Category Archives: Cell Biology

Cell Biology

Repairing spinal cord injuries with a protein that regulates axon regeneration – FierceBiotech

When the axons that extend from neurons break during a spinal cord injury, the result is often a lifelong loss of motor functioning, because vital connections from the brain to other body parts cannot be restored. Now, researchers from Temple Universitys Lewis Katz School of Medicine say they may have found a way to recover some functions lost to axon breaks.

The researchers discovered that boosting levels of a protein called Lin28 in injured spinal cords of mice prompts the regrowth of axons and repairs communication between the brain and body. Lin28 also helped repair injured optic nerves in the animals, they reported in the journal Molecular Therapy.

The Temple team zeroed in on Lin28 because its a known regulator of stem cells, meaning it controls their ability to differentiate into various cells in the body. The researchers examined the effects of Lin28 on spinal cord and optic nerve injuries using two mouse models: one that was engineered to express extra Lin28 and another that was normal and was given the protein after injury via a viral vector.

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All of the mice experienced axon regeneration, the researchers reported. But they found that the best results occurred in the normal mice that received Lin28 injections post-injury. In fact, in animals with optic nerve injuries, the axons regrew to the point where they filled the entire tract of the nerve.

Lin28 treatment after injury improved coordination and sensation in the mice, the researchers reported.

"We observed a lot of axon regrowth, which could be very significant clinically, since there currently are no regenerative treatments for spinal cord injury or optic nerve injury," said senior author Shuxin Li, M.D., Ph.D., professor of anatomy and cell biology at the Lewis Katz School of Medicine, in a statement.

RELATED: Gene therapy with 'off switch' restores hand movement in rats with spinal cord injury

Lin28 is already a target of interest, though it has garnered the most attention so far in cancer research. Startup Twentyeight-Seven Therapeutics is developing a small molecule that inhibits the protein in the hopes that doing so will boost Let-7, a cancer-suppressing microRNA. The company raised more than $82 million in a series A financing last year.

Several new approaches for repairing spinal cord injuries are under investigation, most notably gene therapy. King's College researchers are working on a gene therapy that repairs axons by prompting the production of the enzyme chondroitinase. A UT Southwestern team is targeting the gene LZK to increase levels of supportive nervous system cells called astrocytes in response to spinal injuries.

The Temple team has a two-pronged approach to further developing their Lin28-directed treatment. They hope to develop a vector that can be safely delivered by injection and that would deliver the therapy directly to damaged neurons. They also plan to study other molecules in the Lin28 signaling pathway.

"Lin28 associates closely with other growth signaling molecules, and we suspect it uses multiple pathways to regulate cell growth," Li said, potentially revealing other therapeutic molecules that could further boost neuron repair.

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Repairing spinal cord injuries with a protein that regulates axon regeneration - FierceBiotech

Cell Biology

USC Professor Andrew P. McMahon elected to the National Academy of Sciences – USC News

Andrew P. McMahonwho is the W.M. Keck Provost and University Professor in USCs departments of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine, and Biological Sciences at the Dornsife College of Letters, Arts and Scienceshas been elected as a new member of the National Academy of Sciences in honor of his outstanding contributions to developmental biology. The National Academy of Sciences brings together nearly 3,000 leading researchers to provide objective, science-based advice on critical issues affecting the nationin accordance with an Act of Congress approved by President Abraham Lincoln in 1863.

Were delighted that Dr. McMahon is being recognized as a newly elected member of the National Academy of Sciences, said Dean Laura Mosqueda from the Keck School. Because new members are elected by current members, this represents recognition of Dr. McMahons achievements by his most esteemed peers in all scientific fields.

Being elected to the National Academy of Sciences is one of the highest honors that can be bestowed upon a scientist. Dr. McMahon has had a truly remarkable career in the field of developmental biology. This honor is well deserved. We are proud of Dr. McMahons accomplishments and of his contributions to research and education at USC, said USC Provost Charles F. Zukoski.

McMahons group is well-known for identifying key signals coordinating cell interactions directing the assembly, composition and functional organization of mammalian organ systems. This research led to the founding of a biotechnology startup and the first drug treatment for an invasive form of skin cancer.

Currently, the McMahon Lab has narrowed its focus from multiple organ systems to a single, exquisitely complex organ: the kidney. With one in 10 people worldwide affected by chronic kidney disease, McMahon has a pragmatic desire to advance stem cell research in response to this medical need.

His lab has uncovered detailed genetic and molecular clues about how developing kidneys form, as well as how adult kidneys respond to injury and disease. These discoveries inform efforts to build synthetic mini kidneys, called organoids, that can be used to study disease, identify potential drug therapies, and eventually provide functional tissue for transplantation.

McMahon laid the groundwork for his career in developmental biology when he was still a high school student in the United Kingdom, studying for his university entrance exams.

The great thing about sitting the exam for Oxford University was that it excused me from taking the regular classes at school and allowed me to just read things that I thought were interesting, he said. So I started reading books about how our genes worked.

During his undergraduate studies at Oxford University, McMahon became fascinated by how genes orchestrated the intricate process of human embryonic development.

