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64 human genomes as new reference for global genetic diversity

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Credit: David Porubsky, University of Washington

In 2001, the International Human Genome Sequencing Consortium announced the first draft of the human genome reference sequence. The Human Genome Project, as it was called, had taken more than eleven years of work and involved more than 1000 scientists from 40 countries. This reference, however, did not represent a single individual but instead is a composite of humans that could not accurately capture the complexity of human genetic variation.

Building on this, scientists have carried out many sequencing projects over the last 20 years to identify and catalog genetic differences between an individual and the reference genome. Those differences usually focused on small single base changes and missed larger genetic alterations. Current technologies now are beginning to detect and characterize larger differences – called structural variants – such as insertions of several hundred letters. Structural variants are more likely than smaller genetic differences to interfere with gene function.

An international research team has now published an article in Science announcing a new, considerably more comprehensive reference dataset obtained using a combination of advanced sequencing and mapping technologies. The new reference dataset reflects 64 assembled human genomes, representing 25 different human populations from across the globe. Importantly, each of the genomes was assembled without guidance from the first human genome and as a result better captures genetic differences from different human populations. The study was led by scientists from the European Molecular Biology Laboratory Heidelberg (EMBL), the Heinrich Heine University Düsseldorf (HHU), The Jackson Laboratory for Genomic Medicine in Farmington, Conn. (JAX), and the University of Washington in Seattle (UW).

“With these new reference data, genetic differences can be studied with unprecedented accuracy against the background of global genetic variation, which facilitates the biomedical evaluation of genetic variants carried by an individual,” emphasizes the co-first author of the study, Dr. Peter Ebert from the Institute of Medical Biometry and Bioinformatics at HHU. The distribution of genetic variants can differ substantially between population groups as a result of spontaneous and continuously occurring changes in the genetic material. If such a mutation is passed on over many generations, it can become a genetic variant specific to that population.

The new reference data provide an important basis for including the full spectrum of genetic variants in so-called genome-wide association studies. The aim is to estimate the individual risk of developing certain diseases such as cancer and to understand the underlying molecular mechanisms. This, in turn, can be used as a basis for more targeted therapies and preventative medicine.

This work might enable further applications in precision medicine. Drug efficacy, for example, can vary between individuals based on their genomes. The new reference data now represent the full range of different genetic variant types and incorporates human genomes of great diversity. Therefore, this new resource might contribute to developing novel approaches in personalized medicine, where the selection of therapies is tailored to a patient’s individual genetic background.

This study builds on a new method published by these researchers last year in Nature Biotechnology) to accurately reconstruct the two components of a person’s genome – one inherited from a person’s father, one from a person’s mother. When assembling a person’s genome, this method eliminates the potential biases that could result from comparisons with an imperfect reference genome.

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Peter Ebert*, Peter A. Audano*, Qihui Zhu*, Bernardo Rodriguez-Martin*, David Porubsky, Marc Jan Bonder, Arvis Sulovari, Jana Ebler, Weichen Zhou, Rebecca Serra Mari, Feyza Yilmaz, Xuefang Zhao, PingHsun Hsieh, Joyce Lee, Sushant Kumar, Jiadong Lin, Tobias Rausch, Yu Chen, Jingwen Ren, Martin Santamarina, Wolfram Höps, Hufsah Ashraf, Nelson T. Chuang, Xiaofei Yang, Katherine M. Munson, Alexandra P. Lewis, Susan Fairley, Luke J. Tallon, Wayne E. Clarke, Anna O. Basile, Marta Byrska-Bishop, Andre Corvelo, Uday S. Evani, Tsung-Yu Lu, Mark J.P. Chaisson, Junjie Chen, Chong Li, Harrison Brand, Aaron M. Wenger, Maryam Ghareghani, William T. Harvey, Benjamin Raeder, Patrick Hasenfeld, Allison A. Regier, Haley J. Abel, Ira M. Hall, Paul Flicek, Oliver Stegle, Mark B. Gerstein, Jose M.C. Tubio, Zepeng Mu, Yang I. Li, Xinghua Shi, Alex R. Hastie, Kai Ye, Zechen Chong, Ashley D. Sanders, Michael C. Zody, Michael E. Talkowski, Ryan E. Mills, Scott E. Devine, Charles Lee#, Jan O. Korbel#, Tobias Marschall#, Evan E. Eichler#, Haplotype-resolved diverse human genomes and integrated analysis of structural variation, Science 2021

