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Many different types of nanoparticles, magnetic nanoparticles being just a category among them, offer exciting opportunities for technologies at the interfaces between chemistry, physics and biology. Some magnetic nanoparticles have already been utilized in clinical practice as contrast enhancing agents for magnetic resonance imaging (MRI). However, their physicochemical properties are constantly being improved upon also for other biological applications, such as magnetically-guided delivery systems for different therapeutics. By exposure of magnetic nanoparticles with attached therapeutics to an external magnetic field with appropriate characteristics, they are concentrated and retained at the preferred site which enables the targeted delivery of therapeutics to the desired spot.
The idea of binding chemotherapeutics to magnetic nanoparticles has been around for 30 years, however, no magnetic nanoparticles as delivery systems have yet been approved for clinical practice. Recently, binding of nucleic acids to magnetic nanoparticles has been demonstrated as a successful non-viral transfection method of different cell lines in vitro. With the optimization of this method called magnetofection, it will hopefully become another form of gene delivery for the treatment of cancer.
Nanotechnology is an interdisciplinary field of technological developments on the nanometer scale offering comprehensive applications also to biomedicine. Engineering particles a several tens of nanometers in diameter has opened new possibilities for targeting cells within an organism either for diagnostic or therapeutic purposes.
Magnetically-guided drug or gene targeting using magnetic nanoparticles is a promising approach for cancer chemotherapy and cancer gene therapy. The rationale behind these two treatment modalities is based on binding either chemotherapeutics or nucleic acids onto the surface of magnetic nanoparticles which are directed to and/or retained at the tumor by means of an external magnetic field. Researchers have been studying magnetically-guided drug targeting since the late 1970’s1, however, magnetically-guided gene targeting has emerged as rapid and efficient approach in the beginning of the new millennium.2 Magnetic nanoparticles have been explored predominantly in basic and translational research in the field of oncology although some of them have been already clinically approved as contrast enhancing agents for magnetic resonance imaging (MRI).3
To date, there is no uniform definition of a nanoparticle. According to Kreuter, a nanoparticle is a solid colloidal particle ranging in size from 1 to 1000 nm.4 In nanomedicine, »nano« can be applied to materials or surfaces that are intentionally altered and manipulated at nanometer scale resulting in new properties.5 Besides the differences in size, nanoparticles are also distinguished based on their shape and chemical composition (Table 1).
Despite the fact that many nanoparticles measure more than 100 nm in one dimension, a novel explanation of a nanoparticle based on the following foundations has emerged. First, the majority of nanoparticles for biomedical applications are prepared as colloidal dispersions, i.e. homogenous chemical mixtures of two separated phases. The homogeneity of dispersed-phase particles into a continuous-phase aqueous medium is only possible if dispersed-phase particles have a diameter between 5 and 200 nm.6 Second, unique differences of physical properties that distinguish nanoparticles from atoms as well as from the bulk material are the most prominent below 100 nm. Hence, a nanoparticle is defined as a particle of any kind of material which has one or more dimensions equal to or smaller than 100 nm (Figure 1).7
Nanoparticles consisting of iron, nickel and/or cobalt which exhibit magnetic properties are called magnetic nanoparticles.8 Elemental manganese which has a complex crystal structure and unusual magnetic properties can also display magnetic behavior after special physicochemical treatment.9
Briefly, the magnetic properties of a material are the reflection of magnetization which arises from magnetic moments of unpaired electrons due to their orbital motion around the nucleus of an atom and intrinsic spinning around their axes. Due to the thermal fluctuations of magnetic moments that reverse direction, some magnetic nanoparticles exhibit superparamagnetic properties which are defined as the nonappearance of magnetic behavior when the magnetic field is not present.10 Superparamagnetic properties are observed at sizes smaller than 15 nm for iron oxide maghemite (γ-Fe2O3).11 Hence, magnetic nanoparticles which are small enough, composed of iron oxide and display magnetic behavior only in the presence of a magnetic field are called superparamagnetic iron oxide nanoparticles (SPIONs). It is essential to use SPIONs in biomedical applications since the permanent magnetic behavior of magnetic particles within an organism would be redundant or even destructive when the magnetic field is removed. For example, magnetically induced deformation of endosomes containing paramagnetic nanoparticles was shown by the transmission electron microscope (TEM).12
Most studies discussed in this review refer to SPIONs, however not all of them. Hence, the superior term magnetic nanoparticles will be used also for SPIONs in order to make the manuscript more lucid and organized whereas the term SPIONs will be used only when emphasizing the importance of superparamagnetic behavior of the nanoparticles. The majority of magnetic nanoparticles as targeted delivery systems are chemically iron oxides (Table 1). Iron is essential to nearly all known organisms and even endogenic iron oxide nanoparticles were detected in the human hippocampus.13,14 However, at the cellular basis, iron oxide causes direct cytotoxicity due to the generation of oxygen and nitrogen-based atoms with an unpaired electron, i.e. reactive oxygen and nitrogen species (ROS and RNS).15 Therefore, magnetic nanoparticles are predominantly prepared through the use of core-shell methodology. As reviewed by Gupta and Gupta, the magnetic core of iron oxide nanoparticles is composed of magnetite (Fe3O4) and/or maghemite (γ-Fe2O3) whereas their shell surface coating can be of organic compounds, including surfactants and synthetic or natural polymers, or inorganic material, such as silica, carbon, precious metals or oxides.16 Synthesis of core-shell type magnetic nanoparticles is important due to the several reasons: (i) protection of the magnetic core from oxidation, (ii) protection of the surface from chemical reactions, (iii) avoidance of aggregates and agglomerates formation due to Van der Waals forces, hydrophobic effects and magnetic attractions, (iv) facility of the various therapeutics attachment and (v) amplification of the cellular uptake rate.17
Biocompatibility of magnetic nanoparticles depends on the type of their surface coating which can be biodegradable (e.g. certain polymers) or non-biodegradable (e.g. silica) as well as on their size. The thickness of the coating determines the total size of magnetic nanoparticles, i.e. coating with an inorganic material in general results in smaller particles below 100 nm whereas a polymer coating is predominantly reflected in larger particles above 100 nm.18,19 The type of the coating determines characteristics of the particle surface, such as hydrophilicity and surface charge.
For biomedical applications magnetic nanoparticles are predominantly prepared as ferrofluids, i.e. magnetic liquids, thus their surface charge is established by ionization of surface groups or by adsorption of charged species of a surrounding liquid medium onto the particle surface which results in a layer around the particle. The potential difference between the surrounding liquid medium and the layer around the particle is called the zeta potential. Particles with a zeta potential higher than 30 mV, either positive or negative, will repel each other, stay asunder and result in a stable ferrofluid.6
The use of magnetic nanoparticles as drug or gene delivery systems can contribute to the effectiveness of cancer therapy in many ways. First, an advantage of using magnetic nanoparticles over non-magnetic ones is that magnetic behavior allows monitoring and quantitative determination of their biodistribution by MRI, which facilitates optimal dosing in cancer therapy. Second, targeting of tumors by magnetic nanoparticles can overcome some supplementary hindrances in more efficient treatment of cancer, such as insufficient penetration of certain therapeutics from the bloodstream into the tumor. Third, targeting of tumors with magnetically-guided nanoparticles provides site specificity and thus selectivity of the therapy, which results in reduced side effects and lower cost of the therapy. And last, exploiting the magnetic field as the driving force represents a non-invasive therapeutic approach.10
The basic principle of using magnetic nanoparticles for targeting in oncology is to increase antitumor efficacy while at the same time reduce undesired systemic side effects towards normal tissues by (i) passive targeting, (ii) active targeting and/or (iii) targeting with an external magnetic field. Passive and active targeting can be achieved irrespective of nanoparticles possessing magnetic behavior. Passive targeting is referred to the extravasation of nanoparticles from the blood-stream into the tumor due to disorganized and leaky tumor vasculature.20 Active targeting is related to appropriate ligands, predominantly monoclonal antibodies, their fragments, inhibitors of tyrosine kinase domains and most recently aptamers, which actively target tumor markers and are attached to nanoparticles.21 Ligands can target extracellular matrix, surface receptors on endothelial cells of tumor vessels or pericytes and tumor cell surface receptors.22 On the other hand, targeting by means of an external magnetic field can only be possible in the case of magnetic nanoparticles. Combining active targeting and targeting with a magnetic field provides double-targeting where the magnetic field represents an initial targeting vector that concentrates magnetic nanoparticles in the tumor followed by second level active targeting by means of ligands, bound onto the surface of magnetic nanoparticles that are specific for tumor cells.
Magnetic nanoparticles are in most cases manipulated by a magnetic field which is generated by high-field, high-gradient, rare earth magnets, such as neodymium iron boron (Nd-Fe-B) magnets. Nd-Fe-B magnets are the strongest type of permanent magnets which have been commercialized not earlier than 1986.23 The basic principle of magnetically-guided targeting is to place a magnet over a targeted site, i.e. a tumor, in order to in situ concentrate and/or retain magnetic nanoparticles.
If targeting with an external magnetic field is in conjunction with bare magnetic nanoparticles with no attached therapeutics, such a kind of cancer therapy relies on intentional obstruction of tumor vessels. Cancer therapy aiming to obstruct tumor vessels with magnetically guided microparticles composed of carbonyl iron was performed in the early 1970s. Unfortunately, the material displayed low in vivo stability as well as a low ability to be guided by the magnetic field.24 More than two decades later, magnetic nanoparticles were intravenously administrated to mice prior to applying the magnetic field with a flux density of 200–500 mT for 20 min above the subcutaneously transplanted colon carcinomas or hypernephromas. This caused complete and permanent tumor remissions due to tumor blood vessels obstruction.25 Compared to active targeting with antibody-bound magnetic nanoparticles, targeting with bare magnetic particles by sufficiently long exposure (6 h) to the magnetic field with a flux density of only 2.5 mT resulted in comparable retention at the targeted site, in this case lungs and heart.26
Efficient internalization of magnetic nanoparticles into targeted cells and subsequent therapy outcome are limited by several factors, such as (i) cytotoxicity, (ii) nanoparticle aggregation due to increased surface/volume ratio and (iii) short plasma half-life due to their elimination from the bloodstream by phagocytic cells. In general, biocompatibility of magnetic nanoparticles mainly depends on their physicochemical properties whereas the route of administration and characteristics of an applied magnetic field also affect cellular uptake and biodistribution.27,28
It is known that different therapeutics get in contact with cells mainly by Brownian motion during a given incubation time. Hence, the crucial limitation in achieving more efficient delivery of therapeutics to the cells is the lack of contact between the delivery system and cellular surface. The contact between the therapeutics and cellular surface can be increased by exploiting the gravitational force29 as well as magnetic force.
Manipulating the magnetic force in vitro leads to accelerated sedimentation of magnetic nanoparticles onto the cellular surface and does not directly affect their internalization.30,31 Magnetic nanoparticles exposed to Nd-Fe-B magnets with the remanence of approximately 1 T, i.e. the strength of the magnetic field at the core of the magnet, were detected in vitro onto the cellular surface within a few minutes.32
Once the magnetic nanoparticles are located onto the cellular surface, fast internalization begins. Results obtained by mechanics modeling demonstrate that particles in the size range of tens to hundreds of nanometers can enter cells even in the absence of clathrin or caveolin-mediated endocytosis.33 However, the majority of experimental studies concluded that internalization of magnetic nanoparticles was mediated through endocytosis, beginning with the invagination of the plasma membrane at either clathrin-coated pits or caveolaes.18,31,34–36 The extent of involvement of clathrindependent and caveolae-mediated endocytosis seems to be cell dependent.31
Irrespective of nanoparticles possessing magnetic behavior, authors of studies have reported about more efficient membrane crossing and cellular uptake of smaller particles in comparison to larger ones, e.g. 10–20 nm vs. 1000 nm and 70 nm vs. 200 nm.37,38
Malignant cells are more prone to internalization of magnetic nanoparticles than normal cells (Figure 2).18,35,39,40 The reason is that malignant cells possess a higher endocytotic potential than normal cells due to their enhanced requirement for nutrients in virtue of their high metabolic activity and proliferation rate.41 This makes magnetic nanoparticles especially suitable for delivery of anticancer therapeutics into tumor cells.
