Category Archives: Cell Biology

Cell Biology

RNA therapy restores gene function in monkeys modeling … – Spectrum – Autism Research News

Relative success: A gene therapy now in clinical trials works in macaques and targets a UBE3A antisense transcript shared by people.

Tim Laman / Minden Pictures

A drug injected into the spinal canal of monkeys activates expression of the paternal copy of UBE3A a gene linked to Angelman syndrome in their brain, raising hopes for the success of a human clinical trial currently underway.

Angelman syndrome is a debilitating condition marked by seizures, intellectual disability, deficits in communication and coordination, and sometimes autism. The syndrome arises primarily from an absence of E3A ubiquitin-protein ligase (UBE3A) in a childs brain. People typically inherit working copies of the UBE3A gene from both parents but develop Angelman if the maternal copy is missing or contains mutations.

Thats because a process called imprinting usually silences the paternal copy. Researchers have long sought a way to restore UBE3A levels by unsilencing it a strategy that three competing companies are pursuing using short strands of RNA known as antisense oligonucleotides, or ASOs.

One of these ASOs from Ultragenyx, a biotechnology company in Novato, California was able to increase UBE3A levels by 40 percent in the brains of crab-eating macaque monkeys, according to a report published in Science Translational Medicine on 22 March. Ultragenyx began testing the drug in people in a Phase 1/2 clinical trial in 2020.

This study shows the potency of that lead compound in a non-human primate, which is probably as close to a human situation as we can get in an animal model, says Ype Elgersma, professor of neuroscience and head of the ENCORE expertise center at Erasmus University in Rotterdam, the Netherlands, who was not involved in the study.

To achieve such results, however, the researchers had to use three 5-milligram doses injected at two-week intervals, Elgersma notes, which is much higher than the dose currently used in the clinical trial. The human trial had initially tested higher doses but was temporarily halted and modified after all of the participants experienced leg weakness a side effect that may be inherent to injecting higher doses of ASOs into the spinal canal. Interim results from the trial suggest that a lower dose is safe, and the participants showed improvements in certain areas.

But Elgersma asks, Will the current dose used in the clinical trial be high enough to induce sufficient levels of UBE3A in Angelman syndrome patients?

The new study not only demonstrates the promise of the ASO candidate in monkeys, but also provides one of the most detailed looks to date at the imprinting mechanism that silences the paternal copy of UBE3A in the brain, the so-called UBE3A antisense transcript.

The antisense transcript breaks all the rules of what we teach in genetics, says lead author Scott Dindot, associate professor of genetics at Texas A&M University in College Station and executive director of molecular genetics at Ultragenyx.

The UBE3A antisense transcript represents just one end of a massive, complex piece of RNA that contains both coding and noncoding regions that serve various functions in the cell. I was determined to figure this [locus] out, he says.

One of the first surprises Dindot discovered on his quest was that the UBE3A antisense transcript in mice is completely different from that in monkeys and humans. If you were developing an ASO in mice, it wasnt going to work in humans, he says.

Dindot and his collaborators used this knowledge to their advantage to home in on one or more ASOs that would halt transcription of the UBE3A antisense and thereby reactivate the paternal copy of UBE3A. Dindot identified a sweet spot in the UBE3A antisense transcript called cluster 2 that is evolutionarily conserved in placental mammals, reasoning that it had a high likelihood of stopping transcription.

He and his colleagues then generated six candidate oligonucleotides, including three for which the sequence is identical in humans and crab-eating macaques. Those sequences could be tested in both a primate model and in human neuron cell cultures before entering clinical trials. Their lead candidate among the three proved more effective at blocking the UBE3A antisense than did topotecan, a chemotherapy drug that has also been explored for that purpose.

This is the first comprehensive picture of what the antisense really looks like at a sequence level and what regions one would want to target, says Mark Zylka, professor of cell biology and physiology at the University of North Carolina at Chapel Hill, who was not involved in the work but whose lab has been employing a CRISPR-based strategy to boost UBE3A levels in mice.

The next step, Zylka says, will be to see whether one companys molecule or all three of them ends up succeeding in human trials. Its good to have multiple products against a single thing, because you dont know short-term and long-term what the side effects might be, he says.

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RNA therapy restores gene function in monkeys modeling ... - Spectrum - Autism Research News

Cell Biology

Traumatic brain injury interferes with immune system cells’ recycling … – Science Daily

Each year about 1.5 million people in the U.S. survive a traumatic brain injury due to a fall, car accident, or a sports injury, which can cause immediate and long-term disability.

University of Maryland School of Medicine (UMSOM) researchers wanted to better understand what happens in the brain during injury, so they conducted a study in mice to determine how different types of brain cells in mice react to severe trauma. In a new study published in the January issue of Autophagy, they found that after traumatic brain injury, the brain's immune system cells' internal recycling function slowed dramatically, allowing waste products to build up and interfere with recovery from injury.

The researchers also found that treating mice that had traumatic brain injury with a drug to promote cellular recycling improved the mice's ability to recover from injury and solve a water maze, a measure of memory function in mice.

"Many drugs and potential solutions have been proposed to treat traumatic brain injury, but none have ever worked in practice," said lead researcher Marta Lipinski, PhD, Associate Professor of Anesthesiology and Anatomy & Neurobiology at UMSOM and a member of the Shock, Trauma, and Anesthesiology Research (STAR) Center at the University of Maryland Medical Center (UMMC). "It could be that designing drugs for patients that promote this cellular recycling might reverse or prevent damage from traumatic brain injury as we saw in our animal studies. We are continuing to learn more about the molecular and cell biology mechanisms in trauma, so we can use a more guided approach for developing solutions."

The body's cells regularly recycle their own worn-out or damaged parts that accrue through normal wear and tear, infection, or injury in a process known as autophagy. Most cells in the brain use that process for cleaning up their own waste and recycling it on a smaller scale. In a previous study, Dr. Lipinski's group showed that traumatic brain injury reduced the ability of neurons -- the cells that send electrical impulses -- to recycle their own damaged parts, which then led to these neurons dying off. However, some cells in the brain can perform greater feats of recycling, such as the resident immune cells in the brain known as microglia, which can engulf, digest, and recycle entire damaged or dead cells in the tissue.

After a traumatic brain injury, white blood cells -- normally excluded by the blood-brain barrier -- can also get into the brain and work alongside the microglia cells to eat and remove damaged cells. For this new study, Dr. Lipinski's team focused on the immune cells -- microglia and white blood cells -- in the brain after traumatic brain injury and found that, like the neurons, their recycling function was also suppressed.

"Dr. Lipinski's discovery of the recycling function suppression in both neurons and immune cells demonstrates how important it is for neuroscientists to fully understand the complex system involved in a traumatic brain injury," said Dean Mark Gladwin, MD, who is Vice President for Medical Affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor at UMSOM. "Developing effective drugs for traumatic brain injury treatment requires a deeper understanding of these cell-to-cell interactions and what impact each cell type has on the brain's ecosystem."

