Search

Introduction:Desmodium gangeticum is the accepted source of Shalaparni, a herb commonly used in Ayurveda clinical practice. It has been indicated in Ayurveda treatise and ethnomedicinal texts to treat cough disorders (Kasa). Desmodium velutinum is popular as the substitute of D. gangeticum and is also used to treat cough by the tribals. The present study designed to assess the antibacterial activity and antihistaminic activity of D. gangeticum plus D. velutinum whole plant powder.Methods:The cylinder plate method was adopted using Muller Hinton agar as media and augmentin 625 mg as standard, against Streptococcus pneumonia, Streptococcus pyogens, Haemophilus influenza, and Pseudomonas aeruginosa. Antihistaminic activity was evaluated on secluded guinea pig ileum and standard procedure was adopted.Results:It was observed that D. gangeticum was found effective against three bacterial strains and D. velutinum showed zone of inhibition against all four strains compared to standard. The anti-bacterial activity of the two samples can be attributed to abundance of polyphenols detected in the phytochemical screening. Antihistaminic study revealed that at the dose of histamine (100 ng/mL bath fluid), D. gangeticum produced 41.33% inhibition of histamine prompted reduction of guinea pig ileum, while D. velutinum produced 26.71% histamine prompted shrinkage of guinea pig ileum.Conclusion:The findings in this study indicate that the both the test samples possess anti-bacterial activity and antihistaminic activity.

A key challenge faced by extension projects is to design and implement effective feedback collection processes to improve service delivery and demonstrate impact to funders. We used standardised evaluation forms with questions relating to the KASA (Knowledge, Attitudes, Skills and Aspirations) framework to capture impact on key precursors to practice change. Attendee feedback was documented at the end of each extension activity. Grower feedback highlighted opportunities to enhance service delivery while also generating powerful quantitative and qualitative data about the impact of the project on KASA. This information was used to inform the design of activities in the latter part of the project. The data discussed in this paper is collated feedback from all project activities over a three-year timeframe of 2019-2022. A key outcome was 60% of attendees indicating they are planning on implementing a practice change within the next 12 months because of the information provided. [ABSTRACT FROM AUTHOR]

This paper uses "A Travel to Diamond Mountains" (1930) and its author Jo Aeyeong (1911-2000) to explore gender and modernity, community and individuality, and distinctions between tradition and modern in a literary genre. It starts by juxtaposing Jo and her contemporaries, especially Baek Sinae (1908-1939), to examine the complexities of a woman writer situating herself in the early twentieth century. Noting the contexts and opportunities that affected each woman's path forward, it challenges the usefulness of established stereotypes or slogans such as "New Women" and "Wise Mother Good Wife" in understanding this era. The paper then reads Jo's travelogue alongside other travelogues by women, including those communally written in kasa form. In doing so, it complicates the implicit contrast between tradition and modern and illuminates changes to the "traditional" form of kasa. Along with Jo's "Diamond Mountains," women writers and their writings featured in this paper as a whole embody a moment of adaptation, flourishing, and decline within the evolution of women's literature in Korea. [ABSTRACT FROM AUTHOR]

Human anatomy and physiology is considered one of the most difficult courses a student can take in a pre-health professional major in the US (Slominski, et. al., 2017). Research has revealed benefits of the use of art and anatomy within medical education, including improved clinical observational skills, greater understanding of disease and patient perspectives, and greater ability to empathize (Bell & Evans, 2014). Bell and Evans (2014) argue that observational skills are often overlooked in medical education. Use of art assignments in a graduate anatomy and physiology course will be discussed with reference to design and learning outcomes. The purpose of this study was to evaluate the relationship between art and medical education for audiology students. This study aimed to incorporate STEAM education (art assignments, the teaching effect, and community outreach) into audiology curriculum. Auburn University's Au.D. class of 2022 participated in this study, consisting of 10 students. The Student Assessment of Learning Gains (SALG) questionnaire was conducted and provided qualitative and quantitative evidence supporting the integration of art in the Doctor of Audiology curriculum. BASE (pre) and SALG (post) outcomes assessed that the use of STEAM assignments can help improve the retention of the anatomy and physiology within of the auditory system. Cross-tabulations of pre and post course responses show a positive increase in student understanding of course material. A positive perception that art assignments enhanced student confidence and clinical observation skills related to the course was observed. Many students felt they had a great gain in understanding covered topics. The effects of utilizing the teaching effect and community outreach were also positively seen by student participants. Students' opinions following coursework and cross-tabulations support a place for art in health education and healthcare. [ABSTRACT FROM AUTHOR]

