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Bioinformatics identifies key genes and cellular pathways in COVID-19 – News-Medical.Net

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The COVID-19 pandemic is showing no signs of waning or extinction anytime soon. Now, a new study published on the preprint server bioRxiv* in August 2020 shows a new bioinformatics approach to studying the pathogenesis of this disease, by uncovering the differentially expressed genes (DEGs) and cell signaling pathways that cause the disease characteristics. This will help develop better therapies to counter the effects of these genes.

This transmission electron microscope image shows SARS-CoV-2—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S. Virus particles are shown emerging from the surface of cells cultured in the lab. The spikes on the outer edge of the virus particles give coronaviruses their name, crown-like. Image captured and colorized at NIAID’s Rocky Mountain Laboratories (RML) in Hamilton, Montana. Credit: NIAID

The Viral Target and Disease Process

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus with a genome size that ranges between 26 and 32 kB. It has both structural proteins, including the spike glycoproteins, membrane proteins, envelope proteins and nucleocapsid, and non-structural proteins, including proteases. The infection of the host cell by this virus sets off an antiviral response. However, an unregulated immune response can contribute to the severe tissue damage seen in serious COVID-19 disease.

While a majority of COVID-19 patients are asymptomatic or show only mild symptoms, a significant minority develop severe lung inflammation, acute respiratory distress syndrome (ARDS), and some die. The disease involves not only ciliary dysfunction but also pro-inflammatory signaling pathways, leading to a macrophage activation syndrome, also called a cytokine storm. The pathogenesis of this severe deterioration in COVID-19 patients is unclear.  

The virus primarily targets the human bronchial epithelium, which possesses the viral receptor, the angiotensin-converting enzyme (ACE) 2. In order to understand the pathogenesis of the disease, scientists have carried out microarray testing, but the small size of the sample limits these experiments.

The current study used a variety of technologies, including analysis of the GEO data, from the Gene Expression Omnibus to find the DEGs and the associated biological processes. The researchers worked on human bronchial organoids (hBOs).

Identification of DEGs

The mechanism of infection in the human bronchus was explored by comparing the transcriptional signature of these hBOs with uninfected controls. They found that the level of expression of 89 genes was different in these two types of cells. These DEGs comprised 59 up-regulated and 30 downregulated genes, in the hBOs, relative to the negative controls.

To understand the mechanism on SARS-CoV-2 infected human bronchus, the modular transcriptional signature of SARS-CoV-2 infected human bronchial organoids (hBOs) was compared to that of the uninfected controls. A total of 89 genes were identified to be differentially expressed in SARS-CoV-2 infected hBOs with the threshold of P<0.01. Among these DEGs, 59 were up-regulated and 30 down-regulated in SARS-CoV-2 infected hBOs compared with the negative controls.

Enrichment analysis of DEGs

The researchers then examined the DEGs using the KEGG pathway and the Gene Ontology (GO) categories for an enrichment analysis. KEGG is an integrated database resource which also has a computationally generated database in many categories such as metabolism, as well as other functions at the cellular and organism level. In their enrichment analysis, gene sets are interpreted by assigning genes to several predefined areas, based on their functional features.

The three top KEGG pathways led them to identify the top-ranking three components of the cells. These are the Cell fraction, Insoluble fraction, and Membrane fraction.

The Importance of Apoptosis

They then went on to identify the most important three biological processes, namely, Death, Cell Death, and Apoptosis. The researchers found that the death and apoptosis process was seen chiefly in the set of biological processes. The apoptosis pathway, with death signaling, is critical to clearing SARS-CoV-2 from hBOs. Genes such as XAF1, TNNF, and FAS are involved in T cell apoptosis in these patients.

Earlier research indicated that ciliary abnormalities in the bronchial epithelium are found in this disease. This, in turn, predisposes to secondary infections, apoptosis, and cell death. The infected airways show changes such as apoptosis and pericyte loss in the alveolar capillaries, as well as cell death caused by oxidative stress. As the disease progresses, the virus infects tracheal cells extensively, causing them to enter apoptosis and necrosis.

