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The distributed information systems experimentation (DISE) team, at the Naval Postgraduate School, uses knowledge management to plan and execute Department of Defense experiments. For example, the annual Trident Warrior series involves year-round coordination with geographically disparate organizations and personnel using both classified and unclassified networks.
During planning, execution, and the post-experiment stages of TW, data is collected through online feedback forms. The analysis of this and other collected data culminates in multiple decision informing reports.
DISE has been on the forefront of using KM for nearly a decade. The initial DISE team implemented a KM solution called FIRE (FORCEnet Innovation and Research Enterprise) in 2004 with the Oracle Collaboration Suite for Trident Warrior planning. OCS is comprised of a "shrinkwrapped" server with portal and collaboration applications. Before the advent of Web 2.0 collaboration and the flexibility of service oriented architecture, FIRE was considered somewhat advanced, and it served the needs of KM well.
The core backend of OCS is the database server which made Oracle a good choice. The "out-of-the-box" software was both a plus and a curse. For those just beginning KM and collaboration, the out-of-the box approach simplified many aspects of maintenance, but could also serve as a straightjacket because of the inability for customizing to meet ever-changing user requirements. Nevertheless, the simplified approach allowed extensive portal post-development work that included the development of forms and reports needed by the experimenters.
Over time the FIRE solution grew into an enterprise-wide product. With growth came production challenges, including the need for hardware upgrades; software updates and security patches; backup and recovery decisions; and a requirement for help desk support. In addition, because DoD-wide systems must be certified and accredited according to information assurance policies to operate on a defense network, we had to satisfy security requirements.
Many of the collaborative and data collection tools were limited on FIRE, and not flexible enough to expand capability and functionality when needed. The options for backup and recovery solutions were limited. In addition, our servers were reaching the five-year end of life cycle, and there was an opportunity to migrate to faster and cheaper servers to meet the new demands.
Since the heart of the system is the database, we decided to stay with an industry leader, so we chose Oracle Database 11g. The added bonus to using Oracle 11g is that the Navy has an Oracle Database Enterprise License which provides significant benefits, including substantial cost avoidance for the DON. (See page 66 for more information about the Navy's Oracle Enterprise License Agreement which requires mandatory use for Navy programs and activities covered by the agreement.)
For designing the next-generation architecture to build around the database, we determined that the system must:
Because our team is small, and we are risk averse, we took an evolutionary approach. There are many good KM collaboration products, but we used a conservative approach while creating options to add best-of-breed products when users required additional capability.
We stayed with Oracle products to minimize costs for licensing and training developers and maintainers because we concluded Oracle's features best met our requirements.
While the products are Oracle-specific, they are Java-based; therefore, the chance of vendor lock-in is reduced, and we could use other products, for example, from IBM or Microsoft, with the new KM portal. Because of our conservative approach, we reluctantly ruled out virtualization for this KM portal iteration, but it will remain a goal for future upgrades.
The Oracle solution consists of two major parts each connecting to an Oracle database. One part is Oracle Fusion Middleware that consists of the WebLogic Server, and the Oracle Portal 11g, which supports knowledge management efforts with seeded portlets, forms and reports.
Oracle Portal also comes with a suite of developer tools, including JavaServer Faces and Application Express (APEX), which allow custom development.
The second part of the new solution is collaboration and social networking capability using Oracle Beehive for chat, team workspaces, tasks, wikis, discussion groups, content management and Web conferencing. These features are tied together with Oracle Single Sign-On and Oracle Internet Directory (SSO/OID) which provide a single sign-on, not only for Oracle products, but any third-party products, such as SharePoint, that you might decide to add later.
Research and Learning
Even if your staff is experienced in IT management and programming, reaching a solution requires extensive research, learning about options and analysis. Prior to proposing an architecture to sponsors, a requirements and feasibility study should be conducted with a review of technology candidates that includes how easily a proposed technology can be bridged to your legacy system.
Technology is always in a state of flux so there is a point you just have to pull the trigger and go with the best technology at the time. Great care should be taken to explain backend improvements from a management perspective because users naturally concentrate on user enhancements and not necessarily in understanding management issues related to selecting enterprise software.
Production systems cannot just be thrown away and replaced by a new system, so decision makers must carefully consider how a new technology can be implemented without risking the whole enterprise.
Both Oracle and Red Hat products can be downloaded and used at no charge if you are testing concepts. Oracle also provides many of its applications (pre-built appliances) virtually through VirtualBox (www.virtualbox.org/), including Oracle 11g, WebLogic, TimesTen, APEX SQL Developer Data Modeler and JDeveloper. VirtualBox allows a quick way to explore software candidates without extensive installation or new hardware.
Once the basic architecture and requirements are determined in the critical research and learning stage, you will need a test lab. Our plan was to first build a lab to test various vendor software and hardware candidates, and on successful completion, move them to the production environment.
To build the lab we salvaged old server hardware and restored hard drives using SpinRite, a disk recovery tool. For some older servers we had to upgrade memory and central processing units. We then rack mounted all the servers, added a network switch, a kernel-based virtual machine, and an uninterruptible power supply to make the lab simulate the production environment.
Our small lab was not only a test environment but a learning one as well. We reinstalled test systems so many times that we could do it almost without thinking about it. We made many mistakes, but they were not costly because they were made in the lab and not in production. Installation mistakes can be fatal in a production environment, but in a test environment, they are instructional.
While you do not need to test the exact same architecture, you must mimic the general design of the production system. We emphasize that you must have test servers available even after moving into production.
Manpower and IA Challenges
Hardware and licensing are but a small part of the cost of any KM system. Initially, one person managed FIRE. But, with growth in the number of users, FIRE went through a major upgrade in 2007 using industry consultants working with DISE team members. By 2008, due to budget constraints, DISE faculty team members learned to run FIRE by attending Oracle and Red Hat classes.
The effort to modernize FIRE was spearheaded by DISE team members who began by researching new collaboration solutions at Oracle OpenWorld 2008. Most DISE team members are faculty who teach two to four classes a year, as well as working on other projects, so we had to identify additional team members for the project.
NPS students were unavailable because most were working full-time on master's or doctorate degrees. We eventually decided to recruit computer science interns from local colleges to assist. The resulting team was comprised of two faculty members and up to two to four interns. Although we all worked part-time on the project, we worked round-the-clock to ensure rapid progress.
Before going live on operational networks, all our servers went through a certification process conducted by an NPS information assurance team. Because DISE members are typically researchers who work on KM, and not IA professionals, this was particularly challenging. Approximately 80 percent of manpower costs may be related to IA requirements.
Anyone fielding a system in a classified environment should be careful not to underestimate the level of effort required. Instead of a standard Red Hat Enterprise Linux installation, which requires extensive post-installation rework to comply with IA security requirements, we installed a mini version of Red Hat using a custom configuration file known as Kickstart. Kickstart manages the operating system installation process to ensure required files and correct security and network settings are used.
Our Kickstart approach is based on the Defense Information Systems Agency's DoD Bastille, one of the projects of Forge.mil (www.forge.mil/), a DISA collaboration activity designed to improve the ability of the DoD to rapidly deliver dependable software, services and systems in support of net-centric operations and warfare.
Forge.mil capitalizes on concepts proven in open source software development that have already reaped tremendous benefits for software and technology development communities. Along with accelerating technology development and fostering innovation, Forge.mil can also enable early and continuous collaboration and information sharing among all stakeholders in a secure development environment.
Bastille integrates the specific security, technical and implementation guidelines required by DoD. We further modified Kickstart so that the Red Hat installation would also meet Oracle technical requirements. The Kickstart file can be reused for other OS installations with minimum modification, thus ensuring consistency and simplicity that would automatically implement our security and technical best practices.
Using Kickstart was only a first step; we then had to run DISA's approved Security Readiness Review (SRR) and Retina Network Security Scanner. The SRR produces a detailed report and delineates alerts based on severity as Category 1, 2 or 3, with CAT-1 as the most severe. Retina reports are more detailed and provide more specific fixes. Since the two software tools detect virtually all possible security holes, the reports are extensive, with each IA alert corrected one-by-one.
We resolved most of the more complex alerts with help from DISA documents and NPS faculty members, who were Linux experts. At times, the IA solutions made our system unstable so we had to reverse some changes. For this we used a server with a RAID 1 mirrored pair and always maintained a system backup to revert back to the original version. RAID, an acronym for redundant array of independent disks, is a technology that provides increased storage functions and reliability through redundancy.
Oracle server software uses a wide range of ports that may not be compatible with DoD network policy so it is important to consult with your network administrator and IA office. We recommend that you illustrate your architecture using Microsoft Visio, or a similar program, so that all parties have a clear understanding of the proposed architecture and how it fits into the overall infrastructure.
Oracle default ports can be changed, but this should be done prior to installation. The installation may need a reverse proxy; we used Squid, an open source high-performance caching proxy server designed to run on Unix systems.
Opening a port is complicated and tedious; involving a lot of time and paper work, so the Squid reverse proxy server was a quick and adequate solution. Our solution involved four physical servers residing on the DMZ and the internal network.
A DMZ, or demilitarized zone, is a subnetwork that exposes an organization's external services to a larger untrusted network, usually the Internet; it also adds an additional layer of security. We recommend that the database and Oracle Single Sign-On and Oracle Internet Directory reside on internal networks.
The Oracle Portal and Beehive should reside in the DMZ. To get this configuration to work properly, we had to construct unique port configurations. Finally, all Web connections had to be encrypted connections (HTTPS), which required testing DoD root certificates in a development lab to ensure trusted site identification for users accessing FIRE, and generating new certificates for production servers.
Handling Database Growth
Originally, the servers were running from a single server with approximately 300 gigabytes of storage. We quickly realized the storage disks were reaching capacity, and we were routinely deleting files to increase available disk space.
In our lab we tested a Dell disk storage array dedicated to the database that gave us more room to work with and expand. We are also exploring automatic storage manager (ASM) solutions to seamlessly grow Oracle database storage. Changing RAID configurations to allow growth might be difficult or impossible after installation so it's better to get it right the first time.
Vendor Support
Selecting the right hardware and software greatly depends upon the quality of support available for your system. For Oracle support we purchased a plan for 24/7, 365 days of online and telephone support. The Oracle support team has experts for each of its applications, and we talked to them whenever we had a problem to resolve.
In some cases, Oracle support staff would call us or set up a Web conference if we were dealing with an issue that was critical to our mission. They were also great teachers if we didn't understand a concept. For this support we chose a pricing model based on number of users as opposed to number of processors. This worked well within our budget, and it is the cheapest way to go if you have less than 300 users.
In addition to the savings we obtained by using the Navy Oracle Database Enterprise License Agreement, we used contract models, like the GSA Schedule, to bring costs down.
Testing Your System and Going Live
Even with a well-planned system, it is vital that you thoroughly test and not only within your environment. We tested our system on the Navy Marine Corps Intranet and found additional port problems so having users access the system via different networks is important to eliminating problems.
We made a major effort to respond quickly to our representative users to quickly resolve any connectivity problems, but it may take several weeks to resolve site specific network or specific client problems. The success of these efforts begins with a well-written test plan.
With little developer work required, Oracle Beehive provides collaboration and social networking tools right out of the box. Some development work is required for the Web portal to provide users with dynamic content and an interactive experience. Portal 11G offers developers a variety of tools and seeded portlets to capture and display data and reports.
We chose the Linux operating system to run Oracle products, and we used the NPS Information Technology and Communications Services (ITACS) contract with Red Hat, Inc. Red Hat's Web and phone support is comparable to the support that Oracle and Dell offer.
On the hardware side, we chose Dell servers. ITACS has a contract with Dell, and Dell support is provided around-the-clock. We could also get replacement parts within one workday.
The architecture leaves a small foot print, just 5U (a rack unit measurement), consisting of five rack-mounted PowerEdge R610 servers featuring reduced power consumption. The 610s offer room to grow with two sockets and up to 48 gigabytes of memory. The servers have room for six 2.5-inch Serial Attached SCSI (SAS) drives that allowed us to configure RAID 1 mirrored (two) hard drives for the operating system and RAID 5 striping (four) hard drives for the databases and Web servers. This configuration allowed some fault tolerance in case of hard drive failure.
SAS is a computer bus used to move data to and from computer storage devices. In computer data storage, data striping is the technique of segmenting logically sequential data, such as a file, in a way that accesses of sequential segments are made to different physical storage devices.
Striping is useful when a processing device requests access to data more quickly than a storage device can provide access. By performing segment accesses on multiple devices, multiple segments can be accessed concurrently. This provides more data access throughput, which avoids causing the processor to idly wait for data accesses. Striping is used across disk drives in RAID storage, network interfaces in grid-oriented storage, and RAM in some systems.
The DISE and ITACS teams signed a memorandum of understanding that enabled us to host servers in a production grade network operations center. The temperature and dust-controlled NOC has high-speed connectivity to the Internet and to military (.mil) networks. In addition, it provides power backup using batteries and generators.
Backup and Recovery
Because we are running several different servers, we had to implement separate backup strategies. For the Oracle Database 11G, we used information gleaned from the database training class and ran the database in archive log mode, which enables hot backup (also called a dynamic backup), point-in-time recovery and scheduled daily backup.
A hot backup can be performed on data even though it is actively accessible to users and may be in a state of being updated. Hot backups can provide a convenient solution in multi-user systems because they do not require downtime, as does a conventional cold backup.
We use Dell Storage Enclosure to store backups on a single array. The servers are connected to the single storage array with multiple disk controllers for redundancy. We also produce large capacity tape drive backups for off-site storage.
Lessons Learned
We believe that a small team can create an effective enterprise KM system if the team plans well and addresses the issues we discussed. Critical in all of the efforts is a robust test environment and strong support from your IA team.
Nothing we did was extremely technical. If your team is willing to do some "homework" and has the patience to persevere though occasional setbacks, the reward could be a KM portal that will specifically meet the needs of small groups doing important work.
Arijit Das is a faculty member in the computer science department at the Naval Postgraduate School.
Tony Kendall is a faculty member in the information sciences department at the Naval Postgraduate School.
CHIPS is an official U.S. Navy website sponsored by the Department of the Navy (DON)
Chief Information Officer, the Department of Defense Enterprise Software Initiative
(ESI) and the DON's ESI Software Product Manager Team at Space and Naval Warfare
Systems Center Pacific.
Online ISSN 2154-1779; Print ISSN 1047-9988
Hyperlink Disclaimer


