Small Cell Lung Cancer: Scientists Identify Two New Approaches For Therapy (Medicine)

Using samples of small cell lung tumours, a research team led by biologist Dr Silvia von Karstedt has discovered two new ways to induce tumour cell death. One of two subsets of tumour cells can be targeted by activating ferroptosis: iron-dependent cell death caused by oxidative stress. In the second subtype, oxidative stress – and hence cell death – can also be induced in a different way. Both types of cell death must be triggered simultaneously by drugs to kill the majority of the tumour mass. The results of the study have been published in Nature Communications.

Despite many advances in treatment, a diagnosis of small cell lung cancer means a particularly poor prognosis. In Germany, up to 8000 new cases of small cell lung cancer (SCLC) are diagnosed each year. At the time of diagnosis, cancer has already found many loopholes to escape the body’s immune system. ‘Traditional’ cell death mechanisms, such as regulated cell death by apoptosis, are usually already inactivated at this stage. That way, tumour cells can continue to divide and spread almost unperturbed.

A high cell division rate is characteristic of small cell lung cancer, which initially promises a good response to chemotherapy. ‘Unfortunately, in many cases the success of chemotherapy is short-lived because tumour cells rapidly develop resistance to therapy. In addition, a tumour consists not only of one, but of several cell types – the so-called subtypes – each of which uses unique strategies to escape lethal therapy,’ said von Karstedt, research group leader at the CECAD Cluster of Excellence for Aging Research, the Department of Translational Genomics at the University of Cologne and the Center for Molecular Medicine Cologne (CMMC). This is where her research comes in. The biologist explores which cell death mechanisms are already inactivated in cancer cells and which ones can still be targeted by therapies to kill the tumour.

The research team used patient samples taken at the time of diagnosis, thus depicting the treatment-naïve tumour. To find out which pathways of cell death are still available, the scientists compared gene activity between patient cells taken inside and outside the tumour. Signalling pathways important for traditional cell death mechanisms were already switched off inside the tumour at this early stage, before therapy. In contrast, genes important for the activation of iron-dependent cell death by oxidative damage (ferroptosis) were strongly activated in the cancer cells.

Put in simple terms, small cell lung cancer cells can be divided into two subtypes: neuroendocrine cells and non-neuroendocrine cells. In the neuroendocrine cell subtype, more genes are active which are otherwise typically found in nerve cells that produce hormones. Cells belonging to the other subtype do not have this property and are therefore grouped as non-neuroendocrine cells. ‘Several experiments showed that cells of the non-neuroendocrine type can be killed using buthionine sulfoximine, which induces ferroptosis. In cells belonging to the neuroendocrine subtype, we found that they protect themselves from oxidative stress – and thus cell death – by producing antioxidants. However, by adding the antioxidant inhibitor Auranofin, we were able to kill these cells as well,’ explains doctoral researcher Christina Bebber, the lead author of the paper.

Regarding a possible application of these findings to the therapy of small cell lung cancer, the biologists made an important observation: When targeting just one of the two pathways – i.e., either activating ferroptosis or inhibiting antioxidant production – in a tumour consisting of cells of both subtypes, cancer cells were able to evade the lethal therapy. They did so by adjusting their gene expression to switch to the subtype that could resist the respective single pathway-targeting treatment. ‘When we applied a combination therapy, we took away this route of escape. What is also special about the study is that we used drugs that have already been tested in extensive clinical trials or even approved for the treatment of other diseases,’ von Karstedt explained. Buthionine sulfoximine, which triggers ferroptosis, is already in clinical trials for cancer treatment. The gold salt Auranofin, which blocks the production of protective antioxidants in cancer cells, has been in use for decades to treat rheumatoid arthritis.

Future clinical studies using this combined therapy will clarify to what extent this targeted therapy option will improve the prognosis of small cell lung cancer patients.

