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Patent application title: Modified peptides with antiviral properties and methods for obtaining them
Artur Martynov (Kharkov, UA)
Artur Martynov (Kharkov, UA)
Boris S. Farber (Brooklyn, NY, US)
Boris S. Farber (Brooklyn, NY, US)
Sonya Sophya Farber (New York, NY, US)
Sonya Sophya Farber (New York, NY, US)
IPC8 Class: AA61K3802FI
Class name: Designated organic active ingredient containing (doai) peptide (e.g., protein, etc.) containing doai cystic fibrosis affecting
Publication date: 2012-05-24
Patent application number: 20120129760
This invention may be used in human and veterinary medicine for the
creation of a drug that is effective perorally in the treatment of many
viral infections, such as influenza, herpes, and cytomegalovirus.
Summary of the Invention
Modified peptides with antiviral properties and methods for obtaining
them, distinct in that in the capacity of the main active ingredient, a
mixture (assembly) of oligopeptides is used that are the products of the
hydrolysis of proteins with changes in their molecular charges to the
opposite are used, and to obtain them, first a partial hydrolysis of
protein-containing raw material is conducted, and then a process of
chemical modification of the quantity of oligopeptides obtained with a
change in the charge to the molecules is conducted; this is used as an
antiviral vehicle for the composition of the oligopeptides obtained. This
quantity of modified oligopeptides is capable of slowing down the
activity of the heterodimer of b-importin cells and slowing the
replication of viruses whose replication cycle depends on the function of
An assembly of modified oligopeptides based on a quasi-life, dynamic,
self-organizing system that is effective in the treatment of viral
infections such as influenza, herpes, and animal viruses at all stages of
the development of the infectious process where other drugs are
ineffective. This drug has a wide spectrum of activity and a low level of
toxicity; it is accessible for industrial production and effective at any
stage of the viral replication cycle that depends on cell nuclei.
1. Modified peptides with antiviral properties distinct in that in the
capacity of peptides, a mixture (assembly) of oligopeptides are used that
are products of the hydrolysis of proteins with molecules changed to the
2. Modified oligopeptides with antiviral properties according to claim 1, distinct in that the charge of the molecules are changed through the formation of an amino group as a result of an acylation reaction between di- and tri-carboxylic acids and the remains of lysine and histidines in the oligopeptide mixture with the creation of new carboxyl groups.
3. Modified oligopeptides with antiviral properties according to claim 1, distinct in that the charge of the molecules are changed through the formation of a mixed amino group as a result of an alkylation reaction between monochloracetic acid and the remains of lysine and histidines in the oligopeptide mixture with the creation of new carboxyl groups.
4. A method of obtaining modified peptides with antiviral properties distinct in that to obtain them, first a partial hydrolysis of protein-containing raw material is conducted, and then a process of chemical modification of the quantity (assembly) of oligopeptides obtained with a change in the charge to the molecules is conducted; this is used as an antiviral vehicle for the composition of the oligopeptides obtained.
5. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that as a protein-containing raw material, an individual protein is used.
6. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that as a protein-containing raw material, a mixture of proteins is used.
7. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that as a protein-containing raw material, milk is used.
8. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that as a protein-containing raw material, initial egg albumen is used.
9. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that for the partial hydrolysis of protein-containing raw material, enzymatic hydrolysis is used.
10. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that for the partial hydrolysis of protein-containing raw material, acidic hydrolysis is used.
11. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that for the partial hydrolysis of protein-containing raw material, alkaline hydrolysis is used.
12. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that for the partial hydrolysis of protein-containing raw material, synthetic peptidases are used.
13. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that for the chemical modification of an amount of oligopeptides, succinic anhydride is used.
14. A method of obtaining modified peptides with antiviral properties according to claim 4, distinct in that for the chemical modification of an amount of oligopeptides, monochloracetic acid is used.
 This invention is related to veterinary and human medicine--specifically, to virology--and is intended to treat viral illnesses in humans and animals.
PREVIOUS LEVEL OF TECHNOLOGY
 Viral illnesses make up more than 90% of all registered infectious pathologies. However, there are very few antiviral substances that have been put into production. These substances often have toxic properties and a small spectrum of activity; also, a tolerance effect soon manifests against them in the body. The development of antiviral properties that would not have toxic properties and would be effective in the treatment of a wide spectrum of viral infections is therefore an important task in modern medicine. At present, very few substances are known that would be effective at all stages of a viral infection. Except for interferons and their inductors, substances are not yet known that would simultaneously unite curative and antiviral properties in relation to widespread viral illnesses, such as HIV/AIDS, herpes, influenza, and so on. The best-known drug for flu treatment is Rimantadine. This substance, which only blocks the stage in which the virus penetrates into the cell and the early stage of specific reproduction; it does not work on the pathogenesis of the illness. Long-term use of this drug is impossible, as it has neuro-tropic effects and may cause hallucinations and disrupt brain function due to a slowdown in the passage of impulses along nerve
 Leucocytic a-interferon is known to be one of the substances effective in the treatment of influenza. This protein is synthesized in activated human leukocytes. It has the property of evoking resistance to the flu in nasopharyngeal epithelial cells. However, its treatment properties are quite insignificant. It has a low level of effectiveness on the second through sixth day of the flu and is a preventive substance. Recombinant interferons are very expensive and often provoke an allergic reaction. Moreover, with the development of the illness, the effectiveness of interferon therapy declines, while the virus's resistance to the interferon increases.
 The nearest prototype of a substance that is being patented is modified proteins and their use for the control of viral infections . These are proteins that have been treated with various anhydrides and acylated substances: albumins, lactoferrin, transferin, and lactalbumin. The authors have also patented the mechanism of action for these proteins: a slowing of viral adhesion. These proteins must have a molecular mass of more than 60000 with a small amount of variance. The significant preventive antiviral activity of these proteins has been demonstrated in experiments on cell cultures. The drugs demonstrated activity against HIV (human and Old World monkey), influenza, cytomegalovirus, the polio virus, the Semliki forest virus, the Sendai virus, the paraflu, and the Coxsackie virus. The authors have proven that acylated proteins are non-toxic and may protect animals from viral infection.
 The prototype has some shortcomings: it is strictly a preventive drug (these proteins did not demonstrate a therapeutic effect on cells already infected by viruses) and do not have therapeutic properties for infected animals. In connection with the fact that the prototype is a high-molecular protein, it may only be taken parenterally; the drug is an individual combination and does not demonstrate the production of dynamic, self-organizing systems, and correspondingly, the viruses will quickly adapt to the drug.
DISCLOSURE OF THE INVENTION
 At the basis of the invention is the task of synthesizing modified oligopeptides with anti-viral properties and with a new mechanism of action whose use will allow a significant increase in the effectiveness of the treatment and reduce the treatment times of viral illnesses such as influenza and herpesvirus infections.