Once internalized, magnetic nanoparticles with attached therapeutics remain within the maturing endosomes until they fuse with lysosomes where they are exposed to digestive enzymes. Linkage between a magnetic nanoparticle and a therapeutic has to overcome degradation within body fluids but has to achieve fast and simple cleavage once magnetic nanoparticles are internalized into cells. Various molecules can be linked to magnetic nanoparticles in order to release their cargo from the endocytotic-degradative pathway.
In the case of gene delivery, endosomal escape of nucleic acids is in most cases achieved by the proton sponge effect of endosomolytic polymers, such as polyethylenimine (PEI).31,42–44 Due to the large number of amino groups PEI possesses a high buffering capacity which in the acidic environment of the endolysosomes induces proton entry and accumulation, followed by passive chloride influx leading to osmotic swelling of the endolysosomes. Endolysosomes burst releasing their content into the cytoplasm.45 Irrespective of the applied magnetic field, binding of PEI to the surface of magnetic nanoparticles increased transfection efficiency of anti-GFP siRNA in stably transduced cervical cancer HeLa cells with GFP for 20% at siRNA concentrations as low as 8 nM.42 Moreover, under magnetic field guidance, addition of free PEI to already PEI-modified magnetic nanoparticles resulted in an approximately 8-fold increase in transfection efficiency of the luciferase reporter gene to Swiss albino mouse fibroblasts (NIH 3T3) in comparison to transfection using just PEI-modified magnetic nanoparticles.42
However, as PEI is vastly cytotoxic44,46, also other molecules are attached to magnetic nanoparticles, such as fusogenic peptides and cell-penetrating peptides (CPPs).28,47,48 Fusogenic peptides, e.g. INF-7, are able to form membrane channels in response to low pH which leads to the disruption of an endosome.49,50 CPPs, e.g. Tat peptides, are a family of proteins containing short cationic or amphiphatic polypeptide sequences, termed the protein transduction domain that have the ability to cross cellular membranes while carrying macromolecules.51,52
The nuclear membrane allows passive transport of substances below 50 kDa whereas other substances can only enter the nucleus by active transport through nuclear pore complex (NPC). NPC consists of importins, heterodimeric proteins of α and β subunits, which bind to a specific recognition sequence called the nuclear localization signals (NLSs) of the importing substance. NLSs consist of arginine and lysine sequences which help in the transportation of the substance from the cytoplasm to the nucleus.53 In order to avoid the use of the intrinsic machinery of the viruses to enter the nucleus and to enhance transfection efficacy, synthetic NLSs have been produced and bound to magnetic nanoparticles. For example, magnetic nanoparticles successfully entered the nucleus of HeLa cells only when modified with NLSs peptide.54
As reviewed by Soenen and Cuyper, biodistribution of magnetic nanoparticles depends on their physicochemical properties, such as size, hydrophilicity and surface charge.15 Irrespective of nanoparticles possessing magnetic behavior, with increasing their surface charge and decreasing hydrophilicity, the capacity of plasma protein absorption increases which leads to their recognition by phagocytic cells.55 By increasing the size, renal clearance is omitted, however, nanoparticle recognition by phagocytic cells increases which results in their accumulation in the liver, spleen and lymph nodes.56
Different in vivo studies in mice and rats showed that magnetic nanoparticles after intravenous administration predominantly accumulated in the liver and spleen: 55% of the injected iron composing 190 nm magnetic nanoparticles localized in the liver after 6 h, but was reduced to 20% after 24 h.57 The level of iron in the spleen after 3 weeks corresponded to 25% of the injected dose.58 Significantly increased iron levels were also detected in the heart and brain, however these were notably lower than these in the liver and spleen.57 Biodistribution of magnetic nanoparticles in the mice after intra-peritoneal route was similar to that of intravenous administration: the highest concentrations of magnetic nanoparticles were observed in liver and spleen.59 If magnetic nanoparticles are guided by means of a magnetic field, they concentrate in the area of interest (Figure 3). For example, when 70 nm magnetic nanoparticles were injected into mice through the tail vein and directed to the heart and kidneys by means of magnetic field with flux density of only 2.5 mT for 6 h, they concentrated in the heart and kidneys as well as in the lungs.26 Biodistribution of magnetic nanoparticles after different administration routes is schematically presented in the Figure 3.
Toxicity studies of magnetic nanoparticles are scarce. The first tolerance study with carbohydrate-coated magnetic nanoparticles as potential delivery systems was performed in nude mice and showed no median lethal dose (LD50), no alterations in the blood haematological and biochemical profiles as well as no organomegalies were observed after injection of magnetic nanoparticles. However, when 10–20% of the blood volume was infused with the ferrofluid, short episodes of lethargy and resistance of food uptake were detected.25 On the other hand tartrate and citrate-coated magnetic nanoparticles, administrated intra-peritoneally in mice, caused severe inflammatory reactions in the peritoneal cavity and around the hilum of spleen and kidneys, indicating that adsorption of carboxylic acids at physiological pH and isotonic conditions did not inevitably result in a biocompatible ferrofluid.60 Coating of magnetic nanoparticles with dextran despite of more than 6 months retention in the liver and spleen of mice caused no alterations observable in histology specimens of these organs.61 Similarly, histological analysis of liver, spleen and kidney after intravenous administration of oleic acid-coated magnetic nanoparticles did not show any alterations in these organs. However, lipid peroxidation indicating oxidative stress was elevated and returned to a normal value within 3 weeks.57
Questions remain about the possibility of adverse side effects related to electromagnetic fields. According to the U.S. National Institute of Environmental Health Sciences (NIEHS), there is a weak association between magnetic field exposure of flux density as small as 0.0003 mT and an increased risk of childhood leukemia.62 According to numerous MRI examinations, a static magnetic field of flux densities from 0.5 to 2 T does not cause any known side effects and therefore the patient compliance is high.63 On the other hand, rats developed aversive and avoidance behavior when the field was increased up to ultra-high fields of flux densities of 4 T and 7 T, respectively.64
There are some inconsistent reports about cellular toxicity or adverse side effects caused by magnetic field exposure which might be due to the cell type dependent mechanisms. It seems that cells deriving from mesenchymal descent are more prone to the magnetic field exposure than other normal and malignant cells.47,65–68 Evidently, in order to provide assurance that the magnetic field accurately does not cause any side effects there is a vital need to perform additional in vitro as well as in vivo studies.
For diagnostic purposes magnetic nanoparticles are utilized as contrast enhancing agents for MRI in order to improve spatial resolution and provide earlier lesion detection.69 SPIONs are replacing paramagnetic gadolinium-based MRI contrast agents due to their superior in vivo behavior and biocompatibility with some of them already being FDA-approved. Earliest magnetic nanoparticles for MRI were administered into the bloodstream and within minutes cleared by mononuclear phagocytic cells of the reticuloendothelial system. Their subsequent accumulation into the liver and spleen improved visualization of focal lesions with a few millimeters diameter.70–72 In 1996, the first liver-specific MRI contrast agent, Feridex I.V.®, came to the market which was soon followed by GastroMARK®, a contrast agent for MRI of the gastrointestinal tract. Modification of physicochemical properties of magnetic nanoparticles resulted in their prolonged blood half-life and vascular penetration which enabled visualization of other tissues and organs within the rats.73,74 For example, Chertok et al. visualized accumulation of magnetically-guided nanoparticles in experimentally-induced rat gliosarcomas after intravenous administration by MRI.75 Currently, magnetic nanoparticles are being investigated for visualization of lymph node metastases which are otherwise undetectable by existent technology equipment.76 Moreover, as reviewed by Jain et al., SPIONs with minor macrophage uptake and prolonged blood half-life have found preferential application in sentinel lymph node imaging as contrast enhancing agents for MRI.77
Concerning diagnostic, prognostic and even therapeutic implications, magnetic nanoparticles are also used in magnetic-activated cell sorting (MACS®) for magnetic separation of different tumor cells and cancer stem cells out of the bloodstream or tissue by the recognition of CD surface antigens.78–81 Briefly, magnetic nanoparticles coated with immunospecific agents tag target cells which are then separated from other biological entities by passing through an external magnetic field.
For therapeutic purposes no magnetic nanoparticles have yet been approved for clinical use. However, the majority are being investigated as drug or gene delivery systems whereas to a considerably smaller extent they are being explored for the treatment of cancer by magnetic hyperthermia.
Magnetic hyperthermia is local therapeutic modality for the treatment of cancer which is founded on the fact that magnetic nanoparticles produce heat when exposed to an alternating current (AC) magnetic field. The therapy comprehends administration of magnetic nanoparticles into the tumor followed by an AC magnetic field exposure. Cancer cells loaded with magnetic nanoparticles are subjected to irreversible damage of temperatures above 42–43°C whereas normal cells withstand temperatures up to 46°C.39 Moreover, heat alters some receptor molecules on the surface of cancer cells which enhances their recognition by natural killer cells.82 In 2005, the first phase I clinical trial was carried out in a patient with a recurrent prostatic tumor concluding that magnetic hyperthermia is a feasible and well tolerated treatment modality.83 Two years later in combination with radiotherapy, magnetic hyperthermia was performed in 14 brain-cancer patients demonstrating that the therapy was well tolerated by all the patients with minimal or no clinical effect.84
Magnetically-guided drug carriers in the treatment of cancer date back to the late 1970s, however, no such magnetic nanoparticles have yet been clinically approved. Only nanoparticles without magnetic properties, i.e. liposomes encapsulating anthracyclines (daunorubicin and doxorubicin), and nanoparticulate albumin-bound paclitaxel are used for the treatment of different types of solid tumors and metastatic breast cancer, respectively.85
The idea of using magnetic microspheres as vehicles for drug delivery in cancer therapy was first introduced by Widder et al.1 In 1983 they performed the first preclinical study in rats. Selective targeting with intravenously administrated magnetic albumin microspheres containing low doses of doxorubicin resulted in total remission of 77% (17/22) of tumors after only one regimen of drug therapy.86
As late as 1996, the very first preclinical and clinical studies on magnetic nanoparticles for cancer therapy were done. It is essential to mention that the following magnetically-guided drug carriers were barely classified among nanoparticles since they measured 0.5 - 5.0 μm. A preclinical study of magnetically-guided nanoparticles as delivery systems in cancer therapy was performed in a xenotransplanted human colon as well as renal cancer tumor-bearing mice. After intravenous injection and magnetic guidance of epidoxorubicin attached to magnetic nanoparticles, complete remissions of tumors were observed.25 The first clinical phase-I magnetically-guided drug-targeted study was carried out in 14 patients with advanced unsuccessfully pretreated solid tumors. Intravenous administration of epidoxorubicin attached to magnetic nanoparticles resulted in transient serum iron elevations in almost all patients after the therapy, which did not cause any clinical symptoms, and in some patients increased ferritin levels in the blood were observed. In 50% (7/14) of the patients, magnetic nanoparticles were detected within the tumors. However, only a slight reduction of tumor size occurred in merely 14% (2/14) of the patients.87
Later, the same research group utilized mitoxantrone attached to magnetic nanoparticles of the ferrofluid (magnetic liquid) (FF-MTX) aiming to compare the antitumor efficacy of FF-MTX given by different administration routes. The treatment was performed in rabbits bearing squamous cell carcinomas (VX-2) which showed complete and permanent remission after intra-arterial administration of FF-MTX. However, intravenous application of FF-MTX did not result in statistically significant tumor remission in comparison to the control group.88
The following preclinical and clinical trials of two research groups focused on the delivery of doxorubicin hydrochloride adsorbed to magnetic targeted carriers (MTC-DOX) by selective arterial catheterization of the hepatic artery.89–91 A preclinical trial was performed in a swine model. By magnetic targeting, extravasation of MTC-DOX through the vascular wall was obtained, leading to their localization and retention in the tissue at the targeted site. The severity of liver necrosis correlated to the severity of embolization following treatment and was observed only in the animals which received the highest dose of MTC-DOX whereas no adverse effects were determined at the MTC-DOX low-dose group.89 Clinical trials with MTC-DOX were carried out in patients with inoperable hepatocellular carcinomas. No clinically significant toxicity was observed. However, all patients experienced abdominal pain during MTC-DOX administration which was intravenously controlled with analgesics.90,91 In the first phase I/II study, localization of MTC-DOX in the tumors was achieved in 94% (30/32) of all the patients with one complete and two partial responses.90 In the second study MTC-DOX was observed in 100% (4/4) of the tumors with 64–91% of the tumor volume loaded with magnetic nanoparticles. However, this resulted in only one partial response.91 A subsequent phase II/III multinational clinical study with MTC-DOX enrolling 240 patients with hepatocellular carcinoma was prematurely stopped as there was no increase in median survival time for MTC-DOX treated patients relative to patients treated with IV doxorubicin.92
