“It was a risk, and it took a long time,” said Toh, an assistant project scientist in cell biologist Dennis Clegg’s lab, continuing work that she started in the lab of UCSB emeritus professor of biology Dr. Jamie Thomson. “But when you’re assembling a new genome, you have to be aware of various sequencing errors.” Toh is the lead author in a paper that appears in BMC Biology.

‘Highly Complete Genome’

Model organisms are among our best aids in understanding some of our more complex diseases, and are often chosen for, among other things, their similarity to humans in some physical or genetic way. Such is the case with the house mouse and the brown rat, which are used to investigate the underlying genetics of some human diseases.

But it’s not a one-size-fits-all situation, particularly in the case of Type 2 diabetes, which affects more than 35 million individuals in the U.S. today. While researchers have been using common laboratory mice and rats to improve our understanding of the disease, tracing the development of diet-induced diabetes and its complications in the more typical rodent models has not been very rewarding.

“A major problem in modeling Type 2 diabetes is that laboratory rats and mice are not particularly susceptible to diet-induced diabetes,” Toh said. “Obesity-induced mice are in fact models of pre-diabetes, and genetic or chemical manipulation are often required to push these conventional rodents to develop diabetes and its complications, thus not mimicking the natural progression of Type 2 diabetes in humans.”

Over the last couple of decades, however, the Nile rat has emerged as a potential model for Type 2 diabetes. Hailing from the grasslands of sub-Saharan Africa, these rodents live on a high-fiber, low carbohydrate diet, unlike their more city-dwelling cousins who may have already adapted to a more human-like high carbohydrate diet. Laboratory food, it turned out, was hypercaloric for the Nile rats, and they would, like humans, spontaneously develop diet-induced diabetes.

Previously, the Thomson lab demonstrated that the Nile rat could develop diabetic retinopathy with key vision loss features — similar to humans — and lacking in other rodent models, thus solidifying the Nile rat as a model of well-developed Type 2 diabetes. What was missing was a reference genome, a genetic sequence that represents the animal in general and can serve as a touchstone or starting point in the search for genetic variations that could indicate susceptibility to certain diseases and other gene-related conditions. In partnership with the Vertebrate Genome Project, Morgridge Institute for Research and University of Southern California, the international collaboration of researchers assembled a “highly complete and highly contiguous” genome.

Among the things they noticed in comparing the Nile rat genome to the genome of the laboratory mouse was that the Nile rat had fewer copies of a gene that encodes for the carbohydrate processing enzyme called amylase, possibly reflecting the lack of adaptation of high-starch diets.

“We think that the Nile rat is not adapted to eat high carbohydrate foods, which makes sense because they normally eat grass in Africa,” Toh said. “I think this is why they are so susceptible to diabetes.” Conversely, laboratory mice — having lived near and around humans — had more copies of this gene, a sign of evolutionary adaptation to their environment.

In fact, Toh said, one of the benefits of having a reference genome is that it becomes possible to witness the genetic consequences of environmental impact. “Currently, we are using this reference genome to study transcriptomic changes relevant to the initial development of diet-induced diabetes,” she said, “and eventually we hope to take a look at the epigenetics as well.”

This study was supported by the Garland Initiative for Vision, funded by the William K. Bowes Jr. Foundation.

As cheese ages, beneficial bacteria degrade proteins and lipids (from milk fat) and produce the molecules responsible for characteristic aromas of ripening cheeses. (1) The diversity of “non-starter” bacteria, which spontaneously develop during ripening and form flavor compounds, is the key factor for developing the characteristics of cheese.

The role of microorganisms in flavor formation had not been fully understood, “due to the diversity of cheese varieties and the complexity of cheese microbial consortia,” said corresponding author Morio Ishikawa, Ph.D., a professor at the Department of Fermentation Science, Faculty of Applied Bioscience at the Tokyo University of Agriculture in Japan.

