Publisher Health

During the COVID-19 pandemic, the world has become aware of the value of using sewage analyses to monitor disease development in an area. However, at DTU National Food Institute, a group of researchers has been using sewage monitoring from throughout the world since 2016 as an effective and inexpensive tool for monitoring infectious diseases and antimicrobial resistance.
By analysing sewage samples received by DTU from 243 cities in 101 countries between 2016 and 2019, the researchers have now mapped where in the world the occurrence of resistance genes is highest, how the genes are located, and in which types of bacteria they are found.
The results from the new metagenomic study — which have just been published in Nature Communications — have surprised the researchers. In fact, the study shows that the genes have appeared in many different genetic contexts and bacterial types, indicating greater transmission than the researchers had expected.
“We’ve found similar resistance genes in highly different bacterial types. We find it worrying when genes can pass from a very broad group of bacteria to a completely different group with which there is no resemblance. It’s rare for these gene transmissions to occur over such long distances. It’s a bit like very different animal species producing offspring,” explains Assistant Professor Patrick Munk.
If the genes are in bacteria that don’t usually make people sick — such as lactic acid bacteria — it’s of less concern. However, if the resistance genes find their way into bacteria that are important to human health — such as salmonella — it’s a completely different story.
“This makes it much more likely that the bacteria will actually kill people — for example in a hospital — because no treatment is available,” emphasizes Patrick Munk.

Researchers at the University of York are a step closer to identifying ways to support clinicians in predicting drug treatment outcomes for patients with visceral leishmaniasis in Brazil.
Scientists at York had previously shown that the absence of four particular genes in some strains of Leishmania infantum parasite found in Brazil makes it less susceptible to an oral drug called miltefosine.
The absence of these genes correlates with resistance to the drug, which means that Brazilian patients would benefit from a prognostic test, but in order to do this scientists first had to identify what it was about the gene that made the parasite drug-resistant.
During a clinical trial using miltefosine treatment, 40% of patients relapsed within six months, but the presence of the genes in the parasite found in India, however, meant that after a month of treatment, the disease could be cured with a lower risk of relapse.
As a result of its ‘failure’ in Brazil the medication is not licensed in the country and therefore there is very little that can be done to manage the disease in patients, other than intravenous drugs which can prove to be a burden on medical facilities who have to deliver it.
The team, in collaboration with colleagues from the Universidade Federal do Piauí and and the Universidade Federal do Espírito Santo, have now taken the work a step further and identified the enzymes that make the difference between treatment success and failure.

Visual cells in the human retina may not simply die in some diseases, but are mechanically transported out of the retina beforehand. Scientists from the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden have now discovered this. For their research, they used miniature human retinas produced in the laboratory, so-called organoids. In the new issue of the journal Nature Communications, they report on their discovery, which paves the way for completely new research approaches, especially in connection with age-related macular degeneration (AMD).
“This principle, known as cell extrusion, has not yet been studied in neurodegenerative diseases,” says Prof. Mike Karl, who heads the research group. AMD is the main cause of blindness and severe visual impairment in Germany. It is estimated that a quarter of people over the age of 60 suffer from AMD. The macula is a special region within the human retina that is needed, among other things, for high resolution color vision. In AMD, thousands of light-sensitive visual cells, the so-called photoreceptor cells, are lost in the macula.
“This was the starting point for our research project: we observed that photoreceptors are lost, but we could not detect any cell death in the retina,” explains Mike Karl, who conducts research at the Dresden site of the DZNE and the CRTD at TU Dresden. “Half of all photoreceptors disappeared from the retinal organoid within ten days, but obviously they did not die in the retina. That made us curious.”
For the researchers — the DZNE and the CRTD were involved, as well as the Helmholtz Centre for Environmental Research (UFZ) — an elaborate search for the causes began. This led them to a study from 2012 (doi: 10.1038/nature10999): Jody Rosenblatt from King’s College in London was the first to describe the extrusion of living cells — the mechanical ejection of cells from epithelia. The thereby extruded cells then only die in succession. She demonstrated this mechanism in simple epithelial cells of the kidney. Mike Karl and his team now showed in their pioneering work that this extrusion can also be triggered in the much more complex retina, consisting of several different cell types, and leads to neurodegeneration. Interestingly, this cell extrusion could explain the outlying cells that have been previously reported in the ageing and diseased retina of patients with AMD and other diseases, but have not been studied in detail until now.
