‘Bespoke’ analysis of DNA packaging sheds light on the intricacies of the fundamental process
Researchers from Skoltech and their colleagues have optimized data analysis for a common method of studying the 3D structure of DNA in single cells of a Drosophila fly. The new approach allows the scientists to peek with greater confidence into individual cells to study the unique ways DNA is packaged there and get closer to understanding this crucial process’s underlying mechanisms.
The paper was published in the journal Nature Communications.
The reason a roughly two-meter-long strand of DNA fits into the tiny nucleus of a human cell is that chromatin, a complex of DNA and proteins, packages it into compact but very complex structures. To study the way DNA is packaged, researchers worldwide have developed so-called chromosome conformation capture (3C) techniques, the most efficient of which is called Hi-C. Hi-C essentially catalogs all interacting fragments of a DNA strand via high-throughput sequencing.
Therein lies the problem, however: to work, Hi-C needs tens of micrograms of DNA, which means millions of cells, each with its unique spatial organization of chromatin, have to be averaged to get a snapshot that will inevitably miss some peculiarities of DNA packaging in single cells. Much like the ‘average person’ does not really exist, conventional Hi-C cannot tell you which of the multitudes of interactions actually happen in the same cell. Furthermore, this snapshot will hardly be useful in unraveling the physical processes that led to chromatin’s particular 3D structure.
“We see certain structures, such as so-called Topologically Associating Domains, or TADs, in averaged contact maps, but we do not know whether they are artifacts of averaging or indeed exist in individual cells. Moreover, we know that cells even in one tissue may be quite diverse in terms of gene expression – so a natural question arises whether this diversity also exists on the structural level,” says Mikhail Gelfand, Skoltech Vice President for Biomedical Research and a co-author of the new paper.
To overcome this hurdle and make the Hi-C process more suitable for single cells, researchers from several institutes advanced a single-cell Hi-C technique. The Skoltech team, led by Gelfand and assistant professor at the Skoltech Center of Life Sciences Ekaterina Khrameeva, took a challenge to optimize data processing for single-cell Hi-C and uncover the fundamental properties of Drosophila cells.
Their colleagues from the Institute of Gene Biology RAS and Lomonosov Moscow State University collaborate with researchers from French-Russian Interdisciplinary Scientific Center J.-V. Poncelet
optimized the snHi-C procedure to make it suitable for experiments with Drosophila cells.
For the technique to work, the teams had to start with the same Hi-C steps of chemically ‘freezing’ the chromatin in place, strategically cutting the DNA and reassembling it so that fragments that were spatially close end up stitched together. But then, instead of using the DNA in bulk, they amplified the miniscule amounts of DNA from a single cell in each well using a polymerase from a phi29 bacteriophage. This phi29 polymerase is widely used in DNA amplification methods thanks to its ability to generate a lot of DNA from the tiniest of templates and make significantly fewer errors than other commonly-used polymerases.
However, it turned out that the handy DNA polymerase, while less error-prone, can still make random ‘hops’ between DNA molecules, creating artificial ‘links’ that Hi-C algorithms cannot distinguish from real interactions. So the researchers had to come up with an authenticity test, weeding out the random hops from real traces of interacting fragments.
They used their new technique on Drosophila cells to determine whether the fundamental ways of chromatin folding are the same across organisms. Earlier studies in mammalian cells pointed to the existence of TADs in average contact maps from Hi-C analysis, but not in individual cells. However, in Drosophila, single-cell data show that there are TADs in each particular cell. More research is needed to elucidate the biological mechanism that forms these stable domains, but the researchers suggest two models for these TADs. One implies that Drosophila chromatin is ‘sticky’ in a particular way, with different regions having different affinity to form contacts. The other, so-called loop extrusion mechanism, posits that large protein complexes create loops in the strand, bringing distant regions close together and creating a larger-scale structure.
“Perhaps, one of the most interesting questions to ask is whether chromatin folding rules are similar between different species of living organisms. Having single-cell Hi-C for the individual cells of Drosophila, we noticed that the genome of this insect is folded into domains, similar to the domains observed in single mammalian cells. However, these structures are much more ordered than in mammals,” Aleksandra Galitsyna, PhD student at Skoltech and one of the paper’s first co-authors, notes.
“We will continue studying chromatin architecture and dig into the mechanisms of loop and TAD formation. There are lots of unanswered questions in this area. We already know that these mechanisms might differ between some organisms, but what is the full picture of chromatin folding evolution? If we want to understand it at a sufficient scale, we would need to bridge gaps between well-studied organisms by resolving chromatin structure in the weird ones. To do that, we are already working on sponges, yeasts, and amoeba,” Ekaterina Khrameeva says.