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Sometimes, the best treatment for certain diseases may not be in your home country. And Australia is a go-to spot for foreigners seeking for better medical care. After all, Australia's healthcare system is ranked number 2 in the developed world in a recent study done by American researchers.
With this knowledge, how can you get one of the best treatments available as a foreigner? The Australian Government offers Medical Treatment Visa (Subclass 602) for you.
Who is This Visa for?
The Medical Treatment Visa (Subclass 602) allows you to enter Australia for medical services.
This visa is for you if you are either traveling:
- For medical treatment and consultations
- To support someone needing medical treatment who holds or applied for this visa
- To donate an organ
You must NOT have a medical condition hazardous to the public. And you should not be a holder of Visa Subclass 426 and Visa Subclass 403 (Domestic Worker Stream).
In applying for the visa, the applicant should prove that you are financially fit to support yourself and the treatment for the duration of the trip.
Also, you must meet health requirements and character requirements for visa approval.
What Can You Do With This Visa?
Aside from the medical treatment period, this visa allows you to study for up to three months in Australia. Also, it allows you to stay in Australia until the treatment is completed or go back-and-forth while your visa is valid.
What are the Costs and Length of Stay?
Generally, your period of stay will depend on the period of treatment.
If you applied for the visa outside Australia, there will be no cost for the visa application. And the length of stay is usually up to 3 months.
If you applied for the visa inside Australia, you are charged $285 AUD for the application. But the length of stay is usually granted for up to 12 months.
It is important to note that this cost does not include health assessments, police certificates, and other certificates or tests. It is best to ask immigration for additional requirements that you might need.
With that, I hope you get well soon. Welcome to Australia!

