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Cells-Based Drug Delivery for Cancer Applications
Nano Review
Ying Du1,
Shujun Wang1,
Meilin Zhang1,
Baoan Chen1 &
Yanfei Shen2
The application of cells as carriers to encapsulate chemotherapy drugs is of great significance in antitumor therapy. The advantages of reducing systemic toxicity, enhancing targeting and enhancing the penetrability of drugs to tumor cells make it have great potential for clinical application in the future. Many studies and advances have been made in the encapsulation of drugs by using erythrocytes, white blood cells, platelets, immune cells and even tumor cells. The results showed that the antitumor effect of cell encapsulation chemotherapy drugs was better than that of single chemotherapy drugs. In recent years, the application of cell-based vectors in cancer has become diversified. Both chemotherapeutic drugs and photosensitizers can be encapsulated, so as to achieve multiple antitumor effects of chemotherapy, photothermal therapy and photodynamic therapy. A variety of ways of coordinated treatment can produce ideal results even in the face of multidrug-resistant and metastatic tumors. However, it is regrettable that this technology is only used in vitro for the time being. Standard answers have not yet been obtained for the preservation of drug-loaded cells and the safe way of infusion into human body. Therefore, the successful application of drug delivery technology in clinical still faces many challenges in the future. In this paper, we discuss the latest development of different cell-derived drug delivery systems and the challenges it will face in the future.
Cancer is still an insurmountable disease in the medical field. Chemotherapy is the main treatment for cancer. However, the systemic toxicity and drug resistance brought by chemotherapy drugs lead to the increase of failure rate [1]. In recent years, researchers have focused on the study of drug encapsulation by cells or nanoparticles (NPs). Intravenous administration of chemotherapeutic drugs will have great side effects on human body. At the same time, many drugs have poor penetration and targeting to tumor cells. Poor water solubility of chemotherapeutic drugs is also a common clinical problem. Fortunately, the emergence of new drug loading technology may solve these problems [2]. Drugs are usually infiltrated into cells by the hypotonic method when using cells to load drugs. However, the change of permeability will lead to deformation of cells and reduce the stability of cell membrane. The combination of NPs and cells can improve drug encapsulation and release, which has become a hot research topic in recent years [3, 4]. Increasing the biocompatibility of NPs, enhancing the ability of tumor targeting and prolonging the circulation are the main advantages of cell-derived vector. Among them, the enhancement of targeted drug delivery has become an important concern [5]. In order to solve this problem, researchers modify the cell surface to improve the targeting of DDS to tumor tissue, improve the drug concentration in tumor tissue and achieve effective tumor inhibition effect finally [6]. This review introduces the development of encapsulation of drugs or NPs with erythrocytes, platelets, immune cells, tumor cells and stem cells (Table 1) [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35].
Table 1 Application of drug delivery technology based on different cells in cancer
Erythrocyte
Erythrocytes are regarded as a promising cell-mediated drug delivery platform due to the inherent advantages of biocompatibility, long life span and easy access [7, 36]. Initially, erythrocytes often encapsulate drugs directly. With the development of research, erythrocytes combined with functional NPs were appeared. The transformation of single drug chemotherapy to targeted therapy, immunotherapy, photothermal therapy (PTT) and so on has been realized. Erythrocyte membrane can combine with NPs in many ways. Sun et al. summarized several technologies of erythrocyte membrane carrier constructed by covalent and noncovalent binding methods including lipid insertion, biotin-avidin bridge, EDC/NHS coupling, antibody/ligand–receptor conjugation and passive adsorption (Fig. 1) [36]. Wang et al. studied the erythrocyte-cancer cell hybrid membrane to achieve drug delivery. The hybrid membrane not only has the ability of immune camouflage, but also has the ability of tumor targeting [4]. The delivery efficiency of therapeutic NPs based on tumor passive targeting strongly depends on the proper regulation of blood circulation time or tumor microenvironment. Based on this theory, Sousa Junior et al. proposed a new scheme of camouflaged magnetofluorescent nanocarrier (MMFn) by erythrocyte membrane. The blood circulation time of MMFn is up to 92 h, and it has high transfer efficiency, which has been verified in the mouse tumor model [8]. The objective clinical development of cancer vaccine is limited. This is related to the high level of programmed death ligand-1 (PD-L1) expression in tumor cells, which leads to the immunosuppressive characteristics of tumor microenvironment. The expression of PD-L1 on antigen-presenting cell (APCs) can induce T regulatory cells [37]. Hence, the combination of anti-PD-L1 (aPD-L1) and cancer vaccine may be beneficial. Aging erythrocyte has a unique ability to target spleen antigen-presenting cells. Therefore, the combination of aPD-L1 blockade with nano-erythrocytes can cause antigen reaction in vivo, which can valid inhibit tumor growth and reduce tumor metastasis [9]. PTT is a new method for the treatment of tumor, which has great development potential and will become an important method for the treatment of tumor. Prussian blue (PB) NPs with high photothermal conversion, strong blue, magnetic, good biocompatibility and stability are considered to be suitable for cancer PTT. However, the blood retention time of PB NPs is short, which makes its antitumor effect reduced greatly. The CD47 on the surface of erythrocytes is the self-recognition protein of reticuloendothelial system in vivo, so the nanomaterials coated with erythrocytes can improve the immune escape ability and prolong the half-life in the circulation. The erythrocyte membrane was used to improve the drug accumulation of PB in the tumor site [10]. As a new drug delivery system (DDS), extracellular vesicle (EV) carrier has the advantages of safety, high efficiency and long circulation. However, the disadvantages of low yield, high cost and heterogeneity limit the application of EV [38]. The preparation of membrane-derived artificial vesicles by fracture and self-assembly has become an effective strategy to overcome the problem. The size and uniformity of the multifunctional mimic vesicles derived from red blood cells can be well controlled. The researchers used erythrocyte-derived mimic vesicles (MVs) loaded with P-glycoprotein (P-gp) siRNA and Doxorubicin (DOX) for the targeted treatment of multidrug-resistant tumors. This MV-based DDS provide a new direction for the collaborative targeted therapy of tumor [11]. The transport platform derived from erythrocytes can be designed by mechanical operation, which can make the diameter from micrometer to nano. The research results indicate that the real-time circulation dynamics of erythrocytes vector is related to its diameter. The researchers designed a micro- and nano-erythrocytes optical carrier based on the real-time fluorescence imaging of particles in the subcutaneous vascular system of healthy mice and studied the circulation dynamics. The result suggests that the average emission half-life of the micro- and nanocarriers in the blood vessels was ~ 49 min and 15 min, respectively. After 7 days, the second injection of particles increased the average emission half-life of the microsize carrier to 1 h, and the variable half-life of nanocarriers ranged from 25 to 60 min [39]. Phosphatidylserine exposed on the carrier surface is an important mechanism for their removal from the circulation [40]. The emission half-life of NPs in blood is shorter after the first injection, which indicates that macrophages may be more effective in removing these particles when mediated by the mechanism of phosphatidylserine surface exposure. The shape and deformation characteristics of the microsize carriers contribute to the cycle time of these particles. These biochemical and biomechanical characteristics are important factors for the safe and effective translation of the red blood cell-derived platform [39]. Therefore, these series of research results show that it is necessary to carry out more detailed research on erythrocytes-derived vectors. Only in this way, can we understand the mechanism of the carrier acting on the disease and use these mechanisms to design better erythrocytes-derived carrier.
Reprinted with permission from Ref. [30]. Copyright © 2019, Theranostics
Schematic diagram of binding method between erythrocyte membrane and NPs (A), biotin-avidin bridges (B), EDC/NHS coupling (C), antibody/ligand-receptor conjugation (D), and passive adsorption (hitchhiking) (E) methods for refunctionalization of erythrocyte-based nanomedicine.
Platelet
Platelet is a kind of blood cell without nuclear. The life span of platelets is about 8–10 days. Compared with the long circulating time of erythrocytes for four months, the proper circulating time of platelets can avoid unnecessary accumulation in vivo [41]. The CD47 membrane protein of platelets can send a "don't eat me" signal to macrophages to avoid phagocytosis by macrophages. Therefore, platelet biomimetic DDS is expected to improve the escape of macrophages in vivo and enhance the retention in tumor tissue [17]. Studies have indicated that platelets play an important role in promoting tumor cell proliferation, tumor vascular integrity and tumor cell invasion due to their multiple angiogenic regulators. Platelet-derived microparticles (P-MPs), such as vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), can induce the activation of MAPK and AKT signaling pathways in tumor cells, so as to stimulate the over expression of proteins required for tumor cell proliferation [42]. Platelet aggregation is related to circulating tumor cells (CTC). In addition, Platelets can prevent vascular extravasation of CTC by enhancing the adhesion between platelets and endothelial cells. More importantly, platelets can protect CTC from immune surveillance of natural killer cells. Hence, it is promising to establish platelet membrane-based DDS using the advantage of platelet targeting to tumor cells. The common method of preparing the platelet membrane is ultrasound and repeated freeze–thaw [41]. In an earlier study on platelet-encapsulated NPs, Hu et al. showed that platelets can encapsulate loaded NPs effectively. Platelet-derived vector has strong targeting capability to injured blood vessels and tumors and plays a good therapeutic role in disease [43]. Liu et al. developed a pH responsive platelet membrane-lipid hybrid drug carrier for tumor targeted delivery. The drug loading platform system showed longer plasma half-life and enhanced tumor accumulation when doxorubicin is triggered and released into mouse tumor models. This result is superior to the traditional pH sensitive liposome (Fig. 2) [18]. The platelet DDS combines immunotherapeutic drugs with photothermal agents. In the latest research, platelet DDS combines immunotherapeutic drugs with photothermal drugs. Drug-modified platelets are recruited to the tumor site to further activate the anticancer immune response, inhibit the growth of residual tumor and improve the survival rate. This is due to inflammation and injury at the tumor site after thermal ablation [19]. The existing researches on platelet-derived nanocarriers show that platelet-mediated DDS has broad prospects.
Reprinted with permission from Ref. [14]. Copyright © 2019, Wiley
Schematic illustration of the preparation of PEOz-platesome-dox. PEOz-platesome-dox was generated by coextrusion of PEOz-liposome-dox and PNV.
Immunological Cell
At present, many people focus on the surface modification of NPs carriers to match the biological environment and complexity. However, mononuclear phage system has the ability to recognize and isolate foreign substances, which leads to the decrease in drug concentration in tumor site [25]. NPs can also deliver drugs to tumor areas according to enhanced permeability and retention, but the permeability of tumor vessels is often affected by vascular structural abnormalities and blood supply heterogeneity. Another reason we have to consider is that the size and charge of NPs also affect the amount of them entering the tumor. For example, NPs larger than 100 nm in diameter can be phagocytized by macrophages or filtered by the liver [22]. Therefore, the existence of these factors often leads to NPs cannot enter the tumor site efficiently. Immune cells play an important role in tumor targeting and preventing drug diffusion to normal tissues. Macrophages become one of the ideal drug carriers for DDS because of their natural phagocytic ability, blood barrier and chemotaxis to solid tumors. NPs encapsulated by macrophages will enhance the permeability of NPs to tumor tissue. And the antitumor effect will be further enhanced when the antitumor drugs are combined with photothermal therapy, which has been confirmed in a certain research (Fig. 3) [23]. Monocytes are considered to be the precursor of macrophages, with the ability of phagocytosis, elimination of injured cells and participation in immune response. Moreover, monocytes are the largest cells in the blood which make it easy to load therapeutic NPs. They will differentiate into macrophages when monocytes are recruited to the tumor site. NPs encapsulated by macrophages will then migrate and chemotactic to the anoxic area of the tumor [24, 44].
Reprinted with permission from Ref. [20]. Copyright © 2016, Sci Rep
Schematic diagram of the macrophage-based microrobot with PLGA-DTX-Fe3O4 (left). Describe the targeting and treatment of tumors in the in vivo environment (right).
Cytotoxic T lymphocytes (CTL), a subdivision of white blood cells, are specific T cells that secrete various cytokines to participate in immune function. It has killing effect on virus and tumor cells and forms an important defense line against virus and tumor together with natural killer cells. CTL, also known as killer T lymphocyte, is an important part of the antitumor of body and one of the main effect cells of tumor immunotherapy. It has long blood circulation time and high expression of adhesion molecules. Therefore, CTL has the ability to recruit and locate the tumor sites. All of these advantages lay the foundation for treatment tumor with CTL-derived NPs [26].
Leukocytes are a kind of colorless, spherical and nucleated blood cells. The total number of leukocytes in normal adults was (4.0–10.0) × 109/L [45]. When inflammation occurs, leukocytes were activated to fight bacteria or viruses, which is a manifestation of their important role in the immune system. Leukocytes participate in various immune reactions, cell interactions and have the ability to migrate [46]. They are ideal carriers of chemotherapeutic drugs and regulatory factors of tumor microenvironment (TEM), which are mainly due to the homing characteristics of leukocytes in inflammatory and tumor sites. Roberto Molinaro et al. used the targeting characteristics of leukocyte to tumor-related blood vessels with inflammation to deliver DOX to mouse models with breast cancer and melanoma effectively. The results showed that DOX-loaded leukocytes showed stronger antitumor activity in reducing tumor volume and prolonging survival time [27, 47]. Neutrophils are the most abundant type of leukocytes, accounting for 40–75% of the total number of leukocytes. What's more, neutrophils are the first cell type to reach the site of inflammation. The accumulation of neutrophils mediated DDS in tumor site is further enhanced when photothermal therapy triggers tumor site inflammation [48]. In noncancer diseases, the migration characteristics of neutrophils also provide a new idea for disease treatment. Research show that neutrophils can selectively carry cRGD liposomes as cell carriers, when cerebral ischemia occurs. Thus, neutrophils enter the blood–brain barrier and penetrate into the brain parenchyma, and eventually deliver the drug to the site that needs treatment [49]. CTCs in the blood are easy to proliferate and form metastasis in anatomically distant organs. However, it is difficult to be targeted therapy because of the circulatory state and low concentration of CTCs. Fortunately, they are easy to gather near endothelial cells which is similar to the migration characteristics of white blood cells. The main reason is that CTC is similar to leukocyte in volume and shape, so it is also surrounded by endothelial cell wall when blood flows. This kind of edge phenomenon can surround CTC in white blood cells effectively. In other words, leukocytes are also potential therapeutic vectors for CTC [50].
Natural killer cell (NK) is an important immune cell in the body, which is not only related to antitumor, antivirus infection and immune regulation, but also involved in hypersensitivity reaction and autoimmune diseases in some cases. NK can recognize target cells and killing media. Unlike T and B cells, it is a kind of lymphocyte that can kill tumor cells and virus-infected cells without pre sensitization [51]. Deng et al. found that NK-derived NPs have targeted effect on tumor according the proteomic analysis of NK cell membrane. It is more satisfactory that NK cells can also induce or enhance the polarization of pro-inflammatory M1 macrophages, thus producing antitumor immunity. Supported by this theory, Deng and other researchers encapsulated photodynamic agents in NK cells. The result showed that NK cell DDS showed a strong immunotherapeutic effect in the antitumor process. It not only can inhibit the growth of primary tumor effectively, but also has obvious inhibitory effect on distant tumor [28].
The infinite ability of cancer cells to replicate is a nuisance, but the ability of cancer cells to resist cell death allows them to overcome immune clearance [30]. Cancer cells that express surface adhesion molecules such as epithelial cell adhesion molecules, n-cadherin and galectin-3 have homologous adhesion domains, which can promote the occurrence of multicellular aggregation. The ability to homologous bind to membrane proteins leads to the use of cancer cells for surface functionalization of NPs. Chen et al. used cancer cell membrane to encapsulate ICG (Indocyanine green)/poly (lactic co glycolic acid) (PLGA) core and cancer cell membrane shell to achieve synchronous targeting and tumor treatment. The results showed that this method not only had high homologous targeting effect at the cell level, but also had superior spatial resolution and deep penetration at the animal level (Fig. 4) [29]. Studies have shown that mitochondria play an important role in regulating the proliferation of cancer cells. The initiation of apoptosis in mitochondria leads to the release of cytokines such as cytochrome c, which leads to a cascade of cytosolic activity and cell death [52]. Mitochondrion is also closely related to multidrug resistance (MDR) of cancer [53]. Targeted intervention of mitochondrion will become a promising strategy for cancer treatment. Accumulation of mitochondrial targeted drugs can trigger mitochondrial apoptosis pathway, leading to programmed cell death and cancer cell suicide. Studies have shown that metal oxides such as zinc, copper and ceria can inhibit the proliferation of cancer cells in a variety of cancer cell lines through this mechanism. Therefore, some researchers have developed nanoparticles targeting mitochondria. For example, Zn-doped CuO NPs (TPP-ZC-IR-PNPs) and co-loaded with docetaxel and lonidamine (cl-M/DL) system studied by Ruttala et al. All of them have strong targeting ability and therapeutic effect in tumor therapy [52, 54].
Reprinted with permission from Ref. [24]. Copyright © 2016, ACS Publication
Illustration of the cancer cell membrane–biomimetic NPs for targeting recognition of source cancer cell, dual-modal imaging, and photothermal therapy. (A) Preparation procedure of ICNPs. Extracting cancer MCF-7 cell membrane hybridized with PEGylated phospholipids (DSPE-PEG) and then coated onto ICG-loaded polymeric cores by extrusion. (B) Schematic of homologous targeting ICNPs for dual-modal imaging guided photothermal therapy. Through specific homologous targeting and the EPR effect (passive targeting), ICNPs realized perfect tumor accumulation, dual-modal FL/PA imaging, and effective photothermal therapy after intravenous injection.
Tumor can emit chemokines to recruit mesenchymal stem cells (MSCs) to form supporting matrix for tumor growth [55]. MSC is a kind of pluripotent stem cell, which has the ability of self-renewal, multi-directional differentiation and regulation of immune response. It was isolated from brain, lung, liver, kidney, cord blood, placenta and other tissues successfully. It is speculated that MSCs may be able to migrate to the site of injury or inflammation and repair the injury by producing tissue-specific cells and/or releasing paracrine factors. MSCs can also secrete immunomodulatory soluble molecules to regulate immunity and is mainly used in the treatment of Crohn's disease, liver failure, fibrosis and other diseases. The presence of MSCs in the microenvironment of malignant tumors is helpful for tumor growth and metastasis [56]. However, some studies have shown that MSCs derived from umbilical cord can inhibit the growth of pancreatic cancer cells in mice [57, 58]. MSCs can efficiently transduce adenovirus, lentivirus, mouse retrovirus and other major viral vectors. The transformed and gene-modified MSCs can be widely expanded in vitro which makes them become the ideal vector of gene transfer [59]. Tumor formation requires new cells to support it, just like developing or damaged tissue. The migration of MSCs to tumor tissue makes it widely used as a carrier of antitumor drugs. Stefania Lenna et al. have made achievements in the inhibition of osteosarcoma growth based on the photodynamic technology of MSCs loaded with NPs. They prepared Chlorin e6 (Ce6)-coupled polydopamine NPs (PDA-Ce6) were prepared and loaded into MSCs. The MSCs loaded with PDA-Ce6 (MSC-PDA-Ce6) can target and penetrate the tumor. It is worth mentioning that the effective release rate is up to 60% within 72 h. MSC-PDA-Ce6 is a "Trojan horse" like transport through the endocytosis–exocytosis–endocytosis process between MSCs and cancer cells. What's more gratifying is that there may be a certain degree of hope even in the face of small inoperable tumors or drug-resistant patients [33]. Similarly, it has a good effect in the treatment of melanoma [34].
Proteins on the membrane surface retain the biological function of cell in cell mediated drug delivery technology. As mentioned above, many studies have shown that cell-based drug delivery enhance biocompatibility, targeting capability and immune escape ability, reduce toxic side effects and prevent the formation of protein corona. All of these advantages avoid and reduce the complexity in the preparation of NPs [55]. Nanotechnology has been widely studied in the field of medicine because of its advantages of easy surface functionalization, controllable design and reducing drug side effects. The diameter of NPs used in the studies is similar to that of bacteria, viruses and other pathogens, generally about 100 nm, so the clearance mechanism of reticuloendothelial system in vivo is easy to be activated. Cell-derived NPs reduce the stimulation of macrophages to release cytokines greatly [60]. A serious problem of NPs is that they will come into contact with plasma proteins when they enter the blood system. Plasma proteins adsorbed on the surface of NPs form protein corona which affects the interaction between NPs and blood components, further leads to increased cell activation and may lead to coagulation or even thrombosis eventually [61]. Therefore, the combination of NPs and cell provides a new prospect for the clinical application of DDS. The progress of DDS is also reflected in the combination of treatment and diagnosis. The addition of ICG and other fluorescent dyes with photothermal effect makes it easy to track drug traces in the process of antitumor cells. At the same time, it is also convenient for tumor imaging and easy to evaluate the therapeutic effect [62]. Unfortunately, the current cell drug delivery technology is only used for preclinical in vitro research. It is not foreseen whether the changes of cell membrane composition and surface modification will lead to immune response when the drug delivery technology used in human body. It is not clear whether the drug can be released into the body in time to produce cytotoxicity, and whether the degradation of NPs in the body will affect human health. These problems will lead to the further study of DDSs based on cells [63].
Compared with chemotherapy alone, DDS based on cells has the advantages of improving biocompatibility, enhancing immune escape, long circulation and enhancing targeting. At the same time, encapsulation of photosensitizers, chemotherapy drugs and other reagents in the carrier can promote the cooperative treatment of tumor. Erythrocytes, platelets, leukocytes and other cells in DDS have been widely studied and achieved many results. At present, the research on the combination of blood cells and NPs is the most. NPs have the advantages of enhanced permeability and retention effect (EPR), high drug loading efficiency and certain targeting ability, which have clear benefits for tumor therapy.
NPs:
PTT:
Photothermal therapy
MMFn:
Magnetofluorescent nanocarrier
PD-L1:
Programmed death ligand-1
APCs:
Antigen-presenting cell
PB:
DDS:
EV:
Extracellular vesicle
MVs:
Mimic vesicles
P-gp:
P-glycoprotein
DOX:
P-MPs:
Platelet-derived microparticles
VEGF:
MMP:
EGF:
Epidermal growth factor
PDGF:
Platelet-derived growth factor
CTCs:
Circulating tumor cells
CTLs:
Cytotoxic T lymphocytes
Tumor microenvironment
MDR:
Multidrug resistance
TPP-ZC-IR-PNPs:
Zn-doped CuO NPs
cl-M/DL:
Co-loaded with docetaxel and lonidamine
MSCs:
Ce6:
Chlorin e6
PDA:
Polydopamine
ICG:
Indocyanine green
Enhanced permeability and retention effect
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Wu M, Le W, Mei T et al (2019) Cell membrane camouflaged NPs: a new biomimetic platform for cancer photothermal therapy. Int J Nanomed 14:4431–4448
Papaccio F, Paino F, Regad T et al (2017) Concise review: cancer cells, cancer stem cells, and mesenchymal stem cells: influence in cancer development. Stem Cells Transl Med 6(12):2115–2125
Chopra N, Choudhury S, Bhargava S et al (2019) Potentials of "Stem cell-therapy" in pancreatic cancer: an update. Pancreatology 19(8):1034–1042
Doi C, Maurya DK, Pyle MM et al (2010) Cytotherapy with naive rat umbilical cord matrix stem cells significantly attenuates growth of murine pancreatic cancer cells and increases survival in syngeneic mice. Cytotherapy 12(3):408–417
Almeida-Porada G, Atala AJ et al (2020) Therapeutic mesenchymal stromal cells for immunotherapy and for gene and drug delivery. Mol Ther Methods Clin Dev 16:204–224
Malhotra S, Dumoga S, Sirohi P et al (2019) Red blood cells-derived vesicles for delivery of lipophilic drug camptothecin. ACS Appl Mater Interfaces 11(25):22141–22151
de la Harpe KM, Kondiah PPD, Choonara YE et al (2019) The hemocompatibility of NPs: a review of cell–nanoparticle interactions and hemostasis. Cells 8(10):1209
Dong Y, Liu B, Yuan Y (2018) AIEgen based DDSs for cancer therapy. J Control Release 290:129–137
Banskota S, Yousefpour P, Chilkoti A (2017) Cell-based biohybrid DDSs: the best of the synthetic and natural worlds. Macromol Biosci 17(1):1600361
This work was supported by the Key Medical of Jiangsu Province (ZDXKB2016020), the Key Medical Projects of Jiangsu Province (BL2014078), the Key Department of Jiangsu Province (2016–2020), Jiangsu Social Development Project (Project No.: BE2018711).
Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, School of Medicine, Southeast University, Ding JiaQiao Street 87, Nanjing, 210009, People's Republic of China
Ying Du, Shujun Wang, Meilin Zhang & Baoan Chen
Department of Chemistry and Chemical Engineering, Southeast University School of Medicine, Ding JiaQiao Street 87, Nanjing, 210009, People's Republic of China
Yanfei Shen
Ying Du
Shujun Wang
Meilin Zhang
Baoan Chen
YD made substantial contributions to the conception, paper collecting and analyzing of the work; and drafting the work; and final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SW and MZ made contributions to the paper collecting and analyzing of the work; and drafting the work; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. BC made substantial contributions to conception of the work; and revising it critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. YS made substantial contributions to conception of the work; and revising it critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.
Correspondence to Baoan Chen or Yanfei Shen.
Du, Y., Wang, S., Zhang, M. et al. Cells-Based Drug Delivery for Cancer Applications. Nanoscale Res Lett 16, 139 (2021). https://doi.org/10.1186/s11671-021-03588-x
DOI: https://doi.org/10.1186/s11671-021-03588-x


