Search

Abstract: Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, was approved by the US FDA to entered clinical trials in 2019 to treat patients suffering from locally advanced or metastatic ER-positive/HER2-negative breast cancer, and has since been approved by the US FDA. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.

BACKGROUND: Papillary renal cell carcinoma (PRCC) is the 2nd most common type of renal carcinoma; however, there is limited data about PRCC, and strategies for the diagnosis and treatment of PRCC need to be identified. METHODS: In this study, the stemness-associated senescence (SAS) phenotype of PRCC was obtained by a bioinformatics analysis. We acquired the gene expression profiles of patients with PRCC and calculated the PRCC messenger ribonucleic acid stemness index (mRNAsi). We then screened the SAS genes from the GenAge database. A least absolute shrinkage and selection operator–Cox regression was conducted to examine correlations between risk signatures and the abundance of the SAS genes in the PRCC samples. Functional enrichment analyses were then performed via molecular co-expression studies of mRNAsi, and the risk scores of PRCC patients were calculated. RESULTS: We identified the following 8 SAS signatures that were strongly associated with prognosis in PRCC patients: cyclin-dependent kinase 1, heat shock protein family D member 1, platelet-derived growth factor receptor A, cyclin-dependent kinase inhibitor 2B, pyrroline-5-carboxylate reductase 1, sequestosome-1, sirtuin-3, and cyclin-dependent kinase inhibitor 1A. The SAS signatures were significantly associated with the stage and type of PRCC. The calculated risk scores can be used to divide PRCC patients into low- and high-risk groups, and provide guidance in determining treatment plans. CONCLUSIONS: We have developed a reliable prognostic tool to predict the clinical outcomes of PRCC patients. This tool could improve treatment decisions regarding drug therapy, surgery, and conservative options.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies frequently associated with extrathyroidal extension and metastasis through pathways that remain unclear. Analysis of the cancer genome atlas (TCGA) database and an independent cohort showed that the expression of hematological and neurological expressed 1 (HN1) was higher in thyroid cancers than in normal tissues, and negatively correlated with progression-free survival. RT-PCR and immunohistochemistry revealed higher HN1 expression in ATC compared to healthy tissues and papillary thyroid carcinoma (PTC). HN1 knockdown attenuated migration and invasion of ATC cells, whereas HN1 overexpression increased migration and invasion of PTC cells. HN1 reduced the acetylation of α-tubulin and promoted progression through epithelial-mesenchymal transition of ATC cells and mouse xenografts. HN1 knockdown significantly attenuated TGF-β-induced mesenchymal phenotype, and inhibited tumor formation and growth of ATC xenografts in nude mice. Loss of STMN1 decreased the malignant potential of HN1, whereas HN1 knockdown in combination with STMN1 overexpression restored the aggressive properties of ATC cells. HN1 increased STMN1 mRNA expression, and prevented STMN1 ubiquitination and subsequent degradation. These results demonstrate that HN1 interacts with STMN1 and drives ATC aggressiveness.

Tetra(3-mercaptopropyl)-silsesquioxanes with double-decker (DDSQ) or ladder nano-cores were easily prepared from the corresponding tetraallyl derivatives through fast and convenient thiol-ene reactions. An additional tetrathiol-DDSQ with more flexible arms was also synthesized in high yield from the corresponding tetrachloro-DDSQ derivative. The three novel tetrathiol silsesquioxanes described represent versatile building blocks for the preparation of hybrid organic-inorganic materials.

In this paper, we studied the effect of glycosylation reaction on the molecular structure and functional properties of whey protein isolate (WPI), and studied the effect of reaction temperature (50 to 90 °C) on the molecular structure and functional properties of WPI-dextran conjugates (WPI-D). The results of the extent of glycation (EG) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis confirmed the formation of WPI-D. Circular dichroism (CD), Fourier transform infrared spectrum, and fluorescence spectroscopy indicated that the molecular structure of WPI was changed after glycosylation-the β-sheet content was decreased and the tryptophan content was increased. The emulsifying properties and the ability to encapsulate β-carotene of WPI-D were improved compared with WPI (P < 0.05). When the reaction temperature was 70 and 80 °C, the EG and the ability to encapsulate β-carotene of WPI-D were better (P < 0.05), which was related to protein unfolding. However, due to the polymerization between the WPI molecules, the emulsion activity index of WPI-D and the ability to encapsulate β-carotene were lowered at 90 °C (P < 0.05). Therefore, the glycosylation reaction can change the molecular structure and functional properties of WPI; the emulsifying properties and the ability to encapsulate β-carotene of WPI-D can be changed by controlling the reaction temperature of glycosylation. PRACTICAL APPLICATION: The glycosylation reaction can change the molecular structure and functional properties of Whey protein isolate; the emulsifying properties and the ability to encapsulate β-carotene of WPI-dextran conjugates can be changed by controlling the reaction temperature of glycosylation.

OBJECTIVES Massive research has examined the cause of major depressive disorder (MDD) and accumulating evidence has revealed that the gene for the norepinephrine transporter (NET) is involved in MDDs etiology as well as the antidepressant response. The G1287A (rs5569, GRCh38, Chromosome 16, 55697923) is located in the exon 9 region of the SLC6A2 gene. It was found to be connected with MDD and antidepressant response in people of different genetic ancestries. However, the results are still inconsistent. METHODS A meta-analysis was conducted to evaluate the overall association of rs5569 polymorphisms with MDD and the antidepressant response. RESULTS Sixteen articles that studied the connection between the G1287A polymorphism and MDD or antidepressant response were identified, and their outcomes revealed there was a significant connection between the polymorphisms and MDD and antidepressant response. Our study indicated that the GG genotype may be a protection factor against the development of MDD [odds ratio (OR = 0.78, 95% confidence interval (CI) = 0.64-0.96, P = 0.02 for Asian population; OR = 0.79, 95% CI = 0.63-0.98, P = 0.03 for Han Chinese population] while the GG genotype had a worse antidepressant response (OR = 0.49, 95% CI = 0.25-0.94, P = 0.03). CONCLUSIONS NET G1287A polymorphisms are involved in the etiology of MDD and antidepressant response.

