Tag: 20/1/25

Developing a Grapefruit that Won’t Interfere with Medication Levels

Photo by Olga Petnyunene on Unsplash

Grapefruit and pummelo contain compounds called furanocoumarins that may affect the blood levels of more than 100 prescription drugs, so that people taking these medications are advised to remove these fruits from their diets. Research published in New Phytologist reveals genetic information about the synthesis of furanocoumarins in different citrus plant tissues and species and provides new insights that could be used to develop grapefruit and pummelo that lack furanocoumarins.

The research indicates that the production of furanocoumarins in citrus fruit is dependent on the integrity of a single gene within a multi-gene cluster that encodes enzymes of the 2-oxoglutarate-dependent dioxygenase family.

“This research helps us to understand why fruit of certain citrus species produce furanocoumarins and demonstrates how breeders and researchers could develop furanocoumarin-free citrus varieties,” said co–corresponding author Yoram Eyal, PhD, of the Volcani Center, in Israel.

Source: Wiley

Decoding How HIV Hijacks our Cellular Machinery

Colourised transmission electron micrograph of an HIV-1 virus particle (yellow/gold) budding from the plasma membrane of an infected H9 T cell (purple/green).

A team of scientists at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg and the University of Regensburg has unveiled insights into how HIV-1 skilfully hijacks cellular machinery for its own survival. By dissecting the molecular interplay between the virus and its host, the researchers identified novel strategies that HIV-1 employs to ensure its replication while suppressing the host’s cellular defences. The study was published in the journal Nature Structural and Molecular Biology.

HIV-1, like other viruses, lacks the machinery to produce its own proteins and must rely on the host cell to translate its genetic instructions. After entering host cells, it seizes control of the translation process, which converts messenger ribonucleic acid (mRNA) into proteins. “In this study, we combined ribosome profiling, RNA sequencing and RNA structural probing to map the viral and host translational landscape and pausing during replication of the virus in unprecedented detail,” says corresponding author Neva Caliskan.

Cheat Codes of Viral Translation

One of the key findings was the discovery of previously unrecognized elements in HIV-1 RNA called upstream open reading frames (uORFs) and internal open reading frames (iORFs). These “hidden gene fragments” may play a crucial role in fine-tuning the production of viral proteins as well as the interaction with the host immune system. “For instance, uORFs and iORFs can act as regulators, ensuring precise timing and levels of protein synthesis”, explains Anuja Kibe, a postdoctoral researcher at the HIRI and first author of the study.

Another important discovery was an intricate RNA structure near the critical “frameshift site” in the viral genome. This frameshift site is essential for the virus to produce the correct proportions of two key proteins, Gag and Gag-Pol, which are necessary for assembling infectious particles and replication of HIV-1. The researchers demonstrated that this extended RNA fold not only promotes ribosome collisions upstream of the site (a mechanism that appears to regulate translation) but also maintains the frameshifting efficiency. “Our team also showed that targeting this RNA structure with antisense molecules could significantly reduce frameshift efficiency by nearly 40 percent, offering a promising new avenue for antiviral drug development”, reports Caliskan. 

A Game of Priorities

Redmond Smyth, a former Helmholtz Young Investigator Group Leader at the HIRI and currently a group leader at the Centre National de Recherche Scientifique (CNRS) in Strasbourg, France, mentions, “Interestingly, our analysis revealed that, while HIV-1 mRNAs are translated efficiently throughout infection, the virus suppresses the protein production of the host, particularly at the translation initiation stage.” This allows HIV-1 to prioritise its own needs while effectively stalling the host defence mechanisms. Thus, the virus can manipulate the host cell machinery in ways that remain robust even under stress conditions.

More Than Traffic Jams

The researchers also observed that ribosomes collide at specific regions of the viral RNA, particularly upstream of the frameshift site. “These collisions are not accidental but are instead tightly regulated pauses that may influence how ribosomes interact with downstream RNA structures,” says Florian Erhard, study co-author and Chair of Computational Immunology at the University of Regensburg.

Overall, the study provides not only a detailed map of the translational landscape of HIV-1 infected cells but also a wealth of potential targets for therapeutic intervention. The identification of RNA structures and genetic elements critical for viral replication highlights new opportunities for the development of drugs aimed at disrupting these processes. “By understanding how the virus cleverly manipulates our cells, these discoveries will bring us closer to innovative treatments that could one day turn tables and outsmart the virus itself,” Caliskan adds.