To demonstrate the full impact of the recycling process on traumatic brain injury and recovery, Dr. Lipinski and her team blocked one of the essential proteins needed to carry out the immune cell's recycling function in the brains of mice with a brain injury. These mice experienced an even greater suppression of their cell recycling processes, resulting in more inflammation in their brain. They even performed worse, as measured by their ability to solve the water maze, than the mice with only brain injury. These findings suggested that the recycling function of the immune cells in the brain is essential for recovery after brain trauma. Conversely, boosting it may possibly lessen the impact of the trauma.

To test that, the researchers used a drug, rapamycin (normally used as a cancer drug or to prevent organ rejection), to promote cellular recycling in the brains of mice who had traumatic brain injury. The researchers found that with the treatment, the mice had lower levels of inflammation in the brain and these mice did better in navigating the water maze.

"The drug we used in our study blocks a set of proteins that are important for regenerating the body's cells, so it cannot be used for extended time periods," said Dr. Lipinski. "We need to continue this line of research to identify the exact mechanism of how autophagy protects against neurological damage in order to find more targeted drugs that increase this process without targeting the vital proteins needed by the brain to regenerate."

This study was funded by grants from the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS) (R01NS094527, R01NS091218, R01NS115876).

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Traumatic brain injury interferes with immune system cells' recycling ... - Science Daily

Cell Biology

Researchers reveal mechanism of polarized cortex assembly in migrating cells – Phys.org

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The cell cortex is defined as a thin layer of filamentous actin, myosin motors, and regulatory proteins beneath the plasma membrane. Assembly and contraction of this actin meshwork generates cortical tension, which enables cells to resist external mechanical stresses, change shape, and exert forces. Consequently, the cortex plays a critical role in a variety of cellular processes, including division, migration and morphogenesis.

The mechanical properties of the cortex are key to its physiological function. Changes in cortical mechanics can originate from changes in the architecture of the actin network. However, the complete inventory of assembly factors driving formation of the actin cortex and how their activities are spatiotemporally controlled are not well understood.

In a study published in the Journal of Cell Biology, Prof. Cai Huaqing's group at the Institute of Biophysics of the Chinese Academy of Sciences uncovered a signaling cascade responsible for building the rear actin cortical subcompartment in rapidly migrating cells.

Using Dictyostelium as a model for polarized and rapidly migrating cells, the researchers found that a RhoGEF domain-containing protein named GxcM localizes specifically in the rear of directionally migrating cells. Overexpression of GxcM induces excessive actin polymerization in the rear cortex, and these structures can be marked by the Arp2/3 complex, suggesting that GxcM possesses the ability to promote branched actin assembly. By generating a series of truncations and mutations, they demonstrated that the function of GxcM relies on its C-terminal proline-rich motifs and GEF activity.

Co-immunoprecipitation, mass spectrometry, and microscopic imaging experiments showed that GxcM binds to and recruits F-BAR protein, Fbp17, through its C-terminus. In fbp17 knockout cells, GxcM still localizes in the posterior of the cell, but loses the ability to stimulate actin polymerization, resulting in a decrease in cortical actin content, a significant reduction in the cell's ability to resist external mechanical forces, and defects in cell division and migration. Biochemical and in vitro actin polymerization experiments showed that Fbp17 is capable of binding and activating the actin nucleation promoting factor WASP through its SH3 domain, which in turn activates Arp2/3 and mediates branched actin polymerization.

Additionally, the researchers found that GxcM regulates actin assembly by stimulating the activity of the small GTPase, RacC. Yeast two-hybrid and biochemical experiments showed that active RacC binds to both Fbp17 and WASP. Inducing the expression of constitutively active RacC in cells produces effects similar to GxcM overexpression, in Fbp17- and WASP-dependent manner. Deletion of racC causes phenotypes similar to deletion of fbp17, resulting in defects in cortical integrity and function.

This study delineates a signaling cascade composed of GxcM, Fbp17, RacC, WASP, and Arp2/3, which regulates the formation of the rear cortical subcompartment in rapidly migrating cells and maintains cortical integrity. Therefore, apart from its well-defined role in formation of the protrusions at the cell front, the Arp2/3 complex-based actin carries out a previously unappreciated function in building the rear cortex. How the same core actin polymerization machinery drives the formation of different types of cellular structures and, thus, mediates diverse cell functions remains a question for future studies.

More information: Dong Li et al, GxcM-Fbp17/RacC-WASP signaling regulates polarized cortex assembly in migrating cells via Arp2/3, Journal of Cell Biology (2023). DOI: 10.1083/jcb.202208151

Journal information: Journal of Cell Biology

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Researchers reveal mechanism of polarized cortex assembly in migrating cells - Phys.org

Cell Biology

Lab-grown fat could give cultured meat real flavor and texture – EurekAlert

Researchers have successfully bulk-produced fat tissue in the lab that has a similar texture and make-up to naturally occurring fats from animals.

The results, described in a study published today in eLife, could be applied to the production of cultured meat grown entirely from cells, giving it a more realistic texture and flavour.

Cultivated meat has been making waves in the news lately, with reports from startup companies around the world developing cell-grown chicken, beef, pork and fish mostly in early stages of development, not ready for large-scale production and with a couple of exceptions, not yet approved for commercial sale. Most of those products in development are in the form of an unstructured mixture of cells like chicken nuggets rather than a slice of chicken breast. What is lacking is the texture of real meat, created by muscle fibres, connective tissue and fat and its the fat that gives meat flavour.

In fact, consumer testing with natural beef of different fat content showed that the highest scores were registered for beef containing 36% fat.

However, producing cultured fat tissue in sufficient quantities has been a major challenge because, as the fat grows into a mass, the cells in the middle become starved of oxygen and nutrients. In nature, blood vessels and capillaries deliver oxygen and nutrients throughout the tissue. Researchers still have no way to replicate that vascular network at a large scale in lab grown tissue, so they can only grow muscle or fat to a few millimetres in size.

To get around this limitation, the researchers grew fat cells from mice and pigs first in a flat, two-dimensional layer, then harvested those cells and aggregated them into a three-dimensional mass with a binder such as alginate and mTG, which are both already used in some foods.

Our goal was to develop a relatively simple method of producing bulk fat. Since fat tissue is predominantly cells with few other structural components, we thought that aggregating the cells after growth would be sufficient to reproduce the taste, nutrition and texture profile of natural animal fat, says first author John Yuen Jr, a graduate student at the Tufts University Center for Cellular Architecture (TUCCA), Massachusetts, US. This can work when creating the tissue solely for food, since theres no requirement to keep the cells alive once we gather the fat in bulk.

The aggregated fat cells immediately had the appearance of fat tissue, but to see if they truly reproduced the features of native fat from animals, the team carried out a series of further experiments.

First, they explored the texture, by compressing the fat tissue and seeing how much pressure it could withstand compared to natural animal fat. They found that cell-grown fat bound with sodium alginate was able to withstand a similar amount of pressure to fat from livestock and poultry, but the cell-grown fat that was bound with mTG behaved more like rendered fat similar to lard or tallow. This suggests it could be possible to fine-tune the texture of cultured fat, so it best resembles the real-life texture of fat within meat, using different types and amounts of binders.

