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Highlight for Query ‹Coronaviridae infectious disease risk›
Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?
The central nervous system (CNS), a marvel of intricate cellular and molecular interactions, maintains life and orchestrates homeostasis. Unfortunately, the CNS is not immune to alterations that lead to neurological disease, some resulting from acute, persistent or latent viral infections. Several viruses have the ability to invade the CNS, where they can infect resident cells, including the neurons. Although rare, viral infections of the CNS do occur. However, their incidence in clinical practice is difficult to evaluate precisely. For instance, in cases of viral encephalitis involving the most prevalent viruses known to reach the CNS (mainly herpesviruses, arboviruses and enteroviruses), an actual viral presence can only be detected in 3 to 30 cases out of 100,000 persons. Considering all types of viral infections, between 6000 and 20,000 cases of encephalitis that require hospitalization occur every year in the United States, representing about 6 cases per 100,000 infected persons every year. As the estimated charge for each case lies between $58,000 and $89,600, an evaluation of the total annual health cost is of half a billion dollars. Due to the cost associated with patient care and treatment, CNS viral infections cause considerably more morbidity and disabilities in low-income/resource-poor countries.
Very common worldwide, viral infections of the respiratory tract represent a major problem for human and animal health, imposing a tremendous economic burden. These respiratory infections induce the most common illnesses and are a leading cause of morbidity and mortality in humans worldwide, causing critical problems in public health, especially in children, the elderly and immune-compromised individuals. Viruses represent the most prevalent pathogens present in the respiratory tract. Indeed, it is estimated that about 200 different viruses (including influenza viruses, coronaviruses, rhinoviruses, adenoviruses, metapneumoviruses, such as human metapneumovirus A1, as well as orthopneumoviruses, such as the human respiratory syncytial virus) can infect the human airway. Infants and children, as well as the elderly represent more vulnerable populations, in which viruses cause 95% and 40% of all respiratory diseases, respectively. Among the various respiratory viruses, some are constantly circulating every year in the human populations worldwide, where they can be associated with a plethora of symptoms, from common colds to more severe problems requiring hospitalization. Moreover, in addition to the many "regular" viruses that circulate and infect millions of people every year, new respiratory viral agents emerge from time to time, causing viral epidemics or pandemics associated with more serious symptoms, such as neurologic disorders. These peculiar events usually take place when RNA viruses like influenza A, human coronaviruses, such as MERS-CoV and SARS-CoV, or henipaviruses, present in an animal reservoir, cross the species barrier as an opportunistic strategy to adapt to new environments and/or new hosts. These zoonoses may have disastrous consequences in humans, and the burden is even higher if they have neurological consequences.
2. Viruses as Plausible Etiologic Agents in Neurological Disorders
Epithelial cells that line the respiratory tract are the first cells that can be infected by respiratory viruses. Most of these infections are self-limited and the virus is cleared by immunity with minimal clinical consequences. On the other hand, in more vulnerable individuals, viruses can also reach the lower respiratory tract where they cause more severe illnesses, such as bronchitis, pneumonia, exacerbations of asthma, chronic obstructive pulmonary disease (COPD) and different types of severe respiratory distress syndromes. Besides all these respiratory issues, accumulating evidence from the clinical/medical world strongly suggest that, being opportunistic pathogens, these viruses are able to escape the immune response and cause more severe respiratory diseases or even spread to extra-respiratory organs, including the central nervous system where they could infect resident cells and potentially induce other types of pathologies.
Like all types of viral agents, respiratory viruses may enter the CNS through the hematogenous or neuronal retrograde route. In the first, the CNS is being invaded by a viral agent which utilizes the bloodstream and in the latter, a given virus infects neurons in the periphery and uses the axonal transport machinery to gain access to the CNS. In the hematogenous route, a virus will either infect endothelial cells of the blood-brain-barrier (BBB) or epithelial cells of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus (CP) located in the ventricles of the brain, or leukocytes that will serve as a vector for dissemination towards the CNS. Viruses such as HIV, HSV, HCMV, enteroviruses such as coxsackievirus B3, flaviviruses, chikungunya virus (CHIKV) and echovirus 30 have all been shown to disseminate towards the CNS through the hematogenous route. Respiratory viruses such as RSV, henipaviruses, influenza A and B and enterovirus D68 are also sometimes found in the blood and, being neuroinvasive, they may therefore use the hematogenous route to reach the CNS. As they invade the human host through the airway, the same respiratory viruses may use the olfactory nerve to get access to the brain through the olfactory bulb. On the other hand, these viruses may also use other peripheral nerves like the trigeminal nerve, which possesses nociceptive neuronal cells present in the nasal cavity, or alternatively, the sensory fibers of the vagus nerve, which stems from the brainstem and innervates different organs of the respiratory tract, including the larynx, the trachea and the lungs.
Although the CNS seems difficult for viruses to penetrate, those pathogens that are able to do so may disseminate and replicate very actively and will possibly induce an overreacting innate immune response, which may be devastating. This situation may lead to severe meningitis and encephalitis that can be fatal, depending on several viral and host factors (including immunosuppression due to disease or medications) that may influence the severity of the disease.
Recently, a very interesting manuscript produced by Bookstaver and collaborators underlined the difficulties of precisely deciphering the epidemiology and identifying the causal agent of CNS infections. These difficulties are mainly due to the tremendous variation in the symptoms throughout the disease process and to the myriad of viruses that can cause CNS infections. As stated in their report, these authors underlined that the clinical portrait of viral infections is often nonspecific and requires the clinician to consider a range of differential diagnoses. Meningitis (infection/inflammation in meninges and the spinal cord) produces characteristic symptoms: fever, neck stiffness, photophobia and/or phonophobia. Encephalitis (infection/inflammation in the brain and surrounding tissues) may remain undiagnosed since the symptoms may be mild or non-existent. Symptoms may include altered brain function (altered mental status, personality change, abnormal behavior or speech), movement disorders and focal neurologic signs, such as hemiparesis, flaccid paralysis or paresthesia. Seizures can occur during both viral meningitis and encephalitis. Furthermore, viral encephalitis may also be difficult to distinguish from a non-viral encephalopathy or from an encephalopathy associated with a systemic viral infection occurring outside the CNS. Considering all these observations, it is therefore mandatory to insist on the importance of investigating the patient's history before trying to identify a specific viral cause of a given neurological disorder.
In humans, a long list of viruses may invade the CNS, where they can infect the different resident cells (neuronal as well as glial cells) and possibly induce or contribute to neurological diseases, such as acute encephalitis, which can be from benign to fatal, depending on virus tropism, pathogenicity as well as other viral and patient characteristics. For instance, 30 years ago, the incidence of children encephalitis was as high as 16/100,000 in the second year of life, while progressively reducing to 1/100,000 by the age of 15. More recent data indicate that, in the USA, the herpes simplex virus (HSV) accounts for 50–75% of identified viral encephalitis cases, whereas the varicella zoster virus (VZV), enteroviruses and arboviruses are responsible for the majority of the other cases in the general population. Several other viruses can induce short-term neurological problems. For example, the rabies virus, herpes simplex and other herpes viruses (HHV), arthropod-borne flaviviruses such as the West Nile virus (WNV), Japanese encephalitis virus (JEV), chikungunya virus (CHIKV), Zika virus (ZIKV), alphaviruses such as the Venezuelan, Western and Eastern equine encephalitis viruses and enteroviruses affect millions of individuals worldwide and are sometimes associated with encephalitis, meningitis and other neurological disorders. The presence of viruses in the CNS may also result in long-term neurological diseases and/or sequelae. Human immunodeficiency virus (HIV) induces neurodegeneration, which lead to motor dysfunctions and cognitive impairments. Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease associated with reactivation of latent polyoma JC virus (JCV). Progressive tropical spastic paraparesis/HTLV-1-associated myelopathy (PTSP/HAM) is caused by human T-lymphotropic virus (HTLV-1) in 1–2% of infected individuals. Measles virus (MV), a highly contagious common virus, is associated with febrile illness, fever, cough and congestion, as well as a characteristic rash and Koplik's spots. In rare circumstances, significant long-term CNS diseases, such as post-infectious encephalomyelitis (PIE) or acute disseminated encephalomyelitis (ADEM), occur in children and adolescents. Other examples of rare but devastating neurological disorders are measles inclusion body encephalitis (MIBE), mostly observed in immune-compromised patients, and subacute sclerosing panencephalitis (SSPE) that appears 6–10 years after infection.
Yet, with the exception of HIV, no specific virus has been constantly associated with specific human neurodegenerative disease. On the other hand, different human herpes viruses have been associated with Alzheimer's disease (AD), multiple sclerosis (MS) and other types of long-term CNS disorders. As accurately stated by Majde, long-term neurodegenerative disorders may represent a "hit-and-run" type of pathology, since some symptoms are triggered by innate immunity associated with glial cell activation. Different forms of long-term sequelae (cognitive deficits and behavior changes, decreased memory/learning, hearing loss, neuromuscular outcomes/muscular weakness) were also observed following arboviral infections.
Including the few examples listed above, more than one hundred infectious agents (much of them being viruses) have been described as potentially encephalitogenic and an increasing number of positive viral identifications are now made with the help of modern molecular diagnostic methods. However, even after almost two decades into the 21st century and despite tremendous advances in clinical microbiology, the precise cause of CNS viral infections often remains unknown. Indeed, even though very important technical improvements were made in the capacity to detect the etiological agent, identification is still not possible in at least half of the cases. Among all the reported cases of encephalitis and other encephalopathies and even neurodegenerative processes, respiratory viruses could represent an underestimated part of etiological agents.
3. Respiratory Viruses with Neuroinvasive and Neurotropic Properties: Possible Associated Neuropathologies
Respiratory syncytial virus (RSV), a member of the Orthopneumovirus genus, infects approximately 70% of infants before the age of 1 and almost 100% by the age of 2 years old, making it the most common pathogen to cause lower respiratory tract infection such as bronchiolitis and pneumonia in infants worldwide. Recent evidence also indicates that severe respiratory diseases related to RSV are also frequent in immunocompromised adult patients and that the virus can also present neuroinvasive properties. Over the last five decades, a number of clinical cases have potentially associated the virus with CNS pathologies. RSV has been detected in the cerebrospinal fluid (CSF) of patients (mainly infants) and was associated with convulsions, febrile seizures and different types of encephalopathy, including clinical signs of ataxia and hormonal problems. Furthermore, RSV is now known to be able to infect sensory neurons in the lungs and to spread from the airways to the CNS in mice after intranasal inoculation, and to induce long-term sequelae such as behavioral and cognitive impairments.
An additional highly prevalent human respiratory pathogen with neuroinvasive and neurovirulent potential is the human metapneumovirus (hMPV). Discovered at the beginning of the 21st century in the Netherlands, it mainly causes respiratory diseases in newborns, infants and immunocompromised individuals. During the last two decades, sporadic cases of febrile seizures, encephalitis and encephalopathies (associated with epileptic symptoms) have been described. Viral material was detected within the CNS in some clinical cases of encephalitis/encephalopathy but, at present, no experimental data from any animal model exist that would help to understand the underlying mechanism associated with hMPV neuroinvasion and potential neurovirulence.
Hendra virus (HeV) and Nipah virus (NiV) are both highly pathogenic zoonotic members of the Henipavirus genus and represent important emerging viruses discovered in the late 1990s in Australia and southern Asia. They are the etiological agents of acute and severe respiratory disease in humans, including pneumonia, pulmonary edema and necrotizing alveolitis with hemorrhage. Although very similar at the genomic level, both viruses infect different intermediate animal reservoirs: the horse for HeV and the pig for NiV as a first step before crossing the barrier species towards humans. In humans, it can lead to different types of encephalitis, as several types of CNS resident cells (including neurons) can be infected. The neurological signs can include confusion, motor deficits, seizures, febrile encephalitic syndrome and a reduced level of consciousness. Even neuropsychiatric sequelae have been reported but it remains unclear whether a post-infectious encephalo-myelitis occurs following infection. The use of animal models showed that the main route of entry into the CNS is the olfactory nerve and that the Nipah virus may persist in different regions of the brain of grivets/green monkeys, reminiscent of relapsing and late-onset encephalitis observed in humans.
Influenza viruses are classified in four types: A, B, C and D. All are endemic viruses with types A and B being the most prevalent and causing the flu syndrome, characterized by chills, fever, headache, sore throat and muscle pain. They are responsible for seasonal epidemics that affect 3 to 5 million humans, among which 500,000 to 1 million cases are lethal each year. Associated with all major pandemics since the beginning of the 20th century, circulating influenza A presents the greatest threat to human health. Most influenza virus infections remain confined to the upper respiratory tract, although some can lead to severe cases and may result in pneumonia, acute respiratory distress syndrome (ARDS) and complications involving the CNS. Several studies have shown that influenza A can be associated with encephalitis, Reye's syndrome, febrile seizure, Guillain–Barré syndrome, acute necrotizing encephalopathy and possibly acute disseminated encephalomyelitis (ADEM). Animal models have shown that, using either the olfactory route or vagus nerve, influenza A virus may have access to the CNS and alter the hippocampus and the regulation of neurotransmission, while affecting cognition and behavior as long-term sequelae. The influenza A virus has also been associated with the risk of developing Parkinson's disease (PD) and has recently been shown to exacerbate experimental autoimmune encephalomyelitis (EAE), which is reminiscent of the observation that multiple sclerosis (MS) relapses have been associated with viral infections (including influenza A) of the upper respiratory tract.
