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Since 2007, diamide insecticides have been widely used in Korea to control various types of lepidopteran pests including Spodoptera exigua. For nearly a decade, diamide resistance in field populations of S. exigua across 18 localities has been monitored using bioassays. Despite their short history of use, resistance to diamide insecticides has emerged. Based on the LC50 values, some field populations showed a higher level of resistance to chlorantraniliprole, a diamide insecticide, compared to that of the susceptible strain, although regional and temporal variations were observed. To investigate resistance at a molecular level, we examined three mutations (Y4701C, I4790M, and G4946E) in the ryanodine receptor (RyR), which is the primary mechanism underlying diamide insecticide resistance. DNA sequencing showed that only the I4790M mutation was found in most field populations. As resistance levels varied significantly despite the uniform presence of the I4790M mutation, we considered the presence of another resistance factor. Further, the I4790M mutation was also found in S. exigua specimens collected prior to the commercialization of diamide insecticides in Korea as well as in other countries, such as the USA. This finding led us to hypothesize that the I4790M mutation were predisposed in field populations owing to selection factors other than diamide use. For further clarification, we conducted whole-genome sequencing of S. exigua (449.83 Mb) and re-sequencing of 18 individual whole genomes. However, no additional non-synonymous mutations were detected in the RyR-coding region. Therefore, we concluded that the high level of diamide insecticide resistance in Korean S. exigua is not caused by mutations at the target site, RyR, but is attributed to other factors that need to be investigated in future studies.
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Inseticidas , Canal de Liberação de Cálcio do Receptor de Rianodina , Animais , Spodoptera/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Museus , Diamida/farmacologia , Inseticidas/farmacologiaRESUMO
Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase against type 2 diabetes through molecular docking, molecular dynamics simulation, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The molecule apigenin-7-O-glucoside showed the highest binding affinity among 123 (one hundred twenty-three) tested compounds. This compound simultaneously bound with the two-target proteins alpha-amylase and alpha-glucosidase, with high molecular mechanics-generalized born surface area (MM/GBSA) values (ΔG Bind = -45.02 kcal mol-1 for alpha-amylase and -38.288 for alpha-glucosidase) compared with control inhibitor acarbose, which had binding affinities of -36.796 kcal mol-1 for alpha-amylase and -29.622 kcal mol-1 for alpha-glucosidase. The apigenin-7-O-glucoside was revealed to be the most stable molecule with the highest binding free energy through molecular dynamics simulation, indicating that it could compete with the inhibitors' native ligand. Based on ADMET analysis, this phytochemical exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities and had no significant side effects, making them prospective drug candidates for type 2 diabetes. Additional in vitro, in vivo, and clinical investigations are needed to determine the precise efficacy of drugs.
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Diabetes Mellitus Tipo 2 , Piper betle , Apigenina/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismoRESUMO
Genome-wide long non-coding RNAs (lncRNAs) in low, moderate, and high pyrethroid insecticide-resistant and -susceptible strains of Helicoverpa armigera were identified in this study. Using 45 illumina-based RNA-sequencing datasets, 8394 lncRNAs were identified. In addition, a sublethal dose of deltamethrin was administered to a Korean-resistant strain (Kor-T). The average length of lncRNAs was approximately 531 bp, and the expression ratio of lncRNAs was 28% of the total RNA. The identified lncRNAs were divided into six categories-intronic, intergenic, sense, antisense, cis-RNA, and trans-RNA-based on their location and mechanism of action. Intergenic and intronic lncRNA transcripts were the most abundant (38% and 33%, respectively). Further, 828 detoxification-related lncRNAs were selected using the Gene Ontology analysis. The cytochrome P450-related lncRNA expression levels were significantly higher in susceptible strains than in resistant strains. In contrast, cuticle protein-related lncRNA expression levels were significantly higher in all resistant strains than in susceptible strains. Our findings suggest that certain lncRNAs contribute to the downregulation of insecticide resistance-related P450 genes in susceptible strains, whereas other lncRNAs may be involved in the overexpression of cuticle protein genes, potentially affecting the pyrethroid resistance mechanism.
