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Viruses 2009, 1(3), 965-978; doi:10.3390/v1030965
Published: 18 November 2009
Abstract: Apoptosis is triggered as an intrinsic defense against numerous viral infections. Almost every virus encodes apoptotic modulators, and the herpes simplex viruses (HSV) are no exception. During HSV infection, there is an intricate balance between pro- and anti-apoptotic factors that delays apoptotic death until the virus has replicated. Perturbations in the apoptotic balance can cause premature cell death and have the potential to dramatically alter the outcome of infection. Recently, certain cellular genes have been shown to regulate sensitivity to HSV-dependent apoptosis. This review summarizes current knowledge of the cellular genes that impact the apoptotic balance during HSV infection.
1. Introduction
Apoptosis is a form of programmed cell death that is triggered during normal development and as a response to cellular stresses. Apoptotic cells display unique biochemical and morphological changes that distinguish them from cells dying through other pathways. Apoptotic morphological characteristics include membrane blebbing, chromatin condensation, nuclear fragmentation, and exposure of phosphatidylserine moieties [1-3]. There are two well defined pathways for the induction of apoptosis [4,5]. In one pathway, the extrinsic pathway, the signal is initiated at the cell surface [6]. Here, death factors bind to receptors embedded in the plasma membrane. The ligand:receptor binding triggers the assembly of large multiprotein complexes called death inducing signaling complexes (DISCs). A key biochemical characteristic of classical apoptosis is the activation of a specific set of cysteinyl aspartate proteases, called caspases. DISC formation includes the recruitment of the initiator caspase 8 to the complex that causes its autoactivation. Active caspase 8 cleaves and activates downstream effector caspases, such as caspases 3 and 7. Effector caspases cleave cellular proteins which maintain the integrity of the cell, which leads to the biochemical and morphological changes associated with apoptosis.
The other major signaling pathway leading to apoptosis is the intrinsic pathway [7]. Intrinsic triggers of apoptosis include DNA damage, heat-shock, and damage due to reactive oxygen species. This response causes changes in the ratio of pro- and antiapoptotic Bcl-2 family members within the mitochondrial membrane, which leads to a release of cytochrome c into the cytoplasm [8,9]. Cytochrome c forms complexes with apaf-1 and procaspase 9 to form a large multicomponent structure known as the apoptosome, causing the activation of caspase 9 [5,8]. Active caspase 9 goes on to activate effector caspases and the apoptosis inducing signaling pathways converge at this point. An additional layer of complexity is added to these apoptotic signaling pathways as crosstalk between the two pathways exists. For example, caspase 8 activated during the extrinsic pathway cleaves the Bid Bcl-2 family member [5]. The cleaved product, tBid, acts as a positive regulator of mitochondrial cytochrome c release. This release, in turn, initiates the intrinsic apoptotic pathway and amplifies the extrinsic apoptotic death signal.
The apoptotic pathway is often triggered as a consequence of viral infection. Therefore, almost all viruses encode genes to modulate the apoptotic pathway. It is important to note that although DNA viruses seem to universally express anti-apoptotic proteins, RNA viruses rarely do [10]. One potential explanation for this observation is that the ability of RNA viruses to replicate rapidly may allow them to avoid the problems associated with apoptosis. [11]. DNA viruses use a diverse array of mechanisms to impair the apoptotic response of cells. Small DNA tumor viruses, like human papillomavirus and adenovirus block the effects of p53 that normally functions to upregulate multiple pro-apoptotic cellular genes during times of cell stress [12-14]. Insect viruses, such as Baculovirus, produce proteins which inhibit caspases [15]. A subset of herpesviruses, including Kaposi's sarcoma herpes virus / human herpes virus 8 and Epstein Barr virus encode genes that are homologous to cellular anti-apoptotic Bcl-2 family members [16-18]. Herpes simplex viruses (HSVs) encode a number of genes that modulate cellular apoptotic pathways.
HSV infection triggers the apoptotic pathway early in infection [19-22]. However, as the viral infection progresses, anti-apoptotic proteins produced by the early and late herpes viral genes block apoptosis from ensuing [19,23,24]. This sets up an intricate balance between the pro- and anti-apoptotic factors in the cell. When the anti-apoptotic factors are not efficiently produced, the balance is upset and the HSV-infected cells die through an apoptotic pathway, Herpes Simplex Virus-Dependent Apoptosis (HDAP) [19,25,26]. Initial research on HDAP focused on the viral factors modulating apoptosis during infection. These studies identified a number of viral proteins which act to block apoptosis during infection. They include immediate early genes, such as ICP27 and ICP4, that likely act as upstream regulators of later anti-apoptotic viral genes [19,25,26]. Deletion of either of these genes from the viral genome results in a replication defective and pro-apoptotic virus. The early gene, ICP10 PK, plays an anti-apoptotic role during HSV-2 infection [27,28]. Late viral genes shown to possess anti-apoptotic properties include Us3, gD, gJ, and the latency associated transcripts [29-33]. Single deletions of these late genes generate viruses that fail to cause apoptosis to the same extent as ICP27 and ICP4-null viruses, suggesting that the late viral genes act in concert to prevent apoptosis during a wild type HSV infection.
HSV is best known as the causative agent of cold sores and genital herpes. However, when the virus reaches tissues other than the mucosal epithelium, it causes much more serious disease such as potentially blinding cases of keratitis and life threatening encephalitis. Animal and human studies have provided support for a role for apoptosis in the pathogenesis severe HSV disease. Specifically, apoptotic cells have been detected in animal models of herpes simplex keratitis [34-36]. The amount of apoptosis inversely correlates with the severity of disease [37,38]. This result suggests that apoptosis is acting as an antiviral defense mechanism of infected cells. Apoptosis has also been found to be a feature of herpes simplex encephalitis (HSE) [28,39,40]. In this case, however, there seems to be a positive correlation between the severity of disease and extent of apoptosis [40,41]. Thus, triggering apoptosis may contribute to the virulence of HSV during encephalitis. Together, the evidence suggests that cell-type determinants mediate the way in which apoptosis impacts HSV pathogenesis.