Mitochondria have an essential function in cell survival due to their role in bioenergetics, reactive oxygen species generation, calcium buffering, and other metabolic activities. Mitochondrial dysfunctions are commonly found in neurodegenerative diseases (NDs), and diabetes is a risk factor for NDs. However, the role of mitochondria in diabetic neurodegeneration is still unclear. In the present study, we review the latest evidence on the role of mitochondrial dysfunctions in the development of diabetes-related NDs and the underlying molecular mechanisms. Hypoglycemic agents, especially metformin, have been proven to have neuroprotective effects in the treatment of diabetes, in which mitochondria could act as one of the underlying mechanisms. Other hypoglycemic agents, including thiazolidinediones (TZDs), dipeptidyl peptidase 4 (DPP-4) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, have gained more attention because of their beneficial effects on NDs, presumably by improving mitochondrial function. Our review highlights the notion that mitochondria could be a promising therapeutic target in the treatment of NDs in patients with diabetes.

CaCO3 nanoparticles are very suitable as intelligent carriers because of their ideal biocompatibility and biodegradability, especially their sensitivity to pH. In this paper, we use mesoporous CaCO3 nanoparticles as intelligent carrier, sodium alginate, and chitosan as alternating assembly materials, folic acid as target molecules, and exploit layer-by-layer assembly technology to achieve sensitive molecular targeting and pH response drug release. Mesoporous CaCO3 hybrid nanoparticles have high drug loading on doxorubicin. The effects of different pH values on drug release in vitro were studied by regulating simulated body fluids with different pH values. The cytotoxicity, targeting effect, and drug release of human cervical cancer cell line (HeLa) were studied by cell vitality and imaging experiments. All the evidence suggests that the smart mesoporous CaCO3 nanoparticles may be a potential clinical application platform for cancer therapy.

Uric acid (UA) is the end-product in the human purine metabolism pathway. The UA that accumulates in silkworm tissues is excreted as a nitrogen waste product. Here, we first validated that Bombyx mori has a homolog of the human gene that encodes the 5′-nucleotidase (5′N) involved in purine metabolism. The B. mori gene, Bm5′N, is located upstream of other genes involved in UA metabolism in the silkworm. Disruption of Bm5′N via the CRISPR/Cas9 system resulted in decreased UA levels in the silkworm epidermis and caused a translucent skin phenotype. When Bm5′N mutant silkworms were fed with the uric acid precursor inosine, the UA levels in the epidermis increased significantly. Furthermore, the metabolomic and transcriptomic analyses of Bm5′N mutants indicated that loss of the Bm5′N affected purine metabolism and the ABC transport pathway. Taken together, these results suggest that the UA pathway is conserved between the silkworm and humans and that the Bm5′N gene plays a crucial role in the uric acid metabolism of the silkworm. Thus, the silkworm may be a suitable model for the study of UA metabolism pathways relevant to human disease.

Grassland plays a vital role in the development of animal husbandry and ecological security. Grassland protection is an important part of my country’s land resource management, and it is of great significance to ensure people’s living environment, ecological safety, and food safety. For a long time, the poisonous and harmful herbification of grassland has been a serious threat to the healthy and sustainable development of our country’s animal husbandry. In order to effectively monitor and prevent the aggravation of poisonous weeds, this article takes the typical poisonous grass diphtheria aconitum in the Nalati grassland of Xinyuan County, Ili Prefecture, Xinjiang as the research object, uses photoscan software to process the drone aerial images and obtain the research area Based on the DSM data, the relative elevation threshold method is used to extract diphtheria aconitum, and the multi-temporal UAV remote sensing image is used to obtain its migration direction. The results show that 1) The relative elevation threshold method can clearly and accurately reflect the distribution characteristics of ground features, and is suitable for extracting ground features with obvious height differences. 2) When $\leqslant$ T

Background: Gastric cancer is one of the most common fatal disease worldwide, but its mechanism and therapeutic targets are still unclear. In this study, we have analyzed the differences in gene modules and key pathways in gastric cancer patients, then elaborated the mechanism and effective treatment of gastric cancer with microarray data from the gene expression omnibus(GEO) database. Methods: GEO2R tools were used to identify differential expression genes (DEGs), String database was employed to construct a protein-protein interaction (PPI) network. We imported the PPI network into the Cytoscape software to find key nodes, and employed statistical approach of MCODE to cluster genes. After that the ClueGO was used to enrich and annotate the pathways of key modules. To investigate the relationship between the upstream regulator and hub genes, the transcriptional regulatory network was built based on TFCAT database. Results: 63 characteristic genes of gastric cancer are involved in regulation of ECM-receptor interaction, focal adhesion and protein digestion and absorption. SPARC, FN1, BGN and COL1A2 are four key nodes relating to tumor proliferation and metastasis, and their expression were strongly associated with poor survival (pConclusions: The present study defined the gene expression characteristics and transcriptional regulatory network that promote our understanding of the molecular mechanisms underlying the development of gastric cancer, and might provide new insights into targeted therapy and prognostic markers for the personalized treatment of gastric cancer.

Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sitesviawhat are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

Patient-consistent xenograft model is a challenge for all cancers but particularly for thyroid cancer, which shows some of the greatest genetic divergence between human tumors and cell lines. In this study, proteomic profiles of tumor tissues from patients, included anaplastic thyroid carcinoma (ATC) and papillary thyroid carcinoma, and xenografts (8305C, 8505C, FRO, BAPAP and IHH4) were obtained using HPLC-tandem mass spectrometry and compared based on all proteins detected (3,961), cancer-related proteins and druggable proteins using pairwise Pearson's correlation analysis. The human tissue showed low proteomic similarity to the ATC cell lines (8305C, r = 0.344-0.416; 8505C, 0.47-0.579; FRO, 0.267-0.307) and to PTC cell lines (BCPAP, 0.303-0.468; IHH4, 0.262-0.509). Human tissue showed the following similarity to cell lines at the level of 135 cancer-related pathways. The ATC cell lines contained 47.4% of the cancer-related pathways (19.26%-33.33%), while the PTC cell lines contained 40% (BCPAP, 25.93%; IHH4, 28.89%). In patient tumor tissues, 44-60 of 76 and 52-53 of 93 druggable proteins were identified in ATC and PTC tumors, respectively. Ten and 29 druggable proteins were not identified in any of the ATC and PTC xenografts, respectively. We provide a reference for CDX selecting in in vivo studies of thyroid cancer.