The researchers made use of a technique they had previously developed: They worked with so-called retinal organoids — an organ-like, three-dimensional model of the human retina grown from human stem cells in the laboratory. These organoids provide some characteristics of the human macula. The team found that two substances previously described in various neurodegenerative diseases — the proteins HBEGF and TNF — are sufficient to trigger degeneration in the retinal organoid.
During this process, the researchers filmed the organoids in real time by so-called live imaging, considered as the gold standard for cell tracking. “We were able to capture the degeneration of photoreceptors through cell extrusion in the lab,” says Mike Karl. The scientists found that this extrusion is triggered by activation of the protein PIEZO1, a sensor for biomechanical forces.
That biomechanics may play a larger role in retinal degeneration is a new finding. “The retina is not known to be a biomechanically active tissue such as a muscle. It was known that diseases of the nervous system are associated with changes in the shape of cells, but to which extent biomechanical regulators are involved has not yet been studied in detail,” says Karl. Thanks to the organoids, he and his team were able to observe the processes in an accelerated manner, so to speak: While it takes several years or even decades for photoreceptors to disappear in patients, such a process could now be reproduced in the laboratory in just 40 days. In the next step, the researchers now want to find out whether this mechanism occurs in human patients in the same way as in organoids. Initial findings suggest that this might be the same mechanism, but proof is still lacking.
In their study, the Dresden researchers also found that pharmacological agents could prevent extrusion in an experimental setting in their model. They used a special snake venom to block the mechanosensor PIEZO1 on the cells. As a result, not only were the photoreceptors not ejected, but further pathological changes in the retina were prevented. “This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD,” Mike Karl sums up.
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Materials provided by Technische Universität Dresden. Note: Content may be edited for style and length.

A medication used to treat MS also has a beneficial effect on the composition of the intestinal flora, according to researchers from the University of Basel and the University Hospital Basel. Conversely, the gut flora also plays a role in which side effects occur during treatment with the medication.
Few previous studies have examined the effects of MS treatments on intestinal flora and on the role their composition plays with regard to efficacy and side effects. A team of researchers at the University of Basel and the University Hospital Basel has now examined these questions in a group of 20 MS patients being treated with dimethyl fumarate. The team led by Professor Anne-Katrin Pröbstel, senior physician in Neurology and research group leader, and Professor Adrian Egli, who recently moved to the University of Zurich, published their findings in the journal Gut Microbes.
The medication, which is sold under the brand name Tecfidera, reduces the number of MS flare-ups by interfering with the metabolic processes of certain immune cells. However, the therapy is also associated with side effects, including hot flashes and gastrointestinal complaints, and in some cases lymphopenia, a lack of lymphocytes such as B cells and T cells in the blood. This can lead to severe complications.
More “good” bacteria
In their study, the researchers examined stool and blood samples from participants before and during the first twelve months of the treatment. Their focus was on the composition of the gut microbiome. Pröbstel and her team also measured the number of lymphocytes in the blood in order to identify patients who were experiencing lymphopenia as a side effect.
After only three months of treatment, the research team was already able to identify changes to the gut microbiome: “We were able to show that the gut bacteria of patients receiving the medication started to become more like the composition seen in healthy individuals,” Pröbstel explained. Treatment with dimethyl fumarate reduced the proportion of pro-inflammatory types of bacteria, which have been associated with MS, and supported the growth of “good” bacteria.
Furthermore, the researchers were able to draw a connection between the composition of the gut microbiome and the development of lymphopenia: The presence of Akkermansia muciniphila bacteria combined with the lack of Prevotella copri bacteria emerged as a risk factor for this side effect. The authors therefore suspect that P. copri may protect against lymphopenia.
