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A promising approach to develop a birth control pill for men

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A promising approach to develop a birth control pill for men


The world’s population has increased by more than 2.6-fold in the last 60 years. The growing trend continues — projections indicate that the number of people living on our planet will grow to 9 billion by 2037 from 8 billion in 2022. These numbers underscore the need for considering family planning; however, there have been limited breakthroughs in contraception in recent decades. Specifically for men, there are no oral contraceptive pills available.

In a study published in the journal Science, researchers at Baylor College of Medicine and collaborating institutions show in animal models that a novel, non-hormonal sperm-specific approach offers a promising option for reversible human male contraception.

“Although researchers have been investigating several strategies to develop male contraceptives, we still do not have a birth control pill for men,” said corresponding author Dr. Martin Matzuk, director of the Center for Drug Discovery and chair of the Department of Pathology and Immunology at Baylor. “In this study we focused on a novel approach — identifying a small molecule that would inhibit serine/threonine kinase 33 (STK33), a protein that is specifically required for fertility in both men and mice.”

Previous research has shown that STK33 is enriched in the testis and is specifically required for the formation of functional sperm. In mice, knocking out the Stk33 gene renders the mice sterile due to abnormal sperm and poor sperm motility. In men, having a mutation in the STK33 gene leads to infertility caused by the same sperm defects found in the Stk33 knockout mice. Most importantly, mice and men with these mutations have no other defects and even have normal testis size.

“STK33 is therefore considered a viable target with minimal safety concerns for contraception in men,” said Matzuk, who has been on faculty at Baylor for 30 years and is Baylor’s Stuart A. Wallace Chair and Robert L. Moody, Sr. Chair of Pathology and Immunology. “STK33 inhibitors have been described but none are STK33-specific or potent for chemically disrupting STK33 function in living organisms.”

Finding an effective STK33 inhibitor

“We used DNA-Encoded Chemistry Technology (DEC-Tec) to screen our multi-billion compound collection to discover potent STK33 inhibitors,” said first author Dr. Angela Ku, staff scientist in the Matzuk lab. “Our group and others have used this approach before to uncover potent and selective kinase inhibitors.”

The researchers uncovered potent STK33-specific inhibitors, from which they successfully generated modified versions to make them more stable, potent and selective. “Among these modified versions, compound CDD-2807 turned out to be the most effective,” Ku said.

“Next, we tested the efficacy of CDD-2807 in our mouse model,” said co-author Dr. Courtney M. Sutton, postdoctoral fellow in the Matzuk lab. “We evaluated several doses and treatment schedules and then determined sperm motility and number in the mice as well as their ability to fertilize females.”

Compound CDD-2807 effectively crossed the blood-testis barrier and reduced sperm motility and numbers and mice fertility at low doses. “We were pleased to see that the mice did not show signs of toxicity from CDD-2807 treatment, that the compound did not accumulate in the brain, and that the treatment did not alter testis size, similar to the Stk33 knockout mice and the men with the STK33 mutation,” Sutton said. “Importantly, the contraceptive effect was reversible. After a period without compound CDD-2807, the mice recovered sperm motility and numbers and were fertile again.”

“In our paper, we also present the first crystal structure for STK33,” said co-author Dr. Choel Kim, associate professor of biochemistry and molecular pharmacology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Our crystal structure showed how one of our potent inhibitors interacts with STK33 kinase in three dimensions. This enabled us to model and design our final compound, CDD-2807, for better drug-like properties.”

“This study was a tour de force by our team in the Center for Drug Discovery at Baylor and our collaborators,” said co-author Dr. Mingxing Teng, assistant professor of pathology and immunology and of biochemistry and molecular pharmacology at Baylor. Teng also is a Cancer Prevention Research Institute of Texas Scholar and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Starting with a genetically validated contraceptive target, we were able to show that STK33 is also a chemically validated contraceptive target.”

“In the next few years, our goal is to further evaluate this STK33 inhibitor and compounds similar to CDD-2807 in primates to determine their effectiveness as reversible male contraceptives,” Matzuk said.

Additional co-authors of the paper affiliated with Baylor College of Medicine are Kiran L. Sharma, Hai Minh Ta, Kurt M. Bohren, Yong Wang, Srinivas Chamakuri, Ruihong Chen, John M. Hakenjos, Ravikumar Jimmidi, Katarzyna Kent, Feng Li, Jian-Yuan Li, Lang Ma, Chandrashekhar Madasu, Murugesan Palaniappan, Stephen S. Palmer, Xuan Qin, Zhi Tan, Yasmin M. Vasquez, Jian Wang, Zhifeng Yu, Qiuji Ye and Damian W. Young. Co-authors Matthew B. Robers and Jennifer Wilkinson are affiliated with Promega Corp., and Banumathi Sankaran is affiliated with Lawrence Berkeley National Laboratory.



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Are mixed emotions real? New research says yes

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Are mixed emotions real? New research says yes


In Pixar’s latest film, Inside Out 2, complex feelings like envy and embarrassment join the cast of characters. Nostalgia, however, is hurried out the door to cries of “too early!” when she appears.