2. Results and Discussion
The majority of the early studies on HDAP utilized immortalized cell lines typically used to propagate HSV, i.e., Vero and HEp-2/HeLa cells, which provided insight into the viral factors involved in this response. Yet, later studies demonstrated the existence of cell-type differences in the response to HDAP, indicating that cellular factors play an important role in this process. For example, primary epithelial cells from mammary tissues and primary skin fibroblasts display resistance to HDAP [42,43]. Primary murine neuronal cells also seem to show a similar apoptotic regulation during wild type HSV-1 infection [44-46]. Recently, a number of specific cellular factors modulating HDAP have been identified. These cellular genes can be classified as caspases, Bcl-2 family members, NF-κB, and oncogenic genes.
2.1 Caspases
Multiple studies demonstrate that HDAP is caspase-dependent [19,23,47-50]. The small peptide pan-caspase inhibitors, e.g., z-VAD-fmk, are efficient suppressors of the biochemical and morphological apoptotic phenotypes found during HDAP. The use of specific caspase inhibitors has allowed elucidation of the pathway by which apoptosis is triggered during infection [47]. An inhibitor of caspase 9, z-LEHD-fmk, suppressed HDAP in HEp-2 cells to an extent similar to that of the pan-caspase inhibitor. However, a caspase 8 inhibitor, z-LETD-fmk failed to suppress HDAP, even though it was capable of suppressing apoptosis induced by tumor necrosis factor and cycloheximide. Furthermore, cytochrome c was released in a caspase-independent manner during HDAP [47]. These results led to the conclusion that HDAP occurs through the intrinsic pathway of apoptosis.
One effector caspase commonly utilized in the intrinsic pathway is caspase 3. Studies in our laboratory using genetic analysis demonstrated that caspase 3 is necessary for HDAP. This work stemmed from our observation that the tumor cells that were resistant to HDAP were also highly resistant to other forms of apoptotic induction. We hypothesized that the HDAP resistance was due to the acquisition of mutations in cellular apoptotic pathways, which blocked apoptosis in general [43]. One such tumor cell line was the breast cancer MCF-7 cells. MCF-7 cells are known to be defective for a key component of the apoptotic cascade, caspase 3 [51]. When MCF-7 cells in which caspase 3 expression was restored (MCF-7 C3) and caspase 3-null counterparts (MCF-7 PV) were infected with a pro-apoptotic HSV mutant, the MCF-7 C3 cells displayed membrane blebbing and biochemical features of apoptosis, while similarly infected MCF-7 PV cells did not [49]. This finding not only demonstrated that restoring the apoptotic pathway sensitized these cells to HDAP, but also identified caspase 3 as a cellular determinant for HDAP. Interestingly, caspase 3 has also been found to play a role in the apoptosis during influenza virus infection [52]. Inhibition of caspase 3 leads to a reduction in the influenza virus titer. A subset of caspase 3 is found in the active form during a wild type HSV infection [49]. Whether caspase 3 similarly contributes to HSV replication efficiency has yet to be determined.
It is of note that the ICP22 protein of HSV has been shown to be cleaved by caspases during infection with a mutant, pro-apoptotic virus [53]. The biological significance of this cleavage has yet to be elucidated, as the cleaved form of the protein does not accumulate during a wild type HSV-1 infection, and the function of the cleaved form has not been defined.
2.2. Bcl-2 Family Members
The Bcl-2 family comprises of pro-and anti-apoptotic proteins all sharing conserved protein motifs, known as Bcl-2 homology (BH) domains [54]. Most of these members reside within the mitochondrial membrane. The ratio and activities of the pro- and anti apoptotic Bcl-2 family members in this region determines the release of cytochrome c from the mitochondria and subsequent initiation of the intrinsic apoptotic pathway. HSV has been shown to block the activities of certain pro-apoptotic Bcl-2 family members. HSV Us3 blocked cell death and caspase activation induced by overexpression of Bax, Bad, or Bid [55,56]. In fact, Bax appears to accumulate at mitochondria during HDAP [47]. Cartier et al. determined that Bad is phosphorylated in a Us3 dependent manner during HSV infection [57]. This may contribute to its ability to block Bad activity. In other studies, exogenous expression of the anti-apoptotic Bcl-2 protein blocked apoptosis induced by HSV infection of HEp-2 and the U-937 lymphoma cell line [48,58]. In U-937 cells this Bcl-2 overexpression led to increased HSV-2 yields, suggesting that manipulation of apoptotic pathways can influence the efficiency of virus replication, at least in certain cell types [58].
2.3. NF-ĸB
NF-ĸB is a transcription factor that plays a major role in inflammation and the immune response [59]. Inactive NF-ĸB is bound to an inhibitory protein, IĸB, and sequestered in the cytoplasm. Following exposure to a proper stimulus, IĸB is phosphorylated and degraded, and NF-ĸB translocates to the nucleus [60,61]. There, it induces the expression of a number of genes involved in cell survival, proliferation, and inflammation [62,63]. Early studies demonstrated that NF-ĸB translocates to the nucleus during HSV-1 infection and the timing of this translocation coincides with apoptosis prevention [64-67]. A pro-apoptotic mutant virus of HSV-1 did not cause a similar translocation [65]. Furthermore, cells which expressed a dominant negative form of IĸBα, IĸBαDN, display apoptosis when infected with wild type HSV [65-67]. These results support a role for NF-ĸB in the prevention of apoptosis during HSV-1 infection. However, others have reported that NF-ĸB may provide important functions other than apoptosis prevention during HSV-1 infection [68,69]. For example, studies suggested that NFĸ-B activation is linked to the activation of a key regulator of the innate immune response, PKR [68,69].