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Athletics: London Anniversary Games – BBC1
Airs at 1:15pm on Saturday 20 July 2019
Michael Hall Tue, July 16 12:01am
In Athletics: London Anniversary Games, track and field stars converge on London for the fifth annual celebration of athletics
Athletics: The London Anniversary Games sees the London Stadium hosting the two-day event for the fifth successive year.
Today's highlights include the women's 1500m, with Britain's Laura Muir hoping to see off the challenge of Kenya's Faith Kipyegon.
Death in Paradise star Nina Wadia: 'I've slightly fallen in love with The Commissioner!'
EastEnders fans CONVINCED they've worked out who DIES in 35th anniversary drama
7 things you didn't know about EastEnders' Kellie Bright – AKA Linda Carter
Then it's onto the men's 100m final, where Brit Zharnel Hughes hopes to be involved as he bids to go one better than last year.
Back then, he was pipped by US star Ronnie Baker in a race which – incredibly – saw six athletes go below 10 seconds.
Tomorrow, the Men's High Jump and Women's 400m hurdles catch the eye, before the competition wraps up with the Women's 100m final.
TV Times rating: ***
Coronation Street spoilers: Bethany Platt gets mixed signals from Daniel
Neighbours spoilers: Yashvi Rebecchi drops BOMBSHELL on Ned Willis!
Doctors spoilers: Jimmi Clay goes to EXTREME measures…
Home and Away spoilers: What's wrong with Bella Nixon?
Hollyoaks spoilers: Liam Donovan hatches a plot involving Maxine

