Genome-scale CRISPR-Cas9 screen identifies PAICS as a therapeutic target for EGFR wild-type non-small cell lung cancer.

Epidermal growth factor receptor-targeted (EGFR-targeted) therapies show promise for non-small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild-type NSCLC. A genome-wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild-type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild-type NSCLC cells. Additionally, PAICS silencing led to cell-cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild-type NSCLC. PAICS silencing also caused DNA damage and cell-cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K-AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild-type NSCLC and represents a potential therapeutic target for this disease.

Overview and prospect of NAFLD: Significant roles of nutrients and dietary patterns in its progression or prevention.

NAFLD is the most common chronic liver disease worldwide, characterized by lipid accumulation in the liver, and usually evolves from steatohepatitis to fibrosis, cirrhosis, or even HCC. Its incidence is rapidly rising in parallel with the increasing prevalence of obesity and metabolic syndrome. Current therapies are limited to lifestyle changes including dietary intervention and exercise, in which dietary modification exerts an important part in losing weight and preventing NAFLD. In this review, we briefly discuss the roles and mechanisms of dietary components including fructose, non-nutritive sweeteners, fat, proteins, and vitamins in the progression or prevention of NAFLD. We also summarize several popular dietary patterns such as calorie-restricted diets, intermittent fasting, ketogenic diets, Mediterranean diets, and dietary approach to stop hypertension diets and compare the effects of low-fat and low-carbohydrate diets in preventing the development of NAFLD. Moreover, we summarize the potential drugs targeting metabolic-related targets in NAFLD.

Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup of patients were constantly improving owing to the continuous iteration and optimization of EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved for the treatment of NSCLC patients carrying EGFR T790M mutations, and has currently become the dominant first-line targeted therapy for most EGFR mutant lung cancer. Unfortunately, resistance to osimertinib inevitably develops during the treatment and therefore limits its long-term effectiveness. For both fundamental and clinical researchers, it stands for a major challenge to reveal the mechanism, and a dire need to develop novel therapeutics to overcome the resistance. In this article, we focus on the acquired resistance to osimertinib caused by EGFR mutations which account for approximately 1/3 of all reported resistance mechanisms. We also review the proposed therapeutic strategies for each type of mutation conferring resistance to osimertinib and give an outlook to the development of the next generation EGFR inhibitors. Video Abstract.

Crucial role of T cells in NAFLD-related disease: A review and prospect.

Nonalcoholic fatty liver disease (NAFLD) includes a series of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or even hepatocellular carcinoma (HCC). Its incidence is increasing worldwide. Several factors including metabolic dysfunction, oxidative stress, lipotoxicity contribute to the liver inflammation. Several immune cell-mediated inflammatory processes are involved in NAFLD in which T cells play a crucial part in the progression of the disease. In this review, we focus on the role of different subsets of both conventional and unconventional T cells in pathogenesis of NAFLD. Factors regarding inflammation and potential therapeutic approaches targeting immune cells in NASH are also discussed.

Manufacturing of Soft Contact Lenses Using Reusable and Reliable Cyclic Olefin Copolymer Moulds.

We present experimental evidence of reusable, reliable cyclic olefin copolymer (COC) moulds in soft contact lens manufacturing. The moulds showed high performance surface roughness characteristics despite >20 kW exposure to 365 nm ultraviolet (UV) light from repeated use. Ultra-precision manufacturing techniques were used to fabricate transparent COC mould inserts and to produce soft contact lenses from liquid monomer compositions. Both polymer and silicone hydrogels were fabricated with more than 60 individual uses of the moulds. White light interferometry measured the surface roughness (Sa) of the COC moulds to be almost unchanged before and after repeated use (Sa 16.3 nm before vs. 16.6 nm after). The surface roughness of the prototyped lenses and that of commercially available soft contact lenses were then compared by white light interferometry. The surface roughness of the lenses was also nearly unchanged, despite undergoing more than 60 uses of the COC moulds (lens Sa 24.4 nm before vs. after Sa 26.5 nm). By comparison the roughness of the commercial lenses ranged from 9.3−28.5 nm, including conventional and silicone lenses, indicating that the reusable COC moulds produced competitive surface properties. In summary, COC moulds have potential as reusable and reliable mould inserts in the manufacturing of soft contact lenses, yet maintain high quality optical surfaces even after sustained exposure to UV light.

Analysis of changes in population's cross-city travel patterns in the pre- and post-pandemic era: A case study of China.

