text:
Method of using lectins for contraception, prophylaxis against diseases transmittable by sexual contact, and therapy of such diseases, and apparatus for administering lectins
United States Patent 6743773
In order to prevent conception and/or the spread of sexually transmitted diseases (STD's) one or more lectins capable of binding sperm and/or the pathogenic microorganisms responsible for STD's are administered to the vagina prior to sexual intercourse. The lectins immobilize the sperm to render them incapable of fertilization and also bind to the microorganisms to render them non-pathogenic or to the cells to prevent infection by the microorganisms. Lectins can also be administered to treat sexually transmitted vaginal infections. The invention also encompasses a device for to be placed in the vault of the vagina which comprises a ring which surrounds the cervix and a membrane spanning the central aperture of the ring to prevent the direct contact of ejaculate with the cervical tissues. The device is impregnated or coated with lectins and releases them into the vaginal environment over a period of time.
Inventors:
Oldham, Michael J. (Oxnard, CA)
Rose, Bruce F. (Ventura, CA)
Export Citation:
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Legere Pharmaceuticals, Ltd. (Carson City, NV)
Other Classes:
514/2.3, 514/931
International Classes:
A61F6/08; A61K38/16; A61K38/17; (IPC1-7): A01N37/18; A61K38/00; A61K38/06
Field of Search:
514/21, 514/6, 514/8, 514/2, 514/931
View Patent Images:
Download PDF 6743773
Balzarini et al, "The mannose-specific plant lectins . . . inhibitors of human immunodeficiency virus and cytomegalovirus replication in vitro.", Antiviral Res 1992;Jun 18(2):191-207.*
Hansen et al, "Inhibition of human immunodeficiency virus 1 (HIV-1) and herpes simplex virus 1 (HSV-1) infectivity with a broad range of lectins.", Scand J Infect Dis 1991;23(4):425-30.
Primary Examiner:
NUTTER, NATHAN M
Attorney, Agent or Firm:
SHOOK, HARDY & BACON LLP (KANSAS CITY, MO, US)
Parent Case Data:
RELATIONSHIP TO OTHER APPLCATIONS
This application is a continuation of application Ser. No. 09/156,696, filed Sep. 18, 1998, which is a continuation of application Ser. No. 08/938,831, filed Sep. 26, 1997, now U.S. Pat. No. 5,840,771, which is a continuation of application Ser. No. 08/759,517, filed Dec. 4, 1996, abandoned, which is a continuation of application Ser. No. 08/609,104, filed Feb. 29, 1996, abandoned, which is a continuation of application Ser. No. 08/462,666, filed Jun. 5, 1995, abandoned, which is a divisional of application Ser. No. 08/317,599, filed Oct. 3, 1994, abandoned, which is a continuation-in-part of application Ser. No. 08/130,190, filed Oct. 1, 1993, abandoned.
We claim:
1. A method of preventing the transmission of one of gonorrhea and Chlamydia comprising administering to the vagina an amount of a composition containing at least one lectin capable of binding to a pathogenic microorganism or to carbohydrate moieties expressed on the vaginal epithelial cell surface, said lectin being effective to diminish the infective capability of said microorganism, said lectin being dispersed in a biocompatible non-toxic vehicle.
2. The method of claim 1 wherein one or more lectins are administered.
3. The method of claim 1 wherein said sexually transmissible disease is gonorrhea and said lectin is selected from the group consisting of BPA, CPA, CSA, GNA, LAA, LBA, LCH, LEA, MAA, MPA, NPA, PSA, RPA, SBA, STA, sWGA, TKA, VVA, WFA, and WGA.
5. The method of claim 1 wherein said sexually transmissible disease is infection with Chlamydia trachomatis and said lectin is selected from the group consisting of ABA, TKA, DSA, WFA, VFA, Jacalin, and MPA.
7. The method of claim 1 wherein said vehicle is selected from the group consisting of creams, ointments, foams, suppositories, ovules, lubricants, lotions, oils, and combinations thereof.
This invention relates generally to methods of contraception and prophylaxis against diseases transmittable by sexual contact and therapy of such diseases, and more particularly to a method using intravaginally administered lectins for contraception and to protect against the transmission of diseases that are transmissible by sexual contact and to treat such diseases. The invention also relates to devices for intravaginal administration of lectins.
2. Brief Summary of the Prior Art
Sexually transmitted diseases (STD's) are epidemic in this country and worldwide. Furthermore, other diseases that have not traditionally been considered to be STD's have also been found to be transmitted by sexual contact, e.g., hepatitis B. The medical and public health problems associated with these epidemics have motivated a search for methods of controlling these diseases by limiting their transmission from person to person. Similarly, although many methods of contraception have been employed, no universally satisfactory method has been developed.
Hitherto it has been generally agreed that barrier methods which prevent the contact of body fluids between individuals are the most effective means of preventing transmission of such diseases. Such barrier methods are also effective contraceptive procedures. However, such methods are somewhat inconvenient and require some cooperation between individuals.
An alternative method for preventing the transmission of sexually transmitted diseases is to kill the pathogenic microorganisms in semen and vaginal secretions so that they are incapable of invading the tissues and causing the disease. While intravaginally placed spermatocides have been used for contraception, alone or in combination with barrier methods, antimicrobial materials have not been so used to prevent STD's, probably because many of such materials are irritating to adjacent tissues.
Administration of biologically active materials to the vagina for whatever purpose is usually accomplished by the use of some device that provides for convenient application of the medication by the user herself. A variety of devices exist for delivery of bioactive substances such as spermatocides and various medications. Each has its place in the medical armamentarium but each has certain deficiencies for application of contraceptive or anti-microbial agents in the context of sexual activity. Conventional vaginal suppositories and ovules may not provide medication to the entire vagina because of their shape and placement by the user in the vagina. Such suppositories are generally comprised of a material that melts at body temperature to allow the medication to spread and contact the tissues. However, when the dosage form melts, the medication may drain out of the vagina rather quickly, thus minimizing its potential effectiveness and significantly reducing the extended exposure of the tissues and pathogens to the medication which is often necessary for effective treatment. Similarly, the effective duration of contraceptives applied in this way tends to be relatively brief. In addition, such delivery vehicles, even when freshly applied, do not provide any physical barrier to deposition of male ejaculate on the cervix. Such ready access of sperm to the cervix may allow them to escape the action of spermatocides that are diffused throughout the vagina. Furthermore, because cells at the cervix are uniquely sensitive to several pathogens such as Chlamydia trachomatis, the absence of a barrier deprives these cells of a significant means of protection.
In order to provide for a longer retention of medication in the vagina and assure a more continuous delivery of active ingredients to the tissue, several types of vaginal rings have been proposed. Such devices are disclosed, for example, in Duncan, U.S. Pat. No. 3,545,439; Roseman, U.S. Pat. No. 3,920,805; Schopflin, U.S. Pat. Nos. 4,012,496 and 4,012,497; Wong et al., U.S. Pat. Nos. 4,237,885 and 4,286,587; and Nash et al., U.S. Pat. No. 4,292,965. The vaginal rings are generally impregnated with a spermatocide and are designed to be retained in the vaginal vault and to release the spermatocide slowly over a period of time to maintain an effective contraceptive concentration of the active material in the vagina. However, such devices do not prevent the direct contact of ejaculate with the tissues of the cervix, and therefore do not protect those tissues from contact with pathogenic organisms which might be contained in the ejaculate. They are also of questionable efficacy in supplying the spermatocide where it is most needed.
Another approach is to use a cervical cap or a diaphragm to serve as a mechanical barrier to the sperm and to dispense medication. These devices are designed for a relatively tight fit either to the cervix or the walls of the vagina to serve as a mechanical barrier to the passage of sperm. Such devices can be effective, especially as contraceptives and when combined with spermatocides. However, because of the need to provide a sperm-resistant seal they are frequently relatively complex devices incorporating metallic springs within a rubber or synthetic resin structure to provide the required sealing force.
Another approach to providing an effective concentration of spermatocide in the vagina is to provide a sponge impregnated with a spermatocide. Such applicators are not intended to be precisely located and may permit the contact of ejaculate with the tissues of the cervix, with the undesirable consequences outlined above.
Accordingly, a need has continued to exist for a method of contraception and prophylaxis against STD's by vaginal administration of a spermatocide and/or antimicrobial material, and for a simple and effective device to protect the tissues at risk from contact with microorganisms while dispensing a spermatocidal and/or antimicrobial material.
This need has now been alleviated by the method and device of this invention, according to which one or more lectins capable of binding sperm and/or the pathogenic microorganisms responsible for STD's are administered to the vagina or site of infection prior to sexual intercourse. The lectins immobilize sperm to render them incapable of fertilization and also bind to the microorganisms to render them non-pathogenic or to the cells to prevent infection by the microorganisms.
The invention also encompasses a device for to be placed in the vault of the vagina which comprises a ring which surrounds the cervix and a membrane spanning the central aperture of the ring to prevent the direct contact of ejaculate with the cervical tissues. The device is impregnated or coated with lectins and releases them into the vaginal environment over a period of time.
Accordingly, it is an object of the invention to provide an improved method for prophylaxis against sexually transmitted diseases.
A further object is to provide a method of contraception.
A further object is to provide a method for binding and immobilizing pathogenic microorganisms in the vagina.
A further object is to provide a method for treating vaginal infections.
A further object is to provide a device for delivering lectins to the vagina over a period of time.
A further object is to provide an intravaginal device that protects the tissues of the cervix from direct contact with ejaculate.
Other objects of the invention will become apparent from the following detailed description when considered in conjunction with the drawings.
FIG. 1 is a top plan view of a lectin-delivery device according to the invention.
FIG. 2 is a bottom view of the lectin-delivering device of FIG. 1.
FIG. 3 is a cross section of the lectin-delivering device of FIGS. 1 and 2, taken along the line 3—3.
FIG. 4 is a top plan view of another embodiment of the lectin-delivering device of this invention.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
Lectins are carbohydrate-binding proteins of nonimmune origin that agglutinate cells or precipitate polysaccharides or glycoconjugates, i.e., proteins or lipids conjugated to oligo- or polysaccharides. They are widely distributed, and have been isolated from both plant and animal sources. Their reactions with living cells are based on their ability to bind with antibody-like specificity to particular arrangements of the sugar residues that make up oligo- or polysaccharides.