Featured image: Small cell lung cancer cells in culture (blue), non-endocrine cells are stained red. © Christina Bebber


Reference: Bebber, C.M., Thomas, E.S., Stroh, J. et al. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nat Commun 12, 2048 (2021). https://doi.org/10.1038/s41467-021-22336-4


Provided by University of Cologne

Tiny Brains Grown In 3D-printed Bioreactor (Physics)

Small device contains wells to let small bits of tissue grow, develop, and be studied in real time

Scientists from MIT and the Indian Institute of Technology Madras have grown small amounts of self-organizing brain tissue, known as organoids, in a tiny 3D-printed system that allows observation while they grow and develop. The work is reported in Biomicrofluidics, by AIP Publishing.

Current technology for real-time observation of growing organoids involves the use of commercial culture dishes with many wells in a glass-bottomed plate placed under a microscope. The plates are costly and only compatible with specific microscopes. They do not allow for the flow or replenishment of a nutrient medium to the growing tissue.

Recent advances have used a technique known as microfluidics, where a nutrient medium is delivered through small tubes connected to a tiny platform or chip. These microfluidic devices are, however, expensive and challenging to manufacture.

The current advance uses 3D printing to create a reusable and easily adjustable platform that costs only about $5 per unit to fabricate. The design includes imaging wells for the growing organoids and microfluidic channels to provide a nutrient medium and preheating that supports tissue growth.

A biocompatible type of resin used in dental surgery was used for the 3D-printed device. The printed chip was cured by exposing it to UV light, then sterilized before live cells were placed in the wells. After sealing the top of the wells with a glass slide, the nutrient medium and drugs for use in the study were added through small inlet ports.

“Our design costs are significantly lower than traditional petri dish- or spin-bioreactor-based organoid culture products,” said author Ikram Khan. “In addition, the chip can be washed with distilled water, dried, and autoclaved and is, therefore, reusable.”

The investigators tested their device with organoids derived from human cells. They observed the growing brain organoids with a microscope and were able to successfully follow their growth and development for seven days. The small bit of brain tissue developed a cavity or ventricle surrounded by a self-organizing structure that resembles a developing neocortex.

The percentage of cells in the core of the organoid that died during this one-week period was smaller in the 3D-printed device than in regular culture conditions. The investigators believe that their cell design protects the tiny growing brain.

Khan said, “One advantage offered by our microfluidic device is that it allows constant perfusion of the culture chamber, which more closely mimics a physiological tissue perfusion than conventional culture, and thus reduces cell death at the organoid core.”

The investigators hope to increase the capacity of their device by scaling up the number of available wells. Other improvements will allow for additional instruments to be integrated into the design.

The article “A low-cost 3D printed microfluidic bioreactor and imaging chamber for live-organoid imaging” is authored by Ikram Khan, Anil Prabhakar, Chloe Delepine, Hayley Tsang, Vincent Pham, and Mriganka Sur. The article will appear in Biomicrofluidics on April 6, 2021 (DOI: 10.1063/5.0041027). After that date, it can be accessed at https://aip.scitation.org/doi/10.1063/5.0041027.

Featured image: A 3D-printed microfluidic bioreactor for organ-on-chip cell culture © Ikram Khan


Provided by American Institute of Physics

Activated Carbon Increases Cryocooler Efficiency (Physics)

At ultracold temperature of 4 kelvins, the carbon increased efficiency by more than 30%.

Cryocoolers are ultracold refrigeration units used in surgery and drug development, semiconductor fabrication, and spacecraft. They can be tubes, pumps, tabletop sizes, or larger refrigerator systems.

The regenerative heat exchanger, or regenerator, is a core component of cryocoolers. At temperatures below 10 kelvins (-441.67 degrees Fahrenheit), performance drops precipitously, with maximum regenerator loss of more than 50%.

In their paper, published in Applied Physics Letters, by AIP Publishing, researchers at the University of Chinese Academy of Sciences used superactivated carbon particles as an alternative regenerator material to increase cooling capability at temperatures as low as 4 kelvins.

