Kidney disease hampers immune response to the flu

A new study shows that advanced kidney disease compromises the survival of B cells and significantly reduces the immune response to the influenza virus.

B cells are a type of infection-fighting white blood cell that produces antibodies to kill microbes.

Fighting off infections when one has chronic disease is a common problem, and during the COVID-19 pandemic that scenario often turned out to be dangerous and deadly.

Comorbid health conditions are critical determinants of immune function. One comorbid condition associated with increased risk of severe infection and infection-related deaths is kidney disease. Infections are the second major cause of death in patients with kidney disease.

According to the International Society of Nephrology, an estimated 20% of patients with kidney disease die from infection. During the COVID-19 pandemic, mortality rates were as much as 10 times higher for those who had kidney disease compared to those with normal kidney function.

Lead author Partha Biswas, a professor in the microbiology and immunology department in the Renaissance School of Medicine at Stony Brook University, and colleagues, set out to better understand why those who have kidney disease are unable to mount a protective immune response. The study centered on the condition experienced during kidney disease called uremia—the accumulation of toxic metabolites in the body in the absence of kidney filtration of the blood.

To date clinical studies often show a poor B cell-mediated antibody response after an infection or vaccination in those with kidney disease. Additionally, kidney disease is a known predisposing factor for infection complications, however the reasons are not clear.

“Most studies linking kidney disease with abnormal B cell response were either performed in kidney transplant patients or are correlative in nature. Since kidney transplant patients are immune compromised, it is difficult to assess the impact of kidney disease on B cell response per se,” explains Biswas.

The researchers used a multiple well-characterized murine model of kidney disease that progresses to renal dysfunction in the subjects. Healthy mice and those with kidney disease were immunized with model immunogens or infected with the influenza virus to trigger a germinal center (GC) response in the spleen, which is central to the development of protective antibody level and infection-fighting response.

They discovered several cellular changes that helps to illustrate the poor immune response in the kidney disease model:

• Kidney dysfunction leading to accumulation of toxic metabolites triggered cell death in GC B cells leading to poor antibody response during immunization.
• A previously unidentified role of uremic toxic metabolites hippuric acid (HA) is responsible for increased cell death of GC B cells.
• HA drove increased death of GC B cells via activating a specific G protein coupled receptor for niacin, which appears to further affect normal B cell response.
• Kidney disease had a negative impact on and inhibits GC and antibody response following influenza virus infection.

According to Biswas, the paper provides mechanistic insights on how kidney disease negatively impacts protective B cell response infection and immunization. He and his co-investigators believe that the knowledge gained from the laboratory study may shed light on how to generate protective antibody response following vaccination in individuals with kidney disease.

Currently, Biswas and colleagues are tooling up to use this experimental system to address the apparent lack of response to SARS-CoV 2 vaccination in kidney disease individuals, which may have broader implications for other respiratory virus and bacterial infections seen in these patients.

The findings appear in Nature Communications. Collaborators included scientists from numerous departments and facilities at the University of Pittsburgh and the Medical College of Georgia.

Support for the research came in part from numerous grants from the National Institutes of Health (NIH), including several to Biswas.

Source: Stony Brook University

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Antibodies can improve spinal cord injury rehab

Antibodies can improve the rehabilitation of people with acute spinal cord injury, researchers report.

Researchers at 13 clinics in Germany, Switzerland, the Czech Republic, and Spain have investigated this with promising results. For the first time, it was possible to identify patient groups that displayed a clinically relevant treatment effect.

A multi-center clinical trial (NISCI trial: Nogo-A Inhibition in acute Spinal Cord Injury Study) investigated the antibody NG 101 (anti-Nogo-A), which blocks and thus neutralizes the body’s own Nogo-A protein.

Several international studies in animal models have shown that this Nogo-A protein inhibits the regeneration of damaged nerve fibers in the spinal cord following an acute injury.

The antibody is intended to slow down these inhibiting mechanisms in the body and thus enable the injured nerve tracts to regenerate and the spinal cord to recover.

126 people aged between 18 and 70 took part in the clinical study. They were all suffering from acute complete to incomplete spinal cord injury in the neck region (so called tetraplegia that also affects the arm and hand functions).

