ABC Type Research Articles

Chemoenzymatic Synthesis of ABC-Type Enantiostructured Triacylglycerols by the Use of the p-Methoxybenzyl Protective Group.

This report demonstrates the first asymmetric synthesis of enantiopure structured triacylglycerols (TAGs) of the ABC type presenting three non-identical fatty acids, two of which are unsaturated. The unsaturated fatty acids included monounsaturated oleic acid (C18:1 n-9) and polyunsaturated linoleic acid (C18:2 n-6). This was accomplished by a six-step chemoenzymatic approach starting from (R)- and (S)-solketals. The highly regioselective immobilized Candida antarctica lipase (CAL-B) played a crucial role in the regiocontrol of the synthesis. The synthesis also benefited from the use of the p-methoxybenzyl (PMB) ether protective group, which enabled the incorporation of two different unsaturated fatty acids into the glycerol skeleton. The total of six such TAGs were prepared, four constituting the unsaturated fatty acids in the sn-1 and sn-2 positions, with a saturated fatty acid in the remaining sn-3 position of the glycerol backbone. In the two remaining TAGs, the different unsaturated fatty acids accommodated the sn-1 and sn-3 end positions, with the saturated fatty acid present in the sn-2 position. Enantiopure TAGs are urgently demanded as standards for the enantiospecific analysis of intact TAGs in fats and oils.

NONDOMESTIC FELID ABC BLOOD PHENOTYPING, GENOTYPING, AND CROSSMATCHING.

Based upon previous clinical experience with domestic cats (Felis catus), the ability to assess ABC blood types and blood (in-)compatibilities of nondomestic felids, and adequately consider and plan for blood transfusions, may be important. Although nondomestic felids appear to have an ABC blood group system similar to domestic cats, typing with point-of-care kits and by CMAH genotyping for domestic cats have not been reported. In this study, 162 blood samples from 18 different nondomestic felid species (cheetah [Acinonyx jubatus, n = 42], lion [Panthera leo, n = 33], tiger [Panthera tigris, n = 23], Canada lynx [Lynx canadensis, n = 11], snow leopard [Uncia uncia, n = 10], puma [Puma concolor, n = 7], clouded leopard [Neofelis nebulosa, n = 6], serval [Leptailurus serval, n = 5], jaguar [Panthera onca, n = 5], fishing cat [Prionailurus viverrinus, n = 4], Pallas cat [Felis manul, n = 3], bobcat [Lynx rufus, n = 3], ocelot [Leopardus pardalis, n = 3], black footed cat [Felis nigripes, n = 2], leopard [Panthera pardus, n = 2], African wildcat [Felis lybica, n = 1], caracal [Caracal caracal, n = 1], and sand cat [Felis margarita, n = 1]) were ABC blood typed by laboratory and point-of-care tests, genotyped for four known CMAH variants for type B and type C (AB) phenotypes, and crossmatched with one another and domestic type A cats. Traditional tube typing identified blood type A (n = 106), type B (n = 8), type C (n = 43), and no discernible ABC type (n = 4). Several discrepancies were found between point-of-care and traditional typing test results. None of the tested felids possessed the four CMAH variants responsible for type B and C (AB) in domestic cats. Crossmatch incompatibilities (≥2+ agglutination) were identified within and between nondomestic felid species and beyond ABC incompatibilities. Of 26 crossmatches performed between domestic cats and various nondomestic felids, only 7 (27%) were compatible. In conclusion, point-of-care typing kits and CMAH genotyping, successfully used in domestic cats, may not identify the correct ABC blood type in nondomestic felids. Prior crossmatching is recommended to increase the likelihood of compatible transfusions between any nondomestic felids.

