Responsibility to Protect and Obstacles in Its Implementations Essay

Responsibility to Protect and Obstacles in Its Implementations - Essay Example In so doing, the Assembly deliberately rejected the old paradigm that viewed sovereignty and human rights as diametric opposites of a horizontal continuum, and embraced the notion that the two principles necessarily reinforce each other. In paragraph 139 of the Document, the Security Council was recognized as possessing the right to authorize force under Chapter VII to prevent genocide, war crimes, ethnic cleansing, and crimes against humanity where "national authorities manifestly fail" to protect their own populations" (World Summit Outcome 31). This recognition has decisively broadened the legal effect of Article 39 of the Charter - it is now fully settled in law that the Security Council may use force in contained domestic crises where atrocities are being committed. The principal argument of this paper is that notwithstanding the advancements of "responsibility to protect", the doctrine in its present form has serious shortcomings that could leave the Security Council without cl ear parameters and guidelines for dealing with future genocides. R2P fails to meet the needs of civilians due to the non-intervention norm enshrined within the Charter. It is vital that more work be done to develop clearer standards and benchmarks in the determination of responsibility to protect. Barriers Implementing R2P R2P, while specifically addressing humanitarian interventions, is a doctrine which is not legally binding. R2P merely serves to clarify the criteria permitting intervention. The criteria are just cause, right intention, last resort, right authority, proportional means, and reasonable prospects. Just cause determines the grounds under which humanitarian interventions may occur. The ICISS identified genocide and large-scale ethnic cleansing, actual or imminent. Right intention prohibits intervention for the sake of regime change or other national interests. The intervention must be solely based on humanitarian motives. The last resort criterion determines that all n on-military means of conflict prevention must be exhausted before relying on the use of military force. The right authority criterion clarifies that while the UN Security Council is the primary vehicle for authorising intervention, it may also, in the case of UNSC paralysis, be authorised by regional organisations such as North Atlantic Treaty Organisation (NATO), the European Union (EU), or the African Union (AU). Proportional means is the idea that the scale, duration, and planned military intervention are the minimum of what is necessary to secure the defined objective. This assures the country in which the intervention is taking place that the intervention is merely temporary and that sovereignty will be returned in the shortest time possible. The final criterion; reasonable prospects, is perhaps the most important. It is the idea that an intervention will only take place if the consequences of such action will not be worse than doing nothing (Matt 31). However, like all legal c onventions, R2P is subject to interpretation. There is nothing in R2P which prevents states from arguing that the just cause threshold has not been crossed or that the responsibility to protect lies with the host state and not the international community. It is stated within the R2P report that it is a pro-sovereignty doctrine, and that the responsi

Compare between SAP system and Microsoft Dynamics system in ( Bill of Research Paper

Compare between SAP system and Microsoft Dynamics system in ( Bill of material) - Research Paper Example Others include NAV, SL, and AX. Dynamics NAV is designed in a way to suite mid-size companies. It is an ERP that incorporates both basic PM and accounting functions that are offered by other types like SL. Dynamics SL is best suited for managing projects and other accounting roles across many divisions in a firm. It was made to target construction management firms, distributors and any other contractor. Dynamics GP which will be our focus of discussion in this analysis is used mainly in the Americas, UK and Ireland, the Middle East, Australia and New Zealand. It was one of the first accounting packages released in the USA and was meant to run on Windows 32 bit machines. It was designed to be used in financial management, supply chain management, human resource management, project management and manufacturing. Dynamics AX was designed for global corporations and modern manufacturing firms. It offers all the functionalities of GP and also provides advanced business reporting and intell igence. SAP Business One This is an ERP that is used by all type of businesses i.e. small, medium and even in large companies. It is applied in business functions ranging from customer relationship management, purchasing and supplies, financial management and business analytics. It also provides comprehensive business intelligence and reporting. In 2011, SAP introduced a solution that was meant to consolidate business and enable intercompany integration. This was to enable multinationals to manage transactions and activities across multiple databases. The functions of the SAP ERP system can be broadly categorized into four broad modules i.e. Financial, Human Capital Management, Operations and Corporate Services. In financial management, it supports for multiples currencies, bank reconciliation and budgeting. In human capital management, it is applied in functions of managing the payroll, recruitment, human resources, learning and development and analysis of work functions. In operat ions, it provides functions like purchasing, manufacturing and research and development. In corporate services, it helps in asset management in areas ranging from real estate, travel management and project management. The business area chosen for comparison in this paper is supply chain management functions with respects to each ERP package. Supply Chain Management When we discuss about supply chain management, the discussion is based on two main core ideas; Every product that reaches the customers will represent a collective effort of many corporate organizations and this firms will be collectively referred collectively as a supply chain Unfortunately most businesses have only focused what happens within their premises in as much supply chains have existed for a long time. Therefore few business have understood the entire chain of activities that leads to the ultimate delivery of the final products to the customer Therefore supply chain management can be referred to the management of all the supply chain activities in order to improve

