New paradigm of drug discovery with world's first atomic editing?

In pioneering drug development, the new technology that enables the easy and rapid editing of key atoms responsible for drug efficacy has been regarded as a fundamental and "dream" technology, revolutionizing the process of discovering potential drug candidates. KAIST researchers have become the first in the world to successfully develop single-atom editing technology that maximizes drug efficacy.

On October 8th, KAIST (represented by President Kwang-Hyung Lee) announced that Professor Yoonsu Park's research team from the Department of Chemistry successfully developed technology that enables the easy editing and correction of oxygen atoms in furan compounds into nitrogen atoms, directly converting them into pyrrole frameworks, which are widely used in pharmaceuticals.

This research was published in the scientific journal Science on October 3rd under the title "Photocatalytic Furan-to-Pyrrole Conversion."

Many drugs have complex chemical structures, but their efficacy is often determined by a single critical atom. Atoms like oxygen and nitrogen play a central role in enhancing the pharmacological effects of these drugs, particularly against viruses.

This phenomenon, where the introduction of specific atoms into a drug molecule dramatically affects its efficacy, is known as the "Single Atom Effect." In leading-edge drug development, discovering atoms that maximize drug efficacy is key.

However, evaluating the Single Atom Effect has traditionally required multi-step, costly synthesis processes, as it has been difficult to selectively edit single atoms within stable ring structures containing oxygen or nitrogen.

Professor Park's team overcame this challenge by introducing a photocatalyst that uses light energy. They developed a photocatalyst that acts as a "molecular scissor," freely cutting and attaching five-membered rings, enabling single-atom editing at room temperature and atmospheric pressure -- a world first.

The team discovered a new reaction mechanism in which the excited molecular scissor removes oxygen from furan via single-electron oxidation and then sequentially adds a nitrogen atom.

Donghyeon Kim and Jaehyun You, the study's first authors and candidates in KAIST's integrated master's and doctoral program in the Department of Chemistry, explained that this technique offers high versatility by utilizing light energy to replace harsh conditions. They further noted that the technology enables selective editing, even when applied to complex natural products or pharmaceuticals. Professor Yoonsu Park, who led the research, remarked, "This breakthrough, which allows for the selective editing of five-membered organic ring structures, will open new doors for building libraries of drug candidates, a key challenge in pharmaceuticals. I hope this foundational technology will be used to revolutionize the drug development process."

The significance of this research was highlighted in the Perspective section of Science, a feature where a peer scientist of prominence outside of the project group provides commentary on an impactful research.

This research was supported by the National Research Foundation of Korea's Creative Research Program, the Cross-Generation Collaborative Lab Project at KAIST, and the POSCO Science Fellowship of the POSCO TJ Park Foundation.

Journal Reference:

1. Donghyeon Kim, Jaehyun You, Da Hye Lee, Hojin Hong, Dongwook Kim, Yoonsu Park. Photocatalytic furan-to-pyrrole conversion. Science, 2024; 386 (6717): 99 DOI: 10.1126/science.adq6245 

Courtesy:

The Korea Advanced Institute of Science and Technology (KAIST). "New paradigm of drug discovery with world's first atomic editing?." ScienceDaily. ScienceDaily, 11 October 2024. <www.sciencedaily.com/releases/2024/10/241011141546.htm>.

 

 

 

 

Kerala is detecting ‘brain eating amoeba’ cases like never before – and saving its patients too

 

An alert medical fraternity and public, aggressive investigation, and a standard operating procedure – these are the major reasons why Kerala has been able to bring down mortality rate in the rare primary amoebic meningoencephalitis (PAM), commonly called the “brain eating amoeba”, from the 97 percent globally to 26 percent in Kerala.

Amoebic meningoencephalitis is caused by Naegleria fowleri, a free-living amoeba found in warm, fresh water and soil, and infects people when it enters the body through the nose.

According to the data submitted by Kerala health minister Veena George in the state Assembly early this week, of the 29 PAM cases that Kerala has reported so far in 2024, only five have died. State health department pegs the mortality rate for the disease at 26 percent – considerably lower than the 97 percent globally.

