Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural insights from a computational model.

Lung cancer is one of the leading causes of cancer-related deaths worldwide and is characterized by hijacking immune system for active growth and aggressive metastasis. Neutrophils, which in their original form should establish immune activities to the tumor as a first line of defense, are undermined by tumor cells to promote tumor invasion in several ways. In this study, we investigate the mutual interactions between the tumor cells and the neutrophils that facilitate tumor invasion by developing a mathematical model that involves taxis-reaction-diffusion equations for the critical components in the interaction. These include the densities of tumor and neutrophils, and the concentrations of signaling molecules and structure such as neutrophil extracellular traps (NETs). We apply the mathematical model to a Boyden invasion assay used in the experiments to demonstrate that the tumor-associated neutrophils can enhance tumor cell invasion by secreting the neutrophil elastase. We show that the model can both reproduce the major experimental observation on NET-mediated cancer invasion and make several important predictions to guide future experiments with the goal of the development of new anti-tumor strategies. Moreover, using this model, we investigate the fundamental mechanism of NET-mediated invasion of cancer cells and the impact of internal and external heterogeneity on the migration patterning of tumour cells and their response to different treatment schedules.

Revisiting the Classical Wide-Bandgap HOMO and Random Copolymers for Indoor Artificial Light Photovoltaics.

Organic indoor photovoltaics (IPVs) are attractive energy harvesting devices for low-power consumption electronic devices and the Internet of Things (IoTs) owing to their properties such as being lightweight, semitransparent, having multicoloring capability, and flexibility. It is important to match the absorption range of photoactive materials with the emission spectra of indoor light sources that have a visible range of 400-700 nm for IPVs to provide sustainable, high-power density. To this end, benzo[1,2-b:4,5-b']dithiophene-based homopolymer (PBDTT) is synthesized as a polymer donor, which is a classical material that has a wide bandgap with a deep highest occupied molecular orbitals (HOMO) level, and a series of random copolymers by incorporating thieno[3,4-c]pyrrole-4,6,-dione (TPD) as a weak electron acceptor unit in PBDTT. The composition of the TPD unit is varied to fine tune the absorption range of the polymers; the polymer containing 70% TPD (B30T70) perfectly covers the entire range of indoor lamps such as light-emitting diodes (LEDs) and fluorescent lamp (FL). Consequently, B30T70 shows a dramatic enhancement of the power conversion efficiency (PCE) from 1-sun (PCE: 6.0%) to the indoor environment (PCE: 18.3%) when fabricating organic IPVs by blending with PC71 BM. The simple, easy molecular design guidelines are suggested to develop photoactive materials for efficient organic IPVs.

Intracellular Zn2+ Signaling Facilitates Mossy Fiber Input-Induced Heterosynaptic Potentiation of Direct Cortical Inputs in Hippocampal CA3 Pyramidal Cells.

