Lassa fever and COVID-19 in Africa: A double crisis

 

• A recent article in the Journal of Medical Virology discusses the dual impact of Lassa fever and COVID-19 in Africa.
• The authors say that the emergence of COVID-19 has directed resources away from other infectious diseases, including Lassa fever.
• To contain the disease, they recommend a mix of public hygiene information, enhanced research, and the development of treatments and vaccines.

Lassa feverTrusted Source is an infectious disease transmitted from rodents to humans. ApproximatelyTrusted Source 2 million people get Lassa fever each year, resulting in 5,000–10,000 deaths. The disease is endemicTrusted Source in West African countries, such as Guinea, Liberia, Nigeria, and Sierra Leone.

One of the major challenges when diagnosing the disease is the similarity of its symptomsTrusted Source, including sore throat, joint pains, and weakness, with many other diseases, such as dengue and typhoid fever.

Because of this, the condition is commonly under- and misdiagnosed.

The emergence of COVID-19 has further aggravated the identification and treatment of the condition due to the extra burden placed on public health systems around the worldTrusted Source.

Earlier this year, an international team of researchers published an article highlighting the situation of Lassa fever in Africa following COVID-19, alongside public health strategies to contain it.

“Lassa fever is endemic to West Africa, “ Matt Price, Ph.D., told Medical News Today. Dr. Price is director of epidemiology at the International AIDS Vaccine Initiative (IAVI) and assistant clinical professor of epidemiology and biostatistics at the University of California San Francisco (UCSF). He was not involved in the article.

“However, reporting on the disease in the past has not been systematic, and our understanding of the epidemiology is incomplete. In recent years, Nigeria has been the epicenter for annual outbreaks of the disease, with case numbers peaking in 2020,” he added.

“Active disease surveillance is ongoing in Nigeria, and large, population-based epidemiology studies are underway in Sierra Leone, Guinea, Liberia, and Benin. This work will help us get a better understanding of the epidemiology of Lassa fever, “ he explained.

The article appears in the Journal of Medical VirologyTrusted Source.

High fatality ratio

Currently, early diagnosis of Lassa fever is key for effective treatment. Doctors recommend Ribavirin, an antiviral medication, within the first 6 days of contracting the virus. If left untreated, the disease can lead to:

• swollen airways
• abdominal pains
• diarrhea
• vomiting
• respiratory symptoms
• loss of hearing
• acute hemorrhagic fever
• multiple organ failure
• death

After the declaration that COVID-19 was a pandemic, medical resources were directed towards COVID-19, leading to compromised care for infectious diseases with higher fatality ratiosTrusted Source, such as Lassa fever.

“Amid epidemiological Week 9 of 2020, when the first affirmed case of COVID‐19 was recorded in Nigeria, there was an increase in the number of affirmed [Lassa fever] cases,” write the researchers.

“Indeed, with steady care and treatment with ribavirin, case fatalities were still as high as 24%–33% in tertiary clinic settings […] whereas almost 13.5% of survivors [had] sensorineural hearing loss. Also, [Lassa fever] accounts for almost 22% of hospital maternal mortality in endemic ranges,” they add.

Source: Medical News Today

Diet, nutrition, and skin conditions: What's the evidence?

 

• Many dermatologists and nutritionists are interested in understanding the connection between diet, nutrition, and dermatological health.
• A review that includes 150 studies has found that few rigorous randomized controlled trials have looked at these potential links.
• The authors conclude that despite the varying levels of association, diet and nutrition, with limited exceptions, do not modify dermatological conditions.

There is substantial interest in the relationship between diet, nutrition, and dermatological conditions. New research assesses the existing research literature.

The review reports that much of the evidence supporting such relationships is based merely on associations or laboratory studies rather than on randomized controlled trials, which are the gold standard for medical research.

The study is the work of lead author Dr. Kabir Sardana and senior investigator Dr. Soumya Sachdeva, both of whom are affiliated with Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital in Delhi, India.

“While it is plausible,” write the authors, “that certain nutritional supplements may help, they may not transcend research settings to real-life clinical scenarios. Apart from the role of gluten in celiac disease, very few dietary factors have been irrevocably linked to disease in dermatology.”

After reviewing 150 published articles about diet, nutrition, and dermatology over the last 15 years, they report that the “data is not on a firm footing and leaves the dermatologist in a quandary and the patient confused.”

This is unfortunate, the authors say, since “[a] proper knowledge of the role of nutritional supplements in dermatological diseases can be a useful tool in advising the patients and, in certain cases, ameliorating the disorder.”