 The task set is addressed through the synthesis of modified peptides with antiviral proper-ties, distinct in that first a partial hydrolysis of protein-containing raw material is conducted, and then a process of chemical modification of the quantity (assembly) of oligopeptides obtained with a change in the charge to the molecules is conducted. For synthesis, proteins may be used such as: ovalbumin (OA), human seralbumin (HSA), bovine seralbumin (BSA), a mixture of milk proteins (MMP), rabbit seralbumin (RSA), lysozyme (LZ), lactoalbumin (LA), casein (CS), soy protein (SP), a mixture thereof, milk (M), and whole egg white (WEW). For the purposes of enzymatic hydrolysis, pepsin, trypsin, chymotrypsin, papainase, K-proteinase, clostripain, thrombin, thermolysine, and elastase may be used. The synthesized oligopeptides are capable of slowing the activity of the heterodimers of the a-b-importins of the cell, which transport viral polynucleotides from the cytoplasm to the nucleus. Accordingly, the slowing of these transport proteins will lead to the blockage of viruses whose replication depends on cell nucleus functions. In addition, the drug is effective when taken orally.
 The modifiers presented in FIG. 1 may be used as acylating agents.
 In the experiment, the effectiveness of the drug on influenza and herpes on in vivo and in ovo models was demonstrated, as described below. The authors used an assembly of oligopeptides that were the product of the hydrolysis of proteins or mixtures thereof (egg, milk, etc.), but the molecules' charges were changed to the opposite. "Assembly" is a term from supramolecular chemistry. The objects of supramolecular chemistry are supramolecular assemblies that self-assemble out of their complements--that is, fragments that have geometrical and chemical correspondence--similar to the self-assembly of the most complex three-dimensional structures in a live cell[2,3]
SHORT DESCRIPTION OF DRAWINGS
 FIG. 1. Structures of Chemical Modifiers Applied to Change the Charges of Modified Peptide (MP) Oligopeptide Molecules
 FIG. 2. Micro-Photographs of Infected and Non-Infected Cells Obtained through the Use of a Luminescent Microscope
 FIG. 3. Photos of the Eye of a Rabbit Infected with the Type 1 Herpes Virus, and after Treatment (FIG. 3). Wounded Cornea after Introduction of Virus: Hyperemia with "Leukoma" Infection (1, 2) (In the Second Shot, the Wound Location Is Contrasted with Fluorescence). Healthy Cornea after Treatment (3): Hyperemia Is Not Present.
 FIG. 4. Electronic Microphotography of Cells Infected with the Herpes Virus: Treated with MP (b) and Not Treated with MP (a)
BEST INVENTION IMPLEMENTATION OPTION
Obtaining Mixtures (Compositions) of Modified Peptides (MPs) with Antiviral Properties that are Capable of Self-Organizing into Importins
 Under aseptic conditions, 500 mg of ovalbumin is dissolved in 50 ml of distilled water and the pH is brought to 8.0 using 1 M of a sodium hydroxide solution. Trypsin is added, the solution is allowed to sit for 3-45 hours, and the hydrolysis of the ovalbumin with the formation of a peptide mixture is observed. To this mixture, 501-2000 mg of succinic anhydride are mixed for 20 minutes at a temperature of 16-65° C. The mixture is run through membrane filters with the goal of sterilization, and is then poured into glass flagons.
 To determine the maximum tolerable concentration (MTC) in the toxological experiments and to study the antiviral activity of the MP drug, the following types of passaged cells of human and animal origin were used:  HS--passaged cells from the kidneys of the embryos of large, horned stock  Tr--passaged cells from the trachea of the embryos of large, horned stock  Hep-2--passaged human larynx cancer cells  Hela--passaged cervical cancer cells  Chicken embryos
 The cells were cultured in a 199 medium with the addition of 10% bull blood serum and antibiotics (penicillin and streptomycin). In the capacity of test viruses, the flu virus (H3N2), the vesicular stomatitis virus (Indiana strain), the coronavirus (X 343/44) and the type 1 herpes simplex virus (L-2 strain).
 The study was conducted in accordance with the methodology recommended by the State Pharmacological Center of the Ukrainian Ministry of Health.
A Study of the Toxicity and Determination of the MTC of the MP Drug on Cell Cultures and Chicken Embryos
 To determine the MTC, two-day cultures of cells with well-formed cell monolayers were used. The MP drug was tested five separate times on each of the four types of cells listed above. In each experiment, no fewer than 10 test tubes were used for each of the cultures. After removal of the growth medium from the test tubes, 0.2 ml of the experimental solution and 0.8 ml of support culture medium was added to each test tube. The cells were incubated at a temperature of 37° C. over 7-8 days.
 Test tubes containing cell cultures to which the drug was not added served as controls.
 Calculation of the result was conducted according to the presence or absence of cytopathic activity in the cell when examined under a microscope at ×10. The level of cytotoxic action was determined through changes to the morphology of the cells (cells becoming round or wrinkled, degenerating cells pulling away from the glass) and evaluated according to a four-plus system from + to ++++.
 The maximum tolerable concentration was determined by the maximum amount of the substance that could be used without causing cytopathic activity in the cell. For these purposes, various dilutions of the drug at a dosage of 0.2 ml were introduced to the cell cultures.
 For a study of toxicity in vivo, the drug was introduced at various doses at a volume of 0.2 ml into the allantoic layer of 9-10-day-old chicken embryos (5 embryos per MP dilution) according to the following method:
 10-11-day-old embryos were candled, and a pencil was used to note the location of the air sac on the side opposite to the location of the embryo, where there are fewer blood vessels. The area marked was disinfected with an alcohol and iodine solution; the eggshell was then pierced in that place and 0.1 ml of the material was injected with a tuberculin syringe. In order to reach the allantoic layer, the syringe needle was inserted at a depth of 10-15 mm parallel to the long axis of the egg. After infection, the openings were disinfected again with an alcohol and iodine solution, sealed with paraffin, and placed in an incubator at a temperature of 35-37° C. for 72 hours. Before dissection, the embryos were placed for 18-20 hours in a refrigerator at a temperature of 4° C. for maximum congealing of the blood vessels. After this, the eggs were placed on a tray blunt end up, the shell over the air sac was disinfected with a solution of iodine and 96% ethyl alcohol; then they were punctured and removed with sterile forceps. The cover over the air sac was also removed after having first separated it from the nearby chorion-allantois membrane. After 24 and 48 hours of incubation at a temperature of 37° C., the number of live and normally developing embryos was counted. The calculations of LD50 and MTD were done according to the Kerber method.
 As a result of the study on various cultures, it was established that MPs are non-toxic to cell cultures at a dose of more than 50 mg/ml. (To increase the concentration of the drug, it was lyophilized and then diluted to a concentration of 5%. The results of the toxicity study in various cultures are presented in Table 1.
TABLE-US-00001 TABLE 1 The Toxicity of MP in Cell Cultures No. Cell Culture MTC (mg/ml) 1 Pathogen more than 50 2 Tr --//-- 3 Hep-2 --//-- 4 Hela --//--
 The MTC for cell cultures treated with MP comes to more than 50 mg/ml.
A Study of the Antiviral Activity of the MP Drug on the Influenza A Virus (H3 N2)
 Water solutions of MP in various dosages (tenfold dilution) were introduced into 15 chicken embryos in the allantoic layer in a volume of 0.2 ml every 12 hours after introduction of the virus in a working dosage (100 TCD 50/0.2 ml).
 Each experiment was accompanied by a control of the test virus in a working dosage. The infected and uninfected (control) embryos were incubated at a temperature of 36° C. over 48 hours. Then the embryos from which the allantoic fluid was removed were dissected. The titration of the virus in the allantoic fluid was conducted via the generally accepted methodology with 1% erythrocytes of human blood type 0(1).
 The protection factor (PF) was determined in accordance with . The titer of the virus in the experimental and control groups of chicken embryos is presented in Table 2.
TABLE-US-00002 TABLE 2 Effective Concentration of MP in in ovo Influenza Infection Models Minimum Virus Titer Effective Drug (lg TCD 50/ml) Concen- Concentration Experi- tration (MEC Group (mg/ml) ment Control mg/ml) Control (injected -- 12 12 -- with a 0.9% saline solution) Control Group 50 ± 5 0 12 0.05 5 ± 1 0 12 0.5 ± 0.05 2 12 0.05 ± 0.005 4 12 0.005 ± 0.0005 10 12 5
 As may be seen in Table 2, the minimum effective concentration of MPs in relation to the influenza virus that fully stops viral synthesis is equal to 0.05 mg/ml. When the dilution of the drug is increased, the effectiveness of the MP declines and has a dose-dependent nature. This fact bears witness to the presence of a direct antiviral effect against the H3N2 virus in the MP drug.
Study of the Antiviral Activity of the MP Drug on Cytopathic Viruses (Vesicular Stomatitis Virus, the Coronavirus, and HSV-1)
 The antiviral activity in relation to this group of viruses was determined in cultures of the abovementioned cells. The reaction was produced in the following manner 0.2 ml each of the corresponding virus in a working dosage (100 TCD50/0.2 ml) was introduced into a two-day rinsed cell culture. 0.8 ml of supporting medium was added. When cytopathic activity was observed in the culture, the MP drug was introduced in various doses. As a control, the same test viruses were used without the drug. The cells were incubated at a temperature of 37° C. Reports on the experiment were done on the third, fifth, and seventh days.