In most cryocoolers, a compressor drives room temperature gas through the regenerator. The regenerator soaks up heat from the compression, and the cooled gas expands. The oscillating ultracold gas absorbs the heat trapped in the regenerator, and the process repeats.

Nitrogen is the most commonly used gas in cryocoolers. But for applications requiring temperatures below 10 kelvins, such as space telescope instruments and magnetic resonance imaging systems, helium is used, because it has the lowest boiling point of any gas, enabling the coldest attainable temperatures.

However, helium’s high specific heat (the amount of heat transfer needed to change the temperature of a substance) results in large temperature fluctuations during the compression and expansion cycle at low temperatures, which seriously affects cooling efficiency.

To address this problem, researchers replaced the regenerator’s conventional rare-earth metals with activated carbon, which is carbon treated with carbon dioxide or superheated steam at high temperatures. This creates a matrix of micron-size pores that increases the carbon’s surface area, enabling the regenerator to hold more helium at low temperatures and remove more heat.

The researchers used a 4 kelvins Gifford-McMahon cryocooler to test the helium adsorption capacity in superactivated carbon particles with a porosity of 0.65 within varying temperature ranges of 3-10 kelvins.

They found when they filled the regenerator with 5.6% of carbon with diameters between 50 and 100 microns, the obtained no-load temperature of 3.6 kelvins was the same as using precious metals. However, at 4 kelvins, cooling capacity increased by more than 30%.

They confirmed improved performance by placing coconut shell-activated carbon into an experimental pulse tube they built and using a thermodynamic calculation model.

“In addition to providing increased cooling capacity, the activated carbon can serve as a low-cost alternative to precious metals and could also benefit low-temperature detectors that are sensitive to magnetism,” author Liubiao Chen said.

The article “Study on the use of porous materials with adsorbed helium as the regenerator of cryocooler at temperatures below 10 K” is authored by Xiaotong Xi, Biao Yang, Yuanheng Zhao, Liubiao Chen, and Junjie Wang. The article will appear in Applied Physics Letters on April 6, 2021 (DOI: 10.1063/5.0044221). After that date, it can be accessed at https://aip.scitation.org/doi/10.1063/5.0044221.

Featured image: 4 K pulse tube cryocooler developed by researchers at the Technical Institute of Physics and Chemistry, Chinese Academy of Sciences © Liubiao Chen/University of Chinese Academy of Sciences


Provided by American Institute of Physics

New Species Discovered In Norway (Biology)

This brand new species of cuckoo wasp was discovered because of its own language.

Cuckoo wasps – also called emerald wasps – are some of the most beautiful insects we have, with colourful exteriors that shine like jewels. However, these beauties have also created a lot of headaches.

“Normally we distinguish insects from each other by their appearance, but cuckoo wasps are so similar to each other that it makes it difficult,” says Frode Ødegaard.

When a new species is described, it must be given a name, and Frode Ødegaard was lucky and got to name the newcomer. Photo: Jake Bryant

Ødegaard is an insect researcher at the NTNU University Museum and belongs to the European research group that has now described this recent contribution to species diversity. The new species is very rare, and is only a single specimen has been found on the Lista peninsula in Agder county in Norway.

For more than 200 years, insect researchers have struggled to sort cuckoo wasps into the right “species boxes,” and to determine which characteristics are variations within a species and which are species-specific differences.

Chemical language in insects

In the last 10 years, DNA barcoding has brought about a major breakthrough by making it possible to distinguish different species of cuckoo wasps from each other by looking at the differences in their genetic material.

“But it’s not always that easy, either. In this case, we had two cuckoo wasps with microscopic differences in appearance and very small differences in DNA,” Ødegaard says.

“The cuckoo wasp is an insect with above-average linguistic abilities.”

“The next step was to look at the language of each of the wasps to find out if they belonged to different species,” he says.

There are a total of over 2,500 described golden wasp species, with 40 recorded in Norway. Photo: Arnstein Staverløkk, NINA, CC BY3.0

Insects communicate with each other through pheromones – in other words, they have a chemical language. Very closely related species often have completely different languages to prevent them from interbreeding.

