Category: Diseases, Syndromes and Conditions

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Scientists Snip Muscular Dystrophy Gene, Yielding Shorter but Now-functional Proteins

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CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

The most common inherited muscular disorder and one of the most severe, Duchenne muscular dystrophy (DMD) results from mutations of the dystrophin gene. In the journal Stem Cell Reports, researchers used a dual CRISPR RNA method to restore dystrophin protein function in stem cells derived from DMD patients. By removing large sections of the dystrophin gene, the cells were able skip faulty or misaligned sections of the genetic code, yielding shortened but still functional proteins for a wide variety of mutation patterns associated with DMD.

“Dual CRISPR-Cas3 is a promising tool to induce a gigantic genomic deletion and restore dystrophin protein via multi-exon skipping induction,” says senior author Akitsu Hotta of Kyoto University. “We expect this study to enlighten new ways to treat DMD patients and other genetic disorders that require extensive deletions.”

Due to significant variations in the mutation patterns affecting the dystrophin gene, deleting a small section of the gene can only be used for a limited number of DMD patients. For example, the most common mono-exon skipping of exons 51, 53, and 45 can be applied to 13%, 8%, and 8% of DMD patients, respectively.

Multi-exon skipping (MES) has broad applicability to various DMD mutation patterns. By targeting the mutation hotspots in the dystrophin gene, MES from exon 45 to 55 was estimated to benefit more than 60% of DMD patients. Unfortunately, few techniques are available to induce a large deletion to cover the target exons spread over several hundred kilobases.

To overcome this hurdle, Hotta and his team used CRISPR-Cas3 to induce a deletion of up to 340 kilobases at the dystrophin exon 45-55 region in various DMD mutation patterns. Because it was rare to observe a deletion of more than a hundred kilobases using a single CRISPR RNA – which helps to locate the correct segment of DNA – the researchers used a pair of CRISPR RNAs inwardly sandwiching the target genomic region.

Limitations of the dual CRISPR RNA system include is variation in the deletion pattern, and the precise start and end points of the deletion cannot be fully controlled. This could be a drawback when a large but precise deletion is required. The study also did not demonstrate the functionality of the recovered dystrophin protein. Future research should aim to improve the overall genome editing efficiency of the Cas3 system.

“Our dual-Cas3 system might apply to future gene therapies once we’re able to deliver the dual-Cas3 components in vivo to skeletal muscle tissues safely and efficiently,” says Hotta. “The ability to induce several hundred kilobases of DNA deletion itself also has broad applicability for basic research when a large deletion is needed.”

Source: Science Daily

Categories : Diseases, Syndromes and ConditionsTags :

Python Roundworm Removed from Australian Woman’s Brain

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Detection of Ophidascaris robertsi nematode infection in a 64-year-old woman from southeastern New South Wales, Australia. A) Magnetic resonance image of patient’s brain by fluid-attenuated inversion recovery demonstrating an enhancing right frontal lobe lesion, 13 × 10 mm. B) Live third-stage larval form of Ophidascaris robertsi (80 mm long, 1 mm diameter) removed from the patient’s right frontal lobe. C) Live third-stage larval form of O. robertsi (80 mm long, 1 mm diameter) under stereomicroscope (original magnification ×10). Source: Hossain et al. 2023

Australian researchers have discovered the world’s first case of a new parasitic infection in humans after they detected a live eight-centimetre roundworm from a carpet python in the brain of a 64- year-old Australian woman. The researchers at the Australian National University (ANU) and the Canberra Hospital described the novel case in the journal Emerging Infectious Diseases.

The Ophidascaris robertsi roundworm was pulled from the patient after brain surgery – still alive and squirming. It is suspected that larvae, or juveniles, were also present in other organs in the woman’s body, including the lungs and liver.

“This is the first-ever human case of Ophidascaris to be described in the world,” leading ANU and Canberra Hospital said Associate Professor Sanjaya Senanayake, infectious disease expert and co-author of the study.