 A decline in the virus titer under the influence of the drug being tested of 2 lg or more in comparison with the control was determined to indicate antiviral activity.
 The results of the study of the antiviral activity of the MP drug are presented in Table 3.
TABLE-US-00003 TABLE 3 Study of the Antiviral Activity of the MP Drug on Vesicular Stomatitis Virus, the Coronavirus, and HSV-1. MEC, Maximum Decline in Titer Drug Virus mg/ml of the Virus, lg TCD 50/ml MP VVS 0.05 3.8 CV 0.05 2.8 HSV-1 0.05 4.8
 As may be seen in Table 3, MPs have antiviral activity and ability to stop the reproduction of all viruses we studied at a concentration of 0.05 mg/ml with a MTC of 50 mcg/ml. The drug's CTI is 1000. Moreover, MP was active in relation to all the viruses studied, while not one comparison drug showed the same kind of activity. Thus the drug is not connected with the specific characteristics of the virus or cell culture, but rather affects mechanisms that all cells have in common.
A Study of the Antiviral Activity of MP In Vitro in Models of Farm Animal Viruses
 The tests were run on 96-lunula plastic panels with viruses of the transmissible gastroenteritis of swine (TGS), strain D-52, with an initial titer of 104.0 TCD50/ml (tissue cytopathic doses) in a test tube culture of piglet testicle cells (PTC) and the diarrhea virus for large horned stock of the Oregon strain with an initial titer of 1070 TCD50/ml in a test tube culture of saiga kidney cells (SKC).
 In a study of virustatic (inhibiting) activity, the cell cultures were infected with the viruses in doses of 100 and 10 TCDunits/ml and incubated at a temperature of 37° C. MPs were introduced in various doses to the cell cultures (CC) 1-1.5 hours after infection (after the absorption period). Eight titer wells were used for each dilution. After introduction of the sister compounds, the cell cultures were incubated at 37° C. for 72-144 hours until clear evidence of cytopathic activity was found in the virus control.
 The cell cultures infected by the virus, inactive CCs, and CCs to which only various concentrations of MPs were introduced served as the control groups. The virustatic activity was determined by the difference in the titers of the viruses in the experimental and control groups.
 When virucidal (inactivating) activity was determined in various dosage levels of the solution of sister compounds, they were mixed in various amounts with virus-containing materials and incubated at a temperature of 37° C. over a 24-hour period. The control was the virus-containing material, to which, in addition to the solution of the sister compounds was added a placebo (physical solution) and inactive cell cultures. After contact, the mixtures were titered in parallel with the control. The results were calculated 72-144 hours after incubation at 37° C., after an obvious manifestation of cytopathic activity in the control viruses. The virucidal action was determined by the differences in the titers of the experimental and control group viruses and were expressed in 1 g TCD50.
 As a result of the studies conducted, it was established that an MP compound in a concentration of 4000 mcg/ml stopped the reproduction of the TGS virus at 2.75 lg TCD50/ml at an infectious dosage of 100 TCD50/ml and in the same does at 3.75 lg TCDunits/ml at an infectious dosage of 10 TCD50/ml. At a dose of 4000 mcg/mg the TGS virus was inactivated at 2.0 lg TCD50/ml. The MP compound at a dose of 4000 mcg/ml inactivated the diarrhea virus for large horned stock at 3.5 lg TCD50/ml.
 When toxicity was studied, it was discovered that MPs at a dose of 4000 mcg/ml were not toxic to either cell culture.
 Thus the MP compounds have virustatic (inhibiting) and virucidal (inactivating) activity on the TGS virus and the diarrhea virus in large horned stock; chemical drugs may be created based on these compounds for the treatment and prevention of infectious illnesses of viral etiology.
A Study of the Antiviral Activity of MP in an Experiment on Animals (Herpes-Virus Kerato-Conjunctivitis/Encephalitis in Rabbits)
 The specifics of the experimental system and the level of its adequacy against natural human illness undoubtedly play a decisive role in the evaluation of the effect of antiviral substances on the course of an infection. Experimental herpes infections are of interest in that diseases caused by herpes are widespread and extremely variable in clinical symptomology. The models of experimental herpes on animals are finding increasingly wide application in the study of new antiviral substances.
 As is well-known, one of the clinical forms of systemic herpes is herpetic encephalitis, which occurs in guinea pigs, hamsters, rats, mice, rabbits, dogs, and monkeys.
 Herpetic keratoconjunctivitis (FIG. 3(1,2)) was caused in rabbits with an average weight of 3.5 kg through introduction of infected material (herpes 1 virus, L-2 strain) into a wounded cornea (FIG. 3(3)). The animal was immobilized and its eye was anesthetized with dicaine (eye drops). The eyelids were pulled back, and several scratches were made on the cornea with a syringe needle. Then the virus-containing material was introduced. The eyelids were closed and rubbed in a circular motion against the cornea. Viral dose: 0.05 ml In the experiment, 16 rabbits were used; of these, 10 were given MPs (daily, beginning on the second day of infection; 14 days at a dosage of 21 mg/kg [which is 7.5 ml of a 1% solution per animal per day]), while six were given a placebo (0.9% sodium chloride).
 After the rabbits were infected with HSV-1, the condition of their corneas was observed daily for presence of keratoconjunctivitis, encephalitic damage, and presence in the lymphocytes of the peripheral blood of HSV-1 antigens through the immunofluorescence reaction method before and after infection (FIG. 2). Before infection, all the animals' lymphocytes were missing the specific luminescence, which indicated that they did not have antigens to the HSV-1 virus in their peripheral blood. On the third day after infection, the blood of all the animals showed an antigen of HSV-1, IF=70%. In addition, three rabbits (two from the experimental group before treatment and one from the control group) showed encephalitis symptomology: convulsive disorder, loss of appetite. Keratoconjunctivitis developed in all the animals. On the fourth day after infection, the experimental group was administered MPs to the ear vein at a dosage of 21 mg/kg body mass; the control group was administered 0.9% solution of sodium chloride. Over the course of two weeks, this procedure was repeated once a day. In the experimental group, all the animals survived and HSV-1 antigens were not found on the 13th or 14th day. Moreover, in the experimental group, the encephalitis symptoms disappeared by the seventh day of drug administration, whereas in the control group, two animals died. By the 14th day, one animal in the control group had died, while six had died in the control group. Accordingly, the effectiveness indicator was equal to 83.3%, which indicates the high treatment effectiveness of MPs in the model of herpes keratoconjunctivitis/encephalitis in rabbits. In addition, the rabbits in the experimental group gained weight and none showed signs of keratoconjunctivitis. The chemotherapeutic index for rabbits for the MP drug came to 1000, which indicates the promise of MPs as a highly effective antiviral drug with a wide spectrum of activity and low level of toxicity.
Confirmation of Albuvir's Mechanism of Action
 To confirm the MP's mechanism of action, we used DNA from the type 1 L-2 herpes viral strain. They were distinguished as indicated in . DNA conjugation with gold particles was conducted according to the method from . The compound obtained was introduced into the liposomes according to method . This experiment was described in detail for the SV40 virus in .
 These liposomes merged with the cell membranes from the chicken fibroblast culture. After the merging of the liposome with the cell membrane, the virus's DNA entered the cytoplasm along with the gold particles (FIG. 4a).
 The α-β-importin complex carried the colloidal particles into the nuclear pores with the polynucleotide. If the cells were incubated in the presence of the MP, aggregation of the particles of colloidal gold in the nuclear pores was not observed. (FIG. 4b). All the particles were equally distributed throughout the cells' cytoplasm. In this case, the cytopathic activity of the herpes virus was not observed.
 Thus the MP slow the process of the transportation of viral DNA to the cell nucleus, which was to be proven.
The Effectiveness of the MP Drug on Ko66-500 Cross Chickens