The surface of eucaryotic cells contain very numerous molecules of glycoproteins and glycolipids. Similarly, the cell walls of bacteria and the envelopes and capsids of viruses contain structural polysaccharides and/or glycoproteins. The carbohydrate moieties of these molecules which are displayed on the cell surfaces exhibit great variety in composition and structure that serves to distinguish the types of cells and to serve as a signal to other cells or materials which come into contact with the cell. For, example, variation in the carbohydrate moieties of glycoproteins in the membrane of red blood cells serves as the basis for the conventional blood typing classification. When lectins recognize and bind to certain carbohydrate moieties they may serve to cross-link and agglutinate the cells bearing the binding groups, a property that earns for them the alternate name of agglutinins. Furthermore, because the same sort of carbohydrate moieties often serve as attachment points for pathogens to bind to target cells and invade them, lectins may block infection of target cells by blocking the sites used by pathogens as recognition markers. The same type of specific binding occurs between sperm and egg in conception, and can be blocked by lectins. The binding ability of lectins may be very specific for certain mono- or oligosaccharides, allowing lectins to be used as a powerful tool for investigating the oligosaccharide epitopes on the surface of organisms or cells. Lectins can distinguish between blood cells of specific blood type, malignant from normal cells, and among species and genus of organisms. While glycoproteins, glycolipids, and bacterial cell walls are believed to be the main lectin-binding locations on the surface of cells, it is not excluded that carbohydrate moieties derived from other molecules or cellular structures may be displayed on the cell surface or that other lectin-binding structures may be present on cell surfaces. All such lectin-binding structures may be targets for the lectins used in the method of this invention.
Current medical uses of lectins include distinguishing erythrocytes of different blood types (blood typing). More recently, lectins have been used ex-vivo in depleting T cells of patients undergoing bone marrow transplantation.
In the context of this application the term microorganism includes any microscopic organism within the cataegories of algae, bacteria, fungi, protozoa, viruses, and subviral agents.
Among the microorganisms that are bound by certain lectins are infectious organisms such as bacteria, protozoa, and viruses. Lectins may be used to identify such microorganisms in vitro and are also capable of binding to them in vivo, thereby preventing them from infecting living cells. Human disease-causing organisms (and the diseases caused by them) that can be bound by lectins include Neisseria gonorrhoeae (gonorrhoea); Chlamydia trachomatis (chlamydia, lymphogranuloma venereum); Treponema pallidum (syphilis); Haemophilus ducrei (chancroid); Donovania granulomatis (donovanosis); Mycoplasma pneumoniae, M. hominis, M. genitalium, Ureaplasma urealyticum (mycoplasmas); Shigella flexneri (shigella); Salmonella typhi, S. choleraesuis, S. enteritidis (salmonella); Campylobacter fetus, C. jejuni (campylobacter); human immunodeficiency virus HIV-1 and HIV-2 (HIV, AIDS); HTLV-1 (T-lymphotrophic virus type 1); herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2); Epstein-Barr virus; cytomegalovirus; human herpesvirus 6; varicella-zoster virus; human papillomaviruses (many types) (genital warts); molluscum contagiosum (MSV); hepatitis A virus, hepatitis B virus (viral hepatitis); Trichomoniasis vaginalis (trichomoniasis); yeasts such as Candida albicans (vulvovaginal candidiasis). Other diseases that are transmitted by contact with bodily fluids may also be transmissible by sexual contact and are capable of being prevented by administration of lectins according to this invention. Accordingly, the term sexually transmitted diseases (STD's) is to be interpreted in this application as including any disease that is capable of being transmitted in the course of sexual contact, whether or not the genital organs are the site of the resulting pathology.
Inasmuch as lectins are also capable of agglutinating human sperm and other components of the male ejaculate, and thereby rendering the sperm immobile, intravaginal administration of lectins can also serve as a method of contraception.
According to the invention a dose of lectins adapted to bind and agglutinate pathogenic microorganisms and/or block the recognition sites on target cells is administered to the vagina prior to sexual intercourse. The active ingredients may also include lectins capable of binding and/or inactivating sperm to serve as a contraceptive.
Because of the specificity of lectins for certain microorganisms, it is preferred to administer a mixture of lectins chosen for their properties of agglutinating specific pathogens. It is also according to the invention to administer a mixture of sperm-agglutinating lectins and lectins capable of binding to pathogenic organisms to provide simultaneous contraception and protection against infection.
A representative listing of lectins, the abbreviations by which they are referred to, and their sources is given in Table 1.
Lectins and Abbreviations
Lectin Source
AAnA Anguilla anguilla (Eel serum)
AAurA Aleuria aurantia (Orange peel fungus)
ABA Agaricus bisporus (Mushroom)
ABrA Amphicarpanea bracteata (hog-peanut)
AL Hippaestrum hybrid (Amaryllis bulbs)
APA Abrus precatorius (Jequirity bean)
BPA Bauhinia purpurea alba (camel's foot tree)
CAA Caragana arborescens (Siberian pea tree)
ConA Concanavalia ensiformis (Jack bean)
CPA Cicer arietinum (chick pea)
CSA Cytisus scoparius (Scotch broom)
DBA Colichos biflorus (horse gram)
DSA Datura Stramonium (Jimson weed, Thorn apple)
ECA Erythrina crystagalli (Coral tree)
ECorA Erythrina coralldendron (Coral tree)
EEA Euonymus europaeus (spindle tree)
DBA Dolichos biflorus (horse gram)
GNA Galanthus nivalis (Snowdrop bulb)
GSA-1/GSA-lI Griffonia simplicifolia
HAA Helix aspersa (Garden snail)
HPA Helix pomatia (Roman or edible snail)
JAC (Jacalin) Artocarpus integrifolia (jackfruit)
LAA Laburnum alpinum
LBA Phaseolus lunatis (also limensis) (Lima bean)
LCA (LcH) Lens culinaris (lentil)
LEA Lycopersicon esculentum (Tomato)
LOA Lathyrus oderatus (Sweet pea)
LTA (LOTUS) Lotus tetragonolobus (Asparagus pea)
MAA Maackla amurensis (maackla)
MPA Maclura pomifera (Osage orange)
NPL (NPA) Narcissus pseudonarcissus (daffodil)
PAA Phytolacca americana (Pokeweed)
PHA (PHA-L) Phaseolis vulgaris (Red kidney bean)
PNA Arachis hypogaea (Peanut)
PSA Pisum sativum (Pea)
PWA Phytolacca americana (pokeweed)
PTAgalactose Psophocarpus tetagonolobus (winged bean)
PTAgalNac Psophocarpus tetagonolobus (winged bean)
RCA-I/RCA-II Ricinus communis (Castor bean)
RPA Robinia pseudoaccacia (black locust)
SBA Glycine max (Soybean)
SJA Sophora japonica (Japanese pagoda tree)
STA Solanum tuberosum (Potato)
TKA Trichosanthes kinlowii (China gourd)
UEA-I/UEA-Il Ulex europaeus (Gorse or Furz seeds)
VAA Viscum album (European mistletoe)
VFA Vicia faba (Fava bean)
VGA Vicia graminea
VRA Vigna radiata (mung bean)
VSA Vicia Sativa
VVA Vicia villosa (Hairy vetch)
WFA Wisteria floribunda (Japanese wisteria)
WGA Triticum vulgaris (Wheat germ)
suc-WGA Succinyl WGA
For example, N. gonorrheae is agglutinated by lectins that bind to N-acetyl-D-glucosamine residues on their surfaces. Such lectins include WGA and STA, which are known to agglutinate all 193 clinical isolates of N. gonorrheae. WGA is effective for such agglutination at a concentration of 3.1 micrograms per milliliter. Other lectins showing some agglutination activity with respect to N. gonorrheae include RCA-I, RCA-II, GSA-I, and SBA.
Certain species of Chlamydia (trachomatis, psittaci, and pneumoniae) are known to be bound by the lectins ConA, DBA, UEA-1, SBA, and PNA. WGA also binds to the receptors on certain cells, thereby blocking infection by C. trachomatis and C. psittaci.
PHA binds to several isolates of H. ducrei, suggesting that N-acetyl-D-glucosamine is present in the cell envelope polysaccharide.
WGA has been found to agglutinate a variety of bacterial cells, including Escherichia coli, Micrococcus luteus, and some types of Staphylococcus aureus. WGA, specific for N-acetyl-D-glucosamine and SBA, specific for N-acetyl-D-galactosamine, are capable of agglutinating the many bacterial species which contain these sugar residues in their cell wall polysaccharides.
Various lectins are capable of binding to certain glycoproteins present in the envelope of HIV virus. For example, ConA has been found to block infection of certain cell lines against infection by HIV in vitro, and conglutinin, a lectin derived from bovine serum, has been found to bind to the HIV envelope precursor protein gp 160, thereby preventing attachment to CD-4 receptors of target cells in vitro. GNA has been found to prevent infection of T-cells by HIV in vitro. Consequently, ConA, GNA and WGA have been found to be effective at preventing infection of target cells by HIV-1 and HIV-2 in vitro. NPL and conglutinin have shown some activity as well.
HPA and ConA have demonstrated efficacy in the prevention of infection of target cells by HSV-1 and HSV-2.
Lectins are also useful in aggregation of sperm. PHA, WGA, STA, ConA, PSA, APA, ECA, ECorA have demonstrated varying degrees of efficacy in agglutination of sperm.
While the lectins discussed above and the organisms against which they are effective are representative of useful lectins according to the invention, it is to be understood that other lectins may be discovered which are active in the binding and agglutination of the pathogens of sexually transmitted diseases, and that the use of such lectins is intended to be included within the scope of the invention.
In determining the amount of lectin to be administered for effective binding and/or agglutination of the pathogenic organisms of STD's, the amount of lectin that might be bound to vaginal tissues and thereby made unavailable for agglutination of pathogens must be considered. In studies on murine vaginal tissue, DBA, LAA, LBA, LCA, LTA, RCA-I, RCA-II, SJA, STA, VGA, WFA have been found not to bind to the tissue at any stage of the estrus cycle. In contrast, ABA, MPA, PHA-E, PHA-L, Suc ConA, and WGA bound strongly to vaginal tissues at all stages of the estrus cycle. CSA, GSA-I, GSA-II, HAA, HPA, JAC, PNA, PAA, SBA, Suc WGA, UEA-I, VFA, and VVA exhibited intermediate degrees of binding to murine vaginal tissues. The amount of lectin to be administered for effective prophylaxis can be determined from the relative binding effect of the various lectins to the pathogen and to the vaginal tissues.
The selection of particular lectins to be administered will depend on the diseases sought to be prevented. It is preferred to administer a mixture of lectins, each selected for best agglutinative efficacy against a particular pathogen.
The lectins may be administered in any fluid or ointment vehicle suitable for topical administration of pharmaceutical compounds. Thus creams, ointments, foams, suppositories, ovules and the like may be formulated in which the selected lectins are dispersed in a non-toxic vehicle suitable for topical and in particular for vaginal administration. Such vehicles include white petrolatum, hydrophilic petrolatum, lanolin emulsions, polyethylene glycols, cocoa butter and the like. Useful vehicles include emollient oils such as water-soluble oils, e.g., liquid polyethylene glycols, which promote complete and uniform distribution of the medicament within the vagina. Representative suitable vehicles include a lubricating jelly comprised of water, propylene glycol, hydroxyethyl cellulose, benzoic acid and sodium hydroxide, a water-soluble oil comprised of water, glycerin, propylene glycol, polyquaternium #5, methyl paraben and propyl paraben; a cream comprised of benzyl alcohol, cetearyl alcohol, cetyl esters wax, octyldodecanol, polysorbate 60, purified water, and sorbitan monostearate; and a suppository comprised of polyethylene glycol (PEG) 18, PEG-32, PEG-20 stearate, benzethonium chloride, methyl paraben and lactic acid.
