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A reductive cross-coupling strategy for the synthesis of sulfone-containing oxindoles via palladium-catalyzed domino cyclization/alkylsulfonylation reaction of N-substituted arylacrylamides with unactivated alkyl bromides and Na2S2O5 is presented. Moreover, using amines instead of alkyl bromides, a palladium-catalyzed domino cyclization/aminosulfonylation was also established. [ABSTRACT FROM AUTHOR]

Background: In high resolution manometry (HRM), distal contractile integral post multiple rapid swallow augmentation is considered as contraction reserve. The relationship between contraction reserve and esophageal acid reflux remains unclear. The aim of this study was to explore the correlation between contraction reserve and esophageal acid exposure in ineffective esophageal motility (IEM) and normal HRM. Methods: Patients who underwent HRM and ambulatory reflux monitoring were retrospectively screened. Those with diagnosis of normal HRM or IEM were included in the analysis. The proportion of patients with abnormal acid exposure time (AET) was compared between patients with and without contraction reserve. Multivariate regression analysis was performed to determine the predictors of abnormal AET and contraction reserve. Results: A total of 338 patients, including 264 normal HRM and 74 IEM, were included in the analysis. In patients with normal HRM, proportion of abnormal total AET (AET > 6.0%) was significantly lower in patients with supine contraction reserve than patients without contraction reserve (13.85% vs. 24.63%, p = 0.027). Multivariate regression analysis showed that supine contraction reserve could independently predict abnormal total AET (OR = 0.468, 95% CI: 0.249–0.948, p = 0.034), while upright contraction reserve trended strongly (OR = 0.558, 95% CI: 0.290–1.071, p = 0.079). Subgroup analysis showed that upright contraction reserve was an independent predictor of abnormal total AET in patients with 50–70% infective swallows (OR = 0.205, 95% CI: 0.051–0.821, p = 0.025), whereas supine contraction reserve did not have predictive value (p = 0.359). Conclusions: Supine contraction reserve correlates with esophageal acid reflux in patients with normal HRM, while only upright contraction reserve correlates with esophageal acid reflux in patients with infective swallows of 50–70%. [ABSTRACT FROM AUTHOR]

Background: Patients with dyslipidemia are at increased risk for suicide, especially those with major depressive disorder (MDD). Few studies have investigated the independent effects of suicide attempts on comorbid dyslipidemia in patients with MDD. Moreover, there are no comparisons of differences in factors associated with suicide attempts among patients with MDD with dyslipidemia at different ages of onset. The aim of this study was to investigate the prevalence of suicide attempts and associated variables in first episode and untreated patients with MDD with comorbid dyslipidemia at different ages of onset. Methods: We recruited 1718 patients with first-episode untreated MDD in this study. Demographical and clinical data were collected, and lipid profiles, thyroid function, and blood glucose levels were measured. The Hamilton Depression Scale 17 (HAMD-17), Hamilton Anxiety Scale (HAMA), Clinical Global Impression Severity Scale (CGI), and Positive and Negative Syndrome Scale (PANSS) positive subscale were assessed for depression, anxiety and illness severity, as well as psychotic symptoms, respectively. Results: The percentage of patients with MDD with comorbid dyslipidemia was 61% (1048/1718). Among patients with MDD with comorbid dyslipidemia, the incidence of suicide attempts was 22.2% (170/765) for early adulthood onset and 26.5% (75/283) for mid-adulthood onset. Independent factors associated with suicide attempts in early adulthood onset patients with MDD with dyslipidemia were as follows: HAMA score (B = 0.328, P < 0.0001, OR = 1.388), Suspicion /persecution (B = -0.554, P = 0.006, OR = 0.575), CGI (B = 0.878, P < 0.0001, OR = 2.406), systolic blood pressure (B = 0.048, P = 0.004, OR = 1.049), hallucinatory behavior (B = 0.334, P = 0.025, OR = 1.397), and TPOAb (B = 0.003, p < 0.0001, OR = 1.003). Independent factors associated with suicide attempts in mid-adulthood onset patients with MDD with comorbid dyslipidemia were as follows: HAMA score (B = 0.182, P < 0.0001, OR = 1.200), CGI (B = 1.022, P < 0.0001, OR = 2.778), and TPOAb (B = 0.002, P = 0.009, OR = 1.002). Conclusion: Our findings suggest an elevated risk of suicide attempts in patients with MDD with comorbid dyslipidemia. The incidence of suicide attempts was similar in the early- and mid-adulthood onset subgroups among patients with MDD with dyslipidemia, but the factors associated with suicide attempts were different in these two subgroups. [ABSTRACT FROM AUTHOR]