Linguistic parasite

The cuckoo wasp is an insect with above-average linguistic abilities. They are parasites, which means that they behave like cuckoos and lay their eggs in the nests of other bees and wasps. The larvae grow quickly and hatch before the host’s eggs. Then they eat the eggs, the larvae and the food supply that the host has arranged in the nest.

“When you live as a parasite, it’s important not to be discovered, and therefore the cuckoo wasp has also learned the language of its host,” says Ødegaard.

By conducting an ever-so-small language study, the researchers were able to discover that the two almost identical cuckoo wasps did indeed belong to different species. They use different hosts – and that means that they also speak completely different languages.

“The evolutionary development associated with sponging off another species happens very fast. That’s why you can have two species that are really similar genetically but still belong to different species,” says Ødegaard.

Honoured to name the new species

When a new species is described, it has to be given a name. Frode Ødegaard had the good fortune to receive the honour of naming the newcomer.

“A naming competition was announced among researchers in Europe who work with cuckoo wasps, and then the proposals that came in were voted on. It turned out my proposal actually got the most votes!” Ødegaard says.

“As mentioned, the new wasp is very similar to another species called Chrysis brevitarsis, so the new species was named Chrysis parabrevitarsis, which means ‘the one standing next to brevitarsis’.”

Ødegaard was also responsible for giving the species its slightly simpler Norwegian name of sporegullveps. He makes no secret of the fact that he found it great to be able to name a new species.

“In a way, you have to think from the perspective of eternity, because that species will always have that name. There’s something very fundamental about it.”

Conservation biologist and mass murderer

The picture at the top, as mentioned, shows the only known specimen of this cuckoo wasp. So it may seem both morally reprehensible and unnecessary that this one lone individual was stuck onto a needle.

“Even with today’s advanced methods, using live animals for studies like this isn’t possible, but collecting individual specimens fortunately has no impact on the population,” Ødegaard says.

“The insects have enormous reproductive potential, and the size and quality of the habitats are what determine the viability of the population, not whether any specimens are eaten by birds or collected by an insect researcher.”

He adds that the collected insects are absolutely crucial for researchers to be able to map and describe their diversity and thus take care of viable populations for posterity.

Featured image: The new species was discovered in the dunes on Lista in Farsund municipality. Photo: Arnstein Staverløkk


Reference: Frode Ødegaard et al.: Cuticular Hydrocarbon Profile Analyses Help Clarify the Species Identity of Dry-Mounted Cuckoo Wasps (Hymenoptera: Chrysididae), Including Type Material, and Reveal Evidence for a Cryptic Species Insect Systematics and Diversity, Volume 5, Issue 1, January 2021, 3, https://doi.org/10.1093/isd/ixab002


Provided by Norwegian Science tech

Cancer Discovery Could Revive Failed Treatments for Solid Tumors (Medicine)

New research from the UVA Cancer Center could rescue once-promising immunotherapies for treating solid cancer tumors, such as ovarian, colon and triple-negative breast cancer, that ultimately failed in human clinical trials.

The research from UVA’s Jogender Tushir-Singh, PhD, explains why the antibody approaches effectively killed cancer tumors in lab tests but proved ineffective in people. He found that the approaches had an unintended effect on the human immune system that potentially disabled the immune response they sought to enhance.

The new findings allowed Tushir-Singh to increase the approaches’ effectiveness significantly in lab models, reducing tumor size and improving overall survival. The promising results suggest the renewed potential for the strategies in human patients, he and his team report.

“So far, researchers and protein engineers around the globe, including our research group, were focused on super-charging and super-activating tumor cell-death receptor targeting antibodies in the fight against cancer. Here at UVA, we took a comprehensive approach to harness the power of the immune system to create dual-specificity and potentially clinically effective oncologic therapeutics for solid tumors,” said Tushir-Singh, of the UVA School Medicine’s Department of Biochemistry and Molecular Genetics. “Our findings also have significant potential to improve further the clinical efficacy of currently FDA-approved PD-L1 targeting antibodies in solid tumors, particularly the ones approved for deadly triple-negative breast cancer.”