Interaction between therapy and gut flora
“Our data suggest that immunomodulatory therapies affect not only immune cells, but also positively influence the gut microbiome,” Pröbstel explains. The connection between gut bacteria and clinical side effects of the treatment may eventually enable early identification of patients at risk of developing lymphopenia. Microbiologist Egli continues: “In the future, this relatively new field of microbiology may help us better understand the effects and side effects of many medications with regard to gut bacteria, and to personalize treatment accordingly.”
“What we have so far is only a pilot study with a relatively small number of participants,” she cautioned. Larger-scale studies are needed to confirm the results and explore the potential for supporting MS therapies via gut flora and for predicting side effects in advance.
The research team from the Departments of Neurology, Biomedicine, Clinical Research, and the Research Center for Clinical Neuroimmunology at the University of Basel and the University Hospital Basel received funding for the study from the University Hospital of Basel’s Propatient Foundation, the Goldschmidt-Jacobson Foundation, Biogen, the National Multiple Sclerosis Society and the Swiss National Science Foundation.
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Materials provided by University of Basel. Original written by Angelika Jacobs. Note: Content may be edited for style and length.

Researchers at Johns Hopkins Medicine say they have created a laboratory-grown three-dimensional “organoid” model that is derived from human tissue and designed to advance understanding about how early stages of cancer develop at the gastroesophageal junction (GEJ) — the point where the digestive system’s food tube meets the stomach.
A report on the organoid model findings, published Nov. 30 in Science Translational Medicine, also reveals a possible biological target for treating GEJ cancers with a drug that the researchers have already shown can slow down or stop growth of such tumors in mice.
According to the American Cancer Society, gastroesophageal cancers claim more than a million lives every year worldwide, with rates of GEJ cancer increasing more than twofold in recent decades, from 500,000 to 1 million new cases annually. Acid reflux, smoking and Helicobacter pylori bacterial infection of the stomach are well-established risk factors for tumors of the esophagus and stomach. But experts say it’s been difficult to show how cancer begins at the junction of the stomach and the esophagus, in part due to a lack of biologically relevant GEJ-specific early disease models for research.
“Because we don’t have a unique model that distinguishes GEJ tumors, gastroesophageal cancers often are classified as either esophageal cancer or gastric cancer — not GEJ cancer,” says gastroenterologist Stephen Meltzer, M.D., the Harry and Betty Myerberg/Thomas R. Hendrix and American Cancer Society Clinical Research Professor of Medicine at the Johns Hopkins University School of Medicine and corresponding author of the study. “Our model not only helps identify crucial changes happening during tumor growth at the GEJ, but also establishes a strategy for future studies to help understand tumors of other organs.”
Meltzer and a team of experts in cell biology, epigenomics, lipid profiling and big data analysis created the GEJ disease model by taking normal human biopsy tissue from patients receiving upper endoscopies. Organoids comprise three-dimensional collections of cells derived from stem cells that can replicate characteristics of an organ or what an organ does, such as making specific kinds of cells.
Using clustered regularly interspaced palindromic repeats (CRISPR/Cas9), a gene editing technology, the researchers then knocked out two key tumor suppressor genes (TP53 and CDKN2A) in the organoids. Dual knockout of these genes caused cells to become more cancerous, with more rapid growth and microscopic features closer to malignancy. These altered organoids also formed tumors in immunodeficient mice.
The team further found abnormalities in a class of molecules (lipids) that store energy but also exert a variety of other functions, and identified platelet activating factor as a key upregulated lipid in GEJ organoids. Platelets circulate in the bloodstream and bind together or clot when they recognize damaged blood vessels, and they can cause clotting diseases in some people. Researchers used WEB2086, which stopped the growth of implanted GEJ organoid tumors. WEB2086, a compound approved by the Food and Drug Administration and used to treat platelet diseases, inhibits platelet activating factor receptors in mine.
Meltzer says more preclinical studies may be needed before using the compound for human patients, but that organoids may help advance such studies.
