Overexpression of the FBA and TPI genes promotes high production of HDMF in Zygosaccharomyces rouxii.

4-Hydroxy-2,5-dimethyl-3 (2H)-furanone (HDMF) is widely used in the food industry as a spice and flavoring agent with high market demand. In this study, fructose-1,6-bisphosphate aldolase (FBA) and triose phosphate isomerase (TPI) were overexpressed in Zygosaccharomyces rouxii in the form of single and double genes, respectively, via electroporation. High-yield HDMF-engineered yeast strains were constructed by combining the analysis of gene expression levels obtained by real-time fluorescence quantitative PCR technology and HDMF production measured by HPLC. The results showed that there was a significant positive correlation between the production of HDMF and the expression levels of the FBA and TPI genes in yeast; the expression levels of the FBA and TPI genes were also positively correlated (p < 0.05). Compared with the wild type (WT), the engineered strains F10-D, T17-D, and TF15-A showed marked increases in HDMF production and FBA and TPI gene expression (p < 0.05) and exhibited great genetic stability with no obvious differences in biomass or colony morphology. In addition, the exogenous addition of d-fructose promoted the growth of Z. rouxii. Among the engineered strains, when fermented in YPD media supplemented with d-fructose for 5 days, TF15-A (overexpressing the FBA and TPI genes) generated the highest HDMF production of 13.39 mg/L, which is 1.91 times greater than that of the wild-type strain. The results above indicated that FBA and TPI, which are key enzymes involved in the process of HDMF biosynthesis by Z. rouxii, positively regulate the synthesis of HDMF at the transcriptional level. d-fructose can be used as a precursor for the biosynthesis of HDMF by engineered yeast in industrial production.

Tunable Hydrogel Electronics for Diagnosis of Peripheral Neuropathy.

Peripheral neuropathy characterized by rapidly increasing numbers of patients is commonly diagnosed via analyzing electromyography signals obtained from stimulation-recording devices. However, existing commercial electrodes have difficulty in implementing conformal contact with skin and gentle detachment, dramatically impairing stimulation/recording performances. Here, this work develops on-skin patches with polyaspartic acid-modified dopamine/ethyl-based ionic liquid hydrogel (PDEH) as stimulation/recording devices to capture electromyography signals for the diagnosis of peripheral neuropathy. Triggered by a one-step electric field treatment, the hydrogel achieves rapid and wide-range regulation of adhesion and substantially strengthened mechanical performances. Moreover, hydrogel patches assembled with a silver-liquid metal (SLM) layer exhibit superior charge injection and low contact impedance, capable of capturing high-fidelity electromyography. This work further verifies the feasibility of hydrogel devices for accurate diagnoses of peripheral neuropathy in sensory, motor, and mixed nerves. For various body parts, such as fingers, the elderly's loose skin, hairy skin, and children's fragile skin, this work regulates the adhesion of PDEH-SLM devices to establish intimate device/skin interfaces or ensure benign removal. Noticeably, hydrogel patches achieve precise diagnoses of nerve injuries in these clinical cases while providing extra advantages of more effective stimulation/recording performances. These patches offer a promising alternative for the diagnosis and rehabilitation of neuropathy in future.

Evacetrapib Elicits Antitumor Effects on Colorectal Cancer by Inhibiting the Wnt/ß-Catenin Signaling Pathway and Activating the JNK Signaling Pathway.

Despite advances in colorectal cancer (CRC) treatment, most advanced CRC patients who experience disease progression after chemotherapy, targeted therapy, and immunotherapy face a situation in which there is no available medicine. Thus, new therapeutic drugs for CRC are urgently needed. Studies have shown that cholesteryl ester transfer protein (CETP) has a vital role in tumor development and is a possible target for CRC therapy. We found that Evacetrapib, a CETP inhibitor, suppressed CRC cell growth by inhibiting the Wnt/ß-catenin signaling pathway and activating the c-Jun NH2-terminal kinase (JNK) signaling pathway in CRC. Therefore, Evacetrapib displays an anti-cancer effect and is a possible option for treating CRC.

