U.S financial crisis Term Paper Example | Topics and Well Written Essays - 1000 words

U.S financial crisis - Term Paper Example It was a steady and gradual pace that caught up that finally brings the entire structure crashing down. Some say that it is already over while others argue that it is far from being so and that it will take years to be able to say the country has rid of it completely. Regardless of these arguments, it is of the most import that causes be analyzed to provide for an effective solution to the ailing financial state of the country. There is of course the palpable difference between the dynamics of the economy years ago to the current intricacies of today’s government laden with globalization and a multifaceted area that encompasses the interlocutory status of a country to many others. The crisis as experienced today can be traced back decades ago to the time of Pres. Ronald Reagan and the heyday of capitalism. This is not a direct attack on the merits of Reaganism but merely serves proof that the way business was done then does not necessarily carry with it its applicability decades after. The sheer size of businesses today renders this trite from the time when it was at its prime efficiency. This ideology as Francis Fukuyama states in his article titled ‘The Fall of America, Inc.’ carries two sacred concepts, â€Å"first, that tax cuts would be self-financing, and second, that financial markets could be self-regulating (p. 26). The demand for the dollar by majority of international traders allowed the government to push over as inconsequential the budget deficit. The latter, as we know it, is the very essence of free-market capitalism. The problem reverts back to the issue of housing in the United States. The 1980’s created a mentality for the need of homeownership as definitive of self-identity among Americans. They have then identified themselves as investors and real property was the trend of investment (Shiller, p. 29). â€Å"In Britain as it was in the United States, it wasn’t just owning a home. It was being a better person† (Karabell,

Explain the concepts of both individual and cultural relativism Essay

Explain the concepts of both individual and cultural relativism - Essay Example Of importance to note is that, at times this concept counters itself and its subsequent argument of what might be perceived as right of wrong could be concluded as baseless (Brooks, 2011). This ethical relativism concept articulates that the perception of what is ethically right is dependent on a given culture. For instance, one culture might believe in cannibalism as being morally right while another culture is against the practice. Needless to say, this concept assists in understanding why certain practices are common in some cultures and not others (Brooks, 2011). Apparently, the concept Utilitarianism argues that action could be defined as morally right or wrong when the consequences are at hand unlike ethical relativism where right or wrong is determined by an individual or culture (Brooks, 2011). Kantian theory is described as one of the best ethical principles as it articulates that human beings have the opportunity to effectively use their reasoning faculty to determine what their obligated to do and do it diligently. Conversely, ethical relativism does not entail actual reasoning on a particular action but simple perception (Brooks, 2011). This contract theory revolves around an agreement that is formed by two differently organized groups of people where responsibilities are assigned to each member of the group. Moreover, limitations and rights about certain issues are defined. In ethical relativism, cultural relativism where society is incorporated does not have limitations and rights, but practices that are perceived morally right or wrong (Brooks, 2011). Actually, divine command theory argues that actions deemed to be moral rightly ought to be equivalent to what God has commanded and that being moral is following what God has commanded unlike Ethical Relativism where an individual or culture decides what is right or wrong (Brooks, 2011). This theory articulates that natural laws that are created as a result of human reasoning could

Human African Trypanosomiasis Treatment

Human African Trypanosomiasis Treatment THE synthesis of novel hydrazone compounds to determine the potential anti-parasitic properties and efficacy in the treatment of Human African Trypanosomiasis. ABSTRACT Human African Trypanosomiasis is caused by two sub-species of trypanosome, Trypanosoma brucei gambiense and Trypanosoma brucei rhodeisense. The protozoan parasite has complex mechanisms to evade immune destruction and hence survives in the host, leading to eventual death without treatment. Treatment such as Suramin and Melarsoprol are limited and have high toxicity, often leading to further complications. Alternative therapies are drastically needed to combat trypanosomal infection, with novel hydrazone compounds currently in development promoting trypanocidal activity. The aims and objectives of this research project include the synthesis of novel hydrazone compounds, with aims of high efficacy and low toxicity, namely against Trypanosoma brucei rhodesiense. This was achieved through a series of reactions, with proton NMR spectra used to confirm the structures of novel hydrazone compounds, and biological screening analysis used to assess the trypanocidal activity in vitro. IC50 valu es were obtained for all hydrazones synthesized, the best results coming from HD1, 9.29 ÂÂ µM, and HD6, 16.18 ÂÂ µM. Overall, the presence of chlorine in the compound typically lowered trypanocidal activity when compared to HD1, which lacked chlorine atoms. Despite other compounds in literature having much lower IC50 values, the results remain promising, demonstrating trypanocidal activity against T. brucei brucei, the infective form of trypanosome that affects animals. Trypanocidal activity against Trypanosoma brucei brucei suggests potential activity against Trypanosoma brucei rhodesiense, signifying the IC50 values obtained from novel hydrazones. Furthermore, the biological properties of hydrazone structures demonstrate the potential to develop