The coronavirus disease (COVID-19) outbreak has immensely changed people's travel behaviour. The changes in travel behaviour have had a huge impact on different industries, such as consumption, entertainment, commerce, office, and education. This study investigates the impact of COVID-19 on population travel patterns from three aspects: total trips, travel recovery degree, and travel distance. The result indicates that COVID-19 has reduced the total number of cross-city trips and flexible non-work travel; in the post-pandemic era, cross-city travel is mainly short-distance (distance <100 km). This study has significant policymaking implications for governments in countries where the population shares a similar change in travel behaviour.

Biomimetic Functional Surfaces towards Bactericidal Soft Contact Lenses.

The surface with high-aspect-ratio nanostructure is observed to possess the bactericidal properties, where the physical interaction between high-aspect-ratio nanostructure could exert sufficient pressure on the cell membrane eventually lead to cell lysis. Recent studies in the interaction mechanism and reverse engineering have transferred the bactericidal capability to artificial surface, but the biomimetic surfaces mimicking the topographical patterns on natural resources possess different geometrical parameters and surface properties. The review attempts to highlight the recent progress in bactericidal nanostructured surfaces to analyze the prominent influence factors and cell rupture mechanism. A holistic approach was utilized, integrating interaction mechanisms, material characterization, and fabrication techniques to establish inclusive insights into the topographical effect and mechano-bactericidal applications. The experimental work presented in the hydrogel material field provides support for the feasibility of potentially broadening applications in soft contact lenses.

Weeping candidate genes screened using comparative transcriptomic analysis of weeping and upright progeny in an F1 population of Prunus mume.

Weeping is a specific plant architecture with high ornamental value. Despite the considerable importance of the weeping habit to landscaping applications and knowledge of plant architecture biology, little is known regarding the underlying molecular mechanisms. In this study, growth and phytohormone content were analyzed among the progeny of different branch types in an F1 mapping population of Prunus mume with varying plant architecture. Bulked segregant RNA sequencing was conducted to compare differences among progeny at a transcriptional level. The weeping habit appears to be a complex process regulated by a series of metabolic pathways, with photosynthesis and flavonoid biosynthesis highly enriched in differentially expressed genes between weeping and upright progeny. Based on functional annotation and homologous analyses, we identified 30 candidate genes related to weeping that merit further analysis, including 10 genes related to IAA and GA3 biosynthesis, together with 6 genes related to secondary branch growth. The results of this study will facilitate further studies of the molecular mechanisms underlying the weeping habit in P. mume.

Enhanced reductive removal of ciprofloxacin in pharmaceutical wastewater using biogenic palladium nanoparticles by bubbling H2.

To treat waste with waste and efficiently remove the organic pollutant, waste palladiums(ii) were adsorbed and reduced on microorganism surface to catalyze the reductive removal of ciprofloxacin in pharmaceutical wastewater. By optimizing conditions such as pH and temperature, the amount of biogenic palladium adsorbed and reduced on E. coli reached 139.48 mg g-1 (Pd/microorganisms). Moreover, most of the Pd(ii) was reduced to nanometer-sized Pd(0) as characterized by TEM and SEM with EDXA. Using the obtained biogenic palladium, the reductive removal of ciprofloxacin is up to 87.70% at 25 °C, 3.03 folds of that achieved in the absence of H2. The results show that waste E. coli microorganisms can efficiently adsorb and remove waste Pd(ii) and produce Bio-Pd nanoparticle catalysts in the presence of H2. This biogenic palladium presents high catalytic activity and great advantages in the reductive degradation of ciprofloxacin. Our method can also be applied to other waste metal ions to prepare the biogenic metals, facilitate their recovery and reuse in degrading organic pollutants in wastewater to achieve "treating waste using waste".

Genome-wide analyses of the bHLH gene family reveals structural and functional characteristics in the aquatic plant Nelumbo nucifera.