To sum up, preclinical studies turned out in complete and permanent tumor remission; however, dose escalation clinical trials resulted in no clinically significant toxicities but had a relatively poor tumor response.
In addition to chemotherapy, recent progress in gene therapy has made it a realistic option for the treatment of cancer.93,94 The idea of using magnetic nanoparticles as gene delivery systems emerged in the year 2000, combining expertise of chemistry, biology, medicine and physics. This new interdisciplinary approach has already shown some promising results in preclinical studies.95–98
Until the new millennium, the majority of studies focusing on gene delivery for therapeutic approaches used viruses as transport vehicles for nucleic acids. In order to avoid the disadvantages of viral based gene delivery, such as receptor dependent host tropism, pre-existing immunity of the host, induced immune response by the virus, potential recombination of viral and host cell genetic material and large-scale infrastructure for virion production, new methods have begun developing.99
Non-viral methods of gene transfer can be divided into three major groups: injection of naked plasmid DNA (pDNA), chemical and physical approaches.100 In 1990, first in vivo study injecting naked pDNA into mouse muscle was performed. In the injected tissue significant elevations of all three reporter genes encoding chloramphenicol acetyltransferase, luciferase and beta-galactosidase were observed.101 Later, injection of naked pDNA was repeated by others, as well as in other organs.102,103 In an effort to increase transfection efficiency, development of various physical approaches has begun. The general principle of nucleic acid internalization by physical approaches, which include microinjection, hydrodynamic delivery, biolistics, electroporation, sonoporation and impalefection, is based on disruption of the cell membrane to facilitate nucleic acid uptake.104–109 However, nucleic acids still remain exposed to biochemical degradation which reduces transfection efficacy; thus attaching or encapsulating nucleic acids within nanoparticles, which mediate their internalization by membrane fusion and/or endocytosis, results in increased transfection efficiency in vitro in comparison to some physical approaches.110
Progress in the field of nanotechnology and new trends in gene biology contributed to the development of a novel method called magnetofection, which unites the advantages of physical and chemical approaches in one system (Figure 4). The method is based on binding the nucleic acids to magnetic nanoparticles that concentrate and transfect cells in the area of interest by means of a magnetic field.2 For cancer therapy, a high-field, high-gradient, rare earth permanent magnet, such as Nd-Fe-B magnet, is placed above the solid tumor in order to retain administrated magnetic nanoparticles with bound nucleic acids in situ until they internalize and transfect malignant cells.97,98 Although magnetofection is considered a non-viral method of gene transfer, viral vectors can be supplementary attached to magnetic nanoparticles in order to additionally increase transfection efficiency.111 In 2000, the use of magnetic microparticles for transfection in vitro was first demonstrated in carcinoma C12S cells and in vivo in mice using an adeno-associated virus linked to magnetic microspheres via heparin. The study resulted in enhanced green fluorescent protein (GFP) expression due to the increase in contact between the delivery system and the cell.112 In these terms, the immunity-based problems arising from the use of viral vectors for gene transfer remain; therefore, studies of virus-associated magnetic nanoparticles will not be discussed in this review.
Currently there are several commercially available magnetic nanoparticles measuring 50 to 200 nm in diameter, e.g. CombiMAG, PolyMAG and TransMAGPEI, which have been used in many in vitro and some in vivo studies of magnetofection.2,28,31,42,95–98,113 It is noteworthy that these vectors represent a hybrid system characterized by the iron oxide inner core and a coat consisting of PEI, which is a well known transfection agent.114
All in vitro studies confirmed efficient magnetofection of a variety of cell lines with various nucleic acids, in most cases pDNA followed by small interfering RNA (siRNA), short hairpin RNA (shR-NA) and antisense oligonucleotides, associated to magnetic nanoparticles and guided by a magnetic field generated by Nd-Fe-B magnets.2,28,31,42,95,96 Magnetofection of pDNA encoding GFP on mouse melanoma B16F1 cells is presented in Figure 4. The studies also demonstrated that magnetofection is superior to other standard transfection protocols, mostly lipofection.95,115
The first in vitro study demonstrated enhancement in LacZ reporter gene transfection of mouse embryonic fibroblasts NIH3T3 and Chinese hamster ovary (CHO) cells up to several 100-fold compared to transfection in the absence of magnetic field. In addition, a minimal dose of pDNA (0.1 μg) was sufficient to achieve high transfection levels.2 The highest increase in transfection efficiency of human umbilical vein endothelial cells (HUVEC) with the luciferase reporter gene by magnetofection was about 360-fold compared to various conventional transfection methods.95 However, it is worth to note that magnetic nanoparticles in the latter study were additionally coupled to lipid-based transfection reagents, Effectene® and FuGENE®, as well as to a combination of the polymer-lipid transfection enhancer PEI/DOTAP-cholesterol, which greatly contributed to the increase in transfection efficiency. Other in vitro and ex vivo magnetofection-based studies also showed enhanced transfection efficacy of luciferase, enhanced GFP (EGFP) and Discosoma sp. red fluorescent protein (DsRed) reporter genes to various cell lines, however, to a lesser extent, i.e. from 3-fold to 36-fold.116–119
Refinements of the technique resulted in significantly reduced time needed for the transfection process to be completed (transfection time) in comparison to other non-viral gene delivery approaches. Under magnetic field guidance, the transfection time of HUVEC with oligodesoxy-nucleotides (ODN) against the p22phox subunit of endothelial NAD(P)H-oxidase bound to magnetic nanoparticles was decreased to a few minutes whereas it required 24 h when ODN were coupled only to Effectene®.96 Cationic lipid-coated magnetic nanoparticles associated with transferrin demonstrated a 300-fold increase in transfection efficiency of the luciferase reporter gene in comparison to well established and efficient PEI polyplexes and Lipofectin™ after 15 min incubation.115 Similarly, Chorny et al. managed to efficiently transfect aortic smooth muscle cells A10 and bovine aortic endothelial cells (BAEC) with the use of polymer-coated magnetic nanoparticles attached to pDNA encoding EGFP just after 15 min of exposure to the magnetic field. The negligible transfection was observed in the absence of the magnetic field.120
Therefore, magnetofection is defined as enhanced delivery of nucleic acids associated with magnetic nanoparticles to the cells under the influence of a magnetic field.2
The majority of magnetofection studies utilized a static magnetic field, however, two research groups have also focused on the application of a pulsed magnetic field. The Swiss group utilized electromagnets and reported that transfection efficiency of reporter genes was the highest when magnetic nanoparticles were first sedimented by exposure to the permanent magnet before application of the pulsating magnetic field.121 The mechanism behind this observation could be an alteration in the permeability of cell membranes by pulsed magnetic field after the increased sedimentation by a static magnetic field enhanced the contact between the cells and magnetic nanoparticles. In another study of the same group, at least a 6-fold increase in transfection efficiency of the EGFP reporter gene to various primary cell lines was shown when a combination of static and pulsating magnetic field was used compared to the presence of static magnetic field alone. The transfection was the lowest when the cells were exposed only to the pulsed magnetic field.119 On the other hand, the American group utilized a computer-controlled stepper motor-driven horizontally oscillating magnet array system which produced increased magnetic field strength and a gradient with no heating in comparison to electromagnets used by the Swiss group. The lateral motion of the horizontally oscillating magnet array system at an amplitude 200 μm and frequency 2 Hz promoted extra energy and mechanical stimulation which increased particles sedimentation onto the cellular surface. The result was a 4-fold greater transfection of the luciferase reporter gene to human lung epithelial NCI-H292 cells than that of Lipofectamine™ 2000 and more than a 2-fold greater than transfection performed under a static magnetic field. The oscillating array system also had little or no effect on cell viability.122
Although authors of several studies have reported about the suitability of magnetofection of reporter genes in vitro, some improvements are still required to make the method efficient enough to be widely used for in vivo applications.
To demonstrate that magnetofection of reporter genes in vivo is feasible, two studies using pDNA encoding beta-galactosidase and luciferase were performed in rats, mice and pigs.2,113 In addition, a magnetofection study using Cy3-fluorescence-labeled antisense ODN was carried out in mice by the same extended research group.96 Initial pre-clinical in vivo trial of LacZ reporter gene delivery was performed in ilea lumens of rats using viral vector-free magnetic nanoparticles and in stomach lumens of mice using adenovirus-associated magnetic nanoparticles. Efficient transfection was observed in lamina propria of ileum as well as in crypts of fundic glands after 20 min of exposure to the magnetic field. For additional proof-of-principle, magnetofection of the luciferase reporter gene was done in the ear veins of pigs. Luciferase expression was observed in all vein samples under the influence of magnetic field whereas no transfection was found distally from the magnet position and in other organs.2 In another study, the same magnetic nanoparticles were coupled to lipid 67 (GL67) and pDNA encoding luciferase, thus forming ternary complexes. GL67 is a cationic lipid considered as the gold standard for in vivo airway gene transfer. The authors aimed to compare magnetofection efficacy of ternary complexes to transfection efficacy of plane GL67/pDNA. Surprisingly, in vivo transfection of the murine nasal epithelium with plane GL67/pDNA resulted in an approximately 90-fold higher luciferase expression than that observed by magnetofection. The authors referred the poor outcome of magnetofection to the size of magnetic nanoparticles (200 nm), their coating and characteristics of the magnetic field applied, suggesting that smaller particles with a modified surface coating could have been more efficient in crossing extracellular barriers as well as intracellular membranes in the airway epithelium.113 The third in vivo study was performed in mice in order to investigate whether magnetofection is feasible strategy for directing antisense ODN, complexed to magnetic nanoparticles, to a targeted site via arterial catheterization. Nd-Fe-B magnet was held above the right testis throughout the infusion of Cy3-labeled antisense ODN, coupled to magnetic nanoparticles, via femoral catheter and for another additional 4 min. The study demonstrated site-specific magnetofection of the ipsilateral arterioles of the cremaster muscle whereas contralateral vessels of the same muscle, which were not exposed to an external magnetic field, were not transfected.96
Magnetofection of therapeutic genes in vivo was published in two papers, both dealing with veterinary clinical trial consisting of dose-escalation neoadjuvant gene therapy to surgery.97,98 The aim of neoadjuvant immunostimulatory gene therapy in the treatment of cancer is to induce local production of cytokines which triggers systemic anti-tumor immunity.123 Both studies were carried out in feline fibrosarcomas by the same research group in which immunostimulatory therapeutic genes were applied by magnetofection. In the study of Jahnke et al., dose-escalation study was performed with a combination of pDNA encoding three different cytokines: feline interleukin-2 (feIL-2), feline interferon-gamma (feIFN-γ) and feline granulocyte-macrophage colony-stimulating factor (feGM-CSF). Altogether six cats developed local recurrences during 1-year observation period, four of them received the highest dose of the total amount of pDNA (1350 μg pDNA; 450 μg per plasmid).97 That was clarified by bell-shaped dose dependence of IL-2.124,125 Moreover, one cat in this group (12.5%) showed adverse events. However, the study concluded that the highest dose was well tolerated as the only adverse events occurred once and were self-limiting. Due to the early recurrences the authors suggested to include in a subsequent phase-II study also the second highest dose of pDNA (450 μg pDNA; 150 μg per plasmid).97 In the study of Hüttinger et al., magnetofection of pDNA encoding feGM-CSF was performed 14 days prior to surgery. Results of the study demonstrated that ten of the treated animals (50%) were recurrence-free after 360 days of observation. Moreover, the highest dose (1250 μg) of pDNA applied was shown to be safe for phase-II testing.98
New technologies have enabled synthesis of biocompatible magnetic nanoparticles that can be functionalized with therapeutic molecules. The transfection method using magnetic nanoparticles, which are manipulated by an external magnetic field, is called magnetofection. It is a promising strategy that can lead to targeted delivery of pDNA carrying therapeutic genes, siRNA or other gene therapy approaches. Due to its physical properties of delivery, the approach is feasible on different tissues; foreseen can be tumors, muscle, skin and others. In this field of research very little was done. When the protocols for synthesis of magnetic nanoparticles and their functionalization with nucleic acids are standardized along with contemporary optimization of magnetic field parameters, the field will open for broader and in depth investigations, that may in near future also bring magnetofection into the clinical trials.
The authors thank Andrej Žnidaršič, PhD, and Vladimir B. Bregar, PhD, from Nanotesla Institute for introducing us to the »nano world«. Useful comments and criticism of the manuscript by Maja Čemažar, PhD, are considerably recognized. We thank Mireille Treeby, PhD, for proof-reading of the manuscript. The authors acknowledge the financial support of the Slovenian Research Agency (program P3-0003, project J3-2069).