Another source of concern when considering human respiratory pathogens associated with potential neuroinvasion and neurovirulence is the Enterovirus genus, which comprises hundreds of different serotypes, including polioviruses (PV), coxsackieviruses (CV), echoviruses, human rhinoviruses (HRV) and enteroviruses (EV). This genus constitutes one of the most common cause of respiratory infections (going from common cold to more severe illnesses) and some members (PV, EV-A71 and -D68, and to a lesser extent HRV) can invade and infect the CNS, with detrimental consequences. Even though extremely rare, HRV-induced meningitis and cerebellitis have been described. Although EV infections are mostly asymptomatic, outbreaks of EV-A71 and D68 have also been reported in different parts of the world during the last decade. EV-A71 is an etiological agent of the hand–foot–mouth disease (HFMD) and has occasionally been associated with upper respiratory tract infections. EV-D68 causes different types of upper and lower respiratory tract infections, including severe respiratory syndromes. Both serotypes have been associated with neurological disorders like acute flaccid paralysis (AFP), myelitis (AFM), meningitis and encephalitis.
Last but not least, human coronaviruses (HCoV) are another group of respiratory viruses that can naturally reach the CNS in humans and could potentially be associated with neurological symptoms. These ubiquitous human pathogens are molecularly related in structure and mode of replication with neuroinvasive animal coronaviruses like PHEV (porcine hemagglutinating encephalitis virus), FCoV (feline coronavirus) and the MHV (mouse hepatitis virus) strains of MuCoV, which can all reach the CNS and induce different types of neuropathologies. MHV represents the best described coronavirus involved in short- and long-term neurological disorders (a model for demyelinating MS-like diseases). Taken together, all these data bring us to consider a plausible involvement of HCoV in neurological diseases.
4.1.1. Possible Mechanisms of HCoV Neuroinvasiveness
In the human airways, HCoV infection may lead to the disruption of the nasal epithelium and, although they bud and are released mostly on the apical side of the epithelial cells, a significant amount of viruses is also released from the basolateral side. Thus, although HCoV infections are, most of the time, restricted to the airways, they may under poorly understood conditions pass through the epithelium barrier and reach the bloodstream or lymph and propagate towards other tissues, including the CNS; this was also suggested for other respiratory viruses that can reach the human CNS, namely, RSV, Nipah virus and influenza virus.
Different strains of HCoV, including SARS-CoV, can infect different myeloid cells to manipulate the innate immunity and to disseminate to other tissues, including the CNS, where they may be associated with other type of pathologies, especially in immunocompromised individuals as it was observed for murine cytomegalovirus (MCMV). Moreover, persistently-infected leukocytes may serve as a reservoir and vector for neuroinvasive HCoV. Therefore, neuroinvasive HCoV could use the hematogenous route to penetrate into the CNS.
The second form of any viral spread towards the CNS is through neuronal dissemination, where a given virus infects neurons in the periphery and uses the machinery of active transport within those cells in order to gain access to the CNS. Although the olfactory bulb is highly efficient at controlling neuroinvasion, several viruses have been shown to enter CNS through the olfactory route. After an intranasal infection, both HCoV-OC43 and SARS-CoV were shown to infect the respiratory tract in mice and to be neuroinvasive. Over the years, we and others have gathered data showing that HCoV-OC43 is naturally neuroinvasive in both mice and humans. Experimental intranasal infections of susceptible mice also indicate that, once it has invaded the CNS, the virus disseminated to several regions of the brain and the brainstem before it eventually reaches the spinal cord. Furthermore, based on more recent work, Figure 1 illustrates the olfactory route, which is clearly the main route of neuroinvasion used by HCoV-OC43, as well as the early steps of subsequent neuropropagation within the CNS in susceptible mice and recapitulates the suggested equivalent pathway in humans. Nevertheless, our data suggest that HCoV-OC43 may also invade the CNS from the external environment through other pathways involving other cranial peripheral nerves, reminiscent of what was shown for other human respiratory viruses such as RSV and influenza virus. Therefore, on the one hand, an apparently innocuous human respiratory pathogen such as the HCoV may reach the CNS by different routes and induce short-term illnesses, such as encephalitis. On the other hand, it may persist in resident cells of the human CNS and may become a factor or co-factor of neuropathogenesis associated with long-term neurological sequelae in genetically or otherwise predisposed individuals.
Potential Short-Term Neuropathologies
SARS-CoV, HCoV-OC43 and -229E are naturally neuroinvasive and neurotropic in humans and therefore potentially neurovirulent. Furthermore, animal models showed that SARS-CoV could invade the CNS primarily through the olfactory route or even after an intra-peritoneal infection, and induce neuronal cell death. To our knowledge, no reports on the presence of the three other coronaviruses that infect humans in the CNS have been published. However, neurological symptoms have been described in patients infected by all three viruses.
Making use of our in vivo model of HCoV neuropathogenesis, relying on the natural susceptibility of mice to HCoV-OC43—the most prevalent strain among endemic HCoV—encephalitis and transient flaccid paralysis associated with propagation towards the spinal cord and demyelination and long-term persistence in surviving mice were observed; thus, recapitulating the neurological afflictions reported in some patients infected by HCoV. Although we must interpret data obtained in rodents with all the caution dictated by the use of a non-human host, it is likely that the underlying mechanisms described will have relevance to the human situation or at least provide leads to investigate neurotropic HCoV in humans.
In susceptible mice, HCoV-OC43 has a selective tropism for neurons in which it is able to use axonal transport as a way of neuron-to-neuron propagation. These results, together with data harvested with the use of microfluidic devices (Xona microfluidic), helped to elaborate a putative model of propagation adapted from Tomishima and Enquist, in which infectious HCoV-OC43 could either be assembled in the cell body or at different points along the axon using the anterograde axonal transport to propagate between neurons or from neurons to glial cells surrounding neurons in the CNS (Figure 2). Furthermore, based on previous data using different mutant recombinant viruses harboring mutation in the S protein and making use of a luciferase expressing recombinant HCoV-OC43, we are now showing that the rate and success of virus propagation towards the spinal cord, in part through the neuron-to-neuron pathway, correlates with the exacerbation of neurovirulence (Figure 3).
HCoV-OC43 structural and accessory proteins are important for infection and some clearly represent virulence factors. Using neuronal cell cultures and our murine model, we gathered data indicating that some of these proteins also play a significant role in viral dissemination and now aim to exploit these promising leads to fully understand the course and determinants of propagation to and through the CNS and complete the neurologic portrait of short term HCoV neuropathogenesis.
Potential Long-Term Neuropathologies and Sequelae
The presence of HCoV RNA in the human CNS establishes the natural neuroinvasive properties of these respiratory viral agents. Moreover, it also suggests that they persist in human CNS as they do in human neural cells and in the CNS of mice that survive acute encephalitis. These surviving mice exhibited long-term sequelae associated with decreased activity in an open field test and a reduced hippocampus with neuronal loss in the CA1 and CA3 layers, reminiscent of what was observed after infection by the influenza A virus and RSV and to the significant loss of synapses within the CA3 region after infection by WNV.
The precise and complete etiology of several long-term neurological pathologies still represent a conundrum. Multiple sclerosis (MS) represents one such neurological disease for which an infectious agent or agents may play a triggering role, with viruses the most likely culprit in genetically predisposed individuals. It has been suggested that several neurotropic viruses could be involved in MS pathogenesis but that they may do so through similar direct and/or indirect mechanisms. However, although research has not yet led to a direct link to any specific virus, association of coronaviruses with MS has been suggested. Even though HCoV-OC43 and -229E were detected in some control brains and in some brains coming from patients with different neurological diseases, there was a significantly higher prevalence of HCoV-OC43 in brains of MS patients. Moreover, autoreactive T cells were able to recognize both viral and myelin antigens in MS patients but not in controls during infection by HCoV-OC43 and HCoV-229E. Thus, the immune response may participate in the induction or exacerbation of long-term neuropathologies such as MS in genetically or otherwise susceptible individuals. Furthermore, it was shown that in recombination activation gene (RAG) knock-out mice, HCoV-OC43-induced encephalitis could be partially mediated by the T-cell response to infection. This underlines the possibility that, like its murine counterpart MHV, long term infection of the CNS by HCoV may participate in the induction of demyelinating MS-like lesions.
4.1.3. Mechanisms of HCoV-Induced Neurodegeneration: Possible Associated Neuropathologies
Immune cell infiltration and cytokine production were observed in the mouse CNS after infection by HCoV-OC43. This immune response was significantly increased after infection by viral variants, which harbor mutations in the viral glycoprotein (S). These variants also induced glutamate excitotoxicity, thus increasing damage to neurons and/or disturbing glutamate homeostasis and thereby contributing to neuronal degeneration and hind-limb paralysis and possible demyelination. The degeneration of neurons may eventually lead to death of these essential cells by directly generating a cytotoxic insult related to viral replication and/or to the induction of different regulated cell death (RCD) pathways. Our results indicate that the underlying mechanisms appear to involve different cellular factors and pathways of RCD, described and reviewed elsewhere.
Virus–cell interactions are always important in the regulation of cell response to infection. For HCoV-OC43, we clearly showed that the viral S and E proteins are important factors of neurovirulence, neuropropagation and neurodegeneration of infected cells. We have also demonstrated that the HE protein is important for the production of infectious HCoV-OC43 and for efficient spreading between neuronal cells, suggesting an attenuation of the eventual spread into the CNS of viruses made deficient in fully active HE protein, potentially associated with a reduced neurovirulence. Coronavirus accessory proteins have been extensively studied and are now considered as important viral factors of virulence implicated in pathogenesis while counteracting innate immunity. Two of these accessory proteins (ns2 and ns5) produced during infection by HCoV-OC43 play a significant role in virulence and pathogenesis in the mouse CNS.
Like for several other respiratory viruses, accumulating evidence now indicate that HCoV are neuroinvasive in humans and we hypothesize that these recognized respiratory pathogens are potentially neurovirulent as well, as they could participate in short- and long-term neurological disorders either as a result of inadequate host immune responses and/or viral propagation in the CNS, which directly induces damage to resident cells. With that in mind, one can envisage that, under the right circumstances, HCoV may successfully reach and colonize the CNS, an issue largely deserted and possibly underestimated by the scientific community that has impacted or will impact the life of several unknowing individuals. In acute encephalitis, viral replication occurs in the brain tissue itself, possibly causing destructive lesions of the nervous tissue with different outcomes depending on the infected regions. As previously mentioned, HCoV may persist in the human CNS as it does in mice and potentially be associated with different types of long-term sequelae and chronic human neurological diseases.
In their famous review on CNS viral infection, published a few years ago, Koyuncu et al. insisted that, under the right conditions, all viruses can have access to the CNS. What "under the right conditions" means certainly represents a subject of debate among virologist and physicians. Nevertheless, as stated in the introduction of this review, viral factors (mutations in specific virulence genes), host factors (immunodepression, age) or a mixture of both (underlining the importance of virus–host interactions), are all good candidates to refer to if one intends to find the beginning of an explanation. A fast and accurate diagnosis would certainly improve prognosis for patients with a suspected CNS infection. Identification of a specific virus provides relevant information on how to treat a patient; therefore, the development of modern technologies, such as high throughput sequencing (Next Generation Sequencing) are warranted as it represents a potentially unbiased marvelous tool for rapid and robust diagnosis of unexplained encephalitis or other types of encephalopathies or neuronal manifestations, especially in the context where more traditional techniques have failed to identify the etiological agent. Therefore, although our attention is mainly on a few different viruses such as HSV, arboviruses and enteroviruses, it may now be the time to look at CNS viral infection from another perspective. These viruses truly represent an important proportion of CNS viral infection associated with encephalitis, meningitis, myelitis and long-term neurological disorders. Nevertheless, accumulating evidence in the scientific literature strongly suggest that many other viral candidates could be underestimated in that matter.
Several human respiratory viruses are neuroinvasive and neurotropic, with potential neuropathological consequences in vulnerable populations. Understanding the underpinning mechanisms of neuroinvasion and interaction of respiratory viruses (including HCoV) with the nervous system is essential to evaluate potentially pathological short- and long-term consequences. However, viral infections related to diseases that are rare manifestations of an infection (like long term chronic neurological diseases), represent situations where Koch's postulates need to be modified. A series of new criteria, adapted from Sir Austin Bradford Hill, for causation was elaborated by Giovannoni and collaborators concerning the plausible viral hypothesis in MS. These criteria certainly represent a pertinent tool to evaluate the involvement of human respiratory viruses as a factor that could influence long-term human neurological diseases. To continue the gathering of epidemiological data is justified to evaluate the clear cause and effect link between neuroinvasive respiratory viruses and short- and long-term human neurological diseases. Understanding mechanisms of virus neuroinvasion and interactions with the central nervous system is essential for different reasons. First, to help better understand potentially pathologically relevant consequences of infection, and second in the design of novel diagnostic and intervention strategies that will help uncover potential "druggable" molecular virus–host interfaces highly relevant to symptoms of various neurological diseases with a viral involvement.