“Combining organoids with this gene editing method [CRISPR/Cas9] is a potentially fruitful strategy for studying other human tumors in general,” says Meltzer.
Other researchers who worked on this study include Hua Zhao, Yulan Cheng, Andrew Kalra, Ke Ma, Eun Ji Shin, Saowanee Ngamruengphong, Mouen Khashab, Vikesh Singh and Simran Jit of the Division of Gastroenterology and Hepatology, Department of Medicine, at The Johns Hopkins University School of Medicine; Robert Anders of the Department of Pathology, Johns Hopkins University School of Medicine; Kristine Glunde and Nicolas Wyhs of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Caitlin Tressler of the Johns Hopkins University School of Medicine Division of Cancer Imaging Research; Benjamin Ziman and Dechen Lin of the University of Southern California (USC); Wei Chen and Xu Li with the First Affiliated Hospital of Xi’an Jiaotong University; and Yueyuan Zheng at the Cedars-Sinai Medical Center.
Authors report no conflicts of interest in this study.
Supported by grants from the National Institutes of Health, the DeGregorio Family Foundation, the Emerson Collective Cancer Research Fund, and the Herman Ostrow School of Dentistry of the USC Center for Craniofacial Molecular Biology.

A link has been found between joint hypermobility and the emergence of depression and anxiety in adolescence, according to a new study by Brighton and Sussex Medical School (BSMS) published in BMJ Open.
Researchers found that young people with joint hypermobility were more likely to have depression and anxiety, and that psychiatric symptoms were also more severe among hypermobile participants.
Dr Jessica Eccles, Clinical Senior Lecturer BSMS and MQ Arthritis Research UK Fellow and lead author said: “Many psychiatric problems, including depression and anxiety, start before the age of 25. It is therefore important to identify the factors that may increase the risk for these disorders. Being aware of the link between hypermobility and depression and anxiety means that we can work on developing appropriate and effective treatments.”
Joint hypermobility is caused by a genetic difference in our connective tissue, and because connective tissue is present everywhere in the body, it also influences our fight-or-flight nervous system. When this part of our nervous system works differently, mental health problems are more likely to develop.
The study, which was funded by the Medical Research Council and by MQ and Versus Arthritis, also found that joint hypermobility was more common in females than males. However, it was only among males that joint hypermobility at age 14 years increased the risk for depression at 18 years old.
Although joint hypermobility is associated with anxiety disorders in adults, this link has not previously been explored in a large sample of children or young people.
Lea Milligan, CEO MQ Mental Health Research, said: “MQ is very proud to have supported the ground-breaking work of Dr Eccles and her team. This study has highlighted the need for more targeted and bespoke support for hypermobile teenagers, particularly girls. The findings don’t just show the need for support for this group of individuals, but also demonstrate the importance of research that takes a whole mind, body brain approach to health and uses longitudinal studies to improve our understanding of which demographics are at higher risk of depression and anxiety. Congratulations to Jess and her team and we look forward to the next stages in this work so that we can ensure better clinical care and treatment is provided.”
Dr Neha Issar-Brown, Director of Research and Health Intelligence at Versus Arthritis, said: “Hypermobility affects one in four people in the UK. Like other musculoskeletal (MSK) conditions it can have a profound and far-reaching impact on life, causing daily pain, fatigue and often disrupted sleep.
“Previous studies in adults have shown that you are more likely to suffer from anxiety if you have hypermobility, and that the daily toll of painful symptoms can lead to depression. Dr Eccles’ research helps identify who is at risk at a young age, which will enable better, earlier, more targeted treatments to help young people live well with hypermobility, and prevent or reduce the impact of the condition later in life.”
Researchers used an existing data base from The Avon Longitudinal Study of Parents and Children (ALSPAC), which collected data from over 14,000 children and their parents or carers, and assessed them for joint hypermobility at both 14 and 18 years old, and depression and anxiety at 18. They then used statistical tests to assess the link between joint hypermobility and depression and anxiety.
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Sinks and P-traps are home to a surprising number of fungal organisms, according research from the University of Reading.