Gut Bacteria Erysipelatoclostridium and Its Related Metabolite Ptilosteroid A Could Predict Radiation-Induced Intestinal Injury.

It is difficult to study the intestinal damage induced by space radiation to astronauts directly, and few prediction models exist. However, we can simulate it in patients with pelvic tumor radiotherapy (RT). Radiation-induced intestinal injury (RIII) is common in cancer patients who receieved pelvic and abdominal RT. We dynamically analyzed gut microbiota and metabolites alterations in 17 cervical and endometrial cancer patients after pelvic RT. In patients who later developed grade 2 RIII, dysbiosis of gut microbiota and metabolites were observed. Univariate analysis showed that Erysipelatoclostridium and ptilosteroid A were related to the occurrence of grade 2 RIII. Notably, a strong positive correlation between gut bacteria Erysipelatoclostridium relative abundance and gut metabolite ptilosteroid A expression was found. Furthermore, combinations of Erysipelatoclostridium and ptilosteroid A could provide good diagnostic markers for grade 2 RIII. In conclusion, gut bacteria Erysipelatoclostridium and its related metabolite ptilosteroid A may collaboratively predict RIII, and could be diagnostic biomarkers for RIII and space radiation injury.

Evidence Supporting Substrate Channeling between Domains of Human PAICS: A Time-Course Analysis of 13C-Bicarbonate Incorporation.

Human phosphoribosylaminoimidazole carboxylase phosphoribosylaminoimdiazole succinocarboxamide synthetase (PAICS) is a dual activity enzyme catalyzing two consecutive reactions in de novo purine nucleotide synthesis. Crystallographic structures of recombinant human PAICS suggested the channeling of 4-carboxy-5-aminoimidazole-1-ribose-5'-phosphate (CAIR) between two active sites of PAICS, while a prior work of an avian PAICS suggested otherwise. Here, we present time-course mass spectrometric data supporting the channeling of CAIR between domains of recombinant human PAICS. Time-course mass spectral analysis showed that CAIR added to the bulk solution (CAIRbulk) is decarboxylated and re-carboxylated before the accumulation of succinyl-5-aminoimidazole-4-carboxamide-1-ribose-5'-phosphate (SAICAR). An experiment with 13C-bicarbonate showed that SAICAR production was proportional to re-carboxylated CAIR instead of total CAIR or CAIRbulk. This result indicates that the SAICAR synthase domain selectively uses enzyme-made CAIR over CAIRbulk, which is consistent with the channeling model. This channeling between PAICS domains may be a part of a larger channeling process in de novo purine nucleotide synthesis.

Pyrimethamine inhibits cell growth by inducing cell senescence and boosting CD8+ T-cell mediated cytotoxicity in colorectal cancer.

BACKGROUND: The emergence of nonresponse or resistance to traditional chemotherapeutic agents is one of the main challenges of colorectal cancer (CRC) therapies. Thus, novel therapeutic drugs that can improve the clinical outcomes of CRC patients are urgently needed. The purpose of this study was to investigate the effects and mechanisms of pyrimethamine in CRC. METHODS AND RESULTS: In this study, we assessed the role of pyrimethamine on CRC cell growth by cell counting kit-8 and colony formation assays. Cell cycle distribution and cellular senescence were determined by flow cytometry and senescence-associated ß-galactosidase staining respectively. RNA-seq analysis and western blotting were used to investigate the potential pathways of pyrimethamine in CRC development. Moreover, animal experiments were performed to evaluate the effect of pyrimethamine in vivo. Our results demonstrated that pyrimethamine could inhibit cell growth by inducing S phase arrest followed by cellular senescence in CRC cells, and the p38MAPK-p53 axis was probably involved in that effect. In addition, pyrimethamine could also boost CD8+ T-cell mediated cytotoxicity and exert antitumor activity in vivo. CONCLUSION: These results indicated that pyrimethamine may be a promising candidate agent for CRC treatment.

Circ-MTO1 correlates with favorable prognosis and inhibits cell proliferation, invasion as well as miR-17-5p expression in prostate cancer.

BACKGROUND: This study aimed to investigate circular RNA-mitochondrial tRNA translation optimization 1 (circ-MTO1) expression in tumor tissue and its correlation with clinical characteristics and survival profiles, as well as its effect on cancer cell functions in prostate cancer. METHODS: A total of 298 primary prostate cancer patients were included. Reverse transcription-quantitative polymerase chain reaction was conducted to evaluate circ-MTO1 expression in tumor tissue and paired adjacent tissue. Disease-free survival (DFS) and overall survival (OS) were recorded. In in vitro experiment, prostate cancer cells were transfected with circ-MTO1 over-expression and negative-control over-expression plasmids. Then cell proliferation, cell invasion and miR-630 as well as miR-17-5p expressions in prostate cancer cells were detected. RESULTS: Circular RNA-mitochondrial tRNA translation optimization 1 expression was downregulated in tumor tissue compared with paired adjacent tissue (P < .001) in patients with prostate cancer. Circ-MTO1 high expression in tumor tissue was correlated with decreased pathological T stage (P = .001) as well as lower pathological N stage (P = .020). As for survival profiles, the DFS (P = .006) and OS (P = .018) were both longer in patients who had circ-MTO1 high expression compared with patients who had circ-MTO1 low expression. In addition, circ-MTO1 high expression independently predicted favorable DFS and OS. Besides, further in vitro experiments illustrated that circ-MTO1 inhibited proliferation (P < .05) and invasion (P < .05) as well as downregulated miR-17-5p expression in prostate cancer cells (P < .05). CONCLUSION: Circ-MTO1 correlates with decreased pathological T/N stage and favorable survival profiles, and it also inhibits cell proliferation, invasion as well as miR-17-5p expression in prostate cancer.

Impact of Ocean Warming on Tropical Cyclone Size and Its Destructiveness.

The response of tropical cyclone (TC) destructive potential to global warming is an open issue. A number of previous studies have ignored the effect of TC size change in the context of global warming, which resulted in a significant underestimation of the TC destructive potential. The lack of reliable and consistent historical data on TC size limits the confident estimation of the linkage between the observed trend in TC size and that in sea surface temperature (SST) under the background of global climate warming. A regional atmospheric model is used in the present study to investigate the response of TC size and TC destructive potential to increases in SST. The results show that a large-scale ocean warming can lead to not only TC intensification but also TC expansion. The TC size increase in response to the ocean warming is possibly attributed to the increase in atmospheric convective instability in the TC outer region below the middle troposphere, which facilitates the local development of grid-scale ascending motion, low-level convergence and the acceleration of tangential winds. The numerical results indicate that TCs will become stronger, larger, and unexpectedly more destructive under global warming.

Effect of thalidomide in combination with gemcitabine on human pancreatic carcinoma SW-1990 cell lines in vitro and in vivo.

Pancreatic cancer is one of the most frequently occurring malignancies worldwide and it is the fourth most common cause of cancer-associated mortality in Western countries. Thalidomide (THD) plays an important role in tumor therapy, as it is able to promote early stage apoptosis and inhibit the process of angiogenesis. The present study evaluated the ability of the combination of THD and gemcitabine (GEM) to inhibit the growth of the pancreatic cancer SW-1990 cell line in vitro and in vivo. Early apoptosis in the SW-1990 cells was detected by the Annexin V/propidium iodide double staining method, the level of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. In addition, the expression of vascular endothelial growth factor in transplanted tumor tissue was measured by RT-PCR, immunohistochemistry and western blot analysis. Cluster of differentiation 34 positivity was considered to indicate the microvessel density. Subsequent to treatment with THD and GEM alone or in combination, it was found that the expression of Bax was upregulated, while the expression of Bcl-2 was downregulated, and the growth of SW-1990 cells and transplanted tumors in nude mice was evidently inhibited. The administration of THD in combination with GEM may demonstrate a potent antitumor effect that increases with increasing dose. The mechanism behind the antitumor effect may be associated with the inhibition of tumor angiogenesis and induction of the apoptosis pathway.