In the study, the investigators presented an approach to identifying and examining certain bacteria known to be involved in cheese production, including 3 phyla of bacteria, Firmicutes, which are lactic acid bacteria, and Actinobacteria and Proteobacteria, which produce characteristic flavors in certain cheeses. By comparing bacteria from across the 3 phyla to other known flavor-producing bacteria in a cheese ripening test, the researchers showed a relationship between specific microbes and flavor.

Ishikawa and his collaborators had used statistical analysis to reveal relationships between bacterial types and the various volatile flavor-producing organic compounds that each produces in surface-mold ripened cheeses. To test that relationship of specific microbes to flavor, they then selected non-starter bacteria of taxa that were strongly correlated with specific volatile compounds and flavors, and performed cheese-ripening tests. These tests showed that the bacteria from the correlational research were in fact responsible for the flavors of the cheeses.

Additionally, this research could provide a scientific basis for improving the safety and quality of cheese. “By isolating and investigating microorganisms involved in flavor formation as targets, rather than blindly examining them, we will be able to scientifically evaluate the safety of these microorganisms. At the same time, it may be possible to construct a cheese production method that uses only those microorganisms that play a major role in flavor production,” said Ishikawa.

“The comprehensive insights into the complex associations between microbiota and flavor improve our systematic understanding of mechanism of cheese flavor production,” said Ishikawa. The new research will not only provide a scientific basis for the traditional method of cheese production, but might also enable the creation of novel cheeses.

1. per Ishikawa, little or no lactose remains in cheese during ripening.

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In fact, early warning systems designed to do just this have been developed in recent years to help control outbreaks of malaria, dengue fever and other diseases in parts of the Tropics. But their implementation has been undercut by funding uncertainties, overburdened local health systems, insufficient training for local health technicians, and a lack of buy-in from decision makers in government.

An analysis by an international team of researchers from 15 institutions evaluates these barriers to implementation and proposes new ways forward. The team published its recommendations Nov. 9 in The Lancet Planetary Health.

One key, the researchers say, is early engagement with crucial decision makers.

“We looked at five case studies and most of the barriers we identified likely could have been resolved by getting policymakers and community leaders on board right from the start,” said William Pan, the Elizabeth Brooks Reid and Whitelaw Reid Associate Professor of Population Studies at Duke University, who was co-lead author of the analysis.

In the case studies, scientists often placed a higher initial priority on getting their monitoring systems, disease-control protocols and local partners in place before turning their attention to briefing national or regional policymakers about it. In hindsight, the problem with this approach, Pan said, is that the local partners who were supposed to take over running the system once it was set up were not necessarily the government decision makers with the authority to commit ongoing financial or political support for it.

“You need to engage with these key decisions makers immediately so they understand what the benefits of the system will be and buy into it,” he said. Without this support, scaling up the system to a regional or national level can become an insurmountable challenge.

Training local health providers and technicians in environmental science also needs to be an immediate priority.

Local health systems, especially in poor or remote regions, are typically stretched thin and the people who do on-the-ground disease surveillance often have limited training in climate science or environmental epidemiology, Pan said. They’re trained in medicine or public health but not in how climate-sensitive environmental conditions such as extreme heat, drought, or flooding can drive disease outbreaks. So, they don’t know what to look for, how to project future impacts, or how or when to adjust their disease-control interventions in anticipation of them, he said.

“There’s currently no place in the world that has an early warning system for infectious diseases that integrates climate and environmental data with disease surveillance data,” Pan said. “Policymakers just haven’t picked up on it yet, even though it is what science tells us we need to be doing. It’s like trying to bake a cake with only half the ingredients.”

In the new paper, he and his coauthors use knowledge and tools from the emerging field of implementation science to propose a four-step, science-based framework for overcoming such barriers and enhancing the success of early warning systems.

First, you need to understand and anticipate potential barriers. Second, you need to engage key stakeholders at the outset and co-create the system with them. Third, you need to identify promising strategies to overcome barriers and test how they work in pilot studies under various conditions, using both quantitative data and qualitative measures, such as stakeholder interviews, to inform your analysis. Fourth, after implementing the strategies, you need to measure the outcomes of their implementation across a broad range of considerations, including acceptability, feasibility, sustainability and cost-effectiveness.