This is despite the jump in the number of cases in Kerala – according to state government data, cases have gone from just eight between 2016 and 2023 to 29 this year. Significantly, six districts had reported the PAM cases during the period, with Thiruvananthapuram having recorded the bulk of it at 15.

Of the 29 cases seen so far this year, 24 have survived. In contrast, according to the US Centres for Disease Control and Prevention, between 1962 and 2023, there were 164 reported cases of PAM in the United States, and only four survived.

The first case of PAM in India was reported in 1971, and the country has seen just around two dozen cases since then until last year. The first case in Kerala was reported in 2016.

All reported cases in India had led to the patient’s death – that is, until July this year, when 14-year-old Afanan Jasim from Thikkodi in Kerala’s Kozhikode district became the first Indian to survive the disease. He was only the 11th PAM survivor in the world.

The spike in cases this year is attributed to increased testing for acute encephalitis syndrome (AES) – a condition that can be caused by various diseases including amoebic meningoencephalitis – as well as other factors such as climate change and environmental pollution.

In July, Kerala issued a special treatment protocol and a standard operating procedure for the management of amoebic meningoencephalitis cases – the first state in India to do so.

According to Dr R Aravind, head of department of infectious diseases at the Government Medical College Thiruvananthapuram, the guidelines issued by the state health department on prevention, diagnosis and treatment of amoebic meningoencephalitis were a game changer for the state’s battle against the disease.

“The guidelines had stated a clear protocol to be followed, in which case one should suspect amoebic meningoencephalitis and what should be the medicine. Use of miltefosine was another major factor in the treatment, leading to reducing mortality. Until last year when we used a combination of four drugs (Amphotericin B, Rifampicin, Fluconazole and Azithromycin) and nobody survived. But the cocktail of these five drugs, including miltefosine, was another milestone in our fight against the fatal disease. As miltefosine was not easily available in India, the state health department took a very proactive stand and procured it from abroad.’

More cases are being detected because of aggressive search for amoebic meningoencephalitis cases.

Dr T S Anish, who is a member of the state medical board for PAM, said the increase in awareness of the disease among the doctors and the public helped detect more cases. According to him, the high instances of diagnosis of AES in the state was another major reason why doctors in Kerala were able to detect amoebic meningoencephalitis and Nipah cases more than anywhere else in the country.

“A few back-to-back deaths have also increased this awareness. Doctors have been sensitised. Now, if a patient is admitted with symptoms of encephalitis, they are ready to share the history of swimming in ponds or lakes, if any. This helps early diagnosis, which is vital for treatment of PAM. Thus, we have saved lives (in cases where PAM) would have gone undetected,” said Dr Anish, a professor of community medicine at the Government Medical College Manjeri, Malappuram.

The tropical climate of the state increases the chances of infection, he said.

“Due to global warming, the presence of naegleria fowleri has increased in ponds… We have other amoebae, too, which have become ubiquitous. But finding them is very tricky and there is a knowledge gap” he said.

Despite the fatality rate being pegged at 26 percent, sources in the health department believe the actual rate would be much lower.

According to the health department source, Kerala has reported two types of amoebae that cause brain infections. “We have cases reported from Kerala due to amoebas naegleria, which has a mortality rate of 97 percent, and acanthamoeba, which has mortality 60-90 percent. Hence, the state’s fatality rate was pegged at 26 percent,” the source said.

This finding of meningoencephalitis due to acanthamoeba, according to Dr Aravind, helped Kerala health department to go a step further in detecting the infection.

“When we were doing molecular diagnosis of meningoencephalitis, we learned that apart from naegleria fowleri, another genus acanthamoeba is also causing the infection. The notion that water exposure leads to amoebic meningoencephalitis is applicable only to cases caused by naegleria fowleri. Water exposure is not essentially applicable to meningoencephalitis caused by other amoeba including acanthamoeba, which has an incubation period from days to months,” he said.