Background: High levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3-knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis. Methods: An sgRNA anchored to exon 2 of APOC3 was designed to edit embryo genomes using the CRISPR/Cas9 system. The founder rabbits were sequenced, and their lipid profile, inflammatory cytokines, and atherosclerotic plaques were analyzed. Results: When given a normal chow (NC) diet, all APOC3-KO rabbits had 50% lower triglyceride (TG) levels than those of the matched age control group. Additionally, their plasma lipoprotein lipase increased. When fed a high-fat diet, APOC3 deficiency was observed to be more conducive to the maintenance of plasma TG, total cholesterol, and low-density lipoprotein cholesterol levels, and the inhibition of the inflammatory response and the protection against atherosclerosis in rabbits. Conclusion: APOC3 deficiency can delay the formation of atherosclerosis-induced HFD in rabbits, indicating this is a novel therapeutic target to treat atherosclerosis. [ABSTRACT FROM AUTHOR]

Intrusion detection technology can actively detect abnormal behaviors in the network and is important to the security of Industrial Internet of Things (IIOT). However, there are some issues with the current intrusion detection technology for IIOT, such as extreme imbalance in the number of samples of different classes in the dataset, redundant and meaningless features in the samples, and the inability of traditional intrusion detection methods to meet the requirements of detection accuracy in the increasingly complex IIOT. In view of the extreme imbalance of classes, this paper applies the hierarchical clustering algorithm to the under-sampling technology, which reduces the number of majority samples while reducing the loss of information of majority samples, and solves the problem of missing detection and false detection of minority samples caused by sample imbalance. In order to avoid feature redundancy and interference, this paper proposes an optimal feature selection algorithm based on greedy thought. This algorithm can obtain the optimal feature subset of each type of data in the data set, thus eliminating redundant and interfering features. Aiming at the problem of insufficient detection ability of traditional detection methods, this paper proposes a deep neural network intrusion detection model based on the parallel connection of global and local subnetworks. This model obtains the overall benchmark detection of the dataset through the deep neural network, and then strengthens the detection effect of each subclass through the parallel connection of subnetworks, greatly improving the performance of the intrusion detection algorithm. The experimental results show that the method described in this paper can improve the intrusion detection for IIOT. [ABSTRACT FROM AUTHOR]

ABL tyrosine kinase inhibitors (TKIs) act an irreplaceable role in the management of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). The treatment of these diseases has been revolutionized by the application of immunotherapeutic modalities. However, diseases with ABL kinase domain mutation T315I are resistant to the majority of TKIs, which is responsible for treatment failure. Olverembatinib is a third-generation TKI that has been approved for the treatment of T315I-mutated chronic myeloid leukemia (CML) in China; its usage in Ph+ ALL needs further exploration. Here, we present two cases with relapsed T315I mutation Ph+ ALL who received the combination regimen of blinatumomab and olverembatinib. This regimen, which has not been reported yet, was safe and effective as the patients achieved minimal residual disease (MRD) negative after 1 cycle of therapy. The management of these cases provides evidence of this new chemo-free regimen as an efficient approach for relapsed or refractory(R/R)Ph+ ALL. [ABSTRACT FROM AUTHOR]