Repetitive action potentials (APs) in hippocampal CA3 pyramidal cells (CA3-PCs) backpropagate to distal apical dendrites, and induce calcium and protein tyrosine kinase (PTK)-dependent downregulation of Kv1.2, resulting in long-term potentiation of direct cortical inputs and intrinsic excitability (LTP-IE). When APs were elicited by direct somatic stimulation of CA3-PCs from rodents of either sex, only a narrow window of distal dendritic [Ca2+] allowed LTP-IE because of Ca2+-dependent coactivation of PTK and protein tyrosine phosphatase (PTP), which renders non-mossy fiber (MF) inputs incompetent in LTP-IE induction. High-frequency MF inputs, however, could induce LTP-IE at high dendritic [Ca2+] of the window. We show that MF input-induced Zn2+ signaling inhibits postsynaptic PTP, and thus enables MF inputs to induce LTP-IE at a wide range of [Ca2+]i values. Extracellular chelation of Zn2+ or genetic deletion of vesicular zinc transporter abrogated the privilege of MF inputs for LTP-IE induction. Moreover, the incompetence of somatic stimulation was rescued by the inhibition of PTP or a supplement of extracellular zinc, indicating that MF input-induced increase in dendritic [Zn2+] facilitates the induction of LTP-IE by inhibiting PTP. Consistently, high-frequency MF stimulation induced immediate and delayed elevations of [Zn2+] at proximal and distal dendrites, respectively. These results indicate that MF inputs are uniquely linked to the regulation of direct cortical inputs owing to synaptic Zn2+ signaling.SIGNIFICANCE STATEMENT Zn2+ has been mostly implicated in pathological processes, and the physiological roles of synaptically released Zn2+ in intracellular signaling are little known. We show here that Zn2+ released from hippocampal mossy fiber (MF) terminals enters postsynaptic CA3 pyramidal cells, and plays a facilitating role in MF input-induced heterosynaptic potentiation of perforant path (PP) synaptic inputs through long-term potentiation of intrinsic excitability (LTP-IE). We show that the window of cytosolic [Ca2+] that induces LTP-IE is normally very narrow because of the Ca2+-dependent coactivation of antagonistic signaling pairs, whereby non-MF inputs become ineffective in inducing excitability change. The MF-induced Zn2+ signaling, however, biases toward facilitating the induction of LTP-IE. The present study elucidates why MF inputs are more privileged for the regulation of PP synapses.

The influence of sequential ligand exchange and elimination on the performance of P3HT: CdSe quantum dot hybrid solar cells.

We report on a sequential ligand exchange and elimination process for the fast and easy surface modification of CdSe quantum dots (QDs) in order to improve the electronic interaction between poly(3-hexylthiophene) (P3HT) and CdSe QDs in P3HT:CdSe hybrid solar cells. We systematically investigated the influence of surface treatment on the insulating ligand shell of CdSe QDs using (1)H-NMR analysis, and correlated their influence on the photovoltaic properties of P3HT:CdSe hybrid solar cells. A decrease in the average thickness of the ligand shells directly improved carrier transport properties. Moreover, the presence of remnant 1-hexylamine ligands provided efficient surface trap passivation. As a result, overall solar cell performance (especially fill factor and power conversion efficiency) was enhanced and the recombination mechanism was dominated by monomolecular recombination due to enhanced carrier collection length (l(C0)).

Optimal strategies of oncolytic virus-bortezomib therapy via the apoptotic, necroptotic, and oncolysis signaling network.

Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to the accumulation of unfolded proteins that induce apoptosis. On the other hand, virotherapy uses genetically modified oncolytic viruses (OVs) to infect cancer cells, trigger cell lysis, and activate anti-tumor response. Despite progress in cancer treatment, identifying administration protocols for therapeutic agents remains a significant concern, aiming to strike a balance between efficacy, minimizing toxicity, and administrative costs. In this work, optimal control theory was employed to design a cost-effective and efficient co-administration protocols for bortezomib and OVs that could significantly diminish the population of cancer cells via the cell death program with the NF$ \kappa $B-BAX-RIP1 signaling network. Both linear and quadratic control strategies were explored to obtain practical treatment approaches by adapting necroptosis protocols to efficient cell death programs. Our findings demonstrated that a combination therapy commencing with the administration of OVs followed by bortezomib infusions yields an effective tumor-killing outcome. These results could provide valuable guidance for the development of clinical administration protocols in cancer treatment.

Origin of the mixing ratio dependence of power conversion efficiency in bulk heterojunction organic solar cells with low donor concentration.