Analytical Research Paper Example | Topics and Well Written Essays - 1000 words - 1

Analytical - Research Paper Example Furthermore, information systems assist the decision makers to have a clear perception about the present situation of the organization by proving strong evidences about the organization. However, healthcare information systems have certain demerits as well. Implementation of the systems is quite an expensive process and it also requires a lot of efforts and trained individuals to operate effectively. The management of information system is fundamentally done to gather data from the different departments of an organisation and then to present the data in a systematic format. Management of information system furthermore includes processing of the gathered data. Management of information system plays a vital role in most of the organisations. This system ensures the collection of appropriate data from the different sectors of the organisation and further facilitates to deliver the collected data when it is required (University of Mumbai, 2012). According to Colesca and Dobrica (2009), information system management plays a significant role in improving the efficiency of the healthcare organizations. Furthermore, it facilitates in improving the effectiveness of the services provided by the organizations while maintaining the costs at a minimum level. In addition, the system aids the organizations to remain competitive according to current market scenario and also enables them to provide high quality services as per the requirements of the customers (Colesca & Dobrica, 2009). According to Carlson (2007), management information systems can provide a numerous significant benefits to the healthcare organizations. These systems facilitates in the decision making process of the organizations and enable them to control the emerging related difficulties and also provide a basis to the organisations to monitor their progress towards the organisational goals. In addition, these systems educate the individuals as well as communities about the

The problem of the huge gap between the rich and poor in China and the Essay

The problem of the huge gap between the rich and poor in China and the solutions - Essay Example In contrast to them the poorest 10 per cent of China’s population’s income increased by no more than 12-fold. This sustained trend ranging over a period of almost 2.5 decades has distanced the rich and the poor so much that they almost find themselves at opposite poles today. The Gini coefficient suggests that the yawning gap between the two populations in China has become so wide that it is now disturbing the limits of social stability. The hukou system in China The growing inequality between the rich and the poor in China is integrally linked with the hukou system of the permits of residency according to which the internal migration of the poor is restrained to the towns. Economic gap between the rich and the poor in China has increased with the growing scarcity of the rural labor. The hukou system has limited the poor to the access of public services only where they are registered which are mostly the very places where they are born. â€Å"[M]aking individualsâ€⠄¢ hukou status salient and public significantly reduces the performance of rural migrant students on an incentivized cognitive task by 10 percent, which leads to a significant leftward shift of their earnings distribution† (Afridi, Li, and Ren). The rules applying limits to migration in China that limit the poor in the countryside are blatantly unfair. The concept of Guanxi The growth of business in general and the small and medium sized enterprises (SME) in China has recently grabbed the attention of the whole world. One factor that has played a prime role in the growth of business and the consequential strengthening of economy in China is the concept of Guanxi, that encourages people to build social connections and networks and seek benefits from them. â€Å"The concept of Guanxi or a network of connections is a well known and central aspect of life in China, both in business and social life. It's no different from the 'old boys network' in the UK† (Walker). This sys tem has not only increased the economic divide between the rich and the poor in China, but has also helped the cultivation of corruption and injustice in the systems. Chinese politicians today recognize and appreciate the Old Etonian bonds among the City Hall and the Downing Street. China’s upcoming leaders are linked through families. Economist Mao Yushi has described the problem in these words, â€Å"The wealth in China is not only allocated by the market, but also by power. The people with power have money. The marriage between power and money allows people to make money by using illegal methods. It increases further the income gap between the rich and the poor beyond the market itself† (Yushi cited in Taylor). The system is unfair and the poor do not stand any chance even in the long run. Solutions Decreasing disparity of income between the rich and the poor Since it is one of the most important contributing factors in the widening economic gap between people of

A Ghost Story by Mark Twain Essay Example | Topics and Well Written Essays - 750 words

