Synthetic Approaches to Skeletally Diverse Sultams Using Vinyl- and α-Halo Benzenesulfonamides

The development of new chemical methods to generate novel and diverse structures to probe chemical space is an important aspect of early phase drug discovery. Diversity-Oriented Synthesis (DOS) is a powerful strategy that seeks to generate chemical methods capable of delivering an array of molecular scaffolds with structural and functional diversity. Ultimately, these methods can be adapted to produce molecular libraries. It is the purpose of this thesis to highlight a series of new chemical methods that deliver an array of drug-like sultam scaffolds to be screened for broad biological activity in the molecular library program run by the National Institutes of Health. The first project described in chapter one of this dissertation includes the synthesis of a collection of diverse bi- and tricyclic sultams in an overall DOS approach utilizing a ring-opening metathesis / ring-closing metathesis / cross metathesis (ROM-RCM-CM) cascade strategy. A variety of functionalized, tricyclic sultams were generated as precursors derived from a diastereoselective IMDA reaction in good yields and selectivity. The ROM-RCM-CM strategy to produce skeletal and appendage-based diverse sultams is presented. The second project is the generation of diverse sultams utilizing α,β-unsaturated 5- and 6-membered sultams. These 5- and 6-membered sultams were prepared and applied to further diversifications using aza-Michael reactions, cycloadditions, alkylation/benzylations and propargylation-[3+2]-cycloadditions. Utilizing the aza-Michael reaction, we have developed an efficient protocol for the synthesis of a 141-member library collection of isothiazolidine 1,1-dioxide derivatives. The last project outlined in chapter four is the synthesis of novel 7- and 8- membered tricyclic, biaryl sultams using an intramolecular Pd-catalyzed C-arylation reaction. Namely, in the amino ester-derived sultams, remote 1,5- and 1,6-asymmetric induction emanating from the external stereogenic center is operative, whereby a favorable Cα-H/S=O syn pentane interaction, is the source of asymmetric induction for a highly atropdiastereoselective thermodynamic equilibration process yielding a low energy conformer of "like" configuration (S,Sa). In the course of X-ray crystallographic analysis, as well as detailed NMR studies, we uncovered a number of notable and interesting structural features of the 7-membered amino ester-derived sultams in both solid and solution phases that confirm a structure as a single conformer (95:5) containing biaryl axial chirality of "like" configuration (S,Sa) with respect to the stereogenic center in the external side chain. Moreover, variable temperature NMR analysis has indicated that the axis of chirality at the biaryl bond has a relatively small interconversion barrier that allows for this rapid thermodynamic equilibration of the "like" and "unlike" atropdiastereomers. Detailed variable NMR analyses on a number of analogs, vide infra, point to rotamer dynamics (about the N-C bond in the external side chain) and ring size of the corresponding benzothiazepine (n = 1)/benzothiazocine (n = 2) 1,1-dioxides as governing factors in this notable thermodynamic equilibration of atropdiastereomers. Current efforts are focused on the computational calculation for the energy barrier between two atropdiastereomers interconversion, as well as the further development of an "atropdiastereoselective" C-arylation process. In addition, future studies will continue to probe the dynamic factors involved in the origins of atropselectivity. Utilizing this methodology, we are also generating additional libraries of diverse tricyclic, biaryl sultams for high throughput screening of biological activity with our collaborators at the National Institutes of Health

Integrated Arts and Culture Education Model for Public Schools in Indonesia: The Case Study of 'Made in Cirebon' as a Cooperation Project with an Artist Community

There is an urgency to improve arts and culture education in public schools in Indonesia. Currently, the sector faces various challenges, such as insufficient course hours, limited topics, as well as inadequate number and expertise of teachers. With the Covid-19 pandemic, the situation has become even more precarious. To solve these problems, ARCOLABS organized an alternative arts and culture education program for local public-school students in 2020 as part of the Official Development Assistance (ODA) for Arts and Culture Education. Entitled ‘Made in Cirebon’, this pilot project served as preliminary research to look for the most appropriate models to encourage innovations and sustainability in arts and culture education in local public schools in Cirebon through cooperation with local artists. This project-based study utilized several research methodologies, including seminars and discussions to develop learning contents, implementation of an online/on-site learning model, a mini showcase of learning outcomes by students, along with participant interviews, surveys, and evaluation by all stakeholders to prepare for a successive project in 2021. Through the inclusive, innovative and productive outcomes of the project, this research has drawn several positive conclusions: (1) various genres and disciplines can be integrated into an interdisciplinary subject that could overcome the limited course hours and topics within the school curriculum; (2) local artists can be important artistic and educational assets that could fill the gaps in formal education; and (3) a creative approach to local issues is a significant catalyst for the sustainability of the implemented model

Integrated Arts and Culture Education Model for Public Schools in Indonesia: The Case Study of 'Made in Cirebon' as a Cooperation Project with an Artist Community