additional analogues and derivatives, which could contribute to combatting Trypanosoma brucei rhodesiense infection. Likewise, alternative therapies that can cross the blood-brain-barrier are another interest regarding research i n the field. Trypanosoma brucei rhodesiense proceeds rapidly once an individual has been exposed to the parasite, with severe side effects and high mortality rates. This reinforces the need for better and more effective treatment and management of the disease. Key words: Trypanosomiasis, Trypanosoma brucei rhodesiense, hydrazone, Suramin, Melarsoprol, proton NMR, IC50 values 1.1. Background of Human African Trypanosomiasis Human African Trypanosomiasis (HAT), or African sleeping sickness, is a disease affecting a large proportion of Africa, with a suspected 60 million people at risk (Kennedy, 2013).It is caused by two subspecies of trypanosome, a unicellular and flagellated protozoan parasite, with Trypanosoma brucei rhodesiense (T.b.r) causing East- African sleeping sickness, and Trypanosoma brucei gambiense (T.b.g) causing West-African sleeping sickness. West African sleeping sickness is much more prevalent in terms of the whole continent, with 6228 cases reported in 2013. Incidence has decreased massively since 2000, with 25,865 reported cases, although this figure is suspected to be higher due to unreported disease incidence. It is the causative sub-species in 98% of cases. The other 2% of cases are classified as East-African sleeping sickness, with 86 cases reported in 2013, approximately 88% lower than in 2000 (709 cases reported) (Franco et al., 2014). Despite the low incidence of T.b.r infectio n, symptoms are severe and death occurs in almost all patients without treatment. Treatment for suchinfections are limited and have high toxicity, signifying the need for development. Transmission of the protozoan parasite is via the vector, the tsetse fly. Infections with T.b.r proceed rapidly, with entry of infectious metacyclic trypomastigotes into the human bloodstream, lymphatic system and cerebrospinal fluid (CSF) following the initial bite, where proliferation occurs. The tsetse fly ingests a blood meal from an infected animal, with cattle and ungulates acting as reservoirs (Palmer Wells, 2012), and hence ingests trypomastigotes. Various cell divisions and binary fission occur in the mid-gut of the fly to form procyclic trypomastigotes, and conformational changes occur to allow the trypomastigotes to bind to the salivary epithelia. Once attached, the parasite can once again replicate via asymmetric division (Pepin, 2014) to form metacyclic trypanosomes. It is in this way that a person becomes infected with T.b.r (Langousis Hill, 2014). 1.2. Immunology The causative parasite manifests in hosts due to the evasion of the immune system through antigenic variation, delaying the immune response and therefore allowing the parasite to complete its complex lifecycle (Stijlemans et al., 2016). The parasite expresses variant surface glycoproteins (VSGs) on its cell membrane via a glycophosphatidylinositol anchor to serve as a protective barrier. While the immune response induces antibody development against the VSG being expressed, the parasite can switch VSG due to the large amount of VSG genes the genome possesses. This causes new antibodies to form against the newly expressed VSG, and the parasite continues to change VSGs to avoid destruction. Furthermore, the parasites alter their energy metabolism and internal structure, presenting further issues for the immune system (Stijlemans et al., 2016). T.b.r. is resistant to human trypanosome lytic factors (TLFs) containing apolipoprotein L1 (ApoL1), and this is due to the existence of the seru m resistance protein (SRP) coded for by the SRA gene. This binds to TLF-1 and therefore prevents ApoL1-mediated lysis of the infected parasitic cells (Kennedy, 2013; Bart et al., 2015). Kato et al. noted the upregulation of certain cytokines following T.b.r infection, namely IFN-ÃŽÂ ³, IL-10, IL-6 and TGF-ÃŽÂ ² (Kato et al. 2015). Furthermore, these cytokines may play a key role in the inflammatory immune response. IL-6 and IL-10 were upregulated upon CSF examination of late stage patients, and those with CSF trypanosomes had higher levels of WBCs, positively correlating with IL-6 CSF levels. Despite this, no significant changes in levels of cytokines at different stages in HAT were noted. Both subspecies of trypanosome cause non-specific inflammatory responses, resulting in non-specific symptoms. This demonstrates the difficulty in diagnosis and staging of T.b.r infection, and therefore poses a hindrance in regards to timely treatment (Lamour et al. 2015). 1.3. Symptoms Symptoms, typically manifesting 1-3 weeks after bite, include myalgia, hyperplasia of the lymph nodes and spleen, and weight loss in the haemolymphatic stage, and there is clear central nervous system (CNS) involvement in later stages (Pepin, 2014; Kennedy, 2013). It is in this meningoencephalitic stage where patients often exhibit behavioural and motor disturbances including tremors, speech complications, anxiety, confusion, personality changes and others. Further complications may manifest, including ocular difficulties, acute renal failure, multi-organ failure and chronic lymphocytic meningoencephalitis. Death is highly likely to occur in those who do not receive treatment. Trypanosoma brucei produces an aromatic compound called tryptophol, and this induces sleep in humans. Other complications with sleep include irregular patterns of sleep or interrupted sleep, insomnia during the night and sleepiness during the daytime. 