“To our knowledge, this is also the first case to involve the brain of any mammalian species, human or otherwise.

“Normally the larvae from the roundworm are found in small mammals and marsupials, which are eaten by the python, allowing the life cycle to complete itself in the snake.”

Ophidascaris robertsi roundworms are common to carpet pythons. It typically lives in a python’s oesophagus and stomach, and sheds its eggs in the host’s faeces. Humans infected with Ophidascaris robertsi larvae would be considered accidental hosts.

Roundworms are incredibly resilient and able to thrive in a wide range of environments. In humans, they can cause stomach pain, vomiting, diarrhoea, appetite and weight loss, fever and tiredness.

The researchers say the woman, from southeastern New South Wales in Australia, likely caught the roundworm after collecting a type of native grass, Warrigal greens, beside a lake near where she lived in which the python had shed the parasite via its faeces.

The patient used the Warrigal greens for cooking and was probably infected with the parasite directly from touching the native grass or after eating the greens.

Canberra Hospital’s Director of Clinical Microbiology and Associate Professor at the ANU Medical School, Karina Kennedy, said her symptoms first started in January 2021.

“She initially developed abdominal pain and diarrhoea, followed by fever, cough and shortness of breath. In retrospect, these symptoms were likely due to migration of roundworm larvae from the bowel and into other organs, such as the liver and the lungs. Respiratory samples and a lung biopsy were performed; however, no parasites were identified in these specimens,” she said.

“At that time, trying to identify the microscopic larvae, which had never previously been identified as causing human infection, was a bit like trying to find a needle in a haystack.”

The patient was first admitted to a local hospital in late January 2021 after suffering three weeks of abdominal pain and diarrhoea, followed by a constant dry cough, fever and night sweats. By 2022, the patient was experiencing forgetfulness and depression, prompting an MRI scan. It revealed an atypical lesion within the right frontal lobe of the brain, Associate Professor Kennedy said.

A neurosurgeon at Canberra Hospital explored the abnormality and it was then that the unexpected eight-centimetre roundworm was found. Its identity was later confirmed through parasitology experts, initially through its appearance and then through molecular studies.

Associate Professor Senanayake said the world-first case highlighted the danger of diseases and infections passing from animals to humans, especially as we start to live more closely together and our habitats overlap more and more.

“There have been about 30 new infections in the world in the last 30 years. Of the emerging infections globally, about 75 per cent are zoonotic, meaning there has been transmission from the animal world to the human world. This includes coronaviruses,” he said.

He added that “the snake and parasite are found in other parts of the world, so it is likely that other cases will be recognised in coming years in other countries.”

The patient continues to be monitored by the team of infectious diseases and brain specialists.

“It is never easy or desirable to be the first patient in the world for anything. I can’t state enough our admiration for this woman who has shown patience and courage through this process,” Associate Professor Senanayake said.

Source: Australian National University

Categories : COVID Diseases, Syndromes and ConditionsTags :

Wristbands a Breeding Ground for Bacteria, Including E. Coli

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Photo by Jonathan Borba on Unsplash

The COVID pandemic took disinfecting to new heights. Now, a new study has uncovered a niche for bacteria to colonise: despite being worn daily, routine cleaning of wristbands is generally overlooked or simply ignored. Researchers from Florida Atlantic University tested wristbands of various materials to determine their risk for harbouring potentially harmful pathogenic bacteria, and found that plastic and rubber bands had a particularly high load, especially if worn at the gym.

For the study, researchers tested plastic, rubber, cloth, leather and metal (gold and silver) wristbands to see if there is a correlation between wristband material and the prevalence of bacteria. They investigated the hygienic state of these various types of wristbands worn by active individuals and identified the best protocols to properly disinfect them.

