“The Bachman’s warbler is the only songbird known to have recently gone extinct in North America,” said David Toews, assistant professor of biology in the Penn State Eberly College of Science and the leader of the research team. “It is one of three species in the genus Vermivora. Our lab studies the two living species of this genus, which are known to mate with each other producing hybrid offspring.”

Golden-winged and blue-winged warblers produce a spectrum of hybrids, but two distinct types of hybrid offspring, each with a unique combination of the parent species’ coloration, have been the focus of bird watchers and ornithologists. This is because these two hybrids were thought to be distinct species themselves, known as Brewster’s warbler and Lawrence’s warbler, until careful study of wild hybrids and, now, modern genetic analysis has confirmed their hybrid origins. The extinct Bachman’s warbler resembles one of these hybrid offspring in coloration, so there was some question as to whether the Bachman’s warbler was itself a distinct species or if it might also have been a hybrid.

The research team collected seven specimens of the Bachman’s warbler from museum collections and extracted DNA from the birds’ toepads. They then performed whole-genome sequencing to compare the Bachman’s warbler genome to existing genomes for the two living species in the genus.

“It’s never easy to get DNA for sequencing from museum specimens,” said Andrew Wood, the first author of the paper, who was a research technologist in Toews’ lab at the time of the research and is now a postdoctoral researcher at the University of Minnesota. “These birds were collected over a hundred years ago and were not preserved in any special way, but we were able to extract enough DNA to get genome sequences that are comparable to those from the living species.”

The genomes of the golden-winged and blue-winged warblers are very similar to each other, except for a few regions that are involved in determining the coloration patterns of the bird’s feathers. In comparison, the Bachman’s warbler genome was very different, which indicated to the researchers that it was, in fact, a distinct species.

“We only have a small sample size for the Bachman’s warbler genome, but one of the interesting findings we saw by comparing the seven specimens was that there were long ‘runs of homozygosity,'” said Toews. “These are regions of the genome where the two copies of the genome — one inherited from each parent — are identical to each other and is an indication that the population may have been small and there was a lot of inbreeding. We see similar patterns in the living species, so understanding if this might have contributed to the extinction of Bachman’s warbler could help us to better understand the health and conservation of the living population.”

The researchers also compared the genomes of the three species to look for regions of the genome that may have evolved differently in each lineage. These differences can be indicators that a particular region of the genome evolved via natural selection for a particular trait or because of another evolutionary process. Having a third species’ genome to compare allowed the researchers to identify a region that contained a new candidate gene involved in warbler pigmentation.

“We began this study because we were interested in learning about the history and biology of Bachman’s warbler,” said Woods. “But our results also highlighted how we can use extinct species to learn about their living relatives. We lose a lot of biological and evolutionary context through the process of extinction and being able to compare Bachman’s warbler to the two living species allowed us to identify a gene that we might not have otherwise found. Context is crucial to understanding biology. Natural history collections allow us to place new observations into contexts that may have disappeared from the natural world. This fuels discovery, and makes museums powerful, and underappreciated, tools.”

In addition to Toews and Wood, the research team includes Zachary A. Szpiech, assistant professor of biology at Penn State; Irby J. Lovette at the Cornell Lab of Ornithology; and Brian Tilston Smith at the American Museum of Natural History in New York. The research was funded by the U.S. National Science Foundation, the Huck Institutes of the Life Sciences at Penn State, and the Penn State Eberly College of Science. Computations were performed using the Penn State’s Institute for Computational Data Sciences’ Roar supercomputer.

Cognitive tasks showed that these patients have difficulty with the ability to plan ahead, display self-control, sustain focus despite distractions and suppress inappropriate behavior; imaging showed decreased activity in two brain regions responsible for those tasks.

Because depression has traditionally been defined as a mood disorder, doctors commonly prescribe antidepressants that target serotonin (known as selective serotonin reuptake inhibitors or SSRIs), but these are less effective for patients with cognitive dysfunction. Researchers said that targeting these cognitive dysfunctions with less commonly used antidepressants or other treatments may alleviate symptoms and help restore social and occupational abilities.

The study, published June 15 in JAMA Network Open, is part of a broader effort by neuroscientists to find treatments that target depression biotypes, according to the study’s senior author, Leanne Williams, PhD, the Vincent V.C. Woo Professor and professor of psychiatry and behavioral sciences.

“One of the big challenges is to find a new way to address what is currently a trial-and-error process so that more people can get better sooner,” Williams said. “Bringing in these objective cognitive measures like imaging will make sure we’re not using the same treatment on every patient.”

Finding the biotype

In the study, 1,008 adults with previously unmedicated major depressive disorder were randomly given one of three widely prescribed typical antidepressants: escitalopram (brand name Lexapro) or sertraline (Zoloft), which act on serotonin, or venlafaxine-XR (Effexor), which acts on both serotonin and norepinephrine. Seven hundred and twelve of the participants completed the eight-week regimen.