We studied the origin of the improvement in device performance of thermally evaporated bulk heterojunction organic photovoltaic devices (OPVs) with low donor concentration. Samples with three different donor-acceptor mixing ratios, 0:10 (C70-only), 1:9 (low-doped) and 3:7 (high-doped), were fabricated with 1,1-bis-(4-bis(4-methyl-phenyl)-amino-phenyl)-cyclohexane (TAPC):C70. The power conversion efficiencies (PCEs) of these samples were 1.14%, 2.74% and 0.69%, respectively. To determine why the low-doped device showed a high PCE, we measured various properties of the devices in terms of the effective energy band gap, activation energy, charge carrier mobility and recombination loss. We found that the activation energy for charge carrier transport was increased as we increased the TAPC concentration in the blends whereas the hole and electron mobilities became more balanced as the TAPC concentration was increased. Furthermore, the recombination loss parameter alpha (from the light intensity dependence) remained alpha to approximately 0.9 in the low-doped device, but it decreased to alpha to approximately 0.77 in the high-doped device, indicating a large recombination loss as a result of space charge. Therefore, the improved PCE of low-doped OPVs can be attributed to the balance between carrier mobilities with no increase in recombination loss.

Bright and efficient full-color colloidal quantum dot light-emitting diodes using an inverted device structure.

We report highly bright and efficient inverted structure quantum dot (QD) based light-emitting diodes (QLEDs) by using solution-processed ZnO nanoparticles as the electron injection/transport layer and by optimizing energy levels with the organic hole transport layer. We have successfully demonstrated highly bright red, green, and blue QLEDs showing maximum luminances up to 23,040, 218,800, and 2250 cd/m(2), and external quantum efficiencies of 7.3, 5.8, and 1.7%, respectively. It is also noticeable that they showed turn-on voltages as low as the bandgap energy of each QD and long operational lifetime, mainly attributed to the direct exciton recombination within QDs through the inverted device structure. These results signify a remarkable progress in QLEDs and offer a practicable platform for the realization of QD-based full-color displays and lightings.

All-Solution-Processed Quantum Dot Light-Emitting Diode Using Phosphomolybdic Acid as Hole Injection Layer.

In this study, we investigate phosphomolybdic acid (PMA), which allows solution processing of quantum dot light-emitting diodes. With its low cost, easy solution processes, and excellent physical and optical properties, PMA is a potential candidate as the hole injection layer (HIL) in optoelectronic devices. We evaluate the physical and electrical properties of PMA using various solvents. The surface morphology of the PMA film was improved using a solvent with appropriate boiling points, surface tension, and viscosity to form a smooth, pinhole-free film. The energy level was regulated according to the solvent, and PMA with the appropriate electronic structure provided balanced charge carrier transport in quantum dot electroluminescent (QD-EL) devices with enhanced efficiency. A device using PMA dissolved in cyclohexanone was demonstrated to exhibit improved efficiency compared to a device using PEDOT:PSS, which is a conventional solution HIL. However, the stability of PMA was slightly poorer than PEDOT:PSS; there needs to be further investigation.

The bifidogenic effects and dental plaque deformation of non-digestible isomaltooligosaccharides synthesized by dextransucrase and alternansucrase.

Non-digestible isomaltooligosaccharides (NDIMOS) are functional food and beverage ingredients that contributed to human health benefits through metabolism of gastrointestinal microorganism. In this study, NDIMOS were synthesized by combine dextransucrase from Leuconostoc mesenteroides B512F/KM and alternansucrase from L. mesenteroides NRRL 1355CF10/KM using sucrose as substrate and maltose as acceptor. Their digestibility was confirmed by using digestive enzymes including α-amylase and amyloglucosidase. NDIMOS inhibited insoluble glucan formation through mutansucrase from Streptococcus mutans. The bifidogenic effect of NDIMOS was investigated by growth of four strains of Bifidobacterium in MRS broth containing NDIMOS, compared with MRS broth contain glucose and negative control. Additionally, Bifidobacterium bifidum or Bifidobacterium adolescentis inhibited the growth of Salmonella enterica serovar typhimurium when they were co-cultivation in MRS broth containing NDIMOS. These results suggested that NDIMOS is potential functional ingredient for food, beverage, and pharmaceutical application.