78 people were treated with the antibody that was injected directly into the spinal canal; the remaining 48 people received placebo. A complete treatment cycle consisted of six injections in parallel to comprehensive inpatient care.

The study was randomized, double-blind, and placebo-controlled, i.e. neither those being treated nor those administering the treatment knew who received the antibody and who was given the placebo. The patients were randomly assigned to a group.

The researchers investigated the recovery of motor functions in the hand-arm muscles of the patients in a standardized manner. These muscle groups are particularly important for everyday life in patients with tetraplegia. After six months, the effect on the treated and untreated (placebo) patients was compared.

The treatment did not improve the recovery of motor functions in patients with complete spinal cord injury. In patients with incomplete spinal cord injury, the treatment led to significantly more improvement in the voluntary activation of the paralyzed muscles and in everyday life functional independence. The antibody was generally well tolerated, with no related side effects reported to date. The many years of research into antibodies in rehabilitation conducted under the leadership of Balgrist University Hospital are showing encouraging success.

These initial positive clinical findings in patients with acute tetraplegia must now be confirmed in further studies. A follow-up study with an improved antibody will start in December 2024. Patient subgroups with anticipated responsiveness to the treatment based on the results to date will be selected.

The production of the test antibody was made possible as part of the CeNeReg project through collaboration with the Regenerative Medicine Technology Platform of the Wyss Zurich Translational Center. The NISCI study was financed by the EU’s Horizon 2020 Research and Innovation Programme, the Swiss State Secretariat for Education, Research and Innovation (SBFI), the Swiss Paraplegic Foundation, the Wings for Life research foundation, the “CeNeReg” project from the Wyss Zurich (University of Zurich and ETH Zurich), and the “International Research in Paraplegia” foundation.

The research appears in The Lancet Neurology.

Source: University of Zurich

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Could a fungal pandemic make The Last of Us a reality?

In a new podcast episode, a scientist warns against the threat of a future fungal pandemic.

Five years after COVID became a global pandemic, could another health crisis be on our horizon?

According to scientists who study diseases, the possibility of a fungal pandemic—the subject of science fiction TV shows like The Last of Us—could be more of a reality, thanks to climate change and our warming planet.

As fungi are adapting to warmer climates, they are becoming increasingly stronger and more resistant against the drugs we have to fight them.

Arturo Casadevall is one of the scientists who is warning against fungi’s powerful potential. He’s a professor of microbiology and immunology at the Johns Hopkins’ Bloomberg School of Public Health and the author of the new book, What If Fungi Win? (Johns Hopkins University Press, 2024).

In this episode of the Big Brains Podcast, he digs into why fungi are becoming a growing public health threat and what tools we have to protect ourselves from a future fungal outbreak:

Source: University of Chicago

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DNA rewrites when Neanderthals bred with modern humans

A new analysis of DNA from ancient modern humans (Homo sapiens) in Europe and Asia has determined, more precisely than ever, the time period during which Neanderthals interbred with modern humans.

The findings show the interbreeding started about 50,500 years ago and lasted about 7,000 years—until Neanderthals began to disappear.

That interbreeding left Eurasians with many genes inherited from our Neanderthal ancestors, which in total make up between 1% and 2% of our genomes today.

A more precise timeline for modern human interactions with Neanderthals can help scientists understand when humans emigrated out of Africa and peopled the globe, while understanding the DNA that Neanderthals shared with our ancestors provides information on the role Neanderthal genes play in human health.

The genome-based estimate is consistent with archeological evidence that modern humans and Neanderthals lived side-by-side in Eurasia for between 6,000 and 7,000 years. The analysis, which involved present-day human genomes as well as 58 ancient genomes sequenced from DNA found in modern human bones from around Eurasia, found an average date for Neanderthal-Homo sapiens interbreeding of about 47,000 years ago. Previous estimates for the time of interbreeding ranged from 54,000 to 41,000 years ago.

The new dates also imply that the initial migration of modern humans from Africa into Eurasia was basically over 43,500 years ago.

