Phosphatidylserine Receptors Enhance SARS-CoV-2 Entry (Biology)

A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor—angiotensin-converting enzyme 2 (ACE2)—in humans.

Now, Dana Bohan and colleagues recognized another set of receptors called Phosphatidylserine (PS) which enhances the SARS-CoV-2 entry. They found that the PS receptors, AXL, TIM-1 & TIM-4, synergize with low levels of ACE2 to enhance SARS-CoV-2 infection.

They also examined the mechanism by which PS receptors interact with SARS-CoV-2 and found that, PS receptors interact with SARS-CoV-2 virions through a well-established mechanism of virion-associated PS binding to TIM-1 and AXL.

“If we shall be able to inhibit AXL, TIM-1 or both, it will block SARS-CoV-2 entry”

In addition, it has been demonstrated that, SARS-CoV-2 utilizes AXL to enhance virion binding and entry in some lung cell lines, and that this mechanism can be effectively disrupted by small molecule inhibitors like Bemcentinib and genetic albation of AXL.

“Appreciation of this route of entry provides an additional pathway that could be therapeutically targeted to inhibit virus entry and subsequent infection”

— concluded authors of the study

Featured image credit: Unsplash

Reference: Dana Bohan, Hanora Van Ert, Natalie Ruggio, Kai J. Rogers, Mohammad Badreddine, José A. Aguilar Briseño, Roberth Anthony Rojas Chavez, Boning Gao, Tomasz Stokowy, Eleni Christakou, David Micklem, Gro Gausdal, Hillel Haim, John Minna, James B. Lorens, Wendy Maury, “Phosphatidylserine Receptors Enhance SARS-CoV-2 Infection: AXL as a Therapeutic Target for COVID-19”, bioRxiv 2021.06.15.448419; doi:

Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article

New Research Is First To Show How Key Gut Bacterium Trains Infant Immune System (Biology)

Study published in cell reveals critical role of activated B. infantis EVC001 in using human milk to program immune cells early in life to control inflammation and autoimmune disease risk

Research published today in the journal Cell is the first to establish how a specific gut bacterium, activated Bifidobacterium infantis EVC001 (B. infantis), influences immune system development in infants, and could thereby reduce the risk of allergic and autoimmune conditions later in life.

While prior studies have shown a correlation between a lack of beneficial bacteria in the infant gut and the development of allergies and autoimmune diseases, this groundbreaking research, Bifidobacteria-mediated immune system imprinting in early life, found the presence of bifidobacteria, specifically the B. infantis EVC001 bacterial strain, early in a breastfed infant’s life, programs naïve immune cells away from responses associated with immune-related conditions while producing regulatory cells that improve the body’s ability to control inflammation.

The study also confirms the critical window of opportunity for impacting immune system development and reducing systemic inflammation is within the first 100 days of infancy.

The immune system normally guards against bacteria and viruses by marshalling specific immune T-cells to recognize and attack the foreign invaders in the body. The adaptive immune system at birth is naturally a blank slate; it has had very little exposure to viruses or dangerous bacteria, so immune cells, called naïve T-cells, have yet to be programmed accordingly. In immune disorders and allergies, these cells are misprogrammed early on, by harmful bacteria or inflammation, to attack normal healthy cells in the body. Researchers have been working to determine how this misprogramming happens, to enable clinicians with solutions to reduce the risk of childhood allergic and autoimmune conditions.

Study Details

For the study, researchers found that infants who lacked beneficial microbes able to metabolize complex sugars in breast milk, human milk oligosaccharides (HMOs), had disordered development of immune cell networks and significantly increased systemic inflammation.

Furthermore, in vitro experiments showed that gut bacterial metabolites and host factors from breastfed infants that lacked B. infantis EVC001 in their gut microbiome programmed naïve immune cells toward Th2 and Th17, two immune cell types associated with the development of autoimmune and allergic diseases.

In contrast, breastfed infants fed B. infantis EVC001 skewed those naïve immune cells toward Th1, an immune cell type that allows the body to properly react and rid itself of dangerous pathogens. Researchers also found far greater levels of interferon Beta (IFNβ) in the B. infantis EVC001 isolates, which is an important regulatory mediator that improves the body’s ability to control inflammation and viral infections.