 The goal of this experiment was the study of the effect of the MP drug on the reproduction of vaccine strains of viruses in the reduction of the titers of the corresponding specific antibodies. It is known that many antiviral drugs, when stopping the reproduction of the live vaccine strains of the viruses lead to the depression of the synthesis of specific antiviral antibodies. This effect is connected with a shortfall in intensity of the infectious process caused by the vaccine in the birds' bodies, and to a weak immune reaction. It is known that in many cases--for example, in infectious bursal disease--the use of live vaccine leads to the induction of the synthesis of such an excessive antibody titer that the bursa becomes exhausted, the bird becomes sensitive to other viruses, and a decrease in weight and increase in mortality occurs. The application of the MP drug should have indicated that it contained antiviral properties according to several parameters: reduction in the excess level of antibody (titers), a decrease in the mortality rate (preservation), and an increase in weight.
 For the experiment, 15 chickens per group were used; each was between 36 and 41 days old. The MPs were applied a day before vaccination with live IBD, Gamboro Disease (GB), and infectious bronchitis (IB) vaccines. In the control group were birds that had not been treated with MPs but had been vaccinated. The results of the study are presented in Tables 4 and 5.
TABLE-US-00004 TABLE 4 Weight Gain of Chickens (at Time of Slaughter) in Experimental and Control Groups Indicator Weight Gain**, +% Survival**, +% Experimental Group 5.2 ± 0.7* 1.1 ± 0.3* (n = 15) Control Group -1.2 ± 0.3* -2.1 ± 0.5* (n = 15) *against the unvaccinated control, which is taken for the base. **(P = 0.01)
 As may be seen in Table 4, in the experimental group, the animals' weight increased by (5.2±0.7) %, while a decrease in weight of (-1.2±0.3) % was observed in the group that was vaccinated but not treated. Also, an increase in survival rates of (1,1±0,3) % was observed in the experimental group.
 In Table 5 is presented the change in the titers of specific antiviral antibodies in the group that was treated with MPs and vaccinated, the group that was vaccinated but not treated, and the group that was not vaccinated.
TABLE-US-00005 TABLE 5 Changes in the Titer of Antibodies to Infectious Bursal Disease (IBD), Gamboro Disease (GD), and Infectious Bronchitis (IB) in Vaccinated Groups and an Un-Vaccinated Control Average Change in the Titer of Specific Antibodies, ±T IBD GD IB Experimental Group -1000 ± 400 -600 ± 200 -1200 ± 400 (vaccinated and treated with MPs) (n = 15) Control Group No. 1 +2600 ± 700 +3200 ± 1200 +2700 ± 1000 (vaccinated, but not treated with MPs) (n = 15) Control Group 0 (not treated or vaccinated)
 As may be seen in Table 5, the MP has a direct (not immune stimulating) action against all three viruses. The most inhibiting effect was observed in the group with infectious bronchitis: a reduction in the antibody titer by 1200 units. In the vaccinated but untreated control group, the titers of antibodies grew from 2600 units to 3200 units, which indicated that the process of multiplication of the live vaccine in the birds' bodies had been effective.
 Thus the application of MPs allows an average of a 5% weight gain in the chickens and a 1% decrease in mortality.
 MPs have a direct antiviral action, which stops the reproduction of the viruses that cause infectious bursal disease, Gamboro Disease, and infectious bronchitis.
 MPs allow the reasonable restriction of the replication of the vaccine viruses, facilitating a sufficient level of protective antibodies and preventing the exhaustion of the birds' immune systems and the corresponding decrease in weight and increase in mortality.
The Effect of MPs on the Effectiveness of the Vaccination of Chickens with Live Vaccine
 The effect of MPs on the effectiveness of the vaccination was observed directly in an aviaculture business during raising of chickens. When a pathological and anatomical study of the chickens was conducted, characteristic changes were seen for colibacillosis and coccidiosis, as well as many hemorrhages in the mucous membranes of the large intestines and in the transition section between the proventriculus and the gizzard and grinding glands. The contents of the proventriculus were dyed green. The chickens' death rates came to about 15-20% When blood serum of chickens from 38-42 days of age were studied in a hemagglutination inhibition test (HI), specific antibody titers to the Newcastle Disease virus were found that were higher than protective levels (1:1024, 1: 2048).
 The study of the effect of MPs at a dosage of 0.03 ml/kg of live weight on the effectiveness of the Newcastle Disease vaccine. For this purpose, one of the aviaries was taken as the control; the others were experimental (Table 6).
TABLE-US-00006 TABLE 6 Results of the Study of the Effect of MPs on the Effectiveness of Vaccination in Aviculture No. of Aviary Heads Group No. No. (thousands) MP Dosage Schedule Control 4 40.0 MP Not Given Experiment 1 8 40.0 From an age of seven days over the course of the three days before vaccination with live viral vaccine Experiment 2 7 40.0 1 Day before Newcastle Disease Vaccination Experiment 3 5 40.0 Over the 3 Days before Vaccination and 7-10 Days after Newcastle Disease Vaccination
 The conditions of observation, the microclimate parameters, the lighting regime, the amount of floor space per bird, and the feeding schedule were identical throughout all groups in accordance with the methodological recommendations for raising ROS 308 crosses.
 The immune system load was determined at an age of 42 days through HI. Simultaneously, the clinical condition of the birds, their retention rate, their growth, and food loss were calculated.
The results of the experiments for the determination of the effectiveness of MPs when vaccinating chickens against Newcastle Disease are presented in Table 7.
TABLE-US-00007 TABLE 7 The Effect of MPs on the Effectiveness of the Newcastle Disease Vaccine Experiment Experiment Experiment Indicators Control 1 2 3 Average 21 ± 7.55 39.0 ± 15.30 84.5 ± 29.39 124.0 ± 31.09 ** Titer, in HI Immune 75 87.5 100 100 System Stress, % Notes: Reliability in comparison with the control: * P < 0.05, ** P < 0.01 *** P < 0.001
The average titer of specific antibodies to the Newcastle Disease virus were on the protective level in both the control and experimental groups. However, when the 42-day-old chickens' serum was studied, the ones with MPs used established a significant increase in the average titer in experimental group 3 in comparison with the control group by a factor of 6 (<0.01). In the experimental groups (1, 2), a reliable difference in the antibody titers in comparison to the control could not be established; however, they were on the protective levels, and a tendency to increase this indicator by factors of 1.8 and 4.3 was discovered. The group immunity in the control came to 75%, while it was 100% in experimental groups 3 and 4 and 87.5% in another experimental group. The death rate of the chickens in the control group was 9.8%, while the death rates fell in the experimental groups by a factor of 2.8, 3.3, and 4 respectively in comparison with the control. The average daily growth of the chickens in the experimental groups fluctuated from 52-54 g, while the growth in the control group was 48 g.
 Thus a conclusion may be drawn that the optimum scheme for the use of MPs for chickens in regions with complex epizootic situations with Newcastle Disease is the use of the drug at a dosage of 0.03 ml/kg of live weight over the course of 3 days before vaccination and 7-10 days after vaccination against Newcastle Disease. The use of the drug according to the abovementioned scheme will lead to an increase in the average titer of specific antibodies to the Newcastle Disease virus by a factor of 6 and a decrease in the death of the chickens by a factor of 4.
 This invention is related to veterinary and human medicine--specifically, to virology--and may be used for the creation of new drugs on the basis of dynamic, self-adapting and self-organizing systems for the treatment of viral infections in animals and humans. The drugs obtained in this manner are completely ecologically safe, biodegradable, and fully metabolized both in patients' bodies and in the environment; the technology required to make them is completely without waste. The production of the product being patented can be done on the existing equipment of pharmaceutical companies and does not require the development of new, unique equipment; it does not require an expenditure of energy and is waste-free and ecologically clean.
 1 Robert Walter Jansen, Dirk Klaas Fokke Meijer, Grietje Molema, Erik Desire Alice De Clercq, Rudi Wilfried Jan Pauwels, Dominique Schols Modified proteins and their use for controlling viral infection//A61K 3804; A61K 3816, U.S. Pat. No. 5,869,457, Reg. Sep. 2, 1999. Appl. Sep. 4, 1997  2 http://dic.academic.ru/dic.nsf/ruwiki/79240  3 Jean-Marie Lehn. Supramolecular Chemistry. Concepts and Perspectives.--Weinheim; New York; Basel; Cambridge; Tokyo: VCH Verlagsgesellschaft mbH, 1995.--P. 103 (Chapter 7)  4 Feldherr C., Kaltenbach E, Schultz N.//J. Cell. Biol.--1984.--Vol. 99, P. 2216-2222  5 Lanford R. E., Butel J. S. Cell.--1984. Vol. 37., P. 801-813
Patent applications by Artur Martynov, Kharkov UA
Patent applications by Boris S. Farber, Brooklyn, NY US
Patent applications by Sonya Sophya Farber, New York, NY US
Patent applications in class Cystic fibrosis affecting
Patent applications in all subclasses Cystic fibrosis affecting