Im always looking for answers to what I consider to be the most interesting question of all, said McMahon. How do our genes direct one cell, the egg, to generate the remarkable diversity of different cell types in our bodies?

He continued this line of inquiry during his PhD studies at University College London, and his postdoctoral training at the California Institute of Technology. He started his independent research career at the National Institute for Medical Research in London, then moved to the Roche Institute for Molecular Biology, before joining the faculty at Harvard University in 1993.

After a nearly 20-year career at Harvard, McMahon joined USC as the Director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research in 2012. He established a new Department of Stem Cell Biology and Regenerative Medicine, which he chairs, and recruited a large cohort of early-career scientists at the start of their faculty careers.

In addition to his most recent accolade from the National Academy of Sciences, McMahon is an elected fellow of the American Association for the Advancement of Science, the American Academy of Arts and Sciences, the European Molecular Biology Organization, and the Royal Society.

His group has published more than 300 primary research articles, and 22 US patents and 30 foreign patents have been issued around his research.

It may be a clich, but its true: this recognition is really a recognition of the many talented students, postdoctoral fellows and research staff I have been privileged to work with at several institutions throughout my career, said McMahon. I am glad my good fortune continues at USC.

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USC Professor Andrew P. McMahon elected to the National Academy of Sciences - USC News

Cell Biology

Sweden Bucked Conventional Wisdom, and Other Countries Are Following – National Review

A man wearing a protective face mask walks near people sitting on the stairs at the Royal Dramatic Theater during the coronavirus outbreak in Stockholm, Sweden April 22, 2020. (TT News Agency/Janerik Henriksson via Reuters)No lockdown, no shuttered businesses or elementary schools, no stay-at-home. And no disaster, either.

Spring is in the air, and it is increasingly found in the confident step of the people of Sweden.

With a death rate significantly lower than that of France, Spain, the U.K., Belgium, Italy, and other European Union countries, Swedes can enjoy the spring without panic or fears of reigniting a new epidemic as they go about their day in a largely normal fashion.

Dr. Mike Ryan, the executive director of the World Health Organizations Emergencies Program, says: I think if we are to reach a new normal, I think in many ways Sweden represents a future model if we wish to get back to a society in which we dont have lockdowns.

The Swedish ambassador to the U.S., Karin Ulrika Olofsdotter, says: We could reach herd immunity in the capital of Stockholm as early as sometime in May. That would dramatically limit spread of the virus.

A month ago, we first wrote about Swedens approach, which we said relies more on calibrated precautions and isolating only the most vulnerable than on imposing a full lockdown.

A fortunate constellation of circumstances ensured that Dr. Anders Tegnell, the chief epidemiologist of Sweden, was in charge of that countrys response to the COVID-19 pandemic, despite the misgivings of many Swedish politicians and foreign observers. Tegnell heroically bucked the conventional wisdom of every other nation and carefully examined the insubstantial evidence that social-isolation controls would help reduce COVID-19 deaths over the full course of the virus.

As Tegnell told NPR in early April: Im not sure that there is a scientific consensus on, really, about anything when it comes to this new coronavirus, basically because we dont have much evidence for any kind of measures we are taking.

Well, a month later we now know more.

Myth No. 1: Swedens policy was not carefully thought out or well considered.The number of cases in Sweden and other countries is still rising, but in Sweden one-third of intensive-care beds remain empty. Tegnell has looked at other nations that are loosening their lockdowns. To me it looks like a lot of the exit strategies that are being discussed look very much like what Sweden is already doing, he told Canadas Globe & Mail.

Tegnell and his colleagues recognized that the decision to shut down a country was not solely a medical decision based only on the virus The economic costs and health impacts caused by lockdowns are enormous, they realized, so they factored into their analysis the broader societal effects of any restrictions. The saw, for instance, that there is no evidence that children easily transmit the virus. Tegnell told NPR:

We look at other consequences for public health, like closing schools. That causes enormous problems, not least for the health of the children. I mean, children that already are disadvantaged, if you close down the schools, this is the one good thing they have sometimes in life. This is where they get their food. This is where they get their social context. So closing schools is not a good thing.

Jan Albert, a professor in the Department of Microbiology, Tumor, and Cell Biology at Swedens Karolinska Institute, told CNN that strict lockdowns only serve to flatten the curve, and flattening the curve doesnt mean that cases disappear they are just moved in time. He added: And as long as the health-care system reasonably can cope with and give good care to the ones that need care, its not clear that having the cases later in time is better.

Myth No. 2: Sweden did much worse than the U.S. or other countries in managing COVID-19 cases and deaths.Sweden has about 2,200 reported COVID-19 cases per million population. This is lower than the number in the U.S. (3,053 per million), the U.K., France, Spain, Italy, and also lower than in many other EU countries. Its slightly above the number in Germany, which has been hailed for its approach to the virus.

Sweden has 265 reported COVID-19 deaths per million population. That is somewhat higher than in the U.S. (204 per million) but lower than the number in many other EU countries.

Tegnell admits that his country failed to contain the initial outbreak in crowded senior homes. Something like 50 percent of our death toll comes from the rather small population living in care homes, he said. We know that we have had a problem with the elderly homes, this has been a discussion for years.