Quality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impact in vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors. Although significant work has been performed for biopharmaceutics risk assessment for new molecules, there is a need for harmonized biopharmaceutics risk assessment workflow for generic submissions. In this manuscript, we attempted to provide a framework for performing biopharmaceutics risk assessment for generic regulatory submissions. A detailed workflow for performing biopharmaceutics risk assessment includes identification of initial CBA (iCBA), their confirmatory evaluation followed by definition of the control strategy. Tools for biopharmaceutics risk assessment, i.e., bio-discriminatory dissolution method and physiologically based biopharmaceutics modeling (PBBM) were discussed from a practical perspective. Furthermore, a case study for CBA evaluation using PBBM modeling for an extended-release product for regulatory submission has been described using the proposed workflow. Finally, future directions of integrating CBA evaluation, biopharmaceutics risk assessment to the FDA Knowledge Aided Structured Assessment (KASA) initiative, the necessity of risk assessment templates, and knowledge sharing between industry and academia are discussed. Overall, the work described in this manuscript can facilitate and provide guidance for biopharmaceutics risk assessment for generic submissions. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium tuberculosis is a bacterium that has historically had a substantial impact on human health. Despite advances in understanding and management of tuberculosis (TB), the disease remains a crucial problem that necessitates ongoing work to discover effective drugs, minimize transmission, and improve global health outcomes. Methods: The purpose of this study is to use molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses to explore the molecular interactions of different proteins that are involved in mycolic acid biosynthesis (HadAB, InhA, KasA, FabD, and beta-ketoacyl-acyl carrier protein synthase III) of M. tuberculosis with Demospongiae metabolites. The docking findings were evaluated using the glide gscore, and the top 10 compounds docked against each protein receptor were chosen. Furthermore, the selected compounds underwent ADMET analysis, indicating that they have the potential for therapeutic development. Results: Among the selected compounds, makaluvamine G showed the highest binding affinity against HadAB, psammaplysin E showed highest binding affinity against InhA, pseudotheonamide D showed the highest binding affinity against KasA protein, dinordehydrobatzelladine B showed the highest binding affinity against FabD, and nagelamide X showed the highest binding affinity against beta-ketoacyl-acyl carrier protein synthase III. Additionally, molecular mechanics generalized born surface area (MM-GBSA) binding free energy and molecular dynamics simulations were used to support the docking investigations. Conclusion: The results of the study suggest that these compounds may eventually be used to treat TB. However, computer validations were included in this study, and more in vitro research is required to turn these prospective inhibitors into clinical drugs.

Background: Mycobacterium tuberculosis is a bacterium that has historically had a substantial impact on human health. Despite advances in understanding and management of tuberculosis (TB), the disease remains a crucial problem that necessitates ongoing work to discover effective drugs, minimize transmission, and improve global health outcomes. Methods: The purpose of this study is to use molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses to explore the molecular interactions of different proteins that are involved in mycolic acid biosynthesis (HadAB, InhA, KasA, FabD, and beta-ketoacyl-acyl carrier protein synthase III) of M. tuberculosis with Demospongiae metabolites. The docking findings were evaluated using the glide gscore, and the top 10 compounds docked against each protein receptor were chosen. Furthermore, the selected compounds underwent ADMET analysis, indicating that they have the potential for therapeutic development. Results: Among the selected compounds, makaluvamine G showed the highest binding affinity against HadAB, psammaplysin E showed highest binding affinity against InhA, pseudotheonamide D showed the highest binding affinity against KasA protein, dinordehydrobatzelladine B showed the highest binding affinity against FabD, and nagelamide X showed the highest binding affinity against beta-ketoacyl-acyl carrier protein synthase III. Additionally, molecular mechanics generalized born surface area (MM-GBSA) binding free energy and molecular dynamics simulations were used to support the docking investigations. Conclusion: The results of the study suggest that these compounds may eventually be used to treat TB. However, computer validations were included in this study, and more in vitro research is required to turn these prospective inhibitors into clinical drugs. [ABSTRACT FROM AUTHOR]