1.4. Current problem Current pharmaceutical treatment including intravenous Suramin or Melarsoprol is ineffective and potentially toxic, with patients suffering with neurological dysfunction and post- treatment reactive encephalopathy. Co-administration with eflornithine and nifurtimox has been used to treat T.b.r infection also, but remains somewhat ineffective. Suramin is provided intravenously as the first line treatment for the haemolymphatic stage of T.b.r infection, however this treatment can lead to side effects such as renal failure, peripheral neuropathy and anaphylactic shock, amongst others. It acts by binding to enzymes in the glycosome and disrupts glycolysis within the trypanosome (Babokhov et al., 2013). Should the parasite cross the blood-brain barrier in the later stages of the disease, the treatment options are toxic and limited to the arsenic compound, Melarsoprol, which acts by disrupting trypanosomal redox mechanisms. Treatment with this can lead to further complications such as post-treatment reactive encephalopathy seen in 10% of patients (Palmer Wells, 2012), subsequently causing comas, seizures and cerebral oedema for example. Co-administration of eflornithine with nifurtimox, a hydrazone of 5-nitro-2-furaldehyde, has been shown to demonstrate trypanocidal activity, and is routinely used to treat T.b.g. It has shown trypanocidal activity against T.b.b in mice, however has been relatively ineffective against T.b.r. Furthermore, although eflourthrine abides Lipinskis rule of five in theory, in practice it is a highly hydrophobic compound, and is therefore unlikely to cross inner membranes once administered (Gilbert, 2014). It is therefore administered intravenously. Due to there being no self-cure for T.b.r, treatment is required for a recovery to be made. Furthermore, many of the drugs developed are only applicable to bloodstream trypomastigotes, rather than those that have crossed the blood-brain barrier (Palmer Wells, 2012). Factors such as this demonstrate the problematic nature of the disease, as well as the need for alternative therapies to combat the infection. 1.5. Current research Currently, novel treatments are in development with the hope that toxicity is reduced and efficacy is increased against trypanosomal parasites, namely T.b.r and T.b.b. To determine whether a proposed therapeutic compound is likely to be membrane permeable and therefore orally bioavailable, the Lipinskis rule of 5 is applied. To be within the limits of the rule means that the compound is orally bioavailable and easily absorbed by the body (Leeson, P. 2012). The rules state that the molecular weight of the compound must be less than 500 Daltons, the lipophilicity value is less than 5, represented as a LogP value, the number of hydrogen bond acceptors must be less than 10, and the number of hydrogen donators must be less than 5. Hydrogen bond acceptors include highly electronegative atoms not bound to a hydrogen atom and with free electrons on its outer shell, including oxygen and nitrogen. In newer literature, fluorine may be considered and counted as a hydrogen acceptor. This contrasts with a hydrogen bond donor, any atom that donates a hydrogen atom that it is bound to break or form a bond. All novel compounds are assessed under these rules to dete rmine properties involved in pharmacokinetics (absorption, distribution, metabolism and excretion). Oral administration is non-invasive, more bioavailable and simpler for patient use, all of which is desirable for a new treatment for T.b.r infection. Furthermore, a compound designed may still be orally bioavailable if a single rule is not adhered to. Benzoxaborole compounds have recently been suggested as a new, novel treatment for Trypanosoma brucei (T.b.r and T.b.g) in vitro, namely SCYX-7158 oxaborole(Jacobs et al., 2011). The orally-active treatment is suggested to have high efficacy for both acute and chronic stages of the disease due to the treatment being permeable to the CNS, and properties such as distribution, metabolism, elimination, absorption and toxicology are apparent in vitro. A viability assay combined different whole cell T. brucei spp.and the novel compound to gain positive results of anti-parasitic activity. This treatment demonstrated concentration-dependency, and most trypanocidal activity came from the first 8 hours of a 24-hour exposure. Furthermore, the irreversibility of trypanocidal activity was noted during a short exposure. In vivo, SCYX-7158 was examined against an infection with T.b.b to monitor passage across the blood-brain barrier, with mice models providing an 80% cure rate over a 7 day-treatmen t. Benzoxaboroles, like hydrazones, have demonstrated anti-cancer, anti-fungal, anti- bacterial, anti-viral, anti-inflammatory and anti-parasitic properties with a low intrinsic toxicity similar to table salt when decomposed (Liu et al., 2014). This is due to the metabolites of benzoxaboroles being found to be boric acid and oxidative deboronation products, both with very low toxicity. Per Lipinskis law, it is an orally bioavailable drug with very low IC50 values ranging from 0.19 to 1.008 ÂÂ µM, demonstrating high trypanocidal activity in vitro. An IC50 value is value is the inhibitory concentration value at which 50% inhibition of target cells has occurred. It is important when comparing the difference in the potency of compounds. A higher value represents less efficacy, with smaller values representing good trypanocidal activity in this case. It is a pharmacokinetic parameter, measuring the relationship between drug target and drug. Other research at the forefront include the development of hydrazone compounds of 5-nitro-2-furaldehyde and adamantine alkanohydrazine (Foscolos et al., 2016). Adamantine and derivatives have been previously shown to have trypanocidal activity, increasing for the more hydrophobic, phenyl and cyclohexyl substituents. These compounds and derivatives demonstrated good trypanocidal activity, approximately 20 times greater than nifurtimox. The lowest IC50 value obtained was 0.386 ÂÂ µM. Following the same study, it was found that in the absence of the nitro group, no trypanocidal activity was demonstrated, highlighting the trypanosomal nitro reductase mechanism these novel compounds work by. In terms of the structure-activity relationship, it was seen that the selectivity of compounds against T. brucei species increased when the distance between the carbonyl group and the adamantine skeleton was increased, with derivatives containing 3-cyclopentyl and 3-phenyl being more biologically active than other compounds. In conjunction, the lipophilicity and conformational structure contributed to the efficacy of these novel compounds, with increased lipophilicity and conformational flexibility promoting trypanocidal activity. 