Lung cancer represents one of the most common and deadliest cancers in the world. Chimeric antigen receptor-T cell (CAR-T) therapy which can recognize antigens in a major histocompatibility complex (MHC)-independent manner provides a new approach for tumor treatment. However, lung cancer, as a solid tumor, faces several formidable barriers to adoptive cell transfer, which includes inhibition of T-cell localization and suppression of T-cell function. Therefore, lung cancer fails to respond significantly to infusions of CAR-T cells in most trials until now. PubMed was researched using the terms "CAR-T" and "lung cancer" only in English from 2000 through June 2020. We also included results presented in international conferences, such as the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO). Besides, we found new progress in CAR-T therapy for solid tumors as a supplement. To enhance the efficacy and conquer the limitations, we collected some applications in lung cancer. In recent years, there have been some improvements in selecting the proper target and reducing toxicity. CAR-T technology provides an excellent way for tumor treatment, which does not depend on MHC molecules and provides a new method for the utilization of tumor targets. Targeting different antigens and overcoming the solid barrier, there are some improvements in responding significantly and reducing toxicity. CAR-T technology will play a decisive role in the treatment of lung cancer.

Sperm, which have a vital role in sexual reproduction in the animal kingdom, can display heteromorphism in some species. The regulation of sperm dichotomy remains a longstanding puzzle even though the phenomenon has been widely documented for over a century. Here we use Bombyx mori as a model to study a form of sperm dimorphism (eupyrene and apyrene sperm), which is nearly universal among Lepidoptera. We demonstrate that B. mori Sex-lethal (BmSxl) is crucial for apyrene sperm development, and that B. mori poly(A)-specific ribonuclease-like domain-containing 1 (BmPnldc1) is required for eupyrene sperm development. BmSXL is distributed in the nuclei and cytoplasm of somatic cyst cells in a mesh-like pattern and in the cytoplasm of germ cells enclosed in spermatocysts and sperm bundles. Cytological analyses of dimorphic sperm in BmSxl mutants (∆BmSxl) showed deficient apyrene sperm with abnormal nuclei, as well as loss of motility associated with malformed mitochondrial derivatives. We define the crucial function of apyrene sperm in the process of fertilization as assisting the migration of eupyrene spermatozoa from bursa copulatrix to spermatheca. By contrast, BmPnldc1 deficiency (∆BmPnldc1) caused eupyrene sperm abnormalities and impaired the release of eupyrene sperm bundles during spermiation. Although apyrene or eupyrene sperm defects impaired fertility of the mutated males, double copulation of a wild-type female with ∆BmSxl and ∆BmPnldc1 males could rescue the sterility phenotypes induced by single copulation with either gene-deficient male. Our findings demonstrate the crucial functions of BmSxl and BmPnldc1 in the development of sperm dimorphism and the indispensable roles of nonfertile apyrene sperm in fertilization.

The gut microbiota has been presumed to have a role in the pathogenesis of type 1 diabetes (T1D). Significant changes in the microbial composition of T1D patients have been reported in several case-control studies. This study is aimed at systematically reviewing the existing literature, which has investigated the alterations of the intestinal microbiome in T1D patients compared with healthy controls (HCs) using 16S ribosomal RNA-targeted sequencing. The databases of MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched until April 2019 for case-control studies comparing the composition of the intestinal microbiome in T1D patients and HCs based on 16S rRNA gene sequencing techniques. The Newcastle-Ottawa Scale was used to assess the methodological quality. Ten articles involving 260 patients with T1D and 276 HCs were included in this systematic review. The quality scores of all included studies were 6–8 points. In summary, a decreased microbiota diversity and a significantly distinct pattern of clustering with regard to β-diversity were observed in T1D patients when compared with HCs. At the phylum level, T1D was characterised by a reduced ratio of Firmicutes/Bacteroidetes in the structure of the gut community, although no consistent conclusion was reached. At the genus or species level, T1D patients had a reduced abundance of Clostridium and Prevotella compared with HCs, whereas Bacteroides and Ruminococcus were found to be more enriched in T1D patients. This systematic review identified that there is a close association between the gut microbiota and development of T1D. Moreover, gut dysbiosis might be involved in the pathogenesis of T1D, although the causative role of gut microbiota remains to be established. Further well-controlled prospective studies are needed to better understand the role of the intestinal microbiome in the pathogenesis of T1D, which may help explore novel microbiota-based strategies to prevent and treat T1D.

Best known as the powerhouse of the cell, mitochondria have many other important functions such as buffering intracellular calcium and reactive oxygen species levels, initiating apoptosis and supporting cell proliferation and survival. Mitochondria are also dynamic organelles that are constantly undergoing fission and fusion to meet specific functional needs. These processes and functions are regulated by intracellular signaling at the mitochondria. A-kinase anchoring protein 1 (AKAP1) is a scaffold protein that recruits protein kinase A (PKA), other signaling proteins, as well as RNA to the outer mitochondrial membrane. Hence, AKAP1 can be considered a mitochondrial signaling hub. In this review, we discuss what is currently known about AKAP1′s function in health and diseases. We focus on the recent literature on AKAP1′s roles in metabolic homeostasis, cancer and cardiovascular and neurodegenerative diseases. In healthy tissues, AKAP1 has been shown to be important for driving mitochondrial respiration during exercise and for mitochondrial DNA replication and quality control. Several recent in vivo studies using AKAP1 knockout mice have elucidated the role of AKAP1 in supporting cardiovascular, lung and neuronal cell survival in the stressful post-ischemic environment. In addition, we discuss the unique involvement of AKAP1 in cancer tumor growth, metastasis and resistance to chemotherapy. Collectively, the data indicate that AKAP1 promotes cell survival throug regulating mitochondrial form and function. Lastly, we discuss the potential of targeting of AKAP1 for therapy of various disorders.

Egg ovalbumin (OVA) as a macromolecular carrier has the potential to improve the solubility and stability of insolubility bioactive molecules, however, their binding behavior and the mechanism is still ambiguous. In this work, the curcumin was selected as the target to study the interaction and binding mechanism between curcumin and OVA by thermodynamic titration technique in combination with molecular dynamic simulation. The results suggested that the binding included two steps: first, curcumin molecule entered into the hydrophobic pocket of OVA by hydrophobic interaction; and second the interaction was enhanced via hydrogen bonds, resulting in static fluorescence quenching and secondary structural change of OVA. This study provided further evidence in support of the proposed mechanism of the polyphenol-protein binding by the “Hands-gloves” model. Furthermore, when the OVA was as a carrier, the solubility of curcumin has been increased ~370 times to 32.73 μg/mL compared to that of free curcumin at pH 7.0. The photostability was enhanced significantly indicating that it is an efficient way to improve the stability of curcumin in contributing to its application in nutritional supplements or functional foods.