Before and after treatment with the antidepressants, the participants’ depressive symptoms were measured using two surveys — one, clinician-administered, and the other, a self-assessment, which included questions related to changes in sleep and eating. Measures on social and occupational functioning, as well as quality of life, were tracked as well.

The participants also completed a series of cognitive tests, before and after treatment, measuring verbal memory, working memory, decision speed and sustained attention, among other tasks.

Before treatment, scientists scanned 96 of the participants using functional magnetic resonance imaging as they engaged in a task called the “GoNoGo” that requires participants to press a button as quickly as possible when they see “Go” in green and to not press when they see “NoGo” in red. The fMRI tracked neuronal activity by measuring changes in blood oxygen levels, which showed levels of activity in different brain regions corresponding to Go or NoGo responses. Researchers then compared the participants’ images with those of individuals without depression.

The researchers found that 27% of the participants had more prominent symptoms of cognitive slowing and insomnia, impaired cognitive function on behavioral tests, as well as reduced activity in certain frontal brain regions — a profile they labeled the cognitive biotype.

“This study is crucial because psychiatrists have few measurement tools for depression to help make treatment decisions,” said Laura Hack, MD, PhD, the lead author of the study and an assistant professor of psychiatry and behavioral sciences. “It’s mostly making observations and self-report measures. Imaging while performing cognitive tasks is rather novel in depression treatment studies.”

Pre-treatment fMRI showed those with the cognitive biotype had significantly reduced activity in the dorsolateral prefrontal cortex and dorsal anterior cingulate regions during the GoNoGo task compared with the activity levels in participants who did not have the cognitive biotype. Together, the two regions form the cognitive control circuit, which is responsible for limiting unwanted or irrelevant thoughts and responses and improving goal selection, among other tasks.

After treatment, the researchers found that for the three antidepressants administered, the overall remission rates — the absence of overall depression symptoms — were 38.8% for participants with the newly discovered biotype and 47.7% for those without it. This difference was most prominent for sertraline, for which the remission rates were 35.9% and 50% for those with the biotype and those without, respectively.

“Depression presents in different ways in different people, but finding commonalities — like similar profiles of brain function — helps medical professionals effectively treat participants by individualizing care,” Williams said.

Depression isn’t one size fits all

Williams and Hack propose that behavior measurement and imaging could help diagnose depression biotypes and lead to better treatment. A patient could complete a survey on their own computer or in the doctor’s office, and if they are found to display a certain biotype, they might be referred to imaging for confirmation before undergoing treatment.

Researchers at the Stanford Center for Precision Mental Health and Wellness, which Williams directs, in partnership with the Stanford Translational Precision Mental Health Clinic, which Hack directs, are studying another medication — guanfacine — that specifically targets the dorsolateral prefrontal cortex region with support from Stanford University Innovative Medicines Accelerator. They believe this treatment could be more effective for patients with the cognitive subtype.

Williams and Hack hope to conduct studies with participants who have the cognitive biotype, comparing different types of medication with treatments such as transcranial magnetic stimulation and cognitive behavioral therapy. In transcranial magnetic stimulation, commonly referred to as TMS, magnetic fields stimulate nerve cells; in cognitive behavioral therapy, patients are taught to use problem-solving strategies to counter negative thoughts that contribute to both emotional dysregulation and loss of social and occupational abilities.

“I regularly witness the suffering, the loss of hope and the increase in suicidality that occurs when people are going through our trial-and-error process,” Hack said. “And it’s because we start with medications that have the same mechanism of action for everyone with depression, even though depression is quite heterogeneous. I think this study could help change that.”

Researchers from the Sierra-Pacific Mental Illness Research, Education and Clinical Center; the Veterans Affairs Palo Alto Health Care System; Brain Dynamic Centre, Westmead Institute for Medical Research; and the University of Sydney, Westmead, contributed to the work.

The study was funded through Brain Resource Company Operations Pty Ltd. and Stanford University’s Clinical and Translation Science Award Program overseen by the National Center for Advancing Translational Sciences at the National Institutes of Health (grant UL1TR003142-01).

A new study projecting the economic futures of four income groups of countries over the next century finds growth will be slower than predicted, with developing countries taking longer to close the wealth gap and approach the income of wealthier nations. What economists have thought of as a worst-case scenario for global economic growth may, in fact, be a best-case scenario, according to the new study published today in Communications Earth & Environment.

The findings suggest governments need to start planning for slower growth and wealthier countries may need to help lower-income nations finance climate change adaptations in the coming decades, according to the study authors.

