The synthesis and accumulation of long chain polyunsaturated fatty acids such as eicosapentaenoic acid has previously been demonstrated in the seeds of transgenic plants. However, the obtained levels are relatively low, indicating the need for further studies and the better definition of the interplay between endogenous lipid synthesis and the non-native transgene-encoded activities. In this study we have systematically compared three different transgenic configurations of the biosynthetic pathway for eicosapentaenoic acid, using lipidomic profiling to identify metabolic bottlenecks. We have also used genetic crossing to stack up to ten transgenes in Arabidopsis. These studies indicate several potential approaches to optimize the accumulation of target fatty acids in transgenic plants. Our data show the unexpected channeling of heterologous C20 polyunsaturated fatty acids into minor phospholipid species, and also the apparent negative metabolic regulation of phospholipid-dependent Δ6-desaturases. Collectively, this study confirms the benefits of iterative approaches to metabolic engineering of plant lipid synthesis.
The microRNA miR-17-92 cluster plays a fundamental role in heart development. The aim of this study was to investigate the effect of a member of this cluster, miR-17, on cardiac senescence. We examined the roles of miR-17 in senescence and demonstrated that miR-17-3p attenuates cardiac aging in the myocardium by targeting Par4 (also known as PAWR). This upregulates the downstream proteins CEBPB, FAK, N-cadherin, vimentin, Oct4 and Sca-1 (also known as stem cell antigen-1), and downregulates E-cadherin. Par4 has been reported as a tumor suppressor gene that induces apoptosis in cancer cells, but not in normal cells. Repression of Par4 by miR-17-3p enhances the transcription of CEBPB and FAK, which promotes mouse cardiac fibroblast (MCF) epithelial-tomesenchymal transition (EMT) and self-renewal, resulting in cellular senescence and apoptosis resistance. We conclude that Par4 can bind to the CEBPB promoter and inhibit its transcription. Decreased Par4 expression increases the amount of CEBPB, which binds to the FAK promoter and enhances FAK transcription. Par4, CEBPB and FAK form a senescence signaling pathway, playing roles in modulating cell survival, growth, apoptosis, EMT and self-renewal. Through this novel senescence signaling axis, miR-17-3p represses Par4 expression, acting pleiotropically as a negative modulator of cardiac aging and cardiac fibroblast cellular senescence.
BackgroundNowadays, more and more novel enzymes can be easily found in the whole enzyme pool with the rapid development of genetic operation. However, experimental work for substrate screening of a new enzyme is laborious, time consuming and costly. On the other hand, many computational methods have been widely used in lead screening of drug design. Seeing that the ligand-target protein system in drug design and the substrate-enzyme system in enzyme applications share the similar molecular recognition mechanism, we aim to fulfill the goal of substrate screening by in silico means in the present study.ResultsA computer-aided substrate screening (CASS) system which was based on the enzyme structure was designed and employed successfully to help screen substrates of Candida antarctica lipase B (CALB). In this system, restricted molecular docking which was derived from the mechanism of the enzyme was applied to predict the energetically favorable poses of substrate-enzyme complexes. Thereafter, substrate conformation, distance between the oxygen atom of the alcohol part of the ester (in some compounds, this oxygen atom was replaced by nitrogen atom of the amine part of acid amine or sulfur atom of the thioester) and the hydrogen atom of imidazole of His224, distance between the carbon atom of the carbonyl group of the compound and the oxygen atom of hydroxyl group of Ser105 were used sequentially as the criteria to screen the binding poses. 223 out of 233 compounds were identified correctly for the enzyme by this screening system. Such high accuracy guaranteed the feasibility and reliability of the CASS system.ConclusionThe idea of computer-aided substrate screening is a creative combination of computational skills and enzymology. Although the case studied in this paper is tentative, high accuracy of the CASS system sheds light on the field of computer-aided substrate screening.
Diminished social motivation is hypothesized to explain abnormal face scanning pattern in individuals with autism spectrum disorder (ASD), especially reduced eye‐looking time in ASDs than typically developing (TD) people. Here, we tested an alternative explanation that children with ASD may use a compensatory strategy to avoid direct eye contact by processing the eyes through peripheral vision. We compared the face scanning patterns of children with and without ASD in two conditions: in the clear condition, the face was completely visible; in the blur condition, by using the gaze‐contingent paradigm, the whole face was blurred except for a small region being fixated at, thus children could not rely on the peripheral information to process the eyes. We found that children with ASD fixated less on the eyes than TD children in both conditions. Temporal‐course analyses further revealed the possible motivation‐based guidance of attention to process the eyes in the TD group but not in the ASD group. Additionally, we found that children with ASD scanned faces more randomly and less strategically than TD children. These results have ruled out the alternative hypothesis that the abnormal face scanning pattern in ASDs was due to their compensatory strategy to process eyes through peripheral vision, furthering our understanding of the mechanisms underlying their abnormal face scanning.
We examined explicit and implicit processes in response to third-party moral transgressions in children with autism spectrum disorder (ASD). Twenty 4-to 7-year-old children with ASD and 19 typically developing controls evaluated dynamic visual stimuli depicting intentional or accidental harm to persons or damage to objects. Moral evaluations, eye fixations, and pupil dilations toward the stimuli were collected. Results indicate a preserved capacity to understand the mental states of perpetrators and an implicit moral sensitivity to the third-party harms in children with ASD. Nonetheless, children with ASD showed specific sensitivity and emotional arousal when viewing damage to objects. These findings contribute to the understanding of the underlying mechanisms of moral reasoning in ASD and its possible association with the autistic symptoms.
Autistic children show audiovisual speech integration deficits, though the underlying mechanisms remain unclear. The present study examined how audiovisual speech integration deficits in autistic children could be affected by their looking patterns. We measured audiovisual speech integration in 26 autistic children and 26 typically developing (TD) children (4-to 7-year-old) employing the McGurk task (a videotaped speaker uttering phonemes with her eyes open or closed) and tracked their eye movements. We found that, compared with TD children, autistic children showed weaker audiovisual speech integration (i.e., the McGurk effect) in the open-eyes condition and similar audiovisual speech integration in the closed-eyes condition. Autistic children viewed the speaker's mouth less in non-McGurk trials than in McGurk trials in both conditions. Importantly, autistic children's weaker audiovisual speech integration could be predicted by their reduced mouth-looking time. The present study indicated that atypical faceviewing patterns could serve as one of the cognitive mechanisms of audiovisual speech integration deficits in autistic children. Lay SummaryMcGurk effect occurs when the visual part of a phoneme (e.g., "ga") and the auditory part of another phoneme (e.g., "ba") uttered by a speaker were integrated into a fused perception (e.g., "da"). The present study examined how McGurk effect in autistic children could be affected by their looking patterns for the speaker's face. We found that less looking time for the speaker's mouth in autistic children could predict weaker McGurk effect. As McGurk effect manifests audiovisual speech integration, our findings imply that we could improve audiovisual speech integration in autistic children by directing them to look at the speaker's mouth in future intervention.
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