The new analysis is based on case studies of early warning systems for climate-related disease outbreaks or public health risks that have been recently developed in Peru, Barbados, Ethiopia, India, and the Federated States of Micronesia and the Marshall Islands.

Pan holds faculty appoints at Duke’s Nicholas School of the Environment and the Duke Global Health Institute. He co-led the new analysis with Gila Neta of the National Cancer Institute, part of the National Institutes of Health.

The paper was co-authored by researchers from the University of Washington; the Pan American Health Organization; the National Institute of Environmental Health Sciences; the Barcelona Supercomputing Center; the Catalan Institution for Research and Advanced Studies; the London School of Hygiene and Tropical Medicine; the University of Florida; the Inter-American Institute for Global Change Research; the Pacific Island Health Officers Association; the Energy and Resources Institute of New Delhi, India; the University of Oklahoma; the Barbados Ministry of Health and Wellness; and the University of Pittsburgh School of Public Health.

The team’s analysis was conducted with no new external funding.

Researchers at the University of Maryland School of Medicine, however, now posit that Crick may have been incorrect: They developed a new theory — built on data — that the claustrum behaves more like a high-speed internet router, taking in executive commands from “boss” areas of the brain’s cortex that forms complex thoughts to generate “networks” in the cortex. Acting like a router, the claustrum coordinates these networks to work together to accomplish the many different cognitively demanding tasks we perform on a moment-to-moment basis in everyday life.

Understanding how the brain forms and coordinates these networks in the cortex through the claustrum is important, since disorganized networks are a typical feature across many disorders, such as addiction, Alzheimer’s disease, and schizophrenia. This insight may help lead to better therapies to address cognitive dysfunction in these disorders.

“The brain is the most complex system in the known universe. It is these data-driven theoretical advances that propel our knowledge forward toward harnessing that complexity for improving human life,”said Brian Mathur, PhD, Associate Professor of Pharmacology at UMSOM. “As the most highly connected structure in the brain, the claustrum is a window into the enigma of the brain, the mind.”

Their new findings and hypothesis were published on Sept. 30, 2022, in Trends In Cognitive Sciences.

In an effort to identify the precise role of the claustrum, Dr. Mathur and his colleagues conducted a serious of experiments on both animals and people. One experiment used modern neuroscience approaches to turn off the claustrum in conscious mice. These mice didn’t lose consciousness and kept running around normally. One strike against Crick’s theory!

Next, the researchers gave mice a cognitively simple or a difficult task and compared how they responded when the claustrum was turned off. Normally, a mouse can perform both the simple and the difficult tasks. Yet, when the researchers turned off the claustrum, the mice could no longer perform the difficult task.

Wondering if this finding had any relevance to humans, Dr. Mathur collaborated with his colleagues David Seminowicz, PhD, Professor of Neural and Pain Sciences at the UM School of Dentistry, and Fred Barrett, PhD, Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine. The three organized a research study where they conducted functional MRI brain scans on healthy volunteers who were engaged in either simple or complicated mental tasks. The researchers observed that their claustrum only “lit up” when performing the difficult version of the task. This event coincided with the activation of a network in the cortex involved in optimal cognitive performance. Strike two against Crick’s consciousness theory!

Dr. Mathur said that strike three will be when additional experiments support their theory of claustrum function. In doing so, Dr. Mathur and his colleagues now seek to understand how the claustrum learns and adapts to orchestrate networks in the cortex to help support cognition.

“Understanding how the brain flexibly forms and coordinates these networks — through the claustrum — is essential to treat cognitive decline, which happens in addiction, Alzheimer’s disease, and schizophrenia,” said Mark T. Gladwin, MD, Vice President for Medical Affairs at University of Maryland, Baltimore and the John Z. and Akiko K. Bowers Distinguished Professor and Dean of UMSOM.

Dr. Mathur added, “Our hypothesis provides us with a much-needed conceptual framework to devise new therapeutic strategies.”