Kerala had PAM cases without a history of water exposure, he said.

“The research papers published by School of Tropical Medicine, Kolkata, last year, had mentioned meningoencephalitis cases without water contact. Their experience also made us go for aggressive testing of meningoencephalitis cases without history of water contact. That helped us pick up more cases, particularly in Thiruvananthapuram,” he said.

Meanwhile, the state government has commissioned a study to analyse the organic and inorganic factors that contribute to increase in the density of amoeba in water bodies. The study will be conducted by Kerala University’s Department of Environmental Sciences and the State Pollution Control Board.

According to the University Prof Salom Gnana Thanka, who is part of the expert team, the density of amoeba will be high in contaminated water. “Besides, increase in temperature is also another contributing factor. We have literature from abroad in this regard but we have to study this situation in Indian conditions. We will be collecting samples of water mainly from areas where PAM cases were reported,” she said.

 https://indianexpress.com/article/india/kerala-is-detecting-brain-eating-amoeba-cases-like-never-before-and-saving-its-patients-too-9617472/

Courtesy: © The Indian Express Pvt Ltd 

 

 

 

  

 

Extreme rainfall poses health risks

 

An international study led by Helmholtz Munich investigates the health consequences of heavy rainfall events. Researchers analyzed the relationship between precipitation patterns and mortality rates at 645 locations across 34 countries from 1980 to 2020. The key finding: Extremely heavy rainfall, which occurs approximately every five years, significantly increases the risk of death, particularly among individuals with cardiovascular and respiratory diseases. The impacts, however, vary greatly by region and depend on local climate and environmental conditions.

"From East Asia, it was already known that extreme rain events have a strong impact on human health," says Dr. Alexandra Schneider, Deputy Director of the Institute of Epidemiology and Head of the Environmental Risks research group at Helmholtz Munich: "With our current study, we wanted to investigate the global impacts of extreme rainfall events on health." The team analyzed extensive data covering four decades and a wide geographical spread. 

"To examine the precise effects of heavy rain on mortality, we differentiated the rainfall events by their so-called return periods -- the statistical frequency of such extreme events -- and analyzed their impact on various health risks," Schneider explains.

Extreme Rain Disrupts Medical Treatment and Leads to Stress

The detailed insights into the connections between extreme weather events and health consequences revealed: The data show a significant increase in mortality rates within a 14-day lag period associated with extreme rainfall, which statistically occurs about every five years.

"In addition to the increase in general mortality, the negative effects of these extreme weather events were particularly evident in people with cardiovascular and respiratory diseases," says Dr. Cheng He, lead author of the study and a scientist at Helmholtz Munich: "The health risks from extremely heavy rain can arise from medical treatments being disrupted, medications being unavailable, or affected individuals suffering from severe psychological stress. Airborne pathogens, facilitated by high humidity, are also a possible explanation."

On the other hand, the research team observed protective effects on people's health during comparatively moderate rainfall events with a return period of one to two years.

These may be due to improved air quality and reduced air temperatures following the precipitation.

The study also highlights the importance of regional factors that modify the impacts of extreme rainfall on health: climate zone, vegetation coverage, and variability in daily precipitation of each city.

Minimizing Health Risks From Heavy Rain

Given the clear results of the study, political action is essential, says Prof. Annette Peters, Director of the Institute of Epidemiology: "In light of climate change and more frequent extreme rainfall events, we need robust health prevention strategies and adaptation measures worldwide, particularly focusing on improving infrastructure and strengthening health systems in the most affected regions." The implementation of early warning systems for extreme weather events and the promotion of green infrastructure in urban areas could also help minimize the health risks caused by heavy rainfall. "It's not just about responding to emergencies, but proactively taking measures to protect the population from the foreseeable consequences of climate change," says Peters: "It's about saving lives."