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2012 REBNY Watch Columns
Home > Newsroom > Columns > 2014 REBNY Watch Columns
Lessons in diplomacy from RAB, service workers union
By Steven Spinola, president
Real Estate Board of New York
With residential contract negotiations underway between SEIU 32BJ and the real estate industry's negotiating arm, the Realty Advisory Board, the atmosphere would appear ripe for conflict and general animosity between the two parties involved.
Far from it, the positive and productive tone of negotiations is a mark of pride not only for REBNY, but for the real estate industry as a whole.
As the business world evolves, so too must the people who comprise it, and the relationship between RAB and 32BJ is a prime example of that evolution.
Together, 32BJ and the real estate industry have created over 60,000 jobs throughout New York City, ranging from superintendent positions to building maintenance workers, concierges, and porters.
These are good jobs that come with health insurance, paid vacation, retirement savings plans and other important benefits.
These jobs are vital in keeping the wheels of our city turning, and it is through the relationship between these two organizations that they remain not only filled, but the individuals filling them properly compensated and trained for their services.
Since its founding in 1934, 32BJ has grown to be the largest property service workers union in the United States, and today represents more than 120,000 members. We are proud to say that thousands of those members are part of our REBNY family.
Were it not for the professionalism and hard work of 32BJ's members, our buildings would not be able to live up the standards we hold ourselves to and that we hope the public has come to expect from us. These workers are the ones who benefit from and contribute to the real estate economy in New York, which I firmly believe to be the most important part of New York City's economy.
As with any relationship, in order to be prosperous and beneficial to all parties, they must come to a balance between themselves.
The Realty Advisory Board has done an exemplary job forming a relationship with 32BJ based on respect and common interests, from protecting members from having to pay healthcare premiums when the healthcare fund was dangerously low, to keeping employees compensated in the aftermath of Hurricane Sandy.
The results of positive relationships such as these are evident in both tangible and abstract ways, and most of them are things we take for granted every day. Safe and clean buildings with functioning elevators and other accessories are just some of the visible effects.
In terms of intangible results, REBNY's recent report, "The Invisible Engine: The Economic Impact of New York City's Real Estate Industry," explores the enormous amount of tax revenue and jobs generated by the real estate industry. Too often, we don't recognize the impact an office building or hotel has on funding the city services that contribute to the quality of life in our city.
In fact, the real estate industry generates enough tax revenue to pay the city's share of salaries for every single police officer, school teacher and firefighter and still have more than $2 billion left over to fund things like public parks and libraries. The full report can be found on our website, rebny.com.
As with any good-faith negotiation there are bound to be some tough days, but I sincerely wish both sides will continue the positive tenor of contract talks and stay on the path to compromise.
We look forward to a fair and equitable contract and our long-term partnership with the hard-working members of 32BJ.
In other REBNY News:
On April 1, The Members' Luncheon will take place at the Grand Ballroom of The Hilton New York, located at 1335 Avenue of the Americas. Refreshments will be served from 11:45 a.m. to 12:15 p.m., and the Program will be from 12:20 p.m. to 2 p.m. To register contact Desiree Jones at djones@rebny.com.
On April 4, Brooklyn Residential Seminar "Running Your Business From Apps: Essential Tools for Today's Agent" will be held at St. Francis College in Brooklyn. The seminar is free for Residential Members. Registration is required and available through the REBNY events calendar at rebny.com.
On April 9, we are starting a seminar series: "Legal Line LIVE!" with REBNY Broker Counsel Neil Garfinkel. This seminar will take place quarterly. The seminars are open to Residential Principals and Managers. RSVP to adonovan@rebny.com.
On May 29, REBNY is holding its 11th Annual Commercial Management Leadership Breakfast at the Hilton NY in the Grand Ballroom. Coffee will be served from 7:30 a.m. to 8:30 a.m., and the program will take place from 8:30 a.m. to 10 a.m. For more information contact Cindy Ramotar at cramotar@rebny.com.
On June 10, the winners of the Retail Committee Retail Deal of the Year 2013 Awards will be announced at a cocktail party hosted by the Retail Committee on Tuesday. You are invited to review your New York City retail transactions completed in 2013 and submit any that you consider a likely candidate for the Retail Deal of the Year Award. There will be two awards in total, and the deadline date is at 5 p.m. on Thursday, April 10.
James Whelan,
REBNY President
Mr. Whelan authors REBNY Watch, this weekly column highlighting timely topics in real estate. It is published in the print version of Real Estate Weekly.