According to the invention, the dispersion, suspension, or solution of lectins in the vehicle may be applied to the site of a lesion on the external genitalia, such as the lesions produced by herpes simplex virus type 1 or type 2, chancroid, genital warts, chancre of syphilis, and the like, to prevent the transfer of pathogens. The lectins may also be introduced into the vagina in order to prevent conception or infection by pathogens introduced during sexual intercourse. The amount of lectins to be applied will be an amount that is effective to prevent conception or infection or substantially reduce the risk thereof. The amounts needed to achieve these goals will depend on the effectiveness of the individual lectins, their affinity for the target cell and the like. The effective amounts can be determined by the skilled practitioner by routine experimentation.
Because of their ability to bind pathogenic micro-organisms, thereby interfering with their mobility, growth and reproduction, lectins are also useful in therapy of topical infections of the vagina. For those diseases wherein the pathogens grow and reproduce within the lumen of the vagina, administration of lectins, alone or in combination with other antimicrobial materials, can assist in the treatment and cure of the infection.
Because some of the conventional means of administering medications to the vagina have certain drawbacks, as discussed above, it is preferred to incorporate the lectins into a device which will remain in the vagina and dispense the lectins over a prolonged period of time in order to maintain an effective concentration of the lectins in the vagina. Such a device may also be designed to provide a barrier that will prevent the access of pathogenic organisms into the uterus and may also function as a contraceptive device.
The device of the invention is generally a ring of elliptical or circular cross-section made, e.g., from a biocompatible, nontoxic thermoplastic polymer or polymeric open-cell polyurethane. Bonded to one side of the ring or molded integral with it is a web of the same material.
A device according to the invention having a ring of elliptical cross-section is illustrated in FIGS. 1-3, wherein the reference numerals indicate the same elements in each figure. A ring 102 of generally elliptical cross section constitutes the main structural member of the device and is sized to fit comfortably in the vaginal vault surrounding the cervix. To one side of the ring 102 is fastened a relatively thin web 104, preferably made of the same material as the ring. In some embodiments the web may be molded integrally with the ring.
FIGS. 4-6 illustrate another embodiment of the invention wherein a ring 202, of generally circular cross section, carries a thin web 204 spanning the central aperture on one side of the ring.
The device may be manufactured from any material that has been shown to be biocompatible with the environment of the vagina and to be capable of holding lectins within its bulk and releasing them slowly to the surrounding environment. Several materials suitable for this function are already known from the vaginal devices already in use or disclosed in the technical literature. Consequently, the skilled practitioner can easily select a suitable material from which to make the device of this invention. The lectins may also be incorporated into a thin flexible coating, placed on the ring or web or both, and designed to release the lectins therefrom over a period of time, e.g., by diffusion out of the coating or by gradual erosion and dissolution of the coating in the vaginal environment.
The device of the invention is designed to deliver one or more lectins locally in the vagina for:
1) contraception, by binding to the glycoproteins, glycolipids and other glycoconjugates on the surface of sperm and by binding to the glycoproteins, glycolipids, and other glycoconjugates in the seminal fluid, thereby creating an ejaculate with significantly greater viscosity, and thereby preventing sperm from exiting the ejaculate;
2) prophylaxis against various sexually transmitted diseases by binding to the glycoproteins, glycolipids, and other glycoconjugates on the surface of the bacterial agent or viral coat of the virus and the glycoproteins, glycolipids, and other glycoconjugates in the seminal fluid thereby preventing the infectious agent from reaching the target tissue;
3) prophylaxis against various sexually transmitted diseases by binding to the glycoproteins, glycolipids and other glycoconjugate receptor sites on the vaginal stratified squamous epithelium and cervical columnar epithelium, whereby the recognition sites for attack by pathogens are blocked or concealed; and
4) treatment of topical infections of the vagina by interfering with the growth and reproduction of the pathogenic microorganism, thereby hindering their ability to infect healthy cells.
The device of the invention also operates by providing a physical barrier to the direct deposition of ejaculate on the cervix. This design assures that the concentration of protective lectins in the cervical region will not be diluted and overwhelmed by the ejaculate. Rather, the sperm and the pathogens present in the ejaculate can only reach the cervical region gradually by diffusion and transport around the outside of the peripheral ring of the device. This slow transport of the sperm and pathogens from the ejaculate to the cervical region assures that the lectins will have an opportunity to bind to all appropriate constituents of the ejaculate. The presence of the lectins, which will coagulate and inhibit the transport of sperm and pathogens, makes it unnecessary to have a device that fits tightly either around the cervix or against the wall of the vagina.
Accordingly, the device of the invention has several advantages over the vaginal medication and contraceptive devices currently available:
1) It is easily inserted and comfortable to use.
2) Because of its position in the top of the vaginal canal, it ensures that the lectins are carried down through the vagina.
3) Since it is placed next to the cervix it can also deliver lectins targeted to the cervix.
4) Gradual release of lectins provides a more consistent delivery over time, thus ensuring more efficient treatment.
This example illustrates the utility of various lectins in binding to certain microorganisms and to seminal plasma, sperm, human serum and cervical mucus.
The efficacy of binding of various lectins to human sperm and seminal plasma and cervical mucus, an indicator of the effectiveness of such materials as vaginally-applied contraceptives, was investigated in vitro by the following procedures. Similarly the efficacy of lectin binding to Neisseria gonorrhoeae, the pathogen responsible for gonorrhoea, was investigated by the following in vitro procedures. Such binding efficacy is an indication of the capability of such lectins to bind the pathogen and prevent infection when used intravaginally as a prophylactic material.
Growth of bacteria: A cervical isolate of Chlamydia trachomatis serovar G ATCC VR-878 was grown in McCoy cell monolayers in the presence of 1 μg of cycloheximide per ml. The culture medium was 90% Eagle's minimum essential medium-10% fetal calf serum-10 mM HEPES (pH 7.3) supplemented with 100 μg of vancomycin per ml. Elementary bodies were purified by differential centrifugation followed by density gradient centrifugation In Percoll as described by Newhall et al. (Newhall, W. J., Baheiger, B. and Jones, R. B. 1982, Analysis of the human serological response to the proteins of Chlamydia trachomatis, Infection Immunity 38: 1181-1189). The purified elementary bodies were washed twice in 10 mM HEPES-145 mM NaCl (pH 7.4) and resuspended in bicarbonate buffer (100 mM NaHCO3 containing 0.01% NaN3, pH 9.5). The density of elementary bodies was adjusted to a McFarland No. 2 standard using the same buffer. Neisseria gonorrhoeae ATCC 19424 were grown on chocolate agar plates for 48-72 hrs at 37° C. in a CO2 incubator (5% CO2 and 80% humidity) and were harvested by scraping bacteria from the agar surface and resuspending the cells in sterile phosphate buffered saline. The cells were washed three times by centrifugation at 5000× g and resuspended in bicarbonate buffer, the density of which was adjusted to a McFarland No. 2 standard (optical density as measured by a spectrometer—0.4 at 650 nm). The cells were stored on ice prior to immediately testing in the lectin binding assay. Lactobacillus jensenii ATCC 25258 was grown 48-72 hrs. at 37° C. in a shaking (incubator in MRS broth at pH 5.5 containing 2% glucose. After incubation, cells were centrifuged at 5000× g for 10 min and washed twice in phosphate buffered saline, and the density was adjusted to a McFarland No. 2 standard with bicarbonate buffer. Haemophilus ducreyi was grown on chocolate agar plates for 72 hrs in a CO2 incubator (10% CO2 and 80% humidity) t 31° C. Bacteria were harvested by scraping bacteria from the agar surface and resuspending the cells in sterile phosphate buffered saline. The cells were washed three times by centrifugation at 500× g, resuspended in bicarbonate buffer and the cell density adjusted to a McFarland No. 2 standard. The cells were stored on ice prior to immediately testing in the lectin binding assay.
Lectin Binding Assay: Biotinylated lectins were reconstituted in phosphate buffered saline (10 mM sodium phosphate-150 mM NaCl, pH 7.2) and stored in a freezer at −70° C. until used. Microtiter plates washed with 95% ethanol and dried were coated with bacteria. (Chlamydia trachomatis or Neisseria gonorrhoeae or Haemophilus ducryei or Lactobacillus Jensenii) by adding 200 μl of a bacterial suspension (in bicarbonate buffer) to each well and incubating overnight at room temperature. Wells coated with bacteria were washed three times In either sodium acetate buffered saline, pH 4.0, containing 0.1% Tween detergent (ABST) or phosphate buffered saline containing 0.1% Tween (PBST). Lectins defrosted at room temperature were diluted in each buffer, and 100 μl of various lectins was added to bacteria-coated wells at a fInal concentration of 50 μg/ml. After incubation in a humid chamber at room temperature for 2 hours, wells were washed three times with either ABST or PBST followed by the addition to each well of 100 μl of alkaline phosphatase streptavidin (10 μg/ml). After incubation for 1 hour at room temperature, wells were washed three times with ABST or PBST and 100 μl of freshly prepared p-nitrophenylphosphate (1 mg/ml) in 0.1 M Tris buffer-0.15 M NaCl was added and color development was quantified with a spectrophotometer at 405 nm.
Cervical Mucus: A sample of cervical mucus was obtained from a healthy donor and the gel phase separated by centrifugation. The pellet was washed three times by centrifugation and the mucin stabilized and alkylated before dialysis against a low ionic strength, pH 8.0 buffer. The cervical mucus was bound to flat-bottomed plates by incubating in bicarbonate coating buffer at 4° C. overnight. The plates were washed to remove unbound ligand. Biotinylated lectins were serially diluted across the plates in the wash buffer and the plates incubated at room temperature for 2 hrs. Unbound lectin was removed by washing, and the bound lectins were tagged by incubating with streptavidin-alkaline phosphatase at room temperature for 1 hr. Unbound streptavidin-alkaline phosphatase was removed by washing and the assay completed by adding freshly prepared p-nitrophenylphosphate (1 mg/ml) in 0.1 M Tris buffer-0.15 M NaCl) and monitoring the rate of color production.
Seminal Plasma and Sperm: A sample of ejaculate was donated by a healthy donor and the seminal plasma (supernatant) removed by centrifugation and frozen at −20° C. The binding assay was performed in the same way as for cervical mucus.
The sperm pellet resulting from centrifugation of the ejaculate was washed twice and total sperm count determined using a hemocytometer. Sperm were added to plates, left to settle at room temperature for 2 hrs. and fixed using glutaraldehyde. The plates were then washed and unbound sites blocked with protein solution and stored at +4° C. until use. The remainder of the binding assay was performed in the same way as for cervical mucus and seminal plasma.
Serum: A sample of blood was collected from a healthy donor, the serum separated by centrifugation and stored at −20° C. The binding assay was performed in the same way as for cervical mucus and seminal fluid.
