While buildup of amyloid protein has been associated with Alzheimer’s-related neurodegeneration, little is known about how the protein relates to normal brain aging, said University Professor Caleb Finch, the study’s senior author and holder of the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging at the USC Leonard Davis School.

To explore the levels of Aβ in human brains, the researchers analyzed tissue samples from both healthy brains and brains of patients with dementia. More severe Alzheimer’s cases were indicated by higher Braak staging scores, a measurement of how widely signs of Alzheimer’s pathology are found within the brain.

The analysis revealed that older, cognitively healthy brains showed similar amounts of dissolvable, non-fibrillar amyloid protein as brains of Alzheimer’s patients. But, as the researchers expected, the brains of Alzheimer’s patients had higher amounts of insoluble Aβ fibrils, the form of amyloid protein that aggregates to form the telltale “plaques” seen in the disease, said Max Thorwald, the study’s first author and a postdoctoral researcher at the USC Leonard Davis School.

The findings challenge the idea that simply having higher amounts of amyloid protein in general is an underlying cause of Alzheimer’s, say Finch and Thorwald. Instead, the increase in soluble Aβ may be a general aging-related change in the brain not specific to Alzheimer’s, while higher levels of fibrillary amyloid appear to be a better indicator of poorer brain health.

Rather than Alzheimer’s simply involving increased production of Aβ protein, the more important issue may be a reduced ability to effectively clear the protein and stave off the creation of plaque-contributing fibrillary amyloid, Thorwald said.

“These findings further support the use of aggregated, or fibrillary, amyloid as a biomarker for Alzheimer’s treatments,” Thorwald said. “The site in which amyloid processing occurs has less precursor and enzyme available for processing, which may suggest the removal of amyloid as a key issue during Alzheimer’s.”

Increases in amyloid levels happen during early adulthood and differ by brain region. Further studies, including those investigating drugs to possibly break down amyloid, should incorporate positron emission tomography (PET) imaging in both healthy individuals and Alzheimer’s patients of a wide range of ages to determine how and where amyloid processing and removal changes in the brain over time, he added.

“The brain’s frontal cortex has more amyloid production compared to the cerebellum during the aging process in human brains, which coincides with their Alzheimer’s-correlated pathologies in late life,” Thorwald said. “Future projects should examine amyloid over the life course in both cognitively normal and Alzheimer’s patients with both modulation of amyloid processing or removal of amyloid through monoclonal antibodies currently used in clinical trials for Alzheimer’s treatment.”

Monoclonal antibody treatment lemanecab has been observed to reduce Aβ plaques in clinical trials and recently received FDA approval for its potential to slow cognitive decline in Alzheimer’s patients, but the results warrant further careful research regarding long-term impact, Finch said.

“Lecanemab clearly works to diminish fibrillar amyloid,” he said. “However, we are concerned with major side effects, including brain swelling and bleeding, that were 100% more than in controls, with unknown delayed or latent impact.”

Learning more about how the brain processes and removes proteins such as Aβ could provide important insights into Alzheimer’s disease and its causes. Finch noted that very few cases of dementia occur with amyloid plaques, or masses of aggregated Aβ protein, as the only pathology present in affected patients’ brains. Instead, most cases present with more complicated tissue abnormalities, from buildup of additional types of protein to small bleeds in the brain: “The aging brain is a jungle.”

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Materials provided by University of Southern California. Original written by Beth Newcomb. Note: Content may be edited for style and length.

The researchers said this work can help us understand the environmental challenges experienced by our ancestors and may also help us in predicting the effects of future environmental change on human societies.

“Through our research on modern humans, we noticed that we could predict the age at which people had children from the types of DNA mutations they left to their children,” said study co-author Matthew Hahn, Distinguished Professor of biology in the College of Arts and Sciences and of computer science in the Luddy School of Informatics, Computing and Engineering at IU Bloomington. “We then applied this model to our human ancestors to determine what age our ancestors procreated.”

According to the study, published today in Science Advances and co-authored by IU post-doctoral researcher Richard Wang, the average age that humans had children throughout the past 250,000 years is 26.9. Furthermore, fathers were consistently older, at 30.7 years on average, than mothers, at 23.2 years on average, but the age gap has shrunk in the past 5,000 years, with the study’s most recent estimates of maternal age averaging 26.4 years. The shrinking gap seems to largely be due to mothers having children at older ages.