redpajama_set_name: RedPajamaCommonCrawl


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The Accountant  é um filme americano de ação e suspense dirigido por Gavin O'Connor e escrito por Bill Dubuque. O filme é estrelado por Ben Affleck, Anna Kendrick, J. K. Simmons, Jon Bernthal, Jeffrey Tambor e John Lithgow. O filme está previsto para ser lançado pela Warner Bros em 14 de outubro de 2016.

Enredo
Christian Wolff é diagnosticado com autismo na Harbor Neuroscience quando criança. Seu pai se recusa a deixá-lo ficar durante o verão, acreditando que seu ambiente doméstico é melhor para seu distúrbio de processamento sensorial e que ele deve superar as dificuldades de sua condição sendo exposto a mais estímulos sensoriais, não menos. Com a mãe sobrecarregada leva a abandonar a família. Temendo que outros explorem Chris, seu pai, um oficial PSYOP do Exército dos Estados Unidos, inicia um regime brutal de estoicismo e treinamento de artes marciais para Chris e seu irmão mais novo, Braxton.

No presente, Chris é um contador forense com um pequeno escritório em Plainfield, Illinois. Ele desmascara fraudes financeiras internas, muitas vezes para empresas criminosas. Seus clientes o contatam através da Voz, uma mulher não identificada que o chama de "Barco dos Sonhos". Ele se expõe diariamente a luzes piscantes para se acostumar a qualquer tipo de sobrecarga sensorial e escutar heavy metal.

Chris é contratado para auditar a empresa Living Robotics depois que o fundador e CEO da empresa, Lamar Blackburn, e sua irmã Rita, são informados de discrepâncias financeiras da contadora interna Dana Cummings. Revisando uma década dos registros financeiros da empresa, ele descobre que mais de 61 milhões de dólares foram desviados. O diretor financeiro Ed Chilton é forçado por um assassino a ter uma overdose de insulina. Lamar descarta Chris, alegando que Chilton se matou por causa do roubo. Isso deixa Chris perturbado porque ele não pode terminar sua auditoria forense.

Enquanto isso, o diretor do Financial Crimes Enforcement Network (FinCEN), Ray King, persegue Chris, conhecido por ele apenas como "o Contador". King chantageia a analista de dados do departamento do tesouro, Marybeth Medina, ameaçando revelar que falsificou seus antecedentes em seu pedido de emprego no governo para forçá-la a localizar o contador. Suas pistas incluem nomes de capa de Chris, várias fotos e uma gravação de sua morte de nove membros da família Gambino.

Medina isola a voz de Chris da gravação do assassinato de Gambino, repetindo a canção de ninar "Solomon Grundy". Ela descobre que sua cadência vocal é uma reminiscência de indivíduos autistas e que os pseudônimos de Chris são matemáticos famosos, incluindo sua identidade atual, Christian Wolff. Usando dados e registros do Internal Revenue Service (IRS), ela localiza seu escritório em Illinois.

Assassinos tentam matar Chris, que os subjuga facilmente; um revela que Dana é o próximo alvo. Chris a salva, levando-a para sua unidade de armazenamento. Ele contém um trailer Airstream que ele pode usar para fugir rapidamente quando necessário e contém obras de arte, outros objetos de valor e as ferramentas de seu comércio de matança. Enquanto eles conversam, Dana fica mais afeiçoada a ele e se inclina para um beijo. Nesse momento, ele se levanta e percebe que o desfalque na Living Robotics é um esquema como o de Crazy Eddie : o dinheiro roubado da empresa é devolvido a ela, aumentando os lucros e aumentando a avaliação da empresa enquanto se prepara para uma oferta pública inicial. Quando ele vai confrontar Rita, ele descobre que ela foi assassinada por contrato, agora expondo Lamar como o bandido por trás da fraude.