Analysis of data: Sigma Plot was used for graphing and curve fitting of binding plots. Velocity of the color-forming reaction versus concentration of lectin added was plotted. Binding curves were fitted to the hyperbolic equation f(x)=ax/(b+x) where "x" is the concentration of lectin, "f(x)" is the rate of reaction measured by change in optical density (OD) of the reaction solution per unit time, "a" is the asymptotic value of maximum reaction velocity measured as change in optical density per minute (represented in the following tables as mOD/min) and "b" is the concentration of lectin where half of maximum binding occurs (represented in the following tables as [Lectin]1/2 max). The binding "quotient" is defined as a/b.
The data for lectin binding to sperm, seminal plasma, cervical mucus, human serum, Neisseria gonorrhoeae, and Lactobacillus jensenii are summarized in the following tables.
SUMMARY OF BINDING DATA
QUOTIENT
Seminal Cervical Human
Lectin Sperm Plasma Mucus Serum
ABA WB 0.44 WB WB
AL NB NB NB NB
BPA 0.60 0.86 20.76 WB
CAA 0.46 1.04 7.82 WB
ConA 2.59 2.68 1.11 3.29
CPA WB WB WB WB
CSA WB 0.30 7.30 WB
DBA WB WB WB WB
DSA 1.09 WB WB WB
ECA WB WB WB WB
EEA NB NB 0.39 NB
GNA 0.36 0.58 0.24 WB
GSA-I/GSA-II WB WB WB WB
HAA NB WB WB WB
Jacalin 3.43 11.63  21.55 8.93
LAA NB 0.57 WB WB
LBA WB WB WB WB
LcH 7.26 2.58 8.64 1.60
LES WB WB WB WB
LOTUS NB 0.94 4.13
MAA NB WB WB NB
MPA 2.29 3.17 13.8 1.18
NPA NB NB NB NB
PWA WB NB NB NB
PHA-L WB WB WB NB
PNA WB WB 7.25 NB
PSA 3.44 2.70 14.5 1.12
PTAgalactose NB WB 1.31 WB
PTAgalNacnb NB NB 1.39 WB
RPA 1.28 0.84 0.45 WB
SBA NB WB WB NB
SJA NB WB WB NB
STA NB WB WB NB
sWGA 1.32 7.50 WB WB
TKA WB 0.87 WB WB
UEA-1 WB WB 14.72 WB
VPA WB 2.78 5.21 2.02
VRA WB 3.35 WB WB
VVA N/A 0.81 WB WB
WFA 2.48 1.96 26.24 WB
WGA 19.38  4.87 12.77 1.13
1. N/A—not available
2. NB—no binding
3. WB—weak binding
LECTIN BINDING TO SPERM
Max [Lectin]1/2 Max
Lectin (mOD/min) (μg/ml) Quotient
WGA 155 8 19.38
LcH 196 27 7.26
PSA 141 41 3.44
Jacalin 103 30 3.43
ConA 57 22 2.59
WFA 67 27 2.48
MPA 48 21 2.29
sWGA 41 31 1.32
RPA 120 94 1.28
DSA 63 58 1.09
BPA 67 112  0.60
CAA 33 71 0.46
GNA 27 74 0.36
LECTIN BINDING TO SEMINAL PLASMA
Jacalin 93 8 11.63
sWGA 45 6 7.50
WGA 112  23 4.87
VRA 208  62 3.35
VFA 125  45 2.7
PSA 100  37 2.70
LcH 147  57 2.58
LOTUS 32 34 0.94
BPA 64 74 0.86
RPA 56 64 0.88
VVA 25 31 0.81
TKA 39 45 0.87
LAA 37 65 0.57
ADA 0.44
CSA 25 82 0.30
LECTIN BINDING TO CERVICAL MUCUS
WFA 656 25 26.24
Jacalin 237 11 21.55
BPA 353 17 20.76
UEA-1 265 18 14.72
PSA 58 4 14.50
MPA 138 10 13.80
WGA 562 44 12.77
CAA 352 45 7.82
CSA 445 61 7.30
PNA 174 24 7.25
VFA 203 39 5.21
LOTUS 194 47 4.13
PTAgalNac 110 79 1.39
PTAgalactose 113 86 1.31
EEA 27 70 0.39
LECTIN BINDING TO HUMAN SERUM
WGA 160 142  1.13
PSA 84 75 1.12
LECTIN BINDING TO NEISSERIA GONORRHOEAE pH 4
BPA 1190  82 14.51
CPA 80 33 2.42
CSA 560 7 80.00
GNA 294 18 16.33
LAA 176 42 4.19
LBA 275 14 19.64
LCH 213 176 1.21
LEA 106 7 14.29
MAA 235 56 4.20
MPA 159 5 31.80
NPA 299 38 7.87
RPA 233 10 23.30
SBA 414 8 51.75
STA 194 24 7.57
sWGA 49 0.50 90.00
TKA 178 55 3.24
VVA 411 3 137.00
WFA 331 3 110.33
WGA 125 0.78 160.26
LECTIN BINDING TO LACTOBACILLUS JENSENII
ABA 216 2 108.00
BPA 557 57 9.77
Jacalin 148 7 21.14
SBA 523 63 8.30
LEA 45 82 0.55
MPA 2047  328  6.24
ConA 301 7 43.00
CSA 624 387  1.61
NPA 425 36 11.81
VVA 260 33 7.88
In the above tables the affinity of the lectin for a particular substrate is inversely proportional to the maximum velocity of the color-forming reaction. Consequently, those lectins having a smaller b value ([lectin]1/2 max) bind more firmly to the substrate. A high binding efficacy (low mOD/min) is preferable for binding to sperm or seminal plasma for contraceptive purposes or to a pathogen, such as Neisseria gonorrhoeae, whose infections activity is to be inhibited. However, it must be recognized that some microorganisms of the vaginal flora, e.g., Lactobacillus jensenii, are desirable and may even provide some protection against pathogenic organisms. Accordingly, if possible, it is desirable to select a lectin for contraception and/or prophylaxis against sexually transmitted diseases that combines great binding affinity for the constituents of the male ejaculate or for a pathogenic microorganism, but has a lesser, preferably minimal, binding affinity for beneficial vaginal flora. A skilled practitioner may select the most efficacious lectins by consulting the data provided in the tables of this example.
This example illustrates the effectiveness of lectins in inhibiting the infective activity of Chlamydia trachomatis.
Chlamydia trachomatis serovar G was cultured as described in Example 1. Lyophilized lectins were reconstituted in phosphate buffered saline (PBS) to a concentration of 1 mg/ml and frozen at −20° C. The lectins were prepared for testing in the Chlamydia trachomatis inactivation assay by diluting them in McCoy growth medium (MEM) to appropriate concentrations. Chlamydia trachomatis serovar G was added to the diluted lectins and the mixture was incubated for 1 hour at 37° C. After incubation, the Chlamydia-lectin mixture was added to McCoy cells in 15×45 mm shell vials and centrifuged at 3500× g for 60 minutes at 37° C. Following centrifugation, the medium in the vials was removed and 1 ml of Chlamydia overlay medium (with cycloheximide) was added to each vial. The vials were incubated for 42-43 hours and the cells were then fixed and stained for Chlamydia trachomatis using Syva Microtrak™ Chlamydia trachomatis culture confirmation reagent.
Samples of the infected cell culture were then examined under the microscope and evaluated for the effect of the lectin on the infectivity of the microorganism. Table 9 shows the number of Chlamydia trachomatis inclusions per 160× microscopic field on a 12 mm circular glass coverslip as a percentage of a positive control sample which was not exposed to any lectins. WGA (118%) and ConA (121%) show enhanced infectivity of Chlamydia trachomatis serovar G in having more inclusions per 160× field than the positive control which had not been exposed to any lectins. In contrast, exposure to Jacalin shows significantly reduced infectivity of Chlamydia trachomatis serovar G as evidenced by the 65% reduction in the number of inclusions per 160× field (35% of the positive control value).
Lectin Concentration Infectivity
ABA 150 59
TKA 150 80
WGA 50 118
DSA 50 75
WFA 150 48
VFA 150 61
ConA 150 121
Jacalin 150 35
MPA 150 55
This example illustrates the effectiveness of lectins in blocking the infectivity of human immunodeficiency viruses Type 1 and 2 (HIV-1/HIV-2).
The effect of lectins on the infectivity of HIV-1 and HIV-2 toward human lymphocytes was investigated in vitro by a standard technique (Balzarini et al. 1991, Antimicrobial Agents and Chemotherapy, March 1991, pages 410-416) wherein the toxicity of the lectins toward the infected cells was determined (human T-lymphocytes CEM/0) and also the ability of the lectins to block the fusion of infected cells (HUT-78/HIV-1(IIIB)) with other cells (MOLT/4 clone 8). The results of these tests are set forth in Tables 10 and 11 below. The results are expressed in terms of the concentration of lectins required to reduce by 50% the number of viable cells in the virus-infected cell cultures (EC50) and in the control cell cultures (mock-infected) (CC50), respectively.
Anti-HIV-1 and -HIV-2 Activity and cytotoxicity of
Lectins in Human T-Lymphocyte (CEM/0) Cells
EC50a (μg/ml) CC50b
Compound HIV-1 HIV-2 (μg/ml)
ABA >100 −> 100 >100 −> 100 83 − 62
>100 >100 73 ± 15
CAA >100 −> 100 >100 −> 100 140 −> 200
>100 >100 ≧140
ConA 2.4 − 0.8 − 1.4 1.8 − 0.8 − 2.4 20 − 19
1.5 ± 0.79 1.4 ± 0.77 20 ± 0.71
CPA >100 −> 100 −> 100 >100 −> 100 −> 100 >200 −> 200 −> 200
>100 >100 >200
CsA >100 −> 100 −> 100 >100 −> 100 −> 100 >200 −> 200 −> 200
DSA >20 >20 >10.5
ECA >100 −> 100 >100 −> 100 12 − 15
≧100 ≧100 14 ± 2.5
EEA >0.16 −> 0.16 >0.16 −> 0.16 0.47 − 0.53
>0.16 >0.16 0.50 ± 0.04
GSA-I >100 −> 100 >100 −> 100 >200 −> 200
GSA-II >100 −> 100 −> 100 >100 −> 100 −> 100 >90 −> 200 −> 200
>100 >100 ≧90
HAA 20 − 9 11.5 − 11.5 9.7 − 18
15 ± 7.8 11.5 14 ± 5.9
JAC >20 −> 20 >20 −> 20 16 − 27
>20 >20 22 ± 7.4
LAA >100 −> 100 >100 −> 100 >200 −> 200
LBA >100 −> 100 >100 −> 100 >200 −> 200
LCH 9 − 4 − 20 >100 −> 100 −> 100 17 − 17 − 12
11 ± 8.2 >100 15 ± 2.9
LEA >100 −> 100 >100 −> 100 >200 −> 200
Lotus >100 −> 100 >100 −> 100 90 −> 200 −> 200
MPA >0.8 −> 4 >0.8 −> 4 6.8 − 11
>0.8 >0.8 8.9 ± 3.0
PAA >100 −> 100 >100 − 58 >200 −> 200
>100 ≧58 ≧140
PHA-L 11.5 − 11.5 − 45 >100 −> 100 > 100 11 − 23
23 ± 19 >100 17 ± 8.5
PNA >100 −> 20 −> 20 >100 −> 20 −> 20 95 − 80
>20 >20 88 ± 11
PSA 20 − 9 − 20 − 45 45 − 100 − 100 25 − 17
16 ± 6.4 82 ± 32 21 ± 5.7
PTAgal >100 −> 100 −> 100 >100 −> 100 −> 100 >200 −> 200
PTAgalNac >100 −> 100 >100 −> 100 >200 −> 200
SJA >100 −> 100 >100 −> 100 >200 −> 200
sWGA >100 −> 100 >100 −> 100 >200 −> 200
TKA >100 −> 100 >100 −> 100 100 − 95
>100 >100 98 ± 3.5
UEA-1 >100 −> 100 >100 −> 100 >200 −> 200
VFA 9 − 34 − 38 >100 −> 100 −> 100 120 − 77 − 95
34 ± 25 ≧100 97 ± 22
VVA >100 −> 100 >100 −> 100 >200 −> 200
WFA >100 −> 100 >100 −> 100 >200 −> 200
WGA 11.5 − 20 −> 20 9 −> 20 − 20 11.5 − 15
≧16 ± 6.0 ≧15 ± 7.8 13 ± 2.5
aEffective concentration or concentration required to protect CEM cells against the cytopathogenicity of HIV by 50%.
bCytotoxic concentration or concentration required to reduce CEM cell viability by 50%.
* Cluster formation of the cells after 4 days incubation with the compound.
Inhibitory Effect of Lectins on Giant Cell Formation Between
HUT-78/HIV-1(IIIB) and MOLT/4 clone 8 cells
EC50 (μg/ml)
Compound Individual Values Average
ABA >100 −> 100 >100
CAA >100 −> 100 >100
ConA 1.7 − 9 5.4 ≧ 5.2
CPA >100 −> 100 >100
CSA >100 −> 100 >100
ECA >100 −> 100 >100
EEA >4 −> 4 >4
GSA-I >100 −> 100 >100
GSA-II >100 −> 100 >100
HAA >100 −> 100 >100
JAC >100 −> 100 >100
LAA >100 −> 100 >100
LBA >100 −> 100 >100
LCH 45 − 45 45
LEA >100 −> 100 >100
Lotus >100 −> 100 >100
MPA >100 −> 100 >100
PAA >100 −> 100 >100
PHA-L 44 − 12 − 44 33 ± 18
PNA >100 −> 100 >100
PSA 45 − 58 − 58 54 ± 7.5
PTAgal >100 −> 100 >100
PTAgalNac >100 −> 100 >100
SJA >100 −> 100 >100
sWGA >100 −> 100 >100
TKA >100 −> 100 >100
UEA-I >100 −> 100 >100
UFA >100 −> 100 >100
VVA >100 −> 100 >100
WFA >100 −> 100 >100
WGA 20 −> 4 ≧20
* Cluster formation of the cells after 1 day incubation with the compound
The invention having now been fully described, it should be understood that it may be embodied in other specific forms or variations without departing from its spirit or essential characteristics. Accordingly, the embodiments described above are to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.
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Samsung has finally launched a duo of its midrange smartphones – Galaxy A30 and Galaxy A50 in Pakistan. The major hallmark for both the siblings is their premium design, Infinity-U displays, large batteries and new chipsets offered in a decent price range.
The duo of new Galaxy A series smartphones features a new Prism design with a lot of 3D rounded edges, 6.4-inch FHD+ Super AMOLED display with a waterdrop cutout at the top. Both the devices are power packed by a 4,000mAh battery that is expected to last for days with average usage.
The Galaxy A30 is powered by an Exynos 7904 chipset supported by a memory setup of 4GB RAM and 64GB native storage. On the other hand, the Galaxy A50 becomes superior with its 10nm Exynos 9610 chipset that has four Cortex A73 cores for processing more efficiently. Moreover, the internal storage of the device is backed by 4GB RAM and 128GB ROM.
The photography department of the Galaxy A30 is packed by a dual camera setup on the rear comprising of 5MP and 16MP configuration offering 123° Ultra Wide Angle coverage, while the front camera brings 16MP lens for selfie shooting and video calling.
Being the elder sibling, the Galaxy A50 is packed by a triple rear camera setup consisting of a 25MP primary sensor along with an 8MP wide-angle lens and a 5MP depth sensor. On the other hand, the front camera of the device also offers more powerful lens of 25MP resolution.
Where Galaxy A50 comes with a fingerprint scanner mounted within the display, the A30 has a conventional fingerprint scanner on the back. You can also unlock your phones with Face Recognition technology.
Both Galaxy A30 and Galaxy A50 have been made available in Pakistan in white, blue and black color options. The price tag for Galaxy A30 is set at Rs. 40,000 whereas Galaxy A50 will cost you Rs. 52,000.
The phones are currently available to all distributors of Samsung phones in Pakistan such as Airlink, Greentech, and M&P. They will go live on markets and online stores in a day or two.