A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation.

We cloned the GbABR1 gene from highly resistant Gossypium barbadense Xinhai15 based on the candidate genes screened by transcriptome sequencing that were related to resistance to Verticillium wilt. A sequence characteristic analysis showed that GbABR1 was an ERF subfamily B4 member and was a new member of the AP2 family of sea-island cotton. The GbABR1 gene was expressed highly in roots compared with the levels in leaves and stems in cotton. Expression was enhanced significantly in cotton after infection by Verticillium dahliae, indicating that GbABR1 probably plays an important role in the response to biotic stress. The results of subcellular localisation showed that GFP:GbABR1 was localised to the nucleus. GbABR1 silencing via the virus-induced gene silencing (VIGS) method indicated that the incidence of disease and the disease index in VIGS-silenced plants were much higher than in the control after infection by Verticillium dahliae. The GbABR1-overexpressing Arabidopsis plants showed similar resistance to Verticillium dahliae compared to the wild type. These results indicate that the GbABR1 gene plays a positive role in resistance to Verticillium wilt. The GbABR1-overexpressing Arabidopsis plants presented dwarfism, early maturation and early bolting compared with wild-type plants, suggesting that GbABR1 also participates in growth and development.

In this study, nine microbial strains with oil-degrading function were isolated from oil-contaminated soil near four oil wells in the 0.6 km2 area of the Jinnan Oil Field, Huaian, Jiangsu, China (32 57' N, 119 02' E). Based on morphological observations, physiological and biochemical responses, and molecular identification, we confirmed that the nine strains belong to five genera: Pseudomonas, Raoultella, Lysinibacillus, Escherichia, and Klebsiella. The degradation capacity of the nine strains in crude oil medium ranged from 2.43% to 32.63% with an average rate of 21.64%. Further plasmid and chromosome analyses on the oil-degrading genes of the nine microbial strains were conducted. The GST gene (degradable polycyclic aromatics) was widely distributed in the chromosomes of eight strains and the plasmids of three strains. The alkB gene was detected in the chromosomes of seven strains and the plasmids of two strains. The LmPH gene (degradable phenolic substances) was only detected in the chromosome of one strain. Molecular biological analyses on the isolation, identification, and degradation characteristics of oil-degrading microbial strains provide a foundation for microbial remediation in oil-polluted environments.

BACKGROUND: Botrychium schaffneri Underw. has been popularly consumed since ancient times as a traditional medicine in China to treat whooping cough, bronchial asthma, and febrile convulsive twitch disease. This led us to investigate whether Botrychium schaffneri Underw. extract (BSE) may be effective against lung cancer, especially non-small cell lung carcinoma (NSCLC). METHODS: In this study, we extracted the ethanolic root extract of the grass, Botrychium schaffneri Underw. In vitro study, the change of NCI-H1299 cell proliferation was observed with CCK8 and MTT assays. Cell apoptosis was assessed using a kit based on staining with FITC-conjugated annexin V. In vivo study, we establish a stable animal model of NSCLC in nude mice, tumor volume and weight was measured twice a week. We conduct gene microarray screened for differentially expressed genes (DEGs), between NCI-H1299 cells treated by BSE or not. Then the DEGs were functionally annotated and path enriched. RESULTS: It was revealed that BSE significantly suppressed NSCLC cell proliferation (IC(50) 134 μg/mL) and induced apoptosis. It also slowed tumor growth without affecting body weight, and a dose of 25 g/kg led to significantly smaller tumors than in control animals (13.85±3.36 vs. 23.40±6.05, P=0.044). Apoptosis-related protein direct IAP Binding protein with low PI (DIABLO) expression was up-regulated by BSE, and DIABLO knockdown significantly attenuated the anti-tumor effects of the extract. CONCLUSIONS: In conclusion, BSE reduces the viability of NSCLC cells and promotes apoptosis, and these effects may be mediated by DIABLO.

Compared with other algorithms, the performance of sparrow algorithm is better, but it also has shortcomings such as insufficient convergence and large randomness. For this reason, this paper proposes an improved sparrow search algorithm, which uses K-means to initialize the population to reduce the influence of randomness. Use sine and cosine search to improve the quality of the position of followers, and finally use adaptive local search to update the optimal solution, and apply it to concrete strength prediction. The results show that various improved sparrow search algorithms have certain advantages and high stability.

Protein as a carrier to improve the solubility and bioavailability of curcumin has been studied widely. However, to date the researches were mainly focused on its binding mechanism and the applications in aqueous solution. Systematic study on the characteristics and properties of the complex in solid phase after the binding of curcumin with protein is scarce. In this work, a powder composite of curcumin bound to ovalbumin was prepared by freeze-drying. The FTIR and X-ray diffraction results indicated that the crystal structure of curcumin and secondary structure of ovalbumin were changed because of the binding of curcumin to ovalbumin, leading to the formation of an amorphous complex with the sizes in the range of 924.20 ± 72.34 nm. Thermogravimetric analysis showed that the maximum weight loss point of ovalbumin/curcumin complex was at 289 °C, which was lower than that of pure ovalbumin and curcumin, implying that the complex was more prone to pyrolyze. Furthermore, the improved antioxidant activity was evaluated by DPPH radical scavenging activity and reducing power assay compared with pure ovalbumin and curcumin. This work could help to understand the characteristics of the curcumin-protein complex which has the potential to be applied in functional foods.

In the present study, we assessed benzyl isothiocyanate (BITC), an organosulfur compound from cruciferous vegetables, as a potential inducer of aldehyde dehydrogenase (ALDH) activity using murine hepatoma Hepa1c1c7 cells. BITC was shown to enhance not only the total ALDH activity, but also the ALDH activity of the cytosolic/microsomal and mitochondrial fraction. BITC also significantly increased the gene and protein expression of ALDH1A1, ALDH2 and ALDH3A1 in a concentration-dependent manner. Simultaneously, the gene expression of phase 2 drug-metabolizing enzymes, such as NAD(P)H: quinone oxidoreductase 1 and heme oxygenase-1, was increased by the BITC treatment. Western blot experiments revealed that BITC not only up-regulated the Nrf2 protein expression, but also stimulated the nuclear translocation of Nrf2. Furthermore, silencing Nrf2 reduced the basal and BITC-enhanced levels of the total activity and gene expression of ALDHs. The pretreatment of BITC completely mitigated the acetaldehyde-induced cytotoxicity, which was impaired by silencing Nrf2. The present study demonstrated that BITC has been identified as a potential inducer of the total ALDH activity to prevent the acetaldehyde-induced cytotoxicity.

