The interactions of microplastics (MPs) with other chemicals and the range of outcomes are of great importance to enhance understanding of their environmental impacts and health risks. Cadmium (Cd) and cadmium compounds are widely used as pigments and stabilizers in plastics, but they readily leach out. Here we addressed the impacts of MPs, Cd, and their joint exposure in a tractable Drosophila melanogaster model. We show that exposure to MPs lead to extensive particle size depended gut damage early in life and an enhancement of Cd-induced inhibition of locomotor-behavioral function in adult flies. In addition, we show that Cd exposure induces epigenetic gene silencing via position-effect variegation (PEV) in somatic tissues that was dramatically enhanced by co-exposure with MPs. The results indicate that MPs can aggravate the toxicity of other environmental contaminants and induce adverse effects across a range of diverse outcomes in a tractable and widely used model organism. These observations raise the prospects of using Drosophila as a tool for the rapid assessment of MP-mediated toxicity.

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.

Cervical cancer is one most common cancer types among females over the world. While its underlying mechanisms remain unclear. Circ-CCDC66 has been revealed to participate in multiple biological functions, and contribute to various diseases' progression. In the current study, we aimed to demonstrate the role of circ-CCDC66 in cervical cancer progression.

The etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear. In humans, the level of homocysteine is mainly affected by two enzymes: methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR). While the activity of these two enzymes is mainly affected by three missense mutations, namely C677T (MTHFR), A1298C (MTHFR), and A66G (MTRR). This study aims to examine the association between the three missense mutations and PCOS and investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level.

Ambrosia artemisiifolia is a noxious invasive alien weed, that is harmful to the environment and human health. Ophraella communa is a biocontrol agent for A. artemisiifolia, that was accidentally introduced to the Chinese mainland and has now spread throughout southern China. Recently, we found that upon artificial introduction, O. communa can survive in northern China as well. Therefore, it is necessary to study the cold hardiness of O. communa. Many genes have been identified to play a role in cold-tolerance regulation in insects, but the function of the gene encoding non-muscle myosin regulatory light chain (MRLC-sqh) remains unknown. To evaluate the role played by MRLC-sqh in the cold-tolerance response, we cloned and characterized MRLC-sqh from O. communa. Quantitative real-time PCR revealed that MRLC-sqh was expressed at high levels in the gut and pupae of O. communa. The expression of MRLC-sqh was shown to decrease after cold shock between 10 and 0 °C and ascend between 0 and -10 °C, but these did not show a positive association between MRLC-sqh expression and cold stress. Silencing of MRLC-sqh using dsMRLC-sqh increased the chill-coma recovery time of these beetles, suggesting that cold hardiness was reduced in its absence. These results suggest that the cold hardiness of O. communa may be partly regulated by MRLC-sqh. Our findings highlight the importance of motor proteins in mediating the cold response in insects.

To explore the non-linear relationship between platelet count (PLT) and hepatocellular carcinoma (HCC) overall survival (OS).

The identification and functional characterization of natural variants in plants are essential for understanding phenotypic adaptation. Here we identify a molecular variation in At2g47310 that contributes to the natural variation in flowering time in Arabidopsis thaliana accessions. This gene, which we term SISTER of FCA (SSF), functions in an antagonistic manner to its close homolog FCA. Genome-wide association analysis screens two major haplotypes of SSF associated with the natural variation in FLC expression, and a single polymorphism, SSF-N414D, is identified as a main contributor. The SSF414N protein variant interacts more strongly with CUL1, a component of the E3 ubiquitination complex, than the SSF414D form, mediating differences in SSF protein degradation and FLC expression. FCA and SSF appear to have arisen through gene duplication after dicot-monocot divergence, with the SSF-N414D polymorphism emerging relatively recently within A. thaliana. This work provides a good example for deciphering the functional importance of natural polymorphisms in different organisms.

Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O2) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O2 with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O2-dependent and O2-independent antisickling properties of fetal hemoglobin. The latter mechanism of action-as elucidated through crystallographic and biological studies-is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate.

Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-β (TGF-β), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1β, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.

