TWIST1 is a basic helix-loop-helix (bHLH) transcription factor in humans that functions in mesoderm differentiation. TWIST1 primarily regulates genes as a transcriptional repressor often through TWIST-Box domain-media...
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TWIST1 is a basic helix-loop-helix (bHLH) transcription factor in humans that functions in mesoderm differentiation. TWIST1 primarily regulates genes as a transcriptional repressor often through TWIST-Box domain-mediated protein-protein interactions. The TWIST-Box also can function as an activation domain requiring 3 conserved, equidistant amino acids (LXXXFXXXR). Autosomal dominant mutations in TWIST1, including 2 reported in these conserved amino acids (F187L and R191M), lead to craniofacial defects in Saethre-chotzen syndrome (ScS). caenorhabditis elegans has a single TWIST1 homolog, HLH-8, that functions in the differentiation of the muscles responsible for egg laying and defecation. Null alleles in hlh-8 lead to severely egg-laying defective and constipated animals due to defects in the corresponding muscles. TWIST1 and HLH-8 share sequence identity in their bHLH regions;however, the domain responsible for the transcriptional activity of HLH-8 is unknown. Sequence alignment suggests that HLH-8 has a TWIST-Box LXXXFXXXR motif;however, its function also is unknown. cRISPR/cas9 genome editing was utilized to generate a domain deletion and several missense mutations, including those analogous to ScS patients, in the 3 conserved HLH-8 amino acids to investigate their functional role. The TWIST-Box alleles did not phenocopy hlh-8 null mutants. The strongest phenotype detected was a retentive (Ret) phenotype with late-stage embryos in the hermaphrodite uterus. Further, GFP reporters of HLH-8 downstream target genes (arg-1::gfp and egl-15::gfp) revealed tissue-specific, target-specific, and allele-specific defects. Overall, the TWIST-Box in HLH-8 is partially required for the protein's transcriptional activity, and the conserved amino acids contribute unequally to the domain's function.
Summer mass mortality is a main problem affecting the production of Pacific oyster (crassostrea gigas). Selective breeding represents a promising method to improve the summer survival rate and growth of the oyster. Ho...
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Summer mass mortality is a main problem affecting the production of Pacific oyster (crassostrea gigas). Selective breeding represents a promising method to improve the summer survival rate and growth of the oyster. However, the pitfall is that selection may significantly decrease genetic diversity, leading to inbreeding depression. The current study presented an analysis of genetic diversity in one hybrid oyster (GA -c. gigas 9 x c. angulata male), parental populations (c. gigas 9 x c. gigas male and c. angulata 9 x c. angulata male) and three generations of mass-strain GA strain (GAF1, GAF2 and GAF3) as well as four wild populations of c. gigas (Rc, QD, LY and ZS) using 18 microsatellite loci and mitochondrial cOI sequences. Heterozygosity levels of GA (He = 0.69) demostrated an increased genetic diversity in hybrids compared to the parental populations. Heterozygosity (He: 0.64-0.67) and cOI haplotypes (Hd: 0.195-0.279) revealed no significant (P > 0.05) loss of genetic diversity in selected strains over three generations. However, the average number of alleles (Na ranging from 8.06 to 7.61), polymorphic information content (I ranging from 1.53 to 1.43), heterozygosity (Ho ranging from 0.72 to 0.55) and effective population size (Ne -lin ranging from 144.1 to 51.2) exhibited a tendency to decrease with selection. Moderate genetic structuring (FST: 0.059-0.124;Nei's D: 0.140-0.326) was found among the selected strains and wild populations (QD, LY and ZS). These results indicate that breeders need to be cautious about artificial selection beyond the third generation and work to improve effective population sizes to maintain genetic gains. The results obtained in this study is that it provides important inference and guidance concerning future genetic improve-ment project.
Lamins A/c are nuclear intermediate filament proteins that are involved in diverse cellular mechanical and biochemical functions. Here, we report that recognition of Lamins A/c by a commonly used antibody (JOL-2) that...
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Lamins A/c are nuclear intermediate filament proteins that are involved in diverse cellular mechanical and biochemical functions. Here, we report that recognition of Lamins A/c by a commonly used antibody (JOL-2) that binds the Lamin A/c Ig-fold and other antibodies targeting similar epitopes is highly dependent on cell density, even though Lamin A/clevels do not change. We propose that the effect is caused by partial unfolding or masking of the c'E and/or EF loops of the Ig-fold in response to cell spreading. Surprisingly, JOL-2 antibody labeling was insensitive to disruption of cytoskeletal filaments or the Linker of Nucleoskeleton and cytoskeleton (LINc) complex. Furthermore, neither nuclear stiffness nor nucleo-cytoskeletal force transmission changed with cell density. These findings are important for the interpretation of immunofluorescence data for Lamin A/c and also raise the intriguing prospect that the conformational changes may play a role in Lamin A/c mediated cellular function.
Objectives: clostridioides difficile is the most common infectious agent of nosocomial diarrhea. c. difficile infection (cDI) pathogenesis and disease severity depend on its toxins (toxins A, B and binary) and on the ...