TEACHING SENTENCE READING AND RETELLING AND ANSWERING COMPREHENSION QUESTIONS IN A CHILD WITH AUTISM SPECTRUM DISORDER

Children diagnosed with autism spectrum disorder (ASD) frequently show difficulties in the acquisition of multiple repertoires, including verbal behavior. One type of verbal operant behavior is the intraverbal. It involves the emission of a verbal response under the control of a verbal discriminative stimulus, without point-to-point correspondence between them, and the response is maintained by a generalized conditioned reinforcer. This study focused on narrative retelling, which is a skill that comprises intraverbal chains. It is also discussed in the literature that the teaching of this repertoire may improve gains in text comprehension, which also involves the emission of intraverbals, that is, answering questions. Regarding this skill, previous research investigated procedures that may produce the emergence of answering comprehension questions referred as complex ABC intraverbals (related to the stimulus equivalence paradigm) in typically developing children. In general, they were exposed to cycles in which they first read short texts/sentences relating information on three different stimuli (A, B, and C), Thereafter, the children answered several questions representing all possible complex intraverbal relations among the three stimuli from the sentences. Some learners demonstrated the emergence of all complex relations, and further investigations were carried out with the teaching of simpler intraverbal relations of the type of exemplars and categories before the cycles of reading sentences – probing complex ABC intraverbals. Data indicated that more learners showed the emergence of all, or nearly all, complex relations. The present study comprised two systematic replication experiments, with the inclusion of a child with ASD as participant. Both also involved the teaching of sentence reading and retelling through script fading, to analyze the effects of narrative production on the possible emergence of complex intraverbals. In Experiment 1, cycles of teaching sentence reading and retelling – probing ABC intraverbals were administered. As a result, all possible complex relations emerged. Experiment 2 involved the teaching of simpler intraverbal relations of the type of exemplars and categories before the cycles of teaching sentence reading and retelling – probing ABC intraverbals. All possible complex intraverbal relations also emerged. Data were discussed in the sense that, although positive, it is not clear whether the teaching of sentence retelling and simpler intraverbal relations facilitated the establishment of the complex intraverbals. It is possible that reading the sentences was sufficient. The limitations of the research were presented and discussed, as well as recommendations for future investigations that may more clearly isolate the effects of each manipulated independent variable. Anyway, the current study extended previous investigations by showing that complex intraverbal relations of the ABC type may also be established in a learner diagnosed with ASD.<p> </p><p><strong> Article visualizations:</strong></p><p><img src="/-counters-/soc/0019/a.php" alt="Hit counter" /></p>

Effects of Weizhuan'an on rats with precancerous lesions of gastric cancer based on regulating gastric mucosal microflora and inflammatory factors.

This study aimed to observe the intervention of Weizhuan'an prescription on rats with precancerous lesions of gastric cancer (PLGC) as well as its regulation on gastric mucosal microflora and inflammatory factors and explore the pharmacodynamic mechanisms of Weizhuan'an Formula. The rats were classified into the blank control group (BCG); low-, medium-, and high-dose groups of Weizhuan'an prescription (LDG, MDG, and HDG, respectively); and natural recovery group (NRG) at random. The rats in the traditional Chinese medicine (TCM) group were given corresponding doses of Weizhuan'an formula, while the rats in the NRG and BCG were given an equivalent volume of distilled water for 12weeks. After that, gastric mucosa samples of rats were collected to observe the general and pathological changes in the gastric mucosa; the changes in gastric mucosal microflora were detected by 16S rDNA amplicon sequencing, and the inflammatory factors were analyzed by cytokine antibody microarray and Western blotting. The results suggest that compared with the BCG, the pathology of gastric mucosa and gastric mucosal microflora and inflammatory factors in rats with PLGC have changed significantly, while Weizhuan'an formula effectively improved them, especially in the MDG and HDG (p < 0.05). Compared with the NRG, the abundance of probiotics such as Lactobacillus and Veillonella were increased, while the abundance of pathogens such as Proteobacteria and Pseudomonas was decreased (p < 0.05, p < 0.01), and the relative contents of IL-2, IL-4, IL-13, and MCP-1 in gastric mucosa were decreased (p < 0.05). Moreover, it can upregulate the DNA-binding transcriptional regulator, ABC type multidrug transport system, and related enzymes and affect the signaling pathways such as viral protein interaction with cytokine and cytokine receptor and T cell receptor signaling pathway significantly (p < 0.05, p < 0.01), which can promote drug absorption and utilization and repair damaged gastric mucosa. The study confirmed that Weizhuan'an prescription can treat rats with PLGC by regulating gastric mucosal microflora and inflammatory factors.