Rapid dissemination of plasmid-borne polymyxin resistance mcr-1 genes threatens the efficacy of polymyxins. Acquisition of mcr-1 imposes a fitness cost on bacteria; identifying the molecular mechanisms underpinning this fitness cost will help in the development of adjunctive antimicrobial therapies that target polymyxin-resistant Gram-negative pathogens. Phenotypic assays and transcriptomics were acquired to investigate the impact of mcr-1 expression on membrane characteristics and transcriptomic responses in Escherichia coli TOP10 carrying the empty vector pBAD (TOP10+pBAD) and harbouring pBAD- mcr-1 (TOP10+pBAD- mcr-1). The overexpression of mcr-1 increased outer membrane permeability and caused membrane depolarisation, reflective of the transcriptomic results that showed downregulation of multiple genes involved in lipopolysaccharide core and O -antigen biosynthesis. Overexpression of mcr-1 also caused considerable gene expression changes in pathways involving carbohydrate metabolism (phosphotransferase system, pentose phosphate pathway, and pantothenate and coenzyme A biosynthesis), ABC transporters and intracellular responses to stress, especially those associated with oxidative and nucleic acid damage. Expression of mcr-1 also triggered the production of reactive oxygen species. These findings indicate that overexpression of mcr-1 results in persistent transcriptomic changes that primarily involve disruption to cell envelope synthesis via the reduction of LPS modifications, as well as dysregulation of carbon metabolism, redox balance and nucleic acids. These consequences of expression dysregulation may act as the main factors that impose a fitness cost with mcr-1 expression. [ABSTRACT FROM AUTHOR]

Background: Antidepressants have been empirically used in the treatment of functional dyspepsia (FD). However, results from recent clinical trials investigating their efficacy are conflicting. The aim of this study is to evaluate the efficacy of antidepressants in the management of FD in adults. Methods: Databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and BIOSIS Previews were searched for all randomized controlled trials (RCT) investigating efficacy of antidepressants in the management of FD in adult patients. Data of overall symptom unimproved and adverse events were compared between the antidepressants and placebo group. Results: The search strategy identified 432 citations. Of those, eight RCTs met the inclusion criteria and were included in the meta-analysis. The pooled relative risk (RR) of symptom unimproved with tricyclic antidepressants (TCAs) versus placebo was 0.76 (95% CI: 0.62 to 0.94, P = 0.01; I2 = 0%, P = 0.39). By contrast, selective serotonin reuptake inhibitors (SSRIs) did not show a benefit over placebo (RR = 1.00, 95% CI: 0.86 to 1.17, P = 0.95; I2 = 0%, P = 0.82). Adverse events were significantly more frequent among patients receiving antidepressants than those receiving placebos (RR = 1.64, 95% CI: 1.14 to 2.35, P = 0.007). Conclusion: TCAs but not SSRIs, are effective in the treatment of FD, but antidepressants were also associated with more adverse events compared with placebo. [ABSTRACT FROM AUTHOR]

Background. Chickens serve as an intermediate host for Toxoplasma gondii and Neospora caninum; infection of free-range (FR) chickens with these organisms is a useful indicator of soil and environmental contamination with oocysts. A total of 700 FR chicken serum samples and 300 heart samples were collected from Henan province from March to July 2015. Antibodies to T. gondii were found in 18.86% (132/700) of the chickens by modified agglutination test (cut-off 1 : 25), while 23.14% (162/700) were positive for N. caninum by indirect fluorescent antibody test (cut-off 1 : 25). T. gondii DNA was detected in the myocardium digestion liquids of 4/25 (16%) FR chickens. The PCR results of N. caninum DNA from FR chicken myocardium digestion liquids (n=25) were all negative. Attempts to isolate viable T. gondii were unsuccessful. The results showed that there were antibodies to T. gondii and N. caninum in FR chickens from Henan province. Accordingly, effective control of feces from cats and dogs and improved pets hygiene habits were needed. To the author’s knowledge, this is the first report of the presence of N. caninum antibody in chickens from China. [ABSTRACT FROM AUTHOR]