Additionally, the research shows that the unique genetic capacity of B. infantis EVC001 to fully metabolize human milk oligosaccharides (HMOs) produced the bacterial metabolite indolelactate (ILA). ILA, in turn, amplifies a broadly immunoregulatory factor, Galactin-1, effectively silencing Th2 and Th17.

“More than 90 percent of newborns have a severe deficiency of B. infantis; this study is an exciting step forward in our understanding of the role of B. infantis EVC001 in the positive programming of immune cells and how it actually changes the trajectory of immune system development to protect against inflammation,” said Dr. Bethany Henrick, PhD, first and corresponding author of the study and Director of Immunology and Diagnostics at Evolve BioSystems. “For the first time we’ve been able to demonstrate that the unique ability of B. infantis EVC001 to fully break down HMOs and the abundance of HMO utilization genes in the microbiome is directly correlated with decreased enteric and systemic inflammation.”

The study examined the development of immune system changes in 208 infants born at the Karolinska University Hospital in Sweden between April 2014 and December 2019, evaluating bifidobacterial species and other microbes expressing HMO utilization genes. To further assess the beneficial effects of HMO utilization gene expressing microbes, a second cohort of the study involved 40 breastfed infants in California, with half receiving B. infantis EVC001, a strain of Bifidobacterium possessing all HMO utilization genes, and the other half given no supplementation.

“These are important findings because, while they point to the disturbing fact that infants lacking B. infantis – unfortunately, now the norm in developed countries – can’t properly metabolize HMOs and are missing the critical window to develop a healthy immune system, it also shows that there’s a simple fix; feeding breastfed babies B. infantis EVC001 early in infancy can shut down inflammatory processes and reduce the life-time risk of developing immune-mediated diseases,” said Dr. Petter Brodin, MD, PhD, consultant pediatrician and lead author of the study and Professor of Pediatric Immunology at the Karolinska Institute in Sweden.

The study, “Bifidobacteria-mediated immune system imprinting early in life”, Cell, 2021. DOI:

Featured image: Graphical abstract by authors © authors

Provided by Evolve Biosystems

First Evidence That Medieval Plague Victims Were Buried Individually With ‘Considerable Care’ (Archaeology)

In the mid-14th century Europe was devastated by a major pandemic – the Black Death – which killed between 40 and 60 per cent of the population. Later waves of plague then continued to strike regularly over several centuries.

Plague kills so rapidly it leaves no visible traces on the skeleton, so archaeologists have previously been unable to identify individuals who died of plague unless they were buried in mass graves.

Whilst it has long been suspected that most plague victims received individual burial, this has been impossible to confirm until now.

By studying DNA from the teeth of individuals who died at this time, researchers from the After the Plague project, based at the Department of Archaeology, University of Cambridge, have identified the presence of Yersinia Pestis, the pathogen that causes plague.

These include people who received normal individual burials at a parish cemetery and friary in Cambridge and in the nearby village of Clopton.

Lead author Craig Cessford of the University of Cambridge said, “These individual burials show that even during plague outbreaks individual people were being buried with considerable care and attention. This is shown particularly at the friary where at least three such individuals were buried within the chapter house. Cambridge Archaeological Unit conducted excavations on this site on behalf of the University in 2017.”

Individuals buried in the chapter house of the Augustinian friary, Cambridge, who died of plague. © Cambridge Archaeological Unit

“The individual at the parish of All Saints by the Castle in Cambridge was also carefully buried; this contrasts with the apocalyptic language used to describe the abandonment of this church in 1365 when it was reported that the church was partly ruinous and ‘the bones of dead bodies are exposed to beasts’.”

The study also shows that some plague victims in Cambridge did, indeed, receive mass burials.

Yersinia Pestis was identified in several parishioners from St Bene’t’s, who were buried together in a large trench in the churchyard excavated by the Cambridge Archaeological Unit on behalf of Corpus Christi College.

This part of the churchyard was soon afterwards transferred to Corpus Christi College, which was founded by the St Bene’t’s parish guild to commemorate the dead including the victims of the Black Death. For centuries, the members of the College would walk over the mass burial every day on the way to the parish church.

Cessford concluded, “Our work demonstrates that it is now possible to identify individuals who died from plague and received individual burials. This greatly improves our understanding of the plague and shows that even in incredibly traumatic times during past pandemics people tried very hard to bury the deceased with as much care as possible.”