Cyclic ether and anhydride ring opening copolymerisation delivering new ABB sequences in poly(ester-alt-ethers).

Poly(ester-alt-ethers) are interesting as they combine the ester linkage rigidity and potential for hydrolysis with ether linkage flexibility. This work describes a generally applicable route to their synthesis applying commercial monomers and yielding poly(ester-alt-ethers) with variable compositions and structures. The ring-opening copolymerisation of anhydrides (A), epoxides (B) and cyclic ethers (C), using a Zr(iv) catalyst, produces either ABB or ABC type poly(ester-alt-ethers). The catalysis is effective using a range of commercial anhydrides (A), including those featuring aromatic, unsaturated or tricyclic monomers, and with different alkylene oxides (epoxides, B), including those featuring aliphatic, alkene or ether substituents. The range of effective cyclic ethers (C) includes tetrahydrofuran, 2,5-dihydrofuran (DHF) or 1,4-bicyclic ether (OBH). In these investigations, the catalyst:anhydride loadings are generally held constant and deliver copolymers with degrees of copolymerisation of 25, with molar mass values from 4 to 11 kg mol-1 and mostly with narrow dispersity molar mass distributions. All the new copolymers are amorphous, they show the onset of thermal decomposition between 270 and 344 °C and variable glass transition temperatures (-50 to 48 °C), depending on their compositions. Several of the new poly(ester-alt-ethers) feature alkene substituents which are reacted with mercaptoethanol, by thiol-ene processes, to install hydroxyl substituents along the copolymer chain. This strategy affords poly(ether-alt-esters) featuring 30, 70 and 100% hydroxyl substituents (defined as % of monomer repeat units featuring a hydroxyl group) which moderate physical properties such as hydrophilicity, as quantified by water contact angles. Overall, the new sequence selective copolymerisation catalysis is shown to be generally applicable to a range of anhydrides, epoxides and cyclic ethers to produce new families of poly(ester-alt-ethers). In future these copolymers should be explored for applications in liquid formulations, electrolytes, surfactants, plasticizers and as components in adhesives, coatings, elastomers and foams.

Comparative metaproteomics reveal co-contribution of onion maggot and its gut microbiota to phoxim resistance

Pesticide resistance inflicts significant economic losses on a global scale each year. To address this pressing issue, substantial efforts have been dedicated to unraveling the resistance mechanisms, particularly the newly discovered microbiota-derived pesticide resistance in recent decades. Previous research has predominantly focused on investigating microbiota-derived pesticide resistance from the perspective of the pest host, associated microbes, and their interactions. However, a gap remains in the quantification of the contribution by the pest host and associated microbes to this resistance. In this study, we investigated the toxicity of phoxim by examining one resistant and one sensitive Delia antiqua strain. We also explored the critical role of associated microbiota and host in conferring phoxim resistance. In addition, we used metaproteomics to compare the proteomic profile of the two D. antiqua strains. Lastly, we investigated the activity of detoxification enzymes in D. antiqua larvae and phoxim-degrading gut microbes, and assessed their respective contributions to phoxim resistance in D. antiqua. The results revealed contributions by D. antiqua and its gut bacteria to phoxim resistance. Metaproteomics showed that the two D. antiqua strains expressed different protein profiles. Detoxifying enzymes including Glutathione S-transferases, carboxylesterases, Superoxide Dismutase, Glutathione Peroxidase, and esterase B1 were overexpressed in the resistant strain and dominated in differentially expressed insect proteins. In addition, organophosphorus hydrolases combined with a group of ABC type transporters were overexpressed in the gut microbiota of resistant D. antiqua compared to the sensitive strain. 85.2% variation of the larval mortality resulting from phoxim treatment could be attributed to the combined effects of proteins from both from gut bacteria and D. antiqua, while the individual contribution of proteins from gut bacteria or D. antiqua alone accounted for less than 10% of the variation in larval mortality caused by phoxim. The activity of the overexpressed insect enzymes and the phoxim-degrading activity of gut bacteria in resistant D. antiqua larvae were further confirmed. This work enhances our understanding of microbiota-derived pesticide resistance and illuminates new strategies for controlling pesticide resistance in the context of insect-microbe mutualism.

Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.

Mathematical Model on Minimality of Vaccination Costs of Covid-19 Using Fractional Order

An extremely efficient method of halting the horrible spread of pandemics is vaccination. This research investigates the cost-effectiveness of vaccine doses using a fractional-order commensurate model. The ABC type fract-integrals of COVID-19 multi-compartmental model is used to investigate the efficacy of vaccination dosages, vaccine shortages, and dose distribution. In order to assess the costs of vaccination and its use to combat COVID-19 in India, we created a fractional order model with 4 compartments of vaccinated and people waiting for booster shots have beed framed. Vaccination cost control model for this study is designed and analysed through the existence, stability and threshold measures. Through numerical convergence and simulations, the increase in disease severity brought on by microbial pathogens is investigated. Using fixed point theorems, the existence and singularity of the solution space for the framed model are assessed. Inventory control entropy on fractional derivative is used to assess the minimisation of vaccine costs

Multiband acoustic reflection metasurface with split hollow cubic

A kind of acoustic metasurface (AMS) with multiple response frequency bands based on the replace method was proposed, which composed of six units, each containing three split hollow cubics (SHCs) (denoted as the AAA type of AMS). The simulation results demonstrated that the presented AMS can achieve the flexible modulation of the reflected wave direction. The AAA type of AMS had one response band, the AAC type of AMS had two different response bands, and the ABC type of AMS had three different response bands. Furthermore, the response bandwidth of the ABC type of AMS declined the most in the middle-frequency band, followed in the low-frequency band, and the least in the high-frequency band, when compared to the corresponding AAA type of AMS with single bandwidth. In addition, it was worth noting that the ABC type of AMS not only enlarged the manipulation direction of reflected acoustic wave, but also improved the effects of the wavefront distribution at the same frequency. This multiple band AMS will be beneficial for the application of architectural acoustics, and acoustic absorption and noise reduction.

Polymer membrane based on ABC type triblock co-polymer for safer lithium-ion solid-state batteries

Polymer membrane based on ABC type triblock co-polymer for safer lithium-ion solid-state batteries

Functional consequences of inhibition of Bruton's tyrosine kinase by ibrutinib in chronic lymphocytic leukemia.

The leukemic B cells from patients with chronic lymphocytic leukemia (CLL) require interactions with non-malignant cells and matrix in the tissue microenvironment to survive and grow. These interactions are mediated through the B-cell antigen receptor (BCR), C-X-C chemokine receptor type 4 (CXCR4), and a variety of integrins, including VLA-4. Exciting each receptor type leads to activation of Bruton's tyrosine kinase (BTK), which in turn helps initiate trophic signals that prevent cell death and promote cell activation and growth as well as allowing cells to return to anatomic sites for rescue signals. These represent the two major functional actions targeted by inhibitors of Btk. Here we relate some of the therapeutic actions of ibrutinib, a Btk inhibitor that is extremely helpful for patients with CLL, certain Diffuse Large B-cell Lymphomas (ABC type), and other non-Hodgkin's lymphomas, emphasizing that ibrutinib's value results from blocking beneficial signals, not by inducing lethal ones.

Solution of fractional Sawada–Kotera–Ito equation using Caputo and Atangana–Baleanu derivatives

In the present work, the fractional‐order Sawada–Kotera–Ito problem is solved by considering nonlocal Caputo and nonsingular Atangana–Baleanu (ABC) derivatives. The methodology used is an application of the Shehu transform and the Adomian decomposition method. The obtained solution is more accurate when using the ABC type derivative as compared to the Caputo sense, when using the proposed ADShTM method (Adomian decomposition Shehu transform method). The results so obtained by the ADShTM using Caputo and ABC operators are compared, establishing the superiority of the proposed method. The numerical results demonstrate that the application of the ABC derivative is not only relatively more effective and reliable but also straightforward to achieve high precision solution.

Phenotypes characterization and ABC genotypes distribution of clinical Candida albicans isolates.