1.6. Aims of research Better pharmaceutical treatments with high efficacy and less lethal side-effects are drastically needed for T.b.r infection. Current research demonstrates the potential use of hydrazone compounds and derivatives in combatting parasitic infections, amongst others. Guidance from project supervisor Dr A Bhambra was given throughout the project regarding the structures of compounds. Hydrazones are defined as having the structure R1R2C = NNH2, the N=H bond is conjugated with a lone pair of electrons on the functional nitrogen atom (Verma et al. 2014). Research suggests hydrazone compounds also demonstrate anticancer, anti-inflammatory and anti-HIV properties, signifying biological variety and the potential to treat other diseases (Verma et al., 2014). It is because of these properties that new hydrazone compounds are in development, with the aim of synthesising novel compounds which demonstrate similar properties when applied against Trypanosoma brucei infection, and hence a potential the rapeutic for T.b.r. 2.1. Chemistry/ experimental synthesis The synthesis of four novel hydrazone compounds of reactants A-D and Pentafluorophenyl hydrazine (PFH) (Figure 3) was performed. All solvents and reactants were commercially available. Reflux condensation reactions with relevant reactant (3 mmol) and PFH (3 mmol) were performed, with continuous heating (oil bath) and stirring of compounds at 100-150 ÂÂ °C approximately. Compounds were separated with ethyl acetate (60 ml) and distilled water (50 ml). Excess magnesium sulphate was added to remove any excess water and products were vacuum filtered. Recrystallization reactions with boiling ethanol (10 ml approximately) not in excess were performed, and compounds were vacuumed down to give final compounds. Thin Layer Chromatography (TLC) analysis was performed for all compounds throughout the stages of experiment to monitor the constituents of the final product. Prior to NMR analysis, compounds were dissolved in chloroform (800 ÂÂ µL) with exception of HD6 (with reactant D), dis solved in DMSO (400 ÂÂ µL). 2.2. Biological Screening Analysis Further viability tests were carried out to assess the trypanocidal activity of each compound. Compounds were sent to the London School of Tropical Medicine for biological screening analysis against T.b.b. Stock drug solutions were prepared in DMSO at 20 mg/ml and further diluted appropriately. All assays were performed with use of 96-well microtiter plates, each well containing 100 ÂÂ µL of parasite culture, and serial dilutions of the compound in triplicate. Wells were incubated at 37ÂÂ °C for 72 hrs in 5% CO2. Control wells contained no compound, and blanks consisted of medium only. Following this, the MIC was determined and assurance of growth in control wells. 20 ÂÂ µL of Alamar Blue was added to wells, and plates were incubated for 2-4 hrs more. Plates were read on Gemini Plate Reader with an excitation wavelength of 530 nm and emission wavelength of 580 nm. Following this, IC50 values were obtained. Four novel hydrazone compounds were synthesised, shown in table 1. The electrophilic carbonyl group of appropriate reactants A-D reacted with the nucleophilic nitrogen (hydrazine portion) of PFH by nucleophilic addition. IC50 values gained demonstrated potential, especially HD1 and HD6. Proton NMR analytical results from spectra obtained are demonstrated below, showing the amount of hydrogens (or protons) in each compound as well as their corresponding intensities. Throughout synthesis, TLC was performed for each compound to visualize the two reactants, the formed product and any other substance that may be present. Rf values and appropriate TLC analysis results are illustrated in alongside compounds in table 1. 3.1. HD1 Beige crystals (50% yield); ÃŽÂ ´H (CDCl3) 7.28 (1H, s), 7.32-7.42 (3H, m), 7.64 (2H, dd), 7.82 (1H, s). 3.2. HD4 Pink crystals (50% yield) ÃŽÂ ´H (CDCl3) 7.30 (2H, s), 7.35 (1H, s), 7.45-7.50 (1H, m), 7.62 (1H, s), 7.73 (1H, s). 3.3. HD5 Beige crystals (H (CDCl3) 7.32-7.38 (3H, s), 7.54-7.60 (2H, d), 7.78 (1H, m). 3.4. HD6 Red crystals (H (CDCl3) 7.37 (1H, s), 7.45 (2H, s), 7.70 (2H, s). 3.5. Biological screening analysis Results obtained from the London School of Tropical Medicine included IC50 values for all hydrazones synthesised. These are listed alongside appropriate compounds in table 1. HD1 had an IC50 value of 9.29 ÂÂ µM; HD4 34.37 ÂÂ µM; HD5 34.09 ÂÂ µM and HD6 16.18 ÂÂ µM. Formation of all compounds HD1, HD4, HD5 and HD6 (table 1) followed the general mechanism illustrated in appendix 1. R1 should be substituted with relevant reactant (A-D) benzene rings. Electrophilic reactants accept free pairs of electrons from the nucleophilic nitrogen atom of PFH by nucleophilic addition. The formation of a biologically active centre was documented (Verma, 2014). All compounds synthesised contain phenyl groups, which has been suggested in literature to promote trypanocidal activity (Foscolos et al., 2016). Hydrazones synthesised are also non-polar and hydrophobic compounds, meaning that they carry no net charge and are not soluble in water. Furthermore, an increase in hydrophobicity also promotes trypanocidal activity, however has been suggested to make the compound less bioavailable (Gilbert et al., 2014). Proton NMR spectra demonstrate relative intensities in parts per million (ppm) of protons or hydrogens in the compound. Despite only hydrogens being of interest, it is important to consider the other electronegative groups that exist within the compound such as phenyl groups or -OH groups, which produce different peaks. The solvent peak demonstrates as a sharp, well distinguished peak to exclude it from the compound results. Singlet, doublet and Name Reactant Structure IC50 value (ÂÂ µM) TLC (illustrated- not to scale) Rf value (cm) HD1 Benzaldehyde (reactant A) 9.29 0.73 HD4 3-chlorobenzaldehyde (reactant B) 34.37 0.48 HD5 4-chlorobenzaldehyde (reactant C) 34.09 0.43 HD6 3,4-dichlorobenzaldehyde (reactant D) 16.42 0.57 multiplet peaks were all demonstrated on the spectra. NMR analysis reflects the structures synthesised, confirming the number and positioning of hydrogens. The spectra observed