The study is published open access today in the European Journal of Archaeology.

Featured image: Reconstruction of plague victim from All Saints, Cambridge © Mark Gridley

Reference: Cessford, C., Scheib, C., Guellil, M., Keller, M., Alexander, C., Inskip, S., & Robb, J. (2021). Beyond Plague Pits: Using Genetics to Identify Responses to Plague in Medieval Cambridgeshire. European Journal of Archaeology, 1-23. doi:10.1017/eaa.2021.19

Provided by University of Cambridge

A New “Twist” To Break Viscoelastic Liquid Bridges (Physics)


  • Scientists have developed a new method that improves dispensing of viscoelastic fluids – a vital process for circuit board production, 3D printing and other industrial applications
  • Viscoelastic fluids are difficult to dispense as liquid bridges that form between the substrate and nozzle must be broken
  • New research has found that twisting these liquid bridges breaks them in a quicker and cleaner way than the conventional method of stretching them
  • Researchers used high speed imaging to observe that when twisted, a crack forms at the edge of the liquid bridge and propagates towards the center
  • The underlying mechanism that breaks the liquid bridge was found to be “edge fracture” and is the first time that scientists have found a useful application for this phenomenon

Press release

If you’ve ever tried to lift a pizza slice covered in hot, melted cheese, you’ve no doubt encountered the long, cheesy strings that bridge one pizza slice from the next. Keep lifting the pizza slice and these cheese bridges eventually break, covering the plate, table (or even your lap) in long, thin strands of cheese. While this is just a minor inconvenience with pizza, it is a longstanding problem in industry, where liquids with similar properties to melted cheese – dubbed viscoelastic fluids – need to be cleanly and speedily dispensed.

Now, scientists have developed a new technique that uses rotation to break these liquid bridges. Their findings, published 11 June 2021 in PNAS, could improve the speed and precision of dispensing viscoelastic fluids, in applications ranging from circuit board production and food processing to live tissue engineering and 3D printing.

“Viscoelastic fluids, like ketchup, silly putty and toothpaste, have very strange properties – when squeezed slowly, they flow like a fluid, but at faster speeds, they act like an elastic solid,” said co-first author, San To Chan, who is a PhD student and JSPS DC2 Fellow in the Micro/Bio/Nanofluidics Unit at the Okinawa Institute of Science and Technology Graduate University (OIST). “These unique properties make dispensing these fluids quite difficult.”

Currently, the standard method in industry involves lifting the nozzle away from the surface on which the liquid has been deposited. Although this effectively breaks the bridge, it draws the deposited liquid up into a long, thin peak, known as a capillary tail. If the liquid bridge breaks in multiple places, small droplets of fluid, called satellite droplets, also form. Capillary tails and satellite droplets can contaminate products or short-circuit electronic chips. 

When the nozzle (or plate) is lifted, the liquid bridge extends and breaks. This can form capillary tails and satellite droplets.

“The higher the nozzle is retracted, the longer the capillary tail, so the greater the chance for contamination,” Chan explained.  “Since the nozzle can’t be lifted too high, the liquid bridge is thicker and takes longer to break, which slows down the whole dispensing process.”

To overcome these challenges, Chan and his colleagues devised a simple solution: instead of stretching the liquid bridge, it could be destabilized through twisting.

In the study, the research team tested this idea on viscoelastic silicone oil, which is 60,000 times more viscous than water. The scientists placed a droplet of silicone oil between an upper and lower plate. Using high-speed imaging, they found that when the liquid bridge was twisted by rotating the upper plate, it caused a crack halfway between the ends of the liquid bridge. The crack then spread inwards from the edge towards the center, cutting the bridge cleanly in two without forming capillary tails or satellite droplets.

Importantly, this process took about a second, compared to the ten seconds typically needed to dispense the same fluid using the conventional retraction method.

Video: When the upper plate is rotated at 35.5 cycles per second (Hz), the silicone oil bridge is placed under torsion. Such rotation causes a crack to appear that propagates from the edge of the bridge to the center. The video is slowed down to 0.2x speed and takes one second in real-time. © OIST

For their next step, the scientists uncovered the underlying mechanism that causes the liquid bridge to break when placed under torsion. They teamed up with a research lab from Eindhoven University of Technology, who simulated what Chan and his colleagues had observed experimentally. The simulations provided concrete information about how the liquid bridge reacted, validating what the scientists had suspected: the crack was caused by “edge fracture”.