The review appears in JCD: The Journal of Cosmetic DermatologyTrusted Source.

Studies so far

“There have been interesting studies looking at the role of diet and/or specific supplements in acne, atopic dermatitis, psoriasis, vitiligo, [and] photoprotectionTrusted Source, and as anti-aging agentsTrusted Source,” dermatologist Dr. Patricia Farris told Medical News Today.

“And while every study may not meet the most rigorous study design criteria,” she continued, “the information gleaned from these studies can still be of value to dermatologists.”

Regarding the lack of randomized controlled trials, Dr. Farris explained:

“It’s important to remember that most of the large, randomized placebo-controlled studies are funded by manufacturers or pharmaceutical companies marketing the products being tested. In the case of foods or supplements, these treatments do not have to go through the FDA [Food and Drug Administration] approval process. Thus, there is little incentive for companies to undertake rigorous and expensive studies.”

There is another potential obstacle, as diet and dermatology expert Dr. Rajani Katta told MNT. ”We have a lack of safety data on supplements in general because manufacturers don’t have to investigate safety at all before bringing a supplement to market.”

Source: Medical News Today

Can intermittent fasting help treat or even reverse type 2 diabetes?

 

• Intermittent fasting involves a regular pattern of eating few or no calories for a fixed period, which can vary from 12 hours every day to 1 or more days each week.
• Some people follow these diets hoping to lose weight, improve their overall health, or both.
• A review of the available evidence suggests that these diets can also reduce or even remove the need for medication in people with type 2 diabetes.
• More research is necessary before doctors can recommend widespread use of the diets for people with the condition.

In recent years, intermittent fasting has gained popularity as a way toTrusted Source lose weight, improve health, and enhance performance.

Some studies suggest that this dietary approach may even extend healthy lifespan without the need for the severe caloric restriction that classic anti-aging diets entail.

People who practice intermittent fasting eat few or no calories for anything from 12 hours a day to 1 or more days every week. The former technique is known as time-restricted feeding, whereas the latter is known as periodic fasting.

A recent review of the evidence suggests that this type of diet may help people with type 2 diabetes safely reduce or even remove their need for medication.

However, people should seek the advice of a diabetes professional before embarking on such a diet.

The review, by Dr. Michael Albosta and Jesse Bakke, Ph.D., of Central Michigan University College of Medicine in Mount Pleasant, appears in Clinical Diabetes and EndocrinologyTrusted Source.

Insulin resistance

According to the Centers for Disease Control and Prevention (CDC), diabetes affects 34.2 millionTrusted Source people in the United States, which equates to about 1 in every 10 people. In 2017, it was the seventh leading cause of deathTrusted Source in the country.

People with type 2 diabetes have abnormally high concentrations of glucose in their blood, known as hyperglycemia.

Several factors may contribute to hyperglycemia in type 2 diabetes. These include reduced secretion of the hormone insulin, which regulates blood sugar levels, and reduced sensitivity of the body’s tissues to the hormone. Doctors refer to this reduced sensitivity as insulin resistance.

The condition can cause a range of severe complications, including kidney failure and blindness.

The goal of treatment for type 2 diabetes is to prevent or delay these complications and maintain the person’s quality of life.

Healthcare professionals encourage people with type 2 diabetes to exercise regularly, reach a moderate weight, and eat a well-balanced diet. However, most individuals also need to take drugs to lower their blood glucose levels.

Most of these drugs raise insulin levels, which the authors of the review say can have an unintended negative consequence.

“While this works to reduce hyperglycemia in these patients, the idea of treating a disease of insulin resistance by increasing insulin may be counterproductive, leading to the requirement of increasing amounts of medication over a long period of time,” they write.

People who take the drugs can gain weight and develop increased insulin resistance.

In addition, they can have raised levels of a hormone called leptin, which normally reduces appetite. This may suggest that they become increasingly resistant to this hormone, too.

They also have lower levels of a third hormone, called adiponectinTrusted Source, which usually counters diabetes and inflammation.

Source: Medical News Today

Paleo diet: Is there any evidence that it benefits health?

 The promotion of certain eating patterns as a way to improve overall health is very common. In recent years, an eating pattern called the Paleolithic diet

Trusted Source — also known as the paleo diet, for short — has taken the health and wellness world by storm.

Despite the popularity of the paleo diet, many researchers and healthcare professionals argue that it is not necessarily the best diet to benefit overall health. In fact, some believe that it may be harmful.