subset: commoncrawl


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נמצאו זבין וטמאי מתים משתלחין חוץ למחנה אחת והתורה אמרה (במדבר ה, ג) ולא יטמאו את מחניהם
it would consequently be found that both zavim and those who are ritually impure from impurity imparted by a corpse are sent out of one camp, i.e., the camp of the Divine Presence, and both are permitted in the Israelite camp. But the Torah said with regard to sending the ritually impure out of the camp: "Outside the camp you shall put them; that they will not defile their camps" (Numbers 5:3).
תן מחנה לזה ומחנה לזה
The use of the plural "camps" indicates: Give a specific camp to this group, i.e., those who are ritually impure from impurity imparted by a corpse, who may enter the Levite camp but are forbidden to enter the camp of the Divine Presence, and give a specific camp to this group, i.e., those who are zavim, who may enter the Israelite camp but are forbidden to enter the camp of the Divine presence or the Levite camp. If there were no Levite camp in Shiloh, it would follow that both a zav and one who is ritually impure from the impurity imparted by a corpse are sent out of only one camp, and there is no distinction between them.
א"ל רבא אלא מאי מחנה ישראל לא הואי נמצאו זבין ומצורעין משתלחין למקום אחד והתורה אמרה (ויקרא יג, מו) בדד ישב שלא ישב טמא אחר עמו
Rava said to him: Rather, what would you say instead? Would you say that the Israelite camp was not present in Shiloh? If so, it would be found that zavim and lepers are both sent to one place, i.e., outside the Levite camp. But the Torah said with regard to the leper: "He shall dwell alone; outside the camp shall his dwelling be" (Leviticus 13:46). The word "alone" teaches that another ritually impure person should not dwell with him.
אלא לעולם כולהו תלתא הוו ומאי לא היו אלא שתי מחנות לקליטה מכלל דבמדבר הואי קלטה מחנה לויה
Rather, it must be that actually, all three camps were present in Shiloh, and what is the meaning of that which was taught with regard to Shiloh: There were only two camps? It is with regard to the fact that the Levite camp did not provide refuge to one who unintentionally killed another. The Gemara asks: By inference, does this mean that in the wilderness the Levite camp did provide refuge to those who unintentionally killed others?
אין והא תניא (שמות כא, יג) ושמתי לך מקום בחייך מקום מקומך (שמות כא, יג) אשר ינוס שמה מלמד שמגלין במדבר להיכן גולין למחנה לויה
The Gemara replies: Yes, and so it is taught in a baraita with regard to the verse concerning the cities of refuge. The verse states: "And one who did not lie in wait…and I will appoint for you a place where he may flee" (Exodus 21:13). The phrase "I will appoint for you" teaches that God said to Moses: There will be a place that provides refuge for unintentional murderers even during your lifetime. The term "a place" means that it will be from your place, meaning the Levite camp served as the place that provided refuge in the wilderness. "Where he may flee" teaches that the Jews would exile unintentional murderers in the wilderness as well, before they entered the land. To where did they exile unintentional murderers when they were in the wilderness? They exiled them to the Levite camp, which provided refuge.
מכאן אמרו בן לוי שהרג גולה מפלך לפלך ואם גלה לפלכו פלכו קולטו
From here the Sages said: A Levite who killed unintentionally is exiled from one Levite city to another Levite city. And if he was exiled to another area within his city, he is admitted to his city, i.e., it provides him with refuge.
מאי קרא אמר רב אחא בריה דרב איקא (במדבר לה, כח) כי בעיר מקלטו ישב עיר שקלטתו כבר:
The Gemara asks: What is the verse from which the principle is derived that one who was already exiled to a city of refuge and who then killed another person is exiled to another area in that same city? Rav Aḥa, son of Rav Ika, says that the verse: "For in his city of refuge he shall dwell" (Numbers 35:28), indicates that he can be exiled to a city in which he was already admitted, as the verse is referring to it as his city, and he shall continue to reside there.
באו לגלגל: ת"ר כל נידר ונידב היה קרב בבמה שאין נידר ונידב אין קרב בבמה מנחה ונזירות קריבין בבמה דברי ר"מ וחכ"א לא קרבו יחיד אלא עולות ושלמים בלבד
§ The mishna teaches that when the Jewish people arrived at Gilgal private altars were permitted. The Gemara elaborates: The Sages taught in a baraita: Any offering that was brought due to a vow, or contributed voluntarily, was sacrificed on a private altar; and any offering that is neither brought due to a vow nor contributed voluntarily, but rather is compulsory, was not sacrificed on a private altar. Therefore, a meal offering, which is generally brought voluntarily, and offerings of a nazirite, which have the status of vow offerings as no one is compelled to become a nazirite, were sacrificed upon a private altar. This is the statement of Rabbi Meir. And the Rabbis say: Only burnt offerings and peace offerings were sacrificed upon a private altar, not meal offerings or offerings of a nazirite.
ר' יהודה אומר כל שהצבור והיחיד מקריבין באהל מועד שבמדבר מקריבין באהל מועד שבגלגל מה בין אהל מועד שבמדבר לבין אהל מועד שבגלגל אהל מועד שבמדבר לא היו במות מותרות אהל מועד שבגלגל היו הבמות מותרות ובמתו שבראש גגו לא היה מקריב עליה אלא עולה ושלמים
Rabbi Yehuda says: Any offering that the public or an individual could sacrifice in the Tent of Meeting in the wilderness could also be sacrificed in the Tent of Meeting in Gilgal. What, then, is the difference between the Tent of Meeting in the wilderness and the Tent of Meeting in Gilgal? During the period of the Tent of Meeting in the wilderness private altars were not permitted and offerings could be sacrificed only in the Tabernacle, while during the period of the Tent of Meeting in Gilgal private altars were permitted. But even if one desired to sacrifice an offering upon his private altar on his roof, he could still sacrifice upon it only burnt offerings and peace offerings.
וחכ"א כל שהצבור מקריבין באהל מועד שבמדבר מקריבין באהל מועד שבגלגל וכאן וכאן לא קרבו יחיד אלא עולה ושלמים בלבד ר' שמעון אומר אף צבור לא הקריבו אלא פסחים
And the Rabbis say: Any offering that the public could sacrifice in the Tent of Meeting in the wilderness could also be sacrificed in the Tent of Meeting in Gilgal, and here, in the Tabernacle in Gilgal, and there, upon private altars, only burnt offerings and peace offerings were sacrificed for an individual. Rabbi Shimon says: Even the public did not sacrifice every type of offering in the Tent of Meeting in Gilgal; they sacrificed only Paschal offerings