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BACKGROUND: The Oriental tobacco budworm, Helicoverpa assulta, a specialist herbivorous insect that exclusively feeds on plants of the Solanaceae family, causes considerable damage to crops, such as tobacco and hot pepper. The absence of a genome sequence for this species hinders further research on its pest management and ecological adaptation. RESULTS: Here, we present a high-quality chromosome-level genome of a Korean strain of H. assulta (Pyeongchang strain, K18). The total assembly spans 424.4 Mb with an N50 length of 14.54 Mb and 37% GC content. The assembled genome (ASM2961881v1) comprises 31 chromosomes, similar to other congeneric generalist species including H. armigera and H. zea. In terms of genomic assembly quality, the complete BUSCOs and repeat content accounted for 98.3% and 33.01% of the genome, respectively. Based on this assembly, 19 485 protein-coding genes were predicted in the genome annotation. A comparative analysis was conducted using the identified number of protein-coding genes in H. armigera (24154) and H. zea (23696). Out of the 19 485 predicted genes, 137 genes in 15 orthogroups were found to have expanded significantly in H. assulta, while 149 genes in 95 orthogroups contracted rapidly. CONCLUSION: This study revealed specific gene expansions and contractions in H. assulta compared to those in its close relatives, indicating potential adaptations related to its specialized feeding habits. Also, the comparative genome analysis provides valuable insights for the integrated pest management of H. assulta and other globally significant pests in the Heliothinae subfamily. © 2024 Society of Chemical Industry.
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Climate change-induced saline intrusion into both surface and groundwater, extreme weather events, and unregulated water usage are serious threats to the drinking water supply in coastal areas worldwide, especially in least-developed countries. This research developed a data-driven decision-making methodology to evaluate the performance of rainwater harvesting (RWH) systems in the saline-prone southwestern coastal region of Bangladesh. Twenty-five community managed RWH systems, recently piloted in two major coastal districts, were considered the case study to develop and validate this evaluation tool. The evaluation methodology integrates daily water models, lifetime cost analysis, Geographic Information System (GIS)-based parameters supported by the Analytical Hierarchy Process (AHP), and field observation. While the meteorological parameters as well as the hydrological and economic performance were found to be highly suitable, 36 % of the systems showed moderate performance, as challenges remain in ensuring proper operation and maintenance practices at the community level. However, 40 % of the systems showed high performance, with two systems showing very high suitability, which suggests community managed RWH systems as a sustainable adaptation for coastal water supply.
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Lumpy skin disease (LSD), caused by a virus within the Poxviridae family and Capripoxvirus genus, induces nodular skin lesions in cattle. This spreads through direct contact and insect vectors, significantly affecting global cattle farming. Despite the availability of vaccines, their efficacy is limited by poor prophylaxis and adverse effects. Our study aimed to identify the potential inhibitors targeting the LSDV-encoded DNA polymerase protein (gene LSDV039) for further investigation through comprehensive analysis and computational methods. Virtual screening revealed rhein and taxifolin as being potent binders among 380 phytocompounds, with respective affinities of -8.97 and -7.20 kcal/mol. Canagliflozin and tepotinib exhibited strong affinities (-9.86 and -8.86 kcal/mol) among 718 FDA-approved antiviral drugs. Simulating the molecular dynamics of canagliflozin, tepotinib, rhein, and taxifolin highlighted taxifolin's superior stability and binding energy. Rhein displayed compactness in RMSD and RMSF, but fluctuated in Rg and SASA, while canagliflozin demonstrated stability compared to tepotinib. This study highlights the promising potential of using repurposed drugs and phytocompounds as potential LSD therapeutics. However, extensive validation through in vitro and in vivo testing and clinical trials is crucial for their practical application.
