This finding may explain why many animals besides turtles have temperature-dependent sex determination and why the system persists, despite seeming like a risky strategy. It may also provide a troubling glimpse of what could lie ahead in a warming world.

What the researchers found, as published June 23 the journal Current Biology, is that the number of “germ cells” — pre-eggs — that an embryo carries is increased by higher incubation temperatures. In fact, they found that those germ cells themselves play a role in the embryo becoming female.

“Sex determination by temperature isn’t just one mechanism,” said senior author Blanche Capel, the James B. Duke Distinguished Professor of Cell Biology in the Duke School of Medicine. “Higher temperatures seem to affect sex determination in incremental ways through multiple cell types in the embryo.”

The more abundant germ cells themselves seem to drive feminization, said Boris Tezak, a postdoctoral researcher in the Capel lab who led this project. “The temperatures that produce females are also the temperatures that increase germ cell number,” he said.

Higher numbers of germ cells are known to control female development in fish as well, Capel said. But to prove the point that more germ cells lead to female turtles, they removed some germ cells from red-eared slider embryos raised at an intermediate temperature that should have yielded 50-50 proportions, and saw more males than expected.

Scientists have known about temperature-dependent sex development for decades and have found it in many different parts of the tree of life, apparently because it evolved multiple times in multiple ways.

“It popped up everywhere,” Tezak said. “It seems like a really risky strategy, especially in the context of weather variations and climate change, so why would this system persist?”

They think it’s because temperature-dependent sex development creates a reproductive advantage.

“A female that hatches with more germ cells is presumably more reproductively fit — it increases her reproductive potential to carry more eggs,” Tezak said. “We’ve linked the female pathway to the increased number of germ cells, and if that does make her more reproductively fit, that would go a long way toward explaining why temperature-dependent sex development persists.”

As global temperatures continue to rise, the question becomes: what will happen to the turtles and other temperature-sensitive breeders? “We’ll be looking at how further increases in temperature will affect the pool of germ cells,” Tezak said. “Will it produce less-fit females?”

To answer these questions, Tezak carefully nurtures clutches of red-eared slider eggs obtained from a Louisiana breeder in plastic boxes filled with moist medium and kept at a constant temperature in the lab. One incubator runs at 26 degrees Celsius, producing more males. Another is at 31 degrees, the optimum temperature for producing more females.

When he takes out one of each to check on their progress with a very bright light, the embryo that was incubated warmer is markedly larger and more active inside the egg.

“We are hypothesizing that there’s a temperature ‘sweet-spot,'” Capel said. “There is a short range where you get a large number of germ cells, and beyond that you start to see declines,” Capel said.

“We have incubated some eggs at 33.5 degrees, only two and a half degrees higher than the optimal temperature for females,” Tezak said. “It created some really wonky embryos — there were cyclops and two-headed embryos. We haven’t counted their germ cells yet.”

The lab is also about to take delivery on some alligator eggs to continue the temperature experiments. Alligators are known to produce females at low temperatures and males at high temperatures, the opposite pattern from the red-eared slider turtle. However, the low temperature in alligators is the same as the high temperature in turtles, so both species produce females at 31 degrees Celsius. “The interesting question is whether we see more germ cells in both species at this temperature,” Tezak said.

Funding for this study was provided by the U.S. National Science Foundation (1854642) and the Czech Science Foundation (23-07658S).

“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,