Cooking releases hundreds of compounds that add flavour to the meat, and most of those compounds originate from fat, including lipids and their component fatty acids. The team therefore examined the composition of molecules from the cell-grown fat and found that the mix of fatty acids from cultured mouse fat differed from native mouse fat. However, the cultured pig fat had a much closer fatty acid profile to the native tissue. The teams preliminary research suggests it might be possible to supplement growing fat cells with the required lipids to ensure that they more closely match the composition of natural meat.

This method of aggregating cultured fat cells with binding agents can be translated to large-scale production of cultured fat tissue in bioreactors a key obstacle in the development of cultured meat, says senior author David Kaplan, Stern Family professor of Biomedical Engineering at Tufts University and director of TUCCA. We continue to look at every aspect of cultured meat production with an eye toward enabling mass production of meat that looks, tastes and feels like the real thing.

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About eLife

eLife transforms research communication to create a future where a diverse, global community of scientists and researchers produces open and trusted results for the benefit of all. Independent, not-for-profit and supported by funders, we improve the way science is practised and shared. In support of our goal, weve launched a new publishing model that ends the accept/reject decision after peer review. Instead, papers invited for review will be published as a Reviewed Preprint that contains public peer reviews and an eLife assessment. We also continue to publish research that was accepted after peer review as part of our traditional process. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

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And for the latest in Stem Cells and Regenerative Medicine, see https://elifesciences.org/subjects/stem-cells-regenerative-medicine.

Aggregating in vitro-grown adipocytes to produce macroscale cell-cultured fat tissue with tunable lipid compositions for food applications

4-Apr-2023

No competing interests declared

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Lab-grown fat could give cultured meat real flavor and texture - EurekAlert

Cell Biology

Probing Selfish Centromeres Unveils an Evolutionary Arms Race – The Scientist

The Portuguese island of Madeira is home to six different chromosomal races of mice, each with dramatically reduced diploid chromosome numbers compared to mice elsewhere. This striking diversity, first identified at the turn of the 21st century, can be explained by the repeated fusions of separate chromosomes. Each race has a different set of fusions, and a hybrid between two races would likely have reduced fertility or be sterile because of problems with chromosome pairing. Such reproductive isolation among populations is a key step on the road to speciationand in the mices case, these chromosomal changes have all occurred within the 1,000 years since their ancestors arrived on the island, possibly on Viking ships.

The so-called Robertsonian (Rb) fusions that led to these rapid karyotype changes are relatively common chromosomal rearrangements. But their accumulation in the populations of Madeira Island and in multiple other isolated mouse populations elsewhere is likely due to another influencing factor: the preferential segregation of the Rb fusion into the egg rather than into the discarded polar bodies that form during female meiosis.

We usually think of the chromosome segregation machinery as ensuring unbiased, random segregation. As we learn in high school biology, if a diploid individual carries two different alleles of a gene (i.e., is heterozygous), then either allele is equally likely to end up in a haploid gamete. This law explains the 3:1 ratio of phenotypes that Mendel observed in his classic studies of heredity. Scientists have known for decades, however, that selfish genes can subvert Mendelian segregation to increase their frequency in the next generation, a phenomenon known as meiotic drive. The Madeira mice suggest that fusion chromosomes can also drive unequal inheritance.

Because Rb fusions are easy to identify morphologically, and because mouse oocytes are an established model system, studying these fusions in mice provided an entry for my lab at the University of Pennsylvania to investigate the cell biology of meiotic drive, starting in 2010. Focusing on the centromerethe part of each chromosome that interacts with spindle microtubules to direct segregation in mitosis or meiosiswe found that the structures size determines the direction of biased segregation, with bigger centromeres preferentially segregating into the egg. Centromere DNA is typically highly repetitive, and we found that larger centromeres have more of the satellite repeats characteristic of mouse centromeres and more centromere proteins associated with that DNA. Thus, it seemed that newly formed Rb fusions could result in larger centromeres that would drive and become fixed in natural populations.

Centromere drive depends on a combination of asymmetries in female meiosis.

Meiotic drive of Rb fusions illustrates an idea proposed more than 50 years ago in a paper by zoologist Michael J. D. White: It may be that the very few chromosomal rearrangements which play a critical role in speciation through the ability to generate powerful isolating mechanisms are precisely those which happen to possess a segregational advantage in the female meiosis. Rb fusions are an example of such a rearrangement that can generate a segregational advantage (i.e., drive) through centromere expansion. The chromosomal races on Madeira Island and elsewhere show how drive can lead to rapid karyotype change and reproductive barriers between populations that have accumulated different sets of fusions.

Geneticist Marcus Rhoades introduced the concept of meiotic drive in 1942 based on observations of abnormal chromosome 10 (Ab10) in maize. Ab10 contains an extra DNA segment, termed a knob, that includes a repetitive DNA sequence. Rhoades showed that Ab10 preferentially segregates into the egg in female meiosis. He also proposed a model to explain the phenomenon, involving shifting the position of Ab10 toward the meiotic spindle poles in anaphase. The four products of meiosis are arranged in a linear tetrad, and only the lower cell develops into an egg, so this polar positioning increases the likelihood that Ab10 ends up in the egg. This model turned out to be correct, conceptually, and researchers recently discovered a molecular motor responsible for positioning Ab10.

The maize knobs are not necessary for chromosomal function or even beneficial except in the selfish sense of increasing their own transmission through female meiosis. In contrast, centromeres are ubiquitously used for faithful chromosome segregation during cell division. As stated by pioneering cell biologist Dan Mazia in 1961, The role in mitosis of the chromosome arms, which carry most of the genetic material, may be compared with that of a corpse at a funeral: they provide the reason for the proceedings but do not take an active part in them. Rather, the action is at the centromere, which mediates the chromosomes interactions with spindle microtubules.

Because the core centromere function of connecting to the spindle is highly conserved across eukaryotes, we expect that centromere components would also be conserved. Contrary to this expectation, many centromeric proteins evolve rapidly in multiple eukaryotic lineages, with patterns of amino acid changes suggesting positive selection. The repetitive DNA at centromeres, which does not code for any proteins, is also highly variable even between closely related species. This rapid evolution of both the protein and DNA components of the centromere, despite the structures conserved function, appears paradoxical.

Investigating centromeres or other selfish loci as pathogens in the context of genetic conflict can provide a unique window into the biology of chromosome segregation and inheritance.

To explain this paradox, in 2001, researchers proposed the idea that centromeres could play a role in meiotic drive. According to the centromere drive hypothesis, centromere DNA sequences (like the maize knobs) can act like selfish genetic elements, promoting their transmission to the next generation by hijacking the chromosome segregation machinery. This centromere drive may impose fitness costs, such as an increased chance of segregation errors that produce aneuploid gametes. These costs impose a selective pressure for adaptive evolution of centromere proteins to suppress the fitness costs.

But the repetitive, noncoding DNA at centromeres constantly changes, putting the rest of the genome, where centromere proteins are encoded, under recurrent pressure to adapt. This continual genetic conflict is analogous to immune factors evolving under pressure from a constantly changing pathogen, but with an essential chromosomal locus as the pathogen. The result is centromeric DNA and proteins that are highly variable even between closely related species. For this reason, the drive theory suggests that proteins adapted to centromeres in one population may not function optimally when confronted with divergent centromeres from another population, leading to hybrid incompatibilities, reproductive isolation, and speciation, analogous to the isolation induced by differences in karyotype.