A Ghost Story by Mark Twain - Essay Example The paper is aimed to discuss and to analyze A Ghost Story which is written by Mark Twain. It is a story of the interaction between the narrator and the ghost of the Cardiff Giant. The narrator is a person who rented a huge old building in Broadway which had not been occupied for a long time.While in bed, the blankets were pulled and other actions were made by the ‘ghost.’ Different paranormal images had been perceived by narrator and in the end the ghost finally shown himself. He is the ghost of the gentle Cardiff Giant. When the narrator recognized him, the atmosphere of the story completely changed and they talked about the reason for the haunting. There are two characters in the story, the narrator and the ghost. The main focus of the story is the ghost of Cardiff Giant. In the course of the story, the characteristics of the ghost changed, thus, he can be classified as a dynamic character. In the beginning of the story, the main objective of the Giant was to haunt an d get attention and justice because of the use of his remain in unjust manner. Prior to the end of the story, the conversation between the narrator and the ghost of Cardiff Giant changed his views regarding his situation. Through the information given by the narrator that the Giant’s remains were just duplicated and the real ones were in Albany, he was freed and he found no reason to continue his haunting in the said place anymore. The story has both the internal and external conflicts. The external conflict was observed in the first part of the story when the haunting of the ghost along with his friends caused fear to the narrator and to other people before him. The said conflict had been exhibited through the antagonistic treatment of the ghost to the residence of the building. The internal conflict was perceived in the latter part of the story, through the conversation between the Giant and the narrator. The internal conflict defined the main purpose of the ghost of the Ca rdiff Giant which was the feeling of tiredness of the ghost versus the need to seek help and justice for his remains. He wanted to rest for a very long time already but the need to bury his remains to a rightful place kept him haunting for a long time. The setting of the story is figuratively and literally descriptive of the characters of the story. The readers can accept the setting as strong part in the story since the basic information had been presented such as the names and the landmarks. Readers know that the story occurred in New York, near a museum and near a street with old buildings. May that be fictitious or real, it had contributed to the whole atmosphere of the story. The distinct imagery brought about by the setting inside the house. The point of view of the story was achieved through the perspective of the narration. This gave credibility to the story by being in the first person thus being a primary experience. Another effect of the point of view was the primal effec t of the story in terms of the feelings being conveyed, for example fear. The story is rich in metaphors and other figurative forms of language. One example is the description of the building which had â€Å"surrendered to dust and cobwebs, to solitude and sadness.† Other figures of speech are â€Å"locking out mould and darkness† and â€Å"cheery fire† which can be found in the first two paragraphs. Thus it meant that the whole story was enriched by these literary treasures. The author used these figures of speech in a casual and relaxed manner which can easily be related to and understood. The main idea of the story is that not everything is what it seems. The story teaches lesson of

Process and Content Theories of Motivation Essay Example for Free

Process and Content Theories of Motivation Essay There are several process theories of motivation: The Vroom Expectancy Theory, the Adams’ Equity Theory, the Needs-Goal-Setting Theory, and the Reinforcement Theory of Motivation. Here our centre of attention is on helping you make a clear-cut distinction between process and content. Basically, process theories of motivation focus on how workers needs influence their own behaviour. Here our attention goes beyond motivation, our focal point is on giving you a key conceptual tool to help you manage both the performance of your direct reports (management) and the performance of your entire organization (leadership). â€Å"Process† is how employees work together, as opposed to the what – the â€Å"content,† the task, the issue – they are working on. An example of â€Å"process† is the way in which people interact with each other during a meeting; on the contrary, an example of â€Å"content† is the decision they make in that meeting. Process is hiring (the hiring processes that a company practices); content is the selected candidate that becomes the new employee. Process is the nature in which day-to-day performance conversations take place between the manager and her direct reports; content is what gets talked about, agreed upon, and actually understood. Process is the way in which people interact with each other in order to solve a problem; content is the actual solution to the problem. Most executives have the unconscious tendency to focus on content – which is great, that’s what they get paid for – but unfortunately most executives also have the unconscious tendency to forget about the process they are using. However, the quality of the â€Å"process† that is used (the type of meeting that is used to make a decision for example), has an impact on the quality of the resulting â€Å"content† (if the meeting is poorly designed, the quality of the resulting decision is likely to be poorer, but if the meeting is well designed, the quality of the resulting decision is likely to be better). Again, the better the process used, the better the resulting content, and vice versa: The poorer the process used, the poorer the resulting content. Do the people in your company hate meetings because they spend too much time in them? The problem is not in the meetings themselves, but in the way your company runs those meetings. Does your company have several low performers? The problem is not in those poor people who perform below standards, but in your company’s management practices. Is your company lagging behind its competition? The problem is not in those high performing organizations, but in the leadership skills of your company’s leaders. The process by which a company is led and managed determines its long-term success.heori of Motivation A great company is successful in the long run not because of its great products or services, but because of the nature of its leadership and management processes. You can have the greatest product or service, but if you don’t have the appropriate management and leadership processes, your company won’t get too far. It’s that simple. The next time something doesn’t go as you wanted it to go, stop for a second, step back, get your focus off the content, and take a closer look at the process you are using. How can you improve the process that you are using?