IMMUNOTHERAPY FOR SOLID TUMORS

Immunotherapy aims to harness the body’s immune system to recognize and destroy cancer cells. Lab-engineered antibodies remain the core facilitator of immunotherapies and CAR T-cell therapies, which have generated tremendous excitement in the last decade. But these therapies have proved less effective against solid tumors than against melanoma (skin cancer) and leukemia (blood cancers). One major obstacle: It is difficult for immune cells to make their way efficiently into the core of solid tumors.

To overcome that problem, scientists have developed an approach that selectively uses antibodies to target a receptor on the cancer cells’ surface called death receptor-5 (DR5). This approach essentially tells the cancer cells to die and enhances the permeation of the body’s immune cells into a solid tumor. And it does so without the toxicity associated with chemotherapy.

Previously tested DR5-targeting antibodies have worked very well in lab tests and reduced tumor size in immune-deficient mouse models. But when tested in phase-II human clinical trials, these antibodies consistently failed to improve survival in patients – despite many big-name pharmaceutical companies spending billions of dollars on them.

Tushir-Singh, an antibody engineer, and his collaborators wanted to understand what was happening – why didn’t this promising approach work in patients who need it desperately? They found that the anti-DR5 antibody approaches unintentionally triggered biological processes that suppress the body’s immune response. This allowed the cancer tumors to evade the immune system and continue to grow. 

Tushir-Singh and his team could restore the potency of the DR5-based antibody approach in human cancer cells and immune-sufficient mouse models by co-targeting the negative biological processes with improved, immune-activating therapy. The new combination therapy “markedly” increased the effectiveness of cancer killer immune cells known as T cells, shrinking tumors and improving survival in lab mice, they report in a new scientific paper. 

That is an encouraging sign for the combination therapy’s potential in patients with solid tumors, such as ovarian cancer and triple-negative breast cancer – the deadliest cancers in women.

“We would like to see these strategies in clinical trials, which we strongly believe have huge potential in solid tumors,” Tushir-Singh said. “Our findings are extraordinary: Along with the translational impact, our work also explains, after more than 60 years of research in the field, why most approaches targeting apoptosis [cell death] have not done well in clinical trials and ultimately develop resistance to therapies.”

FINDINGS PUBLISHED

The researchers have published their findings in the scientific journal EMBO Molecular Medicine. The research team consisted of Tanmoy Mondal, Gururaj N. Shivange, Rachisan G.T. Tihagam, Evan Lyerly, Michael Battista, Divpriya Talwar, Roxanna Mosavian, Karol Urbanek, Narmeen S. Rashid, J. Chuck Harrell, Paula D. Bos, Edward B. Stelow, M. Sharon Stack, Sanchita Bhatnagar and Tushir-Singh. UVA is seeking a patent based on the new combination approach.

The work was supported by National Cancer Institute/National Institutes of Health grant R01CA233752, U.S. Department of Defense Breast Cancer Research Program (BCRP) breakthrough level 1 awards BC17097 and BC170197P1, Department of Defense Ovarian Cancer Research Program (OCRP) funding award OC180412 and a Cancer Center Support Grant, P30CA044579, to UVA.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

Featured image: Jogender Tushir-Singh is an antibody engineer at UVA Cancer Center. © UVA


Reference: Tanmoy Mondal et al., “Unexpected PD‐L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies”, EMBO Mol Med (2021)13:e12716. https://doi.org/10.15252/emmm.202012716


Provided by UVA Health

Origins of Life Could Have Started With DNA-like XNAs (Biology)

Nagoya University scientists in Japan have demonstrated how DNA-like molecules could have come together as a precursor to the origins of life. The findings, published in the journal Nature Communications, not only suggest how life might have begun, but also have implications for the development of artificial life and biotechnology applications.

