Robust competitive facility location model with uncertain demand types.

In competitive settings, firms locate their facilities according to customers' behavior to maximize their market share. A common behavior is consuming from different motivations: one is for convenient demand, and the other is for quality demand. In this behavioral pattern, consumers patronize facilities within convenience for some demands, and patronize high quality facilities beyond convenience range for other demands. This behavior has never been included in competitive facility location problems. Given several other companies' facilities in the market offering similar products or services, we study how a new entrant company can locate facilities based on this customer behavior to maximize its market share. A two-level robust model for the new entrant company is proposed to locate its facilities by taking into account the uncertainty of the types of customers' demands. For medium size problems, we propose an equivalent mixed binary linear programming to obtain exact solutions. For large size problems, an exact algorithm (GCKP-A) for solving the inner-level model is given first by exploring the optimal solution. Then a heuristic algorithm is proposed by imbedding (GCKP-A) and 2-opt strategy into the framework of the improved ranking-based algorithm. The performance of the proposed heuristic algorithm is checked for different size problems. The sensitivity analysis of a quasi-real example shows that: (1) in most cases, the uncertainty between two types of demands does not affect the location scheme; (2) the convenience range, the quality range and the quality threshold play an important role in the market share of the new entrant company.

Self-Reinforced Cancer Targeting (SRCT) Depending on Reciprocally Enhancing Feedback between Targeting and Therapy.

Conventional cancer targeting methodology needs to be reformed to overcome the intrinsic barriers responsible for poor targeting efficiency. This study describes a concept of self-reinforced cancer targeting (SRCT) by correlating targeting with therapy in a reciprocally enhancing manner. SRCT is achieved on the basis of two prerequisites: (1) target molecules have to be expressed on cancer cell membranes but not on normal cells, and (2) notably, their expression on cancer cells must be actively upregulated in response to cellular attack by cancer treatments. As a proof-of-concept, a GRP78-targeting nanovehicle for chemotherapy was designed. Resultant data showed that chemotherapeutic drugs could effectively elevate GRP78 expression on the plasma membranes of cancer cells while having minimal influence on normal cells. DOX pretreatment of cancer cells and tumor tissues can greatly increase the targeting efficacy and therapeutic performance of the prepared GRP78-targeting nanomedicine while somewhat disfavoring the nontargeting counterpart. In vivo and in vitro results demonstrated that this GRP78-targeting nanomedicine could accurately target cancer cells to not only implement chemotherapy but also induce GRP78 upregulation on cancer cells, eventually benefiting continuous cancer-cell-targeted attack by the nanomedicines remaining in the blood circulation or administered in the next dose. The GRP78-targeting nanomedicine displays much better antitumor performance compared with the nontargeting counterpart. SRCT is expected to advance cancer-targeted therapy based on the positive dependency between targeting and therapeutic modalities.

[Phylogenetic structure of Abies georgei var. smithii community at different spatial scales in Sygera Mountains of Tibet, China]. / 不同空间尺度西藏色季拉山急尖长苞冷杉群落谱系结构特征.

We analyzed the phylogenetic structure of trees within six diameter classes (1-2, 2-4, 4-7, 7-11, 11-16, >16 cm) in quadrats with different size of 5 m×5 m,10 m×10 m, 20 m×20 m, 50 m×50 m, 100 m×100 m in a Abies georgei var. smithii community in a 4 hm2 stem-mapping plot located in subalpine dark coniferous forest of Sygera Mountains, southeast Tibet. In various spatial scales, both net relatedness index (NRI) and nearest taxon index (NTI) of the community were larger than zero, indicating a clustered phylogenetic structure with the largest clustering intensity at small spatial scale (5 m×5 m). Community of small-size classes were phylogenetically clustering. In large-size classes (DBH>7 cm) phylogenetic over dispersion became more common, with dispersion increased with increasing tree size under all spatial scales. The intensity of phylogenetic clustering in young trees increased with increasing spatial scales, while the intensity of over dispersion in large trees (DBH>7 cm) increased with spatial scale. Our results suggested that environmental filtering in small-size trees and competitive exclusion in large-size trees might be the main ecological processes driving community assembly in this region.

pH-sensitive MOF integrated with glucose oxidase for glucose-responsive insulin delivery.

