Combined analysis of secreted proteins and glycosylation identifies prognostic features in cholangiocarcinoma.

Secreted proteins are overexpressed in cholangiocarcinoma (CCA) and actively involved in promoting metastatic spread. Many of these proteins possess one or more sites of glycosylation and their various glycoforms have potential utility as prognostic or diagnostic biomarkers. To evaluate the effects of secretome glycosylation on patient outcome, we elucidated the glycosylation patterns of proteins secreted by parental and metastatic CCA cells using liquid chromatography-mass spectrometry. Our analysis showed that the secretome of CCA cells was dominated by fucosylated and fucosialylated glycoforms. Based on the glycan and protein profiles, we evaluated the combined prognostic significance of glycosyltransferases and secretory proteins. Significantly, genes encoding fucosyltransferases and sialyltransferases showed favorable prognostic effects when combined with secretory protein-coding gene expression, particularly thrombospondin-1. Combining these measures may provide improved risk assessment for CCA and be used to indicate stages of disease progression.

Nanoparticle-based nanocomposite coatings with postprocessing for enhanced antimicrobial capacity of polymeric film.

Bacterial adhesion and biofilm formation on surfaces pose a significant risk of microbial contamination and chronic diseases, leading to potential health complications. To mitigate this concern, the implementation of antibacterial coatings becomes paramount in reducing pathogen propagation on contaminated surfaces. To address this requirement, our study focuses on developing cost-effective and sustainable methods using polymer composite coatings. Copper and titanium dioxide nanoparticles were used to assess their active antimicrobial functions. After coating the surface with nanoparticles, four different combinations of two postprocessing treatments were performed. Intense pulsed light was utilized to sinter the coatings further, and plasma etching was applied to manipulate the physical properties of the nanocomposite-coated sheet surface. Bacterial viability was comparatively analyzed at four different time points (0, 30, 60, and 120 min) upon contact with the nanocomposite coatings. The samples with nanoparticle coatings and postprocessing treatments showed an above-average 84.82% mortality rate at 30 min and an average of 89.77% mortality rate at 120 min of contact. In contrast, the control sample, without nanoparticle coatings and postprocessing treatments, showed a 95% microbe viability after 120 min of contact. Through this study, we gained critical insights into effective strategies for preventing the spread of microorganisms on high-touch surfaces, thereby contributing to the advancement of sustainable antimicrobial coatings.

A PSGL-1 glycomimetic reduces thrombus burden without affecting hemostasis.

Events mediated by the P-selectin/PSGL-1 pathway play a critical role in the initiation and propagation of venous thrombosis by facilitating the accumulation of leukocytes and platelets within the growing thrombus. Activated platelets and endothelium express P-selectin, which binds P-selectin glycoprotein ligand-1 (PSGL-1) that is expressed on the surface of all leukocytes. We developed a pegylated glycomimetic of the N terminus of PSGL-1, PEG40-GSnP-6 (P-G6), which proved to be a highly potent P-selectin inhibitor with a favorable pharmacokinetic profile for clinical translation. P-G6 inhibits human and mouse platelet-monocyte and platelet-neutrophil aggregation in vitro and blocks microcirculatory platelet-leukocyte interactions in vivo. Administration of P-G6 reduces thrombus formation in a nonocclusive model of deep vein thrombosis with a commensurate reduction in leukocyte accumulation, but without disruption of hemostasis. P-G6 potently inhibits the P-selectin/PSGL-1 pathway and represents a promising drug candidate for the prevention of venous thrombosis without increased bleeding risk.

Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans.

Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.

Laser Sintering of CNT/PZT Composite Film.

The discovery of piezoelectricity inspired several sensing applications. For these applications, the thinness and flexibility of the device increase the range of implementations. A thin lead zirconate titanate (PZT) ceramic piezoelectric sensor is advantageous compared with bulk PZT or a polymer when it comes to having minimal impacts on dynamics and high-frequency bandwidth provided by low mass or high stiffness, while satisfying constraints regarding tight spaces. PZT devices have traditionally been thermally sintered inside a furnace and this process consumes large amounts of time and energy. To overcome such challenges, we employed laser sintering of PZT that focused the power onto selected areas of interest. Furthermore, non-equilibrium heating offers the opportunity to use low-melting-point substrates. Additionally, carbon nanotubes (CNTs) were mixed with PZT particles and laser sintered to utilize the high mechanical and thermal properties of CNTs. Laser processing was optimized for the control parameters, raw materials and deposition height. A multi-physics model of laser sintering was created to simulate the processing environment. Sintered films were obtained and electrically poled to enhance the piezoelectric property. The piezoelectric coefficient of laser-sintered PZT increased by approximately 10-fold compared with unsintered PZT. Moreover, CNT/PZT film displayed higher strength compared with PZT film without CNTs after the laser sintering while using less sintering energy. Thus, laser sintering can be effectively used to enhance the piezoelectric and mechanical properties of CNT/PZT films, which can be used in various sensing applications.