text:
Now it's time to mix the mortar. We have taken sand and cement from our store, so we have to add water now. Not too much water, otherwise the stones will float away and the mortar will not solidify properly. On the other hand, too little water is not good, otherwise the mortar does not stick to the stone and we can align the stones badly.
With the right consistency the walls can be build easier.
At last the mortar is ready for use.

domain: hobby


text:
Great drinks, but that's about it. Overpriced for bad food, even worse service. Had to flag someone down to seat us in an uncrowded restaurant. Chips were nasty, stale, cold, tiny fragments. Seafood smelled old and the current state of my stomach tells me I'm going to pay for ordering it. Husband's vegetarian meal had pork in it. Mediocre, small portions are hidden under an overabundance of rich creamy sauce. I've had better food at some of the crappy, family chain restaurants around town and for half the price. If you're looking for Mexican food in the Arboretum, Z-Tejas is worth the wait. I've been to three Iron Cactus locations a total of four times and I've had good service once. Again, great drinks, but avoid the food.
we had happy hour at the iron cactus and it was great. for families with small kids, the patio area is great. kids can run around in the square in front of the restaurant. amy's ice cream is also next door.
Located on the shores of Lake Travis in the rolling Texas Hill Country, Lakeway Resort and Spa boasts comfortable style,
pristine sunsets and a genuine southern charm truly unique to Texas. Minutes from Austin, this lakeside resort features three ...

domain: food


- Small, discreet design incorporating microPOWER technology.
- Jabra Assist App helps you locate your headset using GPS tracking.
- Noise Blackout, HQ Voice for crystal clear sound at both ends of phone calls and music streaming.
- Easy pairing to smartphones and other devices with NFC, as well as Multiuse to pair to 2 devices at the same time.
- 6 hours of talk time and an energy-saving PowerNap function!