More recently, studies from our group have provided additional information regarding a role for NF-ĸB in apoptosis prevention. HEp-2 cells infected with HSV-2 were found to display NF-ĸB nuclear translocation during the time of apoptosis prevention [70]. This result suggested that NF-ĸB's role in the prevention of apoptosis during infection with HSV-2 is similar to that of its role in HSV-1 infection. Additionally, HSV infection led to NF-ĸB translocation in corneal epithelial cells, implicating NF-ĸB in apoptosis prevention in herpes simplex keratitis [71]. However, not all of HSV's capacity to block apoptosis can be attributed to NF-ĸB. Results from our group have demonstrated that HSV-1 is effective at blocking apoptosis in HEp-2 cells induced by Fas ligand and cycloheximide [72]. Although this prevention corresponded with NF-ĸB nuclear translocation, HSV-1 was still capable of blocking Fas-mediated apoptosis in HEp-2 cells constitutively expressing IĸBαDN [72]. This result led to the conclusion that HSV-1 possesses NF-ĸB-independent mechanisms of blocking apoptosis.
2.4. Oncogenic Genes
Oncogenes were first implicated as mediators of HDAP in studies comparing the sensitivities of human cancer cells with that of primary cells [42]. The studies indicated that the transformation status of cells correlates with their sensitivity to the viral induced apoptosis. Subsequently, differences between the immortalized, but not transformed Vero cell line and that of the highly sensitive transformed HEp-2 cells revealed the existence of a cellular protein that facilitates apoptosis during infection [73]. The Vero cells require production of the facilitator protein, while HEp-2 cells are independent of it. All primary cells tested to date have been resistant to HDAP based upon caspase substrate cleavage, chromatin condensation, membrane blebbing, and DNA laddering analyses [43]. Remarkably, even cells of the same patient derived from a mammary tumor and the surrounding normal tissue displayed opposite sensitivity to HDAP [43]. These data led to the hypothesis that genetic changes occurring during tumor development sensitized cells to HDAP.
Our group tested the aforementioned hypothesis using a tumor model system in which the cellular transformation status could be experimentally manipulated. This model makes use of the fact that the human cervical cancer derived HeLa cell line requires continuous expression of human papillomavirus (HPV) genes in order to maintain a tumorigenic phenotype [74-76]. Suppressing the HPV 18 E6 and E7 via the expression of the papillomavirus E2 transcriptional repressor leads to reductions in cell growth, and eventually senescence of the cells [74,77-79]. We found that repression of HPV E6 and E7 reduced the sensitivity of HeLa cells to HDAP [80]. Furthermore, adding back expression of HPV E6, but not E7, restored HeLa cell HDAP sensitivity. These studies allowed us to narrow our search for oncogenic HDAP mediators to those altered by HPV E6. HPV E6 is a multifunctional protein, known to affect the function of at least a dozen cellular proteins [81]. So far, two of these proteins, p53 and telomerase, have been identified as regulators of HDAP sensitivity.
2.4.1. p53
HPV E6's most well studied function is the inactivation of the cellular tumor suppressor, p53. The p53 protein has been dubbed the "guardian of the genome" due to its role in preventing genetic mutations in the cell lineage [82]. The levels of p53 protein are usually kept low in healthy cells due to an extremely rapid turnover mediated by mdm2. However in response to cell stresses, p53 is stabilized, accumulates within the cell, and forms tetramers. The tetramers of p53 act as a transcriptional factor to induce a variety of genes that are involved in DNA repair, cell cycle arrest, and apoptosis. HPV E6 forms complexes with p53 and the cellular ubiquitin ligase, E6AP/UBE3A, to cause p53 ubiquitination and degradation [83,84]. Inactivation of p53 can also be achieved by expressing a mutant p53 molecule, which oligomerizes with wild type p53, but lacks the ability for transcriptional activation [85,86]. In the HeLa cells, we found that constitutive expression of a dominant negative p53 mutant was capable of sensitizing the HeLa cells to HDAP to the same extent as HPV E6 [80]. This result demonstrated that p53 inactivation can sensitize cells to HDAP.
Interestingly, several reports provide evidence for direct effects of HSV on p53 levels. Like HPV E6, the ICP0 protein of HSV-1 was found to bind to and mediate the ubiquitination of p53 in vitro [87]. A similar ICP0-dependent ubiquitination was apparent in murine fibroblasts cotransfected with human p53 and ICP0 expression plasmids. However, the destabilization of p53 is not detected during an HSV infection. In fact, p53 was found to be phosphorylated and stabilized in human foreskin fibroblasts and primary mammary epithelial cells infected with HSV-1 [88] and [Nguyen and Blaho, unpublished results]. Furthermore, human embryonic lung cells infected with a replication defective mutant of HSV, which expresses ICP0, displayed p53 stabilization and p21 upregulation [89]. Therefore, the effects of ICP0 on p53 may be overridden by other HSV genes during a complete virus infection.
2.4.2. Telomerase
The hTERT gene encodes the catalytic component of human telomerase [90-93]. Telomerase is the enzyme which replicates the ends of chromosomes (telomeres) [94]. Telomeres are typically shorter in adult somatic cells than those of embryonic and tumor origin [95-97]. Without telomerase, telomeres progressively shorten and when they reach a critical length, cells stop dividing or die through a process known as crisis [98]. Because HPV E6 is known to increase telomerase activity through upregulation of hTERT [99], we studied the effects of hTERT expression on sensitivity to HDAP. HeLa cells constitutively overexpressing hTERT, were as sensitive to HDAP as those cells expressing only HPV E6 [80]. Furthermore, primary mammary epithelial cells immortalized by hTERT expression are sensitive to HDAP, while primary mammary epithelial cells are resistant [Nguyen and Blaho, unpublished results]. Therefore, hTERT overexpression sensitizes cells to viral apoptosis. Contrary to HDAP, hTERT expression has been reported to decrease sensitivity to various other apoptotic stimuli, including oxidative stress, serum deprivation, dsDNA breaks, and cisplatinum [100-103]. Thus, HSV seems to be manipulating the apoptotic pathway in a unique way.