Using standard microbiological assays, researchers looked at bacterial counts, type of bacteria and their distribution on the wristband surfaces. They also conducted a bacteria susceptibility assay study screening the effectiveness of three different disinfectant solutions: Lysol™ Disinfectant Spray; 70% ethanol, commonly used in hospitals and alcohol wipes; and a more natural solution, apple cider vinegar.

Results of the study, published in the journal Advances in Infectious Diseases, suggest you stick with the ‘gold standard’ or at least silver the next time you purchase a wristband. Nearly all wristbands (95%) were contaminated. However, rubber and plastic wristbands had higher bacterial counts, while metal ones, especially gold and silver, had little to no bacteria.

“Plastic and rubber wristbands may provide a more appropriate environment for bacterial growth as porous and static surfaces tend to attract and be colonissd by bacteria,” said Nwadiuto Esiobu, PhD, senior author and a professor of biological sciences in the Charles E. Schmidt College of Science.

The most important predictor of wristband bacteria load was the texture of wristband material and activity (hygiene) of the subject at sampling time. There were no significant differences between males and females in the occurrence or distribution of the bacteria groups.

Intestinal organisms of the genera Escherichia, specifically E. coli. Staphylococcus spp was prevalent on 85% of the wristbands; researchers found Pseudomonas spp on 30% of the wristbands; and they found E. coli bacteria on 60% of the wristbands, which most commonly begins infection through faecal-oral transmission.

The gym-goer showed the highest staphylococcal counts, which emphasises the necessity of sanitising wristbands after engaging in rigorous activity at the gym or at home.

“The quantity and taxonomy of bacteria we found on the wristbands show that there is a need for regular sanitation of these surfaces,” said Esiobu. “Even at relatively low numbers these pathogens are of public health significance. Importantly, the ability of many of these bacteria to significantly affect the health of immunocompromised hosts indicates a special need for health care workers and others in hospital environments to regularly sanitize these surfaces.”

Findings from the study showed that Lysol™ Disinfectant Spray and 70% ethanol were highly effective regardless of the wristband material with 99.99% kill rate within 30 seconds. Apple cider vinegar was not as potent and required a full two-minute exposure to reduce bacterial counts. While these common household disinfectants all proved at least somewhat effective on all materials (rubber, plastic, cloth and metal), antibacterial efficacy was significantly increased at two minutes compared to thirty seconds.

Different disinfectants, depending on their active ingredients, kill bacteria in different ways, such as by disrupting cell membrane integrity, altering or removing proteins or interfering with metabolic activities.

“Other potential forms of bacterial transmission and facilitation of infection, such as earbuds or cell phones, should be similarly studied,” said Esiobu.

Source: Florida Atlantic University

Categories : Diseases, Syndromes and ConditionsTags :

Inflammation Impedes the Development of Malaria Parasites

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Photo by Ekamelev on Unsplash

Researchers have found that inflammation can slow down the development of malaria parasites in the bloodstream, which may lead to a new strategy for preventing or limiting severe disease.

The malaria-causing Plasmodium parasites invade and multiply within red blood cells. Studies have shown that the parasites can rapidly sense and respond to conditions within the host by intimately syncing with their internal body clocks. While it is known that the body’s nutrient levels and daily circadian rhythms affect the parasites’ development, little was known about the impact of host inflammation on the parasites.

This animal-model study, led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) and the Kirby Institute and published in the journal mBio, reveals that when the body’s immune system responds to inflammation it alters the plasma’s chemical composition, directly impeding the maturation of the Plasmodium parasites in the bloodstream.

University of Melbourne’s Associate Professor Ashraful Haque, a senior author of the paper, said this work highlights the captivating dynamic of the host-parasite relationship.

“First, we discovered that inflammation in the body prevented the early stage of the parasites from maturing. We also noticed that inflammation triggered significant changes in the composition of the plasma – we were actually quite surprised by the magnitude of these changes,” said Associate Professor Haque.