Types of Mitochondrial Diseases

Types of Mitochondrial Diseases Abstract: Mitochondrion is the primary site of energy and ATP generation so it is called â€Å"power house† of the cell. Mitochondria are composed of two different types of membranes like an outer membrane, an inner membrane and a protein-rich matrix. Protein kinases can localize to specific cytoplasmic sub compartments and mediates many important processes like cell motility and many signaling events. The mitochondrion is a point of integration for these signaling cascades due to its role in cellular metabolism, redox processes, and cell survival-death. PI3K/Akt/Protein Kinase B(PKB) ,Protein kinase C(PKC),Raf-MEK-ERK,JNK/SAPK and p38 MAPK, Apoptosis signal-regulating kinase 1 (ASK1),Glycogen synthase kinase 3ÃŽ ² (GSK-3ÃŽ ²),Protein kinase A (PKA),PTEN-induced kinase 1 (PINK1) are associated with mitochondria and modulate mitochondrial activity and the release of mitochondrial products affects mitochondrial respiratory chain, transport, fission-fusion events, calcium turnover, reactiv e oxygen species (ROS) production, mitochondrial autophagy and apoptotic cell death. Mitochondrial diseases are due to degeneration of the mitochondria in specialized compartments present in every cell of the body. Mitochondria diseases causes damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems. So this review focuse on various kinases associated with mitochondria, their role in progression of neurodegenerative diseases and treatment. Introduction 1 Mitochondria: Mitochondrion is present in every eukaryotic cell having size range of 0.5 to 10 ÃŽ ¼m in diameter (Munn et al., 1974). It is the primary site of energy and ATP production so it is called â€Å"power house† of the cell. Mitochondria are composed of two different types of membranes like an outer membrane, an inner membrane and a protein-rich matrix. The molecular machinery of chemiosmosis is associated with the inner membrane. Mitochondrial energy production is same in all cells but there are variations in shape, connectivity, and membrane morphology (Munn et al., 1974, Fawcett et al., 1966). There might be changes in the â€Å"energization† state of the mitochondrial membrane integral to energy production (Green et al., 1973). Structural diversity and dynamics of mitochondria were studied with the help of light and electron microscopy and their relationship with other cellular components. This technique gives idea about changes in shape and structure of mitochondria dur ing biological processes. Electron tomography shows remodeling of the inner membrane in the case of apoptosis and cytochrome c release (Scorrano et al., 2002) and mitochondrial fragmentation (Sun et al., 2007). Cell controls the mitochondrial structure, its function and response against various stimuli (Mannella et al., 2006) 1.1 Structure: A mitochondrion has double layer structure composed of phospholipids and proteins (Munn et al., 2007). These two double membranes have five compartments like the outer membrane, the intermembrane space ( between the outer and inner membranes), the inner membrane, the cristae formed by unfolding of the inner mitochondrial membrane, and the matrix (space in the inner mitochondrial membrane). 1.2 Inner Mitochondrial membrane: The inner membrane contains invaginations called cristae. The cristae are not random folds but these are small regions that open through narrow tubular channels into the peripheral region of the membrane (Fig. 2) (Mannella et al., 2001). Topographic analysis of intact, frozen-hydrated, rat liver mitochondria(Mannella et al., 2001) describes the inner diameter of the tubular â€Å"cristae junctions† is 10-15 nm (Fig. 2).This is enough to pass metabolites and many soluble proteins and the inner membrane restrict internal diffusion rates. For example, computer simulations indicate that the steady-state level of ADP inside cristae with long small junctions can drop below the Km for the adenine nucleotide translocator, leading to a local drop in ATP generation. Like that truncated (t)-Bid-induced remodeling in the inner mitochondrial membrane of isolated mouse liver mitochondria (Fig. 2) causes mobilization of a large fraction of the internal pool of cytochrome c lead to increased rates of reduction by the NADH cytochrome b5 redox system on the outer membrane of the organelle(Scorrano et al.,2002).The inner-membrane remodeling involves fivefold widening of the cristae and diffusion of cytochrome c between intracris tal and peripheral (intermembrane) compartments. These shows that the topology of the mitochondrial inner membrane can have effect on mitochondrial functions by influencing the kinetics of diffusion of metabolites and soluble proteins between the internal compartments defined by this membrane (Mannella et al., 1997). 1.3 Mitochondrial Inner-membrane Dynamics: Isolated mitochondria has two morphologic states, condensed and orthodox.Condence state is characterized by a contracted, very dense, matrix compartment and wide cristae while orthodox having an expanded, less-dense matrix and more compact cristae(Hackenbrock et al.,1966 ). Changes between these two morphological states has been detected in real time by light scattering or simply by adjusting the osmotic pressure of the external medium, causing water to flow into or out of the matrix. A reversible condensed-to-orthodox transition also occurs during respiration when ADP is in excess amount and fully phosphorylated form (Hackenbrock et al., 1966). Electron micrograph shows changes in inner mitochondrial membrane as passive unfolding and refolding of the inner membrane. 3D images of rat liver mitochondria obtain by electron tomography indicate that condensed rat liver mitochondria have large pleiomorphic cristae and multiple junctions to each other and to the peripheral region of the inner membrane, that is the region opposed to the outer membrane and the Orthodox rat liver mitochondria have cristae either tubular or flattened lamellae, both types usually having only one junction to the periphery of the inner membrane. For this to occur the inner mitochondrial membranes must undergo fusion and fission, with tubular forms merging into the larger cisternae during matrix condensation. Large lamellar compartment are formed via cristae fusion is strongly suggested by their appearance in tomograms of frozen-hydrated mitochondria (Fig. 2).so that the structural variations that mitochondria undergo in response to osmotic and metabolic changes involve not only the contraction and dilation of the matrix and intracristal space but also by remodeling of the inner mitochondrial membrane. A review of mitochondrial morphologies associated with a variety of osmotic, metabolic, and disease states suggests that inner-membrane topology represents a balance between fusion and fission, with defects (such as crista vesiculation) corresponding to an imbalance in this process (Mannella et al.,2006). 