Candidemia and vaginitis are the most common types of candidiasis mostly caused by Candida albicans species. C. albicans has several genotypes and the potential ability to form different phenotype colonies on specific media. This study aimed to evaluate the genotype distribution of blood and vaginal C. albicans isolates and phenotype characteristics on Spider and yeast peptone dextrose agar medium. A total of 40 clinical Candida albicans isolates comprising vagina (20) and blood (20) were used. ABC typing using CA-INT-R and CA-INT-L primers was performed to span the transposable group I intron of the 25S rDNA gene. For colony phenotypic characteristics, the Spider and YPDA media were used. Among the blood and vaginal isolates, genotype A (12/60%) and genotype C (10/50%) were the most common types, respectively. The highest phenotype shape frequency of the colonies in blood and vaginal samples was the ring and the lowest was the hat/ring. The dominant color phenotype in blood and vaginal samples was gray. There was a significant relationship between genotype and phenotype forms in the blood sample on YPDA medium (p = 0.02). In the Spider medium, there were no significant differences between genotypes and phenotypes. In this study, genotype A and genotype C were predominant in blood and vaginal samples, respectively. In both groups, YPD agar medium demonstrated the most variety of phenotypes that was related to genotypes A and C. The variety of phenotypes in both groups was the same in genotypes A and C on the Spider medium.

Thermal and Bulk Properties of Triblock Terpolymers and Modified Derivatives towards Novel Polymer Brushes.

We report the synthesis of three (3) linear triblock terpolymers, two (2) of the ABC type and one (1) of the BAC type, where A, B and C correspond to three chemically incompatible blocks such as polystyrene (PS), poly(butadiene) of exclusively (~100% vinyl-type) -1,2 microstructure (PB1,2) and poly(dimethylsiloxane) (PDMS) respectively. Living anionic polymerization enabled the synthesis of narrowly dispersed terpolymers with low average molecular weights and different composition ratios, as verified by multiple molecular characterization techniques. To evaluate their self-assembly behavior, transmission electron microscopy and small-angle X-ray scattering experiments were conducted, indicating the effect of asymmetric compositions and interactions as well as inversed segment sequence on the adopted morphologies. Furthermore, post-polymerization chemical modification reactions such as hydroboration and oxidation were carried out on the extremely low molecular weight PB1,2 in all three terpolymer samples. To justify the successful incorporation of -OH groups in the polydiene segments and the preparation of polymeric brushes, various molecular, thermal, and surface analysis measurements were carried out. The synthesis and chemical modification reactions on such triblock terpolymers are performed for the first time to the best of our knowledge and constitute a promising route to design polymers for nanotechnology applications.