redpajama_set_name: RedPajamaCommonCrawl


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Home News iOS 13 Rumors: Dual Monitor Support and Redesigned Files App
iOS 13 Rumors: Dual Monitor Support and Redesigned Files App
Juana Rivers December 14, 2018 0 Comment
As 2018 is nearing its end Apple has already started to work hard on the next iOS update. Rumors suggest that it will be focused on iPads, which is great news as iPad owners may have felt neglected when iOS 12 was released. Below you can find a list of possible changes that would make iOS 13 great for iPad users.
Enhanced text selection
Text selection is an obvious challenge on every touch screen device. Apple would attract cheers from loyal fans if they were able to develop a new method that would allow users to select and highlight text without struggling to find the right combination of gestures.
Yes the iPad can be connected to a projector or TV but it still lacks true dual monitor support. While the new iPad Pro brought some features the option to use dual monitors will bring more value for those that use their iPad for productivity tasks.
A revamped AirPrint
AirPrint is a reliable solution for both consumers and enterprises but it is hardly noteworthy. The interface is still quite limited in comparison to the richness of options available on a Mac. Offering a unified API to printer vendors would allow them to make the standard better and easier to use at the same time. The option to remotely control what a printer can and can't do would be a worthy addition.
The option to disable accessibility features
While accessibility features are valuable for certain users Apple should integrate a toggle that can globally deactivate any accessibility function that has been previously enabled.
A superior Safari experience
iPads should receive a Safari version that is on par with the one that is currently available for Mac users. The ability to support webpages in their desktop format should be implemented since the device natively supports accessories that can profit from it.
Redesigned Files app
While the Files app is still good a revamp could bring a variety of new and useful features.
Let's hope that at least some of these ideas will surface when the iOS 13 is released next year.