text:
Two German Facility Openings for BLG Group
3rd October 2018
The BLG Group is celebrating the opening of its second logistics centre in Falkensee near Berlin and the start of operations in its new DC for IKEA in Elsdorf between Hamburg and Bremen.
The 45,000 sq m Falkensee facility has been in operation for Siemens Power & Gas since May. Some 100 guests, including many BLG customers from the Berlin/Brandenburg area, attended the official opening ceremony.
At the same time, Thomas Krüger, Managing Director of BLG Retail Logistics, Andreas Bellmann, mayor of Elsdorf, and Johannes Ferber, Property Manager of IKEA Germany, opened the distribution centre in Elsdorf. Here, BLG LOGISTICS takes care of incoming goods management as well as storage and picking operations for its customer IKEA for all products ordered online. In the warehouse with more than 36,000 storage spaces, goods for customers in the Hamburg, Kiel, Lübeck, Bremerhaven, Bremen and Oldenburg regions are picked and shipped. At peak times, up to 130 employees of the logistics service provider will be in action on the 35,000 sq m site.
Jan-Marc Lischka (Siemens), Jens Wollesen (BLG), and Falkensee’s mayor Heiko Müller at the Falkensee opening.

domain: economics


text:
Divyansh Kaushik is the Associate Director for Emerging Technologies and National Security at the Federation of American Scientists. He holds a PhD from Carnegie Mellon University in Pittsburgh, where he focused on designing reliable artificial intelligence systems that align with human values. In addition to his work on Capitol Hill advocating for defense, science, innovation, and immigration issues, he has also played a key role in the establishment of the Congressional Graduate Research and Development Caucus. He is also a frequent contributor to leading publications, including National Defense Magazine, The Dispatch, Daily Caller, and Forbes, sharing his insights and expertise on a variety of topics relevant to national security and innovation.
The looming competition for global talent has brought forth a necessity to evaluate and update the policies concerning international visa holders in the United States.
We believe this strategic investment into critical and emerging technologies will empower our nation to confront 21st-century challenges with solutions that are timely, scientifically rigorous, and security-enhancing.
Despite their importance, programs focused on AI trustworthiness form only a small fragment of total funding allocated for AI R&D by the National Science Foundation.
FAS is launching this live blog post to track all proposals around artificial intelligence (AI) that have been included in the NDAA.
With U.S. companies creating powerful frontier AI models, the federal government must guide this technology’s growth toward public benefit and risk mitigation. Here are six ways to do that.
Even though the COVID emergency is over, personal appearance waivers should be a standing policy in low risk cases.
Before releasing a new, powerful system like GPT-4 to millions of users, we must ask: “How can we know that this system is safe, trustworthy, and reliable enough to be released?”
The J1 visa Exchange Visitor Program, a pivotal mechanism fostering global cultural exchange and dissemination of specialized knowledge, remains regrettably stagnant since its last renewal in 2009.
The 21st century will be shaped by the US-China strategic competition. The United States and China are locked in a battle for global power, influence, and resources, and are fighting for control of the world’s most important geopolitical regions, including the Indo-Pacific and Africa. They are also vying for leadership in cutting-edge technologies such as […]
To help seed the ground for bipartisan progress, we’ve put together a menu of the best policy ideas on a range of critical topics.
If we want to keep America at the forefront of scientific discovery, we need to make sure that we are constantly replenishing our pool of scientists with the best and brightest minds.
It’s no secret that the world is becoming increasingly complex and interconnected. And as our societies become more technologically advanced, the risks of a global catastrophe become greater. Natural disasters or severe climate change in one part of the world can quickly become a humanitarian crisis in another, an airborne virus can spread around the […]

domain: politics


What's the last creative project you embarked on?
A wrap-up video for The Red Pencil’s mission in Lombok! Work aside, I just filmed a couple of K-pop dance cover videos with my friends from my university dance club. I’ve always liked dancing, and K-pop choreographies are really easy to learn through YouTube. It’s a great way to have fun and destress!
If you could listen to just one song for the remainder of your life, what would it be and why?
Wow, tough question. I would choose Take Heart by the Sam Willows. It’s a song with an inspiring message to keep going even when people keep putting you down (or at least that’s what I interpret of the lyrics). While I’m more of a K-pop / R&B kind of person, if there’s just one song that I can listen to, I would choose one which I can count on whether I’m happy or sad. And also because #supportlocal. ??
What is your most used emoji?
??♀ I’m a girl who likes to show affection to my friends and family!
As a 22-year old who’s graduating from university, the transition to adulthood can get a little worrying at times with concerns about issues such as schoolwork, our career choices, and relationships. This
How would you use a red pencil to change the world?
Changing the world is a really ambitious goal because there’s so many forces that shape the current state of the world – the government, businesses, social institutions such as the media, family, schools, as well as habits, cultural practices and other environmental factors. Currently, the consumerist society that we live in is highly unsustainable, and I would really love to change the way we consume things –from prioritizing economic cost and convenience to a more sustainable, environmentally-friendly way of living.
Maybe I would use the red pencil and go to supermarkets and draw a big cross on all the products that could be made more environmentally-friendly, so shoppers wouldn’t buy those products. /laughs/. Crazy hypothetical idea, I’m just joking.
The pencil is a humble but effective tool for expression, and the colour red is a really strong symbol for change. I would approach people and ask them to draw the future of our planet, keeping in mind the way we’ve been consuming the Earth’s resources. Hopefully it’ll get them thinking about mankind’s selfish consumption practices and encourage them to change their ways.
What plans do you have when you leave The Red Pencil?
I’m interested in working in the PR industry, as it’s a really exciting industry which is always changing. It’s challenging but also fulfilling when you come up with solutions that bring value to your company or clients. But first – I’ll be going for a long-awaited trip overseas with my family, followed by a beach holiday with my university friends, before embarking on working life.
“The pencil is a humble but effective tool for expression, and the colour red is a really strong symbol for change."
“If you’re looking for an opportunity to do good while gaining some valuable work skills, look no further."
Why should others intern at The Red Pencil?
The Red Pencil is a small but closely-knit team that’s passionate about its cause to bring the benefits of arts therapy to the underprivileged. If you’re looking for an opportunity to do good while gaining some valuable work skills, look no further.
Depending on your skills and interests, you’ll be able to help with strategic planning, raise awareness about arts therapy, and produce communication collaterals for The Red Pencil. You’ll also be guided by caring and competent colleagues who are concerned about your personal development (speaking from personal experience).
What are some of your responsibilities as a marketing and communications intern?
One of my main tasks was to assist with the production of online collaterals, such as social media posts to help raise awareness of arts therapy, as well as wrap-up videos for The Red Pencil missions. I also helped to propose ideas and designed our Instagram Story Highlights. Other tasks include helping to collate feedback to ensure effective monitoring and evaluation of our programs, as well as liasing with vendors in preparation for our office relocation.
What did you like most about working at The Red Pencil?
I love the company culture – it’s a small but tight-knit team that is always ready to help one another. You’re trusted to take ownership of your work and am able to get feedback really quickly.
How has the internship been beneficial to your personal and professional development (so far)?
Skills-wise, it has allowed me to hone my skills in social media copywriting and content creation. I gained insights into the workings of a charity organisation, and got to know some of the nicest colleagues. It’s a valuable experience which I’m grateful for the opportunity to undertake while doing my last semester at SMU.
Why do you think The Red Pencil’s mission is important?
Sometimes, words just aren’t enough. When one’s thoughts and emotions are heightened to the point that it becomes overwhelming, art provides an alternative mode of expression and communication. It acts as a form of release, and a representation of our subconscious thoughts and emotions.
While some of us may be able to work through our emotions by ourselves, others may not. This is why The Red Pencil’s mission is important: it helps to bring arts therapy to communities who may benefit from the guidance of an arts therapist. Beneficiaries may range from underprivileged children to victims of natural disasters from all over the world. With each humanitarian mission and workshop, it is hoped that individuals are able to better understand and empower themselves, regardless of unfavourable life circumstances.
“The Red Pencil’s mission is important: it helps to bring arts therapy to communities who may benefit from the guidance of an arts therapist."


This Mens Frost DWR Insulated Duck Work Bib Overalls are for the tradesmen, who need to keep warm in the cold element. Frost bib overall gets nods of respect among men whose hands stay dirty. To build it we start with 12-ounce Super Duck that stands up to wear, grit and grime. Then we add a DWR coating to shed weather, layer in waterproof double-knee patches and stitch in six-ounce polyfill insulation to trap thermal heat. To finish it we add hardworking features�including venting side zips, surface scuff guards and heavy metal bib hardware.
FEATURES & MATERIALS: Keep the bone chilling cold from seeping all the way through to your core with our Blizzard-Pruf� insulated bib, Elastic insets at back waist for ease of movement, 100% Polyester ripstop diamond-quilting with 205 weight insulation and ENERGY orange stitching, Double knee patches with waterproof barrier for additional protection, Hammer loop, Durable Water Repellent surface coating Sheds snow, sleet or drizzle even after multiple washings, Adjustable length bib straps with heavy metal hardware, Easy grab, ankle-to-thigh side venting zipper with storm flap allows access and heat release without stripping down, Back hem scuff guard resists wear from dirt, grime, gravel and pavement, Triple and double-needle stitching for greater toughness.
Choosing a selection results in a full page refresh.