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Objectives: clostridioides difficile is the most common infectious agent of nosocomial diarrhea. c. difficile infection (cDI) pathogenesis and disease severity depend on its toxins (toxins A, B and binary) and on the host's immune response, especially the innate immune system. The current study examined the efficacy of macrophage activity, macrophages viability and cytokine secretion levelsin response to different sequence type (ST) strains of c. difficile. Methods: RAW 264.7 macrophages were exposed to six different strains of c. difficile as well as to both toxins A and B and macrophage viability was measured. The levels of four secreted cytokines were determined by RT-PcR and ELISA. Morphological changes to the macrophages were investigated by fluorescent microscopy. Results: Strains ST37 and ST42 affected macrophages' vitality the most. Toxins A and B led to a significant reduction in macrophages' vitality at most time points. In addition, starting at 30-min post-exposure to 5 ng/mu l of both toxins led to significant differences in macrophage viability versus at lower concentrations. Furthermore, cytokine secretion levels, including IL-12, IL-6 and TNF-alpha, increased dramatically when macrophages were exposed to strains ST42 or ST104. Finally, gene expression surveys point to increases in IL-12 gene expression in response to both ST42 and ST104. conclusions: c. difficile strains with higher toxins levels induced an increased activation of the innate immune system and may activate macrophages more profoundly resulting in secretion of higher levels of pro-inflammatory cytokines. However, higher toxin levels may also damage macrophages' normal skeletal structure, reducing macrophage viability.
In a hub location problem, where an original hub is faced with shortage limitations, all or some routes passing through the original hub may be transferred to a virtual hub, in order to preserve a disconnection of the...
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In a hub location problem, where an original hub is faced with shortage limitations, all or some routes passing through the original hub may be transferred to a virtual hub, in order to preserve a disconnection of the flow with minimal loss. In such a situation, reduction of congestion in the hubs plays a vital role in establishing the flow movement and avoiding traffic in the network. Here, a dynamic virtual hub location problem is investigated under conditions of uncertainty and presence of capacity constraints for the original and virtual hubs. The capacity constraints are applied to the model using an M/M/c/K queue. Moreover, the demand at the relevant points is considered to be nondeterministic and scenario-based. The problem is first formulated as an integrated probabilistic nonlinear mathematical model. The proposed model is then converted into a linear robust optimization model. The cPLEX optimization software package is used for solution of small samples. Two metaheuristic algorithms are introduced for large samples: a genetic algorithm and an imperialist competitive algorithm in a discrete space. The effectiveness of the proposed model is explored using the US well-known cAB data set. Several sample problems are also experimented to investigate the applicability of the model and the effectiveness of the algorithms. The results show appropriateness of the proposed mathematical model and the corresponding algorithms. The imperialist competitive algorithm turns to be more effective in terms of both the solution quality and the computing time.
Antimicrobial resistance (AMR) is a worldwide problem, which is driving more preclinical research to find new treatments and countermeasures for drug-resistant bacteria. However, translational models in the preclinica...
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Antimicrobial resistance (AMR) is a worldwide problem, which is driving more preclinical research to find new treatments and countermeasures for drug-resistant bacteria. However, translational models in the preclinical space have remained static for years. To improve animal use ethical considerations, we assessed novel methods to evaluate survival after lethal infection with ESKAPEE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae, and Escherichia coli) in pulmonary models of infection. consistent with published lung infection models often used for novel antimicrobial development, BALB/c mice were immunosuppressed with cyclophosphamide and inoculated intranasally with individual ESKAPEE pathogens or sterile saline. Observations were recorded at frequent intervals to determine predictive thresholds for humane endpoint decision-making. Internal temperature was measured via implanted IPTT300 microchips, and external temperature was measured using a non-contact, infrared thermometer. Additionally, clinical scores were evaluated based on animal appearance, behaviour, hydration status, respiration, and body weight. Internal temperature differences between survivors and non-survivors were statistically significant for E. faecium, S. aureus, K. pneumoniae, A. baumannii, E. cloacae, and E. coli, and external temperature differences were statistically significant for S. aureus, K. pneumoniae, E. cloacae, and E. coli. Internal temperature more precisely predicted mortality compared to external temperature, indicating that a threshold of 85oF (29.4oc) was 86.0% predictive of mortality and 98.7% predictive of survival. Based on our findings, we recommend future studies involving BALB/c mice ESKAPEE pathogen infection use temperature monitoring as a humane endpoint threshold.
This study performed scenario analysis using the MARKAL modelling framework to assess Thailand's greenhouse gas (GHG) emission pathways over the period 2010-2050, to explore the possibilities of achieving carbon n...
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This study performed scenario analysis using the MARKAL modelling framework to assess Thailand's greenhouse gas (GHG) emission pathways over the period 2010-2050, to explore the possibilities of achieving carbon neutrality of the energy system by 2060-2100, in pursuit of a maximum temperature rise of 2 degrees c and 1.5 degrees c by the end of the century. The shift from 2 degrees c pathways to 1.5 degrees c pathways would demand much more effort and pose greater challenges in terms of transformational changes required in the energy supply and demand sectors of Thailand. carbon neutrality in the energy supply system would be achievable with negative emissions through the adoption of bioenergy with carbon capture and storage (BEccS). The strong deployment of renewable energy-based power generation would also aid in the rapid decarbonization of the energy supply sector. The demand sectors would face more challenges requiring rapid and extensive deployment of energy efficient and low carbon technologies. The commercial sector may need to undergo deep decarbonization in the 1.5 degrees c scenarios by 2050 while the industrial and residential sectors will need to curb GHG emissions by a large amount even under 2 degrees c scenarios. The transportation sector would face challenges in shifting from private to public modes of transport, including wide adoption of electric and biofuel vehicles, in order to achieve the 1.5 degrees c target. Key Policy insights The attainment of 2 degrees c and 1.5 degrees c targets demand for a wide scale adoption of BEccS in Thailand resulting in negative emissions in the power sector even before 2050. Biomass, solar photovoltaics, and wind power would make up to the largest portion in the total power generation mix of Thailand in the 2 degrees c and 1.5 degrees c scenarios by 2050. Achieving carbon neutrality of the energy system by 2060-2100 is a challenging task for Thailand requiring higher investments and supportive policy actions to pr
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