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Asian planthoppers (Hemiptera: Delphacidae) that include brown planthoppers (BPH, Nilaparvata lugens, Stål), white-backed planthoppers (WBPH, Sogatella furcifera, Horváth), and small brown planthoppers (SBPH, Laodelphax striatellus, Fallén) are the primary sucking-type pests of rice. These three insects share morphological and sequence similarities. As insecticide resistance patterns and control strategies vary according to species, the accurate discrimination of these species is important. Here, we developed six species-specific primers based on partial mitochondrial genome sequences. The primers were successfully used in multiplex PCR, loop-mediated isothermal amplification (LAMP) assays, and conventional PCR. Here, we used genomic DNA obtained using the DNA-releasing technique (tissue samples were incubated at 95 °C for 5 min with 30 µL nuclease-free water, and the supernatant was used). We showed that multiplex PCR could analyze the density of each species following a mass collection in the field; the LAMP assay can diagnose the species within 40 min; conventional PCR can be widely applied to a large number of field samples, as well as individuals or mass collections. In conclusion, these results demonstrate the potential of the species-specific primers and DNA-releasing technique for accurate multiplex PCR and LAMP assays, which may assist the intensive field monitoring of integrated management of these species.
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Aedes albopictus is native to Southeast Asia and has emerged as a major vector for vector-borne diseases that are spreading rapidly worldwide. Recent studies have shown that Ae. albopictus populations have different genetic groups dependent on their thermal adaptations; however, studies on Korean populations are limited. In this study, we analyzed the genetic diversity and structure of two mitochondrial genes (COI and ND5) and sixteen microsatellites in mosquitoes inhabiting Korea, Japan, and Laos. The results indicate that the Korean population has low genetic diversity, with an independent cluster distinct from the Laos population. Mixed clusters have also been observed in the Korean population. On the basis of these findings, two hypotheses are proposed. First, certain Korean populations are native. Second, some subpopulations that descended from the metapopulation (East Asian countries) were introduced to Japan before migrating to Korea. Furthermore, we previously demonstrated that Ae. albopictus appears to have been imported to Korea. In conclusion, the dengue-virus-carrying mosquitoes could migrate to Korea from Southeast Asian epidemic regions, where they can survive during the severe winter months. The key findings can be used to establish an integrated pest management strategy based on population genetics for the Korean Ae. albopictus population.
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Polydnaviruses (PDVs) exhibit species-specific mutualistic relationships with endoparasitoid wasps. PDVs can be categorized into bracoviruses and ichnoviruses, which have independent evolutionary origins. In our previous study, we identified an ichnovirus of the endoparasitoid Diadegma fenestrale and named it DfIV. Here, DfIV virions from the ovarian calyx of gravid female wasps were characterized. DfIV virion particles were ellipsoidal (246.5 nm × 109.0 nm) with a double-layered envelope. Next-generation sequencing of the DfIV genome revealed 62 non-overlapping circular DNA segments (A1-A5, B1-B9, C1-C15, D1-D23, E1-E7, and F1-F3); the aggregate genome size was approximately 240 kb, and the GC content (43%) was similar to that of other IVs (41%-43%). A total of 123 open reading frames were predicted and included typical IV gene families such as repeat element protein (41 members), cysteine motif (10 members), vankyrin (9 members), polar residue-rich protein (7 members), vinnexin (6 members), and N gene (3 members). Neuromodulin N (2 members) was found to be unique to DfIV, along with 45 hypothetical genes. Among the 62 segments, 54 showed high (76%-98%) sequence similarities to the genome of Diadegma semiclausum ichnovirus (DsIV). Three segments, namely, D22, E3, and F2, contained lepidopteran host genome integration motifs with homologous regions of about 36-46 bp between them (Diadegma fenestrale ichnovirus, DfIV and lepidopteran host, Plutella xylostella). Most of the DfIV genes were expressed in the hymenopteran host and some in the lepidopteran host (P. xylostella), parasitized by D. fenestrale. Five segments (A4, C3, C15, D5, and E4) were differentially expressed at different developmental stages of the parasitized P. xylostella, and two segments (C15 and D14) were highly expressed in the ovaries of D. fenestrale. Comparative analysis between DfIV and DsIV revealed that the genomes differed in the number of segments, composition of sequences, and internal sequence homologies.