Glucose-responsive insulin delivery system mimicking the function of pancreatic ß-cells to maintain blood glucose homeostasis would effectively alleviate diabetes. Here, a new glucose-responsive delivery (ZIF@Ins&GOx) for self-regulated insulin release was constructed by encapsulating insulin and glucose oxidase (GOx) into pH-sensitive zeolitic imidazole framework-8 (ZIF-8) nanocrystals. After entering the cavities of ZIF-8, glucose can be oxidized into gluconic acid by GOx, causing a decrease in local pH. Then, ZIF-8 nanocrystals would be degraded under the acidic microenvironment that in turn triggers the release of insulin in a glucose responsive fashion. In vitro studies indicated that the biological activity of insulin could be protected by the rigid structure of ZIF-8 and the release of insulin could be modulated in response to glucose concentrations. In vivo experiments demonstrated that a single subcutaneous injection of the ZIF@Ins&GOx would facilitate the stabilization of blood glucose level of normoglycemic state for up to 72 h in type 1 diabetes (T1D). The multifunctional insulin delivery system shows a new proof-of-concept for T1D treatment by using ZIF-8 nanocrystals loaded with insulin and enzyme.

A leader-follower model for discrete competitive facility location problem under the partially proportional rule with a threshold.

When consumers are faced with the choice of competitive chain facilities that offer exclusive services, current rules do not properly describe the behavior pattern of these consumers. To eliminate the gap between the current rules and this kind of customers behavior pattern, the partially proportional rule with a threshold is proposed in this paper. A leader-follower model for discrete competitive facility location problem is established under the partially proportional rule with a threshold. Combining with the greedy strategy and the 2-opt strategy, a heuristical algorithm (GFA) is designed to solve the follower's problem. By embedding the algorithm (GFA), an improved ranking-based algorithm (IRGA) is proposed to solve the leader-follower model. Numerical tests show that the algorithm proposed in this paper can solve the leader-follower model for discrete competitive facility location problem effectively. The effects of different parameters on the market share captured by the leader firm and the follower firm are analyzed in detail using a quasi-real example. An interesting finding is that in some cases the leader firm does not have a first-mover advantage.

Platelet-Mimicking Biotaxis Targeting Vasculature-Disrupted Tumors for Cascade Amplification of Hypoxia-Sensitive Therapy.

Tumorous vasculature plays key roles in sustaining tumor growth. Vascular disruption is accompanied by internal coagulation along with platelet recruitment and the resulting suppression of oxygen supply. We intend to artificially create this physiological process to establish the mutual feedback between vascular disruption and platelet-mimicking biotaxis for the cascade amplification of hypoxia-dependent therapy. To prove this concept, mesoporous silica nanoparticles are co-loaded with a hypoxia-activated prodrug (HAP) and a vessel-disruptive agent and then coated with platelet membranes. Upon entering into tumors, our nanotherapeutic can disrupt local vasculature for tumor inhibition. This platelet membrane-coated nanoplatform shares the hemorrhage-tropic function with parental platelets and can be persistently recruited by the vasculature-disrupted tumors. In this way, the intratumoral vascular disruption and tumor targeting are biologically interdependent and mutually reinforced. Relying on this mutual feedback, tumorous hypoxia was largely promoted by more than 20-fold, accounting for the effective recovery of the HAP's cytotoxicity. Consequently, our bioinspired nanodesign has demonstrated highly specific and effective antitumor potency via the biologically driven cooperation among intratumoral vascular disruption, platelet-mimicking biotaxis, cascade hypoxia amplification, and hypoxia-sensitive chemotherapy. This study offers a paradigm of correlating the therapeutic design with the physiologically occurring events to achieve better therapy performance.

Enzyme-Driven Membrane-Targeted Chimeric Peptide for Enhanced Tumor Photodynamic Immunotherapy.

Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide, PpIX-C6-PEG8-KKKKKKSKTKC-OMe (PCPK), was designed for PM-targeted photodynamic therapy (PM-PDT) and enhanced immunotherapy via tumor cell PM damage and fast release of damage-associated molecular patterns (DAMPs). The PM targeting ability of PCPK originates from the cellular K-Ras signaling, which occurs exclusively to drive the corresponding proteins to PM by PFTase. With the conjugation of the photosensitizer protoporphyrin IX (PpIX), PCPK could generate cytotoxic reactive oxygen species to deactivate membrane-associated proteins, initiate lipid peroxidation, and destroy PM with an extremely low concentration (1 µM) under light irradiation. The specific PM damage further induced the fast release of DAMPs (high-mobility group box 1 and ATP), resulting in antitumor immune responses stronger than those of conventional cytoplasm-localized PDT. This immune-stimulating PM-PDT strategy also exhibited the inhibition effect for distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy.

Nanotherapeutics interfere with cellular redox homeostasis for highly improved photodynamic therapy.

Redox homeostasis inside malignant cells is a defense mechanism against the reactive oxygen species (ROS)-induced therapy means, but little importance has been paid to this innate barrier. The present study intends to make cancer cells more sensitive to the ROS-induced therapy by disturbing cellular redox homeostasis. To verify this concept, a porous metal-organic framework (MOF) serves not only as the photodynamic therapy (PDT) agent but also as the carrier to transport alkaloid piperlongumine (PL), a thioredoxin reductase (TrxR) inhibitor used to disturb cellular redox homeostasis. The PL-loaded MOF was further coated with cancer cell membranes to gain homologous tumor-targeting capability. Inside tumor cells, the released PL can effectively block the TrxR-mediated ROS elimination pathway. The resultant data show that compared to traditional PDT alone, the combination of PDT and TrxR inhibition causes profound promotions in cellular ROS level by about 1.6 times, in cytotoxicity by about 2 times, and in cellular apoptosis/necrosis rate by about 3 times. Consequently, this strategy based on the interference with cellular redox homeostasis has demonstrated high potency to improve the anticancer PDT performance, adumbrating a new way to boost the power of ROS-induced therapy.

Hydrogen gas improves photothermal therapy of tumor and restrains the relapse of distant dormant tumor.

Inflammation during photothermal therapy (PTT) of tumor usually results in adverse consequences. Here, a biomembrane camouflaged nanomedicine (mPDAB) containing polydopamine and ammonia borane was designed to enhance PTT efficacy and mitigate inflammation. Polydopamine, a biocompatible photothermal agent, can effectively convert light into heat for PTT. Ammonia borane was linked to the surface of polydopamine through the interaction of hydrogen bonding, which could destroy redox homoeostasis in tumor cells and reduce inflammation by H2 release in tumor microenvironment. Owing to the same origin of outer biomembranes, mPDAB showed excellent tumor accumulation and low systemic toxicity in a breast tumor model. Excellent PTT efficacy and inflammation reduction made the mPDAB completely eliminate the primary tumors, while also restraining the outgrowth of distant dormant tumors. The biomimetic nanomedicine shows potentials as a universal inflammation-self-alleviated platform to ameliorate inflammation-related disease treatment, including but not limited to PTT for tumor.

Cytomembrane nanovaccines show therapeutic effects by mimicking tumor cells and antigen presenting cells.

Most cancer vaccines are unsuccessful in eliciting clinically relevant effects. Without using exogenous antigens and adoptive cells, we show a concept of utilizing biologically reprogrammed cytomembranes of the fused cells (FCs) derived from dendritic cells (DCs) and cancer cells as tumor vaccines. The fusion of immunologically interrelated two types of cells results in strong expression of the whole tumor antigen complexes and the immunological co-stimulatory molecules on cytomembranes (FMs), allowing the nanoparticle-supported FM (NP@FM) to function like antigen presenting cells (APCs) for T cell immunoactivation. Moreover, tumor-antigen bearing NP@FM can be bio-recognized by DCs to induce DC-mediated T cell immunoactivation. The combination of these two immunoactivation pathways offers powerful antitumor immunoresponse. Through mimicking both APCs and cancer cells, this cytomembrane vaccine strategy can develop various vaccines toward multiple tumor types and provide chances for accommodating diverse functions originating from the supporters.

Expandable Immunotherapeutic Nanoplatforms Engineered from Cytomembranes of Hybrid Cells Derived from Cancer and Dendritic Cells.