domain: chemistry


Emmet County still weighing transit options amid divided local opinions
PETOSKEY — The future of public transit in Emmet County remains unclear, but vocal segments of the population are pushing back against one as-yet unapproved proposal.
That proposal, which entails forming a “transit authority” to create and oversee a taxpayer-funded local bus system, is the primary strategy that has emerged in response to calls for increased public transportation infrastructure in the county. But, so far, Emmet County leaders have not taken any official steps toward accepting or rejecting that idea.
Members of the board of commissioners have not brought the topic up since last year, when county administrator Mike Reaves said he and his office would conduct a thorough study of all the options.
“We have not finished or completed our review, or made any type of recommendation to the board,” Reaves said in an email.
Still, some citizens are urging the county away from the issue altogether. The agenda for a board of commissioners meeting this week includes copies of roughly half a dozen emails and communications directed at the local officials attacking the transit authority idea.
“There is a track record to prove that there is a substantial loss to operate such a system,” citizen Bill De Lyon said in an email to the county. “The annual cost to run the system far exceeds any rational decision to have it exist. While I have compassion on the very few that even use the transit, it makes no logical or financial sense.
“The taxpayers should never have to subsidize such a waste of money.”
Others argued that such services should be left to the free market.
So far, there have been no large scale transit operations to propose a system in Emmet County. The county’s last foray into a public system, EMGO, was launched after many business owners expressed support for the idea, and suggested an interest in partnering with the county financially on developing the system. Those commitments failed to materialize.
Reaves said he did not know why there was such a sudden influx of communications, adding “it seems these type of things take on a life of their own."
Meanwhile, the proposal has been strongly favored by other segments of the community, including some citizens who have spoken at public meetings in recent months, and local governments which have drafted formal letters of support for the idea.
Among the most recent of those governmental units is Harbor Springs. City council members for the municipality voted in favor of endorsing the transit authority proposal at a meeting last month, resulting in a letter that appeared in Emmet County’s public agenda materials for the most recent previous board of commissioners meeting last week.
“We are familiar with the proposal at hand, and we believe the establishment of a separate Transit Authority to develop and operate a transit system is the best path forward,” the letter said. “We understand that a county-wide millage issue is likely to be placed on the ballot to support the transit service, and we support allowing the voters of Emmet County to decide on this.”
Petoskey officials approved a letter last year encouraging the county to take steps toward implementing a new transit system.
But smaller townships, like Bliss Township and Readmond Township, have been less eager. Both of those townships also sent their own letters in to the county, with Bliss Township protesting that the option would lead to, “Wayne County Syndrome," in which areas with higher populations would strongly favor a millage, outvoting those in the outer townships, “even though the lesser populated townships that make up a larger geographic portion of Emmet County will overwhelmingly be opposed to the millage.”
The "authority” option came forward through a citizen-led process, and proponents presented the solution to county officials in June. Since then, they have been seeking support from municipalities and other community entities.
Under the plan, commissioners would appoint an independent group of decision makers with the intent of formulating a setup and financial strategy for a public bus system in the county.
Commissioners would draft the articles of incorporation for the authority, which gives them significant wiggle room to exercise as much or as little direct oversight on the body as they see fit. But, generally speaking, one primary feature of authorities is to shift some of the regulatory duties away from the central governmental board and to an autonomous third party.
In the most likely setup, the county board would potentially choose members to serve on the authority, and participating entities like Petoskey and Harbor Springs would also be expected to appoint representatives.
At this point, Emmet County has not committed to any particular strategy, but county commissioners last week gave the go-ahead for Reaves to begin conducting independent research and collecting data on both a transit authority and other possible arrangements.
That potentially could include either a partnership with Charlevoix County’s government-run bus system, or at the very least using it as a model.