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Mini Review ARTICLE
Cell death paradigms in the pathogenesis of Mycobacterium tuberculosis infection
- 1Department of Immunology, National Institute for Research in Tuberculosis, Chennai, India
- 2Department of Immunology, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
Cell death or senescence is a fundamental event that helps maintain cellular homeostasis, shapes the growth of organism, and provides protective immunity against invading pathogens. Decreased or increased cell death is detrimental both in infectious and non-infectious diseases. Cell death is executed both by regulated enzymic reactions and non-enzymic sudden collapse. In this brief review we have tried to summarize various cell death modalities and their impact on the pathogenesis of Mycobacterium tuberculosis.
Cell death is a primordial event in embryogenesis, metamorphosis, and in innate immune response against the invading pathogens. Cell death as a defense mechanism is also documented in the plant kingdom (Kabbage et al., 2013). Cell death is executed in a series of ordered biochemical cascades and is referred as programmed cell death or PCD.
Till early 2000, cell death was discussed as dichotomy in terms of either apoptosis or necrosis. However, with the growth of science many distinct modes of cell death with well-organized signaling cascades were unraveled. Currently, there exists nine different forms of cell death namely apoptosis (Fink and Cookson, 2005), autophagy (Fink and Cookson, 2005), mitoptosis (Chaabane et al., 2012), necrosis (Fink and Cookson, 2005), necroptosis (Galluzzi and Kroemer, 2008), netosis (Remijsen et al., 2011), oncosis (Fink and Cookson, 2005), pyroptosis (Fink and Cookson, 2005), and pyronecrosis (Willingham et al., 2007). It is still a puzzle whether these pathways are different features of the same response or physiologically distinct responses. Apoptosis as an defense mechanism initiates both innate and adaptive immunity (Behar et al., 2010). However, pathogenic organisms have developed mechanisms to modulate apoptosis for their survival. Apoptosis of the infected cells have been reported to be a favorable outcome for the dissemination of infections like Yersinia, Francisella, etc. (Ruckdeschel et al., 1997; Wickstrum et al., 2009). On the contrary, impairment of apoptosis provides a survival niche to many intracellular pathogens including Mycobacterium tuberculosis (Behar et al., 2010), leads to auto immunity, cancer and degenerative disorders (Elmore, 2007). Studies in M. tuberculosis have identified a causal relationship between virulence of the strain and induction of apoptosis. Inhibition of apoptosis favors M. tuberculosis survival in many ways like preventing bactericidal effects, T-cell priming, etc. (Velmurugan et al., 2007). In contrast, a recent report states that apoptosis inducing strains could disseminate M. tuberculosis infection (Aguilo et al., 2013). Necrotic cell death of burdened M. tuberculosis infected cells was shown to pave way for re-infection (Butler et al., 2012). In here, we summarize various apoptotic modalities and their role in the pathogenesis of M. tuberculosis. Furthermore, we share our experience in analyzing these responses in M. tuberculosis infection.
Models of Cell Death
First represented in the article by Kerr, Wyllie, and Currie in 1972 (Elmore, 2007). Apoptosis is an energy dependent regulatory process that disintegrates the dying cell by enclosing the cytoplasmic contents inside membrane bound vesicles called apoptotic bodies. These apoptotic bodies are engulfed by the phagocytic cells by a process called efferocytosis thereby efficiently clearing the dying cell without any inflammatory responses (Lee et al., 2009). Three pathways namely extrinsic/ligand-mediated pathway, intrinsic/mitochondrial pathway, and the granzyme B-mediated pathway regulate the process of apoptosis upon activation by physiological or pathological conditions (Elmore, 2007). The major players in apoptosis are caspases, adaptor proteins, tumor necrosis factor (TNF) receptor (TNF-R) super family, and Bcl-2 family of proteins (Strasser et al., 2000). There are three categories of caspases; initiators (caspase-2,-8,-9,-10), effectors or executioners (caspase-3,-6,-7), and inflammatory caspases (caspase-1,-4,-5) (Elmore, 2007). Caspase-activated DNases activate endonuclease that produce the typical internucleosomal DNA cleavage during apoptosis (Strasser et al., 2000). Adapter proteins play a major role in apoptosis as a link between caspases and the TNF-R by mediating homotypic interactions between the domains death domain, the death effector domain, and the caspase recruitment domains (Strasser et al., 2000).
Bcl-2 family of proteins are classified into three types that fall into pro-survival and pro-apoptotic categories based on the amino acid sequence homology to Bcl-2 homology regions BH1–BH4. Pro -survival Bcl-xL, Bcl-w, A1/Bfl-1, Mcl-1, and Boo/Diva have three or four bcl-2 homology regions while the pro-apoptotic members called Bax-like death factors Bax, Bcl-xS, Bak, and Bok/Mtd contain two or three homology regions (Pecina-Slaus, 2010). The third group of proteins Bad, Bik/Nbk, Bid, Hrk/DP5, Bim/Bod, and Blk, etc. that possess only a BH3 region are potent inducers of apoptosis (Strasser et al., 2000).
Apoptotic pathways
• Extrinsic pathway is initiated by binding of the ligands like TNF-α, FasL, CD95L, TRAIL, etc. to their respective receptors TNFR, Fas/CD95, and DR3 on the cell surface. This activates the initiator caspases such as caspases 8 and 10 that results in the formation and activation of death inducing signaling complex (DISC) that activates caspase 3 (Pecina-Slaus, 2010; Kalimuthu and Se-Kwon, 2013). Caspase 3 activation leads to cleavage of various death substrates that results in the characteristic hallmarks of apoptosis like DNA fragmentation, membrane blebbing, etc. (Kalimuthu and Se-Kwon, 2013).
• Intrinsic pathway of apoptosis is trigged due to the intracellular death signals. Mitochondrial enzyme endonuclease G, Bcl-2 family of proteins like Bax, Bid, and other mitochondrial proteins AIF, DIABLO [SMAC (second mitochondria-derived activator of caspases)], and cytochrome C plays a major role in this response (Kalimuthu and Se-Kwon, 2013). Upon the stimulus, the BH3-only protein Bid activates Bax and Bak that results in conformational change and oligomerization, forming an oligomeric pore in the outer mitochondrial membrane called permeability transition pores (Ferri and Kroemer, 2001; Kalimuthu and Se-Kwon, 2013). This results in the release of cytochrome C and other pro-apoptotic factors from the mitochondria into the cytosol. Cytochrome C interacts with Apaf and activates caspase-9 forming a multi-protein subunit complex called casposome (apoptosome) comprising cytochrome C, Apaf-1, procaspase-9, and ATP. In the absence of death stimulus, inhibitor of apoptosis family proteins (IAP) inactivates the caspase activity by direct binding. However, upon apoptotic stimuli IAPs are negatively regulated by SMAC and that leads to the activation of caspase-3 (Pecina-Slaus, 2010; Kalimuthu and Se-Kwon, 2013). Furthermore, extrinsic pathway was found to influence the intrinsic pathway of apoptosis by truncation of Bid (Cillessen et al., 2007).
• Granzyme B-mediated pathway utilizing the extrinsic mode of apoptosis is used by cytotoxic T lymphocytes as a mechanism to kill its target. Besides this, the secretion of pore forming granules containing serine proteases granzyme A and granzyme B also execute apoptosis that is both dependent and independent of caspase activation (Elmore, 2007).
It is a regulated homeostatic response conserved in all living cells degrading their own cytoplasm. Autophagy is a predominant cell survival response that is involved either in nutrient turnover or energy production during stress or removal of long lived cells or to protect against invading intracellular pathogens (Chaabane et al., 2012). Three forms of autophagy namely macroautophagy, microautophagy, and chaperone-mediated autophagy exist. During the autophagy, damaged organelle is lined with an isolation membrane called the phagophore that enlarges forming the double membrane structure called autophagosome. The autophagosome fuses either with late endosomes or lysosomes causing cell death (Levine and Deretic, 2007; Remijsen et al., 2011). Autophagy is regulated by autophagy-related proteins, serine/threonine kinase, mammalian target of rapamycin (mTOR), class I and class III phosphoinositide 3-kinases (PI3Ks) (Levine and Deretic, 2007; Su et al., 2013).
Apoptotic changes inside the mitochondria are called mitoptosis. Mitoptosis is still in infancy and no specific factors have been identified. The identification is based on morphological changes like disintegrating cristae, swollen mitochondria, etc. (Chaabane et al., 2012).
Accidental cell death induced due to pathological or physiological conditions are called necrosis. During necrosis, swelling of organelles like endoplasmic reticulum, mitochondria occurs thereby rupturing the plasma membrane. This leaks the intracellular contents of the necrotic cell into the intercellular space causing inflammatory responses (Fink and Cookson, 2005; Chaabane et al., 2012).
In the year 2008, Hitomi et al. reported that necrosis could be a regulated process of cell death. The activation of serine/threonine kinase RIP1, BH3 only protein Bmf, and mitochondrial dysfunction executes necroptosis (Galluzzi and Kroemer, 2008).
In 2004, the findings of Brinkman group unveiled another cell death program named by Steinberg in 2007 called NETosis (Mesa and Vasquez, 2013). One among the defense mechanisms used by neutrophils is the extrusion of intracellular material in the form of extracellular traps (ETs) to the surrounding extracellular medium. This concentrates the microbicidal substances to trap and kill pathogens (Mesa and Vasquez, 2013). Release of ETs by neutrophils is called NETs and mast cells as MCETs. NETs are composed of DNA and histones, and they are resistant to degradation by proteases, insensitive to caspase inhibition and necrostatins (cytoprotective agents) (Mesa and Vasquez, 2013). During NETosis both the nuclear and granular membranes disintegrate leaving the plasma membrane intact (Remijsen et al., 2011). NETosis is activated by pathogens, platelets activated with LPS and in eosinophils (Remijsen et al., 2011). Formation of NET is both nuclear and mitochondrial in origin.
It is the swelling of cells that involves rapid plasma membrane breakdown, and swollen nuclei without internucleosomal DNA fragmentation. Oncosis depletes cellular energy and leads to failure of the ionic pumps in the plasma membrane. It is elicited by agents that disrupt the ATP production of the cell (Fink and Cookson, 2005).
Apoptosis in general does not induce an inflammatory response. However, apoptosis in Shigella, Salmonella, Francisella, and Legionella infections produce inflammatory responses that are called as pyroptosis (Carneiro et al., 2009; Lee et al., 2011). Pyroptosis is executed by the formation of inflammasomes by bacterial products involving NLRC 4 (Nod-like receptor—NLR), that activates caspase-1 and the processing of IL-1β and IL-18 cytokines promoting cell death (Fink and Cookson, 2005; Carneiro et al., 2009).
Cathepsin B-dependent apoptosis that is independent of caspase-1 activation and inflammasome formation is called pyronecrosis. This mode of apoptosis is observed in shigellosis (Willingham et al., 2007; Carneiro et al., 2009).
Other Apoptotic Models
• Tumor suppressor protein 53 (TP53) induced apoptosis involves the transcriptional induction of redox proteins, generation of reactive oxygen species, and oxidative degradation of mitochondrial components that results in cell death. TP53 was shown to transcriptionally regulate proapoptotic proteins like Bax and NOXA (Yamada et al., 2002).
• NF-kB expression is implicated in the survival of living cells. NF-kB family contains five proteins namely c-Rel, RelA, RelB, p50/p105, and p52/p100. NF-kB as a homo or hetero dimers bind to the kB sites on their target DNA and regulate their expression (Barkett and Gilmore, 1999). NF-kB is activated by various stimuli like pathogens, mitogens, proinflammatory cytokines, etc. It plays a major role in immune responses and affects the expression of genes c-IAP-1 and c-IAP-2, Fas ligand, c-myc, p53, etc. involved in apoptosis (Zhang and Ghosh, 2001). Two TNF receptors TNFRSF8 and TNFRSF9 were shown to promote apoptosis, former activating, and latter inactivating NF-kB expression (Wang et al., 2008).
Apoptosis and Mycobacterium Tuberculosis
M. tuberculosis infections with virulent strains have been reported to inhibit macrophage apoptosis (Behar et al., 2010). Varied mechanisms of apoptotic suppression have been reported in M. tuberculosis infections (Table 1) unraveling the tactics of this pathogen to generate a protective niche inside the host. Among the various cell death modalities described above, only three apoptotic responses were documented in M. tuberculosis infection namely apoptosis (nuoG, SecA2, pknE, lpqH, esxA (ESAT-6), PE_PGRS33, pstS-1, Rv3654c, and Rv3655c), pyroptosis (zmp1, Rv3364c), and autophagy (eis) (Hinchey et al., 2007; Velmurugan et al., 2007; Jayakumar et al., 2008; Master et al., 2008; Sanchez et al., 2009, 2012; Danelishvili et al., 2010, 2012; Shin et al., 2010).
Serine/Threonine Protein Kinases (STPK)
Two component signaling systems were considered as the standalone mechanism of signaling in prokaryotes in response to environmental cues. However with the availability of various molecular techniques serine, threonine, and tyrosine mediated phosphorylation events unique to eukaryotes were documented in pathogenic prokaryotes like M. tuberculosis, Streptococcus species, Staphylococcus spp, Pseudomonas spp, etc. (Chao et al., 2009; Chakraborti et al., 2011). Among the 11 STPKs that M. tuberculosis encodes, only five of them pknE, pknG, pknH, pknI, and pknK were reported to support intracellular survival (Walburger et al., 2004; Papavinasasundaram et al., 2005; Jayakumar et al., 2008; Gopalaswamy et al., 2009; Malhotra et al., 2010). Our data for the first time proved that PknE was the only STPK to inhibit apoptosis (Jayakumar et al., 2008).
pknE in Innate Immunity
The function of pknE was established from our studies using the deletion mutant ΔpknE generated using specialized transduction. Deletion of pknE had reduced intracellular survival, increased apoptosis, and reduced proinflammatory responses (Jayakumar et al., 2008). Subsequent molecular pathogenesis studies revealed that the deletion of pknE promotes macrophage cell death dependent on intrinsic pathway of apoptosis, TP53, and Arg2. This apoptosis was independent of TNF-α, iNOS, Akt, Arg1, and pro-inflammatory cytokines (Kumar and Narayanan, 2012). M. tuberculosis encounters reactive nitrogen and oxygen intermediates inside the macrophages as one among the host defenses. Characterization of the promoter of the pknE gene showed its elevated expression during nitric oxide (NO) stress (Jayakumar et al., 2008). Macrophage experiments performed using NO donor sodium nitroprusside to mimic the host microbicidal activity confirmed that, pknE in response to NO stress suppresses innate immune responses (Kumar and Narayanan, 2012). In vitro studies carried with the deletion mutant showed defective growth in pH 7.0 and lysozyme (a cell wall-damaging agent) with better survival in pH 5.5, SDS (surfactant stress), and kanamycin (a second-line anti-tuberculosis drug). ΔpknE was reduced in cell size during growth in liquid media and exhibited hypervirulence in a guinea pig model of infection (Kumar et al., 2012). The data from the in vitro studies highlighted the role of pknE in adaptive responses of M. tuberculosis. Recently we reported that, deletion of pknE results in defective phosphorylation kinetics of MAPKs (p38MAPK, Erk½, and SAPK/JNK) and their transcription factors ATF-2 and c-JUN. Deletion of pknE also revealed crosstalks in the host macrophages where Erk½ signaling was found to be influenced by SAPK/JNK and p38 pathways independently. Modulations in intra cellular signaling altered the expression of coreceptors CCR5 and CXCR4 in macrophages infected with the deletion mutant of pknE that were authenticated using HIV tropic strains (Parandhaman et al., 2014). For the first time, our data showed that difference in apoptosis and intracellular signaling events, and the virulence capacity of the M. tuberculosis strain could influence the copathogenesis of HIV infection (Parandhaman et al., 2014). Collectively the reports show that pknE has a role suppression of innate immunity and help M. tuberculosis to adapt to the different environmental condition that it encounters.
Molecular techniques have revolutionized our understanding of pathogenic organisms and their interactions with the immune system. Pathogenic organisms have evolved host mimicking properties and utilize the host responses for their own survival and propagation. This review has addressed the various mechanisms of cell death that is vital for initiating an innate and adaptive immunity against the invading pathogen. As novel cell death paradigms evolve, it adds to the complexity of how temporally and spatially the immune system coordinates these responses. Most of the cell death models described here disrupt the energy source of the cell, mitochondria indicating whether these paradigms are interconnected response of a single biochemical event and this still remains a puzzle. Adding complexity to this conundrum is that, pathogenic organisms like M. tuberculosis is able to inhibit the various apoptotic models that were discovered so far. This arise the question whether M. tuberculosis by educating itself avoids cell death or has antigens that are poor inducers of cell death and that await further studies.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Ryan, R. C., O'Sullivan, M. P., and Keane, J. (2011). Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells. BMC Microbiol. 11:237. doi: 10.1186/1471-2180-11-237
Sanchez, A., Espinosa, P., Esparza, M. A., Colon, M., Bernal, G., and Mancilla, R. (2009). Mycobacterium tuberculosis 38-kDa lipoprotein is apoptogenic for human monocyte-derived macrophages. Scand. J. Immunol. 69, 20–28. doi: 10.1111/j.1365-3083.2008.02193.x
Sanchez, A., Espinosa, P., Garcia, T., and Mancilla, R. (2012). The 19 kDa Mycobacterium tuberculosis lipoprotein (LpqH) induces macrophage apoptosis through extrinsic and intrinsic pathways: a role for the mitochondrial apoptosis-inducing factor. Clin. Dev. Immunol. 2012:950503. doi: 10.1155/2012/950503
Santucci, M. B., Amicosante, M., Cicconi, R., Montesano, C., Casarini, M., Giosue, S., et al. (2000). Mycobacterium tuberculosis-induced apoptosis in monocytes/macrophages: early membrane modifications and intracellular mycobacterial viability. J. Infect. Dis. 181, 1506–1509. doi: 10.1086/315371
Schaible, U. E., Winau, F., Sieling, P. A., Fischer, K., Collins, H. L., Hagens, K., et al. (2003). Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat. Med. 9, 1039–1046. doi: 10.1038/nm906
Shin, D. M., Jeon, B. Y., Lee, H. M., Jin, H. S., Yuk, J. M., Song, C. H., et al. (2010). Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling. PLoS Pathog. 6:e1001230. doi: 10.1371/journal.ppat.1001230
Sly, L. M., Hingley-Wilson, S. M., Reiner, N. E., and McMaster, W. R. (2003). Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. J. Immunol. 170, 430–437.
Stenger, S., Hanson, D. A., Teitelbaum, R., Dewan, P., Niazi, K. R., Froelich, C. J., et al. (1998). An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282, 121–125. doi: 10.1126/science.282.5386.121
Strasser, A., O'Connor, L., and Dixit, V. M. (2000). Apoptosis signaling. Annu. Rev. Biochem. 69, 217–245. doi: 10.1146/annurev.biochem.69.1.217
Su, M., Mei, Y., and Sinha, S. (2013). Role of the crosstalk between autophagy and apoptosis in cancer. J. Oncol. 2013:102735. doi: 10.1155/2013/102735
Velmurugan, K., Chen, B., Miller, J. L., Azogue, S., Gurses, S., Hsu, T., et al. (2007). Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells. PLoS Pathog. 3:e110. doi: 10.1371/journal.ppat.0030110
Walburger, A., Koul, A., Ferrari, G., Nguyen, L., Prescianotto-Baschong, C., Huygen, K., et al. (2004). Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304, 1800–1804. doi: 10.1126/science.1099384
Wang, M., Windgassen, D., and Papoutsakis, E. T. (2008). A global transcriptional view of apoptosis in human T-cell activation. BMC Med. Genomics 1:53. doi: 10.1186/1755-8794-1-53
Wickstrum, J. R., Bokhari, S. M., Fischer, J. L., Pinson, D. M., Yeh, H. W., Horvat, R. T., et al. (2009). Francisella tularensis induces extensive caspase-3 activation and apoptotic cell death in the tissues of infected mice. Infect. Immun. 77, 4827–4836. doi: 10.1128/IAI.00246-09
Willingham, S. B., Bergstralh, D. T., O'Connor, W., Morrison, A. C., Taxman, D. J., Duncan, J. A., et al. (2007). Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2, 147–159. doi: 10.1016/j.chom.2007.07.009
Yamada, T., Goto, M., Punj, V., Zaborina, O., Kimbara, K., Das Gupta, T. K., et al. (2002). The bacterial redox protein azurin induces apoptosis in J774 macrophages through complex formation and stabilization of the tumor suppressor protein p53. Infect. Immun. 70, 7054–7062. doi: 10.1128/IAI.70.12.7054-7062.2002
Zhang, G., and Ghosh, S. (2001). Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity. J. Clin. Invest. 107, 13–19. doi: 10.1172/JCI11837
Keywords: apoptosis, pyroptosis, intrinsic pathway, extrinsic pathway, autophagy, Mycobacterium tuberculosis
Citation: Parandhaman DK and Narayanan S (2014) Cell death paradigms in the pathogenesis of Mycobacterium tuberculosis infection. Front. Cell. Infect. Microbiol. 4:31. doi: 10.3389/fcimb.2014.00031
Received: 20 December 2013; Accepted: 17 February 2014;
Published online: 05 March 2014.
Edited by:Yongqun "Oliver" He, University of Michigan Medical School, USA
Reviewed by:Dario S. Zamboni, Universidade de São Paulo, Brazil
Subramanian Dhandayuthapani, Texas Tech Health Sciences Center, USA
Copyright © 2014 Parandhaman and Narayanan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sujatha Narayanan, Department of Immunology, National Institute for Research in Tuberculosis (Formerly Tuberculosis Research Centre), Indian Council of Medical Research, Mayor Sathayamoorthy Road, Chetpet, Chennai 600031, Tamilnadu, India e-mail: firstname.lastname@example.com