IBS-D is a functional bowel disease without clear diagnostic markers and exact pathogenesis. Studies have proved that non-coding RNAs participate in IBS-D. However, tRNA-derived small RNAs (tsRNAs), as a new type of non-coding RNAs that are more suitable as markers, remain to be clarified in IBS-D. Hence, we focused on the identification and potential functions of tsRNAs in IBS-D. Intestinal biopsies were obtained from IBS-D patients and healthy volunteers, and twenty-eight differential tsRNAs were screened by high-throughput sequencing. The changes of tiRNA-His-GTG-001, tRF-Ser-GCT-113, and tRF-Gln-TTG-035 by q-PCR in expanded samples were consistent with the sequencing results. Meanwhile, target gene prediction and bioinformatics showed that the three differential tsRNAs may be involved in some key signal pathways, such as GABAergic synapse, tumor necrosis factor-α (TNF-α), etc. Their regulation on target genes were demonstrated through cell experiments and luciferase reporter assays. In addition, the receiver-operating characteristic (ROC) analysis showed that the three tsRNAs all could be used as candidate markers of IBS-D. The correlation analysis indicated they were related to the degree of abdominal pain, abdominal distension, and stool morphology. So, we believe that the abnormal tiRNA-His-GTG-001, tRF-Ser-GCT-113, and tRF-Gln-TTG-035 are related to the clinical symptoms of IBS-D, and can target regulate the important molecules of the brain-gut axis, even could be expected as potential biomarkers for the diagnosis and treatment of IBS-D. [Display omitted] • The tsRNA profiles of the intestinal tissues from IBS-D patients are firstly analyzed. • tiRNA-His-GTG-001, tRF-Ser-GCT-113 and tRF-Gln-TTG-035 are related to symptoms of IBS-D. • tiRNA-His-GTG-001 and tRF-Gln-TTG-035 can target GABBR2, TLR4 as well as GABARAP. • The three differential tsRNAs are expected to potential biomarkers for IBS-D. [ABSTRACT FROM AUTHOR]

Latrophilin (LPH) is an adhesion G protein-coupled receptor (aGPCR) that participates in multiple essential physiological processes. Our previous studies have shown that lph is not only indispensable for the development and reproduction of red flour beetles (Tribolium castaneum), but also for their resistance against dichlorvos or carbofuran insecticides. However, the regulatory mechanism of lph -mediated insecticide susceptibility remains unclear. Here, we revealed that knockdown of lph in beetles resulted in opposing changes in two chemoreception genes, chemosensory protein 10 (CSP10) and odorant - binding protein C01 (OBPC01), in which the expression of TcCSP10 was downregulated, whereas the expression of TcOBPC01 was upregulated. TcCSP10 and TcOBPC01 were expressed at the highest levels in early pupal and late larval stages, respectively. High levels of expression of both these genes were observed in the heads (without antennae) of adults. TcCSP10 and TcOBPC01 were significantly induced by dichlorvos or carbofuran between 12 and 72 h (hrs) after exposure, suggesting that they are likely associated with increasing the binding affinity of insecticides, leading to a decrease in sensitivity to the insecticides. Moreover, once these two genes were knocked down, the susceptibility of the beetles to dichlorvos or carbofuran was enhanced. Additionally, RNA interference (RNAi) targeting of lph followed by exposure to dichlorvos or carbofuran also caused the opposing expression levels of TcCSP10 and TcOBPC01 compared to the expression levels of wild-type larvae treated with insecticides alone. All these results indicate that lph is involved in insecticide susceptibility through positively regulating TcCSP10 ; and the susceptibility could also further partially compensated for through the negative regulation of TcOBPC01 when lph was knockdown in the red flour beetle. Our studies shed new light on the molecular regulatory mechanisms of lph related to insecticide susceptibility. lph was involved in insecticide susceptibility through positively regulating TcCSP10 , and it could further partially compensate for insecticide susceptibility by negatively regulating TcOBPC01 when lph was knockdown in Tribolium castaneum. Unlabelled Image • TcCSP10 was down-regulated and TcOBPC01 was up-regulated after knockdown of Tclph. • TcCSP10 and TcOBPC01 were significantly induced by insecticides of dichlorvos or carbofuran. • RNAi of TcCSP10 and TcOBPC01 increased the susceptibilities of larval to insecticides. • Tclph related to insecticide susceptibility via regulating TcCSP10 and partially compensated by TcOBPC01. [ABSTRACT FROM AUTHOR]