The study was funded by the NIH’s National Institute on Alcohol Abuse and Alcoholism (grant R01AA028070).

Dr. Barrett is on the scientific advisory board for Wavepaths, Ltd. and a scientific advisor for Mindstate Design Labs, Inc.

The findings, just reported in the journal Marine Ecology Progress Series, indicate that while other populations of oceanic manta rays are typically small and vulnerable to human impacts, this population is large and potentially quite healthy, said Joshua Stewart, an assistant professor with the Marine Mammal Institute in OSU’s College of Agricultural Sciences and a co-author of the paper.

“It’s clear that something different is happening here,” Stewart said. “This is a rare story of ocean optimism. In other regions, we typically have population estimates of 1,000 to 2,000 animals, which makes this species very vulnerable. In this area, we’ve estimated that the population is more than 22,000 mantas, which is unprecedented.”

Oceanic manta rays are the largest species of ray, with wingspans that can reach more than 20 feet. They are filter feeders that eat large quantities of krill and other zooplankton and tend to live in small subpopulations in tropical, subtropical and temperate waters, spending much of their time in the open ocean.

Oceanic manta rays were listed as threatened under the U.S. Endangered Species Act in 2018, and in 2019 their threat category increased from vulnerable to endangered on the International Union for the Conservation of Nature’s Red List. The biggest threat to oceanic manta rays is commercial fishing, both as the target of some fisheries and as unintentional bycatch in many others.

The new study was led by Proyecto Mantas Ecuador of Fundación Megafauna Marina del Ecuador, a conservation organization based in Ecuador, in collaboration with The Manta Trust, the Marine Megafauna Foundation and the Ocean Ecology Lab at OSU’s Marine Mammal Institute, which is led by Stewart.

Oceanic manta rays are a challenging species to study in part because they tend to spend their time in offshore locations that are hard for researchers to access, and their visitation patterns can be unpredictable.

But in the late 1990s, researchers from Proyecto Mantas Ecuador discovered that a population of oceanic manta rays aggregate in August and September each year around Isla de la Plata off the coast of Ecuador, where they are relatively easy to locate and study. It is also a popular diving area, and visitors take numerous photographs of the animals, providing researchers with a trove of data.

“Many of the photos used in our study were contributed by recreational divers who became citizen scientists when they snapped photos of manta rays,” said the study’s lead author, Kanina Harty of The Manta Trust. “We get a huge amount of information about each animal just from these photographs.”

Each manta ray has a unique spot pattern on its belly, similar to a human fingerprint, which allows researchers to identify individual animals and track their movements and locations over time. Photos of individual rays can also be used to document injuries, evidence of mating and maturity.

The researchers used data collected through their own observations and from recreational SCUBA diver photos between 2005 and 2018 to identify more than 2,800 individual rays and estimate a total population of more than 22,000.

“That is significantly larger than what we’ve seen in oceanic manta ray populations elsewhere,” said Guy, Stevens, chief executive and founder of The Manta Trust. “This is by far the largest population that we know of.”

The researchers’ findings suggest that conditions in the region are particularly favorable for a large, healthy manta ray population, Stewart said. The rays tend to straddle the region around the border of southern Ecuador and Peru, though a handful were found to have traveled as far as the Galapagos Islands.

“This work solidifies Isla de la Plata, and Ecuador more broadly, as a globally important hot spot for this endangered species,” said Michel Guerrero of Proyecto Mantas Ecuador, which is a Fundación Megafauna Marina del Ecuador project. “While this population may be healthy thanks in part to its large size, it is essential that we take the necessary steps to protect and prevent the declines that many other manta ray populations have faced.”

Manta rays are likely drawn to the area due to availability of food, the researchers said. The ocean off the coast of Ecuador and Peru is one of the most productive in the world, due to cold, nutrient-rich water rising to the surface in a process called upwelling.

“It seems that this productive upwelling region is able to support huge populations of even very large animals,” Stewart said.