Using the cytomembranes (FMs) of hybrid cells acquired from the fusion of cancer and dendritic cells (DCs), this study offers a biologically derived platform for the combination of immunotherapy and traditional oncotherapy approaches. Due to the immunoactivation implicated in the cellular fusion, FMs can effectively express whole cancer antigens and immunological co-stimulatory molecules for robust immunotherapy. FMs share the tumor's self-targeting character with the parent cancer cells. In bilateral tumor-bearing mouse models, the FM-coated nanophotosensitizer causes durable immunoresponse to inhibit the rebound of primary tumors post-nanophotosensitizer-induced photodynamic therapy (PDT). The FM-induced immunotherapy displays ultrahigh antitumor effects even comparable to that of PDT. On the other hand, PDT toward primary tumors enhances the immunotherapy-caused regression of the irradiation-free distant tumors. Consequently, both the primary and the distant tumors are almost completely eliminated. This tumor-specific immunotherapy-based nanoplatform is potentially expandable to multiple tumor types and readily equipped with diverse functions owing to the flexible nanoparticle options.

O2 Economizer for Inhibiting Cell Respiration To Combat the Hypoxia Obstacle in Tumor Treatments.

Hypoxia, a ubiquitously aberrant phenomenon implicated in tumor growth, causes severe tumor resistance to therapeutic interventions. Instead of the currently prevalent solution through intratumoral oxygen supply, we put forward an "O2-economizer" concept by inhibiting the O2 consumption of cell respiration to spare endogenous O2 and overcome the hypoxia barrier. A nitric oxide (NO) donor responsible for respiration inhibition and a photosensitizer for photodynamic therapy (PDT) are co-loaded into poly(d,l-lactide- co-glycolide) nanovesicles to provide a PDT-specific O2 economizer. Once accumulating in tumors and subsequently responding to the locally reductive environment, the carried NO donor undergoes breakdown to produce NO for inhibiting cellular respiration, allowing more O2 in tumor cells to support the profound enhancement of PDT. Depending on the biochemical reallocation of cellular oxygen resource, this O2-economizer concept offers a way to address the important issue of hypoxia-induced tumor resistance to therapeutic interventions, including but not limited to PDT.

Laser-treated glass platform for rapid wicking-driven transport and particle separation in bio microfluidics.

In this work, we present a laser-based fabrication technique for direct patterning of micro-channels consisting of interconnected micro-cracks on soda-lime glass. Using a CO2 laser to deposit energy at a linear rate of 18.75 to 93.75 mJ mm-1, we were able to manipulate the micro-crack formation, while enabling rapid manufacturing and scalable production of cracked-glass microfluidic patterns on glass. At the higher end of the energy deposition rate (93.75 mJ mm-1), the laser fabricated microfluidic channels (1 mm wide and 20 mm long) had extremely fast wicking speeds (24.2 mm s-1, ×10 faster than filter paper) as a result of significant capillary action and laser-induced surface hydrophilization. At the lower end (18.75 mJ mm-1), 3-4 µm wide micro-cracked crevices resulted in an increased mesh/sieve density, hence, more efficiently filtering particle-laden liquid samples. The reproducibility tests revealed an averaged wicking speed of 10.6 ± 1.5 mm s-1 measured over 21 samples fabricated under similar conditions, similar to that of filter paper (∼85%). The micro-cracked channels exhibited a stable shelf life of at least 82 days with a wicking speed within 10-13 mm s-1.

A two-photon excited O2-evolving nanocomposite for efficient photodynamic therapy against hypoxic tumor.