Journal Reference:

1. Cheng He, Susanne Breitner-Busch, Veronika Huber, Kai Chen, Siqi Zhang, Antonio Gasparrini, Michelle Bell, Haidong Kan, Dominic Royé, Ben Armstrong, Joel Schwartz, Francesco Sera, Ana Maria Vicedo-Cabrera, Yasushi Honda, Jouni J K Jaakkola, Niilo Ryti, Jan Kyselý, Yuming Guo, Shilu Tong, Francesca de’Donato, Paola Michelozzi, Micheline de Sousa Zanotti Staglior Coelho, Paulo Hilario Nascimento Saldiva, Eric Lavigne, Hans Orru, Ene Indermitte, Mathilde Pascal, Patrick Goodman, Ariana Zeka, Yoonhee Kim, Magali Hurtado Diaz, Eunice Elizabeth Félix Arellano, Ala Overcenco, Jochem Klompmaker, Shilpa Rao, Alfonso Diz-Lois Palomares, Gabriel Carrasco, Xerxes Seposo, Susana das Neves Pereira da Silva, Joana Madureira, Iulian-Horia Holobaca, Noah Scovronick, Fiorella Acquaotta, Ho Kim, Whanhee Lee, Masahiro Hashizume, Aurelio Tobias, Carmen Íñiguez, Bertil Forsberg, Martina S Ragettli, Yue Leon Guo, Shih-Chun Pan, Samuel Osorio, Shanshan Li, Antonella Zanobetti, Tran Ngoc Dang, Do Van Dung, Alexandra Schneider. Rainfall events and daily mortality across 645 global locations: two stage time series analysis. BMJ, 2024; e080944 DOI: 10.1136/bmj-2024-080944 

Courtesy:

Helmholtz Munich. "Extreme rainfall poses health risks." ScienceDaily. ScienceDaily, 10 October 2024. <www.sciencedaily.com/releases/2024/10/241010124903.htm>.

 

 

 

Large variation in how girls grow after their first period

 

There is unexpectedly large variation in height growth in girls after their first period. Every second girl grows either more or less in length than the 6-8 centimeters that is considered standard. This has been shown in a study conducted at the University of Gothenburg.

The aim of the study, published in the journal Frontiers in Pediatrics, was to investigate how the timing of the first menstruation is related to the subsequent height growth in girls and the factors behind it.

The study included 793 healthy women in the Gothenburg region and Halland in southwest Sweden who were followed from birth, through childhood, puberty and into adulthood. Data were extracted from surveys of participants, interview questionnaires and registry data. Data on parental height are also included.

The average age of first period was 13.0 years with an age range from 8.2 to 17.2 years. After their first period, the girls grew an average of 8.0 centimeters and a median of 7.0 centimeters, which were expected levels.

One in two outside the chart

However, the range was strikingly wide: from 0.2 to 31.1 centimeters in height growth. Of the participants, only one in two grew 6-8 centimeters, which is often considered normal height growth after the first period.

The study reinforces the idea that early onset of menstruation is followed by greater height growth and vice versa. The onset of menstruation before the age of 12 was followed by a growth in the median of almost 13 centimeters. For study participants who had their first period after just over 14 years of age, the corresponding growth was about 3 centimeters.

"This variation in growth after menstruation and to final height is much greater than previous studies have shown. The variations depend very much on when they get their period. There is a huge difference between those who get their period early and those who get it later," says Jenni Gårdstedt Berghog, a Doctor at the women's healthcare clinic at Halland Hospital in Halmstad and one of the lead authors.

The study confirms that childhood BMI also plays a role. Both low childhood BMI and tall parents can separately be associated with later menstrual onset. A high childhood BMI, which in itself drives height growth in the child, is followed by earlier onset of menstruation -- and shorter final length. Everything is measured at group level and variations are very large.

Unexpectedly large variations

The principal investigator of the study is Anton Holmgren, a Pediatric Researcher at Sahlgrenska Academy at the University of Gothenburg, a Pediatrician at Halland Hospital in Halmstad, and active within Research and Development in Region Halland.