There is an urgency to improve arts and culture education in public schools in Indonesia. Currently, the sector faces various challenges, such as insufficient course hours, limited topics, as well as inadequate number and expertise of teachers. With the Covid-19 pandemic, the situation has become even more precarious. To solve these problems, ARCOLABS organized an alternative arts and culture education program for local public-school students in 2020 as part of the Official Development Assistance (ODA) for Arts and Culture Education. Entitled ‘Made in Cirebon’, this pilot project served as preliminary research to look for the most appropriate models to encourage innovations and sustainability in arts and culture education in local public schools in Cirebon through cooperation with local artists. This project-based study utilized several research methodologies, including seminars and discussions to develop learning contents, implementation of an online/on-site learning model, a mini showcase of learning outcomes by students, along with participant interviews, surveys, and evaluation by all stakeholders to prepare for a successive project in 2021. Through the inclusive, innovative and productive outcomes of the project, this research has drawn several positive conclusions: (1) various genres and disciplines can be integrated into an interdisciplinary subject that could overcome the limited course hours and topics within the school curriculum; (2) local artists can be important artistic and educational assets that could fill the gaps in formal education; and (3) a creative approach to local issues is a significant catalyst for the sustainability of the implemented model

Nutritional, Bone, and Physical Fitness States of Jockeys in Chronic Repetition of Short-Term Weight Loss

Professional jockeys are required to fit their weight, mainly weight loss, for two game days every weekend during racing season which usually lasts 10 months a year in Korea. The repetitive routine weight loss protocol is performed for 4 to 5 days a week include two game days. This situation would have brought some negative effects on the professional jockeys\u27 overall health and physical condition with the relation of their performance. The purpose of the present study was: 1) to examine the weight loss habits of pro-jockeys, and 2) effects of chronic short-term weight loss on nutritional status, bone health, and physical fitness of them. Pro jockeys (n=43) completed a questionnaire for the assessment of weight loss habits. Pro jockeys (n=10, around 12 years of career) were compared with trainee jockeys (n=10, less than 1 years of career) for their nutritional status, bone health, and physical fitness. The nutritional status was measured by a computerized program (CAN Pro 2.0). Bone mineral density was measured by DEXA (Hologic, QDR-4500W, USA). All participants performed grip strength test, standing on one leg with eyes closed test, and side step test for the assessment of physical fitness. According to the result, more than 80% of pro jockeys underwent a routine weight loss process every week, for around 1 kg, within 2 to 3 days prior to the game days by diet mainly and/or exercise/sauna. Around 70% of them reported severe fatigue during the weight loss period. There were no significant differences in nutritional status between two groups. However, they consume average of 1,100 Kcal a day reflecting 21 to 80% of recommended daily consumption during weight loss periods. In bone health, six trainee jockeys and two pro jockeys were diagnosed as osteopenia. One pro jockey was diagnosed as osteoporosis. No significant difference was found in fitness factors between two groups. In conclusion, chronic exposure to short-term weight loss may result in serious health problems especially on bone health. For the jockeys in Korea, balanced diet program and the related education on weight management are strongly required.

Effect of different seeding methods on green manure biomass, soil properties and rice yield in rice-based cropping systems

The cultivation of green manure crops plays an important role in soil quality and the sustainability of agricultural systems. Field experiments were conducted during one season (2007/2008) to evaluate the effects of different seeding methods on the biomass and N production of hairy vetch (Vicia villosa) and barley (Hordeum vuglare). The effects of treatments on rice yield and its components were also investigated. Specifically, the following four treatments were evaluated: broadcasting before rice harvesting (BBRH), partial tillage seeding (PTS), group seeding (GS) and drill seeding (DS). The overall results showed the following ranking of biomass and nitrogen production of hairy vetch by different seeding methods: BBRH > PTS > DS > GS. Additionally, biomass and nitrogen production of barley was lower than those of hairy vetch at all tested seeding treatments. BBRH and PTS treatments led to an increase in soil bulk density, porosity and soil organic content. The application of green manure with BBRH and PTS treatments led to a significant increase in rice yield (5,330 and 5,320 kg ha-1) when compared to conventional fertilization. Based on the results, BBRH and PTS are good practices for production of green manure in paddy soil. Chemical fertilizers can be replaced with hairy vetch as green manure in rice-based cropping systems.Key words: Green manure, rice, biomass, soil property, seeding method

Effects of Angelica gigas

We investigated the cellular and molecular mechanisms mediating the effects of Angelica gigas Nakai extract (AGNE) through the mitogen-activated protein kinases (MAPKs)/NF-κB pathway using in vitro and in vivo atopic dermatitis (AD) models. We examined the effects of AGNE on the expression of proinflammatory cytokines and chemokines in human mast cell line-1 (HMC-1) cells. Compound 48/80-induced pruritus and 2,4-dinitrochlorobenzene- (DNCB-) induced AD-like skin lesion mouse models were also used to investigate the antiallergic effects of AGNE. AGNE reduced histamine secretion, production of proinflammatory cytokines including interleukin- (IL-) 1β, IL-4, IL-6, IL-8, and IL-10, and expression of cyclooxygenase- (COX-) 2 in HMC-1 cells. Scratching behavior and DNCB-induced AD-like skin lesions were also attenuated by AGNE administration through the reduction of serum IgE, histamine, tumor necrosis factor-α (TNF-α), IL-6 levels, and COX-2 expression in skin tissue from mouse models. Furthermore, these inhibitory effects were mediated by the blockade of the MAPKs and NF-κB pathway. The findings of this study proved that AGNE improves the scratching behavior and atopy symptoms and reduces the activity of various atopy-related mediators in HMC-1 cells and mice model. These results suggest the AGNE has a therapeutic potential in anti-AD