Lemmaphyllum intermedium is a valuable medicinal fern in China. We have determined its complete chloroplast genome using Illumina paired-end sequencing. The genome is 157,795 bp in length with 132 genes, including 88 protein-coding genes, eight ribosomal RNA genes, 35 tRNA genes, and one pseudogene. It has a quadripartite structure consisting of a small single-copy (SSC) of 21,764 bp, a large single-copy (LSC) of 81,189 bp, and two inverted repeats (IRs) of 27,421 bp each. A maximum-likelihood phylogenetic tree reconstructed by using complete chloroplast genome sequences reveals that L. intermedium is closely related to Lemmaphyllum carnosum var. microphyllum with strong support.

Protein nanoparticles represent a promising system for the encapsulation and delivery of bioactive compounds or highly sensitive ingredients. In this study, whey protein isolate nanoparticles (WPINs) were prepared by using supercritical carbon dioxide (scCO2) treatment. The effects of scCO2 on the size and stability of the WPINs were investigated. The average particle diameter ranged from 100 to 300 nm when the WPIN solution was treated with scCO2 at 8–24 MPa and 45 °C for 30 min. ScCO2-treated WPINs had more uniform size distribution and smaller particles than WPINs prepared without scCO2. However, particle aggregation was observed during heating to 55–75 °C. Fluorescence and differential thermogravimetric analysis showed that CO2 pressure did not cause secondary and tertiary structure changes or denaturation of WPINs. The change in WPINs size was likely caused by the high diffusibility of scCO2, which could slightly modify WPINs local structure, affecting hydrophobic interactions and hydrogen bonding within the molecule. These results indicate that the size of nano-particles can be modulated by adjusting CO2 pressure, which may facilitate WPINs use in food and biomedical products.

Sex determination pathways are astoundingly diverse in insects. For instance, the silk moth Bombyx mori uniquely use various components of the piRNA pathway to produce the Fem signal for specification of the female fate. In this study, we identified BmGTSF1 as a novel piRNA factor which participates in B. mori sex determination. We found that BmGtsf1 has a distinct expression pattern compared to Drosophila and mouse. CRISPR/Cas9 induced mutation in BmGtsf1 resulted in partial sex reversal in genotypically female animals by shifting expression of the downstream targets BmMasc and Bmdsx to the male pattern. As levels of Fem piRNAs were substantially reduced in female mutants, we concluded that BmGtsf1 plays a critical role in the biogenesis of the feminizing signal. We also demonstrated that BmGTSF1 physically interacted with BmSIWI, a protein previously reported to be involved in female sex determination, indicating BmGTSF1 function as the cofactor of BmSIWI. BmGtsf1 mutation resulted in piRNA pathway dysregulation, including piRNA biogenesis defects and transposon derepression, suggesting BmGtsf1 is also a piRNA factor in the silkworm. Furthermore, we found that BmGtsf1 mutation leads to gametogenesis defects in both male and female. Our data suggested that BmGtsf1 is a new component involved in the sex determination pathway in B. mori.

The inhibitory effects of soybean peptides (SPTs) with four different molecular weights (MWs) (SPT1, SPT2, SPT3, and SPT4) on porcine pancreatic α-amylase (PPA) were evaluated by spectrofluorimetry and enzyme inhibition analysis. SPT1, SPT2, and SPT3 were mixed inhibitors with competitive and uncompetitive inhibitory effects on α-amylase. SPT with lower MWs inhibited PPA more strongly than those with higher MWs. SPT binding interactions with PPA were mainly non-covalent, i.e., van der Waals interactions and hydrogen-bonding. SPT interacted with Tyr, Trp and Phe residues in PPA and quenched its intrinsic fluorescence, via a static quenching mechanism. SPT of higher MW had stronger binding interactions and more stable complexes with PPA than those of lower MW. SPT1, SPT2 and SPT3 have potential inhibitory effects on PPA activity in vivo, which could delay the digestion of starchy foods. These findings have laid a theoretical foundation for slowing starch digestibility by formulation with peptides and thereby developing novel low-glycaemic index functional foods.

Verticillium wilt causes devastating loss of yield and quality in many crops, including cotton. To determine the molecular mechanism of resistance to verticillium wilt in cotton, we isolated a new cytochrome P450 gene, CYP94C1, and analysed its function. We obtained the complete open reading frame, which encodes a protein of 500 amino acids. The results of the functional analysis showed that resistance to verticillium wilt was enhanced when the gene was silenced using the virus-induced gene silencing (VIGS) method in cotton. GbCYP94C1-overexpressing Arabidopsis was more susceptible to Verticillium dahliae compared with the wild-type. In addition, GbCYP94C1 played a role in plant wound responses and in the expression of certain jasmonic acid (JA) signalling pathway. The results suggest that GbCYP94C1 plays a role in verticillium wilt resistance in cotton via the JA signalling pathway.

Nuclear factor erythroid 2‑related factor 2 (Nrf2) is a key transcription factor that serves a critical role in protecting against cellular stress induced by exercise. The effects of exercise training on Nrf2 expression have been widely studied; however, the post‑transcriptional/translational regulation of Nrf2 is poorly understood. The aim of the present study was to identify the exercise‑induced microRNAs (miRNAs/miRs) targeting Nrf2. A total of 20 C57BL/6J mice were divided into the control (n=10) and exercise (n=10) groups. Following eight weeks of aerobic exercise training, Nrf2 mRNA expression in the hind‑limb muscles was significantly increased in the exercise group, while that of Nrf2 protein remained unchanged. In addition, 58 differentially expressed miRNAs have been detected; among them, miR‑101a‑3p and miR‑340‑5p were predicted to target the 3' untranslated region of Nrf2 mRNA by analysis with three bioinformatics tools. The binding affinity of the two miRNAs were verified via a dual luciferase reporter assay; only miR‑340‑5p was determined to bind directly to Nrf2 mRNA. Additionally, miR‑340‑5p mimics and inhibitors were transfected into C2C12 cells to investigate the biological effects of endogenous miR‑340‑5p on the expression of Nrf2. The results revealed that the expression levels of Nrf2 protein in C2C12 cells were significantly decreased in the miR‑340‑5p mimics group and significantly increased in the miR‑340‑5p inhibitors group, while Nrf2 mRNA expression levels were unchanged. The results indicated that miR‑340‑5p serves a role in the post‑transcriptional regulation of Nrf2 expression. In conclusion, the novel findings of the present study were that miR‑340‑5p may be a potential direct regulator of Nrf2 gene expression and might be involved in the regulation of Nrf2 protein expression in mouse skeletal muscles following aerobic exercise. These results may provide insight into the underlying regulatory mechanisms of Nrf2 protein expression in skeletal muscle during aerobic exercise.

