Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway.

Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation

Mars: Modeling Context & State Representations with Contrastive Learning for End-to-End Task-Oriented Dialog

Traditional end-to-end task-oriented dialog systems first convert dialog context into belief state and action state before generating the system response. The system response performance is significantly affected by the quality of the belief state and action state. We first explore what dialog context representation is beneficial to improving the quality of the belief state and action state, which further enhances the generated response quality. To tackle our exploration, we propose Mars, an end-to-end task-oriented dialog system with two contrastive learning strategies to model the relationship between dialog context and belief/action state representations. Empirical results show dialog context representations, which are more different from semantic state representations, are more conducive to multi-turn task-oriented dialog. Moreover, our proposed Mars achieves state-of-the-art performance on the MultiWOZ 2.0, CamRest676, and CrossWOZ.Comment: Findings of ACL202

Effects of mTOR inhibitor, everolimus, on proliferation, autophagy and temozolomide sensitivity of glioma cells

Purpose: To study the effect of the mTOR inhibitor, everolimus, on glioma cell proliferation, autophagy, and drug sensitivity to temozolomide (TMZ).Methods: Human glioma cell lines were cultured in vitro, and the effects of different concentrations of everolimus on the proliferation of brain glial cells were determined using CCK-8 method. The effect of different concentrations of everolimus on brain glial cell levels of autophagy protein were assayed by western blot method.Results: The results of CCK-8 analysis showed that everolimus inhibited the proliferation of glial cells in a time- and concentration-dependent manner. Western blot results showed that the expression levels of autophagy proteins, LC3-II and LC3-II/I, were gradually and concentration-dependently up-regulated, while p62 protein level was gradually decreased concentration-dependently, when compared with blank control (p < 0.05). Treatment with different concentrations of TMZ alone, and in combination with everolimus for 48 h inhibited the proliferation of brain glial cells in a concentration-dependent manner, but the inhibition due to TMZ-everolimus combination was significantly higher than that of TMZ singletreatment (p < 0.05). After 48 h, the expression level of Beclin-1 increased with the ratio of LC3-II/LC-I in TMZ-everolimus group, while the expression level of p62 decreased, when compared with TMZ alone, or control (p < 0.05).Conclusion: Everolimus significantly inhibits the proliferation of glioma cells and promotes the occurrence of autophagy. Combined use of TMZ and everolimus significantly enhances the sensitivity of TMZ to glioma cells, inhibits cell proliferation, and promotes autophagy better than TMZ alone. Keywords: mTOR inhibitor, Everolimus, Glioma cells, Proliferation, Autophag

Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure.

Background Branched-chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a small-molecule inhibitor of branched-chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle-treated mice, whereas the BT2-treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure

Catabolism of Branched-Chain Amino Acids in Heart Failure: Insights from Genetic Models

Genetic defects in amino acid metabolism are major causes of newborn diseases that often lead to abnormal development and function of the central nervous system. Their direct impact on cardiac development and function has rarely been investigated. Recently, the authors have established that a mitochondrial targeted 2C-type ser/thr protein phosphatase, PP2Cm, is the endogenous phosphatase of the branched-chain alpha keto acid-dehydrogenase complex (BCKD) and functions as a key regulator in branched-chain amino acid catabolism and homeostasis. Genetic inactivation of PP2Cm in mice leads to significant elevation in plasma concentrations of branched-chain amino acids and branched-chain keto acids at levels similar to those associated with intermediate mild forms of maple syrup urine disease. In addition to neuronal tissues, PP2Cm is highly expressed in cardiac muscle, and its expression is diminished in a heart under pathologic stresses. Whereas phenotypic features of heart failure are seen in PP2Cm-deficient zebra fish embryos, cardiac function in PP2Cm-null mice is compromised at a young age and deteriorates faster by mechanical overload. These observations suggest that the catabolism of branched-chain amino acids also has physiologic significance in maintaining normal cardiac function. Defects in PP2Cm-mediated catabolism of branched-chain amino acids can be a potential novel mechanism not only for maple syrup urine disease but also for congenital heart diseases and heart failure

Graphene-assisted microfiber for optical-power-based temperature sensor

Combined the large evanescent field of microfiber with the high thermal conductivity of graphene, a sensitive all-fiber temperature sensor based on graphene-assisted micro fiber is proposed and experimentally demonstrated. Microfiber can be easily attached with graphene due to the electrostatic 6 force, resulting in an effective interaction between graphene and the evanescent field of microfiber. The change of the ambient temperature has a great influence on the conductivity of graphene, leading to the variation of the effective refractive index of microfiber. Consequently, the optical power transmission will be changed. The temperature sensitivity of 0.1018 dB/°C in the heating process and 0.1052 dB/°C in the cooling process as well as a high resolution of 0.0098 °C is obtained in the experiment. The scheme may have great potential in sensing fields owing to the advantages of high sensitivity, compact size, and low cost

Three novel α-L-iduronidase mutations in 10 unrelated Chinese mucopolysaccharidosis type I families

Mucopolysaccharidosis type I (MPS I) arises from a deficiency in the α-L-iduronidase (IDUA) enzyme. Although the clinical spectrum in MPS I patients is continuous, it was possible to recognize 3 phenotypes reflecting the severity of symptoms, viz., the Hurler, Scheie and Hurler/Scheie syndromes. In this study, 10 unrelated Chinese MPS I families (nine Hurler and one Hurler/Scheie) were investigated, and 16 mutant alleles were identified. Three novel mutations in IDUA genes, one missense p.R363H (c.1088G > A) and two splice-site mutations (c.1190-1G > A and c.792+1G > T), were found. Notably, 45% (nine out of 20) and 30% (six out of 20) of the mutant alleles in the 10 families studied were c.1190-1G > A and c.792+1G > T, respectively. The novel missense mutation p.R363H was transiently expressed in CHO cells, and showed retention of 2.3% IDUA activity. Neither p.W402X nor p.Q70X associated with the Hurler phenotype, or even p.R89Q associated with the Scheie phenotype, was found in this group. Finally, it was noted that the Chinese MPS I patients proved to be characterized with a unique set of IDUA gene mutations, not only entirely different from those encountered among Europeans and Americans, but also apparently not even the same as those found in other Asian countries

Microfiber-based inline Mach-Zehnder interferometer for dual-parameter measurement

An approach to realizing simultaneous measurement of refractive index (RI) and temperature based on a microfiber-based dual inline Mach-Zehnder interferometer (MZI) is proposed and demonstrated. Due to different interference mechanisms, as one interference between the core mode and the lower order cladding mode in the sensing single-mode fiber and the other interference between the fundamental mode and the high-order mode in the multimode microfiber, the former interferometer achieves RI sensitivity of -23.67 nm/RIU and temperature sensitivity of 81.2 pm/oC, whereas those of the latter are 3820.23 nm/RIU, and -465.7 pm/oC, respectively. The large sensitivity differences can provide a more accurate demodulation of RI and temperature. The sensor is featured with multiparameters measurement, compact structure, high sensitivity, low cost, and easy fabrication