Simultaneous Clamping and Cutting Force Measurements with Built-In Sensors.

The intensity of the clamping force during milling operations is very important, because an excessive clamping force can distort the workpiece, while inadequate clamping causes slippage of the workpiece. Since the overall clamping force can be affected by the cutting forces throughout machining, it is necessary to monitor the change of clamping and the cutting forces during the process. This paper proposes a hybrid system in the form of a vise with built-in strain gauges and in-house-developed piezoelectric sensors for simultaneous measurement of clamping and cutting forces. Lead zirconate titanate (PZT) sensors are fabricated and embedded in a layered jaw to measure the dynamic forces of the machine tool. A cross-shaped groove within the jaw is designed to embed strain gauges, which predominantly measure the static clamping forces. Sensor fusion technology combining the signals of the strain gauges and PZT piezoelectric sensors is used to investigate the interactions between cutting forces and clamping forces. The results show average errors of 11%, 17%, and 6% for milling forces in X, Y, and Z directions, respectively; and 19% error for clamping forces, confirming the capability of the setup to monitor the forces in milling.

Development of Nanocomposite-Based Strain Sensor with Piezoelectric and Piezoresistive Properties.

Sensors provide aninterface between mechanical systems and the physical world. With the move towardsIndustry 4.0 and cyber-physical systems, demands for cost-effective sensors are rapidly increasing. Conventional sensors used for monitoring manufacturing processes are often bulky and need complex processes. In this study, a novel high-sensitive nanocomposite-based sensor is developed for measuring strain. The developed sensor is comprised of polyvinylidene fluoride (PVDF) as a piezoelectric polymer matrix, and embedded carbon nanotube (CNT) nanoparticles creating a conductive network. Exhibiting both piezoelectric and piezoresistive properties, the developed sensors are capable of strain measurement over a wide frequency band, including static and dynamic measurements. The piezoresistive and piezoelectric properties are fused to improve the overall sensitivity and frequency bandwidth of the sensor. To simulate the sensor, a 3D random walk model and a 2D finite element (FE) model are used to predict the electrical resistivity and the piezoelectric characteristics of the sensor, respectively. The developed models are verified with the experimental results. The developed nanocomposite sensors were employed for strain measurement of a cantilever beam under static load, impulse excitation, free and forced vibrations, collecting both piezoelectric and piezoresistive properties measurements. The obtained signals were fused and compared with those of a reference sensor. The results show that the sensor is capable of strain measurement in the range of 0⁻10 kHz, indicating its effectiveness at measuring both static and high frequency signals which is an important feature of the sensor.

Anomeric O-Functionalization of Carbohydrates for Chemical Conjugation to Vaccine Constructs.

Carbohydrates mediate a wide range of biological interactions, and understanding these processes benefits the development of new therapeutics. Isolating sufficient quantities of glycoconjugates from biological samples remains a significant challenge. With advances in chemical and enzymatic carbohydrate synthesis, the availability of complex carbohydrates is increasing and developing methods for stereoselective conjugation these polar head groups to proteins and lipids is critically important for pharmaceutical applications. The aim of this review is to provide an overview of commonly employed strategies for installing a functionalized linker at the anomeric position as well as examples of further transformations that have successfully led to glycoconjugation to vaccine constructs for biological evaluation as carbohydrate-based therapeutics.

Fragmented care in localized pancreatic cancer: Is commission on cancer accreditation associated with improved overall survival?