“The RNA world is widely thought to be a stage in the origin of life,” says Nagoya University biomolecular engineer Keiji Murayama. “Before this stage, the pre-RNA world may have been based on molecules called xeno nucleic acids (XNAs). Unlike RNA, however, XNA replication probably didn’t require enzymes. We were able to synthesize an XNA without enzymes, strongly supporting the hypothesis that an XNA world might have existed before the RNA world.”

XNAs are formed of chains of linked nucleotides, similar to DNA and RNA but with a different sugar backbone. XNAs can carry genetic code very stably because the human body can’t break them down. Some researchers have reported that XNAs containing specific sequences can act as enzymes and bind to proteins. This makes XNAs exciting in the field of synthetic genetics, with potential biotechnology and molecular medicine applications.

Murayama and his colleagues showed that L-aTNA fragments could interlink on complementary L-aTNA, RNA and DNA templates without the need for enzymes. © Keiji Murayama

Murayama, Hiroyuki Asanuma and colleagues wanted to find out if conditions likely present on early Earth could have led to XNA chain formation. They synthesized fragments of acyclic (non-circular) L-threoninol nucleic acid (L-aTNA), a molecule that is thought to have existed before RNA came to be. They also made a longer L-aTNA with a nucleobase sequence that complemented the sequences of the fragments, similar to how DNA strands match up.

When placed together in a test tube under controlled temperature, the shorter L-aTNA fragments came together and linked up with each other on the longer L-aTNA template. Critically, this happened in the presence of a compound, called N-cyanoimidazole, and a metal ion, like manganese, both of which were possibly present in early Earth. The fragments interlinked when a phosphate at the end of one chemically attached to a hydroxyl group at the end of its neighbour, without the help of an enzyme.

“To the best of our knowledge, this is the first demonstration of template-driven, enzyme-free extension of acyclic XNA from a random fragment pool, generating phosphodiester bonding,” says Murayama.

The team also demonstrated that L-aTNA fragments could interlink on DNA and RNA templates. This suggests that genetic code could be transferred from DNA and RNA onto L-aTNA and vice versa.

“Our strategy is an attractive system for experimenting with the construction of artificial life and the development of highly functional biological tools composed of acyclic XNA,” says Murayama. “The data also indicate that L-aTNA could have been an RNA precursor.”

The team plans to continue their investigations to clarify whether L-aTNA could have been synthesized in early Earth ‘pre-life’ conditions and to examine their potential for developing advanced biological tools.

Featured image: Some scientists think that XNA evolved into RNA, which then evolved into DNA, forming the very beginnings of life. © Keiji Murayama


Reference: Murayama, K., Okita, H., Kuriki, T. et al. Nonenzymatic polymerase-like template-directed synthesis of acyclic L-threoninol nucleic acid. Nat Commun 12, 804 (2021). https://www.nature.com/articles/s41467-021-21128-0 https://doi.org/10.1038/s41467-021-21128-0


Provided by Nagoya University

How Do Lakes Affect Energy, Heat, and Carbon Exchange Processes in Mountainous Areas? (Earth Science)

Lakes are important in the Earth-atmosphere system. They can maintain ecological balance and regulate climate, as well as the nearby landscape. More than one third of lakes in China are distributed in the southern plateau region. The topography around the plateau lakes is complex and diverse, which leads to a unique local air circulation.

This meteorological phenomenon results from the interaction between lake-land breeze and mountain-valley breeze circulations. Local energy sources and material circulation rely on this mechanism. Therefore, scientists want to better understand how this process affects the carbon and water cycles as well as regional heat exchange.

“Due to the difficulty and high cost of continuous observation in lakes, the understanding of lake-air interactions is still very limited,” said Prof. LIU Huizhi, a researcher at the Institute of Atmospheric Physics (IAP) of the Chinese Academy of Sciences.

Since 2011, LIU and his research group have maintained an observation site at Erhai Lake within the Dali Basin in southwest China. Along with basic meteorological data, they were particularly interested in measuring eddy covariance at the lake surface.