Source: Helmholtz Centre for Infection Research

Brain Changes in Huntington’s Disease Seen Decades ahead of Symptoms

Photo by Robina Weermeijer on Unsplash

Subtle changes in the brain, detectable through advanced imaging, blood and spinal fluid analysis, happen approximately twenty years before a clinical motor diagnosis in people with Huntington’s disease, finds a new study led by UCL researchers which appears in Nature Medicine.

The team found that although functions such as movement, thinking or behaviour remained normal for a long time before the onset of symptoms in Huntington’s disease, subtle changes to the brain were taking place up to two decades earlier. These findings pave the way for future preventative clinical trials, offer hope for earlier interventions that could preserve brain function and improve outcomes for individuals at risk of Huntington’s disease.

Huntington’s disease is a devastating neurodegenerative condition affecting movement, thinking and behaviour. It is a genetic disease and people with an affected parent have a 50% chance of inheriting the Huntington’s disease mutation, meaning they will develop disease symptoms – typically in mid-adulthood.

The disease is caused by repetitive expansions of three DNA blocks (C, A and G) in the huntingtin gene. This sequence tends to continually expand in certain cells over a person’s life, in a process known as somatic CAG expansion. This ongoing expansion accelerates neurodegeneration, making brain cells more vulnerable over time.

For the new study, the researchers studied 57 people with the Huntington’s disease gene expansion, who were calculated as being on average 23.2 years from a predicted clinical motor diagnosis.  

They were examined at two time points over approximately five years to see how their bodies and brains changed over time. Their results were compared to 46 control participants, matched closely for age, sex and educational level.

As part of the study, all participants volunteered to undergo comprehensive assessments of their thinking, movement and behaviour, alongside brain scans and blood and spinal fluid sampling.

Importantly, the group with Huntington’s disease gene expansion showed no decline in any clinical function (thinking, movement or behaviour) during the study period, compared to the closely matched control group.

However, compared to the control group, subtle changes were detected in brain scans and spinal fluid biomarkers of those with Huntington’s disease gene expansion. This indicates that the neurodegenerative process begins long before symptoms are evident and before a clinical motor diagnosis.

Specifically, the researchers identified elevated levels of neurofilament light chain (NfL), a protein released into the spinal fluid when neurons are injured, and reduced levels of proenkephalin (PENK), a neuropeptide marker of healthy neuron state that could reflect changes in the brain’s response to neurodegeneration.

Lead author, Professor Sarah Tabrizi (UCL Huntington’s Disease Research Centre, UCL Queen Square Institute of Neurology, and UK Dementia Research Institute at UCL), said: “Our study underpins the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in living humans with the Huntington’s disease gene expansion. I want to thank the participants in our young adult study as their dedication and commitment over the last five years mean we hope that clinical trials aimed at preventing Huntington’s disease will become a reality in the next few years.”

The findings suggest that there is a treatment window, potentially decades before symptoms are present, where those at risk of developing Huntington’s disease are functioning normally despite having detectable measures of subtle, early neurodegeneration. Identifying these early markers of disease is essential for future clinical trials in order to determine whether a treatment is having any effect.

Co-first author of the study, Dr Rachael Scahill (UCL Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology) said: “This unique cohort of individuals with the Huntington’s disease gene expansion and control participants provides us with unprecedented insights into the very earliest disease processes prior to the appearance of clinical symptoms, which has implications not only for Huntington’s disease but for other neurodegenerative conditions such as Alzheimer’s disease.”

This study is the first to establish a direct link between somatic CAG repeat expansion, measured in blood, and early brain changes in humans, decades before clinical motor diagnosis in Huntington’s disease.

While somatic CAG expansion was already known to accelerate neurodegeneration, this research demonstrates how it actively drives the earliest detectable changes in the brain: specifically in the caudate and putamen, regions critical to movement and thinking.

By showing that somatic CAG repeat expansion changes measured in blood predicts brain volume changes and other markers of neurodegeneration, the findings provide crucial evidence to support the hypothesis that somatic CAG expansion is a key driver of neurodegeneration.

With treatments aimed at suppressing somatic CAG repeat expansion currently in development, this work validates this mechanistic process as a promising therapeutic target and represents a critical advance towards future prevention trials in Huntington’s disease.

Co-first author of the study, Dr Mena Farag (UCL Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology) added: “These findings are particularly timely as the Huntington’s disease therapeutic landscape expands and progresses toward preventive clinical trials.”

The research was done in collaboration with experts at the Universities of Glasgow, Gothenburg, Iowa, and Cambridge.

Source: University College London

Windows in ICU Rooms Increase the Risk of Post-surgical Delirium

Photo by Rodnae Productions on Pexels

Delirium is a condition common in the post-surgical intensive care unit (ICU) setting, affecting up to 50-70% of those admitted, depending on individual risk profiles. ICU delirium can be associated with a multitude of factors including underlying and acute medical conditions, pharmacologic agents or treatment regimens like surgery. Currently there is no definitive consensus on drug interventions that aid in the prevention of delirium or its treatment.