3. Conclusions
Apoptosis is a common cellular defense against pathogens. As a consequence, many successful pathogens possess an ability to modulate the apoptotic response. Over a decade of research has revealed much about the regulation of apoptosis during HSV infection. We know that apoptosis is initially triggered during the expression of viral immediate early genes, but this cell death signal is later squelched by the production of antiapoptotic viral factors. In this way, an HSV-infected cell walks a fine line of apoptotic balance during a productive infection, delaying cell death, presumably until the moment optimal for virus replication.
Soon after the viral factors involved in apoptosis were elucidated, cell specific differences in sensitivity to HSV induced apoptosis were recognized. The identification of cellular proteins which mediated these cell type specificities followed (Figure 1). The cellular mediators of apoptosis Bcl-2 family members and caspases relay the signal from the initiation to execution of cell death during HSV infection. Exploiting the apoptotic proteins that are necessary for HDAP may clarify HDAP's impact on viral pathogenesis. Less predictably, perhaps, were the findings that at least two genes involved in tumorigenesis, p53 and hTERT, influence the ability of the infected cell to respond to viral apoptotic triggers. At this time, the molecular mechanisms whereby these genes confer their effects is still unclear. What is clear is that the regulation of apoptosis within an HSV infected cell is much more complex that originally anticipated. We have yet to learn how many more cellular players may impact the HSV dependent apoptosis balancing act.
We would like to thank Rachel Kraft, Kristen Peña, and Elisabeth Gennis for their work that contributed to the studies described in this review. The studies which serve as the basis of this review were supported by grants from the U.S.P.H.S. (AI038873 and AI48582 to J.A.B. and AI07647 and CA088796 for M.L.N.) M.L.N. would also like to thank the Iowa Osteopathic Education and Research Fund for support.
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© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Written by Dr. Cynthia Paulis, email@example.com Wednesday, 23 April 2014 00:00
Tundra, the arctic snowy owl, fixed her golden eyes upon me, clucked her beak, then turned her head, ready for her close-up. Two months earlier she was near death at LaGuardia Airport, emaciated with a broken wing, but was saved by a dedicated group of people called Volunteers for Wildlife. The organization located at Bailey Arboretum in Lattingtown houses not only the rehabilitation hospital for wildlife but has aviaries where the public can see the rescued birds.
Earlier this month at the Seawanhaka Yacht Club, 160 people arrived for the organization's fundraising gala.
Jean Thatcher, the president of Volunteers for Wildlife and also the deputy mayor of Lloyd Harbor, was thrilled with the turnout.
"Wildlife rehabilitators cannot charge for their care so we rely on membership, donations, grants, educational programs and big benefits like this to support us," she said.
It costs $15,000 a month to maintain the organization. Volunteers for Wildlife was first started in 1982 by a World War II nurse named Sallie Ruppert out of her garage. The organization was later run out of Caumsett State Park and two years ago was relocated to the beautiful Bailey Arboretum.
"Each year we admit roughly 750 to 1,000 animals and those animals are Long Island native wildlife. About 300 to 400 are birds, 300 to 400 are mammals and a small portion are reptiles," wildlife rehabilitator Alecia Grubessi told the Enterprise-Pilot while giving a tour. "We do not take in the rabies vector species (raccoons, skunks, and bats), but we do ask that the public call us when they find those animals injured because we do know wildlife rehabilitators who are licensed to take care of them."
Grubessi explained the process of what happens at the center. "We have a wildlife advisory telephone which is manned by one of the staff members every day when we are here 7 a.m. to 5 p.m. and after 5 p.m. we have an e mail address that one of the staff members checks throughout the night. There is always someone on call and able to answer wildlife concerns and we speak to the public and determine what is going on with the animal if it is sick, injured or needs our care or if it is behaving normally and should be left out in the wild where it belongs. If the animal does need to come into our hospital if they can safely transport the animal to our hospital we ask them to do so, that's because we have a very small staff and limited resources and we can't go out and pick up every animal. Once they are at the hospital we have wildlife rehabilitators who assess their condition and determine treatment and protocol."
Grubessi, along with board members and wildlife rehabilitators, greeted guests at the gala displaying some of the wildlife. Rachel Neville, wildlife rehabilitator of Massapequa, recently joined the organization after graduating Cornell with an environmental science and biology degree. Holding a box turtle,she shared her thoughts on why she took this path. "I do it because I love animals and this is such a great organization. You feel like you make a difference in an animal's life."
Neville is also a talented artist and was taken by Tundra; she drew a beautiful sketch that went up for auction at the gala to raise funds for the organization.
"I felt she was a good representation of what we do at Volunteers for Wildlife. Her injury was a result of unfair human interaction and we used our resources to give her another chance. Unfortunately, the injury was severe enough not to allow her release. Because of that I felt she was a symbol of how humans are having a negative impact on wildlife and how we need to change our ways and have a more mutualistic relationship with wildlife."
As guests mingled with owls, kestrels, red tailed hawks and " Millie" the opossum, they bid on the silent auction items including tickets to Yankee Stadium, Broadway tickets, a trip to Disney and a round of gold on Fisher's Island as a few of the items. Wines featuring pictures all of the animals recently rescued and saved were for sale. After cocktails, guests sat down for a buffet dinner. Such notables in attendance were Bernadette Castro, former parks commissioner under Governor Pataki, and State Senator Carl Marcellino, who were acknowledged and thanked by Thatcher for their help.
"It's wonderful to save the wildlife, but if the wildlife has no home to live then we are not going to have any wildlife eventually," said Thatcher. "Bernadette Castro has done more to preserve huge tracks of land such as Caumsett State Park."
"This organization is phenomenal," said Castro. "It's wonderful and it brings awareness and visibility to wildlife and as she explained tonight, the wildlife requires open space."
Board member and 14-year-volunteer Leslie Block, holding Millie the opossum, concurred. "It's important people see these animals, especially children. The wildlife are losing their habitats and pesticides have been the death for many of them. The only way we can protect and maintain wildlife is to try to educate and come to appreciate wildlife."