WORKING WITH VIDEO IN ASSESSMENT AND PSYCHOTHERAPY OF AFFECTIVE-BEHAVIORAL DEVELOPMENT DISORDERS

The included therapeutic observation with videography and analysis of video recordings of patients’ behavior during the psychotherapeutic consultations provides a convincing alternative to cognitive and verbal methods of studying affect and behavior. This refers especially to the patients of early age and the ones with severe disorders of affect and behavior. The nature of affect is easier and more natural to detect by a method that directly elicits and works with it and is sensitive to current changes in a child’s emotional states. We propose a new direction – the use of videography and analysis of video recordings of a child’s behavior in the framework of psychotherapeutic consultations with the open participation of the operator. The analysis uses the author’s dynamic classifi cation of affective-behavioral development with a qualitative-quantitative form of results’ presentation. The data show the directions of development in different affective-behavioral complexes (ABC, Bardyshevskaya, -). Each ABC is determined by its motive of development. The ABC includes a special repertoire of emotions, behaviors, connections with objects and people (types of connections within each ABC and with other ABC refl ect them), symbolic activity, ways to prevent emotional breakdowns. There are  early-forming ABCs: the ABC of psychophysiological survival, the symbiosis-based ABC, the ABC of expansion, the play-dialogue and attachment ABC, the role-play ABC. According to the dynamics of emotions, behavior, contact, symbolic activity, the vectors of development of  types of behavior are defi ned. The central vector of abnormal development is distortion. The vectors going from it and to it (from high norm, norm, delay, damage, decay to distortion, and in the opposite direction) are easily seen in video and can be used for prognosis of further development. We spread N.A.Bernstein’s idea of the role of anticipation and an image of the future in the construction of movements to the whole development, which is at least partly under child’s choice and control. An open video recording of a consultation has therapeutic impact for the child: general activation, disclosure of latent, incomplete patterns, opening of hidden achievements, strengthening of refl ection and forming autobiographical memory. Analysis of video recordings according to the suggested scheme has advantages: () accuracy and funding of diagnostics due to expert evaluation, a directed selection of episodes (for the certain ABC and for the certain vector of development); () fl exibility: from express diagnostics (just the dominant and leading ABCs at the moment, the birth and dynamics of a new behaviour) to a longitudinal study, confi rming the primary short assessment; () unique diagnostics of the symbolizing of current experience; () refi ned selection of optimal therapeutic loads. For students video study of previously identifi ed and systematized developmental patterns gives a time-saving and deeper alternative to traditional perennial supervisions “in words”. We do such trainings at the psychology department at Moscow State University. More information can be found in the author’s book “Videography of development and analysis of video recordings in clinical psychology” (Bardyshevskaya M., Moscow University Publishing House, ).

Genotyping of candida albicans isolates obtained from vulvovaginal candidiasis patients in Zanjan, Iran, based on ABC and RPS typing systems.

Genotyping of pathogenic microorganisms is important for epidemiological studies and the adoption of appropriate strategies to control infectious diseases. In this regard, the present study aimed to genotype Candida albicans strains isolated from vulvovaginal candidiasis (VVC) patients using combined ABC type (25SrDNA) and repetitive sequence (RPS) typing systems. using combined typing systems of ABC type (25SrDNA) and repetitive sequence (RPS). In total, 140 patients with VVC were investigated. Vaginal discharges were collected on Sabouraud dextrose agar and identified by CHROMagar. After species identification, a polymerase chain reaction system targeting 25S rDNA as well as ALT repeats in the RPS was designed to determine C. albicans genotypes. The dendrogram was constructed by zero-one matrix data based on the combination of ABC and RPS typing systems. Statistical analysis of data was performed in SPSS software (version 23). In total, 41 (29.3%) Candida isolates were obtained from 140 VVC patients. The most common Candida species that were identified included C. glabrata (56.1%) and C. albicans (39%). Genotype A3 with five isolates (31.25%) had the highest frequency, followed by B2/3 with three isolates (18.3%), A3/4, C3/4, and B3/4 with two isolates (12.5%), and C2/3 and C3 with one isolate (6.25%), respectively. No significant association was found between the genotypes and antifungal resistance (P<0.05). The results showed that non-albicans Candida species are more prevalent in VVC patients, compared to C. albicans. The results also indicated that ABC and RPS typings are useful for rapid genotyping and differentiation of C. albicans isolates in regional and small-scale studies.

New Multidrug Efflux Systems in a Microcystin-Degrading Bacterium Blastomonas fulva and Its Genomic Feature.

A microcystin-degrading bacterial strain, Blastomonas fulva T2, was isolated from the culture of a microalgae Microcystis. The strain B. fulva T2 is Gram-stain-negative, non-motile, aerobic, non-spore-forming and phototrophic. The cells of B. fulva T2 are able to grow in ranges of temperature from 15 to 37 °C, with a pH of 6 to 8 and a salinity of 0 to 1% NaCl. Here, we sequenced the complete genome of B. fulva T2, aiming to better understand the evolutionary biology and the function of the genus Blastomonas at the molecular level. The complete genome of B. fulva T2 contained a circular chromosome (3,977,381 bp) with 64.3% GC content and a sizable plasmid (145.829 bp) with 60.7% GC content which comprises about 3.5% of the total genetic content. A total of 3842 coding genes, including 46 tRNAs and 6 rRNAs, were predicted in the genome. The genome contains genes for glycolysis, citric acid cycle, Entner–Doudoroff pathways, photoreaction center and bacteriochlorophylla synthesis. A 7.9 K gene cluster containing mlrA, mlrB, mlrC and mlrD1,2,3,4 of microcystin-degrading enzymes was identified. Notably, eight different efflux pumps categorized into RND, ABC and MFS types have been identified in the genome of strain T2. Our findings should provide new insights of the alternative reaction pathway as well as the enzymes which mediated the degradation of microcystin by bacteria, as well as the evolution, architectures, chemical mechanisms and physiological roles of the new bacterial multidrug efflux system.