Avaleha (linctus) is a unique dosage form of Ayurveda pharmaceutics, which is frequently used in various disorders and especially in respiratory disorders. Kantakari Avaleha (KA) is one such formulation being used extensively for Shwasa (asthma) and Kasa (cough) along with its classical use in various other disorders too. Because of its demand in clinical settings, many pharmaceutical companies are also preparing this, and hence freely available in market. This review was carried out to get thorough idea related to its composition, method of preparation, and therapeutic uses along with its pharmaceutical standards. For this review, classical and compiled texts having subject of Ayurveda pharmaceutics were screened from Central Library of Institute of Teaching and Research in Ayurveda, Jamnagar. Out of total 15 texts screened, 7 texts had mentioned KA, and hence reviewed for its ingredients, dose, Anupana, and therapeutic uses. Synonyms, Rasapanchaka (Ayurveda principles of drug action), and Dosha Karma (therapeutic action) of ingredients were compiled from Bhavaprakasha Nighantu. Pharmaceutical parameters of KA were compiled from original research articles from peer-reviewed journals through Google Scholar, PubMed, ResearchGate, and J-Gate portal. After review, it was found that Acharya Sharangdhara (12th Century) had described this formulation for the first time. There are four variations available in formulation composition. Milk or water should be the Anupana for this drug as per Ayurvedic Formulary of India and Pharmacopoeia of India (API). Almost all references have recommended its use in Shwasa and Kasa, along with Arati (distress), Shula (colicky pain), Gulma (a type of lump), Hikka (hiccup), and Hradroga (heart disease) mentioned in one and the other classics. Maximum ingredients of this formulation possess hot potency (12 out of 18 drugs) and pungent biotransformation property (11 out of 18 drugs). As per available original research works, two laboratory samples and one market sample of KA had fulfilled almost all analytical parameters, mentioned in API. The current review work may be helpful as stepping stone for various researches on KA such as network pharmacology, in silico, pharmacology, and longitudinal cross-sectional, clinical study.

Amaç: Bu çalışmada, etik ve hukuk dışı işletme uygulamalarından biri olan raf ve kasa fiyatı uyumsuzluğuna yönelik tüketici tutumlarının incelenmesi amaçlanmıştır. Tüketicilerin mevzuat farkındalıkları ölçülerek ilgili durum karşısında sergiledikleri davranışın ve çalışanların hizmet yeterliliklerinin bu süreçteki önemi ortaya çıkarılmaya çalışılmıştır. Yöntem: Araştırmada nicel veri toplama yöntemlerinden anket yöntemi kullanılmış olup kolayda örneklemeden yararlanılmıştır. Araştırma kapsamına yalnızca daha önceden gıda marketlerinde en az 1 kere raf ve kasa fiyatı uyumsuzluğu durumunu tecrübe eden katılımcılar dahil edilmiştir. Toplamda 391 adet anket SPSS 20 programı ile analiz edilmiştir. Bulgular: Katılımcıların yarısından fazlasının hala belirli bir farkındalıktan ve hak arayışından uzak olduğu bulgusuna ulaşılmıştır. Raf ve kasa fiyatı uyumsuzluğuna konu olan ürünler içinde gıda ürünleri toplamda %73,2 ile başı çekmektedir. Raf ve kasa fiyatı uyumsuzluğuna yönelik mevzuat farkındalığı olan tüketiciler farkındalığa sahip olmayanlara kıyasla bu süreçten daha olumsuz etkilenmektedir. Sonuç: Raf ve kasa fiyatı uyumsuzluğu farkındalığı konusunda tüketicilerin hala ciddi bir eksikliğe sahip olduğu sonucuna ulaşılmaktadır. Özellikle, yüksek fiyatlı ürünlerin etiket fiyatlarının kasıtlı olarak düşük gösterilmesi yoluyla tüketicilerde satın alma dürtüsü oluşturulmaya çalışılması, bu durumu daha da etik ve hukuk dışı bir hale getirmektedir.