As elsewhere, Swedish COVID-19 deaths are overwhelmingly among the frail elderly and those with serious chronic disease. Over half of Swedish deaths are in nursing homes. Of those who died, 90 percent were over 70 and half were over 86, with just 1 percent younger than 50.

It is ironic that half of the Swedish deaths are in people over the age of 86. Life expectancy in Sweden is 83, whereas its 79 in the U.S., so it isnt surprising that there are relatively more frail elderly in Sweden. Out of every 100,000 births, about 10,000 more Swedes are still alive at age 85 than Americans are, so Swedens slightly higher COVID-19 death rate, compared with ours, mostly reflects the fact that a larger percentage of Swedes live well past 79.

So, on an age-adjusted basis, Sweden has done significantly better than the U.S. in terms of both cases per million and deaths per million and with no lockdowns.

Myth No. 3: Swedens relatively low number of intensive-care beds would spell disaster for its response to the virus.Initially, the main justification for the global lockdowns was that they were necessary to prevent a crush of patients from overwhelming hospital intensive-care units. But Sweden has shown that shutting down the economy and essentially imprisoning the young and healthy are not necessary to avoid ICU overcrowding. Despite no lockdowns and few social-isolation controls other than proper spacing in restaurants and a ban on gatherings of more than 50 people, the Swedish hospital system never experienced anything remotely like the crush of ICU patients in Italy, Spain, and New York City. Swedens ICU COVID-19 patient census (updated nationwide daily) peaked in early April, with about 50 new admissions daily. Now it is gradually declining to about 35 new ICU cases a day.

Unlike its Nordic neighbors and everywhere else, Sweden doesnt have to worry about when to reintroduce its vulnerable isolated population to social mixing and risk their exposure to the virus. That has been already happening naturally and has generated a defensive reservoir of population viral resistance to COVID-19 that puts it just like SARS, MERS, and the seasonal flu in Swedens rearview mirror.

Sweden doesnt have to worry about when and how to end social isolation. They dont have to decide who to keep locked down and who to let out. They dont have to get into civil-liberty arguments over involuntary restrictions or whether to fine people for not wearing masks and gloves.

Of course, Sweden paid a price during the pandemic. But whatever price the Swedes paid for their COVID-19 policy, they will tell you it was worth it. And it is easy to figure out that price. They never cratered their economy or blocked nonemergency surgeries. They had more deaths than their Nordic neighbors, but nothing even close to the 650 deaths per million the U.S. suffered during the 1968 Hong Kong flu, a pandemic that was handled with few social-isolation controls and no lockdowns.

Now many countries and U.S. states are beginning to follow Swedens lead. But California and other states continue to pile up isolation-induced health costs and blow gigantic holes in their budgets with lockdowns that, nationwide, have generated more than 30 million newly unemployed.

John Fund is a columnist for National Reviewand has reported frequently from Sweden. Joel Hay is a professor in the department of Pharmaceutical Economics and Policy at the University of Southern California; the author of more than 600 peer-reviewed scientific articles and reports, he has collaborated with the Swedish Institute for Health Economics for nearly 40 years.

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Sweden Bucked Conventional Wisdom, and Other Countries Are Following - National Review

Cell Biology

Scientists of the future at the 15th European Conference on Fungal Genetics – On Biology – BMC Blogs Network

Aspergillus fumigatus colony growth perturbed upon drug exposure. Are lncRNAs involved in antifungal drug response? (photo credit: Darren Thomson)

One of the greatest threats facing global wheat production is the disease, Septoria tritici Blotch, which is caused by the fungus Zymoseptoria tritici. In Europe alone, Z. tritici is responsible for up to 700 million worth of wheat yield loss annually, and an estimated 70% of the total annual fungicide usage is targeted against it. Z. tritici can rapidly evolve resistance in the field and so novel management strategies are urgently required.

Circadian clocks are molecular machineries which are entrained by environmental signals, such as light and temperature, and which regulate key life processes. The aim of this project is to understand whether the circadian clock regulates pathogenicity and development in Z. tritici.

Z. tritici is responsible for up to 700 million worth of wheat yield loss annually, and an estimated 70% of the total annual fungicide usage is against it, with consequent risk of resistance.

Our initial results demonstrated that Z. tritici can detect light, and that this signal influences vegetative growth. We therefore hypothesised that light could be a primary input which regulates the circadian clock of the pathogen.

In the model fungus Neurosopora crassa, the circadian clock is encoded by the three genes white collar-1 (wc-1), white collar-2 (wc-2) and frequency (frq). Our bioinformatic analyses identified homologs in Z. tritici to all three of the N. crassa genes, and these were designated ztwco-1, ztwco-2 and ztfrq. Yeast-two hybrid assays demonstrated that the ZTWCO-2 and ZTWCO-2 proteins interact; a result which is also similar to observations from N. crassa.

In order to understand the role of the putative circadian clock genes in Z. tritici, we generated deletion mutants. Our results to date show that deletion of some of these candidate genes causes defects in vegetative growth, but that the mutants are still able to infect the wheat host.

This is the first in-depth study of the circadian clock in Z. tritici, and our findings open up multiple avenues for future investigation. The long-term aim of this research is to inform future control strategies against Z. tritici, such as timing of fungicide application and identification of novel targets for future fungicide screens.