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Question : I'm A Student Of B.A. (Political Science) Second Year. And I'm Preparing For UPSC CSE, So I Want A Strategy That Will Help Me To Clear UPSC Without Attaining Any Coaching Centre. And Please Also Give Me Some Suggestions To Prepare For Political Science As An Optional Subject.
( Raj Pandey, Via: E-Mail )
Question : Sir/Ma'am, Can I Prepare For Judiciary Branch And Executive Branch Simultaneously?
( Rahul Saini, B.A. (Hons.), L.L.B., Haryana, Via: E-Mail )
Question : Sir/Ma'am, I Am A Second Year Student Of B.A. Preparing For UPSC 2020. How Can I Manage Time Between My College Studies And UPSC Preparation?
( Amanpreet Singh, B.A. (History, Economics, Pol. Science, Punjabi, English), Ludhiana, Punjab , Via: E-Mail )
Question : Sir/Ma'am, I Am Second Year History Undergraduate. I Want To Prepare For Civil Services. Which Small Habits Can Ensure My Selection In UPSC CSE?
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Question : Sir/ Ma'am, I Am A Final Year Student Preparing For Civil Services. I Want To Know The Strategy For Writing Skills In UPSC Mains. Please Guide Me Through The Same.
( Hriday Bhandari, B.A. (Pol Science), Dehradun, Via: E-Mail )


