The digestive system is home to trillions of bacteria, many of which produce short-chain fatty acids (SCFAs) that help fight harmful pathogens. But Salmonella manages to grow and spread in the gut, even though these protective compounds are present. The study asks: How does Salmonella get around this defense?

“We knew that Salmonella invades the small intestine, although it is not its primary site of replication. The colon is,” said the lead author of the study Andreas Bäumler. Bäumler is a UC Davis distinguished professor and vice chair of research in the Department of Medical Microbiology and Immunology.

Bäumler and his team discovered that the answer lies in how the pathogen changes the gut’s nutrient balance. When Salmonella enters the small intestine, it causes inflammation in the gut lining and disrupts the normal absorption of amino acids from food. This creates an imbalance in nutrients in the gut.

The imbalance gives Salmonella the resources it needs to survive and multiply in the large intestine (colon), where beneficial bacteria usually curb its growth. The study showed that salmonella causes inflammation in the small intestine in order to derive nutrients that fuel its replication in the colon.

Salmonella alters gut nutrient environment to survive

Using a mouse model, the team looked closely at how Salmonella changed the chemical makeup of the gut. They traced amino acid absorption in the small and large intestines.

They found that in mice that were infected with Salmonella, there was less absorption of amino acids into the blood. In fact, two amino acids, lysine and ornithine, became more abundant in the gut after infection. These amino acids helped Salmonella survive by preventing the growth-inhibiting effects of SCFAs. They did this by restoring Salmonella’s acidity (pH) balance, allowing the pathogen to bypass the microbiota’s defenses.

“Our findings show that Salmonella has a clever way of changing the gut’s nutrient environment to its advantage. By making it harder for the body to absorb amino acids in the ileum, Salmonella creates a more favorable environment for itself in the large intestine,” Bäumler said.

In the study, the team showed that Salmonella uses its own virulence factors (disease causing molecules) to activate enzymes that break down key amino acids like lysine. This helps the pathogen avoid the SCFAs’ protective effects and grow more easily in the gut.

New insights could lead to better gut infection treatments

The new insights potentially explain how the gut environment changes during inflammatory bowel disorders , such as Crohn’s disease and ulcerative colitis, and could lead to better treatments for gut infections. By understanding how Salmonella changes the gut environment, researchers hope to develop new ways to protect the gut microbiota and prevent these infections.

“This research uses a more holistic approach to studying gut health. It not only gives us a better understanding of how Salmonella works, but also highlights the importance of maintaining a healthy gut microbiota,” said Lauren Radlinski, the study’s first author and postdoctoral fellow in the Bäumler Lab. “Our findings could lead to new treatments that help support the microbiota during infection.”

The study’s results could inspire future treatments, including probiotics or dietary plans designed to strengthen the body’s natural defenses against harmful pathogens.

“By learning how a pathogen manipulates the host’s system, we can uncover ways to boost the host’s natural defenses,” Radlinski said.

Coauthors of the study are Andrew Rogers, Lalita Bechtold, Hugo Masson, Henry Nguyen, Anaïs B. Larabi,Connor Tiffany, Thaynara Parente de Carvalho and Renée Tsolis of UC Davis.

T cells are a type of immune cell that seeks out and destroys cells infected by viruses, bacteria as well as tumour cells. Originally designed to detect SARS-CoV-2-specific T cells, this technology has now been adapted for use in cancer immunotherapy applications. The test, which uses less than a quarter teaspoon of blood, works by stimulating the target T cells in the blood to release chemical signals, called cytokines, through which the quantity and quality of the target T cells can be measured.

In this proof-of-concept study, which was published in Immunotherapy Advances,the research team introduced fragments, called peptides, that stimulate the T cells engineered to fight Hepatitis B virus-related liver cancer present in the treated patients. Using their test, they assessed whether the engineered T cells remained in the blood and continued to function properly after infusion into the patient.

Assistant Professor Anthony Tan, from Duke-NUS’ Emerging Infectious Diseases Programme and first author of the study, commented:

“Our innovative test enables us to swiftly detect and analyse engineered T cells in patient blood samples. Its simplicity and speed could have a significant impact on the clinical field helping to make advanced treatments more accessible.”

With engineered T-cell therapies becoming more widely used to treat malignancies, including Hepatitis B virus-induced liver cancer and a range of blood cancers, being able to accurately and easily track how these engineered cells behave in the body over time will be crucial in monitoring the effectiveness of these therapies in individual patients.

At the same time, this plug-and-play concept can help accelerate the translation of new T-cell-based therapies from the laboratory to patient bedside. The research team has already demonstrated that the test can be adapted for use in numerous viral infections, but this is their first foray into cancer therapies, where the test can be harnessed for T-cell receptor (TCR) engineered T cells, as well as chimeric antigen receptor (CAR) T-cell therapies.

