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Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved.

Metasurfaces can realize the flexible manipulation of electromagnetic waves, which have the advantages of a low profile and low loss. In particular, the coding metasurface can flexibly manipulate electromagnetic waves through controllable sequence encoding of the coding units to achieve different functions. In this paper, a three-layer active coding metasurface is designed based on vanadium dioxide ( V O 2 ), which has an excellent phase transition. For the designed unit cell, the top patterned layer is composed of two split square resonant rings (SSRRs), whose gaps are in opposite directions, and each SSRR is composed of gold and V O 2 . When V O 2 changes from the dielectric state to the metal state, the resonant mode changes from microstrip resonance to LC resonance, correspondingly. According to the Pancharatnam-Berry (P-B) phase, the designed metasurface can actively control terahertz circularly polarized waves in the near field. The metasurface can manipulate the order of the generated orbital angular momentum (OAM) beams: when the dielectric V O 2 changes to metal V O 2 , the order l of the OAM beams generated by the metasurface changes from −1 to −2, and the purity of the generated OAM beams is relatively high. It is expected to have important application values in terahertz wireless communication, radar, and other fields. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Regulating spin crossover (SCO) behavior, especially controlling the spin transition steps, is an important scientific issue, mainly because people aim to control spin bistability and multistability. Presently, SCO bistability can be regulated by changing the ligand‐modifying species, non‐coordinated anions, guest molecules, and metal‐ion dopant. However, the control of multistability is extremely challenging, especially in Fe(III) SCO compounds. Here, we report that [FeIII(H‐5‐Br‐thsa)(5‐Br‐thsa)]·H2O (5‐Br‐thsa = (5‐bromo‐2‐hydroxybenzylidene)hydrazinecarbothioamide), a compound we have reported before, exists in two polymorphic forms: polymorph 1 exhibits three‐step SCO, and polymorph 2 shows five‐step SCO, with multi‐step SCO behavior effectively regulated by polymorphism. According to single‐crystal and powder X‐ray diffractometry, polymorphs 1 and 2 crystallize in different space groups during their spin transitions, with two‐step symmetry breaking observed (Pbcn → Pnc2 → Pbcn for polymorph 1; P21/n → Pn → P21/n for polymorph 2). We realized that the behavior of these two polymorphs depends significantly on the structure, including (i) the average Fe—N bond distance, (ii) deformation of octahedral FeIII atoms, and (iii) distinct crystal packing, which account for the large differences observed in magnetic properties. [ABSTRACT FROM AUTHOR]

Hydraulic switching actuators are high-efficiency, fast response, and low-cost solutions for hydraulic control systems. One of the challenging problems is throttling losses during valve transitions. Previously, the authors proposed a zero-flowrate switching method to reduce the throttling energy loss of the switching valve, where a hydraulic resonator is applied to make the flowrates through the lines approaching zero before the valves are switched off. The major challenge of this approach is fast switching valves whose transition times are less than 2 ms. In this paper, an improved zero-flowrate switching method is presented. It utilizes the capacity with independent inlet/outlet ports to regulate flowrates through the lines. Models of capacity applied in a simple line with different pressure signals are developed to explore characteristics of the capacity, based on which a complete actuation system is developed. In the complete model, resistance and inductance are optimized to achieve the desired flowrate response. The improved zero-flowrate switching method reduces throttling energy losses by 99.945% compared to a hard switching system. The simulation results demonstrated that the improved zero-flowrate switching method performs as expected in the design condition. A capacity with proper volume is able to regulate flowrates through all the lines to zero, with the help of appropriate resistance and inductance. Compared to the previous zero-flowrate switching method, the novel strategy allows slower switching valves applied in hydraulic actuation systems and achieves better efficiency performance. This research paves a new avenue for reducing throttling energy losses and improves system efficiency in hydraulic switching actuators, as well as most of the hydraulic switch-mode circuits. [ABSTRACT FROM AUTHOR]

Selective laser melting (SLM) was used to fabricate Hastelloy X alloy. The characteristics of grains and precipitates in Hastelloy X alloy processed by heat treatments (HT) and hot isostatic pressing (HIP) was analyzed. Furthermore, the tensile property of Hastelloy X alloys at ambient temperature and elevated temperature was investigated. Some grains exhibit columnar crystal morphology in vertically built samples, while the grains are equiaxial in horizontally built samples. The carbide phases with cubic structure are formed within grains and at grain boundaries simultaneously after a combination of HT and HIP. The horizontally built samples exhibits high tensile strength and low plasticity compared with the vertically built ones. Both of vertically built and horizontally built samples show predominantly ductile failure as characterized by dimpled microstructure. The tensile strength of Hastelloy X alloy at ambient temperature produced by SLM is 95% higher than that of hot forged alloy, while the tensile strength at 600℃ is about 85% of hot forged ones.

BACKGROUND: Post-transcriptional regulation of mRNA induced by microRNA is known crucial in tumor occurrence, progression, and metastasis. This study aims at identifying significant miRNA-mRNA axes for stomach adenocarcinomas (STAD). METHOD: RNA expression profiles were collected from The Cancer Genome Atlas (TCGA) and GEO database for screening differently expressed RNAs and miRNAs (DE-miRNAs/DE-mRNAs). Functional enrichment analysis was conducted with Hiplot and DAVID-mirPath. Connectivity MAP was applied in compounds prediction. MiRNA-mRNA axes were forecasted by TarBase and MiRTarBase. Real-time reverse transcription polymerase chain reaction (RT-qPCR) of stomach specimen verified these miRNA-mRNA pairs. Diagnosis efficacy of miRNA-mRNA interactions was measured by Receiver operation characteristic curve and Decision Curve Analysis. Clinical and survival analysis were also carried out. CIBERSORT and ESTIMATE was employed for immune microenvironment measurement. RESULT: Totally 228 DE-mRNAs (105 upregulated and 123 downregulated) and 38 DE-miRNAs (22 upregulated and 16 downregulated) were considered significant. TarBase and MiRTarBase identified 18 miRNA-mRNA pairs, 12 of which were verified in RT-qPCR. The network of miR-301a-3p/ELL2 and miR-1-3p/ANXA2 were established and verified in external validation. The model containing all 4 signatures showed better diagnosis ability. Via interacting with M0 macrophage and resting mast cell, these miRNA-mRNA axes may influence tumor microenvironment. CONCLUSION: This study established a miRNA-mRNA network via bioinformatic analysis and experiment validation for STAD. [ABSTRACT FROM AUTHOR]

Cell-free RNA (cfRNA) allows assessment of health, status, and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases. Nevertheless, there is a lack of highly efficient and bias-free cfRNA isolation technologies due to the low abundance and instability of cfRNA. Here, we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids (containing cfRNA and viral RNA) in serum/plasma based on the inclusion of nucleic acids by metal-organic framework (MOF) materials, which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method. Importantly, the quality of cfRNA extracted by the MOF method is about 10-fold that of the kit method, and the MOF method isolates more than three times as many different RNA types as the kit method. The whole transcriptome mapping characteristics of cfRNA in serum from patients with liver cancer was described and a cfRNA signature with six cfRNAs was identified to diagnose liver cancer with high diagnostic efficiency (area under curve = 0.905 in the independent validation cohort) using this MOF method. Thus, this new MOF isolation technique will advance the field of liquid biopsy, with the potential to diagnose liver cancer. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP., Introduction Acute pancreatitis (AP) is an inflammatory disease that originates in the exocrine pancreas, where inactive pancreatic proenzymes become prematurely activated inside the pancreatic acinar cells (PACs), digesting the pancreas [...]