If animators wish to give nostalgia more consideration in a future film, new data from researchers at the USC Dornsife College of Letters, Arts and Sciences could guide them in determining how to animate this sort of “mixed emotion.”

What’s new: In a recent study, the USC Dornsife neuroscientists found that brains display distinct neural activity when experiencing emotions such as bittersweetness.

  • The advance could help solve a longstanding scientific debate: whether “mixed emotions” arise from unique activity in the brain, or if we’re just flip-flopping back and forth between positive and negative feelings.

Why it matters: Mixed emotions are a common experience, but they’ve been understudied scientifically for several reasons.

  • Emotions are often thought to exist only on a spectrum from negative to positive.
  • It’s easier to study one feeling at a time.

In his words: “It’s hard to evoke these complex emotions in a realistic way inside the lab,” says Jonas Kaplan, associate professor (research) of psychology and co-author of the study, published in the journal Cerebral Cortex in April.

Key findings:

  • Mixed feelings elicited unique neural activity in the amygdala and nucleus accumbens areas of the brain.
  • This activity was different than the brain activity seen when a subject reported a purely positive or negative emotion.

What else? The researchers could predict when someone was going to shift emotions.

  • Particular regions of the brain, like the insular cortex, displayed significant changes as subjects reported an emotional transition.

“Not only did we find brain activity that was correlated with mixed emotions, but we found that it held steady over time,” says Anthony Vaccaro, lead author of the study and a postdoctoral researcher at the Neuroendocrinology of Social Ties Lab at USC Dornsife. Vaccaro recently completed his PhD in psychology at USC Dornsife. “You’re not ping-ponging between negative and positive. It’s a very unique, mixed emotion over a long period.”

Graphs show consistent brain activity during positive, negative and mixed emotions, demonstrating that mixed emotions are distinct from other feelings. (Image: Jonas Kaplan.)

How they did it: As study subjects watched a poignant animated short film, researchers monitored their brain activity using a magnetic resonance imaging (MRI) machine.· The researchers chose One Small Step by TAIKO Studios for its ability to evoke simultaneous happy and sad feelings. · After the first viewing, participants rewatched the video without MRI and indicated when they experienced positive, negative or mixed emotions. The researchers then compared these reports with the MRI imaging results.

Opportunity: The study lays out practical groundwork for future scientific research into this understudied phenomenon, research that Kaplan says would also be beneficial for understanding human psychology.

  • “There’s a certain sophistication that’s required to sit with a mixed emotion and to allow yourself to feel positive and negative at the same time. Looking into that more, exploring the benefits of being able to accept positive and negativity at the same time within yourself, is something we think is worth study,” he says.

What’s next: Kaplan and Vaccaro will next look at how emotional reactions fluctuate in group settings, such as watching a movie together in a cinema.



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Paleontology: New fossil fish genus discovered

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Paleontology: New fossil fish genus discovered


Gobies or Gobioidei are one of the most species-rich groups of marine and freshwater fish in Europe. Spending most of their lives on the bottom of shallow waterbodies, they make substantial contributions to the functioning of many ecosystems. With the identification of a new genus of a fossil freshwater goby, students of the international master program ‘Geobiology and Paleobiology’ at LMU and paleontologist Bettina Reichenbacher, professor at the Department of Earth and Environmental Sciences at LMU, have made a discovery that provides critical insights into the evolutionary history of these fish.

Measuring up to 34 mm, the small fish of the new genus †Simpsonigobius were discovered in 18-million-year-old rocks in Turkey and are marked by a distinct combination of morphological features, including otoliths (hearing stones) with a unique shape.

Modern research techniques elucidate position in family tree

To determine the relationships of †Simpsonigobius within the gobioid phylogenetic tree, the researchers utilized a “total-evidence” phylogenetic dataset, which they enhanced in order to combine a total of 48 morphological characters and genetic data from five genes for 48 living and 10 fossil species. In addition, the team employed “tip-dating” for fossil gobioid species for the first time. This is a phylogenetic method in which the age of the fossils (= tips) included in the phylogenetic tree is used to infer the timing of the evolutionary history of the entire group.

The results show that the new genus is the oldest skeleton-based member of the family Oxudercidae — which is classified among the “modern” gobies (families Gobiidae and Oxudercidae) — and the oldest freshwater goby within this modern group. The tip-dating analysis estimated the emergence of the Gobiidae at 34.1 million years ago and that of the Oxudercidae at 34.8 million years ago, which is consistent with previous dating studies using other methods. Moreover, stochastic habitat mapping, in which the researchers incorporated fossil gobies for the first time, revealed that the gobies probably possessed broad salinity tolerance at the beginning of their evolutionary history, which challenges previous assumptions.

“The discovery of †Simpsonigobius not only adds a new genus to the Gobioidei, but also provides vital clues about the evolutionary timeline and habitat adaptations of these diverse fishes. Our research highlights the importance of analyzing fossil records using modern methods to achieve a more accurate picture of evolutionary processes,” says Reichenbacher. First author Moritz Dirnberger, currently a doctoral candidate at the University of Montpellier, adds: “The findings are expected to pave the way for further studies on gobioid evolution and the role of environmental factors in shaping their diversity.”