Ooops. See hou.setCurrentDopNet() ... I think it'll do what you want.
> If you're not risk-averse, you can try monkey patching .
> where myGetCurrentDopNetwork returns the path to your own dopnet.
> simulation" as set according to the simulation menu on the status bar to me.
>> I am wrting some tools in python that have to deal with dynamics.
>> force them to use this one instead of the default.
>> the getCurrentDopNetwork() method in doptoolutils.py.
>> return the same path.
>> doptoolutils method, is it possible?


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Q: Record audio permission on android 6 based on Unity I have an issue with Android 6.0 Marshmallow. when I try to use the microphone and record user input, I get the following error.
12-09 18:26:42.226 204-10957/? W/ServiceManager: Permission failure: android.permission.RECORD_AUDIO from uid=10274 pid=757
12-09 18:26:42.226 204-10957/? E/: Request requires android.permission.RECORD_AUDIO
12-09 18:26:42.226 204-10957/? E/AudioFlinger: openRecord() permission denied: recording not allowed
12-09 18:26:42.226 757-1251/com.facebook.singApp E/AudioRecord: AudioFlinger could not create record track, status: -1
12-09 18:26:42.228 204-1253/? I/AudioFlinger: AudioFlinger's thread 0xafa40000 ready to run

And the application crashs, it happends only on Android 6.0 Marshmallow, all other platforms works prefectly.
In android manifest I already added this code part:
   <uses-permission android:name="android.permission.RECORD_AUDIO" android:maxSdkVersion="1" />

And on Unity I added the following code: (I know it's for webplayers but I figure, what the hack)
private IEnumerator mobilePremissions()
{
    yield return Application.RequestUserAuthorization(UserAuthorization.Microphone | UserAuthorization.Microphone);
    if (Application.HasUserAuthorization(UserAuthorization.WebCam | UserAuthorization.Microphone)) {
        Debug.Log ("Great");
        ViewerSwitchSence.Recording();
    } else {
        Debug.Log ("Crapping");
    }
}

I don't know why Unity doesn't promot user for authorization at click time, that's what is expected on Android 6.0 Marshmallow.
Thanks ahead for your help.

A: Alright, solved this issue.
If you are getting the same problem, update to lastest Unity, however, if you already added android.permission.RECORD_AUDIO to your manifest.
Make sure you delete this line from manifest, it will collide will Unity self added permissions and cause the application to crash on microphone request.
Hope it helps someone.

redpajama_set_name: RedPajamaStackExchange


October 10, is World Mental Health Day. As we learn more and more about mental health, it has become more evident just how big of an impact it can have on your employees' performance. Mental health is just as important of a factor on productivity as physical health.
And, like physical health, it's beneficial for your company to track and promote your employees' mental wellbeing. For example, depression alone costs U.S. businesses over $44 billion annually in lost productivity.
Similarly, in 2015 alone, major depressive disorder had an estimated economic impact of $210 billion. So, if mental health is having such an effect on business, how do you help employees struggling with mental health issues?
Unfortunately, there is no, one, right answer. There are; however, a plethora of moves any organization can make to support its employees. One of the best opportunities for a company to promote positive mental health is through your employee benefits policy.
Employee benefits can have a significant impact on your staff's mental wellbeing. These 11 benefits will support your staff's mental health at work.
There's a plethora of employee benefits and perks that an organization can offer its employees. Still, many of these benefits range from unrelated, to ineffective, in regards to combating negative mental health issues.
With that being said, there are multiple benefits and perks that aid individuals who are dealing with mental health issues. These ten benefits can improve employees' mental health at work.
Employee Assistance Programs are work-based intervention programs designed to identify and assist employees in resolving issues. These issues can range from marital, to financial, to substance abuse and mental health concerns.
Companies usually offer EAPs at no cost to team members. Most employers operate their EAP through a third-party administrator. Using a third-party administrator is crucial to the success of your EAP.
Employees have to feel comfortable discussing professional and personal problems with the EAP administrator. Your staff needs to be able to talk about issues such as mental health, with confidence. They cannot fear they are putting their jobs or social lives in jeopardy.
If your business administers your EAP, it could prevent employees from coming forward and asking for the help they require. Still, EAPs are a terrific way to point employees struggling with mental illness, in the right direction, so they can receive the treatment they need.
Health insurance is a critical tool for helping staff members who have a mental illness. As an employer, it is essential to select a health plan that includes mental health coverage.
There is an extensive list of mental health services your health plan should provide your staff. These services include outpatient and inpatient treatment, telemedicine, medication, and counseling. Each of these attributes can be vital for treating mental illnesses.
The improvements and prevalence of telemedicine are especially promising for addressing some of the challenges surrounding mental health.
According to BenefitsPro, telemedicine can make getting care anonymous and convenient, so patients can receive care where they're most comfortable. These attributes are especially valuable when dealing with a subject as sensitive as mental health.
Learn the ins and outs of health insurance.
One of the most significant problems regarding mental health at work is the stigma. There continues to be a stigma surrounding the discussion of mental health, which only serves to exacerbate the problems that mental health issues can create.
Because of this stigma, an important benefit to offer your staff is employee training. Train your managers, and leadership that mental illness is not a bad topic and one to avoid. Instead, teach them how to recognize employees with potential mental health issues.
Not only do your managers have to know how to spot mental illness, but they also need to be able to have intelligent and empathetic conversations with other employees. Your managers have to know the importance of speaking openly about mental illness rather than avoiding the topic.
Mobile technology has affected almost every aspect of modern life. Mental health is no exception. As previously stated, telemedicine is a tremendous tool for treating mental illness.
New applications, such as MoodKit and Happify, are specifically geared towards recognizing and improving mental health issues. MoodKit, for example, uses principles and techniques of cognitive behavior therapy to treat mental health issues.
These tools can be invaluable to your team members. New technology allows your employees to improve their mental health, on their own time, and where they feel the most comfortable.
Additionally, these applications focus on preventative care, which can be highly valuable for mental health. Because mental health carries a stigma, it has traditionally been an area of health that goes neglected or is only addressed until it reaches a crisis. Preventative care can reduce health care costs for both employer and employee.
Resiliency training and stress management, like the applications discussed above, focus on preventative care. According to Workforce, resiliency training aims to give workers the skills necessary to handle change and crises, positively and efficiently.
Both resiliency training and stress management work to lessen the impact of stress, and hopefully other mental health issues such as anxiety and depression. These courses are becoming more popular too. According to a 2015 Mercer survey, 42 percent of large employers offer resiliency or stress management programs.
Another benefit that can aid workers' mental health is parental leave. It's important to note that parental leave is much preferable to just maternal leave. Although, maternal leave is a terrific place to start.
Paternal leave is paid time off for new parents, mom or dad, after the birth or adoption of a child. This leave provides parents with an opportunity to take care of their child without the stress of work getting in the way.
Becoming a new parent is an enormously stressful life event. If you don't offer parental leave, and force parents to take unpaid time off, such as FMLA, this stress is compounded.
A Harris Poll conducted for Purchasing Power found that 80 percent of employees are under financial stress. This stress can have a significant adverse impact on business. Stress costs employers an average of $300 billion a year in stress-related health care and missed work.
Paid leave for new parents helps alleviate the financial portion of their situation, at least. Parents who are less stressed are also positive for your business because they can return, and be more productive, sooner.
Additionally, offering parental leave is vital to lessening gender discrimination in the workplace. When fathers (in addition to mothers) are taking leave for new children, it normalizes the act across genders. This normalization helps to reduce the likelihood of gender discrimination in hiring and promotion decisions.
Read more about parental and paid leave.
Financial literacy helps employees by giving them the knowledge and ability to reach self-sufficiency in their daily financial lives. Without this education, according to Investopedia, your staff may fall victim to predatory lending, subprime mortgages, fraud, and high-interest rates.
Paid time off, or PTO, is a paid leave plan that combines sick leave and vacation time. PTO gives employees a set bank of time off at the beginning of each year. Employees can then choose whenever and however they want to use this time off.
PTO gives your employees a more considerable amount of flexibility in how they take their paid leave. Your staff now gets their entire bank of time off to use for sickness, vacation, running errands, or appointments. They no longer have to be one, or the other.
Flexible work options include flexible location, flexible schedule, and flexible time. Each of these options presents unique benefits that can work to aid those dealing with mental health issues.
Flexible location gives your employees the ability to choose where they work. A flexible schedule allows your staff the ability to decide when they work. Flexible hours give your employees the power to select the number of hours they work during the week.
Flexible work is a terrific benefit for those with mental health issues. This benefit allows these employees to work around periods of time during which they are dealing with their mental health. Team members can also work around treatment they receive such as counseling or doctor's appointments.
Find out more about flexible work.
This benefit, like parental leave, is critical for your employees with children. Every parent knows that kids, like consuming too many adult beverages, can oscillate between joyful and awful in minutes.
Looking after a small person's life is a huge responsibility. This responsibility carries a level of stress that is oppositely proportional to the size of these tiny people. So, as an employer, it can be beneficial to both your staff and you to provide childcare benefits.
For example, dependent care assistance programs, child care subsidies, flexible spending accounts, and onsite daycare are all employee benefits that can improve the mental health of your employees with children.
Dependent care assistance programs, child care subsidies, flexible spending accounts, and onsite daycare are all examples of child care employee benefits.
One of the signs of depression and anxiety can be isolation. It becomes a vicious cycle as those depressed isolate themselves, only to find themselves missing the interaction and becoming further depressed.
Still, there are many ways your company can help employees break this negative cycle. Company luncheons, team building activities, or even going out for happy hour are all examples of events your business can use to get your employees out and socializing with their colleagues.
These activities can positively impact your organization in multiple ways too. Obviously helping depressed employees break out of a rut is a positive impact. But they these events also help your team become closer and, hopefully, work more effectively.
The more we learn about mental health, the more we are finding out how much it impacts an individual's total health and their workplace effectiveness. Your employee benefits can be the difference between an employee being lost in the shadows, or breaking through and finding success.
So, make a mental note, and use these 11 benefits to support your staff's mental health at work.