Initial support for the centromere drive theory came from observations in yellow monkeyflowers (Mimulus spp.) published in 2008. In these plants, an expanded centromere, with more copies of the centromeric DNA repeat, exhibits a dramatic transmission bias. When plants are heterozygous for this expanded centromere, it can end up in offspring as much as 98 percent of the time. Plants homozygous for the expanded centromere exhibit reproductive fitness costs, however, in the form of reduced seed and pollen production, although the underlying mechanisms are unclear. Subsequent findings have shown that the magnitude of the transmission bias varies across different genetic backgrounds. Specifically, research points to a variant of the H3 histone protein as a potential suppressor of drive. This variant, known as CENP-A or CenH3, plays a key role in packaging centromeric DNA and serves as the foundation for the kinetochore, a multiprotein complex that binds the spindle microtubules.

These observations are consistent with the centromere drive hypothesis and raise fascinating mechanistic questions for cell biologists: How do selfish centromeres bias their segregation? How might adaptations of centromere proteins prevent drive or otherwise suppress the costs of nonrandom segregation? And what does all this mean for the evolution of populations and species?

Random segregation leads to each of parents alleles having an equal chance (0.5 probability) of being passed down. This can be visualized in a traditional Punnett square (left), which leads to a 3:1 ratio of offspring phenotypes and a 1:2:1 ratio of offspring genotypes (represented by orange, dark blue, and light blue shading, respectively).

If there is a meiotic drive, those ratios are shifted, sometimes dramatically (right). For example, in hybrid yellow monkeyflowers (Mimulus guttas x M. nasutus), the distorter locus (D) exhibits a whopping 98:2 segregation bias in the seed parent, resulting in an overabundance of DD offspring.

Centromere drive depends on a combination of asymmetries in female meiosis. First, there is the cell fate asymmetry that leads to the creation of one functional gamete while the other haploid cells are degraded and are therefore evolutionary dead ends. Second, there is the asymmetric positioning of the spindle close to the cell cortex, a thin layer of actin and other proteins just beneath the plasma membrane, leading to production of a large egg and a small polar body. Half of the chromosomes are attached to the cortical side of the spindle and are thus destined for the polar body. Third, there is functional asymmetry between the centromeres of homologous chromosomes, with selfish centromeres more likely to remain in the egg. Centromere drive depends on coupling these asymmetries. The spindle provides spatial cues indicating which side leads to the egg versus the polar body, and selfish centromeres interact with the spindle such that they preferentially orient away from the polar body and toward the egg.

For the past eight years, my colleagues and I have used mice to interrogate these dynamics, and have found that spindle asymmetry is indeed coupled with cell fate asymmetry. Previous studies had shown that activation of a GTPase called Ran, by GTP binding, is induced by chromosomes and creates a diffusible signal that the cortex detects, resulting in the cells polarization. Another GTPase, Cdc42, is enriched on the polarized cortex near the spindle. In 2017, we showed that the combination of spindle positioning, polarization-triggering Ran signaling, and Cdc42 signaling from the cortex back to the spindle leads to asymmetry within the spindle. This spindle asymmetry is based on differences in a post-translational modification of tubulin, the protein that makes up microtubules. The cortical side of the spindle is enriched for tyrosinated -tubulin, which contains a C-terminal tyrosine, while the egg side is enriched for detyrosinated -tubulin, from which the tyrosine has been removed by a peptidase. We tested the significance of this asymmetry in a hybrid mouse model made by crossing a strain that has larger centromeres with a strain that has smaller centromeres. When homologous chromosomes pair in female meiosis in the hybrid, larger and smaller centromeres compete for transmission to the egg. We showed that larger, selfish centromeres capitalize on the spindle asymmetry to preferentially orient toward the detyrosinated side destined for the egg.

Preferential orientation depends on the third asymmetry: functional differences between centromeres of homologous chromosomes. Selfish centromeres exploit the well-studied machinery that prevents segregation errors in every cell division. In mitosis, for example, centromeres of sister chromosomes can attach to the same spindle pole, an error that would lead to segregation of both sister chromosomes into one daughter cell. To correct the error before segregation can occur, microtubule destabilizing proteins at centromeres mediate detachment from spindle microtubules, providing an opportunity for one centromere to attach to the opposite pole. In 2019, we showed that selfish centromeres in hybrid mouse models recruit more of these destabilizers relative to the homologous chromosome. From the perspective of a selfish centromere, attachment to the cortical side of the spindle is detrimental because it leads to the polar body. The destabilizers resolve this issue by preferentially detaching the selfish centromere from tyrosinated microtubules and reorienting it toward the egg side.

During oogenesis, only one of the haploid cells created by meiosis survives. The others, called polar bodies, die. This sets up an opportunity for cheating, or nonrandom segregation, for example during the first round of meiosis when bivalents are split into paired chromosomes, as chromosomes with centromeres facing away from the cell cortex are retained in the future egg cell. One example of this is that larger centromeres hijack the machinery that attaches to the spindle, resulting in them facing away from the cortex preferentially (zoom).

The fitness costs to organisms of centromere drive are still unclear, but we expect that these costs depend on functional differences between the paired centromeres of homologous chromosomes: differential interaction of these centromeres with spindle microtubules, for example, may lead to segregation errors. Reducing these differences would reduce fitness costs to the organism.

Functional equalization of different centromeres could happen in two ways: by weakening the pathway selfish centromeres exploit to recruit destabilizing proteins, and/or by strengthening another recruitment pathway that is equal at all centromeres. Previous studies had shown that destabilizing proteins can be recruited both through kinetochores and through heterochromatin adjacent to the centromere. Our studies showed that selfish centromeres drive by amplifying the kinetochore pathway to recruit destabilizers, thus increasing functional differences. In contrast, heterochromatin is symmetric between centromeres of homologous chromosomes in our model systems, suggesting that this pathway makes centromeres more similar. These observations suggest that making the heterochromatin pathway dominant relative to the kinetochore pathway would suppress drive.

To test this idea experimentally in our hybrid mouse model system, we introduced a divergent variant of a centromere protein (CENP-C) that is rapidly evolving. We predicted that the divergent variant (taken from rat) would not interact optimally with mouse proteins involved in kinetochore formation, thereby weakening the kinetochore pathway. As a readout for functional asymmetry, we measured the position of the paired homologous chromosomes on the meiotic spindle. Chromosomes are positioned at the spindle equator when centromeres are functionally similar, as in a typical metaphase configuration, and off center when centromeres are functionally different. We found that chromosomes are positioned closer to the spindle equator when the kinetochore pathway is weakened, consistent with our prediction that the centromeres become functionally more similar. Conversely, when we weakened the heterochromatin pathway by knocking out the centromere protein CENP-B, which contributes to formation of heterochromatin near the centromere, we found that centromeres becamefunctionally more different (i.e., more off center).

