The couple announced their separation in July 2023, but have remained on good terms and enjoy spending time with their daughters together
The Real Housewives of Beverly Hills alum, 55, reposted a scene from the Bravo show's first season, when she and her castmates celebrated Easter in Palm Springs, as well as a throwback photo of an Easter bunny with herself and a daughter when they were younger.
In July 2023, a source close to Richards and Umansky told PEOPLE that the couple had chosen to separate after 27 years of marriage.
"Kyle and Mauricio have been separated for a while now but are still living under the same roof,” the insider said at the time. “They remain amicable as they figure out what’s next for them and their family."
"Obviously it's not going to stay like that, it can't stay like that forever," she told host Barrymore. "Because of my kids' ages, it's not like they're toddlers, so eventually we'll figure it out and take it to the next step, whichever that step may be."
The pair first met in 1994 and married two years later in January 1996. They share daughters Alexia, 27, Sophia, 24, and Portia, 16. Umansky is also stepfather to Richards' eldest daughter, Farrah Brittany (née Aldjufrie), 35, whom she shares with her ex Guraish Aldjufrie.
Speaking about the pair's separation during the RHOBH season 13 reunion, Richards said that problems in their marriage got worse over time and she initially thought the separation would be "temporary."
"With any marriage, there's issues that you have and they come up," she said, explaining how their busy schedules pushed their problems to the periphery rather than solved them. "Some of the issues never went away and they were never really like worked on."
"I care about my family first and I mean I tried, I really did try," Richards continued, speaking through tears. "And so then when I couldn't, the kind of things I had been — don't want to say put up with, but you know, just became more apparent to me I guess."
"I guess I couldn't do that anymore. I finally decided a breaking point, but I really thought [our marriage] would come back," Richards added. "I thought, 'Okay this is just a temporary thing,' and it didn't."
She shared that she had "random people" that consisted of both "men and women messaging me now" online.
Never miss a story — sign up for PEOPLE's free daily newsletter to stay up-to-date on the best of what PEOPLE has to offer, from celebrity news to compelling human interest stories.
"I mean, it's just so funny, but it didn't used to be like that," she said during the episode, adding that she hasn't taken any of her potential suitors seriously.
"It's really hard to wrap my head around that, but of course I thought about that and my friends make all kinds of jokes and stuff, you know," she continued. "I mean that day will come regardless because we are separated and we're allowed to do what we want to do right now. That's the way it is."
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Read the original article on People.