In this Honest Nutrition feature, we dig a little deeper into the research behind the paleo diet to uncover its potential health benefits. We also discuss the risks that may come with following a paleo diet.

What is a paleo diet?

A paleo diet, also known as the stone age diet or caveman diet, is an eating pattern that aims to mirror the way hunter-gatherers ate thousands of years ago.

People who follow a paleo diet eat large quantities of meat, fruit, vegetables, nuts, and seeds but restrict legumes, dairy, and grains.

Foods and beverages that a person following a paleo diet will frequently consume include:

• meat, with an emphasis on meat from wild game or grass-fed animals
• fish
• eggs
• water
• herbal tea
• fruit
• herbs and spices
• nuts
• seeds
• healthy oils, such as walnut or olive oil

Foods that a person following a paleo diet will often avoid include:

• dairy products
• refined sugar
• salt
• legumes, which include beans, peanuts, and peas
• artificial ingredients
• processed foods
• soft drinks
• grains, including rice, wheat, and oats
• potatoes

One of the most common misconceptions about the paleo diet is that our ancestors primarily survived on a meat-based diet.

As we learn more about the Paleolithic age, we are discovering that those who lived during it ate a plant-based diet, with merely an estimated 3%Trusted Source of their diet coming from animal-based foods.

Source: Medical News Today

Climate change and mental health: How do we mitigate the risks?

 

• Researchers have explored the relationship between climate change and mental health in a major literature review.
• The authors found a significant amount of research demonstrating how climate change poses risks to mental health.
• However, they conclude that more research is needed to explore how to mitigate these risks.

A major literature review highlights the connections that researchers have found between climate change and mental health.

The review, which appears in the International Journal of Environmental Research and Public Health, demonstrates that climate change is a major risk to people’s mental health.

However, most research on this topic has focused on generating insight into the importance of these risks but not mitigating them.

The authors call for continued investigation in this growing field, with a particular emphasis on protecting people’s mental health from the threats posed by climate change.

Climate change and health

Researchers have argued that human-influenced climate change poses an existential threat to civilization, with many associated ecological, social, political, economic, and health risks.

In terms of human health, there is a wealth of research exploring the adverse physical health effects of climate change.

However, there has been less investigation into the effects of climate change on mental health.

Speaking to Medical News Today, Prof. Tahseen Jafry, director of the Centre for Climate Justice at Glasgow Caledonian University, Scotland, said that this lack of research was particularly the case concerning people’s experience in low-income countries.

“Globally, there is very little research that pays attention to the mental health impacts of climate change, particularly in the poorest nations.”

“The lack of qualitative data regarding on-the-ground realities and lived experiences, particularly from the poorest countries in the world, makes this one of the most prolific and least understood areas of study,” said Prof. Jafry

Source: Medical News Today

COVID-19: Can mental health experts help improve vaccine hesitancy?

 

• Mental health professionals may be uniquely positioned to address a wide range of concerns, including vaccine hesitancy.
• This hesitancy must be overcome to boost vaccination rates and recover from the ongoing COVID-19 pandemic.
• Without adequate vaccination, it is not possible to achieve herd immunity.

Given that uptake of vaccines is low among young adults — and young adulthood is the age of onset for many mental health problems, mental health experts are uniquely suited to help overcome resistance to COVID-19 vaccination. This is the message of an opinion column that appeared in September in JAMA PsychiatryTrusted Source.

As we approach the second anniversary of the emergence of the pandemic illness now known as COVID-19, it has become clear that available vaccines confer significant protection against the worst ravages of the disease. Of course, COVID-19 is a potentially life-threatening, multisystem illness caused by the coronavirus known as SARS-CoV-2.

The authors, Dr. Noel T. Brewer and Dr. Neetu Abad, of the column note: “Mental health professionals and teams are trained to use empathy, reflective listening, and cooperative goal setting to help patients address challenges. […] Engaging new approaches for increasing adult vaccination is a national priority.”

Dr. Brewer is the Gillings Distinguished Professor in Public Health at the University of North Carolina.

In an email interview with Medical News Today, Dr. Brewer wrote: “COVID-19 vaccination is our passport to greater personal freedom. It allows us to safely go to stores, hang out with friends, and visit loved ones who are ill. It may even be required by airlines soon. We have seen COVID-19 cases overwhelm hospitals in several states.”

The stakes are high, Dr. Brewer notes, adding: “To avoid a national meltdown in emergency care this winter, the nation needs to get its COVID-19 vaccine coverage up higher. Mental health professionals can work with their clients to work through concerns and help them navigate getting a COVID-19 vaccine.”