Acute Effects of Different Stretching Protocols Combined with Potentiating Exercise on Flexibility, Power, and Muscle Performance

The purpose of this study was to investigate the acute effects of different stretching protocols combined with potentiating exercise on flexibility, power, and muscle performance. This study was conducted in repeated and cross-over designed. Thirteen collegiate males aged 25.4±3.46 years voluntarily participated in this study. Prior to conduct stretching session, participants performed jogging on the treadmill for 5 min. Then, four different stretching protocols (non stretching; NS, static stretching; SS, dynamic stretching; DS, and proprioceptive neuromuscular facilitation stretching; PNFS) specially targeted for lower limb muscles combined with potentiating exercise (PE, 3 sets x 5 times tuck jumps) were randomly applied at the same time of the day with 7-days interval. Straight leg raise, and vertical jump tests were measured at baseline, post jogging, stretching, and potentiating exercise. Isokinetic muscle strength, anaerobic power, and agility T-test were measured after each stretching combined with potentiating exercise. Repeated measure ANOVAs were used with significant level set at p\u3c.05. Our results indicate that greater improvement in straight leg raise was observed in SS (9.6%) and PNFS (12.1%) compared to NS (0.6%) and DS (5.0%) at post stretching (p\u3c.001). However, vertical jump performance was significantly improved only in DS (1.8%) (p\u3c.001). After potentiating exercise, greater improvement of vertical jump performance was observed in NS (2.2%), SS (3.2%), and PNFS (6.5%) than DS (-0.4%) (p\u3c.01). Isometric leg flexion was significantly higher in DS and PNFS than NS and SS after completion of PE (p\u3c.05). However, no significant differences in leg extension, anaerobic power, and agility were observed among trials. Our study demonstrated that dynamic and PNF stretching protocols combined with potentiating exercise are efficient for generating muscle strength as well as improving flexibility. It is also noted that potentiating exercise plays a major role for preventing the acute loss of power induced by static and PNF stretching

A proteomic atlas of senescence-associated secretomes for aging biomarker development.

The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the "SASP Atlas," a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA). Our findings will facilitate the identification of proteins characteristic of senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus, and tissue of origin of senescent cells in vivo

Effect of biochars pyrolyzed in N2 and CO2, and feedstock on microbial community in metal(loid)s contaminated soils

Little is known about the effects of applying amendments on soil for immobilizing metal(loid)s on the soil microbial community. Alterations in the microbial community were examined after incubation of treated contaminated soils. One soil was contaminated with Pb and As, a second soil with Cd and Zn. Red pepper stalk (RPS) and biochars produced from RPS in either N2 atmosphere (RPSN) or CO2 atmosphere (RPSC) were applied at a rate of 2.5% to the two soils and incubated for 30 days. Bacterial communities of control and treated soils were characterized by sequencing 16S rRNA genes using the Illumina MiSeq sequencing. In both soils, bacterial richness increased in the amended soils, though somewhat differently between the treatments. Evenness values decreased significantly, and the final overall diversities were reduced. The neutralization of pH, reduced available concentrations of Pb or Cd, and supplementation of available carbon and surface area could be possible factors affecting the community changes. Biochar amendments caused the soil bacterial communities to become more similar than those in the not amended soils. The bacterial community structures at the phylum and genus levels showed that amendment addition might restore the normal bacterial community of soils, and cause soil bacterial communities in contaminated soils to normalize and stabilize

Effects of green manure crops and mulching technology on reduction in herbicide and fertilizer use during rice cultivation in Korea

Green manure crops are primarily used in environmentally friendly agricultural practices to reduce the application of chemical fertilizer and herbicide. In this study, a two-year field experiment was conducted to evaluate the effects of paper and plastic mulching with hairy vetch alone or in combination with barley on weed control and rice yield. In addition, treatment effects on soil redox potential (Eh) and the concentration of ammonium (NH4+) in rice paddy were investigated. The results showed that plastic film (10 or 20 μm) and paper mulching with hairy vetch alone had no significant effects on weed density and rice yield when compared with conventional practice (herbicide and fertilizer application) during the first year. However, during the second year, plastic film (20 μm) with partial tillage of hairy vetch alone increased rice yield and decreased weed occurence; but barley and hairy vetch mixture showed opposite trends. Plastic film mulching led to a decrease in soil redox potential, mainly due to the decomposition of soil organic matter. In addition, plastic film mulching increased NH4+-N contents in rice paddy soil. These results suggest that the combination of plastic film with hairy vetch and barley mixture can be used in rice fields to reduce the use of chemical fertilizer and herbicide.Keywords: Green manure, hairy vetch, mulching, rice, weed co