Playing Hide-and-Seek with Ransomware, Part 1
- Intel SGX technology enables developers to isolate and encrypt a portion of code and data in the processor and memory in a trusted execution environment, known as an enclave.
- As enclaves are increasingly adopted to enable confidentiality-preserving applications, numerous researchers, including CrowdStrike, have asked the question of whether enclaves could be leveraged by ransomware authors to evade detection and ensure the decryption key cannot be retrieved by the victim after a successful attack.
- Numerous studies have investigated the viability of ransomware authors using enclaves for cryptographic key management. These studies underscore the significant complexity of executing this method as part of an attack, especially vis-à-vis more straightforward and proven alternatives, a likely contributing factor to the extremely low risk attributable to this tactic.
- The CrowdStrike Falcon®® platform delivers unparalleled attack surface visibility for customers, including the attempted use of enclaves and related process behavior to rapidly detect malicious behavior and stop breaches.
At CrowdStrike, our mission is to stop breaches. To achieve this, we’re always on the lookout to defend customers against active attacks and preemptively protect them against emerging threats.
In July 2021, researchers from Royal Holloway, University of London, published a white paper, “RansomClave: Ransomware Key Management using SGX,” that presents a novel ransomware based on an Intel feature called Software Guard Extension (SGX). The SGX technology aims to isolate a portion of memory from the rest of the system by encrypting it on a reserved part of the processor.
This protected memory allows ransomware authors to manage their cryptographic operations without processing keys within the operating system’s memory, enabling them to evade forensic methods of key retrieval (e.g., memory dumps) and ultimately depriving victims of the means of retrieving their data after the attack. With SGX appearing to be such a highly effective method for ransomware authors, it stands to ask: Why does this model have such low prevalence in the wild?
To answer this question, we will first examine how the Intel SGX technology works. We will present the challenges of key management that ransomware faces today and explain the extent to which enclaves provide a potential solution to this issue. In Part 2 of this blog series, we’ll dive into how ransomware using enclaves could be implemented and discuss the limits of this approach.
The CrowdStrike Falcon® platform sets the new standard in security. Watch this demo to see the Falcon platform in action.
The Intel SGX technology consists of a set of CPU instructions and structures released with the Skylake generation of Intel processors (launched in 2015). This feature provides a trusted execution environment (TEE) for Windows and Linux operating systems (OS) that allows kernel and user mode code to be executed within a protected memory context: an enclave.
Architecture and Mechanisms
The enclave code is similar to the code of regular applications, with key differences in its loading method and execution context. Under the hood, the enclave code is stored encrypted in a dedicated part of the dynamic random-access memory (DRAM) called processor reserved memory (PRM). DRAM is a prevalent type of random-access memory (RAM), that differentiates itself from the static random access memory (SRAM) by its electronic composition. The enclave code encryption is based on the Intel Memory Encryption Engine (MEE), which uses keys generated at boot time and later stores them in the CPU. As the encrypted enclave pages can only be decrypted inside the CPU, the enclave code is inaccessible, even to code from ring-0.
Executing within this environment prevents the enclave from accessing all regular processor instructions. This limitation includes instructions that may require privileges or execution-mode transition such as SYSCALL or INT, instructions that could result in a VMEXIT like CPUID, and I/O instructions such as IN or OUT (because errors they might cause can’t be handled in the TEE).1 Furthermore, as far calls, far jumps and far ret are also illegal, enclaves executing any of the forbidden instructions will trigger a #UD (Undefined Instruction) error.
Still, the enclave may have legitimate cause to interact with OS-provided functionalities. To enable this, the architecture of applications using enclaves is divided into two parts:
- The Trusted Space (the enclave): This is the portion of code and data isolated from OS and hypervisors.
- The Untrusted Space: This is also referred to as the classic core of the application, which is in charge of the enclave setup and serves as an intermediary between the enclave and the regular OS space.
This architecture supports the isolation of the enclave while enabling bidirectional communication with the regular cores of applications. To use enclave functionalities, the classic core of one application can invoke functions inside an enclave through what Intel calls an ECALL (“enclave call”). Similarly, to interact with the classic OS environment, enclaves perform an OCALL (“out call”) to the regular core of the applications, which passes it on to the OS. This enables enclaves to access the functionality they need through the classic core of the application. As ECALLs and OCALLs define the enclave’s boundaries, they need to be explicitly defined in the enclave’s source code (in an .edl file).
To prevent malicious actors from exploiting enclaves, Intel has also integrated a signing requirement in the SGX architecture. While the enclave code can be locally compiled in debug mode without constraint, failure to comply with signing requirements will prevent the enclave load from compiling in release mode. For the sake of simplicity, we will focus here on the signing process for Intel Core processor-based platforms, as the process for Xeon platforms differs slightly.
In debug mode, a signing tool called
sgx_sign is automatically run by Microsoft Visual Studio to allow the load of enclaves on a local machine. In release mode, things get trickier. The entity that develops the enclave, called the enclave signer, first needs to be allowlisted by Intel, which requires a signed Commercial Use License Agreement. Once the agreement is completed, the enclave is submitted to Intel for approval via their Whitelist Registration Form. This form requires a hash of the enclave author’s public key, which is computed at the enclave load and is stored in the MRSIGNER register. If approved, this allowlisted signature allows one application to create, sign and use enclaves compiled in release mode with an enclave signing key.
The signature embeds the hash result of the measurement of the enclave memory pages (code, data, stack, heap) and its metadata, which are computed at build time. Each time there is an attempt to load the enclave, the measurement is taken and the resulting hash is stored in the MRENCLAVE register. The value is then compared to the one embedded in the signature. If the results are inconsistent or if the enclave signer is not allowlisted, the load of the enclave is blocked.
For Intel, this enclave signing key both guarantees that the enclave is “safe” to be executed and doubles as a means for the enclave to further protect its secrets: with a process known as sealing.
From time to time, enclaves may need to access private data across reboots or share information with other enclaves. To support these scenarios, the Intel SGX technology created a process known as sealing. This operation allows enclaves to keep their data encrypted outside of the enclave boundaries and remain persistent across reboots. Sealing consists of an encryption process based on a value unique to the enclave, which is one of the two singing keys discussed in the previous section: the MRENCLAVE or the MRSIGNER.
Sealing can either rely on:
- The enclave identity, which is based on the MRENCLAVE value. As the MRENCLAVE value of one enclave remains the same across reboots, each enclave can use this value to access sealed data from a prior instance.
- The signer identity, which is based on the MRSIGNER value. This allows two distinct enclaves developed by the same entity to share data, as long as they have the same author’s signature. This option also allows an application to use different versions of an enclave, a common requirement with software updates.
As data encryption happens inside the enclave, sealing allows data to be returned to the classic core of the application and safely stored for future use.
Why Ransomware Authors Use Enclaves
As mentioned earlier, the SGX technology provides a trusted execution environment (TEE), one that can be used to support specific purposes. As this environment supports a very narrow scope of functionality — allowing little more than arithmetic operations — enclaves are primarily used for managing sensitive data, most notably cryptographic keys. The isolation of the enclave within the application architecture makes the enclave the perfect place to run cryptographic operations as it guarantees that cryptographic keys will be inaccessible for the rest of the system.
Brief Overview of Ransomware Key Management
One of the most challenging parts of writing secure cryptographic software is the creation, exchange and storage of cryptographic keys, a process collectively referred to as key management. Many early variants of ransomware families have vulnerabilities related to their key management. For example, an early version of Nemty passed an improper value within the
dwflag argument to the function
CryptAcquireContext, which instructed Windows to write the newly generated public and private RSA key to disk. What might seem like a minor flag passed as an argument led to an insecure cryptographic implementation; which gives victims a potential opportunity to recover the key needed to decipher their data.2
Most ransomware families use a combination of symmetric and asymmetric cryptography, but for our purposes we’ll focus on ransomware using only asymmetric encryption. A ransomware model that mixes both types of encryption would follow the same logic, so for the sake of simplicity we’ll detail only the asymmetric part. Within the context of asymmetric encryption, we’ll refer to the public key, which is used to encrypt the victim’s data, as Vpub, and to the private key, which is the deciphering key, as Vpriv. Assuming the deciphering key can be retrieved, we can consider that the key management in asymmetric cryptographic implementations will commonly occur via one of the following four scenarios:
- Generate a pair of keys on the victim’s machine and send the private key to a command-and-control server.
- Generate a pair of keys per victim on the attacker’s server and send the public key to the victim’s system for encryption.
- Generate a pair of keys on the victim’s system, and encrypt the victim’s data with Vpub. Then, encrypt Vpriv with the attacker’s public key embedded in the binary and save it on the victim’s system.
- Embed the public key in the malicious binary to use for encryption, and keep the private key on the attacker’s system.
Despite the range of approaches that ransomware authors could take, each of these scenarios has flaws that pose significant risks to the success of their attack.
In Scenario 1, keys are generated locally and the private key is extracted through the network. If the targeted system is offline, the encryption process cannot be performed as there is no way for the attacker to extract the private key. Furthermore, there are two potential means for forensic investigators to retrieve the deciphering key after a successful infection: through OS memory dumps or network traffic captures.
In Scenario 2, the attacker generates a pair of keys for each victim on the malicious server and sends the public key to each infected machine. This involves a setup of at least one malicious server with anonymity measures, but more importantly, has some important maintenance constraints. It requires constant monitoring to check the server is up and running to ensure that the victim’s infection process isn’t compromised. Furthermore, as with Scenario 1, the infection process requires victims to be online to successfully send keys.
In Scenario 3, a pair of keys is generated on the local machine, and the private key is encrypted with the attacker’s public key embedded in the malicious binary. In this scenario, the private key will appear at some point as clear-text in memory and can therefore be retrieved with forensic methods.
In Scenario 4, a ransomware campaign with one malicious binary encrypts the data of different victims with the same public key, which is embedded in the binary. Thus, if one victim is able to obtain the deciphering key, it can be used to decipher every other victim’s data. Alternatively, the ransomware authors could generate a unique binary per target and maintain a list of private keys associated with binaries, but this process requires much more work.
Across these scenarios, attackers using asymmetric cryptography for key management face the challenges of either not being able to target offline hosts or being thwarted by forensic retrieval of the deciphering keys.
The Enclave Benefit for Ransomware
Enclaves allow ransomware authors to circumvent both obstacles, allowing them to use a single binary to generate local cryptographic keys on target systems and ensuring that the victim cannot retrieve the deciphering key. Indeed, cryptographic keys are generated inside the enclave, which can’t be accessed by any other process, and deciphering keys can be safely stored without ever appearing in clear-text on the OS memory. Furthermore, this method independently infects each target regardless of whether the victim’s machine is online or not.
Regarding encryption methods, enclaves support both symmetric and asymmetric encryption. In a symmetric encryption scenario, the enclave generates the key and receives the victim’s data to encrypt from the regular core of the application. The enclave encrypts and returns the ciphered data, which the regular core uses to override the victim’s file content. Then the enclave seals the symmetric key and returns it to the regular core that writes the sealed key on disk for a potential future decryption.
The same logic applies to the asymmetric encryption process, as shown in Figure 2. First, the enclave generates the asymmetric pair of keys. The encryption can be performed either in the enclave, as in the previous case, or the ciphering key can be sent to the untrusted area, for the regular core of the application to directly encrypt the victim’s files. Then the enclave seals the deciphering key and returns it to the regular core, which saves it on disk.
In both cases, enclaves allow ransomware to meet three of the ideal attack conditions:
- Only requires a single malicious binary to generate unique cryptographic keys for each victim
- Prevents the deciphering key from retrieval with common forensic methods
- Does not require a control-and-command server, enabling infection of disconnected systems
Enclaves can be a useful means of managing cryptographic operations, making sure the decryption key can’t be retrieved (in theory). In order to protect customers from this particular tactic, the CrowdStrike Falcon® sensor gives customers visibility on the use of enclaves and uses this data alongside event telemetry to determine whether a process is malicious and to respond to detected threats.
See for yourself how the industry-leading CrowdStrike Falcon® platform protects against modern threats like ransomware. Start your 15-day free trial today.
It is worth noting that this method also presents significant limitations that complicate the successful execution of ransomware attacks. In Part 2, we’ll illustrate how this ransomware approach could be implemented and we’ll discuss this model’s limitations.
- Learn more about how CrowdStrike protects customers from ransomware.
- Find out about CrowdStrike’s ransomware protection solutions.
- Read about adversaries tracked by CrowdStrike in 2021 in the 2022 CrowdStrike Global Threat Report and in the 2022 Falcon OverWatch™ Threat Hunting Report.
- Test CrowdStrike next-gen AV for yourself. Start your free trial of Falcon Prevent™ today.
- “Intel® Software Guard Extensions (Intel® SGX) Developer Guide”, revision 2.7, page 35, March 2020
- Pranshu Bajpai, “Extracting ransomware’s keys by utilizing memory forensics”, 2020, Michigan State University


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Photo credit: Noah Berger for Associated Press
Friday 5th June is World Environment Day, which encourages worldwide awareness and action for the protection of the environment. This year, the main theme is ‘Time for Nature,’ with a focus on its role in providing the essential infrastructure that supports life on Earth and human development.
For the second edition of the World Press Photo House livecast, WPP invited photographers and organizations that are advocating for more impactful, engaging environment and conservation photography to talk about their initiatives and projects.
Toby Smith, Climate Visuals Programme Lead, will present an introduction to the 7 Climate Visuals Principles, an accessible evidence based guide to what makes not just illustrative but truly impactful imagery. This will be demonstrated with curated examples from the past Environment and Nature winners within the World Press Photo Collection. Finally, there will be a short reflection on the phenomenon of environmental photography during COVID and the challenges ahead as we emerge.
Moderated by Lars Boering, managing director of the World Press Photo Foundation, the program includes presentations from the following speakers, in addition to Toby Smith:
Cristina Mittermeier is the marine biologist and activist who pioneered the concept and field of conservation photography. Mittermeier founded the International League of Conservation Photographers (ILCP) in 2005 to provide a platform for photographers working on environmental issues. In 2015, Mittermeier co-founded SeaLegacy, a non-proﬁt organization dedicated to the protection of the ocean.
In 2020, on the 50th anniversary of Earth Day, Mittermeier announced the most ambitious project of her career: Only One, a new collective of organizations that uses digital technology and visual storytelling to catalyze lasting cultural change, with the ultimate goal of conserving the world’s oceans from now into perpetuity. During her presentation, she will tell us more about this initiative and her work as a conservation photographer.
Esther Horvath is a Fellow at ILCP, member of The Photo Society and science photographer for Alfred Wegener Institute in Germany. Since 2015, Horvath has dedicated her photography to the polar regions, especially to the Arctic Ocean, documenting scientific expeditions and behind the scene science stories. She follows the work of multiple science groups that are working to better understand the changing polar regions.
In 2020, she was awarded 1st prize, singles in the Environment category of the 2020 Photo Contest for her photo ‘Polar Bear and her Cub’. During her talk, she will tell us the story behind her awarded image and discuss her work in the Arctic Ocean.
In addition, Jerzy Brinkhof, World Press Photo exhibitions manager, will tell the stories behind some of the awarded images in the Nature and Environment categories of the 2020 Photo Contest. Edie Peters, manager of the PhotoQ Bookshop, will present one of the nature and environment photo books to watch out for in 2020.
The World Press Photo livecasts showcase the stories that matter to a global audience. Through a rich and diverse program of presentations, talks and discussions, we encourage diverse accounts of the world that present stories with different perspectives, educate the public and the profession on the making of stories, and encourage debate on their meaning.