demonstrated some sharp peaks and others more broad. Furthermore, some peaks were somewhat distorted due to the presence of chlorine on the aromatic benzene ring. Limitations of the experimental synthesis included low yields obtained from synthesised hydrazones. This could have been possibly due to the recrystallization step or some of the reactants not converting into product. Factors such as this could have been improved to gain better results. In addition, yields were estimated due to not weighing compounds beforehand, therefore weighing the compounds when they were initially synthesised would improve the data. 4.1. HD1 From the NMR spectra, HD1 contained 7 hydrogen atoms, one at 7.28 ppm as a singlet peak, three at 7.32 7.42 ppm as a mutliplet peak, two at 7.64 ppm as a doublet peak and one hydrogen at 7.82 ppm as a singlet peak. All novel compounds synthesised differ in terms of the aromatic benzene ring on the relevant reactants, therefore the positioning and amount of chlorine attached to this aromatic ring demonstrates the difference in IC50 values. This coincides with the biological activity against T.b.b. HD1 is formed of benzaldehyde and PFH, and therefore does not possess any chlorine atoms. The IC50 values were the lowest for HD1 at 9.29ÂÂ µM, which suggests that the presence of chlorine in the compound may decrease trypanocidal activity. 4.2. HD4 HD4 contained six hydrogen atoms, two at 7.30 ppm as a singlet peak, one hydrogen at 7.35 ppm as a singlet peak, one hydrogen at 7.45-7.50 ppm as a multiplet peak and a one hydrogen as a singlet peak at 7.73 ppm. HD4 contained a chlorine group on the 3rd carbon of the reactant benzene ring, with displacement of chlorine by (bio)nucleophiles, facilitated by the electrophilic carbon centre determining biological properties observed. However, it has been suggested that the presence of a chlorine atom at a non-reactive aromatic double bond diminishes reactivity (Naumann, 2003). The IC50 value for HD4 was 34.37 ÂÂ µM, the highest value from all the compounds synthesised. This supports the notion that chlorine atoms present in the compound reduces trypanocidal activity rather than improving it. 4.3. HD5 HD5 also contained six hydrogens, with three hydrogens at 7.32 7.38 ppm in a singlet peak, 2 hydrogens at 7.54 7.60 ppm in a doublet peak, and one hydrogen at 7.78 ppm in a multiplet peak. HD5 also contained a chlorine atom but on the forth carbon of the benzene ring, as opposed to the third. Altering the position of the chlorine atom did allow for an improved IC50 value to be obtained, which was 34.09 ÂÂ µM. This however remains much less effective than HD1. 4.4. HD6 HD6 contained five hydrogen atoms, one at 7.37 ppm as a singlet peak, one at 7.35 ppm as a singlet peak, two at 7.45 ppm in a singlet peak, and 2 hydrogens at 7.70 ppm in a singlet peak. Despite the presence of chlorine in both HD4 and HD5 causing less effective activity against T.b.b, HD6 contained two chlorine atoms attached to the benzene ring, and the IC50 value obtained was nearly half that of HD4 and HD5 at 16.18 ÂÂ µM. This suggests that the presence of one chlorine atom existing at any carbon on the benzene ring does not promote trypanocidal activity, however the presence of 2 attached chlorine atoms did aid activity. 4.5. Oral bioavailability Per Lipinskis rule of 5, all novel compounds fall within the laws except from HD1, which contains 6 hydrogen bond donors. HD1 therefore would be more bioavailable if administered intravenously, however may still be orally bioavailable as only one rule has been violated, with the rest all being adhered to. Despite this, the other novel compounds alone demonstrate progression in seeking an orally bioavailable treatment for HAT, linked with reducing toxicity amongst being easier and more accessible for those who require it. Furthermore, the use of PFH incorporates many fluorine atoms, which increases lipophilicity (Citation), increasing activity in vivo, as well as increasing fat solubility and therefore allowing the compounds to easily pass through membranes in the body. Retaining fluorine is a desirable property due to the improvement of metabolic stability as a result of the high strength C-F bond. It is a relatively small molecule, with a high electronegativity value. All properties such as this contribute to biological responses within the body. 4.6. Comparison to literature IC50 values HD1 and HD6 demonstrated the most promising results of 9.29 and 16.18 ÂÂ µM. For comparison intentions, alternative novel therapies at the forefront of science such as adamantine alkanohydrazine hydrazones and benzoxaborole SCYX-7158 have IC50 values of 0.386ÂÂ µM and 0.19 to 1.008ÂÂ µM respectively (Foscolos et al., 2016; Jacobs et al., 2011). Although the results from the synthesised compounds are promising and suggest trypanocidal activity against Trypanosoma brucei, both SCYX-7158 and the adamantine alkanohydrazine hydrazones have much lower IC50 values, suggesting that the structures of novel compounds could be improved and altered to gain better trypanocidal activity. Furthermore, current treatment Melarsoprol and Suramin have IC50 values of 0.046 and 0.004-0.009 ÂÂ µM, much lower than the compounds synthesised (Torreele et al., 2010). However, as stated above, these treatments offer high toxicity and high mortality rates following administration, and the fa ct that the novel compounds synthesised (HD1 especially) have low IC50 values remains promising. Furthermore, both Suramin and Melarsoprol are administered intravenously, posing more problems in terms of accessibility as developing countries where the disease is endemic possibly do not possess the facilities to administer treatment. This is unlike the synthesised hydrazone compounds, which all theoretically can be administered orally, therefore moving towards better treatment and management of T.b.r infection. HD4 and HD5 demonstrate lower trypanocidal activity than HD1 and HD6, therefore further progression on HD1 especially would allow for potentially more effective trypanocidal compounds, represented by lower IC50 values upon testing. Furthermore, new compounds in other literature with the highest trypanocidal activity, namely 5-nitro-2-furaldehyde and adamantine alkanohydrazine hydrazones and benzoxaboroles, provide a platform for future work and development of structural analogues of hydrazones to promote trypanocidal activity. To confirm that the novel compounds synthesised are in fact effective against T.b.r, further testing is required in a controlled level 3 laboratory where the p