“As we dug deeper, we found substances in the altered plasma that, we believe, are what may inhibit parasite growth in the body. This work reveals a new mechanism that slows down the malaria parasite’s development in the bloodstream. Our research was done using animal models, so it would be really interesting to study if such inhibitory mechanisms occur in humans too.”

Dr David Khoury, co-senior author of the paper, said the scientists found a remarkable response by the parasites to the changes in their environment.

“Parasites residing in red blood cells rapidly sense and respond to their new environment, showing fascinating adaptability. Using cutting-edge genome sequencing technology, we observed that even after just four hours in this changed plasma, the parasites adjusted their genetic and protein activity, resulting in slower maturation within red blood cells. It’s almost like the parasites actively sense an inhospitable host environment, and as a result trigger a coping mechanism,” said Dr Khoury.

“We believe this is the first study to show that inflammation can change how individual parasites behave genetically in the body.”

Professor Miles Davenport, co-senior author of the paper, said this work on the interaction between systemic host inflammation and malaria parasite maturation offers several potential benefits.

“This study, while based on animal models, broadens our understanding of malaria. It provides a foundation for further investigations into the specific mechanisms involved in the modulation of parasite maturation by inflammation, and opens avenues for future studies to explore the identified inhibitory factors, genetic changes and their implications for malaria development,” said Professor Davenport.

Source: The Peter Doherty Institute for Infection and Immunity

Categories : Diseases, Syndromes and Conditions HospitalsTags :

How the Hospital Pathogen Acinetobacter Baumannii can Adapt so Quickly

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Photo by National Cancer Institute on Unsplash

Acinetobacter baumannii is a notorious hospital pathogen, and there is great pressure to devise novel therapeutic approaches to combat this growing threat. German researchers have now detected an unexpectedly wide diversity of certain cell appendages known as pili in A. baumannii that are associated with pathogenicity. This finding, published in PLOS Genetics, could lead to treatment strategies that are specifically tailored to a particular pathogen.

Each year, over 670 000 people in Europe fall ill because of antibiotic-resistant pathogens, and 33 000 die from the infections. Especially feared are pathogens with resistances against multiple, or even all, known antibiotics. One of these is the bacterium Acinetobacter baumannii, feared today above all as the “hospital superbug”: According to estimates, up to five percent of all hospital-acquired and one tenth of all bacterial infections resulting in death can be attributed to this pathogen alone. This puts A. baumannii right at the top of WHO’s list of pathogens for which there is an urgent need to develop new therapies.

Understanding which characteristics make A. baumannii a pathogen is one of the prerequisites for this. To this end, bioinformaticians led by Professor Ingo Ebersberger of Goethe University Frankfurt and the LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG) are comparing the genomes and the proteins encoded therein across a wide range of different Acinetobacter strains. Conclusions about which genes contribute to pathogenicity can be drawn above all from the differences between dangerous and harmless strains.

Due to a lack of suitable methods, corresponding studies have so far concentrated on whether a gene is present in a bacterial strain or not. However, this neglects the fact that bacteria can acquire new characteristics by modifying existing genes and thus also the proteins encoded by them. That is why Ebersberger’s team has developed a bioinformatics method to track the modification of proteins along an evolutionary lineage and has now applied this method for the first time to Acinetobacter in collaboration with microbiologists from the Institute for Molecular Biosciences and the Institute of Medical Microbiology and Infection Control at Goethe University Frankfurt.

In the process, the researchers concentrated on hair-like cell appendages, known as type IVa (T4A) pili, which are prevalent in bacteria and that they use to interact with their environment. The fact that they are present in harmless bacteria on the one hand and have even been identified as a key factor for the virulence of some pathogens on the other suggests that the T4A pili have repeatedly acquired new characteristics associated with pathogenicity during evolution.