BACKGROUND: Prior studies of fragmentation of care in pancreatic cancer have not adjusted for indicators of hospital quality such as Commission on Cancer accreditation. The effect of fragmentation of care has not been well defined. METHODS: We queried the National Cancer Database to identify patients undergoing pancreaticoduodenectomy and distal pancreatectomy with perioperative systemic therapy for clinical stages I-III pancreatic cancer between 2006 and 2019. Patients who received systemic therapy at a center different than the center performing surgery were categorized as having fragmentation of care. Patients having fragmentation of care were further categorized on the basis of whether (fragmentation of care Commission on Cancer) or not (fragmentation of care non-Commission on Cancer) systemic therapy was administered at a facility accredited by the Commission on Cancer. RESULTS: A total of 11,732 patients met inclusion criteria; 5,668 (48.3%) underwent fragmentation of care, and 3,426 (29.2%) fragmentation of care non-Commission on Cancer. Patients undergoing fragmentation of care non-Commission on Cancer were less likely to receive neoadjuvant systemic therapy than those undergoing fragmentation of care Commission on Cancer or non-fragmented care (27.7% vs 40.1% vs 36.8%, P < .001). On Cox analysis, advanced age, comorbid disease, node-positive disease, and facility type were associated with risk of overall survival. Fragmentation of care was not (adjusted hazard ratio = 0.99, 95% confidence interval [0.94-1.06], P = .8). On Kaplan-Meier analysis, there were no significant differences in 5-year overall survival between treatment cohorts. CONCLUSION: In patients undergoing fragmentation of care for localized pancreatic cancer, those treated with systemic therapy in Commission on Cancer accredited facilities are more likely to be given neoadjuvant therapy but demonstrate no significant improvement in survival relative to those undergoing non-fragmented care or those undergoing fragmentation of care but receiving systemic therapy in nonaccredited facilities.

Does commission on cancer (CoC) accreditation mitigate the effect of care fragmentation on clinical outcome in localized rectal cancer?

BACKGROUND: Studies of fragmented care (FC) in rectal cancer have not adjusted for indicators of hospital quality and may misrepresent the effects of FC. METHODS: We queried the National Cancer Database to identify patients undergoing care for clinical stage II and III rectal adenocarcinoma between 2006 and 2019. Those undergoing FC were sub-categorized based on whether (FC CoC) or not (FC non-CoC) they received systemic therapy at CoC accredited facilities. RESULTS: 44,339 patients met inclusion criteria; 23,921 (54 â€‹%) underwent FC, 16,929 (71 â€‹%) FC non-CoC. Differences in utilization of neoadjuvant therapy (92.3 â€‹% vs 89.7 â€‹% vs 89.5 â€‹%, p â€‹< â€‹0.01) and 5-year overall survival (76.1 vs 75.5 vs 74.1 %, p â€‹< â€‹0.01) between treatment cohorts were marginal. CONCLUSION: In patients undergoing multimodality therapy for rectal cancer, care fragmentation is not associated with long-term clinical outcome. Decisions regarding where these patients go for systemic therapy may be safely made on the basis of ease of access.

Recent Advances in Organ-on-Chips Integrated with Bioprinting Technologies for Drug Screening.

Currently, the demand for more reliable drug screening devices has made scientists and researchers develop novel potential approaches to offer an alternative to animal studies. Organ-on-chips are newly emerged platforms for drug screening and disease metabolism investigation. These microfluidic devices attempt to recapitulate the physiological and biological properties of different organs and tissues using human-derived cells. Recently, the synergistic combination of additive manufacturing and microfluidics has shown a promising impact on improving a wide array of biological models. In this review, different methods are classified using bioprinting to achieve the relevant biomimetic models in organ-on-chips, boosting the efficiency of these devices to produce more reliable data for drug investigations. In addition to the tissue models, the influence of additive manufacturing on microfluidic chip fabrication is discussed, and their biomedical applications are reviewed.

Chemokine binding to PSGL-1 is controlled by O-glycosylation and tyrosine sulfation.

Protein glycosylation influences cellular recognition and regulates protein interactions, but how glycosylation functions alongside other common posttranslational modifications (PTMs), like tyrosine sulfation (sTyr), is unclear. We produced a library of 53 chemoenzymatically synthesized glycosulfopeptides representing N-terminal domains of human and murine P-selectin glycoprotein ligand-1 (PSGL-1), varying in sTyr and O-glycosylation (structure and site). Using these, we identified key roles of PSGL-1 O-glycosylation and sTyr in controlling interactions with specific chemokines. Results demonstrate that sTyr positively affects CCL19 and CCL21 binding to PSGL-1 N terminus, whereas O-glycan branching and sialylation reduced binding. For murine PSGL-1, interference between PTMs is greater, attributed to proximity between the two PTMs. Using fluorescence polarization, we found sTyr is a positive determinant for some chemokines. We showed that synthetic sulfopeptides are potent in decreasing chemotaxis of human dendritic cells toward CCL19 and CCL21. Our results provide new research avenues into the interplay of PTMs regulating leukocyte/chemokine interactions.

Optimized 3D Bioprinting Technology Based on Machine Learning: A Review of Recent Trends and Advances.