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95min Video on PPC Basics… Get BACK to PPC Basics to Refocus
There are a lot of e-books and courses online that teaches the same old Pay Per Click "crap".
You probably bought various IM ebooks – so you probably know exactly what I'm talking about…
So, the PPC Bully "gang" are providing a great video that you should check out to get you back on track.
It's a recording of a 95 min webinar they hosted with Ran Aroussi as part of the PPC Bully Training program.
They've decided to release this video for free to help "fill in" some of the gaps most people have in their
PPC education.
Watch it here:
95 mins of PPC Basics
The video covers:
==> the anatomy of a successful campaign
==> how to build a good keyword list
==> writing converting ads
==> dealing with quality score
==> 3 strategies to use on your campaigns NOW
… and more!
Here's the link again:
95 mins of PPC Basics
Nothing to buy. No list to join. Just pure content.
Don't miss out.
Talk soon


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Nicolas Petit was in to Finger Lake early this morning taking an early lead in the Iditarod. He was followed by Brent Sass of Eureka, Tom Thurston of Oak Creek, Co. and Ray Redington, Jr. of Two Rivers.
Defending champion John Baker of Kotzebue was not far behind leaving Skwentna.
This is Petit's second Iditarod. He lives in Girdwood.


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People in Florida who are creating an estate plan might want to consider whether there are any elements that could cause family conflict. In some cases, the problem may be the choice of executor. Some family members might start to think the executor is stealing from them. Sometimes, the executor might not respond to communication and might fail to complete important documents. One solution is to appoint a corporate trustee or a professional fiduciary to manage the estate.
Some families may fight over sentimental items that have little or no monetary worth. People should talk to their families beforehand about what items they want and create a list that they place with the estate planning documents.
Some people might want to set up a trust that manages distribution of assets to family members over a period of time. This kind of arrangement is not uncommon to avoid leaving a significant sum to younger people, but it should not stretch over decades or be overly restrictive. Another issue may be one in which children from an earlier relationship do not get any assets until the surviving spouse dies. This could be a long wait. Finally, some parents may want to distribute assets unequally among children. They should talk to the children about this beforehand.
Working with an attorney is another way to help ensure that an estate plan is less likely to cause conflict or be challenged. An attorney may be able to ensure that the legal language is clear and the plan adequately spells out a person's intentions. Beneficiary designations can also raise issues. Assets such as life insurance and retirement accounts are passed using these. In a conflict between instructions in a will or trust and the beneficiary designation, the beneficiary designation usually overrides the other documents, so it is important to keep it updated.


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Android users probably encounter errors in mobile network connectivity. Most of the time, it displays as "Mobile network not available" which is common among the Android errors that you would encounter. When you encounter this error, you will lose connectivity, as you are unable to fetch the network signal.
Here are a number of methods that you can do to fix this type of error in your mobile network. But first, you need to switch your phone off by removing the battery and SIM card and reinsert them when you turn it off. If you see the same error when you have restarted the SIM, here are some quick fixes that you can mimic.
Fixing Network Issues
- Open the Settings -> Wireless and Networks -> More -> Mobile Networks
- Then, you have to click Network Operators -> Manual
- Restart your Android device after doing these steps to get rid of the issues.
Fixing Improper Radio Signals
Simply change your battery and try a different one for your type of Android mobile device. This could resolve the problem effectively when you encounter the said issue. When the device works, this means that your battery has been damanged or has overheated.
Correcting Radio Signal Broadcasts
- Simply dial the character combinations "*#*#4636#*#" from the dialer
- A prompt will lead you to a testing menu
- Click the device information of your mobile device
- Run the ping testing procedure
- Choose GSM auto (PRL) from the dropdown list
- Then, click the Turn off radio option
- Restart the device after performing the steps
Additional Fixes
If in case the steps didn't work for you, then you have to mimic another process. Here are a few steps that you have to follow. Just go to Settings -> About device -> Software update -> Check for update. By following this step, you can fix the mobile network that is not functioning as expected.
More Options
If all else fails, you can apply a factory reset procedure. Simply go to Settigns -> Backup and Reset -> Factory Data Reset. On the other hand, you can choose to turn off your device, then hold down the Power, Home, and Volume Up buttons altogether.
When the Android logo would appear on the screen, you have to release the buttons that you have held earlier. Now, use the volume rocker in order to select the options presented on the screen of your mobile device. If you need to confirm that option you have chosen, just click on the Power key.
In this case, you have to highlight the factory reset option and confirm the process by using the Power button. Then, you need to choose "Delete all user data" from the menu and confirm the choice. You only need to wait a few seconds in order to see the "Reboot system now" and choose it. As you do this, take note that you have to set it up again, as you would any new Android phone.