Glycosylation is one of the more studied methods used to improve the emulsification properties of proteins, and glycosylation products are often used as transport carriers for nutrients. In this study, we investigated the structure and emulsifying properties of whey protein isolate (WPI)-sugar conjugates formed with different sugars (glucose, lactose, and dextran) under different pH (2–10) conditions. The results show that pH affected the degree of glycosylation (DG), and alkaline environments were conducive to the formation of WPI-sugar conjugates. As the pH increased from 6 to 10, the protein unfolded, DG, apparent viscosity and emulsifying properties increased. At pH 8–10, the free sulfhydryl content of the WPI-sugar conjugates decreased, disulfide bonds formed, aggregation occurred between protein molecules, the DG, surface hydrophobicity and apparent viscosity decreased, thus the emulsion stability decreased. Different sugars had an effect on DG, with glucose increasing the DG and decreasing surface hydrophobicity and free sulfhydryl content. Dextran increases the apparent viscosity and emulsifying properties of the WPI-sugar conjugates. Therefore, it can be concluded that pH affected the structure and emulsifying properties of the WPI-sugar conjugates, pH has a certain effect on the secondary and tertiary structures of the WPI, the DG and emulsifying properties being better for conjugates formed in alkaline environments. Different sugars affected the emulsifying properties and surface structures of the WPI-sugar conjugates, but had little effect on the secondary and tertiary structures.

Lycii Fructus is the dried ripe fruits of Lycium chinense and L. barbarum, which has long been used as a traditional food material in East Asia. The purpose of this study was to investigate the role of the indirect antioxidative action in the Lycii fructus extract (LFE)-induced cytoprotective effect in vitro. LFE significantly enhanced the expression of the drug-metabolizing enzyme genes and intracellular glutathione level in mouse hepatoma Hepa1c1c7 cells. LFE stimulated the nuclear translocation of aryl hydrocarbon receptor as well as nuclear factor (erythroid-derived 2)-like 2. The pretreatment of LFE for 24 h, but not for 30 min, completely inhibited the cytotoxic effect of hydrogen peroxide. Furthermore, chlorogenic acid, one of the main constituents of LFE, showed cytoprotection against hydrogen peroxide with the enhanced phase 2 enzyme gene expression. These results suggested that LFE exhibits a cytoprotective effect, possibly through the enhancement of the antioxidant gene expression. abbreviations: LFE: Lycii Fructus extract; GSH: glutathione; NQO1: NAD(P)H:quinone oxidoreductase 1; HO-1: heme oxygenase-1; GCLC: glutamate-cysteine ligase, catalytic subunit; xCT: a component of cysteine/glutamate antiporter (cystine/glutamate exchanger); CYP1A1: cytochrome P450 1A1; GSH: glutathione; AhR: aryl hydrocarbon receptor; Nrf2: nuclear factor (erythroid-derived 2)-like 2; CGA: chlorogenic acid; RT-PCR: reverse transcription-polymerase chain reaction; DTT: dithiothreitol; PMSF: phenylmethylsulfonyl fluoride; ARE: antioxidant response element; XRE: xenobiotic responsive element.

We have developed a reliable and rapid immunoassay based on a facile synthesis of fluorescent nanoparticles integrated in immunochromatography technique to quantitatively detect C-reactive protein (CRP). The method is based on a sandwich immunoassay using the Nile-red doped nanoparticles/CRP monoclonal antibody conjugate. The method is simple and fast, with a detection limit of 0.091 mg/L. It provides quantitative analysis in the range of 0.1–160 mg/L, which is adequate for detecting CRP of acute inflammatory or cardiovascular disease. This strategy displayed a good reproducibility and stability to straightforwardly analyze the plasma samples without complicated washing steps, thereby reducing the operating procedures for non-professionals and promoting the detection efficiency and the whole detection process can be completed in 3 min. This approach for carrying out immunoassays can be applied to the detection of CRP in the point-of-care tests.

Background and Purpose Regular physical activity is an effective non-pharmacological therapy for prevention and control of hypertension. However, the underlying mechanisms are not fully understood. Accumulating evidence shows that the elevated vascular tone in hypertension is a consequence of the ‘ion channel remodelling’ that occurs during sustained high BP. The present study investigated the effects of aerobic exercise on the electrical remodelling of L-type Ca2+ (Cav1.2) and large-conductance Ca2+-activated K+ (KCa1.1) channels in mesenteric arteries (MAs) from spontaneously hypertensive rats (SHRs).

3,4-Dihydroxyphenylacetic acid (DOPAC) is one of the major colonic microflora-produced catabolites of quercetin glycosides, such as quercetin 4′-glucoside derived from onion. Here, we investigated whether DOPAC modulates the aldehyde dehydrogenase (ALDH) activity and protects the cells from the acetaldehyde-induced cytotoxicity in vitro. DOPAC was shown to enhance not only the total ALDH activity, but also the gene expression of ALDH1A1, ALDH2 and ALDH3A1 in a concentration-dependent manner. DOPAC simultaneously stimulated the nuclear translocation of NFE2-related factor 2 and aryl hydrocarbon receptor. The pretreatment of DOPAC completely protected the cells from the acetaldehyde-induced cytotoxicity. The present study suggested that DOPAC acts as a potential ALDH inducer to prevent the alcohol-induced abnormal reaction.

Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 μmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS-based metabolite assay. In general, ordonin has induced effects on the major member of CYP450s mRNA and protein expression, as well as on the enzyme activity in human HepaRG cells, especially on CYP3A4 and CYP2C9. To our knowledge, this is the first systematic research about the inductive effects of oridonin on the major member of CYP450s in human cell line. These results may provide at least partly of the basis for potential drug-drug interactions and oridonin should be used with caution to avoid potential risk.