text:
There is something wonderfully accessible about Advent.
Perhaps part of it is the long lack of focus that tends to obtain during Ordinary Time. That is certainly true for me, wherefore I have been looking forward to the season for quite some time. But I think that mostly Advent is accessible for much the same reason that Dante's Purgatorio is the most accessible part of the Divine Comedy- it's where we are.
Who is not acquainted with longing? Who does not know the desire for something just out of reach? Who has not felt the thrill and sweet pain of awaiting something promised but not yet received? The spring in the step as one embarks upon a long journey, the accelerated heartbeat as the plane takes off on its way to a foreign country, the joy of anticipated reunion- sehnsucht is part of the universal human experience. "How long, O Lord?", we ask in eager anticipation.
Or it can have its darker side. Orwell speaks in 1984 of the way in which pain drives out principles until all one desires is simply for it to stop. Many of us, young, affluent and comfortable, are insulated from such an experience, but myriad others are not. Persecutions and injustices and bloodshed go on, and those in the middle of them cry out, "How long, O Lord?" in agony and desperation.
Advent is where all of us are. If we allow ourselves to be free of our distractions long enough (or even, sometimes, if we don't) we are aware that all is not right in the cosmos. There is a lack. There are problems. There are atrocities and petty selfishnesses and parasitic wasps. We know within ourselves that the world is not the way it is supposed to be. Much closer to home, we know that we are not as we are supposed to be. At a most basic human level, we sense our alienation and dislocation.
Some of us know that that for which we long, that for which we hope, is Christ. He Who will put all to rights, the universe's rightful sovereign, is coming. We try to strengthen in ourselves the desire for Him. He, cure of our miseries, better than our hopes, will not delay.
He came once before, and we know His face. We had the opportunity to get to know Him. And He has left behind Him, for our sake, the Church which bears witness to Him, and the Spirit through Whom it speaks and which sanctifies its members.
But He has not come back yet.
And so we Christians wait, knowing Him for Whom we wait. Knowing Him, Who brings into focus our hopes, desires and longings, our distresses, difficulties and failures, knowing that He will fulfill them all and bring them to their predestined end.
Please help a family that has suffered a great tragedy - A reader writes: This family belongs to our parish in Atlanta. The Go Fund Me page (link below) has the details, but they were in a horrific car accident o...
6 hours ago

domain: literature


Armed with a revolutionary new tracking device, cave divers map threats to Florida's main water source
Heading out the door? Read this article on the new Outside+ app available now on iOS devices for members! Download the app.
RENOWNED UNDERWATER cave explorer and filmmaker Wes Skiles has twisted his way through hundreds of miles of submerged passageways over the past 30 years, but to make Water’s Journey: Hidden Rivers of Florida, a documentary that airs this October on PBS, he needed a new tool.
“We wanted to demonstrate how surface pollution can contaminate drinking water,” says Skiles, a 45-year-old Florida native. “To do this, we needed to present hard proof in a dramatic way.”
Water’s Journey follows cave divers through the Floridan Aquifer, a vast network of saturated limestone underlying Florida and southern Georgia that includes up to 1,000 miles of swimmable tunnels. Though the labyrinth has been explored for decades, the persistence of archaic survey techniques has led to only rudimentary maps. If Skiles was going to deliver a solid environmental punch, the film had to clearly connect aboveground pollution to the hidden waterways below.
Enter Brian Pease, a 60-year-old retired Navy electronics engineer who used technology similar to that in avalanche transceivers to develop a new tracking system that allowed surface teams to precisely monitor divers through hundreds of feet of rock. Before this, the best systems could only identify static locators that had to be tediously placed in caves. With Pease’s invention, a diver carries a footlong antenna that emits a magnetic field. On the surface, a tracker detects the field with a laptop-size receiver that gives off an audible hum, then goes silent when it crosses directly over the diver. Putting it to work allowed surface crews to follow along above divers as they swam routes linking residential wells with passages underlying parking lots, construction zones, and other sites that can potentially leach toxic runoff into the aquifer through its porous ceiling. “This totally revolutionizes cave mapping,” says Jill Heinerth, 38, a veteran cave diver with Skiles’s High Springs, Florida–based Karst Productions. “What used to take years can start coming together in a single dive.”
Near the end of filming, Pease combined a diving radio with technology closely related to the tracking system’s, allowing cave divers to speak with ground teams. The payoff? Improved safety and the ability to direct divers into corridors passing under surface features.
“We don’t even understand the potential of all this,” says Skiles. “We haven’t begun using our imaginations yet.”


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Apple launched the iPhone 13 series at the Apple event on September 14. The company unveiled four new iPhone models, including two Pro variants. Alongside the iPhone 13 series, Apple also unveiled its new Series 7 smartwatch and new iPads. The new Apple Watch Series 7 comes with a bunch of new upgrades over its predecessor. It also features an improved design with softer, more rounded corners. This is unlike the pre-launch rumours that suggested a flat-edged design. Surprisingly, the new Apple Watch comes with the same processor found on last year’s Series 6. Let’s take a look at the Apple Watch Series 7 specifications, features and other details.
Apple Watch Series 7 gets an upgraded design but no new processor
Apple launched the Watch Series 7 with some major improvements and features. It comes with a slightly bigger screen, more workout modes, faster charging, etc. However, it looks like Apple did not introduce any significant performance gains over the Series 6 smartwatch. The new Apple Watch features the same S6 chip, which was launched last year in the Apple Watch Series 6. The company’s product tech specs page is not live yet. However, some key details about the performance unit were revealed via the latest Xcode version spotted by developer Steve Troughton-Smith.
The developer states that the new Apple Watch and the Series 6 smartwatch share the same CPU called t8301. While the S6 chip is no slouch, it does come as a surprise that Apple did not make any performance improvements in Watch Series 7 – something that it typically does year over year for its devices. One of the possible reasons could be the ongoing chip shortage. Apple has also reportedly struggled with the manufacturing process of the Series 7 due to the design improvements. There is no official word from Apple regarding the same.
The Series 7 comes with a bunch of other improvements. Apple has pushed the bezels even further, resulting in a 20 per cent more screen. The casing is also 40 per cent thinner and is claimed to be the most durable Apple Watch ever. In addition to this, the new Apple Watch is also IP6X rated along with a WR50 water resistance rating. Lastly, it charges 33 per cent faster than Series 6.


text:
Spain’s antitrust watchdog CNMC has conducted a series of raids at major power utilities, including the most recent one last Friday. These raids are part of an investigation into suspected abuse of dominant position and other anti-competitive practices, as stated by the CNMC on Wednesday.
The CNMC stated that the alleged illegal practices had an impact on the markets of equipment and meter installation, electricity trading, and auto-consumption operations.
The regulator conducted raids from April 24-28 and then from June 19-23 on “relevant companies in the electricity sector,” as stated in a press release. The names of the firms were not disclosed.
Last week, power utility Endesa, a subsidiary of Italy’s Enel, announced that its headquarters had been searched by CNMC as part of an investigation, without providing details on the reasons.

domain: news


Main / Photography / Anna bond songs for
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text: "Here I am," British rock star Phil Collins told a handful of reporters Monday night at the Dan Hotel in Tel Aviv. The former Genesis drummer and solo singer will play Monday night at the city's Bloomfield stadium in front of a crowd of some 15,000 fans. Collins's visit was doubtful just last week when he came down with a cold and postponed two concerts in Prague for a later date. But his voice is okay now, and the man behind such hits as "Sussudio," "In the Air Tonight" and "Another Day in Paradise" said he was excited to be here and give Israeli fans a show to remember. "From my point of view, this tour is a series of firsts," said Collins about this leg of his First Final Farewell Tour. "Except for some [places in Europe], this is my first time in a lot of the cities... A few years ago it wasn't possible to play in many of these places." Before coming to Tel Aviv, Collins rocked Beirut on November 5. He is next headed to Dubai. "The Middle East route is one that has been trod often in the past, and, should the calm in the region remain, it will again become a popular route," producer Shuki Weiss told The Jerusalem Post. "It would be nice if the Middle East would become part of the rock route," Collins agreed. "The show in Beirut was wonderful and the show in Tel Aviv will hopefully be as wonderful," said the rock-pop musician, who now also dabbles in jazz and has scored a number of Disney soundtracks. "Unless people have seen me play abroad most people here have no idea what they're going to see. It's really a great show." While asked a number of politically charged questions, Collins instead said, "I'm an entertainer. I'm not here to preach politics." In answer to questions shot at him, Collins said he was not afraid to be here. He noted that he was not continuing on to the Palestinian Authority areas because he 'was not invited.' He also mused that he doesn't understand what all the fuss is about in the region. "To me there are no boundaries," he said. "We had to stop at Larnaca from Beirut to here. I don't get it but those are the rules. I wish it wasn't like this ... I think it's a shame, that's all." "You can see Phil Collins's visit as an opening of gates for other musicians. Tel Aviv is safer than in the past few years, and if this continues more artists will want to come here," said Weiss. The top cities in the world in which to catch concerts include London, New York, Toronto and Sydney. "Tel Aviv could be on the list. Until five or six years ago, I'd say it was one of the main places artists wanted to perform. If Tel Aviv were in North America it would already be at the top of the list," Weiss told the Post. "Again, so long as the political situation remains calm, people will continue to perform here. When I'm in contact with musicians, they only ask about the safety here. They already know Tel Aviv is a hopping city with a great culture beat." Although titled a 'farewell' tour, Collins told reporters this is not the end of his run on stage. He said this will be his last large-scale tour because he wants more family time, but foresees showcase concerts in the future. "I won't ever give up performing. It's who I am. And I love it," he said. Phil Collins plays Bloomfield Stadium at 20:00 on Monday in Tel Aviv. Tickets, NIS 360 to 420, are still available at all ticket agencies.


text:
There is a certain satisfaction that comes from being good at something. We go to school and try to get good grades. We want to be the best at our jobs to have good performance reviews. We want to get a few goals and hit the right notes in our extracurricular activities. We want to be the best friend, spouse, parent, child, and sibling that we can be. We want to be good at what we do – it feels good.
But what happens to us when we try something new for the first time when our sense gratification comes from success? What happened the first time you learned long division – were you good at it? I certainly was not. What about your first week at your new job? That promotion? Starting a new business? Playing an instrument? I’m guessing that like most of us, you weren’t the best you could be on that first day, that first week, even that first year!
Somewhere along the development of our western society, we moralized failure and success. Being successful means that you are good at something and that is right. Failing at something means that you are bad at something and that is wrong. But, doesn’t failing at something at the outset mean that you have room for growth and improvement? If you are intent on growing within yourself, your strengths, and your limitations, you have to be willing to fail. Failure can simply be the beginning of something great.
Intently doing something that you know you are bad at or that you are uncomfortable with feels like running into a burning building – it is risky, it is not pretty, and you might fail. If you are serious about starting something new, you need to find your purpose within it and then make the risk worth it. You have to become comfortable being uncomfortable. Sara Blakely, the founder of a successful company says if she doesn’t do something new that’s going to grow her every week, she starts feeling uncomfortable. What would be possible for you if instead of being afraid of failure, you were excited to fail so that you could grow?
Some specific steps that you can take to help you be comfortable with failing are:
- Find the “why” behind what’s worth it for you to be bad at.
- Try it – you may be bad at it at the beginning but you will get better! It’s the beginning of growth.
- You don’t have to be great to start, but you have to start to be great.
This change in mindset will radically transform your life. You will find the strength to do the things you have wanted to do instead of finding fear around every longing and desire. You will not be great at everything, but you will never know if you don’t try. Begin growing today and take a risk at trying something new that you are almost certain you will fail at.