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All News > Deworming Pill For Kids Linked To Better Wages When They Grow Up | NPR
Deworming Pill For Kids Linked To Better Wages When They Grow Up | NPR
News | Aug 11 2020
NPR recently featured research co-authored by CEGA faculty co-director Ted Miguel revealing the twenty-year impacts of a deworming study in Kenya. In the interview, co-author Michael Kremer discusses the study design and updated results of the program.
"An inexpensive way to help kids in poor countries: hand out deworming pills so they're healthy enough to stay in school. A study by a Nobel Prize winner finds 20 years on, they earn higher wages too.
A pioneering study discovered that giving schoolchildren in poor countries a pill that costs as little as 50 cents and protects them from parasitic infections has dramatic effects. This research over 20 years reveals the benefits carry over into adulthood. NPR's Nurith Aizenman reports.
NURITH AIZENMAN, BYLINE: In the mid-1990s, economist Michael Kremer was visiting Kenya.
MICHAEL KREMER: I mean, I was on vacation. I wasn't there for a research trip or something.
AIZENMAN: A friend there mentioned he was starting an aid program to help elementary school kids, including by giving them deworming pills against all sorts of nasty intestinal parasites that can cause kids to miss school.
KREMER: I suggested that if he chose twice as many schools and then they initially started working in half of them and then later, you know, expanded, then they could measure the impact of what they were doing.
AIZENMAN: By comparing what happened to the kids who got the pills first versus those who got them in the expansion up to three years later, you could see if it made a difference. This kind of experiment is called a randomized controlled trial, and it's long been the way that scientists like, say, biologists determine whether a new medication works. But at the time, randomized controlled trials were just starting to gain ground as a tool for economists to check if programs to alleviate poverty worked."
Read the full transcript or listen to the interview at NPR.
Source: Deworming Pill For Kids Linked To Better Wages When They Grow Up : NPR
2022-2023 CEGA Visiting Fellow Request for Applications
January 2022 Impact Note
Health & Psychology
Request for Proposals: 2022 Psychology and Economics of Poverty (PEP) Funding Competition