The GENCODE project annotates human and mouse genes and transcripts supported by experimental data with high accuracy, providing a foundational resource that supports genome biology and clinical genomics. GENCODE annotation processes make use of primary data and bioinformatic tools and analysis generated both within the consortium and externally to support the creation of transcript structures and the determination of their function. Here, we present improvements to our annotation infrastructure, bioinformatics tools, and analysis, and the advances they support in the annotation of the human and mouse genomes including: the completion of first pass manual annotation for the mouse reference genome; targeted improvements to the annotation of genes associated with SARS-CoV-2 infection; collaborative projects to achieve convergence across reference annotation databases for the annotation of human and mouse protein-coding genes; and the first GENCODE manually supervised automated annotation of lncRNAs. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.

Circular RNAs (circRNA) have been shown to be involved in the pathogenesis of colorectal cancer (CRC). CircCTNNA1 was found to be one of the upregulated circRNAs in CRC. However, there are few studies on circCTNNA1, so it is necessary to carry out further studies.

Non-small-cell lung cancer (NSCLC), with its aggressive biological behavior, is one of the most diagnosed cancers. Tumor-associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer, however the mechanisms involved are far from defined. In the present study, by developing an orthotopic NSCLC mouse model based on chronic inflammation, we proved that an inflammatory microenvironment accelerated the growth of orthotopic xenografts in vivo. Tumor-associated macrophages, the most abundant population of inflammatory cells, were identified. Treatment with macrophage-conditioned medium (MCM) promoted the growth and migration of NSCLC cells. Using bioinformatics analysis, we identified downregulated PP2Ac expression in NSCLC cells upon treatment with MCM. We further confirmed that this downregulation was executed in an NF-κB pathway-dependent manner. As IκB kinase (IKK) has been proved to be a substrate of PP2Ac, inhibition on PP2Ac could result in amplification of NF-κB pathway signaling. Overexpression of PP2Ac, or the dominant-negative forms of IKK or IκB, attenuated the acceleration of growth and metastasis by MCM. Using bioinformatics analysis, we further identified that CXCL1 and COL6A1 could be downstream of NF-κB/PP2Ac pathway. Luciferase assay and ChIP assay further confirmed the location of response elements on the promoter regions of CXCL1 and COL6A1. Elevated CXCL1 facilitated angiogenesis, whereas upregulated COL6A1 promoted proliferation and migration.

The mortality rate of non-small-cell lung cancer (NSCLC) remains high worldwide. Although cisplatin-based chemotherapy may greatly enhance patient prognosis, chemotherapy resistance remains an obstacle to curing patients with NSCLC. Therefore, overcoming drug resistance is the main route to successful treatment, and combinatorial strategies may have considerable clinical value in this effort. In this study, we observed that both parthenolide (PTL) and cisplatin (DDP) inhibited the growth of NSCLC cells in a dose- and time-dependent manner. The combination of PTL and DDP presented a synergistic inhibitory effect on NSCLC at a ratio of 50:1. The combination of PTL and DDP synergistically inhibited cell migration and invasion, inhibited cell cycle progression, and induced apoptosis of A549 and PC9 cells. Bioinformatics and network pharmacology analysis indicated that PTL may primarily affect the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway. After treatment with PTL and DDP either alone or in combination, Western blot analysis revealed that the proteins levels of Bax and cleaved Caspase-3 were upregulated, while p-PI3K, p-Akt, Caspase-3, and Bcl-2 proteins were downregulated. Among these alterations, the combination of PTL and DDP was found to exhibit the most significant effects. PTL might therefore be considered as a new option for combination therapy of NSCLC.

The aim of this work was to characterize biogenic amines (BAs) in different parts of Lycium barbarum L. using HPLC with dansyl chloride derivatization, and jointly, to provide referential data for further exploration and utilization of Lycium barbarum L. The linear correlation coefficients for all BAs were above 0.9989. The limits of detection and quantification were 0.015-0.075 and 0.05-0.25 μg/mL, respectively. The relative standard deviations for the intra-day and inter-day precision were 0.66-2.69% and 0.91-4.38%. The described method has good repeatability and intermediate precision for the quantitative determination of BAs in different parts of Lycium barbarum L. Satisfactory recovery for all amines was obtained (79.3-110.3%). The result showed that there were four kinds of BAs. The highest putrescine content (20.9 ± 3.2 mg/kg) was found in the flower. The highest histamine content (102.7 ± 5.8 mg/kg) was detected in the bark, and the highest spermidine (13.3 ± 1.6 mg/kg) and spermine (23.7 ± 2.0 mg/kg) contents were detected in the young leaves. The high histamine (HIS) content in the bark may be one of the reasons why all of the parts of Lycium barbarum L., except the bark, are used for medicine or food in China. Meanwhile, the issue of the high concentration of HIS should be considered when exploiting or utilizing the bark of Lycium barbarum L.