Other than the recent uptick in maternal age at childbirth, the researchers found that parental age has not increased steadily from the past and may have dipped around 10,000 years ago because of population growth coinciding with the rise of civilization.

“These mutations from the past accumulate with every generation and exist in humans today,” Wang said. “We can now identify these mutations, see how they differ between male and female parents, and how they change as a function of parental age.”

Children’s DNA inherited from their parents contains roughly 25 to 75 new mutations, which allows scientists to compare the parents and offspring, and then to classify the kind of mutation that occurred. When looking at mutations in thousands of children, IU researchers noticed a pattern: The kinds of mutations that children get depend on the ages of the mother and the father.

Previous genetic approaches to determining historical generation times relied on the compounding effects of either recombination or mutation of modern human DNA sequence divergence from ancient samples. But the results were averaged across both males and females and across the past 40,000 to 45,000 years.

Hahn, Wang and their co-authors built a model that uses de novo mutations — a genetic alteration that is present for the first time in one family member as a result of a variant or mutation in a germ cell of one of the parents or that arises in the fertilized egg during early embryogenesis — to separately estimate the male and female generation times at many different points throughout the past 250,000 years.

The researchers were not originally seeking to understand the relationship of gender and age at conception over time; they were conducting a broader investigation about the number of mutations passed from parents to children. They only noticed the age-based mutation patterns while seeking to understand differences and similarities between these pattens in humans versus other mammals, such as cats, bears and macaques.

“The story of human history is pieced together from a diverse set of sources: written records, archaeological findings, fossils, etc.,” Wang said. “Our genomes, the DNA found in every one of our cells, offer a kind of manuscript of human evolutionary history. The findings from our genetic analysis confirm some things we knew from other sources (such as the recent rise in parental age), but also offer a richer understanding of the demography of ancient humans. These findings contribute to a better understanding of our shared history.”

Additional contributors to this research were Samer I. Al-Saffar, a graduate student at IU at the time of the study, and Jeffrey Rogers of the Baylor College of Medicine.

Scientists from the University of Nottingham, China, Germany and the UK led by Professor Liu Feng from Nanjing Institute of Geology and Palaeontology have developed a new method to detect plant’s sunscreen-like compounds in fossil pollen grains. The research has been published today in Science Advances.

The end-Permian mass extinction event (250 million years ago) is the most severe of the big five mass extinction events with the loss of ~80% of marine and terrestrial species. This catastrophic loss of biodiversity was a response to a palaeoclimate emergency triggered by the emplacement of a continental-scale volcanic eruption that covers much of modern-day Siberia. The volcanic activity drove the release of massive amounts of carbon that had been locked up in Earth’s interior into the atmosphere, generating large-scale greenhouse warming. Accompanying this global warming event was a collapse in the Earth’s ozone layer. Support for this theory comes from the abundant occurrence of malformed spores and pollen grains that testify to an influx of mutagenic UV irradiation.

Professor Barry Lomax from the University of Nottingham explains “Plants require sunlight for photosynthesis but need to protect themselves and particularly their pollen against the harmful effects of UV-B radiation. To do so, plants load the outer walls of pollen grains with compounds that function like sunscreen to protect the vulnerable cells to ensure successful reproduction.”

Professor Liu Feng adds: “We have developed a method to detect these phenolic compounds in fossil pollen grains recovered from Tibet, and detected much higher concentrations in those grains that were produced during the mass extinction and peak phase of volcanic activity.”

Elevated UV-B levels can have even further-reaching and longer-lasting impacts on the entire Earth System. Recent modelling studies have demonstrated that elevated UV-B stress reduces plant biomass and terrestrial carbon storage, which would exacerbate global warming. The increased concentration of phenolic compounds also makes plant tissue less easily digestible, making a hostile environment even more challenging for herbivores.

Summarising the groups findings Dr Wes Fraser based at Oxford Brookes University commented: “Volcanism on such a cataclysmic scale impacts on all aspects of the Earth system, from direct chemical changes in the atmosphere, through changes in carbon sequestration rates, to reducing volume of nutritious food sources available for animals.”

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The Brazilian Amazon encompasses the largest tropical forest area with the highest biodiversity in the world. Since 2000, Indigenous territories and protected areas have increased substantially in the region and by 2013, Indigenous territories and protected areas accounted for 43% of the total land area and covered approximately 50% of the total forest area.

However, tensions between forest conservation and socioeconomic development goals persist. In recent years, forest conservation has been threatened by large socio-ecological changes in Brazil. Weakened forest and environmental policies and enforcement as well as impacts from the COVID-19 pandemic had devastating impacts on Indigenous groups in the region.