Capturing manta rays in fisheries has been illegal in Ecuador since 2010, and since 2016 in neighboring Peru, but the species likely still faces threats from fishing activity, including line entanglement, vessel strikes and bycatch, Guerrero said. There were 563 manta rays identified in the study with visible injuries or scars, and more than half of those were either entangled in fishing gear or showed evidence of previous fishing line scarring.

Continued monitoring of the population is needed to understand how human activity and climate change may affect food availability, distribution and overall population health, Stewart said.

“While there is good news about this population, it is a cautionary tale,” he said. “Manta rays appear to be sensitive to environmental disruptions such as changes to ocean temperatures and food availability. They will likely be impacted by a warming climate if upwelling strength and the abundance of food changes alongside ocean temperatures.”

Additional co-authors of the study are Anna Knochel of the Fundacion Megafauna Marina del Ecuador and Andrea Marshall and Katherine Burgess of the Marine Megafauna Foundation.

The findings, published in the journal Pharmaceutics, could not be timelier or more in demand: Over 150 people die every day from overdoses of synthetic opioids including fentanyl, which is 50 times stronger than heroin and 100 times stronger than morphine. Consumption of about 2 milligrams of fentanyl (the size of two grains of rice) is likely to be fatal depending on a person’s size.

“We believe these findings could have a significant impact on a very serious problem plaguing society for years — opioid misuse. Our vaccine is able to generate anti-fentanyl antibodies that bind to the consumed fentanyl and prevent it from entering the brain, allowing it to be eliminated out of the body via the kidneys. Thus, the individual will not feel the euphoric effects and can ‘get back on the wagon’ to sobriety,” said the study’s lead author Colin Haile, a research associate professor of psychology at UH and the Texas Institute for Measurement, Evaluation and Statistics (TIMES), and a founding member of the UH Drug Discovery Institute.

In another positive finding, the vaccine did not cause any adverse side effects in the immunized rats involved in lab studies. The team plans to start manufacturing clinical-grade vaccine in the coming months with clinical trials in humans planned soon.

Fentanyl is an especially dangerous threat because it is often added to street drugs like cocaine, methamphetamine and other opioids, such as oxycodone and hydrocodone/acetaminophen pills, and even to counterfeit benzodiazepines like Xanax. These counterfeit drugs laced with fentanyl add to the amount of fentanyl overdoses in individuals who do not ordinarily consume opioids.

“The anti-fentanyl antibodies were specific to fentanyl and a fentanyl derivative and did not cross-react with other opioids, such as morphine. That means a vaccinated person would still be able to be treated for pain relief with other opioids,” said Haile.

The vaccine tested contains an adjuvant derived from E. coli named dmLT. An adjuvant molecule boosts the immune system’s response to vaccines, a critical component for the effectiveness of anti-addiction vaccines. The adjuvant was developed by collaborators at the Tulane University School of Medicine and has proven vital to the efficacy of the vaccine. Also on the team are Greg Cuny, Joseph P. & Shirley Shipman Buckley Endowed Professor of Drug Discovery at the UH College of Pharmacy along with researchers from Baylor College of Medicine and Michael E. DeBakey Veteran’s Affairs Medical Center.

Current treatments for OUD are methadone, buprenorphine and naltrexone, and their effectiveness depends upon formulation, compliance, access to medications and the specific misused opioid.

Therese Kosten, professor of psychology and director of the Developmental, Cognitive & Behavioral Neuroscience program at UH, calls the new vaccine a potential “game changer.”

“Fentanyl use and overdose is a particular treatment challenge that is not adequately addressed with current medications because of its pharmacodynamics and managing acute overdose with the short-acting naloxone is not appropriately effective as multiple doses of naloxone are often needed to reverse fentanyl’s fatal effects,” said Kosten, senior author of the study.

The study was funded by the Department of Defense through the Alcohol and Substance Abuse Disorders Program managed by RTI International’s Pharmacotherapies for Alcohol and Substance Use Disorders Alliance, which has funded Haile’s lab for several years to develop the anti-fentanyl vaccine.

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Materials provided by University of Houston. Original written by Laurie Fickman. Note: Content may be edited for style and length.