Recent studies have reported the β-ketoacyl-acyl carrier protein KasA as a druggable target for Mycobacterium tuberculosis. This review summarizes the current status of major classes of KasA inhibitors with an emphasis on significant contributions from structure-based design methods leveraging Xray crystal structures of KasA alone and in complex with inhibitors. The issues addressed within each inhibitor class are discussed while detailing the characterized interactions with KasA and structure-activity relationships. A critical analysis of these findings should lay the foundation for new KasA inhibitors to study the basic biology of M. tuberculosis and to form the basis of new antitubercular molecules of clinical significance with activity against drug-sensitive and drug-resistant infections. [ABSTRACT FROM AUTHOR]

Recent studies have reported the β-ketoacyl-acyl carrier protein KasA as a druggable target for Mycobacterium tuberculosis. This review summarizes the current status of major classes of KasA inhibitors with an emphasis on significant contributions from structure-based design methods leveraging X-ray crystal structures of KasA alone and in complex with inhibitors. The issues addressed within each inhibitor class are discussed while detailing the characterized interactions with KasA and structure-activity relationships. A critical analysis of these findings should lay the foundation for new KasA inhibitors to study the basic biology of M. tuberculosis and to form the basis of new antitubercular molecules of clinical significance with activity against drug-sensitive and drug-resistant infections.

Background: The global rise in drug-resistant Mycobacterium tuberculosis (M.tb), and especially the significant prevalence of isoniazid (INH)-resistance constitute a significant challenge to global health. Therefore, the present study aimed to investigate mutations in prevalent gene loci—involved in INH-resistance phenotype—among M.tb clinical isolates from southwestern Iran. Methods: Drug susceptibility testing (DST) was performed using the conventional proportional method on confirmed 6620 M.tb clinical isolates, and in total, 15 INH-resistant and 18 INH-susceptible isolates were included in the study. Fragments of six genetic loci most related to INH-resistance (katG, inhA promoter, furA, kasA, ndh, oxyR-ahpC intergenic region) were PCR-amplified and sequenced. Mutations were explored by pairwise alignment with the M.tb H37Rv genome. Results: The analysis of gene loci revealed 13 distinct mutations in INH-resistant isolates. 60% (n = 9) of the INH-resistant isolates had mutations in katG, with codon 315 predominately (53.3%, n = 8). Mutation at InhA − 15 was found in 20% (n = 3) of resistant isolates. 26.7% (n = 4) of the INH-resistant isolates had kasA mutations, of which G269S substitution was the most common (20%, n = 3). The percentage of mutations in furA, oxyR-ahpC and ndh was 6.7% (n = 1), 46.7% (n = 7), and 20% (n = 3), respectively. Of the mutations detected in ndh and oxyR-ahpC, 5 were also observed in INH-susceptible isolates. This study revealed seven novel mutations, four of which were exclusively in resistant isolates. Conclusions: This study supports the usefulness of katG and inhA mutations as a predictive molecular marker for INH resistance. Co-detection of katG S315 and inhA-15 mutations identified 73.3% (11 out of 15 isolates) of INH-resistant isolates. [ABSTRACT FROM AUTHOR]

Two survey instruments were used to gather information from speech-language pathologists (SLPs) and university personnel (UP) regarding their perceptions of the adequacy of SLP training for providing early intervention (EI) services. In the SLP survey, respondents were asked to rate their perceptions of training adequacy in specific EI Knowledge and Skill Acquisition (KASA) areas. UP were also surveyed regarding their perceptions of the adequacy of their programs' academic preparation in EI. Results from 189 SLPs employed in EI settings indicated that less than 50% agreed that their academic preparation in the majority of EI knowledge and skill areas was adequate. However, with the exception of service coordination and linguistic diversity, the majority of UP (90%–100%) perceived that their graduate programs provided students with adequate training for serving EI populations. Implications of respondents' differing perspectives will be discussed. [ABSTRACT FROM AUTHOR]

About terms of Korean literature history: the correlation of Korean, Chinese and Russo-European terminology In medieval Korea there was no own national theory of poetry, there were used Chinese, much later – Japanese poetics. Korean literary terminology was formed spontaneously, it is still not much studied and systematized. Not all the phenomenons of Korean literature have the conformity in western and Russian terminology. The translators and the philologists face the problem: how wide can they use the unusual Korean and Chinese words in the editions, assigned for the readers with the absolutely other cultural skills, in what quantity proportion with the usual terms, which, never the less, do not reproduce the national specific? The practice of Russian studies of Korean literature in this regard is not always successful.

