Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier.

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment, significantly curtailing the efficacy of these treatments and, in some cases, resulting in fatal consequences. Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis, the paucity of effective treatments for such damage is evident. In our study, we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells, thereby fortifying the integrity of the intestinal mucus barrier. This enhanced barrier function serves to resist microbial invasion and subsequently reduces the inflammatory response. Importantly, this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs. Mechanistically, E. copr up-regulates the expression of AUF1, leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells. An especially significant finding is that E. copr activates the AhR pathway, thereby promoting the expression of AUF1. In summary, our results strongly indicate that E. copr enhances the intestinal mucus barrier, effectively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUF1 pathway, consequently enhancing Muc2 mRNA stability.

Monomer Emission Mechanism Research of Tetraphenylethene Derivative with Supramolecular Self-Assembly in Polymer Microspheres.

The monomer emission property of the tetraphenylethene (TPE) derivative is rarely reported, and its photoluminescence (PL) mechanism related to supramolecular self-assembly needs further in-depth research. Two long alkyl chain modified derivatives, the TPE derivative (TPE-C10) and pyrene derivative (Pyrene-C10), are designed and synthesized, which possess similar supramolecular assembly behavior but exhibit different PL properties. TPE-C10 not only forms self-assembly morphologies with monomer emission but also emits aggregation-induced emission (AIE). Moreover, the polymer microspheres containing TPE-C10 and Pyrene-C10 are prepared, which can dissolve or swell in different organic solvents. The changed binding effect of polymer chains achieves the luminescence transformation of TPE-C10 from AIE to monomer emission. This work hopefully can enrich luminescent materials based on the monomer emission of the TPE derivative and provide a new method for mechanism studies about supramolecular self-assembly and luminescence.

The flavonoid GL-V9 alleviates liver fibrosis by triggering senescence by regulating the transcription factor GATA4 in activated hepatic stellate cells.

BACKGROUND AND PURPOSE: Liver fibrosis is a critical risk factor for the progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL-V9, a newly synthesized flavonoid derivative, exhibits anti-inflammatory activity, but whether it has anti-hepatic fibrosis actions remains unclear. This study aimed to investigate the anti-fibrotic activities and potential mechanisms of GL-V9. EXPERIMENTAL APPROACH: Bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) challenges were used to assess the anti-fibrotic effects of GL-V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX2 also served as a liver fibrosis model in vitro. Cellular functions and molecular mechanism were analysed using senescence-associated beta-galactosidase staining, real-time PCR, western blotting, immunofluorescence, and co-immunoprecipitation. KEY RESULTS: GL-V9 attenuated hepatic histopathological injury and collagen accumulation, as well as decreasing the expression of fibrotic genes in vivo. GL-V9 promoted senescence and inhibited the expression of fibrogenic genes in HSCs in vitro. Mechanistic studies revealed that GL-V9 induced senescence by upregulating GATA4 expression in HSCs. Further studies confirmed that GL-V9 stabilized GATA4 by promoting autophagic degradation of P62. CONCLUSION AND IMPLICATIONS: GL-V9 exerted potent anti-fibrotic effects both in vivo and in vitro by stabilizing GATA4, thereby promoting the senescence of HSCs, and by avoiding its activation and ultimately inhibiting liver fibrosis. This action indicated that the flavonoid GL-V9 is a potential therapeutic candidate for the treatment of liver fibrosis.

Study on the Durability of Acid Rain Erosion-Resistant Asphalt Mixtures.

Acid erosion can accelerate the process of early damage of asphalt pavement and decrease the durability of asphalt pavement. However, there are limited research results for asphalt mixtures that can resist acid rain erosion. To systematically evaluate the impact and action law of acid rain erosion on the durability of asphalt mixtures, three gradation schemes were used: periodic dry-wet cycle immersion test, contact angle test and road performance test. The acid rain erosion resistance of epoxy asphalt mixture, SBS-modified asphalt mixture and 70# matrix asphalt mixture were tested from three aspects of anti-aging performance, freeze-thaw cycle performance and fatigue performance. The results show that the erosion of acid rain can significantly decrease the adhesion between asphalt and aggregate, and affects the road performance of the asphalt mixture. Acid rain erosion can significantly decrease the mechanical properties, adhesion and durability of asphalt mixtures. Epoxy asphalt has better physical properties, adhesion and acid rain erosion resistance than 70# matrix asphalt and SBS-modified asphalt. Epoxy asphalt has excellent adhesion due to its polar group, high cohesion and thermosetting resin with low shrinkage, which can effectively resist moisture erosion, spalling and temperature stress cracking, thereby effectively resisting the erosion of acid rain. Epoxy asphalt mixture has the strongest acid rain erosion resistance, which can be further enhanced when used together with waste rubber powder and modified bamboo fiber. On the whole, asphalt mixture with high-density structure and thicker asphalt film can effectively resist acid rain erosion. The durability of asphalt concrete (AC)-type gradation mixture and stone mastic asphalt (SMA)-type gradation mixture are equivalent, and both are superior to open-graded friction courses (OGFC)-type gradation mixture. The gradation of asphalt mixtures and the type of asphalt binder have great influence on their acid rain erosion resistance and durability. In order to realize the directional control of the acid rain erosion resistance and durability of different asphalt mixtures, a multi-parameter comprehensive assessment indicator system between the type and property of asphalt, the gradation of asphalt mixture, and the acid rain resistance and durability of the mixture need to be established in the future.