“This is particularly striking as edge fracture has been characterized as a really undesirable phenomenon that scientists try to stop from occurring,” said Dr. Simon Haward, who is the group leader for Micro/Bio/Nanofluidics Unit. “This is the first time that edge fracture has been found to have a beneficial application.”

In the next phase of their research, the team plans to experiment with different viscoelastic fluids to confirm that the same effect applies. They also plan to increase the speed of the dispensing process further, potentially by combining both rotating and retracting the upper plate.

“For many industries, swapping from a nozzle that retracts to one that spins is relatively easy, but it has far-reaching ramifications,” said senior author, Professor Amy Shen. “Faster and more precise liquid dispensing could lower energy consumption, and fewer contaminated products could mean that less raw material used.”

Header image by Sofiamcfly, CC BY-SA 3.0 , via Wikimedia Commons

Article Information

  • Title: Torsional fracture of viscoelastic liquid bridges
  • Journal: PNAS
  • Authors:  San To Chan*, Frank P. A. van Berlo*, Hammad A. Faizi*, Atsushi Matsumoto, Simon J. Haward, Patrick D. Anderson, and Amy Q. Shen
  • Date: 11 June 2021
  • DOI: 10.1073/pnas.2104790118

*These authors contributed equally to the study.

Provided by OIST

Hybrid Membrane Doubles The Lifetime of Rechargeable Batteries (Material Science)

Chemists from the University of Jena prevent dendrite formation in lithium metal batteries

The energy density of traditional lithium-ion batteries is approaching a saturation point that cannot meet the demands of the future – for example in electric vehicles. Lithium metal batteries can provide double the energy per unit weight when compared to lithium-ion batteries. The biggest challenge, hindering its application, is the formation of lithium dendrites, small, needle-like structures, similar to stalagmites in a dripstone cave, over the lithium metal anode. These dendrites often continue to grow until they pierce the separator membrane, causing the battery to short-circuit and ultimately destroying it.

For many years now, experts worldwide have been searching for a solution to this problem. Scientists at Friedrich Schiller University in Jena, together with colleagues from Boston University (BU) and Wayne State University (WSU), have now succeeded in preventing dendrite formation and thus at least doubling the lifetime of a lithium metal battery. The researchers report on their method in the renowned journal “Advanced Energy Materials”.

Two-dimensional membrane prevents dendrite nucleation

During the charge transfer process, lithium ions move back and forth between the anode and the cathode. Whenever they pick up an electron, they deposit a lithium atom and these atoms accumulate on the anode. A crystalline surface is formed, which grows three-dimensionally where the atoms accumulate, creating the dendrites. The pores of the separator membrane influences the nucleation of dendrites. If ion transport is more homogeneous, dendrite nucleation can be avoided.

“That’s why we applied an extremely thin, two-dimensional membrane made of carbon to the separator, with the pores having a diameter of less than one nanometer,” explains Professor Andrey Turchanin from the University of Jena. “These tiny openings are smaller than the critical nucleus size and thus prevent the nucleation that leads to the formation of dendrites. Instead of forming dendritic structures, the lithium is deposited on the anode as a smooth film.” There is no risk of the separator membrane being damaged by this and the functionality of the battery is not affected.

“To test our method, we recharged test batteries fitted with our Hybrid Separator Membrane over and over again,” says Dr Antony George from the University of Jena. “Even after hundreds of charging and discharging cycles, we couldn’t detect any dendritic growth.”

“The key innovation here is stabilizing electrode/electrolyte interface with an ultra-thin membrane that does not alter current battery manufacturing process,” says Associate Professor Leela Mohana Reddy Arava from the WSU. “Interface stability holds key in enhancing the performance and safety of an electrochemical system.”

Applied for a patent

High energy density batteries extend the driving range of electric vehicle (EVs) for the same weight/volume of the battery that a modern EV possesses and make portable electronic devices last longer in a single charge. “The separator gets the least amount of attention when compared to the other components of the battery,” says Sathish Rajendran, a graduate student at WSU. “The extent to which a nanometer thick two-dimensional membrane on the separator could make a difference in the lifetime of a battery is fascinating.”