Tuberculosis (TB) is a leading infectious disease which kills a huge number of people every year over a decade, caused by Mycobacterium tuberculosis. The conventional drugs in the market are no longer effective due to the increasing mycobacterial resistance to antibiotics. Hence, the need of finding efficient drugs to solve this multiple drug resistant factor is becoming an immediate issue. The first-line drugs in current practice for the treatment of TB emphasize on mycolic acid, which protects the bacteria from an immune response generated by the host. A key enzyme involved in this mycolic acid biosynthesis, M. tuberculosis beta-ketoacyl-ACP synthase A (MTB-KasA) is a prime candidate in this study. Thiolactomycin is a natural product inhibitor has shown good inhibitory activity against MTB-KasA. Hence, several thiolactomycin derivatives collected from the literature were taken for absorption, distribution, metabolism, excretion and toxicity prediction, molecular docking and molecular dynamics simulation studies with MTB-KasA. The in silico drug designing methods used in this study suggests that the thiolactomycin derivatives are having a better binding activity against MTB-KasA and among them the ligand C14 is identified as a promising lead molecule to inhibit multidrug resistance of tuberculosis by showing a long time binding activity. [ABSTRACT FROM AUTHOR]

ABSTRACT We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB). IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

Rasayana is a specialized section of Ayurveda, which mainly deals with the prevention of disease and promotion of the health. Agastya Haritaki Rasayana is a popular Avaleha kalpana, used in the pranavaha sroto vikaras like Kasa, Shwasa, Hikka, Kshaya, etc. The study was taken with a view to enlist the ingredients of Agastya Haritaki Rasayana from different Classical text of Ayurveda and critical analysis was done based on the properties of ingredients and their indications. A thorough and comprehensive review of Agastya Haritaki Rasayana from different Ayurvedic classical texts, contemporary texts, online journals, articles and internet materials has been done. Most of the ingredients of Agastya Haritaki Rasayana are having -Tikta, Kashyaya, Madhura rasa, laghu, ruksha, tikshna guna, katu vipaka, ushna veerya and having kaphavata shamaka properties. Thus, Agastya Haritaki Rasayana is used in the management of diseases which are mainly vatakapha pradhana. Agastya Haritaki Rasayana is indicated as main line of treatment in Shwasa, Kasa roga as well as used as the Naimittika Rasayana in various other diseases like grahani, aruchi, arsha etc. [ABSTRACT FROM AUTHOR]

The article focuses on the use of poetry forms kasa and sijo which are being used from the Chosŏn period. It talks about it's use being popular among the yangban aristocrats depicting rural life and beautiful sceneries. It tells about the kasa being formed by using syllables which were divided into two groups and were later formed by women and commoners. It discusses the transition of Korean literature and the use of kasa in modern literature.

Quality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impact in vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors. Although significant work has been performed for biopharmaceutics risk assessment for new molecules, there is a need for harmonized biopharmaceutics risk assessment workflow for generic submissions. In this manuscript, we attempted to provide a framework for performing biopharmaceutics risk assessment for generic regulatory submissions. A detailed workflow for performing biopharmaceutics risk assessment includes identification of initial CBA (iCBA), their confirmatory evaluation followed by definition of the control strategy. Tools for biopharmaceutics risk assessment, i.e., bio-discriminatory dissolution method and physiologically based biopharmaceutics modeling (PBBM) were discussed from a practical perspective. Furthermore, a case study for CBA evaluation using PBBM modeling for an extended-release product for regulatory submission has been described using the proposed workflow. Finally, future directions of integrating CBA evaluation, biopharmaceutics risk assessment to the FDA Knowledge Aided Structured Assessment (KASA) initiative, the necessity of risk assessment templates, and knowledge sharing between industry and academia are discussed. Overall, the work described in this manuscript can facilitate and provide guidance for biopharmaceutics risk assessment for generic submissions., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