Enzyme Dysregulation in COVID-19

Thirdly, they picked out the top three molecular functions, which are the Enzyme Inhibitor activity, Peptidase Inhibitor activity, and Endopeptidase Inhibitor activity. The disease causes enzyme dysregulation in hBOs. Viral synthesis requires polyproteins to be translated from the viral RNA genome. Thus, the top three molecular processes in these infected cells are “Enzyme inhibitor activity”, “Peptidase inhibitor activity”, and “Endopeptidase inhibitor activity”.

The researchers comment, “These findings indicated that SARS-CoV-2 may inhibit the enzyme inhibitor activity in hBOs to create more polyproteins and viruses. Thus, hBOs may be a potential virus production base during COVID-19 diseases.”

Cytokine Binding and COVID-19 Severity

The researchers suggest that the main signaling pathways on KEGG analysis in SARS-CoV-2-infected hBOs are cytokine-cytokine receptor interaction, the P53 pathway, and apoptosis. Some of the cytokines that are secreted when the cell is exposed to an activator include IL-1, IL-6, and TNFα. These molecules interact with specific cell receptors on the cell surface to trigger a cell response. The SARS-CoV-2 also interacts with the surface receptor ACE2 via its spike protein, to achieve cell entry. This suggests that many cytokines bind to the surface of the infected cell and trigger inflammation simultaneously with the binding and entry of the virus. This could lead to the identification of these cytokines and suppression of such binding to reduce COVID-19 severity.

Central Role of the NF-κB pathway

The next step was to simulate a PPI network using a Cytoscape program. This protein-level PPI connects 84 nodes, with 30 interactions between the infected and uninfected hBOs. The functions of the most important gene modules of the infected vs uninfected hBOs were analyzed, and the top 10 biological pathways in terms of significance were identified. This showed the involvement of the NF-κB pathway in COVID-19.

This is a central pathway in inflammation since it is involved in the subsequent expression of pro-inflammatory genes, including cytokines, chemokines, and adhesion molecules. Its activation is known to underlie the induction of many genes in inflammatory conditions as well as regulating a multitude of signaling pathways, including STAT3, RGS12, and P53. The inhibition of this molecule could potentially reduce the severity of SARS-CoV-2 infection.

Conclusion

The study sums up: “NFKBIA, C3, and CCL20 may be key genes in SARS-CoV-2 infected hBOs. Our study suggested that “Cytokine-cytokine receptor interaction,” “P53 signaling pathway”, and “Apoptosis” were the main signaling pathways during SARS-CoV-2 infection. “ Appropriate intervention in these pathways could potentially turn around the course of the disease, these findings suggest.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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What’s the greatest holiday gift: lips, hair, skin? Give the gift of great skin this holiday season

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Give the gift of great skin this holiday season

Skinstitut Holiday Gift Kits take the stress out of gifting

Toronto, October 31, 2024 – Beauty gifts are at the top of holiday wish lists this year, and Laser Clinics Canada, a leader in advanced beauty treatments and skincare, is taking the pressure out of seasonal shopping. Today, Laser Clincs Canada announces the arrival of its 2024 Holiday Gift Kits, courtesy of Skinstitut, the exclusive skincare line of Laser Clinics Group.

In time for the busy shopping season, the limited-edition Holiday Gifts Kits are available in Laser Clinics locations in the GTA and Ottawa. Clinics are conveniently located in popular shopping centers, including Hillcrest Mall, Square One, CF Sherway Gardens, Scarborough Town Centre, Rideau Centre, Union Station and CF Markville. These limited-edition Kits are available on a first come, first served basis.

“These kits combine our best-selling products, bundled to address the most relevant skin concerns we’re seeing among our clients,” says Christina Ho, Senior Brand & LAM Manager at Laser Clinics Canada. “With several price points available, the kits offer excellent value and suit a variety of gift-giving needs, from those new to cosmeceuticals to those looking to level up their skincare routine. What’s more, these kits are priced with a savings of up to 33 per cent so gift givers can save during the holiday season.

There are two kits to select from, each designed to address key skin concerns and each with a unique theme — Brightening Basics and Hydration Heroes.

Brightening Basics is a mix of everyday essentials for glowing skin for all skin types. The bundle comes in a sleek pink, reusable case and includes three full-sized products: 200ml gentle cleanser, 50ml Moisture Defence (normal skin) and 30ml1% Hyaluronic Complex Serum. The Brightening Basics kit is available at $129, a saving of 33 per cent.