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Tag: Storytelling
VIRO – Proposal for TV Series – Introduction
July 9, 2020 ~ Barnaby Taylor	~ Leave a comment
And so the task begins, as I start to turn the highly successful VIRO book series into a proposal for a TV series. Over the coming weeks, I will be sharing insights and updates as to how this process is going. So let's begin at the beginning.
VIRO – The TV Series Proposal
GENRE: Horror/Science Fiction – Post-Apocalypse
TAG LINE: Four Kids, One Apocalypse
LOG LINE: As a viral pandemic turns the world into bloodthirsty creatures, a boy with special needs looks for his missing mum.
VIRO tells the story of Jake, a boy born with special needs who wakes one morning to find that the world has been catastrophically overrun by a deadly virus and his mum has not come home after work. Determined but unused to being out on his own, Jake sets off to find her.
The book series is set in the south east of England and Season One takes place in Burton-on-Sea, a fictional seaside town modelled on Hastings. The time is somewhere in the 1970s.
There is no knowing exactly where the virus came from and the point of the series is that no-one will ever know. There is a lot of speculation but no definitive explanation. This makes VIRO darker and bleaker as we soon come to realise that the world will not be saved.
The story is not a race to find a cure but about finding a way to simply survive. Science, like God, and society, is broken now. It makes no difference, especially to a group of teenage friends who don't really have time to try and make sense of what has happened. They just want to stay alive.
VIRO – the Book Series – NEWS FLASH
As a viral outbreak turns the world into bloodthirsty creatures, a boy with special needs looks for his missing mum.
'The writing style is beautifully compelling, and after the first couple of pages I couldn't put it down. The author very skilfully creates a world and characters through deceptively simple prose that draws the reader right in. It is a fascinating blend of one-after-the-other edge-of-the seat scares, alongside a haunting narrative about what it is to be human.'
'Capturing the voice of a young character with special needs (I spent 25 years as a special education teacher/administrator), Taylor's story of a group of young people coping with a world disintegrating in front of them; with the loss of structure and trust, and with betrayal by the adults who should be protecting them is both uplifting and horrifying. Do not be fooled by the simple language of the narrator: there are hard questions asked and realistic, unsentimental consequences to the apocalypse confronting the children, and an ending that you are unlikely to forget easily.'
'I absolutely loved this book. Powerful and poignant, VIRO packs a punch. Sad and haunting, VIRO is a new take on the zombie genre. The characters are dynamic and interesting, finding strength despite their horrifying circumstances. Jake is a character that will stick with you long after the final page. The action sequences are thrilling. I was on the edge of my seat!'
Get your copy today – Book One FREE for download HERE
Inteachán – Book Two: A New Signal 2: 7 'People missing people'
December 6, 2019 December 2, 2019 ~ Barnaby Taylor	~ Leave a comment
And then the posters started.
Like petals fallen from the most hopeless of blooms. Handwritten. Photocopied. Badly printed.
Missing people. People missing people.
Everyone who attended the concert never returned home. Including Inteachán.
Though he knew it was helpless, Mac pinned his poster with the rest of them.
Inteachán – Book Two: A New Signal 2: 6 'The Weeds of Priory Hall'
Cities normally return to nature after desertion.
Sand can cover office blocks.
Shopping centres fall in on themselves.
Civic buildings lose all semblance of significance.
Sewers clog and silt.
Vehicles return their elements to the earth.
Or house new tenants.
Fountains fall silent.
Slowly, troublingly, desperately, inexorably, the weeds of Priory Hall exerted their cosmic influence on the city.
Inteachán – Book Two: A New Signal 2: 5 'It started with the weeds'
As he walked across Front Square Mac felt now that the world was only different.
He knew the First of the TheFive was here. The disturbance was now unignorable. The weight of this fact caused the world to spin ever so slightly out of kilter.
'I knew this was always going to happen,' Mac said to himself. And he steeled himself for the worst.
It started with the weeds.
Inteachán – Book Two: A New Signal 2: 4 'A Brand-New Loneliness'
Loss hits hard and holds firm and deep and long.
After a lifetime of solitude Mac now found himself unable to deal with a brand-new loneliness.
There simply is no substitute for presence.
'I'm a selfish cowardly fool,' he told himself.
'That a man should send a child to stop the darkness.'
Inteachán – Book One: The Song of the NotBeSpeak 1: 29 'The Rock Star'
November 9, 2019 November 5, 2019 ~ Barnaby Taylor	~ Leave a comment
'Look,' said the Rock Star, 'she's awake.'
Inteachán opened her eyes.
'Where am I,' she asked the Rock Star. His eyes were hidden behind giant sunglasses.
'Where we want you to be,' he replied. The Rock Star smiled.
'We know all about you, Inteachán,' he sneered, 'and your silly baby quest to save the world.'
Inteachán didn't respond. The Rock Star continued.
'We know you are the puppet of that old doddering fool of a professor. He says where and you race off on your fool's errands.'
Inteachán still didn't respond. The Rock Star loomed large over her.
'Mac may think he knows what is going on but let me tell you he hasn't got a clue.'
Inteachán – Book One: The Song of the NotBeSpeak 1: 23 'The Fomhóire's Howl'
Inteachán starts to climb the slippery rope. Her small arms are strong. She pulls herself hand over hand. What was once a simple sigh is now a deafening shriek. A shriek that will consume her if Inteachán doesn't get away.
The rope sways violently. Inteachán climbs faster. The shriek swells again and now starts to fill the night. With a final kick Inteachán is free of the darkness. Quickly now she unties the rope and lets it fall to be swallowed by the Fomhóire's howl.
Off the Radio and Other Scary Stories
October 9, 2019 October 9, 2019 ~ Barnaby Taylor	~ Leave a comment
Voices from beyond.
Imaginary friends.
Unsettling sights.
New houses.
Dead dogs.
The scares go on and on.
Off the Radio
'I haven't seen this for years,' Mum said. 'I used to record music off the radio with it.'
We were in the attic. I didn't know what it was. Mum saw I was confused.
'It's my old cassette player.'
Mum picked up something else from the tin. It was a small box with two wheels on it. There was some writing on it. Mum read it out loud.
'Top of the Charts, May 1982.'
She showed me the player.
'You push this button.'
A door in the top popped up.
'You put the cassette inside.'
Mum pushed the small box into the slot. She put the lid down. There was a clear plastic window. There was also a row of buttons along the bottom. One said 'Rec.' Another said 'Play.' Mum pushed down the 'Play' button.'
I looked through the plastic window. The two wheels started turning. Mum was all excited. She was smiling. This made me excited too. I smiled at her. She hugged me.
'This makes me feel like a teenager again.'
A wobbly voice came out of the recorder. It was strange and angry.
'?eM dEbRUtsiD OuY evAH yHw .DLrOw eHT lLa 4 MrAH sI tNAw I Lla'
The Taylor Detective Agency and Other Scary Stories
The Taylor Detective Agency
My name is Ellis. My friends and me are detectives. Olaf and Izzy and Windy. We are the Taylor Detective Agency. We all live on the same street and meet every day under the Waiting Tree in my garden. We do lots of detective things. These are the stories of our adventures.
It is Tuesday morning and there is no sunshine. I am sitting under the Waiting Tree waiting. We meet every morning in the summer holidays. We are a team. We work together well. That makes us better detectives. It was my Dad's idea to form the agency to give me and him something to do. I carried the notepad and a pencil. He carried a camera and a telephone. We would walk around the streets near my house looking for clues. Once we found some pieces of pasta that must have fallen from a shopping bag. Dad said that was the Case of the Broken Spaghetti.
Another time we found a dead bird – Dad called it the Case of the Bird That Doesn't Fly Anymore. I would write down any important details in my notebook and phone them through to Mum at home.
'Mum, we have found a dead bird – D-E-A-D.'
I spelled out the word carefully so that she could write everything down.
'We request permission to proceed with the investigation.'
'Roger that,' said Mum. 'Permission to proceed.'
Olaf is my best friend. He lives next door and only has to climb over the garden wall to meet me under the Waiting Tree.
'I think I saw something important today,' he says. 'I was looking out my window and I saw it.'
I get out my notepad and pencil.
'Now begin at the beginning and tell me what you saw,' I say.
'It was Mister Birdfoot,' says Olaf. 'He had a big box that he put into the boot of his car.'
Mister Birdfoot lived next door to Olaf and all the kids in the street think he is a bit mad. He has bright red hair and lived alone. Mum said his wife had died recently. Just like my dad.
'Why would Mister Birdfoot have a big box?' asks Olaf. 'What has he got inside it?'
I say I don't know. Windy appears.
'Hi Windy,' we say. 'Mister Birdfoot has got a big box and we are wondering what is in it.'
'I don't know,' says Windy. 'It sounds like a job for the Taylor Detective Agency.'
Windy thinks that we should sneak into Mr. Birdfoot's house and take a look.
'We should sneak into Mr. Birdfoot's house and take a look.'
Olaf doesn't like the idea of that. He thinks we might get caught.
'I don't like the idea of that. What if we get caught?'
'Get caught doing what?' asks Izzy who has just sat down next to me.
'Sneaking into Mr. Birdfoot's house,' I say. 'Olaf saw a big box and we think it is a mystery for us to solve.'
'I hope so' says Izzy. 'I love us solving mysteries.'
'I have a plan,' says Windy. 'We should all sit on the bench opposite Mr. Birdfoot's house and wait to see what happens next.'
'Follow me,' says Olaf. 'Don't forget your notepad, Ellis.'
'I have it here,' I say, patting my small rucksack. 'I've also got my pencil and a tape measure.'
'Why a tape measure?' asks Izzy.
'Just in case,' I say. 'My dad always said you never know what you might need to know.'
It makes me happy to remember what my dad used to say. But it makes me sad that he's not here anymore to say it.
'I've got four apples,' says Izzy. 'One for each of us as always.'
'I think that my bottle has some water left in it,' says Windy. He shakes it to see. We all hear the slosh.
It was later. We had been waiting a long time. All the apples were gone. And the water. I felt a bit strange.
'Maybe we shouldn't be doing this.'
Olaf pointed at some bushes.
'Would you feel better if we were hiding?'
'Hiding,' said Izzy. 'I love hiding. Let's do that.'
I looked at the bushes. They were big. It would be safe there.
'Yes,' I said. 'Let's hide in those bushes.'
'We can still see Mr Birdfoot's house,' said Olaf, 'but he won't see us.'
It was more later when Mr Birdfoot finally came home. He stopped his car.
'Ssssh!,' said Olaf. He put his fingers to his lips.
Mr Birdfoot opened the boot of his car. He looked around. He didn't want anyone to see him. We kept watching. I felt scared and safe together.
Mr Birdfoot got out the big box. It was really heavy. He looked around again. The box had all red stuff coming out of it. The red stuff fell on the pavement. Mr Birdfoot went inside his garage. When he came back he had a big brush and a bucket of water. He scrubbed the red stuff on the pavement until it went away.
It was the next day. Me and my friends sat under the Waiting Tree. Olaf and Izzy and Windy. We talked about Mr Birdfoot.
'Who carries a box of red stuff around in their car?' Olaf says.
'I don't know,' said Izzy.
'Me neither. I don't understand.'
Windy had an idea.
'I think this is definitely a job for the Taylor Detective Agency.'
'Me too,' said all of us.


But the question remains, will these fruit be fun enough to capture your imagination or just leave you feeling like a sour lemon? Take a look at this review of Fruit Fest from Novomatic for all the information you could possible need.
With all of the fruit characters on the reels exploding with life, it's kind of obvious that the graphics in this game are more cartoon like than based in realism! After all, when did you last see a grinning strawberry….?!
And these fruit punnets are jam packed with personality with a whole range of facial expressions that simply defy you not to fall in love!
From beaming stars (OK, not technically a fruit…) to coquettish lemons and alarmed oranges, there's no end to the interesting features you'll find in this game.
Novomatic have deliberately designed the game so that all of the emphasis is on the reels. The background is a deep red – considered a very lucky colour in some cultures! – and this swirls and sparkles without being a distraction.
Before you send your fruity friends whizzing around the reels you'll need to take a look at the betting set-up so you don't blow your budget in a single move.
It's an unusual set up because there's neither 3 reels nor 5 reels, Novomatic have opted for the odd decision to create four! And on these four reels there's 10 paylines with the possibility of betting between 4 and 1,000 per line. This creates a total max bet of 10,000 for those who want to bet high.
You might want to check out the prizes before you decide how much to bet so head over to the paytable.
You'll get a payout for matching up three or four symbols along an active payline with the wins starting at 60 for a combination of three. This increases to 20,000 for a line of four of the top value symbol.
As well as lining up the regular symbols on the board, you can also increase your prizes in other ways too.
Look out in particular for the party games which appear on the reels when unlocked. Match three to win 10 party games or match four to land 30 party games.
During the party games, just like the main game, you'll be looking for a match on the reels but once a win has been identified and the credits added to your balance, these symbols then disappear. The rest of the board moves down and new symbols are added. The process is then repeated with any more winning lines being added.
The party games only stop once there are no more winning combinations visible on the board.
You can play the slots whether you're naturally a cautious individual or an adrenaline-seeking risk-taker! Simply alter your strategy to suit your outlook and start to play.
However, if it's the really big prizes you're chasing then the Gamble feature might be of interest but it's not a game for the faint of heart.
If you win the Gamble feature, you can opt to repeat it again up to five times. Of course, the more you play it the greater the chance that you'll eventually fail with your luck running out so it's up to you how often you want to gamble, if at all.
Fruit Fest by Novomatic is an online slot which doesn't look particularly modern but offers a flawless play even if it isn't the most innovative on the market. Fusing classic slots with a more contemporary feel, this game is likely to be enjoyed by a wide variety of players.


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This is a list of video games for the PlayStation 2 video game console that have sold or shipped at least one million copies. The best-selling game on the PlayStation 2 is Grand Theft Auto: San Andreas. An action-adventure game developed by Rockstar North, San Andreas was originally released in North America on October 26, 2004, and went on to sell 17.33million units worldwide. The second-best-selling game on the console is Gran Turismo 3: A-Spec (2001), which sold  units. The top five is rounded out by Gran Turismo 4 (2004) selling 11.76million units, Grand Theft Auto: Vice City (2002) with  units sold, and Final Fantasy X (2001) with 8.5million units sold.