This paper reported on a two-photon excited nanocomposite FCRH to overcome tumor hypoxia for enhanced photodynamic therapy (PDT). Through modified by ruthenium (Ⅱ) complex (Ru(bpy)32+) and hyperbranched conjugated copolymer with poly (ethylene glycol) arms (HOP), the water-splitting mediated O2 generation can be triggered via two-photon irradiation from iron-doped carbon nitride (Fe-C3N4) for the first time. While exposured to two-photon laser, Ru(bpy)32+ was activated to generate singlet oxygen (1O2) and Fe-C3N4 was triggered to split water for oxygen supply in the mean time. Owing to the injection of photoinduced electrons from excited Ru(bpy)32+ to Fe-C3N4, O2 generation by Fe-C3N4 was significantly accelerated. After accumulation of the nanocomposite by enhanced permeability and retention (EPR) effect, FCRH was demonstrated to alleviate the tumorous hypoxia and consequently enhance the antitumor efficacy of PDT. Furthermore, tumor metabolism evaluations explained the capability of the nanocomposite in reducing intratumoral hypoxia. Our results provide a new diagram for ameliorating the hypoxic tumor microenvironment and accelerating 1O2 generation under two-photon excitation, which will find great potential for spatiotemporally controlled tumor treatment in vivo.

Ferrous-Supply-Regeneration Nanoengineering for Cancer-Cell-Specific Ferroptosis in Combination with Imaging-Guided Photodynamic Therapy.

Non-apoptotic ferroptosis is of clinical importance because it offers a solution to the inevitable biocarriers of traditional apoptotic therapeutic means. Inspired by industrial electro-Fenton technology featured with electrochemical iron cycling, we construct ferrous-supply-regeneration nanoengineering to intervene tumorous iron metabolism for enhanced ferroptosis. Fe3+ ion and naturally derived tannic acid (TA) spontaneously form a network-like corona onto sorafenib (SRF) nanocores. The formed SRF@FeIIITA nanoparticles can respond to a lysosomal acid environment with corona dissociation, permitting SRF release to inhibit GPX4 enzyme for ferroptosis initiation. TA is arranged to chemically reduce the liberated and the ferroptosis-generated Fe3+ to Fe2+, offering iron redox cycling to, thus, effectively produce lipid peroxide required in ferroptosis. Sustained Fe2+ supply leads to long-term cytotoxicity, which is identified to be specific to H2O2-overloaded cancer cells but minimal in normal cells. SRF@FeIIITA-mediated cell death proves to follow the ferroptosis pathway and strongly inhibits tumor proliferation. Moreover, SRF@FeIIITA provides a powerful platform capable of versatile integration between apoptosis and non-apoptosis means. Typically, photosensitizer-adsorbed SRF@FeIIITA demonstrates rapid tumor imaging owing to the acid-responsive fluorescence recovery. Together with ferroptosis, imaging-guided photodynamic therapy induces complete tumor elimination. This study offers ideas about how to advance anticancer ferroptosis through rational material design.

Aggressive Man-Made Red Blood Cells for Hypoxia-Resistant Photodynamic Therapy.

Extreme hypoxia of tumors represents the most notable barrier against the advance of tumor treatments. Inspired by the biological nature of red blood cells (RBCs) as the primary oxygen supplier in mammals, an aggressive man-made RBC (AmmRBC) is created to combat the hypoxia-mediated resistance of tumors to photodynamic therapy (PDT). Specifically, the complex formed between hemoglobin and enzyme-mimicking polydopamine, and polydopamine-carried photosensitizer is encapsulated inside the biovesicle that is engineered from the recombined RBC membranes. The mean corpuscular hemoglobin of AmmRBCs reaches about tenfold as high as that of natural RBCs. Owing to the same origin of outer membranes, AmmRBCs share excellent biocompatibility with parent RBCs. The introduced polydopamine plays the role of the antioxidative enzymes existing inside RBCs to effectively prevent the oxygen-carrying hemoglobin from the oxidation damage during the circulation. This biomimetic engineering can accumulate in tumors, permit in situ efficient oxygen supply, and impose strong PDT efficacy toward the extremely hypoxic tumor with complete tumor elimination. The man-made pseudo-RBC shows potentials as a universal oxygen-self-supplied platform to sensitize hypoxia-limited tumor treatment means, including but not limited to PDT. Meanwhile, this study offers ideas to the production of artificial substitutes of packed RBCs for clinical blood transfusion.

A Smart Capsule With a Hydrogel-Based pH-Triggered Release Switch for GI-Tract Site-Specific Drug Delivery.