Abstract A07: BTM 3566, a novel activator of the mitochondrial stress response promotes robust therapeutic responses in vitro and in vivo in diffuse large B-cell lymphoma

Abstract Relapsed/refractory diffuse large B-cell lymphomas (r/r-DLBCL) are a therapeutic challenge as they are highly heterogeneous both clinically and molecularly, which imposes a pressing need to develop novel therapies to improve outcomes in patients independently of the molecular subtype. We describe here BTM-3566, a first-in-class, orally active compound with activity against DLBCL. BTM-3566 induces apoptosis and complete cell killing in DLBCL lines a with an IC50 of ~200 – 500 nM. Responsive DLBCL cell lines include ABC, GCB, and double-hit and triple-hit lymphoma type. Pharmacokinetic studies in mice showed suitability for once daily dosing, with &amp;gt; 50% oral bioavailability and ~6 hours of serum half-life. In xenograft models using the double-hit DLBCL line SU-DHL-10, BTM-3566 treatment resulted in complete response in all tumor-bearing animals and durable remission in 50% of animals with no tumor growth occurring for 2 weeks after dose cessation. Expansion studies into human DLBCL PDX models harboring a range of high-risk genomic alterations demonstrated response in 100% of the lines with complete response in 6 of 9 PDX models tested. Dose scheduling studies indicate that 7 days of continuous dosing is sufficient to induce tumor regression and maintenance of a complete response. The therapeutic activity of BTM-3566 is related to a novel effect on mitochondrial proteostasis and a robust induction of the ATF4 ISR. Of the four eIF2α -kinases in the human genome we determined that HRI was uniquely required for BTM-3566 activity in DLBCL. HRI is activated by mitochondrial-related stress resulting in activation of the mitochondrial protease OMA1. Molecular analysis revealed that BTM-3566 activates OMA1, leading to induction of the ATF4 ISR pathway and apoptosis in DLBCL cell lines. Deletion of OMA1 reduces the ability of BTM-3566’s to induce apoptosis in DBLCL. Substrates of OMA1 include the dynamin OPA1 and DELE1, a protein recently shown to signal mitochondrial dysfunction through activation of HRI kinase and ATF4. Transfection of BJAB cells with a cleavage resistant OPA1 mutant has no effect on BTM-3566 induced apoptosis. In contrast, DELE1 KO suppresses BTM-3566 mediated apoptosis. BTM-3566 activates OMA1 without acting as a classical mitochondrial toxin. Instead, BTM-3566 induces OMA1 activity through a novel mechanism regulated by the mitochondrial protein FAM210B. FAM210B expression is negatively correlated with response to BTM-3566, and overexpression of FAM210B blocks OMA1 activation and causes complete resistance to BTM-3566 induced apoptosis. Taken together, these data support a novel antitumor mechanism in DLBCL, where BTM3566 induces mitochondrial stress, activating the OMA1-DELE1-HRI-eIF2a-ATF4 pathway leading to apoptosis and tumor regression. An Investigational New Drug application for BTM3566 in B-cell malignancies will be submitted in Q2 2022 with initiation of first in human clinical trials planned for fall 2022. Citation Format: Adrian Schwarzer, Matheus Oliveira, Marc-Jens Kleppa, Andy Anantha, Alan Cooper, Mark Hannink, Todd Hembrough, Jedd Levine, Michael Luther, Michael Stocum, Linsey Stiles, Marc Liesa-Roig, Matthew Kostura. BTM 3566, a novel activator of the mitochondrial stress response promotes robust therapeutic responses in vitro and in vivo in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A07.

