charge/discharge cycles.

The action of low doses of persistent organic pollutants (POPs) on mitochondrial function in zebrafish eyes and comparison with hyperglycemia to identify a link between POPs and diabetes.

Type 2 diabetes (T2D) is characterized by defects in insulin action to target tissues, resulting in hyperglycemia, insulin resistance, and mitochondrial dysfunction. The eye is one of the organs susceptible to T2D, but knowledge regarding mitochondrial dysfunction in the eyes after hyperglycemia and T2D is based mainly on epidemiological evidence, with little experimental data. Persistent organic pollutants (POPs) are known as endocrine-disrupting chemicals and are associated with uncontrolled glucose and lipid metabolism, leading to the onset of diabetes. To determine the relationship between POPs and T2D, two model systems were developed: glucose-immersed zebrafish to induce hyperglycemia, and zebrafish exposed to low-dose POPs in a water circulating system for three months. To examine the role of mitochondrial function, the activity of mitochondrial complexes I, II, III, and IV from the eyes of the two zebrafish models was measured spectrophotometrically. Enhanced enzymatic activities of mitochondrial complexes III and IV were observed in the eyes of both hyperglycemia and low-dose POPs exposed models, especially in male zebrafish. These results demonstrate that POPs alleviate mitochondrial oxidative phosphorylation (OXPHOS) in a sex-dependent manner through a compensatory mechanism, which is also observed in acute hyperglycemia.

African Swine Fever Virus in Pork Brought into South Korea by Travelers from China, August 2018.

We tested samples of pork products confiscated from travelers to South Korea for African swine fever virus (ASFV). We detected ASFV in 4 food items confiscated from travelers from Shenyang, China, in August 2018. Surveillance of pork products at country entry points is needed to mitigate the risk for ASFV introduction.

Ruegeria lutea sp. nov., isolated from marine sediment, Masan Bay, South Korea.

A Gram-stain-negative, non-motile, mesophilic, short rod-shaped, aerobic bacterium designated as 318-1T was isolated from a marine sediment collected from Masan Bay, South Korea. Strain 318-1T grew optimally at pH 6-7, at 30 °C and in the presence of 2-3 % (w/v) NaCl, tolerant of up to 8 % (w/v) NaCl, and accumulated poly-ß-hydroxybutyrate (PHB). A comparative analysis of 16S rRNA gene sequences revealed that strain 318-1T formed a distinct phyletic lineage in the genus Ruegeria (family Rhodobacteraceae, class Alphaproteobacteria) and showed high sequence similarity to Ruegeria halocynthiae DSM 27839T (96.5 %) and Shimia haliotis DSM 28453T (96.3 %). Comparing the genome sequence of 318-1T with those of the type strains of seven species of the genus Rugeria and two species of the genus Shimia, the values obtained were below the thresholds with analysis of average nucleotide identities (ANI, 71.6-76.8 %) and in silico DNA-DNA hybridisation, Genome-to-Genome Distance Calculator (GGDC, 18.5-20.6 %). The DNA G+C content was 65.75 mol%. Chemotaxonomic data [predominant quinone ubiquinone Q10; polar lipid profile consisting of major compounds phosphatidylcholine (PC), phosphatidylglycerol (PG), an unidentified aminolipid and an unidentified lipid; major fatty acids summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c)] supported the affiliation of strain 318-1T to the genus Ruegeria. Genomic, chemotaxonomic, and phenotypic differentiation of strain 318-1T from the members of the genus Ruegeria support it as a novel species. On the basis of the results in this study, a novel species, Ruegeria lutea sp. nov., is proposed. The type strain is 318-1T (=JCM 30927T=KEMB 7306-525T=KCTC 72105T).

Enhanced Electron Transfer Mediated by Conjugated Polyelectrolyte and Its Application to Washing-Free DNA Detection.

Direct electron transfer between a redox label and an electrode requires a short working distance (<1-2 nm), and in general an affinity biosensor based on direct electron transfer requires a finely smoothed Au electrode to support efficient target binding. Here we report that direct electron transfer over a longer working distance is possible between (i) an anionic π-conjugated polyelectrolyte (CPE) label having many redox-active sites and (ii) a readily prepared, thin polymeric monolayer-modified indium-tin oxide electrode. In addition, the long CPE label (∼18 nm for 10 kDa) can approach the electrode within the working distance after sandwich-type target-specific binding, and fast CPE-mediated oxidation of ammonia borane along the entire CPE backbone affords high signal amplification.