Five University of Reading undergraduate students, and a PhD student, tested more than 250 restroom sinks for fungi, such as black moulds, and relatives of baker’s yeast. Each of the sinks had a very similar community of yeasts and moulds, showing that sinks in use in public environments share a role as reservoirs of fungal organisms.
Dr Soon Gweon led the project. He said: “We spend 90% of our time indoors so we are exposed to fungi in our homes and workplaces. For most people, this isn’t a problem, but for those who are immunocompromised, certain fungal species can cause serious infections.
“It isn’t a big surprise to find fungi in a warm, wet environment. But sinks and P-traps have thus far been overlooked as potential reservoirs of these micro-organisms. This could be a really important finding for those who are trying to help immunocompromised people avoid infections by some of the opportunistic pathogens that may be lurking in sinks, such as Fusarium.”
The technique the students used to identify organisms gave them the broader families represented. Further studies will look in detail at exactly which species are present and will identify potential disease-causing fungi.
Zoe Withey, the University of Reading PhD student involved in the project, said: “It has been great to give undergraduate students a real-life hands-on experience of environmental microbiology. And the fact that we found interesting results, worthy of a peer-reviewed publication, is an experience that many students won’t have until their PhD studies, or beyond.”
The types of fungi that live in sinks can tolerate high temperatures, low pH (acidic), and low nutrients. Some will even use detergents, found in soap, as a source of carbon-rich food.
There was no difference observed between male and female restrooms. In fact the 250 sinks tested, all had a very similar population of fungi present.
Dr Gweon said: “Although these findings don’t present a health concern in the environment we are in, were the location a hospital or care home, with many immunocompromised people, this finding could point to a serious risk to health.
“We would like to see cleaning protocols developed that can address the colonisation of sinks and P-traps, particularly in environments where many people will use a single sink.”
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Materials provided by University of Reading. Note: Content may be edited for style and length.

Long-term use of high-dose green tea extract may provide some protection against cancer, cardiovascular disease, obesity and type 2 diabetes, but it also may create liver damage in a small minority of the population.
Who is at risk? Research from Rutgers, published in The Journal of Dietary Supplements, provides the first solid clue: two genetic variants that predict some of the risk.
“Learning to predict who will suffer liver damage is potentially important because there’s growing evidence that high-dose green tea extract may have significant health benefits for those who can safely take it,” said Hamed Samavat, senior author of the study and an assistant professor of nutrition sciences at the Rutgers School of Health Professions.
Using data from the Minnesota Green Tea Trial, a large study of green tea’s effect on breast cancer, the research team investigated whether people with certain genetic variations were more likely than others to show signs of liver stress after a year of ingesting 843 milligrams per day of the predominant antioxidant in green tea, a catechin called epigallocatechin gallate (EGCG).
Researchers led by Laura Acosta, then a doctoral student, now a graduate, selected two genetic variations in question because each controls the synthesis of an enzyme that breaks EGCG down. They selected the Minnesota Green Tea Trial because it was a large, well-designed study of a unique population. The year-long, placebo-controlled trial included more than 1,000 postmenopausal women and collected data at 3, 6, 9 and 12 months.
An analysis by researchers showed that early signs of liver damage were somewhat more common than normal in women with one variation in the catechol-O-methyltransferase (COMT) genotype and strongly predicted by a variation in the uridine 5′-diphospho-glucuronosyltransferase 1A4 (UGT1A4) genotype.
On average, participants with the high-risk UGT1A4 genotype saw the enzyme that indicates liver stress go up nearly 80 percent after nine months of consuming the green tea supplement, while those with low-risk genotypes saw the same enzyme go up 30 percent.
“We’re still a long way from being able to predict who can safely take high-dose green tea extract,” said Samavat, who noted the risk of liver toxicity is only associated with high levels of green tea supplements and not with drinking green tea or even taking lower doses of green tea extract. “Variations in this one genotype don’t completely explain the variations in liver enzyme changes among study participants. The full explanation probably includes a number of different genetic variations and probably a number of non-genetic factors.”