1.4 Inner mitochondrial membrane proteins: Mitochondrial proteins responsible for maintenance of normal cristae morphology and dynamics are also responsible for mediate inter mitochondrial fusion and organelle division since these processes involve fusion and fission of the inner as well as the outer membranes. For example, the dynamin-like GTPase called Mgm1p in yeast and OPA1 in mammalian cells is required for the fusion of mitochondria. Mutations in this protein cause a progressive, autosomal, dominant retinopathy, dominant optic atrophy (Alexander et al.,2000, Delettre et al.,2002) giving the physiological importance of mitochondrial dynamics. Another protein that directly influences inner-membrane topology is F1F0 ATP synthase. Mutations in subunits e or g of the F0 domain cause lateral dimerization and subsequent oligomerization of these inner membrane complexes and are associated with wrapped cristae lacking tubular junctions (Paumard et al., 2002). This also occurs with the down regulation of the protein mitofilin tha t regulate interactions of the ATP synthase (John et al., 2005). In ATP synthase dimers, close packing of the bulky extra membrane F1 domains causes the smaller, intramembrane F0 domains , which could induce local bending of the inner membrane.Mgm1/OPA1 has a chaperone-like function for subunit e of the ATP synthase. The loss of the function of Mgm1/OPA1 mutants inhibits ATP synthase dimer formation, which lead to the deficiency of normal tubular crista junctions in these mitochondria. 2 Mitochondrial kinases: Activated protein kinases can localize to specific cytoplasm sub compartments and mediates many important processes like cell motility (Glading et al., 2001), and signaling endosomes may facilitate communication between neurons(Howe CL et al.,2004). Like hormone- or growth factor-induce signaling cascades, recent advances in redox signaling pathways have very complex function. The mitochondrion is a point of integration for these redox signaling cascades due to its role in cellular metabolism, redox biochemistry, and survival-death decisions. Recent studies have demonstrated that certain components of protein kinase signaling cascades are specifically targeted to mitochondria, where they modulate mitochondrial activity and the release of mitochondrial products that ultimately affect the entire cell. 3 List of Mitochondrial kinases: PI3K/Akt/Protein Kinase B(PKB) Protein kinase C(PKC) Raf-MEK-ERK JNK/SAPK and p38 MAPK Apoptosis signal-regulating kinase 1 (ASK1) Glycogen synthase kinase 3ÃŽ ² (GSK-3ÃŽ ²) Protein kinase A (PKA) PTEN-induced kinase 1 (PINK1) (1) PI3K/Akt/Protein Kinase B(PKB) The protein kinase B (serine/threonine kinase Akt) has a major role in cell proliferation and survival in many cells of the body. Akt is activated by phosphoinositide-dependent kinases to the plasma membrane by products of the type I phosphoinositide 3- kinase (Vanhaesebroeck et al., 2000). Antiapoptotic effects of nitric oxide may be partially mediated by cGMPdependent activation of phosphoinositide 3-kinase and Akt (Ha KS et al., 2003). Inspite of direct effects of Akt in phospho-inactivating the proapoptotic protein BAD (Datta et al., 1997), Akt also activate Raf-1 in the mitochondria (Majewski et al., 1999) and cause expression of proteins involved in the mitochondrial permeability transition pore(Nebigil et al.,2003). Akt can also having role in cell survival through regulation of forkhead transcription factors (Linseman et al., 2005). In Neuroblastoma and human embryonic kidney cells, insulin-like growth factor 1 Cause rapid translocation of phospho-Akt into mitochondrial subcellular fractions (Bijur et al., 2003). This effect may be cell type specific, as Akt was not observed in mitochondria of mesangial cells stimulated by insulin-like growth factor 1(Kang et al.,2003). Activated mitochondrial Akt can also phosphorylate ÃŽ ² subunit of ATP synthase and of glycogen synthase kinase 3ÃŽ ² (GSK3ÃŽ ²) (Bijur et al., 2003). GSK3ÃŽ ² has been localized by immunoelectron microscopy to the mitochondria, where it functions to phosphorylate and inhibit mitochondrial pyruvate dehydrogenase activity (Hoshi M et al., 1996) and to promote apoptosis (Hetman et al., 2000). Akt can localize within the mitochondria rather than on its surface most commonly in the mitochondrial membrane fractions and to a lesser degree in the matrix (Bijur et al., 2003). It has pro survival role in mitochondrial membrane permeation. The antioxidant selenite has neuroprotective effects and increases AKT activation by PI3K (Wang et al., 2007). Inhibition of PI3K enhance RGCs survival upon axotomy, in a fashion that depended on the presence of local macrophages PI3K inhibition suppressed the neuroprotective effects of sodium Orthovanadate (Wu et al., 2006). (2) Protein kinase C (PKC) The protein kinase C (PKC) family consists of multiple isozymes with distinct distribution patterns in different tissues of the body (Dempsey et al., 2000). Extracellular ligand binds to a receptor tyrosine kinase or G protein-coupled receptor activates phospholipase C and produces inositol triphosphate (IP3) and diacylglycerol (DAG). Calcium released by IP3 causes PKC to bind to membranes, where DAG then activates PKC. Activated PKC phosphorylates many cellular targets, including c-Fos and NF-ÃŽ ºB. The isozymes of PKC differ not only in their localization but also in their responsiveness to IP3, DAG, and calcium. There are three subgroups of PKC isoforms, conventional, novel, and atypical, classified on the basis of their responsiveness to these regulators (Parker et al., 2004). The ÃŽ ± and ÃŽ ² isoforms of PKC were found in a subset of mitochondria in carp retinal Mà ¼ller cells (Fernandez et al., 1995) Immunoelectron microscopy