Available vaccines have proved highly effective at preventing the worst symptoms of SARS-CoV-2 infection.

The Pfizer-BioNTech and Moderna shots are mRNA vaccines. This means that they contain instructions for our cells to make just one small segment of a key component of the SARS-CoV-2 virus: the spike protein. The “m” stands for “messenger.”

By itself, this snippet of protein is harmless. But it supplies enough “information” to the immune system for the body to identify and neutralize the living virus if it encounters it.

Unlike older, inactivated virus-based vaccines, mRNA vaccines do not contain any potentially infectious material. Whether these vaccines actually prevent infection is less clear. But they can help prevent hospitalizations and deaths.

In fact, emerging data from the United States and elsewhere indicate that the vast majority of COVID-19 deaths and hospitalizations are now occurring among unvaccinated people.

Clearly, vaccinating as many people as possible is of paramount importance to public health.

Old alarm, new urgency

Back in 2017, well before the present pandemic, health experts in the U.S. and Australia wrote in the journal Psychological Science in the Public InterestTrusted Source, “Psychology offers three general propositions for understanding and intervening to increase uptake where vaccines are available and affordable.”

Perhaps anticipating our current situation to some extent, the authors offered several tools that healthcare professionals may leverage to boost public health through greater use of available vaccines.

Dr. Neetu Abad, the co-author of the JAMA Psychiatry opinion piece, is a behavioral scientist in the Global Immunization Division of the Centers for Disease Control and Prevention (CDC). Her work there focuses on “assessing and intervening on the behavioral drivers of vaccine hesitancy globally.”

In an email interview with MNT, Dr. Abad commented on the significance of the call for mental health professionals to help overcome vaccination hesitancy.

Untapped resources

“The potential of mental health professionals and agencies to address barriers to COVID-19 vaccination has received inadequate attention,” Dr. Abad told MNT.

Source: Medical News Today

Scientists retool CAR T cells to serve as ‘micropharmacies’ for cancer drugs

 Immunotherapies called chimeric antigen receptor (CAR) T cells use genetically engineered versions of a patient's own immune cells to fight cancer. These treatments have energized cancer care, especially for people with certain types of blood cancers. Now, scientists at Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute (SKI) have developed new CAR T cells that can do something their predecessors cannot: Make drugs.

Standard-issue CAR T cells are designed in the lab to recognize specific markers on cancer cells. When these CAR T cells are given back to a patient, they proliferate and go on the attack, acting as a kind of "living drug."

Despite their usefulness for treating blood cancers, there are several limitations of current CAR T models. One is that the CAR T cells can only kill cancer cells that contain the marker they are designed to recognize. But it is not uncommon for cancer cells to stop making this marker and thus to "escape" from the therapy.

A second problem is that CAR T cells can become "exhausted" -- and even inhibited by the cancer cells themselves. Lastly, existing CAR T cells work well only against blood cancers that the CAR T cells can easily reach. Against dense solid tumors in the lung or breast, they are mostly powerless.

To overcome these hurdles, a team of SKI researchers has designed an entirely new type of CAR T cell that acts as a "micropharmacy": It can deliver a toxic drug payload directly to a tumor, killing both tumor cells that contain the cancer marker as well as those cancer cells nearby that do not. What's more, the engineered cells can produce the drug even after they become exhausted, and the drug is not suppressed by the cancer.

"We call them SEAKER cells," says physician-scientist David A. Scheinberg, Chair of the Molecular Pharmacology Program in SKI who also directs the Center for Experimental Therapeutics. "SEAKER stands for Synthetic Enzyme-Armed KillER cells. These cells combine the target-seeking power of immune cells with the ability to locally generate a potent anticancer drug for double effect."

The cancer-fighting molecule is one that SKI Chemical Biology Program Chair Derek Tan -- Dr. Scheinberg's collaborator on the project -- discovered previously while developing antibiotics. The molecule, called AMS, is so powerful that it cannot be injected directly into an animal's bloodstream. But when it is produced locally just at the site of a tumor, it is effective at safely killing cancer cells in mice. The scientists have not yet tested the technology in people.

Details about the SEAKER platform, which the scientists say has applicability to both cancer and other diseases, were published on December 30, 2021, in Nature Chemical Biology.

A Unique Drug-Delivery Approach

The idea of using CAR T cells to deliver additional therapeutic agents isn't brand new. Several research groups have shown it's possible to get them to make immune proteins like antibodies and cytokines. But getting CAR T cells to produce a small-molecule cancer drug is a trickier prospect.