She adds that the team is also interested in how chromatin organization changes might be associated with the disease, organism development, and aging. “Assuming that chromatin architecture is tightly linked to gene expression, answering these questions might unravel the regulatory prerequisites of human development, aging, and disease,” Khrameeva notes.
Other organizations involved in this research include the Institute of Gene Biology (Russian Academy of Sciences), Lomonosov Moscow State University, French National Centre for Scientific Research, French-Russian Interdisciplinary Scientific Center J.-V. Poncelet and other organizations.
How to check if someone else accessed your Google account
Review your recent Gmail access, browser sign-in history, and Google account activity to make sure no one other than you has used your account.
Whenever a computer is out of your direct view and control, there’s always a chance that someone other than you can gain access. A person who returns from a trip might wonder if their computer and accounts have been accessed during their absence. A person might notice odd activity in Gmail, not aware that their password has been made public (or “pwned“). Or, in some cases, a person might be surveilled by a partner, a family member, a colleague, or even an unknown party.
To secure an account, you might first change your password, enable two-factor authentication, or even enroll in Google’s Advanced Protection Program. Those steps will help you secure your account. However, in cases where people are unsafe because of domestic abuse, these steps will likely not be encouraged by an abuser–help is available.
The following steps can help you figure out if someone, other than you, is accessing your Gmail or Google account.
SEE: Google Sheets: Tips and tricks (TechRepublic download)
Did someone access my Gmail account?
In a desktop web browser, Gmail allows you to review recent email access activity. Select Details in the lower-right area below displayed emails, below Last Account Activity (Figure A).
The system will show you information about the most recent 10 times your Gmail account has been accessed, along with the access type (browser, POP, mobile, etc.), location (IP address), and the date and time of access. This can help you identify if any of this access is from an unexpected device, place, or time.
Note: If you use a virtual private network or a hosted desktop, the location data may reflect information related to your service provider, instead of your physical address.
In a few cases, I’ve had clients concerned about access in an expected location, but at an unexpected time. Sometimes, this was simply because they’d left a computer on, with their browser or mail client open: The system could be configured to auto-check mail periodically. In one case, access occurred after a power outage. They’d configure the system to automatically power on after an outage, so it signed in and downloaded new mail shortly after power was restored.
Did someone access my browser?
In the Chrome browser–and on any Chromebook or Chrome OS device–press Ctrl+H to display browser history. Alternatively, type chrome://history in the omnibox, or select the three-vertical dot menu in the upper-right, then choose History | History. On macOS, press Command+Y. You may scroll through all available sites visited. Review these to see if any sites displayed are unexpected.
Additionally, you may enter search terms in the box displayed above the historical URLs listed. For example, search for “sign in,” or copy and paste this link into your browser omnibox: chrome://history/?q=sign%20in to display most site login pages (Figure B). Again, review the results for any sites you don’t expect. You might search for “gmail.com” as well.
Did someone access my Google account?
Go to https://myactivity.google.com/ to access your Google account history across all devices and Google services, such as YouTube, Google Maps, Google Play, and more (Figure C). Depending on your security settings, you may need to re-authenticate when you attempt to access this information. Again, review any recorded data to make sure it corresponds with your usage.
Similarly, go to https://myaccount.google.com/device-activity to review a list of devices to which you’ve signed in with your Google account (Figure D). You may select the three-vertical dots in the upper-right of any displayed devices, then choose Sign Out to prevent any future access without re-authentication on a device.
Go through Google’s Security Checkup (https://myaccount.google.com/security-checkup) for a step-by-step review of every item Google’s system identifies as a potential security issue (Figure E).
Use Google Workspace (formerly G Suite)? Ask an administrator for help.
If you use Gmail and Google Workspace as part of an organization (e.g., work or school), an administrator may be able to do additional review of your account access data. To do this, the administrator will need to sign in to the admin console at https://admin.google.com. From the Admin console, they might go to https://admin.google.com/ac/, select your account, then review security settings as well as connected apps and devices. Next, they might review all login information by going to the login report at https://admin.google.com/ac/reporting/audit/login, then filtering for your account (Figure F). Since this information is centrally logged by the system, access records will remain, even if the person accessing your account attempts to cover their tracks (e.g., by locally deleting browser history).
What’s your experience?
If you’ve wondered whether someone else has accessed your Google account, what steps have you taken? What did you learn when you completed the above access review of your Google account? Let me know any additional steps you suggest, either in the comments below or on Twitter (@awolber).
New computational method detects disrupted pathways in cancer
Cancer is a notoriously complex disease, in part because it may be caused by mutations among hundreds or even thousands of genes. In addition, most cancers exhibit an extraordinary amount of variation among genetic mutations, even between patients with the same types of cancers.
