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As an emerging neurodegenerative disease, Alzheimer's disease (AD) has become a leading cause of dementia in older adults. Visinin-like protein-1 (VILIP-1) is an increasingly used biomarker for AD besides the widely accepted Aβ

Anticancer peptides are promising drug candidates for cancer treatment, but the short circulation time and low delivery efficiency limit their clinical applications. Herein, we designed several lasso-like self-assembling anticancer peptides (LASAPs) integrated with multiple functions by a computer-aided approach. Among these LASAPs, LASAP1 (CRGDKGPDCGKAFRRFLGALFKALSHLL, 1-9 disulfide bond) was determined to be superior to the others because it can self-assemble into homogeneous nanoparticles and exhibits improved stability in serum. Thus, LASAP1 was chosen for proving the design idea. LASAP1 can self-assemble into nanoparticles displaying iRGD on the surface because of its amphiphilic structure and accumulate to the tumor site after injection because of the EPR effect and iRGD targeting to αVβ3 integrin. The nanoparticles could disassemble in the acidic microenvironment of the solid tumor, and cleaved by the overexpressed hK2, which was secreted by prostate tumor cells, to release the effector peptide PTP-7b (FLGALFKALSHLL), which was further activated by the acidic pH. Therefore, LASAP1 could target the orthotopic prostate tumor in the model mice after intraperitoneal injection and specifically inhibit tumor growth, with low systematic toxicity. Combining the multiple targeting functions, LASAP1 represents a promising design of self-delivery of peptide drugs for targeted cancer treatments.

A viscoelastic microfluidic device for shape-based separation of drug-treated Escherichia coli.

Water-in-oil-in-water (w/o/w) double emulsion (DE) encapsulation has been widely used as a promising platform technology for various applications in the fields of food, cosmetics, pharmacy, chemical engineering, materials science, and synthetic biology. Unfortunately, DEs formed by conventional emulsion generation approaches in most cases are highly polydisperse, making them less desirable for quantitative assays, controlled biomaterial synthesis, and entrapped ingredient release. Microfluidic devices can generate monodisperse DEs with controllable size, morphology, and production rate, but these generally require multistep fabrication processes and use of different solvents or bulky external instrumentation to pattern channel wettability. To overcome these limitations, we propose a rapid, simple, and inexpensive method to spatially pattern wettability in microfluidic devices for the continuous generation of monodisperse DEs. This is achieved by applying corona-plasma treatment to a select zone of the microchannel surface aided by a custom-designed corona resistance microchannel to strictly confine the plasma-treatment zone in a single polydimethylsiloxane (PDMS) microfluidic device. The properties of PDMS channel surfaces and key microchannel regions for DE generation are characterized under different levels of treatment. The size, shell thickness, and number of inner cores of generated DEs are shown to be highly controllable by tuning the phase flow rate ratios. Using DEs as templates, we successfully achieve a one-step generation and collection of gelatin microgels. Additionally, we demonstrate the biological capability of generated DEs by flow cytometric screening of the encapsulation and growth of yeast cells within DEs. We expect that the proposed approach will be widely used to create microfluidic devices with more complex wettability patterns.

Rheumatoid arthritis (RA) is a severe inflammatory autoimmune disease, but its treatment has been very difficult. Recently, stem cell-based therapies have opened up possibilities for the treatment of RA. However, the hostile RA pathological conditions impede the survival and differentiation of transplanted cells, and it remains challenging to fabricate a suitable biomaterial for the improvement of stem cells survival, engraftment, and function. Here we construct an optimal scaffold for RA management through the integration of 3D printed porous metal scaffolds (3DPMS) and infliximab-based hydrogels. The presence of rigid 3DPMS is appropriate for repairing large-scale bone defects caused by RA, while the designed infliximab-based hydrogels are introduced because of their self-healable, anti-inflammatory, biocompatible, and biodegradable properties. We demonstrate that the bioengineered composite scaffolds support adipose-derived mesenchymal stem cells (ADSCs) proliferation, differentiation, and extracellular matrix production in vitro. The composite scaffolds, along with ADSCs, are then implanted into the critical-sized bone defect in the RA rabbit model. In vivo results prove that the bioengineered composite scaffolds are able to down-regulate inflammatory cytokines, rebuild damaged cartilage, as well as improve subchondral bone repair. To the best of the authors' knowledge, this is the first time that using the antirheumatic drug to construct hydrogels for stem cell-based therapies, and this inorganic-organic hybrid system has the potential to alter the landscape of RA study.