Helicobacter Pylori Genotyping Among Mongolian Dyspeptic Patients

Objective: The prevalence of H. pylori infection varies significantly and developing countries are found to be the highest in Asia. In the present study, we have aimed to perform a combined analysis of histochemical stains and IHC to confirm the H.pylori infection of patients in 5 different provinces and Ulaanbaatar city, Mongolia. Method: Five hundred and thirty-eight patients were enrolled in this study (142 gastric mucosal atrophy, 333 gastritis and 62 gastroesophageal reflux). Results: 67.1 % of participants had CagA positive and 69.3 % were immunohistochemically positive. All histological results showed that the gastritis group was significantly higher in patients who were positive for H. pylori than in antral-predominant gastritis. By the hematoxylin and eosin staining with May– Giemsa confirmation by IHC, the prevalence of H. pylori infection in the gastric mucosal atrophy group was 62.1 %, while in the gastritis and gastroesophageal reflux group, the rate was 74.3 % and 59.1 %, respectively. Conclusion: CagA sequence profile in each group of patients revealed that 22.6 % of the gastric mucosal atrophy group was ABC type, 43.4 % was ABCC type and 33.9 % was ABTC type. On the other hand, in the gastritis group, the dominant type was ABTC (41.3 %). In the gastroesophageal reflux group, the ABCC type was dominant while 23.1% was the ABC type.

Abstract 3271: BRD4 inhibition enhances the acalabrutinib tumor response by modulating PAX5 and interferon signaling in ABC-DLBCL

Abstract AZD5153 is a bivalent bromodomain and extraterminal (BET) inhibitor that simultaneously engages the two bromodomains of bromodomain-containing protein 4 (BRD4). Here, we initially tested AZD5153 in combination with acalabrutinib, a Bruton tyrosine kinase (BTK) inhibitor, in a panel of diffuse large B-cell lymphoma (DLBCL) cell lines. The ABC type DLBCL cells responded to the AZD5153 and acalabrutinib combination at lower drug concentrations compared to other DLBCL cell lines. Many of these lower concentrations were below the clinical equivalent dose for each drug. Similar results were achieved in DLBCL patient-derived xenografts, with most ABC-DLBCL tumors having more growth inhibition than the other B-cell lymphoma tumors after combination dosing at fixed concentrations. To delineate the mechanism of ABC-subtype preference for combination therapy, we performed RNA sequencing on ABC-DLBCL tumor samples treated with AZD5153, acalabrutinib, and the combination of AZD5153 and acalabrutinib. Pathway meta-analyses identified significant alterations of PAX5 signaling and interferon pathways in combination-treated tumors compared to monotherapy-treated samples. PAX5 is a key gene for B-cell activation and is associated with lymphoma pathogenesis. Protein levels of PAX5 and corresponding downstream transcription targets were also decreased by the combination of AZD5153 and acalabrutinib in ABC-DLBCL cell lines. In addition, STAT proteins related to PAX5 activation, the alternative RelB-NFκB pathway, and toll-like receptors in the interferon type I pathway were also modulated at the protein level by this drug combination in ABC-DLBCL cell lines. We hypothesized the AZD5153 and acalabrutinib combination induces changes to interferon signaling that impacts PAX5 activation. This mechanism is supported by evidence of AZD5153 and acalabrutinib combination-induced downregulation of interferons alpha and beta, as well as interferon gamma and IP-10 in vivo. In summary, our results demonstrate AZD5153 enhances the efficacy of acalabrutinib, and our in vitro data suggest adding AZD5153 to acalabrutinib concentrations much lower than the clinical equivalent dose results in a similar biomarker response. We show that this drug combination attenuates interferon signaling, which supports the mechanism of AZD5153 and acalabrutinib inhibiting PAX5 signaling in ABC-DLBCL. Citation Format: Derek B. Oien, Samanta Sharma, Ye Xu, Maureen Hattersley, Michelle DuPont, Kathleen Burke, Steven W. Criscione, Laura Prickett, Jingwen Zhang, Ho Man Chan, Lisa Drew, Yi Yao. BRD4 inhibition enhances the acalabrutinib tumor response by modulating PAX5 and interferon signaling in ABC-DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3271.