Thus, there appear to be competing parallel pathways: the kinetochore pathway exploited by selfish centromeres, and the heterochromatin pathway that promotes equal segregation. This means that proteins in both pathways can evolve to suppress drive by either weakening the kinetochore pathway or strengthening the heterochromatin pathway. Consistent with this prediction, by comparing rodent genomes in our study, we found signatures of adaptive evolution in components of both pathways, suggesting that changes in multiple centromere proteins can suppress the costs of drive.

Our and other groups analyses are just beginning to probe the genetic conflict between selfish centromere DNA and rapidly evolving centromere proteins. We have experimental mouse model systems and a conceptual framework for drive and suppression, and we know which amino acid changes in centromere proteins have signatures of positive selection. We now face the challenge of designing experiments to dissect the functional consequences of these changes, which may be subtle. Meanwhile, other researchers are continuing to use monkeyflowers as a model system to study this conflict, taking advantage of the aforementioned natural variation and powerful population genetics. And these arent the only chromosomal loci that can drive: Loci such as the maize knobs provide opportunities to probe centromere-independent mechanisms of cheating in female meiosis and adaptations that suppress the associated fitness costs.

Microbial pathogens have evolved to exploit basic cellular processes, such as cytoskeletal dynamics, membrane trafficking, signal transduction, and the cell cycle, and studies of diverse pathogens have propelled many advances in cell biology. Similarly, investigating centromeres or other selfish loci as pathogens in the context of genetic conflict can provide a unique window into the biology of chromosome segregation and inheritance.

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Probing Selfish Centromeres Unveils an Evolutionary Arms Race - The Scientist

Cell Biology

Meet the 2023 Outstanding Graduating Students – UMaine News … – University of Maine

Twelve undergraduates have been named 2023 Outstanding Graduating Students at the University of Maine. Read their short biographies:

Mille Baartvedt of Oslo, Norway is the Outstanding Graduating International Student in the College of Education and Human Development. The kinesiology and physical education major is a Presidential Scholar. On campus, she has worked at the New Balance Student Recreation Center and as a teaching assistant, and been a member of the Maine chapter of Pi Beta Phi and the Womens Soccer Club. Baartvedt did her student teaching at Hampden Academy and Orono Middle School. She will pursue a graduate degree in sports management at Boston College, and plans a career as an educator and athletic director.

A full Q&A with Baartvedtis online.

Samantha Costanza from Norwalk, Connecticut is the Outstanding Graduating Student in the Division of Lifelong Learning. Costanza is a university studies major in the labor studies track, and an Online Flagship Scholarship recipient. Costanza has worked full-time as a communications professional for a national retirement company while pursuing an associate degree at a local community college, then transferring to UMaine. Her research as part of her academic work included how COVID impacted the union construction industry; how the legalization of marijuana has changed the landscape of workplace drug testing; and the pay gap and working conditions for women in many industries. Beyond her coursework, Costanza is active in her community choir. She plans to continue her now 23-year career with Transamerica.

A full Q&A with Costanza is online.

Emily Davison of North Waterboro, Maine is the Outstanding Graduating Student in the College of Education and Human Development. She is majoring in athletic training with a minor in child development and family relations. The UMaine Presidential Scholarship recipient also received the 2023 Eastern Athletic Trainers Association Joseph Abraham Scholarship and 2022 Maine Athletic Trainers Association Wes Jordan Scholarship. Davison did her athletic training internship this spring at Foxcroft Academy and has had numerous athletic training clinical experiences with athletics teams at UMaine, Husson University and Hampden Academy. On campus, she also worked in the UMaine Ticket Office. Davison plans to pursue a masters degree in sport management at the University of Central Arkansas while working full time as a high school athletic trainer. Her goal is to be an athletic director at a class AA high school in southern Maine.

A full Q&A with Davison is online.

Kell Fremouw of Orono, Maine is the Outstanding Graduating Student in the College of Engineering. The Honors College student is majoring in engineering physics, with a concentration in mechanical engineering and a minor in mathematics. Last summer, he was awarded a National Science Foundation Undergraduate Research Fellowship in Sensor Science and Engineering, and he has worked as a teaching assistant in physics. His honors thesis is: Thermal Stability of Platinum-Silicon Alloy Films Grown on Langasite Substrates for Use in Microwave Acoustic Sensor Technology. Fremouw has been a student researcher examining optical microscopy data in the laboratory of professor Samuel Hess and modeling graphene transistors in the laboratory of professor Sheila Edalatpour. In addition, Fremouw worked on a materials science project with professor Robert Lad. He also participates in STEM outreach with the Society of Physics Students. Fremouw is a competitive kayaker and canoeist who qualified in the U.S. trials for the Wildwater Canoeing World Championships. He has been awarded a Deans Fellowship for Excellence at the University of Colorado Boulder where he will pursue a Ph.D. in materials science and engineering. He plans to work in academia or in a lab on improving sustainable energy production and energy efficiency.

A full Q&A with Fremouw is online.

Anna Kahelin of Helsinki, Finland is the Outstanding Graduating International Student in the Maine Business School. She is a business administration major in management with a minor in psychology, and member of the Womens Basketball team. Kahelin received an America East Elite 18 award, and was a member of Team Maine from 202122. She plans to pursue an MBA at UMaine and play basketball for another year.

A full Q&A with Kahelin is online.

Abigail Mulligan of Thunder Bay, Ontario, Canada is the Outstanding Graduating International Student in the College of Liberal Arts and Sciences. Mulligan is an Honors College student triple-majoring in chemistry with a pre-med concentration; in food science and human nutrition, with a concentration in dietetics; and in zoology. She is minoring in psychology, sustainable food systems and neuroscience. Among her numerous honors is the Charles A. Brautlecht Scholarship, the S.P. Livermore Award, and the Dr. Melanie Gershman-Tewksbury 77 Scholarship. Her honors thesis is: The Development of Sustainable, Flax-Integrated, Plastic Composite. Mulligan has been a student researcher in professor William Gramlichs laboratory, studying the development of sustainable, flax-integrated biocomposites. She is president of the Nutrition Club, secretary of the UMaine chapter of Kappa Omicron Nu and a 4-H STEM Ambassador. Mulligan also has been a member of the UMaine Swimming and Diving team and was a peer tutor. She plans to attend medical school to pursue a career in pediatric neurosurgery.

A full Q&A with Mulligan is online.

Theophile Nkulikiyinka of Kigali, Rwanda is the Outstanding Graduating International Student in the College of Engineering. Nkulikiyinka, a biomedical engineering student, is a Presidential Scholar and the recipient of the International Presidential Scholarship. He has been an undergraduate researcher in the laboratory of professor Michael Mason, evaluating the potential of cellulose nanofiber as a biomaterial for bone replacement. His academic experiences off campus included shadowing at Hanger Orthotics and Prosthetics Clinic, and working as a cardiac technician at Northern Light Health and a direct support professional for adults with disabilities at MERT Enterprises and Peace Residential Care. Nkulikiyinka is president of UMaines African Student Association. He plans to pursue a masters degree in prosthetics and orthotics at the University of Hartford.

A full Q&A with Nkulikiyinka is online.