The zona pellucida domain protein Dusky (Dy) plays a vital role in wing morphogenesis in insects, but little information on its function has been reported. In this study, we found that dy regulated wing cell size, larval and pupal duration, and the metabolism of amino acid and 20‐hydroxyecdysone in Tribolium castaneum. Using RNA‐seq, 413 differentially expressed genes were identified between physiological buffer‐injected and dy‐double‐stranded RNA‐treated larvae, including 88 downregulated genes and 325 upregulated genes. Among these genes, dy knockdown increased CYP18A1 expression to elevate the 26‐hydroxylation of 20‐hydroxyecdysone, which ultimately led to growth defects in wing cells. Silencing of dy upregulated the transcription of genes encoding tyrosine aminotransferase, 4‐hydroxyphenylpyruvate dioxygenase, homogentisate 1, 2‐dioxygenase, and Pale to promote the catabolism of tyrosine and phenylalanine, which eventually reduced amino acid content. Furthermore, dy knockdown upregulated 4E‐BP expression, and 4E‐BP silencing partially phenocopied dy RNA interference‐mediated wing morphogenesis. These results suggest that Dy controls 20‐hydroxyecdysone and amino acid metabolism to regulate wing morphogenesis in the insect. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii is widely distributed and can infect many species of warm-blooded animals, including swine. This study aimed to evaluate the prevalence of T. gondii in swines from the central of China. A total of 2798 samples, including 305 hearts, 2086 diaphragms, and 407 sera were collected from different swine in Henan Province, China. The modified agglutination test was used to detect antibodies against T. gondii in sera from jugular vein blood and heart blood (cut-off: 1:25), diaphragm juice (cut-off: 1:10). T. gondii DNA was screened from the digestive fluids of all diaphragm tissue samples and seropositive hearts, and attempt to isolate viable T. gondii strain by bioassay in mice. A total of 9.94% (278/2798) swine tested positive for T. gondii antibodies. Region, but not gender, was associated with T. gondi seropositivity in swine. T. gondii nucleic acid was not found in the tissue digestive fluids (2090 swines). Three groups of mice showed T. gondii antibodies after having been bioassayed with diaphragm samples (n = 81, which came from 2090 swine). No viable T. gondii strain was isolated from muscle of swine. This is the first large-scale survey T. gondi infection in swine from the central of China. Overall, the prevalence of viable T. gondii in swine was low. Nevertheless, T. gondii infection is present in swine from the central of China. Consumers may acquire T. gondii infection from ingestion of raw or undercooked pork. [ABSTRACT FROM AUTHOR]

Brain injury has been proposed as the major cause of the poor outcomes associated with intracerebral hemorrhage (ICH). Emerging evidence indicates that the nuclear receptor, peroxisome proliferator-activated receptor β/δ (PPAR-β/δ), plays a crucial role in the pathological process of central nervous impairment. The present study was undertaken to evaluate the protective effects of PPAR-β/δ activation using a selective PPAR-β/δ agonist, GW0742, against brain injury after ICH in a mouse model. ICH was induced by intravenous injection of collagenase into the right caudate putamen. To examine the protective effect of PPAR-β/δ activation against ICH-induced brain injury, mice were either intraperitoneally injected with GW0742 (3 mg/kg, body weight) or saline (control group) 30 min before inducing ICH. Behavioral dysfunction was evaluated 24 and 72 h after injury. Then, all mice were killed to assess hematoma volume, brain water content, and blood–brain barrier (BBB) permeability. TUNEL and Nissl staining were performed to quantify the brain injury. The expression of PPAR-β/δ, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, Bcl-2-related X-protein (Bax), and B-cell lymphoma 2 (Bcl-2) in the perihematomal area was examined by immunohistochemistry and western blotting analysis. Mice treated with GW0742 showed significantly less severe behavioral deficits compared to the control group, accompanied by increased expression of PPAR-β/δ and Bcl-2, and increased expression of IL-1β, TNF-α, and Bax decreased simultaneously in the GW0742-treated group. Furthermore, the GW0742-pretreated group showed significantly less brain edema and BBB leakage. Neuronal loss was attenuated, and the number of apoptotic neuronal cells in perihematomal tissues reduced, in the GW0742-pretreated group compared to the control group. However, the hematoma volume did not decrease significantly on day 3 after ICH. These results suggest that the activation of PPAR-β/δ exerts a neuroprotective effect on ICH-induced brain injury, possibly through anti-inflammatory and anti-apoptotic pathways. [ABSTRACT FROM AUTHOR]