Jim Jones, an 18-year volunteer, shared the story of Duncan, an 11-year-old Eastern screech owl, with the audience. "He is a dropout from kindergarten. Duncan was injured, treated and released but kept coming back, so he either thinks I'm a really big ugly screech owl or he is a really attractive little human being," he laughed. "There is nothing better than rescuing an animal that you know is not going to make it unless you are there, treating it and then releasing it. It's fantastic, it's magical, nothing like it."

subset: commoncrawl


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Man robs Blanding Boulevard CVS store
Updated On: Jun 27 2014 05:28:42 PM EDT
Police are asking the public for help finding the man who used a knife to hold up a Westside drug store on Wednesday morning.
The Jacksonville Sheriff's Office released surveillance photos of a man who officers said entered the CVS store at 7790 Blanding Blvd. about 11:30 a.m., walked behind a counter and tried to pry the cash register open.
When confronted by the cashier, the man displayed a knife, according to officers. The store manager came over and gave the man money, who then ran from the business.
Police describe the robber as a white man, 40 to 50 years old, between 5 feet 5 inches and 5 feet 7 inches tall and weighing 120 to 140 pounds. He was wearing a pink shirt, tan shorts and was armed with a pocket knife.
Anyone who has any information about the robbery or recognizes the man in the photos is asked to call Crimestoppers at 866-845-TIPS. Callers can remain anonymous and may be eligible for a reward.
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Headlines & Global News
HNGN EXCLUSIVE INTERVIEW: Billy Dean Reveals The Story Behind His Viral ...
Headlines & Global News
The patriotic, anti-terrorist song written in a few hours by Billy Dean and Larry Gatlin just over a month ago in their dressing room before a performance - and captured on a cell phone video with an acoustic version uploaded to their Facebook pages - has now ...
'Remington' tops 16 million hits; Special Sunday for 'Pierce Arrow'
Branson Tri-Lakes news
Last month local entertainers Billy Dean and Larry Gatlin got to talking about the strong feelings they shared about the state of the world right now and faster than you can say "God Bless the USA," there they were on Fox News debuting a new song called "An ...
and more »
Headlines & Global News
Larry Gatlin Produces New Clothing Line With 'Made In America' Companies
Headlines & Global News
Larry Gatlin is dressing for success to promote a "buy American" movement. The country star has teamed up with a number of American companies that have the same goal, according to Absolute Publicity. The result is the new Larry Gatlin Collection.
The News-Press
Singer Billy Dean to terrorists: We're armed and ready.
The News-Press
Billy Dean was mad as hell. So he decided to write a song about it. The result — with the help of fellow country-music star Larry Gatlin of The Gatlin Brothers —became a viral hit on Facebook last month. And who knows? Maybe those ISIS terrorists in Iraq saw ...
FOX News Radio
VIRAL VIDEOS: An American With A Remington
FOX News Radio
Recently performing this song on "FOX and Friends," country music artists Larry Gatlin and Billy Dean team-up, singing a duet they wrote to express their feelings on the recent beheadings by ISIS. Taking a strong stance against terrorism, Gatlin and Dean ...
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Quick Links
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Item 4: Order Paper 173/11-15 – 25 November 2013
Motion: Transfer of Broadcasting Powers
That this Assembly calls on the Minister of Culture, Arts and Leisure to explore with the Secretary of State the potential for transferring broadcasting powers from the Department for Culture, Media and Sport to her Department and for funds for the Irish Language Broadcast Fund and the Ulster Scots Broadcast Fund to be transferred and mainstreamed.
[Mr C Ó hOisín][Ms R McCorley][Mr O McMullan]
The Speaker has selected the following Amendment for debate:
Amendment 1
Proposed: Leave out all after the second 'Department' and insert:
'through the establishment of an independent advisory panel in order to assess the viability of any potential transfer and of the transfer and mainstreaming of the Irish Language Broadcast Fund and the Ulster Scots Broadcast Fund.'
[Mrs K McKevitt][Mr D Bradley]
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European high-yield bond market hits its stride
They used to be called junk bonds, but that moniker is less common now. Given record low rates, high-yield bond doesn't seem quite right either. Whatever name you use, the subject is companies raising finance by issuing bonds of less than investment grade – higher risk, therefore somewhat higher yield – and bankers are unanimous that there has finally been a fundamental and permanent change in the European market after a couple of false dawns.
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Don't Miss
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- Fight! River celebrate at the final whistle while Boca players clash with pitch-invading fans [Video]
- Lionel Messi sits shotgun as Gerard Pique test drives a new Audi in reckless fashion [Video]
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- PSG attacker Lucas casually juggles the ball and balances it on his head in training [Video]
Ghana 2 – Congo 2. All Goals.
- Updated: January 20, 2013


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Welcome to Cross Plains, Texas
The Cross Plains Chamber if Commerce held Ribbon Cuttings for two new businesses!
The first ribbon cutting took place at Buffalo Donuts. Dustin Hawk, of Clyde saw the need for a donut shop in Cross Plains and the idea of Buffalo donuts was born. These donuts are second to none. They offer many different pastries that are delicious as well as breakfast sandwiches, cloche, and drinks to satisfy even the pickiest of coffee connoisseurs. They are located at 416 SW 5th Street.
The second ribbon cutting took place at Hutton Automotive. Hutton Auto Repair is owned and operated by Anthony & Robert Hutton. The Hutton's specialize in all makes and models of vehicles and can take care of all of your automotive needs. The Hutton's offer oil & filter change for $20 plus the oil & filter and are happy to top off all the other fluids. Located at 117 SE 2nd .