*Co-first authors #Co-senior and co-corresponding authors

Quotes

“For each human individual that participated in the study, we identified not one but two genomes – one for each set of chromosomes,” says Jan Korbel, Ph.D., Head of Data Science at the European Molecular Biology Laboratory (EMBL) in Heidelberg who led the research at EMBL. Korbel added: “Humans have two sets of chromosomes which they receive from their parents. Previously we could not distinguish whether genetic variation came from one chromosome set or the other, and we were now able to solve this thanks to advances made by the Human Genome Structural Variation Consortium. It represents a remarkable achievement for the discovery of genetic variation in humans, which can now be studied much more comprehensively, leading the way to better find disease-causing genes.”

“These genomes will pave the way to a new wave of scientific discoveries about the biology of the human genome and the connection between genetic variation and disease”, says Bernardo Rodriguez-Martin, researcher at EMBL and co-first author. Rodriguez-Martin added: “As an example, we were able to estimate the age of highly mutagenic L1 repeats. Very surprisingly, although these sequences originated up to 3 Million of years ago, they continue to mutate the human genome frequently, which occasionally leads to diseases such as cancer.”

“Just a few years ago, I would not have imagined that resolving genomes to this completeness would become possible so fast. This was enabled by exciting advances both of biotechnological and computational methods.” says Dr. Peter Ebert, co-first author and computational biologist at Heinrich Heine University Düsseldorf, Germany. “Great to see this technology applied to a diversity panel of human genomes. These genome sequences will be an important resource for fundamental research and clinical genomics going forward.”

Senior author Prof. Dr. Tobias Marschall, who led the research at HHU, added that “it was especially exciting to see that these new genome sequences enable a much more detailed analysis of data from standard sequencing technologies, which are routinely applied to millions of genomes by researchers and clinicians across the globe.” He believes that “future studies to find associations between genetic variants and disease susceptibility will clearly benefit from this new approach.”

“The first human genome sequence was a huge step forward, but was incomplete,” said Charles Lee, Ph.D., FACMG, director and professor, The Jackson Laboratory for Genomic Medicine. “In addition to single base variation, we now know that structural variants also contribute very substantially to genomic differences between individuals. Our work provides a far more thorough and accurate window into that genomic variation across individuals and populations, and it represents an incredibly valuable new resource for the research community.”

“Capturing the full spectrum of structural variation found in human genomes is vital for clinical applications,” says Qihui Zhu, Ph.D., computational scientist. “These variants affect gene function and can contribute to diseases, drug response differences, and more. Knowing how they differ across individuals and across populations is needed to implement more effective genomic medicine.”

“Each of these individual genomes is being resolved more completely for a fraction of the price of the first human genome” commented senior author, Evan Eichler, Professor of Genome Sciences, University of Washington School Medicine who was also a member of the original Human Genome Project. “We are discovering remarkable differences in genomic organization which have been missed until now, understanding these differences will enhance our ability to make genetic discoveries related to health and disease especially in groups that have been traditionally under-served by genomics research”.

Peter Audano, co-first author, University of Washington School Medicine, adds, “the technology we have today can see into blindspots that have hidden information about diseases and our history. With these advances, we have discovered more than 100,000 structural variants, many of which are novel and affect genes or gene regulatory elements.”

About EMBL

EMBL is Europe’s flagship laboratory for the life sciences. Established in 1974 as an intergovernmental organisation, EMBL is supported by 27 member states, 2 prospective member states and 2 associate member states.

EMBL performs fundamental research in molecular biology, studying the story of life. The institute offers services to the scientific community; trains the next generation of scientists and strives to integrate the life sciences across Europe.

