DUSP1 promotes muscle atrophy by inhibiting myocyte differentiation in cachectic patients.

Background: Skeletal muscle atrophy is the major hallmark of cancer cachexia. The mechanisms underlying muscle wasting remain elusive in cachectic patients. Our research seeks to identify differentially expressed genes (DEGs) between non-cachectic and cachectic cancer patients and elucidate their functions. Methods: We screened the DEGs of skeletal muscle between patients with and without cachexia from microarray data. Biological function of DEGs is analyzed through gene enrichment analysis, while an interaction network is constructed to visualize how genes are related. A Spearman's correlation analysis demonstrated the clinical significance of DUSP1 related to cancer cachexia. Skeletal muscle samples were collected and histomorphology studies were conducted. Function of DUSP1 on myogenesis was clarified by qPCR, western blotting, and immunofluorescence. Results: We screened 324 DEGs in skeletal muscle from patients with and without cachexia. The results of the gene enrichment analysis indicated that inflammatory cytokines and immune responses contribute significantly to the pathological condition of cachexia. DUSP1 was one of the key genes in the regulating network. DUSP1 protein and mRNA levels were increased significantly in skeletal muscle tissues from patients with cancer cachexia. DUSP1 expression in cachectic group was found to have negative correlation with SMA, prealbumin and BMI and positive correlation with TNFα, IL6 and weight loss. Significant changes of myogenesis related genes were observed in myocyte after DUSP1 was overexpressed and knocked down. Conclusion: In skeletal muscle of cachectic patients, DUSP1 expression was observed to be higher and thus DUSP1 promote muscle atrophy by inhibiting myogenesis. DUSP1 is expected to be a specific target in cancer cachexia for preventing and treating muscle atrophy.

A Low Temperature Coefficient Time-to-Digital Converter with 1.3 ps Resolution Implemented in a 28 nm FPGA.

Time-to-digital converter (TDC) is the key technology to realize accurate time delay measurement in high-precision optical fiber time-frequency transmission and synchronization, optical sensing and many scientific applications. The performance of FPGA-TDC based on the carry chain is sensitive to the operating temperature. This paper presents a parallel multichain cross segmentation method, without multitime measurements, which merges multichain into an equivalent chain, achieving low temperature coefficient and maintaining high precision. The equivalent chain breaks the limit of the intrinsic cell delay of a single carry chain, improves the precision and reduces the impact of temperature variation significantly. A two-channel TDC based on parallel multichain cross segmentation method is implemented in a 28 nm fabrication process Kintex-7 FPGA. The results show that the performance of TDC is improved with the increase of the number of chains. The 10-chain TDC with 1.3 ps resolution, 4.6 ps single-shot precision performs much better than the plain TDC with 11.4 ps resolution, 8.7 ps single-shot precision. The resolution is stable with 0.0002 ps/°C temperature coefficient under an operating temperature range from 25 °C to 70 °C. Moreover, the proposed method reduces the complexity of the circuit and the resource usage.

Cooperative carbon emission reduction through the Belt and Road Initiative.

Carbon emission reduction under the Belt and Road Initiative has great significance on China's goal of carbon peak. To better promote carbon emission reduction, based on the background of the Belt and Road Initiative, this paper analyzes the collaborative carbon emission reduction through investment between Chinese enterprises and local enterprises in developing countries along the Belt and Road Initiative. Considering the efforts of enterprises in carbon reduction, low-carbon infrastructure investment, and promotion of low-carbon products, this paper constructs a differential game model of collaborative carbon reduction cooperation between Chinese enterprises and local enterprises in developing countries along the Belt and Road Initiative. By horizontally comparing Nash non-cooperative mode, Stackelberg master-slave mode, and cooperative mode, the results shows that Chinese enterprises can encourage local enterprises in developing countries along the Belt and Road Initiative to coordinate carbon emission reduction through subsidies, which is Stackelberg master-slave mode. Under the cooperative mode, with the maximum carbon emission reduction efforts of both parties, the total benefit of carbon emission reduction reaches the optimal Pareto equilibrium. In addition, this paper also discusses the influence of related factors on the benefits of carbon emission reduction.

Phosphorylation of Dynamin-Related Protein 1 (DRP1) Regulates Mitochondrial Dynamics and Skeletal Muscle Wasting in Cancer Cachexia.

BACKGROUND: Cancer-associated cachexia (CAC) is a syndrome characterized by skeletal muscle atrophy, and the underlying mechanisms are still unclear. Recent research studies have shed light on a noteworthy link between mitochondrial dynamics and muscle physiology. In the present study, we investigate the role of dynamin-related protein 1 (DRP1), a pivotal factor of mitochondrial dynamics, in myotube atrophy during cancer-associated cachexia. METHODS: Seventy-six surgical patients, including gastrointestinal tumor and benign disease, were enrolled in the study and divided to three groups: control, non-cachexia, and cancer-associated cachexia. Demographic data were collected. Their rectus abdominis samples were acquired intraoperatively. Muscle fiber size, markers of ubiquitin proteasome system (UPS), mitochondrial ultrastructure, and markers of mitochondrial function and dynamics were assayed. A cachexia model in vitro was established via coculturing a C2C12 myotube with media from C26 colon cancer cells. A specific DRP1 inhibitor, Mdivi-1, and a lentivirus of DRP1 knockdown/overexpression were used to regulate the expression of DRP1. Muscle diameter, mitochondrial morphology, mass, reactive oxygen species (ROS), membrane potential, and markers of UPS, mitochondrial function, and dynamics were determined. RESULTS: Patients of cachexia suffered from a conspicuous worsened nutrition status and muscle loss compared to patients of other groups. Severe mitochondrial swelling and enlarged area were observed, and partial alterations in mitochondrial function were found in muscle. Analysis of mitochondrial dynamics indicated an upregulation of phosphorylated DRP1 at the ser616 site. In vitro, cancer media resulted in the atrophy of myotube. This was accompanied with a prominent unbalance of mitochondrial dynamics, as well as enhanced mitochondrial ROS and decreased mitochondrial function and membrane potential. However, certain concentrations of Mdivi-1 and DRP1 knockdown rebalanced the mitochondrial dynamics, mitigating this negative phenotype caused by cachexia. Moreover, overexpression of DRP1 aggravated these phenomena. CONCLUSION: In clinical patients, cachexia induces abnormal mitochondrial changes and possible fission activation for the atrophied muscle. Our cachexia model in vitro further demonstrates that unbalanced mitochondrial dynamics contributes to this atrophy and mitochondrial impairment, and rebuilding the balance by regulating of DRP1 could ameliorate these alterations.

