Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression.

Colorectal cancer (CRC) is the second most common malignant tumor world-wide. Analysis of the changes that occur during CRC progression could provide insights into the molecular mechanisms driving CRC development and identify improved treatment strategies. Here, we performed an integrated multi-omics analysis of 435 trace-tumor-samples from 148 colorectal cancer (CRC) patients, covering non-tumor (NT), intraepithelial neoplasia (IEN), infiltration (IFT), and advanced-stage CRC (A-CRC) phases. Proteogenomics analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidation phosphorylation in the IEN phase. Chr17q loss and chr20q gain were also mutually exclusive, occurred predominantly in the IEN and IFT phases, respectively, and impacted the cell cycle. Mutation of TP53 was frequent in the A-CRC phase and associated with tumor microenvironment, including increased extracellular matrix rigidity and stromal infiltration. Analysis of the profiles of CRC based on CMS and CRIS classifications revealed the progression paths of each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Additional comparison of molecular characteristics of CRC based on location showed that ANKRD22 amplification by chr10q23.31 gain enhanced glycolysis in the right-sided CRC. The AOM/DSS-induced CRC carcinogenesis mouse model in mice indicated that DDX5 deletion due to chr17q loss promoted CRC development, consistent with the findings from the patient samples. Collectively, this study provides an informative resource for understanding the driving events of different stages of CRC and identifying the potential therapeutic targets.

Rubber-glass nanocomposites fabricated using mixed emulsions.

Many composites consist of matrices of elastomers and nanoparticles of stiff materials. Such composites often have superior properties and are widely used. Embedding elastomers with nanoparticles commonly necessitates intense shear, using machines like extruders and roll millers, which cut polymer chains and degrade properties. Here, we prepare a rubber-glass nanocomposite by using two aqueous emulsions. Each emulsion is separately prepared with a single species of polymer chains. Each polymer chain is copolymerized with a small amount of silane coupling agent. Upon mixing the two emulsions, as water evaporates, the glassy particles retain the shape, and the rubbery particles change shape to form a continuous matrix. Subsequently, the silane coupling agent condensates, which cross-links the rubbery chains and interlinks the rubbery chains to the glassy particles. The cross-links and interlinks stabilize the nanostructure and lead to superior properties. The nanocomposite simultaneously achieves high modulus (~30 MPa), high toughness (~100 kJ m-2), and high fatigue threshold (~1,000 J m-2). The method of mixed emulsion is environmentally friendly and compatible with various open-air manufacturing processes, such as coat, cast, spray, print, and brush. Additionally, the silane coupling agent can interlink the nanocomposite to other materials. The method of mixed emulsion can be used to fabricate objects of complex shapes, fine features, and prescribed spatial variations of compositions.

Conducting Polymer Coatings Prepared by Mixed Emulsions Are Highly Conductive and Stable in Water.

An aqueous emulsion of conducting polymer is commonly applied on a substrate to form a coating after drying. The coating, however, disintegrates in water. This paper reports a coating prepared using a mixture of two emulsions: an aqueous emulsion of conducting polymer, and an aqueous emulsion of hydrophobic and rubbery chains copolymerized with silane coupling agents. When applied on a substrate and dried, particles of the mixed emulsion merge into a continuous film. While the conducting polymer forms percolated nanocrystals, the silane groups crosslink the rubbery chains and interlink the rubbery chains to the substrate. The percolated nanocrystals make the coating highly conductive. The covalent network of hydrophobic polymer chains stabilizes the coating in water. The high conductivity and stability in water may enable broad applications.

Amphiphilic monomers bridge hydrophobic polymers and water.

Water dissolves a hydrophilic polymer, but not a hydrophobic polymer. Many monomers of hydrophilic polymers, however, are amphiphilic, with a hydrophobic vinyl group for radical polymerization, as well as a hydrophilic group. Consequently, such an amphiphilic monomer may form solutions with both water and hydrophobic polymers. Ternary mixtures of amphiphilic monomer, hydrophobic polymer, and water have recently been used as precursors for interpenetrating polymer networks of hydrophilic polymers and hydrophobic polymers of unusual properties. However, the phase behavior of the ternary mixtures of amphiphilic monomer, hydrophobic polymer, and water themselves has not been studied. Here we mix the amphiphilic monomer acrylic acid, the hydrophobic polymer poly(methyl methacrylate), and water. In the mixture, the hydrophobic polymer can form various morphologies, including solution, micelle, gel, and polymer glass. We interpret these findings by invoking that the hydrophobic and hydrophilic groups of the amphiphilic monomer enable it to function as a bridge. That is, the hydrophobic functional group binds with the hydrophobic polymer, and the hydrophilic functional group binds with water. This picture leads to a simple modification to the Flory-Huggins theory, which agrees well with our experimental data. Amphiphilic monomers offer a rich area for further study for scientific insight, as well as for expanding opportunities to develop materials of self-assembled structures with unusual properties.

Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease.

Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age-the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case-control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis.

Composite elastomers with on-demand convertible phase separations achieve large and healable electro-actuation.

Phase separation has been widely exploited for fabricating structured functional materials. Generally, after being fabricated, the phase structure in a hybrid material system has been set at a specific length scale and remains unchanged during the lifespan of the material. Herein, we report a strategy to construct on-demand and reversible phase switches among homogenous, nano- and macro-phase separation states in a composite elastomer during its lifespan. We trigger the nanophase separation by super-saturating an elastomer matrix with a carefully selected small-molecule organic compound (SMOC). The nanoparticles of SMOC that precipitate out upon quenching will stretch the elastomer network, yet remain stably arrested in the elastomer matrix at low temperatures for a long time. However, at elevated temperatures, the nano-phase separation will transform into the macro-one. The elastic recovery will drive the SMOC onto the elastomer surface. The phase-separated structures can be reconfigured through the homogeneous solution state at a further elevated temperature. Taking advantage of the reversible phase switches leads to a novel strategy for designing high-performance dielectric elastomers. The in situ formed nanoparticles can boost the electro-actuation performance by eliminating electro-mechanical instability and lead to a very large actuation strain (∼146%). Once the actuator broke down, SMOC could on-demand be driven to the breakdown holes and heal the actuator.

Dielectric Polymer with Designable Large Motion under Low Electric Field.

Dielectric elastomers (DEs) can demonstrate fast and large in-plane expansion/contraction due to electric field (e-field)-induced Maxwell stress. For robotic applications, it is often necessary that the in-plane actuation is converted into out-of-plane motions with mechanical frames. Despite their performance appeal, their high driving e-field (20-100 V µm-1 ) demands bulky power accessories and severely compromises their durability. Here, a dielectric polymer that can be programmed into diverse motions actuated under a low e-field (2-10 V µm-1 ) is reported. The material is a crystalline dynamic covalent network that can be reconfigured into arbitrary 3D geometries. This gives rise to a geometric effect that markedly amplifies the actuation, leading to designable large motions when the dielectric polymer is heated above its melting temperature to become a DE. Additionally, the crystallization transition enables dynamic multimodal motions and active deployability. These attributes result in unique design versatility for soft robots.

Leveraging SOLOv2 model to detect heat stress of poultry in complex environments.

Heat stress is one of the most important environmental stressors facing poultry production. The presence of heat stress will reduce the antioxidant capacity and immunity of poultry, thereby seriously affecting the health and performance of poultry. The paper proposes an improved FPN-DenseNet-SOLO model for poultry heat stress state detection. The model uses Efficient Channel Attention (ECA) and DropBlock regularization to optimize the DenseNet-169 network to enhance the extraction of poultry heat stress features and suppress the extraction of invalid background features. The model takes the SOLOv2 model as the main frame, and uses the optimized DenseNet-169 as the backbone network to integrate the Feature Pyramid Network to detect and segment instances on the semantic branch and mask branch. In the validation phase, the performance of FPN-DenseNet-SOLO was tested with a test set consisting of 12,740 images of poultry heat stress and normal state, and it was compared with commonly used object detection models (Mask R CNN, Faster RCNN and SOLOv2 model). The results showed that when the DenseNet-169 network lacked the ECA module and the DropBlock regularization module, the original model recognition accuracy was 0.884; when the ECA module was introduced, the model's recognition accuracy improved to 0.919. Not only that, the recall, AP0.5, AP0.75 and mean average precision of the FPN-DenseNet-SOLO model on the test set were all higher than other networks. The recall is 0.954, which is 15, 8.8, and 4.2% higher than the recall of Mask R CNN, Faster R CNN and SOLOv2, respectively. Therefore, the study can achieve accurate segmentation of poultry under normal and heat stress conditions, and provide technical support for the precise breeding of poultry.

Adaptively reconstructing network of soft elastomers to increase strand rigidity: towards free-standing electro-actuation strain over 100.

Soft biological tissues and muscles composed of semiflexible networks exhibit rapid strain-hardening behaviors to protect them from accidental rupture. In contrast, synthetic soft elastomers, usually featuring flexible networks, lack such behaviors, leading to a notorious issue when applying them to a promising artificial muscle technology (dielectric elastomer, DE), that is electromechanical instability (EMI) induced premature breakdown. We report that a facile thermomechanical training method can adaptively reconstruct the network of a soft triblock copolymer elastomer to transform its flexible network strands into semiflexible ones without extra chemical modifications and additives so that the electro-actuation performance is significantly enhanced by avoiding EMI. The free-standing actuators of trained elastomers exhibit a large stable electro-actuation strain and a high theoretical energy density (133%, 307 kJ m-3 at 158.1 V µm-1), and the capacity of actuating at low-temperature environments (-15 °C).