EMBL is international, innovative and interdisciplinary. Its more than 1800 staff, from over 80 countries, operate across six sites in Barcelona (Spain), Grenoble (France), Hamburg (Germany), Heidelberg (Germany), Hinxton (UK) and Rome (Italy). EMBL scientists work in independent groups and conduct research and offer services in all areas of molecular biology.

EMBL research drives the development of new technology and methods in the life sciences. The institute works to transfer this knowledge for the benefit of society.

https://www.embl.de/

About HHU

Heinrich Heine University Düsseldorf is one of the younger higher education institutions in the state of North Rhine-Westphalia – founded in 1965. Since 1988 our university has carried the name of one of the city’s finest sons. Today around 35,000 students study at a modern campus under conditions ideally suited to academic life.

As a campus university where everything is close together, all buildings including the University Hospital and the specialised libraries are easily reachable. Our university departments enjoy an excellent reputation due to an exceptionally high number of collaborative research centres. Moreover, the state capital Düsseldorf provides an attractive environment with a high quality of life.

https://www.hhu.de/en/

About The Jackson Laboratory

The Jackson Laboratory is an independent, nonprofit biomedical research institution with more than 2,300 employees. Headquartered in Bar Harbor, Maine, it has a National Cancer Institute-designated Cancer Center, a genomic medicine institute in Farmington, Conn., and facilities in Ellsworth and Augusta, Maine, in Sacramento, Calif., and in Beijing and Shanghai, China. Its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. For more information, please visit http://www.jax.org.

About University of Washington School Medicine

http://www.uwmedicine.org/school-of-medicine

Media Contact
Dr. Arne Claussen
arne.claussen@hhu.de

Related Journal Article

http://dx.doi.org/10.1126/science.abf7117

Source: https://bioengineer.org/64-human-genomes-as-new-reference-for-global-genetic-diversity/

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USC Stem Cell study identifies molecular ‘switch’ that turns precursors into kidney cells

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Kidney development is a balancing act between the self-renewal of stem and progenitor cells to maintain and expand their numbers, and the differentiation of these cells into more specialized cell types. In a new study in the journal eLife from Andy McMahon’s laboratory in the Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, former graduate student Alex Quiyu Guo and a team of scientists demonstrate the importance of a molecule called β-catenin in striking this balance.

β-catenin is a key driver at the end of a complex signaling cascade known as the Wnt pathway. Wnt signaling plays critical roles in the embryonic development of multiple organs including the kidneys. By partnering with other Wnt pathway molecules, β-catenin controls the activity of hundreds to thousands of genes within the cell.

The new study builds on the McMahon Lab’s previous discovery that Wnt/β-catenin can initiate progenitor cells to execute a lengthy and highly orchestrated program of forming structures in the kidney called nephrons. A healthy human kidney contains a million nephrons that balance body fluids and remove soluble waste products. Too few nephrons results in kidney disease.

Previous studies from the UT Southwestern Medical Center laboratory of Thomas Carroll, a former postdoctoral trainee in the McMahon Lab, suggested that Wnt/β-catenin signaling plays opposing roles in ensuring the proper number of nephrons: promoting progenitor maintenance and self-renewal, and stimulating progenitor cell differentiation.

“It sounded like Wnt/β-catenin is doing two things–both maintenance and differentiation–that seem to be opposite operations,” said Guo. “Therefore, the hypothesis was that different levels of Wnt/β-catenin can dictate different fates of the nephron progenitors: when it’s low, it works on maintenance; when it’s high, it directs differentiation.”

In 2015, it became more possible to test this hypothesis when Leif Oxburgh, a scientist at the Rogosin Institute in New York and a co-author of the eLife study, developed a system for growing large numbers of nephron progenitor cells, or NPCs, in a Petri dish.

Relying on this game-changing new system, Guo and his collaborators grew NPCs, added different levels of a chemical that activates β-catenin, and saw their hypothesis play out in the Petri dishes.