The interrogation of single cells has revolutionised biology and medicine by providing crucial unparalleled insights into cell-to-cell heterogeneity. Flow cytometry (including fluorescence-activated cell sorting) is one of the most versatile and high-throughput approaches for single-cell analysis by detecting multiple fluorescence parameters of individual cells in aqueous suspension as they flow past through a focus of excitation lasers. However, this approach relies on the expression of cell surface and intracellular biomarkers, which inevitably lacks spatial and temporal phenotypes and activities of cells, such as secreted proteins, extracellular metabolite production, and proliferation. Droplet microfluidics has recently emerged as a powerful tool for the encapsulation and manipulation of thousands to millions of individual cells within pico-litre microdroplets. Integrating flow cytometry with microdroplet architectures surrounded by aqueous solutions (e.g., water-in-oil-in-water (W/O/W) double emulsion and hydrogel droplets) opens avenues for new cellular assays linking cell phenotypes to genotypes at the single-cell level. In this review, we discuss the capabilities and applications of droplet flow cytometry (DFC). This unique technique uses standard commercially available flow cytometry instruments to characterise or select individual microdroplets containing single cells of interest. We explore current challenges associated with DFC and present our visions for future development.

Yeast Saccharomyces cerevisiae (S. Cerevisiae) is one of the most attractive microbial species used for industrial production of value-added products and is an important model organism to understand the biology of the eukaryotic cells and humans. S. Cerevisiae has different shapes, such as spherical singlets, budded doublets, and clusters, corresponding to phases of the cell cycle, genetic, and environmental factors. The ability to obtain high-purity populations of uniform-shaped S. Cerevisiae cells is of significant importance for a wide range of applications in basic biological research and industrial processes. In this work, we demonstrate shape-based separation and enrichment of S. Cerevisiae using a coflow of viscoelastic and Newtonian fluids in a straight rectangular microchannel. Due to the combined effects of lift inertial and elastic forces, this label-free and continuous separation arises from shape-dependent migration of cells from the Newtonian to the non-Newtonian viscoelastic fluid. The lateral position of S. Cerevisiae cells with varying morphologies is found to be dependent on cell major axis. We also investigate the effects of sheath and sample flow rate, poly(ethylene oxide) (PEO) concentration and channel length on the performance of the viscoelastic microfluidic device for S. Cerevisiae enrichment and separation by shape. Moreover, the separation efficiency, cell extraction yield, and cell viability after sorting operations are studied.

Bone and bone-related diseases are the major cause of mobility hindrance and mortality in humans and there is no effective and safe treatment for most of them, especially, for bone and bone metastatic cancers. Bisphosphonates (BPs) are a group of small-molecule drugs for treating osteoporosis and bone cancers but have a very short half-life in circulation, requiring high doses and long-term repeat use that can cause severe side effects. Previous attempts of using nanoparticles to deliver BPs have issues of drug loading capacity and endosome escape/drug release. The present study reports the direct synthesis of BP nanoparticles by precipitating bone-favorable calcium ions and a third-generation BP, risedronate (Ca-RISNPs), to achieve high drug loading, endosomal release, and strong bone-targeting properties. The Ca-RISNPs are monodispersed with high stability at physiological pH but readily dissociate at endosomal pH conditions. They demonstrate strong penetration ability and uniform distribution in human bone and cartilage tissues and the superior drug and DNA (plasmid and oligo double strand DNA) delivery capacity in bone cells. These NPs also exhibit high specificity in killing tumor-associated macrophages (TAMs) and inhibit TAM-induced tumor cell migration. Collectively, our data indicate that this BP nanodrug platform has a great potential in managing bone-related diseases and cancers as a prolonged BP nanodrug and simultaneously as the bone-targeted drug delivery system.