[Electroacupuncture in the treatment of acute gastrointestinal injury in patients with severe traumatic brain injury: a prospective randomized controlled trial].

OBJECTIVE: To evaluate the therapeutic effect of electroacupuncture on acute gastrointestinal injury (AGI) in patients with severe traumatic brain injury (sTBI). METHODS: A prospective randomized controlled trial was conducted. 126 consecutively hospitalized patients with AGI after sTBI admitted to intensive care unit (ICU) of the First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine from January 2018 to December 2019 were enrolled. The patients were divided into observation group and control group by random number table. All the patients of two groups were given conventional treatment of western medicine for consecutive 7 days, including the treatments of primary diseases, indwelling nasogastric tube to extract gastric contents every 6 hours to determine gastric residual volume (GRV). When vital signs were basically stable, enteral nutrition (EN) was implemented and EN feeding amount and speed were adjusted according to GRV. On the basis of conventional western medicine treatment, the observation group was treated with electroacupuncture at Zusanli, Tianshu, Shangjuxu, Xiajuxu and Zhongwan, once in the morning and once in the evening, 30 minutes each time. The gastrointestinal function parameters including intra-abdominal pressure (IAP), serum diamine oxidase (DAO) and gastrointestinal failure (GIF) scores were observed before treatment and at day 3 and day 7 of treatment. The incidence of ICU hospital-acquired pneumonia (HAP-ICU), duration of mechanical ventilation (MV), length of ICU stay, 28-day mortality and adverse reactions of electroacupuncture were also observed in the two groups. Kaplan-Meier method was used for 28-day survival analysis. RESULTS: During the 7-day treatment and observation, 26 cases of 126 patients withdrew from the study, and 100 cases were actually enrolled, 50 cases in the observation group and 50 cases in the control group. IAP and DAO at day 3 of treatment in both groups were significantly lower than those before treatment [control group: IAP (cmH2O, 1 cmH2O = 0.098 kPa) was 13.75±2.76 vs. 18.11±3.97, DAO (U/L) was 129.88±24.81 vs. 158.01±22.64; observation group: IAP (cmH2O) was 13.56±2.19 vs. 18.50±3.54, DAO (U/L) was 129.11±29.32 vs. 159.36±28.65; all P < 0.01]. The gastrointestinal function parameters of the two groups improved gradually with the extension of treatment time, and the IAP, DAO and GIF scores at day 7 of treatment in the observation group were significantly lower than those in the control group [IAP (cmH2O): 11.28±3.61 vs. 12.68±3.23, DAO (U/L): 49.69±17.56 vs. 57.27±20.15, GIF score: 2.02±0.74 vs. 2.40±0.70, all P < 0.05). The duration of MV and the length of ICU stay in the observation group were significantly shorter than those in the control group [duration of MV (days): 15.72±4.60 vs. 18.08±4.54, length of ICU stay (days): 16.76±4.68 vs. 19.26±5.42, both P < 0.05], and the incidence of ICU-HAP and 28-day mortality were significantly lowered (12.0% vs. 30.0%, 22.0% vs. 32.0%, both P < 0.05). Survival analysis showed that the 28-day cumulative survival rate in the observation group was significantly higher than that in the control group (86.4% vs. 76.1%; Log-Rank test: χ2 = 37.954, P < 0.001). The patients in the observation group had no significant adverse reaction of electroacupuncture treatment. CONCLUSIONS: Electroacupuncture at corresponding acupoints can effectively improve gastrointestinal function in patients with AGI after sTBI, which is beneficial to shortening the length of ICU stay, promoting the recovery of the patients, and reducing the 28-day mortality.

Anisotropic electroactive elastomer for highly maneuverable soft robotics.

Dielectric elastomers (DEs) are promising electroactive artificial muscles for use in soft machines. However, achieving anisotropy and sub-kV actuation voltage remains a great challenge for DE actuators. Herein, we report a facile method to fabricate ultrathin anisotropic DE films of an amorphous triblock copolymer poly(styrene-b-butyl acrylate-b-styrene) (SBAS) for soft actuators. The modulus of anisotropic SBAS in one direction can be modulated from 0.3 MPa to 10.5 MPa, and the modulus in the orthogonal direction remains the same as that of the pristine film (0.3 MPa). The anisotropy endows soft DE actuators with the directional-preferred response to an applied electric field and programmable multiple actuation morphs. These anisotropic SBAS films allowed us to fabricate compact soft robotics with high maneuverability, including soft grippers for object manipulation and crawling robots with reversible moving ability under an actuation voltage around 800 V.