They observed that high levels of β-catenin triggered a “switch” in part of the Wnt pathway that relies on another family of transcription factors known as TCF/LEF. There are two types of TCF/LEF transcription factors: one type inhibits genes related to differentiation, and the other activates these genes. In response to high levels of β-catenin, the “activating” members of TCF/LEF switched places with the “inhibiting” members, effectively taking charge. This “switch” triggered NPCs to differentiate into more specialized types of kidney cells.

When they looked at low levels of β-catenin, they saw NPCs self-renewing and maintaining their populations, as expected. However, they were surprised to learn that β-catenin was not engaged with any of the known genes related to self-renewal and maintenance.

“β-catenin does something,” said Guo. “That is for sure. But how it does it is kind of mysterious right now.”

After publishing these results in eLife, Guo earned his PhD from USC, and began his postdoctoral training at UCLA. Helena Bugacov, a current PhD student in the McMahon Lab and a co-author of the eLife study, is now taking the lead in continuing the project–which has implications far beyond the kidney field, due to the broad role of Wnt throughout the body.

“Understanding how Wnt regulates these two very distinct cell outcomes of self-renewal and differentiation, which is very important for kidney development, is also important for understanding the development of other organs and adult stem cells, as Wnt signaling plays important roles in almost all developmental systems,” said Bugacov. “There is also a lot of attention from cancer researchers, as this process can go awry in cancer. Many therapeutics are trying to target this process.”

She added, “The more we know about things, the better we can inform work on developing human kidney organoid cultures, which can be more readily used to understand problems in human health, regeneration and development.”

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Additional co-authors of the eLife study include: Albert Kim, Andrew Ransick, Xi Chen, and Nils Lindstrom from USC; Aaron Brown from the Maine Medical Center Research Institute; and Bin Li and Bing Ren from the University of California, San Diego. The research was supported by federal funding from the National Institute of Diabetes and Digestive and Kidney Diseases (grant number R01 DK054364).

https://stemcell.keck.usc.edu/usc-stem-cell-study-identifies-molecular-switch-that-turns-precursors-into-kidney-cells/

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Evidence of Antarctic glacier’s tipping point confirmed for first time

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Researchers have confirmed for the first time that Pine Island Glacier in West Antarctica could cross tipping points, leading to a rapid and irreversible retreat which would have significant consequences for global sea level

Researchers have confirmed for the first time that Pine Island Glacier in West Antarctica could cross tipping points, leading to a rapid and irreversible retreat which would have significant consequences for global sea level.

Pine Island Glacier is a region of fast-flowing ice draining an area of West Antarctica approximately two thirds the size of the UK. The glacier is a particular cause for concern as it is losing more ice than any other glacier in Antarctica.

Currently, Pine Island Glacier together with its neighbouring Thwaites glacier are responsible for about 10% of the ongoing increase in global sea level.

Scientists have argued for some time that this region of Antarctica could reach a tipping point and undergo an irreversible retreat from which it could not recover. Such a retreat, once started, could lead to the collapse of the entire West Antarctic Ice Sheet, which contains enough ice to raise global sea level by over three metres.

While the general possibility of such a tipping point within ice sheets has been raised before, showing that Pine Island Glacier has the potential to enter unstable retreat is a very different question.

Now, researchers from Northumbria University have shown, for the first time, that this is indeed the case.

Their findings are published in leading journal, The Cryosphere.

Using a state-of-the-art ice flow model developed by Northumbria’s glaciology research group, the team have developed methods that allow tipping points within ice sheets to be identified.

For Pine Island Glacier, their study shows that the glacier has at least three distinct tipping points. The third and final event, triggered by ocean temperatures increasing by 1.2C, leads to an irreversible retreat of the entire glacier.

The researchers say that long-term warming and shoaling trends in Circumpolar Deep Water, in combination with changing wind patterns in the Amundsen Sea, could expose Pine Island Glacier’s ice shelf to warmer waters for longer periods of time, making temperature changes of this magnitude increasingly likely.

The lead author of the study, Dr Sebastian Rosier, is a Vice-Chancellor’s Research Fellow in Northumbria’s Department of Geography and Environmental Sciences. He specialises in the modelling processes controlling ice flow in Antarctica with the goal of understanding how the continent will contribute to future sea level rise.

