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BackgroundThe small mother against decapentaplegic proteins (SMADs) are a family of transforming growth factor (TGF)-β signal transduction molecules, playing a vital role in the initiation and development of tumors. This research aimed to determine SMADs' prognostic values and their involvement in immune infiltration.MethodsExpression patterns and prognostic values of SMADs were evaluated by pan-cancer analysis in multiple cancer cohorts based on The Cancer Genome Atlas data. cBioPortal database was used for genetic mutation analyses. UALCAN and LinkedOmics databases were applied for the analysis of the methylation level and its correlation with gene expression, respectively. The correlation of gene expression was analyzed by Gene Expression Profiling Interactive Analysis platform. Additionally, we utilized the Tumor Immune Estimation Resource database to explore the correlation between SMAD expressions and the number of tumor-infiltrating immune cells. Functional prediction was performed by Gene Set Enrichment Analysis (GSEA) method.ResultsWe found that the expressions of SMAD1, 2, 3, 4, 6 were significantly decreased whereas the expression of SMAD9 was significantly increased in kidney renal clear cell carcinoma (KIRC) tissues than in normal control tissues. And aberrant DNA methylation in the promoter regions may cause the dysregulation of these differentially expressed SMADs. Also, we found that the expressions of SMAD1, 2, 3, 4, 6 decreased significantly with the progression of KIRC tumors, and their high expression level was significantly associated with favorable prognoses of KIRC patients. Genetic mutations analysis using the cBioPortal database found that there were missense mutations in SMAD2 and 4, and truncation mutations in SMAD2 and 3. Further, SMAD1, 2, 3, 4, 6 expressions showed correlations with diverse immune infiltrating cells and immune markers. In particular, SMAD1, 2, 4 expressions were strongly correlated with monocyte, tumor-associated macrophage, M1/M2 macrophage, revealing their potential to regulate the polarity of macrophages. Finally, function prediction by GSEA indicated that SMAD1, 2, 3, 4, 6 were closely involved in immune-related signaling pathways.ConclusionsOur findings indicate that SMAD1, 2, 3, 4 and 6 were potent biomarkers for predicting the prognosis and immune cell infiltration of KIRC patients.

Traffic congestion is a major concern in urban transportation in supply chain management. Road-based logistic companies can mitigate their Carbon dioxide (CO2) emissions effectively by optimising their operation. In this study, we observed a low-carbon, fixed-tour scheduling problem with time windows (LC-FTSP-TW) that is designed to consider the factors that can minimise the greenhouse-gas emissions of logistics systems. Through better planning of the delivery times, we delineated a system to control the schedules of two vehicle types: fossil-fuel-powered and electric-powered vehicles. We formulated the LC-FTSP-TW as a mixed-integer linear programming model that can take into consideration time-varying traffic conditions, customer time windows, and vehicle energy-consumption functions. The proposed model was observed to be convenient for practical use, as it could be solved directly using commercial optimisation toolboxes, such as CPLEX and Gurobi, with continuous optimal results. In addition, we developed an efficient dynamic programming algorithm for solving large-sized problems with discrete optimal results. Computational experiments were conducted on a group of test instances to verify the proposed model and algorithm, which demonstrated considerable reductions in CO2 emissions compared to non-optimised solutions for both the tested fossil-fuel-powered and electric-powered vehicles. [ABSTRACT FROM AUTHOR]

Amorphous solids are non‐equilibrium states of matter that lack long‐range structural order, and are recognized as key materials in electronics. Although 2D van der Waals materials have been intensively studied in the wide field of materials science, their amorphous states have been less studied experimentally. Here, a van der Waals ferromagnetic semiconductor CrGeTe3 transforms into an amorphous ferromagnetic metal upon irradiation with high‐energy Xe ions. Notably, the Curie temperature of the amorphous state reaches 200 K, which is three times higher than that of the crystalline phase. The anomalous Hall conductivity in the amorphous phase is governed by the extrinsic skew‐scattering mechanism, although conventional theory predicts that skew scattering is dominant only in ultra‐clean ferromagnetic metals. The present results call for a new theory of the anomalous Hall effect in highly disordered ferromagnetic conductors. Moreover, the unique change in magnetic and transport properties due to amorphization of the van der Waals material is expected to open up a new research field in materials science. [ABSTRACT FROM AUTHOR]