In the study, a series of polypyrrole (PPy) samples were prepared by a method of template synthesis at different indigo carmine (IC) concentrations while keeping the amount of pyrrole and FeCl as well as the reaction conditions unchanged. Effects of IC concentration (M) on the morphology, conductivity and microwave absorbing behavior of the obtained PPy products were investigated. The results showed that the morphology of PPy transformed from granular flocking to rods and then to spiral rods as M increased from 0.05 to 7.50 mM, and the morphology transformation mechanism of PPy was attributed to the structural transformation of IC micelles caused by the change of M. The conductivity of PPy was also found to be influenced by M. Further investigation indicated that the spiral rod-shaped PPy (S-5) showed obviously superior microwave absorbing behavior compared with that of the granular flocking shaped PPy or that of the rod-shaped PPy, which was attributed to the benefits of its spiral structure and the comparably higher dielectric loss resulted from its lower conductivity. [ABSTRACT FROM AUTHOR]

Natural products are a major source of biological molecules. The 3-methylfuran scaffold is found in a variety of plant secondary metabolite chemical elicitors that confer host-plant resistance against insect pests. Herein, the diversity-oriented synthesis of a natural-product-like library is reported, in which the 3-methylfuran core is fused in an angular attachment to six common natural product scaffolds-coumarin, chalcone, flavone, flavonol, isoflavone and isoquinolinone. The structural diversity of this library is assessed computationally using cheminformatic analysis. Phenotypic high-throughput screening of β-glucuronidase activity uncovers several hits. Further in vivo screening confirms that these hits can induce resistance in rice to nymphs of the brown planthopper Nilaparvata lugens. This work validates the combination of diversity-oriented synthesis and high-throughput screening of β-glucuronidase activity as a strategy for discovering new chemical elicitors. [ABSTRACT FROM AUTHOR]

• Chat knockdown severely affected larval development and pupal eclosion, but vacht RNAi only disrupted pupal eclosion. • Parental RNAi of chat or vacht would reduce egg production and completely inhibite egg hatchability in T. castaneum. • Reduction of chat or vacht decreased the resistance to carbofuran and dichlorvos. Choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are essential enzymes for synthesizing and transporting acetylcholine (ACh). But their functions in metamorphosis, reproduction, and the insecticide susceptibility were poorly understood in the insects. To address these issues, we identified the orthologues of chat and vacht in Tribolium castaneum. Spatiotemporal expression profiling showed Chat has the highest expression at the early adult stage, while vacht shows peak expression at the early larval stage. Both of them were highly expressed at the head of late adult. RNA interference (RNAi) of chat and vacht both led to a decrease in ACh content at the late larval stage. It is observed that chat knockdown severely affected larval development and pupal eclosion, but vacht RNAi only disrupted pupal eclosion. Further, parental RNAi of chat or vacht led to 35 % or 30 % reduction in fecundity, respectively, and knockdown of them completely inhibited egg hatchability. Further analysis has confirmed that both the reduction in fecundity and hatchability caused through the maternal specificity in T. castaneum. Moreover, the transcript levels of chat and vacht were elevated after carbofuran or dichlorvos treatment. Reduction of chat or vacht decreased the resistance to carbofuran and dichlorvos. This study provides the evidence for chat and vacht not only involved in development and reproduction of insects but also could as the potential targets of insecticides. [ABSTRACT FROM AUTHOR]