text:
First Strike 12+
Nuclear Superpower Simulation
Blindflug
4.5 • 5.6K Ratings
Multiplayer mode! New nuclear superpower nations! And new superweapons! The iconic nuclear war game keeps expanding with new content.
Millions of commanders already played First Strike all over the world. Now it is back and ready for the new decade. The new First Strike has been completely rebuilt and now is more stable, more beautiful and more with more cunning enemies than ever. And this is just the start for tons of new updates to come.
Play the iconic strategy game about blowing up the world in the nuclear armageddon and stay tuned for more, commanders!
**** - "A thought provoking and fast-paced strategy game" - pocketgamer
**** - "A gorgeous game with a message, that doesn't forget that it's a game" - 148apps
****½ - "An awesome game suited for casual and professional nukers alike" - appszoom
**** - "For my money, there is no better-looking game on the App Store" - pockettactics
****½ - "One of the best releases of the year" - whatsoniphone
Escalation is a downward spiral.
A nuclear armageddon is no one's dream scenario. So choose your steps carefully, it's a small path between war and peace. FIRST STRIKE is a great strategy simulation featuring snappy gameplay and an intuitive interface that makes dropping the big one as easy as ABC. But be sure to take the right measures to guarantee your people's safety.
Pick one of the big nuclear players – from known Superpowers to an upstart hellraiser like North Korea – and plan your strategy wisely: Limited but clever options let you as the leader of your superpower steer your nation's fate: Expand to other countries, build bombs or debuild in order to restructure your arsenal. Or use research to widen your options, such as: Ability to act quicker and build bigger bombs, better recon on your enemies actions, automated self-defense-sequences and many more.
Whether you're a bloodthirsty warmonger or a tree-hugging hippie – it's time to put your cards on the table. A quick and fun game with beautiful graphics, FIRST STRIKE shows you how little it takes to heat things up. With the tip of your finger you can control the destiny of the precious and vulnerable rock floating through space, the rock we call mothership Earth.
*Winner "Best Mobile Game" - Indie Prize Amsterdam*
*Winner "Most Innovative Game" - Best App Ever Awards*
*Winner "Game of the Year" - BOSA Awards*
*Winner "Newcomer of the Year" - SwissICT Awards*
*Finalist "Best Upcoming Game" - International Mobile Game Awards*
*Finalist "Most Meaningful Play" - International Mobile Game Awards*
*Finalist "Best Hardcore Game" - Game Connection USA Awards*
*Finalist "Most Innovative Game" - Game Connection USA Awards*
*Finalist "Best Strategy Game" - Best App Ever Awards*
*Finalist "Best International Game" - Ludicious Game Festival*
*Finalist "Best Swiss Game" - SGDA Awards*
** Compatability:
Recommended: iPhone 6S or higher, iPad (7th generation) or higher
Required: iPhone SE or higher, iPad (5th generation) or higher, iPod Touch (7th generation) or higher
EULA: https://www.apple.com/legal/internet-services/itunes/dev/stdeula/
The Smashers of the Doomsday Machine are here! This fan-released update introduces the faction of the Doomsday Smashers to First Strike.
- The Doomsday Smashers as a playable superpower
- A new superweapon: a satellite that hacks nuclear bombs
- New singleplayer game mode: Arcade Mode
- First War Training: An onboarding mode for new players
5.6K Ratings
person032 , 03/31/2022
Great game but some minor improvements
First Strike is a great game but I think that there can be some minor improvements that would go a long way. One of them could be a way to select multiple territories at once or select them all so that I can make a missile in multiple of them at once without having to tap on all of them. After playing for an hour I have to quit because I am tapping stuff so much and my hand and fingers hurt so that feature would really help. It would be cool to be able to change the colors of stuff too because when I play it is sometimes hard to see where the individual territories are at because if they were damaged or something and it is night time it is hard to see. Maybe highlight the borders or change the color of territories that you own a different color. Other than that the game is fun to play. Sometimes the little touches make the gameplay so much easier.
Thank you for your feedback! We appreciate all your ideas and suggestions. We will have more updates for First Strike in the future, so stay tuned! Make sure to subscribe to the First Strike mailing list on www.firststrike.mobi and follow us on Instagram. https://www.instagram.com/first_strike_game/
Reporting 101 , 08/30/2022
Blindfug Please Read This!!!
Evening Blindfug, I'm going to be straight forward, you need to go about a smarter way with this. Why do I care you ask? Because is an extraordinary and unique game! As a consumer I have come up with a way to satisfy both consumers, and producers. Here's my plan: 1). Remove all in-game-purchases along with a big and exiting update, and get Apple Arcade to show it off for a good advertising strategy. In result you will get thousands of more people to play this game and perhaps others made by your company. 2). Produce merchandise that attracts your many fans (consumers) and make your money to make new and improved First Strike. The more the consumers enjoy the game the more they will support and buy from your company. 3). Repeat. Use the earned profits to make new updates alongside with Apple Arcade supporting you. Apple is a big asset for this plan considering how big they are. This benefits them to so don't worry about them declining your offer. Use the earned profits to finish and refine the game to its peak and create more attractive merchandise. 4). Be patient and wait for the enjoyment of your fans and your money rolling in. Note: use popular social medias to advertise too. That's were people spend most of their lives :D. (TikTok, Instagram, Snapchat, Facebook, Twitter, and Reddit) I think this will benefit everyone. Personally I think this is a great plan. But then again I am only 14. Sincerely, Your biggest Fan
jman😐 , 07/21/2022
Great game…. at least it was until recently
The first time I played this game was around a year ago. It was very fun and enjoyable with many different countries to play, as well as many different weapons to use. One thing that kept me towards this game was it being free to play as well as the endless fun that the game brought. Upon recently downloading the game to reminisce on the fun memories I made with it, I stumbled upon a pay wall, while this didn't prevent me from playing as a few different countries, it limited the amount of weapons I could use as well as the different countries that were available. This doesn't mean it was it wasn't an enjoyable experience, but it greatly limits what you can do. I would be fine paying a premium to get extra countries, but what they offer is a monthly subscription plan, but my main issue with this is that they're charging you more money than before and not adding any new content at the moment. If this was changed to a one time purchase I would consider buying it, but at the moment the game is not very enjoyable and doesn't have much content for new players, especially considering the multiplayer the greatest, because there aren't many players. Overall a great game, that would be better if it gave more content to new player, or at least offers a one time purchase to get additional content.
Thank you so much for your detailed feedback! We know it was a big change but sadly also a necessary one. We plan on releasing more content soon so stay tuned ;) - Paula from Blindflug
The developer, Blindflug, indicated that the app's privacy practices may include handling of data as described below. For more information, see the developer's privacy policy.
Blindflug Studios AG
English, Arabic, French, German, Italian, Japanese, Korean, Polish, Portuguese, Russian, Simplified Chinese, Spanish, Swedish, Thai, Traditional Chinese, Turkish, Ukrainian
12+ Infrequent/Mild Mature/Suggestive Themes Frequent/Intense Cartoon or Fantasy Violence Infrequent/Mild Horror/Fear Themes
© 2015-2022 Blindflug Studios AG
Nuclear Club $2.99
United States $7.99
Mexico $0.99
Russia $2.99
Israel $0.99
United Kingdom $2.99
South Africa $0.99
Pakistan $0.99
China $4.99
Brazil $1.99
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Idle Siege: Army Tycoon Game