ALDOA maintains NLRP3 inflammasome activation by controlling AMPK activation.

ABBREVIATIONS: ALDOA: aldolase A; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG5: autophagy related 5; ATP: adenosine triphosphate; BMDMs: bone marrow-derived macrophages; CALCOCO2: calcium binding and coiled-coil domain 2; CASP1: caspase 1; CQ: chloroquine; FOXO3: forkhead box O3; IL1B: interleukin 1 beta; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MT: mutant; mtDNA: mitochondrial DNA; MTORC1: mechanistic target of rapamycin kinase complex 1; mtROS: mitochondrial reactive oxygen species; NLRP3: NLR family, pyrin domain containing 3; OPTN: optineurin; PBS: phosphate-buffered saline; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; SN: supernatant; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; v-ATPase: vacuolar type H+-ATPase; WT: wild-type.

Performance and Characteristics of Wearable Sensor Systems Discriminating and Classifying Older Adults According to Fall Risk: A Systematic Review.

Sensor-based fall risk assessment (SFRA) utilizes wearable sensors for monitoring individuals' motions in fall risk assessment tasks. Previous SFRA reviews recommend methodological improvements to better support the use of SFRA in clinical practice. This systematic review aimed to investigate the existing evidence of SFRA (discriminative capability, classification performance) and methodological factors (study design, samples, sensor features, and model validation) contributing to the risk of bias. The review was conducted according to recommended guidelines and 33 of 389 screened records were eligible for inclusion. Evidence of SFRA was identified: several sensor features and three classification models differed significantly between groups with different fall risk (mostly fallers/non-fallers). Moreover, classification performance corresponding the AUCs of at least 0.74 and/or accuracies of at least 84% were obtained from sensor features in six studies and from classification models in seven studies. Specificity was at least as high as sensitivity among studies reporting both values. Insufficient use of prospective design, small sample size, low in-sample inclusion of participants with elevated fall risk, high amounts and low degree of consensus in used features, and limited use of recommended model validation methods were identified in the included studies. Hence, future SFRA research should further reduce risk of bias by continuously improving methodology.

All-Solid-State Self-Healing Ionic Conductors Enabled by Ion-Dipole Interactions within Fluorinated Poly(Ionic Liquid) Copolymers.

Self-healing ionic conductors in all solid state without evaporation or leakage offers great potential for the next-generation soft ionotronics. However, it remains challenging to endow ionic conductors with all solid state while keeping their essential features. In this study, an intrinsically conducting polymer is developed as all-solid-state self-healing ionic conductors based on ion-dipole interactions within a fluorinated poly(ionic liquid) copolymer. This unique material possesses good self-healing ability at room temperature (96% of healing efficiency in 24 h), large strain (1800%), optical transparency (96%), and ionic conductivity (1.62 × 10-6 S/cm). The self-healing polymer itself is intrinsically conductive without any additives or fillers, thus it is almost free of evaporation or leaking issues of traditional conducting gels. An alternating-current electroluminescent device with self-healing performance is demonstrated. It is anticipated that this strategy would provide new opportunities for the development of novel self-healing ionotronics.

Oroxylin A maintains the colonic mucus barrier to reduce disease susceptibility by reconstituting a dietary fiber-deprived gut microbiota.