“We’re at a point where we maybe need to significantly increase financing for [climate] adaptation in developing countries, and we’re also at a point where we might be overestimating our future ability to provide that financing under the current fiscal paradigm,” said Matt Burgess, a CIRES fellow, director of the Center for Social and Environmental Futures, and assistant professor of environmental studies at CU Boulder who led the new study.

“We can now start to winnow down the range of possibilities and move forward in more tangible ways,” said Ryan Langendorf, a postdoctoral scholar at CU Boulder and co-author of the new study.

In the new study, Burgess and his colleagues used two economic models to project how much the global economy will grow over the next century and how quickly developing countries will approach the income levels of wealthier nations.

Both models found the global economy will continue to grow, but that growth will be slower than most economists expected and there will be a larger income gap between wealthier and poorer nations. This means richer countries may need to help finance climate adaptations for poorer countries, and debt-ceiling crises, like what the United States experienced this spring, may become more common.

“Slower growth than we think means higher deficits than we expect, all else equal,” Burgess said. “That means debt would likely become more contentious and important over time, and could mean more frequent debt-ceiling fights.”

Similar to a flight emergency, where individuals should put their own oxygen masks on first, wealthier nations should focus on getting their own financial houses in order so they can be in a position to support lower-income nations in financing climate adaptations, according to the researchers.

“We’re talking about relatively less growth, relatively more inequality, but we’re still talking about a world that is richer than today and more equal across countries than today’s world,” Burgess said.

Still, many wealthy nations are accustomed to growing their way out of debt, but that may not be possible under the new scenario, according to Ashley Dancer, a graduate student at CU Boulder and co-author of the study.

“The next question is: what are some ways that we should be or could be helping [lower-income countries] adapt, if the expectation is that they’re not going to meet the level of wealth that would allow them to do that quickly and aggressively?” Dancer said.

Now, Salk scientists have found that pairing specific diets with disease-causing bacteria can create lasting immunity in mice without the costs of developing sickness, revealing a new potential vaccination strategy. Their findings, published in Science Advances on June 23, 2023, pave the way for the development of new vaccines that could promote immunity for those with diarrheal diseases and possibly other infections.

“We discovered that immunization against diarrheal infections is possible if we allow the bacteria to retain some of its disease-causing behavior,” says senior author Professor Janelle Ayres, Salk Institute Legacy Chair and head of the Molecular and Systems Physiology Laboratory. “This insight could lead to the development of vaccines that could reduce symptoms and mortality, as well as protect against future infections.”

In 2018, Ayres’ lab looked at how dietary interventions can create an asymptomatic infection, which Ayres calls a cooperative relationship between bacteria and host (the person or animal that the bacteria have infected) where the host does not experience any symptoms. They discovered that an iron-rich diet enabled mice to survive a normally lethal bacterial infection without ever developing signs of sickness or disease. The high-iron diet increased unabsorbed sugar (glucose) in the mice’s intestines, which the bacteriacould feast on. The excess sugar served as a “bribe” for the bacteria, keeping them full and incentivized to not attack the host.

This process produced long-term asymptomatic infection with the bacteria, leading the researchers to believe that the adaptive immune system (cells and proteins that “remember” infections) may be involved.

“Being able to generate lasting immunity against bacteria like C. rodentium or E. coli has not been possible using established vaccination strategies. We wanted to figure out what mechanism was sustaining this lasting immunity, so we could use that mechanism to create an impactful solution to these diarrheal diseases,” says first author Grischa Chen, a former postdoctoral researcher in Ayres’ lab.

The researchers moved to figure out how the body suppresses infection symptoms, whether infection without symptoms can create long-term immunity, and whether that immunity is reproducible as a vaccination strategy.

The team compared mice with iron-rich and normal diets after C. rodentium infection to find whether the diet impacted symptomless infection. Immediately after infection, mice fed an iron-rich diet had no symptoms whereas mice fed a normal diet did have symptoms. All mice were then put on a normal diet to see whether the asymptomatic infection would last.

Mice with nonfunctional adaptive immune systems (the immune system that “remembers” previous infections), regardless of whether they had ever been on an iron-rich diet, could not continue to maintain a cooperative relationship with the bacteria. Although the iron-rich diet suppressed symptoms immediately after infection, the adaptive immune system was required for lasting cooperation. Importantly, the mice with functional adaptive immune systems had the disease without any symptoms, with lastingimmunity, as demonstrated by survival upon reinfection after a month.

Ayres and team concluded that an iron-rich diet alone can prevent bacteria from creating deadly symptoms in mice during active infection. But a functional adaptive immune system is required for immunity against future infection in the absence of dietary supplementation.