Hydration Heroes is a mix of hydration essentials and active heroes that cater to a wide variety of clients. A perfect stocking stuffer, this bundle includes four deluxe products: Moisture 15 15 ml Defence for normal skin, 10 ml 1% Hyaluronic Complex Serum, 10 ml Retinol Serum and 50 ml Expert Squalane Cleansing Oil. The kit retails at $59.

In addition to the 2024 Holiday Gifts Kits, gift givers can easily add a Laser Clinic Canada gift card to the mix. Offering flexibility, recipients can choose from a wide range of treatments offered by Laser Clinics Canada, or they can expand their collection of exclusive Skinstitut products.

 

Brightening Basics 2024 Holiday Gift Kit by Skinstitut, available exclusively at Laser Clincs Canada clinics and online at skinstitut.ca.

Hydration Heroes 2024 Holiday Gift Kit by Skinstitut – available exclusively at Laser Clincs Canada clinics and online at skinstitut.ca.

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Here is how to prepare your online accounts for when you die

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LONDON (AP) — Most people have accumulated a pile of data — selfies, emails, videos and more — on their social media and digital accounts over their lifetimes. What happens to it when we die?

It’s wise to draft a will spelling out who inherits your physical assets after you’re gone, but don’t forget to take care of your digital estate too. Friends and family might treasure files and posts you’ve left behind, but they could get lost in digital purgatory after you pass away unless you take some simple steps.

Here’s how you can prepare your digital life for your survivors:

Apple

The iPhone maker lets you nominate a “ legacy contact ” who can access your Apple account’s data after you die. The company says it’s a secure way to give trusted people access to photos, files and messages. To set it up you’ll need an Apple device with a fairly recent operating system — iPhones and iPads need iOS or iPadOS 15.2 and MacBooks needs macOS Monterey 12.1.

For iPhones, go to settings, tap Sign-in & Security and then Legacy Contact. You can name one or more people, and they don’t need an Apple ID or device.

You’ll have to share an access key with your contact. It can be a digital version sent electronically, or you can print a copy or save it as a screenshot or PDF.

Take note that there are some types of files you won’t be able to pass on — including digital rights-protected music, movies and passwords stored in Apple’s password manager. Legacy contacts can only access a deceased user’s account for three years before Apple deletes the account.

Google

Google takes a different approach with its Inactive Account Manager, which allows you to share your data with someone if it notices that you’ve stopped using your account.

When setting it up, you need to decide how long Google should wait — from three to 18 months — before considering your account inactive. Once that time is up, Google can notify up to 10 people.

You can write a message informing them you’ve stopped using the account, and, optionally, include a link to download your data. You can choose what types of data they can access — including emails, photos, calendar entries and YouTube videos.

There’s also an option to automatically delete your account after three months of inactivity, so your contacts will have to download any data before that deadline.

Facebook and Instagram

Some social media platforms can preserve accounts for people who have died so that friends and family can honor their memories.

When users of Facebook or Instagram die, parent company Meta says it can memorialize the account if it gets a “valid request” from a friend or family member. Requests can be submitted through an online form.

The social media company strongly recommends Facebook users add a legacy contact to look after their memorial accounts. Legacy contacts can do things like respond to new friend requests and update pinned posts, but they can’t read private messages or remove or alter previous posts. You can only choose one person, who also has to have a Facebook account.

You can also ask Facebook or Instagram to delete a deceased user’s account if you’re a close family member or an executor. You’ll need to send in documents like a death certificate.

TikTok

The video-sharing platform says that if a user has died, people can submit a request to memorialize the account through the settings menu. Go to the Report a Problem section, then Account and profile, then Manage account, where you can report a deceased user.

Once an account has been memorialized, it will be labeled “Remembering.” No one will be able to log into the account, which prevents anyone from editing the profile or using the account to post new content or send messages.

X

It’s not possible to nominate a legacy contact on Elon Musk’s social media site. But family members or an authorized person can submit a request to deactivate a deceased user’s account.