In this study, a Ni-based composite incorporating Ni4N and La2O3 supported on carbon nanotubes (Ni–La–Ni4N/CNT) was synthesized as an efficiency electrocatalyst towards the hydrogen evolution reaction in different electrolytes with the kinetics and energy consumption investigated in detail. The Ni–La–Ni4N/CNT exhibits overpotentials of 124 mV and 200 mV at the current density of 10 mA cm−2 in 1.0 M KOH and alkaline seawater, respectively. As quantitative comparison, the exchange current density (j°) based on Volmer–Heyrovsky–Tafel mechanism was calculated from various polarization curves, which indicated that the addition of NaCl in alkaline medium or using seawater alone reduced the reactivity of the catalyst. The activity of Ni–La–Ni4N/CNT in alkaline seawater was equal to 91% of that in 1.0 M KOH. Furthermore, dynamic polarization resistance and corresponding current were obtained by the analysis of the equivalent circuit model with the extended Kalman filter algorithm. The analysis of the resistance power at 1 mW also shows that the current between the conditions in KOH and in seawater is 2.76 times. Adding alkaline substances to seawater can narrow it to 1.19 times. These strategies provide novel approaches for inspecting the activity changes of materials in different electrochemical environments. [ABSTRACT FROM AUTHOR]

Mitophagy, which selectively eliminates the dysfunctional and excess mitochondria by autophagy, is crucial for cellular homeostasis under stresses such as hypoxia. Dysregulation of mitophagy has been increasingly linked to many disorders including neurodegenerative disease and cancer. Triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype, is reported to be characterized by hypoxia. However, the role of mitophagy in hypoxic TNBC as well as the underlying molecular mechanism is largely unexplored. Here, we identified GPCPD1 (glycerophosphocholine phosphodiesterase 1), a key enzyme in choline metabolism, as an essential mediator in hypoxia-induced mitophagy. Under the hypoxic condition, we found that GPCPD1 was depalmitoylated by LYPLA1, which facilitated the relocating of GPCPD1 to the outer mitochondrial membrane (OMM). Mitochondria-localized GPCPD1 could bind to VDAC1, the substrate for PRKN/PARKIN-dependent ubiquitination, thus interfering with the oligomerization of VDAC1. The increased monomer of VDAC1 provided more anchor sites to recruit PRKN-mediated polyubiquitination, which consequently triggered mitophagy. In addition, we found that GPCPD1-mediated mitophagy exerted a promotive effect on tumor growth and metastasis in TNBC both in vitro and in vivo. We further determined that GPCPD1 could serve as an independent prognostic indicator in TNBC. In conclusion, our study provides important insights into a mechanistic understanding of hypoxia-induced mitophagy and elucidates that GPCPD1 could act as a potential target for the future development of novel therapy for TNBC patients. Abbreviations: ACTB: actin beta; 5-aza: 5-azacytidine; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; ChIP: chromatin immunoprecipitation; co-IP: co-immunoprecipitation; CQ: chloroquine; CsA: cyclosporine; DOX: doxorubicin; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; GPCPD1: glycerophosphocholine phosphodiesterase 1; HAM: hydroxylamine; HIF1A: hypoxia inducible factor 1 subunit alpha; HRE: hypoxia response element; IF: immunofluorescence; LB: lysis buffer; LC3B/MAP1LC3B: microtubule associated protein 1 light chain 3 beta; LC-MS: liquid chromatography-mass spectrometry; LYPLA1: lysophospholipase 1; LYPLA2: lysophospholipase 2; MDA231: MDA-MB-231; MDA468: MDA-MB-468; MFN1: mitofusin 1; MFN2: mitofusin 2; MKI67: marker of proliferation Ki-67; OCR: oxygen consumption rate; OMM: outer mitochondrial membrane; OS: overall survival; PalmB: palmostatin B; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; SDS: sodium dodecyl sulfate; TOMM20: translocase of outer mitochondrial membrane 20; TNBC: triple-negative breast cancer; VBIT-4: VDAC inhibitor; VDAC1: voltage dependent anion channel 1; WT: wild type. [ABSTRACT FROM AUTHOR]