Agentes do governo vasculham a casa fortemente protegida de Chris. King diz a Medina que Chris foi preso em Leavenworth por causa de uma briga no funeral de sua mãe, onde seu pai foi morto protegendo Chris. Durante seu encarceramento, ele aprendeu contabilidade forense com Francis Silverberg, o contador da família Gambino, que se tornou um agente do Federal Bureau of Investigation (FBI). King era o manipulador de Silverberg, mas sua inação levou Silverberg a ser brutalmente torturado e assassinado pelos Gambinos. Durante sua vigilância dos Gambinos, Chris veio para vingar seu mentor. Ele poderia facilmente ter matado King, mas o deixou ir depois de perguntar se ele era um bom pai. A partir daí, King começou a obter informações vitais através da Voz sempre que os criminosos violavam o código moral de Chris, King se tornando diretor do FinCEN como resultado. King revela que espera que Medina assuma o cargo quando ele se aposentar. O telefone toca e a Voz informa Medina sobre a situação da Living Robotics.

Chris vai para a mansão de Lamar, onde o assassino e sua equipe aguardam. Durante a batalha que se seguiu, o assassino reconhece Chris repetindo a canção de ninar e revela que ele é seu irmão, Braxton; eles não se viam desde a prisão de Chris uma década antes. Braxton ataca Chris, culpando-o pela morte de seu pai. Após a luta, Lamar aparece e tenta justificar suas ações criminosas; Chris o mata com um único tiro quando já ouviu o suficiente. Chris concorda em se encontrar com Braxton em uma semana, dizendo que o encontrará.

Na Harbor Neuroscience, outro grupo de pais visita seu filho. Ele conhece Justine, filha do diretor da clínica, que é paciente residente no local; ela também é secretamente a Voz, com Chris financiando privadamente as atividades do centro. Dana recebe uma pintura emoldurada de cães jogando pôquer que eles discutiram anteriormente. Ela logo descobre a pintura de Jackson Pollock de Chris escondida embaixo e fica impressionada com seu gesto. Enquanto isso, Chris deixa a cidade com o Airstream atrás de sua caminhonete.

Elenco
 Ben Affleck como Christian "Chris" Wolff
 Anna Kendrick como Dana Cummings
 J. K. Simmons como Raymond "Ray" King
 Jon Bernthal como Braxton "Brax" Wolff
 Cynthia Addai-Robinson como Marybeth Medina
 Jeffrey Tambor como Francis Silverberg
 John Lithgow como Lamar Blackburn

Produção
No dia 12 de novembro, 2014, Variety informou que Anna Kendrick deu início as negociações para estrelar junto com Affleck. Mais tarde naquele dia, J. K. Simmons também iniciou as negociações para se juntar ao elenco do filme. No dia 14 de novembro de 2014, Jon Bernthal estava em negociações para se juntar ao elenco do filme. Em 6 de janeiro de 2015, a Variety informou que a atriz Cynthia Addai-Robinson foi adicionada ao elenco. Em 14 de janeiro de 2015, Jeffrey Tambor foi adicionado ao elenco do filme, com a adição de John Lithgow no mesmo dia.

As filmagens começaram em 19 de janeiro de 2015, em Atlanta, Geórgia. A partir de março entre os dias 16 e 20, as filmagens estavam ocorrendo no Instituto de Tecnologia da Geórgia.

Cenas de luta
As sequências de luta do filme contou com artes marciais indonésias, chamadas de Pencak Silat .

Marketing
Em 9 de julho de 2015, um ano antes do lançamento do filme, o filme tinha recebeu uma novelização gráfica publicada pela Vertigo, uma marca de quadrinhos limitada de propriedade da Warner Bros. Pictures.

Lançamento
The Accountant está agendado para ser lançado no dia 14 de outubro de 2016, devido à alteração da data que a Warner Bros. planeava para 7 de outubro de 2016. Anteriormente, seu lançamento estava definido para o dia 29 de janeiro de 2016.

Bilheteria
A partir de 25 de dezembro de 2016 , O Contador arrecadou $ 85.4 milhões nos Estados Unidos e no Canadá, em outros países foram arrecadados $ 63.2 milhões para um total mundial de $ 148.600.000, contra um orçamento de produção de $ 44 milhões.

O contador foi lançado juntamente com Max Steel e Kevin Hart: What Now? , E esperava-se que arrecadassem US $ 20-25 milhões de 3.332 teatros em seu fim de semana de abertura, embora o estúdio estivesse projetando uma abertura conservadora de US $ 15 milhões.  O filme fez US $ 1,35 milhões do seu noite previews de quinta-feira, mais de de Affleck Girl Gone ($ 1,2 milhões) em 2014. Ele arrecadou US $ 9,1 milhões em seu primeiro dia e US $ 24,7 milhões em seu primeiro fim de semana, terminando em primeiro lugar nas bilheterias e foi a segunda maior estréia para um filme policial da carreira de Affleck, atrás Girl Gone ($ 37500000).  Em seu segundo fim de semana, o filme arrecadou US $ 13,6 milhões (uma queda de apenas 44,8%), terminando em 4º na bilheteria.

Resposta da crítica
No Rotten Tomatoes, o filme tem um índice de aprovação de 52%, com base em 231 avaliações, com uma média aritmética ponderada de 5.6/10. O consenso crítico do site lê, " O Contador baixa um desempenho comprometido de Ben Affleck, deixando os espectadores com um thriller de ação assolado por uma série de deduções mal-aconselhadas."  No Metacritic , o filme tem uma pontuação de 51 em 100, baseado em 45 críticos, indicando "críticas mistas ou médias".  De acordo com CinemaScore, o público deu ao filme um "A" nota média, em um A + em escala F.

Vince Mancini de Uproxx deu ao filme uma crítica positiva, escrevendo: "É transparente em sua tentativa de criar uma franquia futura e dar às crianças autistas seu próprio super-herói. Há uma verdadeira doçura a este último que me converte no primeiro. Headshots, problemas matemáticos e interações sociais de dor? Inscreva-me. Dos dois filmes de Ben Affleck lançados em 2016, O contador e o Batman V Superman, O contador tem de longe o maior potencial".

Filmes dos Estados Unidos de 2016
Filmes de mistério dos Estados Unidos
Filmes de mistério da década de 2010
Filmes de suspense dos Estados Unidos
Filmes de suspense da década de 2010
Filmes de drama dos Estados Unidos
Filmes de drama da década de 2010
Filmes policiais dos Estados Unidos
Filmes policiais da década de 2010
Filmes em língua inglesa da década de 2010
Filmes gravados em Atlanta
Filmes sobre política
Filmes da Warner Bros.
Filmes com trilha sonora de Mark Isham

redpajama_set_name: RedPajamaWikipedia


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Media: CESR's Niko Lusiani writes in FACTCoalition about CESR bringing the human rights costs of the proposed U.S. tax cuts to the attention of leading UN human rights official Philip Alston now investigating poverty in the country.
Media: CESR's Allison Corkery writes in Open Society Foundations Voices blog about using OPERA tool with Legal Resources Centre to identify indicators and analyze data for tracking implementation in South African education rights case.
6 December: CESR Statement: As U.S. Congress considers drastically altering its tax code, CESR presented human rights costs of proposed cuts to the attention of visiting UN human rights and poverty official.
How can human rights advocacy help design policies that tackle economic inequality and social exclusion?
Agenda 2030: repeating the same mistakes and expecting different results?
Agenda 2030 promised a more just future for all people but two years later, familiar dysfunctions have returned to the discourse of global development.
CESR statement: The tax marches held across and beyond the US on April 15 were an opportunity to focus on the alarming implications of proposed US tax reforms.
Panel: CESR Executive Director Ignacio Saiz's comments from a side event hosted by the UN missions of Ecuador and South Africa.
Over the past fortnight since International Women's Day, CESR has been engaging actively in the Global Days of Action on Tax Justice for Women's Rights.
CESR's recent collaborations with human rights defenders in Uganda and our partnership with the Asia-Pacific Forum are bearing fruit.