domain: artistic


text:
No eggs please chocolate chip cookies should be a keeper in our recipe arsenal.
Most kids like chocolate chip cookies but may not be able to consume eggs, hence this recipe should be in your recipe box.
Today it is very common that many of us have some type of food allergy which can prevent us from eating some of our favorite foods.
This particular no egg chocolate chip cookie recipe is one I’ve been making for the past 4 or 5 years, way back when my daughter’s friend requested an egg free cookie recipe since her son is allergic to eggs. He loved cookies and as a concerned parent she wanted to be sure he had a snack that was safe for him to eat while in school.
There are many cookie recipes that do not include eggs but I thought chocolate chip cookies would be a good place to start for young children. I’m not sure 3 or 4 year olds would appreciate biscotti, though shortbread cookies are always yummy.
I named this recipe in honor of Andy who was the inspiration for this eggless chocolate chip cookie recipe.
I’ve been making these for quite a while, and I’m always excited when I can whip these cookies up while my dinner is cooking. In less than 45 minutes you can make the cookie dough and bake them, cleaning up as they bake, and they are ready for an evening snack with a glass of milk.
All you need to do is blend the butter and sugar, stir in the chips, then blend in the flour and BAKE!
No Eggs Please! Andy's Chocolate Chip Cookies
SUBSTITIONS: Use stevia for the sugar: Use 1 cup AP flour and 1 cup white whole wheat flour.
- 1 Cup Butter, room temperature
- 1 Cup Brown Sugar
- 2 Cups AP Flour
- 3/4 Cup Chocolate Chips
- 1 tsp. baking soda
- 2 tsp. milk
- 1 tsp. vanilla extract
- Pre-Heat oven 350 degrees
- Cream butter and sugar with electric mixer.
- Add chocolate chips to mixture and stir in by hand
- Add the flour and baking soda and stir by hand then add milk and blend - do not over-mix.
- (If the butter you use has softened too much the batter will be too soft - just refrigerate for 20 minutes before baking.)
- Drop by teaspoonfuls onto greased cookie sheet.
- Bake for 10-12 minutes. Cool for 5 minutes on cookie sheet and then transfer to cooling racks.
This is a very flexible recipe. You can make this a dairy free cookie if you substitute the butter and milk with a butter alternative and non-dairy milk (almond or coconut). I’ve made this cookie many times using coconut milk and the results were excellent — grampy’s discriminating palate never even knew there was a difference.
Another no egg chocolate cookie recipe I’ve made is Chocolate Chip Cookie with Spelt Flour.
For a bakery style chocolate chip cookie you might like this Jumbo Bakery Style Chocolate Chip Cookie from Bunnys Oven blog.
I’ve shared this with:

domain: food


text:
While I've already visited and written about FoodParc (29th & 6th Ave.), I only just learned that in addition to the great sandwiches, Chinese dishes & burgers, they also have awesome Ramen. A few nights ago when it was chilly out, I was in the mood for some warm comfort food and Ramen was just what I needed.
I ordered the Roasted Pork Ramen with Wontons to go (two actually, one for me and one for Patrick) and we took our dinner up to the roof of our building. When I removed the lid from my soup I was pleasantly surprised by how incredible it both looked and smelled.
I know there are a lot of places in NYC to get great Ramen like Ippudo and Momofuku, but I was truly surprised to find a great version right in my own neighborhood at FoodParc.
Where is the best Ramen you've ever had? The dish sure has come a long way since the three-for-a-dollar variety I used to eat in college!
-The Fabulous Foodie
PS: I went back to FoodParc a few days later to have it again and took a better picture of the soup:


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domain: medical


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UK women have shortest life expectancies18th November 2008
According to the results of a study carried out by Leicester University, women in the UK have some of the lowest rates of life expectancy in Europe.
British women came 16th in a list of 20 European countries, with an average life expectancy of 82 years and eight months. France, Italy and Spain topped the list, with an average of over 85 years. British men came 7th in a list of male life expectancy, with an average of 79.5 years.
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Title: UK women have shortest life expectancies
Author: Jess Laurence
Article Id: 9247
Date Added: 18th Nov 2008