There are a total of 163 PlayStation 2 games on this list which are confirmed to have sold or shipped at least one million units. Of these, 30 were published in one or more regions by Sony Computer Entertainment. Other publishers with multiple million-selling games include EA Sports with twenty games, Electronic Arts with eighteen games, Capcom with fourteen games, Activision and THQ with twelve games each, and Konami with ten games. The developers with the most million-selling games include EA Tiburon with twelve games and Capcom and EA Canada, with nine games each in the list of 113. The most popular franchises on PlayStation 2 include Grand Theft Auto ( combined units), Gran Turismo (29.61million combined units), Madden NFL (23.48million combined units), Final Fantasy ( combined units), and Pro Evolution Soccer ( combined units). The oldest game on this list is Tekken Tag Tournament, first released on the platform on March 30, 2000.

As of March 31, 2007, a total of 1.24billion copies of PlayStation 2 software had been shipped worldwide. Between April 1, 2007, and March 31, 2012, an additional 297.5million copies had been sold. Note that since the former figure refers to shipments and the latter refers to sales, there may be overlap between the two figures.

List

Notes

References

PlayStation 2
Best-selling PlayStation 2 video games

redpajama_set_name: RedPajamaWikipedia


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Home » Trending » Michigan Shooting Suspect Ethan Crumbley Mugshot Photos And His Background Details To Know
Michigan Shooting Suspect Ethan Crumbley Mugshot Photos And His Background Details To Know
Ethan Crumbley Mugshot Photos Displayed On Social Media
More On Ethan Crumbley Origin And Ethnicity
Did Ethan Crumbley Have A Girlfriend?
Michigan shooting suspect from Oxford High School Ethan Crumbley's mugshot and his parent's photos has been shared on the internet. See his origin and ethnicity below.
Ethan Crumbley is a kid who shot four students for being bullied on Wednesday. He allegedly opened fire in the classroom that injured seven individuals, and four students were killed in the school massacre.
Reportedly, Crumbley continuously fired 16 or 17 rounds on the school premises. He was under arrest on Wednesday with an armed weapon, police confirmed.
Moreover, Ethan is a sophomore student at Oxford High School, and he is an active shooter that left seven students wounded, plus four students killed.
As per the recently updated news from New York Post, before the deadly shooting at the Oxford High School on Tuesday, Ethan's parents were called out for a meeting due to his behavior in the classroom.
Ethan's mugshot has been displayed in the media. His photos were being shared on several news channels and social media platforms.
Ethan Crumbley made his first court appearance after being charged in connection with the Oxford High School shooting. Details of the allegations were shared and a transfer from the Children's Village to the Oakland County Jail was requested. https://t.co/yZp8O86AsM
— Local 4 WDIV Detroit (@Local4News) December 1, 2021
The 15-year-old student Ethan was a suspected shooter. According to the Detroit News, Police discovered a backpack. Crumbley has a journal on his school backpack with a complete plan of attacking in the school.
Nevertheless, Ethan's desire to shoot all the students is possibly described as a hate crime. Also, he has access to a firearm and practiced with a Sig Sauer handgun.
Currently, Ethan has been detained in Oakland County Children's Village, reports confirmed.
Ethan's ethnicity is white. Also, he is originally from Michigan. The white native American killed four students in November 2021.
Regarding Ethan's nationality, he holds an American nationality.
For Hana, Tate, Madisyn, Justin, and their families. For the entire Oxford community.
Michigan stands together. pic.twitter.com/gbsRdK58qO
— Governor Gretchen Whitmer (@GovWhitmer) December 1, 2021
Discussing his family background, Ethan was born to American parents, James (father) and Jennifer Crumbley (mother). Reports affirmed, Ethan's mom and dad were hauled into the school on Tuesday to meet with administrators, as they are concerned about his strange behavior in the classroom.
Ethan's girlfriend details are missing from the source lately. However, students described him as a silent person. He barely talks to anyone in the school, one of his colleagues said.
Whatsoever, the convicted murderer Ethan has been charged as an adult with terrorism, four counts of first-degree murder, and gun possession, and other charges.
Did you know? Ethan took his dad's 9mm semi-automatic handgun that he bought on Black Friday to execute his plan, which he has been planning for a while.


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Top » Catalog » Geopolitics » IDR Home | My Account | Cart Contents | Checkout
The New Arthashastra: A Security Strategy for India Rs.799.00/-
For a country that has fought five wars and is hemmed in by nuclear-armed states, India surprisingly does not have a formally declared national security strategy. All the major powers of the world publish documents that spell out their national interests, identify their threats " political, economic, diplomatic or with regard to security " and draw up policies to deal with them.
The absence of a similar doctrine makes India's defence policy look ad hoc and creates the impression that the country is unprepared to realize its global ambitions. The New Arthashastra is a path-breaking attempt to recommend a national security strategy for India. It does the difficult groundwork for India's political leaders and policymakers by bringing the best names " from within the community as well as from the armed forces and academia " to the ideating table.
This collection of twenty essays covers a wide range of topics: nuclear deterrence, defence spending, the domestic production of weapons, and bracing for the wars of the future that will be fought in space and cyberspace. Most important, it presents a roadmap to address India's chief concerns: Chinese assertiveness and Pakistan's unrelenting proxy war. Informed by the expertise of analysts with inside-out knowledge of their domains, The New Arthashastra offers enduring and practical insights to strategists and lay readers alike.
Author: Brig Gurmeet Kanwal (Ed)
Features: HB, HarperCollins
This product was added to our catalog on Friday 11 November, 2016.
China: Threat or Challenge?
BOSE: An Indian Samurai Netaji and the INA A Military Assessment
Voices from the Border: Response to Chinese Claims over Arunachal Pradesh
Changing Demographics in India's Northeast and Its Impact on Security
For King and Another Country: Indian Soldiers on the Western Front, 1914-18
India's War: The Making of Modern South Asia 1939-1945
Notify me of updates to The New Arthashastra: A Security Strategy for India


Today's rapid technological and social changes make it increasingly difficult for us to understand and keep pace with the modern world. This has put our school under terrific pressure to re-evaluate what should be taught in an age when no one can predict the skills that our children will need when they reach maturity.
In the past, when mankind's store of knowledge was relatively fixed and limited, the most efficient education consisted of lecture, drill, and memorization.
In an era of technological revolution and social change, the foundation of a good education is to learn how to learn.
Our course of study encompasses the full substance of the traditional curriculum, and goes beyond to teach students how to think clearly, do their own research, express themselves well in writing and speech, and to put their knowledge to practical application.
We have organized our course of study as an inclined spiral plane of integrated studies, rather than a traditional model, in which the curriculum is compartmentalized into separate subjects with given topics considered only once at a given grade level. In Montessori, lessons are introduced simply and concretely in the early years, and are reintroduced several times over the years at increasing degrees of abstraction and complexity.


The International Digital Enterprise Alliance's (IDEAlliance's) G7 methodology for calibrating inkjet printers and other devices improves wide-format graphic production by ensuring colours are more consistent and repeatable throughout the workflow. The successful implementation of this methodology involves adopting industry best practices as day-to-day processes, starting at the design phase.
Many signmakers have never heard about G7, while others have only a limited understanding of it. G7 is not a gadget, quick-fix solution, gimmick or buzzword. It will not fix all of a sign shop's printing problems or even all of its colour problems.
G7 is a process for calibrating a cyan, magenta, yellow and key/black (CMYK) device to a known 'good' print condition, based on a neutral grey point. This calibration process takes into account both the white point and the solid black point of the substrate. Between these two points, a series of curves are created for the CMYK channels to balance them to the black.
About 10 years ago, when the G7 methodology was originally being developed, the calibration was performed with graph paper or a complicated Microsoft Excel spreadsheet. Nowadays, all of the 'heavy lifting' is done by software, whether stand-alone or within a raster image processor (RIP).
All print service providers (PSPs) inevitably have to do at least a little tweaking with client-supplied artwork as it enters their facilities. After all, most such artwork was not designed with the specific substrate, ink type and output device in mind. What designers can do at the beginning to improve the process, however, is to keep colour management in mind.
Today, almost all wide-format graphic files originate in mainstream design software, such as Adobe Creative Suite, which includes PhotoShop, InDesign and Illustrator. No matter which application within Adobe's suite is chosen for file creation, the colour management setup is, conveniently, the same—but the default setting is not optimal for printing. So, for sign shops, it is important to edit the settings, paying special attention to the colour space options for red, green and blue (RGB) workstation screens and CMYK printers.
For RGB, the default working space setting for is standard RGB (sRGB) International Electrotechnical Commission (IEC) 61966-2.1, while for CMYK, it is Specifications for Web Offset Publications (SWOP) version 2. The problem with both of these default settings is they greatly restrict the size of the colour gamut.
In printing, it is recommended to change the RGB working space setting to Adobe RGB (1998) and the CMYK setting to General Requirements for Applications in Commercial Offset Lithography (GRACoL) 2006 Coated and International Organization for Standardization (ISO) 12647-2:2004, Graphic technology: Process control for the production of half-tone colour separations, proof and production prints, Part 2: Offset lithographic processes. Both of these will open up the colour gamut, setting the stage for a better print job with more precise and accurate colours. And they can be saved as 'presets,' so there is no need to change them at the beginning of every new project.