The research team could show that the protein ComC, which sits on the tip of the T4A pili and is essential for their function, shows conspicuous changes within the group of pathogenic Acinetobacter strains. Even different strains of A. baumannii have different variants of this protein. This leads bioinformatician Ebersberger to compare the T4A pili to a multifunctional garden tool, where the handle is always the same, but the attachments are interchangeable. “In this way, drastic functional modifications can be achieved over short evolutionary time spans,” Ebersberger is convinced. “We assume that bacterial strains that differ in terms of their T4A pili also interact differently with their environment. This might determine, for example, in which corner of the human body the pathogen settles.”

The aim is to use this knowledge of the unexpectedly high diversity within the pathogen to improve the treatment of A. baumannii infections, as Ebersberger explains: “Building on our results, it might be possible to develop personalised therapies that are tailored to a specific strain of the pathogen.” However, the study by Ebersberger and his colleagues also reveals something else: Previous studies on the comparative genomics of A. baumannii have presumably only unveiled the tip of the iceberg. “Our approach has gone a long way towards resolving the search for possible components that characterize pathogens,” says Ebersberger.

Source: Goethe University Frankfurt

Categories : Diseases, Syndromes and Conditions VaccinesTags :

More Monkeypox Antibodies with Childhood Smallpox Vaccination

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Mpox (monkeypox) virus. Source: NIH

In a study published in Cell Host & Microbe, scientists studied the sensitivity of MPXV, the virus that causes mpox (formerly monkeypox) to neutralising antibodies (NAbs) generated after infection with the virus and/or vaccination with IMVANEX. They found that those who had been born before 1980 had more antibodies in response to either IMVANEX vaccination or mpox infection, highlighting the lasting protection of smallpox vaccination.

The IMVANEX vaccine has been used as pre- and post-exposure prophylaxis in high-risk populations, but its effectiveness is not yet well characterised. To analyse the sensitivity of the virus, a team of scientists led by Pasteur Institut developed two cellular tests to quantify neutralising antibodies, using either the attenuated virus as a vaccine (MVA) or an MPXV strain isolated in a recently infected individual.

In 2022-2023, an unprecedented epidemic of 87 000 cases of mpox occurred in non-endemic areas, affecting people with no direct link to travel in Central or West Africa, where the virus has historically been present. MPXV is mainly transmitted to humans by rodents, with human-to-human transmission occurring via respiratory droplets or close contact. Symptoms are less severe than those of smallpox, and the case-fatality rate is lower. MPXV is still circulating at very low levels in non-endemic areas, which is why it is important to improve characterisation and analyse the immune response of people infected with the virus or vaccinated with IMVANEX, the third-generation vaccine currently available, initially developed for smallpox.

The large number of sera analysed provided good statistical power, meaning that the analysis could be narrowed to subgroups of patients based on various criteria such as age.

The study demonstrated the role of complement, already known for other poxviruses, and the neutralising activity of the antibodies generated by infection or vaccination. Robust levels of anti-MVA antibodies were detected after infection, vaccination with the historic smallpox vaccine, or administration of IMVANEX or another MVA-based vaccine candidate. MPXV was minimally sensitive to neutralisation in the absence of complement. The addition of complement from sera enhanced detection of individuals with antibodies and increased their level of anti-MPXV antibodies. Four weeks after infection, anti-MVA and -MPXV NAbs were observed in 94% and 82% of individuals, respectively. Two doses of IMVANEX generated anti-MVA and -MPXV NAbs that were detectable in 92% and 56% of vaccinees, respectively.

The highest level of antibodies was found in individuals born before 1980 (who had therefore been vaccinated for smallpox), whether after infection or after administration of IMVANEX, highlighting the impact of historic smallpox vaccination on immune responses to infection or administration of IMVANEX. This suggests that a sort of hybrid immunity was generated in infected individuals who were vaccinated in childhood.