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1950s Hairstyle with Blonde and Brunette Tone
The 50s was the decade of post-war adjustment with the omnipresence of more conservative and secure time. On the other hand, women had plunged into the workforce for the very first time during the war period and were expressing themselves in a more assertive and novel way, socially.
Most of women's hairstyles of the 1950s were so daring and conservative, which were reflective of both of larger societal trends.
The conservative look was created to appear popular by some American stars, such as Lucille Ball, while Marilyn Monroe's style was much more representative of the more daring look of the 50s.
In order to create a poodle cut, the reminiscent of Lucille Ball, you can simply learn the pin curl. Just choose a chin length cut as well as shorter layers right around the face. Y
ou can wash your hair and then let it air dry. Then work your styling gel all over your hair from the roots to the tips. Next, you need to section the front part of your hair by creating a single part on both sides of your head using the rat-tail comb.
Also use the hair clip to pin this particular section away from the remaining part of your hair. Next, you should gather your hair yet the front section and smooth the hair into pony tail.
Work with few small sections of your front part hair. Wrap each section in a spiral pattern.
In order to finish the look, you need to pin each curled section with hair pin. Also, pin the middle part of your curl, so the ends become loose.


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Tuesday, September 18, 2012
Book review: The Twenty-Year Death
The Twenty-Year Death is effectively three separate but linked novels, one set in 1931, one in 1941, and the final in 1951. You could read one without the others without losing too much, but I don't know why anyone would do that. Each section - & here's where my interest hit new heights - is written in the style of a different crime novelist: Georges Simenon, Raymond Chandler and Jim Thompson, respectively. So, it's separate crime novels (check), which are also linked (check), set across decades & different locations (check), and also a clever act of literary mimicry (double check). In other words, a book I was bound to love...
Part one, Malniveau Prison, is set in a small French town. Chief Inspector Pelleter has come up from Paris to speak to a serial killer (whom he caught) held in the nearby prison. While there, though, he gets pulled into helping the small local police force investigate the town's first murder in many years - a former prisoner found beaten to death and left on the side of the road. Pelleter soon uncovers a deeper problem - a string of not just unsolved but unacknowledged murders. He also encounters a local couple - American novelist Shem Rosenkrantz and his young French wife Clotilde. This couple becomes the linking characters between the three novels - sometimes in the foreground, sometimes relatively minor characters, but The Twenty-Year Death is fundamentally their story.
Winter captures Simenon's Inspector Maigret style well. Verargent, the town, is a suitably atmospheric locale - small town, but with a large prison full of some of France's worst criminals just a short drive away. The steady rain through most of the story adds to the gloom as Pelleter's initial reluctance to be there at all, or to get involved in the local crime, becomes an ongoing theme. He wants to leave - and regularly says he's about to - but always the case takes priority. Pelleter himself - the point of view character - while clearly a Maigret stand-in, is developed efficiently. Simenon wrote many many Maigret novels, and Winter somehow conveys the idea that this is just one in an ongoing series about this detective.
Ten years later, we are in the movie business in Hollywood, in The Falling Star. Chandler's Phillip Marlowe is here represented by Dennis Foster, a private investigator asked to keep an eye on aging star Chloe Rose, who believes she is being followed by a mysterious man. (Nobody else, including the studio security chief who hires Foster, believes she is.) Her husband, who wrote the film she is currently making, is cheating on her with her junior supporting actress. This young girl is killed; Foster discovers the body but is warned off investigating the death. Meanwhile, Chloe's male costar is secretly gay, and has asked Foster to help him find his partner, who ran off after an argument and hasn't been seen since.
Like the Chandler novels it draws on, The Falling Star is a complicated, tangled web of relationships and hidden agendas. (It does ultimately make sense, unlike a certain Chandler novel...) Chandler's style - one of the most influential & imitated in English-language 20th century fiction - is not as easy to pull off as many writers think, but Winter does a fine job here, not just in his labyrinthine plotting and in capturing the early 1940s west coast setting so central to Chandler's stories, but also in evoking the two most recognisable aspects of a Marlowe story - the detective's cynical, quippy exterior masking a genuine desire to do the right thing regardless of consequences; and the spot-on similies & descriptions (the first page includes 'It was just about noon on a clear day in the middle of July that wasn't too hot if you didn't mind the roof of your mouth feeling like an emery board', which is about as good as Chandler-aping gets).
And in Police At The Funeral, in 1951 washed-up writer Shem Rosenkrantz is in Calvert City for the reading of his first wife's will. Also there is his estranged son Joe, the latter's fiancee Mary, and Shem's mistress Vee. Shem had succeeded as a novelist, had moderate success as a film writer, but now hasn't written - let alone published - anything in years. He owes money to multiple people, and exists when we catch up with him on what Vee can scam from her other boyfriend, local gangster Carlton.
It's less easy to talk about the plot of Police At The Funeral than the previous two parts without spoilers, but the story follows Thompson's relentlessly grim first-person style. It's a little harder for me to judge this section against Thompson since I've only read one of his novels, the gloriously bleak The Killer Inside Me, but Winter's tone here, through Rosenkrantz's narration, is certainly evocative of that novel's style. Thompson's harsher prose and themes serve this part well, as the story unravels in an increasingly desperate manner. Where Malvineau Prison deals with institutionalised problems, and The Falling Star with the darker side of the glamorous movie lifestyle, Police At The Funeral is a much more personal corruption and collapse.
Each of the three stories that comprise The Twenty-Year Death would have made a fine standalone novel. By combining them, Winter has shown not only an impressive ability to write in the style of these three writers - without ever stooping to parody - but a significant talent for crime novels in their own right. This is not just a faux-clever spoof of three key crime novelists. If you didn't know the three writers he was imitating, or that he was imitating at all, The Twenty-Year Death would still hold up as a compelling and ingenious book. Each of the three has a satisfying conclusion - always the make-or-break factor in crime novels - and I found myself racing through each story. When these are combined in the way that Winter has done here, the result is one of the best novels I've read so far this year. My high expectations for The Twenty-Year Death were more than matched.
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Leonardo DiCaprio And Nina Agdal Were In A Car Accident
Leonardo DiCaprio was driving his Range Rover with Nina Agdal through the Hamptons and got hit by a Mini Cooper. There's no reason to feel bad for him. If you did, read that first sentence again.
The Oscar winner and the model were heading east on Montauk Highway in Wainscott in a Range Rover at about 4:30 p.m. Saturday when they were struck by a woman driving a Mini Cooper. DiCaprio first checked to make sure Agdal was OK before climbing out of the SUV and walking to the driver's side of the much-smaller Mini. He tried to open the door to tend to the woman, but it was locked. When the unidentified driver unlocked the door, DiCaprio helped her out. "She was shaken up. Leo was nice about it. He motioned for her to come with him, and he helped her over to the guardrail so she could rest," the witness said.
Then may favorite part:
The Range Rover suffered little apparent damage. But the Mini, which the witness said was traveling about 10 mph, had extensive front-end damage and had to be towed.
Besides being yet another reason not to own a Mini Cooper, this is why Leonardo DiCaprio takes private jets. You know the one I'm talking about. Your Aunt Carol posted it on Facebook because she cares about the environment.


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Christina Ryan
Christina Ryan, M.D. is a general internist by training. In her clinical role she has focused on people in the hospital for neurosurgical interventions, and has taken a special interest in the management of internal medicine issues in this particular population. This clinical work has led her to research questions at the intersection of chronic medical co-morbidity and traumatic brain injury (TBI). She has particular interest in ensuring patients with TBI receive proper diagnosis and timely treatment. Her research focus is on recognition and management of complex medical co-morbidity and careful transitions of care.
Within the last 24 months, have you rendered, or in the next two years, will you render clinical services or support services (whether diagnostic, therapeutic, educational, case management, or similar) to persons with TBI or their family members and caregivers, as an independent professional or employee of a for-profit or not-for-profit organization?: University of Washington Medicine at Harborview Medical Center. I will provide inpatient care to medically complicated patients admitted with TBI. I will also provide perioperative care to patients having surgical procedures who may have a history of TBI. This accounts for approx 30% of my times.
Within the past 24 months and during the three-year course of the project under consideration, I or one of my immediate family members received or will receive financial or material research support or compensation from the following: My husband, Michael J Ryan MD, is employed as Assistant Dean for Curriculum at the University of Washington School of Medicine and performs educational research as part of this role.