text:
Burbank Karaoke Bar Shutters Its Doors After 33 Years
by: Dave Mecham
Posted: Apr 4, 2015 / 11:27 PM PDT / Updated: Apr 5, 2015 / 02:43 AM PDT
Dimples, a beloved karaoke bar in Burbank, shuttered its doors after 33 years. (Credit: KTLA)
Dimples, a Burbank karaoke bar that was as beloved as it was iconic, shuttered its doors after 33 years. Dave Mecham reports for the KTLA 5 News at 11 p.m. on Saturday, March 4, 2015.
by Joseph Luiz, Nexstar Media Wire / Jan 16, 2021
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 Myrto Hotel Athens Athens. JIMAT di Agoda.com!
Sesuai untuk berehat dan bersantai, Hotel Myrto terletak di area Plaka di Athens. Hanya 0.05 Km dari pusat bandar, lokasi strategik hotel memastikan tetamu boleh ke mana-mana sahaja dengan cepat dan mudah ke tempat-tempat tarikan. Juga terletak berdekatan adalah Muzium Yahudi, Galeri Zygos, Gereja Sotira Lykodimou.
Menawarkan tetamu hotel perkhidmatan yang unggul dan pelbagai kemudahan, Hotel Myrto komited untuk memastikan penginapan anda berada di tahap seberapa selesa yang mungkin. Tetamu hotel boleh menikmati kemudahan seperti Wi-Fi percuma dalam semua bilik, daftar masuk/daftar keluar ekspres, simpanan bagasi, Wi-Fi di tempat awam, layanan bilik.
Hotel Myrto mengandungi 11 bilik yang dihias indah dan menawarkan pendingin hawa, pemanas, telefon, televisyen, peti ais. Di samping itu, pihak hotel menawarkan aktiviti rekreasi untuk memastikan anda mempunyai perkara untuk dilakukan sepanjang penginapan anda. Apapun alasan anda untuk melawat Athens, Hotel Myrto adalah tempat yang sempurna untuk percutian yang menyeronokkan dan menarik.
Anda mesti menunjukkan kad pengenalan bergambar serta kad kredit semasa mendaftar masuk. Harap maklum bahawa semua Permintaan Khas adalah tertakluk kepada ketersediaan dan bayaran tambahan mungkin dikenakan. Sila beritahu Myrto Hotel Athens terlebih dahulu mengenai anggaran waktu ketibaan anda. Anda boleh melakukan ini dengan menggunakan kotak Permintaan Khas semasa membuat tempahan. Anda juga boleh menghubungi tempat penginapan dengan maklumat hubungan yang telah tertera di pengesahan anda.
Very good location. A small hotel but very good pricing. It is just walking distance to Plaka area, Acropolis and you can just walk to reach all the sights and attractions in Athens. You can reach the hotel by going to Syntagma Square by bus X95. When we arrived Athens, the bus X95 stopped one stop before our destination and we had to take the metro which is just one stop to Syntagma Square. Hotel is located just 5 mins walk from Syntagma Square.
The second booking was even worse -- we had to wait an hour to check in. Have a look at our first review. This is just an unreliable hotel.
If you expect on-time check in at 2pm, the lift to be working when you check in when you are supposed to stay in the 4th floor with 160 kilos of luggage (they offered no help and did not seem to care that we had 2 seniors with us), not sharing one key for 4 persons staying in the room, secure luggage storage in case you arrive early or have to check out before your flight or the wi-fi working; FORGET BOOKING THIS HOTEL. We went to 5 hotels in Europe during our trip and this is by far our worst hotel experience. Will never book again. There were police in the lobby at one time because someone called the police because the hotel refused giving to give them a refund after a really bad check-in experience. GO FIGURE!
Really recommended to all tourist. Good location with cheap price. Room quite big and staff very nice too. Breakfast normal, but perfect for short stay.
It would be nice if they provide hair dryer.
super near the heart of acropolis and the city center. however it is a very simple simple inn and small round.
This hotel is located in a great spot. Easy walking distance of the Acropolis. Great restaurants and shopping nearby. Only one small disappointment was that we were not allowed to check in earlier even though room seemed ready. It would have been a great plus after an overnight flight. Definitely would stay there again and will recommend it.
The location is good. It is near to most of the attractions. Howoever, they don't provide the hair dryer in the room and the staff are not trying to help as well. I have asked 4 times for the hair dryer for 2days. First time , the receptionist said they will put it to our room when we went out, at the end , nothing. I asked for the second time, they said someone stole the hairdryer, they will try to get it from another room, nothing at the end. After the forth time , I still haven't gotten the hairdryer in two days .
The hotel is about 10 minutes walk from Syntagma Station. The room is neat with a balcony and can see the parthenon.
I took the small room, everything is okay and clean. Just there is a scent/smell of the room/air which rather uncomfortable to me. AC unit is just at the window behind bedrest, noose creeps through at night...slept without AC.
We had a pleasant stay in this well-located hotel.
not really clean and neat.and the lift is so small. location is good .but not easy to find the hotel.
The staff was great,t the breakfaxt goodhey were very helpful and informative. Breakfasxt was good.
The room was big enough but is was definitely run down and carpets needed some cleaning. Having said that the staff was super. Very helpful! Our view is that you don't spend that much time in the room. The bed was comfortable and the bathroom adequate. It was close to the Plaka and the Acropolis. Good value.


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Portrait Of The Artist As A Young Man
Criminal and Non-Criminal Exploits of Frank Abagnale&nbspTerm Paper
Length: 2 pages Sources: 2 Subject: Criminal Justice Type: Term Paper Paper: #64368034 Related Topics: Broadway, Louisiana Purchase, Beloved, Fake
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¶ … Successful (for a Time) Young Con: Frank Abagnale, Jr.
Frank Abagnale, Jr., is one of America's most beloved con men -- not only because he managed to go undetected in so many professions for a considerable length of time but also because he did so at such an early age when he was practically still a boy. For this reason, it may be more appropriate to suggest that Abagnale is America's favorite con child -- what with a successful film starring Leonardo DiCaprio and Tom Hanks and a Broadway play based on his exploits. Perhaps the biggest reason for his popularity is that after his arrest and conviction, Abagnale went "straight" and began acting as a consultant for the very banks he had helped to defraud as a young man in his teens and very early twenties. This paper will discuss Abagnale's criminal and non-criminal career, provide a limited statistical analysis (the reason that it is limited shall be explained), and compare his real life to the events depicted in the film Catch Me if You Can (2002).
Abagnale's career as a con began when he was 15 -- and his first victim was his own father, who had lent him his credit card, which Abagnale used to purchase items and...
From there, Abagnale moved on to taking advantage of banks and their inexperience with fraudsters such as himself. He would fake checks, deposit them, then ask for a pay advance based on the deposits. He was savvy enough to know that such tricks could not be used long before he would be exposed, so he traveled quite a bit. One way he was able to travel was that he impersonated an airline pilot for Pan Am. It is estimated that Abagnale logged over 1 million air miles, flying as a "deadhead" (a pilot who is traveling rather than actually flying).
Abagnale has stated that he posed as a teacher at BYU, a lawyer in Louisiana, and a doctor in Georgia. Some have questioned the legitimacy of all of Abagnale's claims, stating that there appears to be no corroboratory evidence -- but Abagnale responds by suggesting that no one wants to corroborate his tale because it would only embarrass them to admit that they were conned by a boy (Baker, 2003). Yet, for this reason, it is difficult to determine just…
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Abagnale, F. (2000). Catch Me if You Can. NY: Broadway Paperbacks.
Abagnale, F. (2004). Human Potential: Keep Your Name to Yourself. ASAE.
Retrieved from http://www.asaecenter.org/Resources/EUArticle.cfm?ItemNumber=11539
Baker, B. (2003). Portrait of the Con Artist as a Young Man. Newsthinking. Retrieved from http://web.archive.org/web/20071012201111/http://www.newsthinking.com/story.cfm?SID=166
"Criminal And Non-Criminal Exploits Of Frank Abagnale" (2015, July 21) Retrieved January 18, 2022, from
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"Criminal And Non-Criminal Exploits Of Frank Abagnale", 21 July 2015, Accessed.18 January. 2022,
Words: 1297 Length: 4 Pages Topic: Mythology - Religion Paper #: 64149685
Portrait of the Artist as a Young Man sunandmike Chapter One of James Joyce's A Portrait of the Artist as a Young Man traces Stephen Dedalus's early childhood experiences from his toddler years through his first term at boarding school. As a baby, Stephen's world is a collage of sensations. His first memories are of his father reading him a story, his parent's distinct smells, and the colors of Dante's
Words: 1250 Length: 4 Pages Topic: Literature Paper #: 51951173
Symbolism in Portrait of the Artist If we were to concern ourselves strictly with plot, we might well say of James Joyce's A Portrait of the Artist as a Young Man that there is no there. Not a great deal actually happens in this essentially autobiographical tale of Stephen Dedalus, and the narrative follows no clear single trajectory of cause and effect. Rather, in one of the first important uses of
Themes a Portrait of an Artist As a Young Man James Joyce
Words: 401 Length: 1 Pages Topic: Literature Paper #: 42205279
Portrait of the Artist of a Young Man by James Joyce traces the development of Stephen Dedulas as a writer from infancy to young adulthood. While Joyce shows the maturation of Stephen Deduals, he is also painting a vivid image of Dublin, Ireland and Stephen Dedulas' world. One literary device that Joyce uses throughout his novel is the repetitious appearance of numerous images. Stephen's fascination with women, both real
Significance of Symbolism in a Portrait of the Artist As a Young...
Symbolism in "A Portrait of the Artist as a Young Man" In "A Portrait of the Artist as a Young Man," James Joyce utilizes symbolism to help readers understand Stephen's character development. From a confused young boy to a confident man, Stephen transforms and certain symbols allow us to see this transition to occur. Joyce also uses symbolism to help readers comprehend the setting I which Stephen lives, which influences many
Words: 831 Length: 2 Pages Topic: Mythology - Religion Paper #: 52496299
Portrait of the Artist as a Young Man James Joyce's A Portrait of the Artist as a Young Man tells the story of Stephen Dedalus as he grows from an introspective and conscious young man into a rebellious and disaffected adult. For much of the novel, young Stephen is trying to figure out exactly who he is and what it is that he values in life. It is a stream-of-consciousness story
James Joyce, Portrait of the Artist As
James Joyce, Portrait of the Artist as a Young Man It can be said that throughout his entire novel, A Portrait of the Artist as a Young Man, by James Joyce does not believe that a lot of his revelations actually came from the spiritual realm, or at least to not be swayed by the divine, especially because being that he does not have any real connections to the Catholic Church,
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Essay / 2 pages