Shelby Philips of Buffalo, New York is the Outstanding Graduating Student in the Maine Business School. Philips is a business administration major in management. Her numerous academic awards include the Senior Alumni Non-Traditional Student Scholarship, the Carville Non-Traditional Student Scholarship, and David and Debra Scott Scholarship. Philips interned with Food Rescue Maine, an initiative of the Senator George J. Mitchell Center for Sustainability Solutions, and served as president of MBS Corps. She also was a member of SPIFFY and the International Business and Culture Club, and was a cast member in the School of Performing Arts production of Everybody. This summer, she will be a producer on an independent feature film. Philips plans to pursue a career in management.

A full Q&A with Philips is online.

Aiden Pike of Searsmont, Maine is the Outstanding Graduating Student in the College of Natural Sciences, Forestry, and Agriculture. He is a double major in biochemistry, and molecular and cellular biology, with minors in French and chemistry. The Honors College student, who will receive two bachelors degrees, also is in the 4+1 masters bioinformatics program with the Roux institute at Northeastern University. His numerous academic honors include a Visual and Performing Arts Scholarship, the Professor Frederick H. Radke Award and the Honors INBRE Thesis Fellowships in Comparative Functional Genomics. His honors thesis is: The Role of Calmodulin-Dependent Protein Kinase IV in Regulating JC Polyomavirus Infection. Pike has been a student researcher in professor Melissa Maginnis laboratory, studying how the immune response is implicated in JC polyomavirus infection and the signaling mechanisms that the virus may take advantage of to gain control of the host cell. He also spent a summer as a research fellow at MDI Biological Laboratory. On campus, Pike has been a teaching assistant and a course facilitator, and a member of the Pride of Maine Black Bear Marching Band and the Concert Band. With the completion of his masters degree, Pike plans to apply to an M.D./Ph.D. program to study infectious diseases and practice translational medicine.

A full Q&A with Pike is online.

Elaine Thomas of Hampden, Maine is the Outstanding Graduating Student in the Honors College. She is a business administration major in management with a minor in music. The Honors College student received the 2022 John M. Rezendes Ethics Award for her first-place essay: When We Cannot Care for Ourselves: Ethics, Interdependence, and the Moral Danger of the Self-Care Message. Also in 2022, she received the Maine Campus Compact PILLARS (Philanthropy, Innovation, Learning, Leadership, Action, Responsibility, and Service) Award and participated in the Maine NEW (National Education for Women) Leadership program. Her honors thesis is: Evidence-based Family Strengthening Training in Maine: A Resource Assessment and Proposal to Reduce Barriers and Increase Facilitators. Throughout her time at UMaine, Thomas has been a member of the Attachment Theory Team of the Honors College Servant Heart Research Collaborative. She also has interned with three nonprofit organizations: Heart of Maine United Way, Partners for Peace and the American Red Cross, and donates her time to Literacy Volunteers of Bangor. Thomas plans to work for a nonprofit organization in Maine.

A full Q&A with Thomas is online.

Maria Vina Lopez of Santiago de Compostela, Spain is the Outstanding Graduating International Student in the College of Natural Sciences, Forestry, and Agriculture, and in the Honors College. The biology major with a minor in mathematics is the recipient of numerous awards, including the International Presidential Scholarship and a Center for Undergraduate Research Fellowship. Her honors thesis is: An Organoid Model for Human Brain Aging. As a student researcher, Vina Lopez studied the drug synergy effect of fluconazole and cyclosporine A on Candida albicans in the laboratory of professor Robert Wheeler, and used C. elegans to study the effect of novel small molecule combinations on age reversal in vivo and identify life span-extending cocktails in professor Suzanne Angelis lab. For two summers, she also was a research intern in the microbiology laboratory of professor Darren Higgins at Harvard Medical School, and for eight months last year, collaborated on her honors research in the genetics laboratory of professor David Sinclair, also at Harvard Medical School. At UMaine, Vina Lopez has been president of Engineers Without Borders, a resident assistant, a Maine Learning Assistant and peer tutor in genetics, and a member of the University Volunteer Ambulance Corps. She plans to pursue a Ph.D. in biological and biomedical sciences at Harvard Medical School.

A full Q&A with Vina Lopez is online.

Willow Wind of Rumford, Maine is the Outstanding Graduating Student in the College of Liberal Arts and Sciences. The Honors College student is a communication major with minors in media studies and Spanish. Her academic honors include a McGillicuddy Humanities Center Fellowship and James S. Stevens Outstanding Junior Award, both in 2022, and a 2021 Center for Undergraduate Research Fellowship Award and first-place recognition the Communication and Journalism Showcase for her research project: Communication Goals and Practices of Trans- and Gender Non-conforming (TGNC) Individuals and Their Impact on Mental Health. Her Honors thesis is: Conceptualizing and Enacting Gender Euphoria: Exploring Awareness and Action Across Gender Demographics. Wind has conducted research in collaboration with professor Liliana Herakova, focused on trans and gender-nonconforming communication and mental health, and as a research assistant in the Media Psychology Lab of professor Amelia Couture Bue, working on a project exploring the desirability of STEM to college women. She also has been active in the Scholars Strategy Network, Progressive Pipeline, and Partners for Peace, and in a UMaine collaborative effort to improve classroom belonging. Wind plans to pursue nonprofit advocacy work and a masters degree.

A full Q&A with Wind is online.

Contact: Margaret Nagle, nagle@maine.edu

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Meet the 2023 Outstanding Graduating Students - UMaine News ... - University of Maine

Cell Biology

The Worlds Sexiest Fragrance Unveiled, But Its Not For You – Revyuh

Pheromones are intricate chemical compounds that organisms produce and emit as a form of communication. They enable members of the same species to transmit messages, including signaling their search for a mate.

To mimic the signals of female insects, farmers can place pheromone dispersers among their crops, which either trap or distract male insects from finding a mate.

While some of these molecules can be produced by chemical methods, chemical synthesis often generates harmful byproducts and incurs high expenses.

Researchers at the Earlham Institute in Norwich have used precision gene engineering techniques to transform tobacco plants into solar-powered factories that produce moth sex pheromones.

The key feature is that the scientists have demonstrated how these molecules can be produced without hindering the normal growth of the plant.

The Synthetic Biology Group, headed by Dr Nicola Patron at the Earlham Institute, employs advanced techniques to enable plants to produce highly valuable natural products. Through the principles of synthetic biology, the team constructs genetic modules that provide instructions to produce new molecules, which ultimately transforms plants such as tobacco into highly efficient factories. These plants merely require access to sunlight and water to carry out the production process.

Synthetic biology, as explained by Dr. Tatron, can allow us to engineer plants to make a lot more of something they already produced, or we can provide the genetic instructions that allow them to build new biological molecules, such as medicines or these pheromones.

The research team collaborated with scientists at the Plant Molecular and Cell Biology Institute in Valencia to genetically engineer Nicotiana benthamiana, a species of tobacco, to produce moth sex pheromones. This plant has previously been modified to produce Ebola antibodies and even coronavirus-like particles for use in COVID-19 vaccines. The group created new DNA sequences in the laboratory to imitate the genes of moths and added a few molecular switches to regulate their expression precisely, turning the manufacturing process on and off as needed.

A crucial aspect of the recent study was the capacity to adjust the production of pheromones, as forcing plants to constantly produce these molecules can have negative consequences.