The number of MPXV infections has been constantly on the rise since mass vaccination for smallpox was discontinued in the 1980s. “The neutralisation assays developed in connection with this research may help define correlates of protection against infection or disease severity. The assays can also be used to conduct epidemiological surveys, assess the duration of protection conferred by previous infection or by authorised and candidate vaccines, and analyse the use of immunotherapeutic intervention. The assays represent useful tools to understand the mechanisms of multiplication of MPXV and its effects on public health, and to optimsze patient treatment,” commented Olivier Schwartz, Head of the Institut Pasteur’s Virus and Immunity Unit and last author of the study.

Source: Institut Pasteur

Categories : Diseases, Syndromes and Conditions Obstetrics & GynaecologyTags :

Lactobacillus Combo Stops Bacteria that Cause Toxic Shock Syndrome

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Methicillin resistant Staphylococcus aureus (MRSA) – Credit: CDC

A virulent strain of Staphylococcus aureus produces proteins that trigger toxic shock syndrome (TSS), a disease characterised by the quick onset of fever, a telltale rash, and, without treatment, multi organ failure. In the vagina, TSS is associated with a life-threatening reaction from the immune system. Research published in the journal Microbiology Spectrum shows that probiotics may help prevent the disease before the cytokine cascade ever begins.

Probiotics may help prevent the disease before the cytokine cascade ever begins. This study reports that strains of two bacteria, Lactobacillus acidophilus and Lacticaseibacillus rhamnosus, successfully inhibited the production of the superantigens that cause TSS, in lab experiments. L. acidophilus, in addition, inhibited the growth of the S. aureus strains that produce the problematic proteins.

A combination of the two could both prevent growth and inhibit the immune response. “It’s kind of a double whammy against S. aureus,” said microbiologist Patrick Schlievert, Ph.D., at the University of Iowa Carver College of Medicine, in Iowa City. “If any toxin is made, the probiotics still prevent inflammation.”

He noted that adding these probiotics to tampons or other menstrual products could reduce the risk of TSS associated with menstruation. Such a preventive measure has the potential to benefit millions of vulnerable people, Schlievert said. “We know that 20% of people over age 12 cannot make antibodies and never will make antibodies against toxic shock syndrome,” he said.

Schlievert has been studying TSS and its prevention for decades. In the early 1980s, he was the first researcher to identify the toxin that triggers an overreaction of the immune system, and to show how high-absorbency tampons facilitated production of that toxin if S. aureus was present.

The new work, he said, was motivated by observations made during an earlier study. A few years ago, he and his colleagues recruited 205 women to test whether a novel molecular mixture, when added to tampons, would inhibit pathogenic bacteria. That molecule proved effective against E. coli and other pathogens, but the researchers noticed an unexpected consequence.

“Some of the women in the treatment group had this tremendous growth of Lactobacilli,” Schlievert said.

Source: American Society for Microbiology

Categories : Diseases, Syndromes and ConditionsTags :

Scientists Unravel The Reason Why NSAIDs Exacerbate C. Diff Infections

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Clostridioides difficile. Credit: CDC

Nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate gastrointestinal infections by Clostridioides difficile, the leading cause of antibiotic-associated diarrhoea worldwide – but the reason why has long eluded medical science. In a new paper published in Science Advances, researchers have begun to answer that question, showing that NSAIDs disrupt the mitochondria of cells lining the colon, sensitising them to damage by pathogenic toxins.

C. difficile is a bacterium that leads to a wide range of symptoms, from mild diarrhoea to complex infection and death. The factors that influence this wide spectrum of clinical outcomes remain largely unclear, but emerging evidence suggests that factors like diet and pharmaceutical drugs influence both susceptibility to infection and disease progression. However, little is known about how these factors impact the course of C. difficile infection.