"Human cells cannot normally make this type of compound," Dr. Tan says.

To find a work-around, the team devised a clever approach. They linked the cancer drug to another chemical that "masks" its function. Then, they genetically engineered the T cells to make an enzyme that cuts the masking molecule from the drug.

"In contrast to small-molecule drugs, human cells are very good at making enzymes, so CAR T cells are able to produce it effectively," Dr. Tan adds.

When the inactive version of the drug, called a prodrug, is injected into the bloodstream, it circulates through the body. The enzyme produced by the CAR T cells acts like a scissor, releasing the active part of the prodrug at the site of the tumor.

The scientists tested their SEAKER cells on both cancer cells growing in a dish and in mouse models. In both cases, the SEAKER cells performed better than regular CAR T cells at killing the cancer cells.

The SKI team also showed that their SEAKER cells work with several different prodrugs and several different cleaving enzymes -- hence their referring to this technology as a "platform."

A Risky Bet That Paid Off

The scientists emphasize the "high risk, high reward" nature of their research.

"It's one of the wildest ideas I've ever worked on," Dr. Tan says. "It's very exciting that we got it to work."

Thanks to seed funding from MSK's Center for Experimental Therapeutics and philanthropy, they were able to take a risk and eventually get the idea off the ground. Later, the National Institutes of Health (NIH) provided additional funding.

Dr. Tan adds that this project is a good example of how the pursuit of noncancer-related basic science at MSK can spawn new discoveries with relevance to cancer.

'SEAKING' Out Cancer and Other Diseases

Now that the scientists have shown that their SEAKER cells work in mice, there has been a lot of interest in the approach. In fact, a company called CoImmune has already licensed the technology from MSK to develop the CAR T cell technology for human trials.

"There is an opportunity to better understand the limitations of CAR T cells and specifically engineer new treatment options that have the potential to address challenges with eliminating tumor masses and toxicity," says Charles Nicolette, PhD, chief executive officer of CoImmune. "This exciting collaboration positions us to evaluate this completely novel approach that may provide a new treatment option for patients with solid tumors."

"The collaboration with CoImmune is exciting because we need a company to take this on to scale up and manufacture a standardized product," Dr. Scheinberg adds.

Another part of the appeal of the SEAKER technology is that it has more than one possible application.

"You could imagine it being used to produce drugs to fight other conditions, such as autoimmune diseases and infections," Dr. Scheinberg says.

But for now, the focus of the MSK researchers and CoImmune will be on cancer. Dr. Scheinberg speculates that a clinical trial in cancer is about two to three years away.

Source: ScienceDaily

Healthy diet in early pregnancy reduces risk of gestational diabetes

 Obesity is a significant risk factor for developing gestational diabetes mellitus, and an increasing number of pregnant women are overweight or obese. Dietary habits have an impact on both obesity and the onset of gestational diabetes mellitus.

The mother-child study conducted at the University of Turku and Turku University Hospital in Finland examined the connection between dietary intake and onset of gestational diabetes in 351 overweight or obese women.

The women's nutrient intake was calculated from food diaries, on the basis of which two dietary patterns, a healthier and an unhealthier dietary pattern, were recognised. In addition, the overall quality of the diet in reference to that recommended was described with a diet quality index and the inflammatory potential with a dietary inflammatory index.

"Our research results show that following a healthy diet in early pregnancy reduces the risk of gestational diabetes, says first author," Doctoral Candidate Lotta Pajunen from the Institute of Biomedicine at the University of Turku.

Diet that increases body's inflammation heightens the risk of gestational diabetes

The study also found that a higher dietary inflammatory index, meaning a diet that increases the low-grade inflammatory markers in the body was connected to an increased risk of developing gestational diabetes mellitus. Furthermore, a higher consumption of fat and especially saturated fats was connected to gestational diabetes. This is of interest as the intake of saturated fats is known to increase the body's inflammation.

Several methods were used in the study to examine the dietary intake in early pregnancy. These analyses revealed that a diet comprehensively promoting health is associated with a smaller risk of developing gestational diabetes.

"Eating vegetables, fruit, berries, and wholegrain products as well as unsaturated fats is particularly important. These nutrients and foods reduce inflammation in the body and therefore also the risk of gestational diabetes. Mothers who are overweight or obese already before the pregnancy would most likely benefit from dietary guidance in early pregnancy," says Associate Professor in Nutrition Kirsi Laitinen from the University of Turku, the PI of the Early Nutrition and Health research group that conducted the study.