Lotus (Nelumbo nucifera Gaertn.) is an economically important aquatic plant with multiple applications, but water salinity and cold stress seriously affect lotus yield and distribution. The basic helix-loop-helix (bHLH) transcription factors (TFs) play a vital role in plant growth and development, metabolic regulation processes and responses to environmental changes. However, systematic analyses of the bHLH TF family in lotus has not yet been reported. Here, we report the identification and description of bHLH genes in lotus (NnbHLHs) with a focus on functional prediction, particularly for those involved in stress resistance. In all, 115 NnbHLHs were identified in the lotus genome and classified into 19 subfamilies. The chromosomal distribution, physicochemical properties, bHLH domain, conserved motif compositions and evolution of these 115 NnbHLHs were further analyzed. To better understand the functions of the lotus bHLH family, gene ontology, cis-element, and phylogenetic analyses were conducted. NnbHLHs were predicted to be involved in plant development, metabolic regulation and responses to stress, in accordance with previous findings. Overall, 15 NnbHLHs were further investigated with functional prediction via quantitative real-time PCR analyses. Meanwhile, expression profiles of NnbHLHs in four tissues indicated that many NnbHLHs showed tissue preference in their expression. This study is supposed to provide a good foundation for further research into the functions and evolution of NnbHLHs, and identifies candidate genes for stress resistance in lotus.

Differences in flavonoid pathway metabolites and transcripts affect yellow petal colouration in the aquatic plant Nelumbo nucifera.

BACKGROUND: The Asia lotus (Nelumbo nucifera Gaertn.) is an ornamental aquatic plant with high economic value. Flower colour is an important ornamental trait, with much of N. nucifera breeding focusing on its yellow flowers. To explore the yellow flower colouration mechanism in N. nucifera, we analysed its pigment constituents and content, as well as gene expression in the flavonoid pathway, in two N. nucifera cultivars. RESULTS: We performed metabolomic and gene expression analyses in two N. nucifera cultivars with yellow and white flowers, Molinqiuse (MLQS) and Yeguangbei (YGB), respectively, at five stages of flower colouration. Based on phenotypic observation and metabolite analyses, the later stages of flower colouration (S3-S5) were determined to be key periods for differences between MLQS and YGB, with dihydroflavonols and flavonols differing significantly between cultivars. Dihydroquercetin, dihydrokaempferol, and isorhamnetin were significantly higher in MLQS than in YGB, whereas kaempferol was significantly higher in YGB. Most of the key homologous structural genes in the flavonoid pathway were significantly more active in MLQS than in YGB at stages S1-S4. CONCLUSION: In this study, we performed the first analyses of primary and secondary N. nucifera metabolites during flower colouration, and found that isorhamnetin and kaempferol shunting resulted in petal colour differences between MLQS and YGB. Based on our data integration analyses of key enzyme expression in the putative flavonoid pathways of the two N. nucifera cultivars, NnFLS gene substrate specificity and differential expression of NnOMTs may be related to petal colour differences between MLQS and YGB. These results will contribute to determining the mechanism of yellow flower colouration in N. nucifera, and will improve yellow petal colour breeding in lotus species.

Detection of Highly Differentiated Genomic Regions Between Lotus (Nelumbo nucifera Gaertn.) With Contrasting Plant Architecture and Their Functional Relevance to Plant Architecture.

The lotus (Nelumbo nucifera Gaertn.) is one of the most economically and ornamentally important perennial aquatic plants. Plant architecture is an important trait for lotus classification, cultivation, breeding, and applications. In this study, traits representing plant architecture were measured in 390 lotus germplasms for 3 years. According to the phenotypic distribution, 21 large architecture (LA) and 22 small architecture (SA) germplasms exhibiting extreme phenotypes were selected as representatives of plant architecture. Microscopy analyses revealed that LA lotuses possessed far more vertical cells and longer cell lengths than SA lotuses, and there was a closer linear relationship between vertical cell number and plant architecture than cell length and plant architecture. Furthermore, based on whole genome re-sequencing data from 10 LA and 10 SA lotus germplasms, fixation index (FST) genome scan identified 11.02 Mb of genomic regions that were highly differentiated between the LA and SA lotus groups. Chi-square test revealed that 17,154 single nucleotide polymorphisms (SNPs) and 1,554 insertions and deletions (InDels) showed distinct allelic distribution between the LA and SA lotus groups within these regions. A total of 126 variants with distinct allelic distribution in the highly differentiated region were predicted to cause amino acid changes in 60 genes. Among the 41 genes with functional annotation, the expression patterns of six genes involved in cell division and cell wall construction were confirmed using quantitative reverse-transcription PCR (qRT-PCR). In addition, 34 plant architecture-associated InDel markers were developed and verified in the remaining 11 LA and 12 SA lotus plant architecture representatives. This study identified promising functional markers and candidates for molecular breeding and will facilitate further elucidation of the genetic mechanisms underlying plant architecture in the lotus.