In this paper, we present a smart capsule that can release its payload after a predetermined/adjustable delay subsequent to passing from the stomach into the small intestine. The described capsule (9 mm × 22 mm) comprises a pH-sensitive hydrogel-based switch, an electronic compartment containing a capacitor charged to 2.7 V, and a drug reservoir capped by a taut fusible thread intertwined with a nichrome wire. The nichrome wire, capacitor, and pH-responsive electrical switch are connected in series. The pH transition the capsule encounters when it enters the small intestine triggers controlled swelling of the pH-responsive hydrogel, which pushes a conductive elastic membrane to close an electrical switch. This initiates a sequence of events, i.e., the discharge of the capacitor, heating the nichrome wire, breakage of the fusible thread, and release of the payload stored in the capsule reservoir through the unlatched cap. The time lag between initiation of hydrogel swelling (by the near-neutral pH of the small intestine) and payload release is controlled by the deflection of the conductive elastic membrane and the gap separating the contacts. The release time can be set to within ±5 min after one hour in the small intestine (start of the swelling) increasing to ±40 min after 4 h.

Virus-Inspired Nanogenes Free from Man-Made Materials for Host-Specific Transfection and Bio-Aided MR Imaging.

Many viruses have a lipid envelope derived from the host cell membrane that contributes much to the host specificity and the cellular invasion. This study puts forward a virus-inspired technology that allows targeted genetic delivery free from man-made materials. Genetic therapeutics, metal ions, and biologically derived cell membranes are nanointegrated. Vulnerable genetic therapeutics contained in the formed "nanogene" can be well protected from unwanted attacks by blood components and enzymes. The surface envelope composed of cancer cell membrane fragments enables host-specific targeting of the nanogene to the source cancer cells and homologous tumors while effectively inhibiting recognition by macrophages. High transfection efficiency highlights the potential of this technology for practical applications. Another unique merit of this technology arises from the facile combination of special biofunction of metal ions with genetic therapy. Typically, Gd(III)-involved nanogene generates a much higher T1 relaxation rate than the clinically used Gd magnetic resonance imaging agent and harvests the enhanced MRI contrast at tumors. This virus-inspired technology points out a distinctive new avenue for the disease-specific transport of genetic therapeutics and other biomacromolecules.

Directly embroidered microtubes for fluid transport in wearable applications.

We demonstrate, for the first time, a facile and low-cost approach for integrating highly flexible and stretchable microfluidic channels into textile-based substrates. The integration of the microfluidics is accomplished by means of directly embroidering surface-functionalized micro-tubing in a zigzag/meander pattern and subsequently coating it with an elastomer for irreversible bonding. We show the utility of the embroidered micro-tubing by developing robust and stretchable drug-delivery and electronic devices. Controlled drug-delivery platforms with sustained release are achieved through selected laser ablated openings. We further demonstrate a wearable wireless resonant displacement sensor capable of detecting strains ranging from 0 to 60% with an average sensitivity of 45 kHz per % strain by filling the embroidered tubing with a liquid metal alloy, creating stretchable conductive microfluidics with <0.4 Ω resistance variations at their maximum stretchability (100%). The interconnects can withstand 1500 repeated stretch-and-release cycles at 30% strain with a less than 0.1 Ω change in resistance.

Diaper-Embedded Urinary Tract Infection Monitoring Sensor Module Powered by Urine-Activated Batteries.

Urinary tract infection (UTI) is one of the most common infections in humans. UTI is easily treatable using antibiotics if identified in early stage. However, without early identification and treatment, UTI can be a major source of serious complications in geriatric patients, in particular, those suffering from neurodegenerative diseases. Also, for infants who have difficulty in describing their symptoms, UTI may lead to serious development of the disease making early identification of UTI crucial. In this paper, we present a diaper-embedded, wireless, self-powered, and autonomous UTI monitoring sensor module that allows an early detection of UTI with minimal effort. The sensor module consists of a paper-based colorimetric nitrite sensor, urine-activated batteries, a boost dc-dc converter, a low-power sensor interface utilizing pulse width modulation, and a Bluetooth low energy module for wireless transmission. Experimental results show a better detection of nitrite, a surrogate of UTI, than that of conventional dipstick testing. The proposed sensor module achieves a sensitivity of 1.35 ms/(mg/L) and a detection limit of 4 mg/L for nitrite.