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If you've had a manic Monday, just like I did, then I have the cure for you. And nooooo, it's not the song Manic Monday! I'm saving you from that guilty pleasure today but I do have some amazing 80s tunes to rock your socks off. This is my Top 10 Fave Tunes from the 80s. This was a hard list to put together because apparently I love lots of songs from the 80s.
I was going for an 80s pin-up look for my image, which was captured at Elysion. I hope you enjoy the sights n sounds of a manic Monday. =)
10. Camper Van Beethoven - When I Win the Lottery
9. Whitesnake - Here I Go Again
8. Melissa Etheridge - Bring Me Some Water
7. Billy Joel - It's Still Rock & Roll To Me
6. Motorhead - Ace of Spades
5. Madness - House of Fun
4. John Cougar Mellencamp - Cherry Bomb
3. Paul Simon - You Can Call Me Al
2. Peter Gabriel - Sledgehammer
1. Transvision Vamp - Baby I Don't Care


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The Ain't Them Bodies Saints team is getting the band back together. Saints writer/director David Lowery has closed a deal to write and direct the sci-fi pic To Be Two, and Heat Vision reports that Saints star Casey Affleck is attached to star in and executive produce the film. Described as tonally similar to Looper, the film is an adaptation of Paul Brooks' short story collection Into the Silent Land: Travels in Neuropsychology and takes place in a world where people are able to be teleported to Mars, where they are reconstructed atom by atom, after which their original self is vaporized. When the teleportation machine malfunctions and fails to vaporize the original, questions of self and "who is the real me?" arise.
It's suitably heady stuff for Lowery, who made his directorial debut on Saints after working as an editor on films like Upstream Color. The filmmaker is also working on a Pete's Dragon reimagining for Disney, an adaptation of the graphic novel Torso, and is attached to direct The Old Man and the Gun with Robert Redford set to star.


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Made up of individual but digitally interlinked columns of ever evolving patterns of light and sound, HALO is an immersive, innovative and interactive installation bringing strangers together in a shared moment of spontaneous music making.
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text: Libra 0 Posted May 21, 2011 Share Posted May 21, 2011 I think I read that a new version of CCleaner was developed to work with Windows 7 SP1 (64 bit). Since I don't use the registry cleaner in CCleaner, would it be alright to continue using version 3.02.1343 or would I have problems because of SP1? Thank you. Sincerely, Libra Link to post Share on other sites


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Spring Flowers
You deserve a springtime reward. JAGGARD'S FLORIST & GARDEN CENTRE will design a glorious bouquet of spring flowers for your home. Bring in the spring sunshine with a vase of daffodils. Capture the fresh breeze of a spring day with a basket of flowers. Celebrate the simple pleasures of spring with blue iris, pink gerbera daisies or rosy tulips. Feel the day's delight with spring flower arrangements. Everywhere you turn in Burlington, ON the revival of spring is felt. JAGGARD'S FLORIST & GARDEN CENTRE has a charming collection of spring flowers waiting to brighten your day.


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Ivan Smagghe and Acid Pauli will also play the third edition of the Mexico festival next month.
Las Estacas is a natural water park just outside of Tlaltizapan, a city in the country's south-central region. This will be the third time the two-day festival has been held there. Joining Âme's Kristian Beyer will be a mix of local and international acts, spanning house, hip-hop, indie, cumbia and more. On an electronic tip, Acid Pauli, Ivan Smagghe, Century, Saschienne, Bondax and Studio Barnhus member Kornél Kovács have all been booked. Doors will run from 11 AM on Saturday through 6 PM on Sunday.


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Greyhound Racing Preview – 20th – 22nd November
The Racing Post Greyhound TV cameras move onto Sunderland and Romford tonight with competitive action from both tracks on view, Romford stages the start of the Mitch Millward Essex Vase heats while over at Sunderland we have six open and six graded races to try and work out – the bookmakers have priced up the action so let's crack on and find the winners!
The free PGT selection for tonight is RUN TEDDY RUN who lines up from T3 in the William Hill Standard open race at Sunderland over the four bend 450 meter trip at 10.03. The Pelaw Grange raider ran out a very impressive winner over course and distance last Friday and if the youngster repeats that flying 4.91 sectional he will take all the beating tonight. The key to the race will be the break, it's imperative that we trap well and clear Quick Blaze (T2) at trap rise and hold Calzaghe Teddy (T6) into the corner, do that and it's race on down the back straight.
PGT FREE FRIDAY TIP – RUN TEDDY RUN – T3 – 10.03 Sunderland
Over at Romford look out for Trionas Trust who runs from T1 in the 'Like Coral on Facebook' standard open race at 10.26 over the 400 meter trip at the London road venue. The Jim Reynolds trained son of Droopys Scolari is blessed with blistering early pace and he looks ideally drawn tonight to put that to good use and lead round at the rails, if Trionas leads off the seconds bend the Oi Oi's will surely be heard from his backers on track. Kokcha Blue (T4) rates as the main danger, the Heather Dimmock trained runner has been campaigned over sprint trips of late and is likely to appreciate this slight step up in trip tonight and she would be a runner when a smash break.
Saturday – Belle Vue live on Racing Post Greyhound TV
Moving onto Saturday evening and greyhound punters are in for a treat with the start of the Ecc Timber Oaks live on RPGTV, join the panel on Sky channel 212 from 7.15pm for all the latest market movers, non runners and betting previews.
One that appeals at this early stage is Domino Storm who runs from T1 in the 8.10 at Belle Vue for champion trainer Mark Wallis. The early paced railer looks ideally housed in trap one and with a level break the daughter of Makeshift will take all the beating. The key to the race will be holding kennel mate Evanta Evita (T3) into the first corner, do that and Domino Storm can take this race and book her place in the next round of the competition. As ever the price offered by the bookmakers on the day will determine whether she is worth supporting in the market.
Sunday – Henlow live on Racing Post Greyhound TV
The final RPGTV show of the week will be from Henlow on Sunday evening, with plenty of open races on show and over various distances there's a bit of something for everyone on the card.
Swift Edwards (T3) is an interesting runner in the maiden open race at 7.45 over the 550 meter trip. The Towcester raider has been keeping very good company of late over four bend and he looks an interesting runner here now stepped up in trip for the first time, if he manages to lead round he should go close.
Gordans Alive (T6) stayed on well to win over course and distance last Sunday and the solo wide seed looks well drawn again this week to follow us that success in the 9.15 open over the 692 meter trip. It is however a very competitive race with the classy Bubbly Time (T4) in opposition, Midway Nick (T5) who is more than capable of taking a race like this on a going day plus Droopys Alberta (T1) who our selection beat last week by the shortest of margins in a cracking finish to the stayers event.
Thanks for checking out the latest PGT blog, good luck with whatever you decide to back this weekend.
Be lucky,
Michael @ Premier Greyhound Tips


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How to get Next-Gen investors to financial independence
For many young adults entering the workforce, finding a way to financial independence can seem a daunting task with endless questions and few answers. Assante Vancouver Centre (AVC) of Assante Wealth Management has found a solution to get recent graduates jump-started into this process with their annual Financial Bootcamp.
The program was launched by Senior Wealth Advisor Paul Lermitte at AVC as a full-day interactive session to provide coaching and assistance to the children and grandchildren of his clients after university. After running the boot camp for 11 years, Paul has found the program is not only providing valuable education, but also a tremendous amount of goodwill from their clients, whose main priority is to ensure the next generation is well-equipped financially.
"Parents tell me that the concepts from our Financial Bootcamp aren't taught in school," says Paul. "These parents believe their children need to be equipped with this knowledge in order to succeed financially in life, and they have found what they are looking for in our weekend program."
The Financial Bootcamp is further supported by the rest of AVC's teams, who shared diverse and in-depth knowledge in their areas of expertise at this year's session on January 27, 2018. Topics covered in the program included investment basics and the different types of savings vehicles (RRSP, TFSA, etc.), managing cash flow, goal-setting, and career/lifestyle planning. The ultimate takeaway, however, is to help the next generation of investors develop a sense of confidence in having control over their financial future.


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Fruits & Biscuit Text styles for Photoshop
The text styles for Photoshop can always save and applying them in this case the right typography, the results are obvious.
Biscuit´s Styles is a free pack created by Sonarpos and shared in Deviantart that contains 9 styles to simulate the most varied cookies with just one click.
- Download | Biscuit´s Styles Original Pack
- Download | Original Pack + Fonts (10.66 Mb)
Fruits Styles is another free pack created by Sonarpos and shared in Deviantart.
- Download | Original Fruit Styles Pack
- Alternative Download | Text Styles Pack + Fonts (9Mb)
In the original pack you will find the ASL file of styles to incorporate into Photoshop and a PSD with the styles applied in texts and shapes. In the other link I have uploaded the same plus the sources used in the PSD to have all the combo.


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The Loop (Games)
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Information in this article is about real-life people, companies, and objects, and does not relate to the in-universe Sonic series.
Amit Yosovich ('עמית יוסוביץ?) is an Israeli voice actor who has done voice work for the Isralian dub of the Sonic Boom television series.
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