text:
Update on VCAT Hearings
The Victorian Planning & Environmental Law Association held a seminar this morning in relation to the Government’s recent Omnibus bill.
Of particular interest to us was the inclusion of Justice Michelle Quigley QC, who is the President of the Victorian Civil and Administrative Tribunal (VCAT), who spoke about how VCAT is planning to use/implement the $5.2 million in funding they have received to “digitize” their functions.
Specifically, Justice Quigley QC advised as follows:
- Every hearing which has been adjourned since the closure of VCAT as a consequence of the COVID-19 pandemic have been “triaged”, insofar as they are being given priority for re-listing once physical hearings/video-hearing facilities are made available;
- Whilst the Tribunal has indicated that all hearings up until 15 May 2020 will be adjourned, it appears that this may extend to matters post 15 May 2020. The Tribunal will try and facilitate teleconference hearings for these matters but there will be some which are not suited to this and thus, will be adjourned;
- The Tribunal’s digital platform and funding relates to the Planning and Environment List only and must be rolled out within the next 12 weeks (meaning by the end of July at the latest);
- Once social distancing measures are relaxed, there are physical constraints at 55 King St (i.e. room sizes) which means that not all of its rooms and hearing rooms can be utilized and thus, there will be a reduced capacity for in-person hearings;
- Guidelines/Practice notes will shortly be released for hearings on the papers (we expect within the next few days);
- Some key changes being made to the listing of matters were announced as follows:
- The Short Cases List is being “revamped” and detail on matters which would qualify for inclusion on this list will be released shortly;
- The Major Cases List is also being amended so that all applications no longer automatically receive a Practice Day hearing. Instead, parties will need to apply to the Tribunal requesting a Practice Day hearing if they wish one to be listed and outline the reasons why such Practice Day hearing is required;
- All objector appeals will be listed for compulsory conference (this may need to be via video-hearing or tele-hearing if a physical compulsory conference is not feasible;
- The Tribunal has obtained further administrative resources and allocated these to the Planning and Environment List so that all matters lodged in the last 6 weeks (which have not received initiating orders) will be processed and new hearings listed. Our office has already started receiving such orders.
What this means for you
It is clear that VCAT is now tasked to ensure that the Planning & Environment List continues to list and hear planning appeals and that Applicants who have been affected by recent adjournments are given priority in the new listing/hearing formats.
The difficulty we continue to face is the involvement of third parties in these matters, particularly those who might not have access to electronic resources needed to participate in alternate hearing arrangements. We appreciate the difficulty the Tribunal has in ensuring procedural fairness in this regard and look forward to them taking more of an active role in listing matters rather than allowing parties to try and agree on arrangements between themselves. An option which could be considered for matters involving third parties without access to online means is those third parties being permitted to attend VCAT in person (whilst adhering to any social distancing requirements in place) with others appearing online.
We welcome the changes being made to the Short Cases List and objector appeals and will continue to keep you updated of developments at the Tribunal as they come to hand.
For any questions as to how any of these changes may affect your existing or upcoming planning appeal, please do not hesitate to contact our office.
About Best Hooper – Victoria’s Property, Planning and Land Development Advisory Law Firm
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domain: law


text:
New Jersey Horror Con and Film Festival!
It’s New Jersey’s first true Independent Horror Film Festival!
We will host a number of amazing film premieres and screenings. Some films will be presented with introductions by the filmmakers.The first annual New Jersey Horror Con and Film Festival. March 31-April 2nd 2017 at the Crown Plaza Hotel in Edison, NJ.
Our mission is to inspire and promote talented New Jersey and the Tri-state area independant filmmakers & artists. The New Jersey Horror Con and Film Festival provides opportunities for you to mingle with celebrities, networking, exhibition, and screenings. We provide a unique experience for the public to experience films often with the filmmakers available to answer questions and share experiences with the audiences.
NJHCAFF was created by filmmaker Ryan Scott Weber and Producer and pop cultures Rob Bruce to support independent film and filmmakers in the independent communinty. The film festival is surrounded by a convention atmosphere with celebrates and vendors to create a perfect networking and movie fan and filmmakers event.
One of the festivals creators, Ryan Scott Weber has worked as director, writer, producer, actor, cinematographer and editor on 4 feature films, Mary Horror, Sheriff Tom VS. The Zombies, Witches Blood and his more recent Pretty Fine Things (best actor at Horror Hound Film Festival) and also his TV series ‘ZOMBIES INCORPORATED’ which is in its 3rd season.
Rob Bruce who is also one of the festivals creators is also very well accomplished. He is known for being consulting producer and on -air “Expert” at AMC’s “Comic Book Men”. Comic Book Men is in its 6th season. He also has a role in Comic Book Men as well as other films Burn in Hell and Shooting Clerks. With more than 25+ years experience in the Collectible Pop Culture world Rob Bruce is the perfect person to create something like the New Jersey Horror Film Festival with Ryan Scott Weber.
Meet the New Jersey Horror Film Festival Team
Ryan Scott Weber
Founder & Director
Founder & Director
FILM FESTIVAL DIRECTOR

domain: entertainment


text:
126.96.36.199. Level of exposure
An important issue in field studies is to demonstrate that all age cohorts of bees (forager and in-hive bees), have been exposed to the test pesticide at the level from which we want to protect them when considering the worst case exposure scenario. For spray products, three exposure routes should be considered: oral, contact and inhalation. Honey bees can be exposed orally through nectar, pollen, and water but also directly during flight or when walking on contaminated substrates. These exposure routes should be considered both for forager and in-hive bees, even if in-hive bees are exposed mainly through residues in the food. The contact and inhalation exposures for in-hive bees should be assessed only in certain cases (e.g. fumigant and liposoluble products with high wax-affinity).
In order to determine if the experimental conditions in the field tests allow one to achieve the target exposure level, several observations and analysis should be performed. For forager bees, the level of exposure can be assessed by observing the number of bees on the test crop, the number of bees entering the nest with pollen loads and the flight activity (e.g. counting the number of bees exiting from the nest in 30 seconds (Porrini, 1995). Confirmed contact with the treated crop can derive from the palynological analysis of the pollen load (see Delaplane et al., 2013a). Pesticide residues should be analysed in honey bees, as well as in the plant matrices (nectar, pollen and guttation droplets) and in the hive (honey, wax, stored pollen and larvae) in order to know the amount of the target pesticide potentially available for forager and in-hive bees following the “destiny” of the compounds from the plant to the hive. For systemic compounds or for pesticides sprayed during bloom, residue analysis should be always carried out in the hive matrices. These analyses can be used to know the potential exposure routes for bees and their duration over time.

domain: agronomy


By Astoria Historical Society
By the Astoria Historical Society
As a brutal winter storm buried Queens in December 1960. A slashing blizzard measured more than 18 inches by noon. Packing a howling 35 mph wind, the killer storm was called the worst of the year. Within 24 hours, the mercury dipped to a frigid 7 degrees. The deep freeze slowed the borough from digging out. Long Island tallied 26 dead, with 130 fatalities across the country. LIRR erased the day off its calendar.
In the worst accident in commercial aviation disaster to date, 136 were killed as a DC-8, on approach to Idlewild (today JFK) Airport, and a TWA Constellation bound for LaGuardia Airport, collided over Staten Island. All on board the ill-fated aircraft, some 127 passengers were killed in the mid-air crash.
A few shots of whiskey, and four or five cigars a day were Joseph Deitsch’s formula for longevity. “Live it up a little and stop worrying. Health foods, spas, special liniments, they are all a waste of time. Just wind ‘er up and let ‘er go, that’s the ticket,’ jested the old-timer, cigar in hand.
The nonagenarian claimed that life began at 80. He was the father of six “youngsters,” ages 63 to 52, had 12 grandchildren and at least 10 great-grand children. The spry resident of 146-29 Laburnum Ave. in Flushing traced his ancestry back to Aaron Levy, the Revolutionary War banker and financial wizard who gave his entire personal fortune to the American fight for freedom. Joseph was also related to the late Justice of the Supreme Court, Benjamin Cordozo.
The topflight structure that graced the Queens building scene during the past year was the airy Pan American Airways Passenger Terminal at Idlewild Airport. The Queens Chamber of Commerce selected the futuristic terminal, which gave the impression it might take off along with the planes that used it.
Built to “bring the plane to the passenger,” the “upside down umbrella building”covered more that four acres. The building grounded all other competitors for the title of “Most Outstanding Structure in the Borough.” The Pan Am Building is only the fifth structure to ever win the special Bronze Plaque. The most recent winner (as of 1960) was the “Big A” Aqueduct Race Track in Ozone Park.
The mammoth new Throgs Neck Bridge, whose 12,300-foot span cost $90 million, should put an end to the bumper-to-bumper nightmare of the Whitestone Bridge and help ease congestion on the Triborough.
In an editorial, the Star-Journal pushed for a grander idea: “Now what is needed is a bridge across the Long Island Sound to Connecticut or Rhode Island. It has been pooh-poohed as far fetched, but it too will be built some day.’
The Star-Journal profiled the size of public housing projects in New York. In Queens, 36,340 people lived in 11 city housing projects. Over 13,000 apartments were built at a cost of $112 million.
In the five boroughs, 433,000 lived in 92 projects with another 50 in the planning stage. Federal money was used for Queensbridge, South Jamaica, Hammels, and Baisley Park. City monies financed Woodside, Arverne, Ravenswood and Pomonok. State resources were used for the Astoria, Bland and Redfern Houses. Queensbridge was the largest, housing 10,400 in 3,100 apartments. Queens projects included 11 community centers, 11 pre-school rooms, eight old age clubs, three school annexes, four branch libraries, and two child health stations.
An unclaimed airline suitcase at LaGuardia was thought to contain explosives after a baggage inspector at Hangar Three opened it and saw what he thought were sticks of dynamite.
The Bomb Squad, Fire Department, and Port Authority Police were summoned. They found balloons, feathers, horns, a kettle and trick matches. The dynamite turned out to be an entertainer’s make-up powder. The bag was a magic entertainer’s kit.