Dr Rosier is a member of the University’s glaciology research group, led by Professor Hilmar Gudmundsson, which is currently working on a major £4million study to investigate if climate change will drive the Antarctic Ice Sheet towards a tipping point.

Dr Rosier explained: “The potential for this region to cross a tipping point has been raised in the past, but our study is the first to confirm that Pine Island Glacier does indeed cross these critical thresholds.

“Many different computer simulations around the world are attempting to quantify how a changing climate could affect the West Antarctic Ice Sheet but identifying whether a period of retreat in these models is a tipping point is challenging.

“However, it is a crucial question and the methodology we use in this new study makes it much easier to identify potential future tipping points.”

Hilmar Gudmundsson, Professor of Glaciology and Extreme Environments worked with Dr Rosier on the study. He added: “The possibility of Pine Island Glacier entering an unstable retreat has been raised before but this is the first time that this possibility is rigorously established and quantified.

“This is a major forward step in our understanding of the dynamics of this area and I’m thrilled that we have now been able to finally provide firm answers to this important question.

“But the findings of this study also concern me. Should the glacier enter unstable irreversible retreat, the impact on sea level could be measured in metres, and as this study shows, once the retreat starts it might be impossible to halt it.”

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The paper, The tipping points and early warning indicators for Pine island Glacier, West Antarctica, is now available to view in The Cryosphere.

Northumbria is fast becoming the UK’s leading university for research into Antarctic and extreme environments.

As well as the £4m tipping points study, known as TiPPACCs, Northumbria is also the only UK university to play a part in two projects in the £20m International Thwaites Glacier Collaboration – the largest joint project undertaken by the UK and USA in Antarctica for more than 70 years – where Northumbria is leading the PROPHET and GHC projects. This particular study was funded through both TiPPACCs and PROPHET.

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Source: https://bioengineer.org/evidence-of-antarctic-glaciers-tipping-point-confirmed-for-first-time/

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Diversity can prevent failures in large power grids

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Integrated power grids offer benefits, but also pose challenges best addressed by leveraging differences

The recent power outages in Texas brought attention to its power grid being separated from the rest of the country. While it is not immediately clear whether integration with other parts of the national grid would have completely eliminated the need for rolling outages, the state’s inability to import significant amounts of electricity was decisive in the blackout.

A larger power grid has perks, but also has perils that researchers at Northwestern University are hoping to address to expedite integration and improvements to the system.

An obvious challenge in larger grids is that failures can propagate further — in the case of Texas, across state lines. Another is that all power generators need to be kept synchronized to a common frequency in order to transmit energy. The U.S. is served by three “separate” grids: The Eastern interconnection, the Western interconnection and the Texas interconnection, interlinked only by direct-current power lines. Any persistent deviation in frequencies within a region can lead to an outage.

As a result, researchers are searching for ways to stabilize the grid by looking for methods to mitigate deviations in the power generators’ frequencies.

The new Northwestern research shows that counter to assumptions held by some, there are stability benefits to heterogeneity in the power grid. Examining several power grids across the U.S. and Europe, a team led by Northwestern physicist Adilson Motter recently reported that generators operating on different frequencies return to their normal state more quickly when they are damped by “breakers” at different rates than generators around them.

The paper was published March 5 in the journal Nature Communications.

Motter is the Charles E. and Emma H. Morrison Professor in the department of physics and astronomy in the Weinberg College of Arts and Sciences. His research focuses on nonlinear phenomena in complex systems and networks.

Motter compares power grids to a choir: “It’s a little bit like a choir without a conductor. The generators have to listen to others and speak in sync. They react and respond to each other’s frequencies.”

Listen to an out-of-whack frequency, and the result can be a failure. Given the interconnected makeup of the system, a failure can propagate across the network. Historically, these malfunctions have been prevented by using active controllers. However, failures are often caused precisely by control and equipment errors. This points to a need to build additional stability within the design of the system. To achieve that, the team looked into leveraging the natural heterogeneities of the grid.