domain: psychology


text:
ConocoPhillips Announces Second Oil Discovery Out of Coronado Well
ConocoPhillips (NYSE: COP) today announced another oil discovery in the deepwater Gulf of Mexico. The WR98-1 Coronado wildcat exploration well encountered more than 400 feet of net pay. On March 19, 2013, ConocoPhillips announced an oil discovery at the nearby WR51-2 Shenandoah appraisal well that encountered more than 1,000 feet of net pay in high-quality Lower Tertiary-aged reservoirs. ConocoPhillips holds a 30 percent working interest in Shenandoah.
The Coronado well, located in Walker Ridge Block 98, was drilled to a total depth of 31,866 feet, in 6,127 feet of water. The well is located approximately 190 miles off the coast of Louisiana and approximately 12 miles southeast of the Shenandoah discovery. Results from the Coronado well are still being evaluated, and additional appraisal will be needed to determine the full extent of the resource. ConocoPhillips holds a 35 percent working interest in Coronado. Other co-owners are Chevron Corporation (NYSE: CVX), 40 percent working interest and operator; a subsidiary of Anadarko Petroleum Corporation (NYSE: APC), 15 percent; and Venari Offshore LLC, 10 percent.
© 2017 Benzinga.com. Benzinga does not provide investment advice. All rights reserved.

domain: finance


text:
European Journal of General Medicine
Medical Investigations Society
Vol. 3, No. 1, 2006, pp. 5-10
Bioline Code: gm06002
Full paper language: English
Document type: Research Article
Document available free of charge
European Journal of General Medicine, Vol. 3, No. 1, 2006, pp. 5-10
© Copyright 2006 - Medical Investigations Society
INCIDENCE OF SEVERE GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY IN COUNTRYSIDE VILLAGES OF THE CENTRAL CITY OF MANISA, TURKEY|
Ersin Minareci, Selim Uzunoglu, Orkide Minareci
The primary objective of this study was to determine the incidence of severe G6PD deficiency in selected countryside villages of central city of Manisa in Turkey. Secondarily to inform and protect G6PD deficient people from acute hemolytic crisis and neonatal jaundice by delivery of the updated protective food and drug list prepared in the light of the WHO- G6PD Working Committe reports.
In this study, the incidence of severe G6PD deficiency were screened by Beutler's Fluorescence Spot test among 1604 people living in the contryside villages of central city of Manisa in Turkey.
Thirty five out of 1604 tested people were found to have severe G6PD deficiency. The incidence of severe G6PD deficiency were 2.2 % in sampled population. There was a difference for the incidence between male (3.2%) and female (1.14%) as expected due to X-linked heritance. There was no significant differences in the prevalence of severe G6PD deficiency between the countryside villages connected to central city of Manisa.
The high incidence of severe G6PD deficiency implies that this inherited metabolite disorder is an important health problem in Manisa region and it is necessary to carry out large-scale screening in the whole population since severe- full G6PD deficiency related health problems are preventable. For this reason it must be included in the pool of genetic screening tests in regional health policy.
Severe G6PD deficiency, fluorescence spot test, acute hemolytic anemia, Manisa, Turkey.
Alternative site location: http://www.ejgm.org

domain: health


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RICHMOND / Cinco de Mayo revelers, police clash
Published 4:00 am, Thursday, May 6, 2004
An impromptu Cinco de Mayo celebration that attracted about 3,000 people turned ugly Wednesday night when some of the revelers threw rocks and bottles at police officers and vandalized police cruisers, police said.
The crowd gathered on 23rd Street -- some cruising in cars, others walking along the street -- in the evening, according to Richmond Capt. Lori Ritter, who said people had been celebrating Cinco de Mayo all week.
"We're hoping tonight is the end of the celebration," Ritter said.
Police who showed up to clear the street of pedestrians and parked cars and to cite people for public drunkenness were confronted by some people after 9 p.m. Fights broke out among the crowd.
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At 23rd and Esmond Avenue, a man shattered a bottle over the head of an officer and then ran away. The officer was wearing a helmet and was not injured.
Richmond police called for help from San Pablo police, Contra Costa County sheriffs and the California Highway Patrol. Officers shut down 23rd Street about 9:45 p.m. As the crowd dispersed, some people slashed tires on five police cruisers and smashed the windshield of one police car.


Body Mass Index (BMI) has been used as a measure of obesity from the past 200 years. The BMI is largely used by researchers and doctors across the world. The BMI of a person is calculated by dividing weight in kilograms by height in meters squared.
Scientists have discovered a new measure of obesity called the Body Adiposity Index, or BAI. The BAI is considered as a more flexible alternative to body mass index.
The new measure will help the patients to measure their extra flab without stepping on the scale. Though there were no flaws in BMI but men and women with same BMI might have very different levels of extra flab.
The experts have confirmed the BAI’s accuracy using an advanced device called a dual-energy X-ray absorption or DEXA scanner. The BAI is dependent on the measurements of height and hip. BAI is ratio of hip circumference to height that can be calculated by doctors or nurses with a computer or calculator. The scientists say that the BAI can be used for different racial groups but it requires some modification before it will be used as an alternative of BMI.
Read this and more on ~uTopnews.net.nz#topnews.net.nz/content/212483-new-measure-obesity-body-adiposity-index-bai~


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text:
As we near the month of Love - I'm reminded of this article that I published in the Hometown Treasure last year. Who are these people in your life?
Coming off the holidays, where
I spent time with friends and family and moving into the "month of
love," I've been reflecting on relationships. Conclusion - I've been
blessed with a lot of them!
Some were in my life for a reason, some for a season,
and some are in it forever. No relationship in my life has been wasted. Even if
they ended, there was a purpose. I've learned valuable lessons, shared laughs,
There have been individuals in my life whose paths have
crossed briefly with mine. They have been placed there for a reason. Past
teachers taught me essential lessons or skills. I've encountered people in the
grocery store that I'm convinced were there for a purpose. This is how I
learned to pick a good cantaloupe!
Then there are those people who were in my life for a
season. Classmates, parents who I shared bleachers with and cheered our
children on together, or friends who moved away. We didn't part on complicated
terms but moved on with good memories. I've also endured complex relationships
for a season. I learned valuable lessons there, also.
Then there is the long-haul group. These forever people
are my mainstays who have stuck with me no matter what. They are my parents,
family members, spouse, and lifelong friends. These are the ones that have
loved me through the thick and thin of life. These individuals have grit and
grace, and I can always return to them when I've lost my way. Even if I try, I
can't get rid of them (God love 'em) because their love is deeply rooted in my
Where are you in the lives of other people? Who fills
in these categories in your life?
God created us uniquely and desires us to be in a
relationship with each other. He saw Adam was lonely and created another human
being for him. In Galatians 6:2, we are instructed to carry one another's
burdens. 1 Thessalonians 5:11 says we are to encourage and build each other up.
No matter the status, there is a purpose in each
encounter we make along the way.
Romans 13:8 (NLT) says: Owe nothing to anyone –
except for your obligation to love one another.
Whether you are in someone's life for a reason, a
season, or forever you owe them nothing but love. Easily done if you're in good
standing, but more difficult if there are hard feelings. In time and through
prayer, we can have love in any relationship. However, it must be sincere love,
according to Romans 12.
This passage says we should be devoted to one another
in love and honor one another above ourselves. It gives a list of how sincere
love should look. This list applies no matter how you fit into someone's life.
Here is what sincere love looks like:
It is selfless, zealous, fervent, and service-oriented.
It is joyful in hope, patient in affliction, and faithful in prayer. It's
hospitable, compassionate, and giving. It blesses and doesn't' curse. It
rejoices with the joyful and mourns with the grieving. It is harmonious,
humble, and never conceited. Sincere love does not seek revenge but makes peace
with everyone. It overcomes evil with good!
How many can you check off this list in your
relationships? I’m a work in progress on many of them. Let us strive to love
each other sincerely - whether for a reason, a season, or forever.