domain: geography


text:
Early diagnosis of malignant mesothelioma (MM) is urgently needed because life expectancies and treatment options are limited in advanced stages of the disease. Malignant mesothelioma often presents with recurrent hemorrhagic or inflammatory effusions, which might mask the incipient stages of the disease and thereby delay the diagnosis. Despite difficulties in recognizing the malignant cells present in those early effusions, they are often the first available biologic material for diagnosis. Therefore, awareness is needed, and efforts should be made to distinguish the malignant cells by well-defined morphological criteria, combined with ancillary methods.
To summarize the diagnostic criteria for the cytopathologic diagnosis of MM based on recently published guidelines and to evaluate the clinical utility of those criteria in clinical practice.
The guidelines for the cytopathologic diagnosis of epithelioid and mixed-type MM and data in recent literature constitute the sources of this review. Eighty-five epithelioid or mixed-type MMs diagnosed between 2004 and 2013 at the Department of Clinical Pathology and Cytology, Karolinska University Hospital, Huddinge (Stockholm, Sweden), were evaluated to determine the clinical utility of the criteria defined by the guidelines.
A conclusive diagnosis of MM can be obtained based on the criteria defined by the guidelines with high positive predictive value. When diagnosed in this way, subsequent therapy should be initiated without further delay. With the earlier diagnosis obtained by cytology, a better effect of chemotherapy can be expected, as shown by the longer overall survival in these patients compared with those with a histopathologic diagnosis.
Malignant mesothelioma (MM) is mechanistically linked to previous asbestos exposure,1,2 and it develops several decades after the initial exposure to asbestos fibers. Despite a ban on asbestos in Western countries, MM is still a global concern because of the widespread use of asbestos-like mineral fibers in the developing countries, and the long latency period between asbestos exposure and diagnosis.
ASBESTOS-INDUCED MOLECULAR CHANGES
The molecular oncogenic mechanisms elicited by asbestos on a cellular level are related to the physical properties of the fibers, which deform the cytoskeleton of mesothelial cells,3 interact with the mitotic spindle,4 and can interfere with chromosome segregation, leading to aneuploidy.5 Importantly, asbestos fibers induce chronic inflammation, and the release of reactive oxygen species generated by asbestos can damage DNA double strands.6,7 In addition, the hypoxic microenvironment of mesotheliomas8 may alter the DNA damage-repair pathways9 and reprogram the metabolism by switching from oxidative phosphorylation to anaerobic glycolysis.10
Malignant mesothelioma is characterized by chromosomal losses more frequently than gains, leading to alterations in several tumor-suppressor genes. Consequently, the major feature of MM is the loss of tumor-suppressor genes. Those genes are inactivated by deletions and mutations or by epigenetic changes.11–13 The accumulated loss and/or inactivation of multiple tumor-suppressor genes at chromosome bands 3p, 9p, and 22q has a critical role in the pathogenesis of MM, leading to loss of p16INK4A-p14ARF, located at 9p21; neurofibromatosis type 2 (NF2), at 22q12; and BRCA1-associated protein 1 (BAP1) at 3p21.31-p21.2. Asbestos can also induce the proto-oncogenes c-fos and c-jun, and in turn, those transcription factors may enhance cellular proliferation and could render cells more susceptible to subsequent mutations. Several investigators found jun located at chromosome band 1p32 to be amplified in MM.12–14
Massively parallel sequencing and genome-wide screening15–19 verified the earlier identified genetic alterations in MM15,20 but also added novel mutations to the spectrum of the mesothelioma-related molecular signature. Recently, 116 different aberrations were identified simultaneously in 42 patients with mesothelioma, of which, a median of 3 were potentially actionable in each patient.21 In mesothelioma, no single-driver mutation has, however, been found, but each patient has a unique setting of alterations, motivating an individualized choice of treatment.
EARLY DIAGNOSIS—A CLINICAL CHALLENGE
The prognosis of MM is poor, with a median survival ranging from 4 to 12 months, depending on histologic subtype.22 The earliest manifestation of MM is often an effusion with admixture of blood and inflammatory cells, which can mask the malignant cells and, consequently, delay the diagnosis. To reach a conclusive diagnosis, the cytopathologist must be aware of the spectrum of cellular and molecular alterations and recognize the malignant cells present in those early effusions, which are often the first available biologic material for diagnosis.
The clinical outcome of patients depends largely on the phenotype of the tumor. In pleural effusions, the sarcomatoid tumor components are not exfoliated. Modern diagnostic approaches, however, make an accurate diagnosis possible in most epithelioid and mixed-type MMs, involving a spectrum of adjuvant diagnostic methods. The positive predictive value of such a cytologic diagnosis is as high as of that obtained by histology23 and, therefore, provides a sufficient basis for initiation of treatment. As described in the recently published international guidelines,24,25 the diagnosis of MM cannot be based on routine morphology only but necessitates the use of ancillary techniques.
CYTOMORPHOLOGIC FEATURES OF MALIGNANT EFFUSIONS
The cytomorphologic features of a mesothelioma effusion are described in detail in the “Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma: complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology,”24 with a short summary below.
Highly cellular effusions should always raise the suspicion of a malignant process on routinely stained material. The diagnostic criteria include the presence of numerous papillary cell groups of varying size (Figure 1, a and b) combined with common cytomorphologic criteria, such as pleomorphic cells with enlarged nuclei, the presence of macronucleoli, and variability in structure of the nuclear chromatin.26–29 Some samples show clearly malignant characteristics, whereas, in other cases, it is difficult to distinguish those cells from reactive mesothelial proliferations. In still other cases, there is a substantial admixture of inflammatory cells, mainly lymphocytes, or peripheral blood, which might then mask the malignant cells. In those cases, it is often difficult to recognize the malignant condition and to reach a conclusive diagnosis without adjuvant methods or hemolyzing the sample. Sarcomatoid MMs will not exfoliate sufficient diagnostic cells, and it is not possible to diagnose them by effusion cytology. In cases in which malignancy cannot be established by morphology, the diagnosis should be achieved with ancillary analyses.
The routinely stained, clearly malignant specimen may be indicative of mesothelial tumor phenotype, but the definitive diagnosis of a MM necessitates the use of ancillary analyses, such as immunocytochemistry. A liberal use of immunocytochemistry is, therefore, recommended, whenever the sample is rich in mesothelial cells and cell groups.
The main cytologic findings that indicate a mesothelial origin for malignant cells have been long known30,31 and have recently been reevaluated.24,25,32 Typically, the cell groups show less cohesiveness, which creates openings or “windows,” some containing amorphous cores with an acidophilic staining reaction. Cellular findings include protrusions through the cell membrane (“blebbing”), the presence of organophilic squamoid cells when stained according to Papanocolaou, and a fine vacuolization in the perinuclear area when a May-Grünwald-Giemsa stain is used. The samples show frequent cell-in-cell configurations. In material stained with May-Grünwald-Giemsa, there is sometimes a reddish, granular background, and in those cases, it is also possible to see a red haze around some of the tumor cells. That haze corresponds to the presence of hyaluronan, a biomarker synthesized in the cell membrane of MM cells.
Whenever the effusion is rich in mesothelial cells or is suspicious for malignancy, the possibility of a MM should be explored by ancillary diagnostic measures. Those methods can differentiate malignancy from a reactive condition in highly cellular samples and demonstrate the mesothelial phenotype in less-differentiated malignant effusions. There are mainly 2 diagnostic challenges with a malignant effusion: (1) establishing the malignant condition, and (2) establishing the mesothelial phenotype of the tumor cells (Figure 2).
Malignant Versus Reactive Mesothelial Proliferation
The nuclear atypia in many MMs is quite bland, whereas, in reactive mesothelium—the so-called mesotheliosis—there can be considerable nuclear atypia. There are mainly 3 different adjuvant analyses that are helpful in establishing a malignant condition: immunocytochemistry, ploidy analysis by fluorescence in situ hybridization (FISH), and electron microscopy (EM).
Immunocytochemistry is often the first choice in this situation with the same antibodies recommended for histology.33,34 The analysis should preferably include 2 epitopes in favor of malignancy, as well as 2 epitopes excluding such a condition. Antibodies that have been suggested to indicate malignant proliferations are epithelial membrane antigen (EMA; Figure 1, d [red]), CD146, Imp3, and Glut1. The diagnostic value of different EMA preparations varies, with the E29 clone (DAKO, Copenhagen, Denmark) having superior characteristics. Although EMA reactivity that is accentuated in the cell membrane may also indicate a malignant mesothelial proliferation, EMA is merely an antibody of malignancy because it also labels other cancers.
Several antibodies have been proposed to indicate benign/reactive conditions and to distinguish them from malignant proliferations,35,36 among which, desmin and BAP1 are most often used. Mesothelial cells lose desmin expression (Figure 1, d [brown]) early during oncogenesis. Thus, the presence of desmin corresponds to reactive mesothelial proliferation, and desmin staining is negative in MM. More recently, nuclear reactivity to the BAP1 epitope has been recommended for a similar purpose because the corresponding gene is often being dysfunctional in MM. Various sensitivities have been published for those epitopes. Desmin reactivity is a sensitive marker when applied on unfixed cells. Formalin fixation is, however, harmful to the desmin epitope,37 and the use of BAP1 can be recommended when paraffin-embedded cellblocks are used.
At our laboratory, a double staining of alcohol-fixed cytospin material with EMA and desmin is often helpful when distinguishing a malignant condition from reactive mesothelial proliferation. A dominance of cells with distinct EMA positivity indicates malignancy, whereas preserved desmin reactivity is associated with benign mesothelial cells (Figure 1, d). Scattered reactive mesothelial cells can, however, bind the EMA antibody, and a MM effusion may also contain some benign, reactive mesothelial cells with preserved desmin reactivity. The diagnosis then depends on the dominant staining pattern, and when it is difficult to establish malignancy in that way, further adjuvant analyses are necessary.
An accurate way of establishing malignancy based on an effusion is the analysis of ploidy with FISH (Figure 3, a through c). The commercially available UroVysion test (Abbot, Wiesbaden, Germany), adopted for pleural effusions, is useful in most MM cases.38,39 The test contains centromeric probes for chromosomes 3, 7, and 17, together with a probe hybridizing to band 9p21, where genes for p14 and p16 are located. Two algorithms for interpretation are used: either (1) gains of at least 2 centromeric signals in each of four cells, or (2) loss of both 9p21 signals in 12 cells. Either of those findings indicates aneuploidy associated with a malignant condition. Care is needed, however, so that tetraploidization during reactive proliferation is not misinterpreted. When there are 3 to 4 signals from all 3 centromeric probes, then the 9p21 signals may be helpful: if those probes also show 3 to 4 signals, the cells are probably tetraploid, whereas when only the usual 2 signals are seen in the latter probe, the centromeric probes demonstrate chromosomal gain. When validating the analysis, using these criteria on mesothelioma effusions, aneuploidy can be demonstrated with a sensitivity of around 95%.38 A homozygous loss of the 9p21 signals may point toward a MM, although that is not specific for this tumor.
Other analyses, such as EM and biomarker analyses can also be used to distinguish benign and malignant conditions. This will be further described below.
Malignant Mesothelioma Versus Metastatic Adenocarcinoma
Once the malignant nature of the effusion is established, the next step in a diagnosis of MM is to demonstrate the mesothelial phenotype of the tumor cells. Immunocytochemistry is the first choice of diagnostic means, using the same epitopes as used for histologic sections.33,34 Antibodies indicating mesothelial lineage are calretinin (Figure 1, c and j [red]), podoplanin (D2-40; Figure 1, e), HBME1 (Figure 1, f), mesothelin (Figure 1, g), Wilms tumor protein 1 (WT1), and cytokeratin 5. EMA (Figure 1, d [red, with cell membrane accentuation]) indicates a malignant condition, whereas BerEp4 (Figure 1, c and j [brown]), carcinoembryonic antigen (CEA; Figure 1, h), MOC31, thyroid transcription factor 1 (TTF1; Figure 1, i), CD15, and sialyl-TN are usually negative in MM and positive in metastatic adenocarcinoma. Among different CEA antibodies, the DAKO monoclonal preparation (No. A 0115, Copenhagen, Denmark) has virtually no cross-reactivity to MM cells. The BerEp4 and MOC31 antibodies label different epitopes on the epithelial cell adhesion molecule complex. BerEp4 seems slightly more sensitive in unfixed material, whereas MOC31 is preferred after formalin fixation. The performance of different TTF-1 clones seem to vary. The clone 8G7G3/1 (DAKO, No. M3375), was used throughout the present study (Figure 1, i and k [brown nuclear staining]). TTF-1 specifically labels lung and thyroid cancers, whereas MMs are invariably negative. Ovarian origin is indicated by PAX8 and CA 125 double reactivity (brown and red, respectively; Figure 1, l).
DIAGNOSTIC ANTIBODY PANELS
Because no single antibody is sufficiently specific alone, diagnostic antibody panels are recommended. Positive markers indicating MM, and negative markers excluding the diagnosis, should be used in combination. The use of a minimum of 4 immunocytochemical markers—2 in favor of, and 2 against, the diagnosis—is recommended; but some of the immunoreactivities might show atypical reaction patterns. In those cases, the use of additional markers will provide the correct diagnosis, leaving only a smaller proportion of inconclusive cases.
INTEGRATIVE APPROACH WITH MOLECULAR ANALYSES AND OTHER ANCILLARY METHODS
In cases in which routine cytology, together with immunocytochemistry, is inconclusive, additional ancillary methods can be helpful, such as biomarkers detected in the effusion supernatant, either as a secreted product or from tumor-cell decay. Two such soluble biomarkers have been proven to provide diagnostic information: hyaluronan and mesothelin.40–45
Hyaluronan is a high–molecular-weight polysaccharide, which is synthesized in large amounts by MMs. It is a marker for MM, and diagnostic levels are found in about 60% of MM effusions.45,46 When demonstrated with a chromatographic process, its specificity for MM was very high. Currently, however, the analysis is often performed as an enzyme-linked immunosorbent assay with reagents that occasionally may cross-react to give false-positive results, particularly in effusions from bacterial pleuritis. It is, therefore, advisable to analyze the concentrations of both hyaluronan and mesothelin, and then combine the 2 measures in a simple logistic model,45 which will give the probability of the combination representing MM.
Mesothelin is a protein bound to the cell membrane. It is often produced in large amounts by MM cells. After its synthesis, mesothelin is cleaved in 2 fragments: the cell-bound C-ERC is the receptor for CA 125, and the secreted N-ERC fragment acts as a macrophage-potentiating factor. Both of these ERCs can be recovered in the effusion supernatant, reflecting the synthesis of mesothelin. Mesothelin is not specific for mesothelioma but may act as a marker for malignancy; the hyaluronan content shows the mesothelial phenotype of the tumor.
Malignant mesothelioma can also be diagnosed by EM, which was long considered the gold standard for this diagnosis. The ultrastructural findings are well known, and cells groups recovered from a MM effusion are suitable for this examination, providing the material is glutaraldehyde fixed as soon as it arrives at the laboratory. Typically, the MM cells form polymorphic groups, with highly irregular nuclei, pronounced nucleoli, and desmosomes (Figure 4, a through f). The nuclei tend to be lobulated in a way not visible in light microscopy. The most prominent finding distinguishing MM from adenocarcinoma is the long slender microvilli, devoid of glycocalyx, found in apical membranes. When such microvilli and membrane protrusions are found on the basolateral surface of the cells or in cytoplasmic vacuoles in so-called neo-lumina, the findings strongly indicate malignancy. Other findings indicating mesothelial lineage of the malignant cells are filaments, which often surround the nucleus, and cytoplasmic, coarse tonofilaments, the latter correlating to the expression of cytokeratin 5 and a finding of squamoid differentiation. A major drawback with such ultrastructural examination is the long time needed for plastic embedding. Working ultrathin sections can often not be obtained within 2–3 weeks, a time that may be too long for the clinical demand.
DIAGNOSIS OF MALIGNANT MESOTHELIOMA IN CLINICAL ROUTINES IN RELATION TO THE GUIDELINES
The diagnostic principles reflected in Figure 2 have been used in clinical routines at the Department of Clinical Pathology and Cytology, Karolinska University Hospital, Huddinge (Stockholm, Sweden) since the late 1990s and are in line with the guidelines.24 Between 2004 and 2013, 85 cases were diagnosed with MM at our institution. In 76 cases (89%), an effusion was examined in the cytology laboratory. Forty-seven of those cases fulfilled the cytologic criteria for MM, as defined by the guidelines, corresponding to an absolute sensitivity of 62% which corresponded with conclusive diagnoses only. Forty-four of the 47 cases (94%) were diagnosed with immunocytochemical criteria, as described above, whereas in 3 cases (6%), the diagnosis was based on EM of the cell pellet. In another 13 of the 76 cases (17%). the report was that of a suspicion of MM. The total sensitivity, including cases diagnosed as “suspicious for malignancy”, was 79%. Three of these latter 13 cases (23%) had incomplete adjuvant analyses. In still another 3 cases (23%), the cytology had indicated malignancy without defining the mesothelial phenotype of the tumor.
There was some variation regarding the choice of antibody panels during the 10-year period studied (Table 1). In total, 7 antibodies were used to support the MM diagnosis, and 4 were used to exclude that diagnostic alternative. Except for the 3 cases in which EM replaced immunocytochemistry, 2 to 7 (average, 4.3) antibodies were used to support the diagnosis, and 2 to 5 (average, 3) were used to exclude other diagnostic alternatives. The sensitivities of the individual antibodies to support or exclude MM are shown in Table 2. Principally, their modes of action differ. Calretinin, D2-40, HBME1, WT1, and cytokeratin 5 demonstrate mesothelial lineage, whereas EMA and mesothelin merely indicate malignancy. If the 2 diagnostic outcomes—MM versus carcinoma or reactive versus malignant mesothelial proliferation—remain unresolved, various additional analyses become important. The distinction from reactive mesothelial proliferation can often be resolved with ploidy analysis by FISH, whereas the mesothelial lineage of unequivocally malignant cells can be established by additional immunocytochemistry or biomarker analysis.
In our material, the sensitivity of calretinin to show mesothelial lineage was 98% (42 of 43 cases), whereas EMA reactivity was 95% (40 of 42). Among less commonly used antibodies, reactivity to mesothelin was found in 28 of 30 cases (93%); HBME1, 28 of 30 (93%); WT1, 22 of 27 (81%); D2-40, 20 of 22 (91%); and cytokeratin 5, 18 of 18 (100%). Among reagents excluding the MM diagnosis, BerEp4 was found in 5 of 42 (12%), CEA in 0 of 38 (0%), desmin in 0 of 24 (0%), and TTF-1 in 0 of 26 (0%). In 2 cases, desmin reactivity had originally been reported. Upon rereview, those samples only contained a few scattered desmin-positive cells, representing benign mesothelial cells, which can also be present in a malignant effusion. Dominance of desmin-positive mesothelial cells gives a negative predictive value of 100%.
The use of 2 antibodies in favor, and 2 excluding, MM can be sufficient, providing all reactions, together with their positive and negative controls, give unequivocal results. During the present study period, however, additional antibodies were considered necessary to establish the diagnosis. Other adjuvant analyses were also performed simultaneously, often to ensure the correctness of the diagnosis.
Ploidy analysis by FISH was performed to verify malignancy in 20 of the 85 cases (24%). Aneuploidy, in accord with the manufacturer's criteria, could be demonstrated in 14 cases (70%), and 7 cases (35%) had homozygous deletion of the 9p21 band. Although careful use ensures high specificity, the sensitivity may vary. The 70% of aneuploidy cases seen in this routine use of the analysis was less than what was found when validating the test (95%),38 the difference, however, was not statistically significant.
Electron microscopy of effusion cell pellets was performed in 30 of the 76 cases (39%), 24 of them (80%) showing ultrastructural features diagnostic for MM. Biomarker analyses were performed in 44 of the 76 cases (58%). The established logistic model45 provides a probability of MM based on obtained concentrations of hyaluronan and mesothelin. Such probability levels exceeding 0.95 were obtained in 34 of those 44 cases (77%). Thus, the cytologic diagnoses were supported by typical findings in either EM or biomarker analysis in 41 of 45 cases (91%). These adjuvant analyses improved the sensitivity for detecting MM in 5 of the 45 cases (11%).
In 23 of the 76 cases (30%), the cytologic diagnoses were verified by a simultaneous or later biopsy. All patients with the diagnosis based on effusion cytology showed or developed clinical and radiologic evidence of that malignancy. When using guideline criteria, together with a liberal use of adjuvant analyses, in 10 years of clinical routine the positive predictive value of a cytologic diagnosis fulfilling those criteria was 100%. In 8 of the 76 cases (11%), the findings were suspicious of MM but not conclusive. Two of those 8 cases (25%) could not be verified as MM, so the positive predictive value of such an inconclusive diagnosis was 6 of 8 cases (75%). Thus, when a MM can be diagnosed in this way, the diagnosis is reliable and provides, on its own, sufficient grounds for initiating therapy.
Because the effusion is often the first diagnostic material available in patients with MM, cytology provides a possibility of earlier diagnosis. An earlier diagnosis, based on the first effusion, allows a better effect from chemotherapy because early treatment has been shown to improve the clinical outcome.47 The cytologic diagnosis of MM can be obtained with a high positive-predictive value, applying the criteria defined in the guidelines23 in clinical routine. When diagnosed in this way, subsequent therapy should be initiated without further delay.
In our cohort, the mean survival after a diagnosis of MM by effusion cytology was 20 months, whereas for those diagnosed only by histology, it was 12 months. It thus seems that cases in which it is possible to provide a diagnosis by cytology, including epithelioid and mixed subtypes represent a subgroup of patients with a somewhat better prognosis. In combination with the earlier diagnosis, a better effect of chemotherapy can, therefore, be expected, providing therapy is initiated without delay in cases in which effusion cytology is diagnostic.
The authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the Pulmonary Pathology Society Biennial Meeting; June 13–16, 2017; Chicago, Illinois.