As a result, the research team is confident that their findings have the potential to bring about a new generation of lithium batteries. They have therefore applied for a patent for their method. The next step is to see how the application of the two-dimensional membrane can be integrated into the manufacturing process. The researchers also want to apply the idea to other types of batteries.

Die Dendritbildung (l.) wird durch die Nanomembran (r.) verhindert
a) Regular battery separators with microscale porosity cause non-uniform lithium transport during the battery charge-discharge cycles resulting in needle-like growth of metallic lithium. This leads to short circuits and premature failure of lithium metal batteries. b) By introducing a carbon nanomembrane on the regular battery separator, the growth of lithium needles can be suppressed. The sub-nanometer-sized pores in carbon nanomembranes regulate the transport of lithium ions during the battery charge-discharge cycles, resulting in the deposition of a smooth film and the battery life can be increased significantly.Image: Turchanin et al./Wiley

Featured image: Prototype lithium metal batteries with carbon nanomembrane modified separators being tested at Wayne State University . © (Photo: Sathish Rajendran/Wayne State University)

Original publication

Rajendran, Z. Tang, A. George, A. Cannon, C. Neumann, A. Sawas, E. Ryan, A. Turchanin & L. M. R. Arava: Inhibition of Lithium Dendrite Formation in Lithium Metal Batteries via Regulated Cation Transport through Ultrathin Sub-Nanometer Porous Carbon Nanomembranes, Advanced Energy Materials, 2021, DOI: 10.1002/aenm.202100666

Provided by University of Jena

Antibiotic Novobiocin Found To Kill Tumor Cells With DNA-repair Glitch (Medicine)

An antibiotic developed in the 1950s and largely supplanted by newer drugs, effectively targets and kills cancer cells with a common genetic defect, laboratory research by Dana-Farber Cancer Institute scientists shows. The findings have spurred investigators to open a clinical trial of the drug, novobiocin, for patients whose tumors carry the abnormality.

In a study in the journal Nature Cancer, the researchers found that in laboratory cell lines and tumor models novobiocin selectively killed tumor cells with abnormal BRCA1 or BRCA2 genes, which help repair damaged DNA. The drug was effective even in tumors resistant to agents known as PARP inhibitors, which have become a prime therapy for cancers with DNA-repair glitches.

“PARP inhibitors represent an important advance in the treatment of cancers with defects in BRCA1, BRCA2, or other genes involved in DNA repair. By allowing tumor cells to accumulate additional genetic damage, they essentially incapacitate the cells and cause them to die,” says Alan D’Andrea, MD, director of the Susan F. Smith Center for Women’s Cancers and the Center for DNA Damage and Repair at Dana-Farber and co-senior author of the study with Raphael Ceccaldi, PhD, PharmD, of the Curie Institute in Paris. “They are effective for many patients, but the cancer eventually becomes resistant and begins growing again. Drugs capable of overcoming that resistance are urgently needed.” D’Andrea added.

BRCA mutations – whether inherited or acquired – are found in a sizeable percentage of breast, ovarian, prostate, and pancreatic cancers. The discovery of novobiocin’s effectiveness in PARP inhibitor-resistant tumors arose when two strands of research converged on a key enzyme in tumor cells.

In a study published in 2015, D’Andrea and his colleagues found that tumors with poorly functioning BRCA1 and -2 genes are overdependent for their growth and survival on an enzyme known as POLθ, or POLQ. For the new study, they screened thousands of molecules – some new, some used in approved drugs – in BRCA-deficient tumors to see if any had an effect on tumor growth. The screenings were conducted in laboratory cell lines, in organoids – three dimensional cultures of tumor tissue – and in animal models.

Of the multitude of molecules and drugs tested, one stood out for its ability to kill the tumor cells while leaving normal cells unharmed – novobiocin. The protein that novobiocin targets within cells was eminently familiar to researchers – POLQ, specifically, a portion known as the ATPase domain.

When investigators looked into the medical literature on novobiocin, they found a surprise, D’Andrea relates. Though developed and used as an antibiotic, it had been tested in the early 1990s in a clinical trial for patients with hard-to-treat cancers. While most of the patients didn’t benefit from the drug, a small number had their cancer recede or stabilize.