Consequently, cancer researchers have chosen to study interactions among groups of genes in certain biological pathways that are disrupted.
When genes in certain pathways are frequently mutated or disrupted, that pathway may play a critical role in the initiation or development of cancer. But unravelling the molecular mechanisms underlying those disruptions is extremely complex.
Nw, University at Buffalo researchers have developed a new, statistically more powerful method called FDRnet that can more effectively detect key functional pathways in cancer using genomics data generated by next-generation sequencing technology.
Published in Nature Computational Science, the new method has the potential to give biologists more precise data with which to zero in on therapeutic targets.
“Using the new method, we can find biological pathways in which genes are significantly mutated or disrupted,” explained Yijun Sun, PhD, associate professor of bioinformatics in the Department of Microbiology and Immunology in the Jacobs School of Medicine and Biomedical Sciences at UB and the corresponding author. “It addresses some key challenges in molecular pathway analysis in cancer studies. Once the tumor biologists obtain this information, they can use it to verify our findings, and from there develop new cancer treatments,” he said.
“By overcoming the limitations of existing approaches, FDRnet can facilitate the detection of key functional pathways in cancer and other genetic diseases,” said Sun.
When Sun and his co-authors tested FDRnet on simulation data and on breast cancer and B-cell lymphoma data, they found that FDRnet was able to detect which subnetworks or pathways are significantly perturbed in these cancers, potentially leading tumour biologists to identify new therapeutic targets.
Tom & Jerry Release Date in India Set for February 19, a Week Before the US
Tom & Jerry will now release February 19 in cinemas in India, a full week earlier than originally announced. Warner Bros. India revealed the new release date on Thursday via its social media channels. That puts the Indian release date a week prior to the US, where Tom & Jerry releases February 26 on (US-exclusive streaming service) HBO Max and in cinemas. In India, the hybrid live-action/ animated Tom and Jerry movie will be available in English (the original language), in addition to three local-language dubs: Hindi, Tamil, and Telugu.
However, India won’t be the first market to catch the big-screen return of the iconic cat and mouse duo. Tom & Jerry premieres February 10 in Netherlands, followed by Brazil and Singapore on February 11. India is among the next wave of markets on February 19, alongside Iceland and Lithuania. Russia and Slovakia will follow on February 25, before Tom & Jerry arrives in the US on February 26. Argentina, Czechia, Croatia, and Portugal follow on March 4, with Spain and France release set for March 5. In the UK, Ireland, and Japan, Tom & Jerry is due March 19.
Of course, whether any of this goes according to plan depends on how the COVID-19 situation fares locally. For instance, around 65 percent of theatres remain closed in the US (including the major metropolitan hubs of New York and Los Angeles). Theatres are indefinitely shut across the UK where a third stringent nationwide lockdown is in effect. That is also the case in France, at least until the end of January. In Spain, cinemas are operating at 30–50 percent capacity. But while Americans have the option to watch Tom & Jerry at home (on HBO Max), others do not.
Tom & Jerry Hindi trailer
Tom & Jerry Tamil trailer
Tom & Jerry Telugu trailer
Chloë Grace Moretz (Kick-Ass) is the human lead as event planner Kayla opposite Tom and Jerry in the new movie, alongside the likes of Michael Peña (Ant-Man and the Wasp) the hotel’s deputy general manager Terrance, Rob Delaney (Catastrophe) as the hotel manager Mr. DuBros, Ken Jeong (Community) as the hotel chef Jackie, Colin Jost (Saturday Night Live) as wedding groom Ben, and Pallavi Sharda (Besharam) as the bride Preeta.
William Hanna, Mel Blanc, and June Foray provide vocal effects for Tom and Jerry through archival audio recordings. Hanna is the co-creator of Tom and Jerry along with Joseph Barbera. Tim Story (Ride Along) is directing Tom & Jerry off a script by Kevin Costello (Brigsby Bear). Tom & Jerry is a production of Warner Animation Group, Turner Entertainment Company, and The Story Company.
Here’s the official synopsis of Tom & Jerry, from Warner Bros.:
One of the most beloved rivalries in history is reignited when Jerry moves into New York City’s finest hotel on the eve of “the wedding of the century,” forcing the event’s desperate planner to hire Tom to get rid of him, in director Tim Story’s “Tom & Jerry.” The ensuing cat and mouse battle threatens to destroy her career, the wedding and possibly the hotel itself. But soon, an even bigger problem arises: a diabolically ambitious staffer conspiring against all three of them. An eye-popping blend of classic animation and live action, Tom and Jerry’s new big-screen adventure stakes new ground for the iconic characters and forces them to do the unthinkable… work together to save the day.
Tom & Jerry is out February 19 in India in English, Hindi, Tamil, and Telugu.
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