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Royal Rumble 2013 Match Card Predictions
View Single Post
Terry Gyimah
Challenging SCOTT STEINER's authority
Join Date: Feb 2011
Posts: 4,779
My Royal Rumble 2013 Card
WWE Championship
The Rock vs. CM Punk (c) (Special Guest Referee: John Cena)
The set-up is obviously there from RAW 1000, with Punk turning heel on that show by attacking The Rock just as he was about to hit the People's Elbow on Big Show after hitting him with The Rock Bottom, and Rock has never gotten retribution for that at all, so at the Rumble it would be his chance to finally face Punk, and with the WWE Championship on the line, I would have Cena factor into this feud by being the special guest referee considering he has history with both men, and we don't know just who Cena will favor in this match or if he would call it down the middle, which is what would make it so unpredictable
: New WWE Champion
The Rock
(35:17), right after the match Cena lays out Rock with the Attitude Adjustment
World Heavyweight Championship (Triple-Threat Match)
Dolph Ziggler (c) vs Big Show vs Sheamus
I would have Dolph cash in his briefcase at TLC right after the Sheamus/Show match by having Show retain against Sheamus cleanly, only for Sheamus to be so pissed off after losing to Show, he attacks Big Show laying him out with White Noise and then follows it up with a Brogue Kick leaving Show in the middle of the ring and cue Dolph's music, comes running full-speed to the ring with referee in tow, cashes in his briefcase on Big Show by just covering him 1...2...3 to become the World Heavyweight Champion, and then you have a #1 Contender's match to see just who will face Dolph at the Rumble for the World Heavyweight Championship but Sheamus and Show's match goes to a no contest and then it is announced Dolph has to face both of them in a Triple-Threat for the World Heavyweight Championship
: Still World Heavyweight Champion
Dolph Ziggler
(19:22) after pinning Big Show
Grudge Match
Randy Orton vs Wade Barrett
I would have this rivalry really take off once again but this time to make it even more personal this time around with Barrett targeting Orton's family, and Orton as payback attacks Barrett for weeks on end and even costs Barrett a chance at being World Heavyweight Champion, and then this match here at the Rumble would be the feud ender
Randy Orton
(15:26) after hitting the Punt Kick on Barrett taking Barrett out of action once again but only until Elimination Chamber
WWE Tag Team Championship
Rhodes Scholars (c) vs Rey Mysterio & Sin Cara
I would have Rhodes Scholars win the WWE Tag Team Championship from Team Hell No at TLC in a Tables, Ladders and Chairs match for the WWE Tag Team Championship beating not just them but Prime Time Players and Sin Cara and Rey, but then afterwards they begin feuding with Cara and Rey for the WWE Tag Team Championship
: Still WWE Tag Team Champions
Rhodes Scholars
(9:50) after Rey turns on Cara during the match leaving him high and dry during the match, signalling Rey's heel turn
30-Man Royal Rumble Match
A match where anyone can win, 30 men, 15 RAW superstars, 15 SD superstars, one match, one winner and I would have surprise entrants like Brock Lesnar returning during the Rumble match as an entrant, that would make him one of the favorites to win it, and then there's Ryback who I would have clean house, and there would be superstars like Orton, Cena, Kane, Show, Sheamus, etc.
CM Punk
The Best In The World (63:35) with Punk coming in at like #1 or #2 entrant and he stays in the match for a really long time and goes the distance to win it all
What would be your Rumble match card?
Terry Gyimah
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November 26, 2014
The trial of a homeless man accused of kidnapping and raping a hitch–hiker in Mesa County continued Wednesday. The Prosecution called several local law enforcement officers in to testify, and ended up resting their case just shortly after 2:30 p.m. The defense also rested their case after the defendant, Merle Eaton, announced on record that he would not be testifying. Merle Eaton is charged with three counts of sexual assault.. Second degree kidnapping, menacing and assault in the third degree. However this afternoon the DA's Office dropped the menacing charge after the defense argued for an acquittal on it, saying there was no proof Eaton ever had a deadly weapon particularly a gun.
Merle Eaton is accused of offering the alleged victim a ride, hitting her in the face and raping her on a dirt road before she says she escaped and ran into a business off the of I-70 Business Loop. The Prosecution was never able to serve the alleged victim with a subpoena because she has since disappeared. This is the first time the District Attorney's Office has prosecuted someone for sexual assault without a victim.
Tomorrow morning the Prosecution and Defense will deliver their closing arguments.
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Developments, news and strategies for drug development specific to phase I through Phase III global clinical trial management, execution, project management and outsourcing. Go→
News, articles and issues specific to clinical trial practice and implementation at the investigative site level. Go→
Strategies and innovations related to how clinical professionals are utilizing technology internal and external to their organizations to advance clinical trials. Go→
News, articles and issues specific to laboratories role in the clinical trial, including ECG, imaging, genotyping, tissue samples and more. Go→
News, developments and strategies for clinical trials conduct in relation to the FDA, EMEA and other global regulatory authorities overseeing the drug development industry. Go→
News, articles and strategies related to clinical trial design which impact postmarketing studies, therapeutic areas, adaptive trials, statistics, protocols and more. Go→
PHT Corporation, the leading provider of technologies used to collect patient-driven electronic data for clinical research, has selected Dell Venue 11 Protablets featuring Windows 8.1 to run its SitePad® System. The SitePad System replaces traditional paper data collection methods in clinical research with electronic methods, providing better-quality data, real-time access to that data and, ultimately, faster time to data analysis for pharmaceutical trial sponsors. The SitePad System is used in clinical trials to collect clinician- and patient-reported outcomes for supporting label claims of new therapies.
PHT selected the Dell Venue 11 Pro with Windows 8.1 for the SitePad platform because the device provides a superior user experience. The Venue has a high-resolution touch screen that supports greater ease of use for both clinicians and patients. In addition to providing a superior user experience, the Dell Venue provides multiple modes of data communications including Wi-Fi, Ethernet and an embedded 4G card.
PHT chose the Windows 8.1 tablets because of the flexibility and security aspects of Microsoft technology and because the solution allows PHT to increase the quality of real-time site-based data capture for trial participants and clinicians. It also allows PHT to run custom software that helps decrease clinical trial costs for sponsors by reducing time spent downstream resolving missing and inconsistent data. The superior end-user experience helps provide additional convenience and comfort for end users, enabling rapid entry of electronic source clinical data.