Prior studies have shown that NSAIDs like indomethacin, aspirin, and naproxen negatively affect the gut, both in patients with C. difficile infection and other conditions like inflammatory bowel disease (IBD). Long-term NSAID use can lead to stomach ulcers and intestinal injuries. One hypothesis that this is due to the effects of NSAIDs on cyclooxygenase (COX) enzymes; a process that helps reduce inflammation and pain but also impairs mucosal function in the upper gastrointestinal tract. NSAIDs also have off-target effects and have been shown to affect cellular mitochondria by uncoupling cellular mitochondrial functions, but these had not been studied in C. difficile infections.

To define these effects, Children’s Hospital of Philadelphia (CHOP) researchers, led by graduate student Joshua Soto Ocaña, used in vitro and mouse models of C. difficile infection to test how permeable colonic epithelial cells are in the presence of the NSAID indomethacin. The researchers observed that both indomethacin and C. difficile toxins increased epithelial cell barrier permeability and inflammatory cell death. They also found that the effect was additive: the combined effect on cell permeability of both toxins and indomethacin was increased compared to each independently, suggesting a synergistic effect of NSAIDs and C. difficile in increasing this pathogen’s virulence.

Surprisingly, the researchers found that NSAIDs exacerbate C. difficile infection independent of COX inhibition and instead through off-target effects on mitochondria. They did so by treating colonic epithelial cells with a precursor molecule that is similar in structure to indomethacin but lacks the ability to inhibit the COX enzyme. Not only did they find that this NSAID-like molecule induced cell death, but they also found that adding selective COX inhibitors did not increase cell death, demonstrating that COX enzyme inhibition is not required to induce epithelial cell damage during C. difficile infection and that, instead, this damage occurs through off-target effects of NSAIDs.

To test the role of off-target effects during C. difficile infection, the researchers used mice pretreated either with indomethacin or the NSAID-precursor molecule. When exposed to C. difficile, both groups of mice showed equal enhancement in disease severity and mortality compared to untreated control mice infected with C. difficile only. The researchers also observed a similar effect in mice who were pretreated with the NSAID aspirin. To further define the specific mechanisms driving these off-target effects of NSAIDs, researchers looked at mitochondrial functions in colonic epithelial cells in vitro and in mice. They observed that the combination of NSAIDs and C. difficile toxins increased damage to colonic epithelial cell mitochondria and disrupted several important mitochondrial functions.

“Our work further demonstrates the clinical importance of NSAIDs in patients with C. diff infection and sheds light on why the combination of these two may be so detrimental,” said senior author Joseph P. Zackular, PhD, Investigator and Assistant Professor of Pathology and Laboratory Medicine at CHOP. “Our mechanistic findings are a starting point for further research that aims to understand the impact of mitochondrial functions during C. diff infection. These data could also inform how NSAID-mediated mitochondrial uncoupling affects other diseases, such as small intestinal injury, IBD, and colorectal cancer.”

Source: Children’s Hospital of Philadelphia

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

Peptides May Solve the Sticky Problem of Bacterial Biofilms

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This image shows an intricate colony of Pseudomonas aeruginosa. The bacteria have self-organised into a sticky, mat-like colony called a biofilm, which allows them to cooperate with each other, adapt to changes in their environment, and ensure their survival.
Credit: Scott Chimileski and Roberto Kolter, Harvard Medical School, Boston

Researchers have developed peptides that can help combat bacteria growing in biofilms, which occur in up to 80% of human infections. Their results, published in Nature Chemical Biology, may offer a way to tackle antimicrobial-resistant infections. 

Treating infections becomes significantly more challenging when biofilms are present, as they not only reduce the effectiveness of antibiotics but also give rise to several medical complications. These complications include infections following joint replacements, prosthetic devices, as well as contamination in catheters and other medical equipment. The lack of specific treatments makes the management and treatment of biofilms exceptionally difficult.

The team of researchers, led by Dr Clarissa Melo Czekster and Dr Christopher Harding from the School of Biology at St Andrews, in collaboration with researchers at University of Dundee, developed antimicrobial peptides that can target the harmful bacteria growing in biofilms.