Solution-processable zinc oxide for the polymer solar cell based on P3HT:PCBM.

The device performance of polymer solar cells with zinc oxide (ZnO) nanoparticles inserted as an electron injection layer between the poly(3-hexylthiopene) (P3HT):phenyl-C60-butyric acid methyl ester (PCBM) active layer and the Al electrode was studied. The polymer solar cell consists of molybdenum-oxide (MoO3) as a hole injection layer, P3HT:PCBM bulk heterojunction as an active layer, and ZnO NPs as an electron injection layer. The ZnO layer was formed from a precursor solution on the top part of the P3HT:PCBM film (1:0.8 weight ratio) via sol-gel spin-coating, and was annealed at a low temperature (150 degrees C). The crystallinity, the atomic ratio of Zn and O, the absorption spectra, and the surface morphology of the ZnO thin films were studied. The device with a ZnO layer showed 9-11% higher J(SC) and 8-9% higher PCE compared to the devices without a ZnO layer. These improved device properties are attributed to the efficient electron extraction and the decreased reflectivity owing to the use of a ZnO layer.

Multicolored light-emitting diodes based on all-quantum-dot multilayer films using layer-by-layer assembly method.

A systematic analysis of the exciton-recombination zone within all-quantum dot (QD) multilayer films prepared by a layer-by-layer assembly method was made, using sensing QD layers in QD-based light-emitting diodes (QLEDs). Large area practical multicolored colloidal QLEDs were also demonstrated by patterning and placing variously colored QDs (red, orange, yellow-green, and green) in the exciton-recombination zone.

Mathematical model of STAT signalling pathways in cancer development and optimal control approaches.

In various diseases, the STAT family display various cellular controls over various challenges faced by the immune system and cell death programs. In this study, we investigate how an intracellular signalling network (STAT1, STAT3, Bcl-2 and BAX) regulates important cellular states, either anti-apoptosis or apoptosis of cancer cells. We adapt a mathematical framework to illustrate how the signalling network can generate a bi-stability condition so that it will induce either apoptosis or anti-apoptosis status of tumour cells. Then, we use this model to develop several anti-tumour strategies including IFN-ß infusion. The roles of JAK-STATs signalling in regulation of the cell death program in cancer cells and tumour growth are poorly understood. The mathematical model unveils the structure and functions of the intracellular signalling and cellular outcomes of the anti-tumour drugs in the presence of IFN-ß and JAK stimuli. We identify the best injection order of IFN-ß and DDP among many possible combinations, which may suggest better infusion strategies of multiple anti-cancer agents at clinics. We finally use an optimal control theory in order to maximize anti-tumour efficacy and minimize administrative costs. In particular, we minimize tumour volume and maximize the apoptotic potential by minimizing the Bcl-2 concentration and maximizing the BAX level while minimizing total injection amount of both IFN-ß and JAK2 inhibitors (DDP).

Study of buffer layer thickness on bulk heterojunction solar cell.

We studied the effect of the buffer layer (molybdenum-oxide (MoO3)) thickness on the performance of organic solar cell based on blends of poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C61 butyric acid methyl ester fullerene derivative (PCBM). The thickness of MoO3 was varied from 1 nm to 30 nm for optimization of device performance. The photocurrent-voltage and impedance spectroscopy were measured under dark and AM1.5G solar simulated illumination of 100 mW/cm2 for exploring the role of the buffer layer thickness on carrier collection at an anode. The MoO3 thickness of the optimized device (efficiency approximately 3.7%) was found to be in the range of 5 approximately 10 nm. The short-circuit current and the shunt resistance decrease gradually for thicker MoO3 layer over 5 nm. The device can be modeled as the combination of three RC parallel circuits (each one for the active layer, buffer layer and interface between the buffer layer and the active layer) in series with contact resistance (Rs approximately 60 ohm).