Arisaema erubescens is a well-known medicinal plant in China. In this study, we sequenced the complete chloroplast (cp) genome sequence of A. erubescens to investigate its phylogenetic relationship in the family Araceae. The cp genome was 167,607 bp in length, consisting of a pair of inverted repeats (IRa and IRb: 26,193 bp) separated by a large single-copy region (LSC: 93,660 bp) and a small single-copy region (SSC: 21,561 bp). The GC content of whole cp genome is 35.3%. De novo assembly and annotation showed the presence of 114 unique genes with 80 protein-coding genes, 30 tRNA genes, and four rRNA genes. Phylogenetic analysis indicated that A. erubescens was closely related to A. franchetianum, and the genus Arisaema was sister to the genus Pinellia.

An important mechanism involved in dry eye (DE) is the association between tear hyperosmolarity and inflammation severity. Inflammation in DE might be mediated by the NLRP3 inflammasome, which activated by exposure to reactive oxygen species (ROS). A combination of carboxymethylcellulose (CMC) and α-melanocyte stimulating hormone (α-MSH) may influence DE through this mechanism, thus avoiding defects of signal drug. In this study, we assessed whether treatment comprising CMC combined with α-MSH could ameliorate ocular surface function; we found that it promoted tear secretion, reduced the density of fluorescein sodium staining, enhanced the number of conjunctival goblet cells, and reduced the number of corneal apoptotic cells. Investigation of the underlying mechanism suggested that the synergistic effect of combined treatment alleviated DE inflammation through reduction of ROS level and inhibition of the NLRP3 inflammasome in human corneal epithelial cells. These findings indicate that combined CMC + α-MSH treatment could ameliorate lesions and restore ocular surface function in patients with DE through reduction of ROS level and inhibition of NLRP3 signalling.

For the development of spacecraft with long-servicing life in low earth orbit (LEO), high-temperature resistant polymer films with long-term atomic oxygen (AO) resistant features are highly desired. The relatively poor AO resistance of standard polyimide (PI) films greatly limited their applications in LEO spacecraft. In this work, we successfully prepared a series of novel AO resistant PI composite films containing nanocaged polyhedral oligomeric silsesquioxane (POSS) components in both the PI matrix and the fillers. The POSS-containing PI matrix film was prepared from a POSS-substituted aromatic diamine, N-[(heptaisobutyl-POSS)propyl]-3,5-diaminobenzamide (DABA-POSS) and a common aromatic diamine, 4,4'-oxydianline (ODA) and the aromatic dianhydride, pyromellitic dianhydride (PMDA) by a two-step thermal imidization procedure. The POSS-containing filler, trisilanolphenyl POSS (TSP-POSS) was added with the fixed proportion of 20 wt% in the final films. Incorporation of TSP-POSS additive apparently improved the thermal stability, but decreased the high-temperature dimensional stable nature of the PI composite films. The 5% weight loss temperature (T5%) of POSS-PI-20 with 20 wt% of DABA-POSS is 564 °C, and its coefficient of linear thermal expansion (CTE) is 81.0 × 10-6/K. The former is 16 °C lower and the latter was 20.0 × 10-6/K higher than those of the POSS-PI-10 film (T5% = 580 °C, CTE = 61.0 × 10-6/K), respectively. POSS components endowed the PI composite films excellent AO resistance and self-healing characteristics in AO environments. POSS-PI-30 exhibits the lowest AO erosion yield (Es) of 1.64 × 10-26 cm3/atom under AO exposure with a flux of 2.51 × 1021 atoms/cm2, which is more than two orders of magnitude lower than the referenced PI (PMDA-ODA) film. Inert silica or silicate passivation layers were detected on the surface of the PI composite films exposed to AO.