Professor Antonio Bertoletti, from Duke-NUS Emerging Infectious Diseases Programme and senior author of the study, added:

“Tracking the functionality of adoptively transferred engineered T-cell products could provide important information on treatment efficacy over time, an assessment which at the moment remains largely unexplored. We hope that with this proof-of-concept, we can help accelerate research into other CAR and TCR T-cell therapies as well as support clinicians on the frontline caring for patients receiving these novel therapies.”

In collaboration with Lion TCR Pte Ltd, the test has been deployed in a Hepatitis B virus-TCR T-cell therapy clinical trial, called the SAFE-T-HBV trial, evaluating the effectiveness of a novel therapy in two patients and demonstrating the test’s impact on improving the precision of immunotherapy outcomes.

The team is now looking to advance this proof-of-concept through larger clinical studies.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, said that he sees potential in the new test. He added:

“This innovation isn’t just a step forward in cancer therapy, it’s a significant advancement in patient care that could extend across multiple diseases. By offering clinicians real-time data on the functionality of these engineered T cells, we are paving the way for highly personalised treatment strategies that could significantly enhance patient outcomes.”

As a leader in biomedical research, Duke-NUS combines basic scientific research with translational applications to innovate treatments approaches and diagnostic tools to advance health globally.

This research is supported by the Singapore Ministry of Health through the National Medical Research Council (NMRC) Office, MOH Holdings Pte Ltd under the NMRC Singapore Translational Research Investigator Award (MOH-000019). The SAFE-T-HBV clinical trial was sponsored by Lion TCR Pte Ltd.

In order to produce offspring from xenotransplanted ovaries, Japanese researchers at Niigata University and University of Toyama conducted a study to establish a system to produce offspring from eggs obtained by transplanting rat ovaries into mice.

The researchers implanted rat ovaries under the renal capsules of immunodeficient mice and confirmed their viability. Then, they administered hormones related to oocyte development and succeeded in obtaining mature rat eggs. These eggs were found to develop normally when fertilized in vitro and to become embryos or offspring when transplanted into the rat uterus. When the ovaries from rats expressing a fluorescent protein throughout the body were used for donner, resulting in rat offspring expressing the fluorescent protein. It was confirmed that this genetic trait is inherited to the next generation. These results were published in Scientific Reports on August 29, 2024.

“There have been reports on the acquisition of eggs and embryos using interspecies ovarian transplantation into mouse recipients, but there are no successful cases of offspring production. In this study, we were able to produce fertilized eggs and offspring, overcoming this tough challenge,” says Runa Hirayama, a graduate student at the University of Toyama.

An important point in producing offspring by this method was to obtain mature eggs from the transplanted ovaries. After administering hormones to transplanted mice, both mature and immature eggs were obtained from the transplanted ovaries. Mature eggs could be fertilized immediately after acquisition, while immature eggs needed to be matured before fertilization. In this study, we found that the percentage of eggs that matured and were cultured in vitro and produced offspring was very low, and that the maturity when the eggs were obtained from the ovary was critical for increasing the birth rate.

“This new offspring production system has the potential for the generation of genetically modified rats and could become one of the most effective methods of animal offspring production,” says Dr. Hiroaki Taketsuru of Niigata University. This achievement will not only facilitate the production of genetically modified animals, but also be applied to the creation of offspring of all types of animals, as well as reproductive medicine.

“Parrots are unique birds in many ways, including how they produce their vibrant colour diversity,” begins Professor Simon Yung Wa Sin, co-author from the School of Biological Sciences of The University of Hong Kong (HKU).

“Parrots do their own thing when it comes to colour,” adds Dr Roberto Arbore of BIOPOLIS-CIBIO, and co-first author of the study. Although other birds also produce yellow and red feathers, parrots evolved unique pigments, called psittacofulvins (from the ancient Greek ‘psittakós’ for parrot, and the Latin ‘fulvus’ for reddish-yellow). “Parrots combine these with other pigments to create vibrant yellows, reds, and greens, making these animals among nature’s most colourful,” he mentions.

Parrots are common pets in millions of homes worldwide, and they are appreciated for their colour and intelligence. But for all their flashiness, it was not well understood how these birds evolved a unique way to create their colour palette. “This is a big mystery for scientists and bird lovers alike,” explains Professor Miguel Carneiro, senior author from BIOPOLIS-CIBIO, who adds, “and it ties up to a key question to all of biology, of how does diversity arise in nature?”

To answer such a fundamental question, the scientists started by demonstrating that, across all major parrot lineages, yellow and red in feathers correspond to two specific pigments that do not occur in other birds. “Although there were some indications in the literature about the existence of two chemical forms of psittacofulvins, it was initially hard for us to believe what we were seeing in the results — side by side, clear as day — for the first time ever. Only with genetic data it all started to make perfect sense,” says Dr Jindřich Brejcha from the Faculty of Science at Charles University in Prague, another co-first author.