Anna Tiley is a Government of Ireland Postdoctoral Fellow based in the School of Agriculture and Food Science at University College Dublin, Ireland. She holds a degree in Biological Science from the University of Oxford, and a PhD in Molecular Plant Pathology from the University of Bristol. Anna has over seven years experience working with the wheat pathogen Zymoseptoria tritici, and her research focuses on the genetic basis of development and pathogenicity in this species. Follow on Twitter @tileyanna

I am fascinated by the way how diverse microbial species in the environment establish various modes of molecular interplay. That leads to the formation of complex microbial communities which make remarkable contributions to biogeochemical cycles, biotechnology and maintaining ecosystems.

Our group at the University of Tsukuba, steered under the guidance of Professor Norio Takeshita, contemplates the aspects of reciprocity in environmental microbial communities.

Bacterial-fungal interactions are crucial for understanding the microbial ecosystems that are closely related to agriculture, medicine and the environment.

Currently, our focus falls on fungi and bacteria which comprise a large fraction of the overall soil biomass. Bacterial-fungal interactions are crucial for the understanding of microbial ecosystems that is closely related to agriculture, medicine and the environment.

It is well known that microbial interactions are promoting the activation of cryptic biosynthetic pathways, thereby leading to the production of secondary metabolites. Those metabolites possess not only defense functions but also steer cell to cell communication and other interactive dynamics. However, the majority of studies based on the dynamics of microbiota have used monocultures.

Co-culturing has been proven to be an effective method to mimic conditions existing among microbial interactions within nature. Hence this approach may potentially facilitate the production of novel antimicrobials as well as facilitator molecules.

Together with Momoka Kuchira we were able to characterize the mutualistic relationship between the filamentous fungus Aspergillus nidulans and the gram-positive bacterium Bacillus subtilis (currently under review). Our studies provide evidence of their spatial and metabolic interaction that facilitate inter-species communication thereby exploring untraveled environmental niches and obtaining nutrients. It is understandable that there are extensive untraveled territories of microbial communities. Hence, our next milestone was to further exploit this prospect.

We conducted growth experiments of different combinations of fungal and bacterial species in coculture in selected nutrient rich and minimal conditions to observe the interactive dynamics of bacteria and fungi.

(I) Co-culture of Fungi and Bacteria on solid media. (II & III) Dispersal of bacterial cells (fluorescence) on fungal hyphae. (IV) SEM image denoting fungal-bacterial interaction.

Cocultures were incubated for 1 day up to 4 days prior to microscope imaging. An array of parameters such as velocity of the movement of bacterial cells, travel distance, colonization degree and growth rate were considered to define the specificity of interaction. According to the degree of these interactions and dynamics the combinations were classified into positive, negative and neutral genres.

A selected array of combinations was subjected to LC-MS and tandem spectroscopic analysis and the differences of chemical profiles of pure and co cultures have been analyzed to determine and contrast the production levels of bioactive compounds. By chemically defining the bioactive compounds we subsequently observed the transcriptomic and genomic expression to establish an inference of their genomic potential in the state of co-existence.

We are certain that this approach would gain a more reliable perspective on the ecological context of environmental microbiota in their natural setting. Moreover, it would aid in economical and societal aspects such as bio control and therapeutic value as well as in new possible avenues for yielding antimicrobial compounds.

Gayan Abeysinghe is a graduate student in Microbiology Research Center for Sustainability, Graduate School of Life and Environmental Sciences at the University of Tsukuba, Japan. Gayans research focus directs to impart insights on the microbial communication in the community setting and aims to the discovery and development of novel antimicrobials with better efficiency.

lncRNA remained relatively elusive until sequencing exploded, with the discovery of genomes with small numbers of genes and surprising amounts of junk being transcribed.

In the 1960s, DNA not coding for protein was termed junk DNA. It took another three decades before we begun to understand the gene regulatory potential of this so-called rubbish. In the 1990s, studies discovered small noncoding RNA able to silence gene translation via RNA interference. At this time, a group termed long noncoding RNA (lncRNA) were also uncovered.

Human lncRNAs such as the X chromosome-silencer, Xist, emerged first. Mechanisms included regulating gene expression by altering local epigenetics or by guiding proteins to distant genes. However, lncRNA remained relatively elusive until sequencing exploded, and we were suddenly faced with genomes with unexpectedly small numbers of genes and surprising amounts of junk being transcribed.

Aspergillus fumigatus colony growth perturbed upon drug exposure (photo credit: Darren Thomson).

We now know of numerous regulatory lncRNA which deploy a variety of mechanisms in animals, plants and fungi. For example, Neurospora crassa produces over 2500 lncRNA. However, in the human pathogen, Aspergillus fumigatus, only a handful are known. I sought to uncover A. fumigatus lncRNA and hypothesised that they could influence its response to antifungal drugs.

Using drug exposure RNAseq experiments and a bioinformatics pipeline, we identified over 3000 lncRNA candidates. I was surprised to find over 500 lncRNA were significantly expressed upon exposure to a frontline antifungal, itraconazole. Clustering analysis showed that the lncRNA display similar dose-responsive expression patterns to genes, suggesting these lncRNA are not transcriptional noise. Instead, they are co-ordinately regulated features which may play a role in the A. fumigatus drug response.