Source: ScienceDaily

How brain cells die in prion diseases

 Prion diseases, such as Creutzfeldt-Jakob Disease (CJD), are fast-moving, fatal dementia syndromes associated with the formation of aggregates of the prion protein, PrP. How these aggregates form within and kill brain cells has never been fully understood, but a new study from scientists at Scripps Research suggests that the aggregates kill neurons by damaging their axons, the narrow nerve fibers through which they send signals to other neurons.

The accumulation of protein aggregates in axons, along with axonal swellings and other signs of dysfunction, are also early features of other neurodegenerative disorders including Alzheimer's and Parkinson's diseases. The discovery of how these prion aggregates form in axons and how to inhibit them, reported in Science Advances, may ultimately have a significance that goes far beyond prion diseases.

"We're hopeful that these findings will lead to a better understanding of prion and other neurodegenerative diseases, as well as new strategies for treating them," says study senior author Sandra Encalada, PhD, Arlene and Arnold Goldstein Associate Professor in the Department of Molecular Medicine at Scripps Research.

The researchers in their study closely observed mutant, disease-causing copies of the prion-disease protein PrP forming large aggregates in the axons of neurons, but not in the neurons' main cell bodies. The formation of these aggregates was followed by signs of axon dysfunction and ultimately neuronal death. The scientists found evidence that neurons' waste-disposal processes normally are able to cope with such aggregates when they are within or close to neurons' main cell bodies, but are much less able to do so when the aggregates accumulate far out within axons.

The researchers also identified a complex of key proteins as being responsible for steering PrP into axons and causing aggregation associated with large axonal swellings. They demonstrated that by silencing any one of these proteins they could inhibit the aggregates from forming and protect the neurons from damage and death.

Vulnerable axons

CJD is the most common human prion disease, occurring at the rate of about one case per million people per year worldwide. Most cases are thought to arise spontaneously when PrP somehow is altered in the brain and starts aggregating. Because these aggregates grow by a chain-reaction process that draws in healthy copies of PrP, they can transmit CJD in rare cases -- for example, during corneal transplant surgery -- from one person to another. About 15 percent of cases are hereditary, caused by mutations that make PrP more likely to aggregate. Prion disorders occur in other mammals and are thought to be due to similar toxic aggregations of different species' PrP proteins.

In the study, Encalada's team used mouse brain cells containing mutant PrP, along with microscopic motion-picture techniques, to study the initial accumulation of PrP aggregates in axons. A neuron's axon is often very long in relation to its main body -- the soma -- and has been found to be uniquely vulnerable to disruptions of its delicate systems for transporting essential molecules and getting rid of waste.

PrP's ordinary function in neurons has never been clear, but the protein appears to be normally secreted, via sac-like containers called vesicles, from the soma and the axon, where it sometimes returns to be recycled or degraded as waste. The researchers found in their experiments that mutant PrP produced in the soma is also largely encapsulated in vesicles that get moved into the axon along railways called microtubules.

This movement involves a somewhat complex vesicle trafficking system, and the researchers observed that this system shunts much of the PrP far out into axons, where PrP-containing vesicles gather and merge. Mutant PrP in this situation forms large aggregates -- Encalada calls them endoggresomes -- that axons can't get rid of. The aggregates lead to axonal swellings, and other signs of dysfunction including reduced neuronal calcium signaling, and ultimately a much faster neuronal death rate compared to neurons with normal PrP.

The researchers also found a way of countering endoggresomes formation. They identified four proteins, Arl8, kinesin-1, Vps41, and SKIP, that are responsible for directing PrP-containing vesicles into axons, carrying them far out into the soma, and merging them with other PrP-containing vesicles to trigger aggregate formation. When they silenced any of these proteins, far fewer PrP-containing vesicles entered axons, the axons showed few or no signs of aggregation, and the neurons functioned normally or almost normally and survived just as well as normal brain cells.

The results point to the tantalizing possibility that prion diseases, and perhaps many other protein-aggregate diseases of the brain, can be prevented or treated by interrupting at least transiently the trafficking process that brings vesicle-encapsulated, aggregate-prone proteins out into axons.

"We're very enthusiastic about discovering molecules that can inhibit this aggregate-forming pathway and studying the effects of such inhibitors in animal models of prion and other neurodegenerative diseases," Encalada says.