In this U.S.-Brazil collaborative study, Yuanwei Qin, Ph.D., and Xiangming Xiao, Ph.D., of OU’s Center for Earth Observation and Modeling, with Fabio de Sa e Silva, Ph.D., assistant professor of international studies and Wick Cary Professor of Brazilian Studies in the OU College of International Studies, worked with collaborators from the Brazilian National Institute for Space Research and the National Institute for Research in Amazonia in Brazil. The research team combined multiple data sources to document and quantify the dynamics and impact of forest loss in the Brazilian Amazon over the past two decades.

Because of frequent cloud cover and fire-induced smoke in the Brazilian Amazon, annual forest maps from analyses of optical images have only moderate accuracy. In a 2019 paper published by the same journal, the research team combined image data from both optical and microwave sensors to generate annual Brazilian Amazon forest maps. Using these annual forest maps, they assessed the effects of Indigenous territories and protected areas on deforestation dynamics in the Brazilian Amazon through 2021.

“Between 2000 and 2021, the areas designated as Indigenous territories or protected areas increased to cover approximately 52% of forests in the Brazilian Amazon, accounting for only 5% of net forest loss and 12% of gross forest loss in the period,” said Qin. “This finding highlights the vital role of Indigenous territories and the protected areas for forest conservation in the region.”

The protected areas in the Brazilian Amazon are subject to different state and national governance arrangements and have different management objectives, including strict protection or sustainable use. They found that from 2003 through 2021, gross forest loss fell 48% in the protected areas subject to strict protection and 11% in the protected areas subject to sustainable use.

“These varying effects on forest conservation call for more in-depth causal analyses by researchers and invite stakeholders, decision-makers, and the public to reassess existing policies for these areas. Legal designations are important, but if the law is not enforced, the intended protection of forests and biodiversity will be illusional. This is an area in which Brazil is knowingly failing,” de Sa e Silva said.

The results from this study also show that annual forest area loss was affected by Brazilian forest policies, as evidenced by a large reduction of forest area loss in the early 2000s to mid-2010s, corresponding with Brazilian President Luiz Inácio Lula da Silva administration in 2003-2010, and renewed rise of forest area loss even among Indigenous territories and the protected areas in 2019-2021, corresponding with President Jair Bolsonaro’s administration in 2019-2022.

“How to rebuild effective policies and reduce forest area loss in the Brazilian Amazon in the coming years will be one of the grand challenges for Lula’s administration and international communities,” Xiao said.

This study adds to a portfolio of research efforts to document forest areas in the Brazilian Amazon by Qin and Xiao, including a 2019 paper, “Improved estimates of forest cover and loss in the Brazilian Amazon in 2000-2017,” published in Nature Sustainability; a 2021 paper, “Carbon loss from forest degradation exceeds that from deforestation in the Brazilian Amazon,” published in Nature Climate Change; as well as two others. 

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Materials provided by University of Oklahoma. Original written by Chelsea Julian. Note: Content may be edited for style and length.

The findings are published in the January 6, 2023 issue of the journal Science of the Total Environment.

“This was a pilot study to test the feasibility of using archived samples of plankton from the Continuous Plankton Recorder (CPR) Survey to reconstruct historical trends in marine pollution over space and time,” said senior author Robert K. Naviaux, MD, PhD, professor in the Department of Medicine, Pediatrics and Pathology at UC San Diego School of Medicine. “We were motivated to explore these new methods by the alarming increase in childhood and adult chronic disease that has occurred around the world since the 1980s.

“Recent studies have underscored the tight linkage between ocean pollution and human health. In this study, we asked the question: Do changes in the plankton exposome (the measure of all exposures in a lifetime) correlate with ecosystem and fisheries health?

“We also wanted to lay the groundwork for asking a second question: Can humanmade chemicals in plankton be used as a barometer to measure changes in the global chemosphere that might contribute to childhood and adult illness? Stated another way, we wanted to test the hypothesis that the rapid turnover and sensitivity to contamination of plankton might make them a marine version of the canary in the coal mine.”

Based in the United Kingdom, the CPR Survey is the longest running, most geographically extensive marine ecology survey in the world. Since 1931, almost 300 ships have traveled more than 7.2 million miles towing sampling devices that capture plankton and environmental measurements in all of the world’s oceans, the Mediterranean, Baltic and North seas and in freshwater lakes.