Background: Coronavirus disease 2019 (COVID-19) has resulted in more than 610,000 deaths worldwide since December 2019. Given the rapid deterioration of patients' condition before death, markers with efficient prognostic values are urgently required. During the treatment process, notable changes in plasma potassium levels have been observed among severely ill patients. We aimed to evaluate the association between average plasma potassium (Ka +) levels during hospitalization and 30-day mortality in patients with COVID-19. Methods: Consecutive patients with COVID-19 hospitalized in the Zhongfaxincheng branch of Tongji Hospital in Wuhan, China from February 8 to 28, 2020 were enrolled in this study. We followed patients up to 30 days after admission. Results: A total of 136 patients were included in the study. The average age was 62.1±14.6 years and 51.5% of patients were male. The median baseline potassium level was 4.3 (3.9-4.6) mmol/L and Ka + level during hospitalization was 4.4 (4.2-4.7) mmol/L; the median number of times that we measured potassium was 4 (3-5). The 30-day mortality was 19.1%. A J-shaped association was observed between Ka + and 30-day mortality. Multivariate Cox regression showed that compared with the reference group (Ka + 4.0 to <4.5 mmol/L), 30-day mortality was 1.99 (95% confidence interval [CI]=0.54-7.35, P=0.300), 1.14 (95% CI=0.39-3.32, P=0.810), and 4.14 (95% CI=1.29-13.29, P=0.017) times higher in patients with COVID-19 who had Ka + <4.0, 4.5 to <5.0, and ≥5.0 mmol/L, respectively. Conclusion: Patients with COVID-19 who had a Ka + level ≥5.0 mmol/L had a significantly increased 30-day mortality compared with those who had a Ka + level 4.0 to <4.5 mmol/L. Plasma potassium levels should be monitored routinely and maintained within appropriate ranges in patients with COVID-19.

Plants have evolved genetic and physiological mechanisms to mitigate the adverse effects of high temperature. CARBOXYL TERMINUS OF THE HSC70-INTERACTING PROTEINS (CHIP) is a conserved chaperone-dependent ubiquitin E3 ligase that targets misfolded proteins. Here, we report functional analysis of the SlCHIP gene from tomato (Solanum lycopersicum) in heat tolerance. SlCHIP encodes a CHIP protein with three tandem tetracopeptide repeat (TPR) motifs and a C-terminal U box domain. Phylogenetic analysis of CHIP homologs from animals, spore-bearing and seed plants revealed a tree topology similar to the evolutionary tree of the organisms. Expression of SlCHIP was induced under high temperature and was also responsive to plant stress hormones. Silencing of SlCHIP in tomato reduced heat tolerance based on increased heat stress symptoms, reduced photosynthetic activity, elevated electrolyte leakage and accumulation of insoluble protein aggregates. The accumulated protein aggregates in SlCHIP-silenced plants were still highly ubiquitinated, suggesting involvement of other E3 ligases in ubiquitination. SlCHIP restored the heat tolerance of Arabidopsis chip mutant to the wild type levels. These results indicate that tomato SlCHIP plays a critical role in heat stress responses most likely by targeting degradation of misfolded proteins that are generated during heat stress.

Trans-regulating elements such as noncoding RNAs are crucial in modifying cells, and has shown broad application in synthetic biology, metabolic engineering and RNA therapies. Although effective, titration of the regulatory levels of such elements is less explored. Encouraged by the need of fine-tuning cellular functions, we studied key parameters of the antisense RNA design including oligonucleotide length, targeting region and relative dosage to achieve differentiated inhibition. We determined a 30-nucleotide configuration that renders efficient and robust inhibition. We found that by targeting the core RBS region proportionally, quantifiable inhibition levels can be rationally obtained. A mathematic model was established accordingly with refined energy terms and successfully validated by depicting the inhibition levels for genomic targets. Additionally, we applied this fine-tuning approach for 4-hydroxycoumarin biosynthesis by simultaneous and quantifiable knockdown of multiple targets, resulting in a 3.58-fold increase in titer of the engineered strain comparing to that of the non-regulated. We believe the developed tool is broadly compatible and provides an extra layer of control in modifying living systems.