"Endosomal Sorting Drives the Formation of Axonal Prion Protein Endoggresomes" was co-authored by Romain Chassefeyre, Tai Chaiamarit, Adriaan Verhelle, André Leitão and Sandra Encalada, all of Scripps Research; and Sammy Weiser Novak, Leonardo Andrade and Uri Manor, of the Salk Institute for Biological Studies.

The research was funded by the National Institutes of Health (R01AG049483) and others.

Source: ScienceDaily

DNAzymes – how active DNA molecules with therapeutic potential work

 DNAzymes are precision biocatalysts that destroy unwanted RNA molecules. However, major obstacles to their use in medicine remain. Together with Jülich Research Centre (FZJ) and the University of Bonn, a research team from Heinrich Heine University Düsseldorf (HHU) has investigated with atomic resolution how DNAzymes work in real time. They have now presented these important fundamental findings and their application in the journal Nature.

DNAzymes -- a word made up of DNA and enzyme -- are catalytically active DNA sequences. They comprise a catalytic core comprising around 15 nucleic acids flanked by short binding arms on the right- and left-hand sides, each with around ten nucleic acids. While the sequence of the core is fixed, the binding arms can be modified specifically match virtually any RNA target sequence.

The aim is to target unwanted RNA molecules of viruses, cancer or damaged nerve cells, using DNAzymes to attack and destroy them. This is achieved via binding sequences that match a sequence of nucleotides on the targeted RNA molecule. The DNAzyme docks precisely to the matching position and the core cleaves the RNA molecule, the fragments of which are then quickly degraded in the cell. The binding arms can be exchanged quickly and easily.

The therapeutic benefits are obvious: Unwanted RNA can be destroyed precisely, while other, useful RNA strands in a cell remain untouched. In some viruses like SARS-CoV2 and Ebola, the genetic material is coded on an RNA molecule. Like healthy cells, cancer cells use so-called messenger RNA (mRNA) to copy the blueprints for proteins from their DNA and transfer them to the molecule factories. The mRNA sequence in cancer cells is often slightly different to that of healthy cells or present in different amounts, meaning that DNAzymes can specifically attack cancer cells while sparing others.

"What sounds outstanding in theory and was already proposed 20 years ago, unfortunately doesn't work like that in medical practice," says Dr Manuel Etzkorn, working group leader at the HHU Institute of Physical Biology and last author of the study, which has now been published in Nature. "In a test tube, the DNAzymes are highly effective at destroying the RNA molecules, but this rarely happens in a cell. There must be a competing process that blocks the DNAzymes. However, without a fundamental understanding of how they function, it is very difficult to develop improved DNAzyme variants that can accomplish their work in cells. Our insights have now brought movement into this deadlocked situation."

In their study, the authors from HHU and a team from Jülich Research Centre (FZJ), the University of Bonn and a Swiss company sought to understand how the system as a whole functions dynamically, what steps occur in the binding and cleaving process and what cofactors support the reaction.

The researchers observed the processes at atomic resolution and in part in real time using high-resolution nuclear magnetic resonance (NMR) spectroscopy. This enabled them to depict the three-dimensional atomic arrangement assumed by the DNAzyme to bind to and cleave the RNA: The core wraps around the RNA strand in a highly effective way, cleaving it into two pieces in several intermediate steps. After cleaving, the DNAzyme releases the fragments and can bind again elsewhere.

Professor Dr Holger Gohlke from the HHU Chair of Pharmaceutical and Medicinal Chemistry and the Institute of Bio- and Geosciences at FZJ, whose team conducted molecular dynamics simulations on the DNAzyme/RNA complex, adds: "In the best sense of integrative modelling, we were able to put forward a plausible RNA cleaving mechanism at atomic level and supply information on RNA base preference at the cleavage site."

Jan Borggräfe, doctoral researcher in Etzkorn's working group and lead author of the study, explains why the DNAzymes do not work well in cells: "We established that magnesium, as a key cofactor, plays various essential roles in the mechanism, but that it binds relatively poorly and only briefly to the DNAzyme. There are other components in the cell with a greater affinity for magnesium that "steal" the magnesium from the DNAzyme so to speak."

The next step is to conduct structural investigations into cell cultures and organoids. The goal for therapeutic applications is to improve the magnesium affinity of the DNAzymes through targeted modifications in order to increase their activity in biological tissue.

Dr Etzkorn states a further area of application: "The focus of our Institute lies on research into neurodegenerative diseases, where we also see good potential for DNAzymes. In the case of Parkinson's disease, they may under certain circumstances be able to destroy the mRNA sequence that drives the production of alpha-synuclein which, in large quantities, can promote neurotoxic processes." DNAzymes could also give rise to a new class of antibiotics.