A Two-Photon Fluorescent Probe for Imaging Endogenous ONOO- near NMDA Receptors in Neuronal Cells and Hippocampal Tissues.

In this study, we developed a two-photon fluorescent probe for detection of peroxynitrite (ONOO-) near the N-methyl-d-aspartate (NMDA) receptor. This naphthalimide-based probe contains a boronic acid reactive group and an ifenprodil-like tail, which serves as an NMDA receptor targeting unit. The probe displays high sensitivity and selectivity, along with a fast response time in aqueous solution. More importantly, the probe can be employed along with two-photon fluorescence microscopy to detect endogenous ONOO- near NMDA receptors in neuronal cells as well as in hippocampal tissues. The results suggest that the probe has the potential of serving as a useful imaging tool for studying ONOO- related diseases in the nervous system.

A missense allele of KARRIKIN-INSENSITIVE2 impairs ligand-binding and downstream signaling in Arabidopsis thaliana.

A smoke-derived compound, karrikin (KAR), and an endogenous but as yet unidentified KARRIKIN INSENSITIVE2 (KAI2) ligand (KL) have been identified as chemical cues in higher plants that impact on multiple aspects of growth and development. Genetic screening of light-signaling mutants in Arabidopsis thaliana has identified a mutant designated as ply2 (pleiotropic long hypocotyl2) that has pleiotropic light-response defects. In this study, we used positional cloning to identify the molecular lesion of ply2 as a missense mutation of KAI2/HYPOSENSITIVE TO LIGHT, which causes a single amino acid substitution, Ala219Val. Physiological analysis and genetic epistasis analysis with the KL-signaling components MORE AXILLARY GROWTH2 (MAX2) and SUPPRESSOR OF MAX2 1 suggested that the pleiotropic phenotypes of the ply2 mutant can be ascribed to a defect in KL-signaling. Molecular and biochemical analyses revealed that the mutant KAI2ply2 protein is impaired in its ligand-binding activity. In support of this conclusion, X-ray crystallography studies suggested that the KAI2ply2 mutation not only results in a narrowed entrance gate for the ligand but also alters the structural flexibility of the helical lid domains. We discuss the structural implications of the Ala219 residue with regard to ligand-specific binding and signaling of KAI2, together with potential functions of KL-signaling in the context of the light-regulatory network in Arabidopsis thaliana.

Antartin, a Cytotoxic Zizaane-Type Sesquiterpenoid from a Streptomyces sp. Isolated from an Antarctic Marine Sediment.

Antartin (1), a new zizaane-type sesquiterpene, was isolated from Streptomyces sp. SCO736. The chemical structure of 1 was assigned from the interpretation of 1D and 2D NMR in addition to mass spectrometric data. The relative stereochemistry of 1 was determined by analysis of NOE data, while the absolute stereochemistry was decided based on a comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Antartin (1) showed cytotoxicity against A549, H1299, and U87 cancer cell lines by causing cell cycle arrest at the G1 phase.

Anti-Pigmentary Effect of (-)-4-Hydroxysattabacin from the Marine-Derived Bacterium Bacillus sp.

Bioactivity-guided isolation of a crude extract from a culture broth of Bacillus sp. has led to the isolation of (-)-4-hydroxysattabacin (1). The inhibitory effect of (-)-4-hydroxysattabacin (1) was investigated on melanogenesis in the murine melanoma cell line, B16F10, and human melanoma cell line, MNT-1, as well as a pigmented 3D-human skin model. (-)-4-Hydroxysattabacin treatment decreased melanin contents in a dose-dependent manner in α-melanocyte stimulating hormone (α-MSH)-stimulated B16F10 cells. Quantitative real time PCR (qRT-PCR) demonstrated that treatment with (-)-4-hydroxysattabacin down-regulated several melanogenic genes, including tyrosinase, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2) while their enzymatic activities were unaffected. The anti-melanogenic effects of (-)-4-hydroxysattabacin were further demonstrated in a pigmented 3D human epidermal skin model, MelanodermTM, and manifested as whitening and regression of melanocyte activation in the tissue.