As we increase the efficiency, too much energy is diverted away from normal growth and development, adds Dr. Patron.

The plants are producing a lot of pheromone but theyre not able to grow very large, which essentially reduces the capacity of our production line.

This new study provides a way to regulate gene expression with much more subtlety.

The team conducted experiments in the laboratory to test and improve the regulation of genes responsible for generating a mixture of particular molecules that imitate the sexual pheromones of moth species, such as cotton bollworm and navel orangeworm moths.

Through their research, they demonstrated that copper sulfate could be utilized to precisely adjust the behavior of these genes, enabling them to manage both the extent and timing of gene expression.

This is especially significant since copper sulfate is a cost-effective and easily accessible substance that has already been approved for agricultural use. Moreover, they were able to meticulously regulate the production of diverse pheromone components, which enabled them to modify the combination to better match specific moth species.

Weve shown we can control the levels of expression of each gene relative to the others, points out Dr. Patron. This allows us to control the ratio of products that are made.

Getting that recipe right is particularly important for moth pheromones as theyre often a blend of two or three molecules in specific ratios. Our collaborators in Spain are now extracting the plant-made pheromones and testing them in dispensers to see how well they compare to female moths.

The team aims to establish a pathway for using plants as a standard method for producing an extensive variety of valuable natural products.

A major advantage of using plants is that it can be far more expensive to build complex molecules using chemical processes, adds Dr. Patron. Plants produce an array of useful molecules already so were able to use the latest techniques to adapt and refine the existing machinery.

In the future, we may see greenhouses full of plant factories providing a greener, cheaper and more sustainable way to manufacture complex molecules.

The findings were published in the journalPlant Biotechnology.

Image Credit: Getty

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The Worlds Sexiest Fragrance Unveiled, But Its Not For You - Revyuh

Cell Biology

City of Hope appoints John D. Carpten, Ph.D., as director of its … – BioSpace

LOS ANGELES, April 6, 2023 /PRNewswire/ --City of Hope, one of the largest cancer research and treatment organizations in the United States, today announced the appointment of John D. Carpten, Ph.D., as director of the National Cancer Institute-designated comprehensive cancer center, director of Beckman Research Institute of City of Hope and chief scientific officer. Carpten will also hold the Irell & Manella Cancer Center Director's Distinguished Chair and the Morgan & Helen Chu Director's Chair of the Beckman Research Institute. Carpten will provide overall executive leadership and strategic direction for research at City of Hope. He joins City of Hope from the University of Southern California (USC), where he was professor and chair of the Department of Translational Genomics at the Keck School of Medicine of USC and associate director of the cancer center.

John Carpten to direct City of Hope Comprehensive Cancer Center and its Beckman Research Institute

"We are excited to welcome Dr. Carpten to City of Hope and look forward to his leadership in advancing the research mission of our growing national cancer research and care system," saidRobert Stone, City of Hope's CEO and Helen and Morgan Chu Chief Executive Officer Distinguished Chair. "Dr. Carpten's expertise and unwavering commitment to drive and accelerate cancer research and discovery will benefit our patients across the country."

Carpten is an internationally recognized expert in genome science, with training in multiple disciplines, including germline genetics for disease risk and predisposition, somatic cancer genomics, health disparities research, cell biology, functional genomics and precision medicine. Prior to USC, he served as director of the Division of Integrated Cancer Genomics, and later, deputy director of Basic Research at Translational Genomics Research Institute, now a part of City of Hope. Earlier in his career, Carpten completed a postdoctoral fellowship at the National Human Genome Research Institute (part of the National Institutes of Health) in cancer genetics, where he was later promoted to the tenure track in 2000. Carpten earned his Ph.D. from The Ohio State University in 1994, with a focus on human genetics.

Nationally recognized as a leader in health disparities research, he has been a tireless advocate for reaching underserved populations. Carpten has been a pioneer in the understanding of the role biology plays in disparate cancer incidence and mortality rates experienced by underrepresented populations. As such, his work has impacted our understanding of a variety of cancer types, particularly those that disproportionately affect underrepresented minorities, including prostate cancer, breast cancer, colorectal cancer, multiple myeloma and pediatric cancers.

Carpten has also played a significant role in the national cancer research agenda and has won numerous awards. He has served as a member of the National Cancer Institute (NCI) Board of Scientific Counselors. In 2019, he served as Program Committee chair for the American Association of Cancer Research (AACR) Annual Scientific Conference in Atlanta, which included over 21,500 international participants. In 2021, he was inducted into the AACR Fellows of the Academy.Appropriately, in 2022, President Joe Biden appointed Carpten as the first African-American chair of the National Institutes of Health's National Cancer Advisory Board, a distinguished post that helps set the national cancer research policy agenda.

"Dr. Carpten will be a key catalyst in driving the democratization of cutting-edge cancer care across the City of Hope national network in order to ensure more patients and diverse communities have full access to the leading cancer research, treatment and care they need," said Michael A. Caligiuri, M.D., president of City of Hope National Medical Center and the Deana and Steve Campbell Physician-in-Chief Distinguished Chair. "He has been a leading national voice and expert in ending disparities in cancer outcomes and care, and the importance of building a more diverse workforce in cancer research."

"Along with tremendous honor and humility, I am both thrilled and eager to work with the exceptional leadership, faculty, staff and trainees to build upon the significant success of the research enterprise at City of Hope," said Carpten. "My goal is to create, execute and advance a transformative vision for cancer research that aligns with national priorities to significantly reduce cancer mortality rates and improve outcomes for patients from all walks of life through the unique national patient reach of City of Hope. To have the opportunity to help lead this world-class, translational cancer research platform is a dream come true."

As part of this transition, City of Hope's current provost, chief scientific officer, and Beckman Research Institute and cancer center director, Steven T. Rosen, M.D., will step into a new leadership role as executive vice president and director emeritus of Beckman Research Institute and City of Hope's cancer center, continuing to improve the lives of cancer patients through his research and patient care, and his dedication to building coalitions among like-minded organizations and individuals dedicated to preventing and curing cancer. During his decade-long tenure, Rosen has made countless contributions to faculty recruitment, research and treatment advances in the field, to the growth and reach of City of Hope, to the education, development and mentorship of faculty and staff, and to guiding City of Hope as one of only 53 NCI-designated comprehensive cancer centers, most recently earning an "exceptional" rating by the NCI in the 2023 renewal of this designation.

"City of Hope and the countless patients he has so positively impacted owe a tremendous debt of gratitude to Dr. Rosen for all he has done to advance science and research at City of Hope and save lives," said Caligiuri. "We will benefit tremendously from Dr. Rosen's continued leadership and expertise through this transition and into the future."

About City of Hope

City of Hope's mission is to deliver the cures of tomorrow to the people who need them today. Founded in 1913,City of Hopehas grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis fornumerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center at its core,City of Hope brings a uniquely integrated model to patients spanning cancer care, research and development, academics and training, and innovation initiatives. City of Hope's growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, andtreatment facilities in Atlanta, Chicago and Phoenix. City of Hope's affiliated group of organizations includesTranslational Genomics Research InstituteandAccessHopeTM. For more information about City of Hope, follow us onFacebook,Twitter,YouTube,InstagramandLinkedIn.