Dietary fiber intake helps to maintain gut homeostasis. Fiber deficiency causes commensals to utilize mucins as an energy source to destroy mucus layer, thus promoting susceptibility to inflammatory bowel disease. Here, we reported that oroxylin A, a natural flavonoid, ameliorated low-grade colonic inflammation caused by fiber deficiency, alleviated colitis, and further prevented colitis-associated colon cancer in mice. The anti-inflammatory effect of oroxylin A was due to its alteration of gut microbiota. We found that the levels of Eubacterium coprostanoligenes was significantly increased by oroxylin A and the colonized Eubacterium coprostanoligenes significantly protected against colitis and carcinogenesis in colon of mice. Together, our results in this study suggest that oroxylin A may reduce the susceptibility to intestinal diseases by increasing the level of Eubacterium coprostanoligenes which could provide a therapeutic alternation for the treatment of intestinal diseases.

LT-171-861, a novel FLT3 inhibitor, shows excellent preclinical efficacy for the treatment of FLT3 mutant acute myeloid leukemia.

Rationale: Acute myeloid leukemia (AML) is a common type of haematological malignancy. Several studies have shown that neoplasia in AML is enhanced by tyrosine kinase pathways. Recently, given that aberrant activation of Fms-like tyrosine receptor kinase 3 (FLT3) acts as a critical survival signal for cancer cells in 20‒30% patients with AML, inhibition of FLT3 may be a potential therapeutic strategy. Therefore, we identified LT-171-861, a novel kinase inhibitor with remarkable inhibitory activity against FLT3, in preclinical models of AML. Methods: We determined the inhibitory effects of LT-171-861 in vitro using AML cell lines and transformed BaF3 cells. Target engagement assays were used to verify the interaction between LT-171-861 and FLT3. Finally, a subcutaneous model and a bone marrow engrafted model were used to evaluate the antitumor effects of LT­171­861 in vivo. Results: Our data demonstrated that LT-171-861 had high affinity for FLT3 protein. We also showed that LT-171-861 had an inhibitory effect on FLT3 mutants in cellular assays. Moreover, LT-171-861 had a growth-inhibitory effect on human AML cell lines harboring FLT3 internal tandem duplications (FLT3-ITD) such as FLT3-D835Y, FLT3­ITD-N676D, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-Y842C and AML blasts from patients with FLT3-ITD. Furthermore, LT-171-861 showed potent antileukemic efficacy against AML cells. We also show the efficacy of LT­171-861 in a subcutaneous implantation model and a bone marrow engrafted model in vivo, where administration of LT-171-861 led to almost complete tumor regression and increased survival. Conclusions: Overall, this study not only identifies LT-171-861 as a potent FLT3 inhibitor, but also provides a rationale for the upcoming clinical trial of LT-171-861 in patients with AML and FLT3-ITD mutations.

A novel kinase inhibitor, LZT-106, downregulates Mcl-1 and sensitizes colorectal cancer cells to BH3 mimetic ABT-199 by targeting CDK9 and GSK-3ß signaling.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and is associated with poor prognosis and high mortality. Despite advances in treatment with chemotherapy, CRC remains a major cause of drug resistance-related cancer deaths. One of the main reasons for such resistance is dysregulation of Mcl-1 expression. In this study, we identified LZT-106 as a novel kinase inhibitor that was able to bind to CDK9 with potent inhibitory ability, and indirectly regulate the expression of Mcl-1. However, different regulatory profiles were observed between LZT-106 and the well-studied CDK9 inhibitor flavopiridol with regards to Mcl-1 inhibition. Via Western blotting, real-time PCR and immunoprecipitation, we confirmed that LZT-106 was also able to target GSK-3ß signaling and facilitate the degradation of Mcl-1. And LZT-106 was shown to synergize with ABT-199 to induce apoptosis even in the RKO cell line that overexpressed Mcl-1. Finally, LZT-106 significantly inhibited tumor growth in a xenograft mouse model with minimal toxicity. Overall, our findings suggest that LZT-106 is a promising candidate drug for the treatment of patients with CRC.

Induction of cell cycle arrest and apoptosis by CPUC002 through stabilization of p53 and suppression of STAT3 signaling pathway in multiple myeloma.