"There is a widespread belief that girls grow 6-8 centimeters after their first period, which even medical students are taught," he says. "With this study, we show that there is a huge variation and that those who enter puberty early and get their first period early grow significantly more than previously thought, and that those who are late in getting their first period do not grow that much more."

"Increasing knowledge in this area is good even if it is not linked to any disease. How you grow, when puberty occurs and whether one becomes tall or short, it is something that all people have a relation to," concludes Anton Holmgren.

Journal Reference:

1. Jenni Gårdstedt-Berghog, Aimon Niklasson, Agneta Sjöberg, A. Stefan Aronson, Aldina Pivodic, Andreas F. M. Nierop, Kerstin Albertsson-Wikland, Anton Holmgren. Timing of menarche and pubertal growth patterns using the QEPS growth model. Frontiers in Pediatrics, 2024; 12 DOI: 10.3389/fped.2024.1438042 

Courtesy:

University of Gothenburg. "Large variation in how girls grow after their first period." ScienceDaily. ScienceDaily, 27 September 2024. <www.sciencedaily.com/releases/2024/09/240927173549.htm>.

 

 

 

 

Researchers discover new bacterium that causes gut immunodeficiency

Cleveland Clinic researchers have discovered a new bacterium that weakens the immune system in the gut, potentially contributing to certain inflammatory and infectious gut diseases.

The team identified the bacterium, Tomasiella immunophila (T. immunophila), which plays a key role in breaking down a crucial immune component of the gut's multi-faceted protective immune barrier.

Identifying this bacterium is the first step to developing new treatments for a variety of inflammatory and infectious gut diseases. These conditions, including inflammatory bowel disease, Crohn's and ulcerative colitis, are associated with decreased levels of secretory immunoglobulin A (SIgA), an antibody that protects mucosal surfaces.

The study, published in Science, was led by Thaddeus Stappenbeck, M.D., Ph.D., chair of Cleveland Clinic's Department of Inflammation and Immunity, and Qiuhe Lu, Ph.D., research associate and the paper's first author.

"Our research represents a critical role of a specific component of the gut microbiome in human health and disease," said Dr. Stappenbeck. "By identifying this specific bacterium, we have not only enhanced our understanding of gut diseases but also opened a promising new avenue for treatment. Pinpointing the culprit behind the breakdown of the gut's protective adaptive immune barrier is a significant step toward developing much-needed therapies for conditions like inflammatory bowel disease, Crohn's and ulcerative colitis."

In the gut, SIgA binds continuously to microbes, preventing them from reaching and damaging the body's tissue. In previous research, the team discovered that intestinal bacteria could reduce SIgA levels, which can lead to increased risk of infection and excess inflammation.

In this new study, researchers found that T. immunophila'spresence in the gut increases susceptibility to pathogens and delays repair of the gut's protective barrier. T. immunophila'sname is an homage to a pioneer in immunology. SIgA was discovered by Dr. Thomas Tomasi, who published his findings in a foundational paper in Science in 1963.

"Drs. Stappenbeck and Lu's rigorous and elegant study provides a key insight and an exciting potential mechanism for why some people have low or absent levels of SIgA in their gut, yet retain normal levels of SIgA in their bloodstream," says Michael Silverman, M.D., Ph.D., a physician with the Division of Infectious Diseases at Children's Hospital of Philadelphia.

Dr. Silverman, whose expertise includes immune system development, provided input on the research findings. "This discovery is quite important, as SIgA in the intestine functions as a critical component of the barrier for the trillions of microbes that live in our intestines," Dr. Silverman said. "This study provides a new avenue to develop therapeutics to manipulate SIgA in the gut and improve health."

"We know that there are a substantial number of patients that have this defect in are at risk for infection and inflammation in the intestine," said Dr. Lu. "We surmised that a gut microbe that can degrade SIgA was the culprit. We believe that important therapeutic targets for a variety of inflammatory and infectious diseases in humans can be found through our work."