To dig deeper, the scientists focused on a species with naturally occurring red or yellow forms, a phenomenon that is extremely rare in nature. “The dusky lory is native to the jungles of New Guinea, but we just had to drive a few miles from our lab in Portugal, since local certified breeders helped us get samples to study the genetics of colour in this species,” mentions Pedro Miguel Araújo of the University of Coimbra, who co-led the research, adding, “The solution to our study was almost next door!”

The scientists found that only one protein controlled the colour difference in the lories, a type of aldehyde dehydrogenase (or ALDH), essential ‘tools’ for detoxification in complex organisms — for example, they contribute to elimination of alcohol in the liver of humans. Dr Soraia Barbosa , also co-first author from BIOPOLIS-CIBIO, explains, “Parrot feathers found a way to “borrow” this protein, using it to transform red to yellow psittacofulvins.” According to the scientist, “This functions like a dial, in which higher activity of the protein translates to less intense red colour.”

To understand the general role of this protein in controlling the plumage colour in other parrot species, scientists studied another parrot, the rosy-faced lovebirds, a species that displays both green (i.e., yellow psittacofulvin-containing) and red plumage patches. “The rosy-faced lovebird is a familiar parrot that provides an excellent system to study the genes determining the colour difference between red and yellow psittacofulvin-containing plumage patches,” mentions Simon Yung Wa Sin, who led the team from the School of Biological Sciences at HKU, including Dr Alison Cloutier and Research Assistant Emily Shui Kei Poon. They found that the same aldehyde dehydrogenase gene in the lovebirds to express at high level in yellow psittacofulvin-containing feathers, but not in red feathers. “When this gene expresses at a high level, the psittacofulvins turn from red to yellow,” explains Simon.

To demonstrate this simple dial mechanism, scientists turned to an even more familiar parrot, the budgerigar and, in a world-first, explored how individual cells turn different genes on or off throughout feather growth, pinpointing a small number of cells that use this detox protein for controlling pigment conversion. The final validation came when the scientists genetically engineered yeasts with the parrot colour gene, “Incredibly, our modified yeast produced parrot colours, demonstrating that this gene is sufficient to explain how parrots control the amount of yellow and red in their feathers.” Professor Joseph C. Corbo, Professor at the Washington University in St. Louis (USA) says.

This study showcases how cutting-edge developments in biotechnology are increasingly used to unravel nature’s mysteries. “We now understand how these stunning colours can evolve in wild animals through a simple dial-like ‘molecular switch’ that ‘borrows’ a detoxifying protein to serve a new function,” Carneiro concludes. These findings help scientists paint a new colourful picture of evolution as a process in which complexity can be achieved through simple innovations.

NPC, often referred to as ‘Cantonese Cancer’, affects predominantly 30- to 60-year-old men in southern China, including Guangdong and Hong Kong, and Southeast Asia. The cause is associated with various factors, including genetics, environment and viruses. The researchers emphasise that understanding the role of EBV in NPC’s pathogenesis is crucial since the virus has 100% association with this cancer.

Background

EBV has long been known to be closely associated with the development of NPC. However, recent research by principal investigators at HKUMed and Sun Yat-sen University Cancer Centre has shown that certain EBV variants might elevate the risk of individuals developing NPC, which is typically diagnosed at a late stage of the disease. Early detection will significantly improve the survival rate and reduce the long-term side effects of treatment, underscoring the importance of ongoing research and public awareness of the factors contributing to NPC.

Research results and significance

A HKUMed research team conducted a meta-analysis of genome-wide association studies (GWAS) of two datasets from Hong Kong and one dataset from Guangdong province, comprising a total of 279 and 227 EBV genomic sequences derived from NPC patients and healthy population carriers in Hong Kong and southern China, respectively. The study revealed high-risk EBV haplotype present in about 70% of NPC cases, compared to about 30% of population carriers. The use of nine genetic markers associated with a high-risk EBV lineage might help predict the presence of NPC, thus providing a potential new avenue for NPC screening and diagnosis.

Professor Alan Chiang Kwok Shing, the study’s principal investigator, from the Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, HKUMed, stated that the identification of a distinct high-risk EBV lineage offers valuable insight for future studies of disease mechanisms and the development of targeted screening and diagnostic tests of NPC in endemic regions, such as Hong Kong and southern China, ultimately improving patient outcomes.

“By analysing extensive datasets surveyed in southern China, we confirmed the association of specific genetic variants near the EBER2 region of the EBV genome with NPC. These high-risk variants are tightly linked and form a broader risk haplotype,” added Professor Chiang.