Turkuaz and Alan Evans’ Playonbrother (formerly known as the Alan Evans Trio) will each hold a CD release party at the Putnam Den in Saratoga Springs, Thursday, March 27 at 9 pm. The party is organized through Nectars and tickets are available to those 18-years old and older for $8 (and $12 the day of the show) through Ticketfly.com or at the Putnam Den. Turkuaz launches their latest with Zerbert at the double-CD release party. While Alan Evans Trio sets out to release their Woodstock Sessions in tandem.
Alan Evans recently announced that the group would drop “Trio” from their name, despite remaining a three-piece band. Evans supplies the drums and vocals, Beau Sasser is still on organ and Danny Mayer is on guitar. Though they have now adopted Playonbrother as part of their moniker, Alan Evans Trio will still appear on their latest album. Please don’t refer to them as a jazz trio. In fact, don’t try to put your thumb on them at all. They are three musicians, who happen to play for other bands, but don’t dare call this a side project either. In fact, they would just rather you just tune in and enjoy.
Influenced by the funky ’70s groove and R&B of Sly & The Family Stone, Rick James, Parliament and Bohannon, Turkuaz take their self-described “jittery, world-pop-power groove” to the streets. They just recently finished supporting Future 86, and will continue on the road for this latest installment. Sporting a line-up of nine musicians, Turkuaz throws everything from percussion to brass to guitars in a live performance that can invoke the ghosts of rockers past. Check out our coverage of their show at Drom in NYC on December 30th.


text:
Nothing quite prepared me for an actual day at the track. “Can you feel it, yet?” asked Dave as we pulled into the parking lot of Kansas Speedway in Kansas City, KS. I finally understood what he had been talking about—that palpable buzzing of excitement that surrounds race day. Dave is the big car racing fan in our family, and we were bringing our 7-year-old twin boys to their first race. It was my first race, too. Don’t get me wrong. I’m a big sports fan. I’ve been to more Royals and Chiefs games than I can count. But racing has always been Dave’s thing. Ever the loving wife, I would often watch races on TV with him and listen as he taught Ethan and Simon the ins and outs of the sport. I even picked up a few things, trying to impress Dave with my knowledge of racing lingo. But nothing quite prepared me for an actual day at the track.
We arrived early to meet up with some of Dave’s racing buddies and their families, who had come in from St. Louis to tailgate before the race. They shared their burgers with us and I passed around the potato salad I’d brought from home. It was comforting to learn that this was the first race for Susan, another racing wife, and we quickly bonded over being newbies. Susan’s 9-year-old, Alex, however, had been to the Speedway with his dad a few times. He made fast friends with Ethan and Simon, taking them under his wing and showing them the ropes. After lunch, we all took a stroll through the Midway. Booths filled with paraphernalia from racing sponsors, teams and drivers covered the area outside the grandstand gates. I had to rein the boys in before they spent all their allowance at once. Simon finally decided on a ball cap touting the number 88—for his favorite driver, Dale Earnhardt, Jr.—while Ethan bought a bright yellow t-shirt with an image of Kyle Busch’s car on it. Although, he loves M&Ms, so I’m not sure if he picked the shirt for the car or the candy. Either way, they wore their new duds with pride, and Dave was beaming, too, as he watched his sons share in the love of his favorite sport. Alex had discovered a racing video game set up a few booths away, so we headed over to check it out. The boys (including the grown-up ones) all took turns taking laps around the virtual track. After the third round, I checked my watch and tapped Dave on the shoulder. It was almost starting time.
Once we made our way into the grandstand and found our seats, the adrenaline buzz from earlier became extremely tangible, especially when the loudspeakers crackled and a deep voiced boomed out, “Drivers, start your engines.” Motors revved and engines roared and I felt the reverb deep inside my chest. I handed the boys their earplugs, and had to laugh at the looks on their faces. Wide-eyed wonder melted into grins that went on for days as they looked around the speedway in awe. “Is this for real?!” Ethan shouted over the noise. Dave looked down, tousled Ethan’s hair and smiled. “You bet it is!” The bright green flag waved, and they were off. Everyone was on their feet cheering the drivers on as they blasted their colorful cars down the back straight before whizzing into the turn. Our seats were great, but Simon practically had his binoculars glued to his face, clamoring for a closer look. “Here they come!” he yelled as the pack dove around another turn then rocketed past us in a multi-colored blur. If the adrenaline pulsing through my veins resembled even the smallest bit of the rush the drivers were feeling, I couldn’t imagine how they kept their cars steady on the track. As the race went on, I started daydreaming about taking our minivan into the shop and having my oil changed, pit crew style, before racing through the neighborhood streets and spinning perfectly into a parallel parking spot in the carpool lane at the boys’ school.
I was deep into that daydream when I suddenly heard the crowd roar, and Dave and the boys went nuts beside me. My eyes snapped back to the track and I saw the black and white checkered flag waving. Then came the victory lap and champagne and confetti in the Winner’s Circle, and the crowd went wild again. This time I was paying attention and cheered along with them, feeling the mass euphoria as it swept through the grandstand.
“Dad, you should buy a Camaro,” Ethan cried out as he bounced alongside Dave on our way back to the parking lot.
“Or a Chevrolet SS!” Simon chimed in. “And paint it yellow and red!”
Dave just laughed and said our minivan and his truck would have to do for now.
On the way home, that minivan sure sounded like a stock car thanks to Simon and Ethan’s vrooming and revving noises from the back seat, as they pretended to be behind the wheel.
I had felt the energy of the track from the moment we parked, but the thrill of the race had stayed with us.
“So, when’s the next race?” I tossed the question out with a grin. Dave looked at me with one eyebrow raised and then smiled back. “Welcome to the racing life, babe.”
The boys erupted into cheers, and Dave and I couldn’t help but laugh. Thanks to our exciting day, we all couldn’t wait to get back to the track.


text:
Janning, Spates lead Northeastern to 63-40 win over Drexel
PHILADELPHIA (AP)—Matt Janning and Eugene Spates each scored 19 points and Northeastern held Drexel scoreless for almost 10 minutes in the second half for a 63-40 victory on Saturday.
Janning’s 3-pointer with 17:22 remaining in the game ignited a 24-0 run that spanned 9:28 and culminated with a layup by Chaisson Allen that gave the Huskies a 44-23 lead with 8:58 to play. Janning and Spates combined for 17 points during the rally.
The win was the second straight for Northeastern (5-6 Colonial Athletic Association, 9-12 overall).
The Dragons—without leading scorer Frank Elegar, who did not play due to back spasms—lost their fifth straight game (2-9, 9-14). Drexel shot 23 percent from the field and managed only two points more than the season-lowest 38 points scored at George Mason on Nov. 29.
Tramayne Hawthorne and Gerald Colds each scored 12 points to lead Drexel. Randy Oveneke pulled down 10 of his game-high 13 rebounds in the first half for the Dragons.
Drexel committed nine turnovers and missed eight field goal attempts during the Huskies’ second-half run. Hawthorne’s 3-pointer with 7:55 remaining ended the run and a 9:58 scoreless streak.
Northeastern led 16-15 at halftime despite shooting 23 percent from the field in the first half. The Dragons, meanwhile, shot 19 percent in the opening half.


text:
SILENT & THE KEMPIRE UNCENSORED 'Lip Sync For Your Life' #PodCast EP 10
SILENT & THE KEMPIRE UNCENSORED #PODCAST EP.9
SILENT & THE KEMPIRE UNCENSORED: "THE YEAR OF THE OPPORTUNIST" EP 8 #PODCAST
#TURBO @Hradguitar5 Releases "Low Key" Music Video
Silent & The Kempire Uncensored: "Gimme Back My Grammy" EP 7 #Podcast
Just moments ago, Nicki Minaj debuted her second video ‘Freedom’ from ‘The Re-Up‘ which was just released today. The video is shot beautifully in black & white and is one of the best visuals Nicki Minaj had displayed in her entire career.
Check it out below!
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domain: entertainment


text:
Zordon serves as the mentor to the Power Rangers. Ten thousand years in the past he had a conflict with Rita Repulsa. He ended up banishing her to the moon but not before she encased him in a time warp. Later Zordon created a command centre located in Angel Grove. It is Zordon who recruits a group of teenagers to become the Power Rangers after Rita escapes.
Over the course of the series Zordon upgrades the equipment and powers of the rangers. This is due to newly emerging alien threats. If not for him Rita would have conquered Earth long ago. He is seen as a corporeal being inside a glass tube during the television show. In his final episode this tube is shattered, unleashing an energy wave that turns the evil characters good.
In the 2017 movie Zordon is played by revered actor Bryan Cranston. His appearance is different to that in the TV show. Motion capture and computer generated imagery are used to portray him. In this version of the story his body is destroyed by Rita and he becomes part of a cyber grid. Once he gets the rangers together he sacrifices the opportunity to return to physical form in order to save one of their lives.
Alpha 5 is Zordon’s robot assistant. He helps the rangers in their fight against evil. Serving as a secondary mentor and the comic relief, Alpha is known for the sound he makes when excited. He exclaims “ai yi yi” to covey his nervousness. This has become his catchphrase.

domain: artistic


text:
Exercising for at Least 30 Minutes a Day Improves Sleep Quality
- May 23, 2023
The importance of good sleep cannot be overstated. It is an essential aspect of our overall well-being affecting our physical health, mental health, and cognitive function. In order to achieve optimal sleep, there are a number of factors to consider, such as diet, lifestyle, and exercise habits. A recent study from the John Hopkins Center for Sleep suggests that exercise may be particularly important for improving sleep quality.
The study analyzed data from over 100,000 adults and found that those who met the recommended guidelines for physical activity reported better sleep than those who did not. Specifically, those who engaged in at least 30 minutes of exercise per day had better sleep quality than those who did not. Interestingly, the study also found that exercising for longer periods of time did not necessarily lead to better sleep.
While the study did not focus on the specific benefits of yoga, it is worth noting that many experts consider yoga to be an excellent form of exercise for promoting good sleep. The slow, deliberate movements of yoga, coupled with its emphasis on breathing and relaxation, can help reduce stress and calm the mind, making it easier to fall asleep and stay asleep. In fact, a study published in the Journal of Clinical Sleep Medicine found that participants who practiced yoga for eight weeks reported improved sleep quality and reduced insomnia symptoms.
Of course, exercise alone is not always enough to guarantee good sleep. Other factors, such as diet, stress levels, and sleep environment also play a role. That’s why tests like the Basic Wellness Panel from Access Medical Labs can be helpful in identifying potential health issues that may be affecting sleep quality. This panel includes a comprehensive array of tests designed to assess overall health and wellness including markers for inflammation, metabolic function, and vitamin and mineral status. Individuals can take a more holistic approach to improving sleep and overall well-being by identifying and addressing any underlying health issues.


text:
The front page of this story indicates that this is fourth of the pirate stories in the series; even though it was the fourth written, it probably works better as the third story.
I loved writing this story. I particularly loved the characters and the little, lapidary moments in this story: the girls in the kitchen of the Sea Princess , the service in the cathedral, the cooking competition, the ball and the reconciliation at the end.
When I have read this to children, they are always excited by the way justice works in the story. The theme of redemption is very strong here.