Further investigation into these novel lncRNA may inform our understanding of antifungal drug resistance mechanisms.

Danielle Weaver is a postdoctoral researcher at the Manchester Fungal Infection Group at the University of Manchester, UK. She completed her PhD on glycosylation in the foodborne bacterial pathogen, Campylobacter jejuni, but has since shifted focus to work on fungal pathogens. Her current research aims to harness next generation sequencing technologies to develop pathogen and drug resistance diagnostics and investigate RNA biology in Aspergillus fumigatus. Follow on Twitter@dan_weaver1@UofMMFIG

I have developed synthetic biology based-tools for scalable regulation or activation of transcriptionally silent secondary metabolite (SM) gene clusters in filamentous fungi.

Filamentous fungi produce a large variety of interesting SMs, molecules that are not essential for growth, but typically possess bioactivities that are of great value to medicine, agriculture and manufacturing. Many of these SM gene clusters are not expressed under laboratory conditions and may need to be activated or heterologously expressed before the desired products can be obtained.

Synthetic biology has revolutionized metabolic engineering and brings the exploitation of industrial microorganisms to a new level by enabling fine-tuning of gene expression allows the control of entire pathways.

Although filamentous fungi are attracting increasing interest as biotechnological production hosts, efficient genetic tools for their exploitation are limited.

Our work represents the development of synthetic gene regulatory devices, that enables scalable expression of a target gene, ranging from hardly detectable to a level similar to that of highest expressed native genes. Synthetic promoters, which were transcriptionally silent on their own, could be activated at desired level by the introduction of binding sites for the synthetic transcription factor (STF). A gene cluster may require expression levels tuned individually for each gene which is a great advantage provided by this system.

Fluorescence microscopy image of hyphae of a fungal strain expressing fluorescent reporters (STF-GFP-NLS, RFP-SKL).

In the STF, the DNA-binding domain of the qa-1F transcription factor from Neurospora crassa is fused to the VP16 activation domain. This STF controls the expression of genes under control of a synthetic promoter containing quinic acid upstream activating sequence (QUAS) binding elements. Control devices were characterized with respect to three main features: expression of the STF, number of QUAS elements, and the type of core promoter used downstream of the QUAS element.

The versatility of the control device was demonstrated by fluorescent reporters and its application was confirmed by synthetically controlling the penicillin gene cluster in Penicillium chrysogenum for antibiotic production. We anticipate that these well-characterized and robustly performing control devices will be useful tools for silent SM gene cluster activation and for development of filamentous fungi as production hosts.

Lszl Mzsik is a fourth-year PhD student in the laboratory of Arnold Driessen at the University of Groningen, the Netherlands. Within the Horizon 2020 Marie Skodowska-Curie COFUND ALERT program, his project aims at developing new genetic tools for the discovery of novel antibacterial compounds in fungi to tackle the increasing problem of multi-drug resistant bacteria.

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Scientists of the future at the 15th European Conference on Fungal Genetics - On Biology - BMC Blogs Network

Cell Biology

Researchers Find New Immune Cell Type in Breast Cancer That Could Suggest New Treatments – Clinical OMICs News

Breast cancer researchers in Australia have discovered a new type of immune cell in breast tissue that helps to keep mammary ducts healthy. Using advanced three-dimensional imaging techniques, the scientists, headed by a team at the Walter and Eliza Hall Institute of Medical Research, discovered that these ductal macrophages (DMs) monitor for threats in the mouse mammary ducts and help to maintain tissue health by clearing away dying milk-producing cells once lactation stops. As well as being the sites where milk is produced and transported, mammary ducts are also where most breast cancers arise.

The authors suggest that understanding how these immune cells function could provide valuable insights into potential new approaches to treating breast cancer. We discovered an entirely new population of specialized immune cells, which we named ductal macrophages, squeezed in between two layers of the mammary duct wall, said Caleb Dawson, PhD, co-senior and first author of the teams paper, which is published in Nature Cell Biology, in a report titled, Tissue-resident ductal macrophages survey the mammary epithelium and facilitate tissue remodeling.

Dawsons colleagues on the research included Walter and Eliza Hall Institute scientists Geoff Lindeman, PhD, Jane Visvader, PhD, along with Anne Rios, PhD, who is now based at the Princess Mxima Center for Pediatric Oncology, in the Netherlands.

The mammary gland is a dynamic organ that undergoes dramatic remodeling throughout life, the authors explained. The branching ducts bloom to form milk-producing alveoli during lactation, which must then be eliminated once milk production stops. Mammary ducts are of particular interest to breast cancer researchers because this site is prone to cancer development.

Most organs in the body including the brain, liver, lung, skin, and intestine have their own population of macrophages, immune cells that play important roles in regulating infection, inflammation, and organ function within their sites of residence. But while macrophages in breast tissue have been implicated in mammary gland function, their diversity has not been fully addressed, the investigators continued.