“At the time, no one knew what the drug’s target was,” D’Andrea remarks. “Now we do, and, as a result, we have an indication of which patients are likely to be helped by it.”

On the basis of the study results, Dana-Farber investigators will be launching a clinical trial of novobiocin for patients with BRCA-deficient cancers that have acquired resistance to PARP inhibitors. Because it is an oral drug that is safe and approved for treating another disease, novobiocin offers several advantages as an agent for study, D’Andrea comments.

“We’re looking forward to testing novobiocin, alone and in combination with other agents, in patients whose tumors have molecular characteristics indicating a likely response to the drug,” D’Andrea says.

The first author of the study is Jia Zhou, PhD, of Dana-Farber. Co-authors are Constantia Pantelidou, PhD, Adam Li, Anniina Farkkila, MD, PhD, Bose Kochupurakkal, PhD, and Geoffrey I. Shapiro, MD, PhD, of Dana-Farber; Camille Gelot, PhD, and Hatice Yu?cel, of the Curie Institute; Rachel E. Davis, PhD, and Brian S. J. Blagg, PhD, of the University of Notre Dame; and Aleem Syed, PhD, and John A. Tainer, PhD, of the University of Texas MD Anderson Cancer Center.

The research was supported by a Stand Up To Cancer (SU2C)-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (SU2C-AACR-DT16-15). This work was also supported by the Richard and Susan Smith Family Foundation and the Basser Initiative at the Gray Foundation. It was also supported by the National Institutes of Health (grants R37HL052725, P01HL048546, and P50CA168504); the US Department of Defense (grants BM110181 and BC151331P1); as well as grants from the Breast Cancer Research Foundation, the Fanconi Anemia Research Fund, an ERC starting grant (N° 714162), and the Ville de Paris Emergences Program grant (N° DAE 137). It was also supported by an Ann Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund Alliance (457527) and a Joint Center for Radiation Therapy Award from Harvard Medical School.

Reference: Zhou, J., Gelot, C., Pantelidou, C. et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat Cancer (2021).

Provided by Dana-Farber Cancer Institute

Red Meat Consumption May Promote DNA Damage-associated Mutations in Patients With Colorectal Cancer (Food)

Study provides mechanistic link between red meat consumption and colorectal cancer development

Genetic mutations indicative of DNA damage were associated with high red meat consumption and increased cancer-related mortality in patients with colorectal cancer, according to a study led by Dana-Farber Cancer Institute researchers and published in Cancer Discovery, a journal of the American Association for Cancer Research.

“We have known for some time that consumption of processed meat and red meat is a risk factor for colorectal cancer,” said Marios Giannakis, MD, PhD, an oncologist with Dana-Farber’s Gastrointestinal Cancer Center and an assistant professor of medicine at Harvard Medical School. The International Agency for Research on Cancer declared that processed meat was carcinogenic and that red meat was probably carcinogenic to humans in 2015.

Experiments in preclinical models have suggested that red meat consumption may promote the formation of carcinogenic compounds in the colon, but a direct molecular link to colorectal cancer development in patients has not been shown, Giannakis explained. “What is missing is a demonstration that colorectal cancers from patients have a specific pattern of mutations that can be attributed to red meat,” he said. “Identifying these molecular changes in colon cells that can cause cancer would not only support the role of red meat in colorectal cancer development but would also provide novel avenues for cancer prevention and treatment.”

To identify genetic changes associated with red meat intake, Giannakis and colleagues sequenced DNA from matched normal and colorectal tumor tissues from 900 patients with colorectal cancer who had participated in one of three nationwide prospective cohort studies, namely the Nurses’ Health Studies and the Health Professionals Follow-Up Study. All patients had previously provided information on their diets, lifestyles, and other factors over the course of several years prior to their colorectal cancer diagnoses.

Analysis of DNA sequencing data revealed the presence of several mutational signatures in normal and cancerous colon tissue, including a signature indicative of alkylation, a form of DNA damage. The alkylating signature was significantly associated with pre-diagnosis intake of processed or unprocessed red meat, but not with pre-diagnosis intake of poultry or fish or with other lifestyle factors. Red meat consumption was not associated with any of the other mutational signatures identified in this study. In line with prior studies linking red meat consumption with cancer incidence in the distal colon, Giannakis and colleagues found that normal and cancerous tissue from the distal colon had significantly higher alkylating damage than tissue from the proximal colon.