“The timing is really important because it has direct implications on our understanding of the timing of the out-of-Africa migration, as most non-Africans today inherit 1-2% ancestry from Neanderthals,” says Priya Moorjani, an assistant professor of molecular and cell biology at the University of California, Berkeley, and one of two senior authors of the study.

“It also has implications for understanding the settlement of the regions outside Africa, which is typically done by looking at archeological materials or fossils in different regions of the world.”

The genome analysis, also led by Benjamin Peter of the University of Rochester in New York and the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig, Germany, appears in the journal Science. The two lead authors are Leonardo Iasi, a graduate student at MPI-EVA, and Manjusha Chintalapati, a former UC Berkeley postdoctoral fellow now at the company Ancestry DNA.

The longer duration of gene flow may help explain, for example, why East Asians have about 20% more Neanderthal genes than Europeans and West Asians. If modern humans moved eastward about 47,000 years ago, as archeological sites suggest, they would already have had intermixed Neanderthal genes.

“We show that the period of mixing was quite complex and may have taken a long time. Different groups could have separated during the 6,000- to 7,000-year period, and some groups may have continued mixing for a longer period of time,” Peter says. “But a single shared period of gene flow fits the data best.”

“One of the main findings is the precise estimate of the timing of Neanderthal admixture, which was previously estimated using single ancient samples or samples from present-day individuals. Nobody had tried to model all of the ancient samples together,” Chintalapati says. “This allowed us to build a more complete picture of the past.”

In 2016, Moorjani pioneered a method for inferring the timing of Neanderthal gene flow using often incomplete genomes of ancient individuals. At that time, only five archaic Homo sapiens genomes were available.

For the new study, Iasi, Chintalapati, and their colleagues employed this technique with 58 previously sequenced genomes of ancient Homo sapiens who lived in Europe, Western, and Central Asia over the past 45,000 years and the genomes of 275 contemporary humans worldwide to provide a more precise date—47,000 years ago.

Rather than assuming the gene flow occurred in a single generation, they tried more complex models developed by Iasi and Peter to establish that the interbreeding extended over about 7,000 years, rather than being intermittent.

The timing of the interbreeding between Neanderthals and modern humans was corroborated by another, independent study conducted by MPI-EVA researchers that appears in the journal Nature. That study, an analysis of two newly sequenced genomes of Homo sapiens that lived about 45,000 years ago, also found a date of 47,000 years ago.

“Although the ancient genomes were published in previous studies, they had not been analyzed to look at Neanderthal ancestry in this detailed way. We created a catalog of Neanderthal ancestry segments in modern humans. By jointly analyzing all these samples together, we inferred the period of gene flow was around 7,000 years,” Chintalapati says.

“The Max Planck group actually sequenced new ancient DNA samples that allowed them to date the Neanderthal gene flow directly. And they came up with a similar timing as us.”

The UC Berkeley/MPI-EVA team also analyzed regions of the modern human genome that contain genes inherited from Neanderthals and some areas that are totally devoid of Neanderthal genes. They found that areas lacking any Neanderthal genes, so-called archaic or Neanderthal deserts, developed quickly after the two groups interbred, suggesting that some Neanderthal gene variants in those areas of the genome must have been lethal to modern humans.

Early modern human samples that are older than 40,000 years already contained these deserts in their genomes.

“We find that very early modern humans from 40,000 years ago don’t have any ancestry in the deserts, so these deserts may have formed very rapidly after the gene flow,” says Iasi.

“We also looked at the changes in Neanderthal ancestry frequency over time and across the genome and found regions that are present at high frequency, possibly because they carry beneficial variants that were introgressed from Neanderthals.”

Most of the high-frequency Neanderthal genes are related to immune function, skin pigmentation and metabolism, as reported in some previous studies. One immune gene variant inherited from Neanderthals confers protective effects to the coronavirus that causes COVID-19, for example. Some of the Neanderthal genes involved in the immune system and skin pigmentation actually increased in frequency in Homo sapiens over time, implying that they may have been advantageous to human survival.

“Neanderthals were living outside Africa in harsh, ice age climates and were adapted to the climate and to the pathogens in these environments. When modern humans left Africa and interbred with Neanderthals, some individuals inherited Neanderthal genes that presumably allowed them to adapt and thrive better in the environment,” Iasi says.