The Battle Of Midway Essay -- American History

The Battle of Midway On June 3rd, 1942, the United States declared war on Imperialistic Japan and Nazi Germany. Due to the bombing of the United States' naval base at Pearl Harbor by the Japanese the U.S. was forced to take action. The United States began their first naval battle near the Midway islands in defense of its pacific fleet and positioning. Midway was the Japanese' last goal for its western expansion in the Pacific. Just after midnight on June 4th,1942, the United States attacked a fleet of Japanese transport ships. One American torpedo plane took out fleet tanker "Akabono Maru". Later that morning at about 6:30am, Japanese planes began bombing midway island installations, though causing minimal damage to the U.S. naval base. Between 9:30am and 10:30am the U.S. took out Japanese aircraft carrier's "Kaga, Akagi, and Soryu". During the battle the Japanese recovered three U.S. naval aviators. But after interrogating these men, the Japanese murdered them. On June 5th, 1942, a battleship, under the command of Rear Admiral Spruance, pursued the Japanese fleet westward leaving salvage workers to repair the U.S. aircraft carrier "Yorktown"(which was damaged a day earlier by a Japanese submarine torpedo). The last of the air attacks of the battle took place on June 6th, 1942, with the United States beginning to emerge victorious with the sinking of 2 destroyers, 1 heavy cruiser, and 1 cruiser. Meanwhile a Japanese submarine torpedoed aircraft carrier "Yorktown" and the destroyer "USS Hammann", though it took a day for the carrier to turn over and sink. The Japanese submarine escaped with-out destruction soon after the torpedoing. (Naval Historical Center, Battle of Midway:4-7 June 1942, Department of the Navy... ...he U.S. complete control over the Pacific Ocean. This defeat also gave the Allies an absolute victory over Japan and the remaining Axis powers. The infamous Battle of Midway officially ended on June 7th 1942. Works Cited Baikie, Eric. Ngo, Kevin. Collins, McKenzie. "Major Battles of WWII". Viking Press. January 2002. Bruce, George "Sea Battles of the 20th Century", Stopping the Tide: the Battle of Midway 4th - 7th 1942, Department of the Navy, May 1990 Cressman, Robert, J. "No End Save Victory", Naval Historical Center, June 1998 Dingman, Roger, The origins of naval arms limitation,"Power In The Pacific", Naval Institute Press, 1998. Naval Historical Center, "Battle of Midway: 4th -7th June 1942, Department of the Navy. June, 30, 2003. Naval Historical Center, "Preparation For Battle" Department of the Navy, April 1999

Emile Durkheim – Division of Labor

DIVISION OF LABOR IN SOCIETY The Division of Labor in Society by Emile Durkheim explains how in the modern societies the division of labor affects individuals and society contradicting Marx’s belief that the division of labor will all result to alienation. Durkheim argued that the division of labor is not necessarily â€Å"bad† for it â€Å"increases both the productive capacity and skill of the workman; it is the necessary condition for the intellectual and material development of societies; it is the source of civilization. More importantly, it creates a feeling of solidarity among the people. For Durkheim, the result of Division of Labor is positive for there is no need for competition in the sense of struggling just to survive but the division of labor may signify that there are sufficient material resources for all in the society, and in this division allows a certain form of cooperation and because people need each other this produces a solidarity in the society. *As we noted previously, Marx saw both alienation and class conflict as inevitable (or â€Å"normal†) in capitalist societies.By contrast, rather than seeing social conflict as a â€Å"normal† condition of capitalism, Durkheim maintained that anomie results only in â€Å"abnormal† conditions of overspecialization, when the rules of capitalism become too rigid and individuals are â€Å"forced† into a particular position in the division of labor. *Causes of Division of Labor: division of labor develops regularly as history proceeds. This fact certainly depends on causes that are likewise constant, causes that we shall investigate. † (p. 179). â€Å"THe increase in the DOL is therefore due to the fact that the social segments lose their individuality, that the partitions dividing them become more permeable. IN short, there occurs between them a coalescence that renders the social substance free to enter upon new combinations. † {p. 141} The key to the expansion of the DOL is the increase in social interaction, particularly functional differentiation. * This is what gives moral value to the division of labor. Through it, the individual becomes aware of his dependence upon society; from it come the forces which keep him in check and restrain him.In short, since the division of labor becomes the chief source of social solidarity, it becomes, at the same time, the foundation of the moral order. * Moreover, far from being trammeled by the progress of specialization, individual personality develops with the division of labor. To be a person is to be an autonomous source of action. Man acquires this quality only in so far as there is something in him which is his alone and which individualizes him, as he is something more than a simple incarnation of the generic type of his race and his group.The division of labor itself contributes to this enfranchisement, for individual natures, while specializing, become more complex, and by that are in part freed from collective action and hereditary influences which can only enforce themselves upon simple, general things. The most visible example of social solidarity that Durkheim mentioned was law. Law is the organization of social life in its most stable and