studies showed that the kinase was associated with the inner membrane and cristae. Researchers described that PKC isoforms play a direct role in regulating mitochondrial function. Activated PKC isoforms that translocate to the mitochondria are proapoptotic or inhibitory to mitochondrial function. For example, renal proximal tubular cells respond to oxidative stress by activated PKCÃŽ µ to the mitochondria and inhibit the electron transport chain, ATP production, and Na+ transport by direct phosphorylation of Na+-K+-ATPase (Nowak et al., 2004). Treatment of various neoplastic cells with phorbol esters, H2O2, or anticancer agents such as cisplatin and etoposide causes accumulation of PKCÃŽ ´ to the mitochondria, with subsequent releases cytochrome c and induction of apoptosis (Majumder et al., 2000). In rat cardiac myocytes PKCÃŽ ´ was shown to move to the mitochondria in response to anesthetic exposure or ischemia/reperfusion. PKCÃŽ ´ then activate mitochondrial KATP channels, which then promote cardio protection (Uecker et al., 2003). PKCÃŽ µ also promotes cardioprotection following ischemia/reperfusion through a different mechanism, phosphorylating the voltage dependent anion channel (VDAC) component of the mitochondrial permeability transition pore (Baines et al., 2003). This prevents mitochondrial swelling, outer membrane rupture, release of apoptogenic factors, and decreases in ATP production. PKCÃŽ µ and extracellular signal-regulated kinases (ERKs) interact at the mitochondria to inactivate the proapoptotic protein BAD in cardiac myocytes (Baines et al., 2002). Inactivation of the proapoptotic protein Bax by PKCÃŽ µ in prostate cancer cells renders these cells resistant to androgen-deprivation therapy (McJilton et al., 2003). PKC isoforms translocate from one cell compart ment to another, these responses to PKC signaling may be mediated by association with specific anchoring scaffold proteins, RACKs (receptors for activated C kinase) and RICKs (receptors for inactive C kinase) (Mochly-Rosen et al., 1998). (3) ERK-Raf-MEK The extracellular signal regulated protein kinases (ERK1/2) has a role in regulating the processes like proliferation, differentiation, adaptation (i.e., cell motility, long term potentiating), survival, and even cell death. ERK has been found in the mitochondria of neurons and non-neuronal cells such as in mouse heart, renal epithelial cells, outer membrane and the intermembrane space of rat brain mitochondria, mouse hippocampus, B65 cells, SH-SY5Y cells; Leydig cells and human alveolar macrophages (Ruben K et al., 2009).The three-tiered ERK signaling involves sequential activation of Raf (MAPKKK), MEK1/2 (MAPKK), and ERK1/2 (MAPK). Depending on its intracellular localization and pathway of activation, Raf-1 can affect apoptosis by different mechanisms (Majewski et al.,1999, Alavi et al., 2003).ERK signaling can have opposite responses to injury even within the same cell type (Chu et al., 2004, Hetman et al., 2004). It has Pro-apoptotic role in mitochondrial membrane permeation. Pha rmacological inhibition of ERKs resulted in a reduction of cortical lesion volumes one week after trauma (Mori et al., 2002). Intravenous administration of a specific inhibitor of MEKs after ischemia results in decrease of infarct volume (Namura et al., 2001). The antiapoptotic protein Bcl-2 plays an important role in targeting Raf-1 to the mitochondria, resulting in phosphorylation of proapoptotic BAD, provides evidence for signaling roles for plasma membrane-targeted versus mitochondrially targeted Raf proteins (Wang et al., 1996). Signaling cascade consisting of Raf-1, MEK1, and the adapter protein Grb10 have been localized to mitochondrial membranes (Nantel et al., 1999). The antiapoptotic effects of mitochondrially localized Raf-1 are independent of ERK activity in myeloid cells (Majewski et al., 1999), and MEK/ERK signaling does mediate antiapoptotic effects of B-Raf in fibroblasts (Erhardt et al., 1999). Phosphorylation of S338 and S339 on Raf-1 promotes mitochondrial translocation and protection of endothelial cells from the intrinsic pathway of apoptosis, whereas Src cause phosphorylation of Y340 and Y341 and MEK/ERK activity are important for protection from death receptor-initiated cell death (Alavi et al., 2003). ERK can modulate mitochondrial functions and inhibition of MEK, those associated with cell death. For example, ERK signaling promotes mitochondrial ATP synthase function in glucose-deprived astrocytes (Yung et al., 2004), to maintain mitochondrial membrane potential and prevent cytochrome c release (Lee et al., 2004), and to inactivate the proapoptotic protein BAD (Jin et al., 2002). ERK has also role in promoting oxidative neuronal injuries (Chu et al., 2004) and in neurodegenerative diseases (Tobiume et al.,2002, Kulich et al.,2001) MEK/ERK promotes organophosphate induce mitochondrial vacuolation(Isobe et al., 2003), apoptotic translocation of Bax to the mitochondria(Isobe et al., 2003), and nonapoptotic programmed cell death(Sperandio et al., 2004). As pro- and antiapoptotic effects of MEK/ ERK signaling could be mediated by downstream targets or at the transcriptional level (Bonni et al., 1999), these studies do not necessarily indicate mitochondrial targeting of ERK. Mitochondrial targeting of ERK signaling was first derived from biochemical subcellular fractionation studies. In renal tubular cells, both activated ERK1/2 and PKCÃŽ ± are enriched in mitochondrial fractions during cisplatin injury, where they increase mitochondrial membrane potential, decrease oxidative phosphorylation, and increase caspase-3 activation and apoptosis (Nowak et al., 2002).ERK activity in phosphorylating both Bcl-2(Deng et al., 2000) and BAD (Kang et al., 2003) are associated with increased levels of activated ERK colocalizing or co-immunoprecipitating with the Bcl-2 family members in mitochondria. Immuno-electron microscopy studies shows presence of phosphorylated ERK1/2 within the mitochondrion (Zhu et al., 2003, Alonso et al., 2004). Phospho-ERK was found at high labeling densities within a subset of mitochondria in degenerating neurons from patients of Parkinsons disease and Lewy body dementia (Chu et al., 2003) and distinct granular cytoplasmic pattern of staining are not observed in control patients(Zhu et al., 2002). (4) JNK/SAPK and p38 MAPK The p38 MAPKs and