Journal Reference:

1. Qiuhe Lu, Thomas C. A. Hitch, Julie Y. Zhou, Mohammed Dwidar, Naseer Sangwan, Dylan Lawrence, Lila S. Nolan, Scott T. Espenschied, Kevin P. Newhall, Yi Han, Paul E. Karell, Vanessa Salazar, Megan T. Baldridge, Thomas Clavel, Thaddeus S. Stappenbeck. A host-adapted auxotrophic gut symbiont induces mucosal immunodeficiency. Science, 2024; 385 (6716) DOI: 10.1126/science.adk2536 

Courtesy:

Cleveland Clinic. "Researchers discover new bacterium that causes gut immunodeficiency." ScienceDaily. ScienceDaily, 26 September 2024. <www.sciencedaily.com/releases/2024/09/240926144904.htm>.

 

 

 

Getting the flu and then your shot may benefit immunity

 

In a new study funded by the National Institutes of Health, University of Georgia researchers found that natural immunity from previous flu infections has a significant impact on how well future influenza vaccinations work.

That may mean if you're one of the unlucky estimated 1 in 5 Americans who gets the flu each year, according to the NIH, there may be an unexpected upside to your illness.

It may help you battle future versions of the virus.

"Overall, the preexisting immunity you develop through natural infection helps to strengthen immune responses," said Ye Shen, study corresponding author and a professor in the UGA College of Public Health. "We didn't fully understand how preexisting immunity through natural infection with different influenza strains changes vaccine-elicited immune responses before this study. Now we have a better understanding of how preexisting immunity to influenza influences immune responses to different types of vaccines."

Flu shots aim to keep up with an evolving virus

Each flu season, your flu shot targets certain strains of the virus. So when scientists develop the influenza vaccine, they have to make educated guesses about which strains are most likely to be circulating ahead of time.

While plenty of research goes into developing the shot, it's never going to be right 100% of the time.

The flu virus's ability to constantly evolve and develop new and more virulent strains makes it difficult to fight.

"In some years, we don't have very good protection from the vaccine because of that mismatch," Shen said. "People have started to worry about whether the shot is actually protecting them from the flu because of that. With this study, though, we do see benefits of having preexisting immunity, and that's good to know."

Vaccination post-recovery can bolster immune system

The researchers tested vaccines made of various flu strains. They found when animals were infected with one strain of the flu, the animals had a heightened immune response when given a vaccine targeting that same strain.

But overall immunity also improved significantly when the animals were given a vaccine targeting a different flu strain, after being infected with the original strain of the virus.

With the body protecting itself against one strain with its natural immune response and the vaccine eliciting broader immune responses to a spectrum of flu strains, the body was better shielded.

Animals that were not initially infected with the virus but did get the vaccine were more likely to need a booster because they lacked natural immunity.

This research is part of a larger, seven-year NIH-funded study that aims to create universal influenza vaccines for vulnerable populations.

"Our future studies will further explore more clinically relevant outcomes including actual infections in humans. It may not be enough just to push your antibodies higher," Shen said. "Is that enough to protect you from mutations of different influenza strains? This is where individual-level heterogeneity becomes important, which remains an ongoing area of research in the field."

Published in the journal Vaccine, the study was co-authored by Yao Lu, who also conducted much of the data analysis, and Andreas Handel, from the UGA College of Public Health, and Ted Ross, of the UGA College of Veterinary Medicine. Additional co-authors include Yang Ge, James D. Allen, Tal Einav, Dennis I. Nkaleke and Fengwei Bai.

Journal Reference:

1. Yang Ge, Yao Lu, James D. Allen, Tal Einav, Dennis I. Nkaleke, Fengwei Bai, Andreas Handel, Ted M. Ross, Ye Shen. Pre-existing immunity to influenza aids ferrets in developing stronger and broader H3 vaccine-induced antibody responses. Vaccine, 2024; 42 (21): 126149 DOI: 10.1016/j.vaccine.2024.07.050 

Courtesy:

University of Georgia. "Getting the flu and then your shot may benefit immunity." ScienceDaily. ScienceDaily, 30 September 2024. <www.sciencedaily.com

/releases/2024/09/240930122824.htm>.