precise form. The classification of law depends on the type of solidarity corresponds to it. The first type of law is the repressive law which imposes a fine or injury on the perpetrator.The second one is the restitutory laws which refer to restoring the previous relationship which have been disturbed from before the crime was committed. Repressive law tends to stay diffused througout the society, restitutory law works through more specialized bodies like in courts, magistrates and lawyers. *Despite the removed role of restitutory law from socirty, society still intervenes in restitutory sanctioning. The formation of a contract directly concerns the parties involved: nonetheless, id a contract has a binding forc e, it is a society which confers that force.If society does not give its blessing to the obligations that have been contracted, then these obligations are reduced to only moral promises. Hence the presence of society in restitutory law, although not necessarily felt, is nonetheless essential. negative control – regulations which make a person refrain from acting ex. do not help a farmere with his crop, simply prevent him from stealing his neighbor's positive control – regulations which make a person act ex. impose a certain method of farming upon a farmer. Mechanical Solidarity or solidarity by similarities, it is deeply rooted in everyone doing or feeling the same thing.It is the type of solidarity that is associated with repressive laws that corresponds to crimes resulting in repressive punishments. Durkheim pointed out in his book that how the repressive or penal rules demonstrates the strength of resistance of collective response to a crime. Thus it is now called c ollective consciousness which is the â€Å"totality of beliefs and sentiments common to average citizens of the same society forms a determinate system which has its own life. † Therefore, it is summarized as an act is only criminal if it offends the â€Å"strong, well-defined states of collective consciousness. *Mechanical solidarity is typified by feelings of likeness. Mechanical solidarity is rooted in everyone doing/feeling the same thing. Durkheim maintained that this type of solidarity is characteristic of small, traditional societies. In these â€Å"simple† societies, circumstances compel individuals to be generalists involved in the production and distribution of a variety of goods. Indeed, in small, traditional societies, specialization in one task to the exclusion of others is not possible because the society depends on each individual providing a host of contributions to the group.For instance, men, women, and children are often all needed to pick crops at harvest time, and all partake in the harvest-time celebrations as well. Durkheim argued that a significant social consequence of the shared work experience characteristic of traditional societies is a shared collective conscience. People in traditional societies tend to feel â€Å"one and the same,† and it is this feeling of â€Å"oneness† that is integral in the maintenance of social order. Yet, Durkheim saw that in large, complex societies, this type of solidarity was waning.In large, modern societies, labor is specialized; people do not necessarily all engage in the same work or share the same ideas and beliefs. *â€Å"Since the rules are inscribed upon everyone's consciousness, all are aware of them and feel they are founded upon right. † â€Å"Undoubtedly if an act is punished, it is because it is contrary to a mandatory rule, but this rule is not expressly spelt out. There can be only one reason for this: it is because the rule is known and accepted by ev erybody. † (p. 5) â€Å"we should not say that an act offends the common consciousness because it is criminal, but that it is criminal because it offend that consciousness. † (p. 42) [133] *What separates repressive law from civil law – law that simply restores previous order? First, recall that crimes are those things that affect the common consciousness: Thus, â€Å"†¦since the sentiments that crime offends within a single society are the most universally collective ones of all, since they represent especially powerful states of the common consciousness, they cannot possibly brook any opposition. †¦. e need a more violent form of satisfaction. † (p. 55) The kinds of offenses that give rise to repressive law assault transcendent values, â€Å"when we demand the repression of crime it is not because we are seeking a personal vengeance, but rather vengeance for something sacred which we vaguely feel is more or less outside and above us. † ( p. 56) At this point (right around p. 57 and 58), E. D. makes a subtle and important point. That punishing criminal activity reinforces the common consciousness. â€Å"Crime therefore draws honest consciousnesses together, concentrating them. † He provides an example.In a small town, everyone talks about the criminal scandal. Just like when horrible things happen in the news, we respond. By discussing the crime and punishment with people we know, we reinforce our opinion about the immorality of the action. â€Å"In short, since it is the common consciousness that is wounded, it must also be this that resists; consequently, resistance must be collective. † But why this resistance is organized remains to be explained. Historically, crimes were judged by the WHOLE people, then as society progressed, certain samples of people and judges took the place of the whole. bottom of p. 59) – the organization into courts is a division of labor response: the world got bigger, and needed more people to split up the work of policing the common consciousness. (Note, of course, that this is exactly the moment that greater individual variation in what, exactly, people have in common starts to magnify). â€Å"Thus, it is certainly the nature of the collective sentiments that accounts for punishment, and consequently for crime. † Organic Solidarity, on the other hand is characterized with the other type of law which is the restitutory law.Organic solidarity assumes that people are different from each other and they are interdependent with other forming a complex web of cooperative associations. Unlike the mechanical solidarity, the solidarity