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Fitch Affirms VMTP Shares Issued by 9 Invesco Closed-End Funds at 'AAA'
PsiOxus Therapeutics Raises a £25M Series C Investment to Progress Oncolytic Virus Plus Checkpoint Inhibitor Combination Study in Metastatic Colorectal Cancer
Treasury Bonds Rise; Foreign Investors Pile Into Auctions
Invesco ’s overall corporate culture is headed on the right path.
The asset manager's transformation has resulted in profitability that continues to improve.
New York's 'Helmsley Building' Sells to RXR

domain: finance


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First year teachers--In-service training; Teacher turnover; Teachers--Job satisfaction
Experts attribute the teacher shortage to an increase in population while others
cite the retirement of a critical mass of baby boomers who came into teaching in the mid
to late twentieth century. Other experts argue that the teaching shortage is...

domain: sociology


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This is Emma Locket in a barrel. Looks easy but I haven’t succeed to ride a tube yet, but one day I will. Emma though she did it several times that week.
This is shot at the girls Boot camp with The Surf Experience and with Sam Lamiroy as the Instructor for the camps. In this picture I got really lucky with the light, lighting up Emmas face and also the light shining through the wave. I didn’t have to work with the picture so much in Photo shop, just a little bit cropping and sharpening. The light and the colours was already there. I love to work during the golden hours always gives you that warm nice light.
Emma Lockett is an outdoor instructor from the UK. A really talented, nice and cool person. She does it all, surfing, climbing, down hill, skateboarding, skydiving, cuddling with white sharks etc.

domain: artistic


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Christmas decorating contests bring the creativity out in me. My team exuded inspiration and talent. Santa’s Workshop might not be an extra-ordinary theme, but my team was extra-ordinary. Office doors became reindeer stables, little paper elf’s displayed each team member’s face, pictures became shiny wrapped presents, one gifted individual did all the lettering (North pole sign, Santa’s Toy Factory, etc.) by hand, a big white sled sat appropriately near Santa’s mailbox, and hardworking elves made sure that the cogwheels were working properly. The many hours spent–not only won us second place but also a fun time building relationships.
The fun continued as my Indiana kids came for an early Christmas celebration. Our home was full of our children and grandchildren. Squeals and thank yous from the little ones created an atmosphere of joy. Their snuggles and loves melted this grammy’s heart. I wonder what Joseph and Mary felt as they held their little bundle of joy for the first time—the bundle that was and is the joy to the world.


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domain: game


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Suge Knight founded Death Row Records in 1991
Death Row Records founder Marion 'Suge' Knight has been injured in an shooting at a party that Chris Brown was hosting in Los Angeles.
The rap mogul, is expected to survive, according to a Los Angeles County sheriff's sergeant.
Another man, 32, and a woman, 19, were also shot at around 01:30 (0930 GMT) on Sunday morning at the 1 Oak nightclub, West Hollywood.
All three victims were treated at locals hospitals.
Knight, 49, who helped launch the careers of Tupac, Snoop Dogg and Dr. Dre has been shot before.
In 2005, he was struck in the leg during an MTV awards pre-party in Miami Beach.
Sunday's shooting happened hours before MTV's Video Music Awards, which will take place in Inglewood, California.
Chris Brown was in the building when the shooting took place but the singer was not hit by gunfire.
Hours later, he tweeted: "It's disappointing that we as a society can't have fun or enjoy ourselves without any altercations sometimes."
MTV has said it had no affiliation or connection to the event.
Chris Brown posted several photos and videos from a party on social media around the time of the shooting
It's unclear what instigated the shooting and Los Angeles Sherriff Department has said they currently have no suspects.

domain: news


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A white mother-of-pearl pendant on a yellow gold chain: the drop motif combined with the twisted chain brings this piece into the spirit of the Serpent Bohème collection. Its vintage appearance offers endless combinations. It can be demure with a plain beige outfit or sensual and feminine with a daring red dress.
1 white mother-of-pearl pinctada maxima 0.75 carats
, 1 round diamond 0.03 carats
18K yellow gold
pendant length: 44 cm
Come visit us
We will be delighted to welcome you so that you may discover and try on your favorite creations, at the boutique or remotely.

domain: design


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Be inspired by the performances on offer and enrich that experience further with a cross curriculum workshop tailored to your school’s needs.
Cross Curriculum Collaboration provides professional development for generalist and non-arts specialist teachers. You will collaborate with a Flying Arts Artist to combine visual arts practice with a non-arts area of the curriculum, culminating in an artist-led workshop for your students.
For students, this unique format offers a hands-on approach that appeals to a variety of learning styles and reinforces student retention of curriculum-based material.
For teachers, the collaboration will reveal rich insights into creative learning while also providing templates, support and resources for the development of cross curriculum lessons that engage students and enhance learning outcomes.
What could a cross-curricular extension workshop be for you?
Example 1: The Clown from Snowy River.
Link the development and changes over time in Australian history with our values and perceptions (Humanities and Social Science). Build students’ skills and knowledge in visual art incorporating making and responding, by creating a mixed media artwork that incorporates layers of history with visual art technical skills.
Example 2: Dinosaur Time Machine
Link to the Biological Science (Living Things: features, growth, change, adaption and the environment), students will create their own sculptural dinosaur using plant fibres, recycled materials. ATSI links will be made through responding to the Tjanpi Weavers and Erub weavers.
Cross Curriculum Collaboration is presented in association with Flying Arts Alliance
This can be used as an extension for any performance in this program.
“I will definitely incorporate this idea into the school’s Chemical Patterns unit… it was engaging for the students and allowed them to see the application of chemical reactions in a real-life context. It also tied beautifully as a link between our ecosystem unit and chemistry unit.” – Year 9 Science Teacher, Windaroo Valley State High School