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The fall armyworm (Spodoptera frugiperda, FAW) is an invasive migratory pest that has recently spread to Korea, damaging several corn cultivars with significant economic value. Comparisons of the growth stages of FAW were conducted based on the preferred feed. Therefore, we selected six maize cultivars, including three categories: (i) commercial waxy corn (mibaek 2-ho, heukjeom 2-ho, dreamoak); (ii) popcorn (oryun popcorn, oryun 2-ho); and (iii) processing corn (miheukchal). A significant effect was observed during the larvae period, pupal period, egg hatching ratio, and larvae weight, whereas the total survival period and adult period did not show significant variation among the tested corn cultivars. We identified variations in the FAW gut bacterial community that were dependent on the genotype of the corn maize feed. The identified phyla included Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes. Among these genera, the most abundant bacterial genus was Enterococcus, followed by Ureibacillus. Enterococcus mundtii was the most abundant among the top 40 bacterial species. The intergenic PCR-based amplification and gene sequence of the colony isolates were also matched to the GenBank owing to the prevalence of E. mundtii. These results showed that the bacterial diversity and abundance of particular bacteria in the guts of FAWs were influenced by the six major maize corn cultivars.
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Single-nucleotide polymorphisms (SNPs) are one of the most common forms of genetic variation and as such are powerful tools for the identification of bacterial strains, their genetic diversity, phylogenetic analysis, and outbreak surveillance. In this study, we used 15 sets of SNP-containing primers to amplify and sequence the target Escherichia coli. Based on the combination of the 15-sequence primer sets, each SNP site encompassing forward and reverse primer sequences (620-919 bp) were aligned and an SNP-based marker was designed. Each SNP marker exists in at least two SNP sites at the 3' end of each primer; one natural and the other artificially created by transition or transversion mutation. Thus, 12 sets of SNP primers (225-488 bp) were developed for validation by amplifying the target E. coli. Finally, a temperature gradient triplex PCR kit was designed to detect target E. coli strains. The selected primers were amplified in three genes (ileS, thrB, and polB), with fragment sizes of 401, 337, and 232 bp for E. coli O157:H7, E. coli, and E. coli O145:H28, respectively. This allele-specific SNP-based triplex primer assay provides serotype-specific detection of E. coli strains in one reaction tube. The developed marker would be used to diagnose, investigate, and control food-borne E. coli outbreaks.
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Ambiguous, heterogeneous, endospore-forming Bacillus species, notably Bacillus cereus, often produce fatal toxins that threaten human health. We identified Bacillus from wild animal fecal samples (n = 80), including the Korean water deer (n = 25) and striped field mouse (n = 55). Using traditional culture-based methods, 25 animal fecal samples (31.25%; 25/80) were found to be positive for Bacillus species, whereas using molecular techniques, 19 samples (23.75%; 19/80) were found to be positive for the same. In addition, we designed a Bacillus species-specific 16S ribosomal RNA (rRNA) gene marker and utilized it to identify 19 samples by means of PCR amplification and sequencing, using at least one colony from the 19 Bacillus positive samples. The recovered sequences were matched to sequences of three Bacillus species (B. cereus, B. amyloliquefaciens, and B. megaterium) from the GenBank database. Moreover, the phylogenetic tree generated in this study established specific clades for the Bacillus group. In addition, to differentiate between B. cereus, B. anthracis, and B. thuringiensis, we designed a single nucleotide polymorphism (SNP)-based primer by identifying SNPs in the alignment of 16S rRNA gene sequences of B. cereus group strains. The SNPs were used to design primer sets for discrimination between highly similar species from the B. cereus group. The study could be used in surveillance of agricultural fresh-produce-associated Bacillus outbreaks, for accurate identification of each Bacillus species, and in the development of control measures.