About the research team

The study was led by Professor Alan Chiang Kwok Shing and co-investigator Professor Yang Wanling, both from the Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, HKUMed. The key research team members are Dr Wong Ka-wo and Dr Hui Kwai-fung. Other collaborating researchers are Professor Dora Kwong Lai-wan and Professor Maria Lung Li, both from the Department of Clinical Oncology, School of Clinical Medicine, HKUMed.

Acknowledgements

The study was funded by the Health and Medical Research Fund of the Health Bureau, HKSAR government, and received support from the NPC Tissue Bank, under the Research Grants Council Areas of Excellence (AoE) Scheme, which provided additional NPC samples.

Selenoproteins are crucial for several biological functions, including the breakdown of harmful substances, immune system support, and regulating metabolic processes. However, in specific contexts, these proteins can be misused and shield cancer cells from death. One such protein, glutathione peroxidase 4 (GPX4), is vital in supporting cellular protection and cancer cell survival.

“This protective property of GPX4 creates a significant challenge for standard cancer therapies, as its activity has been shown to promote survival of drug-tolerant states,” says Professor Pedro Friedmann Angeli, chair of Translational Cell Biology at the University of Würzburg (JMU), Germany. “But if we can inhibit GPX4 production, we may be able to target and destroy cancer cells. This is particularly promising for treating neuroblastoma, which primarily affects children.”

Making Cancer Cells More Vulnerable

Together with researchers from the Heidelberg Institute for Stem Cell Technology and Experimental Medicine led by junior group leader Hamed Alborzinia, Friedmann Angeli’s team is therefore focusing on research into the inhibition of enzymes that promote selenocysteine insertion into selenoproteins. “Until now, we only knew of one enzyme, selenocysteine lyase (SCLY), which was responsible for releasing the selenium atom from selenocysteine,” explains Zhiy Chen, a PhD student in Friedmann Angeli’s team and first author of the study. “Our research has now identified an unforeseen pathway that requires the enzyme, peroxiredoxin 6 (PRDX6), which can sustain selenoprotein production without SCLY.”

Through cutting-edge techniques such as mass spectrometry and CRISPR-Cas9-based functional genomics, the research team discovered that PRDX6 binds directly to selenium and acts as a transporter, or “shuttle,” for the trace element, enabling the production of new selenoproteins. The study also demonstrated that inhibiting PRDX6 could impair cancer cell survival, especially in neuroblastomas, offering a new potential therapeutic target.

Next Steps in Cancer Research

Interestingly, the team found that although PRDX6 can compensate for the absence of SCLY, it lacks the specific activity present in SCLY required to remove the selenium atom from its precursors. Friedmann Angeli’s group aims to investigate which other proteins collaborate with PRDX6 to maintain selenium protein synthesis. Additionally, the development of molecular inhibitors targeting both SCLY and PRDX6 is on the horizon, aiming to better hinder cancer cell growth.

The study was collaborative, involving partners from the University of São Paulo in Brazil, the Institute of Stem Cell Technology and Experimental Medicine in Heidelberg, and the German Cancer Research Center (DKFZ). It was financially supported by the Rudolf Virchow Center at the University of Würzburg, the German Research Foundation (DFG), the EU-H2020 (ERC-CoG, DeciFERR) and the José Carreras Leukemia Foundation.

Learning and decision-making change considerably from adolescence into adulthood. Adolescents undergo developmental changes in specific choice behaviors, such as goal-directed behaviors and motivational influences over choice. They also consistently show high levels of decision noise, i.e., choosing suboptimal options. However, it remains unknown whether these observations — the development of specific and more sophisticated choice processes and higher decision noise — are independent or related. It is possible that the development of specific choice processes might be impacted by age-dependent changes in decision noise.

To test this idea, Scholz, Deserno, and colleagues analyzed data from 93 participants between 12 and 42 years of age. The participants completed three reinforcement learning tasks: a task assessing motivational influences over choices, a learning task capturing adaptive decision-making in response to environmental changes, and a task measuring goal-directed behavior.

The results revealed that noise levels were strongly correlated across reinforcement learning tasks. Critically, noise levels mediated age-dependent increases in more sophisticated choice behaviors and performance gains. The findings suggest that unspecific noise mediates the development of highly specific functions or strategies.

One reason for these mediation effects could be a limited availability of cognitive resources in adolescents due to the ongoing development of brain areas related to cognitive control. Having fewer cognitive resources might make adolescents more prone to rely on computationally cheaper decision strategies, rendering them more susceptible to emotional, motivational and social influences.

Overall, the study provides novel insights into the computational processes underlying developmental changes in decision-making. According to the authors, future work may unravel the neural basis as well as the developmental and clinical real-life relevance of decision noise for neurodevelopmental disorders.

The authors add, “Teenagers make less optimal, so-called ‘noisy’ decisions. While these noisy decisions decrease when growing older, this decrease is also linked to the development of improved complex decision-making skills, such as planning and flexibility.”