“The mechanism of the impact of lakes on regional hydrothermal cycle and carbon exchange needs to be further analyzed,” said LIU.

Based on data from the observation site, the team was able to recognize specific characteristics of local air circulations and their impacts on the water, heat, and carbon cycles in and around Erhai Lake. They found that the heat and carbon exchange processes are inversely related. When one mechanism increases its influence, the other one decreases.

“During daytime, lake breeze promotes latent heat flux exchange and reduces sensible heat flux and carbon dioxide flux exchange,” LIU says. “At night, mountain breeze increases the exchange of carbon dioxide flux and decreases the exchange of sensible and latent heat flux. The southeast wind from lake surface at night has the opposite effects.”

Overall, LIU and his team’s data suggest that lakes promote heat (energy) and water exchange, but they suppress carbon dioxide exchange in mountainous lake area.

The findings were published in Adances in Atmospheric Sciences. “Future field experiments in the horizontal and vertical direction are needed to further investigate energy and carbon dioxide exchange at different temporal and spatial scales,” LIU added.

Featured image: The eddy covariance observation site at the Erhai Lake in the Dali Basin. (Image by XU Lujun)


Reference: Xu, L., Liu, H., Du, Q. et al. Characteristics of Lake Breezes and Their Impacts on Energy and Carbon Fluxes in Mountainous Areas. Adv. Atmos. Sci. 38, 603–614 (2021). https://doi.org/10.1007/s00376-020-0298-x


Provided by Chinese Academy of Sciences

How The Fly Selects Its Reproductive Male? (Biology)

Researchers from UNIGE have discovered a very small protein in Drosophila that plays a key role in how females select the semen that will fertilize its eggs when it mates with several males.

Even a well-characterized genome, such as that of the Drosophila the so-called fruit fly, still holds surprises. A team from the University of Geneva (UNIGE), Switzerland, in collaboration with Cornell University (USA) and the University of Groningen (Netherlands), has discovered an RNA coding for a micro-peptide – a very small protein – that plays a crucial role in the competition between spermatozoa from different males with which the female mates. In addition to shedding new light on this biological mechanism, this work, to be read in the journal Proceedings of the National Academy of Sciences (PNAS), highlights the importance of small peptides, a class of proteins that is now emerging as a key player in complex biological processes.

In many species, including insects, mating induces physiological changes in the female aimed at the reproductive success of the couple. This response is induced by substances in the male’s seminal fluid that interact with the female’s reproductive system. These post-coital changes include increased ovulation and egg laying, semen storage and release, dietary changes and gut growth. A mated female also becomes less receptive to other males and can use the semen stored in her spermatheca from her first intercourse for many days. However, this behavior is counterbalanced by the “last male preference” phenomenon. Indeed, despite the decrease in libido normally induced by a first mating, females sometimes decide to mate with a new, healthier or stronger male, probably in order to have more robust offspring. In this case, the semen of the first male is expelled and only that of the last male is kept.

A small peptide with a big role in sperm selection

The authors of this study have studied this phenomenon in Drosophila, the small fly that lingers around overripe or rotting fruit. This model organism, very popular with researchers for genetic and developmental studies, allows for easy observation and study of reproductive behavior. The biologists analyzed the proteins produced by the accessory functional gland, homolog of the human prostate. “Among the proteins we identified as essential for a normal response after mating is a micro-peptide, a very small protein that had never been studied before, as the RNA that codes for it was considered ‘non-coding’”, says Clément Immarigeon, first author of this study conducted in the Department of Genetics and Evolution of the Faculty of Science at UNIGE.

In order to verify if this peptide finally played a determining role, the researchers created mutants that no longer possess it. In females first mated by a mutant male, the phenomenon of “last male preference” is no longer observed. Indeed, if they are then mated by another male, they lay eggs fertilized by the sperm of both males, and not exclusively by the last progenitor, which could reduce the robustness of their offspring. “To our surprise, we found that this micro-peptide – encoded by a putative non-coding transcript – performs important reproductive functions. Such micro-peptides were not previously recognized but are emerging as important players in complex biological processes”, summarizes Robert Maeda, researcher in the Department of Genetics and Evolution at UNIGE and last author of the study.