Source: ScienceDaily

Parkinson’s protein blueprint could help fast-track new treatments

 Researchers have solved a decade-long mystery about a critical protein linked to Parkinson's disease that could help to fast-track treatments for the incurable disease.

The research, published in Nature, has for the first time produced a 'live action' view of the protein, called PINK1, in exquisite molecular detail. The discovery explains how the protein is activated in the cell, where it is responsible for initiating the removal and replacement of damaged mitochondria. When the protein is not working correctly, it can starve brain cells of energy, causing them to malfunction and -- in the long term -- die, as happens to dopamine-producing cells in Parkinson's disease.

The discovery is the culmination of a project spanning eight years and provides the first detailed blueprint for the discovery and development of therapeutic agents that could help to slow or even stop the progression of Parkinson's disease.

Led by PhD student Mr Zhong Yan Gan and Professor David Komander, the multidisciplinary team at WEHI used innovative cryo-electron microscopy facilities and research to make the discovery.

At a glance

• WEHI researchers have, for the first time, visualised the entire process that leads to the activation of PINK1 -- a protein directly linked to Parkinson's disease.
• The team has been able to analyse each process that occurs from when PINK1 is initially made, to how defects in the protein lead to Parkinson's disease.
• The enhanced understanding of the molecular basis of Parkinson's disease created by the researchers has the potential to underpin new treatments.

Turning the switch off

Parkinson's disease is a progressive neurodegenerative disease caused by the death of dopamine-producing cells in the brain. More than 10 million people worldwide are living with Parkinson's disease, including more than 80,000 Australians. Currently there are no approved drugs that can slow or stop the progression of Parkinson's disease, with available therapies only able to treat and alleviate symptoms.

PhD student and first author Zhong Yan Gan said the research provided an unprecedented view of a protein called PINK1, known to play a critical role in early onset Parkinson's disease.

"Many papers from laboratories around the world -- including ours -- have captured snapshots of the PINK1 protein. However, the differences in these snapshots has in some ways fuelled confusion about the protein and its structure," Mr Gan said.

"What we have been able to do is to take a series of snapshots of the protein ourselves and stitch them together to make a 'live action' movie that reveals the entire activation process of PINK1. We were then able to reconcile why all these previous structural images were different -- they were snapshots taken at different moments in time as this protein was activated to perform its function in the cell."

PINK1 protects the cell by tagging damaged mitochondria -- the energy powerhouse of the cell -- to be demolished and recycled. When there are defects in PINK1 or other components of the pathway, it starves the cell of energy by preventing the recycling and replacement of damaged mitochondria with healthy ones.

"One of the critical discoveries we made was that this protein forms a dimer -- or pair -- that is essential for switching on or activating the protein to perform its function. There are tens of thousands of papers on this protein family, but to visualise how this protein comes together and changes in the process of activation, is really a world-first," Mr Gan said.

Drug discovery potential

Professor Komander said his lab's discovery paved the way for developing therapeutic agents that 'switch on' PINK1 to treat Parkinson's disease.

"There are currently no disease-modifying drugs available for Parkinson's disease -- that is no drugs that can slow progression of the disease or halt its development," Professor Komander said.

Malfunctions in PINK1, or other parts of the pathway that control mitochondrial repair, is thought to be a key feature in certain cases of Parkinson's disease. However, this information is particularly relevant for a subset of young people who develop Parkinson's in their 20s, 30s and 40s due to hereditary mutations in PINK1.

Professor Komander said the discovery would lead to new opportunities to exploit this pathway for Parkinson's disease therapies.

"Biotech and pharmaceutical companies are already looking at this protein and this pathway as a therapeutic target for Parkinson's disease, but they have been flying a bit blind. I think they'll be really excited to see this incredible new structural information that our team has been able to produce using cryo-EM. I'm really proud of this work and where it may lead," he said.

Parkinson's disease research at WEHI is supported by the Australian National Health and Medical Research Council, The Michael J. Fox Foundation, Shake-It-Up Australia, a CSL Centenary Fellowship, Bodhi Foundation, Australian Government Research Training Program Scholarship and the Victorian Government, and benefits from generous philanthropic support, including Leon Davis AO and Annette Davis.

The cryo-EM work for this study was performed at the Bio21 Advanced Microscopy Facility and supported by the WEHI Information Technology Services and the WEHI Research Computing Platform.

Source: ScienceDaily