the JNK (c-Jun N-terminal kinase) / SAPK (stress-activated protein kinase) are of MAPK family membranes and involved in prodeath signaling (Matsuzawa et al., 2001). The p38 and JNK are activated by a MAP kinase (MKK), which is activated by a MAPKKK in response to a stimulus like oxidative stress, irradiation, or proinflammatory cytokines such as tumor necrosis factor ÃŽ ±. Role of p38 MAPK signaling in cell death includes translocation of proapoptotic Bax from cytosolic to mitochondrial compartments (Park et al., 2003 Shou et al., 2003), caspase-independent potassium efflux (Bossy-Wetzel et al., 2004), and transcriptional regulation of TR3, a steroid receptor-like protein that translocates from the nucleus to the mitochondria to initiate the intrinsic apoptotic pathway (Bossy-Wetzel et al., 2004). Irradiation causes translocation of both p38 and JNK1 to mitochondrial subcellular fractions (Epperly et al., 2002). The effects of JNK on the mitochondria involve stimulation of apoptosis. Treatment of isolated rat brain mitochondria with active JNK causes the inhibition of antiapoptotic Bcl-2 and Bcl-xL and release of cytochrome c (Schroeder et al., 2003). The mitochondrial JNK is activated by oxidative stress in cardiac myocytes, and cause the release of cytochrome c lead to apoptosis (Aoki et al., 2002). Treatment with phorbol esters cause localization of JNK to the mitochondria in human U-937 leukemia cells, where it binds to and inhibits Bcl-xL, promoting apoptosis (Kharbanda et al., 2000, Ito et al., 2001). Mitochondrial JNK can also cause the release of Smac, the activator of caspase that promotes caspase-9 activity (Chauhan et al., 2003). JNK also phosphorylates and oligomerize proapoptotic BAD (Bhakar et al., 2003). JNK signaling can yield cell survival under some conditions. JNK can inactivate the pro-apoptotic protein BAD (Yu C et al., 2004). Activated JNK phosphorylates Bcl-2 at Ser70 in the mitochondrial membranes of interleukin-3-dependent hematopoietic cells. This occurs under conditions of stress or by exposure to interleukin-3, resulting in enhanced antiapoptotic activity of Bcl-2(Deng et al., 2001). It has Pro-apoptotic role in mitochondrial membrane permeation. JNK3 (but not JNK1 nor JNK2) absence conferred significant neuroprotection to axotomized neurons. The absence of JNK3 (but not of JNK1 nor of JNK2) resulted in a substantial resistance against kainate-induced seizures, which correlated with improved survival (Brecht et al., 2005). Pharmacological JNK inhibitors diminished several manifestations of apoptosis and reduced infarct volume (Gao et al., 2005). Intravitreal administration of a p38MAPK inhibi tor induced apoptosis (Kikuchi et al., 2000). Oral administration of a p38MAPK inhibitor during pre- and post-ischemia provided dose-dependent neuroprotective effects (Legos et al., 2001). Pharmacological inhibition of p38MAPK protects neurons from NO-mediated degeneration (Xu et al., 2006). (5) Apoptosis signal-regulating kinase 1 (ASK1) All living systems are exposed to numerous physicochemical stressors, and appropriate responses to these stresses at the cellular level are essential for the maintenance of homeostasis. The mitogen-activated protein Kinase (MAPK) cascades are having major signaling pathways in regulation of these cellular stress responses (Kazuki et al., 2009). The MAPK pathway consists of a cascade of three protein kinases. These protein kinases are sequentially activated, such as the MAPK kinase kinase (MAPKKK) phosphorylates and activates the MAPK kinase (MAPKK), which then phosphorylates and activates the MAPK. MAPKs have a wide variety of cellular functions, including proliferation, differentiation, migration and apoptosis. ASK1 identified as a member of the MAPKKK family and activate the MAPKK 4 (MKK4) JNK and MKK3/6-p38 pathways but not the MAP/ERK kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway (Ichijo et al., 1997). Tumor necrosis factor-ÃŽ ± receptor-associated factors (TRAFs) having important role in the regulation of ASK1 activity. In TRAF family proteins, TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 are associate with ASK1, but only TRAF2, TRAF5 and TRAF6 increase ASK1 kinase activity (Nishitoh et al., 1998). TNF-ÃŽ ± treatment induces JNK activation in a TRAF2- dependent manner (Yeh et al., 1997, Tobiume et al., 2001). Phosphorylation of Thr845 in mouse ASK1 have role in activation of ASK1 (Tobiume et al., 2002). Endoplasmic reticulum (ER) stress activates ASK1 and involved in variety of neurodegenerative diseases (Lindholm et al., 2006). It has Pro-apoptotic role in mitochondrial membrane permeation. Decreased activation of ASK1/JNK by the antioxidant selenite correlated with neuroprotective effects (Wang et al., 2007). (6) Glycogen synthase kinase 3ÃŽ ² (GSK-3ÃŽ ²) Glycogen synthase kinase-3ÃŽ ² (GSK-3ÃŽ ²) is a constitutively active 47-kDa Ser/Thr protein kinase. It has about 40 substrates and having functions like cell proliferation, growth and death. GSK-3ß has a significant role in the regulation of apoptosis. Apoptotic injury is increased by the over-expression of GSK-3ß lead to cellular injury. During oxidative stress, GSK-3ß can lead to the activation of caspase 3 and cytochrome c release ultimately lead to apoptosis. Mechanism of GSK-3ÃŽ ² is phosphorylation at Ser and Tyr residues, complex formation with scaffold proteins, priming of substrates and intracellular translocation. GSK-3ÃŽ ² has been involved in serious diseases such as Alzheimers disease, bipolar mood disorder, cancer and ischemia/reperfusion injury (Tetsuji et al., 2009). It has Pro-apoptotic role in mitochondrial membrane permeation. Clinical dose of lithium inhibits GSK-3ÃŽ ² resulted in significant axon sprouting and functional recovery (Dill et al., 2008). (7) Protein kinase A (PKA) The protein kinase A (PKA) signaling pathway involves responses to hormonal stimulation which are often cell type specific.The PKA pathway involves the binding of an extracellular molecule to a G protein-coupled receptor, which catalyzes the formation of intracellular cyclic AMP through the activation of adenylate cyclase.Cyclic AMP then binds to the two regulatory subunits of PKA, thereby releasing the two catalytic subunits to phosphorylate serine and threonine residues on target proteins. These subunits enter the nucleus and phosphorylate transcription