Multiple myeloma has always been an important health problem in human beings due to its high morbidity, high mortality, and lack of effective therapeutic drugs. This study investigated the anticancer effect and mechanism of the newly synthesized small molecule compound CPUC002 on multiple myeloma. Our results confirmed that CPUC002 inhibited proliferation and induced G0/G1 cell cycle arrest in multiple myeloma cells. Moreover, CPUC002 also induced apoptosis by mitochondrial pathway and exogenous pathway. In mechanism, CPUC002 triggered apoptosis by stabilizing p53 in NCI-H929 cells which expressed wt-p53. Knockdown of p53 partially suppressed CPUC002-induced apoptosis. This suggests that there are other molecular mechanisms underlying CPUC002's antitumor effect. Further studies showed that the CPUC002 also inhibited the STAT3 signaling pathway, while knockdown of STAT3 abolished CPUC002-induced apoptosis and cell cycle arrest. In vivo, CPUC002 has significant antitumor activity through the same mechanism as our in vitro studies, and is highly safe in xenograft models. Together these findings indicate that CPUC002 induces apoptosis and G0/G1 cell cycle arrest in multiple myeloma cells by stabilizing p53 and inhibiting the STAT3 signaling pathway.

Signal Quality Improvement Algorithms for MEMS Gyroscope-Based Human Motion Analysis Systems: A Systematic Review.

Motion sensors such as MEMS gyroscopes and accelerometers are characterized by a small size, light weight, high sensitivity, and low cost. They are used in an increasing number of applications. However, they are easily influenced by environmental effects such as temperature change, shock, and vibration. Thus, signal processing is essential for minimizing errors and improving signal quality and system stability. The aim of this work is to investigate and present a systematic review of different signal error reduction algorithms that are used for MEMS gyroscope-based motion analysis systems for human motion analysis or have the potential to be used in this area. A systematic search was performed with the search engines/databases of the ACM Digital Library, IEEE Xplore, PubMed, and Scopus. Sixteen papers that focus on MEMS gyroscope-related signal processing and were published in journals or conference proceedings in the past 10 years were found and fully reviewed. Seventeen algorithms were categorized into four main groups: Kalman-filter-based algorithms, adaptive-based algorithms, simple filter algorithms, and compensation-based algorithms. The algorithms were analyzed and presented along with their characteristics such as advantages, disadvantages, and time limitations. A user guide to the most suitable signal processing algorithms within this area is presented.

Morphological, physiological, cytological and phytochemical studies in diploid and colchicine-induced tetraploid plants of Fagopyrum tataricum (L.) Gaertn.

BACKGROUND: Tartary buckwheat are very popular as an important functional food material and its cultivation is very widespread in our whole world, but there obviously lack works in the researches of genetic breeding for agricultural and medicinal utilization. The aim of this study is to obtain good germplasm resources for agricultural and medicinal use of tartary buckwheat (Fagopyrum tataricum) by inducing the tetraploid plants. RESULTS: Four cultivars of F. tataricum, that is, Qianwei 2#, Jinku 2#, Chuanqiao 1#, and Liuqiao 1# were selected to experiment. The tips of seedlings with two true leaves were treated by 0.25% (w/v) colchicine solution for 48, 72, and 96 h, respectively. The chromosome number of treated plants was determined by metaphase chromosome counting of root tip cells and PMCs (pollen mother cells) meiosis observation. Tetraploid induction successfully occurred in all three treatments with an efficiency ranging from 12.13 to 54.55%. The chromosome number of the diploid plants was 2n = 2x = 16, and that of the induced tetraploid plants was 2n = 4x = 32. The typical morphological and physiological qualities were compared between the control diploid and corresponding induced tetraploid plants. Results showed that the induced tetraploid plants had obviously larger leaves, flowers, and seeds. Moreover, the content of seed protein and flavonoid were also increased in the tetraploid plants. The pollen diameter and capsule size of diploid plants were significantly smaller than those of tetraploid plants. CONCLUSION: Fagopyrum tataricum can be effectively induced into tetraploids by colchicines. The tetraploid induction can produce valuable germplasm resources for breeding and is a practicable breeding way in F. tataricum.

Noise Reduction for a MEMS-Gyroscope-Based Head Mouse.

In this paper, four different signal processing algorithms which can be applied to reduce the noise from a MEMS-gyroscope-based computer head mouse are presented. MEMS-gyroscopes are small, light, cheap and widely used in many electrical products. MultiPos, a MEMS-gyroscope-based computer head mouse system was designed for persons with movement disorders. Noise such as physiological tremor and electrical noise is a common problem for the MultiPos system. In this study four different signal processing algorithms were applied and evaluated by simulation in MATLAB and implementation in a dsPIC, with aim to minimize the noise in MultiPos. The algorithms were low-pass filter, Least Mean Square (LMS) algorithm, Kalman filter and Weighted Fourier Linear Combiner (WFLC) algorithm. Comparisons and system tests show that these signal processing algorithms can be used to improve the MultiPos system. The WFLC algorithm was found the best method for noise reduction in the application of a MEMS-gyroscope-based head mouse.