The first view shows the button as it appears normally. The second view shows the button when it has input focus. Its outline is darkened to let the user know that it is an active object. The third view shows the button when the user clicks the mouse over the button, and thus requests that an action be performed.
The gesture of clicking on a button with the mouse is associated with one instance of ActionEvent, which is sent out when the mouse is both pressed and released over the button. If an application is interested in knowing when the button has been pressed but not released, as a separate gesture, it can specialize processMouseEvent, or it can register itself as a listener for mouse events by calling addMouseListener. Both of these methods are defined by Component, the abstract superclass of all components.
When a button is pressed and released, AWT sends an instance of ActionEvent to the button, by calling processEvent on the button. The button's processEvent method receives all events for the button; it passes an action event along by calling its own processActionEvent method. The latter method passes the action event on to any action listeners that have registered an interest in action events generated by this button.
If an application wants to perform some action based on a button being pressed and released, it should implement ActionListener and register the new listener to receive events from this button, by calling the button's addActionListener method. The application can make use of the button's action command as a messaging protocol.
This class implements accessibility support for the Button class.
Constructs a button with an empty string for its label.
Constructs a button with the specified label.
Gets the AccessibleContext associated with this Button.
Returns the command name of the action event fired by this button.
Returns an array of all the action listeners registered on this button.
Gets the label of this button.
Returns an array of all the objects currently registered as FooListeners upon this Button.
Returns a string representing the state of this Button.
Processes action events occurring on this button by dispatching them to any registered ActionListener objects.
Processes events on this button.
Removes the specified action listener so that it no longer receives action events from this button.
Sets the command name for the action event fired by this button.
Sets the button's label to be the specified string.
Creates the peer of the button. The button's peer allows the application to change the look of the button without changing its functionality.
the button's label, or null if the button has no label.
label - the new label, or null if the button has no label.
Sets the command name for the action event fired by this button. By default this action command is set to match the label of the button.
command - a string used to set the button's action command. If the string is null then the action command is set to match the label of the button.
Returns the command name of the action event fired by this button. If the command name is null (default) then this method returns the label of the button.
Adds the specified action listener to receive action events from this button. Action events occur when a user presses or releases the mouse over this button. If l is null, no exception is thrown and no action is performed.
Removes the specified action listener so that it no longer receives action events from this button. Action events occur when a user presses or releases the mouse over this button. If l is null, no exception is thrown and no action is performed.
Returns an array of all the objects currently registered as FooListeners upon this Button. FooListeners are registered using the addFooListener method.
Processes events on this button. If an event is an instance of ActionEvent, this method invokes the processActionEvent method. Otherwise, it invokes processEvent on the superclass.
Returns a string representing the state of this Button. This method is intended to be used only for debugging purposes, and the content and format of the returned string may vary between implementations. The returned string may be empty but may not be null.
Gets the AccessibleContext associated with this Button. For buttons, the AccessibleContext takes the form of an AccessibleAWTButton. A new AccessibleAWTButton instance is created if necessary.


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Illegal Aliens Get The Chopping Block Thanks To GOP
Democrats in Congress decided to use the "nuclear option" to pass their COVID relief plan. Leverage their slim majorities in the House and Senate, they chose to ignore Republicans' request to negotiate. Not much of a "unity" move there, huh Dems?
But that doesn't mean Republicans didn't have any tricks up their sleeve. Because Democrats were using budget reconciliation to force their agenda, it gave Republicans a chance to put forward a blizzard of amendments, called a "vote-a-rama." This would force Democrats in the Senate to vote on issues they would have otherwise liked to avoid. Not great for Democrats in swing states, who might jeopardize their jobs if they voted for a radical agenda.
One of the measures was on whether the country should hand out relief checks to undocumented immigrants. Joe Biden was all fine for shelling out tax dollars to people who are in the country illegally. Republicans were able to put forward a measure to nix that idea, forcing Democrats to decide if they wanted to neglect suffering Americans to help illegals.
All Republican senators voted to block checks to illegals. And they had support from some unlikely allies.
A handful of swing state Senate Democrats joined Senate Republicans on Thursday to add a budget amendment that will help ensure that stimulus checks, funded by American taxpayers, are not given to illegal aliens living in the United States…
All 50 Senate Republicans supported the amendment, as well as eight swing state Senate Democrats. Those Democrats include Sens. Krysten Sinema (D-AZ), Mark Kelly (D-AZ), Debbie Stabenow (D-MI), Gary Peters (D-MI), John Hickenlooper (D-CO), Maggie Hassan (D-NH), Jon Tester (D-MT), and Joe Manchin (D-WV).
"The Biden administration shouldn't reward illegal immigrants for breaking our laws by giving them checks," Cotton said in a statement. "Instead of courting foreigners with U.S. taxpayer funds, President Biden should use that money to aid American schools, businesses, and families." [Source: Breitbart]
This vote proved critical for Joe Biden's administration, as it reveals there are not enough Democrats in the Senate to back his agenda. It's clear Joe wants to push a pro-illegal, open borders immigration plan. But with a 50-50 split in the Senate, he needs every last Democrat to back him. This time around, eight Democrats rejected Biden's attempt to give checks to non-citizens.
What will they do in the future, as Biden pushes for more benefits to illegals? We know that Biden wants to end Trump's "remain-in-Mexico" asylum policy. Biden also wants to increase the number of refugees that come to American by over 100,000 a year. He vowed to give undocumented migrants free health care, skipping over suffering Americans.
Can these eight Democrats, which include West Virginia moderate Joe Manchin and Arizona's Krysten Sinema, be counted on to oppose Biden's most radical agenda? It's hard to say. This time around, they made a calculated move to avoid looking back in front of their states. Voting to use tax dollars in this way would not go over well with many Americans.
But some other parts of Biden's plan, like killing the border wall, might be supported by these Democrats. It comes down to how the party leaders can coerce them. Democrats are determined to blow open our borders, come hell or high water.
It might take the combined effort of every last Republican senator to stave off their radical agenda.


PRINEVILLE, OR -- Firefighters working the 27-acre Allen Creek Fire, 12 miles north of Prineville, report they achieved 100% containment, as of Tuesday morning. Two 20-person crews will continue mop-up activities throughout the day.
Monday, they focused on hot spots and maintaining the perimeter; in some cases, they were able to work 100' into the fire line. With extreme temperatures expected this week, managers are now focusing efforts on making sure the fire does not rekindle or move outside current lines.
The blaze was reported Sunday at about 11:30 a.m. and burned primarily grass and brush on steep and rocky terrain near Allen Creek Road, in northwest Crook County. The cause of the fire remains under investigation.


When watching games on Sunday at the Bearcat Classic, I felt the wings for most teams were the most impressive. I especially like wing players that can score from any level and show versatility defending multiple positions. Several of the guys below have good size and can do just that. Offensively all wings mentioned showed they could get the ball in the bucket consistently and at will. Here are my top wing players from Sunday.