Using techniques including high-resolution three-dimensional imaging and flow cytometry, Dawson and colleagues discovered a type of ductal macrophage that hadnt previously been identified. The cells exhibited a distinct gene expression profile that implied a phagocytic function, and proliferated during pregnancy and lactation. DMs were highly enriched for lysosomal genes, which is indicative of a phagocytic role, they wrote. Although DMs were rare in adult mammary glands (0.64% of total cells), they expanded 40-fold during pregnancy and constituted 25.7% of total cells in lactation.

Further investigation suggested that the DMs phagocytose the alveolar cells during early involution. We were excited to find that these cells play an essential role at a pivotal point in mammary gland function called involution when lactation stops, milk-producing cells die, and breast tissue needs to remodel back to its original state, Dawson said. We watched incredulously as the star-shaped ductal macrophages probed with their arms and ate away at dying cells. The clearing action performed by ductal macrophages helps redundant milk-producing structures to collapse, allowing them to successfully return to a resting state.

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Researchers Find New Immune Cell Type in Breast Cancer That Could Suggest New Treatments - Clinical OMICs News

Cell Biology

Discovery heralds a new strategy in the hunt for antibiotics – News-Medical.net

Reviewed by Emily Henderson, B.Sc.May 3 2020

Scientists have identified a key process in the way bacteria protect themselves from attack - and it heralds a new strategy in the hunt for antibiotics.

The researchers from the University of Leeds have pieced together how bacteria build their outer, defensive wall - in essence, the cell's armor plating.

The research has focused on the gram-negative bacteria Escherichia coli, but the process they have discovered is shared by many pathogenic gram-negative bacteria - so it could have importance for tackling other gram-negative pathogens, including the top three on the World Health Organisation's list of priority pathogens.

The findings are published today (01/05) in the journal Nature Communications.

Our findings are changing the way we think about the way these cells constantly renew and replenish the proteins that make up the outer membrane.

Understanding that process of how bacteria build their cell wall in greater detail may identify ways we could intervene and disrupt it.

In doing so, we can either destroy the bacteria altogether or reduce the rate at which they divide and grow, making bacterial infections less severe.

We are at the start of a quest that could result in new, drug-based therapies that work either alone or with existing antibiotics to target these disease-causing bacteria."

Dr. Antonio Calabrese, University Academic Fellow in the Astbury Centre for Structural Molecular Biology

The research has focused on the role of a protein called SurA. Known as a chaperone, the job of SurA is to martial other proteins from where they are made, at the center of the cell, to where they are needed, in this case to bolster the bacterium's outer wall.

Proteins are long chains of amino acids that must adopt a defined structural shape in order to function effectively. Without the chaperone SurA, the essential proteins needed to build the cell wall run the risk of losing their structural integrity on their journey to the outer membrane.

Using advanced analytical techniques, the scientists mapped how the chaperone SurA recognizes proteins to transport them to the bacterial outer membrane.

Dr. Calabrese said: "For the first time we have been able to see the mechanism by which the chaperone, SurA, helps to transport proteins to the bacterial outer membrane. In effect it does this by cradling the proteins, to ensure their safe passage. Without SurA, the delivery pipeline is broken and the wall cannot be built correctly."

Professor Sheena Radford, FRS, Director of the Astbury Centre for Structural Molecular Biology said "This is an exciting discovery in our quest to find weak spots in a bacteria's armory that we can target to stop bacterial growth in its tracks and build much-needed new antibiotics.

"It's early days, but we now know how SurA works and how it binds its protein clients. The next step will be to develop molecules that interrupt this process, which can be used to destroy pathogenic bacteria."

It was only through the work of a great team from across the Astbury Centre that we were able to finally understand how SurA shuttles proteins to the bacterial outer membrane."

Dr. David Brockwell, Associate Professor in the Astbury Centre for Structural Molecular Biology

The research was funded by the UK Biotechnology and Biological Sciences Research Council and used equipment funded by the BBSRC and Wellcome Trust.

Source:

Journal reference:

Calabrese, A.N., et al. (2020) Inter-domain dynamics in the chaperone SurA and multi-site binding to its outer membrane protein clients. Nature Communications. doi.org/10.1038/s41467-020-15702-1.

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Discovery heralds a new strategy in the hunt for antibiotics - News-Medical.net

Cell Biology

Discovery of new type of immune cell in breast ducts – News-Medical.Net

Australian researchers from Walter and Eliza Hall Institute have discovered a new form of immune cells within the ducts of the breast that keeps the breasts healthy. The study was published this week in the journal Nature Cell Biology.

The researchers explain that they found immune cells called macrophages. The term macrophage from Ancient Greek means "big" (macro) and (phage) "eaters." These macrophages are essential for the normal formation and functioning of the mammary glands, they wrote. The immune cells regulate one of the vital processes of the mammary ducts. The team explains that mammary ducts of breast ducts are thin tubules where milk is produced and then is transported to the nipples for lactation. These ducts are also one of the major sites where cancers appear.

Macrophages are important cells of the immune system that are formed in response to an infection or accumulating damaged or dead cells. Macrophages are large, specialized cells that recognize, engulf, and destroy target cells.