The aim of this study was to investigate the role of NEAT1 in hepatocellular carcinoma (HCC), and probe whether NEAT1 participate in the epithelial-mesenchymal transition (EMT) and metastasis regulated by HIF-2α. Expression of lncRNA NEAT1 was initially assessed in HCC tissues and in a series of HCC cell lines. The correlations between NEAT1 levels and HIF-2α were analyzed through plasmid vector construction. The potential underlying mechanisms of NEAT1 in HCC were performed through in vitro and in vivo functional assays. Expression of NEAT1, HIF-2α were significantly increased in HCC tissues and cell lines. Then, in vitro assays revealed that NEAT1 promotes EMT and metastasis by stimulating the inactivation of HIF-2α in HCC. An in vivo animal model also demonstrated the cancer promotion mechanism of NEAT1. In this study, we found that the NEAT1 was high expression in HCC. NEAT1 promotes tumor cell EMT, migration and invasion capacities by stimulating the activation of HIF-2α in HCC.

Long non-coding RNA nuclear-enriched abundant transcript 1 (NEAT1) plays an important role in the pathogenesis and development of several types of cancer. However, the functional mechanism of NEAT1 in hepatocellular carcinoma (HCC) remains unclear. NEAT1 and microRNA (miR)-129-5p expression in HCC tissues and cell lines was quantified by means of quantitative PCR. The effects of NEAT1 expression inhibition or upregulation in HCC cell lines were analyzed in terms of cell viability and apoptosis. Biological software was used to predict the binding sites of NEAT1 and miR-129-5p. The expression of the miR-129-5p target molecules valosin-containing protein (VCP) and IκB was detected using Western blotting. The effect of NEAT1 on tumor growth was observed in mouse models of transplanted hepatoma. In the present study, it was concluded that the expression of NEAT1 was significantly increased in the HCC tissues and cell lines. Meanwhile, after downregulating NEAT1 expression in HepG2/Huh7 cell lines, the cell viability was significantly lowered, whereas the corresponding rate of apoptosis was significantly increased. Additionally, it was found that the NEAT1 and miR-129-5p expression showed a negative correlation in HCC tissues. It was further proved that there was a certain negative regulatory mechanism between NEAT1 and miR-129-5p, which was related to the expression of VCP and IκB. The mouse model experiments confirmed that the interference with NEAT1 expression inhibited tumor growth. The study concluded that the overexpression of NEAT1 inhibited the expression of miR-129-5p by regulating VCP/IκB, thereby promoting the proliferation of HCC cells. This study provides new insights into the pathogenesis of HCC, as well as identifying new target genes for diagnosis and treatment. NEW & NOTEWORTHY The results provide strong evidence that upregulated NEAT1 promotes the proliferation of cancer cells in hepatocellular carcinoma (HCC) and this regulatory mechanism depends on the microRNA (miR)-129-5p-valosin-containing protein-IκB axis. The study also indicates that NEAT1 could be a potential therapeutic target for HCC.

In this study, the effects of different concentrations (0, 1, 5, 10, and 20 μmol/L) of abscisic acid (ABA) on soluble sugar accumulation in Cyphomandra betacea seedlings under cadmium stress were studied. The results showed that spraying 10 and 20 μmol/L ABA could effectively increase the content of soluble sugar in roots, stems, leaves and aerial parts of C. betacea seedlings. Spraying 1 and 5 μmol/L ABA reduced the soluble sugar content in roots, stems, leaves and aerial parts of C. betacea seedlings. Therefore, the use of 20 μmol/L ABA can increase the accumulation of soluble sugar in C. betacea seedlings.

In this study, we developed a simple and efficient transient transformation system, which can be used in homologous expression or reverse genetic study of the plants. A system for characterizing gene function in response to stress tolerance was also developed based on this transformation method. The overexpression and RNAi-silencing of a bZIP gene from Tamarix hispida, ThbZIP1, were performed in T. hispida using this transformation method. Real-time PCR showed that the expression of ThbZIP1 was highly up- and down-regulated in the plants with overexpression and RNAi-silenced expression of ThbZIP1, respectively, when compared with control plants (transiently transformed with empty pROK2). A physiological study showed that ThbZIP1 can enhance the activities of both peroxidase (POD) and superoxide dismutase (SOD), and decrease electrolyte leakage rate and levels of reactive oxygen species (ROS) and malondialdehyde (MDA) under salt stress conditions. Furthermore, ThbZIP1 is found to mediate stress tolerance by regulating the expression of SOD and POD genes. These results suggested that this transient transformation system is an effective method for determining the function of a gene in response to abiotic stress in plants.

WRKY transcription factors are involved in various biological processes, such as development, metabolism and responses to stress. However, their exact roles in abiotic stress tolerance are largely unknown. Here, we demonstrated a working model for the function of a WRKY gene (ThWRKY4) from Tamarix hispida in the stress response. ThWRKY4 is highly induced by abscisic acid (ABA), salt and drought in the early period of stress (stress for 3, 6, or 9 h), which can be regulated by ABF (ABRE binding factors) and Dof (DNA binding with one finger), and also can be crossregulated by other WRKYs and autoregulated as well. Overexpression of ThWRKY4 conferred tolerance to salt, oxidative and ABA treatment in transgenic plants. ThWRKY4 can improve the tolerance to salt and ABA treatment by improving activities of superoxide dismutase and peroxidase, decreasing levels of O2 − and H2O2, reducing electrolyte leakage, keeping the loss of chlorophyll, and protecting cells from death. Microarray analyses showed that overexpression of ThWRKY4 in Arabidopsis leads to 165 and 100 genes significantly up- and downregulated, respectively. Promoter scanning analysis revealed that ThWRKY4 regulates the gene expression via binding to W-box motifs present in their promoter regions. This study shows that ThWRKY4 functions as a transcription factor to positively modulate abiotic stress tolerances, and is involved in modulating reactive oxygen species.