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You fed your baby what?!
Let’s get real for a second. If you have a baby or toddler, chances are you have taken a look at their poop.
Most likely, if you’ve fed corn to your baby, you have seen it in their diaper.
Yup, we said it. Isn’t parenting glamourous?
This can be scary. We question everything that we do from sleep habits to when it might be safe to start various foods.
Seeing our baby’s tiny systems not thoroughly process something we have fed them can bring about a world of worry.
Here’s the deal. We have been there and we know firsthand how scary parenting can be.
If you are like us, you might be wondering about when it is safe to give corn, or other foods, to your baby, especially if you have seen it come out in, still whole, in their diaper!
Additionally, you might be wondering about starting foods and how they impact your baby’s immature digestive system.
Opinions and suggestions from your loved ones can become overwhelming, specifically when you’re simply searching for the real facts.
Learning about proper nutrition and food safety could mean the difference between an enjoyable experience or a visit to the emergency room. But where should we begin?
Let’s start here.
Which foods are dangerous?
The following list of foods should be avoided altogether when introducing foods to your baby:
Honey is known to cause botulism in children under 1 year of age. Babies don’t have the proper digestive system to fight the bacteria that causes botulism.
Cow and soy milk
Breastmilk and formula are best until their little systems mature.
Fruit juice provides little nutrition and may cause babies to refuse the necessary breastmilk or formula.
Foods like raw vegetables, whole grapes, hot dogs, nuts, seeds, coin shaped foods and more should be avoided until your baby is able to properly chew and handle them.
Try these foods instead:
- Infant cereals
- Fruits and vegetables such as apples, bananas, sweet potatoes, avocados, green beans.
There are some foods that may seem scary for various reasons but they are just fine for your baby to try.
Some examples include:
- Beans and legumes
- Nut butters
What about corn? When Can Babies Have Corn?
At the beginning of this article, we talked about feeding corn to babies and the aftermath, for lack of better terms, in finding it in their diapers.
Is it safe? Is it healthy? What do the experts say about feeding corn to a baby?
The American Academy of Pediatrics says that "yes!", you can give your baby corn. However, there are some important factors to consider when doing so:
- Have you started your baby on other foods first? The recommendation is that you refrain from starting with corn and try other foods (see above) first.
- Is your baby at least 6 months of age? Digestive systems mature as babies grow and this is imperative for digesting corn.
- Does your baby have eczema? If so, consult your pediatrician before you allow your baby to try corn.
- Do you have a family history of food related allergies? If your answer is yes, it is best to wait to give your baby corn.
- Consider pureeing it for digestive ease.
- Is it necessary for your baby to eat corn? While it is a vegetable and comes with certain benefits, there are other, equally, or even more nutritious, vegetables that come without the negative considerations of corn.
- Review product ingredients. Corn sneaks into a lot of foods you may not realize and it should be your choice as to when they should have it.
Some tips for feeding your baby corn:
- Go organic
- Select firm, colorful corn with tight, green stalks
- Frozen corn is okay, but use caution with canned as it is often high in sugar and make sure you know how to thaw it in the correct way
- Watch for signs of an allergy or intolerance which can include hives, stomach upset, antihistamine reactions, and even anaphylaxis.
How to introduce foods to your baby
Now that we’ve discussed some ideas as to which foods we can introduce to our babies, the question as to how to introduce foods arises.
There are a few stages of baby food you need to consider.
However, there is a research to support baby led weaning as well as traditional methods of feeding them various staged purees first.
What is baby led weaning?
Baby led weaning is a technique, originally popular overseas, that migrated to the US based on popularity.
Parents who choose baby led weaning present their children with a variety of foods and allow them to experiment and taste without spoon feeding or serving traditional purees.
Benefits of baby led weaning:
- Starting from a very young age children learn to experiment and try a variety of foods.
- They aren’t influenced by texture, as they’re trying foods that aren’t pureed.
- Babies naturally learn how to chew and handle food.
- No additional food preparations because the baby is eating what your family is eating.
- Babies may learn portion control from an early age.
When are babies ready to try solid foods?
As always, consult with your pediatrician on this one. However, these are a few signs that your little bundle may be ready to join you at the dinner table.
- Baby sits up and holds head up unassisted
- Baby is between 4-6 months
- Baby has lost the tongue thrust reflex
- Baby is showing interest in foods that you’re eating
Introducing foods to your baby is a huge step in their growth, as well as your development as a parent. It should not be taken lightly because your child’s health and safety is at risk.
With that said, knowing what, how, and when to give your baby real food is a wonderful start.
In addition, be sure to speak with your pediatrician and do not be afraid to ask all of the questions that come to your mind.
After you’ve eased any anxieties that may come with this next phase in parenting, be sure to enjoy this time with your baby.
Mealtime is a wonderful bonding experience and can be the foundation for a lifetime of happy and healthy habits.

domain: food


Accurate Brazing, Greenville, SC, USA-“HIP” Installation
In early 2019 Accurate Brazing announced that they were joining a growing trend around the world by investing in a Hot Isostatic Press. The decision proved to be such a success that in November of 2019 the company announced they would be adding a second system (the November 2019 press release is below). Things are proceeding as they should and these two photos show the installation as of just a few days ago. The third picture shows part of the vacuum department.
“Västerås, Sweden, November 19, 2019 – Accurate Brazing, a full-service provider of specialized heat treating solutions, added Hot Isostatic Pressing (HIP) to its thermal processing capabilities earlier this year. “Based on overwhelming feedback from the marketplace, we are pleased to be moving forward with our second Hot Isostatic Press from Quintus Technologies,” says Steven Francis, president of Accurate Brazing. Both presses are of the model QIH 122 M URC®. They are equipped with the Quintus proprietary uniform rapid cooling (URC) feature, which combines HIP and heat treatment in a single process. This process is called High Pressure Heat Treatment (HPHT), and it streamlines the steps involved in material densification and heat treatment. This innovative approach also enables all processed components to cool uniformly, resulting in minimal thermal distortion and non-uniform grain growth. “The Quintus technology allows us to shorten lead times, improve product metallurgy, and eliminate some additional outside operations, which is very attractive to our customers,” says Mr. Francis. Accurate Brazing serves the aerospace and power generation industries, as well as other sectors that demand high quality and short lead times. Many of Accurate Brazing’s customers utilize additive manufacturing (AM). “The versatility of the Quintus units makes them well suited for our service business model,” says Mr. Francis.
The new QIH 122 M URC® will join the first Quintus press and the rest of the state-of-the-art equipment operating in Accurate Brazing’s newest facility in Greenville, S.C., USA. The company’s AS9100 quality management system and Nadcap accreditation attest to its ability to meet the stringent needs of its customers. Quintus will install and commission the new press. Accurate Brazing has also joined the Quintus® Care program, which ensures flawless press operation and optimized functionality at a fixed annual cost. Quintus Care also provides access to in-depth technical expertise to support successful customer applications. Both Quintus presses are configured as Quintus Modularized Solutions, which reduces infrastructure investment and saves space and energy. Both presses offer a work zone of 26.0 inches (660 mm) in diameter and 68.9 inches (1,750 mm) in height. They operate at a maximum temperature of 2,552°F (1,400°C) and a maximum pressure of 30,000 psi (2,070 bar). “The need for Hot Isostatic Pressing is steadily increasing, and we’re pleased to help Accurate Brazing meet this demand,” says Jan Söderström, CEO of Quintus Technologies. “Quintus Technologies has led the industry in advanced Hot Isostatic Pressing technology for over 60 years, so Accurate Brazing and its customers can rest assured that they are using the best equipment available.”
About Accurate Brazing; Headquartered in Goffstown, N.H, Accurate Brazing and Vacuum Heat Treatment has been creatively solving challenges in complex and detailed heat treating and brazing applications since 1989. It has a long history of serving the needs of aircraft, ground turbine and power generation markets, along with other industries that demand high quality and often operate with aggressive lead times. The company’s original New Hampshire operations have grown to include three additional East Coast locations: two facilities in South Carolina and one in Connecticut. Accurate Brazing is a subsidiary of Aalberts N.V., one of the largest thermal processing companies in the world. Committed to adaptation and innovation with a clear focus on customers, Aalberts employs approximately 16,500 people at more than 150 locations in 50 countries across the globe. Read more about Accurate Brazing: www.accuratebrazing.com”