Collective invasion of glioma cells through OCT1 signalling and interaction with reactive astrocytes after surgery.

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with a short median survival time. GBM is characterized by the hallmarks of aggressive proliferation and cellular infiltration of normal brain tissue. miR-451 and its downstream molecules are known to play a pivotal role in regulation of the balance of proliferation and aggressive invasion in response to metabolic stress in the tumour microenvironment (TME). Surgery-induced transition in reactive astrocyte populations can play a significant role in tumour dynamics. In this work, we develop a multi-scale mathematical model of miR-451-LKB1-AMPK-OCT1-mTOR pathway signalling and individual cell dynamics of the tumour and reactive astrocytes after surgery. We show how the effects of fluctuating glucose on tumour cells need to be reprogrammed by taking into account the recent history of glucose variations and an AMPK/miR-451 reciprocal feedback loop. The model shows how variations in glucose availability significantly affect the activity of signalling molecules and, in turn, lead to critical cell migration. The model also predicts that microsurgery of a primary tumour induces phenotypical changes in reactive astrocytes and stem cell-like astrocytes promoting tumour cell proliferation and migration by Cxcl5. Finally, we investigated a new anti-tumour strategy by Cxcl5-targeting drugs. This article is part of the theme issue 'Multi-scale analysis and modelling of collective migration in biological systems'.

Double Metal Oxide Electron Transport Layers for Colloidal Quantum Dot Light-Emitting Diodes.

The performance of colloidal quantum dot light-emitting diodes (QD-LEDs) have been rapidly improved since metal oxide semiconductors were adopted for an electron transport layer (ETL). Among metal oxide semiconductors, zinc oxide (ZnO) has been the most generally employed for the ETL because of its excellent electron transport and injection properties. However, the ZnO ETL often yields charge imbalance in QD-LEDs, which results in undesirable device performance. Here, to address this issue, we introduce double metal oxide ETLs comprising ZnO and tin dioxide (SnO2) bilayer stacks. The employment of SnO2 for the second ETL significantly improves charge balance in the QD-LEDs by preventing spontaneous electron injection from the ZnO ETL and, as a result, we demonstrate 1.6 times higher luminescence efficiency in the QD-LEDs. This result suggests that the proposed double metal oxide ETLs can be a versatile platform for QD-based optoelectronic devices.

Colloidal quantum dot light-emitting diodes employing solution-processable tin dioxide nanoparticles in an electron transport layer.

Colloidal quantum-dot-based light-emitting diodes (QD-LEDs) have gained tremendous attention as great candidates to potentially replace current emissive display technologies. The luminescence efficiency of a QD LED has increased rapidly in the past decade; this was triggered by the use of metal oxides in the charge transport layers, particularly zinc oxide (ZnO) for the electron transport layer (ETL). However, the ZnO ETL often results in undesirable device performance such as efficiency roll-off and poor device stability because of excessive electron injection into the QD emissive layer. Here, we explore solution-processable tin dioxide (SnO2) nanoparticles (NPs) as alternatives to ZnO NPs for the ETL in QD-LEDs. We evaluated the thin-film quality and electrical performance of SnO2 NPs and then applied them to the ETL for constructing QD-LEDs. As a result of the smooth surface morphology, moderate electron-transport ability, and lower carrier concentration compared to ZnO NPs, the QD-LED with SnO2 NP-ETL exhibited improved performance in terms of lower turn-on and operating voltages, maximum luminance, improved efficiency roll-off, and improved power efficiency over the reference device with the ZnO NP-ETL. This shows promising potential for SnO2 NPs in optoelectronic applications.

Enhanced Operating Temperature Stability of Organic Solar Cells with Metal Oxide Hole Extraction Layer.