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A rapid and high-quality single-nucleotide polymorphisms (SNPs)-based method was developed to improve detection and reduce salmonellosis burden. In this study, whole-genome sequence (WGS) was used to investigate SNPs, the most common genetic marker for identifying bacteria. SNP-sites encompassing 15 sets of primers (666-863 bp) were selected and used to amplify the target Salmonella serovar strains, and the amplified products were sequenced. The prevalent Salmonella enterica subspecies enterica serovars, including Typhimurium; Enteritidis, Agona, enterica, Typhi, and Abony, were amplified and sequenced. The amplified sequences of six Salmonella serovars with 15 sets of SNP-sites encompassing primers were aligned, explored SNPs, and SNPs-carrying primers (23 sets) were designed to develop a multiplex PCR marker (m-PCR). Each primer exists in at least two SNPs bases at the 3' end of each primer, such as one was wild, and another was a mismatched base by transition or transversion mutation. Thus, twenty-three sets of SNP primers (242-670 bp), including 13 genes (SBG, dedA, yacG, mrcB, mesJ, metN, rihA/B, modA, hutG, yehX, ybiY, moeB, and sopA), were developed for PCR confirmation of target Salmonella serovar strains. Finally, the SNPs in four genes, including fliA gene (S. Enteritidis), modA (S. Agona and S. enterica), sopA (S. Abony), and mrcB (S. Typhimurium and S. Typhi), were used for detection markers of six target Salmonella serotypes. We developed an m-PCR primer set in which Salmonella serovars were detected in a single reaction. Nevertheless, m-PCR was validated with 21 Salmonella isolates (at least one isolate was taken from one positive animal fecal, and n = 6 reference Salmonella strains) and non-Salmonella bacteria isolates. The SNP-based m-PCR method would identify prevalent Salmonella serotypes, minimize the infection, and control outbreaks.
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The lockdown crisis due to novel coronavirus (COVID-19) mainly affected people who live under economic despair. Since boosting the immune system against the virus depends on a variety of food intake and lifestyle approaches; hence, it is crucial to know how daily food habits and lifestyle modification protect from pathogenic viral infections. This study focused on the benefit of plant-based foods, functional foods and the modified lifestyle which enhance the immunity of all aged groups against COVID-19 in Bangladesh. An online close-ended randomly selected structured multiple-choice questionnaire survey was conducted for people of different parts of Bangladesh (n = 161; male 51.55%, female 48.45%). The total percentage was counted for all variables. We found that plant-based foods, functional foods, and physical exercise played a vital role in enhancing people's immunity to control COVID-19. Plant-based micronutrients, nutraceuticals and antioxidants mainly took part to boost the immune system against the virus. Furthermore, physical activity had a vital role in improving people's immunity to manage COVID-19. Literature suggested that food habits, body immunity, awareness, stress and weight variation were affected by the COVID-19 pandemic. The vaccine or proper medication of COVID-19 still remains in an enigma. In this situation, boosting immunity to combat Coronavirus is the only way to survive.
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Non-typhoidal Salmonella (NTS) is one of the leading bacterial causes of many invasive human infections with a high antibiotic resistance profile. With this concern, the current study aimed to design an effective epitope-based peptide vaccine against NTS species as a successive and substitutive protective measure of invasive NTS disease. To design rationally, the current study considered a comprehensive in silico workflow combination of both immunoinformatics and molecular modeling approaches, including molecular docking and molecular dynamics (MD) simulation. We identified the two most promising T cell epitopes KVLYGIFAI and YGIFAITAL, and three B cell epitopes AAPVQVGEAAGS, TGGGDGSNT, and TGGGDGSNTGTTTT, in the outer membrane of NTS. Using these epitopes, a multiepitope vaccine was subsequently constructed along with appropriate adjuvant and linkers, which showed a good binding affinity and stability with toll-like receptor 2 (TLR2) in both molecular docking and MD simulation. Furthermore, in silico immune simulation described a strong immune response with a high number of antibodies, interferon-γ, and activated B and T cells. This study collectively suggests that predicted vaccine constructs could be considered potential vaccine candidates against common NTS species.Communicated by Ramaswamy H. Sarma.