redpajama_set_name: RedPajamaCommonCrawl


Today was the last round of Andranik Margaryan Memorial Round Robin Tournament. IM Vladislav Artemiev (Russia) scored 6 points out of 9 and became the winner of the tournament. The second place with 5.5 points took GM Wen Yang (China). GM Hovik Hayrapetyan (Armenia) and IM Mads Andersen (Denmark) scored 5 points and shared third-fourth places. IM Vladislav Artemiev fulfilled grandmaster norm, and FM Tigran K. Harutyunyan - international master norm.


A searing, thoughtful film from producer-director Kramer, based on Abby Mann's memorable Playhouse 90 TV drama of the same name. It concerns the proceedings at the Nazi War Crimes Trials in Nuremburg and explores, among other things, the degree to which an individual or a nation can be held responsible for carrying out the orders of their leaders.
"Though unrelentingly bleak, JUDGMENT AT NUREMBERG is absorbing from beginning to end. Dietrich and Tracy contribute polished, seemingly effortless work; at the other end of the thespian spectrum are Clift and Garland, who turn in harrowing, nakedly emotional performances. These are star turns, to be sure, but the Hollywood-style interplay between image, portrayal, and reality is fascinating to behold."
Oscars for Best Actor (Schell) and Adapted Screenplay (Mann). Also nominated for Best Picture, Director, Actor (Tracy), Supporting Actor (Clift), Supporting Actress (Garland), B&W Cinematography (Ernest Laszlo), Editing (Frederic Knudtson), B&W Costume Design (Jean Louis), and B&W Art Direction (Rudolph Sternad, George Milo).


Consumer fraud lawsuits can involve any type of consumer transaction wherein the consumer alleges some type of fraud or inappropriate conduct by the business or its employees. Consumer protection laws are designed to punish businesses for false or fraudulent advertising, marketing and selling of consumer products. Businesses will often be sued under the Illinois Consumer Fraud Act for common law fraud for failing to disclose defects or damage to a product sold to a consumer. In addition, there are a number of Federal statutes which give rise to similar lawsuits such as the Federal Odometer Act, Magnuson-Moss Warranty Act and the Truth in Lending Act. There is also a potential for the allowance of attorneys' fees to prevailing plaintiffs in a consumer fraud lawsuit.
Defending these claims requires attorneys who have an intricate knowledge of the various laws as well as appreciation for the necessity of cost-effective litigation since coverage is generally limited for consumer fraud, warranty, odometer and other such claims.
BVH lawyers have extensive experience defending a variety of businesses from consumer fraud claims and are equipped to handle all such cases. BVH has built a record of success in this area. BVH works closely with our clients to develop a game plan that will limit liability and costs associated with defending these claims.


text:
Revenge Never Gets Old.
Bullet to the Head is a 2013 action film, co-written and directed by Walter Hill based upon Alexis Nolent's French graphic novel Du Plomb Dans La Tete. The film stars Sylvester Stallone, Sung Kang, Jason Momoa, Sarah Shahi, and Christian Slater. The film premiered at the International Rome Film Festival on November 14, 2012 and was released in the United States on February 1, 2013.
In New Orleans, hitman Jimmy Bobo (Sylvester Stallone) and his partner Louis Blanchard (Jon Seda) eliminate a corrupt policeman, Hank Greely (Holt McCallany). Later, at a bar, Blanchard is murdered by Keegan (Jason Momoa), who also attempts to kill Bobo, but fails.
Meanwhile, Korean NYPD cop Taylor Kwon (Sung Kang) shows up in town determined to find out who killed Greely, his former partner. When Kwon tracks Bobo down to find out who hired him, both realize that their best hope for catching their respective partners' killers is to team up.
Before long, their trail of clues has led them to sleazy lawyer Marcus Baptiste (Christian Slater), who is caught up in some shady business dealings with the mysterious and powerful Robert Nkomo Morel (Adewale Akinnuoye-Agbaje) that could implicate some serious power players in Washington, D.C.
Now each new move that Bobo and Kwon make could be their last, and as the cop does his best to stay on the right side of the law, the killer uses the only tactics he knows to get results. But even if they manage to get their man, that doesn't change the fact that they'll have to deal with one another once they've taken down their target.
Summary via Wikipedia.
Sylvester Stallone. Hosted by Ultravoné.


Flexor aponeurotic release for resistant adaptive shortening of long flexors in claw hands in leprosy.
The commonest disabilities in muscles were manifested by complete claw hand in 2 cases, partial claw in 3 cases and foot drop in 3 cases.
Claw hand and z-thumb due to proximal or distal ulnar nerve paralysis, and loss of thumb opposition due to distal median nerve paralysis are the most common deformities affecting the hand in leprosy, and are among the main causes for stigma and de-habilitation.
diana vickers Glee Club, Birmingham WE ALL remember the bare feet on stage, the public relationship with fellow contestant Eoghan Quigg and the infamous claw hand.
June Bloom said: "All of a sudden this little claw hand comes up and taps twice.
We had one patient who had bilateral claw hand while 2 (2%) patients had two disabilities at the time of presentation.
Eggnog or JLS could have been singing it, and Simon Cowell clearly marked Diana to have her Claw Hand on the X Factor trophy, as she'd sung Hallelujah at boot camp.
5) The muscle imbalance that results from ulnar nerve paralysis creates the characteristic claw hand, due to hyperextension at the metacarpophalangeal (MCP) joints and flexion at the proximal interphalangeal (PIP) joints.


text:
Industry 4.0/Industrial IoT
COM-HPC Academy: Introduction to COM-HPC
In the embedded computing space, very few technologies last forever. And those that do tend to get upgrades over the years; sometimes they are significant upgrades. The COM-HPC specification, developed by PICMG, is a good example of that, sort of.
The organization, whose charter is to develop open modular computing standards, has a widely used specification in COM Express. The number of vendors designing and selling products that conform to COM Express is more than a 100 and continues to grow. And the technology, introduced around 2005, still has lots of life remaining, especially in the industrial sector.
But when you move into applications that really push the performance envelope, like medical imaging and gaming, and those that take advantage of AI or machine vision, it starts to run out of steam, particularly if you want to operate those applications at the Edge of the IoT. And if secure is a top priority, keeping your data at the Edge, rather than transmitting it to the Cloud, is always a good idea.
Enter COM-HPC. Almost two years in the making, this leading-edge specification has many advantages over COM Express, including higher bandwidth (more than 2X), more connector pins, and some other key features (see the figure). The larger area on the COM-HPC modules allow for the use of full-size DIMMs; up to eight full-size DIMMs can provide up to 1 Tbyte of DRAM. That puts the COM-HPC module squarely in line for server applications, as they have the ability to act as either a server or a client.
The COM-HPC module shows an obvious upgrade path from the existing (and popular) COM Express module.
"The beauty of an open standard like COM-HPC is that it's interchangeable between different vendors and also between different technologies," says Christian Eder, the Director of Marketing for Congatec. "Because the core functionality is already designed and tested for you, you have a significantly reduced development time and cost for embedded computing applications."
From the OEMs' perspective, it allows them to offer a scalable product range, with varying performance and/or power levels. And of course, this lets the customer focus on what they do best, which is the end application. Another key is that it does not lock the OEM into one module vendor. The open standard ensures that lots of vendors will have offerings.
With a final release of the COM-HPC spec planned for January 2021, the technical committee has had input from 26 member companies. Three groups were formed: a main group, a management interface sub-group, and a signal integrity sub-group. This latter group faced some significant design challenges, requiring lots of simulations, all of which had to be documented. Some rough calculations say that the three groups collectively invested about 3000 man-hours in spec development, including the writing and editing of a 182-page (and counting) design guide.
Software Too
A system management software interface is included in the specification. It's defined for out of band management for general remote manageability, which is a typical server application. Hence, designers can create processor or non-processor modules, like accelerator cards, graphics/video cards, and so on. Thanks to the specifying of larger modules for server applications, the number of PCI Express lanes can be increased to 65, and up to eight 25-Gabit Ethernet interfaces can be accommodated.
A preview of the COM-HPC specification is now available on the PICMG web site. In addition, a video featuring congatec's Christian Elder does a nice job of explaining why there's a need for such a spec. He emphasized that COM Express will continue to be successful for a host of reasons, and COM-HPC will discover new, previously unattainable markets.
1505 N Hayden Road
CEA-Leti Scientists Demonstrate Machine Learning Technique Exploiting RRAM Devices
RTI at Digital embedded world 2021
Winmate to Showcase Internet of Vehicles (IoV) Solution at All-Digital CES 2021
Embedded Executive: Alan Grau, VP of IoT, Embedded Solutions, Sectigo
Sectigo Releases Advancements for IoT Manager
MEMS Timing Enables New Wave of Autonomous Vehicles
The State of Safety Certification of Platforms
Sectigo IoT Security & Identity Management for Integration and Use in Multi-Vendor Ecosystems
RT-Thread Studio IoT IDE v2.0 Offers a Host of New Features
Embedded Software - How Complex Can it Get?
IAR Adds Continuous Integration Support for RISC-V-Based Linux Automation Workflows
RTS Hypervisor Offers Full Support for TenAsys' INtime RTOS
Increase Application Revenue through Feature-Based Software Licensing