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How many calories are in a BBQ chicken pizza?
|For a Serving Size of 1 slice|
|How many calories are in Bbq Chicken Thin Crust Pizza , medium? Amount of calories in Bbq Chicken Thin Crust Pizza , medium: Calories 231||Calories from Fat 76.5 (33.1%)|
|% Daily Value *|
How many calories in a slice of jets BBQ Chicken pizza?
|Calories 310||(1297 kJ)|
|Total Carbohydrate||38 g||13%|
|Dietary Fiber||1 g||4%|
How many calories in a slice of wood fired pizza?
The full pizza is 720 calories with 22g of fat, 13g saturated fat and 4g sugars. The Mozzarella cheese is the largest contributor to the calories and fat as just the base pizza dough is 468 calories per pizza with 3.4g fat, 0.5g saturated fat and 1.8g sugars.
How many calories are in a small slice of Hawaiian pizza?
|Calories 1150||(4812 kJ)|
|Total Fat||33 g||51%|
|Total Carbohydrate||160 g||53%|
|Dietary Fiber||7 g||28%|
How many calories are in a Domino’s BBQ Chicken pizza?
Is pizza really that bad for you?
Like all foods, more processed types of pizza are often higher in unhealthy ingredients than those made from scratch. Frozen and fast-food pizzas can contain ingredients like preservatives, colorings and unhealthy fats. However, all pizzas , no matter how they’re prepared, are typically made using refined wheat flour.
Is wood fired pizza healthier?
Using a wood fired method of cooking can mean a healthy oven pizza too, as fruit and vegetable toppings retain many antioxidants and nutrients because they are cooked a lot more quickly. A pizza just won’t have the same nutritional value if it takes longer to cook, as in your regular kitchen oven .
Why is wood fired pizza better?
Since the pizza cooks very quickly in a wood fired oven, it has the effect of imparting a delightful contrast on the finished pie. The bottom of the crust will cook very quickly, giving it a pleasing charred flavor on the edges that makes it taste just a little smoky, in a good way.
How many calories are in a wood fired pepperoni pizza?
|For a Serving Size of 0.25 pizza (103g)|
|How many calories are in Pepperoni Wood – Fired Thin Crust Pizza ? Amount of calories in Pepperoni Wood – Fired Thin Crust Pizza : Calories 280||Calories from Fat 99 (35.4%)|
|% Daily Value *|
How many calories in a slice of Hawaiian pizza from Dominos?
|Calories 222||(928 kJ)|
|Total Carbohydrate||25.3 g||8%|
|Dietary Fiber||1.5 g||6%|
How many calories should I eat a day?
Estimates range from 1,600 to 2,400 calories per day for adult women and 2,000 to 3,000 calories per day for adult men. Within each age and sex category, the low end of the range is for sedentary individuals; the high end of the range is for active individuals.
How many calories are in a slice of Little Caesars Hawaiian pizza?