Using a predictive model, the researchers identified the KRAS and PIK3CA genes as potential targets of alkylation-induced mutation. Consistent with this prediction, they found that colorectal tumors harboring KRAS G12D, KRAS G13D, or PIK3CA E545K driver mutations, which are commonly observed in colorectal cancer, had greater enrichment of the alkylating signature compared to tumors without these mutations. The alkylating signature was also associated with patient survival: Patients whose tumors had the highest levels of alkylating damage had a 47 percent greater risk of colorectal cancer-specific death compared to patients with lower levels of damage.

“Our study identified for the first time an alkylating mutational signature in colon cells and linked it to red meat consumption and cancer driver mutations,” said Giannakis. “These findings suggest that red meat consumption may cause alkylating damage that leads to cancer-causing mutations in KRAS and PIK3CA, thereby promoting colorectal cancer development. Our data further support red meat intake as a risk factor for colorectal cancer and also provide opportunities to prevent, detect, and treat this disease.”

Giannakis explained that if physicians could identify individuals who are genetically predisposed to accumulating alkylating damage, these individuals could be counseled to limit red meat intake as a form of precision prevention. In addition, the alkylating mutational signature could be used as a biomarker to identify patients at greater risk of developing colorectal cancer or to detect cancer at an early stage. Because of its association with patient survival, the alkylating signature may also have potential as a prognostic biomarker. However, future studies are needed to explore these possibilities, Giannakis noted.

A limitation of the study is the potential selection bias of study participants, as tissue specimens could not be retrieved from all incident colorectal cancer cases in the cohort studies. Current studies from Giannakis and his colleagues are exploring the potential role of red meat intake and alkylating damage in diverse groups of patients.

The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (co-administered by the AACR), the Project P Fund, the Cancer Research UK Grand Challenge Award, the Nodal Award from the Dana-Farber Harvard Cancer Center, the Friends of the Dana-Farber Cancer Institute, the Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance and Stand Up To Cancer.

Giannakis has received research funding from Bristol-Myers Squibb, Merck, Servier, and Janssen unrelated to this study.

Featured image: Study provides mechanistic link between red meat consumption and colorectal cancer development © Dana Farber Cancer Institute

Provided by Dana-Farber Cancer Institute

Slowed Cell Division Causes Microcephaly (Neuroscience)

Scientists from UNIGE demonstrate how the mutation of a single gene can slow down cell division and lead to an abnormally small brain.

The birth of a human being requires billions of cell divisions to go from a fertilised egg to a baby. At each of these divisions, the genetic material of the mother cell duplicates itself to be equally distributed between the two new cells. In primary microcephaly, a rare but serious genetic disease, the ballet of cell division is dysregulated, preventing proper brain development. Scientists from the University of Geneva (UNIGE), in collaboration with Chinese scientists, have demonstrated how the mutation of a single protein, WDR62, prevents the proper formation of the cable network responsible for separating genetic material into two. As cell division is then slowed down, the brain does not have time to build itself completely. These results, to be read in the Journal of Cell Biology, shed new light on cell division, a phenomenon also involved in cancer development.

Cell division is an essential mechanism for the development of any new being. It is precisely regulated and requires coordination and control. To this end, cables called “microtubules” allow the genetic material packed in chromosomes to be distributed equally between the two daughter cells. “These microtubules continually assemble and disassemble to reach their proper size at any moment”, explains Patrick Meraldi, professor in the Department of Cell Physiology and Metabolism at UNIGE Faculty of medicine and coordinator of the Translational Research Centre in Onco-haematology (CRTOH), who led this work. “To regulate their size, the cell uses a protein, katanin (from the Japanese katana for sword) in charge of cutting microtubules to the right length.”

A minor mutation with severe consequences

A mutation of any of the genes involved in cell division is enough to cause an abnormally small brain and serious neuronal problems, thus strongly limiting the autonomy of affected individuals. Primary microcephaly is often linked to consanguineous unions and affects between 1 in 30,000 and 1 in 250,000 people, depending on the region of the world.