The need for organ transplants has risen, but the number of available organ donations for transplants has stagnated worldwide. Regenerative medicine has been developed to make natural organs or tissue-like structures with biocompatible materials and solve the donor shortage problem. Using biomaterials and embedded cells, a bioprinter enables the fabrication of complex and functional three-dimensional (3D) structures of the organs or tissues for regenerative medicine. Moreover, conventional surgical 3D models are made of rigid plastic or rubbers, preventing surgeons from interacting with real organ or tissue-like models. Thus, finding suitable biomaterials and printing methods will accelerate the printing of sophisticated organ structures and the development of realistic models to refine surgical techniques and tools before the surgery. In addition, printing parameters (e.g., printing speed, dispensing pressure, and nozzle diameter) considered in the bioprinting process should be optimized. Therefore, machine learning (ML) technology can be a powerful tool to optimize the numerous bioprinting parameters. Overall, this review paper is focused on various ideas on the ML applications of 3D printing and bioprinting to optimize parameters and procedures.

Rapid detection of ionic contents in water through sensor fusion and convolutional neural network.

Salt contents in soil or groundwater are one of the primary indicators to evaluate contamination levels. Electrical conductivity (EC) or salinity information from the conventional laboratory analysis is typically inefficient in delineating contamination. This study investigated a rapid determination of ionic contents in water through the combination of Ultraviolet Spectroscopy (UVS) and Electrochemical Impedance Spectroscopy (EIS), and the application of convolutional neural network (CNN). Various aqueous salt samples were prepared with Ca2+, K+, Na+, Cl-, Br-, SO42-, and HCO3- ions. Firstly, their spectral data obtained from UVS and EIS were analyzed. The spectral analysis showed that the data fusion of both spectroscopies provided more evidence to distinguish the ionic contents, consequently enhancing prediction performance of CNN. In turn, the fused spectra were handled with CNN to predict ionic contents. The result suggested the validity of the proposed method in detecting ionic contents by showing 48.6 mmol/kg RMSE and 0.95 R2 between actual and predicted ionic concentrations, which outperformed Partial Least Squares Regression (PLSR) and Random Forest. The detection of ionic contents beyond EC or salinity is advantageous since it provides more information on the soil and water contamination, and it facilitates tracking the contaminant sources. The proposed method has the potential to become more accurate with increased datasets and further optimization of CNN, which will further improve the practicability.

Identification and characterization of circulating immune complexes in IgA nephropathy.

The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes containing galactose-deficient IgA1 [Tn(+)IgA1] in the glomerular mesangium. Here, we report that novel anti-Tn circulating immune complexes (anti-Tn CICs) contain predominantly IgM, representing large macromolecular complexes of ~1.2 megadaltons to several megadalton sizes together with Tn(+)IgA1 and some IgG. These complexes are significantly elevated in sera of patients with IgAN, which contains higher levels of complement C3, compared to healthy individuals. Anti-Tn CICs are bioactive and induce specific proliferation of human renal mesangial cells. We found that these anti-Tn CICs can be dissociated with small glycomimetic compounds, which mimic the Tn antigen of Tn(+)IgA1, releasing IgA1 from anti-Tn CICs. This glycomimetic compound can also significantly inhibit the proliferative activity of anti-Tn CICs of patients with IgAN. These findings could enhance both the diagnosis of IgAN and its treatment, as specific drug treatments are now unavailable.

Fabrication of solderable intense pulsed light sintered hybrid copper for flexible conductive electrodes.

Additively printed circuits provide advantages in reduced waste, rapid prototyping, and versatile flexible substrate choices relative to conventional circuit printing. Copper (Cu) based inks along with intense pulsed light (IPL) sintering can be used in additive circuit printing. However, IPL sintered Cu typically suffer from poor solderability due to high roughness and porosity. To address this, hybrid Cu ink which consists of Cu precursor/nanoparticle was formulated to seed Cu species and fill voids in the sintered structure. Nickel (Ni) electroplating was utilized to further improve surface solderability. Simulations were performed at various electroplating conditions and Cu cathode surface roughness using the multi-physics finite element method. By utilizing a mask during IPL sintering, conductivity was induced in exposed regions; this was utilized to achieve selective Ni-electroplating. Surface morphology and cross section analysis of the electrodes were observed through scanning electron microscopy and a 3D optical profilometer. Energy dispersive X-ray spectroscopy analysis was conducted to investigate changes in surface compositions. ASTM D3359 adhesion testing was performed to examine the adhesion between the electrode and substrate. Solder-electrode shear tests were investigated with a tensile tester to observe the shear strength between solder and electrodes. By utilizing Cu precursors and novel multifaceted approach of IPL sintering, a robust and solderable Ni electroplated conductive Cu printed electrode was achieved.

Increased sanitization potency of hydrogen peroxide with synergistic O3 and intense pulsed light for non-woven polypropylene.