While there has been some evidence that the ICU environment plays a role in delirium, more research is needed to understand this association. In a new study appearing in Critical Care Medicine, researchers found windowed patient rooms were associated with an increase in the odds of developing delirium, when compared to patient rooms without windows.

Using electronic medical records, researchers from Mass General Brigham and collaborators at Boston University Chobanian & Avedisian School of Medicine reviewed the association between patients being admitted to an ICU room with or without windows and the presence of delirium. Delirium was observed in 21% (460/2235) of patients in windowed rooms and 16% (206/1292) of patients in non-windowed rooms.

“While the findings of the study were ultimately unexpected due to prior research suggesting the importance of circadian rhythm while in the hospital, our results contribute to a growing body of evidence-based design literature around the importance of healthcare design to patient experience and outcomes,” explained corresponding author Diana Anderson, MD, FACHA, assistant professor of neurology at the school. She notes that because of the study design, these unexpected findings are not causative and may represent different patterns in which some patients – who are potentially at an increased risk of delirium – may be assigned to different room layouts by the clinical teams.

According to the authors, further research into the specific qualities of windows that may impact health is needed to better understand these results. “Although this study adds to our understanding of the relationship between delirium and characteristics of the built environment, it is clear that additional studies may provide further insight to understand these results. For example, it is possible that the window view toward adjacent landscapes or buildings may be important context to interpret these findings, or perhaps another feature of the room such as light or sound that we could consider in our next investigation,” Anderson says.

Source: Boston University School of Medicine

Survey Sheds Light on the Phenomenon of Topical Steroid Withdrawal

Source: Pixabay

Painful skin and trouble sleeping are among the problems reported when tapering cortisone cream for atopic eczema, as shown by a study headed by the University of Gothenburg. Many users consider the problems to be caused by cortisone dependence.

Topical steroid withdrawal (TSW) is a phenomenon commonly described as extremely red and painful skin arising when cortisone cream treatment is tapered or stopped.

While TSW is not an established diagnosis, the name indicates that the skin has become dependent on cortisone. Little research has been conducted to identify a dependency mechanism, so scientific support is lacking. At the same time, the term has become commonplace on social media, raising concerns among patients about cortisone cream safety.

Now, a national research group in Sweden, headed by Sahlgrenska Academy at the University of Gothenburg, has conducted the first study in which a larger group has been asked to provide a detailed account of what they consider to be TSW. The results are published in the journal Acta Dermato-Venereologica.

Questionnaire via social media

The study targeted adults with atopic eczema, a group that often uses cortisone cream, who also identified as suffering from TSW. The study was conducted by means of an anonymous questionnaire presented in Swedish in social media forums, with the option to share a link to invite other potential participants. The questionnaire was answered by almost one hundred people aged 18–39, the majority of whom were women.

“We wanted to gain more knowledge about how those who identify as suffering from TSW define the phenomenon and which symptoms they describe,” says Mikael Alsterholm, a researcher at the University of Gothenburg and a senior consultant in dermatology and venereology at Sahlgrenska University Hospital.

The results show variations in how the participants defined TSW. Most common was to define it as a dependence on cortisone, with symptoms arising when tapering or stopping its use, although many others also defined TSW as a reaction to cortisone already during its use.

It was also common to define TSW on the basis of the symptoms seen in the skin, such as redness and pain. While the symptoms described varied, they were largely similar to the symptoms seen in an exacerbation of atopic eczema.

In addition to the skin becoming red, dry, and blistered – mainly on the face, neck, torso, and arms – the participants also described sleep problems due to itching as well as signs of anxiety and depression.

Healthcare and research involvement

A majority of the participants described concurrent symptoms of both atopic eczema and TSW. Cortisone cream was most often cited as the triggering factor, while some cited cortisone tablets and a few cortisone-free treatments.

“It’s important that healthcare professionals and researchers are involved in the discussion on TSW and contribute science-based knowledge where possible. Cortisone cream is an effective and safe treatment for most people, and at present there’s no support for avoiding its use for fear of the types of symptoms described in the context of TSW,” says Mikael Alsterholm.

“At the same time, there’s a patient group with different experiences, expressed as TSW, and their symptoms and the potential causes need to be investigated by means of both research and practical healthcare. To do this, we first need to define TSW. While we understand that this is complicated, we hope that this study can help establish such a definition,” he concludes.

Source: University of Gothenburg