Abscisic acid (ABA) plays a crucial role in plant responses to abiotic stress. To investigate differences in plant responses to salt and ABA stimulus, differences in gene expression in Arabidopsis in response to salt and ABA were compared using an Agilent oligo microarray. A total of 144 and 139 genes were significantly up- and downregulated, respectively, under NaCl stress, while 406 and 381 genes were significantly up- and downregulated, respectively, under ABA stress conditions. In addition, 31 genes were upregulated by both NaCl and ABA stresses, and 23 genes were downregulated by these stressors, suggesting that these genes may play similar roles in plant responses to salt and ABA stress. Gene ontology (GO) analysis revealed four subgroups of genes, including genes in the GO categories “Molecular transducer activity”, “Growth”, “Biological adhesion” and “Pigmentation”, which were expressed in response to ABA stress but not NaCl stress. In addition, genes that play specific roles during salt or ABA stress were identified. Our results may help elucidate differences in the response of plants to salt and ABA stress.

A 17-year-old Chinese male was hospitalized exhibiting hyperglycemia and increased serum urea nitrogen and creatinine levels in addition to weight loss. The patient was treated with gliclazide. The patient was 150 cm tall, weighed 35 kg and had no family history of diabetes or kidney disease. Physical examination revealed cephalus quadratus, rachitic rosary and a visible toe-out gait. Laboratory examinations revealed that the patient's fasting plasma glucose and glycosylated hemoglobin levels were markedly increased, fasting plasma C-peptide level was slightly increased and no peak 2 h postprandial was observed. Diabetic autoimmune antibodies [islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), isulinoma-2-associated autoantibodies (IA2A) and insulin autoantibodies (IAA)] were negative. Levels of serum electrolytes decreased, uric acid and parathyroid hormone increased, mild albuminuria was detected and there was a low proportion of urine. The patient also presented with low bone mass and cataracts. Abdominal computed tomography (CT) revealed a bilateral atrophic kidney with multiple renal cysts, primarily located at the junction of renal cortex and medulla, with a diameter of 0.3-0.7 cm. CT also revealed hypogenesis of the body and tail of the pancreas. In an oral glucose tolerance test, the mother and paternal uncle of the patient were diagnosed with type II diabetes and the patient's sister, maternal uncle and paternal grandpa were diagnosed with glucose tolerance impairment. Genetic testing revealed an unreported amino acid mutation in exon 2 of hepatocyte nuclear factor 1β (c.391C>T), a nonsense mutation of CAA to TAA at codon 131. This mutation was identified in the proband but not in any other family members.

The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply this therapy to other types of acute myeloid leukemia (AML). However, AML, with the exception of APL, fails to respond to differentiation therapy. Therefore, research strategies to further sensitize cells to retinoids and to extend the range of AMLs that respond to retinoids beyond APLs are urgently needed. In this study, we showed that TAK165, a HER2 inhibitor, exhibited a strong synergy with ATRA to promote AML cell differentiation. We observed that TAK165 sensitized the AML cells to ATRA-induced cell growth inhibition, G0/G1 phase arrest, CD11b expression, mature morphologic changes, NBT reduction and myeloid regulator expression. Unexpectedly, HER2 pathway might not be essential for TAK165-enhanced differentiation when combined with ATRA, while the enhanced differentiation was dependent on the activation of the RARα/STAT1 axis. Furthermore, the MEK/ERK cascade regulated the activation of STAT1. Taken together, our study is the first to evaluate the synergy of TAK165 and ATRA in AML cell differentiation and to assess new opportunities for the combination of TAK165 and ATRA as a promising approach for future differentiation therapy.

Recent studies have shown the positive association between increased circulating BCAAs (valine, leucine, and isoleucine) and insulin resistance (IR) in obese or diabetic patients. However, results seem to be controversial in different races, diets, and distinct tissues. Our aims were to evaluate the relationship between BCAA and IR as well as later diabetes risk and explore the phenotypic and genetic factors influencing BCAA level based on available studies. We performed systematic review, searching MEDLINE, EMASE, ClinicalTrials.gov, the Cochrane Library, and Web of Science from inception to March 2016. After selection, 23 studies including 20,091 participants were included. Based on current evidence, we found that BCAA is a useful biomarker for early detection of IR and later diabetic risk. Factors influencing BCAA level can be divided into four parts: race, gender, dietary patterns, and gene variants. These factors might not only contribute to the elevated BCAA level but also show obvious associations with insulin resistance. Genes related to BCAA catabolism might serve as potential targets for the treatment of IR associated metabolic disorders. Moreover, these factors should be controlled properly during study design and data analysis. In the future, more large-scale studies with elaborate design addressing BCAA and IR are required.

Previously, a bZIP transcription factor from Tamarix hispida, ThbZIP1, was characterized: plants overexpressing ThbZIP1 displayed improved salt stress tolerance but were sensitive to abscisic acid (ABA). In the current study, we further characterized the regulatory network of ThbZIP1 and the mechanism of ABA sensitivity mediated by ThbZIP1. An ABF transcription factor from T. hispida, ThABF1, directly regulates the expression of ThbZIP1. Microarray analysis identified 1662 and 1609 genes that were respectively significantly upregulated or downregulated by ThbZIP1 when exposed to ABA. Gene ontology (GO) analysis showed that the processes including “response to stimulus,” “catalytic activity,” “binding function,” and “metabolic process” were highly altered in ThbZIP1 expressing plants exposed to ABA. The gene expression in ThbZIP1 transformed plants were compared between exposed to ABA and salt on the genome scale. Genes differentially regulated by both salt and ABA treatment only accounted for 9.75% of total differentially regulated genes. GO analysis showed that structural molecule activity, organelle part, membrane-enclosed lumen, reproduction, and reproductive process are enhanced by ABA but inhibited by salt stress. Conversely, immune system and multi-organism process were improved by salt but inhibited by ABA. Transcription regulator activity, enzyme regulator activity, and developmental process were significantly altered by ABA but were not affected by salt stress. Our study provides insights into how ThbZIP1 mediates ABA and salt stress response at the molecular level.

Background Acisarcuatus variradius gen. et sp. nov., an extinct new species representing a new genus, is described from the Middle Jurassic Jiulongshan Formation in Daohugou Village, Inner Mongolia, China. Methodology/Principal Findings In this paper, we revised the diagnosis of Necrotauliidae Handlirsch, 1906. One new genus and species of Necrotauliidae is described. An analysis based on the fossil morphological characters clarified the taxonomic status of the new taxa. Conclusions/Significance New fossil evidence supports the viewpoint that the family Necrotauliidae belongs to the Integripalpia.