"Paper is no longer the gold standard, and clinical trial sponsors are rapidly abandoning paper methods for collecting critical information about how patients feel and function in addition to key clinician observations and assessments," said Sheila Rocchio, vice president of Marketing & Product Management at PHT. "PHT is helping to lead the electronic transformation in clinical research by providing reliable, easy-to-use and regulatory-compliant systems that increase data quality and protocol compliance and reduce costs in monitoring and data management. In one recent trial, the SitePad System saved the sponsor more than 30 percent over the cost of paper."
PHT has purchased more than 2,000 Dell Venue 11 Pros, which will be deployed at clinical trial sites around the globe. Each SitePad is configured for a specific study protocol and used by clinicians and patients participating in the trial to collect study-specific assessments. Data collected on the SitePad device are sent to StudyWorksTM, the PHT online portal that provides real-time information about compliance as well as key measures used for study operations and patient safety monitoring. Each tablet is preconfigured with study-specific schedules, assessments and questionnaires. Patient and clinician compliance with SitePad on average exceeds 98.5 percent.
"The Dell Venue 11 Pro with Windows 8.1 is a modern and sleek device that both patients and clinicians enjoy using — the usability testing feedback has been excellent," Rocchio said. "Sponsors are also very excited about the embedded 4G modem in the Dell Venue 11 Pro, which eliminates the need for an additional wireless hotspot, making setup much easier."
More information about how organizations are turning to Microsoft technology is available on theMicrosoft Customer Spotlight newsroom.


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A Sister Giving Her Testimony of Healing Over Internet
JSarachikMar 7 2012, 95 views
Bishop Salamat Khokhar is a well known Healing Evangelist and Speaker. He is The Founder & Chairman of Grace Bible Church of Pakistan & All Pakistan Council of Churches. God give him the gift of healing of the sick and great miraculs. This Video is the testimony of healing work of God in the lives of His People.
Press the button
if you liked the video! Thank you!
Tennessee Couple 'do a Brangelina' World Record Adoption of 8 Children from Sierra Leone Orphanageby heavensky
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The Truth of The Gospel Surprises Critic
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aquilaonline @ flickr.com CC BY-NC 2.0The Rev. Dr. Martin Luther King, Jr., whose birthday America celebrates on Monday, does not exactly have a lot of recipes associated with him. The good reverend was born in Atlanta, however, and Atlanta and Coke just go together. Recipes with Coke usually tur ... More >>
bevreview.comJason Arango at the Daily Fork posted yesterday about Pepsi Throwback and Mountain Dew Throwback, versions of the popular soft drinks that are made with sugar instead of high-fructose corn syrup, sold in the usual plastic bottles with retro labels.Not to be outdone, the Dr Pepper Sna ... More >>
In another edition of what this writer's going to call "Free Things to Do This Weekend" (it's unofficial!), So-Cal's own barbershop quartet, The Alley Cats, comes home Friday night with a free concert at Chapman University. Formed in 1987 at Fullerton College, the group is considered as "Am ... More >>
Hey! I'm OC Weekly's new clubs editor! You may remember me as the guy who hung out with that one birther lady, but forget about that. I'm here for the drinks now.Thus far, this job has pretty much consisted of me revisiting the places I went during childhood, but getting drunk at them. Yeah, I gr ... More >>
It's a Red-Headed Slut with some Coke in it. Ha! The recipe is as follows: 1 oz peach schnapps, 1 oz Jagermeister, cranberry juice and a splash of Coca-Cola. This shot is a real gem for party girls and people wanting a good laugh. You can order them anywhere fine drinks are made. Have a great weeke ... More >>
Call it a reverse knee-jerk response, but when I saw this story about L.A.'s City Council's ban on new fast-food restaurants in South Los Angeles to combat obesity and the highest incidence of diabetes in the county, it made this blogger realize that he hasn't sunk his teeth into some Popeyes Chicke ... More >>
The J. Flynn Gallery's delicious, nutritious 'Strangest Life' show
Or, How I learned to stop worrying and love sleep deprivation, huge crowds and wonderful toys
Movie of the Week: Grand Hotel
Allow me to write a similar column to !Ask a Mexican! called Ask an American, and lets see which column people like more
Coke Jacker
Orange Countys Sexiest People
Jim Morrisons Birthday
OCDCs vibrant county art survey outperforms the big-pants museum shows
Naw, just a bunch of white kids watching the Doors
Election night with the biggest losers
A Sober Irishman?!?
We don't know whether to be proud, repulsed, jealous--all three? Chapman University grad stud Rosemary Lambert's short film The Reel Monkey won the Grand Prize in a film competition. So far, so good--until you discover it's the 2006 Coca-Cola Refreshing Filmmaker Competition. You see, student filmma ... More >>
This week in the coast
And who at Linbrook Bowl thinks a woman should be President?
Buy Nothing Day Bombs at Fashion Island
Falling in love with the club you love to hate
Cruising Huntington for someone to say hi to
Celebrating T-Day Eve 2003 with Buddha and the boys from Argentina
Kitsch Bars John and Avalons Garron drive me crazy in a good way
Ladies and Gentlemen, Miss Chile Pepper 2003!
All doped-up and nowhere to go
Ping Chong uncovers Lefty ideals! Critic yawns!
The Circle of Life rolls on
Sage Hill School may provide its wealthy students with a lesson in real-world politics
Part Two
Anti-El Toro Airport site grounded
Antojitos, where the sauce is so green
Its a witness and a hoot
Coke Stories tries to figure out a decade
Dogeaters marks the postmodernist triumph of style over truth


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Find records of Sara Loosier
Find birth, death, marriage, military, and other records of Sara Elizabeth Loosier at Ancestry.com.Search for records
Biography & Family History Add details
Sara Elizabeth Loosier (1925 - 2009) was born on July 8, 1925. She was born into the Loosier family.
Sara had no-known relationships. Sara died on September 27, 2009 at age 84.
Sara Elizabeth Loosier's last known residence is at Albany, Dougherty County, Georgia.
The data on this page comes from the official record for Sara Elizabeth Loosier in the SSDI (United States Social Security Master Death Index). The death certificate for this record has been observed. This data can be considered accurate. What is the SSDI?