text:
Search » All » Business » Sponsorships
Business Tech I
Sponsors Organizations, firms, or individuals that give teams money in exchange for naming rights and advertising rights on stadium signage.
Signage The collective use of signs, symbols, or design. Stadiums may reserve areas where sponsors can use signage for advertising purposes.
Naming rights The exclusive right of a sponsor to have its name and logo on a stadium.
Negotiation The process through which two or more parties with competing interests reach an agreement.
Brand An image, logo, or name that consumers associate with a particular company.
Association principle A principle holding that people simplify decision making by relying on visceral responses to questions related to topics such as peer acceptance or rejection.
Passion transference A term used to describe the process by which fans of a sports team strengthen their allegiance to brands associated with that team.
Product promotions/ endorsements When a celebrity recommends that consumers buy a product or service provided by a sponsor.
Bidding war When two or more companies try to outbid the other for something, such as a sponsorship opportunity.
Profit margin The income a team is left with after paying operating and administrative expenses.
TV broadcast rights The rights to broadcast a team's games on TV (and often the Internet).
Perceived value The value attached to something—such as a sports sponsorship—by the person seeking to acquire it.
Created by: millymia01


The building doesn't look like much—one of several nondescript hangars alongside an airstrip on the edge of the Everglades, baking in the eternal monotony of the central Florida sun.
This is the home of Sikorsky Aircraft's Area 31, where the company works on its most advanced rotorcraft projects. Like Area 51, the famously clandestine Air Force base in the Nevada desert, this airfield is home to experimental aircraft being built and tested. The mystery projects here need to be kept not only from other nations but from other aviation companies too. Millions, possibly billions, of dollars are at stake. For that reason, Sikorsky is hesitant to let journalists onto the grounds and does so only if the tour is restricted and the photography limited.
Inside the hangar, bathed in fluorescent light from banks of industrial lamps, is a molasses-dark fuselage with unusual twin fins jutting vertically from its tail. The fin structures are vertical stabilizers with rudders built in. Even at a glimpse, the half-finished airframe is something new.
This is the S-97 Raider. When it takes to the air in 2015, it will be the first production-ready prototype for a new kind of rotorcraft, the compound-coaxial helicopter. The Raider has two rotors that turn in opposite directions on a central mast, enabling it to fly up to 275 mph. That's more than 100 mph faster than a conventional helicopter, giving it twice the range.
The S-97 is among an emerging generation of advanced craft that could redefine the meaning of vertical-lift aviation. In 2011 the Army funded the Joint MultiRole Rotorcraft Technology Demonstrator (JMR-TD) program. This is the first step in an effort to replace the military's entire inventory of helicopters. Retired first will be the UH-60 Black Hawk, to be replaced with the Future Vertical Lift Medium, at the earliest in 2030.
The FVL Medium will have big shoes to fill. The Black Hawk provides the bulk of vertical-lift capability for the U.S. Army, Navy, Marines, Special Operations Command, and Coast Guard. It first entered service with the Army in 1979; over the next 30 years, more than 2300 aircraft saw service at home and abroad. The Black Hawk and its variants have proven track records but are limited by a maximum speed of 183 mph.
Aside from the FVL Medium, the Pentagon envisages three other classes of future flying machines that will have roots in this program: the FVL Light, to replace the Kiowa scout helicopter; the FVL Heavy, to replace the brawny twin-rotor Chinook; and the FVL Ultra, a brand-new class of aircraft that would combine the hauling capacity of a C-130 cargo plane with the ability to take off vertically. If the Pentagon plan comes together, these machines will replace every U.S. military helicopter.
Changes on the battlefield are posing dangers for traditional helicopters. Longer range missiles can target bases and ships, putting helicopter staging areas at risk. Aircraft that can fly faster and travel farther can complete their missions with less risk. And, since more capable rotorcraft can cover more ground, the Pentagon can buy fewer of them.
Today's most advanced vertical-lift aircraft is the V-22 Osprey, used by the Marine Corps and U.S. Special Operations Command. The Osprey tilts its rotors 90 degrees to fly like an airplane and land like a helicopter. But the Army is looking for a smaller combat rotorcraft instead of an Osprey-size heavy lifter. The JMR Technology Demonstrator will be designed to carry 11 troops, compared with the Osprey's carry capacity of 24.
The other type of vertical aircraft is the jump jet, which can vector its engines toward the ground to hover. Examples include the AV-8B Harrier and F-35B Lightning II, both carrier-capable fighter airplanes. These are not well-suited as Army utility lifters and attack helos because they burn too much fuel and are not light or maneuverable enough to fly missions close to the ground.
The goal of the JMR-TD program is to create an aircraft that is as nimble as today's Black Hawk while hovering, but with a ferry range of 2100 miles and a cruise speed of more than 265 mph. Industry engineers declare that it's possible, but the Pentagon launched the JMR-TD program to be convinced. "It's an investment to inform ourselves about the technology that's available," Dan Bailey, the Army program's director, says. "What we are looking at is a leap ahead in capability."
Last year the Army narrowed the field to four JMR-TD competitors, including two giants—Sikorsky of Stratford, Conn., and Bell Helicopter of Hurst, Texas—and two tiny firms, AVX Aircraft Company of Benbrook, Texas, and Karem Aircraft of Lake Forest, Calif. Each was awarded $6 million to produce a design. This summer two of the four will be selected to turn that design into hardware, with flight tests from 2017 to 2019.
The Army has made it clear that whoever survives the downselect will not necessarily be the winner of a $100 billion production contract for building as many as 4000 aircraft. But even losing companies stand to gain by flying demonstration aircraft, since the JMR-TD designs will inspire versions suitable for civilian markets.
In a few decades these futuristic rotorcraft could be as common in the skies as conventional helicopters are today. "This is a step change," says Steve Weiner, Sikorsky's director of engineering sciences. "It's going to be similar to when fixed-wing airplanes went from piston to jet engines."
If next-generation rotorcraft will be more capable than today's fleet, they are also going to be considerably more expensive. It takes a lot of power to go fast, and bigger engines add both weight and cost. "If you want to go above 150 knots [173 mph], you're going to have to pay a premium of 50 to 100 percent," says Richard Aboulafia, an aviation analyst with the Teal Group. Pentagon-funded demonstrator programs allow manufacturers to work out the kinks of new designs and bring down prices.
"Looking downstream, it's obvious that there's certain commercial applications of this technology," Bell's Keith Flail says. Some niches will be easier to exploit than others. "Offshore oil rigs could be a market," Aboulafia says. With exploration moving into ever-deeper waters, a vehicle that can make twice as many trips ferrying rig workers in the same amount of time will be worth the steep price tag to the big energy companies.
Another potential market, Aboulafia says, is the VIP market. Corporate executives and other wealthy individuals already take helicopters on short-hop trips, but more advanced rotorcraft could ferry passengers as far as 500 miles, avoiding airport hassles.
In a more critical application, medevac, speed can mean the difference between life and death. "There's a thing called golden hour," AVX's Troy Gaffey says. "If you can get someone to a hospital within that time, they're a lot more likely to live."
If these early markets pan out for tilt-rotors or compound-coaxial helicopters, there's no telling how many other uses they'll have. Right now vertical lift means a conventional helicopter, with niches occupied by the jump jet and the tilt rotor. Some day that relationship could reverse, if this new generation of vertical-lift aircraft becomes the norm, relegating conventional helicopters to the fringe. "You'll see the ratio change in that direction," Flail predicts confidently. "The evolution is coming."
What Makes Helicopters So Slow?
When a helicopter is stationary, its rotor blades move at the same speed relative to the air. But when a helicopter flies forward, the blades on the advancing side move faster, relative to the wind, and the blades on the retreating side move slower.
As soon as the helicopter's forward speed matches the speed at the tip of the rotor, the retreating rotor tip momentarily experiences zero airspeed. At that point the rotor is generating no lift, a phenomenon known as retreating-blade stall. With half the rotor disc no longer holding the aircraft up, the helicopter tends to roll to the side. This aerodynamic principle limits conventional helicopters to about 200 mph.
Coaxial Rotors: Sikorsky's entry in the Black Hawk replacement program is the SB-1 Defiant. With a top speed of more than 300 mph, the Defiant will be faster than the company's internally funded S-97 Raider. The Defiant uses two rotor discs that move in opposite directions to defeat retreating-blade stall. Counter-rotating rotors have an advancing blade on each side of the aircraft, giving balanced lift at all speeds. Advanced composites make the blades extremely stiff, so they can whir through the air in proximity without hitting each other.
Pusher Prop: This rear-mounted propeller provides extra thrust. "It's an incredible sensation to realize that you're at the cruise-power setting of a normal helicopter but going 250 mph," Sikorsky chief test pilot Kevin Bredenbeck says.
Tiltrotors: Bell is building its entrant, the V-280 Valor, based on its experience with the V-22 Osprey tiltrotor. The smaller, nimbler version will be able to carry 11 soldiers 264 miles, hover for 30 minutes, and return at 320 mph. No need to worry about retreating-blade stall: To go fast, pilots toggle a thumb wheel that tilts the twin rotors 90 degrees, transforming them into propellers. The Valor's two engines will be fixed in a horizontal position, with only the rotors pivoting up and down. The Valor will sport flexible rotor blades for a new level of maneuverability at low speeds, while still providing the range and efficiency that no traditional helicopter can match.
Side Doors: "The bread-and-butter mission for the Army is air assault," V-280 program director Keith Flail says. "When soldiers are coming into a landing zone, they need clear fields of view and clear fields of fire out the sides of the aircraft."
Optimum Speed Tiltrotors: Karem's TR36TD concept uses twin tiltrotors to achieve a top speed in level flight of more than 420 mph. The company developed a technology, the Optimum Speed Tiltrotor, that allows the pilot to adjust the revolutions per minute of the rotor depending on the phase of flight. The rotors don't need extra power to turn during forward flight, so decreasing their rpm increases efficiency.
Ducted Fans: AVX's design relies on a compound-coaxial helicopter like Sikorsky's, but with rotors that are lighter and more flexible, saving weight and therefore reducing power requirements. A pair of ducted fans on the rear of the airframe will give AVX's as-yet-unnamed rotorcraft extra speed. The rotors and the ducted fans push the demonstrator up to a maximum of 265 mph.
Forward Canards: In cruise mode, much of the lift will come from a pair of canard wings near the nose. "Based on our analysis, the coaxial-compound helicopter will outperform a conventional helicopter, and the cost will be essentially the same," AVX president Troy Gaffey says.