“The fact that we find some of these regions already in 30,000-year-old samples shows that some of these regions were actually adapted immediately after the introgression,” Chintalapati adds.

Other genes, such as the gene conferring resistance to coronaviruses, may not have been immediately useful, but became so later on.

“The environment changes, and then some genes become beneficial,” Peter says.

Moorjani is currently looking at Neanderthal sequences in people of East Asian descent, who not only have a greater percentage of Neanderthal genes, but also some genes—up to 0.1% of their genome—from another early hominin group, the Denisovans.

“It’s really cool that we can actually peer into the past and see how variants inherited from our evolutionary cousins, Neanderthals and Denisovans, changed over time,” Moorjani says.

“This allows us to understand the dynamics of the mixture of Neanderthals and modern humans.”

Additional coauthors are from UC Berkeley and MPI-EVA.

Support for Moorjani’s research came from the Burroughs Wellcome Fund and the National Institutes of Health.

Source: UC Berkeley

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Embrace optimism for big emotional and physical benefits

Law lecturer Scott L. Rogers has answers for you about the benefits of embracing optimism.

Most people make New Year’s resolutions that they cannot keep.

Studies show that very few can follow through with losing weight, eating healthier, or starting a regimen of meditation, or whatever else they wanted to do.

According to a recent study by The Ohio State University Max M. Fisher College of Business, only 9% of people who make New Year’s resolutions follow through with them.

Yet many experts agree that there is one change that can bring many benefits, and it is one anyone can pursue. There are many advantages to becoming an optimist.

Optimism is a state of mind. We can all decide to embrace optimism instead of a pessimistic point of view.

The Dalai Lama says, “Optimism does not mean that you are blind to the reality of the situation; it means that you remain motivated to seek a solution to whatever problems arise.”

Here, Rogers, a lecturer at University of Miami School of Law and director of the Mindfulness in Law Program, digs into the many benefits of being an optimist:

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Millions of diabetes and heart disease cases tied to sugary drinks

A new study estimates that 2.2 million new cases of type 2 diabetes and 1.2 million new cases of cardiovascular disease occur each year globally due to consumption of sugar-sweetened beverages.

In developing countries, the case count is particularly sobering. In Sub-Saharan Africa, the study found that sugar-sweetened beverages contributed to more than 21% of all new diabetes cases. In Latin America and the Caribbean, they contributed to nearly 24% of new diabetes cases and more than 11% of new cases of cardiovascular disease.

Colombia, Mexico, and South Africa are countries that have been particularly hard hit. More than 48% of all new diabetes cases in Colombia were attributable to consumption of sugary drinks. Nearly one third of all new diabetes cases in Mexico were linked to sugary drink consumption. In South Africa, 27.6% of new diabetes cases and 14.6% of cardiovascular disease cases were attributable to sugary drink consumption.

Sugary beverages are rapidly digested, causing a spike in blood sugar levels with little nutritional value. Regular consumption over time leads to weight gain, insulin resistance, and a host of metabolic issues tied to type 2 diabetes and heart disease, two of the world’s leading causes of death.

“Sugar-sweetened beverages are heavily marketed and sold in low- and middle-income nations. Not only are these communities consuming harmful products, but they are also often less well equipped to deal with the long-term health consequences,” says Dariush Mozaffarian, senior author on the paper and director of the Food is Medicine Institute at the Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University.

As countries develop and incomes rise, sugary drinks become more accessible and desirable, the authors say. Men are more likely than women to suffer the consequences of sugary drink consumption, as are younger adults compared to their older counterparts, the researchers say.

“We need urgent, evidence-based interventions to curb consumption of sugar-sweetened beverages globally, before even more lives are shortened by their effects on diabetes and heart disease,” says Laura Lara-Castor, first author on the paper who earned her PhD at the Friedman School and is now at the University of Washington.

The study’s authors call for a multi-pronged approach, including public health campaigns, regulation of sugary drink advertising, and taxes on sugar-sweetened beverages. Some countries have already taken steps in this direction. Mexico, which has one of the highest per capita rates of sugary drink consumption in the world, introduced a tax on the beverages in 2014. Early evidence suggests that the tax has been effective in reducing consumption, particularly among lower-income individuals.