But how can a single mutation have such serious consequences? And why, if the mutated gene is so important, is brain development the only to be affected? The first clues to answering these questions came a few years ago, when scientists discovered that the most frequently mutated gene in microcephaly, ASPM, is involved in the location and function of katanin, the molecular sword responsible for cutting microtubules. “But was this the core mechanism of microcephaly or just specific to this mutation?” asked Amanda Guerreiro, postdoctoral fellow in Patrick Meraldi’s laboratory and first author of the study.

Katanin, an essential molecular sword

In vitro experiments with cell lines revealed that the second most common gene involved in microcephaly, WDR62 was, like ASPM, required for the localisation and function of katanin. Similarly, scientists observed that if katanin is not in the right place at the right time, microtubules become too long. As space is limited, they are under compression and become S-shaped rather than straight and tensed. Consequently, when microtubules have to pull chromosomes to distribute them evenly in the two new cells, tension is not strong enough and some chromosomes lag behind others. A slight dysregulation in the mechanics of cell division is enough to slow down the distribution of chromosomes. Since this delay is considered by cells to be a serious failure, many will die. The death of too many cells would then result in the abnormally small size of the brain of people with primary microcephaly.

“Katanin seems to be the central mechanism of this developmental disease,» says Patrick Meraldi. “However, the outcome of our work is much broader: it allows us to understand how cancer cells modify the system to divide endlessly and proliferate in the body.”

Video showing normal cell division.
Video showing a division during which some chromosomes are late.

Featured image: A representation of a normally developed brain vs. a brain with microcephaly. © All rights reserved to University of Geneve

Reference: Amanda Guerreiro, Filipe De Sousa, Nicolas Liaudet, Daria Ivanova, Anja Eskat, Patrick Meraldi; WDR62 localizes katanin at spindle poles to ensure synchronous chromosome segregation. J Cell Biol 2 August 2021; 220 (8): e202007171. doi:

Provided by University of Geneve

Researchers Reveal Defect Properties in Sb2S3 Material (Material Science)

As a new member of photovoltaic family, antimony trisulfide (Sb2S3) has the satisfactory bandgap of 1.7eV, benefiting the fabrication of the top absorber layer of tandem solar cells. Due to special quasi-one-dimensional structure, it shows advantages of less dangling bonds. Based on these advantages, the vacancy defects upon the surface causing the recombination of the carriers could be reduced sharply, which helps to solve the photovoltaic problems in solar cells.

In the previous studies, the relationships between conformation, chemical composition and structure of deep-level defects on Sb2S3 films are unclear from the aspect of experiment.

In a study published in Nature Communications, a research team led by CHEN Tao from University of Science and Technology of China (USTC) of the Chinese Academy of Sciences discovered the unique defect properties of low-dimensional materials particularly Sb2S3 through building the bridge between the deep-level defects of Sb2S3 and anion/cation ratio.  

The researchers prepared both Sb-rich and sulphur-rich Sb2S3 films by using the method of thermal evaporation deposition. Based on the excellent performance of the devices, the deep-level transient spectroscopy (DLTS) was applied to detect the characterizations of defects.  

The sulphur-rich Sb2S3 films showed an excellent performance compared with Sb-rich Sb2S3 films as the lower density of defect and less detrimental to carrier transport were achieved, which matches with the improvement in photovoltaic performance. Based on theoretical calculations, it seems that the defects are trend to appear in Sb-rich Sb2S3 films.  

Notably, the sulphur-rich Sb2S3 devices fabricated by thermal evaporation showed the highest record power conversion efficiency, which means that the material is capable of being more tolerant to vacancy defects, and indicates that the addictive introduce to the vacancy will not lower the lifetime of carriers.  

This study provides a new solution to regulate the photovoltaic properties of Sb2S3.

Featured image: Schematic diagram of quasi-1-dimensional structural Sb2S3. Sideview (a) and aeroview (b) of [Sb4S6] ribbons along c axis. © Lian et al.

Reference: Lian, W., Jiang, C., Yin, Y. et al. Revealing composition and structure dependent deep-level defect in antimony trisulfide photovoltaics. Nat Commun 12, 3260 (2021).

Provided by Chinese Academy of Sciences