factors such as CREB and NF-ÃŽ ºB. PKA signaling in specific subcellular compartments has been recognized with the discovery of specific anchoring scaffold proteins. PKA activity has been identified within the mitochondria in a wide variety of species, including human (Kleitke et al., 1976). Mitochondrial targeted PKA activities have positive effects on the mitochondria. PKA localized to the inner membrane and matrix of mitochondria phosphorylates and promotes the activity of complex I (NADH dehydrogenase) (Technikova-Dobrova et al., 2001). AKAP (A-kinase anchoring proteins)-mediate the activation of PKA to the cytoplasmic surface of mitochondria results in phospho-inhibition of the proapoptotic protein BAD, enhancing cell survival (Harada et al., 1999, Affaitati et al., 2003). A peripheral benzodiazepine receptor-associated protein functions as an AKAP that promotes mitochondrial steroid genesis (Liu et al., 2003). AKAP-121 can also function as targeting of Mn-superoxide dismutase mRNA to the mitochondria for localized translation of this important antioxidant (Ginsberg et al., 2003).The small G-protein Rab32, which regulates mitochondrial fission, appears to function as a mitochondrially targeted AKAP(Alto et al., 2002). Thus, mitochondrial targeting of PKA appears to be involved in regulating most major mitochondrial functions, promoting respiration, antagonizing cell death, and regulating mitochondrial protein expression and biogenesis. (8) PTEN-induced kinase 1 (PINK1) PINK1 is a serine/threonine kinase having similarity to calcium/calmodulin regulated kinases. The primary sequence for PINK1 includes a canonical N-terminal mitochondrial leader sequence (Ruben K et al., 2009). PINK1 has been found in the mitochondria human brain and it is cleaved by matrix proteases. Transmembrane domain of PINK1 is responsible for its insertion in to outer mitochondrial membrane. The C-terminal domain of PINK1 having role of its auto phosphorylation (Liu et al., 2008). Point mutations and truncations of PINK 1 have been mapped throughout the transmembrane, kinase and C-terminal domains lead to impaired kinase activity and promote degradation, or induce misfolding of PINK1. The TNF receptor associated protein 1 (TRAP1, or Hsp75) are substrate for PINK1, and the serine protease Omi/Htra2 and heat shock proteins, Hsp90/Cdc37 are PINK1 binding proteins. So degradation of PINK1 catalytic activity leads to disease like parkinsonian neurodegeneration (DeFeo et al., 1981). 4 Human Diseases associated with Mitochondrial Kinases Mitochondria are important because of the Respiratory chain which is the major sites of energy production in all cells (Taylor et al., 2005). Mitochondria perform many functions in different tissues and cells so there are so many different mitochondrial diseases associated with different tissues of the body. Each disease produces abnormalities that are difficult to diagnose. There are complex relationship between the genes and cells that are responsible for maintaining our metabolic processes running smoothly; it is a basis of mitochondrial diseases. Mitochondrial diseases is due to degeneration of the mitochondria in specialized compartments present in every cell of the body except RBC (red blood cells).When mitochondria fail to generate energy, less energy is generated in the cell so cell injury and even cell death can occur. If this is repeated throughout the whole body, whole systems begin to fail, and the life of the person is severely compromised. The disease affects more in ch ildren as compared to adult but onset is becoming more and more common. Mitochondria diseases causes damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems. Kinases that are associated with mitochondria during neuronal injury include mitogen activated protein kinases (MAPK) such as extracellular signal regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK), protein kinase B/Akt, and PTEN-induced kinase 1 (PINK1). Their sites of action within mitochondria and specific kinase targets are still unclear but these signaling pathways regulate mitochondrial respiration, transport, fission-fusion, calcium buffering, reactive oxygen species (ROS) production, mitochondrial autophagy and apoptotic cell death( Kachergus et al., 2005). 5 List of mitochondrial kinases associated human diseases: A) Neurodegenerative diseases: Parkinsons disease Alzheimers disease B) Cancer 1 Parkinsons disease (PD) Parkinsons disease is a debilitating, movement disorder that affects around 1 million people in North America. Symptoms: Motor symptoms can be due to degeneration of endogenously pigmented midbrain neurons of the nigrostriatal projection. Olfactory, autonomic and cognitive dysfunction. Most of the cases have no known cause; oxidative stress, disordered protein handling/degradation, and mitochondrial dysfunction are mechanistically observed factors in sporadic PD due to toxin/pesticide exposures, and in models of familial PD (Ruben et al., 2009). Factors like Disturbances in mitochondrial function, transport, dynamics and turnover have central role in neurotoxin, environmental and genetic approaches to Parkinsons disease (Ruben et al., 2009). In addition to changes in mitochondrial fission/fusion machinery and trafficking, autophagic degradation process has a critical role in regulating mitochondrial quality and content (Kiselyov et al., 2007). Macroautophagy has a role in membranous engulfment of cytoplasmic cargo bodies for lysosomal degradation, and this the major degradative pathway for organelles and insoluble proteins. There is deregulation of macroautophagy and of chaperone-mediated autophagy observed in toxin and genetic models of PD (Ruben et al., 2009). Gene multiplication and ÃŽ ±-synuclein mutations are autosomal dominant of PD in model of parkinsonian neurodegeneration (Polymeropoulos et al., 1997). Aggregation of ÃŽ ±-Synuclein, Lewy bodie formation and mutation in leucine rich repeat kinase 2 (LRRK2) are found in the sporadic and dominant forms of PD (Kachergus et al., 2005). Parkin, ATP13A2, DJ1 and PTEN induced kinase 1(PINK 1) are involved in autosomal recessive Parkinsonism disease. PINK1 and Parkin regulates mitochondrial morphology and turnover (Ruben et al., 2009). In human PD brain and diffuse Lewy body diseases, Phospho-ERK (p-ERK) in the cytoplasm and mitochondria of midbr