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SOURCE City of Hope

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City of Hope appoints John D. Carpten, Ph.D., as director of its ... - BioSpace

Cell Biology

Modernized Algorithm Predicts Drug Targets for SARS-CoV-2, Other … – GenomeWeb

NEW YORK Researchers in Germany have modernized an aging computational tool for metabolomics and built a new workflow for predicting drug targets to fight SARS-CoV-2. While the COVID-19 pandemic may be winding down, the developers believe the technology can help manage the disease as it becomes endemic and be applied to other RNA viruses.

The method, called pymCADRE, represents an update to a 2012 method called mCADRE, but it is written in the more widely used Python programming language. The researchers then paired it with an algorithm called PREDICATE for Prediction of Antiviral Targets which is based on a method developed by Sean Aller and colleagues at the University of Warwick and at the UK's Defence Science and Technology Laboratory.

The combined workflow enables the creation of metabolic models and analysis of viral biomass functions to predict antiviral targets for host organs using multiple genomes. Viruses, including SARS-CoV-2, have to draw on metabolic resources from host cells in order to replicate in the body.

"Our tool predicts exploitable cellular metabolic pathways that can be inhibited to suppress virus replication with minimal or no effect on the cell," computational biologists at Eberhard Karls University of Tbingen in Germany wrote in a recent paper in PLOS Computational Biology that described both updated algorithms and the combined workflow.

While scientists worldwide were able to develop messenger RNA and viral vector COVID-19 vaccines in record time, the Tbingen group noted that immunity to viral infections wanes over time and vaccines cannot keep up with later mutations. "Hence, effective pandemic preparedness requires discovering broadly acting antivirals with high resistance barriers," they wrote.

The Tbingen researchers chose to adapt mCADRE short for metabolic Context-specificity Assessed by Deterministic Reaction Evaluation because the transcriptomic data of host cells they had at the start of their work fit mCADRE, according to lead author Nantia Leonidou, a PhD student in bioinformatics at the university. Leonidou began the pymCADRE work as part of her thesis for a master's degree she received in 2020.

The group decided to update mCADRE by translating it to the open-source Python language to make it more accessible because Python is more widely used by bioinformaticians mCADRE was written in Matlab, a proprietary language that dates to the 1970s.

"It's nice to see it updated. It makes it more usable," said Nathan Price, one of the developers of mCADRE. "That will make the method more broadly used again."

The pymCADRE and PREDICATE combination workflow looks at metabolic networks and viral genome sequences to predict "robust druggable targets" to fight emerging RNA viruses, as SARS-CoV-2 was when the project started, according to the PLOS Computational Biology article.

With these algorithms, the University of Tbingen team was able to build a metabolic network of primary bronchial epithelial cells that had been infected with the then-novel coronavirus. They subsequently identified "promising" targets in purine metabolism and uncovered evidence of viral inhibition in pyrimidine and carbohydrate metabolism.

"We put everything together to be able to create multiple viral biomass reactions at the time," such as for multiple sequences and multiple variants, Leonidou said. "We try to see what metabolic changes happen" after infection, she said.

The PREDICATE software also provided in silico verification of the targets for all five SARS-CoV-2 variants of concern that the World Health Organization had designated by the time the paper was submitted for publication in July 2022.

Price, who was affiliated with the Institute for Systems Biology in Seattle and with the University of Illinois at the time he worked on mCADRE, said that it was "interesting" that the German team is looking at viral replication because he and his colleagues were not involved in target discovery in the early 2010s.

"The more that we can understand the processes behind viral replication, [the more we can] understand the weaknesses that might be able to be exploited as a drug target for their specific needs to achieve this replication," said Price, who is now CSO of Thorne HealthTech, a data-driven wellness and nutritional supplements company.

Leonidou said that pymCADRE is "fully transferable and applicable to any RNA virus," and PREDICATE can be used to create multiple viral biomass reactions. This makes the technology useful for the next viral epidemic, or even for investigating coronaviruses linked to the common cold. A preprint manuscript by some of Leonidou's colleagues, for instance, tests the pipeline on theinfluenzaAanddengueviruses.

As it stands now, though, pymCADRE is not suitable for bacterial diseases because bacteria have their own metabolic systems and are not dependent on a host.

But Leonidou noted that her team is building models to simulate bacterial metabolism because the epidemiologic world "kind of forgot antibacterial resistance" during the COVID-19 pandemic, which could be a recipe for disaster in the future. "Maybe the next pandemic is not viral [but] bacterial," she said.

Leonidou said that it is too soon to think about commercializing the pymCADRE and PREDICATE technology, though her team at Tbingen has some academic and pharmaceutical industry partners who are working on medicinal chemistry, pharmacokinetics, and pharmacogenomics applications of the workflow in silico and with mouse models. She declined to name any of those partners because their work has not been published.

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Cell Biology

BU researcher wins $3.9 million NIH grant to develop novel therapeutic modalities for Alzheimer’s – News-Medical.Net

Julia TCW, PhD, assistant professor of pharmacology & experimental therapeutics at Boston University Chobanian & Avedisian School of Medicine, has received a five-year, $3.9 million grant from the National Institutes of Health's (NIH) National Institute on Aging. The award will fund her research project, "Elucidating endolysosomal trafficking dysregulation induced by APOE4 in human astrocytes."

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, affecting more than 5.8 million individuals in the U.S. Scientists have discovered some genetic variants that increase the risk for developing Alzheimer's; the most well-known of these, for people over the age of 65, is APOE4.

"APOE4 is the major genetic risk factor for Alzheimer's disease, however we do not fully understand how APOE4-driven endolysosomal trafficking defects influence disease risk in human AD brain cells. The goal of this project is to understand the molecular mechanisms of APOE4 and identify targets that can reverse the phenotype," says TCW, who also is a director of the Laboratory of Human Induced Pluripotent Stem Cell Therapeutics.

One of the important questions is whether these endolysosomal pathway genes reveal novel mechanistic defects that can be targeted for therapeutics.

Human induced pluripotent stem cells (iPSC) model application, and the knowledge gained from this proposal, will be essential to the development of novel AD therapeutic modalities."

Julia TCW, PhD, assistant professor of pharmacology & experimental therapeutics at Boston University Chobanian & Avedisian School of Medicine

TCW received her PhD and AM in molecular and cellular biology from Harvard University. She then pursued her postdoctoral research in the department of neuroscience at the Ronald M. Loeb Center for Alzheimer's Disease at Icahn School of Medicine at Mount Sinai, New York. Subsequently she served there as research faculty in the department of genetics and genomic sciences and neuroscience where her research focus was on the development of iPSC models and AD genetics.

In addition to this grant, TCW has been awarded the Druckenmiller Fellowship award from New York Stem Cell Foundation, a K award from the National Institutes of Health-National Institute of Aging, a BrightFocus Foundation grant, and was named a 2022 Toffler Scholar by the Karen Toffler Charitable Trust.

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BU researcher wins $3.9 million NIH grant to develop novel therapeutic modalities for Alzheimer's - News-Medical.Net