in this case is from each person cultivating individual differences and knowing that each one is doing something for the betterment of everyone. Moreover, Durkheim said that the organic solidarity arises only when the division of labor is spontaneous or voluntary. Because the division of labor is pushed too far the n it becomes dangerous for the individual for t may result to the isolation of in their special activity or skill. Thus making the division of labor a source of disintegration for the individuals and the society. *†Damages awarded have no penal character: they are simply a means of putting back the clock so as to restore the past, so far as possible, to its normal state. † (p. 69) †¢ Restitutory laws put the world back together — they restore what was before. †¢ Restitutory laws are not (usually) part of the collective common consciousness. Instead, they apply to very specific areas (corporate law, accounting law, housing law, contract law, etc. ) and, E. D. laims, a violation of such a law does not elicit the emotional need for expiation that a criminal offense does. â€Å"The idea that murder can be tolerates sets us up in arms, but we very readily accept that the law of inheritance might be modified, †¦. Since these prescriptions do not correspo nd to any feeling within us, an as generally we don no know their scientific justification, since this science does not yet exist, they have no deep roots in most of us. † [137] †¢ Since restitutory laws do not affect everyone, the solidarity that restitutory laws relate to cannot rest on a uniform similarity across everyone in the group. For Durkheim, organic solidarity refers to a type of solidarity in which each person is interdependent with others, forming a complex web of cooperative associations. In such situations, solidarity (or a feeling of â€Å"oneness†) comes not from each person believing/doing the same thing, but from each person cultivating individual differences and knowing that each is doing her part for the good of the whole. Thus, Durkheim argued that the increasing specialization and individuation so readily apparent in modern industrial societies does not necessarily result in a decline in social stability or cohesion.Rather, the growth in a so ciety’s density (the number of people living in a community) and consequent increasingly specialized division of labor can result in simply a different type of social cohesion. Abnormal Forms. (1) Anomic Division of Labor is cause by the lack of regulation or a weakened common morality that can occur in modern society. Usually surfaces when there are industrial or commercial crises or there are conflicts between capital and labor. Durkheim discusses conditions of the worker under capitalism and it somewhat very close to Marx’s description of lienation and exploitation. However, he says that situations like this are not in the normal form but is something resulting from an individual who does not have a sufficient vision of the whole process of production. (2) Forced Division of Labor is where the division of labor is not allowed to develop spontaneously and where some act to protect themselves and their positions. It is the consequence of a structural condition where t he distribution of social functions does not match to the distribution of natural talents. (3) Another Abnormal Form.Durkheim’s observation that the function of an organism can become more active only on the condition that they also become more continuous one organ can do more only if the other organs do more, and vice versa. When this continuity is missing then the functional activity of the specialized parts decreases, resulting in wasted effort and loss of productive capacity. Increased activity also results to a stronger bond of solidarity but when mismanagement arises, the activity of the worker is reduced, functions become discontinuous, and solidarity is destabilized.

A passage to India †Symbolism Essay

Analyse the symbol of the mosque to bring out the complex picture of Islam in the novel A Passage to India. Mosque is the holy place for all Mohammedans, and in the Novel ‘A Passage to India’ it has a greater significance. The first part of the novel is named as Mosque. E M Foster has a unique technique to use symbolism to convey the way society, religion, caste and treatment of different class of people. Foster uses mysticism and complexity throughout the novel, yet he also has real interpretation of the journey the characters take from beginning till the end. Similarly, he brings out the qualities which transpire â€Å"what Islam is, and what it means to Aziz?† using mosque as the symbolism. For this purpose, Mosque is not just portrayed as a religious building but also the significance it has to Islam. As a religion which is against iconography, Mosque is unlike the place of worship compared to Christians or Hindus, where there is a painting or idol is present for worship. Instead, in a mausoleum there is none and just a courtyard that points towards Medina. The Mosque and Muslim faith point out that â€Å"There is no God but God†. The complexities build further when Foster writes about Aziz and his attachment to the Mosque in the beginning of the story. When we read that Aziz is walking down the lane towards the Mosque and is thinking of the place, and in his mind the attachment what it bring to him. The Mosque serves as a place in his heart which no one can take it, the place where his mind and soul can rest and be at ease. With all tensions with British in India and the way the religions were colliding leading to multiple ideas, the educated were starting to question the olden ways of the religion. Here the attachment to Mosque and its symbolism provided not only a sense of how the religion stood in current world of Aziz, but it also provided happiness. The Islamic doctrine dictated equality towards all worshippers under God. There was no priesthood hierarchy in the Mosque, but rather the place provided each person with one’s own way of worship. The house of God also designates an unreachable friendship with the God with every follower of Islam. Foster describes using Aziz, as the mosque has indeterminate sentiments towards the faith.