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Q: Getting a Stack Trace on parallel execution I find debugging very difficult in Mathematica, perhaps because I am unfamiliar with the appropriate tools. Ideally, I would like a "break on error" like Matlab with step control, however for the meantime let me be more specific.
When an error occurs, I can click the little red box with three dots and obtain a stack trace which is helpful in identifying in which function/location the error occurred. In parallel execution this little box doesn't appear, I only get the error message and the kernel id. How can I print out the function stack trace in parallel execution to provide a similar granularity of detail as to where the error occurred?

redpajama_set_name: RedPajamaStackExchange


Shah SR, Kim J, Schiapparelli P, Vazquez-Ramos CA, Martinez-Gutierrez JC, Ruiz-Valls A, Inman K, Shamul JG, Green JJ, Quinones-Hinojosa A.
Mol Pharm. 2019 Apr 1;16(4):1433-1443. doi: 10.1021/acs.molpharmaceut.8b00959. Epub 2019 Mar 11.
A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine.
Plummer S, Wallace S, Ball G, Lloyd R, Schiapparelli P, Quiñones-Hinojosa A, Hartung T, Pamies D.
Sci Rep. 2019 Feb 5;9(1):1407. doi: 10.1038/s41598-018-38130-0.
The Study of Brain Tumor Stem Cell Migration.
Lara-Velazquez M, Al-Kharboosh R, Prieto L, Schiapparelli P, Quiñones-Hinojosa A.
Methods Mol Biol. 2019;1869:93-104. doi: 10.1007/978-1-4939-8805-1_9.
NKCC1 Regulates Migration Ability of Glioblastoma Cells by Modulation of Actin Dynamics and Interacting with Cofilin.
Schiapparelli P, Guerrero-Cazares H, Magaña-Maldonado R, Hamilla SM, Ganaha S, Goulin Lippi Fernandes E, Huang CH, Aranda-Espinoza H, Devreotes P, Quinones-Hinojosa A.
EBioMedicine. 2017 Jul;21:94-103. doi: 10.1016/j.ebiom.2017.06.020. Epub 2017 Jun 21.
Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells.
Huang YJ, Schiapparelli P, Kozielski K, Green J, Lavell E, Guerrero-Cazares H, Quinones-Hinojosa A, Searson P.
J Cell Sci. 2017 Aug 1;130(15):2459-2467. doi: 10.1242/jcs.203752. Epub 2017 Jun 8.
Nanotherapeutic systems for local treatment of brain tumors.
Chakroun RW, Zhang P, Lin R, Schiapparelli P, Quinones-Hinojosa A, Cui H.
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2018 Jan;10(1). doi: 10.1002/wnan.1479. Epub 2017 May 24. Review.
Brief Report: Robo1 Regulates the Migration of Human Subventricular Zone Neural Progenitor Cells During Development.
Guerrero-Cazares H, Lavell E, Chen L, Schiapparelli P, Lara-Velazquez M, Capilla-Gonzalez V, Clements AC, Drummond G, Noiman L, Thaler K, Burke A, Quiñones-Hinojosa A.
Stem Cells. 2017 Jul;35(7):1860-1865. doi: 10.1002/stem.2628. Epub 2017 Apr 24.
Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization.
Yang JM, Schiapparelli P, Nguyen HN, Igarashi A, Zhang Q, Abbadi S, Amzel LM, Sesaki H, Quiñones-Hinojosa A, Iijima M.
Oncogene. 2017 Jun 29;36(26):3673-3685. doi: 10.1038/onc.2016.493. Epub 2017 Mar 6.
Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis.
Kilic O, Pamies D, Lavell E, Schiapparelli P, Feng Y, Hartung T, Bal-Price A, Hogberg HT, Quinones-Hinojosa A, Guerrero-Cazares H, Levchenko A.
Lab Chip. 2016 Oct 18;16(21):4152-4162.
Migration Phenotype of Brain-Cancer Cells Predicts Patient Outcomes.
Smith CL, Kilic O, Schiapparelli P, Guerrero-Cazares H, Kim DH, Sedora-Roman NI, Gupta S, O'Donnell T, Chaichana KL, Rodriguez FJ, Abbadi S, Park J, Quiñones-Hinojosa A, Levchenko A.
Cell Rep. 2016 Jun 21;15(12):2616-24. doi: 10.1016/j.celrep.2016.05.042. Epub 2016 Jun 9.
Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival.
Mangraviti A, Tzeng SY, Gullotti D, Kozielski KL, Kim JE, Seng M, Abbadi S, Schiapparelli P, Sarabia-Estrada R, Vescovi A, Brem H, Olivi A, Tyler B, Green JJ, Quinones-Hinojosa A.
Biomaterials. 2016 Sep;100:53-66. doi: 10.1016/j.biomaterials.2016.05.025. Epub 2016 May 21.
Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells.
Su H, Zhang P, Cheetham AG, Koo JM, Lin R, Masood A, Schiapparelli P, Quiñones-Hinojosa A, Cui H.
Theranostics. 2016 Apr 28;6(7):1065-74. doi: 10.7150/thno.15420. eCollection 2016.
Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151.
Tilghman J, Schiapparelli P, Lal B, Ying M, Quinones-Hinojosa A, Xia S, Laterra J.
Neoplasia. 2016 Mar;18(3):185-98. doi: 10.1016/j.neo.2016.02.003.
Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells.
Huang YJ, Hoffmann G, Wheeler B, Schiapparelli P, Quinones-Hinojosa A, Searson P.
Sci Rep. 2016 Feb 22;6:21583. doi: 10.1038/srep21583.
Effects of the acupoints PC 6 Neiguan and LR 3 Taichong on cerebral blood flow in normal subjects and in migraine patients.
Quirico PE, Allais G, Ferrando M, de Lorenzo C, Burzio C, Bergandi F, Rolando S, Schiapparelli P, Benedetto C.
Neurol Sci. 2014 May;35 Suppl 1:129-33. doi: 10.1007/s10072-014-1754-0.


UPSC has announced recruitment notification for the post of Group A, eligible candidates can submit their application before 16-04-2019.
UPSC Combined Geo-Scientist and Geologist Examination 2019. Union Public Service Commission (UPSC), Online application are invited for recruitment to the posts of Geo-Scientist and Geologist - 106 Vacancies in UPSC which shall be filled up by direct recruitment basis.
(d) a Tibetan refugee who came over to India before the 1st January 1962 with the intention of permanently settling in India.
(e) above shall be a person in whose favor a certificate of eligibility has been issued by the Government of India. A candidate in whose case a certificate of eligibility is necessary may be admitted to the examination but the offer of appointment may be given only after the necessary eligibility certificate has been issued to him/her by the Government of India.


but also three brandnew and exclusive tracks which are not included on the CD.
dedicated to two Stockholm based producers. Joel Mull's "Light Of Dawn"
Jonasson's "Rainy Sunny" on B2 is a dark, stomping techno tune!


1. Overview of different types of cell motility. Mechanisms of bacterial motility and chemotaxis.
2. Eucaryotic cell motility: flagellated and ciliated cells, crawling cell motility.
3. Motile machinery: types of the cytoskeletal structures, principles of assembly of cytoskeletal filaments (treadmilling, dynamic instability).
4. Motile machinery: accessory proteins, regulation of assembly and supramolecular organization of the cytoskeleton.
5. Methods to study cytoskeletal dynamics: live digital fluorescence microscopy, photoactivation, photobleaching, fluorescence speckle microscopy, and others.
6. Mechanisms of actin assembly in protrusion at the leading edge of the cell.
7. Biophysics of protrusion, forces and modeling.
8. Cell-substrate attachment: molecular composition and dynamics of adhesion sites.
9. Introduction to motor proteins, active cycle, steps and forces.
10. Microtubule-dependent motors, role in intracellular transport and mitosis.
11. Myosin superfamily of motor proteins, non-conventional myosins in intracellular transport and hearing.
12. Myosin II, coordination of protrusion, attachment and contraction in the cell translocation.
13. Signaling to motility and the origins of cell polarity (directional sensing in chemotaxis, PH-domain proteins, small GTPases, calcium).
14. Interaction between actin and microtubules in cell polarization and motility (budding yeast model, animal cell mitosis and cytokinesis, cell migration).
The course will be given in 14 weekly sessions, each either a 2h lecture or 1.5h lecture followed by 30 min presentation by one of the attendees and a guided group discussion. Presenters will discuss original papers related to this day's lecture topic.
This course requires a minimum of 4 participants and is limited to 15 participants.