The team determined how a key enzyme (PaAP) in biofilms work and developed a revolutionary new strategy to inhibit the protein. Their inhibitor is potent and targets cells from the human pathogen Pseudomonas aeruginosa in biofilms. P. aeruginosa, a WHO pathogen of concern, causes chronic infections in patients with cystic fibrosis and other conditions, which means a biofilm inhibitor is urgently needed.

Dr Czekster and the team are currently working in collaboration with the University of St Andrews Technology Transfer Centre and industry partner Locate Bio, a biomedicine spinout of the University of Nottingham, to commercialise the technology. The Locate Bio team are trialling the peptides to see how they work with the company’s Programmed Drug Release technology to develop new orthobiologic solutions and products. The Technology Transfer Centre has filed a UK priority patent application.

Dr Czekster said: “Our research reveals how designed inhibitors can target a key enzyme in bacterial virulence, offering molecular insights applicable to aminopeptidases in diverse organisms.

“This remarkable new research presents an innovative strategy to target bacterial biofilms and pave the way for better treatment of bacterial infection.”

Source: University of St. Andrews

Categories : Diseases, Syndromes and ConditionsTags :

In Osteoarthritis, Molecular Changes Weaken Protective Films

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Photo by Towfiqu barbhuiya: https://www.pexels.com/photo/person-feeling-pain-in-the-knee-11349880/

Although osteoarthritis has been extensively studied through a medical perspective, the molecular changes associated with osteoarthritis remain unclear. New research published in Biointerphases suggests that there may be an optimum concentration and size of molecules in the synovial fluid needed to form the protective film in joints.

Osteoarthritis is the most common degenerative joint disease, affecting 22% of adults over 40 globally. The cartilage in the joints, in concert with the synovial fluid, provides a smooth surface to support weight-bearing movements. The fluid contains several molecules, including hyaluronan (HA) and phospholipids. Since the cartilage environment cannot be quickly healed or repaired, researchers have tried to diagnose the early stages of joint disease by monitoring the molecular weight and concentration of HA.

“Although we know that in healthy joints there is very low friction, it is unclear which other molecules are involved and how they change during osteoarthritis,” said Rosa Espinosa-Marzal (EIRH), professor of environmental engineering & science, and materials science & engineering. “During the early stages of osteoarthritis, cartilage starts degrading, and previous research has shown that the molecular composition of the synovial fluid changes. We wanted to see if the two changes are related to each other.”

In a healthy joint, the molecular weight of HA varies between 2–20 MDa with a concentration ranging from 1–4 mg/mL. Studies have shown that in diseased joints, HA is broken down resulting in a lower molecular weight and its concentration is also reduced by 10x. Based on these observations, made by other researchers, the study looked at how the concentration and molecular weight of HA influences the structure of healthy and diseased joints.

To do so, the researchers combined vesicles with high and low molecular weight HA. Using neutron scattering and light scattering, they discovered that the molecular weight of HA can vastly change the structure of the vesicles. Lower molecular weight HA, which mimics osteoarthritis-diseased joints, results in larger vesicle size. Changes in HA’s molecular weight also changed the thickness of the phospholipid layers in the joints.

The researchers also studied how these differences can influence the formation of a protective film; in joints this film is responsible for the very low friction we need for unhindered motion. Once again, they used a combination of techniques, quartz crystal microbalance and atomic force microscopy, to examine how these molecules assemble on gold surfaces.

“The formation of a film is possible only when there is an optimal concentration of HA and phospholipids. Even though the gold surfaces have very little in common with cartilage, our studies indicate that there could also be an optimum concentration under biological conditions,” Espinosa-Marzal said. “This is an important observation because we can use the concentration changes as a diagnostic tool.”

The researchers are now testing this theory using cartilage. They are also interested in studying the other molecular components that are found in joints to build a more comprehensive model of the changes that are associated with osteoarthritis.

Source: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign