A TonB-dependent receptor regulates antifungal HSAF biosynthesis in \u3ci\u3eLysobacter\u3c/i\u3e

Lysobacter species are Gram-negative bacteria that are emerging as new sources of antibiotics, including HSAF (Heat Stable Antifungal Factor), which was identified from L. enzymogenes with a new mode of action. LesR, a LuxR solo, was recently shown to regulate the HSAF biosynthesis via an unidentified mechanism in L. enzymogenes OH11. Here, we used a comparative proteomic approach to identify the LesR targets and found that LesR influenced the expression of 33 proteins belonging to 10 functional groups, with 9 proteins belonging to the TBDR (TonB-Dependent Receptor) family. The fundamental role of bacterial TBDR in nutrient uptake motivates us to explore their potential regulation on HSAF biosynthesis which is also modulated by nutrient condition. Six out of 9 TBDR coding genes were individually in-frame deleted. Phenotypic and gene-expression assays showed that TBDR7, whose level was lower in a strain overexpressing lesR, was involved in regulating HSAF yield. TBDR7 was not involved in the growth, but played a vital role in transcribing the key HSAF biosynthetic gene. Taken together, the current lesR-based proteomic study provides the first report that TBDR7 plays a key role in regulating antibiotic (HSAF) biosynthesis, a function which has never been found for TBDRs in bacteria. Includes Supplementary materials

Treatment of obesity-related diabetes: significance of thermogenic adipose tissue and targetable receptors

Diabetes mellitus is mainly classified into four types according to its pathogenesis, of which type 2 diabetes mellitus (T2DM) has the highest incidence rate and is most relevant to obesity. It is characterized by high blood glucose, which is primarily due to insulin resistance in tissues that are responsible for glucose homeostasis (such as the liver, skeletal muscle, and white adipose tissue (WAT)) combined with insufficiency of insulin secretion from pancreatic β-cells. Treatment of diabetes, especially treatment of diabetic complications (such as diabetic nephropathy), remains problematic. Obesity is one of the main causes of insulin resistance, which, however, could potentially be treated by activating thermogenic adipose tissues, like brown and beige adipose tissues, because they convert energy into heat through non-shivering thermogenesis and contribute to metabolic homeostasis. In this review, we summarize the function of certain anti-diabetic medications with known thermogenic mechanisms and focus on various receptor signaling pathways, such as previously well-known and recently discovered ones that are involved in adipose tissue-mediated thermogenesis and could be potentially targeted to combat obesity and its associated diabetes, for a better understanding of the molecular mechanisms of non-shivering thermogenesis and the development of novel therapeutic interventions for obesity-related diabetes and potentially diabetic complications

Research on blank optimization design based on low-carbon and low-cost blank process route optimization model

The optimization of blank design is the key to the implementation of a green innovation strategy. The process of blank design determines more than 80% of resource consumption and environmental emissions during the blank processing. Unfortunately, the traditional blank design method based on function and quality is not suitable for today’s sustainable development concept. In order to solve this problem, a research method of blank design optimization based on a low-carbon and low-cost process route optimization is proposed. Aiming at the processing characteristics of complex box type blank parts, the concept of the workstep element is proposed to represent the characteristics of machining parts, a low-carbon and low-cost multi-objective optimization model is established, and relevant constraints are set up. In addition, an intelligent generation algorithm of a working step chain is proposed, and combined with a particle swarm optimization algorithm to solve the optimization model. Finally, the feasibility and practicability of the method are verified by taking the processing of the blank of an emulsion box as an example. The data comparison shows that the comprehensive performance of the low-carbon and low-cost multi-objective optimization is the best, which meets the requirements of low-carbon processing, low-cost, and sustainable production

CD54-NOTCH1 axis controls tumor initiation and cancer stem cell functions in human prostate cancer

Cancer stem cells (CSCs) are considered one of the key contributors to chemoresistance and tumor recurrence. Therefore, the precise identification of reliable CSC markers and clarification of the intracellular signaling involved in CSCs remains a great challenge in fields relating to cancer biology. Here, we implemented a novel chemoresistant prostate cancer patient-derived xenograft (PDX) model in NOD/SCID mice and identified CD54 as a candidate gene among the most highly enriched gene expression profiles in prostate tumors exposed to chronic cisplatin administration. Additional in vitro and in vivo assays showed that CD54 played a critical role in the self-renewal and tumorigenesis of prostate CSCs. Moreover, silencing CD54 greatly reduced the tumorigenesis of prostate cancers both in vitro and in vivo and significantly extended the survival time of tumor-bearing mice in a prostate cancer xenograft model. Dissection of the molecular mechanism revealed that the p38-Notch1 axis was the main downstream signaling pathway in CD54-mediated regulation of CSCs in prostate cancers. Together, these results established that CD54 could be a novel reliable prostate CSC marker and provided a new potential therapeutic target in prostate cancer via CD54-Notch1 signaling

Reduction of the HIV Protease Inhibitor-Induced ER Stress and Inflammatory Response by Raltegravir in Macrophages

Background HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages. Methodology and Principal Findings In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages. Conclusion and Significance Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART

An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell–like phenotypes shown by many tumors

A TonB-dependent receptor regulates antifungal HSAF biosynthesis in \u3ci\u3eLysobacter\u3c/i\u3e

Lysobacter species are Gram-negative bacteria that are emerging as new sources of antibiotics, including HSAF (Heat Stable Antifungal Factor), which was identified from L. enzymogenes with a new mode of action. LesR, a LuxR solo, was recently shown to regulate the HSAF biosynthesis via an unidentified mechanism in L. enzymogenes OH11. Here, we used a comparative proteomic approach to identify the LesR targets and found that LesR influenced the expression of 33 proteins belonging to 10 functional groups, with 9 proteins belonging to the TBDR (TonB-Dependent Receptor) family. The fundamental role of bacterial TBDR in nutrient uptake motivates us to explore their potential regulation on HSAF biosynthesis which is also modulated by nutrient condition. Six out of 9 TBDR coding genes were individually in-frame deleted. Phenotypic and gene-expression assays showed that TBDR7, whose level was lower in a strain overexpressing lesR, was involved in regulating HSAF yield. TBDR7 was not involved in the growth, but played a vital role in transcribing the key HSAF biosynthetic gene. Taken together, the current lesR-based proteomic study provides the first report that TBDR7 plays a key role in regulating antibiotic (HSAF) biosynthesis, a function which has never been found for TBDRs in bacteria. Includes Supplementary materials

The Prognostic Value of HRAS mRNA Expression in Cutaneous Melanoma

This study aimed to investigate the prognostic value of HRAS mRNA expression in cutaneous melanoma. Cutaneous melanoma is an aggressive cancer with an increasing incidence. Few studies have focused on the transcriptional level of RAS isoforms (KRAS, NRAS, and HRAS) in cutaneous melanoma. To gain further insight into RAS isoforms at transcriptional level, we obtained the cutaneous melanoma data from cBioPortal and investigated the RAS mRNA expression levels in different stages of melanoma and evaluated their correlation with clinical characteristics and patients’ survival. Furthermore, we retrieved and analyzed the coexpression data and performed pathway enrichment analysis. Totally, 452 cutaneous melanoma cases were included in this study. We found that lower HRAS expression level was associated with longer patient survival. 206 genes that negatively correlated with HRAS expression were positively correlated with KRAS and NRAS expression. In contrast, no gene that positively correlated with HRAS expression was positively correlated with KRAS and NRAS expression. In conclusion, our data showed that transcriptional regulation was different for the three RAS isoforms in cutaneous melanoma. This study highlighted the prognostic value of HRAS mRNA expression and revealed that HRAS greatly differs from KRAS and NRAS at the transcriptional level

Research Progress on the Flexibility of an Implantable Neural Microelectrode

Neural microelectrode is the important bridge of information exchange between the human body and machines. By recording and transmitting nerve signals with electrodes, people can control the external machines. At the same time, using electrodes to electrically stimulate nerve tissue, people with long-term brain diseases will be safely and reliably treated. Young’s modulus of the traditional rigid electrode probe is not matched well with that of biological tissue, and tissue immune rejection is easy to generate, resulting in the electrode not being able to achieve long-term safety and reliable working. In recent years, the choice of flexible materials and design of electrode structures can achieve modulus matching between electrode and biological tissue, and tissue damage is decreased. This review discusses nerve microelectrodes based on flexible electrode materials and substrate materials. Simultaneously, different structural designs of neural microelectrodes are reviewed. However, flexible electrode probes are difficult to implant into the brain. Only with the aid of certain auxiliary devices, can the implant be safe and reliable. The implantation method of the nerve microelectrode is also reviewed