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Ancient ocean slowdown warns of future climate chaos

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Ancient ocean slowdown warns of future climate chaos


When it comes to the ocean’s response to global warming, we’re not in entirely uncharted waters. A UC Riverside study shows that episodes of extreme heat in Earth’s past caused the exchange of waters from the surface to the deep ocean to decline.

This system has been described as the “global conveyer belt,” because it redistributes heat around the globe through the movement of the ocean waters, making large portions of the planet habitable.

Using tiny, fossilized shells recovered from ancient deep-sea sediments, the study in the Proceedings of the National Academy of Sciences demonstrates how the conveyor belt responded around 50 million years ago. At that time, Earth’s climate resembled conditions predicted by the end of this century, if significant action is not taken to reduce carbon emissions.

Oceans play a crucial role in regulating Earth’s climate. They move warm water from the equator toward the north and south poles, balancing the planet’s temperatures. Without this circulation system, the tropics would be much hotter and the poles much colder. Changes in this system are linked to significant and abrupt climate change.

Furthermore, the oceans serve a critical role in removing anthropogenic carbon dioxide from the atmosphere. “The oceans are by far the largest standing pool of carbon on Earth’s surface today,” said Sandra Kirtland Turner, vice-chair of UCR’s Department of Earth and Planetary Sciences and first author of the study.

“Today, the oceans contain nearly 40,000 billion tons of carbon — more than 40 times the amount of carbon in the atmosphere. Oceans also take up about a quarter of anthropogenic CO2 emissions,” Kirtland Turner said. “If ocean circulation slows, absorption of carbon into the ocean may also slow, amplifying the amount of CO2 that stays in the atmosphere.”

Previous studies have measured changes in ocean circulation in Earth’s more recent geologic past, such as coming out of the last ice age; however, those do not approximate the levels of atmospheric CO2 or warming happening to the planet today. Other studies provide the first evidence that deep ocean circulation, particularly in the North Atlantic, is already starting to slow.

To better predict how ocean circulation responds to greenhouse gas-driven global warming, the research team looked to the early Eocene epoch, between roughly 49 and 53 million years ago. Earth then was much warmer than today, and that high-heat baseline was punctuated by spikes in CO2 and temperature called hyperthermals.

During that period, the deep ocean was up to 12 degrees Celsius warmer than it is today. During the hyperthermals, the oceans warmed an additional 3 degrees Celsius.

“Though the exact cause of the hyperthermal events is debated, and they occurred long before the existence of humans, these hyperthermals are the best analogs we have for future climate change,” Kirtland Turner said.

By analyzing tiny fossil shells from different sea floor locations around the globe, the researchers reconstructed patterns of deep ocean circulation during these hyperthermal events. The shells are from microorganisms called foraminifera, which can be found living throughout the world’s oceans, both on the surface and on the sea floor. They are about the size of a period at the end of a sentence.

“As the creatures are building their shells, they incorporate elements from the oceans, and we can measure the differences in the chemistry of these shells to broadly reconstruct information about ancient ocean temperatures and circulation patterns,” Kirtland Turner said.

The shells themselves are made of calcium carbonate. Oxygen isotopes in the calcium carbonate are indicators of temperatures in the water the organisms grew in, and the amount of ice on the planet at the time.

The researchers also examined carbon isotopes in the shells, which reflect the age of the water where the shells were collected, or how long water has been isolated from the ocean surface. In this way, they can reconstruct patterns of deep ocean water movement.

Foraminifera can’t photosynthesize, but their shells indicate the impact of photosynthesis of other organisms nearby, like phytoplankton. “Photosynthesis occurs in the surface ocean only, so water that has recently been at the surface has a carbon-13 rich signal that is reflected in the shells when that water sinks to the deep ocean,” Kirtland Turner said.

“Conversely, water that has been isolated from the surface for a long time has built up relatively more carbon-12 as the remains of photosynthetic organisms sink and decay. So, older water has relatively more carbon-12 compared to ‘young’ water.”

Scientists often make predictions about ocean circulation today using computer climate models. They use these models to answer the question: ‘how is the ocean going to change as the planet keeps warming?’ This team similarly used models to simulate the ancient ocean’s response to warming. They then used the foraminifera shell analysis to help test results from their climate models.

During the Eocene, there were about 1,000 parts per million (ppm) of carbon dioxide in the atmosphere, which contributed to that era’s high temperatures. Today, the atmosphere holds about 425 ppm.

However, humans emit nearly 37 billion tons of CO2 into the atmosphere each year; if these emission levels continue, similar conditions to the Early Eocene could occur by the end of this century.

Therefore, Kirtland Turner argues it is imperative to make every effort to reduce emissions.

“It’s not an all-or-nothing situation,” she said. “Every incremental bit of change is important when it comes to carbon emissions. Even small reductions of CO2 correlate to less impacts, less loss of life, and less change to the natural world.”



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