Traditional Chinese medicine bundle therapy for septic acute gastrointestinal injury: A multicenter randomized controlled trial.

OBJECTIVE: Current conventional treatments for sepsis associated with acute gastrointestinal injury (AGI) have limited efficacy. This study aimed to study traditional Chinese medicine (TCM) bundle therapy (based on TCM syndrome differentiation) as add-on to conventional treatments on the incidence of AGI and on the prognosis of patients with sepsis. DESIGN: This was a prospective multicenter randomized single-blind controlled trial. SETTING: Intensive care units (ICUs) of five university teaching hospitals in Zhejiang Province (China) from December 2012 to December 2014. INTERVENTIONS: The control group received conventional treatment for sepsis and AGI. The intervention group received the conventional treatment combined with TCM bundle therapy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day mortality. The secondary outcomes included the clinical indicators of sepsis. The 28-day mortality (35.3% vs. 48.3%, P = 0.01) and AGI-attributable mortality (15.1% vs. 36.2%, P = 0.02) in the intervention group were significantly lower than in controls. Duration of mechanical ventilation (17.4 ±â€¯10.4 vs. 19.9 ±â€¯11.1 days, P = 0.049) and duration of ICU stay (17.3 ±â€¯10.2 vs. 20.1 ±â€¯11.5 days) were significantly shorter in the intervention group compared with controls. On days 7 and 14, D-lactate, diamine oxidase, lipopolysaccharides, tumor necrosis factor-α, intra-abdominal pressure, and abdominal circumference in the intervention group were significantly lower than in controls, and serum MTL levels and bowel sounds were significantly higher (all P < 0.05). CONCLUSIONS: TCM bundle therapy in the early stage of sepsis can improve survival and the markers of gastrointestinal function in patients with sepsis associated with AGI.

Usefulness of metagenomic analysis in differential diagnosis for pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a rare ulcerative inflammatory dermatosis easily confused with wound infection following surgery. There have been seven case reports of PG occurring after total knee arthroplasty (TKA), all of which used routine tissue culture for differential diagnosis. Notably, all previous cases involved delayed diagnosis. We report a case of PG after TKA where we used shotgun metagenomics for differential diagnosis. Metagenomic analysis is a new method that can be used for pathogen detection; it is fast and sensitive, compared with traditional culture. Early application of metagenomic analysis in cases of suspicious wound infection after surgery can detect the pathogen of the infection for target therapy; it can also exclude infection for differential diagnosis of non-infectious diseases, such as autoimmune disorders. This case is presented to support the use of metagenomic analysis by surgeons and physicians for early and rapid differential diagnosis in patients who exhibit postoperative wound infections.

Shenfu injection alleviates intestine epithelial damage in septic rats.

BACKGROUND: Shenfu injection (SFI) promotes tissue microcirculation and oxygen metabolism. We aimed to assess its effects on intestinal epithelial damage in septic rats. METHODS: Fifty Sprague-Dawley rats were randomly divided into sham operation (Sham), sepsis (cecal ligation and puncture [CLP]), and SFI (low-dose, middle-dose, high-dose) groups (n = 10). For Sham animals, the abdominal cavity was opened and closed. For other groups, severe sepsis was induced by CLP. After surgery, saline (Sham and CLP rats) and SFI (treatment groups) were administered intraperitoneally. Samples were collected 12 hours after injection. Serum tumor necrosis factor α, diamineoxidase, and d-lactate levels and ileal mucosal damage and ultrastructural change, as well as protein and messenger RNA expression of tight junction markers, including Claudin-3 and zonula occludens protein-1 in ileal mucosa's epithelial cells, were assessed. All animal experiments were carried out under aseptic conditions. RESULTS: Compared with Sham animals, serum tumor necrosis factor α, DAO, and d-lactic acid levels in CLP animals were significantly higher; the ileal mucosal damage was more severe; and the expression levels of tight junction markers were significantly decreased. These indexes were significantly improved in SFI groups, in a concentration-dependent manner, compared with CLP rats. Sham animals displayed orderly arranged ileal mucosal villi, continuous tight junctions between epithelial cells, intact organelles, and microvilli. Compared with CLP animals (with obvious damage in these structures), an overt improvement was observed in SFI groups, especially in the high-dose SFI group, with tight junctions clearly visible between epithelial cells. CONCLUSIONS: Shenfu injection significantly alleviates intestinal epithelial damage in septic rats, in a dose-dependent manner.