If you are a proud owner of a 2012 Chevy Silverado, you know how reliable and capable this truck can be. However, like any vehicle, it can develop mechanical issues over time. One common problem that some Silverado owners encounter is the gear shifter not working properly.
Understanding the Gear Shifter Mechanism
Before we delve into the specific issues with the gear shifter, it’s important to understand how the mechanism works. The gear shifter, also known as the gear selector or gear shift lever, is the component that allows the driver to change the transmission gear position, such as from “Park” to “Drive” or “Reverse.”
Most modern vehicles, including the 2012 Chevy Silverado, have an electronic gear shifter system that utilizes sensors and solenoids to send signals to the transmission control module (TCM). When the gear shifter malfunctions, it can lead to a range of issues that affect the drivability and safety of the vehicle.
Common Symptoms of a Faulty Gear Shifter
There are several signs that indicate a potential problem with the gear shifter in your 2012 Chevy Silverado:
- Difficulty shifting gears
- Gear shifter getting stuck in one position
- Inability to shift out of “Park”
- Dashboard indicator not matching the actual gear position
- Strange noises or vibrations when engaging the gear shifter
Possible Causes of Gear Shifter Issues
When dealing with a gear shifter problem, it’s essential to pinpoint the underlying cause. Here are some common reasons why the gear shifter in a 2012 Chevy Silverado may malfunction:
|Faulty Shift Interlock Solenoid
|The shift interlock solenoid is responsible for preventing the gear shifter from moving out of “Park” unless the ignition key is turned to the “On” position. A malfunctioning solenoid can cause the gear shifter to be stuck.
|Transmission Control Module (TCM) Issues
|The TCM regulates the transmission functions based on input from various sensors. If the TCM or its associated components fail, it can lead to erratic gear shifter behavior.
|Shift Cable Problems
|The shift cable connects the gear shifter to the transmission. Over time, the cable may fray, stretch, or become dislodged, resulting in difficulties with shifting gears.
|Issues with the electrical connections, fuses, or wiring related to the gear shifter system can disrupt its normal operation.
|Foreign objects or debris lodged in the gear shifter assembly can impede its movement, leading to malfunctions.
Addressing the Gear Shifter Problem
Once you have identified the specific issue with your 2012 Chevy Silverado’s gear shifter, it’s crucial to take the appropriate steps to address the problem. Here are some potential courses of action:
- Professional Diagnosis: If you are not familiar with automotive repairs, it’s advisable to consult a certified mechanic or dealership service center. They can perform a thorough diagnostic assessment to pinpoint the root cause of the gear shifter issue.
- Replacement of Faulty Components: Depending on the diagnosis, you may need to replace the shift interlock solenoid, TCM, shift cable, or other malfunctioning parts. It’s essential to use genuine OEM components to ensure compatibility and reliability.
- Electrical and Mechanical Checks: Inspect the electrical connections and wiring related to the gear shifter system. Additionally, ensure that there are no obstructions or foreign objects hindering the movement of the gear shifter.
- Regular Maintenance: To prevent future gear shifter issues, adhere to the recommended maintenance schedule for your 2012 Chevy Silverado. This includes periodic inspections, lubrication of moving components, and addressing any warning signs promptly.
Frequently Asked Questions On 2012 Chevy Silverado Gear Shifter Not Working
Why Is My 2012 Chevy Silverado Gear Shifter Not Working?
The gear shifter may not work due to a faulty shift solenoid, low transmission fluid, or a damaged shift cable.
What Are The Signs Of A Malfunctioning Gear Shifter?
Signs include the gear shifter getting stuck, difficulty in shifting gears, or the vehicle not moving when the shifter is engaged.
How Can I Troubleshoot The Gear Shifter Issue?
You can start by checking the transmission fluid, inspecting the shift cable, and ensuring the brake lights are functioning properly.
Is It Possible To Fix The Gear Shifter Problem Myself?
Depending on the issue, you may be able to fix certain gear shifter problems yourself, especially if it involves simple maintenance tasks.
When Should I Seek Professional Help For This Issue?
If troubleshooting steps do not resolve the problem, or if there are complex mechanical issues, it’s advisable to seek the assistance of a professional mechanic.
The gear shifter is a critical component of any vehicle, and when it malfunctions, it can impede the normal operation of the transmission. By understanding the common issues with the 2012 Chevy Silverado’s gear shifter and taking proactive measures to address them, you can ensure that your truck remains reliable and safe for years to come.
If you are experiencing persistent gear shifter problems despite troubleshooting attempts, don’t hesitate to seek professional assistance to safeguard the drivability of your 2012 Chevy Silverado.