“Much more needs to be done, especially in countries in Latin America and Africa where consumption is high and the health consequence severe,” says Mozaffarian, who is also Jean Mayer Professor of Nutrition at the Friedman School. “As a species, we need to address sugar-sweetened beverage consumption.”

The study appears in Nature Medicine.

Source: Tufts University

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New evidence challenges ideas about Mars’ past

Researchers have discovered new evidence for hidden water reservoirs and rare magmas on ancient Mars.

Their new study explores how variations in Mars’ crustal thickness during its ancient history may have influenced the planet’s magmatic evolution and hydrological systems.

The research in Earth and Planetary Science Letters suggests that the thick crust of Mars’ southern highlands formed billions of years ago generated granitic magmas and sustained vast underground aquifers, challenging long-held assumptions about the red planet’s geological and hydrological past.

The study, led by Rice University’s Cin-Ty Lee, demonstrates that the southern highlands’ thick crust—up to 80 kilometers in some areas—was hot enough during the Noachian and early Hesperian periods (3-4 billion years ago) to undergo partial melting in the lower crust. This process, driven by radioactive heating, could have produced significant amounts of silicic magmas such as granites and supported subsurface aquifers beneath a frozen surface layer.

“Our findings indicate that Mars’ crustal processes were far more dynamic than previously thought,” says Lee, a professor of geology and professor of earth, environmental, and planetary sciences. “Not only could thick crust in the southern highlands have generated granitic magmas without plate tectonics, but it also created the thermal conditions for stable groundwater aquifers—reservoirs of liquid water—on a planet we’ve often considered dry and frozen.”

The research team—including Rice professors Rajdeep Dasgupta and Kirsten Siebach, postdoctoral research associate Duncan Keller, graduate students Jackson Borchardt and Julin Zhang and Patrick McGovern of the Lunar and Planetary Institute—employed advanced thermal modeling to reconstruct the thermal state of Mars’ crust during the Noachian and early Hesperian periods. By considering factors such as crustal thickness, radioactive heat generation, and mantle heat flow, the researchers simulated how heat affected the potential for crustal melting and groundwater stability.

Their models revealed that regions with crustal thicknesses exceeding 50 kilometers would have experienced widespread partial melting, producing felsic magmas either directly through dehydration melting or indirectly via fractional crystallization of intermediate magmas. Moreover, due to the elevated heat flow, the southern highlands’ thick crust would have sustained significant groundwater aquifers extending several kilometers below the surface.

The study challenges the notion that granites are unique to Earth, demonstrating that Mars could also produce granitic magmas through radiogenic heating even without plate tectonics. These granites likely remain hidden beneath basaltic flows in the southern highlands, offering new insights into Martian geology. Additionally, the research highlights the possible formation of ancient groundwater systems in Mars’ southern highlands, where high surface heat flux reduced the extent of permafrost and created stable subsurface aquifers. These reservoirs of water might have been periodically accessed by volcanic activity or impacts, resulting in episodic flooding events on the planet’s surface.

The findings have significant implications for habitability as the presence of liquid water and the ability to generate granitic magmas, which often contain elements critical for life, suggest that Mars’ southern highlands may have been more hospitable for life in the past than previously thought.

“Granites aren’t just rocks; they’re geological archives that tell us about a planet’s thermal and chemical evolution,” says Dasgupta, a professor of earth, environmental, and planetary sciences. “On Earth, granites are tied to tectonics and water recycling. The fact that we see evidence for similar magmas on Mars through deep crustal remelting underscores the planet’s complexity and its potential for hosting life in the past.”

The study highlights regions on Mars where future missions could focus on detecting granitic rocks or exploring ancient water reservoirs. Large craters and fractures in the southern highlands, for example, may provide glimpses into the planet’s deep crust.

“Every insight into Mars’ crustal processes brings us closer to answering some of the most profound questions in planetary science, including how Mars evolved and how it may have supported life,” Siebach says. “Our research provides a roadmap for where to look and what to look for as we search for these answers.”

This research was made possible by a NASA grant.

Source: Rice University

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