The benefit of systemic treatment in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain. Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferation. A phase II trial (NCT02649361) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in refractory metastatic ESCC. This study (NCT03387904) aimed at comparing the effects and safety of Anlotinib Plus Irinotecan versus Irinotecan in patients with ESCC. Methods We conducted a prospective randomized, multicenter, phase II trial to compare the efficacy of Anlotinib Plus Irinotecan with Irinotecan in recurrent ESCC patients who had resistance to platinum or taxane-based chemotherapy. Eligible patients were adults with pathologically confirmed recurrent ESCC, and 82 patients were randomized 1:1 to Irinotecan (65 mg/m2/day 1 and day 8) with or without anlotinib (12 mg qd day 1 to 14) of a 21-day cycle till progression or intolerable. The primary endpoint is the disease control rate (DCR) and progression-free survival (PFS) and the secondary end points are objective response rate (ORR) and overall survival (OS). Results Between 13/1 2019 and 20/1 2020, a total of 43 patients were enrolled and randomly assigned to either the anlotinib plus irinotecan (n = 22) or the irinotecan group (n = 21).The mPFS was longer in trial group than in control group (89 days vs 66 days, HR = 0.447, P = 0.055). The Disease control rate (DCR) was 54.5% in trial group and 38.1% in the control group. The treatment-related adverse events (>10%) were fatigue (59.1%), nausea (50.0%), decreased appetite (36.4%), hoarseness (27.3%), thyroid-stimulating hormone elevation (22.7%), diarrhea (9.1%), and decreased lymphocytes count(9.1%) in trial group. Grade 3 AEs included fatigue (4.5% vs 4.8%), nausea (4.5% vs 0%) and diarrhea (4.5% vs 0%) in two groups. Conclusion Anlotinib plus irinotecan was similarly tolerable but prolonged PFS compared to irinotecan monotherapy as a second-line treatment in patients with recurrent ESCC.

Lipid raft microdomain of the plasma membrane is implicated in various biological and pathological processes. The involvement of lipid raft in T cell receptor (TCR) signal transduction has been widely studied, whereas the role of these structures in immunoreceptor signaling by DAP12 in natural killing (NK) cells remains largely unknown. Here, we demonstrate that phosphatidylinositol 4,5-bisphosphate (PIP2) lipid localized to lipid raft boundary in our coarse-grained (CG) model raft-forming membrane, and this negatively charged lipid recruits DAP12 homodimer into lipid raft boundary through protein-lipid interaction between the basic-rich regions and signaling immunoreceptor tyrosine-based activation motifs (ITAMs) of DAP12 and PIP2. Furthermore, our results reveal that the protein-lipid interaction can be disrupted by Ca2+, which competitively binds to PIP2 instead of DAP12. As a result, the cytoplasmic region of DAP12 homodimer is dissociated from the membrane back to the nonraft domain, and the ITAMs are exposed to allow further downstream signaling. These findings provide fundamental insights to understand the mechanism of signal transduction in NK cells regulated by membrane microenvironment.

Yeast

Microfluidic chips have demonstrated unparalleled abilities in droplet generation, including precise control over droplet size and monodispersity. And yet, their rather complicated microfabrication process and operation can be a barrier for inexperienced researchers, which hinders microdroplets from unleashing their potential in broader fields of research. Here, we attempt to remove this barrier by developing an integrated and modular revolving needle emulsion generator (RNEG) to achieve high-throughput production of uniformly sized droplets in an off-chip manner. The RNEG works by driving a revolving needle to pinch the dispersed phase in a minicentrifuge tube. The system is constructed using modular components without involving any microfabrication, thereby enabling user-friendly operation. The RNEG is capable of producing microdroplets of various liquids with diameters ranging from tens to hundreds of micrometres. We further examine the principle of operation using numerical simulations and establish a simple model to predict the droplet size. Moreover, by integrating curing and centrifugation processes, the RNEG can produce hydrogel microparticles and transfer them from an oil phase into a water phase. Using this ability, we demonstrate the encapsulation and culture of single yeast cells within hydrogel microparticles. We envisage that the RNEG can become a versatile and powerful tool for high-throughput production of emulsions to facilitate diverse biological and chemical research.

Yeast has been engineered for cost-effective organic acid production through metabolic engineering and synthetic biology techniques. However, cell growth assays in these processes were performed in bulk at the population level, thus obscuring the dynamics of rare single cells exhibiting beneficial traits. Here, we introduce the use of monodisperse picolitre droplets as bioreactors to cultivate yeast at the single-cell level. We investigated the effect of acid stress on growth and the effect of potassium ions on propionic acid tolerance for single yeast cells of different species, genotypes, and phenotypes. The results showed that the average growth of single yeast cells in microdroplets experiences the same trend to those of yeast populations grown in bulk, and microdroplet compartments do not significantly affect cell viability. This approach offers the prospect of detecting cell-to-cell variations in growth and physiology and is expected to be applied for the engineering of yeast to produce value-added bioproducts.