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Feb 14th Heart
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How has the technical partnership with Ferrari been and how has it evolved as Haas F1 Team went from designing a car to building it first racecar to building the current-generation car?
“Ferrari’s been a really good help for us. From day one we didn’t have to bother about things like the power unit, or suspension or gearbox – a lot of parts that would’ve taken us a long time to build and to get right. So, that has been incredible. Being able to use them every year, and use the new generation every year, it just means that the car is getting better and better.”
How crucial was Dallara and Ferrari in allowing Haas F1 Team to be competitive in not only its first year, but its second year when another new car needed to be built, and this year with an evolution of the 2017 car thanks to rules stability?
“It’s the same thing with Dallara. They’ve been a great partner of the team and a great help to get everything working. It was a challenge for them as well. They didn’t know the exact demands of Formula One initially, but we grew up together.”
A 1:19.525 lap set by Juan Pablo Montoya during practice for the 2004 Italian Grand Prix is widely regarded as the fastest Formula One lap of all time, as his average speed was 262.242 kph (162.950 mph). Will that time be eclipsed this year at Monza and a new benchmark for speed set? (Note: It rained during last year’s qualifying session, thwarting any attempt at a new track record.)
“I don’t know. It will be interesting. It would be nice to try and beat that record, as it’s an old one. It would be nice to get that one. Saying that, the curbs were a bit different, and the chicane was fast at the time. We’ll see.”
Where are the overtaking opportunities at Monza?
“The good thing with Monza is there’s lots of overtaking opportunities. There’s turn one, three, eight and then the Parabolica. It’s more or less every single braking event.”
Is overtaking at Monza a bit like a drag race where it’s about who can get on the power the fastest and most effectively?
“Yes, pretty much. It’s about top speed and getting out of the corner, and the low speed is quite good as well, with the dirty air of the car in front of you.”
Monza is a track with a lot of history and home to some of Formula One’s most passionate fans. Can you describe the atmosphere there?
“The atmosphere is crazy in Monza. The Tifosi, the fans – they’re just great. The track is in the middle of a park. It’s like nowhere else. There are so many people coming and watching, cheering for the drivers and, of course, for Ferrari. The atmosphere is electric. I love it.”
Have you had the opportunity to walk around the old portions of Monza, specifically the oval? If so, what ran through your mind when you saw the banking and realized cars in the late 1950s and early 1960s actually raced wheel-to-wheel there?
“It was crazy! You can barely stand up at the top of the oval. We still go underneath part of it at the Ascari chicane. It was definitely a different time, a different era of safety measures. I’m sure it was good fun, though.”
Would you have liked to have competed in that era just to see what it was like, or do you prefer to compete with the latest and greatest technology available?
“I’d compete anytime. I’ve always loved Formula One racing, no matter the era.”
Do you have any milestones or moments from your junior career that you enjoyed at Monza?
“My first race in Formula Renault 2.0 in 2004 – the Eurocup Series – was at Monza, and I was on the front row after qualifying. That was quite good. Certainly a happy memory.”
What is your favorite part of Monza?
“I like the two Lesmos turns, the ‘Curva di Lesmos’.”
Describe a lap around Monza.
“You cross the start-finish line going into the first chicane with big braking, dropping down to second gear. Then you’ve got important acceleration going into the second chicane, which is a bit faster, a bit more curb usage on the exit. You then try and carry as much speed through the two Lesmos turns. Then you go under the old oval and into the Ascari chicane. There’s big braking here, with a bump. It’s always tricky to get the car there. Then you really want to go early on power to get to the Parabolica. There’s another very long straight line, with very late braking to the Parabolica. Again, tricky throttle application heading toward the start-finish line to set your lap.”


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"Nothing is so exhausting as indecision, and nothing is so futile."
― Bertrand Russell
Susan and I moved into an apartment in Bend, OR this week. It hasn't been an easy transition for me, but I believe having a home base is going to be better in the long run (and for the long run training). It'll give me an opportunity to work on things that need working on — physically, professionally, relationally.
It'll take a focused effort. My downfall has typically been the inability to stave off distractions and place my attention fully into one thing. Distractions abound here. Oddly more so than on the road. It's easy for me to fall into old routines and become stagnant when in a fixed location. On the road, the continued movement creates perhaps an illusion of progress, but over time, making headway across multiple facets of our lives is difficult. I made progress in things that the road allowed. It is a great place to nurture a sense of adventure and exploration, to photograph, to move outside and be immersed in nature. It isn't an easy environment to make a living and it isn't easy to maintain some autonomy while traveling as a couple — which is critical for introverts.
The unstructured, whimsical and uncertain living that "vanlife" afforded was always more my dream than Susan's. In reflection, the truth may be that the lifestyle gets me out of my head. The continual movement and uncertainty puts me in a "doing things" and "solving things" mode. It creates an environment of mild chaos, which is just another form of distraction which I thought I was avoiding. But, that non-threatening type of chaos requires my focus.
I've long created a prison, and placed myself in the non-threatening general population that is cellblock "busyness". Because, the real threat is Isolation. Isolation, time in unintentional thought, is agonizing. Isolation is a dark and hazy hallway of a thousand doors. All the doors are ajar, cracked open for me to easily walk through, but I can't choose one to enter. I remain in purgatory — in my hallway of indecision. More often than not I curl up on the floor and make no decision at all. Then the Warden of Isolation, my faceless ego, begins to castigate me for my inability to act. The doors slam closed and I'm left in darkness with my own negative self-talk echoing off the walls.
Susan thrives when having structure and routine. Perhaps for the same reason I thrive without it. Routine and structure gives her intentional focus, and leaves her with less time in the Isolation. I believe I can thrive with structure and routine if I can step out of the hallway long enough to allow flourishing. My work is to craft better habits and a healthy environment to avoid the indecisions and the Isolation that tends to follow.
STAY CURIOUS — WHAT WE'RE READING
Running Dysmorphic →
This is a pretty awesome (long but worth it) write up of what it feels like searching to be ourselves, yet also searching to belong.
"It’s about identity, isn’t it? All of it. It’s about the fact that this life is not comfortable if you’re aware of your own your-ownness. It’s about the comfort of ritual, and sometimes the comfort of demands, about what it feels like to see someone else’s structure then to mold yourself to fit into it. It’s about not wanting to be judged. I wanted to set myself apart but also be a part. I wanted to say I’m one of you to as many people as I could because I was scared of being myself."
And, as I've struggled with, he writes of the importance of giving ourselves permission to find JOY in our own "absurd" human-ness.
"So much of life is about what you give yourself permission to do or don’t do, and how that act of self-permission leads to joy. This requires the discernment to know what joy is, or how it feels, and in what ways it is true."
Rob Krar's Never-Ending Race →
This is a good read about ultrarunner Rob Krar over on Outside. He discusses his battles with depression, his camps, and the impact his struggles have on his relationship. Always grateful for his openness and sharing his story.
Running Helped Me Cope With—And Ultimately Beat—My Addiction →
Runner and exercise expert Leigh Gerson shares what happened when she swapped drugs for running.
I liked the focus on my breathing, the sound of each step, and the soothing crash of the ocean waves along the beach.
After six weeks, I was running regularly, and the cloud of self-hatred and depression that had surrounded me for most of my life started to evaporate.
We need a major redesign of life →
It’s time to get serious about a major redesign of life. Thirty years were added to average life expectancy in the 20th century, and rather than imagine the scores of ways we could use these years to improve quality of life, we tacked them all on at the end. Only old age got longer.
Long lives are not the problem. The problem is living in cultures designed for lives half as long as the ones we have.
25 Again? How Exercise May Fight Aging →
More science supporting the importance of exercise for longevity, specifically it details the benefit exercise has on managing inflammation.
The study finds that active older men’s muscles resemble, at a cellular level, those of 25-year-olds and weather inflammatory damage much better than the muscles of sedentary older people.

domain: psychology


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This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:
Parents urged to watch weekend tech use as teens settle into school
We all know that teenagers love their sleep. But if your teen is a regular night owl, then they could be overdosing on technology at the expense of their sleep, according to new research from the University of South Australia.
Assessing sleep, well-being, and technology use of Australian teenagers, researchers found that those with a "late sleep chronotype" (a preference for a later bedtime) may be at greater risk of disturbed sleep from excess technology than their counterparts with an "early sleep chronotype."
Published in Child and Adolescent Mental Health, the study compared bedtime "digital diets" of 462 Australian school students (aged 12–18 years) on weekdays and weekends finding that technology use and sleep differ on weekend compared to weekdays.
Specifically, social media or texting was predictive of shorter sleep on weekends (but not weekdays), and TV/streaming was predictive of a later wake time on weekdays (but not weekends).
Teens with a late sleep chronotype were associated with more frequent technology use, with older teens more likely to use social media/texting or TV/streaming, and younger teens more likely to be gaming.
UniSA researcher and postgraduate student, Alexander Reardon, says that understanding the links between sleep and technology use is important, especially as children have recently returned to school.
"Owning a mobile phone and having access to technology is common for many young people, but teenagers are notorious for being 'glued' to their phone or device, and it's important that we understand how this might affect different aspects of their lives," Reardon says.
"We already know that many teenagers don't get enough sleep on school days. This can be quite normal as teenagers tend to experience natural delays in their 'body clocks' as they get older, leading them to go to bed later and get up later. But most of these teens catch up on missed sleep on weekends when they have a chance to 'sleep-in.'"
"Yet when we add technology to the mix, this catch-up sleep is far less likely to happen, leaving many teenagers with a serious sleep deficit."
Australian sleep health guidelines recommend that teenagers get between 8–10 hours of sleep a day.
UniSA researcher Dr. Alex Agostini says that without enough sleep teenagers are more likely to struggle with schooling and well-being.
"When we don't get enough sleep, we can experience problems with thinking, concentration, memory, reaction times and mood, all of which make it harder to perform daily tasks and increase the risks of mistakes," Dr. Agostini says.
"Teenagers often need to learn good sleep habits. This can include everything from the benefits of a sleep routine, finding ways to wind down, as well as cutting back on late night technology use.
"For teens and parents, the message is clear: cut back on night-time tech and not only will get a better night's sleep, but everyone will be in a better head space the next day."
More information: Alexander Reardon et al, Adolescent sleep, distress, and technology use: weekday versus weekend, Child and Adolescent Mental Health (2022). DOI: 10.1111/camh.12616