Some bacterial strains, if mutated enough, don’t cause symptoms. To test whether such bacteria could produce lasting immunity, the team repeated their iron-diet versus normal-diet experiment in mice, but this time using bacteria that could cause disease and bacteria that could not cause disease. They found that only mice that received disease-causing, unmutated bacteria were able to support immunity upon reinfection.

The scientists note that people shouldn’t consume large amounts of iron after reading this study. Their findings are preliminary and will need to be confirmed in human subjects.

The researchers hope their insights will provide a basis for future research in humans and the creation of a vaccination regiment that protects and prevents against diarrheal illness.

Other authors include Natalia R. Thorup, Abigail J. Miller, and Yao-Cheng Li of Salk.

The work was supported by the National Institutes of Health (DPI AI144249, R01AI4929), the NOMIS Foundation, a DARPA Yong Faculty Award (YFA15 D15AP00097), a Hillblom Foundation Fellowship Grant, the Chapman Foundation, the Helmsley Charitable Trust,

The team reports in the journal Science Advances a drug that, in laboratory cultures and animal models, significantly reduces the ability of bacteria to develop antibiotic resistance, which might prolong antibiotic effectiveness. The drug, called dequalinium chloride (DEQ), is a proof-of-concept for evolution-slowing drugs.

“Most people with bacterial infections get better after completing antibiotic treatment, but there are also many cases in which people decline because the bacteria develop resistance to the antibiotic, which then can no longer kill the bacteria,” said corresponding author Dr. Susan M. Rosenberg, Ben F. Love Chair in Cancer Research and professor of molecular and human genetics, biochemistry and molecular biology and molecular virology and microbiology at Baylor. She also is a program leader in Baylor’s Dan L Duncan Comprehensive Cancer Center (DLDCCC).

In this study, Rosenberg and her colleagues looked for drugs that could prevent or slow down E. coli bacteria from developing resistance to two antibiotics when exposed to a third antibiotic, ciprofloxacin (cipro), the second most prescribed antibiotic in the U.S. and one associated with high bacterial resistance rates.

The resistance is caused by new gene mutations that occur in the bacteria during infection. The drug DEQ reduces the speed at which new mutations are formed in bacteria, the team finds.

Previous work from the Rosenberg lab had shown that bacterial cultures in the lab exposed to cipro turn up mutation rate. They found a mutational “program” that is switched on by bacterial stress responses. Stress responses are genetic programs that instruct cells to increase production of protective molecules during stress, including stress from low concentrations of cipro. Low concentrations occur at the beginning and end of antibiotic therapies and if doses are missed.

The same stress responses also increase the ability to make genetic mutations, the Rosenberg group, then many other labs, have shown. Some of the mutations can confer resistance to cipro, while other mutations can allow resistance to antibiotics not yet encountered. Mutation-generating processes that are turned on by stress responses are called stress-induced mutation mechanisms.

Bacteria with antibiotic resistance mutations can then sustain an infection in the presence of cipro. This study is the first to show that in animal infections treated with cipro, the bacteria activate a known stress-induced genetic mutational process. Cipro resistance occurs mostly by the bacteria developing new mutations, both clinically and in the laboratory, rather than by acquiring genes that confer antibiotic resistance from other bacteria.

Looking to prevent the development of antibiotic resistance, the researchers screened 1,120 drugs approved for human use for their ability to dial down the master bacterial stress response, which they showed counters the emergence of resistance mutations. In addition, and counterintuitively, they wanted “stealth” drugs that would not slow bacterial proliferation, which would confer a growth advantage to any bacterial mutants that resist the mutation-slowing drug itself. That is, drugs that are not antibiotics themselves.

“We found that DEQ fulfilled both requirements. Given together with cipro, DEQ reduced the development of mutations that confer antibiotic resistance, both in laboratory cultures and in animal models of infection, and bacteria did not develop resistance to DEQ,” said first author Yin Zhai, a postdoctoral associate in the Rosenberg lab. “In addition, we achieved this mutation-slowing effect at low DEQ concentrations, which is promising for patients. Future clinical trials are needed to evaluate the ability of DEQ to decelerate bacterial antibiotic resistance in patients.”

Other contributors to this work include John P. Pribis, Sean W. Dooling, Libertad Garcia-Villada, P.J. Minnick, Jun Xia, Jingjing Liu, Qian Mei, Devon M. Fitzgerald, Christophe Herman, P.J. Hastings and Mauro Costa-Mattioli. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Dan L Duncan Comprehensive Cancer Center and Rice University.

This work was supported by NIH Directors Pioneer Awards DP1-AI52073 and DP1-AG072751, and NIH grants R35-GM122598 and R01-CA250905, P30-AI036211, P30-CA125123 and S10-RR024574, the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. Further support was provided by the State of Nebraska LB595 and LB692 and NIH/NIEHS R00ES033259 awards.