Myosin Myo20 plays vital roles in the morphogenesis of wings and legs among insects, but the function and signalling of Myo20 remain unclear. We show that Myo20 regulates wing cell division, ecdysteroid and amino acid metabolism, and gene expression in Tribolium castaneum. By RNA-seq, we identified 582 differentially expressed genes (DEGs) between control and ds- Myo20 larvae of T. castaneum. Of these DEGs, silencing Myo20 significantly decreased the mRNA and protein levels of lowfat. During development, lowfat has the highest expression in early pupae and the lowest level in 1-day embryos. Tissue-specific analysis indicated that lowfat was abundantly expressed in the head, fat body and epidermis of late-stage larvae and in wings and legs of 1, 2 and 5-day pupae. Likewise, knockdown of lowfat affected wing and leg morphogenesis, ecdysteroid and amino acid metabolism, and gene expression in T. castaneum. Silencing Myo20 or lowfat activated CYP18A1 to degrade ecdysteroids, stimulated amino acids catabolism to increase the transcription of 4E-BP but reduce S6K and cycE expression. These results suggest that Lowfat works downstream of Myo20 to employ target of rapamycin (TOR) signalling for wing and leg morphogenesis in insects. [Display omitted] • Myo20 regulates wing cell proliferation, ecdysteroid and amino acid metabolism, and gene expression. • Lowfat functions downstream of Myo20. • Myo20 and lowfat work upstream of TOR signalling to regulate wing morphogenesis. [ABSTRACT FROM AUTHOR]

Background: In recent years, an increasing number of studies have proved that circulating miRNAs could be used for the early diagnosis of cardiovascular diseases and even play vital roles in the evaluation of therapeutic effects or prognosis. This study was conducted to examine the correlation between serum microRNAs and hyperlipidemia to provide a theoretical basis for the early screening and intervention of atherosclerotic cardiovascular diseases (ASCVD). Methods: The serum samples and clinical data of 122 patients with hyperlipidemia and 168 healthy subjects were collected. Related clinical information was statistically analyzed for the two groups. Expression of circulating miRNAs was detected by miRNA microarray analysis and further verified by reverse transcription-quantitative PCR (RT-qPCR). Results: Statistical analysis of clinical information revealed a significant difference in the incidence of ASCVD between the two groups. The MiRNA microarray analysis (n = 10) showed 22 miRNAs with significantly different expression, among which 12 showed upregulation, and the others showed downregulation. Those possessing obvious differences and stable expression in the miRNA microarray, including miRNA-191-3p, miRNA-933, and miRNA-425-3p, were chosen for further investigation using RT-qPCR. The results demonstrated that several miRNAs were related to lipid metabolism disorders, especially miRNA-933. The area under the curve (AUC) of miRNA-933 in distinguishing the hyperlipidemia and ASCVD patients was 0.739 (95% CI, 0.682–0.795; P < 0.01) and 0.703 (95% CI, 0.643–0.763, P < 0.01), respectively. Conclusions: In conclusion, miRNA-191-3p, miRNA-933, and miRNA-425-3p may be depressed in the peripheral circulation of patients with lipid metabolism disorders (mainly LDL). Circulating miRNA-933 could be a feasible predictor for ASCVD at the early stage. [ABSTRACT FROM AUTHOR]

Objective: To generate novel rabbit models with a large-fragment deletion of either LDL receptor (LDLR) and/or apolipoprotein (apoE) genes for the study of hyperlipidemic and atherosclerosis. Methods: CRISPR/Cas9 system directed by a multiple sgRNAs system was used in rabbit embryos to edit their LDLR and apoE genes. The LDLR and apoE genes of founder rabbits were sequenced, and their plasma lipids and lipoprotein profiles on a normal chow diet were analyzed, western blotting was also performed to evaluate the expression of apolipoprotein. Sudan IV and HE staining of aortic were performed to confirm the formation of atherosclerosis. Results: Six knockout (KO) rabbits by injection of both LDLR and apoE sgRNAs were obtained, including four LDLR KO rabbits and two LDLR/apoE double- KO rabbits. Sequence analysis of these KO rabbits revealed that they contained multiple mutations including indels, deletions, and substitutions, as well as two rabbit lines containing biallelic large fragment deletion in the LDLR region. Analysis of their plasma lipids and lipoprotein profiles of these rabbits fed on a normal chow diet revealed that all of these KO rabbits exhibited remarkable hyperlipidemia with total cholesterol levels increased by up to 10-fold over those of wild-type rabbits. Pathological examinations of two founder rabbits showed that KO rabbits developed prominent aortic and coronary atherosclerosis. Conclusion: Large fragment deletions can be achieved in rabbits using Cas9 mRNA and multiple sgRNAs. LDLR KO along with LDLR/apoE double KO rabbits should provide a novel means for translational investigations of human hyperlipidemia and atherosclerosis. [ABSTRACT FROM AUTHOR]