The effort, along with complementary programs elsewhere, is intended to document and monitor the general health of oceans, based upon the well-being of marine plankton — a diverse collection of usually tiny organisms that provide sustenance for many other aquatic creatures, from mollusks to fish to whales.

“Marine plankton exist in all ocean ecosystems,” said study co-author Sonia Batten, PhD, former coordinator of the Pacific CPR and currently executive secretary of the North Pacific Marine Science Organization. “They create complex communities that form the base of the food web, and they play essential roles in maintaining the health and balance of the oceans. Plankton are generally short-lived and very sensitive to environmental changes.”

Naviaux, co-corresponding author Kefeng Li, PhD, a project scientist in Naviaux’s lab, and colleagues evaluated plankton specimens taken from three different locations in the North Pacific at different times between 2002 and 2020, then used a variety of technologies to assess their exposure to different humanmade chemicals, including pharmaceuticals; persistent organic pollutants (POPs) such as industrial chemicals; pesticide; phthalates and plasticizers (chemicals derived from plastics); and personal care products.

Many of these pollutants have decreased in amount over the past two decades, the researchers said, but not universally, and often in complex ways. For example, analyses suggest levels of legacy POPs and the common antibiotic amoxicillin have broadly declined in the North Pacific Ocean over the past 20 years, perhaps in part from increased federal regulation and a decrease in overall antibiotic use in the United States and Canada, but the findings are confounded by coinciding increases in use in Russia and China.

The most polluted samples were taken from nearshore areas closest to human activity and subject to phenomena like terrestrial runoff and aquaculture. In these places, there were higher levels and greater numbers of different chemicals found in plankton taxa living in those nearshore environments.

The authors said their pilot project points the way toward follow-up research designed to examine correlations between the plankton exposome, predator-prey relationships and impacted fisheries.

“Follow-up studies by epidemiologists and marine ecologists are needed to test if and how the plankton exposome correlates with important medical trends in nearby human populations like infant mortality, autism, asthma, diabetes, and dementia,” Naviaux said.

Naviaux noted the findings present new clues to explaining the nature of many chronic diseases in which phases of the cell danger response (CDR) persist, leading to chronic symptoms.

For more than a decade, Naviaux and colleagues have posited that accumulating data suggests numerous diseases and chronic illnesses, from neurodevelopmental disorders like autism spectrum disorder and neurodegenerative disorders like ALS to cancer and major depression are at least partly the consequence of metabolic dysfunction that results in incomplete healing, characterized as CDR.

Naviaux has published extensively on the topic, including how CDR can be affected by environmental factors that result in metabolic dysfunction and chronic disease.

“The purpose of CDR is to help protect the cell and jump-start the healing process after injury, by causing the cell to harden its membranes, decrease and change its interaction with neighbors, and redirect energy and resources for defense until the danger has passed,” said Naviaux.

“But sometimes the CDR gets stuck. This prevents completion of the natural healing cycle, altering the way the cell responds to the world. When this happens, cells behave as if they are still injured or in imminent danger, even though the original cause of the injury or threat has passed. We have learned that many kinds of environmental chemicals, trauma, infection, or other kinds of stress can delay or block the completion of the healing cycle. When this happens, it leads to the symptoms of chronic disease.”

“The CDR is a whole-body process that begins with mitochondria and the cell. Mitochondria are organelles in the cell that act as bio-sentinels that are constantly monitoring the chemistry of the cell and its surroundings. Mitochondria regulate metabolic activity needed for energy and movement, innate immunity, for regulating the health of the microbiome, and for making the building blocks needed for tissue repair after injury.”

In the marine plankton study, Naviaux and co-authors found that perfluoroalkyl substances (chemicals commonly used to enhance water-resistance in various everyday products, from packaging to clothing to cookware) were prominent in the plankton exposome.

Such substances are known to inhibit some mitochondrial proteins, including an important enzyme used to regulate cortisol metabolism and organisms’ responses to stress. Other chemicals found included phthalates from plastics and personal care products, such as lotions and shampoos. Phthalates are endocrine-disrupting chemicals that have been increasing in the plankton exposome for more than 20 years, and have both direct and indirect effects on mitochondria.

“Plankton are responding to the chemicals in their exposome, in part by changes in their own mitochondria that change their biology,” said Naviaux, “and so too, I would argue, are humans. It is my hope that the use of our methods by research groups around the world will reinforce the connection between ecosystem health and human health, and provide new tools to monitor how the human chemical footprint has changed over the past century.