Image Credit: Alpha Tauri 3D Graphics/Shutterstock.com

To find out the immune cell machinery within the breasts, the team of researchers used three-dimensional (3D) imaging techniques in real-time. The team looked at the movement of the immune cells when infective organisms threaten the ducts. These immune cells, they saw, were "gobbling up" the dead and dying cells that originally produce milk. Once lactation or breast milk production stops, these milk-producing cells need to be cleared up, say the researchers. The researchers believe that if more insights could be obtained about these cells, it could help breast cancer research.

The preclinical study was led by researchers Dr. Caleb Dawson, Professor Geoff Lindeman, and Professor Jane Visvader, along with Dr. Anne Rios.

Researchers explain that breast ducts have milk-producing cells that produce milk during lactation. Throughout the life of a woman, these cells and the whole of the breast undergoes several changes during puberty, pregnancy, lactation and after menopause. The ducts branch out and develop when milk needs to be produced during lactation. After lactation is over, these cells need to stop. Researchers believe that while the milk-producing cells are essential, these duct cells are often the sites of origin of breast cancers.

The mammary gland is a dynamic organ that undergoes dramatic remodeling throughout life. The branching ducts bloom to form milk-producing 'factories' in lactation, which must be eliminated once lactation stops as part of a process called involution. Image Credit: Dr Caleb Dawson, Walter and Eliza Hall Institute

Dr. Dawson explained that they were looking at these important cells using high-resolution imaging techniques and found these immune cells that play a role in maintaining the health of the breast tissues. He said, "We discovered an entirely new population of specialized immune cells, which we named ductal macrophages, squeezed in between two layers of the mammary duct wall." He added, "We were excited to find that these cells play an essential role at a pivotal point in mammary gland function called involution when lactation stops, milk-producing cells die, and breast tissue needs to remodel back to its original state. We watched incredulously as the star-shaped ductal macrophages probed with their arms and ate away at dying cells. The clearing action performed by ductal macrophages helps redundant milk-producing structures to collapse, allowing them to return to a resting state successfully."

As a next step, they removed these newly found ductal macrophages from the mammary ducts and found that other mammary immune cells could not carry out these essential processes within the breasts and the ducts.

Professor Visvader explained that understanding these mammary duct-specific macrophages was a step towards explaining the interactions between ductal cells and the immune system and would also explain the development of the mammary glands. She said, "As breast cancer researchers, there is a need to understand which cells are doing what, so that we can identify how these intricate cellular processes become dysregulated, such as in the case of breast cancers."

Dr. Dawson and his team believe that this finding could help understand not only breast development but also how the breasts change during puberty, pregnancy, lactation, and breast cancer. He said, "We also want to investigate the role that these duct-specific immune cells play in helping cancer to grow and spread. Ductal macrophages are spread throughout the mammary ducts. As cancer grows, these macrophages also increase in number. We suspect that there's the potential for ductal macrophages to inadvertently dampen the body's immune response, which would have dangerous implications for the growth and spread of cancer in these already prone sites."

Professor Visvader also explained that they aimed to understand the functions of these cells. She said, "Given that tumor macrophages likely promote the growth of the tumor, blocking their activity could serve as a treatment strategy for breast cancer."

This study was funded by the National Health and Medical Research Council, the National Breast Cancer Foundation, the Australian Cancer Research Foundation, The Qualtrough Cancer Research Fund, Cure Cancer Australia, and the Victorian Government.

Journal reference:

Dawson, C.A., Pal, B., Vaillant, F. et al. Tissue-resident ductal macrophages survey the mammary epithelium and facilitate tissue remodelling. Nat Cell Biol (2020). https://doi.org/10.1038/s41556-020-0505-0, https://www.nature.com/articles/s41556-020-0505-0

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Discovery of new type of immune cell in breast ducts - News-Medical.Net

Cell Biology

Molecules identified that reverse cellular aging process – New Atlas

Central to a lot of scientific research into aging are tiny caps on the ends of our chromosomes called telomeres. These protective sequences of DNA grow a little shorter each time a cell divides, but by intervening in this process, researchers hope to one day regulate the process of aging and the ill health effects it can bring. A Harvard team is now offering an exciting pathway forward, discovering a set of small molecules capable of restoring telomere length in mice.

Telomeres can be thought of like the plastic tips on the end of our shoelaces, preventing the fraying of the DNA code of the genome and playing an important part in a healthy aging process. But each time a cell divides, they grow a little shorter. This sequence repeats over and over until the cell can no longer divide and dies.

This process is linked to aging and disease, including a rare genetic disease called dyskeratosis congenita (DC). This is caused by the premature aging of cells and is where the team focused its attention, hoping to offer alternatives to the current treatment that involves high-risk bone marrow transplants and which offers limited benefits.

One of the ways dyskeratosis congenita comes about is through genetic mutations that disrupt an enzyme called telomerase, which is key to maintaining the structural integrity of the telomere caps. For this reason, researchers have been working to target telomerase for decades, in hopes of finding ways to slow or even reverse the effects of aging and diseases like dyskeratosis congenita.

Once human telomerase was identified, there were lots of biotech startups, lots of investment, says Boston Childrens Hospital's Suneet Agarwal, senior investigator on the new study. But it didnt pan out. There are no drugs on the market, and companies have come and gone.