Great Franchise & Business Owners Don't Worry About Passion. Do You Know Why?
Your passion for your business is most critical because it will drive your eventual success."
Who comes up with this stuff? It reminds me of the "expert" who said that most businesses fail for lack of cash flow. Huh? Most businesses fail because the business operators had no clue (no system) about how to operate the business successfully. They had plenty of money, but they ran out because they didn't know how to invest it.
But I bet they had loads of passion?
And what did that get them? A huge financial loss and the despair that follows.
First thing prospective franchisees and others who plan to start a business should know is to avoid and ignore the "experts". At least some of them. Instead, seek the advice of people who actually worked in the trenches, who built businesses, who failed a time or two, who made a payroll over and over again, and who understand the basics of how to succeed in a business.
And understand that passion can lead to success . . . or failure.
Early in my entrepreneurial career, I rented a small office from a guy who owned an insurance agency. Every so often as he was leaving the office at about 6 p.m. he would stop by and say, "If you continue working this hard for another year or two, you're going to be a great success."
I know he meant well; I know he was merely encouraging me, but he was clueless.
You may have loads of passion for what you want to do in your business, and you may work 7 days a week at it, but here's the most important point: If you don't know what you are doing, and why, and how to do it over and over again, you are not going to succeed.
Work your tail off, tell everyone how passionately you love your business, your products, your service, but don't for a moment think any of that bull translates to financial success.
You want to succeed? Buy a system for success. Or develop a system for success. Of course, there too, you must be careful because all systems are not created equal.
By the way, I've identified 12 successful systems in my forthcoming ebook: 12 Amazing Franchise Opportunities for 2015. You can still get a free copy just for asking.


text:
// Copyright 2000-2020 JetBrains s.r.o. Use of this source code is governed by the Apache 2.0 license that can be found in the LICENSE file.
package com.intellij.codeInspection;

import com.intellij.openapi.util.Comparing;
import com.intellij.util.IncorrectOperationException;
import com.intellij.util.SingletonSet;
import gnu.trove.THashMap;
import gnu.trove.TObjectFunction;
import gnu.trove.TObjectObjectProcedure;
import gnu.trove.TObjectProcedure;
import org.jetbrains.annotations.NotNull;

import java.util.AbstractMap;
import java.util.Collection;
import java.util.Map;
import java.util.Set;

/**
 * @deprecated Use {@link java.util.HashMap}
 */
@Deprecated
public class SmartHashMap<K,V> extends THashMap<K,V> {
  private K theKey;   // contains the only element if size() == 1
  private V theValue;

  @Override
  public boolean containsKey(@NotNull Object key) {
    K theKey = this.theKey;
    if (theKey != null) {
      return eq(theKey, (K)key);
    }
    return !super.isEmpty() && super.containsKey(key);
  }

  @Override
  public V put(@NotNull K key, V value) {
    K theKey = this.theKey;
    if (theKey != null) {
      if (eq(theKey, key)) return theValue;
      super.put(theKey, theValue);
      this.theKey = null;
      // fallthrough
    }
    else if (super.isEmpty()) {
      this.theKey = key;
      theValue = value;
      return null;
    }
    return super.put(key, value);
  }

  private boolean eq(K obj, K theKey) {
    return theKey == obj || _hashingStrategy.equals(theKey, obj);
  }

  @Override
  public boolean equals(@NotNull Object other) {
    K theKey = this.theKey;
    if (theKey != null) {
      if (!(other instanceof Map) || ((Map)other).size() != 1 ) return false;
      Map.Entry<K, V> entry = ((Map<K, V>)other).entrySet().iterator().next();
      return eq(theKey, entry.getKey()) && Comparing.equal(theValue, entry.getValue());
    }

    return super.equals(other);
  }

  @Override
  public int hashCode() {
    K theKey = this.theKey;
    if (theKey != null) {
      return _hashingStrategy.computeHashCode(theKey);
    }
    return super.hashCode();
  }

  @Override
  public void clear() {
    theKey = null;
    theValue = null;
    super.clear();
  }

  @Override
  public int size() {
    K theKey = this.theKey;
    if (theKey != null) {
      return 1;
    }
    return super.size();
  }

  @Override
  public boolean isEmpty() {
    K theKey = this.theKey;
    return theKey == null && super.isEmpty();
  }

  @Override
  public V remove(@NotNull Object obj) {
    K theKey = this.theKey;
    if (theKey != null) {
      if (eq(theKey, (K)obj)) {
        this.theKey = null;
        V value = theValue;
        theValue = null;
        return value;
      }
      return null;
    }
    return super.remove(obj);
  }

  @NotNull
  @Override
  public Set<K> keySet() {
    K theKey = this.theKey;
    if (theKey != null) {
      return new SingletonSet<>(theKey);
    }
    return super.keySet();
  }

  @NotNull
  @Override
  public Collection<V> values() {
    K theKey = this.theKey;
    if (theKey != null) {
      return new SingletonSet<>(theValue);
    }
    return super.values();
  }

  @NotNull
  @Override
  public Set<Map.Entry<K, V>> entrySet() {
    K theKey = this.theKey;
    if (theKey != null) {
      return new SingletonSet<>(new AbstractMap.SimpleEntry<>(theKey, theValue));
    }
    return super.entrySet();
  }

  @Override
  public V get(Object key) {
    K theKey = this.theKey;
    if (theKey != null) {
      return eq(theKey, (K)key) ? theValue : null;
    }
    return super.get(key);
  }

  @Override
  public boolean containsValue(Object val) {
    K theKey = this.theKey;
    if (theKey != null) {
      return Comparing.equal(theValue, val);
    }
    return super.containsValue(val);
  }

  @Override
  public THashMap<K, V> clone() {
    throw new IncorrectOperationException();
  }

  @Override
  public void transformValues(TObjectFunction<V, V> function) {
    throw new IncorrectOperationException();
  }

  @Override
  public boolean retainEntries(TObjectObjectProcedure<K, V> procedure) {
    throw new IncorrectOperationException();
  }

  @Override
  public boolean forEachEntry(TObjectObjectProcedure<K, V> procedure) {
    throw new IncorrectOperationException();
  }

  @Override
  public boolean forEachValue(TObjectProcedure<V> procedure) {
    throw new IncorrectOperationException();
  }

  @Override
  public boolean forEachKey(TObjectProcedure<K> procedure) {
    throw new IncorrectOperationException();
  }
}

redpajama_set_name: RedPajamaGithub


text:
Washington Wizards Injuries
Bradley Beal has "mild stress reaction" in right fibula
The Wizards announced Bradley Beal is dealing with a stress reaction in his right fibula, in addition to the sore right toe that's kept him out of the past two games.
By Jake Whitacre@jakewhitacre Feb 11, 2015, 4:13pm EST
Share All sharing options for: Bradley Beal has "mild stress reaction" in right fibula
Rob Carr/Getty Images
Bradley Beal has missed the last two games thanks to an inflamed right toe that he aggravated last Thursday against the Hornets. Unfortunately, that's not the only issue he's dealing with, as we learned today when the Wizards sent out the following press release:
Wizards guard Bradley Beal will miss tonight's game at Toronto. Beal missed the last two games with a sore right big toe and subsequent examinations revealed a mild stress reaction in his lower right fibula. He will be re-evaluated following the All-Star break.
Beal has averaged 15.0 points, 3.8 rebounds and 3.0 assists while shooting .436 from three-point range in 42 games for the Wizards this season.
As you may recall, Bradley Beal has dealt with similar issues before. He missed the last few weeks of his rookie season with a fibula stress injury in 2013. He missed time last season after injuring a different part of his leg, which he later said may have been the result of playing too many minutes. So if you're keeping score at home, Beal has had fibula issues in each of his three seasons in the NBA.
The good news is that the All Star break could not have come at a better time for Beal and the team. After Wednesday's game, the Wizards don't play again until the 20th.


text:
module Dedalus
  module PatternLibrary
    class ApplicationView < Dedalus::ApplicationView
      attr_accessor :library_view

      def app_screen
        ApplicationScreen.new(app_template).hydrate(
          mouse_position: mouse_position,
          library_section_tabs: library_view.library_section_tabs,
          current_entry_name: current_entry_name,
          library_sections: library_view.library_sections,
          library_items: library_view.library_items
        )
      end

      def app_template
        ApplicationTemplate.new
      end

      def current_entry_name
        @current_entry_name ||= "Welcome"
      end

      def route_to(section_name)
        @current_entry_name = section_name
      end
    end
  end
end


text:
Accused in Alberta Mountie shootings not present for first court appearance
A man accused in the attempted murder of two Alberta RCMP officers was not present for his first court appearance Tuesday.
Feb. 21, 2012 6:41 p.m.
KILLAM — A man accused in the shooting of two Alberta RCMP officers was not present for his first court appearance Tuesday.
Sawyer Clarke Robison's defence counsel, Brian Beresh, did not appear either and sent another lawyer to the courthouse in Killam, Alta., on his behalf.
The case was put over to April 3 at which time it's expected Robison will apply for bail. The judge made it clear that both the accused and his lawyer will have to appear in person.
Crown lawyer Rodney Clark told court that prosecutors need considerable time to go over the case material, which is extensive. Twenty police officers have been involved in the investigation, which is still going on.
Clark indicated there will almost certainly be more charges.
Robison faces two counts of attempted murder in the shooting of constables Sheldon Shah and Sid Gaudette on a farm near Killam on Feb. 7. They had come to the house he shared with his uncle, Brad Clarke, to execute a search warrant.
Clarke was found dead in the home.
Robison, 27, was on the run for almost three days before he was arrested peacefully on a rural road in the area. His truck, an unloaded gun and some ammunition were located later in a farmyard.
Police are still looking for a second weapon.
Court also had to reschedule some trials Tuesday that the wounded officers were to testify at. They are out of hospital, but Clark said they need time to recover and will be on leave until at least July.
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