Towards the sterile insect

The study of these mating-induced phenomena is of particular interest in certain insect species responsible for sanitary, economic or environmental problems. A biological alternative to non-selective insecticides is the “sterile insect” method, which limits harmful populations by releasing millions of sterilized males into the wild to prevent females from mating with fertile wild males. A better understanding of the post-mating response will allow the development of even more effective biological control methods.

Featured image: Drosophila accessory glands consisting of two cell types (green “secondary cells” surrounded by red nuclei of the “main cells”). © Robert Maeda


Reference: Clément Immarigeon, Yohan Frei, Sofie Y. N. Delbare, Dragan Gligorov, Pedro Machado Almeida, Jasmine Grey, Léa Fabbro, Emi Nagoshi, Jean-Christophe Billeter, Mariana F. Wolfner, François Karch, Robert K. Maeda, “Identification of a micropeptide and multiple secondary cell genes that modulate Drosophila male reproductive success”, Proceedings of the National Academy of Sciences Apr 2021, 118 (15) e2001897118; DOI: 10.1073/pnas.2001897118


Provided by University of Geneve

Thinking With Your Stomach? The Brain May Have Evolved to Regulate Digestion (Biology)

Researchers from the University of Tsukuba find that sea urchin larvae use light to control digestion

Many life forms use light as an important biological signal, including animals with visual and non-visual systems. But now, researchers from Japan have found that neuronal cells may have initially evolved to regulate digestion according to light information.

In a study published this month in BMC Biology, researchers from the University of Tsukuba have revealed that sea urchins use light to regulate the opening and closing of the pylorus, which is an important component of the digestive tract.

Light-dependent systems often rely on the activity of proteins in the Opsin family, and these are found across the animal kingdom, including in organisms with visual and non-visual systems. Understanding the function of Opsins in animals from different taxonomic groups may provide important clues regarding how visual/non-visual systems evolved in different creatures to use light as an external signal. The function of Opsins in the Ambulacraria groups of animals, which include sea urchins, has not been characterized, something the researchers aimed to address.

A schematic diagram the light ? pylorus signaling pathway in sea urchin larvae. © University of Tsukuba

“The functions of eyes and visual systems have been well-characterized,” says senior author of the study Professor Shunsuke Yaguchi. “However, the way in which light dependent systems were acquired and diversified throughout evolution is unclear especially in deuterostomes because of the lack of data regarding the signaling pathway in the Ambulacraria group.”

To address this, the researchers tested whether light exposure caused changes in digestive tract activity in sea urchins. They then conducted micro-surgical and genetic knockdown experiments to test whether Opsin cells in the sea urchin digestive system mediated the effect of light.

“The results provided new information about the role of Opsins in sea urchins,” explains Professor Yaguchi. “Specifically, we found that stimulation of sea urchin larvae via light caused changes in digestive system function, even in the absence of food stimuli.”

Furthermore, the researchers identified brain serotonergic neurons near the Opsin-expressing cells that were essential for mediating the light-stimulated release of nitric oxide, which acts as a neurotransmitter.

“Our results have important implications for understanding the process of evolution, specifically, that of light-dependent systems controlled via neurotransmitters,” says Professor Yaguchi.

The data indicate that an early function of brain neurons may have been the regulation of the digestive tract in our evolutionary ancestors. Because food consumption and nutrient absorption are critical to survival, the development of a sophisticated brain-gut regulatory system may have been a major step in animal evolution.

The article, “Sea urchin larvae utilize light for regulating the pyloric opening” was published in BMC Biology at DOI:10.1186/s12915-021-00999-1

Featured image: Photoirradiation drives the pyloric opening. Images of five seconds (sec) and 1 min 30 sec © University of Tsukuba


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