Agarwal has been studying the biology of telomerase for the past decade, and back in 2015 he and his team discovered a gene called PARN that plays a role in the action of the telomerase enzyme. This gene normally processes and stabilizes an important component of telomerase called TERC, but when it mutates, it results in less of the enzyme being produced and, in turn, the telomeres becoming shortened prematurely.

For the new study, researchers screened more than 100,000 known chemicals in search of compounds that could preserve healthy function of PARN. This led them to a small handful that seemed capable of doing so by inhibiting an enzyme called PAPD5, which serves to unravel PARN and destabilize TERC.

We thought if we targeted PAPD5, we could protect TERC and restore the proper balance of telomerase, says Harvard Medical Schools Neha Nagpal, first author on the new paper.

These chemicals were tested on stem cells in the lab, made from the cells of patients with dyskeratosis congenita. These compounds boosted TERC levels in those stem cells and restored telomeres to their normal length. However, rather than a scattergun approach, the team really wanted to test for safety and see if the treatment could precisely target stem cells carrying the right ingredients for telomerase formation.

More specifically, the team wanted to see if this could be achieved by having the PAPD5-inhibiting drugs recognize and respond to another important component of telomerase, a molecule called TERT. To do so, in the next round of experiments the team used human blood stem cells and triggered mutations in the PARN gene that give rise to dyskeratosis congenita. These were then implanted into mice that were treated with the compounds, with the team finding the treatment boosted TERC, restored telomere length in the stem cells and had no ill effects on the rodents.

This provided the hope that this could become a clinical treatment, says Nagpal.

The team will now continue its work in an effort to prove these small molecules are a safe and effective way to apply the brakes to dyskeratosis congenita, other diseases, and possibly aging more broadly.

We envision these to be a new class of oral medicines that target stem cells throughout the body, Agarwal says. We expect restoring telomeres in stem cells will increase tissue regenerative capacity in the blood, lungs, and other organs affected in DC and other diseases.

The research was published in the journal Cell Stem Cell.

Source: Boston Childrens Hospital via Harvard University

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Molecules identified that reverse cellular aging process - New Atlas

Cell Biology

Karolinska Institutet publishes study on repurposing cancer care to COVID-19 – Science Business

Comprehensively adapting cancer care and clinical cancer research to the COVID-19 pandemic is a necessity, researchers and doctors at Karolinska Institutet and Karolinska University Hospital write in a paper published in the journal Nature Medicine. In it, seven top European cancer centres propose adaptations to protect patients.

Cancer patients are particularly vulnerable to complications if they get infected by the new coronavirus, saysJonas Bergh, chair ofCancer Research KI, professor at theDepartment of Oncology-Pathologyat Karolinska Institutet and consultant at Karolinska University Hospital. We must therefore protect them from the virus without compromising continuity of care.

The article has been written by representatives of the seven centres that make upCancer Core Europe, which together conduct extensive clinical research and treat 70,000 new cancer patients a year. The centres in Milan, Barcelona, Cambridge, Paris, Amsterdam and Heidelberg are, like Karolinska Institutet, facing very difficult challenges imposed by the pandemic.

Several changes made

Our aim is to quickly communicate our experiences from the first months of the pandemic and give general advice and guidelines to other cancer clinics, saysIngemar Ernberg, chair of Karolinska InstitutetsPersonalised Cancer Medicine (PCM) programmeand professor at theDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet. Were in an earlier essentially unknown medical and ethical reality, which means that caregivers have to muster all their knowhow and experience to make vital clinical decisions.

Treatments have had to be postponed or modified to protect the patients immune systems and many more patient follow-ups are performed remotely. Some clinical research studies have been rescheduled or even put on hold if they are judged to expose patients to extra risk.

We and other cancer centres around the world will continue to compile and report new data on the impact that the pandemic is having on cancer care to provide a solid foundation for future choices and decisions, saysLuigi De Petris, oncologist at the Cancer Theme, Karolinska University Hospital and researcher at the Department of Oncology-Pathology, Karolinska Institutet. This will be a dynamic and swift process in which we hope that our combined experiences will come to benefit others.

Suggested adaptions

The article gives examples of what needs to be considered and possibly changed in order to create continuity in cancer care during the pandemic:

The research was part-financed with a grant from the Cancer Research Funds of Radiumhemmet.

Publication

Caring for patients with cancer in the COVID-19 era. Joris van de Haar, Louisa R. Hoes, Charlotte E. Coles, Kenneth Seamon, Stefan Frhling, Dirk Jger, Franco Valenza, Filippo de Braud, Luigi De Petris, Jonas Bergh, Ingemar Ernberg, Benjamin Besse, Fabrice Barlesi, Elena Garralda, Alejandro Piris-Gimnez, Michael Baumann, Giovanni Apolone, Jean Charles Soria, Josep Tabernero, Carlos Caldas, Emile E. Voest.Nature Medicine,online 16 April 2020, doi: 10.1038/s41591-020-0874-8.

This article was first published on 29 April by Karolinska Institutet.

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Karolinska Institutet publishes study on repurposing cancer care to COVID-19 - Science Business