In this paper a new method is shown to determine the pupil within a digital image of it using binarizations, mathematical morphology and method of Kasa. In addition to locating the pupil, it is possible to determinate the coordinates of its center and its radius. The presented method is an alternative to images in which the pupil is not complete by interference with eyelashes, hair, eyelids or Purkinje image. And again the processing time is significantly reduced compared to the model Hough circle detection. [ABSTRACT FROM PUBLISHER]

Introduction: Vyaghriharitaki Avaleha (VHA), a polyherbal classical Ayurvedic formulation has been used in Kasa (cough), Swasa (asthma), Rajayakshma (tuberculosis) etc., conditions. Aim: To evaluate the clinical efficacy of VHA in the management of chronic bronchitis. Materials and Methods: Patients of chronic bronchitis were given 10 g of VHA twice a day with lukewarm water before meals for 12 weeks. Improvement in clinical symptoms of chronic bronchitis as the primary outcome measures and St. George's Respiratory Questionnaire scores as secondary outcome measure was studied. Results: Out of 66 enrolled patients, 61 completed the treatment schedule. The results show that VHA provides statistically significant improvement with P < 0.001 in both primary and secondary outcome measures. Conclusion: VHA can be considered as a safe and effective formulation in the management of chronic bronchitis. [ABSTRACT FROM AUTHOR]

The purpose of this research was to determine the effect of the differences temperature and relative humidity in cold storage on ambient factors of boxes. Apple was stored in experimental cold storage. Temperature and relative humidity were measured in boxes located at different levels. In addition, spatial variability of ambient factors in the boxes were modelled by using Computational Fluid Dynamics (CFD). Models were compared with measurements for validation. Changing of stored apple quality was determined. Temperature was 2 C, and relative humidity 90%. Developed model estimated temperature with 5.68 % error and relative humidity with 3.23 % error. Effect of measurement levels on quality criteria didn't found statistically important. Although, there were difference between temperature and relative humidity for top, medium and base levels in the cold storage, these differences did not create negative effect on quality criteria. [ABSTRACT FROM AUTHOR]

Inhibition of the production of fatty acids as essential components of the mycobacterial cell wall has been an established way of fighting tuberculosis for decades. However, increasing resistances and an outdated medical treatment call for the validation of new targets involved in this crucial pathway. In this regard, the β-ketoacyl ACP synthase KasA is a promising enzyme. In this study, three molecular dynamics simulations based on the wildtype crystal structures of inhibitor bound and unbound KasA were performed in order to investigate the flexibility and conformational space of this target. We present an exhaustive analysis of the binding-site flexibility and representative pocket conformations that may serve as new starting points for structure-based drug design. We also revealed a mechanism which may account for the comparatively low binding affinity of thiolactomycin. Furthermore, we examined the behavior of water molecules within the binding pocket and provide recommendations how to handle them in the drug design process. Finally, we analyzed the dynamics of a channel that accommodates the long-chain fatty acid substrates and, thereby, propose a mechanism of substrate access to this channel and how products are most likely released. [ABSTRACT FROM AUTHOR]

Abstract: GroEL is a group I chaperonin that facilitates protein folding and prevents protein aggregation in the bacterial cytosol. Mycobacteria are unusual in encoding two or more copies of GroEL in their genome. While GroEL2 is essential for viability and likely functions as the general housekeeping chaperonin, GroEL1 is dispensable, but its structure and function remain unclear. Here, we present the 2.2-Å resolution crystal structure of a 23-kDa fragment of Mycobacterium tuberculosis GroEL1 consisting of an extended apical domain. Our X-ray structure of the GroEL1 apical domain closely resembles those of Escherichia coli GroEL and M. tuberculosis GroEL2, thus highlighting the remarkable structural conservation of bacterial chaperonins. Notably, in our structure, the proposed substrate-binding site of GroEL1 interacts with the N-terminal region of a symmetry-related neighboring GroEL1 molecule. The latter is consistent with the known GroEL apical domain function in substrate binding and is supported by results obtained from using peptide array technology. Taken together, these data show that the apical domains of M. tuberculosis GroEL paralogs are conserved in three-dimensional structure, suggesting that GroEL1, like GroEL2, is a chaperonin. [ABSTRACT FROM AUTHOR]