“Still,” Samavat continued, “we do think we have identified an important piece of the puzzle and taken a step toward predicting who can safely enjoy any health benefits that high-dose green tea extract provides.”
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Materials provided by Rutgers University. Original written by Andrew Smith. Note: Content may be edited for style and length.

One disease is more common in people assigned female at birth, while the other is more common in people assigned male at birth. But a new publication details a “shared complex genetic architecture” between the cardiovascular conditions that could explain why, when one member of a family develops fibromuscular dysplasia, another may develop an abdominal aortic aneurysm.
“We used complementary genetic approaches to validate the relationship between these two highly sex-biased conditions, raising some interesting questions regarding sex differences relating to a common, shared genetic risk profile,” said senior author Santhi K. Ganesh, M.D., an associate professor of internal medicine and human genetics, and a cardiologist at the University of Michigan Health Frankel Cardiovascular Center.
Ganesh and colleagues analyzed family histories from 73 people with FMD and 463 of their first-degree relatives who volunteered to participate in clinical research. They discovered that, in a family where one person had FMD, the risk of a male member of that family developing an abdominal aortic aneurysm was significantly higher. For example, the father of a person with FMD was twice as likely to experience AAA, according to results published in Circulation: Genomic and Precision Medicine.
The research team then compared a new polygenic risk score for FMD and established polygenic risk scores for AAA to verify a shared genetic basis for both diseases, Ganesh says. The results point to specific genes that may underlie both diseases, providing new biological understanding of vascular diseases. The findings also support that screening for abdominal aortic aneurysm in male relatives of patients with FMD may be useful, along with currently established AAA screening guidelines.
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Materials provided by Michigan Medicine – University of Michigan. Original written by Haley Otman. Note: Content may be edited for style and length.

Research on understanding the effect of extra chromosomes for conditions like Down syndrome typically involves examining what genes play a role in the symptoms of these conditions. However, researchers from Germany and the US propose a new way of looking at these conditions, suggesting that when an extra chromosome is present, the impact on the cell depends less on which chromosome is duplicated and more on the presence of extra DNA. This work appears in a review publishing December 1in the American Journal of Human Genetics.
“Understanding the complexity and general nature of disease phenotypes allows us to see a bigger picture and not get stuck focusing on a single gene, due to its presence on the extra chromosome,” says lead author Maria Krivega, developmental biologist at Heidelberg University.
Every cell starts out with extra chromosomes during early embryogenesis; however, this DNA gets sorted into pairs after about a week of growth. When this process goes awry, it often leads to death of the embryo, with only a few being able to survive with the extra DNA, like in the case of Down syndrome.
By taking a step back and looking at the entire cell, researchers were able to create a new understanding of these syndromes. Krivega and her collaborators took a critical look at recent evidence suggesting that Down syndrome phenotypes arise not only because of increased dosage of genes on chromosome 21 but also because of global effects of chromosome gain.
The researchers sifted through published datasets of proteins and RNA of individuals with Down syndrome and compared these to laboratory made cells with trisomies of chromosomes 3, 5, 12, and 21. What they found from this comparison was that it didn’t matter which chromosome was in excess, the cells all had decreased ability to replicate, survive, and maintain their DNA.
“We were interested to find out why cells with imbalanced chromosomal content — in other words, aneuploid — are capable of surviving,” says Krivega. “It was particularly exciting to me to learn if viable aneuploid embryonic cells have similarities with aneuploid cancer cells or cell lines, derived in the laboratory.”
Additionally, they found that the adaptive T cell immune system was underdeveloped in all cells, while the innate immune system seemed to be overactive. The authors suggest that this is a consequence of general chromosome gain. This research can be expanded into autoimmune diseases, such as Alzheimer disease or acute leukemias in trisomy chr. 8 or 21, that also exist without any connection to aneuploidy.
“We hope that our work elucidating a complex trisomy phenotype should help to improve such kids’ development,” says Krivega.
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Materials provided by Cell Press. Note: Content may be edited for style and length.