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Energy Resources | Power Plants | Renewable Resources | Project Updates
John P. Madgett Station
The John P. Madgett Station (JPM) is adjacent to the Alma Station, just south of it on the Mississippi River. JPM was built in the late 1970s at a cost of $179 million.
Named after the late John P. Madgett, general manager of Dairyland Power Cooperative from 1947 to 1978, JPM has been in commercial operation since November 1979. The single unit station has a generating capacity of 400 MW of electricity.


Alibaba offers 1,733 Galvan Steel Plate Suppliers, and Galvan Steel Plate Manufacturers, Distributors, Factories, Companies. There are 1,091 OEM, 971 ODM, 234 Self Patent. Find high quality Galvan Steel Plate Suppliers on Alibaba.


A bold new thriller from one of Britain's finest crime writers.
Germany, September 1944: Dozens of cities lie in ruins. Enemy armies are at the gates, for the Thousand Year Reich, time is running out.
Desperate to avoid the humiliation of unconditional surrender, German intelligence launch Operation Finisterre – a last ditch plan to enable Hitler to deny the savage logic of a war on two fronts and bluff his way to the negotiating table.
Success depends on two individuals: Stefan Portisch, a German naval officer washed ashore on the coast of Spain after the loss of his U-boat, and Hector Gomez, an ex-FBI detective, planted by Director J. Edgar Hoover in the middle of the most secret place on earth: the American atomic bomb complex in Los Alamos, New Mexico. Both men will find themselves fighting for survival as Operation Finisterre plays itself out.


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Male Black Widows Flip Sexual Cannibalism
A black widow spider spinning egg case silk. (Image credit: Biology Department of the University of California, Riverside.)
Black widow spiders get their names from the belief that the female devours her partner after sex. But this gruesome ritual doesn't always happen after mating and sometimes, the roles are even reversed, researchers say.
For choosy female black widows, sexual cannibalism is an extreme way to assert their partner preference, with less desirable males more likely to be chased down and eaten after they insert their sperm-coated palps into a female.
But in the species Micaria sociabilis, males are more likely to eat the females than be eaten, a new study found.
A team at Masaryk University in the Czech Republic studied how different pairings of the spiders interacted in a lab, making sure the creatures were well-fed to rule out hunger-driven cannibalism.
Males ate the females typically after the spiders' first contact and before any mating, with the culprits most often males from the summer generation, the researchers found. These males tend to be larger than their counterparts born into the spring generation, suggesting size matters in aggression.
Meanwhile, age might be a dooming factor for the female Micaria sociabilis. There was a peak in reverse sexual cannibalism when males from the summer generation encountered older females from the spring generation, the researchers found. What's more, not even virginity or big body size, often considered signs of mating quality for spiders, could save the older females from male cannibalization.
The study shows that males in at least one black widow species, M. sociabilis, can make a clear choice about which females they will mate with, and their selection may be highly dependent on age.
"Our study provides an insight into an unusual mating system, which differs significantly from the general model," researchers Lenka Sentenska and Stano Pekar wrote. "Even males may choose their potential partners and apparently, in some cases, they can present their choice as extremely as females do by cannibalizing unpreferred mates."
The research was detailed in the journal Behavioral Ecology and Sociobiology.
Follow Megan Gannon on Twitter and Google+. Follow us @livescience, Facebook & Google+. Original article on LiveScience.com.
Live Science Contributor
Megan has been writing for Live Science and Space.com since 2012. Her interests range from archaeology to space exploration, and she has a bachelor's degree in English and art history from New York University. Megan spent two years as a reporter on the national desk at NewsCore. She has watched dinosaur auctions, witnessed rocket launches, licked ancient pottery sherds in Cyprus and flown in zero gravity. Follow her on Twitter and Google+.


The Kincaids have worked in Guatemala and Mexico for almost fifty years. They have established the largest work among the Chamula Indians in the country of Mexico. Their Bible school, located in Reynosa, Mexico, has produced numerous pastors and Christian workers now ministering throughout Mexico and Central America.


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The Mycelium Revolution Is upon Us
It's the fungus mushrooms are made of, but it can also produce everything from plastics to plant-based meat to a scaffolding for growing organs—and much more
By Eben Bayer on July 1, 2019
Mycelium growing on a tree stump. Credit: Richard Tullis Getty Images
Humans have been harnessing the power of yeast for thousands of years. These fungi allow fermentation, the molecular process whereby living cells typically transform sugar or starch into more complex molecules or chemicals. Discovered 10,000 years ago, the technology of liquid fermentation—from mead to beer to spirits—and solid-state fermentation—bread and cheese—helped put humanity on a rapidly accelerating path of evolution and advancement.
Fast forward 9,950 years. Around three decades ago, humans applied the potential of liquid fermentation to create medicines. In 1978 Arthur Riggs and Keiichi Itakura produced the first biosynthetic insulin using E. coli as a single-celled manufacturing plant. The epiphany that single-celled bacteria and yeast are sugar-powered microfactories that can be utilized to synthesize novel compounds is one of the most powerful discoveries of the past 100 years.
Since that revolutionary insight occurred, science has been devoted to understanding, cultivating and ultimately reprogramming single-celled organisms such as yeast, bacteria and algae, and we've been using the process to make more lifesaving drugs, biobased fuels such as corn ethanol, fragrances and a growing suite of small biological molecules. Liquid fermentation is now a 150-billion-dollar industry and growing rapidly: many of the products we use today are moving from chemical factories to biological fermenters.
But cells can do much, much more than produce compounds. Plants, animals and fungi all make molecules and assemble them into large structures. We can see this in our own bodies: our cells build bones, skin and organs—including human brains, the most powerful supercomputer on Earth. It's the combination of 1) making small molecules and 2) assembling them into structures that gives natural technology its miraculous properties. This is what enables a plant to capture a photon from the sun and generate a berry or apple—gobsmackingly[there's a lovely Britishism!] precise and intricate combinations of materials.
Our own attempts to emulate nature's structure-building capacity has thus far depended on 20th-century technologies such as extrusion and heat extraction, processes that brutalize small molecules to create crude polymerized structures. Ultimately through these processes we end up with products that are far inferior to nature's originals—pleather versus leather, particleboard versus wood and synthetic textiles, to name a few. Without nature's capacity for microassembly, the best properties of natural materials are lost.
Enter mycelium. Mycelium is technically a kind of a yeast, but unlike most yeast cells, which grow as a single cell, mycelium is multicellular and can grow into macro-size structures—which we most often recognize as mushrooms. Not only does mycelium produce small molecules, but it gently and with supreme precision assembles them into complex structures so small that they are invisible to the human eye.
Working much like single-celled yeast, mycelium takes in small molecules of food—typically sugar but often from sources such as wood or plant waste—by excreting enzymes that break these materials down into digestible morsels. As the mycelium grows it assembles a dense network of long, microscopic fibers that grow through the substrate like a superhighway system.
Once the mycelium has fully built its network, it transitions to its next stage: building a mushroom. This is where humans can intervene. Rather than letting a mushroom pop up out of the substrate, the mycelium can be coaxed to build predictable structures by controlling temperature, CO2, humidity and airflow to influence the growth of tissue. This is a rapid process: the accumulation of fibers becomes a visible speck after a few hours, a visible sheet after a day or two, and an 18-by-2-by-12-inch sheet weighing a couple of pounds within the course of a week.
Directing the growth of mushroom fibers may not sound like a big deal, but this evolution in biofabrication stands to transform the way we manufacture, consume and live. What are the possibilities? Mycelium's fast-growing fibers produce materials used for packaging, clothing, food and construction—everything from leather to plant-based steak to scaffolding for growing organs. Mycelium, when harnessed as a technology, helps replace plastics that are rapidly accumulating in the environment.
Mycelium also provides a cruelty-free way to create meatlike structures with a much smaller environmental footprint than traditional livestock, reducing greenhouse gas emissions, the use of food crops for feed and land use conversion. All these benefits come with little environmental cost: the process of growing mycelium results in limited waste (mostly compostable) and requires minimal energy consumption.
This is not hypothetical. The technology for using mycelium to assemble the things that we need at scale already exists. Mushroom® packaging is on the market as a replacement for Styrofoam and is available in both the U.S. and Europe. Meanwhile, research on mycelium is accelerating as groups around the world, including leading academic institutions, are beginning to build programs around mycelium materials. For example, mycelium-based self-repairing structures—just add water and watch them grow—that also respond by synthesizing antidotes when exposed to toxins are currently being developed by DARPA.
Humankind needs to find ways to get ourselves out of the mess we've created. Our world is an ecosystem maintained by self-assembling organisms. Now we have taken the helm, we must use these organisms to steer, repair and rebuild our stressed yet faithful celestial transport. Biological technology is the most powerful technology we have access to, and with the proper harnessing, we can use it to live in harmony on spaceship Earth.
The views expressed are those of the author(s) and are not necessarily those of Scientific American.
Eben Bayer
Eben Bayer is the CEO and co-founder of Ecovative, a firm that uses biology to solve industrial and environmental challenges. He grew up farming in central Vermont, and now lives off-grid in the woods of the Hudson Valley. Follow him on Twitter @ebenbayer.
What Game of Thrones Reveals about Moral Decision-Making
By Jim A.C. Everett and Molly J. Crockett on July 1, 2019
Why City Rankings Matter
By Michele Acuto, Daniel Pejic, Jake Nunley and Tim Moonen on July 2, 2019
© 2019 Scientific American, a Division of Nature America, Inc.