When the frequencies of the power generators are moved away from the synchronous state, they can swing around for a long time and even become more erratic. To mitigate these fluctuations, they came up with something akin to a door mechanism used to close a door the fastest, but without slamming.

“Mathematically, the problem of damping frequency deviations in a power generator is analogous to the problem of optimally damping a door to get it to close the fastest, which has a known solution in the case of a single door,” Motter said. “But it’s not a single door in this analogy. It’s a network of many doors that are coupled with each other, if you can imagine the doors as power generators.”

When creating an “optimal damping” effect, they discovered that rather than making each damper identical, damping the power generators in a way that is suitably different from each other can further optimize their ability to synchronize to the same frequency as quickly as possible. That is, suitably heterogenous damping across the network can lead to improved stability in the power grids studied by the team.

This discovery could have implications for future grid design as developers work to optimize technology and in considerations to further integrate now separated networks.

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The paper is titled “Asymmetry underlies stability in power grids.” Additional co-authors include former postdoctoral researcher Ferenc Molnar and research professor Takashi Nishikawa.

The study was supported by Northwestern University’s Finite Earth Initiative (supported by Leslie and Mac McQuown) and ARPA-E Award No. DE-AR0000702 and also benefited from logistical support from the Northwestern Institute for Sustainability and Energy.

https://news.northwestern.edu/stories/2021/04/diversity-can-prevent-failures-in-large-power-grids/

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How Fortnite and Zelda can up your surgical game (no joke!)

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Scalpel? Check. Gaming console? Check. Study finds video games can be a new tool on surgical tray for medical students

Video games offer students obvious respite from the stresses of studies and, now, a study from a University of Ottawa medical student has found they could benefit surgical skills training.

Arnav Gupta carries a heavy course load as a third-year student in the Faculty of Medicine, so winding down with a game of Legend of Zelda always provides relief from the rigorous of study. But Zelda may be helping improve his surgical education, too, as Gupta and a team of researchers from the University of Toronto found in a paper they recently published in the medical journal Surgery.

“Given the limited availability of simulators and the high accessibility of video games, medical students interested in surgical specialties should know that video games may be a valuable adjunct training for enhancing their medical education, especially in surgical specialties where it can be critical,” says Gupta, whose findings were deciphered from a systematic review of 16 studies involving 575 participants.

“Particularly, in robotic surgery, being a video gamer was associated with improvements in time to completion, economy of motion, and overall performance. In laparoscopic surgery, video games-based training was associated with improvement in duration on certain tasks, economy of motion, accuracy, and overall performance,” explains Gupta, who has been a gamer since age 8.

This study builds on past reviews and is the first to focus on a specific medical student population where this style of training could be feasibly implemented. Their timely study found some of the most beneficial games for students of robotic surgery and laparoscopy were: Super Monkey Ball, Half Life, Rocket League and Underground. Underground is purposely designed to assist medical students with their robotic surgery training via a video game console.

“While video games can never replace the value of first-hand experience, they do have merit as an adjunctive tool, especially when attempting to replicate important movements to surgery. For example, first-person shooting games require you to translate three dimensional motions onto a two-dimensional screen, which is like the concept of laparoscopic surgery,” says Gupta, whose studies are focused on surgery in ophthalmology, which makes games like Resident Evil 4 or Trauma Center: New Blood fitted for his own ambitions.

“I’m not joking when I say that games such as Fortnite have the potential to enhance those necessary movements, providing stronger motivational components and in a low stakes environment.”

Reports suggest 55 percent of university students are gamers and enjoy proficiency with video consoles. Yet, many medical students don’t admit to owning and using a gaming console.

“I think there definitely is some ambivalence towards video games in medicine,” says Gupta, who is also a fan of Witcher 3. “Given how accessible games have become and how video game technology is advancing, video games definitely are an easy go-to for the students who do love them in some capacity. The hope is that maybe this study can inspire someone to take advantage of video games’ unique capabilities, reduce the general ambivalence towards it, and develop some fun ways to let students engage with surgical education.”

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https://media.uottawa.ca/news/how-fortnite-and-zelda-can-your-surgical-game-no-joke

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