Organic solar cells (OSCs) are promising renewable energy sources for replacing fossil fuels. The power conversion efficiency (PCE) of OSCs has increased based on tremendous effort in material and device engineering. Still, the stability of OSC, such as long lifetime, negative temperature coefficient, must be enhanced for commercialization. In this study, we investigated OSC performance at a high operating temperature near 300-420 K, which are typical temperature regions in photovoltaic applications, with a different hole-extraction layer (HEL). The metal oxide-based HEL, MoO3, exhibited stable operating properties with a PCE drop rate of -0.13%/°C, as compared to polymeric HEL, PEDOT:PSS (-0.20%/°C). This performance reduction of polymeric HEL originated from the degradation of the interface in contact with PEDOT:PSS, as compared to the robust inorganic metal oxide HEL.

Deep blue light-emitting diodes based on Cd1-xZnx S @ ZnS quantum dots.

We demonstrate deep blue light-emitting diodes based on chemically synthesized Cd(1-x)Zn(x) S @ ZnS quantum dots (QDs). Composite films of poly-(N,N'-bis(4-butylphenyl)-N,N'-bis(phenyl)benzidine) (poly-TPD) and 4,4',N,N'-diphenylcarbazole (CBP) are employed for facilitated hole injection into Cd(1-x)Zn(x) S @ ZnS QDs and uniform QD deposition. The fabricated devices possess moderate turn-on voltage (6 V) and external quantum efficiency (0.1-0.3%), and exhibit color-saturated blue emission with a narrow spectral bandwidth of full width at half maximum <25 nm (Commission Internationale de l'Eclairage (CIE) coordinates of (0.169, 0.024) and (0.156, 0.028) for devices with electroluminescence (EL) lambda(max) at 434 and 454 nm, respectively). Most of the emission originates from the Cd(1-x)Zn(x) S @ ZnS QD layers (99% of the total EL emission).

Synergistic Effects of Bortezomib-OV Therapy and Anti-Invasive Strategies in Glioblastoma: A Mathematical Model.

It is well-known that the tumor microenvironment (TME) plays an important role in the regulation of tumor growth and the efficacy of anti-tumor therapies. Recent studies have demonstrated the potential of combination therapies, using oncolytic viruses (OVs) in conjunction with proteosome inhibitors for the treatment of glioblastoma, but the role of the TME in such therapies has not been studied. In this paper, we develop a mathematical model for combination therapies based on the proteosome inhibitor bortezomib and the oncolytic herpes simplex virus (oHSV), with the goal of understanding their roles in bortezomib-induced endoplasmic reticulum (ER) stress, and how the balance between apoptosis and necroptosis is affected by the treatment protocol. We show that the TME plays a significant role in anti-tumor efficacy in OV combination therapy, and illustrate the effect of different spatial patterns of OV injection. The results illustrate a possible phenotypic switch within tumor populations in a given microenvironment, and suggest new anti-invasion therapies.

Role of tumor-associated neutrophils in regulation of tumor growth in lung cancer development: A mathematical model.

Neutrophils display rapid and potent innate immune responses in various diseases. Tumor-associated neutrophils (TANs) however either induce or overcome immunosuppressive functions of the tumor microenvironment through complex tumor-stroma crosstalk. We developed a mathematical model to address the question of how phenotypic alterations between tumor suppressive N1 TANS, and tumor promoting N2 TANs affect nonlinear tumor growth in a complex tumor microenvironment. The model provides a visual display of the complex behavior of populations of TANs and tumors in response to various TGF-ß and IFN-ß stimuli. In addition, the effect of anti-tumor drug administration is incorporated in the model in an effort to achieve optimal anti-tumor efficacy. The simulation results from the mathematical model were in good agreement with experimental data. We found that the N2-to-N1 ratio (N21R) index is positively correlated with aggressive tumor growth, suggesting that this may be a good prognostic factor. We also found that the antitumor efficacy increases when the relative ratio (Dap) of delayed apoptotic cell death of N1 and N2 TANs is either very small or relatively large, providing a basis for therapeutically targeting prometastatic N2 TANs.