RAMBAN: District Development Commissioner, Nazim Zai Khan today convened a meeting of officers, representatives of NHAI and construction agencies to resolve land acquisition and other issues besides reviewing the progress on a prestigious Jammu-Srinagar four laning project.
Issues related to maintenance of existing highway, blacktopping and sprinkling of water on road at construction sites to minimize pollution and ensuring hassle free vehicular movement especially during the ensuing winter season were discussed in detail
ADC, Ashok Sharma; Project Director (PD) NHAI, Parshotam Kumar; SDM, Ramsu, Banihal, Tehsildar besides officers of concerned departments attended the meeting.
The DDC asked the construction agencies to station adequate man and machinery including cranes and excavators at all identified vulnerable locations to deal with emergency situations.
He reviewed section wise progress on four-laning of Jammu-Srinagar National Highway including Nashri-Ramban and Ramban-Banihal and set the timeline for the same.
He directed the Executive Engineer, TLMDL to ensure shifting of identified towers to safer places so that road construction work can be completed. He also directed the concerned authorities to ensure smooth passage of the traffic by proper maintenance of the road at all crucial spots.
Highlighting the importance of the prestigious National Highway four -laning project, the DDC resolved most of the issues on the spot and assured the companies full possible support from district administration.
He asked the officers to immediately resolve the bottlenecks and issues in their areas of jurisdiction highlighted by the construction agencies. The DDC directed the agencies to adhere to the guidelines of the National Green Tribunal and conditions of the contract agreement to avoid criminal proceedings.
Agencies were also directed to enhance water sprinkling on the road to minimize the dust besides dumping the muck at only identified dumping yards.


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In the latest photo, posted to her official site and Twitter profile, Gaga poses naked on computer equipment and rocks nothing but black boots, a pair of glasses with long whisker-like features and a long brown wig.
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Another result may deepen the chill for current office-holders: Only 25 percent of registered voters now say theyre inclined to re-elect their representative in Congress; 66 percent are inclined to look around for someone else the highest level of anti-incumbency in ABC/Post polls since 1989.
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domain: news


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Aqua, Coco-Glucoside, Sodium Coco-Sulfate, Disodium Cocoyl Glutamate, Sodium Cocoyl Glutamate, Lactic Acid**, Sodium Chloride, Zinc PCA, Betula Alba Leaf*, Citrus Limon Peel Oil, Guar Hydroxypropyltrimonium Chloride, Alcohol, Parfum, Sodium Benzoate, Potassium Sorbate, Citric Acid, Limonene, Citral, Linalool, Geraniol
* from controlled organic cultivation
** from plant origin
free of synthetic dyes, PEG, paraffin oil
Zinc salt is a neutral salt of citric acid. It is used as a mineral source in food, food supplements and in cosmetics (e. g. toothpaste) and has antimicrobial and anti-inflammatory properties. (Picture credits: ©Sergey Jarochkin/123rf.com)
Zinc is connected to pyrrolidone carboxylic acid (natural moisturizer of the skin). The salt binds water and thus reduces transepidermal water loss. Zinc salt has antimicrobial and sebum regulating properties and is used in case of impure skin as well as oily skin and scalp (dandruff). Furthermore it has the feature to form odourless salts together with the fatty acids of the sweat and thus reduces body odours.
Betula Alba Leaf
Birch can be found in large parts of the Northern hemisphere as for example in Europe, North America and Asia. Traditionally birch is used in the treatment of skin diseases like eczemas and in metabolic stimulation (e. g. of the scalp).
Citrus Limon Peel Oil
Lemon oil is extracted from the fresh peel of the lemon. The lemon tree (citrus x limon) is cultivated in Italy, Spain and Argentina. The essential oil has purifying properties and is also used for scenting.

domain: chemistry


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Known as much for its complexity as its vital role in regulating cellular and organismal growth, the mechanistic target of rapamycin complex 1 (mTORC1) pathway has seemingly been acting in mysterious ways.
Through a variety of mechanistic interactions, mTORC1 interprets cues in the cellular environment, including the availability of nutrients, and signals the organism to act accordingly. mTORC1 is apt to trigger growth during times of abundance and dial back metabolism when food is scarce.
Owing to years of intense scrutiny in the lab of Whitehead Institute Member David Sabatini, the key players of this pathway—whose deregulation is associated with diseases ranging from diabetes to cancer to epilepsy—have gradually been brought to light. Yet, one essential question remained unanswered: How exactly does mTORC1 actually detect the presence of nutrients?
Now, it seems, scientists in Sabatini’s lab have at least a partial answer, describing for the first time a protein that appears to sense the amino acid arginine. The discovery of this transmembrane protein, known as SLC38A9, is reported this week in the journal Science.
“No one doubts that this is an important pathway, with implications for aging, cancer, and diabetes, and we had figured out the core machinery of the pathway,” says Sabatini. “But the mystery has been what are the sensors? Now we’ve found what is likely the first nutrient sensor. This is what connects that core machinery to the world around it.”
The finding suggests a model in which mTORC1, located at the surface of cellular components known as lysosomes, receives “go/no-go” signals from a family of enzymes dubbed Rag GTPases. It had been known that the Rags convey information about nutritional status to mTORC1, but it wasn’t clear how the Rags came by this information. Through a series of experiments, researchers found that SLC38A9 is capable of transporting and directly interacting with amino acids, the building blocks of proteins.
Further, they found that in cells overexpressing SLC38A9, mTORC1 signaling is activated even in the absence of amino acids. On the flipside, they found mTORC1 activation defective in cells engineered to lack expression of SLC38A9. Taken together, such compelling evidence points to SLC38A9 as an amino acid sensor, tipping off the Rags to the availability of nutrients.
“It’s like a relay race and this protein is what starts the race,” says Zhi-Yang Tsun, a graduate student in Sabatini’s lab and co-first author of the Science paper. “We’ve been looking for a long time for a molecule like this. It has all the properties consistent with a sensor.”
As new components of the pathway are identified and their roles elucidated, the number of potential targets that could be manipulated therapeutically increases. Historically, drug development activities in this space have focused on blocking mTORC1 activation, in part because hyperactivation of the pathway can lead to aberrant growth seen in cancer or metabolic abnormalities associated with diabetes. Intriguingly, because SLC38A9 activates the pathway, it may represent a target for clinical situations in which growth stimulation is desirable.
“It would be interesting to have to have small molecular handles to perturb the pathway, turning it on or off,” says Shuyu Wang, another Sabatini lab graduate student and co-first author of the Science paper. “In this case, one could think about situations where you would want to increase protein synthesis, perhaps to treat muscle atrophy and disease-related weight loss.”
Although the discovery of the first nutrient sensor in this pathway represents an important advance, the researchers know much work lies ahead. SLC38A9’s specificity for arginine suggests that many more such sensors—for other amino acids and glucose, for example—interact either directly or indirectly with mTORC1. Identifying them will thus remain a focus of the lab for years to come.
This work was supported by the National Institutes of Health (grants R01 CA103866 and AI47389), the United States Department of Defense (grant W81XWH-07-0448), the Howard Hughes Medical Institute, a National Defense Science and Engineering Fellowship, a National Science Foundation Graduate Research Fellowship, an American Cancer Society - Ellison Foundation Postdoctoral Fellowship, and a German Academic Exchange Service/DAAD Fellowship.
Written by Matt Fearer
* * *
David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
* * *
“Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1”
Science, January 7, 2015
Shuyu Wang (1,2,3,4), Zhi-Yang Tsun (1,2,3,4), Rachel Wolfson (1,2,3,4), Kuang Shen (1,2,3,4), Gregory A. Wyant (1,2,3,4), Molly E. Plovanich (6), Elizabeth D. Yuan (1,2,3,4), Tony D. Jones (1,2,3,4), Lynne Chantranupong (1,2,3,4), William Comb (1,2,3,4), Tim Wang (1,2,3,4), Liron Bar-Peled (1,2,3,4)*, Roberto Zoncu (1,2,3,4)**, Christoph Straub (5), Choah Kim (1,2,3,4), Jiwon Park (1,2,3,4), Bernardo L. Sabatini (5), and David M. Sabatini (1,2,3,4)
1. Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.
2. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
4. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.
5. Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
6. Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA.
* Present address: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
** Present address: Department of Molecular and Cell Biology, University of California
Berkeley, Berkeley, CA 94720, USA
Matt Fearer | newswise
Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden
The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
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domain: biology