Passwords

Besides the major online services, you’ll probably have dozens if not hundreds of other digital accounts that your survivors might need to access. You could just write all your login credentials down in a notebook and put it somewhere safe. But making a physical copy presents its own vulnerabilities. What if you lose track of it? What if someone finds it?

Instead, consider a password manager that has an emergency access feature. Password managers are digital vaults that you can use to store all your credentials. Some, like Keeper,Bitwarden and NordPass, allow users to nominate one or more trusted contacts who can access their keys in case of an emergency such as a death.

But there are a few catches: Those contacts also need to use the same password manager and you might have to pay for the service.

___

Is there a tech challenge you need help figuring out? Write to us at onetechtip@ap.org with your questions.

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Pediatric group says doctors should regularly screen kids for reading difficulties

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The Canadian Paediatric Society says doctors should regularly screen children for reading difficulties and dyslexia, calling low literacy a “serious public health concern” that can increase the risk of other problems including anxiety, low self-esteem and behavioural issues, with lifelong consequences.

New guidance issued Wednesday says family doctors, nurses, pediatricians and other medical professionals who care for school-aged kids are in a unique position to help struggling readers access educational and specialty supports, noting that identifying problems early couldhelp kids sooner — when it’s more effective — as well as reveal other possible learning or developmental issues.

The 10 recommendations include regular screening for kids aged four to seven, especially if they belong to groups at higher risk of low literacy, including newcomers to Canada, racialized Canadians and Indigenous Peoples. The society says this can be done in a two-to-three-minute office-based assessment.

Other tips encourage doctors to look for conditions often seen among poor readers such as attention-deficit hyperactivity disorder; to advocate for early literacy training for pediatric and family medicine residents; to liaise with schools on behalf of families seeking help; and to push provincial and territorial education ministries to integrate evidence-based phonics instruction into curriculums, starting in kindergarten.

Dr. Scott McLeod, one of the authors and chair of the society’s mental health and developmental disabilities committee, said a key goal is to catch kids who may be falling through the cracks and to better connect families to resources, including quicker targeted help from schools.

“Collaboration in this area is so key because we need to move away from the silos of: everything educational must exist within the educational portfolio,” McLeod said in an interview from Calgary, where he is a developmental pediatrician at Alberta Children’s Hospital.

“Reading, yes, it’s education, but it’s also health because we know that literacy impacts health. So I think that a statement like this opens the window to say: Yes, parents can come to their health-care provider to get advice, get recommendations, hopefully start a collaboration with school teachers.”

McLeod noted that pediatricians already look for signs of low literacy in young children by way of a commonly used tool known as the Rourke Baby Record, which offers a checklist of key topics, such as nutrition and developmental benchmarks, to cover in a well-child appointment.

But he said questions about reading could be “a standing item” in checkups and he hoped the society’s statement to medical professionals who care for children “enhances their confidence in being a strong advocate for the child” while spurring partnerships with others involved in a child’s life such as teachers and psychologists.

The guidance said pediatricians also play a key role in detecting and monitoring conditions that often coexist with difficulty reading such as attention-deficit hyperactivity disorder, but McLeod noted that getting such specific diagnoses typically involves a referral to a specialist, during which time a child continues to struggle.

He also acknowledged that some schools can be slow to act without a specific diagnosis from a specialist, and even then a child may end up on a wait list for school interventions.

“Evidence-based reading instruction shouldn’t have to wait for some of that access to specialized assessments to occur,” he said.

“My hope is that (by) having an existing statement or document written by the Canadian Paediatric Society … we’re able to skip a few steps or have some of the early interventions present,” he said.

McLeod added that obtaining specific assessments from medical specialists is “definitely beneficial and advantageous” to know where a child is at, “but having that sort of clear, thorough assessment shouldn’t be a barrier to intervention starting.”

McLeod said the society was partly spurred to act by 2022’s “Right to Read Inquiry Report” from the Ontario Human Rights Commission, which made 157 recommendations to address inequities related to reading instruction in that province.

He called the new guidelines “a big reminder” to pediatric providers, family doctors, school teachers and psychologists of the importance of literacy.

“Early identification of reading difficulty can truly change the trajectory of a child’s life.”

This report by The Canadian Press was first published Oct. 23, 2024.

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