“If the linkages are found to be close enough, plankton exposomics from observatory sites around the world might be used in the future to track and curb pollution that leads to human disease.”

Co-authors include: Jane C. Naviaux, Sai Sachin Lingampelly, Lin Wang and Jonathan M. Monk, all at UC San Diego; and Claire M. Taylor and Clare Ostle, both at the Marine Biological Association.

Funding for this research came, in part, from a consortium of funders through the North Pacific Marine Science Organization, comprised of the North Pacific Research Board, Exxon Valdez Oil Spill Trustee Council through Gulf Watch Alaska, Canadian Department of Fisheries and Oceans and the Marine Biological Association; the UC San Diego Christini Fund and the Lennox Foundation.

Using an approach that simultaneously modifies multiple sites in fungal genomes, Rice University chemical and biomolecular engineer Xue Sherry Gao and collaborators coax fungi into revealing their best-kept secrets, ramping up the pace of new drug discovery.

It is the first time that the technique, multiplex base-editing (MBE), has been deployed as a tool for mining fungal genomes for medically useful compounds. Compared to single-gene editing, the MBE platform reduces the research timeline by over 80% in equivalent experimental settings, from an estimated three months to roughly two weeks.

Fungi and other organisms produce bioactive small molecules such as penicillin to protect themselves from disease agents. These bioactive natural products (NPs) can be used as drugs or as molecular blueprints for designing new drugs.

Using the MBE technology, the Gao lab at Rice’s Brown School of Engineering induced fungi to produce significantly more natural compounds, including some previously unknown to the scientific community.

The study is published in the Journal of the American Chemical Society.

Base-editing refers to the use of CRISPR-based tools in order to modify a rung in the spiral ladder of DNA known as a base pair. Previously, gene modifications using base-editing had to be carried out one at a time, making the research process more time-consuming. “We created a new machinery that enables base-editing to work on multiple genomic sites, hence the ‘multiplex,'” Gao said.

Gao and her team first tested the efficacy of their new base-editing platform by targeting genes encoding for pigment in a fungal strain known as Aspergillus nidulans. The effectiveness and precision of MBE-enabled genome edits was readily visible in the changed color displayed by A. nidulans colonies.

“To me, the fungal genome is a treasure,” Gao said, referring to the significant medical potential of fungi-derived compounds. “However, under most circumstances, fungi ‘keep to themselves’ in the laboratory and don’t produce the bioactive small molecules we are looking for. In other words, the majority of genes or biosynthetic gene clusters of interest to us are ‘cryptic,’ meaning they do not express their full biosynthetic potential.

“The genetic, epigenetic and environmental factors that instruct organisms to produce these medically useful compounds are extremely complicated in fungi,” Gao said. Enabled by the MBE platform, her team can easily delete several of the regulatory genes that restrict the production of bioactive small molecules. “We can observe the synergistic effects of eliminating those factors that make the biosynthetic machinery silent,” she said.

Disinhibited, the engineered fungal strains produce more bioactive molecules, each with their own distinct chemical profiles. Five of the 30 NPs generated in one assay were new, never-before-reported compounds.

“These compounds could be useful antibiotics or anticancer drugs,” Gao said. “We are in the process of figuring out what the biological functions of these compounds are and we are collaborating with groups in the Baylor College of Medicine on pharmacological small-molecule drug discovery.”

Funded by a five-year National Institutes of Health grant, Gao’s research plumbs fungal genomes in search of gene clusters that synthesize NPs. “Approximately 50% of clinical drugs approved by the U.S. Food and Drug Administration are NPs or NP-derivatives,” and fungi-derived NPs “are an essential pharmaceutical source,” she said. Penicillin, lovastatin and cyclosporine are some examples of drugs derived from fungal NPs.

Gao, the T.N. Law Assistant Professor of Chemical and Biomolecular Engineering and an assistant professor of bioengineering and chemistry, is a 2022 recipient of the prestigious CAREER Award from the National Science Foundation. Her lab’s previous discoveries include a fungal biocatalyst that drugmakers can use to control a molecule’s 3D structure and a tool to detect RNA from SARS-CoV-2, the virus that causes COVID-19.

The National Institutes of Health (GM138207) and the Robert A. Welch Foundation (C-1952) supported the research.

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Materials provided by Rice University. Original written by Silvia Cernea Clark. Note: Content may be edited for style and length.