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Possible Relatives
- Grady Loosier
- ·
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- ·
- Walter D Loosier
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- Jerry Loosier
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- Mildred A Loosier
- ·
- Arthur Loosier
- ·
- Carl Loosier
- ·
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1st presidential debate of 2012 is Wednesday night in Denver
Some are calling Wednesday night's presidential a deciding factor in the race to the White House.
The first presidential debate of 2012 will take place between Republican candidate Mitt Romney and President Barack Obama at the University of Denver. They will be face-to-face for the first time Wednesday night in nearly five years.
ClickOnDetroit.com will livestream the debate starting at 9 p.m.
The views expressed below are not those of Click On Detroit, WDIV, or its affiliated companies. By clicking on "Post," you acknowledge that you have read the Terms of Service and your comment is in compliance with such terms. Readers, please help keep this discussion respectful and on topic by flagging comments that are offensive or inappropriate (hover over the commenter's name and you'll see the flag option appear on right side of that line). And remember, respect goes both ways: Tolerance of others' opinions is important in a free discourse. If you're easily offended by strong opinions, you might skip reading comments entirely.


text:
The Goodrich Capital 8 Theaters in Jefferson City is facing a lot of backlash this week over an Iron Man 3 event featuring men in fake tactical gear and some with toy guns. Management says it was all part of a fun event involving local comic book fans -- and that the whole incident is being blown wa ... More >>
The Gut Check One Hundred is our accounting of the 100 dishes in St. Louis that you must eat right now. These are the best dishes at the newest restaurants and the newest dishes at the best restaurants. These are the 100 dishes that define St. Louis dining in 2013. Our list culminates this fall when ... More >>


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Wrinkles aren't the only indicator of age. A recent study conducted by the University of Goettingen and the University of Vienna suggests that discoloration may be just as incriminating, because an even skin tone is equated with youth, health, and fertility.
3 months: Eat right. Dermatologist Dr. Howard Murad says that to protect skin from spots, work from the inside out: "Up your internal SPF by eating raw fruits and vegetables rich in antioxidants, like pomegranates, goji berries, tomatoes, broccoli, strawberries, and green tea." The more consistent you are, the better your skin will look. The goal: a lifetime habit of good eating, and great skin.
1 month: Mix in vitamin C. Ingredients like hydroquinone and kojic acid have been Rx mainstays for years, but the newest and more gentle way to an even skin tone is vitamin C now delivered in high-tech "activated" but stable serums. Shiseido and Kiehl's have just debuted formulas that utilize the ingredient, alongside extracts like peony and angelica root, which together break up spot-causing melanin.
2 weeks: Resurface lightly. As an alternative to lasers and traditional ablative treatments that can take a month to heal, some derms are turning to plasma skin resurfacing, Portrait PSR3 (starting at around $2,500 for a full face treatment), a newly FDA-approved technology that uses high-energy ionized nitrogen to remove brown spots and kick-start a clear complexion overall. Expect redness and tenderness for about 14 days.
5 minutes: Try blemish balms. Also known as BB creams, a phenomenon in Asia, they're hitting the U.S. market full force. The idea? They instantly cover and treat skin imperfections, such as acne, dark spots, and scars. Dr. Fredric Brandt's new one-shade-fits-all formula adjusts to your skin tone after you apply it; Garnier's version comes in two shades and boasts mineral pigments.


text:
- You are here:
- Automobiles >
- Audi >
- Reviews
2013 Audi S4
A Standalone Sleeper Sport Sedan That Still Keeps Us Awake At Night The always-bustling Audi stand at next month's Detroit Auto Show figures to be cluttered with a full range of eighth-generation A4 models, all of which arrive in the States sometime between June and July. The line's real marquee model is, of course, the RS4, but that Rennsport ingredient will not be seen on the stand in Cobo just yet. (So let's change that to almost full range, and some sources are saying that there will not even be an RS4 this go-round.) The sauciest A4 present will be this model, the new S4, considere... Read More
Vital Stats
- Engine:
- Supercharged 3.0L V6
- Power:
- Transmission:
- 6-Speed Manual
We'll just come right out and say it: Audi lost the plot with the last generation S4. Unlike the twin-turbocharged V6-equipped B5, its B6 and B7 brethren did little to stoke the flames in our collective hearts. The "S" simply stood for, "I paid more for a bigger engine and some additional trim." Needless to say, that sort of behavior doesn't cut it when ...


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In British canine agility classes, there are often two sections: Border Collies and Anything but a Border Collie. The often black-and-white Border Collies, made famous in the movie Babe, are considered among the smartest and most agile dogs in the world and are in a class by themselves. I picked up Mr. and Mrs. Dog, by Donald McCaig, hoping for a little more understanding of our Border Collie, Tess, a pull from the local pound. Despite her hard upbringing, she is joyous and full of energy, leaping about like a lamb when it's time for a walk. But she gets down to business, too, gently making sure that everyone is in place and taken care of. Very responsive to commands, gestures, or just a hint of what's wanted, she wants to do what's required of her, almost obsessively. I did wonder, is this normal?
"A Celtic Childhood is the lyrical narrative of a gifted and animated storyteller. With humor and charm, Watkins blends history, song, and Celtic identity into a wonderful tale of misadventure and merriment. With this collection of colorful characters and humorous memories, a lucid picture of one man's history and identity is shaped. When asked how memory played a role--or played tricks--in writing his book, Watkins replied, 'When you're young you're like blottin' paper and you soak everything up. Sitting around the kitchen table, I heard these same stories and songs over and over again. Of course, part of the Celtic psyche is the ability to have memories that you've never had.'"
A Welsh poet recalls the celebration of Christmas in Wales and the feelings it evoked in him as a child. Also available as a video and an audio book.
The Merlin Conspiracy by Diana Wynne Jones
Being a permanent part of the King's Royal Procession isn't all it's cracked up to be, particularly when the realm's magic depends on him tromping up and down the countryside to keep the Isle of the Blest blessed.
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