The common written language of East Asia, classical Chinese (hanmun), did not hinder the Korean ethnic language. With the impact of hanmun, it developed into a written language that had the capacity to express high culture. The civil service examination system that tested candidates' ability in hanmun writing was a literary examination because literature was valued over practical types of knowledge in governing society. The first poetic genre using Korean ethnic language, hyangga, internalized the world by embodying the ideology of an age that placed importance only on the mind, but in an age when both the outer material world and the inner mind were considered important, it was necessary to create didactic poetry, kasa, which globalized the self and lyric poetry sijo that internalized the world. The most important social change of the transitional period from the medieval era to the modem era was the emergence of the bourgeoisie, which demanded a change from a status-based society to a class-based society. The new literature initiated by the bourgeoisie, namely, the novel (sosŏl), was a rebellious child; disguising itself as biography, it destroyed earlier authoritative ways of thinking. Following the same process. East Asian countries created different products. The novels of China were writers' novels, while the novels of Japan were publishers' novels, and the novels of Korea were readers' novels. Modern literature was born through overcoming two unfavorable conditions. As Western literature was introduced second-hand by the Japanese, the tradition of Korean literature offered a wellspring from which to create a modem national literature that may be considered a desirable model for the Third World. Indirect methods such as allusion, symbolism, and satire were all used with good effect as a way of coping with Japanese military rule that denied freedom of the press or of thought, as well as criticizing colonial rule and expressing the desire for national liberation. [ABSTRACT FROM AUTHOR]

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis. • A structure-based optimization of the KasA inhibitor DG167 led to JSF-3285 • The inhibitor evolution focused on metabolic stability and mouse plasma PK • JSF-3285 is efficacious in a mouse model of chronic TB infection at 5 mg/kg • JSF-3285 represents a preclinical lead compound for TB Inoyama et al. disclose the optimization of an indazole antitubercular targeting the β-ketoacyl-ACP synthase KasA. A structure-based approach has overcome significant issues with mouse metabolic stability and pharmacokinetics. A preclinical drug candidate has been delivered with efficacy in a mouse model of chronic M. tuberculosis infection at 5 mg/kg dosing. [ABSTRACT FROM AUTHOR]

In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis , a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.

The enzyme β-Ketoacyl ACP synthase I (KasA) is a potent drug target in mycolic acid pathway of Mycobacterium tuberculosis (Mtb). In the present study, we investigated the structural dynamics of wild-type (WT) and mutants KasA (D66N, G269S, G312S, and F413L) in both monomer and dimer form to provide insight into protein structural stability. To gain better understanding of structural flexibility of KasA, combined molecular dynamics and essential dynamics were employed to analyze the conformational changes induced by non-active site mutations. The results confirm that non-active site mutations lower the structural stability in dimer KasA as compared to WT. The protein network topology and close residue interactions of WT and mutant residues of KasA have been predicted through residue interaction network analysis (RIN). Non-active site mutations distort RIN architecture and subsequently affect the drug binding landscape. T-pad associated with mode vector analysis comprehensively pronounces the structural impact caused by non-active site mutations. It also identified the critical fluctuating residues present in the gate segment (GS) region (115–147). The non-active site mutations altered the structural stability of the mutant protein structures, and these mutations may be a cause for the resistance mechanism of KasA against anti-tuberculosis drugs. Further, it is observed that dimer mutant KasA proteins display much more structural flexibility than WT at the ligand binding site which is evident from the binding site analysis and hydrogen bond interaction patterns. This study provides a better understanding of the structural dynamic behaviour of KasA mutants, thereby facilitating the need to find a novel and potent inhibitor against Mtb. Unlabelled Image • KasA protein is one of the potential drug targets in the treatment of tuberculosis • Variations in conformational behaviour of WT and mutant systems were observed and investigated through PCA and FEL analysis • The significant conformational changes in gate segment (GS) region established its high vibrant nature in monomer KasA • Residue interaction network analysis depicted the impact of non-active site mutations in network architecture • Non-active site mutations caused the protein to exhibit more structural flexibility as compared to the WT protein [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discuss the kasa of the April 1960 revolution and other writings about sijo and kasa.

We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB). IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA-a key component for biosynthesis of the mycolic acid layer of the bacterium's cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars., (Copyright © 2018 Kumar et al.)