Supplies of respiratory masks have recently become a concern due to the onset of the SARS-CoV-2 pandemic. Sanitization and reuse of masks can alleviate high mask consumption and production stresses. In the present work, improved sanitization potency of vaporous hydrogen peroxide (VHP) treatment of resilient bacterial spores while retaining polymeric filter performance was explored. A batch fumigation chamber with hydrogen peroxide (H2O2) vapor and ozone (O3) is featured, followed by intense pulsed light (IPL) flash treatments. A resilient bacterial indicator, Geobacillus stearothermophilus (G. stearothermophilus), was utilized to compare the efficacy of various H2O2 concentrations in combination with O3 and IPL. It was found that exposure to 30 minutes of 4.01 L min-1 0.03% H2O2 aqueous vapor and 3 g h-1 O3 followed by 10 IPL flashes per side completely inactivated G. stearothermophilus. The xenon sourced IPL irradiation was found to synergistically enhance radical production and strengthen the complementary biocidal interaction of H2O2 with O3. Due to the synergistic effects, H2O2 was able to sanitize at a diluted concentration of 0.03% H2O2. The physical properties, such as surface potential, tensile strength, hydrophobicity, and filtration efficiency of >300 nm saline water aerosol of fibrous polypropylene (PP) sheets, were maintained. In addition, no residue of sanitizers was detected, thus confirming the biosafety and applicability of this method to disposable masks. Performance was benchmarked and compared with commercially available processes. The synergistic regime was found to achieve sterilization of G. stearothermophilus at drastically reduced H2O2 concentrations and in ambient conditions relative to commercial methods.

Corrigendum: Corrigendum to 'Enhanced Hybrid Copper Conductive Ink for Low Power Selective Laser Sintering'.

[This corrects the article DOI: 10.1016/j.promfg.2020.05.108.].

Highly selective and sensitive fluorescent zeolitic imidazole frameworks sensor for nitroaromatic explosive detection.

Nitroaromatic explosives, such as 2-4-6 trinitrotoluene (TNT) are dangerous materials that pose safety and environmental risks. Even though many sensors have been reported for the detection of nitroaromatic explosives, a facile, rapid, cost-effective sensor is still sought-after in the field. Here we demonstrate a facile and rapid method to synthesize a fluorescent metal-organic framework for the highly selective and sensitive detection of nitroaromatic explosives. Zeolitic imidazole framework-8 (ZIF-8) is synthesized and enhanced with fluorescent 8-hydroxyquinoline zinc (ZnQ). The synthesized material shows visible colour changes upon exposure to TNT from ivory to light red. In addition, fluorescence quenching is noted under UV illumination when the ZnQ@ZIF-8 is exposed to TNT. The ZnQ@ZIF-8-coated paper sensors show the highest fluorescence quenching at an emission wavelength of 455 nm with TNT concentration as low as 1 ppm. Therefore, the proposed strategy not only offers a fast and convenient protocol for selective detection of TNT but also offers great potential in practical applications, especially for airport/railway security inspection and prevention of terrorist attacks.

Intense Pulsed Light-Treated Near-Field Electrospun Nanofiber on a Quartz Tuning Fork for Multimodal Gas Sensors.

Accurate and portable gas sensors are required for environmental monitoring, locating leakages, and detecting trace chemical vapors or gases. Although many sensors have been developed, few can rapidly and selectively detect parts per million (ppm) concentration changes. In this work, we fabricate multimodal gas sensors by depositing a single nanocomposite fiber between the prongs of a quartz tuning fork (QTF). The resulting sensors are portable and integrate multimodal approaches by applying both chemo-mechanical sensing for sensitivity and electrochemical sensing for selectivity. Near-field electrospinning (NFES) produces a flexible and semiconductive nanocomposite fiber with ∼500 nm diameter that can be integrated into electronic systems as environmental gas sensors. Intense pulsed light (IPL) and sputter coating improve adhesion of the nanocomposite fiber onto a QTF. Furthermore, IPL offers improved sensing performance due to the higher specific surface area and reduction in polymer content. In this study, hydrogen gas (H2) is chosen as a target gas since it is a common energy source in fuel cell applications and byproduct in chemical reactions. An electrospinning solution containing polyaniline, multiwalled carbon nanotubes, and platinum nanoparticles is used to test H2 gas sensing performance. The resulting multimodal sensors are selective to hydrogen versus other gases and vapors including methane, hexane, toluene, ammonia, ethanol, carbon dioxide, and oxygen. Furthermore, the sensors detect ppm levels of hydrogen gas even in the presence of high humidity that typically hinders gas sensor performance. The development of this sensor leads to a new method for compact and portable multimodal gas sensing.