© 2020 IEEE. A method to realize low-cost, optically transparent, flexible, and unidirectional antennas is presented in this article. The key to the method is making a flexible transparent reflector made using a new method-injection of pure water into a flexible transparent cavity that is made out of polydimethylsiloxane (PDMS) polymer and integrating the flexible reflector with a flexible dipole made of transparent conducting mesh. This method is simple and inexpensive. Hence, it is useful for large-scale production of transparent, flexible, robust, and low-cost antennas as well as RF/microwave components for wearable body-area networks and other such systems that require flexible and transparent components. To validate the method, an antenna operating in the 2.45 GHz band was designed, fabricated, and tested under various conditions. Its measured gain is 3.2 dBi and efficiency is 51%. To the best of our knowledge, this is the first water-based transparent flexible antenna. Due to the shielding effect of the water-based reflector, it produces a low specific absorption rate (SAR) in the human body when it is worn, as expected from a unidirectional antenna. Furthermore, it is investigated and confirmed that the use of pure water in the reflector makes the antenna significantly more efficient as opposed to salt water.

Rheumatoid arthritis (RA) is a severe inflammatory autoimmune disease, but its treatment has been very difficult. Recently, stem cell-based therapies open new options for the treatment of RA. However, the hostile RA pathological conditions impede the survival and differentiation of transplanted cells, and it is still a great challenge to fabricate a new biomaterial for the improvement of stem cells survival, engraftment, and function. Here we construct a new scaffold for RA management through the integration of 3D printing porous metal scaffolds (3DPMS) and infliximab-based hydrogels. The presence of rigid 3DPMS is appropriate for large-scale bone defects caused by RA, while the designed infliximab-based hydrogels are introduced because of their self-healable, anti-inflammatory, biocompatible, and biodegradable properties. We demonstrate that the bioengineered composite scaffolds support adipose-derived mesenchymal stem cells (ADSCs) proliferation, differentiation, and extracellular matrix production in vitro. The composite scaffolds, along with ADSCs, are then implanted into the critical-sized bone defect in the RA rabbit model. In vivo results prove that the bioengineered composite scaffolds are able to depress inflammatory cytokines, rebuild damaged cartilage, as well as improve subchondral bone repair. To the best of the authors’ knowledge, this is the first time that using the antirheumatic drug to construct hydrogels for stem cell-based therapies, and this inorganic-organic hybrid system has the potential to alter the landscape for RA study.

This paper presents the fabrication and implementation of novel resistive sensors that were implemented for strain-sensing applications. Some of the critical factors for the development of resistive sensors are addressed in this paper, such as the cost of fabrication, the steps of the fabrication process which make it time-consuming to complete each prototype, and the inability to achieve optimised electrical and mechanical characteristics. The sensors were fabricated via magnetron sputtering of thin-film chromium and gold layer on the thin-film substrates at defined thicknesses. Sticky copper tapes were attached on the two sides of the sensor patches to form the electrodes. The operating principle of the fabricated sensors was based on the change in their responses with respect to the corresponding changes in their relative resistance as a function of the applied strain. The strain-induced characteristics of the patches were studied with different kinds of experiments, such as consecutive bending and pressure application. The sensors with 400 nm thickness of gold layer obtained a sensitivity of 0.0086 Ω/ppm for the pressure ranging between 0 and 400 kPa. The gauge factor of these sensors was between 4.9&ndash, 6.6 for temperatures ranging between 25 &deg, C and 55 &deg, C. They were also used for tactile sensing to determine their potential as thin-film sensors for industrial applications, like in robotic and pressure-mapping applications. The results were promising in regards to the sensors&rsquo, controllable film thickness, easy operation, purity of the films and mechanically sound nature. These sensors can provide a podium to enhance the usage of resistive sensors on a higher scale to develop thin-film sensors for industrial applications.

International audience; The paper presents the design and fabrication of a low-cost and easy-to-fabricate laser-induced graphene sensor together with its implementation for multi-sensing applications. Laser-irradiation of commercial polymer film was applied for photo-thermal generation of graphene. The graphene patterned in an interdigitated shape was transferred onto Kapton sticky tape to form the electrodes of a capacitive sensor. The functionality of the sensor was validated by employing them in electrochemical and strain-sensing scenarios. Impedance spectroscopy was applied to investigate the response of the sensor. For the electrochemical sensing, different concentrations of sodium sulfate were prepared, and the fabricated sensor was used to detect the concentration differences. For the strain sensing, the sensor was deployed for monitoring of human joint movements and tactile sensing. The promising sensing results validating the applicability of the fabricated sensor for multiple sensing purposes are presented.