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Epitopos de Linfócito B , Epitopos de Linfócito T , Humanos , Simulação de Acoplamento Molecular , Vacinas de Subunidades Antigênicas , Simulação de Dinâmica Molecular , Salmonella , Biologia ComputacionalRESUMO
This study aimed to examine the total viable bacteria (TVBC); total coliform (TCC); fecal coliform (TFC); pathogenic Pseudomonas spp., Staphylococcus aureus, and total fungi (TF); and the effect of different low-cost disinfectants (sterile water, salt water, blanched, and vinegar) in decontamination of 12 types of fruit and 10 types of vegetables. In fruit samples, the lowest TVBC was enumerated at 3.18 ± 0.27 log CFU/g in Indian gooseberry and the highest at 6.47 ± 0.68 log CFU/g in guava. Staphylococci (2.04 ± 0.53-5.10 ± 0.02 log CFU/g), Pseudomonas (1.88 ± 0.03-5.38 ± 0.08 log CFU/g), and total fungi (2.60 ± 0.18-7.50 ± 0.15 log CFU/g) were found in all fruit samples; however, no Salmonella was detected in fruit samples. Similarly, the lowest TVBC recorded 5.67± 0.49 log CFU/g in cucumber and the highest 7.37 ± 0.06 log CFU/g in yard long bean. The Staphylococci (3.48 ± 0.13-4.81 ± 0.16 log CFU/g), Pseudomonas (3.57± 0.21- 4.75 ± 0.23 log CFU/g), TCC (1.85 ± 1.11-56.50 ± 37.14 MPN/g), TFC (1.76 ± 0.87- 3.78 ± 3.76 MPN/g), and TF (3.79 ± 0.18-4.40 ± 0.38 log CFU/g) were recorded in all vegetables samples, but no Salmonella was detected in yard long bean, pointed gourd, carrot, tomato, cucumber, or brinjal. However, vinegar showed the highest microbial load reduction of selected fruit and vegetables among the different treatments. With vinegar treatment, the highest reduction of TVBC (1.61-log) and TF (2.54-log) was observed for fruits, and TVBC (2.31-log) and TF (2.41-log) for vegetables. All the disinfectant treatments resulted in significant (p < 0.01) bacterial load reduction compared to control for the studied fruits and vegetable samples.
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Wild animals, such as rodents seem to be competent reservoir of bacteria-borne zoonotic diseases which disseminate in human. We investigated the presence of E. coli, Shiga toxin-producing E. coli (STEC), and Salmonella in the feces of six category wild rodent species (Apodemus agrarius, A. peninsulae, A. sylvaticus, Micromys minutus, Myodes regulus, and R. norvegicus) captured from different agricultural regions in South Korea. Among them, A. agrarius, which account for 65% of total (Nâ¯=â¯52) individuals, are most widely distributed and abundant in various agroecosystems in South Korea. The bacterial identification was performed by cultural and molecular methods. In cultural method, the fecal cultures from 26 individuals formed colonies on E. coli-selective EMB agar media. Of them, the fecal cultures from 18 individuals also produced colonies on the Shiga toxin-producing E. coli-selective CT-SMAC agar media as well as the EMB agar media. In molecular method, polymerase chain reaction (PCR) was carried out to detect two virulence genes (stx1 and stx2) of isolated E. coli. The amplified dataset of stx1 and stx2 genes of E. coli were sequenced. In this manuscript, E. coli and STEC were detected but there were no Salmonella species. The wild rodents' data would provide important information on reservoirs of those pathogenic bacteria.
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Alzheimer's disease (AD) is a dynamic degeneration of the brain with progressive dementia. Considering the uncertainties in its molecular mechanism, in the present study, we employed network-based integrative analyses, and aimed to explore the key molecules and their associations with small drugs to identify potential biomarkers and therapeutic agents for the AD. First of all, we studied a transcriptome dataset and identified 1521 differentially expressed genes (DEGs). Integration of transcriptome data with protein-protein and transcriptional regulatory interactions resulted with central (hub) proteins (UBA52, RAC1, CREBBP, AR, RPS11, SMAD3, RPS6, RPL12, RPL15, and UBC), regulatory transcription factors (FOXC1, GATA2, YY1, FOXL1, NFIC, E2F1, USF2, SRF, PPARG, and JUN) and microRNAs (mir-335-5p, mir-26b-5p, mir-93-5p, mir-124-3p, mir-17-5p, mir-16-5p, mir-20a-5p, mir-92a-3p, mir-106b-5p, and mir-192-5p) as key signaling and regulatory molecules associated with transcriptional changes for the AD. Considering these key molecules as potential therapeutic targets and Connectivity Map (CMap) architecture, candidate small molecular agents (such as STOCK1N-35696) were identified as novel potential therapeutics for the AD. This study presents molecular signatures at RNA and protein levels which might be useful in increasing discernment of the molecular mechanisms, and potential drug targets and therapeutics to design effective treatment strategies for the AD.