Regulation of dynamin-related protein 1 (DRP1) levels modulates myoblast atrophy induced by C26 colon cancer-conditioned medium.

BACKGROUND: Cancer associated-cachexia, which involves progressive skeletal muscle loss, is induced by multiple factors. However, the underlying mechanism remains unclear. Dynamin-related protein 1 (DRP1), a major modulator of mitochondrial fission, has been reported to participate in muscle turnover. This study aimed to explore the role of DRP1 in muscle during the process of cancer associated-cachexia (CAC) via an in vitro model and the mechanisms involved. METHODS: C26 colon cancer cell-conditioned medium (CM) was used to incubate with C2C12 myotubes to simulate cachexia. Myotubes were then transduced with lentiviral vectors of DRP1-small interfering RNA (siRNA), DRP1 overexpression plasmid, or a control plasmid to regulate the DRP1 levels, and their diameters were assessed using a biological microscope. Furthermore, transcriptome sequencing was performed to screen the pathways involved, and real-time polymerase chain reaction (RT-PCR) was used for verification. RESULTS: The cachexia model was successfully established with a decreased myotube diameter and increased DRP1 expression. DRP1 knockdown significantly ameliorated myotube wasting during cachexia, while DRP1 overexpression intensified this phenomenon. Transcriptome sequencing indicated that DRP1 knockdown was associated with the activation of ribosomal biogenesis. However, PCR results showed that compared to the control, one of the ribosomal biogenesis marker's (Ubf) level was decreased by C26 CM, and DRP1 knockdown did not significantly restore its level. CONCLUSIONS: During C26 CM-induced cachexia, DRP1 was activated, while the regulation of DRP1 levels was able to modulate the atrophy of C2C12 myotubes. The underlying mechanism of the alleviated muscle atrophy induced by DRP1 knockdown was likely associated with increased ribosomal activity.

Diastereoselective Synthesis of 1,3-Diyne-Tethered Trifluoromethylcyclopropanes through a Sulfur Ylide Mediated Cyclopropanation/DBU-Mediated Epimerization Sequence.

A one-pot synthesis of 1,3-diyne-tethered trifluoromethylcyclopropanes starting from 2-CF3-3,5-diyne-1-enes and sulfur ylides via a sulfur ylide mediated cyclopropanation and a DBU-mediated epimerization sequence is described in this work. This process is highly diastereoselective with broad substrate scope. Moreover, a series of synthetic transformations based on the diyne moieties were conducted smoothly, affording cyclopropanes featuring trifluoromethyl-substituted all-carbon quaternary centers.

Tandem Cross-Coupling/Spirocyclization/Mannich-Type Reactions of 3-(2-Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines.

Tandem reactions of Pd-catalyzed cross-coupling of 3-(2-isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich-type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich-type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich-type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chemistry, as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.

Ginsenoside Rb1 improves postoperative fatigue syndrome by reducing skeletal muscle oxidative stress through activation of the PI3K/Akt/Nrf2 pathway in aged rats.

Ginsenoside Rb1 is reported to possess anti-fatigue activity, but the mechanisms remain unknown. The aim of this study was to investigate the molecular mechanisms responsible for the anti-fatigue effect of ginsenoside Rb1 on postoperative fatigue syndrome induced by major small intestinal resection (MSIR) in aged rat. Aged rats with MSIR were administrated with ginsenoside Rb1 (15 mg/kg) once a day from 3 days before surgery to the day of sacrifice, or with saline as corresponding controls. Rats without MSIR but going through the same surgery procedure were administrated with saline as blank controls. Anti-fatigue effect was assessed by an open field test; superoxide dismutase, reactive oxygen species and malondialdehyde in skeletal muscle were determined. The mRNA levels of Akt2 and Nrf2 in skeletal muscle were measured by real-time quantitative PCR. The activation of Akt and Nrf2 was examined by western blot and immunohistofluorescence. Our results revealed that ginsenoside Rb1 significantly increased the journey and the rearing frequency, decreased the time of rest in aged rats with MSIR. In addition, ginsenoside Rb1 significantly reduced reactive oxygen species and malondialdehyde release and increased the superoxide dismutase activity of skeletal muscle in aged rats with MSIR. Ginsenoside Rb1 also increased the expression of Akt2 and Nrf2 mRNA, up-regulated Akt phosphorylation and Nrf2 nuclear translocation. These findings indicate that ginsenoside Rb1 has an anti-fatigue effect on postoperative fatigue syndrome in aged rat, and the mechanism possibly involves activation of the PI3K/Akt pathway with subsequent Nrf2 nuclear translocation and induction of antioxidant enzymes.