Correction for ‘Modular off-chip emulsion generator enabled by a revolving needle’ by Yuxin Zhang et al., Lab Chip, 2020, 20, 4592–4599, DOI: 10.1039/D0LC00939C.

© 2020 IOP Publishing Ltd. One of the key challenges of the development of flexible and optically transparent antennas and sensors is the limited availability of the suitable materials. The traditional transparent conductors suffer from the drawback of instability in repeated bending and twisting and, thus, are not appropriate candidates for flexible transparent antenna development. Integration of flexible conductors with flexible substrates is another challenge not only for the realization of flexible transparent antennas but also for other types of flexible antennas, radio-frequency (RF) devices and sensors. Apart from the traditional flexible conductive and substrate materials, Conductive-Mesh-Polymer composite can be an efficient alternative for the realization of flexible transparent antennas. The polymer proposed here is Polydimethylsiloxane (PDMS), which is a flexible transparent substrate and the proposed transparent conductor is mesh-structured flexible conductive textile, VeilShield from Less EMF Inc. USA. Uncured PDMS is a sticky liquid and after curing, it makes a strong attachment with VeilShield. Due to the mesh-structured configuration of this conductor, uncured PDMS penetrates through the gaps among the threads and after curing of the PDMS, a composite is formed that has high optical transparency, flexibility and robustness against repeated mechanical deformations. For these attractive features, this composite material is a good candidate for the realization of optically transparent antennas, sensors and RF devices. In this paper, the feasibility of the VeilShield-PDMS composite towards the realization of flexible, robust and transparent antennas is assessed by investigating the morphology of the composite and exploring the RF performance of a microstrip patch antenna, fabricated using this composite, through 50 times bending cycle. The investigated results demonstrate the suitability of the VeilShield-PDMS composite towards the realization of flexible transparent antennas as well as other electronic components that are frequently exposed to repeated physical deformations.

The design, fabrication, and implementation of novel flexible sensors for electrochemical detection of multiple minerals such as calcium and magnesium in water bodies are presented in this paper. 3D printing technique was utilized to form the master moulds for developing the sensor prototype. The 3D printed moulds were developed initially using Poly Lactic Acid as the printing filament. Multi-Walled Carbon Nanotubes and Polydimethylsiloxane were used for forming the electrodes and substrates of the sensor patches, respectively. The casting of Multi-Walled Carbon Nanotubes powder and Polydimethylsiloxane were done on the 3D printed moulds. The electrodes were patterned in an interdigitated manner to operate on the impedimetric principle. The passive elements of the equivalent circuit of the interdigitated sensors were determined using Complex Non-Linear Least-Square Curve Fitting software. The total change in impedance concerning differently concentrated solutions was due to different resistive and reactive elements of the sensors. The resistance, reactance, and impedance values from the sensor patches were analysed during the experiment for calcium and magnesium solutions. Experimental outcomes proved that the sensor was able to differentiate various concentrations of calcium and magnesium ions between 1 ppm and 200 ppm solutions. The reproducibility, repeatability, and reusability of the sensors were also tested to propose the developed sensors as an alternative solution for the determination of calcium and magnesium ions from unknown samples.

Single-cell analysis is of critical importance in revealing cell-to-cell heterogeneity by characterizing individual cells and identifying minority sub-populations of interest. Droplet-based microfluidics has been widely used in the past decade to achieve high-throughput single-cell analysis. However, to maximize the proportion of single-cell emulsification is challenging due to cell sedimentation and aggregation. The purpose of this study was to investigate the influence of single-cell encapsulation and incubation through the use of neutral buoyancy. As a proof of concept, OptiPrep&trade, was used to create neutrally buoyant cell suspensions of THP-1, a human monocytic leukemia cell line, for single-cell encapsulation and incubation. We found that using a neutrally buoyant suspension greatly increased the efficiency of single-cell encapsulation in microdroplets and eliminated unnecessary cell loss. Moreover, the presence of OptiPrep&trade, was shown to not affect cellular viability. This method significantly improved the effectiveness of single-cell study in a non-toxic environment and is expected to broadly facilitate single-cell analysis.